UBlUKr Digitized by the Internet Archive in 2010 with funding from Open Knowledge Commons http://www.archive.org/details/modernmedicineit01osle CONTRIBUTORS TO VOLUME I ADAMI, J. GEORGE, M.D., F.R.S. ANDERS, JAMES M., M.D. BRUCE, DAVID, C.B., F.R.S., D.Sc, M.B., CM. (Edin.) CALKINS, GARY N., Ph.D. CHITTENDEN, RUSSELL H., Ph.D., LL.D. CRAIG, CHARLES P., M.D. EDSALL, DAVID L., M.D. FUTCHER, THOMAS B., M.B. GORDON, ALFRED, M.D. HOV/ARD, L. O., Ph.D. HUTCHISON, ROBERT, M.D., F.R.C.P. (Lond.) LAMBERT, ALEXANDER, M.D. MENDEL, LAFAYETTE B., Ph.D. NOGUCHI. HIDEYO, Sc.M., M.D. NOVY, FREDERICK G., M.D. OSLER, V/ILLIAM, M.D. STEPHENS, J. V/.V/.. M.D. (Cantab.) STILES, CHARLES V/ARDELL, Ph.D., D.Sc. STILL, GEORGE P., M.A., M.D. (Cantab.)'. F.R.C.P. (Lond.) STRONG, RICHARD P., M.D. TAYLOR, ALONZO ENGLEBERT, M.D. WRIGHT. JAMES HOMER. M.D., Hon. S.D. (Harv.) MODERN MEDICINE ITS THEOEY AND P11A(]TICE IN OEIGINAL CONTRIBUTIONS BY AMEIUCAN AND FOREIGN AUTHORS EDITED J5Y WILLIAM OSLER. M.D. 7 REGIUS PROFESSOR OF MEDICINE IN OXFOKD UMVERSITY, ENGLAND; HONORARY PROFESSOR OF MEDICINE IN THE JOHNS HOPKINS UNIVEIISITV, BALTIMORE; FORMERLY PROFJOSSOlt OF CLINICAL MEDICINE IN THE UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, AND OF THE INSTITUTES OF MJCDICINE IN MCGILL UNIVERSITY, MONTREAL, CANADA ASSISTED BY THOMAS MCCEAE, M.D. ASSOCIATE PROFESSOR OF MEDICINE AND CLINICAL THERAPEUTICS IN THE JOHNS HOPKINS UNIVERSITY, BALTIMORE; FELLOW OF THE ROYAL COLLEGE OF PHYSICIANS, LONDON VOLUME I EVOLUTION OF INTERNAL MEDICINE— PREDISPOSITION AND IMMUNITY-DISEASES CAUSED BY PHYSICAL, CHEMICAL AND ORGANIC AGENTS-BY VEGETABLE PARASITES-BY PROTOZOA-BY ANIMAL PARASITES-NUTRITION- CONSTITUTIONAL DISEASES ILLUSTRATE D PHILADELPHIA AND NEW YORK LEA BROTHERS & CO. /^c ,9s^ llol Entered according to the Act of C!ongress, in the year 1907, by LEA & FEBIGER in the Office of the Librarian of Congress. All rights reserved. I PUBLISHERS' NOTE. A NEW era has come in medicine, the age of cosmopohtanism. As in finance and trade, the world has become a single country. The cause of this solidarity is to be found in modern improvements in communication which obliterate time, distance and the artificial boundaries of geography, making mankind a single family, and immediately distributing for the benefit of its members the knowledge of every advance, wherever attained. Only one obstacle remains, namely, difference of language, and this, though it will always exist, is practically overcome by the familiarity which the leaders in the profession must now possess with the writings of their compeers in other tongues. It is more necessary in medicine than in any other sphere of human effort that the world-knowledge should be placed at the command of all. Physicians of the dominant language, English, have just cause for satisfaction in realizing that this is now to be accomplished in their own tongue, and under the leadership of one best fitted, by common consent, to develop this idea in its most complete and fruitful manner. Physician, philosopher, litterateur, he unites in the highest degree all the necessary qualifications for marshalling the leaders in the most beneficent of professions in a great effort for the common good. Nothing has been spared for the full accomplishment of this purpose, and now, from the record of twenty-three centuries, every sincere follower of the masters of medicine has at command a fund of accumulated knowledge greater than any of them could have possessed. The full resources of the modern world have been brought to bear upon this work, and it is now submitted to the profession for judgment as to its conception and execution. (V) CONTRIBUTORS TO VOLUME I. J. GEORGE ADAMI, M.D., F.R.S., Professor of Pathology in the McGill University, Montreal, Canada. JAMES M. ANDERS, M.D., Professor of the Theory and Practice of Medicine and Clinical Medicine in the Medico-Chirurgical College; Consulting Physician to the Jewish Hospital Association of Philadelphia; Consulting Physician to the Widener Home for Crippled Children, Philadelphia. DAVID BRUCE, C.B., F.R.S., D.Sc, M.B., CM. (Edin.), Colonel, British Army, GARY N. CALKINS, Ph.D., Professor of Protozoology in the Columbia University, New York City. RUSSELL H. CHITTENDEN, Ph.D., LL.D., Professor of Physiological Chemistry in the Sheffield Scientific School of Yale University, New Haven, Conn. CHARLES F. CRAIG, M.D., First Lieutenant and Assistant Surgeon in the U. S. Army. DAVID L. EDSALL, M.D., Assistant Professor of Medicine in the University of Pennsylvania, Medical Department, Philadelphia. THOMAS B. FUTCHER, M.B., Associate Professor of Medicine in the Johns Hopkins University; Associate in Medicine in the Johns Hopkins Hospital, Baltimore, Md. ALFRED GORDON, M.D., Associate in Mental and Nervous Diseases in the Jefferson Medical College, Philadelphia; Examiner of the Insane at the Philadelphia General Hospital; Neurologist to the Mt. Sinai and Douglas Memorial Hospitals, Philadelphia. L. O. HOWARD, Ph.D., Chief of the Bureau of Entomology of the U. S. Department of Agriculture, Washington, D. C. ROBERT HUTCHISON, M.D., F.R.C.P. (Lond.), Assistant Physician to the London Hospital and to the Hospital for Sick Chil- dren, Great Ormond Street, London, England. ALEXANDER LAMBERT, M.D., Professor of Clinical Medicine in the Cornell University Medical College; Attending Physician in the Bellevue Hospital, New York City. LAFAYETTE B. MENDEL, Ph.D., Professor of Physiological Chemistry in the Sheffield Scientific School, Yale University, New Haven, Conn. (vii) vIH CONTRIBUTORS TO VOLUME I HIDEYO NOGUCHI, Sc.M., M.D., Assistant of the Rockeleller Institute for Medical Research, New York City. FREDERICK G. NOVY, M.D., Professor of Bacteriology in the University of Michigan, Ann Arbor, Mich. WILLIAM 08LER, M.D., Rogius Professor of Medicine in Oxford University, England. J. W. W. STEPHENS, M.D. (Cantab.), Walter Myers Lecturer on Tropical Medicine in the University of Liverpool, Liverpool, England. CHARJractise their calling, at their own (liscretion, outside the sacred precincts or even in foreign coimtries. In any case in the century immediately preceding the time of Hip])ocrates, the AsclejMads of Cnidos or Cos were only a shar])ly defined grou]) of (!reek doctors, distinguished from the rest bv a rigid organization which found expression in definite rules and formalities. These had for their object to incorporate in the guild of Askle]Mos those only who, closely united by their common venera- tion of the god of healing, and by similar scientific opinions, made it their goal to excel in the practice of medicine. They bound themselves by oath to maintain the dignity of the art, to preserve a high morality in the practice of their calling, to show gratitude toward their teachers, fraternal feeling toward the offspring of those teachers, and to guard against profanation of the secrets of their profession."^ The view of disease in the Hippocratic writings shows how strong was the influence of the philosophers, particularly of Empedocles and Pytha- goras. As in the Macrocosm there were four elements, fire, air, earth, and water, so in man, the Microcosm, there were four elements, blood, mucus, yellow bile, and black bile, of which the blood represented the heat, the mucus the cold, the yellow bile the dryness, the black bile the moisture. Health consisted in a harmony or due admixture of these humors, disease in a dyscrasia or imperfect admixture. This humoral pathology of the Hippocratic school dominated the profession for more than two thousand years. From Pythagoras may be traced directly the doctrine of critical days, which still lingers in the profession and of which one hears among the" laity. Hippocrates introduced into medicine the art of observation, the critical judgment of observed facts, and a rational induction from them, freed from speculation and theory. This has been the objective, practical method followed since his day by all the great masters of medicine, and it has been the instrument by which we have obtained our descriptive knowledge of disease. Briefly stated, from the Greeks we obtained in the first place the conception of medicine as an art based on careful observation, and as a science an integral part of the science of man and of nature; and, secondly, those high moral ideals which have ahvays inspired the profession, so well expressed in the Hippocratic oathi which has been called one of the most memorable of human documents. After the death of Hippocrates Greek medicine continued to flourish under the INIacedonian regime, and at Alexandria, with the fostering care of the Ptolemies, reached a very high plane. Anatomy and physiology, in particular, were studied with the greatest care and many important discoveries were made, particularly by Herophilus and Erasistratus. ' This is brought out very clearly in Mollet's La Medecine chez Us Grecs avant Hippocrate, 1906. ^ Neuberger, Geschichte der Medizin, vol. i. THE EVOLUTION OF INTERNAL MEDICINE xix Had we full knowledge of the writings of these two great physi(.'ians we should probably find that they had made many valuable observations in clinical medicine and pathology. For example, Erasistratus described ascites with great care, and knew of its associations with hardening of the liver and disease of the spleen. In the intellectual capture of Rome by the Greeks, medicine played a not inconsiderable part, and Greek physicians rose to positions of dignity and importance which have rarely since been equalled in any country or at any period by the leaders of our profession. One of these, Asclepiades, the founder of the school of Methodists, opposed the prevailing humoral pathology and placed the changes met with in diseases largely in the solids of the body. The Methodists made no special contribution to diagnosis, but Asclepiades seems to have been a shrewd and careful physician, placing greater stress upon exercise, baths, massage, and diet than upon the treatment of disease by medicines. The centuries imme- diately preceding and following the birth of Christ saw medicine flourish remarkably throughout the Roman world. In addition to the Methodists there were the Dogmatists, the Eclectics, the Pneumatists, from none of whom did medicine receive any very fertile contributions. Clinically one of the most interesting figures of this period is Aretaeus, whose works have a strong Hippocratic flavor and whose clinical pictures of disease have rarely been equalled. The student who wishes to get a picture of Greco-Roman medicine of this period should read, on the one hand, Celsus, who gives a remarkable summary of the medical and surgical knowledge of the day, and, on the other, Pliny, whose descriptions abound with the fads and fancies of popular medicine. The great Greek practitioner of the period, and in some ways the greatest figure in the history of medicine, is Galen, who was born in Pergamos about the year a.d. 130. He lived only for part of his life in Rome, where he was the physician to successive emperors and occupied a position of commanding dignity. In every department of medicine this remarkable man was a reformer and an innovator. In opposition to the prevailing views of the Empirics and the Methodists, he placed the whole foundation of the art in anatomy and physiology. He restored the Hippocratic methods and the humoral pathology of the master. Galen's researches in anatomy were of the most extensive character, and in this subject, as well as upon the nature and treatment of disease, his views were accepted as gospel until the Renaissance. The four humors were somewhat modified by him under the influence of the Pneumatics, who introduced the doctrine of the spirits — animal, natural, and vital — which so long held sway. The special interest to us here is that to him may be traced the second great instrument which has influenced the advance of clinical medicine, namely, experiment. He was the first great experimental clinician. We owe to him elaborate studies upon the action of the heart, and he narrowly missed discovering the general circulation of the blood. He made careful observations on the physiology of respiration, and recognized the difference between diaphragmatic and intercostal breathing. By experiments on the nervous system he demon- strated the differences between the motor and the sensory nerves, and even distinguished the motor and sensory roots leaving the spinal cord. In these and other studies he far eclipsed his predecessors, and as an XX INTRODUCTION experimcMitor lu" had no successor of llio same calibre until Harvey. In treatment he was a follower of Hippocrates, trusting to nature, and both diet and gymnastics ])layed an important role in his system. Greek medicine had now reached its climax, and with Galen the first great chapter in the history of scientific medicine closes. It is one of the most remarkable and in a way an incxj)licable feature in history that, having made a beginning of such brilliancy, the scientific study of disease should have made little or no progress for the next fourteen or fifteen centuries. Into the causes of this sterility this is not the place to inquire. During the long period three great names ruled all minds, Ptolemy, Aristotle, and Galen, and men were content to accept the geographic system of the one, the natural history and philosophy of the other, while the infalli- bility of the great Pergamitc became the first article of belief among all practitioners of medicine. Through the middle ages the continuity of Greek mcnlicine was main- tained, first, by the writers of the Byzantine school, whose works are of value chiefly as compilations, of which those of Oribasius and Paul of il'jgina are the most im])()rtant; and secondly, by th(^ Arabians, who came in contact with (ireck medicine in the East and in Egypt. For them Aristotle and Galen were the great masters, but departing from the plain methods of observation and induction, Arabian writers rejoiced in dogmatism and subtle dialectics. They introduced a new pharmacy with many new drugs from the East, and with them came many new chemical processes. Sadly mixed as it was with alchemy, in their crude science we find the germs of modern chemistry. Some of the Arabians became great clin- icians and made notable and accurate contributions to clinical medicine. To Rhazes we owe the first good account of smallpox. They also recog- nized measles! Avicenna became the greatest name in Arabian medicine, and throughout the latter part of the middle ages his authority rivalled that of Galen. There was a third narrow stream through which Greek medicine Avas preserved, namely, the old Universities, and particularly the school of Salernum in Southern Italy. In the early middle ages, from the tenth to the twelfth centuries, it maintained the Greek tradition and was recognized as the leading school of medicine in Europe. Though its derivation is unknown, the school possessed a continuity in thought with the old Greek writers. Later the school of Salernum became tinctured with Arabian medicine, but through it the writings of Galen and Hippocrates, mixed with the accretions from Arabian sources, filtered into modern Europe. Practically throughout the middle ages there was no such thing as an accurate study of clinical medicine. In what is known as the scholastic period, the three centuries before the Renaissance, authority and dogma ruled supreme, and philosophy and medicine alike were a confused jumble of Greek and Arabian authorities. The Renaissance influenced clinical medicine in three ways: First, it restored once and for all the methods of Hippocrates and of Galen. The careful study of descriptive anatomy by Vesalius and his successors restored to men the lost art of clear, indepen/Ient vision. Secondly, in the revolt against dogmatism and authority a new chemistry arose, at first, in the hands of Paracelsus and others, crude and unscientific, yet it laid the foundation for all our subsequent studies, and through van Helmont and the seventeenth THE EVOLUTION OF INTERNAL MEDICINE xxi century chemists has led to the present most fruitful results. Thirdly, we may trace as a direct effect of the Renaissance the revival of experi- ment in medicine which had been introduced by Galen. The work on metabolism by Sanctorms, and the demonstration by Harvey of the circulation of the blood gave an immense imjx'tus to the scientific investi- gation of the functions of the body and of the causes of disease. It cannot be said that Harvey's' work had any very special influence on clinical medicine except in conjunction with the mechanical philosophy of Descartes and the foundation of the so-called iatro-mechanical school. How little actual progress had been made in clinical medicine is illus- trated by what a leading practitioner, Willis, in the middle of the seventeenth century thought of such a disease as inflammation of the lungs. The essential cause was believed to be that the blood boiled feverishly, and "sticking within the yiore narrow passages of the lungs engendered there an obstruction causing inflammation." Neither in the description of the symptoms nor in the discussion of the prognosis is there any radical advance upon the position of Hippocrates and of Galen. A case, the particulars of which he gives, shows the heroic character of the treatment: "I drew blood twice or thrice day after day." "Frequent clysters were administered; moreover, apozems, juleps, also spirits of ammoniac and poAvder of fish shells were administered by turns," When phlebotomy was no longer safe very large blisters were applied to the arms and thighs. One is surprised to learn that the patient recovered, but he suffered greatly from the blisters which did "run hugely and afterwards for almost a month daily discharged great plenty of a most sharp ichor." III. Not truly scientific and uninfluenced by his friends, Boyle and Locke, (who appreciated fully the importance of the scientific movement of the day), Sydenham restored in a measure the practical methods of the Hippocratic school, careful observation, guided by common sense. If to that remarkable conception of diseases as objects of study and classifica- tion, as in the subjects of botany and natural history, Sydenham had added the methods of Harvey, experiment and postmortem observation, the real revolution in clinical medicine might not have had to wait until the beginning of the nineteenth century. A prince among practical physicians, the limitations imposed upon himself restricted his view, and Sydenham never got to the "seats and causes of disease" as did his great successor, Morgagni; but as a portrayer of their objective features he has had few equals, and in this he even bettered the instruction of his master, Hippocrates. In his study of fevers Sydenham displayed a remarkable independence, not more in the graphic pictures which he has left us than in his insistence upon the importance of a knowledge of their natural history as a basis of rational treatment. That he was led away by too great belief in an epidemic constitution was only to be expected in so close a follower of Hippocrates. No one before him had so clearly grasped the conception that the manifestations of a fever represented the efforts of nature to get rid of the injurious agents causing the disease. ISIany of his descriptions of chronic diseases have never been surpassed, and hi§ xxii INTRODUCTION account of chorea, of hysteria, and of <2:out have become classical in the literature. But it was in treatment that he showed a still more revolu- tionary spirit. He had a supreme faith in nature as the true healer, to whom the physician played a secondary j)art, assisting her when she was feeble, restraining her when excessive and violent. That many diseases got well if left to themselves was a novel doctrine in the seventeenth century. But it was in his new method of treating fever, and ])articularly smallpox, by cooling measures, plenty of drink and fresh air, that he departetl most strongly from the ])ractice of his day and achieved signal success. One of the most interesting figures in the history of clinical medicine, Sydenham has impressed his method on his countrymen, who have always cared less for the theoretical conceptit)ns than for the prac- tical, common-sense aspects in the consideration of disease. Several of Sydenham's contemj)oraries in England werij keen clinical physicians who have left on record valuable contributions to medicine. Glisson in particular may be mentioned as a man in whom were combined the anatomical and clinical features so characteristic of the teachers of this period. His treatise, de Rachididc, 1G50, is the first extensive monograph on a single disease published in England (Cains' Sweating Sickness, published a century earlier, had not the same ambitious scope). Not only are the clinical aspects of the disease given in great detail, but the morbid anatomy and the etiology also are fully discussed. Morton, too, was an admirable systematic writer and his works Pyretologia (1692) and Phthisiologia (16S9) show accurate study, and the subjects are presented in a more orderly and logical way than in the writings of Sydenham. Brilliant and even revolutionary as was the work of this small group of English physicians, it did not immediately influence the progress of clin- ical medicine until the advent of the Dutch Hippocrates, Boerhaave, upon whom fell the mantle of Sydenham. But meanwhile there had arisen on the Continent the iatro-physical school, based upon the mechanical concep- tions of the Cartesian philosophy and supported by the experiments of Sanctorius, of Harvey, of Borrelli and others. Silvius, of Leyden, and Pit cairn, ]\Iead and Friend were the chief exponents of this system, in which everything was explained in terms of mathematical reasoning; and while it did good service in combating the dominant doctrine of the humors, the extravagance of its professors hastened the downfall of a school which, after all, rested on a strong basis of truth. As with nearly everything of value in the practical aspects of modern life, agriculture, horticulture, banking, colonization, etc., so in clinical medicine the Dutch were our masters. The great Italian teachers of the sixteenth and seventeenth centuries were also practitioners, and there must have been some instruction in the art as well as in the science of medicine, but it was everywhere desultory and unsystematic until the Dutch physicians organized regular clinical instruction as part of the University teaching. Professor Pell tells me that the hospital clinic at Utrecht preceded that at Leyden, but it was at this latter place, under the influence of Boerhaave, that it became most eft'ective. The history of this University illustrates the importance of men in forming an educa- tional centre; students flocked to it from all parts of Europe to sit at the feet of such teachers as Silvius, Grotius, the younger Scaliger, Bidloo, and Pitcairn. After teaching botany and chemistry, Boerhaave succeeded THE EVOLUTION OF INTERNAL MEDICINE xxili to the chair of physic in 1714. With an unusually wide ^u-neva] training, a profound knowledge of the chemistry of the day, and an accurate acquaintance with all aspects of the liistory of the jirofession, he had a strongly objective attitude of mind toward disease, following closely the methods of Hippocrates and Sydenham. He adopted no special system, but studied disease as one of the phenomena of nature. His clinical lectures, held bi-weekly, became exceedingly popular and were made attractive not less by the accuracy and care with which the cases were studied than by the freedom from fanciful doctrines and the frank honesty of the man. He was much greater than his published work would indicate, and, as is the case with many teachers of the first rank, his greatest contributions were his pupils. No teacher of modern times has had such a following. Among his favorite pupils may be mentioned Haller, the physiologist, and van Swieten, the founder of the Vienna school. Edinburgh had had very close affiliations with Leyden, and one of Boerhaave's predecessors was Archibald Pitcairn, who subsequently returned to his native city and had an important influence in building up the university, the medical school of which was not organized until 1726. The Leyden methods of instruction were introduced by pupils of Boerhaave, of whom John Rutherford was the most distinguished. He began to teach at the Royal Infirmary in 1747. I have a manuscript of his clinical lectures delivered in the wdnter session of 1748-49, from which we may get a good idea of his plan of teaching. He says: "The method I propose to pursue is, to examine every patient before you, lest any circumstances should be overlooked. I shall undertake this by a plan which wall be the most useful I can think of. I shall give you the history of his disease in general; secondly, inquire into the cause of it, and, thirdly, give you my opinion how the disease is likely to terminate and lay down the indication of cure, or when any extraordinary symp- toms arise you shall have notice of it that you may see the reason of altering my prescriptions." Those were happy days for the medical student, as a few paragraphs later he says: "I do not mean by this that you should all take degrees, for I am far from thinking that a diploma furnishes a man with medical knowledge. His improvement in this art depends on his own study and industry." Three, four, and even five patients w^ere shown on the same day, and great care was taken to keep the students informed of the progress of patients who had been seen by them. Weeks afterw^ard a memorandum is given, perhaps, of the postmortem. The history, the symptoms, and the prognosis are very well considered, but one misses the physical examination and an accurate consideration of the pathology and morbid anatomy. Groups of cases were considered together, as illustrated by Lecture 23, in wdiich a series of cases of scurvy, that had been "in the house," were considered together. Directly inspired from Leyden, the Edinburgh school soon outstripped all its compeers. In the main thoroughly practical and objective, as witnessed, for example, in the w^ork of Whytt, it illustrated also the specu- lative nature of the Scottish character in two systems of medicine which had great vogue. Cullen, who was Whytt's successor in the chair of institutes, became the most prominent teacher of medicine in his day in xxiv ixrmmvcTioN the Eno'lisli-spcakinf]; world. lie was a most inspiring lecturer and a thoroughly good clinical teacher. While, ])erhai)s, it is scarcely correct to say that he introduced a system, yet he was the first to attach special importance to the nervous system as influencing disease. A more defi- nite system, comparable with the older ones which prevailed on the Continent in the seventeenth and eighteenth centuries, was the Brunonian, introduced by John Brown, a {)upil of Cullen. "^riie essence of this consisted in an insistence upon debility as the fundamental factor in disease, and the necessity of always maintaining a suj^porting line of treatment. Few systems of medicine have ever stirred such bitter con- troversy, and in Charles Creighton's account of Brown^ we read that as late as 1802 the University of Gottingen was so convulsed by contro- versies on the merits of the Brunonian system that contending factions of students in enormous numbers, not unaided by the professors, met in combat in the streets on two consecutive days and had to be dispersed by a troop of Hanoverian hoi-se. In England antl the colonies the influence of the Edinburgh school became supreme. I.ondon had no properly organized medical teaching. In the hospitals the surgeons gave good instruction and there was an admirable system of pupils and dressers. But to medicine proper little or no attention had been paid. One of the physicians of the hospital lectured on medicine, materia medica, and chemistry, chiefly to men who were to become apothecaries or general practitioners. To take the INI.D. degree, men had to go to Edinburgh or abroad, or they took the Oxford or Cambridge INI.D., after keeping a certain number of terms. Throughout the eighteenth century the methods and practice of Boer- haave had great influence in London. Many of the Fellows of the College of Physicians had been his pupils. His works were translated and fre- quently reprinted, but, without university organization and without systematic instruction, the clinical teaching was carried on in a very desultory manner. Toward the end of the century several men trained in Edinburgh methods became distinguished teachers and workers in the London hospitals, of whom William Saunders may be taken as an example. A pupil of Cullen, he became in 1770 physician to Guy's Hospital and at once began to lecture upon medicine and to give clinical instruction. He was a hard worker and a keen clinical observer, as his papers on lead colic, on the diseases of the liver, and on delirium tremens amply testify. Gilbert Blane and Matthew Baillie were both Glasgow men. The latter, a graduate of Oxford, was the best clinical physician of his day in London, but no doubt he got most of his pathological and clinical training from his uncles, William and John Hunter. Fothergill and Lettsom, Halford, Holland, Bright, Paris, Humphry Davy, Caleb Parry, and Marshall Hall were Edinburgh men. To Edinburgh all the abler young men from the English colonies went for their medical education. Bard, M«jrgan, Shippen, Rush, W^istar, Hossack and others brought back to Amt^rica the traditions and methods of its schools; and it was not until the third decade of the nineteenth century that the tide of students turned toward France. Early in that decade it was a group of young Edinburgh men. Holmes, Robertson, ' Dictionari/ of National Biography. THE EVOLUTION OE INTERNAL MEDICINE xxv Stevenson, and Caldwell, who Ijcgan medical instrneiion In Montreal, from which originated the Medical Faculty of McCjriil College. Boerhaave and his pupils extended the range of observation and in a measure restored to medicine that robust common sense which hacl been the distinguishing feature of both Plippocrates and Sydenham. At the end of the eighteenth century men were floundering in a sea of speculation and there was no definiteness in diagnosis nor any safe basis for treatment. The next great step came from an extension of the Hippocratic method to the dead-house, the study of morbid anatomy in association with clinical observation. IV. Many of the sixteenth and seventeenth century physicians had keen appreciation of the value of postmortem examinations. Harvey has a most interesting paragraph on the subject,' and his works testify to the zeal with which he sought for the more hidden causes of disease; but with no one in the seventeenth century did morbid anatomy become a life study, and no one had realized its true position in the science of medicine until Morgagni (1683-1771) published the De Sedibus et Causis Morborum per Anatomen Indagatis (1761). Others before this date had made interesting collections of cases: Ridley in England, and Bonetus of Geneva, who published the Sepulcretum Anatomicum in 1679. Valuable as is this great work, it had not the profound influence of the De Sedibus, as it was a collection of cases from the literature, and lacked that freshness and interest which Morgagni was able to give to his reports. In them for the first time we find a careful clinical study of the symptoms of disease and an equally careful examination of the organs after death. It was the novelty of the mode of presentation quite as much as the vivid picture of disease that made Morgagni's work mark an epoch in the history of clinical medicine. Even today it is a storehouse of valuable facts, and several of the sections, more particularly that on the heart and bloodvessels, are so rich in original descriptions that no man's education in morbid anatomy can be said to be complete without an acquaintance with its pages. The example of the great Italian was soon followed in other countries, particularly in England and in France. John Hunter, with his insatiable hunger for knowledge of all sorts, was equally great as a morbid- and as a comparative anatomist. The Hunterian specimens in the great Museum at Lincoln's Inn Fields bear witness to the accuracy of his descriptions, to the insistence, when possible, upon clinical details, and to the keen appreciation which he had of the importance of the study of morbid anatomy in the education of medical men. His brother William, also an enthusiastic student of morbid anatomy, formed an important collection, and the specimens and notes in his museum, now at Glasgow^ show that he too was alive to the value 1 "The examination of a single body of one who has died of tabes or some other disease of long standing, or poisonous nature, is of more service to med- icine than the dissection of the bodies of ten men who have been hanged." Letter to Riolan. xxvl INTRODUCTION of the new method of combining clinical with anatomical work. ISIatthew Baillie, their nephew, gave to the world the fruits of their researches, combined with his own, in the Morbid Anatomy published in 1793 and followed in 1799 by his well-known Atlas. Texts and plates, alike admirable, formed the most important contribution to practical medicine made in England during the eighteenth ccnturv, if we exclude -Tenner's vaccinations. The Scries of Kngravincjs was the first of its kind to be published, and the accuracy of the drawings and the careful descriptions made it for years a standard work, and indeed the plates may still be used in illustrating lectures. But the new science reached its fullest develop- ment in France, and helped to promote the revolution in clinical medicine which was effected in that country during the first three decades of the nineteenth century. To the school of Bichat, who was essentially a morbid anatomist, we owe the fruitful studies which gave us our modern outlook on the processes of disease. Corvisart and Bayle, Broussais, Laennec, Louis, Chomel, and iVndral revived Das Anatomischen Denken (Virchow) of INIorgagni. With the old Hippocratic method, however, which had been used for cen- turies, and which Morgagni had simply transferred from the bedside to the dead-house, it would have been impossible to get beyond the great Itahan. Hitherto the sense of sight had dominated in the examination of the patient, supplemented to some extent by the sense of touch. Now the hand and ear were to take an equal share, and the eye was to have its powers enormously extended by the use of the microscope. From the Inventum Novum of Auenbrugger (1761) we may date the introduction of modern clinical methods into medicine. His discovery illustrates the fate of a truth announced prematurely. The time was not ripe, and the art of percussion had to await the keen mind of Corvisart before its importance was recognized. The greatest stimulus ever given to internal medicine was the discovery of auscultation by Laennec, whose work V Aiisndtation Mediate (1819) not merely introduced a new method, but was also a treatise on diseases of the heart and lungs, combining the results of clinical study and anatomical investigation. With this book began an entirely new era in medicine. Rich in the descriptions of diseases hitherto unrecognized and unrecognizable, this immortal work not only placed a new and powerful method in the hands of physicians, but also gave an enormous stimulus to the study of internal diseases. The researches of Louis correlated the symptoms and physical signs with the anatomical appearances in pulmonary tuberculosis and in typhoid fever. Chomel, Andral, Bretonneau, Rayer, Piorry, Cruveilhier and others jCaught the new spirit and made Paris the centre of medical instruction for the whole world. This revolution in internal medicine was effected simply by an extension of the Hippocratic method from the bedside to the dead-house and by the correlation of the signs and symptoms of a disease with its anatomical appearances. It was by this method that Richard Bright opened up an entirely new chapter in his studies on the relation of disease of the kidneys to dropsy and to albuminous urine. It had already been shown by Blackwell and by Wells, the celebrated Charleston (S. C.) physician, that the urine contained albumin in many cases of dropsy, but it was not until Bright began a careful investigation of the bodies of patients who had presented these symptoms, that he discovered the THE EVOLUTION OF INTERNAL MEDICINE xxviJ association of various forms of disease of the kidney with anasarea and albuminous urine. In no direction was the liarvcst of this combined study more abundant than in the complicated and confused subject of fever. The work of Louis and of his pupils, W. W. Gerhard and others, revealed the distinction between typhus and typhoid fever, and so cleared up one of the most obscure problems in pathology. Throughout the nineteenth century this clinico-pathological investiga- tion of disease has widened enormously our diagnostic powers, and the physician today who wishes to obtain a sound knowledge of the natural history of disease must adopt Morgagni's method of "anatomical thinking." Skoda in Vienna, Schoenlein in Berlin, Graves and Stokes in Dublin, Marshall Hall, C. J. B. Williams, and many others introduced the new and exact methods of the French and created a new clinical medicine. A very strong impetus was given by the researches of Virchow on cellular pathology, which removed the seat of disease from the tissues, as taught by Bichat, to the individual elements, the cells. The introduction of the use of the microscope in clinical work widened greatly our powers of diagnosis, and we obtained thereby a very much clearer conception of the actual processes of disease. In another way, too, medicine was greatly helped by the rise of experimental pathology, which had been introduced by John Hunter, was carried along by Magendie and others, and reached its culmination in the epoch-making researches of Claude Bernard. Not only were valuable studies made on the action of drugs, but also our knowledge of cardiac pathology was revolutionized by the work of Traube, Cohnheim, and others. In no direction did the experimental method effect such a revolution as in our knowledge of the functions of the brain. Clinical neurology, which had received a great impetus by the studies of Todd, Romberg, Lockhart, Clarke, Duchenne and Weir Mitchell, was completely revolutionized by the experimental work of Hitzig, Fritsch and Ferrier. Under Charcot the school of French neurologists gave great accuracy to the diagnosis of obscure affections of the brain and spinal cord, and the combined results of the new anatomical, physiological, and experimental work have rendered clear and definite what was formerly the most obscure and complicated section of internal medicine. The latter part of the nineteenth century saw a complete revolution in our conception of the etiology of infectious diseases. The idea of a contagium vivum, of a living agent which multiplied in the body and caused the symptoms of disease, had long been entertained, and the analogies between the fermentation of fluids and disease had been fre- quently suggested. The brilliant researches of Pasteur placed the bacterial origin of certain diseases on a firm scientific basis. Grasping the idea that the putrefactive and suppurative processes in wounds were due to bacteria, Lister revolutionized surgery, and has made possible operations which have widened enormously the work of surgeons, with a result that today our art is more medico-chirurgical than it has ever been before. But the full importance of the new studies was not realized until Robert Koch discovered in rapid succession the causes of several of the most destructive of epidemic diseases. Then with Laveran's description of the malarial parasite came the recognition of the importance of protozoa as causes of disease. All this work has modified clinical medicine in several important directions. The detection of specific parasites has been xxvlii INTRODUCTION a great help to diagnosis, as, for example, in tuberculosis. The knowledge of the precise etiology has enal)led us to take intelligent precautions for the prevention of the disease, and the measures for sanitary control of the acute infections have been strenglhened a hundredfold by the studies of the past (piarter of a century. In another direction the new science has had a most frtiitful aj){)lication. With the introduction of vaccination against smalljwx, Jenner laid the foiuidation for the modern work, still only in its beginnings, which deals Mith vaccines, antitoxins, and curative sera. When one considers the comparatively short space of time which has elapsed since Koch's discovery of the tubercle bacillus, we may be grateful that so much has been accomplished, and in spite of many disappointments the situation is one full of hope for the future. However produced, the ultimate processes of disease represent chemical changes in the fluids and tissues of the body, and in this direction, too, the advances of the past half-century have liad a profound influence on clinical medicine. Oin- knowledge of normal metabolism has progressed with startling rapidity and warrants the belief that before long we shall have a safe platform from which to investigate "to a finish" such serious perversions as are present in gout, diabetes, etc. Already the studies upon internal secretions have not only given us a clear conception of the functions of certain organs, but have also enabled us to treat success- fully such otherwise incurable maladies as myxoedema. From the new science of physical chemistry much may be expected, and one of the most encouraging signs is the increasing attention paid by the younger physicians to problems which demand the most accurate chemical technic[ue. In the immediate future it is along chemical lines that we may look for the greatest advance, and of this there is no more satis- factory indication than the simultaneous appearance quite recently in England and the United States of journals devoted to biochemistry. V. A work of the scope of the present one has a very different value to dift'erent persons. It is designed primarily for the practitioner who wishes to keep himself informed of the existing state of our knowledge in clinical medicine. Elaborate discussions upon doubtful problems have been avoided, and, as far as possible, a clear statement is given without unnecessary references to the literature. Authors have been selected who are acknowledged authorities, and while it is not always easy for a writer who is saturated, so to speak, with his subject to keep within limits, and to remember the practical character of the men for whom he is writing, I hope we have been able to keep an even balance between the condensation of the text-book and the elaborate treatment of the monograph. The first consideration in a work of this kind is that it shall be lielpful. To fulfil this reqtiirement we have had some- times to introduce matter whic-h may seem foreign to a system of medicine. A section on Protozoa, for example, such as that given by Professor Calkins, is indispensable for the appreciation of the importance of this class of parasites, and in a brief article written for the purpose the practitioner will get information of a character better suited to his needs THE EVOLUTION OF INTERNAL MEDICINE xxix than from a manual of zoology. So, too, for the stiifly and prevention of malaria and of yellow fever a knowledge (jf the structure, vari(;tie,s, and life history of the mosquito is necessary, but the most recent infor- mation of this sort is not easily to be had from ordinarily procurable books. There are several ways in which a work of this kind may be most helpful to, a man in general practice. It may put him on the right course and give him his bearings when he has been blown about without compass by every wind of doctrine. For instance, studied carefully, the mas- terly presentation of the subject of Auto-intoxication by Dr. Taylor, in the present volume, will give him the "light and leading" necessary for an intelligent appreciation of one of the most complex and confused depart- ments of medicine. While much remains to be done, we have enough positive knowledge to enable us to approach the clinical side of the ques- tion in an intelligent manner, unburdened from much of the nonsense of the auto-intoxication propaganda of the past twenty years. Accurate clin- ical investigation must accompany chemical research, and, while the two cannot often be combined by a man in active practice, there is no reason why he should not appreciate the problem with sufficient clearness to enable him to furnish unbiased observations of the greatest value and to give to his patients the benefit of the most advanced scientific knowledge. Since upon diet more than upon any other single factor depends the health of the community, it behooves every physician to give to this subject his closest attention. In fully one-half of the patients he is called upon to treat, indigestion plays a most important role, and this may be traced to improper food, improper methods of preparation, or to faulty habits of eating. The real difficulty is less with the profession than in getting the public to carry out certain plain and well-recognized rules. The Yale studies bring into prominence the importance of new views which will appeal strongly to physicians who have long held that we all take too much food and particularly too much meat. From the important section on Metabolism by Professors Chittenden and Mendel the practitioner will get the scientific data upon which he may base rational plans of dietetic treatment in many diseases, and much information of the greatest use in his incessant propaganda against the gastronomic follies of the public. In these and in other sections the authors will be found to have simplified the abstruse and complicated knowledge of the chemical laboratories, and to have presented it in a form readily assimilable by the men who have to use it. Such, I believe, is the chief function of a system of medicine. VI. It cannot be too often or too forcibly brought home to us that the hope of the profession is with the men who do its daily work in general practice. Our labors are in vain — all the manifold contributions of science, the incessant researches into the complex problems of life, normal and per- verted, the profound and far-reaching conclusions of the thinkers and originators — all these are Nehushtan, sounding brass and tinkling cymbals, unless they result in making men better able to fight the battle against disease, better equipped for their ministry of healing. Gradually, often XXX INTRODUCTION insensibly, tiie practical advances of the laboratory and of the hospital reach the men Avith whom, after all, rests the final testing of all onr efforts. The work in practical sanitation, the last word in the prevention of disease, the carrying ont- new methods of treatment, the exchange of the old accoutrements for the new weapons and the new methotis of warfare, these rest with the rank and file of the jirofession who make efi'ective and translate into practice the new knowledge. The medical journals, the medical societies, the post-graduate schools all help in this good work, and both the profession and the public now appreciate how im])ortant it is that ])hysicians should keep well abreast of the times. The difficulty lies often with the individual men who fall into routine and slovenly habits of practice, and who never get more than a superficial smattering of the science and of the art of medicine. Even the most industrious and ambitious, absorbed in a limited field, find it hard to get new life into the old material, and, confronted on all sides by difficult jjroblems which press for solution, they turn for aid to the men who have made these problems their special study, and it is in such works as the present that these teachers and workers embody or codify, so to speak, the current knowledge of the day. After all, the important question for each young man to ask himself as he begins practice is : How can I carry on my education so as to get the best possible returns out of life and do the best that is in my power for my fellow-creatures ? There are several cardinal defects which stand in the way of the evolution of the sound clinical practitioner: Lack of preliminanj practical training. The medical curriculum is not yet so arranged as to give our young men enough clinical work in their senior years. So full and complicated has the course become that it is very hard for the teachers to adjust it to the new conditions. We ask too much, and expect too much, of the student; bvit if we could have him properly prepared at the schools and colleges, if everywhere the preliminary sciences were taught outside the medical school, there would be no diffi- culty in giving a man in four years a good start in his profession, and this is all that the best of teachers in the best of medical schools can do for him. In our well-organized physiological, anatomical, histological, embryological, chemical (physiological), pharmacological, and patho- logical laboratories the teaching has become more and more thorough and practical, but when we come to the "bread and butter" subjects we are not always prepared to give teaching of the same character. The hospitals and dispensaries are numerous enough, and there is no lack of patients ; but there is not that constant, close, personal contact of student with patient in which alone the art of medicine can be learned. There is not that control of hospitals by the universities necessary to ensure proper facilities for students, nor are the arrangements of the hospitals always such as to meet the demands of modern clinical Avork. There is still too much theoretical Teaching for senior students, and in a majority of the schools the number of teachers in medicine, surgery, obstetrics and the specialties is wholly inadequate. In only a few hospitals is the out- patient department arranged for clinical teaching, and the clinical laboratory is not everywhere recognized as a .tine qua von. If we could turn our third and fourth year students into the hospitals and make them part and parcel of its machinery (just as much as the nurses who have THE EVOLUTION OF INTERNAL MEDICINE xxxi usurped, I fear, some of their duties, and have advantages that they do not possess) we eould give them at least a good introduction to their Hfe- work; and a man could enter upon practice with a rational outlook on disease, and be prepared to continue his education with the help, not at the expense, of the public. But all this is changing rapidly, and year by year the men who leave our schools are better educated and in every way better fitted to practise medicine intelligently. Lack of critical jndgment is another serious obstacle in the way of the young man. It is hard to get life's spectacles adjusted, so hard to get clear vision, where so much is obscure. The faculty of "right judgment in all things" is granted to few men, but the physician to be of any value must at least aspire to that round-about common sense which was so distinguishing a feature in Sydenham. It may be cultivated, but with caution, as it is one of the virtues more readily acquired when not too consciously sought. Slow of growth, and the fruit of a seasoned experience, good clinical judgment only comes with careful study, and is best seen in men who appreciate the value of thoroughness in their work. The mental attitude controls the course of a man's evolution as a clinical physician. While nothing can be more fatal than a cold Pyrrhonism in which everything is doubted, in the midst of so much credulity, lay and professional, it is well for the young man to take as a motto the saying of that wise old pre-Hippocratic poet-physician, Epicharmus, of Syracuse: "Be sober and distrustful; these are the sinews of the understanding." Credulity is of the very essence of human nature and we physicians are not exempt from the common lot. Our work is an incessant collection of evidence, weighing of e'/idence, and judging upon the evidence, and we have to learn early to make large allowances for our own frailty, and still larger for the weaknesses, often involuntary, of our patients. The history of medicine is full of instances of self-deception on the part of the best of men, and it is well that the young man should at the outset be humble, as he is not likely to escape altogether. Science has done much in revolutionizing mankind, but man remains the same credulous creature as he has been in all ages. Tar-Avater, Perkin's tractors, laying on of hands, Christian Science, Lourdes, and the other miracle-working shrines illustrate the deep, intense credulity from which science has not yet freed mankind and is not likely to do so. It is an aspect of human nature which we must accept and sometimes utilize, remembering the remark of Galen: "He cures the greatest number in whom most men have most faith." It is for the practitioner to make the new facts of science efficient and useful, to translate science into practice Often a very prolonged affair from inherent difficulties connected with the complicated mechanism of man's body, this is sometimes a source of discouragement, and we hear complaints of the slowness of progress in medicine, and of the inability of physicians at once to turn to practical account some striking discovery. The history of science teaches us that it takes many years from the announcement of the fact to its full application. From Faraday's work on electromagnetic induction to the making of dynamos for com- mercial purposes was a longer period than from Claude Bernard's discovery of internal secretion to the successful treatment of a case of myxoedema with thyroid extract. In making a new application of science the stages are well defined. First there is the discovery of the phenom- xxxii IXTRODUCTION enun cajjuhle of utili/.atiuii. Then comes an inventor who recognizes the jK).s.sibihty of its practical a])plication. He may require the help of a skilled engineer who correlates the commercial and manufacturing conditions to be dealt with; and finally there is the capitalist who furnishes the means to make the invention of practical utility. In the science of medicine, to make efficient in everv-day practice the ne^v discoveries regarding the functions of the body and the phenomena of disease is a very difficult matter. There is much knowledge which cannot always be made helpful. It may add to the clearness of the clinical picture and enable us perluips to recognize the nature and state of a disease without benefiting in the slightest the poor victim of it. A knowledge of the structure and of the fimctions of the motor paths may be of no use whatever in a case of com))lete destruction by a clot in the internal capsule; but in the very next case, one of syphilis of the brain, or in one of tumor of the cord, in the full utilization of this same knowledge may rest the issues of life and death. Just as in the mechanical sciences, it takes a combina- tion of human activities in several stages of effort to reap the benefit of any discovery, so it is in medicine. The anatomist, the physiologist, the ]iathologist, the clinician, and the surgeon — in as many stages as from Faraday's discovery of electromagnetic induction to the manufacture of a dynamo — all had to combine before a brain tumor could be removed successfully. Between Claude Bernard's discovery of internal secretion and the cure of a case of myxoedema every department of medicine was taxed. To be exploited prematurely in practice is the common fate of all new scientific facts. Not content to wait for full knowledge, men hastily draw conclusions from imperfect data. Consider the dross with A\hich the ]:)in-e gold of Claude Bernard's discovery has been mixed in an organotherapy often as irrational as that practised in tlie middle ages. VII. Intertwined as the subject is wath the complicated sciences of physiology, organic chemistry, and physics, to make sol d contributions to clinical medicine we must systematize the work much more than has hitherto been possible. The trustees and managers of hospitals should apj^reciate more fully than they do at present the scientific needs of these institutions. To do justice to the patients, to carry out modern lines of treatment, indeed, to diagnosticate skilfully, require now the assistance of trained laboratory workers who should form part of the staff. It is impossible for any man, no matter how industrious, to keep abreast at all points Avith tlie chemical and bacteriological technique. Two important changes are necessary before hospitals are in a position to do the best possible work in clinical medicine: First, in many institutions the number of attending physicians should be reduced. In small hospitals of a total capacity of one hundred and fifty beds the medical w'ards should be placed in charge of one man. In the larger city hospitals separate medical services should be arranged w'ith from sixty to one hundred beds in each. The profession should learn to recognize the worker in internal medicine as a man wdio has to devote so much time to his studies that it is impossible for him to take general THE EVOLUTION OF INTERNAL MEDICINE _ xxxiii practice, and in a way he is a specialist, in the; broad sense of (he term, like the surgeon. The development of clinical medicine is retard(;fl hy the present system of appointing genc^ral practitioners, often the busiest and most successful men, in charge of the wards. Ntjwadays only under exceptional circumstances does a man of energy and perseverance evolve from these surroundings into a thoroughly trained clinical investi- gator. In saying this I do not forget that from these conditions arose the very men who have contributed most to medicine in America, men of the stamp of W. W. Gerhard, Austin Flint, Da Costa and Pepper. But the times are changing, and I know that I express the feelings of hospital physicians themselves when I state that a reorganization is urgently demanded along the lines here indicated. Not only in the larger cities, but in towns of from fifty to one hundred thousand inhaljitants the well-equipped medical clinic is the most urgent need of the profession. Secondly, the internal organization of the hospitals must be changed to meet the new demands. A larger number of house physicians is required, who should be graded so that raw, inexperienced graduates should not be put at once in full charge of patients. A clinical laboratory with chemical and bacteriological assistants should be provided for each service, or, in the smaller hospitals, one would suffice for all departments. This need, now generally recognized for hospitals connected with medical schools, is of equal importance in the smaller hospitals. An example of what organization can do in this direction is afforded by the remarkable clinic which has been built up in Rochester, Minnesota, by the Mayo brothers, who have made that little town a world-known resort for both physicians and surgeons, and whose success has been due as much to their careful attention to the laboratory side of their work as to the technique for which they have become so famous. Lastly, my earnest hope is that this series of volumes may be of service in that education which each one of us has to work out for himself in practice. Set on the right path in the schools it should not be difficult for a man to keep in touch with the advances of science, and to give his patients the benefit of all those accessories which are so important in the recog- nition and successful treatment of disease. Just as the clinical laboratory is a necessity to the hospital physician engaged in the solution of the most advanced problems in medicine, so the private laboratory is indispensable in the every-day work of the busy practitioner. Urine analysis, blood counts, sputum examinations, chemical analysis of stomach contents, all these should be done at home: at first, by the physician himself, while not too busy; later by an assistant. This may seem to be asking a great deal in the heavy routine of the day, but it is not asking too much, and it will be done more and more when we send out our students familiar by long prac- tice with the use of the microscope and other instruments of precision. It makes the practice of medicine of absorbing interest when one feels he is approaching the study of a case equipped with modern methods, and it is the neglect of these accessories that makes so many men fall into slip- shod habits of diagnosis, and still more careless methods of treatment. Asked the single most powerful weapon today in the hands of the pro- fession against quackery of all sorts, I would answer: the little laboratory room attached to the office of the general practitioner. Nor is it asking xxxiv . IXTRODUCTION the impossible. I know many busy men who utihze to the full all these resources of our art. 1 would like to call the attention of my colleagues to the papers on this question by my friend, M. H. Fussell,' of Philadel- phia. Nor is, it impossible in general practice to become an active and valued contributor to the literature of the j)rofcssion. It should not be forgotten that Robert Koch was a district physician when he made his memorable researches upon anthrax. One of the most distinguished scholars of his day was Robert Adams, a village surgeon. The young physician should not be disturbed by the thought that it requires special abilities to rise superior to one's environment. It is the average man with a set and steady determination to equip himself at all points who is more likely to succeed than any other. The way is open to all. For those whose training in the medical school has been defective the post-graduate school is available, and a month or two every few years s])ent at a good hospital and in laboratory work add to a man's mental capital and make him of greater value to the public and to his colleagues. It is astonishing how much there is in the daily round if men would but keep the open mind and look upon life as a progressive education. The times have changed, and we have travelled far from the days when the father of medicine jotted down his notes upon fever cases in Abdera and elsewhere. We know more and enjoy larger opportunities, and with them have greater responsibilities, but could Hippocrates return he would find no change in those essential duties in which he is still our great exemplar. They are four: so to study our cases as to acquire facility in the art of diagnosis, which must everywhere precede the rational treatment of disease; so to grow in critical judgment that we may learn to appreciate the relative value of the symptoms and physical signs, and give to the patient and to his friends a forecast or prognosis; so to conduct the treatment that the patient may be restored to health at the earliest possible period, or, failing that, be given the greatest possible measure of relief, whether by drugs, the action of which he should carefully study, so as to have a strong and abiding faith in those which have been tried and not found wanting, by diet, by exercise, or by all the physical means avail- able, and often by the exercise of his own strong personality; and, lastly, so to arrange sanitary and hygienic measures that, wherever possible, dis- ease may be prevented. Could Hippocrates meet again a class of students at some modern Cos, and discuss the changes which twenty-five centuries had wrought, he would dwell upon this latter development of the science and of the art as the crowning benefit which the profession has bestowed upon the race, and he would repeat again those noble Avords which have found in this triumph their practical realization: To serve the art of medicine as it should be served, one must love his fellow-men. 1 The University Medical Magazine, 1891, 1896, 1898, 1900. The Journal of the American Medical Association, 1901, 1902. The Philadelphia Medical Journal, 1901, 1902. PART I. HEREDITY AND PREDISPOSITION. CHAPTER I. INHERITANCE AND DISEASE. By J. G. ADAMI, M. A., M.D., F.R.S. It is difficult to realize that the essential nature of procreation has been known to us for scarce a generation. That the conjugation of the two parents is essential, was obvious ab ovo; that there resulted from that union an individual possessing characteristics referable to both parents, was equally clear; nay, more: it was well known that characters not pro- nounced in the parents but traceable to an earlier generation on either side could, not infrequently, be made out. But why this should be, remained a profound mystery. True it is that Leeuwenhoeck, in 1677, demonstrated the existence of spermatic filaments in the seminal fluid of various ani- mals, yet for close on two centuries the part played by these spermatozoa was a matter of debate. Only in 1852 was it clearly established that the spermatozoon penetrates the envelope of the ovum; only in the "seven- ties" was it determined through the researches of Van Beneden (1875) and later by those of Strassburger, O. Hertwig, Fol, and Boveri, that the changes following the entrance of the spermatozoon into the ovum, centre round the fusion of the nuclear material of the one with that of the other, and that from the moment of this fusion dates the beginning of the life history of a new individual. Stated in the simplest terms, the new individual is the result of the union of a single cell from the male parent with a single cell from the female. These two cells are in their turn the derivatives of cells which, from a very early period of embryonic life, can be seen to have been segregated for re- productive purposes, and apparently for nothing else.^ The individual ^ Recent studies by Bouin and Ancel demonstrate that the internal secretion of the testicles, and the influence which the presence of this again exerts upon the general metabolism, is connected not with the germinal epithelium (the cells of the tubules), but with certain characteristic interstitial cells lying between the tu- bules. For a very clear resume of the extent to which the germ-cells are thus segre- gated from an early period in the different genera of animals, see Bigelow's article on " Heredity ," Buck' s Reference Hand-hook of the Medical Sciences, 4, '02, 650. 2 17 18 HEREDITY AND PREDISPOSITION ova already exist at birth, and lie latent, or at most very slowly increase in size until close upon the time when they are to be discharj^ed. The spermatozoa similarly are derived from cells of, apparently, a simple un- ditt'ercntiated tvj^e, and are developed from these shortly before they are discharged. In other words, neither ovum nor spermatozoon is the result of a piecing; toijcthcr of contributions from the various tissues and organs of the body; neither is a microcosm — a microscopic representa- tion of the adult organism. They arc not pangenctic; both are derived from the germinal tissue, which is evidently set apart from the first, so as not to be subjected to the performance of functions other than those of reproduction. The only functions we can recognize as performed by them, prior to their liberation, arc assimilation and growth, and, in the case more particularly of the male germ-cells, concomitant multiplication. When we come to study the details of the process of fusion we find that while the cell-substance of the fertilized ovum is contributed by the female cell and the centrosome' by the male, the one constituent contrib- uted with a remarkable quantitative equality Ijy both cells, is the nuclear material, or chromatin.^ So striking, in fact, are the preparatory changes in connection with the nucleus of each cell, so elaborate the coidredanse which precedes the fusion of the nuclear materials of the two cells, that no other conclusion is possible than that here in this fusion of nuclear material is the central act of sexual reproduction; and once we accept — as we are forced to accept — that there may be equally and interchange- ably inheritance of features peculiar to either parental stock,^ we are ' E. B. Wilson and Naohide Yatsu ha^•e brought fonvard positive proof that the centrosome is not of nuclear origin, hut can be reformed in the cytoplasm of cells deprived of their nuclei (Proc. 8oc. Exp. Biology and Medicine; American Medi- cine, 1905, p. 493). ^ To this statement a reservation must be noted as the result of the recent studies of Ilenking, Montgomery, McClung of Kansas, and E. B. Wilson. Among hemipterous insects the sperm mother cells give rise to spermatocj'tes of two orders, so that in certain species one-half of the future spermatozoa recei\'e an "accessory" chromosome; in other species what is a peculiarly large chromosome in the one set of cells is represented by a minute chromosome in the other. The ova of these insects in their development exhiliit no such difference. As McClung first noted {Biological Bulletin 3, 1902, 43) the only distinction which separates the resultant fertilized cells into two approximately equal groups is sex, and we are logically forced to the conclusion that the peculiar chromosome has some liearing upon this differentiation. The distinction has thus far been established for the hemiptera alone. In other insects (Aphides) two types of ova have been noted gi\'ing rise to male and female respectively. Thus it is not yet possible to make any general statement regarding differentiation of chromosomes and the determination of se.x. Even in these cases it is but one or an uneven pair out of the .series of chromosomes that is implicated; sets of chromosomes of varying size and shape are to be recognized in the nuclei that undergo fusion, and these pair with remarkable accuracy {Vide Arnold and Moore, Proceedings of the Royal Society, Series B., 77, 1906, .563). ^ The most striking example of this equality of the male and female elements is contained in the observations of von Giirtner (confii-med by Mendel and others) upon the hybridization of peas, in which by the cross-fertilization of two differ- ent species ("A" and "B") it was found that identical hybrids were produced whether the pollen of A was employed to fertilize the egg-cells of B, or the pollen of B to fertilize the egg-cells of A. It is true we do not get this happening among mammals. Your mule, the offspring of a jackass and a mare, is a different animal from the hinny or jennet, the offspring of a stallion and a jennj^-ass; but here it must be recalled that the inter-uterine development, within the donkey and the mare respectively, must materially modify the progeny in these two cases. INHERITANCE AND DISEASE 19 forced to conclude that what is inherited is contained in, and carried by, the nuclear chromatin. From this it follows surely that the only con- ditions which are capable of being inherited, are conditions which have told upon and modified the nuclear material of the germ-cells of either parent prior to or at the moment of fusion. It is at that moment of fusion that the new individual begins its existence. Any influence acting upon and modifying it after this moment is something acquired by what is already a separate entity; it is not inherited. Starting from this basis, and for the nonce accepting Virchow's dictum that every departure from the normal in the individual is to be regarded as a pathological condition, we are led to classify all pathological condi- tions (including variations, modifications, and actual conditions of dis- ease) into: (1) Inherited conditions — a. Derived from the male parental stock. b. Derived from the female parental stock. c. Due to fusion and interaction of the two nuclear materials. (2) Acquired conditions — a. Of ante-natal acquirement. b. Of parturient acquirement. c. Of post-natal acquirement. CONDITIONS MISTAKENLY REGARDED AS INHERITED. And now to clear the ground. It is obvious from the above that many conditions commonly described as inherited are of ante-natal acquire- ment. Yet other conditions presuppose influences at work on the nuclear matter of the germ-cells of either parent which by no mental effort we can conceive as bringing about the declared results. It will be well to dismiss all these before passing on to consider the conditions truly inherited. Maternal and Paternal Impressions.— The belief in these as causes of local bodily disturbances has not wholly died out, and in the United States, as McMurrich indicates,^ judging from the relative amount of literature on the subject, it dies a hard death. Even could we accept the view that through the influence of the maternal nervous system — for it could under the circumstances only be by this — conditions affecting one area of the maternal organism could reproduce themselves upon the corresponding area in the offspring, the overwhelming majority of the cases cited are clearly not examples of inheritance; for in that majority, studying the histories given, the maternal impression has occurred after conception, and most often after the second month of pregnancy; i.e., the period when the offspring passes from the embryonic to the foetal stage, when already the different organs have received their outline and are recognizable as such. Of maternal and paternal impressions stated to have been in action prior to fertilization, the recorded instances are few and far between. The locus classicus is Jacob's stratagem to increase his flock of ring-straked, ^McMurrich: The Physician and Surgeon, (Ann Arbor,) January, 1905. For full studies of this subject see also Tartuffi, Storia delta Teratologia Bologna;, 1881-1894; and Ballantyne, Trans. Edin. Obstetr. Soc , 21, 1896. 20 HEREDITY AND PREDISPOSITION spotted and speckled sheep and goats at the expense of Laban, his father- in-law. The most recent instance that has come to our notice is that of a well-known Aberdeen breeder of shorthorns, who is convinced that his failure during a recent season to obtain calves having the proper marking — all those cast showing a patch of white on the flank — was due to the fact that instead of the bull serving the cow in the obscurity of the byre, for a time service was conducted in the yard where the family washing was hung out to dry. The cases upon record, in short, are so rare, and the causes adducecl so bizarre, that even if we accept the histories given, it is unnecessa-ry to discuss possibilities. The cases are not more frequent than would occur under the law of chance — a law too often neglected in seeking for an explanation of rare conditions. But if this does not satisfy, it may be asked by what conceivable means can a visual impression affecting either parent at the time of conception, influence either spermatozoon or ovum, when both have become free cells, liberated from organic connec- tion with the parental organisms? There is this difference between the domestic animals and man, that in the latter, conjugation occurs irrespec- tive of periods of the dehiscence of the ova, and these, therefore, may still, in the female, have loose organic connection with the parental organism. Even then it maybe asked, how can preconceptional nerve stimuli in the mother so aiter the mole-cular arrangement of the nuclear material of an individual ovum as to induce a minute specific difference in the progeny? The Non-inheritance of Mutilations. — It is obvious from the prem- ises laid down that gross mutilations of the limbs or trunk of either parent cannot reproduce themselves in the offspring; and as a matter of fact, every experiment made with due regard to scientific accuracy demon- strates that this is the case. One may, following Weismann, cut off the tails of twenty successive generations of long-tailed mice — cut them off immediately after birth — cut them off not in one but in both parents — and the twenty-first generation will be born with tails as long and with as many vertebrae as those of the first. These conclusions have been violently contested, and that because the Lamarckian theory of evolution is based upon the transmission of char- acters acquired or further developed by the parent— so that could it be found that gross changes in the paternal and maternal organism were in- herited, it would have to be conceded that changes of all orders are sim- ilarly capable of inheritance. Now it ic worthy of note that not a single series of experiments has been devised by the Lamarckians which has demonstrated this inheritance of mutilations. Individual cases they have adduced in which the offspring, through one or more generations, have shown defects which more or less definitely imitated the outcome of an injury received by one or other parent-member of an earlier generation. But in the absence of absolute experimental proof, which, if mutilations of any order are transmissible, ought to be forthcoming without difficulty, these isolated instances must again be regarded as coming under the law of chance. Circumcision, we know, has been practised from time immemorial by certain oriental nations, and practised shortly after birth among the Jews, according to their history, for at least six score generations; but the males are still born with fully developed prepuces. It has been urged recently as evidence of the inheritance of mutilations that a greater proportion of INHERITANCE AND DISEASE 21 Jews are born with shortened foreskin and exposed glans than is found among nations which have not practised this rite. This, however, is no argument. The only vahd proof would be afforded if it could be demon- strated that the number of naturally circumcised Jews had been under- going a steady increase during the last thousand years, while no such increase has shown itself in an allied race of the uncircumcised. It may indeed be suggested as eminently probable that circumcision arose, not primarily as a religious rite, but as a hygienic measure of considerable importance in tropical and subtropical regions, and, if so, it must have been based upon not an occasional observation, but upon the common experience that those "naturally circumcised" escaped the troubles to which those having the fully developed foreskin were subjected. In other words, cases of shortened foreskin must have been fairly frequent in those races before circumcision came into vogue. There is one series of experiments that is constantly adduced in this connection — the celebrated observations of Brown-Sequard upon guinea- pigs rendered epileptic by sundry injuries to the nervous system, the off- spring of which were found, some of them, to manifest epileptic and other nervous phenomena. These observations have been confirmed by one group of observers (Westphal and Obersteiner), and have been contra- dicted by others (Sommer and Binswanger). There is no need to enter fully into these cases, because on the face of them they do not enter into the present category. Only by a confusion of ideas are they included as evidence of the transmission of mutilations or injuries. Epilepsy is not a specific anatomical injury; it is the expression of a functional irritation of the higher nervous centres, set up often by injury at a distance — in Brown-Sequard' s cases by injury to the sciatic nerve, etc.; and none of those who adduce these cases demonstrate the transmission to the off- spring of the local disturbances which in the parent had induced the epi- lepsy. At most, these cases come under the heading of the inheritance of acquired functional modifications, which is quite another matter and will be discussed subsequently. There are, however, two instances recorded by Brown-Sequard which have a bearing in this controversy and cannot be passed over without notice. He noted that one of the progeny of a guinea-pig, which exhibited atrophy of a hind limb following upon section of the sciatic nerve, was born with an ill-developed hind limb, and that similarly one of the progeny of another guinea-pig whose eye had been destroyed, suffered also from an imperfectly developed eye. I do not doubt Brown-Sequard' s veracity— that would be absurd; nor will I pretend to explain these cases. I will only say that they are at variance with human experience and that I cannot accept them as examples of inherited mutilations. Whenever the father or the mother has lost a limb, it is a surely ascertained fact that the children are born with the full complement of limbs ; and similarly the accidental destruction of an eye in man is known to be without effect on the chil- dren. Neither Brown-Sequard nor any one else has been able to repeat these observations at will, or to show how these results can be repro- duced. Again I must class them as chance occurrences. Until, therefore, some supporter of the Lamarckian theory can arise and bring forward an experimental mutilation upon one or other animal which is transmitted and reproduces itself not as an exception but in a 22 HEREDITY AND PREDISPOSITION reasonable proportion of the offspring of the mutilated animals, we are forced to adhere to the view that 7/-t».v.s' viuiilaiiun.s- are not iransmiiied — and what is more, must urge that we cannot conceive any sucli transmission. The Non-inheritance of Specific Infectious Diseases.— Like con- siderations indicate that it is impossible for there to be inlicritance proper of infectious diseases. There is no such thing as inherited small- pox, inherited tuberculosis, or hereditary syphilis. For consider what such inheritance necessitates. All infectious disease, we admit now- a-days, is brought about by the growth of pathogenic microorganisms within the system. It is by the nuclear material of the spermatozoon and of the ovum that the ])arental pro])erties are conveyed to the offspring; it is the molecular composition of that nuclear material that controls the organism of the develo})ing individual. Granted that the inert ovum be- fore conception could take up pathogenic bacteria — or, what is still more opposed to general })rinciples, that the bacteria actually made their way into the ovum; granted, again, that the spermatozoon— a mass of nuclear material and little more — could similarly come to contain a pathogenic microbe : in not one of these cases would the microbes be a part or portion of the heritable matter; they would but be associated. At most the dis- ease would be transmitted "from parent to offspring by means of the germ-cells; it would not be strictly inherited. It may be urged that this is a refinement of logic; that, for practical purposes, it matters little whether we have to deal with inheritance, or transmission through the germ-cells; that if the father has syphilis and the child is born with the disease, the fact stands evident that syphilis has passed from the elder .to the younger generation; and most assuredly in- fectious diseases do thus pass. We think, however, that it must be ad- mitted that there is some advantage in realizing with a certain amount of precision the course of events in such a process of infection — a certain advantage in the correct employment of terms — and assuredly the more we inquire into the data bearing upon the conveyance of tuberculosis or syphilis from the parents to their oft'spring, the more it is borne in upon us that even transmission by means of the germ-cells is most doubtful; the facts at our disposal best fit in with an antenatal, intra-uterine ac- quirement — an infection of the embryo or the foetus at a later date. Transmission of microorganisms by the egg is not unknown among lower forms of life. It may happen that the hen's egg is not perfectly ster- ile, and this in eggs that are freshly laid; the eggs of the silkworm may be infected by the organism of pebrine so that the developing caterpillars in their turn are found to exhibit the disease; similarly there is some evi- dence that the eggs of the tick boophilus carry within them the piro- plasma, the organism of Texas fever. Leaving aside the possibility in these last two cases that infection of the interior of the egg may occur at a late period, the germs being at first outside the egg-cases and only subsequently gaining entrance, it has to be pointed out that the eggs in all these cases are different from the human and mammalian ova. All the above have a relatively abundant yolk and food supply, in which the microbes may multiply without at first affecting the embryo. The human ovum, on the contrary, is devoid of yolk; the microbes, if present, would from the first be within the cells of the young embryo, and is it difficult to conceive such intra-cellular microbes lying inert; difficult to imagine that they would INHERITANCE AND DISEASE 23 not set up so serious a perversion of metabolism that if they did not rap- idly destroy the embryo, at least they would induce dcveloj)mental anom- alies incompatible with eventual continued existence. Baumgarten and others believing in germinal infection have found it necessary to predi- cate a latency, or lying latent, of the pathogenic organisms. When we find that the post-natal tuberculosis of early infancy is characterized in general by a much more rapid infection and generalization than occur in the adult, the likelihood that at a yet earlier period the tubercle bacillus is arrested in its activities is at most extremely slight.^ The observations of Schaudinn^ upon trypanosomes (halteridium) and leukocytozoa (spirochsetes) of the stone-owl, may possibly oppose what is here said, for, according to him, both these forms of parasitic protozoon may make their way into the eggs of their hosts (mosquitos) ; and, as re- gards the former, he lays down that they rest during the development of the young gnat, becoming active when the latter is adult and begins to suck blood. In both these protozoon forms the conditions, so far as we may see, differ from what obtains with tubercle bacilli. In them we are dealing with species presenting a pronounced alteration of generations, and so accustomed to long periods of rest before circumstances are favor- able for transmission to another host. In the absence of spores the exis- tence of anything like a resting-stage in the tubercle bacillus is still regarded as doubtful, although, not to be partial, it has to be noted that cer- tain modern authorities describe minute gonidial forms of the bacilli, and these might possess the property of latency. The saner view is that in man, the infection of the offspring from the mother is placental, and this view is supported by (1) the analogy of the acute exanthemata; (2) the absence of any constant stage of tuberculosis or syphilis manifested at birth; (3) the frequent evidence of placental infection; and (4) the gen- eral nature of the lesions in the offspring. Acute exanthemata attacking the mother in the last days of pregnancy can affect the child, which is born showing the acute lesions of the disease; here there can be no ques- tion of germinal infection. Infants may be born showing generalized and advanced syphilis or tuberculosis, or, on the contrary, may present indications only a week or more after birth: this very inconstancy indi- cates irregularity in the period of infection. Regarding the existence of infective lesions of the placenta we need say nothing here ; no one denies their existence. Lastly, as regards the nature of the lesions, syphilis presents a specially instructive picture. In syphilis of postnatal acquire- ment the liver is infrequently involved; in 11,629 autopsies at St. George's Hospital, extending over forty-two years, J. L. Allen found only 37 cases of undoubted hepatic gummata, and 27 cases in which cicatrices alone were present. Flexner, including also cases of syphilitic fibrosis, found in Philadelphia altogether 88 cases of hepatic syphilis in 5,088 autopsies. In congenitaP syphilis the liver, of all internal ^Von Behring's recent theory that most tuberculosis in man is acquired in infancy from cow's milk, also demands a similar latency of the tubercle bacilli. The basis of this theory has been completely shattered by Kitasato's full statis- tical study of conditions in Japan. There tuberculosis at all ages is as common as in Europe and North America; but, in the first place, the native cattle are im- mune to tuberculosis; in the second, infants are not brought up on cow's milk. ^Arb. a. d. Kaiserl. Gesundheitsamte, Berlin, xx, 1904, pt. 3. ^ I have so far refrained from using this term, which, though strictly correct as 24 HEREDITY AXD PREDISPOSITION organs, is that most frequently involved. Aeeording to Chiari, out of 132 S}TDhilitic infants examined, 119 showed hepatic involvement. This is scarce to be explained on the theory of germinal infection; it is exactly what we should expect from placental infection, and this because the blo(xl of the umbilical vein passes first to the liver, which thus bears the brunt of the infection: it is here that the microbes of the disease are liable to be arrested. Yet another method of uterine infection, through the am- nion and anmiotic fluid, has also to be taken into account. With reference to germinal infection through the spermatozoon and its unlikelihood, the following observations of Gartner^ deserve consider- ation. As Wyssokowicz has demonstrated, the minimal number of tubercle bacilli which will set up peritoneal infection in the guinea-pig is eight. Gartner, obtaining with every precaution the ejaculations from guinea- pigs rendered tuberculous by intra-tracheal injections, found that only five out of thirty-two ejaculations contained a sufficient number of bacilli to set up peritoneal tuberculosis in other guinea-pigs. Rohlff, taking se- men from the bodies of men succumbing to pulmonary phthisis, did not once succeed in rendering rabbits tuberculous. (To set up peritoneal in- fection in the rabbit a minimum of twenty-four to thirty tubercle bacilli must be present.) From these and other considerations, Gartner was led to the conclusion that the semen of the advanced phthisical patient, with- out direct tuberculosis of the genital organs, does not on the average contain as many as ten bacilli. A careful computation of twenty-four cases has shown that the aver- age human seminal ejaculation contains more than two hundred and twenty-six millions spermatozoa. (The number appears extraordinary, but is comprehensible Avhen we remember that a cubic millimeter of blood contains five million erythrocytes.) Thus, says Gartner, if the semen contained not ten but one hundred bacilli, the chances that an individual spermatozoon fertilizing an ovum should have with it a tuber- cle bacillus, and so cause germinal infection, are as 1 to 2,260,000. Even did the semen contain 1,000,000 bacilli the chances would be as 1 to 226. He pursues the argument further by showing that on the average only 1 out of about 85,000,000,000 spermatozoa has the chance of fertilizing an ovum. Suffice to say that the chance of germinal infection through the conveyance of tubercle bacilli by the spermatozoon is so absurdly minute that it must be neglected. Infection of the offspring in utero by the father, when it occurs — as we know it does occasionally, and that without apparent infection of the mother — must happen at a later period, and two possibilities present themselves: namely, it is possible that there may be purely local infec- tion of the womb, and more particularly of the placental area, from the seminal fluid of the male parent; or, without direct infection of the womb, there may, at a later period, be conveyance of pathogenic microbes from the uterine cavity through the amnion into the amniotic fluid. Without discussing these possibilities, it is here only necessary to state that it has been positively demonstrated that tubercle bacilli introduced embracing the conditions of ante-natal disease, is so frequently regarded as synonomous with "hereditary" that to employ it is apt to confuse. 'Zeilchr f. Hygiene, 13, 1893, 101. INHERITANCE AND DISEASE 25 into the uterine cavities of pregnant animals may later be detected in the amniotic sacs. To repeat, we are forced to conclude that specific injections are not in- herited, hut are of post-conceptional acquirement. This, however, is not the same as stating that no inheritance of any order can occur in connection with specific diseases. To this latter possibility we shall return later. CONDITIONS TRULY INHERITED. We have now cleared the ground, and it may seem that very little of the nature of disease is left which can be inherited. Of actual dis- ease, it is true, very little is left; of morbid conditions — of departures from the normal (variations), and morbid tendencies (diatheses), — much re- mains to be said: so much, indeed, that it is difficult to know where to stop; for to discuss these subjects adequately demands a study of the whole theory of inheritance. But first, in order to think clearly over these matters, it is well to treat apart as far as possible two broad groups of cases; namely, the cases in which we have to deal with the inheritance of conditions which have passed down from earlier generations (and dealing with that we will for the time leave out of consideration how these departures from the normal gained origin); and, secondly, those cases in which abnormal conditions have manifested themselves first in one or other parent. It is when dis- cussing these that, to gain a grasp of their meaning and extent, we shall have to inquire into their origin and strive to establish an adequate theory of inheritance. We arrive at the same result by classifying the truly inherited morbid conditions into: (1) Ex specie, or specific; (2) racial; (3) familial; and (4) individual. We may rapidly run over ex- amples of the first three classes; it is the fourth that we shall have specially to study. 1. Ex Specie. — The fixity with which specific properties are inherited, as compared with familial or even racial peculiarities, affords the most patent example of the working of the law that those features which have for the longest period been possessed by a given stock are the features most impressed on that stock, and least easily lost. It is in the broad study of species that the existence of heredity is most emphasized. Con- ditions which, we must assume, had originated as variations or as muta- tions have ceased to be pathological and have become attributes of the species. In the majority of these specific variations we have to see a defi- nite advantage; following the present trend of evolutional thought we recognize an inherent probability that it is those features of advantage to the stock that are retained, while valueless variations tend to disappear. Bland Sutton has suggested that this is not always the case; that a useless variation in one part of the organism may show itself along with a variation of advantage in another part, and, being coincident, both may tend to be perpetuated. He cites the "castors" situated on the inner side of either foreleg of the horse — horny cutaneous overgrowths unconnected with the bone. The only suggestion that he can make is that these have shown themselves primarily as a correlated variation along with others more valuable in some prepotent ancestor. Another remarkable example. 26 HEREDITY AND PREDISPOSITION apparently of this class, is seen in that strange fish, the chietodon, with its osteomatoid enlargements of sundry bones. There are more easily recognized functional morbid inheritances. Notably, the ditferent species show strongly defined differences in suscep- tibility to various diseases. Thus each species harbors one or more forms of the grosser parasites which are peculiar to it, and the same may largely be said with regard to niicrobic parasites. We need but suggest that typhoid, gonorrhoea and syjjhilis appear, under natural conditions, to be limited to the hunum species. 2. Racial. — Dealing with races we observe numerous minor anatomical varieties, nor can we in every case comprehend their development, save as "sports" which have appeared in some ancestor of the race and have been perpetuated. Without going far afield abundant examples may be called to mind: the lack of development of the nasal bones in pug dogs; the existence of horned and hornless races of domestic cattle; the ab- sence of tails in certain races of sheep and cats, etc.; while, coming to man himself, we observe pronounced differences in the quality of the hair and the pigmentation of the skin of the different races, not to men- tion deeper structural peculiarities such as the symmetrical exostoses of the malar bones among the Akim (or horned men) of Africa, and the penile bone present in yet other African races. There are among the different races of animals, as of man, different susceptibilities to infectious diseases. The native cattle of Japan, as again the "Buft"el" or native cattle of Austro-Hungary, are relatively insusceptible to tuberculosis; a race of Algerian sheep shows a similar relative insusceptibility to anthrax, whereas sheep in general are highly susceptible. As between human races these differences in susceptibility are well marked. We need but cite the relative susceptibility of Melanesians to measles, of Negroes to tuberculosis, of Malaysians and other oriental races to beri-beri, of those of European descent to yellow fever. 3. Familial. — Taking man alone into consideration the instances of familial inheritance of abnormal conditions are so numerous that it is impossible within the limits of this article to attempt anything approach- ing a complete record. As we have indicated elsewhere, they may roughly be divided into: (A). Gross Anomalies. — There are abundant instances of the inher- itance by successive generations of one family of such conditions as Polydactyly, syndactyly, abnormal shortness of one or more phalanges, hy- pospadias, phimosis, etc. So marked, indeed, is this inheritance that there is recognized a tendency for those possessing such anomalies to be prepotent; i. e., the majority of the progeny of these individuals mated with more normal individuals exhibit the like anomaly, whether in the one sex only or in both. (B). Probable Anomalies of Defect. — Such are haemophilia (exhibited more particularly in the males, but descending through the female line), albinism, Daltonism, myopia, strabismus, ichthyosis. (C). Susceptibility to Specific Infections. — Certain families are notor- iously more prone to certain infections than is the generality of the com- munity. This is especially marked in connection with tuberculosis, and this when due deductions are made for house infection, subjection to similar environment, etc. We recognize, in short, a tuberculous dia- tNlJERITANCE AND DISEASE 27 thesis. In other famiUes the exanthemata, such as measles and scarlet fever, are specially apt to take a severe form. (D). Diathetic. — Other conditions, due, it would seem, to disturbances of metabolism, underlying which may very possibly be finer anatomical variations, have for long been noted as tending to be inherited; such are obesity, diabetes, gout, and chronic rheumatism (though all of them as- sume also a racial aspect) . Upon further consideration it will be seen that this and the preceding class are doubtfully to be separated; the essential feature common to both is an inherited habit of body or vice of organiza- tion — a constitutional weakness in one or the other direction. In all these cases we are apt to observe a form of "homochronous inheritance;" i. e., the disturbance is apt to manifest itself at or about the same life-period in the offspring as in the parent. (E). Nervous. — More and more attention has been paid of late years to familial nervous disturbances, of which two groups may be recognized, the homeomorphic and the heteromor'phic. In the former the offspring show the same lesions and symptoms as did the parent. These are cases more particularly of lack of development or premature atrophy of certain groups of nerve-cells, and among them are to be included familial palsies, pseudohypertrophic and amyotrophic paralyses, Friedreich's disease, Thomsen's disease, etc. It is noteworthy that the more these conditions are being studied, the greater is the number of strictly local- ized familial diseases that is being determined, each group affording a particular syndrome. The heteromorphic disturbances embrace a series of cases in which, the parent suffering from one form of nervous disease, the progeny may individually exhibit one or more of a group of other nervous disturb- ances. Broadly speaking, it would seem that here we have to deal not so much with lack of development and atrophy of particular groups of nerve-cells as with lack of the highest development of the higher centres as a whole; there is wanting perfect stability and coordination of various parts, so that according to the strains to which the individual members of the family are subjected, now one, now the other series of centres may show itself unable to respond adequately, and one or other form of mental disturbance and nervous disease may result. Here are to be in- cluded conditions of insanity, familial epilepsy, hysteria, and the neu- roses. INDIVIDUAL INHERITANCE. Strictly speaking, every property possessed by the individual which is not, or cannot be, ascribed to intra-uterine influences and postnatal acquirement, is the individual inheritance. It has reached him through the parental germ-plasm; thus, specific, racial, and familial traits be- come the individual property. For practical purposes, however, all of these may for the moment be neglected, and merely those properties taken into consideration which, (1) peculiar to the parents as distinct from the family, reappear in the progeny; or, (2) not observable in either parent or parental stock, can only be ascribed to the interaction of the two paren- tal germ-plasms. We have here, in short, to deal with variation, w-hether 28 HEREDITY AND PREDISPOSITION first appearing In the parent or in the ofl'spring, and must of necessity inquire into the factors bringing about incUvidual variation. This inevitably demands an inquiry whether conditions acquired by the parent can be transmitted to the otispring. ^Ye approach the crucial point of the whole debate. If influences telling on the ])arent modify the constitution of the offspring, then not merely do we gain an insight into the ultimate causation of individual variation, and, what is more, an in- sight into the meaning of the evolution of the species, but also to some ex- tent approach the Lamarckian stand})oint. I say "approach" because the full Lamarckian doctrine demands that the identical change acquired by the parent become transmitted — that if, for example, the giraffe by strain- ing towards higher things adds a cubit to his stature, the little giraffe is born with larger forelegs and longer neck than are possessed by his cous- ins. What we have said regarding the non-inheritance of mutilations will have indicated that we cannot see how this extreme doctrine is to be accepted. We must deny the inheritance of acquired gross structural modifica- tions, and if this is the essence of Lamarckianism, then Lamarckianism we cannot entertain. Wliat we here refer to is the possibility that the molec- ular constitution of the germ-plasm may be modified in one or other direction by influences acting upon the parental organism, with the result that the offspring varies in one or other direction according to the nature of this influence. Variations so produced would not be identical with the modification acquired by the parent, but might be specific to this extent, that a given influence acting on the parent would tend to variation in the offspring along certain definite lines. If this is found not to be the case there is but the alternative that each parent hands down to the offspring a fixed germ -plasm; that the molecules constituting this germ-plasm in the ovum and spermatozoon respectively are not of identical composition and arrangement; and that consequently it is to the amphimixis or com- mingling and interaction of the two unlike parental germ-plasms that variations are due. According to this view the laws governing variation are akin to the laws determining the pictures presented by the pieces of glass in the kaleidoscope. It may seem that here we approach matters too intricate for solution — matters altogether too deep and removed from medical practice to re- quire treatment in a work of this nature. And yet a little thought will show^ that for medical men here also is the crux. Upon our answer to this question depends, if not our whole outlook over the inheritance of disease, at least our attitude towards the one problem of heredity regarding which our advice is most often sought. If the germ-plasm is fixed and variation is due simply to amphimixis, then disease in the father should have no ef- fect upon his children, save and except that disease be conveyed by him to the mother and so tell upon the intra-uterine nutrition of the foetus ; or, more remotely, be conveyed by him to these children after birth. If, on the contrary, parental disease not directly affecting the ovaries or testes can nevertheless, by the toxins generated elsewhere and circulating in the blood, deleteriously influence and modify the nuclear material of the ovum or spermatozoon, just as it may modify the other cells of the body and their nuclear material, then, obviously, the molecular constitution of the individual developed from the germ-cell must vary from the normal; or INHERITANCE AND DISEASE 29 otherwise parental disease is liable to affect the offspring very materially. It will be seen that everything leads me to accept the latter view. It will, however, aid our understanding of the problems presented if first we endeavor to classify individual variations and collect certain data bear- ing upon individual inheritance in general. The Different Forms of Individual Inheritance.— As regards any one property, structural, constitutional, or mental, the individual may exhibit the following forms of individual heredity : 1. Inheritance to an Extent Intermediate Between What Has Ob- tained in the Parents. — The blended is the commonest type of inherit- ance, and would seem to indicate an equality of influence on the part of the respective germ-plasms. The broad tendency of sexual conjugation is to preserve the mean and perpetuate the type, rather than to induce extreme varieties and develop new species. 2. Mosaic Inheritance. — This form is rarely to be made f ut dis- tinctly. It may well be more frequently in action than we can recog- nize. It is best exhibited in cases of piebald animals, the offspring of parents of different colors. Here the two colors do not blond in the offspring, but both are represented independently in different areas. It is thus a form of particulate inheritance though not of exclusive. 3. Reproduction of the Condition Found in the One Parent to the Exclusion of That Seen in the Other. — This form of particulate inherit- ance is specially noted in connection with certain properties. Thus where one parent has blue eyes, the other dark brown, the children have either blue or brown eyes, rarely those of an intermediate color. What is more, as shown well by Mendel in his studies upon hybridization, and fully confirmed by numerous biologists during the last few years, while in general the properties of the hybrid are apt to be intermediate be- tween those of the two parents, certain properties are apt to be dominant. The "hybrid character" resembles that of one of the parental forms so closely that the other either escapes observation completely or cannot be detected with certainty. But the character not exhibited by the hybrid is not of necessity entirely lost — only recessive. In studying plant hybrids, which manifest this exclusive inheritance, as the result of self-fertilization of the hybrids, the recessive character has been found to reappear in a certain definite proportion of the plants of the next generation. Grow- ing these hybrids and their offspring, (the result in each case after the first of self-fertilization,) it has been found that each plant presenting the hybrid characters may give, as regards any one pair of exclusive char- acters in the original species (length or shortness of stem, inflated or constricted seed-pods, axial or terminal flowers, etc.), a remarkably definite proportion of offspring. If D be the dominant and R the re- cessive character, the proportion of forms produced from the hybrid parents is expressed by the formula: (DD+2D[R]^+RR.) Two hybrids, though of the dominant type, are produced to any one plant that has the dominant character fixed and every one that has the recessive character fixed. Henceforth plants of the pure D type will by self-fertilization produce only offspring of that type, with no reversion ^Following Castle, we place the Rin brackets to indicate that the recessive character, while possessed by the germ-cells, does not show itself in the individual To external appearance the progeny consists of 3D + R. 30 HEREDITY AXD PREDISPOSITION to the R features; and so with parents possessing the R character. The hybrids D [R], however, in each subsequent generation produce the defi- nite proportion of dominants, hybrids, and recessives. When the species differ in several pairs of features, the result, though following the same lines as regards each individual pair, becomes much more complicated, although eventually, after several generations, individ- uals of the pure ])arent types are reproduced In other words, by this ex- clusive inheritance the results of a m(f>salliance in the pedigree may be completely cast out and the stock become once more pure. Castle and Allen have demonstrated the existence of the same law in animals — mice — in regard to coat color. 4. Production of New Features and a New Strain by Cross-Breed- ing. — There is shown, it may be added, an equal likelihood that the mating of two individuals which, as regards two pairs of contrasted characters (or aUelomorpJis), exhibit each reversely a dominant feature as regards the one and a recessive as regards the other will result in the development of definite proportions of individuals resembling neither stock but showing a commingling of two dominant or two recessive fea- tures. If cither of these new forms be mated strictly with other individ- uals of the same type there results a new strain or variety breeding true and distinct from cither ancestral stock. Thns, to quote Bateson, if a red variety of some plant, say a stock, be crossed with a cream-colored variety, while the hybrids of the first generation are red (red being domi- nant) , in the second generation a small proportion (three-sixteenths of the total progeny) of plants may appear v/ith flowers neither yellow nor red but tvhite, and these white-flowered forms, if crossed among them- selves or allowed to undergo self-fertilization, yield a permanent white strain. The explanation here is that the one ancestral form has red sap (D) with colorless corpuscles (R) floating in it, the other, colorless sap (R) with cream-colored corpuscles (D). In this way some of the second generation come to possess a mingling of the characters, color- less corpuscles and colorless sap. This, it may be noted, is the basal principle underlying the production of new strains or varieties by the horticulturist and undoubtedly helps to explain the production of one order of the "sports" to which we refer in a later paragraph. Interesting as it is, we shall not here enter into a detailed account of the Mendelian doctrine, wliich has provided keen activity of late, more particularly among English and American biologists; to discuss it adequately would demand many pages. A consideration of its bearings upon the inherit- ance of morbid conditions is given by Bateson, the leader of the school, in a lecture to the Neurological Society of London.^ In the human race, where not only there is no self-fertilizing but con- jugation between those of the same stock is largely prohibited, and where, again, the number of points of difference between the individuals is extraordinarily great, Mendel's law can rarely be brought to apply, save in the most general terms. In any case it does not explain, any more than does the law of gravitation. It helps us, however, to harmonize data otherwise not a little confusing — to recognize dominant features in the members of a family (such as, for example, the well-known Hapsburg ^ British Medical Journal, 1906, ii, 61 INHERITANCE AND DISEASE 31 lip), the appearance of recessive features in a certain number of the mem- bers of a later generation, etc. When in gout and haemophilia a given diathesis skips a generation we realize that we are dealing not with isolated phenomena but with conditions subservient to law. Where one parent has a neurotic or alcoholic heredity we realize that it is not essen- tial that all of the progeny be neurotic or show stigmata of degeneration, though at the same time we are bound to realize that while the parents themselves may show no vice of organization, yet, if either comes from an unsound stock, there is the possibility that in them the particular inheri- tance of morbid state is merely in abeyance (recessive) — that it may show itself once more in some of their offspring. There is the lesser possibil- ity that by fortunate mating it may be wholly cast out not to reappear. In these instances we are dealing with true atavism {atavus, a grand- father), or — 5. Reproduction of a Condition Seen in Generations Nearly Pre- ceding the Parental. 6. Reversion. — The reproduction of remote ancestral conditions. Atavism must, we hold, be regarded as distinct from the next condi- tion which may show itself, namely, reversion. In atavism there is no necessary degeneration; the return may be to a better type. By rever- sion is meant at least loss of properties common to the stock or race and the reproduction of the characteristics of the lower type in the line of descent. If ontogeny be an abbreviated phylogeny, then by reversion we understand the development of the individual up to some point short of the completed phylogeny. This again is well exemplified by certain studies in hybridism. Some of the latest are those of von Guaita,^ who found that breeding together a tame albino mouse with a piebald Japanese waltzing mouse the progeny was a "wild gray mouse." The color and general configuration here were not those of either parent : they were those of the presumptive wild ancestor from which both strains had their origin long generations pre- viously. Even more remarkable is Darwin's famous case.^ The ancestors of our domestic pigeons were probably eastern birds; it is known that for now some centuries the leading varieties have been bred in Europe, for still longer centuries in India and the East; and everything indicates that their ancestors were the wild blue-rock pigeon {Columba livia). Crossing a barb-fantail female with a barb-spot male, Darwin produced a bird "which was hardly distinguishable from the wild Shetland species" (of blue-rock). Weismann has supposed that in Darwin's case the similarity was purely in the color and the bars on the wings. Ewart,^ crossing an absolutely white fantail with thirty feathers in its tail with an owl- archangel hybrid, (the owl was powdered blue, with a short beak; the archangel copper-colored, with well-developed crest) obtained a bird which in measurement was almost identical with the blue-rock, while in color and markings it showed complete reversion to the checkered blue- rock of India, and, like that, had only twelve tail-feathers. In this "harking back" we seem to have what may be termed a "greatest-common-measure" action. In this fusion of the germ-plasms ^ Bericht d. Naturf.Gesamml, Freiburg 10, 1898, 317; and 11, 1900, 131. ^ Animals and Plants Under Domestication, I., p. 204. ^The Penycuik Experiments, 1899, p. xxvi. 32 HEREDITY AND PREDISPOSITION those *' constituents," if we may so express it for the moment, which had controlled the racial differences in the respective parents antagonize one another, and the older constituents common to the two germ-plasms alone control the development of the offspring.^ Such a cutting off, or inactivity, is liable to occur generally when widely separated stocks are mated — until the ])oint is reached when no result is obtained, the union being sterile. The cutting oft' is of the recessive type and not absolute, for later generations may furnish individuals returning again to either primary parental type. DeVries nevertheless lays down that Mendel's law does not hold satisfactorily in connection with other racial properties. 7. Degeneration and Degenerates. — Herein we have a condition allied in its results to the reversion just described, but differing in this, that the parents belong to the same stock. Although in externals they may or may not apjiear to be normal, their offspring are of low type, the cranial ca])acity less than normal and reversionary in character, and, more particularly, the intellectual and moral properties approximate toward those of the uncivilized and lower types of mankind. We shall have later to discuss the causes of such degeneration. Here I would only state that under this heading must be included certain less-pronounced con- ditions of defect — conditions in which it may be that only one system, notably the nervous system, shows signs of defective development; or, again, in which no positive structural defect may be made out, but the constitution is feeble and the natural resistance to disease possessed by the race is characteristically lowered. 8. Excess of Development of a Property Over What Obtains in Either Parent. — Mendel noted forty years ago that in hybridization the cross-fertilization of a tall-stemmed (4 to 5 foot) variety or species of pea with a short-stemmed species (1^ to 2 feet), regularly led to the production of hybrids taller (6 to 7 feet) than the taller parents. Within certain limits the cross-fertilization of distinct stocks leads to progeny exhibiting greater vigor of growth than either parent. It is a familiar observation in Canada that the offspring of mixed Anglo-Saxon and French marriages tend to be of better build, brighter, and more active, than the rest of the community whether French or Anglo-Saxon. The same was noted of the Normans centuries ago. 9. Sports. — Mutations. — The abrupt appearance of conditions neither parental nor ancestral. Certain gross anomalies are clearly reversionary; although appearing abruptly in the line of descent, they reproduce obviously organs or parts well developed in some ancestor. Such for example are various persistent ducts and cysts developing along the course of such ducts — the majority of the cardiac anomalies, cleft palate, supernumerary nipples, etc. The list can be greatly extended, although, as will be noted later, it is not al- ways possible to distinguish between the inherited and the acquired con- ditions of this order; by which we mean that everything points to the fact that a considerable number of anomalies are due to influences acting on the embryo. Wholly apart from these is another series of appearances. *This explanation of " harking back " appears to possess greater inherent prob- ability than Bateson's "meeting of two complementary elements which have somehow been separated by variation." INHERITANCE AND DISEASE 33 Once again to take a botanical example: in a bed of single tulips a rare flower-head may show only five petals; another may show seven. The liliacese, to which the tulips belong, are throughout characteristically six partite, and if one of these variations is reversionary to an ancestral con- dition, the other cannot be. From the fact that in neither case is the general character of the tulip greatly altered, the probability is that neither condition represents a reversion, and that both are sports. The four-leaved shamrock is of the same order. We owe to the great Belgian botanist de Vries the fullest study and recognition of this production of 'mutations.'^ Cultivating the plant (Enothera Lamarckiana over a long series of years — in fact since 1886 — he observed the appearance from time to time of individuals which definitely varied from the parents, and, what is more, when fertile, were true to seed. Thus in 1895, to quote an instance, there appeared the relatively huge (Enothera gigas, and that not by gradual variation but by a sudden jump. Subjected to self-ferti- lization this single plant afforded seeds giving origin to plants (several hundreds) of the gigas type. At a bound therefore a new species was seen to develop. As de Vries points out, we have here an example of discontinuous and not of gradual evolution, and he holds that in all cases evolution must be of this discontinuous type. In this as supporting a physico-chemical theory of inheritance we cannot but agree with him. To quote Jacques Loeb,^ "If the (determinants) are comparable to a series of compounds, e. g., of alcohols, there is no more a transition possible between two species separated by a difference in only one determinant than there is a transition possible between two neighbour- ing alcohols of the same series." We meet with similar conditions in animals. Thus it is known that the celebrated royal strain of cream- white horses at Hanover originated by careful inbreeding from a single sport — a, white horse which appeared fortuitously in a breed that had previously shown no tendency to throw white horses. Certain breeds of merino sheep are also traceable back to a single sport possessing silky hair in place of the ordinary wool; and so on. In man we occasionally encounter the same, though it has to be admitted that well-authenticated family histories are rare, and we cannot always assure ourselves that a given sport has appeared in a given family for the first time; i. e., that it is not an inheritance. The most frequent examples are what Bateson has called meristic — alterations in the number of parts in series. Such are in- crease or diminution in the number of the teeth, vertebrae, ribs, fingers, toes, etc. It is difficult to speak with precision of internal organs, but probably some cases at least of double kidneys and ureters, accessory ovaries and testicles, etc., come under this group. In addition there are what may be termed metabolic sports — conditions of albinism, ichthyo- sis, etc. It is common to class most of the examples of the first, meristic, class as instances of reversion; but the more one studies them the more evident it is that they must in general be included as sports. They occur most often in those who present no other signs of reversion, and, as al- ready stated, if numerical increase is an instance of reversion, numerical decrease cannot be; and vice versa. Supernumerary digits crop up in no ^Die Mutationstheorie, 1901. ■ The Dynamics of Living Matter, New York; MacMillan, 1906, 225. 3 34 HEREDITY AND PREDISPOSITION particular position ; they may show themselves at either end of the series, or as a reduplication of the index or the middle finger. When a super- numerary mammary gland appears in the line between the outer end of the clavicle and the pubic symphysis (the line along which the mammary glands are arranged in animals possessing multiple pairs), there is some force in the argument that they arc reversionary, although it has not been shown what direct ancestors of man possessed multiple mammjie. When, as occasionally happens, the su])ernumcrary gland occurs on the shoulder or the hip, to speak of reversion is absurd; this can only be a sport. What is very marked is that sports as a rule arc curiously dominant; once they appear they may reappear through several generations; they may skip one or more generations; they may affect alternate generations. Hey^ has afforded a good instance of this recently, in which the existence of supernumerary digits was first noted in the great-grandfather, was ab- sent in the next two generations, affected one of the seven children of the grandfather, and aft'ected six children, the offspring of three of the above seven. Whereas in the earlier generations the toes were affected, in the last, in some individuals the toes, in others the fingers, were supernu- merary, I. Supernumerary toes II. normal III. normal IV. S. toes normal normal normal normal normal normal V. S. toes S. toes S. toes S. fingers S. toes S. fingers It is almost needless to call attention to the pronounced inheritance, often alternate, of albinism and haemophilia, which may both be placed in the category of metabolic sports. If now we attempt to sum up the various forms of individual inheri- tance brought about by fusion of the germ-plasms of the two parents we make out the following points : I. Inheritance of a property or group of properties may be either blended or particulate. II. There are various grades of blended inheritance: (a) Intermediate, the commonest, with on the one hand the sub-groups: (6) Cumulative, the blend producing a quality superior to that possessed by either parent. (c) Progressive sport 'production (sports of excess), the blend inducing ad- ditional properties in the offspring not possessed by either parent. And on the other hand — id) Antagonistic, certain properties in the two germ-plasms antagonizing one another and leading the offspring to have qualities inferior to those possessed by ^Pey: British Medical Journal, May 28, 1904. INHERITANCE AND DISEASE 35 either parent, and so to revert toward an earlier stage in the ontogeny or phylog- eny. We can distinguish the following varieties: Atavistic. Reversionary. (e) Regressive sport production (sports of defect), the blend leading to defects not to be explained by phylogenetic considerations. III. With regard to partindate inheritance this may well be only a par- ticular case of what we have termed antagonistic blended inheritance. For the present it is perhaps well to treat it as distinct. It may be either — (o) Mosaic — One property in which the two parental stocks differ being con- veyed to and effective in the germ-plasm from which the offspring originates so that in part the offspring exhibits the dominance of the property conveyed from the one parent, in part the property conveyed from the other. (b) Dominant — The germ-plasm of the one parent dominating the offspring as regards one or more properties; that of the other not being wholly neutralized but merely recessive, being contributed also to the germ-plasm of the offspring so that in its turn the property may reappear in a later generation. (c) Exclusive — Certain "'constituents" of the germ-plasm of the one parent wholly replacing or casting out the corresponding constituents of the other, so that the peculiar features of that other parent are not reproduced in any subse- quent generation. Are all these various forms of inheritance the results of chance combina- tions of the constituents of the maternal and paternal germ-plasms, or can we discern certain underlying laws ? It is clear that we are not dealing with mere chance, even though chance also has its law. Certain phenom- ena appear with such regularity (when large series are taken into con- sideration) that clearly they have law^s specially influencing them. One of these laws I have already indicated; namely, that of Mendel on cross- breeding. There are still those biologists who attack it; but the more it is studied the more cases are found to harmonize therewith. This bears on particulate heredity, and it may well be that the apparent exceptions are cases of other phases of what above I have termed "antagonistic blended inheritance." Bearing more particularly upon blended inheri- tance we have another law, that of Francis Galton, recently modified by Karl Pearson. The latter unfortunately has not troubled to translate his law out of an algebraic equation into English,^ and so the ordinary reader would be unable to follow it. Pearson accepts Galton's general principle but holds that the terms of the series are different, the contribution of the different generations being greater than held by Galton. Herein our own line of argument leads us to believe that he is right. For general purposes, however, Galton's law is near enough for purposes of expression. It is that the two parents contribute one-half (or each one-quarter), the four grand- parents one-quarter (or each one-sixteenth), and so on. The series |+J +5+^, etc.=l; i. e., equals the total inheritance. THEORIES OF INHERITANCE. Based upon and deduced from the study of long series of cases these laws are of distinct value. They do not, however, explain what is the nature of heredity that these laws should be in action. In seeking to answer ^The formula is discussed in Pearson's Grammar of Science (2d edit.), Lon- don: 1900. 36 HEREDITY AND PREDISPOSITION this we immediately proceed into the realm of hypothesis. There have of late years been abundant theories brought forward, but none has attracted greater attention than that of Weismann, none has been so fully worked out; and as the distinguished author of the theory in the evening of his life has given us this theory in a rounded and complete form which has, further, been admirably translated/ it will be well to take this as a basis. Weismann accepts, as indeed he was one of the first to emphasize, that inheritance is conveyed by germ-cells which have from the first been set apart for reproductive purposes. These germ-cells as such take no part in the building up of the parental individual of whose organism they form a part; only when liberated and fertilized do they proceed to multiply, giving rise to one set of cells which form the body as a whole, and to another smaller set — the germ-cells. In other words, he holds that the germ-cells contain within them two constituents, the somatic- or body- plasm and the germ-plasm. The tissues built up by the somatic-plasm are mortal, subject to death; the germ-plasm is potentially eternal — it is carried onward from generation to generation. Here is the first Aveak point in Weismann's argument — a false conception which vitiates the whole subsequent train of thought. The germ-plasm is not potentially eternal. If, as already indicated, the individual human being derived from a solitary spermatozoon and a solitary ovum can produce on the average, as already indicated, 85,000,000,000 other spermatozoa each resembling the primordial spermatozoon in size and properties, it is clear that — leaving the body-cells out of account — the germ-plasm contained in that primordial spermatozoon has multiplied itself several thousands of millions of times ; or otherwise it has in the process of growth assimilated vast quantities of other material to itself, and rearranged it so that that new material has come to possess the same constitution, and, with this, the same properties as itself. With growth there is constant new forma- tion of molecules forming the individual cells. In other words, the germ- plasm is not eternal; it is constantly being renewed. What are the nearest to being potentially eternal are the chemical and physical properties of the germ-plasm; and this very fact, that growth implies constant rearrange- ment and assimilation of constituent molecules, makes the chemical composition "eternal" only so long as the assimilable material remains the same. To this I shall revert. Weismann, it is true, admits that there is growth; he does not, however, realize all that this necessitates. He next demonstrates very clearly that this heritable germ-plasm is contained in the nuclei of the conjugating ovum and spermatozoon, (vide p. 18), and regards as a proved proposition that the nuclear chromatin is the hereditary substance. This is present in the germ-cells of every species in the form of a definite number of chromosomes which, in cells destined for fertilization, is reduced to one-half the number; so that the single nucleus — the segmentation nucleus — of the fertilized ovum con- tains the number of chromosomes characteristic of the cells of the indi- vidual of any particular species. The hereditary substance of the child is therefore formed half from the maternal, half from the paternal sub- stance, and as, at each succeeding cell-division, each of the paternal and > August Weismann: The Evolution Theory; translated by J. Arthur Thom- son and Margaret R. Thomson. London Ed., Arnold: 1904. INHERITANCE AND DISEASE 37 maternal chromosomes doubles by dividing, each cell of the individual contains hereditary material derived from both father and mother. This very fact of reduction, he points out, indicates that half the chro- mosomes contain all the essential primary hereditary constituents, or, otherv^^ise, that it is not the chromatin as a whole that conveys hereditary properties. The rather, this must be made up of a series of constituents or ids, each of which is representative and capable of conveying all the paternal or maternal properties. Let us pass back a generation. The germ-cells of the parent are similarly formed by a combination of chromosomes from the two grandparents. These must be represented, as indeed must also be the chromosomes of the great -grandparents, etc. What is more, in the pro- cess of reduction he holds that certain chromosomes derived from certain ancestors are cast out, others retained, and that it is the variation in the series of retained chromosomes that in the main determines the varia- tions between the members of the same generation. The hereditary sub- stance in the fertilized ovum thus consists of several complexes of primary constituents contained in the chromosomes, or "idants," each of which complexes (an "id") comprises within itself all the primary constituents of a complete individual. Fig. 1. Each "id" Weismann conceives as being composed of a mass of differ- ent kinds of parts, each of which bears a relation to a particular part of the perfect animal, and so to some extent represents its primary constituents, although there may be no resemblance between these "Anlagen" and the finished parts. These representatives of individual parts contained in each "id" he terms "determinants" (Bestimmungsstucke). In each "id," therefore, there must be as many determinants as there are regions in the fully formed organism capable of independent and transmissible varia- tion at all stages of development — for the caterpillar stage, for example, as well as for the butterfly; determinants even for the egg, because eggs, caterpillars and butterflies are seen to vary independently. If, as has been noted, the individual hairs on the antennae of insects are capable of transmissible variation, and if, in man, the conformation of particular teeth is inheritable, then determinants there must be for these indi^^Ldual hairs and teeth. If a little patch of scales on the butterfly's wing is peculiar to one variety, for those few scales there must be a determinant. And lastly, each individual determinant must be made up of molecules of living matter, or biophores. Such biophores, he holds, must be larger than any chemical molecule; they must consist of groups of molecules, 38 HEREDITY AND PREDISPOSITION some large and complete, others simpler and more minute; so that ulti- mately it is the interaction of these biophores — the casting out of some from one parental stock, the retention of others in their containing deter- minants and ids — that determines variation. No two individuals contain identical groups of detenninants and identical ids, and, as these control development, therefore no two individuals are identical. If in reversion the characters of an ancestral form, it may be hundreds of generations back, are reproduced, this is because in the process of reduction, followed by fusion, of the two parental germ-plasms, the ancestral ids come to predominate to the exclusion or casting out of the ids of more recent gen- erations. Why this should tend to happen in a special order of cases the theory does not venture to explain. The reader from these data should be able to apply the theory to par- ticular cases. It has also to be added that Wcismann holds that the development of the individual from the ovum proceeds in such a way that by nuclear division it is brought about that the germ-cells are assured of possessing a complete set of ids, whereas the body-cells do not gain this complete set. There is a qualitative differentiation of the chromatin passing to what are to be the eventual tissues of one or other order, so that ultimately the particular determinants find themselves in control of particular groups of cells, destined to produce specific tissues or parts of tissues. There is, we confess, something that savors of medieval scholasticism in this conception, — something remote from our general conception of the order of natural events, and, as a matter of fact, the whole edifice of ids, determinants and biophores collapses when confronted with the findings of physical science. Weismann's biophores, in brief, composed as he im- agines them of numerous molecules, some of them complex and of large size, must be smaller than are individual atoms! We can in certain nuclei recognize rows of granules forming the individual chromosomes — little bodies 0.5 /i or less in diameter, — bodies considerably smaller than the micrococci of suppuration. These Weismann regards as the individual ids. Each id is, he postulates, made up of determinants, of which, as each region capable of variation is supposed to be represented by a separate determinant, there must in the human id be thousands rather than hundreds. Each determinant is made up of biophores or ultimate units of living matter; each biophore, according to him, consists of a group of molecules. Each molecule is, we may add, composed of numerous atoms. Now Lord Kelvin, in his convincing investigation into the size of the molecule of water (by a study of the thinnest possible films of a bubble), has proved that in a line 0.5 fx in length there could be only about 150 molecules of water. Let us be generous and compute the ids as being not on the average 0.5 but 1.0 /x in diameter, and, again being generous, let us compute the ultimate molecule of living matter as being only thirty times the size of the molecule of water — from every considera- tion an absurd underestimate. It will be seen upon calculation that the id (supposing it to be spherical) can contain only about as many molecules as presumably Weismann requires for one or two biophores, or at the most economical rate for a single representative determinant; and not one, or tw^o, or three, but several hundreds of determinants, ought to be compressed into a respectable id. INHERITANCE AND DISEASE 39 We have, in short, the reductio ad ahsurdum of Weismann's theory. But if "idants," "ids" and "determinants" be swept away and we accept the existence of biophoric molecules — of individual molecules of living- matter;^ — if, that is, we very largely dismiss the latter part of the theory, and, in place of this purely morphological conception of heredity, build upon a chemical basis, we can safely utilize much of Weismann's super- structure of carefully collected facts and develop a theory which satisfies. And it is the work accomplished of recent years by the pathologist, the bacteriologist, and the physiological chemist, that indicates the lines such a theory must take. Space forbids that in these pages, that theory be fully developed. We can but indicate its broad outlines. A Physico-Chemical Theory of Inheritance. — 1. The studies of the physiologist and physiological chemist abundantly indicate that all vital activities are ultimately the expression of molecular rearrangements and combinations. Life is therefore the expression of a series of chemical changes, and the material endowed with life must be of such a nature that it, itself, is composed of molecules which react. 2. So many are the vital reactions even of the simplest microorgan- isms known to us that, employing current chemico-physical concepts, we must regard the individual molecule endowed with vital properties — the biophore (to utilize Weismann's term) — as of relatively great size and complexity. We best conceive it as a central ring, resembling the benzol ring, of associated carbon-containing molecules of which each member has side-chains capable of being satisfied, the peculiar feature of the vital system being that as a whole it is never satisfied and so is con- stantly interacting, and has the capacity to act upon and be acted upon by the surrounding medium. When the unsatisfied molecules forming a side-chain attach to themselves other atoms or radicals from the sur- FiG. 2. rounding medium and become satisfied, they tend to form an independent simpler system, which breaks off, leaving once more an unsatisfied affinity in the main system, and so long as the surrounding medium is otherwise ^ It will be seen that our conception of the biophore differs a little from that of Weismann. We regard it as the unit molecule of living matter; Weismann makes it his unit of living matter but composed of several molecules. We employ this self-explanatory term rather than commit the crime of adding one more name to the long list of those intended to convey what is practically the same idea. 40 HEREDITY AND PREDISPOSITION unaltered, similar atoms or radicals are once more attracted or attached, and the process is repeated. 3. The dominant vital activity is growth or increase in the amount of living matter; all the other proj^erties of living matter lead up to and sub- serve this. With the conception above stated of the nature of living matter we are forced to recognize that growth is brought about by a pro- cess of satisfaction of side-cnalns in such a way that in connection with any given biophoric molecule there is attracted and built up an arrange- ment of atoms and radicals identical with those of the central ring, which, when completed, breaks off as above indicated. The accompanying figure (on page 39) diagrammatically represents the process here suggested. Having the same structure, this newly formed molecule must possess the same properties. In other words, by such a process of identical aggre- gation we can conceive the development of two biophoric molecules in place of one. 4. In such a system, so long as the medium and the physical environ-, ment remain the same, for so long will the constitution and properties of the biophoric molecules remain unaltered. There will, it is true, be a continual "come and go" of side-chains, so that at any particular moment the molecule as a whole will vary in weight, number of combined carbon and other atoms, etc., from its constitution the moment before; but the average composition will remain unchanged. 5. Alteration in environment, by inducing alteration in the nature and proportional amounts of the atoms and ions in the surrounding medium, must in such an unstable system bring about alteration in the composition of the molecule, provided always that there exists a positive affinity be- tween the atoms or radicals of a new order entering the medium and the unsatisfied side-chains; the side-chain affinities must become satisfied in a different manner, and, as the form and properties of the individual are the expression of the composition of these biophoric molecules, the form and properties must inevitably undergo variation. 6. So long as a given alteration of medium persists, for so long will the form and properties of the individual present a particular alteration. Variation must tlius he regarded as prirnarily introduced by alteration in enviromnent. This woidd seem to be the only factor causing variation in organisms in which sexual conjugation has not been developed; i. e., in asexual protozoa. 7. Studying such organisms, notably the bacteria, another property of the biophoric substance becomes obvious, the property which alone, with molecular change due to alteration of environment, has made possible the evolution of species. The longer, or the more intensely, a given altera- tion of environment acts upon bacteria, the longer it is before there is a return to the original characters when these bacteria are restored to their usual habitat. We can take a chromogenic microbe like the microba- cillus prodigiosus, and grow it for a short period at 30° C. or thereabouts, when it will produce colorless colonies; brought back to the room tem- perature and more normal environment, and the new colonies will rapidly resume the power of pigment formation. If the microbe be grown for weeks at a temperature just below the maximum, or be subjected for five minutes to a temperature which in ten minutes would surely kill every microbe in the test-tube, then it will be long weeks, and hundreds, not to INHERITANCE AND DISEASE 41 say thousands, of generations, before the power of pigment production is regained. Roux and Nocard cultivated for years, under the ordinary conditions of the laboratory, races of non-spore- bearing anthrax bacilli, in which the power to produce spores had been removed by temporary growth of the parent stock in solutions of carbolic and chromic acid just not powerful enough to destroy the organisms. Or otherwise altered en- vironment does not of necessity merely alter the side-chains of the bio- phoric molecules during the period in which it acts upon the molecules; it may impress upon the general constitution of the molecules such an alteration of constitution that this is retained after reversion to the pre- vious environment. That is to say, the affinities of the molecules may be more or less permanently altered. We can in this way not merely take away, but add properties to bacteria; we can, as Vincent has shown, render non-pathogenic bacteria actively pathogenic. It is only a matter of degree, not of kind, between the loss of these acquired pathogenic properties, when such bacteria are once more grown under ordinary laboratory conditions, and the loss of pathogenicity shown by definitely pathogenic species such as the bacillus typhosus when grown outside the body. The work of the last few years in physiologicpl chemistry indicates more and more clearly that when food-stuffs are assimilated, they are not taken up in an unaltered form and directly combined into the cytoplasm, but, on the contrary, undergo a disintegration into more elementary con- stituents, and these it is that, present within the cell and diffused in the spaces of the cell-substance, form the matter from which the biophoric molecules attract and combine the atoms and radicals which become built up into their substance. Variation and the assumption of new properties indicate, therefore, that under the influence of altered environment the biophoric molecules gain the power of attracting new combinations of atomc and of forming side-chains of altered type. We are forced to realize that once the bio- plasmic molecule has formed a new side-chain it tends to continue to form that particular form of side-chain by attracting particular orders of atoms and radicals from the surrounding medium, even when the old environ- ment is again set up, and what is more, that sooner or later the new biophores built up from the side-chain materials come to differ in their constitution from .the old. The conception of properties of this nature on the part of a chemical substance may seem revolutionary. It appears to demand at first sight that a particular "ring" which at one time attracted as side-chains one particular group of atoms, obtains the habit of attracting another group, and this despite the fact that components of the former group are still in its immediate vicinity. But in imagining this we fall into the same error as did Weismann with his eternity of the germ-plasm. It is not the old "rings" that have taken on the new properties, but newly formed rings, developed primarily, it is true, according to our conception of gro^i;h, in connection with the old; but these nevertheless are separate combina- tions of radicals with sfightly different arrangement of constituents and therefore slightly different properties and affinities. 8. The same is true regarding individual body-cells of the multicel- lular organism. Workers in bacteriology, at the present day recognize 42 HEREDITY AND PREDISPOSITION that the conception of central rings witli side-chains capable of renewal and rephicement by side-chains of another order, of satisfaction of the side-chains and casting loose of the same into the surrounding medium, is the only concept fitted to explain the phenomena of recovery from infection, and immunity. Under the action of bacterial toxins certain cells gain new or exalted properties. Certain side-chains, it is held, combine with and neutralize these toxins, and when satisfied these side-chains are cast loose and others are formed; nay more, arc formed in excess and cast loose in an unsatisfied condition to form the antitoxic substances present in the blood-serum. In cases of long-continued im- munity it is obvious that the bio{)lasm of the cells once incited to form side-chains having a specific reaction with specific toxins, — or with vege- table poisons such as abrin and ricin, is henceforth altered. The new biophoric molecules developed in the course of growth retain for a shorter or longer period the properties impressed on the earlier molecules, and this in the absence of the specific toxin or poison. Heredity, as dis* tinct from variation, must be regarded as the expression of this tendency on the part of biophoric molecules to attract to themselves and build up into new biophoric molecules identical ions of atoms and radicals. 9. Before discussing sexual conjugation and its effects upon inheri- tance and variations, it is necessary to say a word regarding cell structure. The argument that in the nuclear matter is contained the heritable sub- stance seems to us impregnable. We must regard the biophoric molecules as contained in the nucleus, and our conception of the cell and its peculiar structure in all higher forms of life must be that the division into nucleus and cytoplasm is an arrangement whereby the highly differentiated bio- phoric molecules, unable to act directly on the surrounding outer medium, become surrounded by an intermediate preparatory medium, the cyto- plasm, the component molecules of which are not biophores. The nucleus alone cannot maintain life; neither can the cytoplasm alone exhibit growth. At most this latter can assimilate and form paraplasmic sub- stances which in the absence of the nucleus do not become part and parcel of the bioplasm; the nucleus is essential for grototh} 10. If we accept this view of the nature of the biophores it is not neces- sary to demand, as does Weismann, that there is conveyed to the off- spring in the germ two forms of matter — that constituting the germ-plasm and that forming the somatic-plasm, the latter controlling the develop- ment of the individual tissues and cells of the organisms, the former alone able to react at the proper time and initiate the development of the offspring. Such a conception introduces unending confusion. Taking the simplest case, that of a multicellular organism developed asexually by parthenogenesis, our conception must be that as the ovum segments and the cells assume different relationships the one to the other, and to the surrounding medium, the influences acting on the various orders of cells vary, and with this variation the constitution of the biophores present and "growing" in the nuclei of the difFerent cell-groups, undergoes a co- incident alteration; so that, for example, the biophores in the eventual muscle-cell possesses a different constitution from those in a nerve-cell. ^I have discussed more fully this dominance of the nucleus and its relation tc the cytoplasm in an address at the Toronto meeting of the British Medical Asso- ciation. British Medical Journal, 1906, II. INHERITANCE AND DISEASE 43 Whether such a speciahzed cell under any conditions multiplies and gives rise to the complete individual — as happens, to quote trite examples, in the case of certain cells of the hydra and v^^ith the cells of the begonia-leaf — depends upon the extent of the departure of the biophores from their primordial constitution in the germ-cell; or, perhaps more correctly, upon the tenacity with vi^hich they retain that original constitution. We may imagine that in such cases the central ring remains unaltered, the cell differentiation being the result purely of modification in the side- chains; the newly formed biophores, responsive to the change in envi- ronment, develop side-chains of the primordial type, and so are capable of developing the whole individual. The relationship of what are to be the germ-cells in a multicellular organism are such that in the process of their development the contained biophores depart least in constitution from the biophores of the ovum from which they have developed. Thus the properties of any individual cell are to be regarded as the outcome of (a) the constitution of the biophoric molecules passing into the cell at its formation as a separate unit; and (6) the alteration in those molecules and their derivatives induced by the forces acting upon the cell. 11, The biophores contained in the germ-cells of an individual are not those contained in the germ-cells of the parents ; they are the 6utcome of the ovum by growth, and as in general they have been subjected to a like environment, so in general they have (with certain reservations to be discussed later) the same constitution. But just as with growth the bi- ophores of the body-cells are capable of alteration in constitution, so in their growth the biophores of the germ-cells may be modified, and that by like causes; namely, by diffusible substances circulating in the nutritive fluids, as also by purely physical influences telling upon the organism as a whole. The difficulty in determining that influences of this nature, telling upon the body generally, affect also the germ-cells, lies in this, that in man and mammals the growing embryo is nourished by the maternal tissues, and so where the mother is subjected to deleterious conditions it is difficult, not to say impossible, to distinguish surely between conditions due to pre- conceptional disturbance of the ovum and those due to placental absorp- tions after fertilization; and considering man more particularly, it is difficult to collect a sufficient number of cases in which the evidence is positive that the mother has been normal, the father alone the subject of one or other form of intoxication — alcoholic, tuberculous, etc. It is, for example, a matter of common belief that paternal alcoholism is frequently associated with the development of offspring of a lower vi- tality, and more particularly exhibiting mental instability. I am inclined to hold that this belief is well founded. At the same time I must admit that sound statistical evidence in its favor is lamentably lacking. Simi- larly the influence of paternal tuberculosis alone, not as inducing active tuberculosis in the offspring, but in producing what may be termed para- tuberculous lesions, has not been adequately worked out. Too many other factors have to be taken into consideration: possible tuberculous diathe- sis already inherited by the parent, the environment of the young child, etc. Nevertheless we have a certain amount of evidence showing that this is actually the case — that paternal intoxication does influence the semen and leads to the production of vitiated progeny. More than one 44 HEREDITY AND PREDISPOSITION recent observer has directed attention to the fact that in the case of mon- strous births it is noticeable how frequently the history is obtainable that one or other parent had suffered from some acute infection shortly before conception. Mairet and Combcmale' subjected male dogs to acute and chronic alcoholic intoxication and found that the young exhibited various arrests of development and were subject to cpileptoid seizures. And as regards man, 1 have never seen any refutation of Constantine Paul's striking observations made in the "sixties" upon the effects of paternal lead-poisoning — cases in which in the course of his work the father was subjected to plumbism, the mother being unaffected. He obtained the history of 32 pregnancies of this order; of thena 12 resulted in the death of the fcetus before term; 20 children were born alive but 8 of them died during the first year, 4 during the second, 5 during the third; only 2 were living, 1 of whom had reached the age of twenty. Children so born were found particularly liable to various nervous affections. More recent work along the same lines is contained in the interesting* studies by Lustig," of Florence. Lustig was retesting the observations of Ehrhch and others upon the transmission of acquired immunity. To do away with the confusion introduced by intra-uterine existence he employed fowls, and rather than employ bacterial infections or toxins, he chose a vegetable poison abrin. By repeated inoculations of increasing amounts he gained an extremely high grade of immunity, so that for as much as two years the birds were unaffected by minimum fatal doses of the poison. While he was unable to demonstrate that the young had acquired any immunity — on the contrary they appeared to be more sus- ceptible — he notes, without comment, one very remarkable fact, viz., that mating together immunized animals even a year after the injections had ceased, the majority of the eggs did not come to maturity, but con- tained monsters, and even of the few chickens that were hatched several were very feeble and some showed distinct anomalies. The animals had apparently quite recovered from the injections, and the only explanation for this remarkable series of monsters must be that the germ-cells, both paternal and maternal, had been acted upon and permanently modified by the abrin. Unfortunately not realizing, apparently, the bearing of these results, Lustig does not seem to have studied the effects of mating an immunized domestic cock with a non-immunized hen. We have our- selves attempted work along these directions with rabbits, giving the bucks minute doses of lead-salts over long periods, and our results, so far as they go, would indicate that the germ-cells have been seriously affected. But unfortunately an epizootic of rabbit septicaemia so affected our ex- perimental animals that we are unable to state more at the present moment than that our experiments certainly favored and did not contra- dict the view here indicated. It may be objected that in all these cases we are dealing with degenera- tive and not progressive changes in the germ-cells. We would only reply, if our view regarding the constitution of the molecules of living matter at all approximates to the truth, then, if it can be shown that the biophores may be deleteriously affected by diffusible poisons, it is obvious that ^Ctes. rend. Acad. d. Med., Paris, March 15, 1888. ^Lustig: Centralbl. f. ally Pathologic, 15, 1904, 210. INHERITANCE AND DISEASE 45 other combinations are possible, leading to what wc would term favorable or progressive modifications in their side-chains. If^ therefore, we accept this variation of the biophores of the germ-cells by influences which affect the other tissues of the paternal organism, we gain a comprehension of why it is that not merely is the offspring not identical with either parent, but why it is not even the mean of the two parents. 12. We see also why it is that there is not an identical composition of the nuclear material from the two parents, which, uniting, originates the new individual; and that in the amphimixis or fusion of the dissimilar biophores we have another cause of individual variation. What is the nature of this amphimixis ? We cannot, with the data at our disposal, regard it as an immediate chemical combination of maternal and paternal biophores. In not a few forms in which the stages of seg- mentation of the ovum has been carefully followed it has been established that for a considerable period, at least, the paternal and maternal chro- mosomes, while lying side by side, remain nevertheless distinct; and upon chemical and physical grounds it is difficult to conceive a true conjunc- tion or chemical combination between elaborate molecules of closely allied constitution. This does not, however, mean that we are compelled to accept Weis- mann's theory that ids, or groups of biophores, derived from long gen- erations back, each of which has preserved its individual characters, are contained in the germ-cell. No such deduction is necessary. The studies stimulated by Ehrlich's remarkable work indicate another and a more rational conception. We need but to refer what has been observed in connection with the phenomenon of cytolysis. To give an example: histologically, and in their functions, the red corpuscles of a horse and a rabbit or a guinea-pig are curiously similar. Yet clearly they are of differ- ent molecular constitution ; the one cannot replace the other. Introduce the red corpuscles of the horse into the rabbit and they are destroyed; and, what is more, the injection of these corpuscles leads to such a reaction on the part of the rabbit's organism that its blood-serum for some con- siderable period possesses the power of breaking up the horse's red blood-corpuscles. That in nature the equine erythrocytes should gain admission into the blood of the rabbit is a sheer impossibility; never- theless, the rabbit's tissues produce substances which destroy the foreign red corpuscles; they adapt themselves to dealing with a novel compound; and they do more — they continue to discharge into the blood-serum a sub- stance which is capable of breaking up the red corpuscles so that the rab- bit's serum now causes a rapid disintegration of the corpuscles of the horse, although the same serum may be without effect on the red cor- puscles of other species. We explain this according to Ehrlich's theory by the development of side-chains on the parts of the cells {i. e., of the cell molecules) of the one animal, which, uniting with the side-chains of the molecules of the foreign red corpuscles, set up such constitutional disturb- ance that the corpuscles become disintegrated. Here I shall not discuss the process at length. What I wish to call attention to is that now-a-days we accept this view that molecules of organic matter which are apparently closely allied in function and structure act the one upon the other not 46 HEREDITY AND PHEDISPOSITIOX directly, but through their side-chains, whether these chains remain at- tached to the central ring or whether these have become liberated and are free in the surrounding medium. Let us apply this idea to the fertilized germ-cell. Our conception so far has been that the paternal and maternal biophores are of closely allied constitution We may indeed regard the central rings in individuals of the same race as identical, the side-chains, or some of them only, as dif- ferent. It is conceivable that when these allied biophores exist side by side within the germ-cell a process takes place similar to that above indi- cated. If we acce})t Ehrlich's theory in its broad outline we are justified in supposing that such allied though diverse bioi)h()]'es existing side by side are not inert; that as they grow — i. c, as they assimilate other groups of atoms to form side-chains — through these side-chains they are capable of acting one on the other in the same way as molecules of difl'erent species — and even of different individuals of the same species — have been found to act one on the other, i'. e., through their side-chains. If, for example, the biophores of paternal origin form one particular order of side-chains, these, becoming liberated into the cytoplasm, may become attracted to and may satisfy the molecules of the maternal biophore; and just as certain cells in the rabbit in the presence of the horse's red blood-corpuscles gain the property to form new affinities when side-chains of the equine erythrocyte molecules are present in their neighborhood, so gradually with "growth" in association Vv'ith the paternal biophores the maternal biophores may be modified to this extent that in them certain side-chains become replaced by side-chains of paternal type. This we regard as the true amphimixis— ^a gradual progressive inter- change of properties and mutual rearrangement of constituent mole- cules tending in the main to the biophores of the two orders becoming identical, but varying in the results according to the nature and prop- erties of particular side-chains, and this even though we accept Weis- mann's contention and regard the biophores and chromosomes of paternal and maternal origin respectively as continuing to occupy for some con- siderable period a definite position in the nucleus in regard one to the other. Along these lines we can postulate cases in which the side-chains of a particular order from the one source completely replace those from the other — exclusive inheritance. We can further suppose cases in which they antagonize or neutralize each other, leading to the practical loss of the side-chains of one order, whereby the biophore assumes a simpler type of constitution; or, more exactly, the individual developed from the con- junction of the biophores of two orders is deficient in a particular property or group of associated properties. We can thus understand the phenome- non of reversion and of sports of defect. It is further possible to compre- hend along these lines cases in which side-chains of a particular order augment each other — in which, that is, a biophore gains a combination of the side-chains of a particular order of both paternal and maternal origin. Or otherwise we can understand progressive inheritance and production of mutations and sports of excess. In such a process of amphimixis as here indicated the tendency must clearly be that of replacement or augmentation of weaker chemical affinities by stronger ones; and so we should not expect to find that all the various INHERITANCE AND DISEASE 47 side-chains with their peculiar properties belonging to one set of biophores should replace those of the other set; or, in other words, that the biophores of the maternal type, for example, should wholly replace those of the paternal type. There would tend rather to be a certain amount of give and take and interchange depending on the affinities of the particular biophores. Further, it is essential to regard the side-chain molecules as attracted in series to form chains. And, also, judging from what we know regard- ing immunity, we must infer the existence of the law that the i)roperties of the oldest acquirement are most tenaciously retained, and those of most recent acquirement most easily lost. Or, otherwise, granting that a bio- phore or biophoric molecule acquires new side-chains in this interaction with biophores of different origin, if that biophore and its products be re- moved from the influence of this interaction it may, with relative ease, lose the power of forming these newer combinations, and in a new en- vironment revert to the earlier affinities and properties. But to enter at length into these different possibilities regarding the interaction of maternal and paternal biophores in the germ-cells is beyond the scope of this article. It may indeed be urged that we have already entered into this matter at too great a length, even though we have sought to compress our presentation of the theory into the smallest possible space compatible with clearness. But having mentioned and accepted Mendel's law for cases of exclusive inheritance, it is necessary that we should indi- cate how the theory applies to this particular order of phenomena. Suppose we take four marbles, two black and two white, and shaking them together let them fall out of the box two and two, and in doing this test how often we obtain in successive casts, (a) a pair of blacks; (6) a f)air of whites ; and, (c) a combination of one black with one white. A ittle consideration will show that the chances are equal that the first marble to emerge will be either black or white, and that they are equal whether the first combination to be cast will be a pair of the one color or a combination of the two. If the first pair to emerge be a black pair the next must be a white pair; if the first two out of the four marbles be a white and a black, the next two must also be white and black. The same will be true whether we deal with only two pairs or 200 pairs. Or, otherwise, for every B B and W W combination recorded once the B W combination will be recorded twice, and the sum of repeated casts will be some multiple of the formula BB + 2BW + WW. It would seem obvious that to explain Mendel's law we must accept the view that in the germ-cells the paternal and maternal chromosomes (with their contained biophoric molecules) do not fuse, but remain independent if associated series, undergoing coequal growth and multiplication as the germ-cells proliferate (as indeed would seem to be indicated by the studies of Conklin and Hacker). What is the simplest — we do not say that it is the correct — method of grasping what happens is to suppose that the nucleus of the sperm mother cell at one stage, of what Moore terms the maiotic process, presents a complete separation of the chro- matin of paternal and maternal origin respectively, so that of the four spermatozoa which eventually result, two carry on the biophores of paternal origin, two those of maternal. And similarly that in the devel- opment of the ovum, with the discharge of the first polar body all of one group of biophores either paternal or maternal become removed, and 48 HEREDITY AXD PREDISPOSITION with the discharge of the second polar body there is reduction with loss of one-half of the chromatin, whereby the ovum comes to contain an amount of chromatin — or number of biophores — of either paternal or maternal descent, equivalent to the amount of chromatin and number of biophores in the ripe spermatozoon. If now these ova and spermatozoa fuse, as indicated by the diagram, the proportion of progeny afforded by the hybrids will be in the proportion demanded by Mendel's law. In the diagram the black dots indicate dominant, white circles recessive, biophores, as well as paternal and maternal origin. Fig. 3. SfiiT/f/V MOTHER CELL (HYBRID), giving rise to four spermatozoa. OOCYTES (HYBRID), giving rise each to one Oi/am, by reduction. hybrid. DR Recessive. RR To afford Mendel's formula for cases in which there is more than one pair of mutually exclusive properties it is necessary to invoke in addition the principle already dwelt upon; i. e., that of interchange of side-chains between the bioi)hores of the two series. We must suppose that Avhile the series of developing biophores of maternal or paternal origin remain distinct, those of the one set have the greater affinity for particular orders of side-chain radicals. We must conceive them as attracting those orders and leaving the others to be taken up by the other set. By this means, although the biophores of the one set would still remain in series, the side-chains would become crossed, and by successive acts of fertili- zation, there would be developed the series of forms represented by Men- del's formula. Complicated as the theory must seem when first read, the more it is studied the more fully we beUeve it will be found to fit in and accord with the facts at present known and established with regard to heredity. We INHERITANCE AND DISEASE 49 owe it perhaps to ourselves to explain that it has not blossomed suddenly, but is the outcome of more than fourteen years of study, the basal concep- tion — that primarily variation is due to altered environment — having been borne in upon us by an investigation into the variability of bacteria, in 1891.^ Its development, we may add, has essentially been brought about by a consideration of the problems of the inheritance of morbid conditions. We may add that it gains strong support from recent botanical studies which show that by the action of external agents upon the ovules of seed plants, certain parental qualities may be suppressed and new qualities gained, and this it would seem not temporarily, so that actual departures from the course of the hereditary strain may be induced.^ To sum up briefly our views with regard to the inheritance of disease, they may be expressed as follows: 1. There cannot be homologous inheritance of gross structural dis- turbances. 2. There is no true inheritance of infectious disorders. 3. The only possible inheritance of conditions acquired by the parents is that of conditions which act upon and affect the bodily tissues of the parent and affect also the germ-cells. These conditions may be of two orders: (a) Extrinsic and Direct. — Chemical and physical conditions intro- duced from or acting from without may simultaneously bring about modifications in the constitution both of the somatic- and the germ-cells. As the germ-cells are part and parcel of the parent at a period when such a modification could or does occur, it is futile to urge that such modifica- tions are not strictly instances of transmission of parental acquirements. If this be accepted we must admit that parental intoxications, whether from absorbed chemical substances or resulting from the growth of pathogenic organisms, may influence the organism, and that, in all proba- bility the different toxins or poisons, acting differently upon the molecules of the germ-cells, may lead to the offspring becoming modified in its development in one or other particular direction. (b) Intrinsic and Indirect. — It is conceivable that specific influences acting upon one or other organ of the parent, or again the destruction or arrest of action of an organ or part, may so disturb general metabolism that the absence of normal metabolites or presence of abnormal metab- olites in the circulating blood may influence the nutrition of the germ- cells, bringing about alterations in the constitution of the germinal biophores and resulting alteration in the constitution of the offspring. Metabolic disturbances in the parent — gout and the rheumatoid states, for example; defect or excess of internal secretions — may tell upon the germ-cells. It is conceivable that the organism as a whole which origi- nates from the modified or Aveakened germ-cells may exhibit a special sus- ceptibility toward the effects of that particular order of compounds which primarily caused alterations in the constitution of the molecules ^On the Variability of Bacteria and the Development of 'Races, Manches- ter Medical Chronicle, September, 1892. Other articles upon 'Growth' (Jacobi, Festschrift, 1900, and on Inheritance, New York Medical Journal, 1901, and BiLck's Reference Hand-book, Heredity and Disease, 2d edition), show the development of the views here brought forward. 2 See D. T. Macdougall: Popular Science Monthly, September, 1906. 4 50 HEREDITY AND PREDISPOSITION of the germ-ccU. Alono; these hues we best comprehend the development and inheritance of diatheses. While admitting these possibilities, two counteracting influences have nevertheless to be kept in mind: (a) The fact that the individual is the product of the interaction of the germinal matter derived from two sources whereby the constitution of the germinal matter from the one parent may be neutralized in its effects to a greater or less extent by the constitution of the germ-plasm from the other parent (the many different ways in which this interaction may show itself need not here be recalled; they have been discussed and classified in the preceding pages) ; and {h) the action of the law already noted that properties of recent acquirement are those which are most easily lost; so that biophores modified by sub- jection to temporary influences may upon reversion to a more normal environment give rise to new biophores approximating to or gaining the original constitution. There may further be a true inheritance of morbid conditions due not to the transmission of a property or defect through the germ-cells of either parent (and observable, if not in the parent, at least in the parental stock), but to the interaction of the two germ-plasms in fertilization; or, more exactly, due to the modification in the biophoric molecules by the interaction of their side-chains. PART II. DISEASES CAUSED BY PHYSICAL AGENTS. CHAPTER 11. LIGHT. X-RAYS. ELECTRICITY. By ALFRED GORDON, M. D PHYSIOLOGICAL EFFECTS OF LIGHT. The modern conception of organic and inorganic life embraces vari- ous conditions. They are not all equally necessary for living organisms: while some are absolutely indispensable, others play only a secondary role. Light belongs to the category of objects without which both plant and animal life are impossible. Light makes available chemical energy in the plant-cell, and out of this energy are derived all the activities of the plant in a complex series. It is an established fact that out of carbonic acid and water- which leave the animal body, the plant-cell, under the influence of light-rays, creates an endless chemical energy. The favor- able effect of light and chemical rays of the sun upon animal life had been known from most ancient times. The sun was considered as the source of life, and therefore worshipped (Helios, Apollo). The ancient Egyptians and Assyrians devised various appliances which they placed on the roofs, and there they exposed their bodies to the rays of the sun, as they believed in the invigorating influence and great curative power of light. Hippocrates, the father of medicine, was convinced of the curative properties of sunlight; also of its influence on the skin, and of its value in the sick-room. The Italian proverb, "All diseases come in the dark and get cured in the sun," is very significant. It is sufficient to recall Moleschott's experiments on frogs: placed in the same conditions of temperature, they exhaled more COj in the light than in obscurity. Ex- perimental physiology and clinical observation show that the respiratory 51 52 DISEASES CAUSED BY PHYSICAL AGENTS chemistry, formation of hirmoglobin in the blood, growth of the organism, and pigmentation of the skin, are directly dependent in a large measure upon light. Finally, functions of various glands and metabolism in gen- eral are undoubtedly in some relationship to light. Forbes Winslow has shown the efl'ect of light on the growth of man. Growth of children dur- ing the months poor in sunlight is slow; this is particularly noticeable in children of the poor who live in basements. Cretinism is known to ex- ist in dark mountainous valleys where the sunlight penetrates exception- ally. That the very existence of certain organs depends upon light-rays can be seen from the well-known observation that the eyes of animals kept in darkness generally become rudimentary. Besides the direct physiological effect on the functions of the organism, light has also a beneficial effect upon the nervous system and psychic sphere. Disposition, humor, general sensations, Avill certainly be more agreeable in a clear, sunny day than in cloudy and gloomy weather. Nature has provided us with light also as a means of defense against pathogenic microbes. That the tubercle bacillus may be destroyed by light has been proved by Koch and others. The favorable results ob- tained in the treatment of pathological conditions of the skin according to Finsen's method are perhaps due to its effect upon microorganisms. The action of light as described above is, according to the state of our present knowledge, due to the permeability of the skin and other tis- sues. Bouchard has shown that it is principally the ultra-violet rays that penetrate the tissues; the reflex stimulation is then transmitted through the skin and from the latter to the central nervous system, which in its turn influences various organs. The result is that life-processes and meta- bolism are increased. PATHOLOGICAL EFFECT OF LIGHT. If moderate light, as we have seen, has a favorable influence on the en- tire organism, intense light, on the contrary, acts unfavorably. The de- gree of injury naturally depends upon the intensity of and length of exposure to sunlight. Locally one may observe sunburn, which in mild cases is manifested in a simple erythema, and in severe cases in an inflam- mation with swelling and even destruction of skin. Freund, among others, has shown that in such cases a large number of ultra-violet rays traverse the epidermis and reach the deep layers of the skin, in which they affect the cellular elements. When oedema and exudation, with sub- sequent.destruction, take place, a general reaction, with elevation of tem- perature, will follow. In extremely severe cases, when destruction is extensive, internal complications may ensue. In ordinary cases of sun- burn, pigmentation may occur; the latter is, according to Finsen, a natural protection against further effect of light-rays. Exposure to sun-rays may be an exciting cause for various affections of the skin in predisposed individuals. Lentigo, for example, is the well- known freckles, w^hich appear usually on the face, neck, and hands; they disappear almost entirely during winter and reappear in summer. Chlo- asma, xeroderma pigmentosum, hydroa, and even pellagra, are all cutane- ous affections in which sunlight plays a certain role as a causative agent. LIGHT. X-RAYS. ELECTRICITY 53 The skin is not the only organ which may suffer from the immediate effect of intense sunhght. The eye may become affected. Oj)hthalmia and conjunctivitis are not infrequent occurrences in the polar regions and in the mountains. A few cases were reported in which cataract was ap- parently produced in workmen whose eyes were exposed to prolonged action of intense light. ^ All these changes, and particularly those of the skin, are the result of the effect of light-rays in a comparatively mild degree. The produced lesions are usually limited to the tissue exposed to the light. When the effect of intense sunlight is manifested in general disturbances, the condition may become alarming, as it may terminate by death. We speak then of sun- stroke. The term "sunstroke" has been considerably abused. Heat-exhaus- tion, heatstroke, sunstroke, insolation, coup de soleil, heat-asphyxia, and thermic-fever, have been described as one condition. Manson, in his book on tropical diseases, brings some order in the terminology, and his classifi- cation is, in my judgment, the most satisfactory. He considers separately a condition produced by the elevated temperature, to which he gives the name "heat-exhaustion;" another condition produced apparently and only by the direct rays of the sun, to which he gives the name "sun- traumatism;" and, finally, a third morbid state, to which Sambon gave the name "siriasis." The latter is in all probability due to a microorgan- ism which develops only in a high atmospheric temperature. 1. Heat-exhaustion. — This condition is characterized by a sudden tendency to syncope in an atmosphere with a high temperature. It can be brought on indoors or outdoors. The main etiological factor is heat from any source. It is observed in industrial plants where work is carried on at temperatures above 120°F. Individuals suffering from various diseases, those whose physiological activities are lowered by alcoholic or other ex- cesses, or by exhaustion, present very little resistance to the effect of heat. With the syncope occurring from heat-exhaustion are also ob- served the following symptoms : shallow respiration, small and soft pulse, dilated pupils, cold skin, and subnormal temperature. Recovery usually follows, but very occasionally death may ensue. Heat-exhaustion brought on by exposure to the sun is called sunstroke, insolation, or coup de soleil. This condition is of great interest, especially to military surgeons; insolation in the army during summer months is of frequent occurrence. In warm climates those who are compelled to work outside of dwellings are apt to be stricken. Those who use alcohol are particularly predisposed to the effect of intense heat, and they constitute the majority of the victims of sunstroke. Some individuals are peculiarly predisposed to repeated attacks. Four cases came under the writer's personal observation, when the patients, free from alcoholism, had three attacks during three successive summers. Among other predisposing causes we may mention excesses of all kinds, constitutional diseases, or low vitality following protracted diseases. Finally, any cause which pre- vents the evaporation of the perspiration, as, for example, clothing fit only for cold weather and worn on hot days, predisposes to sunstroke. It is interesting to note that the black race is remarkably resistant to the ^Wm. Eobinson, British Medical Journal, January 24, 1903 54 DISEASES CAUSED BY PHYSICAL AGENTS effect of intense sunlight. Cases of insolation in children are also rare. As we see, the subject is of sufficient importance to warrant a more de- tailed description. Sunstroke (Insolation) — Symptoms. — In the majority of cases a sun- stroke is preceded by a few premonitory symptoms before complete prostration sets in. They are headache, dizziness with generalized tingling sensations, and nausea. Pain in the epigastrium, vomiting, and excessive thirst soon make their appearance. Consciousness is retained in mild cases. The patient enters into a state of exhaustion, which may go to complete prostration and end in death quite rapidly. If he survives, a slight fever may be present, which gradually goes down to normal. The above-mentioned symptoms then gradually subside and complete recov- ery takes place. I3cfore recovery occurs the patient will complain for a long time of headache; this is practically the only symptom which per- sists after others have disappeared. In severe cases of insolation there is always a loss of consciousness, which may be followed by death; the latter is rather exceptional. In a great majority of cases the patient re- gains consciousness; but there is extreme pallor, rapid respiration, rapid pulse, which is soon succeeded by a slow pulse; temperature is raised to 104° or 105° and in very severe cases to 108°. In some cases the tem- perature reached 112°-1 13°, which, according to certain observers, is not uncommon in severe forms of insolation. The skin is usually dry or covered with a clammy perspiration. Convulsions, epileptiform in char- acter, may occur, while general muscular twitching is exceedingly com- mon. Delirium is not an infrequent occurrence. The entire body is either in a state of rigidity or absolute flaccidity. Ecch}'mosis, or a petechial rash, was observed in a certain number of cases. The severity of certain cases is not dependent upon the degree of the temperature or upon the state of the pulse, and it is therefore difficult to foretell exactly the issue of a given severe case. Despite the unusually pronounced symptoms, recovery may follow, although not without a per- sistent headache and various parjesthetic disturbances, as tingling, numb- ness, pins and needles, etc., or some physical and intellectual weakness. Generally speaking, patients who remain unconscious for twenty-four or forty-eight hours usually die. Sunstroke is one of the causes of chronic meningitis, and the cephalea which so frequently follows recovery from insolation finds its explanation in the meningeal involvement. Far more important and frequent sequelae of sunstroke consist of distinct mental disturbances, as impairment of memory or of sustained attention. Some writers pretend that delusional insanity, paresis and mania may be caused by insolation. The writer's view is that if insolation is sometimes followed by these mental derange- ments, it is only as an exciting cause similar to trauma; patients of this character undoubtedly were predisposed to insanity or were already in- sane, and exposure to intense sun radiation only intensified the condi- tion. Among other possible consequences of sunstroke we may mention polyuria and glycosuria. Pathology and Pathogenesis. — The gross pathological changes found in cases of sunstroke may be expressed in one phrase: general congestion of the organs. The lungs, liver, spleen, and particularly the meninges of the brain and cord, are in a state of congestion. The blood is very fluid. LIGHT. X-RAYS. ELECTRICITY 55 The microscopical studies of various tissues and organs have shown that the cells of the liver and kidneys and of the nervous system all undergo parenchymatous degeneration. The nervous system suffers particularly, and there the changes are similar to those found in cases of intoxica- tion with poisons, as lead or alcohol; namely, marked chromatolysis of the cells. The condition of the blood deserves special attention. Leukocy- tosis and in some cases destruction of erythrocytes with diminution of the alkalinity of the blood are the changes which occur. As to the pathogenesis of the disease, there is a great divergence in the theories which have been advanced to explain the symptoms and death in insolation. Vallin at first believed that death is due to heat coagula- tion of the cardiac muscle. Hirsh believes that the cause of death lies in alteration of the blood — diminution of oxygen and retention of a toxic principle. Vincent^ arrived at the conclusion that there is a poisoning of the organism by toxic products accumulated in the blood. According to Laveran and Regnard,^ who made an extensive experimental study of the question, death in insolation is due to a direct effect of sun-rays, prin- cipally upon the nervous system ; this effect is first excitant and then par- alyzing. The investigations of more recent writers tend to the conception of a paralyzing action on the nervous system of some toxic elements, with the probable result of metabolic changes in the neurons; and according to the degree of auto-intoxication the effect of the sunstroke will be either an attack of ordinary heat-prostration or syncope with unconsciousness or death. Diagnosis. — It is only in exceptional cases that the diagnosis will be difficult. Usually the history of exposure, with the high temperature and the condition of the skin, render the diagnosis easy. In some cases, however, especially when there is a history of alcoholism or cardiac lesion, the diagnosis will be difficult; apoplexy should then be thought of. In the latter case the temperature is usually normal, the breathing is stertor- ous, the pulse is slow; but the most important symptom is the local paraly- sis, hemiplegia, or monoplegia. In malarial districts, a pernicious malarial paroxysm may give difficulty but a blood examination will make the diagnosis clear. Prognosis. — ^The outlook in cases of sunstroke will naturally depend upon the degree of prostration, and, according to some authors, upon the temperature. The latter condition is not absolute, as the writer has ob- served a patient with 110° who recovered. However, on general principles a very high temperature renders the prognosis unfavorable. The previous general health, and especially whether the patient uses or does not use alcohol, is of utmost importance in forecasting the outcome of his sun- stroke. The promptness of rendered assistance and the character of the treatment are also factors which play an important role in determining the prognosis of a given case- In mild cases of heat-prostration the prognosis is favorable. As to the complications following sunstroke, they are all as a rule temporary, except the grave forms of insanities. As in the latter, sunstroke similar to trauma plays only the role of exciting factor, the prognosis will be not dependent upon the insolation. In some cases the sequelse of sunstroke are very rebellious to treatment, and may ^ Rech. exper. sur Vhyperthermie , 1887. ^Bull d. I' Acad de MH., 1894. 56 DISEASES CAUSED BY PHYSICAL AGEXTS persist for a long time. Finally, as we said above, some patients become predisposed to repeated attacks after they have once had a sunstroke. 2. Sun-trauinatism. — Untler this name Manson describes a morbid state characterized as a rule by sudden death occurring without warning after exposure to" the sun. Paralysis of the heart or respiration seems to be the immediate cause of death. In a certain group death may not ensue, but the patient exhibits symptoms of meningitis; namely, fever, head- ache, dry skin, rapid pulse, photophobia, and vomiting. The condition is not invariably fatal. If recovery follows, there are always sequehe more or less persistent in character, as tremor, amaurosis, amnesia, deaf- ness, epilepsy, and paralysis or ])aresis of the extremities. As to the pathogenesis of sun-traumatism, it is highly probable that caloric is not at fault, as similar eft'ects have not been observed from ex- posure to heat from other sources — as a furnace, for example. Manson is therefore justified in presuming that there is a special element in the solar spectrum capable of injuriously affecting the tissues, particularly if they have not become gradually habituated to sun exposure. To cor- roborate this view Manson calls attention to the phenomena of sun- erythema, of skin pigmentation known as sun-burn, and possibly of leukodermia; also to the sensation of distress brought on by exposure to a hot sun, which is quite different from that produced by the heat of a fire. 3. Siriasis. — ^This is a specific disease developing in high atmospheric temperature, and, similarly to yellow fever or dengue, is not caused by the elevated temperature, but probably by some microorganism which demands for its development a high atmospheric temperature and certain local conditions. It is known on the east coast of the United States and the South Atlantic coast; in Africa, Asia, and Australia. The mortality from this disease is very great. According to Manson (Tropical Diseases) the case mortality among English troops is about one in four. The symptoms observed are almost identical with those of sunstroke, and are characterized mainly by hyperpyrexia, coma, and extreme pulmonary congestion. If a post-mortem examination is made shortly after death and before decomposition changes have set in, the heart is found to be remarkably rigid. Rigor mortis is an early appearance. The blood is remarkably fluid and yields an acid reaction. Venous engorgement of the viscera is a notable feature. Treatment of Heat-exhaustion, Sun-traumatism, and Siriasis .^The first indication in cases of heat-prostration, be it mild or severe, is rest. The patient must be undressed and put to bed; if stricken on the street, his clothing must be loosened and he should be laid on his back in a cool, airy, and shaded place. The next indication is application of cold to the head, and some stimulant (brandy or others) administered. In mild cases this treatment will be sufficient. In more severe cases, in addition to these means, some drug may be given to alleviate the headache and re- duce the high temperature. The coal-tar products, salicylates, etc., will answer both indications, but should always be used with caution. When, on the contrary, the prostration is very pronounced and the temperature is below normal, heat instead of cold will have to be applied, — in con- junction with some internal stimulant, if there is no coma; if coma, stimulants must be given hypodcrmically. Strychnia, camphor, and nitroglycerine, are the usual drugs for the latter purpose. Convulsions LIGHT. X-RAYS. ELECTRICITY 57 can be controlled by placing the patient in a lukewarm bath and by admin- istration of morphine aided by atropine. Restlessness and insomnia are best treated by the bromides. High temperature can be controlled particularly by cold spongings frequently repeated, or by cold baths, the tempera- ture of which is gradually reduced while the patient is in the tub. The patient should be vigorously rubbed. The same procedure can be em- ployed in cases of unconsciousness. These hydrotherapeutic measures can be modified according to the conditions in each individual case. If baths are not convenient, cold packs may take their place. Sometimes a shower-bath, or a douche over the spine, of short duration and followed by a dry rubbing, reduces the temperature admirably besides having a stimulating effect. It should be borne in mind that while the patient is treated with cold water, stimulation with the above-mentioned means be kept up. Among the stimulants the writer lays special emphasis on saline infusions, which in many cases prove to be an excellent adjuvant. If the patient is a full-blooded individual, venesection followed by saline infusions will be of better service than infusion alone. When death is imminent, repeated stimulation with the usual remedies and artificial respiration must be used. After the pronounced symptoms have disappeared, the treatment will be symptomatic. Headache, insomnia, nervousness, parsesthetic disturb- ances, should be treated accordingly. When the hyperpyrexia is great, as, for example, in siriasis or in ex- treme cases of insolation, all the efforts must be directed toward reducing the temperature by rapidly acting measures. Chandler's^ directions are of great value in such cases. He advises to put the patient, undressed, on a stretcher the head of which is raised slightly so as to facilitate the escape of involuntary evacuations and to provide for drainage. A ther- mometer is kept in the rectum. The body is covered with a sheet upon which is laid numerous small pieces of ice, larger pieces being closely packed about the head. Ice-water is then allowed to drip for thirty or forty minutes on the patient, from drippers hung at an elevation of from five to ten feet. A fine stream of iced water poured on the forehead from an elevation will act as a stimulant ; this powerful measure must not be kept up for longer than one or two minutes. A hypodermic injection of forty minims of tincture digitalis is given as soon as possible, its administration being preceded in the case of plethoric patients by a small bleeding. As soon as the rectal temperature has sunk to 104° the application of cold should be at once discontinued. On discontinuing the iced sheet, the patient should be wrapped in a blanket and hot bottles applied to limbs and trunk. In this stage strychnia as a stimulant should be avoided. In case of failure of respiration, artificial respiration should be resorted to; Chandler urges to keep it up for half an hour. There is a very important warning given by Manson. Antipyretics (antifebrine, antipyrine, etc.) should by all means be avoided, as they are dangerous in view of their depressing action on the heart. If the treatment of sunstroke as outlined here will save some patients, the prophylactic measures are of greater importance. The above-men- tioned investigations of Laveran and Regnard, also those of Hiller, show ^Medical Record, New York, 1897. 58 DISEASES CAUSED BY PHYSICAL AGENTS that prolonged physical exercises facilitate the onset of sunstroke. It is therefore advisable in hot days to avoid as much as possible all causes of fatigue. As alcoholic intoxication predisposes to sunstroke, beverages containing alcohol must be avoided. Excesses in the use of animal foods and others, violent exercises, want of sleep, constipation, etc., should be avoided. Indixiduals suffering from malarial or other fevers, or from chronic liver or kidney diseases, run great risk in exposing themselves carelessly to the sun. Unnecessary exposure to the sun in summer is con- traindicated. A hat should be always worn in hot days in order to avoid a direct effect of the sun on tlie head. We should not expose ourselves to sun-rays more than an hour, as very long exposure brings on high excite- ment or complete relaxation. Much sweating weakens and provokes chills ; a skin which perspires is a better conductor for chemical rays than a dry skin. Before the discovery by Rontgen of rays to which the scientific world attached his name, our knowledge of sources of light was limited with the spectrum, and all we know about physiological effect of the latter is that only the blue, violet and ultraviolet have a vital function in animal life. THE X-RAYS. The discovery of ar-rays revolutionized our knowledge of the composi- tion of light. Since 1896, physicists have applied themselves arduously to the further study of various sources of light, and we are now in possession of Becquerel's rays, of radium, of polonium, actinium, Blondlot's and Charpentier's N and N' rays respectively. Some of these rays have proven to be of certain therapeutic value; others are only in an experi- mental stage. Rontgen's rays have almost accomplished their history. Their application in medicine is of inestimable use, both for diagnostic and therapeutic purposes. The therapeutic effects of rr-rays became particularly known since Freund applied them with success for the first time on a nsevus, and Kum- mel with Gocht on lupus. Since then various dermatoses were treated, namely, favus, sycosis, hypertrichosis, acne, eczema, psoriasis, prurigo, alopecia, and ulcerations. Soon neoplasms, both malignant and benign, w^ere submitted to the action of .r-rays. The results were so encouraging in a great many instances that their beneficial effects became universally recognized. At the present day many operable and inoperable cases of tumors, both external and internal, receive the a--ray treatment, before or after surgical interference. The beneficial results obtained so far led a number of men to extend the application of the new treatment, so that there are on record cases of neuroses, and even organic diseases, some symptoms of which — pain, for example — derived benefit from a'-ray treatment. Some observers treated with favorable results cases of progressive pernicious anaemia, leukaemia, Hodgkin's disease, and exophthalmic disease. Inasmuch as good results are obtained from a;-ray treatment, we meet now and then with accidents, in which tlie deleterious effect of rc-rays may go so far as to produce permanent lesions, with complete destruction of tissues. LIGHT. X-RAYS. ELECTRICITY 59 PATHOLOGICAL EFFECT OF X-RAYS. The disturbances produced by a;-rays are (1) local and (2) general. 1. Local — Dermatitis. — The first case of rc-ray burn we find men- tioned by O. Leppia;^ and the first case of alopecia caused by a;-rays was reported by Daniel.^ Since then a large number of observations were made and recorded, all showing that while we have in the ar-rays a pow- erful physical remedy, nevertheless it must be handled with greatest caution and with full knowledge of its physical properties. It is generally accepted that the specific effect of .T-rays consists of eventual destruction of tissue, (analogous to the ultra-violet rays of the spectrum when they are in superabundance). Ulcerations, necrosis, and sloughing of skin, are frequent occurrences in exposures to a;-rays. The consensus of opinion concerning rr-ray burns is that the latter undergo three stages, namely: (1) Hypersemia, leading to exfoliation in scales, degen- erative changes with subsequent atrophy in the tissues depending upon the skin, as hair, nails, glands, etc.; (2) vesiculation ; and (3) escharotic destruction; the intima of the blood-vessels becomes thickened and the whole process presents a chronic inflammation with all its usual conse- quences. Freund described increase of pigment in the cells of the Mal- pighian layer of the epidermis. The histological changes affect chiefly or exclusively the cellular elements of the skin, which undergo a slow degen- eration with destruction, while the connective, the elastic, the muscular, and the cartilagenous tissues are not at all or only in a slight degree altered; or, if they do suffer, it is only secondarily to the inflammatory reactions. As to cells themselves, the epithelial cells are affected first; in a slighter degree are affected the cells of glandular organs and of vessels. The nu- cleus suffers conjointly with the cell-body. If the a:-rays are intense, the leukocytes of the dilated vessels penetrate into the degenerated cells, and as phagocytes bring on their complete destruction and resorption. The cicatrization is of especial character; it is irregular, without a tendency to retraction, and perfectly white. The a:-ray burn has its symptomatology. At first there is a tingling sen- sation, which is followed by redness and swelling similar to the effect of solar rays. Later vesicles appear, which finally break down, leaving a raw surface. In severe cases ulcerations will follow the vesiculation. As the process is inflammatory, a few general symptoms may be present; namely, chills, fever, pain, general malaise, etc. The characteristic fea- ture of the lesions is their late appearance. The initial paraesthetic dis- turbances may exist from a few days to two or three weeks before the erythema with the subsequent symptoms wdh be manifested. Bar-Boulle reports a case of severe burn with ulceration appearing tAvo months after exposure. This is perhaps due to the cumulative property of a:-rays, a fact which is accepted by all workers in that line. The healing process is also slow. Other Local Effects of X-rays— (a) Atrophy of the SMn.— H. E. Schmidt, Kienbock, Gocht, Albers-Schonberg, Hahn, and Scholz, re- ported cases of marked atrophy of the skin, with dystrophy or shedding ^Deut. Med. Wochenschr., 1896, No. 28. ^Medical Record, New York, April 25, 1896. 60 DISEASES CAUSED BY PHYSICAL AGENTS of the nails, following .r-ray exposure. They were probably due to angio- neurotic and trophoneurotic processes. (h) Alopecia. — In connection with this disturbance it is well to men- tion Gerwood's observation: in one case of his, curly hair grew in place of smooth; and in another black hair took the place of white. (c) Scleroderma-like changes have been reported by Hallopeau, Four- nier, Bartheleniy, Gadaud. (d) Gangrene has been observed by some writers. ( Virchow's ArcMv., 79 Bd. S. 124, 1880. AIR , 75 return to the surface, or by subjecting the individual to increased atmospheric pressure in any manner at all (pneumatic cabinet, etc.), the symptoms may disappear. It would be a matter of importance, if not of absolute necessity, to have on hand an apparatus in which the patient could undergo high-pressure stances. Preventive measures constitute the most important part of the treat- ment. Bad physical health, diseases of the kidneys or heart, alcoholism, obesity, and, finally, hunger, are all contra-indications for subjecting one's self to the high atmospheric pressure. As to the limit of time which is permissible to spend in the caisson, CoUingswood's rule is particularly to be recommended. For the first exposure only one hour; for those who are accustomed to the work the number of hours should decrease as the number of atmospheres increase, as, for example, three hours in four atmospheres, four hours in three atmospheres, etc. The locks with which the caissons are supplied, and in which the pressure is gradually reduced, should be used very frequently, according to Smith, CHAPTER IV. HEAT AND COLD. By ALFRED GORDON, M.D. EFFECT OF TEMPERATURE, TROPICAL AND COLD CLIMATES. In the preceding sections we have seen that light and a certain chemical or physical condition of air are indispensable to life. Besides these con- ditions, upon which metabolism directly depends, certain dynamic re- quirements must be fulfilled if life is to be maintained. Among them is the temperature of the air within certain limits. The activity of chemical phenomena of living tissue undergoes consider- able modifications as soon as the temperature of the tissues is subjected to variations. The temperature limits in which life can exist are of course very different for dift'erent organisms. It is well known that a man can resist great variations of temperature. This is probably due to the fact that his internal temperature remains unchanged. However, this natural tendency in maintaining the central temperature unchanged does not go on Avithout certain disturbances in the functions of certain organs. If, for example, the external temperature increases, there is a diminution in the production of COj, the respiration becomes accelerated, and the skin perspires profusely; all the secretory organs eliminate excessively; the nervous system is irritated. If the elevation of temperature is only temporary, the related functional disturbances will be transitory. When the action of heat is prolonged, local as well as general symptoms will make their appearance. Heat. — ^The eft'ect of heat must be considered from three standpoints: (1) Immediate contact of living tissue with a hot object; (2) effect of solar heat (see sunstroke and sun-traumatism) ; (3) effect of hot climates. Solid or liquid objects, and gas and vapors, when their temperatures are elevated, will produce burns on coming in contact with living tissue; local destructions of skin and mucous membranes will be the consequence. Fluids, when they do not reach a temperature of 100°, produce only a slight erythema. Water boils at the temperature of 100° C.; salty water and oil must have a larger quantity of calories and are therefore to be feared. Burns of mucous membranes of the rectum and vagina occur when very hot enemas or injections are administered, ffidema of the glottis may be the consequence of burns of buccal, pharyngeal and oesophageal mucous membranes. Caustic fluids taken by mistake or in attempting suicide lead to very grave injuries of the mucous membranes. 76 HEAT AND COLD 77 Solid objects, especially metals at a red heat, produce deep lesions; but the burn is confined to the point of application if the substance is not adherent. Gas causes accidents through its flame. Those whose work exposes them to explosions (chemists, miners, etc.), are frequently victims of burns; their clothing takes fire and cannot be separated from the body; the skin becomes carbonized and the subcutaneous fat burns; the consequences may be very serious. Hot vapors are particularly ob- noxious. Droplets of hot water accumulated on the skin will burn it, but they may be also inhaled and penetrate the mucous membranes of the larynx and lungs. In burns we meet with all degrees of active hyperfemias and formation of oedema, hemorrhages, and necrosis in the skin. Since Dupuytren, it has been generally accepted to consider six degrees of burns. The first degree is characterized by redness, pain, and tumefaction. The pain is pronounced at the beginning. The swelling is of short duration. The symptoms are transient, and desquamation of the epithelium takes place. In the second degree the Malpighian layer is affected. The epidermis is ele- vated by vesicles. When the latter are ruptured and the epidermis is removed, granulation and suppuration are found on the underlying layer, which is extremely painful. Deformed scars will always form, if the epidermis is removed. It is therefore advisable to leave the epidermis in place. The third degree is characterized by destruction of all the super- ficial layers of the dermis. The vesicles, which are large, do not contain a serous fluid as in the preceding degree, but a dark bloody fluid. Some- times dry, dark or yellow scabs are formed. The pain is exquisite, especially on the sixth or seventh day, when the scab falls off. The latter leaves a granulated and suppurating surface which is replaced later by a deformed cicatrix. In the fourth degree the destruction of the skin is com- plete; even the subcutaneous cellular tissue is affected. The scabs are here more or less large, dark, and dry. Pain is not pronounced, because the nerve-ends are destroyed. The gangrenous layers fall off and cause sometimes an inflammatory condition. The cicatrices are formed very slowly and are very irregular. In the fifth degree we often find destruction of skin, muscles, bloodvessels, and nerve-trunks. When the scabs fall off, sometimes articular cavities are laid open. When the gangrenous tissue falls off, purulent arthritis, visceral inflammation and abundant hemor- rhages may occur. In the sixth degree all the tissues are carbonized, the periosteum is destroyed, the bone is necrosed, and an entire limb may be lost. In addition to local symptoms there are frequently general phenomena more or less pronounced. They depend upon the extent of the lesion. When the burn is grave, the pain may be so intolerable that the patient falls in a stuporous state. He is somnolent, does not speak or move; the face is pale; the skin is covered with a cold perspiration; the tempera- ture goes down below normal; the pulse is imperceptible; and the respir- ation becomes irregular; anuria may occur. In another series of cases with the same lesions the general condition is of a diametrically opposite character; extreme excitement with delirium and convulsions T\dll be ob- served. In a certain number of cases there is a marked elevation of tem- perature, which is due to visceral inflammation. Here we observe loss of appetite; constipation, or else a diarrhoea; generalized bronchitis, bron- 78 DISEASES CAUSED BY PHYSICAL AGENTS chopncumonia, or pleurisy. The kidneys may become involved, and albu- men is found in the urine. Finally, cerebral congestion, with exudation in the ventricles, has also been observed. During the period of disapjiearance of the scabs the suppuration de- scribed above is always accompanied by general symptoms. In pro- nounced cases amyloid degeneration of the viscera may occur and lead to cachexia and death. In other cases new infections may occur in the sup- purating wound: erysipelas, septica?mia, secondary hemorrhages, and tetanus may develop. Pathology and Pathogenesis. — The common findings are congestion of the digestive and respiratory tracts and of the nervous system. But the complications cited above will add other lesions independently of burns. As to the ])athogenesis of burns various views have been advanced, and among them the ideas of Metchnikoff's and Ehrlich's schools are the most acceptable. In burns there is complete or partial destruction of the cell-elements of the blood; this has for consequence formation and absorption of cell poison (hfemotoxin). In extensive burns we have to deal with destruction of a greater number of cells, and therefore with a larger surface for absorption of the products of this destruction. Capillary em- boli, thrombi, and infarcts, especially in the kidneys, are of frequent occurrence; they explain the cases of sudden death so frequent after extensive burns. Prognosis. — It depends largely upon the extent and depth of the burn and upon the importance of the affected organs. A lesion which would be insignificant on the skin will be of paramount gravity if it occurs in the throat, as oedema of the glottis may ensue and be followed by death. On the other hand, a burn of second degree, if it is extensive, may be more serious than one of the third or fourth degree which is less extensive. The complications play a great role in the course and termination of a burn. Treatment. — In burns of the first degree, sedatives for the pain and external applications of liniments containing cocaine or morphine are sometimes sufficient. Prolonged baths at a temperature slightly lower than the body temperature are particularly recommended. In bums of the second degree one must not remove the epidermis raised by the ves- icles. The latter should be punctured at its lowest point. If, however, the epidermis is accidentally removed, the burn should be covered with a thick layer of antiseptic cotton. Cotton is a good filter for air, protects the nerve-ends, and lessens the inflammatory condition by pressure. In case the cotton is moist with exudation from the wound, it must be changed. It should remain in place until a new epidermis is formed. When the burns are deep and scabs are formed, care should be taken to avoid formation of irregular cicatrices. Antiseptic dressings, and particularly carbolized vaseline, or iodoform incorporated in vaseline, and also gauze saturated with a weak solution of sublimate and protected with oiled silk, are all of value; they prevent extensive suppuration with its usual com- plications. In some cases it is extremely difficult if not impossible to avoid deformed cicatrices ; deformities about the mouth, eyelids, nostrils, have been reported. Syndactylism was also observed in cases in which the nude surface of one finger was in contact with the next finger. Similar adhesions have been observed between the arm and thorax. In such cases HEAT AND COLD 79 grafting of skin will be of great service. In extreme cases, when the de- struction of the skin or of a portion of a limb is so great that the function will be hopelessly disturbed, amputation becomes necessary. As to the general symptoms accompanying burns, they must be treated on general principles. For depression use stimulants; for excite- ment and pain, sedatives. Good nutritious food should always be given. Hot Climates and Health. — A question of great practical im- portance is the morbid effect of hot climates on health. If an individual from a moderate climate is thrown accidentally or otherwise into an atmosphere with an elevated temperature, what will be the effect on his health? The first symptom noticeable will be increase of perspiration. This is followed by a low arterial tension. The urine is reduced. While the lungs expand, the number of inspirations is reduced, and as hot air contains less oxygen than cold, the general metabolism is diminished. The tolerability or intolerability of hot air is always associated with humidity. Atmospheric humidity interferes with free evaporation of sweat, and this necessarily interferes with the mechanism concerned in heat generation. A diminution of capacity for intellectual work — with a condition of languor and general weakness, loss of appetite, disturbance of digestion, of respiration, and of circulation, are the usual symptoms observed in individuals who come from a moderate climate to reside a more or less prolonged period of time in tropical countries. There are certain diseases that are most common in the tropics, such as malaria, yellow fever, beri-beri, dengue, cholera, dysentery, leprosy, hepatic abscess, and others. This is probably due to the fertile ground which certain bacteria find in heat associated with humidity. On the other hand, hot air with moisture predisposes to various affections, as intestinal diseases, bronchitis, and meningitis. The latest reports on mortality in tropical climates show that there is a special group of diseases which predominate and are highly fatal. They are nervous diseases, and convulsions in children. According to V. Harvard^ the mortality from nervous disorders is nineteen per thousand. Sleeping sickness, (pro- duced by trypanosoma), cachexia (caused by ankylostomum), leprosy, and hepatic abscess, are, according to the same author, causes of high death-rates in hot climates. Cold. — Similarly to heat, the effect of cold varies with the age, with the state of general health, with constitutional diseases, fatigue, alcoholism, and, finally, upon the degree of cold. We will consider here, first, the local effect of cold, and then its general effect. The effect of extreme cold upon the portions of the body which are exposed (feet, hands, ear, nose) presents three degrees. In the first degree there is a dark redness of the skin. The circulation is poor, the stagnation of the blood in the peripheral capillaries leads to infiltration of the subcu- taneous tissue, and the skin is thickened. When the skin is exposed to heat, tingling and itching will be present. Generally the condition does not last long. In some cases it may become chronic. The second degree is characterized by ulcerations. In acute forms they appear at once. The epidermis is raised by a serous or bloody fluid; the thin membrane be- comes detached, and an ulcerated surface is seen. In the chronic form ^American Medicine, 1905. 80 DISEASES CAUSED BY PHYSICAL AGENTS the skin, which is infihr.itcd, bursts, and the yellow-brownish fluid turns into crusts under which pus is accumulated. The third degree is charac- terized by death of the dermis and sometimes of the other underlying tissues. Elimination of necrosed tissue begins very soon. If it is moder- ate, the sloughing Avill leave a bleeding, ulcerated surface, under which is sometimes found diseased bone. Pathology and Pathogenesis. — Laveran and Cohnheim have studied the effect of cold, and found the bloodvessels to be the main tissue in- volved. The action of cold consists in narrowing the lumen of the blood- vessels, which may go even to its complete obliteration; the blood does not circulate and the involved area becomes white. Soon the cajjillaries dilate so that the circulation is slow and sometimes arrested. Thrombosis is the usual consequence, and small emboli may be detached and thrown into the general circulation. Changes in nerves are sometimes very pro- nounced; ruptures of the vasa nervorum and interstitial hemorrhages have been observed. Laveran and Tillaux sj)eak of fatty degeneration of the myelin sheath, a fact which will explain muscular atrophy, pain, and trophic ulcers, with anaesthesia of the skin. The inflammation of the neuritis may sometimes ascend to the cord. Other lesions were observed. Mathieu and Gubler speak of visceral congestion caused by capillary emboli; Laveran, of loss of mobility of leukocytes. Prognosis. — The first and second degrees may run their course without general disturbances. However, in soldiers who suffer hardships, in aged people and cachectic individuals, cedema of the face and of eyelids, and albuminuria, were observed. Weak individuals, old people, children, those who overfatigue themselves, those who do not eat enough, those who use alcohol to excess, are all very readily predisposed to the eft'ects of cold, and in such cases the prognosis is therefore always serious. During the stage of suppuration general septicaemia may occur. Recovery is usually slow; the cicatrization is very sluggish, and may be arrested from the slightest cause. This is particularly true in regard to individuals of lymphatic nature. Treatment. — Prophylactic measures are of utmost importance. The extremities (hands and feet) should be well protected. Sudden changes of temperature should be avoided. Dry astringent friction and massage are recommended. When the first degree is present, the congestion of the skin will be re- lieved by washing it with a stimulating fluid (alcohol and others). When ulcei'ations make their appearance, they should be protected from infec- tion. The third degree requires special attention. The greatest pre- caution is necessary to avoid extension of the inflammation. The old Avell-known friction of frozen limbs Avith snow or with very cold water is not to be neglected. In case of apparent death artificial respiration is indicated. There are cases on record showing that individuals after having remained under snow for several days could be brought to life with artificial respiration. It is therefore important to have recourse to it in every case. Under normal conditions a temperature which is not very low will pro- duce rather an agreeable sensation; one feels more active, and the respira- tion becomes better. There is more oxygen taken in and more carbon dioxide exhaled. When the temperature is very low, and the organism HEAT AND COLD 81 is exposed to it for a long time, functional disturbances make their appear- ance. At first the circulation becomes more active, and the temperature rises; but soon this excitation disappears, the limbs become numb, and the sight impaired. A general lassitude and an imperative desire to sleep make their appearance; general sensations become obtunded, respi- ration is difficult, the heart rate is slow, and syncope, followed by death, may ensue. There are, however, cases on record showing that individ- uals remained four, six and even eight days under snow and neverthe- less continued to live. Before death occurs, the muscular fibers cease to contract voluntarily; the muscles of the neck and of the extremities become rigid, and thus im- mobilize the body in a position which it had assumed at the time it was overtaken by cold. This explains the bizarre attitudes in which the bodies of individuals who died from extreme cold are found. According to Desgenettes, muscular contractures may spread over the entire body, and epileptiform seizures may carry off the unfortunate victims. It has been also observed that in a certain number of cases the cold air entering the lungs produced excruciating pain and sudden arrest of respiration. In some cases there is a state of delirium, with a tendency to suicide. The degree of cold which is apt to cause death is difficult to determine, because there is a considerable difference in resistance in various individ- uals. A man in perfect health is capable of tolerating a very low tempera- ture which an individual in a state of fatigue or exhaustion is unable to resist. In Tagetthoff's "Le tour du monde, 1896," we see that the crew of the ship lived 812 days in a temperature alternating between 40° and 50° below zero. Other travelers reported similar facts. Adults are able to stand cold provided they are not under the influence of alcohol, because alcohol causes a dilatation of the capillaries and thus facilitates the deleteri- ous effect of cold. Children are less apt to resist low temperature than adults, because they produce less heat. Excessive mental and physical work and inanition are also causes of death from cold. It is interesting to note that insane individuals possess remarkable resistance power; they never complain of cold. At autopsy the muscular tissue is found red; the blood is dark; the heart and bloodvessels are filled with blood; ecchymoses are found on the pleura; the lungs are either ansemic or congested. The brain is either ansemic or congested. Wichniewski^ was the first to observe small hemorrhages in the mucous membrane of the stomach. Since then this sign has been considered pathognomonic. Schrimpton observed an in- flammation of the gastro-intestinal tract in soldiers who died from cold during campaigns. The mechanism of death is as yet not satisfactorily explained. Ac- cording to Magendie, there is a contraction of the peripheral capillaries, with this result, that there is an increase of intravascular tension; con- gestion of lungs and brain follows. Pouchet thinks that the blood becomes frozen and stagnant in the peripheral bloodvessels, and this leads to embolism in central bloodvessels. According to Horwatt, weaknesses of the muscular system and of the heart are the main factors in the causation of death. ^Mess. de Vhyg. publ. et med., leg. 1895. PART III. DISEASES DUE TO CHEMICAL AGENTS. By DAVID L. EDSALL, M.D. As is indicated in the title, the following discussions will be devoted solely to the diseases produced by certain important chemical substances. Acute poisonings, belonging exclusively to special works dealing with toxicology, will not be touched upon except in so far as they produce peculiar disease-pictures (such as that in acute phosphorus poisoning), or are of immediate importance in relation to subsequent symptoms. Many inorganic chemical substances which have been accused of causing disease, but apparently do not produce any definite symptoms, have been excluded; while zinc and copper, for example, concerning which there is much difference of opinion, have been briefly mentioned. Unfortunately, in America the study of dangerous industries must as yet be carried out almost solely through individual effort. The states have only general regulations governing their industries, except in so far as they involve danger of accident or are likely to become public nui- sances, specific regulations protecting the workmen from the dangers peculiar to special trades being almost entirely wanting. Governmental study of the influence of trade upon health has been extremely frag- mentary, and, from a scientific standpoint, usually extremely casual, so far as the writer has determined by somewhat diligent inquiry among the federal and State labor bureaus and the health boards, though Massachusetts is now undertaking an investigation of this sort that bids fair to be of some breadth. Extensive governmental study of the ques- tion, with a view to exercising reasonable control, is very much to be desired in this country, because there are special circumstances which render some European statistics and laws of doubtful applicability here. Among these circumstances are concentration of capital and ownership, the very general use of mechanical apparatus in place of men, peculiarities of the purchasing public, and of the American as compared with the European workman. All these have an influence upon occupation- diseases, and in some instances this is extremely marked. 83 CHAPTER V. CHRONIC LEAD POISONING. In clinical and economical importance, as well as in historical interest, chronic satnrnism largely overshadows all other chronic intoxications except that dne to alcohol. Historical. — Evidence that lead poisoning was known appears even in the works of some of the earlier Greek, Roman, and Arabian authors. Their earliest observations relate largely to the medicinal use of lead, accidental and industrial chronic ]:)oisoning having been apparently but indefinitely recognized or studied at that time. Ramazzani makes an attempt to demonstrate that Hippocrates had a fairly clear idea of the occupational dangers to workers in metals, but the original scarcely indicates this. Ramazzani seems somewhat over-enthusiastic also in his suggestion that the early death of Raphael was largely due to the use of metallic pigments. Tanquerel states, however, that Nicander knew that lead may cause colic and paralysis, and that Dioscorides saw the dangers to workers in lead and some of the clinical results, and even described certain hygienic measvires to prevent them. Galen and some other lay and medical writers of the same general period recognized the dangers from drinking water conducted through lead pipes. The additions to the subject then and later were but fragmentary, however, up to the time of Avicenna, who gave a clear description of lead colic. After this, little that was new was added during the middle ages; but Citois, in 1616, though he failed to recognize the cause, aroused widespread interest in epidemic colic through his description of the conditions resulting from wine drinking by the people about Poitou. The name colica pidonum was derived from this source, and was soon applied to the colic of paint- ers and of others who worked in lead, since this presented symptoms identical with those seen in Poitou colic. Evidence that the colic due to wine was lead colic was furnished by Wepfer, in 1671; and Sir George Baker demonstrated the same thing a century later in regard to the Devon- shire epidemics, which were ascribed to cider. That the danger from this source was recognized much earlier than this is shown by the fact that imperial ordinances were issued in Europe forbidding the use of lead in wine even as early as the first half of the fifteenth century. After Stockhausen showed the frequency of lead colic in the lead miners at Goslar, in 1656, and its dependence upon their occupation, lead poisoning was frequently discussed by medical writers of the seventeenth and eighteenth centuries, one point of some interest being that de Haen appears to have described saturnine gout, though our clinical knowledge of this condition is, of course, essentially due to the initiative of Garrod. Among later writers, two stand out with especial prominence, one of them being supreme. Tanquereldes Planches, in 1838, published the result of a ten 84 CHRONIC LEAD POISONING 85 years' study, including 1,217 cases, which is by far th(! most profound and important work ever devoted to the subject. His countryman, Duchenne, first studied thoroughly by modern methods the nervous disorders pro- produced by lead. From the economist's standpoint it is noteworthy that no chemical so readily capable, in its ordinary uses, of causing chronic poisoning, is handled by such large numbers of persons, and none is employed for such manifold and important purposes. Layet^ made a list of 111 occu- pations in which industrial lead poisoning may more or less readily occur, and my reading and clinical experience have added a consider- able number of others in which poisoning has actually been observed. The influence that may be exerted upon the productiveness of persons engaged in some of these occupations is illustrated by the statement of Kaup,^ that the statistics of the sick benefit societies of Vienna show that among the printers and type founders the cases of definite lead poisoning throughout a period of ten years numbered more than the cases of tuberculosis; and, besides many disturbances of health that were essentially due to lead were probably grouped under other headings. Yet these persons exhibit tuberculosis more frequently than the general populace. The printers, painters, potters, and earthenware makers, in and about Vienna, numbering in all about 44,380, furnish yearly at least 1,563 cases of lead poisoning, with 43,045 sick days from this cause alone; and in the whole of Austria there were in this small group of workers about double this number of lead poisonings yearly, with the result that these persons were pure consumers instead of producers for from 85,000 to 90,000 days yearly. These figures are worse than those from some other sources, and the conditions in Austria are undoubt- edly bad as compared with those in a number of other countries ; but these statistics are given because the manner in which they were gathered is, on the other hand, exceptionally satisfactory for this purpose, and, while they would be somewhat misleading if applied to the world at large, they indicate conditions that may actually exist in other countries where occupations are not specifically controlled by law. They serve to demon- strate the importance that these and some other occupations may have for the economist, and for the clinician as w^ell. The clinical interest in the subject is even wider and more complex than the economic, for many of these industries furnish products that occasionally cause poisoning in those who use them, as w^ell as in those who make them; and lead is, furthermore, used in many other ways that involve little or no risk to the producer but occasionally endanger the consuming public. Accidental lead poisoning is much less important than industrial, and is less common now than it was a decade or two ago; but its sources are almost innumerable, some of them being evident, some most unexpected, and not a few dependent upon the use of lead in preparations which are of secret nature and therefore more dangerous because the risk from them is often discovered only through the occurrence of poisoning. The clinical importance of the subject and its complexity are also very largely increased by the fact that saturnism at times appears in ^Poisons Industrielles. ^ Gesundheitsgefdhrliche Industrien, etc., 1903; edited by Bauer; pub. by Fischer, Jena. 86 DISEASES DUE TO CHEMICAL AGENTS most peculiar clinical guises, and the nature of the condition is extremely likely to be overlooked, particularly if a source of intoxication is not readily suggested by the history. Etiology — Race. — Racial susceptibility is not usually recognized, but Mr. J. T. Monell, of Flat River, Missouri, whose experience as an engi- neer in lead mines is probably unexcelled, and who has observed lead poisoning accurately, states that he is convinced that negroes have an undoubted tendency to lead convulsions; a statement which is very sug- gestive in regard to the general question of race, and which agrees with the general neurotic history of the negro. Investigation of this point in the records in some of the Philadelphia hospitals shows extremely few cases in negroes, since very few are employed here in occupations that cause exposure to lead. Of the 6 cases of which records were found, 3 were ence])halopathies. A point that is not wholly pertinent under this heading, but that is of importance, is that, in this country, a very abnormal jiercentage of cases occurs in foreigners, which may be chiefly attributed to their exposing themselves unduly, owing to imperfect understanding of the English language and to their personal habits. It is of interest to note that some of the lower forms of life seem to be more or less immune to the action of lead, and that the higher types of animals also differ greatly in their susceptibility. In the latter, it is prob- ably largely a question of the facility with which they make soluble, and absorb, the more insoluble forms of lead. For example, Mr. Monell states that he has observed that dogs and cats live but a short time about the mine where he is at present, while the cows in the neighborhood come regularly to drink the turbid water below the place where the ore is washed, and, although the sediment from this water contains as much as 3 per cent, of lead sulphide, the cows show no alterations of health. Similar observations have been made before. The explanation probably is that herbivora have a relatively small amount of hydrochloric acid in their stomach contents, while carnivora have a relatively large amount; the latter, therefore, can get much larger amounts of insoluble lead salts into solution as chloride. Heredity. — Fairly good support for the reasonable proposition that there is a family tendency to lead poisoning is given by various observa- tions, such as that of Oliver, in which a father and four sons had fatal saturnism. Though habits and environment may often have had an im- portant influence in such instances, the latter factors are probably bet- ter excluded in the reports of intense involvement of certain families in some water epidemics. Anker alone has described a case of direct heredity producing lead paralysis; but this case may be excluded, as it developed only when the child was several years old, and the father, not the mother, had plumbism. The observations of Porak and Oliver that foetuses of animals poisoned with lead have the metal in their tissues, and particularly the careful study of Legrand and Winter, which showed relatively large amounts in the organs of a premature sickly infant that died a few days after birth, and that was born of a mother chronically intoxicated with lead, indicate strongly that the frail infants of lead- poisoned mothers, that are so likely to die soon and usually of convulsions, have often acquired saturnism directly from the mother. CHRONIC LEAD POISONING 87 Age. — The argument of Russell for the greater predisposition of those past middle-life is not wholly convincing; but that of Geo. PI. Wood/ is. It is generally agreed that children, when employed in trades that expose to lead, are especially likely to suffer, though this may be partly due to greater carelessness, and partly a question of relative dosage; a child weighing fifty pounds would be more likely to suffer, if equally exposed, than an adult weighing three times as much. Brown, Putnam, Sinkler and others consider, indeed, that children have a relative immu- nity, their most eflfective argument being that in the epidemic in the family of Louis Philippe, at Claremont and in Brown's water epidemic at Tredegar, children were largely spared. Equally impressive testimony for the contrary view is found in the occasional observation of the poisoning of a number of children in a family from causes that affected the adults but little, if at all, such as Baines' fatal cases due to burning staves from barrels that had contained white lead — though here again relative dosage may play a part. But most important indications of a special suscepti- bility of children are seen in the recent reports of Turner and Gibson^ of wholesale poisoning in the Queensland children. A definite answer to the question whether there is a special susceptibility in childhood is, however, of interest, but not of great practical importance; for the essential facts are, that children are less frequently exposed to accidental poisoning, and far less commonly to industrial poisoning; but when exposed they often suffer. Sex. — Oliver^ particularly insists that women show a strong suscepti- bility to lead poisoning, and many authors agree with him. It is unques- tionable that, if equally taxed physically and equally exposed to lead, women suffer more than men; but there is no satisfactory evidence that they exhibit any special susceptibility that is dependent upon sex as against general physical resistance. Lead poisoning in women is of rela- tively little consequence in this country; in the past five years ninety-eight industrial cases in men have been admitted to the wards of the Episcopal Hospital, Philadelphia, while there have been no industrial cases in women. This is sufficient evidence of the recognized fact that women are but little exposed to industrial lead poisoning in this country, for this hospital draws from a large number of such industries. In a few occupations, such as decorating pottery, women are freely employed here, and are then much exposed unless carefully protected. Period of the Year. — Both industrial and accidental poisonings are in- fluenced by this factor. It is generally recognized that workers in lead suffer more frequently during hot months, possibly because they take in more fluid and thus wash down more lead into their stomachs, (increase in the use of alcoholic beverages perhaps also playing a part) ; probably, also, because the more actively functionating skin absorbs lead with rela- tive readiness. The especial frequency during the summer and autumn of accidental cases due to drinking-water has been repeatedly noted, particularly in the more recent English epidemics, and has been shown by the extensive work of Power and Houghton* to be apparently due to ^ Gesundheitsgefdhrliche Industrien. ' Australasian Medical Gazette, 1897, 1899, 1904. ^ Dangerous Trades. * Reports of the Medical Officer of the Local Government Board of Great Britain; for 1895, 1900-01, and 1902-03; Supplements. 88 DISEASES DUE TO CHEMICAL AGEXTS the tendency of waters coming from peaty gathering grouncLs to be especially acid at these periods of the year. The acidity seems to be due chiefly to organic acids produced by bacterial decomposition of vegetable matter in the soil. Previous Diseases and Previous Attacks of Saturnism. — Any preexist- ing disease that reduces ihv resistance, j)erlia])s chronic renal trouble especially, increases the liability to attack. The tendency to further at- tacks, after once suffering from saturnism, is very striking. This is usually due to further exposure, but Bernhard especially has dwelt upon the fact that characteristic sym])toms may appear without any renewal of exposure, one case having shown a new appearance of paralysis twenty years after exposure had ceased. In the last-mentioned instance there must be doubt whether the later attack was due to the renewed pres- ence of circulating lead; but in some less-protracted cases this was almost certainly the cause. Such instances are apparently due to the esca])e into the circulation of previously insoluble deposits of lead. Kaufi'man con- siders that deprivation of food is often responsible for this, through break- ing down of tissue in the process of emaciation and the consequent setting free of tissue combinations of lead; but it is quite as likely that this is due to reduction of general resistance. Habits. — Alcoholism is unquestionably very important in increasing the liability to saturnism, and alcoholic excess frequently determines the actual onset of an attack, particularly of encephalopathy. Maximilian Sternberg's theoretical views to the contrary are opposed to an almost unanimous clinical opinion, and to the experiments of Combemale, Fran- cois, and Oliver. Sexual excesses are especially insisted upon by Oliver as a predisposing factor, women of loose life suffering particularly. All other depressing excesses, lack of exercise, and unhygienic habits, strongly favor poisoning; but the most important factor of all in a vast proportion of industrial cases is carelessness as to cleanliness. In most industrial poisonings, and therefore in the majority of all instances, the lead is actually ingested as a direct result of eating, drinking, using tobacco, and the like, without properly cleansing the hands, and often in k'ad-laden rooms; or lead is taken in through skin absorption, largely as a result of lack of cleanliness of the clothes or person. There is a tradition among some workmen that tobacco chewing is a prophylactic, a mistaken idea in general, though it might possibly act occasionally as a crude but un- hygienic preventive if accompanied by industrious spitting. Occupation. — This is overwhelmingly more important than any other factor and the occupations in which lead poisoning may occur are mani- fold. Some are naturally much more dangerous than others, the worst being those in which lead is freely handled and in which the exposure is most continuous, and particularly those in which there is much lead dust. Bauer mentions the following as the most dangerous: lead mining and smelting; zinc smelting; working in white lead and lead colors; making lead pipes and various other lead objects; making pottery and earthen- ware; t}'pe setting and t\^e making; working in electric-storage-battery factories; file making; diamond cutting, and polishing gems and semi- precious stones ; weaving, especially Jacquard weaving; making tinware; and installing gas and water pipes. Of these, file making and Jacquard weaving may be practically excluded in this country, because of improved CHRONIC LEAD POmONING 89 methods; type setting seems certainly to ])ro(luce saturnism only rarely here, because of improvements in the type and mechanical methods liave largely supplanted handwork; and apparently tinsmithing is not particu- larly dangerous at present, owing to improvements in solder and in general hygienic conditions. Installing gas and water pipes is certainly not a com- mon cause, but it may evidently be more dangerous if in large operations men are exposed more or less continuously to the dangerous parts of the work, for an epidemic occurred recently in Vienna in the men who installed the pipes for the new water works (Kaup). Diamond cutters, who have their diamond chips set in lead staffs, are said by Norden, of Amsterdam, to show saturnism in nearly every instance, if they have been long at this work; but Pel, who also is in the centre of this industry, says that plumbism is uncommon among them. In this country, diamond cut- ting, which is confined almost entirely to New York City, Brooklyn, Cin- cinnati, and Boston, has aroused no interest in relation to lead poisoning; and lapidaries here, as well as others who once used lead wheels in grinding (cutlers, razor-grinders, etc.), appear to be now very little exposed to lead, chiefly because of the increasing substitution of carborundum wheels. In the whole country, diamond cutters and lapidaries together number, at any rate, only a few hundreds. Razor grinders and cutlers are said to have still a somewdiat dangerous custom of rubbing lead on the surfaces of their wheels. The other occupations mentioned by Bauer are all dangerous here. Poisoning in miners occurs principally in carbonate mines, and not in those in which chiefly the sulphide is present, a fact that is usually considered to be due to the insolubility of the sulphide. Mr. Monell, however, considers this to be at least partly due to the fact that carbonate mines are likely to be dry, and therefore more dust is produced in them, while sulphide mines are often wet; and the water in the latter usually contains sulphuric acid, which prevents formation of the carbon- ate from the sulphide. A process recently introduced into several places in this country, of separating the lead in the comminuted ore by means of a blast of air, in order to overcome difficulties previously met in washing some ores, seems likely to be very productive of plumbism through the dust created. Smelting ores containing lead is dangerous, particularly when the ventilating apparatus is not excellent. There is doubt whether this is due purely to inhaling or swallowing solid particles, or partly to inhaling lead vapor; but it is extremely probable that the latter is of little or no consequence, for (Leclerc de Pulligny) at the volatilizing temper- ature of lead, gases are irrespirable; and Lodin also found that at temper- atures between 250° and 300° C, no lead was volatiUzed, although this is far above its melting point. Nevertheless, the heat produced in smelting undoubtedly adds to the danger by increasing the motion of the atmos- phere and hence the intake of lead dust. Of all occupations the manufacture of white lead and of lead colors furnishes the greatest proportion of cases ; though electric storage battery makers, and, in potteries, those engaged in dipping the ware into the glaze and handling it immediately afterward, in spraying decorative glazes, and in dusting on pigment in the decalcomania process, are in practically as much danger as lead workers, unless cleanliness is insisted upon and hygienic improvements such as exhaust fans, proper fritting of the glaze, etc., are used. The possible dangers in white lead works are sufficiently 90 DISEASES DUE TO CHEMICAL AGENTS shown without further discussion, by Kaup's figures for the Blaiberg Leatlworkers' Union in Klagenfurt. In 1894, the 45 members showed 61 attacks of lead poisoning (135.6 per 100), and the average per man was 46.7 sick-days in the year. Since then the conditions have fluctuated and in general have im])roved, but the attacks in a year have never fallen below 56.4 per 100 men. In Herbert's works, in the same town, the attacks each year, per 100 workers, have ranged from 13.2 to 24.6. The influence that has a])parently been exerted by careful regulation of this industry in France is seen in the statement of Lcclerc de Pulligny that although Paris and Lille are the centres for the production of white lead in France, the cases of lead poisoning in the hospitals of Paris among those employed in this occupation numbered only 13 in two years. Electric storage battery factories, though not numerous, are very danger- ous, unless they are well conducted. At the Episcopal Hospital in Phila- delphia there were 23 cases in the wards in a little over two years from one factory, and many others in the out-patient department; since this time they have been going chiefly to a new hospital nearer by. The "lead burning" in this industry has an especially evil name among the workmen; but, as already noted, it is not probable that lead vapors are respired, and most of the patients had done no lead burning themselves. A large proportion of them, as is so commonly the case in any industrial lead poisoning, were unskilled laborers. Most of the trouble could be overcome by exhaust fans, hoods, and scrupulous cleanliness of the rooms and the men. Concerning potteries, Prof. Edward Orton, Jr., of Colum- bus, Ohio, who has been the pioneer in America in putting the teaching of ceramics on a broad basis and who has extensive knowledge of the conditions throughout the country, states that there has been much improvement, particularly in the use of exhaust fans, etc. ; but proper frit- ting and some other important measures are still little used. The dusting and spraying processes are, unless controlled, exceedingly dan- gerous, and in one pottery it is customary to employ frequently in this work persons with tuberculosis, carcinoma, or other diseases, because none who hoped to live would accept the risk, even at high wages. The measures that are frequently used now to protect these persons are not effectual with the dippers and their helpers, who have their hands almost constantly covered with lead glaze. Proper fritting of the glaze is, however, an almost complete preventive. Painters are common sufferers, and usually in inverse proportion to their cleanliness, intelligence, and skill. For example, a large proportion of those affected had been merely acting as " helpers," while out of their usual work, and were not painters by trade. A considerable number of the skilled artisans, however, always suffer; burning off paint, through the dust produced, polishing painted surfaces, particularly when this is done by hand, and to some extent perhaps inhalation of lead laden tur- pentine vapor in interior painting, all make them more or less unavoid- ably liable to intoxication, though, as is always the case, lack of proper cleanliness is the chief factor. The difficulties in controlling poisoning in painters have led to the passing of laws in France and Belgium forbidding the use of lead paints in public buildings, and the new French law for- bidding the use of lead paints in any buildings is, as stated in a letter from the French Bureau of Labor, likely to be in force soon, as at the CHRONIC LEAD POISONING 91 time of writing it was before the Senate, having passed the Chamber of Deputies. Among others in some danger are the makers of rubber goods, partic- ularly the heavier kinds, and of glazed and enameled metal ware; gla- ziers, ship builders, sailors, laborers in structural iron works (handling freshly painted iron), Bessemer steel workers (Ormerod), workers in brass foundries and occasionally in other foundries, makers of the mod- ern "secession" bric-a-brac, etc.; lace and passementerie makers, and workers in silk mills (when the silks are weighted with lead).^ The great number of textile workers makes the determination of the conditions ex- isting in their occupations of extreme importance. Poisoning among them from lead dyes was once rather common; trades people and trade journals tell me, however, that lead chromate is still used a little, but this is now of insignificant importance; a statement that is in consonance with the known general use of aniline dyes and also with the experi- ence of the Episcopal Hospital, in Philadelphia, where in the midst of vast textile industries we have had no industrial cases in women in the past five years, and where among the ninety-eight industrial cases in the men's ward in this time there was but a single weaver, and this man was probably poisoned from another source. In any obscure case the details of the patient's occupation should be investigated most minutely, for occupational sources of lead poisoning are multitudinous and often utterly unexpected. Accidental Poisoning. — Detailed investigation of many points is often necessary in this instance, also, to determine the source and do away with it. Water is, of course, the most common source, though its frequency has been distinctly lessened by the considerable reduction in the use of lead pipes for public and particularly for private supplies. That lead service pipes are still important in towns is evident, however, for causal conditions in most places have not greatly changed since the epidemic in Sheffield, England, a decade and a half ago, in which six physicians alone saw in six months one hundred and twenty-nine cases; and town epidemics have, in fact, been repeatedly discovered here and in Europe since then, as have house epidemics from private water supplies. Lead tanks for domestic water supplies have gradually disappeared in most places, on land as well as on ship-board, since study of the colique seche of the French navy, and other observations, showed their danger; but that tanks containing lead still have opportunity to do extensive harm in some regions is shown by the reports concerning the Queensland children. Drinking-water becomes poisoned in a number of ways. The carbonic acid in rain- or spring-water may be the cause of poisoning, especially when new lead pipes are in use, soluble acid carbonate being formed; a deposit of relatively insoluble basic carbonate is gradually formed on old pipes, and acts as a partial but not absolute protective. Power and Houghton emphasize two especial causes, one of them a direct oxidizing or "erosive" action due to oxygen in solution in the water; the other the formation of soluble salts of nitric, nitrous, or organic acids ; and of these, they consider the latter to be of much the greatest importance. Benjamin Franklin referred to the essential points of these latter obser- ^For recent conditions in Austria concerning this point see Kaup, loc. cit. It has not been well studied recently elsewhere. 92 DISEASES DUE TO CHEMICAL AGENTS vations in 17SG in a letter to Benjamin \'aughan, in which he speaks of a family that had for several years drunk with impunity water col- lected from a. leaden roof, until young trees grew^ up and their falling leaves were deposited on the roof; these then decomposed and "lent to the water its baneful qualities and ])articles" and jjroduced a series of cases of poisoning in the family. This occurrence is probably the same as that described by Tronchin and referred to by Oliver. Lockhart Gibson makes an interesting suggestion concerning the possi- ble poisoning of the Queensland children by ingestion of lead from painted wood work of houses; he found a]:)j)reciable quantities of lead in the dust collected in rooms and also on the hands after they had been rubbed over painted surfaces, especially if the hands Avere moist. Sleeping in freshly ])ainted rooms has occasionally been the cause, the lead in this instance being inhaled and apparently carried by the turpentine vapors. Poisoning of women, practically epidemic in its extent, has been observed from washing the clothes of lead workers, a fact that suggests the possi- bility of occasional poisoning in the wives and children of lead workers, from careless habits as to clothing, etc.; the opportunities of the last men- tioned kind are shown by the fact that plumbism is said to have arisen in the dogs of lead workers from sleeping on their masters' coats, and human cases due to sleeping on horsehair sofas have been reported (horsehair as well as bristles of brushes and some other articles being dyed black w'ith lead sulphide, and the manufacture of these articles having occasionally produced industrial poisoning). Glazed earthenware and enameled me- tallic vessels that are used for cooking and preserving foods, have caused poisoning, though this is uncommon now, and extremely so with the better grades. The lead in the solder or tin itself at one time made the eat- ing of canned goods, or the use of tin vessels for acid foods, somewhat dangerous, but the risk is now^ minimal owing to improvements in the tin, the solder, and the methods of sealing; and the actual number of cases know-n to have been poisoned in this way, even in earlier years, is small. Because of its cheapness, lead is, however, sometimes used in sophisticat- ing tin and other drinking vessels, a point of interest chiefly in relation to children. Variot has recently reported saturnism in a child from this cause. The now nearly obsolete custom of making drinking and other vessels of lead caused many cases in earlier times, especially when such vessels were used for cider, wine, or other acid beverages. Children's toys, w^hen made of lead, have caused poisoning in recent times (Variot), and the same may occur w^hen they are colored with lead pigments, though the latter are now probably used but little for this purpose. Candies w^ere at one time colored with lead dyes, but this is rare at present; and the use of lead chromate in baker's products has hardly been heard of since INIar- shall showed how freely it was being practised in Philadelphia, and D. D. Stewart' very acutely demonstrated here a most dangerous epidemic from this cause. Foods in general are so carefully watched now that there is little danger from them directly, though epidemics are still occasionally reported in Europe as a result of "filling" mill-stones with lead, the lead being gradually ground off into the flour. The opportunities for such an occurrence in this country have been greatly reduced by the fact that rol- ^ Medical Xews, December 31, 1887; and Third Annual Report State Board of Health of Pennsylvania. CHRONIC LEAD POISONING 93 ler mills have practically done away with the old fashioned mill-stones, though where the latter are still used, possibilities of lead poisoning exist in this country, for lead is still used in these mill-stones here. Soda water or carbonated water in siphons may cause poisoning, particularly if the tanks, the siphons, etc., contain lead; and Cao has recently found lead in carbonated water in siphons and reported a series of poisonings due to this cause; but, excepting, perhaps, for some old apparatus, there Is little danger from this source in this country, as block tin and zinc have almost completely supplanted lead for this purpose. The siphons tested here were made of tin or zinc. Cosmetics, hair dyes, and false teeth are commonly known to have been sources of poisoning. Medicinal lead poisoning was known to the physicians of the ancients; it is generally thought to be very uncommon now, but Miller^ has recently reported two personal observations and discussed a series collected from the litera- ture, and he thinks that slight or moderate symptoms from this cause are probably not infrequent. The use of diachylon ointment over large ecze- matous surfaces is certainly dangerous, and has caused fatal poisoning in infants (Passler, Hahn); and poisoning from internal use of diachylon as an abortifacient has also been repeatedly observed in recent years in England (Ransom). Infants have also been poisoned by dusting powders containing lead, or by cosmetics or ointments used on the person of the nurse. As in- stances of extremely odd sources of accidental poisoning. Dodge's case in which the patient was ultimately discovered to have taken for a month a dozen No. 7 shot before each meal "to cleanse his blood," and Klister's case of a soldier who was wounded in 1870, developed lead poisoning in 1888, and recovered after the partially dissolved fragments of the ball had been removed by operation, may be mentioned. Several fairly authentic cases that appeared to be due to the same cause, though less protracted in their course, are on record. The duration of exposure before the development of plumbism has naturally varied greatly. This is usually tacitly or openly attributed to variations in individual susceptibility. A certain degree of immunity undoubtedly exists in some persons, others are certainly especially sus- ceptible, and intercurrent factors are known to increase or decrease sus- ceptibility; but it is difficult to establish the importance of immunity in considering industrial cases, because individuals differ so largely in their care in avoiding exposure; and the matter is far from simple in even water epidemics and other accidental poisonings. Accidental or medicinal ingestion of single large doses has repeatedly caused somewhat prolonged poisoning, usually colic; though encephal- opathy has repeatedly, and paralysis has in rare instances, followed a single dose or a few doses. Quensel mentions a case reported by Sommer, in which furor appeared after a few hours' intense industrial exposure ; the reference appears to be incorrect, and the report could not be foimd. Colic and indefinite sjTuptoms of poisoning often occur soon after beginning work in lead. Tanquerel repeatedly saw wrist-drop after a week's ex- posure, and others have had similar experiences. As a rule marked colic does not occur for several weeks or longer, and symptoms of poisoning 1 Therapeutic Gazette, 1904. 94 DISEASES DUE TO CHEMICAL AGENTS may first appear after even many years of exposure. Paralysis is usually rather a late development, eommonly appearing only after preceding cachexia or colic and therefore after prolonged exposure. Encephalop- athy is not infrequently seen within a few weeks or months, but often arises late. Pathology. — The pathology is chiefly not characteristic or obscure; it has not been extensively studied, especially by modern methods. There is usually general emaciation; the teeth and particularly the gums are fre- quently in bad condition, the latter usually loosened and often slightly ulcerated. The blue line is generally found, particularly in the gums of the central and lateral incisors and the canines, and especially on the lower jaw. This line is due (Fagge, Stewart,' Ruge") to deposits of lead sul- phide in the apices of the papilhe, the granules being found partly in the lumen of the capillaries, but more largely in their walls and in the sur- rounding tissues. The lead sulphide is formed from circulating lead- compounds, through the action of the hydrogen sulphide produced by decomposition of small food particles lying between the teeth and under the edges of the gums. Arteriosclerosis is common in the subjects of saturnism. It is doubtful whether lead produces this directly, ex- perimental work on the subject being inconclusive (Jores); Ruge's observation of proliferative changes of the vessels of the gums in the neigh- borhood of the lead sulphide deposits is, however, somewhat suggestive in this connection. Lead appears also occasionally to cause chronic sclerotic endocarditis. Pulmonary tuberculosis is very common in lead- workers, and they may show also the ordinary lesions due to working in a dusty atmosphere if their occupation has exposed them much to dust. Chronic gastro-enteritis is common, but no special changes have been described in the digestive tract except pigmentation of the walls of the intestine with lead sulphide, and degeneration of the cells in the ganglia of the intestine; the latter and degenerative changes in the abdominal sympathetic ganglia supposedly produce the attacks of colic. In ex- perimental cases (Oliver) the intestine is often found in extreme spasm; and this is very probably the mechanism of producing the pain in colic. In his experimental work on animals and in his postmortems, Oliver found, as the earliest lesions, intercellular cirrhosis of the liver and an acute nephritis, with degenerative changes in the epithelium of the con- voluted tubules ; cellular proliferation within the capsules and around the afferent vessels of the glomeruli, and later within the glomeruli them- selves; and, finally, progressive interstitial nephritis. A considerable number of other observers have noted nephritis in the early stages and have produced it experimentally. Oliver believes that these hepatic and renal changes occur regularly in lead poisoning and are the chief lesions due directly to lead; many and perhaps most of the other symptoms he considers the result of secondary metabolic disturbances.. In old cases interstitial nephritis is a very common lesion, often the most important. In a small proportion of cases the lesions of gout are present. The bones have occasionally shown lesions that have a doubtful relation to lead. Bone-marrow changes were found by Cadwalader. There was marked hyperplasia of the marrow, the granular myelocytes were numerous, and * International Clinics, vol. iv, Seventh Series. 'Deutsch. Archiv. f. klin. Med. Bd., Ivii. CHRONIC LEAD POISONING 95 many nucleated red cells often collected into characteristic erythroblastic areas were found. In cases with nervous lesions, the paralyzed muscles are more or less atrophic and show degeneration of the muscle cells and jn-oliferation of the nuclei; Oppenheim has, indeed found marked changes in non-para- lyzed muscles. The peripheral nerves whose territory was involved clini- cally have been many times investigated and always found degenerated, the radial being the most common seat of changes. I'he alterations are usually parenchymatous, rarely involve the connective tissue severely as a result of lead alone, and are situated chiefly in the peripheral portions of the nerves. Gombault has produced these changes experimentally. The nerve-cells of the anterior horns of the spinal cord usually show no note- worthy changes, though in relatively uncommon instances they are de- generated. Madam Dejerine-Klumpke,^ and later Spiller,^ sifted these down to five or six reliable cases, besides Spiller's own case, in which there were marked alterations. Nissl, Schaft'er, Stieglitz, and Rybakoff, produced spinal changes experimentally. Spiller's case, Philippe and Eide's case, and Steiglitz's animals, also showed lesions of the ganglia on the posterior roots. The usual gross cerebral lesions in encephalopathy have been oedema and anaemia, flattening of the convolutions, thickening of the pia, and small hemorrhages. Microscopical studies have been very few. Quensel found marked changes of the cortical cells, and prolifera- tion of the nuclei in the vessel walls and of the glia-cells about the vessels. Similar changes were found by McCarthy^ in dogs, and Spiller also noted in his case proliferation of the endothelial cells on the surface of the pia. Changes have been observed in the cerebrum in cases without enceph- alopathy; and the changes in the nervous system, in human subjects and various species of animals, are not peculiar to lead poisoning. Mode of Entrance and Pathogenesis.— As already stated, the usual channels of entrance are ingestion into the stomach, or inhalation of par- ticles into the respiratory tract, followed by solution and absorption in either of these places. Skin absorption certainly plays some part, though just how- much is uncertain; it is, indeed, uncertain whether any con- siderable part is played by inhalation, for ingestion is undoubtedly the most important method. Inhalation of the actual vapor of lead is, as al- ready explained, a very questionable occurrence. The digestion experi- ments of Oliver, Bedson, and Best, make it appear probable that most of the lead that reaches the tissues is transformed into chloride in the stomach, and absorbed either there or from the upper intestine. Prob- ably a part of it is got into solution in the intestine by means of bile or organic acids. The gastric juice dissolves lead quite freely through the agency of the hydrochloric acid; other elements of the gastric contents play no part, and this action is even much interfered with by the presence of protein, because protein either forms insoluble lead protein com- pounds or saturates the hydrochloric acid, and thus prevents the forma- ^ Des Polynevrites en general et des Paralysies Saturnines en particular, Paris, Balliere et cie, 1889. ^ Contributions from the William Pepper Laboratory of Clinical Medicine, 1903. ^Contributions from the William Pepper Laboratory of Clinical Medicine, 1902. 96 DISEASES DUE TO CHEMICAL AGENTS tion of lead fhloride, a fact of considerable importance in ))rophylaxis, as it shows the rationale of having workers in lead take a full nienl or plenty of milk before beginning their work and at mid-day. The bile dissolves lead freely, and acitl bacterial-decomposition products in the intestines may also dissolve- a considerable (juantity. It seems, indeed, probable that more absorption takes place in the intestine than the authors men- tioned indicate, for the contents of the small intestine are usually acid throughout. Pancreatic digestion does not increase the solution of lead. The form in which lead reaches the circulation and tissues is not known; it is not as all)uminates or pejjtonates, for these are insoluble. Blum, whose original article \\as inaccessible to the author, is referred to by Bauer as having found that a part becomes insoluble basic carbonate upon reaching the blood and tissue-fluids, and is ])reci))itated as such, — whence comes, perhaps, much of the frequent prolonged immunity from symptoms when only small amounts are taken. Blum finds part of it in the blood in a peculiar stable solution that is not precipitated by hydrogen sulphide; this apparently "undergoes a reaction with the tissues" and produces the symptoms of poisoning. Evidences that definite combinations with the tissues occur, he finds in his observation that after poisoning with lead salts that are insoluble in ether, ether- soluble lead compounds may be extracted from the brain. It seems probable that if tissue compounds are formed, they are unions of lead with the lipoid elements of the nervous tissues, both because of the affinity of lead for these, and because this is definitely known to be the case with some other poisons affecting nervous tissues (chloroform, chloral, etc.). Blyth, however, found most of the lead in the brain in an ether-insoluble form, and probably in the protein fraction. Except for the widely quoted but somewhat questionable observations of Maier, that the cerebral cortex has a special affinity for lead, there is no other evi- dence of a direct chemical action of this metal on the tissues. The greatest amount of lead has been found in the liver, by all ob- servers. Considerable quantities are often found in the kidneys; the brain, cord, nerves, muscles, bones, and other tissues contain various amounts. A number of authors list the various organs in order, according to the amount that they usually contain, commonly placing the brain sec- ond to the liver; but such an arrangement is ill-advised, for the order must vary greatly in individual cases. Certainly in many instances the brain contains little or no demonstrable lead, even in encephalopathic cases. In three of these the Avriter found no lead in portions approximating one-third of a hemisphere. The custom of speaking of a special affinity for lead on the part of the nervous system, particularly the peripheral nerves, is based almost entirely on clinical observation and histological alterations, not on facts. The lesions are not necessarily the result of the direct action of lead. The manner in which lead acts is in many points a subject purely of speculation and controversy. Colic seems to be due to spasm of the bowel, dependent most probably, but not certainly, upon changes in the intestinal ganglia. The changes in the muscles, together with the pecul- iar localization of the paralysis and the absence of sensory symptoms, led to the now relinquished hypothesis that the paralysis is due to muscular changes, and also suggested the view, that is still not wholly disproved, CHRONIC LEAD POISONING 97 that it is spinal in origin. Tlie usual absence of spinal lesions led the supporters of the spinal hypothesis to the conjecture (Remak, Ii^rbj that it may result from undemonstrable functional changes in the cord; but most observers and investigators now lean to the view that the peripheral changes are primary, and Remak himself grants that the spinal origin cannot be very firmly maintained. The constancy of peri[)heral changes, and the infrequency of noteworthy changes in the cord, make the periph- eral the more probable theory; but if it is correct, there is as yet no explanation of the almost regular escape of certain muscles from the paralysis. Whether the lead acts directly upon the nerves and other tissues in producing the symptoms, or indirectly through setting up disturbances of metabolism, cannot now be determined. The first view is difficult to disprove and seems rational; but there are certain facts, such as the apparent absence of lead from the brain in some cases of encephalopathy and its presence in other cases, that presented no cerebral symptoms, that make the other view wholly possible. Definite opinions upon this point are at present based on mere speculation. Disturbances of metabolism do occur, though they have not been ex- tensively studied. Clinical observation demonstrates the common ten- dency to tissue breakdown and emaciation; and destructive increase of metabolism has been shown to occur at the time of the attacks. Some changes in the phosphates, kreatinin, hippuric acid, and uric acid, which are of questionable and as yet undetermined value, have been recorded. Most of the observations on urea excretion, upon which some authors lay stress, have been practically valueless; and the effect on uric acid excre- tion is unimportant (Ltithje). A noteworthy fact, and one that may be of much interest in relation to basic degeneration of the red blood cells, is the frequent occurrence of slight grades of haematoporphyrinuria. Lead is excreted chiefly through the kidneys and may be present in the urine long after the exposure has ceased. It is excreted in the bile in large proportions in animals, and some observations (Mann) indicate that it may be partially excreted in the human faeces. A little excretion occurs through the sweat, but this is of slight importance. It has also been found in mother's milk (Bulland), a fact of interest in relation to the infants of lead poisoned women. Lead has been demonstrated in the parotid glands and saliva. The minimum dose capable of producing poisoning when long continued is not clearly determined. Brouardel considered that 1 mg. daily may suffice. Symptoms. — ^The clinical course of plumbism consists, in most instan- ces, of the development of more or less marked but indefinite general symptoms, followed after a variable time, usually at least several weeks often much longer, by the appearance of colic. Less commonly but still frequently, paralysis supervenes; occasionally the graver cerebral mani- festations occur, also usually after previous colic. There is, however, no constancy in the course of the symptoms: violent colic may open the scene soon after exposure begins; paralysis may develop very early; and in rare cases, without preceding noteworthy symptoms, coma, or an out- burst of convulsions or of more or less dangerous delirium, may be the first recognized evidence of poisoning; and occasionally indefinite ill health without distinctive symptoms lasts for years and ultimately causes death. 98 DISEASES DUE TO CHEMICAL AGENTS usually chiefly from chronic renal disease. Cases of the latter form are rare, however, if histories are searchingly taken. Probably a fair number of subjects, get well early without showing characteristic symptoms, be- cause the exposure ceases; lead workers often change their occupation upon the appearance of slight symptoms of ill health. It is not wholly feasible to classify the signs of actual poisoning under the early and the late symptoms, since no symptoms appear at regular times, and no combinations of symptoms are at all constant. It is, never- theless, important to recognize that general symptoms are practically always present. In the earliest stages they are, usually, chiefly the symptoms of ill-defined disturbances of the gastro-intestinal tract, or they belong to the indefinite sort that are likely to be termed neurasthenia, the patient then presenting more or less weakness, restlessness, insomnia, headache, and mental depression. Frequently mild or pronounced pains in the limbs and trunk are noteworthy early features. A little later, usually when more distinctive symptoms have become apparent but sometimes without these, an earthy or sallow pallor, often very striking and not well explained by the moderate grade of anjemia usually present, emacia- tion, and more pronounced weakness appear, producing the so-called lead cachexia. Still later, signs of renal or cardiovascular sclerosis often become conspicuous, if the poisoning has been prolonged and severe; and at times such features develop long after the distinctive evidences of lead poisoning have vanished. Progressive interstitial nephritis is probably the com- monest ultimate cause of death,' though cardiovascular incompetency or the cerebral results of arteriosclerosis are frequent causes. At any time during the periods previously noted, the more distinctive characteristics of lead poisoning — colic, paralysis, or cerebral symptoms, — may appear with the general symptoms. Colic almost always develops, and usually soon after the first signs of ill health. Paralysis, when it occurs, commonly comes on after some cachexia has appeared; that is after poisoning has lasted for a considerable period. Encephalopathies may develop early if the poisoning has been severe, but they likewise may occur later. Two conditions, the blue line on the sums and basic granulation of the erythrocytes, are usually present at all stages of poisoning, and often even when there are no actual symptoms of intoxication. Basic granula- tion (Grawitz, Moritz, Stengel, White and Pepper, Cadwalader) is indeed, so far as is known, constant during the whole time that lead is present in the system, and it appears even when exposure has been extremely brief; White and Pepper ^ found it after four days' industrial exposure, and even twenty-five hours after a single dose of 7J grs. (0.5 gm.) of lead acetate. Neither of these signs alone constitutes absolute evidence of clinical saturn- ism, and basic granulation is found in many other conditions; but both are of extreme importance in suggesting that lead is being absorbed, and are valuable confirmatory facts in the presence of obscure symptoms. The blue line, when characteristic, is certain evidence that lead has been ab- sorbed; while basic granulation is only suggestive, though it is extremely so under circumstances that will be mentioned directly. ' Contributions from the William Pepper Laboratory of Clinical Medicine, CHRONIC LEAD POISONING '99 The blue line, sometimes called Burton's line, is said (Still6) to have been noted by Spence in 1805, but his description does not seem to refer to the lead line, and certainly it was first actually studied clinically by Burton in 1834, and practically at the same time by Tanquerel; Gull, Fagge, Stewart, and Ruge have made important observations since then. Clinically it appears, upon hasty observation, to be an irregularly linear, or broader, dark-blue discoloration of the margin of the gum. Closer inspection shows that it is frequently a line's breadth from the edge of the gum, though if the latter is loosened and overhanging or is atrophy- ing, the line is often on the very edge. It may appear stippled even to the naked eye, and a hand-lens shows that it is made up of fine, nearly round dots, which are sometimes discrete, sometimes closely clumped together. At times it consists of a few isolated dots or of a very slight and ill-defined line, especially if the gums and teeth are in good con- dition. It is not usually continuous from one tooth over the next ; the portion of the gum situated between the teeth shows it most commonly, but little separate arches, or partial arches may form over the bases of the individual teeth. It is especially marked about the incisors and canines, and particularly in the lower jaw. The common statement that it is absent if the teeth have been lost, Stewart considered inac- curate; he repeatedly saw it in such persons when the gums were not atrophied. Stewart also insists that in its slight forms it is nearly always present, even when the gums are in good condition. Blue patches are sometimes seen on the inside of the lips and cheeks, but these appear to be usually due to a different cause; i. e., to deposit of lead sulphide from the buccal cavity, in areas that have been more or less denuded by rubbing against accretions of tartar on the teeth opposite to them. The blue line must be carefully distinguished from deposits on the surface of the gum or on the teeth. This is best done by the aid of a lens, noting the situation beneath the surface and the dotted appearance; also, as sug- gested by Stewart, by pushing a small slip of white paper between the edge of the gum and the teeth, this making the characteristic line more distinct and excluding deposits on the teeth. The similar line produced by silver, though relatively very unusual, may rarely cause confusion; this is less likely with the green line due to copper. If there is uncer- tainty it may be overcome, if desired, by snipping off a small piece of pigmented gum and observing that the pigment turns white (lead sul- phate) in hydrogen peroxide, and grows blue-black again in ammonium sulphide (Grehant, Ruge). The blue line persists throughout exposure, and from three months (Oliver) to a year or more after all symptoms have vanished. Basic granulation of the erythrocytes gives the appearance of a stip- pling, with granules that vary in size from fine points to others as large as eosinophile granules; it is evident only after staining, the granulations taking basic stains. They are seen in many different diseases, but it is of great importance to note that in lead poisoning they are constantly present, are usually seen in many erythrocytes, individual cells often show large numbers of them, and the granules are ordinarily of rather large size. The latter conditions are extremely rare, especially in diseases that are likely to be confused with lead poisoning, provided the ordinary stains (thionin-phenique, hematoxylin-eosin) are used. The objects 100 DISEASES DUE TO CHEMICAL AGENTS brought out (Cadwaluder ') by the use of jiolychroine methylene blue are, in part at least, probably of different nature, and seem to be very commonly observed in large numbers even in normal blood; hence, this stain is not satisfactory for {)urposes of clinical diagnosis, and it is doubt- ful, indeed, whether any methylene blue stains are wholly reliable for this purpose (Stengel, White). Hematoxylin-eosin does not bring them out pro])erly unless the staining is prolonged. They apparently persist throughout the whole course of poisoning, and vanish soon after lead disappears from the system (White and Pepper), though this })oint is one that has not been sufficiently studied. Together with the basic granulation there is usually some anfemia. Oliver states that he often meets with severe grades; but counts rarely show the red cells below two million, and they are below three million in but few cases. There is some reduction of the haemoglobin; usually not severe and rather less than is proportionate to the decrease in red cells. Nucleated red cells are frequently present in small numbers, occasionally in considerable numbers (Cadwalader). Gilbert finds cosinophilia com- mon in the earliest stages; but this has not been confirmed, and Dr. Cad- walader states that in 37 differential counts he never saw the eosinophiles above 4 per cent., rarely as high as 2 per cent.; the leukocytes show, in- deed, no noteworthy changes. On the whole, the blood shows few alterations excepting the basic granulation and some normoblasts; and in this lies an important contrast with pernicious anaemia, in which dis- ease severe basic clegeneration is common. When actual symptoms of poisoning appear they are both general and local. The general symptoms not referable to any special organs, such as the so-called neurasthenic symptoms and the cachexia, have already been noted. Slight fever (99.5° to 100° ) is present in unusual cases, and at times may be somewhat prolonged; this may cause con- fusion in diagnosis. In somewhat greater detail, the most important local clinical effects are as follows: Digestive Tract. — Anorexia, unpleasant and often sweet or metallic taste, furred tongue and offensive breath, are frequent even early, and the latter symptom is often extreme in well-developed poisoning and has been insisted upon as important, though it is probably due to the common bad state of the mouth and to the disordered nutrition, rather than to any direct influence of the lead. Nausea and vomiting are very common (Tan- querel, Stewart); and Oliver has especially noted attacks of epigastric pain which may be violent. Constipation is the rule, and is frequently extremely obstinate, especially when colic has developed; occasionally constipation alternates with diarrhoea, and rarely there is persistent diarrhoea. Sailer has noted the absence of hydrochloric acid from the stomach contents in seventeen out of twenty-one cases; Stengel and the writer had observed the same in a few cases. This might lead to confusion with gastric carcinoma, if gastric symptoms and cachexia were present ; the discussion of Sailer's paper shoAved that this had actually occurred in one of the cases, and the same mistake was several times recorded before examination of gastric contents became a customary method of observa- tion. Among rarer disorders of the digestive tract are salivation, severe ' American Journal of the Medical Sciences, January, 1905. I CHRONIC LEAD POISONING 101 stomatitis, parotitis (which hitter may be due to the lead, but seems cliiefiy dependent upon infections travehng from iU-kcpt mouths), and ulcera- tive colitis. Some authors, on questionable grounds, consider appendi- citis especially common in subjects of [)lumbism. Colic is the symptom of chief importance referable to the digestive tract. It is, however, not due to disturbed digestion, but apparently to spasm of the bowel of nervous origin. In severe accidental poisoning, colic may appear after a single dose, and occasionally in industrial poison- ing within a few days. Usually weeks or months of poisoning and fre- quently similar periods of indefinite ill health precede it. Generally the patient has been constipated beforehand, often severely so, and commonly forebodings of pain have already been felt when the first attack of actual colic comes on. Severe pain then appears, often in the night, in parox- ysms lasting for a few seconds or minutes, in some cases even for hours. The outbreaks of violent pain are separated by intervals which last for similarly variable periods, in which there is comparative com- fort; the abdomen is often tender in the interval, and dull pain frequently persists, and is sometimes nearly continuous, but violent paroxysms of pain do not often continue for many hours without prolonged remission. The severity of the pain varies a good deal ; when it is extremely marked, the patient is in restless agony, or is almost collapsed from suffering, with a weak, small pulse; while in milder cases the pain is extreme but bearable, the pulse small and of high tension, probably from reflex stimulation. The quality of the pain in severe colic seems to be well described by the centuries-old German name, Hiittenkatze, given to it, it is said, by the miners and smelters because they believed the wildcats of the mines were tearing out their entrails. It is usually situated chiefly about the umbilicus, but may be diffused over the abdomen; in rare in- stances it is focalized in such a way as to resemble somewhat closely renal or hepatic colic. The abdominal walls are usually hard and re- tracted during the paroxysm, and pressure upon them ordinarily gives relief, though in a minority of instances these statements may be reversed. Vomiting is common during the paroxysm, and constipation is usually most obstinate until the spasm of the bowel is over; and it is frequently troublesome long after the pain is wholly past. The secretion of urine is much reduced; occasionally, it is said, it may be suspended for many hours. The duration of an attack, with the paroxysms and remissions, is sometimes a few hours only, more commonly several days, frequently ten days or a fortnight. The severity, however, usually decreases continuously after the first day or two of treatment. Recurrences are the rule if expo- sure continues. They may, indeed, occasionally develop long after exposure has ceased. Respiratory Tract. — Aphonia and dyspnoea from laryngeal paralysis are very rare. Asthma is an occasional though uncommon result of the intoxication. Pulmonary tuberculosis is unduly common in subjects of plumbism, partly as a result of inhalation of irritants, partly from re- duced general resistance. Cardiovascular System. — Arteriosclerosis is common in lead workers even at an early age, and, though the point is disputed, it seems to be a result of plumbism. A considerable number of those poisoned for a long time ultimately exhibit the symptoms of cardiovascular incompe- 102 DISEASES DUE TO CHEMICAL AGENTS tencv, and die from circulatory failure, or occasionally from cerebral accidents. Genito-urinaxy System. — A little albumin, and some casts, are not uncommon in the early stages, especially if the dosage has been large. They are frecjuently present during an attack of colic. After prolonged poisoning, progressive interstitial nej)hritis often becomes the most im- portant feature of the case, and it is probably the commonest late cause of death. Suppression of urine, spasm of the bladder and urethra, and sometimes retention of urine, may be seen with colic. Retention, sometimes with overflow, also incontinence, have several times been observed as persistent symptoms in cases with pronounced nervous lesions of spinal type (J. J. Putnam). Uratic urethritis in a case of saturnine gout, neuralgia of the testicle, epididymitis, and orchitis are rare occurrences, and have a somewhat doubtful relation to lead. The influence upon the generative organs is seen chiefly in woman. Menstruation becomes disturbed, being usually excessive and irregular; and pregnant women with saturnism are extremely likely to abort or to have premature labors. In the latter the child is often still-born, or it is very frail and usually soon dies. After exposure has ceased, women often pass through repeated normal labors. These facts are of much economic importance in Europe, but are scarcely so in America, where exposure to poisoning is comparatively very rare in Avomen. Joints and Bones. — Gout occasionally occurs, though the actual rela- tionship to plumbism has been the subject of warm discussion, many maintaining that its occurrence is merely coincidental, many holding it to be causative. The literature seems to indicate that those who see little gout find it uncommon in lead workers; while those who see much gout see it with relative frequency in lead workers. The positive evidence out- weighs the negative, but it seems clear that other predisposing causes are necessary in addition to plumbism. Saturnine gout is apparently some- what peculiar in that it involves joints ordinarily spared; the rapidity, too, with which many joints are attacked is often striking. Gubler's tumor, so-called, is occasionally seen over the back of the wrist or of the metacarpal bones of the hand. It is an oviod mass due to swelling of the sheath of the tendons, or sometimes of the synovial sac of the wrist- joint, and occurs chiefly in wrist-drop; slight subluxation often exagger- ates the so-called tumor. Bone lesions have been described but have a doubtful relation to lead. Nervous System. — Moderate pain, often indefinitely located, is com- mon in both the extremities and the trunk, especially in early stages. Whether this is due merely to impaired general nutrition, or to essential nerve involvement, is uncertain; but the latter is the probable cause of the actual neuralgic pains, which are not uncommon, and also of the joint pains. These pains in the joints appear in brief or more prolonged paroxysms, which may be very severe, and may last, with intermissions of varying lengths, for days; or they may cjuickly disappear. They are usually most marked in the knees or ankles. True joint-pains do not seem very common; Tanquerel and others, who have found "arthralgia" common, include under this term all pains in the extremities and even in the trunk. The muscles sometimes ache severely, and may be tender. CHRONIC LEAD POISONING 103 especially those that are soon to become paralyzed. Other sensory symp- toms are usually slight. There may be partesthesias, and general sensa- tion may be reduced or lost over the back of the forearm, less commonly over the front of the leg or other localized areas. Hyperalgesia is occa- sionally noted, and in rare instances there is much tenderness over the nerve trunks. Sometimes actual hysterical symptoms are present, with hemiansesthesia or other characteristic stigmatic local areas of anaesthesia. Cerebral accidents (hemorrhage, etc.) if they occur, may produce hemi- ansesthesia. With the diffuse pains, or sometimes in association with colic, and oc- casionally without other symptoms, certain muscles, particularly those of the calves, may go into mild or severe cramp, which may be very painful. This is not very common in adults, but seems to be so in children (Tur- ner). Gowers and Haenel have observed recurring spasm that closely re- sembled tetany, and Gowers has seen flexor spasm precede extensor paralysis. Fibrillary twitching of the affected muscles is common after paralysis has developed, and in slight and localized form it is not rare earlier. Buber has described a case in which myokymia of wide distri- bution was very prominent. The nervous symptoms so far mentioned, except indefinitely localized pains, are mostly rare or inconspicuous. Indefinite pain is frequent, but more common and more important than any other nervous symptom mentioned is tremor. This is frequently noted, especially in old cases. It affects chiefly the hands, and is usually of slight amplitude and not striking, though it is sometimes coarse and may resemble the tremor of paralysis agitans. It usually increases upon any emotional excitement, and, more markedly, upon effort. Its chief diagnostic importance is in rendering confusion with mercurial poisoning occasionally possible, if paralytic symptoms are absent. Stewart has seen actual paralysis agitans follow lead poisoning, and he also observed curious paroxysmal attacks of severe generalized tremor which he believed were not hysterical. Most important of all the nervous symptoms, however, and in its ordi- nary form by all means the most characteristic, is paralysis ; and with its usual distribution is of itself almost distinctive of lead poisoning. When typical, it produces so-called "wrist-drop," which is bilateral. There is at first an increasing degree of weakness in the extension of the fingers at the metacarpo-phalangeal joint (paralysis of the extensor communis digi- torum), followed by weakness and often complete paralysis of the ex- tensors of the wrist. Palsy often begins in one hand, the other following within a fortnight or less; frequently the hand first involved has been subjected to special strain, or has been especially exposed locally to lead (in lead workers, pottery dippers, etc.), the latter point constituting one of the chief arguments in the questionable claim that lead exerts local effects through the skin. Frequently, in the beginning of the paralysis or later, portions of affected muscles show special involvement; for example, extension of the middle and ring fingers is often noted first, and may long remain most marked. The paralysis is usually subacute in its onset, reaching a marked degree within from a few days to a fortnight; occa- sionally it progresses very slowly. When well developed, it produces the well-known "wrist-drop," the hand being in flexion at the wrist from paralysis of the extensors, and the fingers moderately flexed owing to 104 DISEASES DUE TO CHEMICAL AGENTS paralysis of their long extensor. At first, the distal phalanges can be extended if the proximal phahmges "be first passively extended; for the interossei, the proper extensors of the distal joints, arc then uninvolved; the thumb muscles also usually functionate at first. Later, the in- terossei and the muscles of the thumb are affected; distal extension of the fingers and extension and adduction of the thumb are imperfectly per- formed, or impossible. The long abductor of the thumb often becomes in- volved late, but in early stages is usuallyspared; and the supinator longus is almost never included in the common type of ])aralysis, a point that is of great importance. The distinctive characteristics of this paralysis are, that it is almost always bilateral, is purely extensor, spares tiie long supinator and usually tlie long abductor of the thumb, and there are rarely any sensory symptoms, except, perhaps, limited cutaneous anaes- thesia over the backs of the forearms. Atrophy begins soon in the affected muscles, especially those of the back of the forearm; marked reduction or loss of faradic response appears; and the reactions of degen- eration develop. As a rule, some of the muscles other than those distinctly paralyzed are weak, and may even show degeneration reactions. The paralysis ordinarily soon reaches the limit of its intensity and extent. Fresh cases quickly improve within a few weeks after proper treatment is started, and generally recover almost completely within a few months if they are not extremely severe. In older cases recovery is slow, and dependent upon the grade of the palsy and its duration ; if long neglected and severe, compleie recovery is not common, and occasionally very little improvement occurs. Gowers makes two classes of paralysis: in the first, which is the usual one and of good prognosis, the palsy is distinctly primary, atrophy and degeneration reactions follow, and the progress toward more or less complete paralysis, and afterward toward recovery, is rapid; in the second class, which is uncommon, atrophy occurs from the beginning and goes hand in hand with the palsy, faradic and gal- vanic response decrease together, pari jjaasu with the atrophy and the palsy, increase of the palsy is slower, and the prognosis for its recovery is poor. Forms of paralysis other than characteristic wrist-drop may occur. The Aran-Duchenne type is occasionally seen; in it the small muscles of the hand, the interossei, and the thenar and the hypothenar early become atrophied and more or less paralyzed and these changes ])roduce the "simian" hand. This is not a clearly individualized type in lead poison- ing, being usually associated with the previously described form, and simply an exaggeration of some features that are generally present ^yhen wrist-drcp is at all severe. The Aran-Duchenne form has been particu- larly noted in persons whose occupation, such as file making, causes a special strain on the small muscles of the hand. The upper arm or Duchenne-Erb type, in which the deltoid, often the biceps and the bra- «hialis anticus, and sometimes the supra- and infraspinati, are involved, occurs occasionally. In it the arms hang by the side, rotated somewhat outward and incapable of abduction, and in severe cases incapable of flexion at the elbow. This form has repeatedly been seen as a separate condition, though it is usually associated with paralysis of the extensors of the fingers and wrist. Contrary to the conditions in the ordinary fore- arm type, the supinator longus is likely to be involved in this variety. Of CHRONIC LEAD POISONING 105 this group of muscles, the deltoid is especially liable to paralysis, and it has repeatedly been the sole muscle palsied; sometimes it has been para- lyzed on one side only. The lower limbs are infrequently affected in adults, and, when they are, the arms usually suffer also; the conditions in children differ mark- edly in this point, as will be noted later. In the legs, the peronei and the extensor of the toes are the tyj)ical seat of paralysis, the tibialis anticus almost always, like the su])inator longus in the arm, being spared. In rare instances in adults, more commonly in children, the tibialis anticus is paralyzed, while the muscles usually affected escape. The disease in the legs, as in the arms, is practically always bilateral. The small muscles of the feet occasionally show special involvement; Koster has described an isolated case in which they were affected severely without disease of the leg muscles, and this produced a condition analogous to the "ape- hand" in typical Aran-Duchenne paralysis of the hands. Rarely the disease is situated chiefly in the muscles of the thigh. The knee-jerk may be increased when the legs are affected; it may be normal; some- times it is reduced or lost. Paralysis of the cranial nerves is occasionally noted ; this is not usually due to isolated neuritis, but is a part of encephalopathic symptoms. In these latter cases, the cause of the paralysis is not certainly known; in- creased intracranial pressure from congestion or oedema is often present, but direct or secondary toxic effects of the lead on the brain substance are probably more frequently the cause. The nerve most frequently involved is the optic, though fortunately this is rare; the eye symptoms will be mentioned later. Laryngeal paral- ysis, which is much more rare (Remak collected only twelve cases), has not been associated with cerebral symptoms in most instances, and, while human pathological studies have not been made, the condition is probably usually a neuritis; this view is supported by studies of horses, which animals were noted by Tanquerel and by many since his time to be especially subject to laryngeal paralysis after prolonged exposure in lead works. The paralysis has most commonly affected the adductors and caused hoarseness or aphonia, though the abductors have repeatedly been paralyzed and produced marked inspiratory dyspnoea. The facial nerve has several times been paralyzed, once (Bury) with the peripheral type of distribution; hence, in this instance there was probably a neuritis. Other cranial nerves that have certainly been separately paralyzed as the result of lead, are the abducens and the oculomotor; and the clinical importance of these nerves has been materially increased recently by the large series of cases in children observed by Lockhart Gibson; paralysis of these nerves, as of the optic, is commonly associated with cerebral signs. Sometimes several ocular and other cranial nerves have been involved coincidently, usually when other cerebral symptoms were present. Oph- thalmoplegia has occurred. In addition to the localized forms of paralysis, cases are occasionally seen in which generalized paralysis appears, usually advancing from the periphery toward the trunk. In these instances it is probable that both spinal and peripheral changes are frequently present. There are two important varieties, one subacute or acute, the other of slow progress; a third variety is distinguished simply by the presence of fever, with rapidly 106 DISEASES DUE TO CHEMICAL AGENTS extending paralysis. The slow form generally supervenes upon a pre- existing local palsy, usually, of course, of the forearms; but it may be progressive from the beginning. The rapid form is likely to have been preceded by enceplialo|)athy, but this is not always the case. Both ordi- narily end in recovery, the acute form often beginning to mend very rapidly within a few weeks or less, the slower form disappearing after more delib- erate progress. Very rarely death has occurred from asphyxia. In rare instances, paralysis of the diaphragm has occurred, even without general palsy. A few cases have been seen of diffuse paralysis following the type of progressive muscular atrophy. Some cases have been observed in which conspicuous ataxia, sometimes absent knee-jerks, and only slight paralysis or none, produced some resemblance to locomotor ataxia. Remak states that a definite pseudotabctic form has not been observed; but the reports of Teissier, Raymond, Putnam, Walton, and others, show at least that ataxia may be severe even in the absence of paralysis. There is more doubt in regard to the type resembUng spastic spinal palsy, its recognition being based almost entirely upon Putnam's reports, and the diagnosis in these cases was dependent solely upon the discovery of small amounts of lead in the urine. Bechtold, however, has recently reported a rather clear case, and Oppenheim mentions its occurrence. Cerebral Symptoms. — E?icephalopatJiy. — Transitory hemiplegia (Da- Costa) is a rare observation; as is persistent hemiplegia or other cere- bral paralysis, except late in the course in old cases when nephritis and arteriosclerosis may cause apoplexy. Aphasia has been noted and chorei- form movements have repeatedly been seen, but are rare. There may be hysterical symptoms, with hemiansesthesias and other stigmata, or hysterical outbreaks of excitement or convulsions, especially in predis- posed young women. The most common and striking cerebral symptoms are epileptiform convulsions, delirium, and coma; sometimes a picture more or less closely resembling paretic dementia. In Tanquerel's 1,217 cases, encephalop- athy occurred 72 times. Its frequency varies according to the dose, and perhaps according to the nature of the lead compound ingested. In Stew- art's chrome-bun series of 64 cases, encephalopathy occurred 15 times. These latter figures are, however, perhaps partly due to the fact that many children were affected. The outbreak often comes suddenly; those who are alcoholic are especially liable, and the author has several times seen cerebral symptoms appear suddenly after sli-ght indulgence in alcohol. Convulsions or delirium usually occur first, convulsions being the more frequent; if coma appears it usually follows delirium or con- vulsions, particularly the latter. The convulsive attacks are epileptiform with clonic and tonic movements; only one may occur, but, as a rule, the attacks are protracted at varying intervals over days — rarely, even weeks. Epileptiform attacks have occasionally persisted, though this is decid- edly unusual, and their relation to plumbism has not been very certain. In the delirious form there is usually active excitement, and the patient may be very violent; convulsions not uncommonly interrupt the delirium, and there are often striking changes from violent intellectual and motor activity to hebetude and quiet. Delusions of persecution, and particularly hallucinations, especially of terrifying character, are common; though they are not confined to such subjects, hallucinations are very frequent CHRONIC LEAD POISONING 107 in those who are also alcohoUc, and with marked tremor the resemblance to delirium tremens may be very striking. Fever (100° to 101°, occa- sionally even higher) is not uncommon. The duration may be extremely brief, but more commonly delirium lasts from several days to a fortnight or sometimes longer; in unusual instances the patient remains insane. The fact that delirium may be of sudden and violent onset is at times one of grave moment; one of the patients in the Episcopal Hospital, Phila- delphia, who had previously shown very slight symptoms of saturnism (mild colic), aroused the ward suddenly in the night with wild cries of fear, and almost immediately leaped from a third-story window and was killed; a few days later a similar but not fatal accident occurred to one of Dr. Tyson's patients at the University Hospital of Philadelphia. Acute encephalopathies are very dangerous; Tanquerel saw 16 deaths in 72 cases, and as a rule the mortality is put higher than this. Death usually occurs in convulsions, in coma, or from general exhaustion; broncho- pneumonia is also quite common. Symptoms of general paresis have been observed in a considerable number of cases, and it is probable that lead can cause this disorder, though many cases reported under this heading appear to have been other conditions, such as marked exhaustion resulting from acute delirium or from cachexia and marasmus, sometimes a state approaching that in Korsakow's polyneuritis psychosis. When the symptoms resemble general paresis, differences usually exist, in that the onset is very rapid, speech is less disturbed than in ordinary paretic dementia, moral vagaries are less common, and recovery often occurs even from extreme states. Eye Symptoms. — Disease of the external ocular nerves produces the corresponding muscular paralyses. Nystagmus has been observed. Hemianopsia, usually homonymous, once heteronomous, may appear rarely. Transitory blindness may develop suddenly, usually in encephalo- pathic cases; this blindness commonly disappears rapidly and com- pletely. Vision may gradually become impaired, with the symptoms common in other forms of amaurosis, and, of these, probably at least one- half show persistent structural changes in the optic nerve (De Schweinitz). Ophthalmoscopically, the transitory cases may show nothing; the changes found in other cases are those common in amaurosis, except that lead subjects show especially marked vascular lesions ; and it is also noteworthy that in optic neuritis the lesions are not confined to the parenchyma, as they are in the nerves of the extremities, but are also interstitial and perineuritic. Serious eye symptoms are fortunately rare; De Schweinitz saw only 3 instances in over 15,000 eye cases. Lead Poisoning in Children. — Plumbism in infancy and early child- hood commonly shows such wide clinical divergence from that in adults that a brief separate mention of it is demanded. It is, naturally, not com- mon in the very young, since it is always accidental in them; but it is probably somewhat more common than is usually thought, and, in a con- siderable proportion of the cases that occur, it is almost certainly not recognized. J. J. Putnam first directed especial attention to its peculiari- ties, and Newmark, Chapin, Sinkler, Stewart, Brown, Variot, Hahn, and others have added interesting observations, the remarkable reports of Turner and Gibson of its widespread occurrence in Queensland being particularly noteworthy, especially in some of their clinical features. lOS DISEASES DUE TO CHEMICAL AGENTS Symptoms. — It is prohahlc that some of the sickly infants of mothers with pliunbisni have lead ])oisoiiino; and die of it. Infants seem, as is to be exi)ected, prone to convulsions when poisoned by lead from this or other sources. Colic is likewise a commonly noted symptom in proved or suspected cases in infants, although in them it alone is, of course, not good evidence of actual poisoning. In older children there is a striking frequency of cerebral symptoms, though colic and paralysis are more imj)ortant. The spasms of colic may be of the same general character as in adults, but colic alone rarely suggests plumbism in children. The fact, however, that colic occurs repeatedly throughout more or less prolonged periods, and that it may show a lack of dependence upon dietetic error or evitlent digestive derangement, is suggestive. Turner refers to the marked frequency of jiains in the legs, or severe cramps, with colic, these cramps being often the most marked symptoms. In paralysis in children the legs are almost regularly affected, and usually show the most severe lesions when the arms are included; and a further peculiarity, as compared with adults, is noted by Turner: the peroneal muscles usually affected in adults often escape, while the tibialis anticus is usually paralyzed. There is not a great probability of mistaking these cases for poliomyelitis if they are carefully observed; but the likelihood of considering them dii)htheritic or other infectious peripheral palsies, is evident. Of cerebral symptoms, convulsions have been noted by the largest number of observers, but there is a very suggestive interest in the reports of Gibson and Turner of twenty-four instances in which the chief symptoms were prolonged rigidity of the neck, retraction of the head, and ocular symptoms. Of the latter, paralysis of the abducens and the oculomotor were most frequent, though ophthalmoplegia was repeatedly observed, and blindness was common; sometimes the latter disappeared, and some- times it became permanent from progressive optic atrophy. These cases were at first reported as chronic basal meningitis; later the regular re- covery of general health after removal from the homes or from demon- strated sources of lead, the frequent discovery of a blue line, and of lead in the urine in the cases examined for this, demonstrated that many of them at least were lead poisoning. The blue line is said by Brown and Turner to be frequently absent. Their evidence is not given in wholly convincing form, and is somewhat opposed to certain otlier observations; but the lead line appears to be at least less common than in adults. Diagnosis. — Proper knowledge of the sources of lead poisoning, and alert attention to details in the history indicative of exposure, will often give an immediate suggestion of the nature of the case, even when the symptoms are unusual. Colic and wrist-drop, however, are of course much the most common results, and, when characteristic, are sufficient to bring up the diagnosis at once. Their association with a clear source of poisoning, and especially with a blue line, makes the diagnosis practi- cally certain. The absence of a known source of lead is not of much diag- nostic importance, if the other signs are definite; and, even if the blue line is absent (which is unusual), bilateral wrist-drop without involvement of the supinator longus, and with no affection of the flexors and no note- worthy sensory symptoms, is nearly decisive, though to be completely so CHRONIC LEAD POISONING 109 it needs confirmation through finding lead in the urine. The search for lead in any case should be undertaken early ih the treatment and after giving potassium iodide for a few days. A positive result then does away with the occasional possibility of confusion with the unusual instances of similar palsy due to alcohol or other poisons, or to spinal disease, such as poliomyelitis; a negative result, unless the examination has been care- fully and capably carried out, means nothing, even early, and is never of importance late in the case. The slight and fragmentary forms of the blue line, which may require a lens to determine their nature accurately, should be carefully sought when a more characteristic line is absent. Basic granulation that is very marked (with hematoxylin-eosin, or thionin stain), and that is not associated with profound changes of other kinds in the blood cells, is extremely suggestive, and may lead to a correct diagnosis. It is not yet certain whether other metallic poisonings pro- duce basic granulation; Lowenthal had suggestive results with tin, but he considers his experiments of doubtful value; and, too, he used methy- lene blue staining. Cerebral cases and the slight or more unusual forms of paralysis are much more likely to be misinterpreted. If they are of industrial origin attention to the nature of the occupation usually suggests the diagnosis quickly, and a search for the blue line and for basic granulation fur- nishes more direct evidence. It is to be remembered, however, that neither of the latter signs constitutes final evidence that unusual varieties of paralysis are due to lead, and if distinctive symptoms are absent, or a source of poisoning is not known, recourse must always be had to exam- ination of the urine; and in any doubtful case the diagnosis must depend upon this. The chief source of error in the blue line is in the fact that it may persist even for years after lead poisoning has disappeared, and it may, therefore, be present with other conditions that have developed later. When convulsions or eye symptoms are present the possibility of uraemia must be considered. In cases with only general symptoms the finding of lead in the urine is the sole reliable source of diagnosis. In a search for lead in the urine the rougher clinical m^ethods, such as the magnesium- band test, or the observation of a black precipitate of lead sulphide after adding albumin and an alkali and heating, may be tried if desired. If a precipitate is formed and confirmatory tests show it to be lead, this suf- fices; but these tests are usually negative even when lead is present. The only satisfactory method is to oxidize the organic matter by heating as much as 500 c. c. of urine with one-tenth its amount of hydrochloric acid and two or three grams of potassium chlorate, subsequently driving off the chlorine and concentrating by evaporation. The lead is then re- covered by electrolysis, or, as sulphide, by means of hydrogen sulphide. Prognosis. — General disorders that have not caused serious organic lesions, colic, and the mild and recent palsies, recover entirely under proper treatment. The older and more severe forms of paralysis have a prognosis as to complete recovery that is directly related to their dura- tion and intensity, severe protracted cases rarely getting wholly well. Persistent atrophy and progressive decrease or entire loss of response to electricity are bad signs. Cerebral symptoms are always dangerous, coma being particularly so; if, however, the patient escapes death frpm encephalopathy, serious consequences rarely follow. Eye symptoms, of 110 DISEASES DUE TO CHEMICAL AGENTS slow onset especially, are of very doubtful prognosis. About half of them have persistent optic atrophy, and this goes on to blindness in a large pro- portion of cases. The progno.sis as to future attacks depends almost entirely upon the discovery and exclusion of the source of poisoning, renewed outbreaks from old lead deposits in the body being very unusual. If the exposure continues, recurrences arc probable and are of worse prognosis than the original attacks. In renal, cardiovascular, and other changes resulting from lead poison- ing, the prognosis is dependent upon the severity and stage of these lesions. If the further absorption of lead is stopped, the progress of the lesions that have resulted is of course slower. Prophylaxis and Treatment.— Were the industries that cause expos- ure subjected to reasonable regulations and these actually enforced, and were the workmen not only given opportunity to keep themselves clean, but required to do so, industrial lead poisoning would largely disappear. Cleanliness is the most important point in prophylaxis, and the most difficult one to carry out, owing to the utter carelessness of most workmen. Much of this is due to a lack of proper comprehension of the dangers and the methods of avoiding them, and many poisonings are avoided in those works where the policy of instruction is adopted instead of the narrow custom of belittling the danger. But many workmen will not voluntarily keep properly clean, and hence those at all seriously exposed should be required to do so. The effect of such regulations is seen, for example, in one large plant, in which lead poisoning at one time even greatly endan- gered the success of the industry, but in which the workmen are now provided with attractive facilities for cleanliness as to person and clothes, are required to use these facilities under penalty of discharge, and are given full pay for the time consumed in daily bathing, etc. Lead poison- ing has now nearly disappeared from this plant. Most of the details of the hygiene of construction and operation of plants in this country are dependent upon the wisdom and philanthropy of the operator; they should be controlled by law. The regulations existing in a number of European countries ^ are examples of what needs to be done ; the most important of these regulations are those that demand certain forms of ventilation, height of ceiling, isolation of the most dangerous parts of the work from the other portions of the plant, apparatus for the exclusion of dust or for the removal of that which escapes into the atmosphere, daily cleansing, and such construction of the walls and floors as to permit of easy and thorough cleaning, the provision of separate eating-rooms and of free baths, the exclusion of women and children from the dangerous parts of the work, limitation of the hours of work and of continuous ex- posure of the same individuals to the most dangerous parts of the work, and the services of a physician who has power to "lay off" any suspicious cases from w^ork and who must report such cases. In some countries it is also required of the workmen that they change their clothes and bathe after working, wear gloves or rub their hands with grease when at work, and do not eat, drink alcoholic beverages, or smoke or chew tobacco in the ' See Gesundheitsgefahrliche Industrien; Firgau, Gijte and Stark Wirkende Arzneimittel, Berlin, Haering, 1901 (German laws, etc.) ; Poisons Industrielles, Dangerous Trades, ed. by Oliver. CHRONIC LEAD POISONING 111 workrooms. The enforcement of these laws is sometimes unfortunately lax. There are in several countries very specific regulations governing the specific dangers in different industries. Simple examples of this are the requirement that lead colors be ground wet, that {)ottery glaze be properly fritted, etc.; indeed, the English law concerning the latter point is so rigid that Prof. Orton states it is exceedingly difficult to comply with it and continue manufacturing. A more elaborate instance of spe- cific regulations is seen in the fact that in Germany the production of electric storage batteries is governed by twenty-eight regulations, and many of these apply purely to the apparatus, material, and building con- struction to be used in this particular industry. Of the simpler preventive measures, proper cleansing is by far the most important. Respirators are of little use because the men usually will not wear them; sulphuric acid lemonade is of some value, though lead sul- phate is absorbed to a slight extent. Theoretically proper, and practi- cally very valuable, is the free use of protein food before beginning work or at mid-day; milk is provided free in a considerable number of plants, and in several it has gained the reputation, which is too favorable, of being an almost certain preventive. Fats, such as olive oil, also seem to have some preventive action; one plant in Philadelphia has long required the men to take olive oil before beginning work and at the mid-day meal, and excellent results are claimed from this. Exercise in the open air, by increasing eliminative functions and general resistance, has a most important influence; companies owning their workmen's houses have repeatedly built them at a distance in order to necessitate a daily walk to and fro, and with very useful results. When poisoning has developed, exclusion of the source is the first imperative necessity. In industrial cases this means of course, a change of occupation, or, if necessary, cessation of work; in accidental poisoning it often means painstaking and extended search for the source. If the water is at fault lead service pipes should be replaced, if possible. In towns where this often cannot be generally done, the whole supply can be rendered nearly harmless by adding chalk or lime to the reservoirs, or by sand filtration; or the individual may do this himself, or filter the water through charcoal, though these measures are more successful if done be- fore the water passes through the lead pipe. The water should also be allowed to run a long time before any is taken for drinking or cooking purposes, as that which stands in the pipe becomes specially laden with lead. The active treatment consists in elimination of the lead and of general products of metabolism, and in combating general or local symptoms. The initial action in any case should be to expel any lead present in the gastro-intestinal tract, preferably by means of saline purges ; purgatives that act largely through increasing peristalsis should not be used. Pur- gation is frequently difficult to accomplish, for the constipation is often obstinate if there is colic and sometimes when there is not. In such cases it is often necessary to use large and frequent doses of salines (which may have to be combined with simple enemas, or enemas containing a half ounce or an ounce, 15 to 30 gm., of magnesium sulphate), and to give with the purgatives, to control the intestinal spasm, moderate doses of atropine, pilocarpine or other antispasmodic. Large oil enemas are also 112 DISEASES DUE TO CHEMICAL AGENTS very useful and entirely harmless. In cases with severe colic a movement may sometimes be secured only by giving, before the purgatives, moder- ate doses of morphine. Control of the constipation is one of the most important features of the treatment of colic, and colic is the commonest symptom demanding treatment. After the bowels are once opened they should be moved at least once (better two or three times) a day until the local symptoms disaj)pear, in order to encourage elimination and pre- vent return of the spasm. Water should be drunk freely, and if the secre- tion of urine is low diuretics should be used. After the bowels have been moved, potassium iodide should be given in doses of 5 grains (0.3 gm.) three times daily. If increased beyond this it should be carefully watched, as some observers believe that it may temporarily exaggerate the symp- toms by getting more lead into solution. The manner of action of this drug is still a subject of controversy, but it is quite as probable that its influence is indirect, through its alterative effect and through increasing general elimination, as that it acts directly by formation of the soluble double iodide of lead and potassium; the latter action in the body is purely hypothetical. It seems, however, to be in all forms of lead poison- ing the best eliminative available. Baths of potassium sulphuret have been recommended by a number of Avriters; the patient is immersed for twenty minutes in a bath tub containing about six inches depth of water in which six or seven ounces of potassium sulphuret have been dis- solved. The pains of lead colic should be controlled by hot applications, or, if severe, by w^arm baths or hypodermics of atropine or pilocarpine, avoiding morphine unless the pain is so extreme and uncontrollable that it must be used; though it controls the immediate symptoms, morphine interferes with the ultimate purpose of treatment in that it reduces elimi- nation of lead and of general metabolic products through the kidneys, and usually interferes with bowel movements, and, in rare instances, it has brought on dangerous or even fatal cerebral symptoms, probably due to uraemia. Oliver warmly recommends monosulphite of soda in doses of 5 grains (0.3 gm.) for both colic and paralysis in mild cases; my results with it have been unsatisfactory. Paralysis should be treated by the general principles used in managing peripheral neuritis. Active treatment should be begun only when the acute progress of the palsy has ceased. The most important measures are electricity, carefully graduated massage wnth passive exercises, and, so far as possible, very slowly increased active exercise. The treatment must be continued for montlxs, and if complete recovery does not occur it should not be stopped until all improvement has ceased for months. Since there is usually decided impairment of the general health in these cases, general treatment is almost as important as local. Moderate general exercise, provided the paralysis permits of it, as it nearly always does, should be used after a preliminary rest in bed; fresh air, sun- shine, and a generous diet, must be insisted upon at all times when they can be had. Bitter tonics are useful. Strychnia is not in as good repute as a cure for paralysis as it once w^as, but is an excellent general tonic and stomachic, and certainly will do no harm if used only after evidences of increase in the paralysis have clearly ceased. The anaemia that is usually present needs, especially, fresh air and food; but small doses of arsenic (loo grain continued for only short periods, as arsenic also causes CHRONIC LEAD POISONING 113 nerve-degeneration) will often improve both the anjemia and general nutrition. Iron is not very effectual in such anaemias, and if given should be used sparingly, lest it disturb digestion and increase constipation. The general measures mentioned are likely to be necessary in any case, w^hether paralysis is present or not, in order to secure recovery of good general health. Cerebral symptoms need to be managed with much care. There is so much danger of exhaustion that severe eliminative measures should not be used. The bowels must be kept moderately active, and diuresis should be stimulated, especially by free water drinking and by enteroclysis with large amouuts (a quart or more) of normal, or preferably half-normal, salt solution at 115° or 120° F. Convulsions or delirium should be treated with large doses of bromides, combined with hyoscine or chloral. Mor- phine should not be used except as a last resort, and then with care, because of its interfering with elimination. Moderate venesection is a more suitable measure in actively severe cases than is generally taught; there is sufficient evidence of cerebral congestion to justify it in such cases. Good results have several times been obtained from lumbar puncture, and it is possible that it is reasonable to use it if the symptoms are persist- ent and urgent, but only in such cases. In both prophylaxis and treatment it is of the greatest importance to exclude alcohol absolutely. CHAPTER VI. CHRONIC ARSENIC POISONING. By DAVID L. EDS ALL, M. D. The intense general interest in chronic poisoning by arsenic, that was at one time exhibited by the lay public as well as the medical, has well- nigh disappeared; and with good reason, because the opportunities for poisoning are now far less numerous and less obscure. At present, with the exception of arsenical beer, which is of interest chiefly in Great Britain, the occasion for poisoning is given almost solely by a limited number of occupations, by criminal or suicidal use, or by the therapeutic administration of the drug. There are still a small number of articles used by the public in the manufacture of which arsenic is employed in such quantities as to make them somewhat dangerous to those who purchase them; but this is at present of small moment as compared with the past. To the clinician chronic arsenic poisoning remains, nevertheless, and will continue to be, of constant and rather especial interest because, unless somewhat cautious in the use of arsenic, he may see chronic poisoning as a result of his own administration of the drug; he is indeed, much more likely at present to see intoxication from this source than from any other that acts through prolonged ingestion of small quantities, unless he has an unusual situation in regard to occupations that cause exposure. The con- dition is, however, also of special interest because chronic sequels of acute poisoning occur not infrequently. Most of the chemicals, such as lead, that produce chronic disease, if taken for a long time in small amounts, rarely cause lesions of prolonged or persistent course when only a single large dose or a few such doses are taken. Local effects of direct irritation — gastro-enteritis and the like — may, of course, remain; but the patient otherwise, usually gets entirely well without general disorder, if he escapes such accidents with his life. A few of these chemicals, however, do cause chronic general evil effects as a consequence of acute poisoning, and of this group, arsenic is a prominent member; arsenical neuritis not uncommonly results from a single dose taken by accident or in an at- tempt at suicide. Etiology. — Because of the subtle danger to the public at large, more interest has been exhibited in poisoning from various articles in domestic use than from any other source. Wall paper in particular caused many cases of poisoning and excited lively general apprehension. The danger from this source was pointed out by Gmelin, in 1839, but aroused no special interest until Basedow, in 1846, demonstrated its clinical import- ance; and his observations caused the passing of a Prussian law forbid- ding the use of arsenic in dyeing paper. It was not until many years later that active attention was given to the subject in this country and 114 CHRONIC ARSENIC POISONING 115 England. Chiefly as a result of the reports of Draper/ Wood," J J. Putnam, C. P. Putnam, Shattuck and others, so much interest was excited in this country that manufacturers were soon forced into greater caution; but it was only in 1900 that, following the lead of most European countries, a law was passed in Massachusetts strictly limiting the amount of arsenic permissible in papers and articles of dress. This permits only 0.01 grain per square yard in dress-goods, stockings, etc., and 0.1 grain per square yard in papers and fabrics other than dress goods. As a result of this excitement and legislation, the conditions in the country at large have become almost free from danger. Haywood and Warner have made a series of nearly eight hundred quantitative tests of wall paper and in only four did the amount exceed the limit of the Massachusetts state law. Two of these were from England, one of the few European coun- tries that has no laws limiting the amount of arsenic in papers and fabrics; and of five samples that were very close to the limit, four came from abroad. These observations are like those of others; Dr. Charles Har- rington states that he and others in Massachusetts, who have examined many hundreds of samples, find regularly less than 1 per cent, that exceed the limit of the state law. The danger of arsenical poisoning, however, was by no means confined to wall paper; the greatest variety of substances colored with arsenic produced poisoning. It was caused by papers of other kinds, used for wrapping purposes, for making paper flowers, playing cards, and for various other purposes; it was seen as a result of the use of arsenical book covers, crayons, arsenical paint used for interior work, and numer- ous other objects of diverse kinds, particularly bedroom hangings and clothing of various sorts — stockings, hat bands, gloves, and dress goods of numerous kinds. It is not to be wondered at that the public became excited and apprehensive. There was, and to some extent still is, an impression that green is the chief or only color likely to be arsenical. This is a wholly wrong impression. Red was very commonly arsenical, and various other colors frequently so; in Charles Putnam's remarkable observations of poisoning in infants, the cause was the blue dresses worn by the nurses. The danger from this source also is now slight as com- pared with the conditions a decade or two ago, but Haywood and Warner found in 1904 that over 11 per cent, of samples of dress goods and over 29 per cent, of stockings contained amounts that were excessive though not highly dangerous. Goods colored red are particularly likely to contain large amounts, though black and green goods often yielded considerable quantities. Another source that is evidently of some importance at present is furs and rugs, which are cured with arsenic; 8 samples of rugs were found to contain over J grain of arsenic per square yard, 6 of these con- tained over 1 grain, and in one the amount exceeded 5 grains, while in one it was just below 17 grains per yard. The greatest danger from furs is local irritant action because of the manner in which they are worn; but general poisoning may, of course, occur. Foods, in earlier times, were a frequent source of danger, and repeatedly caused both acute and chronic poisoning, arsenic having been used to preserve the color of foods, to keep them from decomposing, and also to ^Report of State Board of Health of Massachusetts, 1872, Ubid., 1884, 116 DISEASES DUE TO CHEMICAL AGEXTS provide attractive artificial colors. Large epidemics, such as those at Wiirzburg, Bronicn, Paris, Hyores, and clsewiiere, resulted at times, and isolated cases were not uncommon. At present this danger has practically disappeared as foods are now too closely watched. There are a t'tw other sources of accidental poisoning that are still occasionally active. Acute cases sometimes occur from arsenical fly paper or rat poisons and may have chronic results. Kebler has suggested that chronic poisoning might occur from the use of certain common drugs that are likely to contain small amounts of arsenic as an impurity; sodium sulphate, for instance, may contain appreciable amounts, and this drug is often used daily throughout years. INIr. Haywood states that, in investigating a factory which tlischarged arsenical fumes, he found that appreciable quantities of arsenic were recoverable from the water of neighboring streams even when collected several miles from the plant; under such circumstances the drinking water might readily be the source of chronic poisoning. The fear that the use of arsenic as an insecticide, more particularly the use of Paris-green against potato bugs, might result in poisoning through eating the potatoes, seems, from the investigations of Kedzie,^ to be groundless. Beer drinking has been an extremely important and very disquieting source of poisoning recently in Great Britain, Kelynack and Kirkby" in particular having studied this point extensively. The arsenic was derived from the sulphuric acid used in manufacturing the glucose that is em- ployed in making beer. The conditions in regard to this point have not been investigated in this country, but probably if there is any such danger here, it is very much less than in Great Britain; the sulphuric acid used in the latter country has heretofore been manufactured largely from markedly arsenical iron pyrites while in this country iron pyrites is much less used, and when used it is much less arsenical. Most of the sulphuric acid used in this country is manufactured from brimstone or by the con- tact method, and is then free from arsenic. The occupations that cause danger are more limited in number than they were. In those that remain dangerous, poisoning can be very largely prevented by insisting upon proper cleanliness and by instituting measures to control dust, etc. The mines at Deloro, Ontario, for example, have become quite distinguished for the care adopted in protecting the workmen, and for the success obtained. The chief dangerous occupa- tions are the mining and smelting of arsenical compounds and of ores containing considerable quantities of arsenic, among the latter being particularly zinc, silver, and lead. Those engaged in Avorking upon the skins of animals and birds, some hat makers, and dye makers, are also exposed to poisoning. In occupational poisoning, skin symptoms are the most common chronic results. The chief sources of poisoning, however, are at present suicidal or accidental ingestion of toxic amounts of arsenic, or large or prolonged dosage for therapeutic purposes. This source in particular has been frequently discussed in this country and abroad, and extensive collections of the literature have been made by Irabert-Gourbeyre, Brouardel, and ' Report of State Board of Health of Michigan, 1875. ^Arsenical Poisoning in Beer Drinkers, Ballidre, Tindall & Cox, London, 1901. CHRONIC ARSENIC POISONING 117 Marik. Poisoning from therapeutic use of arsenic has usually occurred in cases of skin disease, chorea, pernicious aniemia and other severe anaemias, or Hodgkin's disease, in which conditions the drug is likely to be used for a long time and in large doses. It should be remembered that patients with skin diseases particularly, have many times produced chronic intoxication in themselves by continuing the use of arsenic with- out the continued advice of a physician, and they should be warned con- cerning this point. The practice of eating arsenic for the purpose of increasing the powers of general physical endurance, to stimulate sexual capacity, or to improve the condition of the skin and scalp, has been much discussed in connec- tion with the peasants in Styria in particular; the people of some parts of Hungary, India, and elsewhere have, however, carried out the practice, and, in a lesser degree, it has also been prevalent in some countries among women of higher social station. Doubt was cast upon the exist- ence of the practice by publications that followed v. Tschudi's descrip- tion of it, but observations by Marik, ^ Friedrich Miiller, and others have clearly shown that it was once common in Styria, and was being con- tinued only a few years ago in spite of legal restrictions. It is not so free of bad results as it was once popularly considered to be, Marik and Miiller having studied many cases that showed actual chronic poisoning as a consequence. Pathology. — The lesions produced in chronic poisoning have not been extensively studied; opportunity for investigating them occurs indeed only rarely, as death is an unusual result of chronic poisoning. Even severe symptoms are usually recovered from, more or less completely, and if remnants remain, postmortem observations of them are rarely made until long after the original attack. Skin lesions, ansemia, and changes in the nervous system, are most common. Gastro-enteritis, nephritis, and fatty change of the liver, vascular system, and muscles, are conspicuous in the acute poisoning, but much less so in the chronic form. Of the skin lesions, pigmentation is much the most interesting from the pathological as well as the clinical standpoint. It is due to a deposit, most marked in the lymphatics of the papillse, of a pigment that is of some- what uncertain origin; it has not been satisfactorily determined whether or not it is derived from hsemoglobin. The nervous lesions have been studied by Erlicki, Rybalkin, Henschen and Hildebrand in human subjects, and experimentally by Schaffer and others. The effects are, in the severe cases at any rate, probably exerted on both the peripheral nerves and the spinal cord. In the cord, arsenic produces chiefly degeneration and atrophy of the cells of the anterior horns, sometimes degeneration of the white matter. Schaffer described changes in rabbits that he considered somewhat peculiar to arsenic, but there is nothing distinctive of the lesions as a rule. In human subjects the peripheral nerves suffer most markedly; they show degen- eration of the myelin, which is often of segmentary form, and may leave the axis cylinder entirely uninvolved. The latter is, however, often affected, and at times so much so that it can be distinguished only "v\dth difficulty. ' Wien. Klin. Woch., 1891, Nos. 31-40. 118 DISEASES DUE TO CHEMICAL AGENTS Mode of Entrance and Pathogenesis.— The commonest mode of entrance is thenijXHitic, suicidal, or accidental administration by the mouth. It has, however, been clearly shown that severe general lesions may be pro- duced by means of external application; this lias occurred with arsenical "cancer cures." ■ Arsenic may also be inhaled as dust in some occupations, and the volatile compomids of arsenic are, of course, readily taken in by respiration. Chronic poisoning from wall paper proved to be of much inter- est in the latter regard. It was by many thought to be due to arsenical dust from the paper, but it was demonstrated by the work of Fleck, Selmi, Hamberg, Sanger, and others, particularly by Gosio, that the view that a volatile compound was formed, is correct. Poisoning from this source was probably due chiefly to this fact. The volatile compound is apparently arseniuretted hydrogen and is ])roduced by a number of moulds, among which pcniciUium hrcvicanh is the most important. The energetic capacity of the latter organism to produce this volatile arsenical compound has since been used to a considerable extent as a means of demonstrating the pres- ence of arsenic in organic matter, especially in toxicological work, exceed- ingly minute amounts thus becoming apparent. The moulds act well at room-temperature and in the presence of oxygen, and their growth is fur- thered by moisture and by the adhesive paste used in fastening the paper to the wall. The manner in which arsenic acts on entering the system is a subject chiefly of speculation, but some suggestions that have been made are interesting. In small doses, it seems to stimulate the bone-marrow to blood-formation ; in large doses, to produce degeneration of the marrow and cause anaemia. Very large doses set up general tissue destruction. The effect upon the nervous system, as well as some other effects, are thought by certain authors to be due to the formation of arsenic acid from arsenious acid, and to the substitution of the phosphoric acid in lecithin by this arsenic acid. Many of the local effects are due to excretion; this occurs chiefly through the kidneys, but also through the skin and various mucous membranes and glands, such as the liver and the breasts. Mother's milk has caused fatal poisoning of infants. Many instances of disease of the skin, conjunctiva, etc., are due to excretion, though many are due to direct external local action. Individual susceptibility plays a large part in determining the occur- rence of poisoning. Less than a fluid ounce of Fowler's solution taken over a period of a few weeks has caused severe intoxication; while large doses are definitely known to have been taken for therapeutic purposes for even thirty years or longer without ill effects, and arsenic eaters have apparently accustomed themselves to frequent doses of several grains, continued with impunity for very many years. Some animals have considerable natural immunity, and in some birds the immunity is possibly complete. There is still a certain degree of ques- tion whether a natural immunity can be increased in animals or man. It has appeared altogether probable that in some instances this does occur, but the work of Cloetta suggests that the apparent immunity is due to lack of absorption of the solid preparations by the mucous membrane. In animals, accustomed to taking large quantities by mouth, subcutaneous injection of amounts ordinarily toxic produced poisoning, so that there seemed to be no real tissue immunity. CHRONIC ARSENIC POISONING 119 Symptoms. — Peripheral neuritis and skin lesions are the most impor- tant as well as the most common results. If these are severe they may cause secondary disturbance of the general health. In many instances, indeed, some degree of general disorder develops coincidently with the local lesions, or before them; but not infrequently marked disease of the skin or nervous system occurs without other noteworthy disturbance of health. If general symptoms are present, they are chiefly anaemia, ema- ciation, general weakness, irregularity or weakness of the heart action, and vasomotor disturbance. There is also more or less disorder of the gastro-intestinal tract, occasionally evidences of chronic nephritis are present, and exceptionally other symptoms, but one's attention is ordinarily directed chiefly to the skin or the nervous system. Vasomotor changes are probably the chief cause of one of the frequent and somewhat important skin manifestations ; namely, hyperidrosis. This is often very marked and may lead to severe maceration of the skin, especially that of the palms and soles, in which situations hyperidrosis, as is usually the case, is most pronounced. The condition resembling erythromelalgia which was repeatedly seen by Kelynack and Kirkby in beer drinkers, and occasionally by other observers, is probably due chiefly to vasomotor changes, though often associated with arteriosclerosis; in this condition, painful patches of dusky-red or purple color, usually with a well-defined border, appear particularly on the soles and sides of the feet. This condition is often but not always, associated with signs of neuritis. Herpes is an occasional skin-lesion, and is sometimes very severe and refractory; it may occur on the trunk or, at times on the face, extremities, or prepuce. It has frequently been associated with neuritis. Workers in arsenic in particular, sometimes also those poisoned by ingestion of the drug, have a marked tendency to ulcers of the parts especially exposed, particularly those parts subject to attrition; and these ulcers, as a rule, heal very slowly and are often very distressing. Glossiness of the skin is also common. The most striking skin symptoms are keratosis and pigmentation. Keratosis occurs chiefly on the palms and soles; it may be diffuse, or localized in small areas, and may be of any grade up to the most severe. Ordinarily marked desquamation takes place in connection with the kera- tosis and this may occur even in large scales or plates. The localized horny areas have some tendency to become epitheliomatous. Pigmentation is extremely important clinically. It should be watched for when arsenic is being freely administered, as it is both a warning of the possible early appearance of the graver nervous lesions if the drug is continued, and is also itself very disfiguring and at times very distressing to the patient. Furthermore, it has repeatedly been mistaken for other forms of pigmentation, such as that of Addison's disease. It varies in intensity from a slight yellowish-brown tint to a deep brown, and it may be diffused over the whole surface, when it is usually of moderate or slight degree ; or, more frequently, it is collected in local areas, particularly on exposed surfaces, or in the folds of the joints, as the axilla, regions exposed to pressure, or in parts, such as the nipples, that are normally pigmented. Sometimes small spots of pigmentation may occur, somewhat resembling moles. The mucous membranes may show pigmentation. Deep pig- mentation may be present in local areas, together with a higher degree of 120 DISEASES DUE TO CHEMICAL AGEXTS diffuse discoloration. As a rule, the pigment slowly disappears after ces- sation of the poisoning, but it may remain permanently, to a greater or less degree. A variety of other lesions of the skin also occur. Erythema has very frequently been seen and it often shows bilateral symmetry; papular, vesicular, and bullous eruptions, pustules, and boils, are common, as are thickening, brittleness, and roughness of the nails, loss of hair, occasionally urticarial, psoriasis-like, and other eruptions. Among the manifestations suggestive in diagnosis is the condition of the exterior of the eyes. There is often puffiness of the eyelids; the con- junctiva is congested and frequently somewhat swollen; there may be marked chemosis, and there is often marked running from the eyes. These eye symptoms have been particularly noted in the cases due to|external action of the arsenic or to drinking arsenical beer; alcohol is probably an associated factor in the latter instances. Of the symptoms referable to the nervous system, paralysis is much the most important, though a considerable variety may be met. These symptoms are nearly always the result of internal use of arsenic. Paral- ysis following a large toxic dose usually appears a week or ten days, or even more, after the poisoning, when the acute symptoms due to disturb- ance of the gastro-intestinal tract and other direct irritative symptoms have more or less subsided. A number of cases have been described, however, in which transitory palsy appeared within a few hours or a very few days, and in rare instances even severe paralysis has begun to de- velop within three or four days after the acute poisoning. On the other hand, the paralysis may be delayed several weeks, and the patient may show no symptoms in the interval following the acute symptoms. Par- alysis has even been delayed for a year (Perkins), the interval in this in- stance having been filled with distressing pains. In chronic poisoning the time of appearance of paralysis depends, of course, upon the dose, and upon individual susceptibility. It has developed after three or four weeks' use of arsenic, but, naturally, it often appears much later. Paralysis is usually preceded by disturbances of sensation. Contrary to the conditions in lead palsy, paresthesias and particularly pain are very common. Pain is strikingly frequent and extremely distressing, both before the paralysis appears and for some time after it has developed; its frequency and severity constitute, indeed, important indications of arsenic poisoning. The nerve trunks, also, are frequently sensitive to pressure, and the skin may be extremely hyperalgesic upon touch or pres- sure. With the progress of the palsy, all qualities of skin sensation be- come reduced or lost, the legs and feet usually showing the most marked changes. Curious anomalies of sensation — polysesthesia, allochiria, etc., — have been seen. Motor palsy usually develops subacutely in cases which follow acute poisoning; in rare instances it appears very suddenly. It may, however, develop slowly even when due to acute poisoning, and in chronic poison- ing this is generally the case. Like the anaesthesia, it is most marked and most common in the legs. Writers who have collected large series of cases agree in the statement that the legs are almost always affected, that they are often paralyzed when the arms are not, and that they frequently suffer alone. The paralysis has, however, a marked tendency to involve CHRONIC ARSENIC POISONING 121 all extremities. The motor and the senstny j)al,sy alike affect the distal portions of the extremities, and very rarely extend above the knees and elbows; while the upper arms, the thighs, the trunk muscles, and the sphincters, escape. Both the extensors and flexors an; involved and there is no tendency to spare certain muscles as in lead palsy, all muscles of the areas affected suffering. The extensors are, however, usually more severely diseased than the flexors. It is very unusual for the arms to be affected without the legs, and paralysis localized to one extremity is rare, though it has occurred. The knee-jerks are almost always lost when palsy is at all marked. Degeneration reactions are present, and the response to faradism is re- duced or lost. Atrophy develops within a few weeks and often becomes extremely marked. Contractures of much severity are frequent when well-developed poisoning has been present for some time. Cases of rapidly fatal progress are almost unknown, but the disability that develops may be extreme and death may occur with the appearances of general cachexia. Unless, however, the paralysis is very severe or has been long neglected, improvement usually begins after a few months at most, and it progresses in most cases to complete or almost complete recovery, though occasionally marked disability remains permanently. In very rare instances, single cranial nerves have been diseased alone; aphonia from laryngeal paralysis has, for example, been reported by Morell Mackenzie and Brouardel; ptosis has occurred and other exter- nal eye muscles have been paralyzed. Lagophthalmus has been described. Amblyopia and amaurosis occasionally appear. Cloudiness of the lens has been reported after acute poisoning, and is said to occur as a result of chronic poisoning. There is an interesting and important group of cases to which attention was directed by Dana,^ in which ataxia, particularly of the legs, is so conspicuous a feature that it may readily lead to a diagnosis of tabes dorsalis, unless the mode of onset, the presence of neuritis, and the ab- sence of involvement of the sphincters, are carefully noted. Psychic symptoms sometimes occur, more especially in severe and prolonged cases. They are chiefly loss of memory and general weakness of intellect that may progress to pronounced dementia. Sometimes hallucinations are conspicuous. Diagnosis. — If a source of poisoning is recognized and the nature of the case thereby suggested, there is, as a rule, little difficulty in diagnosis. With skin lesions particularly, and more especially with keratosis or pig- mentation, arsenic should be considered and a source sought for. If sug- gestive symptoms develop in a patient who has been under treatment for chronic skin disease, malaria, anaemia, glandular enlargement, chorea, or other disorders in which arsenic is frequently used freely, the possi- bility of poisoning should always be suspected. This will, of course, occur to the attendant if he is himself giving arsenic. The pains, since they may occur without any paralysis, or may long precede paralysis, are likely to be mistaken for neuralgia dependent upon other causes, or be put under the crude class of "rheumatic pains." These mistakes are avoid- able only by a proper investigation of the nature of any persistent pains. 1 Brain., vol. ix, 1886-87. 122 DISEASES DUE TO CHEMICAL AGE}^TS Tlic paralysis may have to be distinguished from lead palsy, alcoholic neuritis, and neuritis due to various infections and other causes. Lead palsy is usually readily excluded by the severe pains and other sensory disturbance, the more marked involvement of the legs than the arms, the distal localization, and the paralysis of muscles that escape in lead poison- ing. The other conditions will be excluded, as a rule, only by finding a source of arsenic, or by searching for arsenic in the urine. If a person ^yho has no history of alcoholic or infectious cause for a neuritis, develops j)eri{)heral palsy, particularly associated with severe pains and the other characteristics of arsenical paralysis, a source of arsenic should be carefully searched for, and the urine should be examined for it. A negative result of the latter examination is not distinctive, for arsenic is not constantly present in the urine even when it is in the system, and it is usually entirely excreted within about two weeks of the time that ingestion ceases; for the latter reason, it may have permanently disappeared from the urine, even though severe symptoms are still present. A distinctly posi- tive result by Reinsch's test is of much importance; this test may be carried out by any one who has a little skill in laboratory technique; 500 to 1,000 c.c. of urine should be evaporated at a low temperature to about one-fourth the original bulk; one-fifth part of hydrochloric acid, free from arsenic, and a piece of copper foil, are added and the fluid boiled for fifteen minutes. If arsenic is present the surface of the copper becomes grayish, or, if there is a large quantity, it turns a deep blackish-gray. The fact that arsenic is present may then be definitely determined by the sublima- tion test, which gives a crystalline mirror of arsenious acid. If this test gives a doubtful result, a trained chemist must be called in to decide the question. Cases due to arsenical wall paper, carpets, dress goods, etc., are now very rare; the diagnosis will depend solely upon chemical investigation of suspicious objects and of the urine. In this class the symptoms have often been obscure, and if so, whatever the source of the arsenic, the diag- nosis is likely to be suspected only in case there is a careful consideration and search for all possible causes of the disorder. Prognosis. — The main points concerning the course of the poisoning have already been discussed. General symptoms, unless very severe and protracted, usually disappear gradually if properly treated ; and, if the poisoning ceases, the skin disorders are usually recovered from, though often slowly. Keratosis or ulcers occasionally become epitheliomatous or run a very long course in spite of exclusion of the cause. Pigmentation, as a rule, greatly improves or disappears, though at times disfigurement remains permanently. The nervous symptoms are, in general, of good prognosis; like all toxic paralyses, however, those due to arsenic are oc- casionally permanent, or show little improvement if they have reached a severe grade, and especially if treatment is long delayed. Marked psychic symptoms are unusual; since they are commonly due to advanced or pro- tracted poisoning, they are of very doubtful prognosis but severe stages may be recovered from. Prophylaxis and Treatment. — The prophylaxis of industrial poisoning should follow the principles discussed under lead poisoning. When these are properly used they prevent a very large proportion of the evil results. Intoxication from therapeutic use of arsenic can usually be avoided by CHRONIC ARSENIC POISONING 123 care in administration; even in diseases such as pernicious anaemia, in which large doses are often necessary for a long time, severe symptoms can be prevented by watching for gastro-intestinal disturbance, signs of renal irritation and, particularly, by observing slight pigmentation and other mild chronic toxic effects. The treatment must be regulated according to the conditions to be cared for. Potassium iodide in moderate doses, 5 grains (0.3 gm.) after meals, is generally considered a useful eliminant, but there is no specific treatment. Skin lesions should be managed in accordance with the individual case, and paralysis should be treated as multiple neuritis is treated. In the earlier stages of the latter, pain will frequently be a troublesome feature, and will require symptomatic treatment, the ex- tremities being protected from pressure of bedclothes, etc., the pains controlled by warm applications, hot baths, or if necessary, coal tar prep- arations or opiates. Rest is essential until all irritative symptoms are past. Carefully graduated massage, electricity, and passive movements, with slowly increased active exercise, must be used persistently. Avoid- ance of alcohol and careful regulation of the hygiene of life are to be in- sisted upon. CHAPTER VII. OTHER METALLIC POISONS, MERCURY, PHOSPHORUS, ETC. By DAVID L. EDSALL, M.D. CHRONIC MERCURY POISONING. Under this heading will not be considered the acute and subacute symptoms included under the term ptyalism, but only those disorders that are of more direct interest to the medical clinician. The fact that mercury, besides causing ptyalism, may produce chronic poisoning has certainly been known since the early part of the Christian era and it has been recognized in medical writings for at least twelve centuries. Marechal, in reviewing the history of chronic mercurialism, refers to distinct medical evidence that it was known as far back as 850 A. D.; and according to Dieterich, Rhazes recognized clearly that it may produce nervous symptoms. Lively interest in the subject was not awakened, however, until the controversy between the mercurialists and the antimercurialists, in the sixteenth century, showed its importance; and the first distinct description of tremor, disturbance of speech, and other nervous disorders, as direct effects of mercury, is said by Marechal to have been written in 1519, by a layman, the chevalier Ulrich von Hutten, who observed them in his own person as a result of treatment for syphilis. In such cases even to the present time, there is doubt whether the symp- toms were due to the mercury or to the syphilis; but Fernel, in 1557, de- scribed a case in which chronic poisoning occurred in a man who was not syphilitic and who had not taken mercury medicinally, but who had worked with the metal. Occupational poisoning, with nervous symp- toms, was recognized by Ramazzani. Jussieu, in 1719, described the conditions in the mines at Almaden; Astruc, in 1738, contributed an elaborate and valuable description; and in the century that has just passed, there were numerous observations and studies, among which that of Kussmaul is classical. Etiology. — The importance of chronic mercurial poisoning has largely decreased in recent years, partly because much greater care is now exer- cised in using mercury medicinally, but much more because in a number of industries in which mercury poisoning was once common, this metal is not now used, or the industries themselves have given way to others that accomplish the same purpose. In mirror making, for example, mercury has been replaced by silver; and fire gilding and silver plating with the aid of mercury have almost or quite disappeared, electroplating and roll 124 OTHER METALLIC POISONS 125 plating having taken their place. Besides the occupations mentioned, the preparation of mercurial pigments, their use in paints, in the making of artificial flowers, dyes, etc.; the use of amalgams in making gold and silver jewelry; the exhausting of incandescent light bulbs with mercury pumps; the preparation of fulminate; the manufacture of fireworks; the production of some aniline colors; and the preparation of the skins of animals and birds, has produced chronic poisoning. Mercury has been used in all these processes, and in some parts of the world is still used in many of them. Most of these occupations, however, are at present of very little consequence in this regard. The chief industries in which this poisoning is now seen are mercury mining and smelting, the manufacture of thermometers, barometers, and other physical apparatus of which mercury is an essential part, and the manufacture of felt hats, the acid nitrate of mercury being used in the latter in treating the felt. Mercury mines have long been recognized as a fruitful source of saliva- tion and chronic poisoning: the mines at Almaden and Idria have fur- nished the basis of a goodly part of the literature on this subject, and there have always been many cases among those working in mercury mines. It is even stated that those living near the mines, but not working in them, sometimes show chronic poisoning, and it is said that through a fire in the Idria mines in 1803, the atmosphere in the surrounding regions became so laden with the vapor of mercury that nine hundred or more persons exhibited mercurial tremor. Since mercury volatilizes at ordinary temperatures, this danger could be controlled only by ventilation that is constant and thorough, an exceedingly difficult problem in mercury mines. Dr. Jamison, of New Almaden, California, states that poisoning is still very common among the workmen in the great mines there, but is less so than it was, partly because the ore is less rich. Among special sources of salivation, which may also be sources of chronic poisoning, he mentions drinking water about the mines, which is usually charged with the metal, entering a drift too soon after a blast, w^hen the air is filled with fine par- ticles of mercury, and standing over the furnaces to free them of wet ore that has become clogged. Because of the comparatively small number of men employed in mercury mining, this source of poisoning is of lim- ited clinical importance, and the restriction of this industry to a few places also serves to make it of relatively little importance to the profession at large. In this country there are but a few persons who are exposed. How- ever, these occupations are of much interest to the medical clinician when he comes in contact with them, because a considerable proportion of those exposed develop more or less severe chronic poisoning, and also because proper hygienic arrangements will prevent a very large percentage of these cases. Hat making, because of the comparatively large number of persons employed at it and because of the fact that it is a widely distributed industry, is of more direct interest to the profession in general. It has been impossible to obtain any satisfactory figures as to the number of per- sons in this industry w^ho are exposed to mercury poisoning; it is generally known, however, that many cases of poisoning occur. A few years ago at the Episcopal Hospital, Philadelphia, employees from one factory fre- 126 DISEASES DUE TO CHEMICAL AGENTS quently appeared in the out-patient department or in the wards; they are now cared for by special j)rovision of the proprietors of this factory. The danger occurs in handUng the felt after the solution of acid nitrate of mercury, with which it has been treated, has dried; and poisoning occurs chiefly through the dissemination of small particles of dust in the course of cutting and fitting the felt, etc., possibly also through some volatiliza- tion and through tlae skin in handling the felt. Chronic mercurialism also occurs among men engaged in the production of various salts of mer- cury in chemical plants, though to what extent is difficult to determine. Salivation is not uncommon among them and chronic poisoning must occur occasionally, but it is probably quite rare. Poisoning from the medicinal use of mercury occurred not infrequently until the danger became thoroughly and generally recognized. At present, chronic mercurial poisoning of this source is extremely rare. It is almost always preceded by more or less ptyalism, and this is of course sufficient to lead almost certainly to the withdrawal of the drug before chronic mercurialism appears. Accidental intoxication very rarely occurs now, but it has developed in most curious and interesting ways. One of the most striking of these is the story of the ship "Triumph," that in 1810 sailed with a cargo includ- ing much mercury that was held in containers; some of the latter burst, and in three weeks, it is said, many of the persons on board had some of the phenomena of chronic mercury poisoning. There are also on record instances of persons having been poisoned by living in buildings where mercury was used for industrial purposes, even when their living- rooms were separated by several stories from the workrooms; and there is an instance in which persons who lived in a tenement developed mer- curial poisoning, which investigation showed to be due to the fact that the rooms had previously been used as a mirror factory. In the last men- tioned series, the mercury had dropped through cracks in the floor and its continual volatilization produced the poisoning; much mercury was discovered when the floor was torn up. The previously mentioned wide- spread poisoning from the fire in the Idria mine is another striking instance of accidental poisoning. Pathology. — So little work has been done on the pathology that it can- not be satisfactorily discussed. Wising has described degeneration and atrophy of the myelin in the lateral columns of the cord and reduction in the number of fibers, and Brauer has noted, experimentally, degenerative changes in the cells of the anterior horns, using the Nissl stain. Letulle and Heller describe experimental neuritis after sublimate injections, but Brauer considers this to have been due to the local effects of the injections, not to the general action; and it is probable that chronic mer- cury poisoning rarely or never produces neuritis. Prolonged medicinal use, and sometimes occupational poisoning, may cause ansemia and marked emaciation, with more or less severe fatty degeneration in various organs, and chronic gastro-enteritis is quite a common result. The occa- sional ansemia and cachexia, the profound changes sometimes seen after severe acute poisoning, especially in the kidneys and bowel, and the re- markable influence of mercury on syphilitic tissues show that it may exert an extremely important effect upon nutritive processes. C. W. Miller and the writer recently studied the influence upon autolysis and have contrib- OTHER METALLIC POISONS 127 uted evidence that mercury increases autolysis. Probably this is one way at least in which the metal acts upon nutrition. Mode of Entrance. — There is overwhelming evidence that mercury may enter the system through inhalation as vapor, and it is probably the chief way in which occupational })oisoning occurs, though absorption through the skin seems to play a role of considerable importance; and in the manufacture of hats, the preparation of skins, and similar processes in which much dust is created, inhalation of actual particles occurs. There are always ready opportunities for inhalation poisoning when mercury itself is used, since it volatilizes at ordinary temperatures, and further- more the heating processes necessary in most of these industries largely increase the volatilization. Frequent ingestion of small particles is probably a factor of much importance, even in occupational poisoning. Workers in mercury, like others exposed to similar dangers, grow sur- prisingly careless, and one may see them eating food or fruit, or smoking cigars or pipes, on which there are visible globules of mercury; the super- intendent of a large thermometer factory directed the attention of the writer to the fact that those whose work-tables were kept neat and who were careful as to cleanliness of the person escaped poisoning in a large proportion of cases, even though engaged in especially dangerous parts of the work. Symptoms. — It is a striking and generally recognized fact that saliva- tion and stomatitis are very often absent in the chronic cases. In exam- ining the mouths of a series of cases in which there were marked nervous symptoms, the writer found in almost every instance that the gums and teeth were in fairly good condition for persons of their social class except that, as is often the case in mercury workers, the teeth showed blackish discoloration. Sometimes, however, persistent ptyalism does develop, generally before the nervous symptoms. In the early stages of poisoning and when the condition is more pronounced, the patients often complain of headache, restless sleep and marked depression and weakness, par- ticularly in the morning; the latter sensation may pass off later in the day so that they often feel quite well toward evening. Several subjects of mild poisoning stated that they had a most abnormal dread of the ex- ertion of going to work in the morning; later on, this passed off and the remainder of the day they felt entirely cheerful. Sometimes anaemia de- velops and, in severe cases, a condition of general cachexia occasionally appears. Gastro-intestinal disturbance, particularly of the stomach, is also not uncommon, though less frequent than one would expect. Neu- ralgic pains, especially in the territory of the trigeminus, are quite common in both early and advanced stages and joint pains also occur. Dr. Jami- son has frequently seen loss of sexual power, which usually improves upon treatment. But the most striking and common features of chronic mercurial poison- ing are the tremor and the emotional disturbance or erythism. These are usually associated with each other in greater or less degree from the begin- ning. The tremor in early stages is absent when the subject is quiet but appears upon voluntary effort, especially upon finely coordinated move- ment; and emotional influences usually have an intense effect in increasing the tremor, bringing it out when not otherwise present. For example, upon attempting to write his name, particularly in the presence of witnesses, a 128 DISEASES DUE TO CHEMICAL AGEXTS man who is ordinarily free from tremor but who is in the early stages of poisoning may develop tremor at once. This may be shght and of small amplitude, but is more likely to be rapid, gross movement, and is fre- quently so severe that it at once becomes wholly impossible for the man to write legibly. After a few moments the tremor and excitement decrease and within a short time they have nearly or quite vanished. The hands and lips are chiefly affected at this stage and usually more severely than other parts at all stages; if the condition is marked, however, most of the facial muscles are involved and all the extremities frequently show tremor. All grades of severity may be seen, and the phenomenon in bad Ccises is most remarkable. ^Yhen the tremor has grown actually troublesome it is ordinarily present in some degree even when the patient is at rest; it may be constantly very marked and in extreme cases may interfere with almost all coordinate muscular action; the patient may become unable to feed himself or to stand, and cases have been described that were of such se- verity that the patient had even to be strapped in bed to avoid injury from the violent and general movements. Frequently, however, the tremor is comparatively slight at most times, even though the response to muscular action or emotional excitement is very severe. For instance, without his knowing, the writer watched a man blow spherical thermometer bulbs of various sizes that were necessarily very accurately graduated. He had slight tremor but it did not interfere with this fine work, but when spoken to, he instantly went into general tremor; he could then scarcely hold the tubing in his hands, the lips, facial muscles, and orbicular muscles showed violent twitchings and contortions, and there was general severe tremor of the body and legs which were so marked that had he not been sitting he would have dropped to the floor. A few minutes later he was calmly at work again. The tremor in bad cases may persist during sleep but often does not. Physical examination, even in severe cases, usually shows nothing be- yond the tremor except, perhaps, slight or moderate muscular weakness. Occasionally weakness is very marked even when other symptoms are absent. Nystagmus has been described but is very rare. A point of im- portance and one that has sometimes caused confusion with multiple sclerosis is that owing to the involvement of the muscles of articulation the speech is frequently much disturbed. It may be of somewhat the same irregularly staccato type seen in multiple sclerosis; but it is usually evi- dent that the disturbance of speech is due merely to the severe tremor of the lips and facial muscles. Another point that sometimes lends resem- blance to multiple sclerosis is the fact that vertigo is a frequent complaint and at times is so severe as to cause the patient to fall. Sometimes there are choreiform movements, chiefly in severe and ad- vanced cases, and in the same t}'pe, disturbances of sensation — usually anaesthesia — may sometimes be seen. Paralysis also occasionally occurs in bad cases; it is likely to be localized and incomplete and is often not permanent. Choreiform movements, anaesthesia, and paralysis are likely to be irregularly distributed and limited to one extremity or to one side. Convulsive attacks are described and may be of true epileptic type, though it is not certain that epilepsy is ever due to mercury. Two other forms of convulsions have been attributed directly to mercury. One of them is tonic and follows violent movements or hard work and affects OTHER METALLIC POLSON^ 129 chiefly the flexors of the forearm. This tonic spasm comes on chiefly in painful paroxysms but may persist to some extent in the interval. During the attack the patient grasps anything at hand with all his might, and at the end of the spasm he is often for some time unable to let go. In the other type the convulsions are clonic and of the form described by Rous- sel as occurring somewhat frequently at Almaden and called there calam- hres. These occur in paroxysms that are said to have some likeness to malarial chills. There is marked oscillation of the head with movements of the eyelids and eyeballs, the facial muscles, and the arms and legs. The violence of the attacks at times makes it necessary for several persons to hold the patient. The attacks are often painful but there is no loss of consciousness. A large proportion of the subjects of these are said to die within a year after the attacks appear. In addition to the disorders mentioned, neuritis has been described. Leyden discussed it in 1893; Remak narrows down Leyden's cases to at most three that are reliable and even these seem to me somewhat doubt- ful as direct results of mercury because of their association with violent dysentery in two and with gastro-enteritis and gonorrhoea in the other instance. A few cases have been described in which there was severe ataxia. Kussmaul has described aphonia from laryngeal paralysis but this is extremely rare. There may be exaggeration of the special senses; the least noise, for example, may be intensely disagreeable. Shivering feelings and sensations of cold are common. The chief other disturbance is of the emotional nature. This is closely associated as a rule with the tremor. Sometimes, however, it is very marked when there is little or no tremor, or it may be very inconspicuous as compared with the tremor. Most of the patients notice this emotional disturbance before anything else; many of them describe it by saying they first notice that they have "lost their nerve." Any sudden occur- ence, even of the most trivial nature, throws them into tremor, usually accompanied by a sudden sense of powerlessness, or of fright. In bad cases the feeling of weakness causes the patient to drop into the nearest seat or grasp the nearest support, lest he should fall. These persons come to dread the least disturbance and they often avoid company because little conventionalities bring on this embarrassing excitement; several men have stated to the author that they would walk around a block if they saw a friend on the street because they dreaded the mere sign of recog- nition in passing. At first their attitude toward this disturbance is merely one of perfectly natural annoyance with themselves because of what they term their own silliness ; later they may become morbid, and in severe and advanced cases may develop a distinct psychosis, which varies in nature but seems usually to be dementia. Actual psychosis seems, however, to be rare now; its frequency has probably decreased since Kussmaul made his classical study, improved hygiene being chiefly responsible for this. The relation of this emotional disturbance to hysteria is interesting, particularly in regard to the question whether hysterical symptoms are directly due to a toxic agent, or are dependent upon a psychic anomaly m the individual and are merely brought out by some toxic agent. Cer- tainly if these symptoms in mercurial poisoning are due to an essential anomaly in the individual, this anomaly must be pretty widely distributed; it looks rather in this instance as if the poisoning produced the sjTuptoms 130 DISEASES DUE TO CHEMICAL AGENTS directly, for they occur in an extremely larjic ])r()portion of cases. In ex- amining and questioning a series of patients who showed various degrees of chronic poisoning, the same emotional condition was usually found, and yet nearly all were well-built, healthy-looking men, who in other respects showed not a shade of the a]:)pearance of hysteria. Diagnosis. — The chief conditions that are likely to cause confusion are disseminated sclerosis, paralysis agitans, general paresis, alcoholism and lead j)oisoning. The nature of the occupation and the knowledge and determination of the fact that mercin-y is used, if necessary the demonstration that mer- cury is present in the urine, are the most important ])oints, and as a rule, settle the diagnosis jiretty thoroughly. The wide amplitude and irregular- ity of the movements, the remarkable effect of emotional influences, the absence of nystagmus and of any evidence of focal cercbrosj)inal lesions, and the strikingly tremulous and emotional character of the stammering, distinguish the condition from multiple sclerosis. The rapid appearance or marked increase of the tremor upon movement or emotional stimulus, the lack of persistent rigidity and of the peculiar expressionless appearance of the features separate it from Parkinson's disease. General paresis is excluded by the absence of focal signs of cerebrospinal changes, and by the lack of delusions of grandeur and changes of the moral sense; also by the fact that tremor is usually by all means the most pronounced feature. Frequently alcoholism is actually associated with mercurial poisoning; in such cases the very severe tremor, the peculiar erythism, and the extremely marked influence of the latter upon the tremor indi- cate the double poisoning. When alcoholism is not present it may be excluded by the history and by the absence of all signs of it except tremor and excitability, and the last mentioned features differ in the two conditions. Lead poisoning will almost always be indicated by the occupa- tion, by attacks of colic and by the blue line, even if evidences of charac- teristic lead neuritis are absent. Basic degeneration is also probably an important distinction, but this has not been definitely determined in relation to chronic mercurial poisoning. Lead poisoning and mercurial poisoning may be combined, but this is unusual; in such cases it is necessary to determine that mercury is used in the work or is present in the urine. Prognosis. — If the tremor has not become constant and there is no marked cachexia, recovery practically always occurs under proper sur- roundings. Even severe and persistent tremor usually disappears ulti- mately, as does the emotional disturbance. If there is paralysis, mental disturbance, or severe cachexia, the outcome is doubtful. Sometimes even moderate tremor never wholly disappears, and in any instance recovery is likely to be very slow. Prognosis depends largely upon free- dom from further exposure and upon abstinence from alcohol and excesses of all kinds. Some persons have recovered from very marked symptoms Avhile continuing at the same work, but this was only when unusual care was exercised, and as a rule is not possible. Prophylaxis and Treatment. — As in almost all similar conditions, the majority of cases of poisoning can be prevented if employers properly protect their workmen. The results of the energetic and successful efforts of Wollner in enforcing proper hygiene in the mirror factories at Fiirth CHRONIC MERCURY POISONING 131 are profoundly impressive in this regard. Thorough ventilation is the most essential point, as is shown by Wollner's experience. A large manu- facturer who is interested in two factories, one old and with poor hygienic arrangements, the other new and well-ventilated, states that men have acquired severe chronic poisoning in the old factory and have recov- ered in the new while doing the same work. Cement floors and other forms of construction that permit of thorough cleanliness and prevent the accumulation of particles of mercury, the use of hoods whenever possible and of well-covered containers for the mercury, with the require- ment that the employees shall be extremely careful to cleanse themselves before eating, to cleanse their persons thoroughly, and to protect their hands with rubber gloves while at dangerous work, are also of the great- est importance. Free and nutritious diet, abstention from alcohol and from sexual and other excesses, with a generous amount of exercise, in the open air, if possible, are of the utmost value in prophylaxis and treat- ment. Many workmen take small doses of potassium iodide at frequent intervals as a prophylactic, particularly if they have already had slight symptoms, and a number have recovered from marked poisoning without cessation of work by treating themselves in the manner indicated. Turk- ish baths and frequent hot baths are also useful. The measures mentioned are the most important in any stage of poison- ing, as well as in prophylaxis. Sometimes the severity of special symptoms particularly the tremor, may demand medicinal treatment. Sedatives such as derivatives of opium, chloral, bromides, and also belladonna and pilocarpine have been found useful. Musk has been very highly praised by some authors of experience. PHOSPHORUS POISONING. The history of phosphorus poisoning practically begins with the inven- tion of phosphorus matches in 1833. A little more than a decade later the descriptions of Lorinser, Heyfelder, Strohl, and particularly of v. Bibra and Geist, of the distressing effects of phosphorus upon workers in match factories, aroused most intense interest, and their studies, together with others that followed, have resulted in some of the most remarkable advances in the history of humanitarian industrial reforms. A number of European countries have forbidden the use of poisonous white or yellow phosphorus in making matches, and, as a consequence, non- poisonous matches are now made in enormous and increasing numbers in these and other countries. Business sagacity and philanthropy have led in this country as well as in Europe to marked improvements in the hygiene of match factories and the care of the health of the workmen; in Europe legal enactments have, to some extent, enforced such measures; the result is that the danger in many plants that still use white phosphorus has been greatly reduced and in some it has almost disappeared. Clin- ical interest in chronic poisoning has, therefore, become greatly lessened. Acute phosphorus poisoning has likewise come to be largely past his- tory as a matter of clinical importance in most parts of the world, and it never was of much consequence in this country. Hence phosphorus poisoning demands but brief discussion. Acute poisoning is still common 132 DISEASES DUE TO CHEMICAL AGENTS in a few countries, sucli as Sweden, and among cities Prague has a most unfortunately large recent record of deatlis from this cause. Phosphorus necrosis also still occurs with some frecjuency in a small number of European countries in which workmen have little or no legal j^rotection and the hygienic conditions are poor. It is not improbable that cases occur in Japan, where matches are manufactured in large quantities. In general, however, both acute and chronic cases are now few, and the industrial cases are chiefly cared for by specially trained medical em- ])loyees of corporations, so that the subject is of little interest to the general profession. Etiology. — Industrial (chronic) poisoning has occasionally occurred in the manufacture of phosphorus itself, but is almost always due to the much more dangerous exj)osure that occurs in the use of the crystalline white or yelfow ])hosphorus in making matches. Phos])horus, of course, volatilizes at room-temperature, and in dipping and packing the matches, exposure to the vapor inevitably occurs unless the workrooms are large, extremely well-ventilated, and kept scrupulously clean. The most serious results have occurred in the small and wretchedly-equipped house indus- tries of European countries, which are now fast disappearing, but larger factories with poor equi])ment have naturally furnished many cases. The degree to which the danger may be overcome is shown by the experi- ence of Dr. Knowlton of Akron, Ohio, who has charge of over two thousand employees of one company. This company now provides com- modious workrooms that have excellent ventilation and are kept thor- oughly clean; separate eating rooms are also furnished, the employees are given facilities for personal cleanliness, and much of the work pre- viously carried out by hand, is now done by machinery. The condition of the mouth and teeth of the workmen is rigidly inspected and local disease is at once treated and the subject removed from further danger. Dr. Knowlton writes that he has at present in this large number of em- ployees only two cases of necrosis and these are mild. A general idea of the earlier as well as the present conditions in other countries may be obtained from Dangerous Trades, the publications of the British Home Office, and the articles of Bauer, Holzer, Kaup, G. H. Wood and others in Gesundheifsgefdhrliche Industrien. "White" phosphorus, which becomes "yellow" phosphorus on exposure to light, forms amorphous "red" phosphorus if subjected to a high tem- perature in an atmosphere free of oxygen. This red phosphorus, which is used in making most safety matches, is almost harmless to those work- ing with it, even if swallowed, apparently because of its slight volatility and solubility. Accidental chronic poisoning has been reported in rare instances, for example, as a result of the phosphorus vapor produced by storing a large number of matches near a stove. Purely accidental acute poisoning has occurred in a few cases, but as a rule is due to attempts at suicide, gener- ally by swallowing match heads. Children have also unknowingly poisoned themselves with matches; twenty-five match heads usually contain enough phosphorus to cause grave or even fatal poisoning of an adult. The very large doses of phosphorus that were once recommended for therapeutic purposes, especially in treating rickets, caused fatal poisoning in a number of instances. Finally, Kobert has suggested that some cases CHRONIC MERCURY POISONING 133 of icterus gravis, or acute yellow atrophy, may be actual instances of phosphorus poisoning resulting fronn reduction, chiefly in the intestinal tract, of the phosphorus compounds contained in such substances as lecithin and nucleins. He and others have conducted interesting experi- ments concerning this point, but have not as yet demonstrated its truth. Pathology.— Experimental chronic poisoning has produced hepatic cirrhosis and chronic interstitial nephritis. The result of chronic poison- ing in human subjects is almost always necrosis of the jaw with subse- quent sequestruni formation and suppuration of the bone and the nearby tissues, the lesions being very extensive in cases not treated early. General fragility of the bones has been described. The changes in acute poisoning have led to some of the most important observations and experiments in the history of pathology. In brief, they are reduction or loss of coagulability of the blood, diffusely scattered small or larger hemorrhages, icterus, loss of elasticity of the vessels, fatty changes in the muscles, heart, kidneys, stomach, and duodenum, en- largement of the spleen, and very extensive changes in the liver; the latter organ is enlarged, of saffron color, a typical fatty icteric liver, the acini, large and easily seen, and microscopically there is an extensive deposit of fat, while some of the liver cells are merely filled with fat, others are undergoing destruction or have been entirely destroyed. Much work has been done on the question of the source of the fat by Lebedeff, Pfliiger, Athanasiu, A. E. Taylor, Kraus, Sommer, and others, and it is now fairly clear that it does not come from transformation of protein into fat, but from deposit of fat that is transferred from depots elsewhere. If, as has often been the case, the phosphorus is taken for the purpose of producing abortion, there are usually hemorrhages into the cavity of the uterus, there is frequently abortion, and the organs of the foetus may show the same changes as those of the mother. The alterations in the chemistry of the organism are very striking and their study has led up to a considerable part of a body of knowledge that has caused profound changes in the teaching concerning many normal and pathological processes. Oxidative processes are reduced, as are syn- thetic processes, such as glycogen production in the liver and muscles, and the supposed synthesis of hippuric acid by the kidneys, while the work of Jacoby has shown a marked increase of autolytic processes. Inter- mediate products of metabolism in abnormal amounts or substances that are entirely abnormal — leucin, tyrosin, cystin, sarcolactic acid and peptone-like or ptomaine-like substances — are found in the blood and urine; glycosuria often occurs; there is very excessive acid production and the power of oxidizing acids is reduced. As a consequence, the am- monia of the urine is greatly increased while the urea is diminished. The last-mentioned conditions are due chiefly to the acid intoxication, not to the loss of the liver's function of producing urea. The action of phosphorus seems, as was stated in 1869 by Schultzen and Riess, to be like that of a ferment: in what manner its results are produced, whether through furtherance of the effects of bacteria or of their growth, or through exciting processes that are normally resident in the cells, is not wholly certain, but recent knowledge makes it much more probable that its chief action is to accelerate certain ferment processes. 134 DISEASES DUE TO CHEMICAL AGENTS Symptoms. — Acute poisoning bears a very close resemblance to "idio- pathic" icterus gravis and acute yellow atrophy; it is therefore of much interest to the medical clinician in tiie few regions where it occurs fre- quently. Some hours after taking phosj)horus, vomiting and often diar- rhoea appear; and" the vomitus may be phosphorescent. The symptoms remit after the digestive tract is emptied, and for two or three days the patient seems almost or quite well. After this, vomiting returns and icterus develops, as do epigastric pains, tenderness of the whole trunk, and distressing pains in the muscles, which are probably in large part the result of hemorrhage into the tissues. Blood is often ])resent in the vomit and stools, and petechiii? occur in the skin and mucous membranes. The liver enlarges a day or two after the return of the symptoms and grows tender; later it may decrease in size, but usually it does not unless recovery occurs. The patient becomes apprehensive, sleepless and pros- trated. There is much less tendency to severe cerebral disturbance than in acute yellow atrophy or icterus gravis, but, in some instances, marked somnolence, coma, or maniacal excitement appears a day or two before death. Phosphorescence of the breath and urine has been described, appar- ently with somewhat doubtful accuracy. The urine, when poisoning is well developed, contains much sarcolactic acid, at times leucin, cystin, oc- casionally tyrosin. The ammonia of the urine is greatly increased, the urea is usually diminished; the total nitrogen excretion is ordinarily increased beyond the intake. In fatal cases, the end generally occurs after about a week, sometimes earlier. Fully half the cases die. If recovery takes place the symptoms gradually subside, the liver decreases in size, and it may ultimately shrink to less than its normal dimensions. There may be sequelae such as neuritis and paralysis from cerebral hemorrhage. Chronic poisoning consists almost entirely of necrosis of the jaw and neighboring tissues, and the consequences of this local disease. General disturbance of health without necrosis is described by some observers, but is not conspicuous at best. Necrosis occurs particularly in those whose mouths and teeth are in bad condition ; it is not the efi'ect of phos- phorus alone, but of bacterial action also, and hence conditions that favor bacterial growth favor necrosis. It begins usually about a single tooth, most commonly in the loAver jaw, with local decay and abscess forma- tion. If not treated quickly, the disease spreads and the gums become loosened. If the tooth is removed, exceedingly foul pus is discharged from the alveolus, the necrosis advances to neighboring teeth and to further portions of the jaw-bone, sequestra form, the suppuration extends to neighboring tissues, sometimes burrowing deeply into the neck, fre- quently breaking through the skin; the patient becomes weak and anaemic and is likely to develop amyloid disease, phthisis, basal menin- gitis, or general septicaemia. Frightful disfigurement has been produced in some cases, and, with the dreadful odor, has made the subjects almost outcasts. Occasionally other bones besides those of the jaw become necrotic, and instances have been reported in which ten or more of the cranial bones were involved. A series of cases is on record in which there was general fragility of the bones, and this was believed to be due to phosphorus; in some cases, also, wounds involving bones of the limbs CHRONIC MERCURY POISONING 135 have been followed by necrosis of these bones. It has been repeatedly observed that necrosis may make its first appearance even years after the subject has ceased working in phosphorus. If local treatment is instituted very early the necrosis is sometimes controlled without serious surgical measures; and if the disease is distinctly developed but not ad- vanced, resection of the bone usually checks it. In severe cases even extensive surgical measures may not stay its progress. Diagnosis. — Acute poisoning is distinguished from acute yellow atro- phy chiefly by the history of poisoning; by the appearance of jaundice, and of other severe symptoms two or three days after temporary gastric symptoms, while in acute yellow atrophy, the grave symptoms are usually preceded for some time by signs of catarrhal or obstructive jaundice; by the enlargement of the liver; by the fact that leucin, and more particularly tyrosin, are less common and less abundant than in acute yellow atro- phy. Cerebral symptoms are also much less frequent. None of these distinctions is absolute or constant. Phosphorus necrosis is diagnosed chiefly by means of the occupational history, with persistent and advanc- ing necrosis of the jaw. Prognosis. — Acute poisoning is always very grave, one-half or more of the cases ending in death. The prognosis depends largely upon the promptness with which the stomach is emptied and further treatment in- stituted. If severe symptoms develop, it depends upon their duration; with each day beyond three or four that such symptoms continue, the outlook grows much more grave. The course of necrosis depends upon the rapidity and thoroughness of treatment. Early resection is usually successful. Advanced disease and long-postponed treatment renders the prospects doubtful as to recovery, and, at best, the disfigurement is likely to be severe. Prophylaxis and Treatment.— Phosphorus necrosis would practically disappear were the use of white phosphorus in making matches every- where forbidden. While this has been done in several countries, it is doubtful whether it can ever be generally carried out with success, and at present it certainly cannot. Constant and thorough care of employees' mouths and teeth and of the hygienic conditions in the workrooms, with the use, whenever possible, of machinery in place of handwork, will, as shown by recent records here and in England, almost entirely prevent serious results. The treatment of the necrosis consists in removing the subject from danger upon the development of the slightest signs of necrosis, immedi- ate dental treatment of the local disease, and, if it does not yield, or ad- vances in spite of this, early resection of the jaw. Acute poisoning should be treated by the immediate administration of copper sulphate, both for its emetic effect and because it forms a coating over the phosphorus match heads and prevents much of the absorption. The stomach should be washed out, using potassium permanganate solution (2 per cent, to 3 per cent.) or hydrogen peroxide (1 per cent, to 3 per cent.) for their oxidative action, since the oxides of phosphorus are little, if at all, poi- sonous. If diarrhoea is not present a purge should be given, avoiding castor oil since oils increase the solution of phosphorus. Old, ozon- ized turpentine should be given in doses of 0.5 c.c. (7^ m.) three or four times daily for a week or more, as it is supposed to favor oxidation of 136 DISEASES DUE TO CHEMICAL AGENTS the phosphorus. Alkalies should be administered. If there arc severe symptoms, tiie dose of alkali should be very large in order to combat the acid intoxication, and intravenous administration of alkaUes may be used as in diabetic coma. CHRONIC SILVER POISONING OR ARGYRIA. Argyria is of two forms, local and general. The former occurs in those who handle silver in their occupations, when it is seen chiefly in the skin of the hands, a condition first described by Lewin.^ It may be due to pro- longed use of silver preparations, particularly in hair dyes, or in treating diseased mucous membranes of the eye, throat, and other parts; recently, however, de Schweinitz- and others have directed attention to the danger accompanying long-continued use in this way of the newer silver prepara- tions, such as protargol. General argyria has also occurred in a few instances from prolonged occupational contact with silver, and, in a smaller number of cases, from its protracted local application. Kobert, indeed, urgently insists that we are likely to enter upon a new era in the history of argyria because of the freedom with which the newer preparations of silver are now being used locally by gcnito-urinary, ophthalmic, and other surgeons, and, even more, because of the recent frequent use of some of these preparations in com- paratively strong solution in the treatment of local disease of the bowel, or intravenously in septic and other conditions. In a great majority of in- stances, however, argyria has been due to the therapeutic internal use of silver nitrate. In slight degree the condition has been set up by as little as 2 grams (30 grains), administered in the course of two months; but when marked general discoloration occurred, the amount has generally been much larger— 15 grams (^ ounce) or more. The comparatively fre- quent occurrence of argyria in earlier times, and the very unfortunate results, led to such general and emphatic warnings against the possible production of it that the condition became, and still is, quite uncommon. Many recent graduates in medicine, however, seem to have an insuffi- cient appreciation of the danger. In the past three years the writer has seen 7 cases, 3 of which were of recent origin. General argyria has occurred through accident; Lewin saw a case as a result of accidental swallowing of a stick of silver nitrate under circum- stances that prevented its removal before it was absorbed. Pathology. — Argyria consists of a deposit of silver, in the skin or mu- cous membranes alone, in the local form; in the internal organs also, in the general form. In argyria due to internal use of silver, the pigment is found in the papillae of the skin and in the glands, but not in the epithelium ; in occupational cases, in which it enters from the exterior, it may be found in the epidermis. In generalized argyria most of the organs may show pigmentation, but it is ordinarily most marked in the kidneys, liver, and choroid plexus. The pigment is situated in the vessel walls and the nearby tissues. In the early stages it is first found in the leukocytes. ' Berl. klin. Woch., 1886, p. 17. ^ Transactions of the American Ophthalmological Society, 1903. CHRONIC MERCURY POISONING 137 Silver salts, when absorbed, form an albuminate;, and this is gradual!}' deposited and reduced; the reduction occurs through photochemical action in surfaces exposed to light, while in the internal organs it is accom- plished by the activity of the cells (Loew). Chronic interstitial changes in the liver, lungs, and kidneys, have been described as a result of the prolonged presence of the pigment in the tissues. Symptoms. — ^The condition consists of a more or less disfiguring pig- mentation without any subjective symptoms. Gastric ulcer, chronic nephritis, pulmonary tuberculosis, headache, and weakness of memory, have, without clear justification, been attributed to prolonged use of silver; and an isolated case of neuritis with symptoms resembling the forearm-extensor palsy of lead poisoning is mentioned by Gowers. Marked mental depression and abnormal shyness may naturally result from the very marked disfigurement. As a rule, however, pigmentation is the sole result. When this is due to local application or to occupation, the discoloration begins in the areas that come directly in contact with the silver, and in such it usually remains localized. If it results from internal use of silver, the first pigmentation is almost always seen in the form of a line on the edge of the gum that resembles the lead line, but is of a more violet color. This line is of diagnostic importance and also serves as an important warning, since it appears well before the pigmenta- tion of the skin, and indicates the necessity of stopping the use of silver at once. When skin pigmentation develops from internal use, it is at first in patches, chiefly in areas much exposed to light; the patches afterward coalesce and the whole surface — skin, conjunctiva, and other visible mucous membranes — ultimately shows more or less pigmentation. Slight grades resemble moderate degrees of cyanosis; in more severe cases there is a very striking and characteristic slate-gray color that makes the appearance of the individual extremely conspicuous. The color is often spoken of as resembling the complexion of the Moorish race, but it is really more of a bluish-gray. If distinct pigmentation is allowed to develop while silver is still being administered, the discolora- tion usually grows more marked after the drug is discontinued, because a considerable amount of unreduced silver is always present in the body under such circumstances, and reduction goes on for some time. The color may indeed continue to deepen slightly for many months; in one case known to the writer it apparently continued to grow darker for years. Diagnosis.— The discoloration may be mistaken for cyanosis, and the line on the gums may be confused with the lead line. The nature of the condition is determined by the history, or, if desirable, by excising small portions of skin and finding that in sections the pigment granules disappear after treating with potassium cyanide or concentrated nitric acid, and reappear upon adding ammonium sulphide. There is no practical likelihood of mistaking the condition for anything else when the color has once been seen and recognized. Prognosis. — Once developed, the pigmentation is permanent. If there is merely a line on the gums, disfigurement of the skin may usually be avoided by discontinuing the use of silver at once. If the skin already shows discoloration, this generally deepens somewhat, even if the drug is stopped. 138 DISEASES DUE TO CHEMICAL AGENTS Prophylaxis and Treatment. — Tlu jirophylaxis consists in the exercise of great care in prescribing silver nitrate, not giving more than one-fourth grain doses and not continuing it for more than six weeks. If it is desired to use the chiig further in the same patient, there should then be an inter- mission of several -weeks. Patients should not be given solutions of silver to use without the supervision of a physician, and they should be warned against the danger of having prescriptions for internal use, or external application, refilled. There is no treatment for argyria, all practicable methods of combating the pigmentation being entirely unsuccessful. CHRONIC ZINC, COPPER, BRASS, TIN AND MANGANESE POISONING. Whether any of these substances produce chronic systemic disease is an unsettled question. There is little doubt that most of them may pro- duce digestive disturbance; and the presence of zinc, copper or tin in preserved foods should therefore be considered prejudicial to health. There is likewise no doubt that the respiratory tract may be damaged by inhalation of dust in the manufacture of any products of these metals. Chronic systemic effects have, however, been but rarely observed, and it has never been clearly shown that the systemic effects described were not due to other unquestionable systemic poisons, particularly lead and arsenic, that are known to be frequently present in the metals under discussion, or to sulphurous and sulphuric acid, carbon monoxide, and other fumes that are given off in the heating of these metals. Character- istic lead poisoning is definitely known to occur occasionally in workers in zinc and copper mines and furnaces, and has been seen as a result of holding brass nails in the mouth. The opinion is now almost general that systemic poisoning, due specifically to zinc and copper, does not occur in those exposed to these metals. Workers in copper, for example, may have so much of this metal in their stomachs that at almost any time a draught of weak sulphuric acid produces vomiting from the copper sulphate formed (Wollner), and they may work in so much dust that, like the employees of the bronze factories at Fiirth, they " resemble walking bronze statues"^ and yet they do not show poisoning. The writer has spent many years in the immediate neighborhood of large zinc mines and furnaces and knows of no zinc poisoning in the men at these works; and Mr. G. G. Convers, of Bethlehem, Pennsylvania, whose opportunities and obser- vations have given him exceptional knowledge in this matter, states that the men who work with the oxide of zinc, which has of course been largely freed from impurities, never show any signs of systemic poisoning even though they spend hours every day in an atmosphere containing much zinc oxide dust. There is also no evidence that drinking-water — which is in some places carried through zinc pipes and in such instances is known to contain frequently considerable amounts of zinc — has caused chronic poisoning. Gimlette attributed digestive disturbance and emaciation to water collected from zinc roofs, but his view was not convincingly ^ Mayer, Penzoldt and Stintzing's Handbuch. CHRONIC MERCURY POISONING 139 proved even though the water did contain zinc. Kobert has found that zinc workers often excrete large amounts of zinc for months without any evidence of poisoning. Professor Koenig, who had been much interested in the question of copper poisoning in the employees of the great copper companies in Mich- igan, has found no evidence of it in them, or in the people who live in the regions about the mines and who drink water that often contains copper. Similar observations have been made by many other writers; ancJ hence even soluble copper salts apparently do not cause chronic poisoning. Certain chronic local symptoms, however, have been ascribed to these metals. Zinc chloride may produce severe skin irritation through external action; Gimlette considered the epidemic mentioned, in which there was gastro-intestinal disturbance and emaciation, to be due to zinc; and systemic effects such as colic, anaemia, paralyses, and tabetic symptoms have been ascribed to zinc by Schlokow and others. Popoff has attributed similar symptoms to working with bronze, while Schnitzler, Seeligmiiller and others have reported neuritis which they considered to be due to copper, but Walton and Carter^ however themselves suggest that in their cases pressure may have been the actual cause of the symp- toms. Suckling reported neuritis in brass workers, and he, Hogben, and Raymond, have described ataxia in brass workers. Murray observed cases in brass workers in which there was colic, anaemia, gastro-intestinal disturbance, emaciation, and even haemoptysis. Brass workers also occasionally show marked respiratory disturbance and the condition that has been termed "brass workers' ague," in which chills, fever, and sweats occur occasionally and may somewhat resemble malaria. It is not prob- able that these conditions are produced by the constituents of pure brass. Copper is known to produce some disfigurement, however, through greenish discoloration of the teeth, the hair, and occasionally the skin of the face and other parts. Even a green color of the sweat has been described. At times other bones than the teeth show this color markedly at necropsy or upon exhuming a body. The cases of tin poisoning that have been described were probably in most instances intoxication from decomposed canned foods. There are no cases on record that were clearly instances of chronic tin poisoning. Ungar and Bodlander^ have, however, produced gastro-intestinal symp- toms, heart weakness, emaciation, paralysis, ataxia, and coma, in animals, through subacute and chronic experimental poisoning, and the possibility of chronic poisoning in man must be recognized, for tin is quite extensively employed in weighing fabrics ; and tin vessels are, of course, used to an enormous extent in preserving foods, and acid contents of such vessels may contain appreciable amounts of tin. This poisoning must, however, be very rare, if it occurs. It is apparently of little clinical importance (K. B. Lehmann) and we have at any rate practically no definite clinical knowledge of it. There are no diagnostic signs of any of the poisonings under discus- sion, as they are not positively known to occur. In cases in which these metals were suspected of producing poisoning, the prognosis seems to ^ American Journal of the Medical Sciences, July, 1892. ^Zeitsch. f. Hygiene, Bd. ii. 140 DISEASES DUE TO CHEMICAL AGE^^TS have been much Hkc that in lead poisoning; and the treatment should follow the same principles. Chronic manganese poisoning is mentioned separately because, while it has been little studied, it seems, from the observations of Embden, to be perhai)s of coiisiderable importance in the limited group of persons who are exposed to it. Embden described a series of cases in which there was oedema, general weakness or pareses without atrophy or degenera- tion reaction, mask-like appearance of the face, disturbance of speech and of the voice, gross tremor of the head and extremities much increased upon intentional movement, excited patellar reflexes and retro])ulsion in complex movements and in attempts to walk backward s]iontaneously. The Romberg sign was absent. There were ptrriiesthesias and pains in the earlier stages but no other sensory symptoms. Sometimes there was uncontrollable laughter, but no other psychic alterations were observed. The condition is not fully recognized as manganese poisoning and needs further study, CHAPTER VIII. CARBON. MONOXIDE POISONING. ILLUMINATING GAS POISONING. COMBUSTION PRODUCT POISONING. CHRONIC CARBON BISULPHIDE POISONING. By DAVID L. EDSALL, M. D., Contrary to the conditions in most of the other intoxications, acute poisoning of the variety now under discussion is of special interest to the medical chnician and neurologist, because it not infrequently produces subacute or chronic disorders. Acute carbon monoxide poisoning is some- what like acute arsenic poisoning in this respect, since it may be followed immediately or after a considerable interval by more or less persistent conditions that are impossible of correct interpretation unless the previous occurrence of poisoning and its nature are known. It is of more general and more complex interest than arsenic poisoning because of its much greater frequency and because its sequelae are more varied in nature and often less characteristic. At the present time also, the sources of poison- ing are more numerous and more readily encountered by accident or design. Considerable technical knowledge too, is necessary in many instances in order to appreciate the fact that carbon monoxide is the toxic agent; and an added source of confusion lies in the fact that many acute poisonings are suicidal, and unsuccessful attempts at suicide are often subsequently concealed. It is necessary, therefore, to lay emphasis not only upon those sources of poisoning that act repeatedly or persistently but also upon those that exert their effects through transitory exposure. The acute poisoning with its sequelae has, indeed, been far better studied than the chronic. The im- portance of the latter is very difficult to determine, and its clinical picture cannot be very clearly given : this is partly due to the fact that it occurs chiefly in persons whose hygienic circumstances are bad in many ways, and it is hard to determine how large a part carbon monoxide plays in producing any resulting symptoms, partly because it is difficult in many instances to demonstrate that carbon monoxide was present and active at all; partly because the rather small number of investigators who have studied the question clinically have often made partisan statements with- out due proof, while most of the profession give the subject only casual thought or none. The forms of poisonings mentioned under this heading are not identical but they are most easily considered together, for the s}Tnptoms are similar in all, and carbon monoxide is the chief toxic agent in all. While various gases other than carbon monoxide are present in illuminating ^as and in combustion products, and while it has been shown both experimentally and clinically that the effects produced by illuminating gas and combus- ■142 DISEASES DUE TO CHEMICAL AGENTS tion products arc not wholly the same as those due to pure carbon mon- oxide, neither the clinical nor the experimental effects of the other gases that are ])resent are sufficiently distinctive to permit of separate descrip- tion of the three conditions. Etiology. — Pure carbon monoxide poisoning has been excessively rare because o])p()rtunities for its occurrence have been most unusual. It has been seen in a few instances in laboratories, and a number of distinguished investigators have had very grave effects as a result of accident or physio- logical experiment. In recent years a new cause of almost pure carbon monoxide poisoning has been coming into some prominence. Moissan, originator of the electric furnace for chemical researches, drew attention to the danger of carbon monoxide poisoning if this furnace was used carelessly, and a certain lunnber of cases are likely to a]:)pear from this source, because electric fiu-naccs are now so exiensively used for commer- cial purposes. Large numbers of these furnaces have been installed in industries such as those at Niagara Falls, and Mr. F. J. Tone, general manager of one of the companies, states that the furnaces of that com- pany discharge about sixteen tons of carbon monoxide daily, which is as a rule oxidized at once to carbon dioxide and carried off by special ventilating apparatus. He has seen no chronic effects, but states that oc- casionally the oxidation or ventilation becomes temporarily imperfect and the workmen are quickly made ill, usually with headache, nausea and circulatory failure. The experience in other companies is much the same. Professor Edgar Smith states that two students of chemistry at the Uni- versity of Pennsylvania had poisoning of moderate severity from this source, which left mild mental symptoms for weeks afterward. Intoxication wdth illuminating gas is commonly looked upon as being practically carbon monoxide poisoning, but Ferchland and Vahlen's experiments^ show that illuminating gas really produces a more severe poisoning than does simple carbon monoxide; nevertheless carbon monoxide is certainly the chief agent in the poisoning. Water gas, as is well known, is particularly dangerous because of the large amount of carbon monoxide that it contains. Acute cases of gas poisoning are, of course, usually due to leaving the gas turned on in sleeping rooms, either by ac- cident or attempt at suicide; in the last-mentioned connection, this poison- ing has a profound economic importance because more deaths are at present due to this cause than to any other form of suicide by poisoning. Intoxication with illuminating gas sometimes occurs in the acute or chronic form in employees of gas works; and protracted poisonings of slight degree, occasionally acute and even fatal cases, may occur in the occupants of buildings from which gas escapes from leaks in the pipes or fixtures. Pettenkofer and others have shown that the leak need not be in the building itself; the gas may travel through the ground for some dis- tance, certainly for many yards, and hence while escaping from the mains may reach the interior of houses that are at a considerable distance from the break. This is especially likely to occur in winter, when the heating of the interior of buildings causes active motion of the atmosphere, and thereby draws the gas into houses by aspiration. This manner of poison- ing at long "range, so to speak, is not confined to illuminating gas; it has ^ Archiv. fiir ex-per. Path, und Pharm., Bd. xlviii, Hefte 1 and 2. CARBON MONOXIDE POISONING 143 occurred from mines situated near dwelling houses. It is also of import- ance and much interest that under these circumstances the odor of the gas is usually lost, and hence its presence may be detected only through the occurrence of poisoning. Intoxication from this source is probably quite uncommon now, however. The exact frequency and importance of chronic illuminating gas poison- ing is not well known, and it is hard to determine because of technical difficulties in the study of the question. It is probably of somewhat greater consequence than is generally recognized, but is almost certainly less important than it has been thought to be by many who have written of it since Pettenkofer's studies were published. Combustion products cause poisoning chiefly as a result of the carbon monoxide they contain, though this is intensified by the other gases present, more particularly carbon dioxide. The amount of carbon mon- oxide in such gases naturally varies greatly, but it may be exceedingly large. In iron furnaces, for example, the escaping gas may contain as much as twenty-five per cent, to thirty per cent. Mild grades of combus- tion product poisoning very frequently occur and severe cases are not ex- tremely uncommon. Nearly every one has experienced transitory effects from gases produced by heating apparatus with poor draughts, and such mild effects are common in persons who are closely confined in rooms heated by badly drawing stoves or house furnaces. More or less severe effects also occur at times in cooks, and in persons employed in charcoal furnaces, iron and similar furnaces, in coke ovens, in gas plants, in tar distilleries, in the moulding of various metals, in kilns of various kinds (brick, tile, pottery, etc.) and in similar occupations. The "miner's disease" that has aroused so much interest, has been shown to be due chiefly to carbon monoxide derived principally from the explosive used in blasting. Carbon monoxide poisoning also occurs at times in the employees of chemical factories. In the various occupations mentioned, severe and even fatal acute poisoning is sometimes seen, and chronic ill health occurs not infrequently. The cases that occur accidentally in households are usually mild but are sometimes very severe; as in several instances in which one or more members of a household suffered from poisoning that was so pronounced as to produce unconsciousness, and in which severe after-effects occurred, a stove or house furnace being the cause. Fatal cases have occasionally occurred even from modern heating appliances ; in some European places, this is considered of such importance that the use of dampers in stove pipes is not permitted. When charcoal braziers, and other fires without chimney connections were much used, domestic poisoning of all grades of severity was quite common, and the brazier, as is well known, has often provided the means of committing suicide. Cases are still occasionally reported from the use of such heat in apparatus for drying out excavations, etc. A few years ago a number of severe and even fatal cases were caused by the cab heaters in Paris, Gautier himself having suffered severely. Recently the common use of gas or oil stoves in small and ill-ventilated rooms, and particularly the use of gas water heaters in bathrooms, has led to a noteworthy number of poisonings, some of which have been very severe; one of the nurses at St. Christopher's Hospital, Philadelphia, had pro- longed and nearly fatal coma from this cause. 144 DISEASES DUE TO CHEMICAL AGENTS Pathology. — The lesions have been studied with reUable results almost solely in acute cases or in those that the while suffering from sequelje of acute poisoning. The striking features in acute eases are the red or bluish- red spots on the surface of the body, chiefly the front of the neck, trunk and thighs; the brilliant cherry-red color of the blood and of many or all the organs; the marked degenerative changes in the muscles; the scat- tered, small hemorrhages and intense hyperjemia of all the organs; and in many cases marked cerebral changes. Among the immediate or more remote sequehie are gastro-enteritis, sometimes pseudomembrane forma- tion on the upper digestive and respiratory passages, bronchitis, bron- chopneumonia, or at times lobar pneumonia. Nephritis is common, sometimes with very severe degenerative changes and interstitial reaction. Peripheral neuritis has repeatedly been described, and poliomyelitis and disseminated encephalomyelitis have been seen. The most important nervous lesions, however, are those in the brain: they are chiefly hyperse- mia; scattered, small hemorrhages, with occasionally more extensive hemorrhage; and striking foci of softening, which ])articularly tend to be situated in the lenticular nucleus and the internal capsule, but may in- volve various parts of the basal ganglia. Cysts may form as a result of the softening. The areas of softening have a striking tendency to be symmetrical; they are probably the result of primary changes in the vessels, though there is some evidence that both the softening and the diffuse changes in the cells of the cortex and in the nerve fibers, that are often seen, are due to a primary encephalitis. Sibelius has recently dis- cussed the literature relating to cerebral symptoms and lesions. In chronic poisoning Koren has described fatty changes in the vessels and heart, with cardiac dilatation, anaemia, splenic enlargement, and pleural effusions. Mode of Entrance and Pathogenesis.— Carbon monoxide enters the system solely by inspiration, unless experimentally introduced otherwise. Its chief effect is in displacing the oxygen from oxyhsemoglobin and forming carbon monoxide haemoglobin, thus rendering the affected por- tion of the red blood corpuscles incapable of performing their function as oxygen and carbon dioxide carriers. This combination is commonly spoken of as a permanently fixed one ; it is relatively fixed, but not abso- lutely so. Oxygen cannot directly displace the carbon monoxide from its haemoglobin combination and it is not probable even that any noteworthy amount of the carbon monoxide that is thus combined, is oxidized to car- bon dioxide and excreted in this way; but it has been established that dissociation of carbon monoxide haemoglobin occurs, and also that carbon monoxide is excreted as such, in the expired air, after poisoning. Detoxi- cation is, therefore, always carried out to some degree and small repeated doses are probably rapidly excreted in this way. There is no evidence that it is gotten rid of by actual destruction of the affected corpuscles. Fodor has claimed that carbon monoxide has a cumulative action when taken in small doses, but there is no good proof of this. It is not yet fully settled whether the gas has any direct toxic action upon animal tissues or whether it acts solely by robbing the blood of its effective haemoglobin, but it is highly probable that both occur. The testimony differs as to whether it poisons animals whose blood contains no haemoglobin, bacteria, and the higher forms of plants; but a number CARBON MONOXIDE POISONING 145 of experimenters consider with much reason that it has a direct toxic effect, in higher animals at any rate, exerting this chiefly upon the central ner- vous system, the muscles, the nervous mechanism of the heart, and some other organs, and also upon the peripheral nerves and the parenchyma of various organs. An atmosphere becomes dangerous when it contains 0.05 per cent, of carbon monoxide (Gruber, Haldane). Severe symptoms may be caused by 0.02 per cent. (Haldane). Fodor has shown the presence of carbon monoxide in the blood of animals that had breathed an atmosphere con- taining only one part in 25,000, but such amounts are not positively known to cause any ill effects. This whole subject has recently been extensively reviewed by W. Sachs. ^ Symptoms. — ^The main symptoms of acute poisoning are an indefinite feeling of illness, usually accompanied by throbbing of the vessels, a burning sensation in the face, and soon by severe headache, vertigo, and very marked muscular weakness, the latter being a somewhat character- istic and peculiar symptom. Nausea and vomiting often occur. If the dose is large, severe symptoms develop; the subject becomes drowsy and then loses consciousness, and with this, there is usually loss of control over the sphincters. Sometimes unconsciousness comes rather gradually, sometimes, as occasionally with miners, for example, it may be the first symptom, and the subject may drop as suddenly as if he had been shot. Muscular twitching is common, even in the earlier stages, and sometimes convulsions occur when the symptoms have become more marked. Very commonly the patient is not seen until he is unconscious, when he shows heavy and unduly rapid breathing, the pulse is sometimes fairly full and strong but generally very rapid, and it is weak if the poisoning is severe or advanced. The skin and mucous membranes are usually more or less cyanotic, but this is sometimes made obscure by a peculiar and character- istic redness of the skin. There are, at times, the red patches on the skin mentioned under pathology. Drawn blood is bright cherry-red in color and gives the characteristic reactions for carbon monoxide. If recovery occurs, there is a gradual awakening, and for some hours, often much longer, a hazy mental state persists. Coma may last many days and then be followed by recovery. Gilman Thompson,^ considers it a bad sign if the leukocytosis, which is usually present, is of high degree. The sequelae are common and interesting. There may be nothing but weakness and fever; these usually occur in some degree and last for variable periods, it may be for only a day, or even for several weeks particularly when pulmonary sequelae develop. The fever is frequently associated with bronchopneumonia, much less commonly with lobar pneumonia, but sometimes no cause for it is evident. This fever has caused interesting errors in diagnosis, particularly in accidental cases, and especially when the poisoning has been prolonged, but not severe enough to cause violent cerebral manifestations at the onset. House epidemics that were very puzzling and in which the cause was traced with great difficulty, have occurred and have repeatedly suggested infec- tions; cases have been considered to be typhoid fever, for example, be- cause of the fever and "typhoid state." Pulmonary sequelae as indicated ^ Die Kohlenoxydvergiftung, etc. 2 Medical Record, July 9, 1904. 10 146 DISEASES DUE TO CHEMICAL AGENTS are very common. Bronchitis, bronchoj)neumonia, rarely lobar pneumo- nia, occur and are of extremely variable duration, sometimes causing death weeks after the poisoning. Tlie vascular system shows marked involvement during the acute attacks, and localized hyperemias, cardiac palpitation, and irregularity often occur for indefinite periods alterw^ard. Gastro-intestinal disturbance is not uncommon and may persist for a long time; gastric irritability, tenderness and pain of long duration have been repeatedly describeil. Icterus has been seen in rare instances. A striking and very common symptom of the poisoning, which is a sequel also, though a transitory one, is glycosuria. Skin lesions are common; local necroses and gangrene in areas ex])osed to pressure occur frequently, and heal slowly, and vesicular, herpetic, and bullous lesions have often been seen and they also heal poorly. Localized oedema (Klebs) or gelatinous infiltration (Litten) and curious areas of redness and swelling, that may closely resemble cellulitis, have occurred. The most important sequelae involve the nervous system. Neuritis, usually localized, with paralysis and anaesthesia, neuralgias, choreiform movements, intention tremor, scanning or stuttering speech, and incon- tinence of urine have been seen alone or associated with other symptoms. Cases with symptoms of Landry's paralysis or of distinct multiple sclero- sis have been described. Ocular disorders are not very common but are extremely interesting; there may be partial or complete blindness of vary- ing duration, with or without ophthalmoscopic changes, xanthopsia, nystagmus, and paralyses of the eye muscles, and there have been re- peated instances of complete ophthalmoplegia with marked protrusion of the eyeballs. Occasionally, deafness or roaring noises in the ears develop. Persistent headache sometimes follows. The most common and the gravest nervous sequelae are those due to cerebral changes; these may be local or diffuse and the results are chiefly paralyses or mental disturbances. These disorders tend to occur chiefly in those well advanced in life, but have been seen even in a five year old child; they may develop a con- siderable time after the poisoning. The paralyses from this cause are, of course, likely to persist; they may be monoplegic or hemiplegic. The mental disturbances vary much in type; they include simple hallucina- tions, simple confusion of more or less pronounced degree, very remark- able instances of amnesia, mania; but most "commonly, the mental disturbances are confusional states or, in persistent cases, actual dementia. It is of very great importance to keep in mind the fact that sequelae of all kinds may appear immediately after the poisoning, or may be post- poned for weeks; blindness, paralyses, mental disturbances and other sequelae have repeatedly been seen days or weeks after the poisoning, and the cerebral changes have a strong tendency to be delayed in their appear- ance. It is of equal importance to UQte that sequelae often of much gravity may be caused by a mild attack of poisoning. Cheneau, in his investiga- tions, was very moderately poisoned but had distinct mental and physical symptoms for months afterward, and Professor Smith's students had in both instances weeks of disturbance, which in the one case was a "far away" mental feeling, in the other marked depression. The symptoms of chronic poisoning have not been satisfactorily studied. They differ qualitatively as well as quantitatively from those seen in acute cases. There are complaints of headache, vertigo, nausea CARBON MONOXIDE POISONING 147 and sometimes vomiting. Often there is slow pulse and usually, there is general weakness, languor, and anaemia; very recently, however. Rein- hold has described two interesting cases in which there was a pronounced polycythsemia with over 11,000,000 red cells. With the above mentioned symptoms, there is usually some mental disturbance, lack of concentra- tion, sluggish intellectual action or poor memory. These symptoms tend to increase, and may be associated with weak or absent tendon and pupil- lary reflexes ; Musso described a series of 5 patients, 2 of whom recovered after nine months, while the other 3 became demented and died with the typical picture of paretic dementia. This subject is one that deserves much more general attention and study, particularly in relation to poi- soning from combustion products. Diagnosis.— This depends upon the history, a knowledge of the tech- nique of the patient's occupation, or demonstration of the presence of carbon monoxide in the blood. The best tests for the latter are Hoppe- Seyler's sodium hydrate test or his spectroscopic test; Katagama's reac- tion; or the Kunkel-Welzer reaction with potassium ferrocyanide and acetic acid. The sodium hydrate test is made with a solution of about 1.30 specific gravity; add this to the blood, and with carbon monoxide poisoning the result is a clotted mass of bright-red color, while normal blood gives a mucoid-like mass of greenish-brown color. The spectro- scopic test depends upon the fact that carbon monoxide haemoglobin is not reduced by such substances as ammonium sulphide. Oxyhsemoglo- bin and carbon monoxide haemoglobin produce two absorption bands that are much alike, the chief difference being that the carbon monoxide haemoglobin bands are somewhat nearer the violet end of the spectrum. If, however, ammonium sulphide is added, normal blood shows the single band of reduced haemoglobin, though this often becomes accompanied soon after by the haematin band; ammonium sulphide, on the contrary, does not affect the carbon monoxide haemoglobin spectrum, and the ab- sorption bands therefore remain as before. With some care they can be easily distinguished from the two bands due to reduced haemoglobin and haematin, for the haematin band lies in the red, while the carbon monoxide bands are both in the yellow. Katagama's test consists in adding to 10 c. c. of blood diluted with water 0.2 c. c. of ammonium sulphide solution and 0.2 c.c. of 30 per cent, acetic acid. Carbon monoxide blood gives a bright-red precipitate, normal blood a greenish precipitate. In the Kun- kel-Welzer test, undiluted blood is used and an equal amount of 20 per cent, potassium ferrocyanide and a small quantity of 30 per cent, acetic acid are added; carbon monoxide blood gives a bright-red color, normal blood blackish-brown; the difference may persist for weeks. Tests may be made with copper salts, lead acetate, etc.; the precipitate that they produce with carbon monoxide blood is bright red while with normal blood it is a dirty dark-brown color. These tests in doubtful acute attacks will occasionally clear up tht> nature of subsequent sequelae. Two years ago, for example, a patient in the care .of the author had for over six weeks insanity of confusional type associated with marked hallucinations, and ending in paralysis and death; the nature of the case would have been very obscure had it not been de- termined by chemical tests when he was admitted, at which time he was comatose. 148 DISEASES DUE TO CHEMICAL AGENTS The poisoning should be easily recognized if tiie history is clear, but may readily be niisinterj)reted if the source is not known. Acute attacks are likely to be mistaken for alcoholism or unemia. Among the points distinguishing them from the former, are the absence of odor of alcohol, the marked hyi)erannia of the surface and the chemical tests. Uraemia is distinguished chiefly by the urinary conditions and the cardiovascular changes, together with the history and the absence of carbon monoxide, if tested for. Chronic cases are very difficult of proj)er interpretation. Pettenkofer insists upon the im])ortance of looking for this cause of poisoning, if various persons in the same house have a tendency to wake with headache or nausea. Proper consideration of the occuy)ation will often lead to a correct diagnosis of chronic cases. The reliability and delicacy of chemical tests of either the blood or the res})ired atmosphere in chronic cases are not very certain as yet, and these have not so far been made very valuable to clinicians. Prognosis. — In acute cases, this depends largely upon the dose, but much more upon the rapidity with which treatment is undertaken. Patients usually recover if they are promptly and energetically treated; in the last five years, there have been received in the EjMscopal Hospital, Philadelphia, 39 cases; of these, 34 recovered; and of the fatal cases several were due to sequelfe. Even with recovery from acute symptoms, the prognosis should be a little guarded for at least a month or six weeks, until it is determined that sequelae are not about to follow, for some of the most serious after-effects have ensued upon mild poisoning. If sequelae occur, their prognosis must be determined by the individual circumstances; naturally, those due to central nervous lesions are especially unfavorable. Sequelae are more likely to occur in persons of advanced years, particularly the cerebral ones. The chronic poisonings are of good prognosis if they have not caused distinct mental changes. In the latter case it must be guarded. Treatment. — The treatment of acute poisoning consists in immediate removal from the poisoned atmosphere, free use of oxygen inhalations, venesection followed by intravenous or hypodermic administration of normal salt solution, artificial respiration if necessary, and the generous exhibition of stimulants (caffeine, digitalis, strychnia) if they are required. Persistent treatment suffices to bring most cases out of even the most des- perate straits. In chronic cases, the removal of the cause is of chief im- portance, with subsequent treatment of the' anaemia or other features. This condition is deserving of greater attention from the standpoint of prophylaxis, particularly in the dwellings and workrooms of the poor, who often have ill-constructed heating apparatus, and who husband warmth at the expense of breathing bad air. The general public also needs to have a better appreciation of the occasional danger attendant upon the use of gas and kerosene stoves and water heaters. The pro- phylaxis of chronic occupational poisoning is dependent chiefly upon hygienic construction and management. ' . CARBON MONOXIDE POISONING 149 CHRONIC CARBON BISULPHIDE POISONING. Chronic intoxication with carbon bisulphide has never received much attention in America, and the number of cases that occur is also much smaller than it was, both because oi hygienic improvements and because local conditions of trade in this country have led to a great reduction in its use here in the manufacture of rubber goods. Other substances have to a large extent replaced it in the manufacture of rubber clothes espe- cially. Carbon bisulphide is to a certain extent still used in making the cheaper grades of rubber clothes and also some other rubber articles, espe- cially those that are not intended for long service; for example, it is pretty generally used in the manufacture of surgeon's rubber gloves. Hence, although this form of poisoning is rare, it occasionally occurs; and it is probable, as Laudenhoimer states, that a very considerable proportion of the cases that do appear are misinterpreted. There are several reasons for the latter statement. In the first place the cases reported have come chiefly from a relatively small number of specially interested observers, while the industries that may cause poisoning are much more widespread, and hence it is probable that there is but a limited appreciation of the fact that carbon bisulphide is freely used in certain industries and that it produces poisoning in those employed. A second important reason is that the clinical picture of the poisoning is extremely varied and there are no symptoms that directly indicate the nature of the intoxication, knowl- edge that exposure has occurred being necessary in order to establish a diagnosis, and usually even to suggest it. Etiology. — Intoxication with this substance occurs almost entirely as an occupational condition. Acute poisoning has occasionally occurred from swallowing large amounts for suicidal purposes or by mistake, and acci- dental intoxication through inhalation has been described, but in most acute and practically all chronic cases occupation is the source. Carbon bisulphide is used chiefly as a solvent for sulphur and various fatty sub- stances. The industry in which most of the reported cases of poisoning have occurred is the making of various forms of rubber goods, vulcaniz- ing having for more than half a century been done with a solution of sulphur in carbon bisulphide. In the beginning of the latter half of the last century, when the substance came into use for this purpose, the vats containing it were freely exposed in rooms that had poor natural ventila- tion and no special ventilating apparatus; and at that time Delpech, who made the earliest and a very thorough and extensive investigation of this form of poisoning, found the health of the workmen so frequently and so seriously affected, that governmental action to control the use of carbon bisulphide was soon taken. Since then, comparatively few cases have been reported from France. In more recent times many cases have occurred in England and Germany, Laudenheimer having reported over aO cases in Leipsic within thirteen years. The gravity of the danger when these industries are practically uncontrolled is illustrated by the fact that vulcanizing "had increased at least tenfold in fifteen years" in and about Leipsic, and yet at most 250 persons were employed as vul- canizers; nevertheless over 50 cases of severe poisoning had occurred in this small group of persons within thirteen years, and from one factory 150 DISEASES DUE TO CHEMICAL AGENTS where only 10 persons did viilcanizino;, 6 eases of psyehosis were sent to the Leipsic Psyehiatric Clinic in the period 1885-87. Hebuilding and in- stituting hygienic arrangements in this factory Avere so effectual that no cases were received from it in the ensuing four years. In this country carbon bisulphide is probably not used extensively in more than half a dozen rubber factories. In one of these, where the ventilating apparatus is excellent, they still have an occasional case of poisoning, especially of transitory acute intoxication in new workmen; in some others they state frankly that no ])recautions against })oisoning are taken, and the work- men employed in them must therefore be dangerously exposed. Other occupations have caused intoxication in unusual instances. Chemists, for example, use carbon bisulphide and in certain lines of work employ it freely and frequently, and this has caused even grave chronic poisoning; but the exposure of chemists is, as a rule, so slight and so brief that serious results are very rare. It is used to some extent in extracting fats from wools, in purifying paraffin and oils, in dissolving asphalt, in extracting sul]>hur from some ores and in separating crystalline from amorphous sulphur, in extracting fats from seeds, in extracting vegetable perfumes, in freeing bones from fat, in making collodion, in removing varnish, and in various other ways, even in exterminating prairie dogs and rabbits. In most of these the manner of use makes the danger of poisoning slight. Serious danger may, however, occasionally be found in new and unexpected sources. Recently a factory producing so-called "artificial silk" has furnished a number of cases at the University Hospital in Philadelphia. Pathology. — The lesions in the condition have been little studied in human beings. Schwalbe, Kiener and Engel, and Poincare have inves- tigated the effects on animals, and Koster has recently reported the most complete and suggestive experimental research that has yet been made. Beyond some emaciation, definite and constant effects do not seem to occur except in the nervous system. Pigmentation of various organs was noted by Schwalbe and by Kiener and Engel, but Koster searched for it with negative results. Changes in the red blood corpuscles have also been observed but are not constant. The same is true of meth;emoglobinuria (Westberg); various observers have found it absent. In human cases any noteworthy blood changes are not usually found. The cause of death in acute poisoning seems to be respiratory paralysis and asphyxia (Lewin, Koster), and any blood changes seen in chronic cases are prob- ably due largely to mild chronic carbon dioxide poisoning. The nervous system suffers severely, however, and Koster considers the changes he found to be somewhat specific. He observed degenerative changes in the medullary sheaths throughout the nervous system, but less marked in the nerve roots and peripheral nerves than in the central nervous system; the myelin was fragmented and along the course of the nerve fibers and near them were large round or oval objects and also numerous granules, both of which took fat stains; the nerves also showed swelling and irregularity of outline and oedema; and the ganglion cells showed several striking forms of change. In the ganglion cells fatty degeneration was common, and it frequently began in the dendrites or in localized portions of the cell body; the nucleus frequently became involved, though later than the cell body; the pericellular spaces were frequently widened; the end CARBON MONOXIDE POISONING 151 branches were often broken oft". Quensel has recently reported a fatal human case in which there were extensive clianges in the central nervous system but none that are not often found in other conditions. Mode of Entrance and Pathogenesis. — As stated, inhalation is the usual mode of entrance, but there is some distinct clinical and experimental evidence that purely local changes (anaesthesia, para'sthesia, neuritis) may be produced by frequently dipping an extremity into carbon bisul- phide. The way in which the poison acts is not wholly clear but it seems certainly to have a special affinity for the central nervous tissue, and from what is generally known about it one would suspect a solvent action upon ihe lipoid elements of this tissue. Acute human or experimental poisoning, except that convulsions often occur, resembles that due to alcohol or to the anaesthetics in that it produces excitement followed by narcosis, and in chronic cases the effects may resemble chronic alcoholism; but the actual chemical action has not been determined. The amount of poisoning necessary to produce symptoms has been studied by Rosenblatt and Hertel. They find an hour's exposure to 2.07 mg. per liter of air (Rosenblatt), or even to 1.1 mg. per liter (Hertel), sufficient to cause symptoms; when seven or eight hours' work must be done, an atmosphere containing 0.5 to 0.8 mg. (Rosenblatt), or (accord- ing to Hertel) 0.8 to 0.9 mg., per liter may cause poisoning. Carbon bisul- phide is soon eliminated, a day or two usually sufficing for the excretion of even large doses. Symptoms. — Some emaciation is common; nausea or vomiting and constipation may occur early; eczema is sometimes observed; strangury has been noted; and disturbance of the sexual function is a very com- mon feature, particularly in more advanced cases with marked psychic or spinal symptoms, but sometimes even when other severe nervous symptoms are absent. The earlier stages of poisoning are often asso- ciated with sexual excitement, while in the late stages, especially when severe nervous symptoms of other form have developed, sexual power is usually reduced or lost. Nocturnal emissions or involuntary seminal discharges also appear to occur frequently. Women show menstrual anomalies, and if they become pregnant abortion or miscarriage is likely to occur. Headache, which may be very severe, vertigo, palpitation, frightful dreams, insomnia, mental depression, and apprehension without distinct psychosis, may be present in the earlier stages, and the English Com- mittee that investigated this poisoning especially insisted upon the fre- quency of visual disturbances even in very early stages. When clearly recognizable intoxication occurs, however, it presents the picture of organic disease of the nervous system with or without psychosis, or it resembles hysteria more or less closely, or organic and "hysterical" symptoms are combined. The grouping of symptoms ap- pears to be of almost endless variety. The common presence of so-called hysterical symptoms, especially of anaesthesias of the hysterical type, usually combined with symptoms of actual organic lesions, is one of the most striking characteristics. A much graver and hence more important feature is the tendency to pronounced and sometimes incurable psychoses. The symptoms of a spinal lesion, particularly symptoms of tabetic type are also often present. 152 DISEASES DUE TO CHEMICAL AGEXTS The important details are tlie followino-. Anivsthesia is extremely com- mon. It may be limited to the area of distribution of one or more nerves and may be associated with other signs of mononeiu'itis or polyneuritis, though actual eyidences of neuritis are apparently yery uncommon, in spite of the earlier statements of the French School. Much more fre- quently the an.vstliesia is glove-like, affecting the hands or feet or both, and having no relation to nerve distribution; Delpech thought the hands were more frequently aniesthetic or paretic in those whose occupation caused the hands to be much exposed to the vapor or fluid, and some other authors have agreed with him, while still others have questioned this. Not infrequently there is hemianifsthesia, diffuse antiesthesia, or local areas of distinctly hysterical type. Delayed sensation may be seen. Parresthesias of various kinds and of varied distribution also occur; a common complaint is a feeling of coldness, especially of the hands, and the extremities may actually be very cold, perhaps as a result of local ac- tion of the poison. Hyperesthesia occurs, particularly in the feet, or more commonly in the ovarian region, in cases with hysterical symptoms. The nerve trunks have occasionally been found tender, Delpech having repeatedly noted this, and Laudenheimer having seen it in cases in which there was also paralysis of the peronei and therefore, perhaps, neuritis. Spontaneous pain, especially along the course of nerves, is sometimes quite marked (Delpech, Rosenblatt, Hertel). The special senses are frequently affected, particularly vision and taste. Ring vision, macropsia, micropsia, obscuration of vision, chromatopsia, muscfe volitantes, and other disturbances may be present with or with- out signs of organic lesion. Ambyopia is extremely common even early in the poisoning. A persistent taste of carbon bisulphide long after the poison must have been completely excreted is a common com- plaint, or everything may taste sweet or bitter. In their experiments Rosenblatt and Hertel noted first a salty and then a bitter taste. Dis- turbances of smell, especially a constant odor of carbon bisulphide, have been repeatedly observed. Delpech and others have noted more or less pronounced unilateral or bilateral deafness or roaring noises in the ears. The reflexes, both superficial and deep, may be normal, excited, re- duced, or lost. The cremasteric reflex is often absent, particularly when sexual power is lost. The knee-jerk shows various changes; the fact that it may be absent is a point of much importance in the pseudotabetic cases, as is also the fact that the pupillary reflex may show any variety of change. There may be also disturbance of the sphincters of the bladder, and loss of sexual power. If ataxia is joined to some or all of these symp- toms, tabes dorsalis is extremely closely simulated. Motor symptoms are very common. Tremor is occasionally observed; Laudenheimer states that it is almost constant in the maniacal form of psychosis, and in other cases it is at times associated with symptoms that produce a resemblance to general paresis or to chronic alcoholism. Tre- mor has been seen in such violent form that it greatly or completely inter- fered with the patient's work. Ataxia is often present ; Koster holds that the ataxia and the common weakness of the peroneal muscles produce a peculiar and characteristic gait with a combination of steppage, ataxia, and shuffling. CARBON MONOXIDE POISONING 153 The most important motor symptom is paresis or paralysis, paresis being the much more common. In severe form it is most frequent in the peroneal muscles, and the especially common involvement of the lovv^er extremities has led many to the view that the poison acts upon them locally, since the vapor is heavy and tends to sink to the lower levels of the workrooms. This idea is, however, pretty well disproved by the fact that in animal experiment the hind legs are especially affected, even though all the extremities are equally exposed. The paresis also fre- quently involves the hands and arms, and a feeling of general weakness is a common, indeed an almost constant complaint, even in the early stages of poisoning. This weakness may be of the most extreme severity so that the patient may become unable even to feed himself. Paresis may be of one extremity alone, or of both legs or arms or of half of the body; and the actual paralysis that occasionally appears may have asimilardistri- bution, producing monoplegia, hemiplegia, or, more commonly, paraplegia. Muscular irritability is often increased in early stages, and there may be cramps and local spasms of the facial, the orbicularis, and other mus- cles. A pseudotetanic condition has been described by Rendu. General convulsions are a peculiar feature of acute poisoning as contrasted with other narcotic intoxications, and they may occur in severe chronic poison- ing and may even become persistent (Laudenheimer). Contractures may follow paralyses. Atrophy is not infrequent in the cases w^ith paresis of the extremities; it involves chiefly the interossei and the peroneal muscles. It is likely to be associated with loss of faradic ir- ritability and degeneration reaction; and a point of much interest in relation to the more or less profound weakness of the extremities, so com- mon both early and late, is that poisoned animals showed pronounced fatigue reaction (Koster). Psychic disturbances are common and very important. Their character varies greatly. Transitory attacks often occur in which there are hilarity and general exaltation resembling acute alcoholism; less commonly there is depression. If the exposure continues, these attacks occur repeatedly and more readily, and a more or less prolonged psychosis may develop. Symptoms of a definite psychosis usually appear rather suddenly, and most commonly in persons who have a hereditary predisposition. As a rule they develop after but a few weeks' exposure, while other severe nervous symptoms (spinal or hysterical) are not likely to occur unless the exposure has been prolonged. Laudenheimer divides the psychoses into three general groups; while the psychic symptoms are so variable that it is doubtful whether any classification can be well adhered to, this group- ing serves to make somewhat clearer a description of the characters that the cases are likely to present. He describes a maniacal, a depressive, and a stuporous form. The first is important in that the prognosis is almost always good; it usually occurs in persons with a good family history; it develops suddenly; and the chief feature is motor and intellectual excite- ment, usually hilarity. Erotism is common; hallucinations rarely occur. Hypochondriacal complaints constitute an odd but frequent feature, and tremor is almost constant. The pupils are usually unequal or react slowly. The duration is rather short, usually one to four months. The depressive form is of much worse prognosis; four of Lauden- heimer' s ten cases persisted. This form exhibits marked hallucinatory 154 DISEASES DUE TO CHEMICAL AGENTS delusions and excitement, with profound apprehension and severe hypo- chondriasis. The favorable cases average three and three-quarters months' duration. Sinijile melancholia, Laudenheinier has never seen. The stuporous form may be acute and raj)idly ini]:)rove, or may persist. This form shows no motor excitement. The pupils are dilated and react slowly. Other varied psychic disturbances also occur, and the indi- vidual cases do not readily come within distinctive groups. The symptoms of hysterical character in this poisoning are of great interest in themselves, and also of special interest because they have been used by some authors, particularly of the French School, in favor of the view that hysteria is due to some essential anomaly in the indi- vidual and is merely brought out by any "provocative agent" such as carbon bisulphide, and is not due to any direct efiects of such agents. It has even been claimed by jMarie and others that carbon bisulphide poisoning is essentially hysteria. Koster, however, has shown that anaes- thesia of characteristically hysterical distribution was produced in a large proportion of the animals poisoned with carbon bisulphide, a sufficient evidence that the anaesthesia need not be "hysterical," even though its distribution is of this type. As has been noted, hysterical signs are often combined with those of chronic disease. The latter signs may be of the most mixed and illogical character, but in such cases organic disease is usually present, and the anaesthesias even, though of hysterical type, are probably due to organic lesions. In other cases careful search for dis- tinct signs of organic disease has apparently shown their absence, and there are only functional symptoms, such as profound weakness, visual and gastric disturbance, and hypochondriasis, together with stigmatic anaesthesia. The interpretation of these cases is difficult, but it seems to me that Koster makes good his contention that there is no definite place to draw a dividing line, and these should be provisionally consid- ered to be actual organic carbon bisulphide poisoning rather than essential hysteria in which carbon bisulphide is a mere collateral provocative agent. Diagnosis. — This depends upon a knowledge of exposure to carbon bisulphide. The only characteristic features of the symptoms are their extremely varied character and the apparently illogical manner in which they are often combined, and these are manifestly insufficient for a diag- nosis if there is not a good suspicion at least of. exposure. The dis- tinction from psychic, spinal, ocular, and hysterical disorders of other source will depend upon demonstration of exposure; the exclusion of tabes dorsalis, for example, may depend almost absolutely upon this, so closely may it be simulated. Occasionally other central nervous lesions will be extremely closely simulated; sometimes neuritis is present, in which case the cause may easily be overlooked; more often neuritis will be simulated by central lesions. The determination of the character of the lesion present demands care- ful study of the symptoms. Peripheral neuritis was accepted as present in many cases by the French School, particularly in the pseudotabetic cases, but more accurate observation almost always demonstrates signs of central disease in such cases. Hysteria is very likely to be diagnosed in a considerable proportion of cases, but more careful study will fre- quently show evidences of organic lesion ; and even when these evidences CARBON MONOXIDE POISONING 155 are absent it is not justifiable, in this poisoning at any rate, to consider hysterical symptoms entirely functional. Prognosis. — Mild transitory attacks of psychic or other disturbances are not likely to be followed by any permanent results unless exposure continues; when the exposuredoes continue and repeated transitory attacks of intoxication occur there is serious danger of a grave psychosis. The outlook in these cases has been already indicated. The cases with spinal symptoms and those with peripheral symptoms usually recover slowly, but if they have lasted for a long time and the symptoms are very severe there may be little or no improvement. The general depression of health and the hysterical symptoms, muscular weakness, etc., appear to last for a long time. The eye symptoms are of much importance. They often recover but the English Ophthalmological Society found that about 20 per cent, showed no improvement and about 25 per cent, more showed imperfect recovery. Recurrence of any symptoms from which the patient has recovered or the development of new symptoms is extremely probable if he returns to worl^ in which he is exposed. Prophylaxis and Treatment.— Prophylaxis should be of very specific character. Treatment is almost entirely symptomatic. Workmen should wear gloves and use instruments for dipping the material into the carbon bisulphide mixture instead of exposing their hands, and they should also be taught extreme care about exposing themselves to inhala- tion of the vapor. All these will be of relatively little avail, however, unless proper ventilation is secured by means of special apparatus and the rooms are so constructed that proper ventilation can be carried out. If these things are done most of the cases can be avoided. When the poisoning has developed, treatment is largely a question of absolute removal from exposure, symptomatic drug treatment when necessary, and the use of the general eliminative measures indicated in any intoxication. Phosphorus was at one time used freely by the French School, they believed with good results ; but apparently it is no longer used, and there is no drug that has any peculiar value. Oxygen inhalations have been recommended but are probably of little use. The most important points are, unquestionably, fresh air; passive or, if possible, moderately active exercise; and seeing to it that the excretion from the intestines and kidneys is satisfactory. Alcohol should be rigidly excluded, as should sexual and other excesses. PART IV. DISEASES CAUSED BY OE&Al^IC AGENTS. CHAPTER IX. AI.COHOL. By ALEXANDER LAMBERT, M.D. Historical. — ^From time immemorial man has used some substances to help increase the joys of life or deaden the keen edge of sorrow. Alcohol in some form has probably been most extensively employed for these purposes and, whenever used, it has been to excess. The monu- ments of the Egyptians show the use and abuse of wine; the oldest Chinese manuscripts contain records of drunkenness; and in the Vedas there are prayers to the Deity beseeching Him to condescend to come and get drunk with his worshippers, that he might grant their requests and bestow favors upon them which, when sober, he would refuse. The Old Testament contains records of its widespread use, of consequent drunkenness, and warnings against the evils which follow alcoholic excess. As civilization developed, man learned to make liquids contain- ing a higher content of alcohol and the civilized races have taught the uncivilized to substitute the distilled for the weaker fermented liquids. Acute and chronic alcoholism have been present from the unknowable past to the present day, and their occurrence has always been bound up in the routine of man's daily toil, in the expression of his emotions, and in the performance of his religious rites. Etiology. — An unstable nervous system is the fundamental basis on which habitual alcoholic excesses develop. There is the weakness of will, the tendency to over-indulgence, the lack of self-control, and when once the narcotic effect of alcohol is felt, the inevitable craving for more cannot be resisted. In these weak individuals there is often the marked self-conceit which deludes them into the belief that they can resist when they wish and that further indulgence will make no difference. Among the very poor the grinding weariness of overwork and insufficient food drives them to seek temporary relief in alcohol, and before long what was first only a luxury becomes a dominating necessity. The false idea that alcohol is a tonic and strength-producer causes many of the poor to give alcohol to their children and thus lay the foundation for early 157 158 DISEASES CAUSED BY ORGANIC AGENTS excess. In Bellevue Hospital, New York, in 259 young male alcoholics in whom there was no mental degeneration from chronic alcoholism and whose statements therefore may be deemed fairly accurate, 4 be- gan before six years of age, 13 between six and twelve, 60 between twelve and sixteen, 102 between sixteen and twenty-one, 71 between twenty-one and thirty, and 8 after thirty years of age. Almost all gave a history of intemperance in other members of their families. The force of example is therefore often a potent cause of alcoholism; the fear of ridicule from their comrades and what is thought to be social necessity or a vain desire to be thought manly, arc also factors in certain individuals. In the struggle to improve their position, in- dividuals are often placed in new environments for which they are un- ])repared, or over-education for the position in life which by force of circumstances they must occupy, produces a mental dissatisfaction, with a consequent strain on their nervous systems, and, turning to alcohol for relief, they soon become addicted to its excessive use. Lives of idle- ness and pleasure-seeking, among the wealthy, not infrequently lead to alcoholism. In this country there is a little appreciated but not uncommon cause of alcoholism in the use of patent medicines and nostrums as tonics and cure-alls. A large number of these nostrums contain from 6 to 47^ per cent, of alcohol and they seem to be popular in ratio to their alcoholic content. Chronic alcoholism has thus been unwittingly acquired. Many acquire alcoholic habits in their endeavors to alleviate the pains of disease or disordered functions. The worries of life, business or domestic, and the desire for relief from sorrow, fre- quently cause men and women to seek oblivion in alcoholic narcosis. While the environment of certain occupations is a factor in producing alcoholism, it is equally true that in other situations it produces tem- perance and sobriety. The demands of modern machinery and elec- trical devices require a clear mind and steady hands, both for the production of good work and also as a matter of self-protection, so that employers are more and more demanding sobriety among their em- ployees. In the large centres of population these have been potent factors in the diminution of alcoholism among the younger working men. Judging from some 10,636 male alcoholics admitted to Bellevue Hospital, New York, the professions in which mental strain with worry, excitement and especially irregular hours, are a predominating factor, show a larger proportion of alcoholics than those in which such conditions are less pronounced. Journalists, actors, and physicians are thus more prone to alcoholism than lawyers, engineers and other profes- sional men. Bookkeepers, clerks, accountants, and stenographers, seem as a class to show a high proportion of those who drink to excess. A craving for excitement as a reaction to what seems a monotonous existence, may account for the large numbers in this class of occupation. Those demanding physical exertion near fires, such as stokers, firemen, black-smiths, iron and brass moulders, have long been recognized as producing a craving for alcohol to relieve the physical exhaustion. Stable men, hostlers, hackmen, and teamsters of all kinds, men whose occupa- tions vary with periods of hard work and rest and idleness, together with exposure to varying weather, form a large class in cities, who unfor- tunately acquire their habits of intemperance in the early and most pro- ALCOHOL 150 ductive years of life. The age of more than half of the admissions in the large numbers belonging to these occupations was from five to fifteen years less than the age at which the greatest number of alcoholics was admitted to the hospital. Among the large number of men employed in the building trades in New York, alcoholism predominated in the following order: stone-cutters, plasterers, painters, masons, roofers and copper- smiths, plumbers and carpenters. From the opportunities and tempta- tions of their occupation, saloon-keepers, bartenders and waiters show a high ratio of alcoholism. Among some 2,700 female alcoholics admitted to Bellevue Hospital, house work and domestic service was given as the occupation in more than half, but this, in a large but unknown number, really hid prostitution. Laundresses and cooks predominated among those whose definite domestic service was given. Seamstresses, dress- makers, and miUiners comprised about six per cent, of the admissions and were more numerous than women working in factories and shops. The influence of heredity is believed by sorne authors to be more potent than environment. Plutarch's saying that "drunkards beget drunkards" has been long recognized. Many descendants of alcoholic parents inherit a weakened and unstable nervous system. How large this proportion is to the total of such descendants it is impossible to calculate, but that it is large is undoubtedly true. The statistics of many institutions show that from 20 to 75 per cent, of these alcoholics have had either an alcoholic father or mother, or both parents given to such excesses. The compelling craving for alcohol in the parent is not inherited but a weak and unstable nervous system which renders the individual liable to excess in all things, and slighter indulgences lead quicker to the formation of the alcoholic habit. It is of interest to note the relation of age to the admissions for var- ious forms of alcoholism in Bellevue Hospital. For comparison, the ages of 10,636 male and 8,132 female admissions were taken. The largest number of admissions for males occurred in the period 33-37, and the largest number of females in the period 28-32. Up to the ag3 of thirty-two there was a greater percentage of women than men. Between thirty-three and fifty-seven there was a greater percentage of men; at 58-62 and older, there was a slightly larger percentage of women. Of the women 20.8 per cent, were in the period of 28-32 and 19.9 per cent, of the men in the period 33-37. Of the women 17.2 per cent., and of the men 9.7 per cent., were younger than twenty-eight years; 37.9 per cent, of the women and 27.5 per cent, of the men were younger than thirty-three years; and 54.5 per cent, of the women and 47.5 per cent, of the men were younger than thirty-eight years. Through the three periods of twenty-eight to forty-two years there were 53 per cent, of the women and 57 per cent, of the men; through the five periods of thirty- three to fifty-seven years there were 66 per cent, of the men and 53.8 per cent, of the women. In the old age periods, after fifty-seven years of age, there were 7.6 per cent, of the women and 6.4 per cent, of the men. The greater relative number of young women is due to the facts that alcohol usually poisons women quicker than men and, among the working classes, the men, by a larger amount of muscular work, burn up more alcohol and thus escape some of its toxic action. These statistics are also influenced by the number of young prostitutes who 160 DISEASES CAUSED BY ORGAXIC AGENTS are necessarily included in tlie stutistics from any large city. Alco- holism, as is well known, i,'^ more prevalent among men than women; dur- ing the ten years, 1S95 to 1905, there were two and a half times more men than women admitted to Bellevue Hospital suffering from alco- holism. The effect of season and other external influences is well shown by the admissions for alcoholism for the ten years, 1895-1905, in Bellevue Hospital. The total admissions in the alcoholic wards in that time were 43,916 males and 1(),07() females. Considering the male and female curves for each of the ten years, there are some variations which are not shown in the average curve for the ten years. Periods of great heat cause a marked rise in the male curves but only a slight corres})onding rise in the female curves. In some 630 cases of insolation collected in August, 1896, in New York, there was a history of alcoholism in nearly 90 per cent, and the men greatly predominated, there being 589 men, 40 women and 1 child. Sociological conditions, such as labor strikes, cause a great increase of alcoholism among both men and women, as occurred in New York, in 1903. The variations in the Bellevue records show more varied and wider excursions in the male than in the female curves, and t^ie rises and falls of the two curves in the same years do not always run parallel. Taking the average curves for the ten years by monthly admissions, the point of the January curves in both sexes is lower than the previous December; in February there is a distinct fall, reaching the lowest period of the year. There is a spring rise in March and April, a May fall, a June rise, a fall in July and iVugust, a marked September rise and here the two curves separate, there being an October fall in the male and an October rise in the female curve, the point of the October rise being the highest point for the year in the female curve, a November rise in the male, the highest point for the year, and a November fall in the female and a December fall in the male and December rise in the female curve. Both agree in having the greatest number and highest daily average during the last four months of the year. Comparing the curve of the alcoholic with those of the general medical and surgical admissions, a striking difference is evident. The two curves are practically reversed for both men and women, as the greatest number of admissions for general diseases occurs in the first four months of the year. The curves for alcoholism here described are not those of the delirious cases alone, but are for all forms of alcoholism, the acute cases forming a minority. Pathology. — There is no drug used in medicine about which more erroneous ideas have been transmitted than concerning alcohol, and the knowledge of the results of experiments on which is based our realiza- tion of its true action in the body, is not widespread among the medical profession. Ethyl alcohol is the one chiefly to be considered, but in the distillation of whiskies there occur other bodies as aldehydes, and some of the higher alcohols which are usually grouped together under the name of "fusel oil," and their action deserves consideration. In the compounding of cheap whiskies, and in their adulteration and manu- facture, methyl alcohol must be considered by itself. In the ageing of wines, the ethers giving the various bouquets are not without their separate action. ALCOHOL 161 Methyl Alcohol. — This is also called wood alcohol and is sold in the United States as Columbian, colonial, union, or eagle spirits. In Canada, it is sold as greenwood or standard wood spirits. This is used instead of ethyl alcohol to adulterate the various essences or colognes and often to adulterate cheap whiskies. In experiments on the toxicity of the different alcohols, considering that of ethyl alcohol as 1, methyl alcohol is from .46 to .8, but this gives a false idea of its true toxicity when taken by man, although idiosyncrasies of resistance to methyl alcohol vary greatly, as the ingestion of two teaspoonsful of it has been followed by bhndness; in other individuals many ounces have been taken, followed only by intoxication. Another peculiarity of methyl alcohol is that, except in very large doses, the serious toxic symptoms may be delayed for twenty-four hours or even several days. Even in animal experimen- tation, while more methyl than ethyl alcohol may be required per gram of body weight to cause death in one or two days, several observers have noted that methyl alcohol, administered to animals over long periods, causes serious nervous symptoms and produces pathological lesions in doses in which ethyl alcohol has little effect. The intolerance for methyl alcohol for long periods is due to the fact that a considerable portion of it is turned into formic acid in its passage through the body. The single constant pathological change found in animals after poison- ing by methyl alcohol is fatty degeneration of the liver, the amount of fat extracted from the dried liver of dogs, thus poisoned, being over double the normal amount. Recently Wood and BuUer published 275 cases of methyl alcohol poisoning, among which there were 122 deaths and ]53 instances of blindness. In New York City, in the winter of 1904r-1905, there were 25 deaths from methyl alcohol poisoning, after drinking whisky adul- terated with it. These authors emphasize the great idiosyncrasies to the toxic effect of methyl alcohol and give three degrees of intoxica- tion. The first shows the ordinary marked symptoms of intoxication with dizziness, nausea and marked gastro-intestinal disturbances, termi- nating in perfect recovery in a few days, sometimes followed by more or less serious damage to vision. In the second degree, the dizziness, nausea, vomiting and gastro-intestinal disturbances are much more pro- nounced; there is marked cardiac depression, w^eak pulse, sweating and slow respiration; there may be delirium or unconsciousness which often deepens into coma and death. If coma once supervenes, recovery seldom takes place, for even if the patients recover consciousness, they usually relapse into coma and die. There is very often a sudden develop- ment of widely dilated, reactionless pupils, with complete or nearly com- plete blindness. After recovery, dimness of vision, often increasing to total blindness, is characteristic of this degree of poisoning. The third degree is that in which an overwhelming prostration comes on, which terminates in coma and death. Nearly all the severe cases which are not fatal, show characteristic bilateral, total blindness, coming on in a few hours or perhaps not for several days; this is followed by partial restoration of vision, which again, after days or weeks, gives place to a more or less complete and permanent blindness and atrophy of the optic nerve. In the majority of fatal cases, death seems to occur in less than twenty-four hours, though methyl alcohol may kill within an l62 DISEASES CAUSED BY ORGANIC AGENTS hour or death may be delayed for one or two days or even longer. Con- sidering the visual disturbances, in 41 instances there were 16 cases of total blindness, 3 total in one eye, 15 partial recoveries and 7 recoveries. In 35 patients, the sight became dim in G, in from three to twelve hours; in 20, in twenty-four hours; in 5, in forty-eight hours; in 2, in seventy-two hours; in 1, in six days. The sight was lost in 2, in twelve hours; in 10, in twenty-four hours; in 5, in from thirty to forty-eight hours; in 12, from the third to the eighth day; in 1, in seventeen days. The ophthalmoscopic (examination shows the visual field contracted, absolute central scoto- mata, the nerve head first congested, followed by gray or white atrophy and contracted vessels. Pathological examination shows a retrobulbar neuritis, papillitis, other inflammatory symptoms and atrophy of the optic nerve. In those dead from methyl alcohol poisoning, at autopsy, intense con- gestion of the stomach and intestines, with a characteristic odor of methylated spirits, is noticeable. For the sake of conciseness, we will consider here the treatment of methyl alcohol poisoning. The treat- ment of the optic nerve atrophy is not very satisfactory in severe cases, although pilocarpine, sweat baths and potassium iodide as soon as the patient's condition permits, in the early stages of neuritis, followed by strychnine, hypodermically, seem to limit the extension of the secondary atrophy. The general treatment consists in washing out the stomach, and vigorous stimulation by strychnine, caffeine and digitalis, hypo- dermically. It seems useless to give these drugs by the mouth. Ergot, hypodermically, will also be found useful. High enemata, of warm saline solution or of glycerine and castor oil, should be given. Higher Alcohols. — These, such as propyl, butyl, and amyl alcohol, are undoubtedly more toxic than ethyl alcohol and their toxicity in- creases as they mount in the chemical scale. This group, with sub- stances such as furfurol, compose what is generally called fusel oil. It has often been claimed that these alcohols cause many of the symptoms of chronic alcoholism, but recent work shows that they practically play no role in the acute or chronic poisoning. It is however claimed that the so-called moonshine whisky, produced in the mountains of some of the Southern states, is very deleterious if drunk when freshly dis- tilled. The fresh rye or corn whisky would contain the greatest amount of fusel oil, for these higher alcohols are oxidized and changed into other substances, which give to old whiskies the various ffavors, and the older they are, the less they contain of these substances. Huss has shown that amyl alcohol, in human beings, taken in doses of J to ^ grain, caused no toxic symptoms; doses of 1 to 2 grains were followed by sensations of oppression in the chest, with temporary feel- ings of dizziness; doses of from 3 to 4 grains acted as a gastro- intestinal irritant, causing a burning sensation in the epigastrium, colic, vomiting and diarrhoea. He estimates that the total amount of amyl alco- hol contained in twelve to fifteen glasses of brandy is only 1 to 1^ grains, and the effect produced by this in ordinary drunkenness would prac- tically be nil. Baer studied the effect of adding a definite percentage of these higher alcohols to ethyl alcohol, and found that the addition of 2 per cent, of amyl alcohol caused an appreciable increase in toxicity, and the addition of 4 per cent., a very considerable increase, so that a ALCOHOL 163 severe type of poisoning resulted in animals. It is evident therefore, that larger percentages of these higher alcohols than are found in even the worst alcoholic beverages must be added to ethyl alcohol, bei'ore we can attribute to them any great share in the fatal outcome of an acute poisoning. Chittenden has shown that these higher alcohols, when present in amounts in which they are likely to occur in the alco- holic beverages, tend rather to increase, than to decrease, the rate of digestive action. Furfurol, or pyromucic aldehyde, is also present in fusel oil. Joffroy has found that the toxic equivalent of this substance is 0.14 for rabbits and 0.20 for dogs as against 8.20 to 8.60, the true toxic equivalent of ethyl alcohol for these animals. But as a liter of rum contains only 0.015 to 0.040 grams, a liter of cognac 0.005 to 0.015 grams, if we assume that man is as sensitive as rabbits to furfurol, it would require from 300 to 700 liters of rum or brandy to furnish the fatal dose. We must therefore leave out the consideration of this aldehyde in the conditions produced by ordinary alcoholic beverages. Ethyl Alcohol. — This is the main constituent of most alcoholic bever- ages and to its action alone are due the symptoms of alcoholism as seen in man. The spirituous liquors contain from 47 to 56 per cent, alcohol; fortified wines, such as sherry, madeira and port contain about 18 to 22 per cent. The Sicilian wines, such as malaga and marsella, contain from 16 to 20 per cent., champagne about 9.2 per cent., the Rhine wines about 10 to 12 per cent, and the clarets 9 per cent. ; of malt liquors, ale 5 to 8 per cent, and beer 2J to 5 per cent, of alcohol. Spirituous liquors may be considered as acting in ratio to their alcoholic content; the wines, however, vary in their action, either from the ethers which they contain or, in some instances, as far as digestion is concerned, in proportion to the contained solid matters, rather than to their alcoholic content. After the ingestion of ethyl alcohol, the first action produced, aside from that on the mucous membrane of the mouth and stomach, is the flushing of the face and skin. This often follows small doses, which show no other effect upon the circulation. Sometimes a slight sweating of the hands and face accompanies this flushing. This may be due to a beginning paralysis of the vasoconstrictors, or as Meltzer believes, to a stimulation of the vasodilators or of some inhibitory function acting on the vasomotor centre and inhibiting its tonus. In either of these last two cases, it would be a stimulation, and not a paralysis, of a normal function. Most observers find that moderate doses dilate the peripheral capillaries without altering the blood pressure, and without any stimulation or depression of the heart action. The pulse rate is not altered after moderate doses, and an increase does not occur until doses sufficiently large to cause a fall in the blood pressure have been given. It has been long noticed, however, that a change in the char- acter of the pulse does occur and it feels as if fuller and stronger after moderate doses of alcohol. Some experiments of Kochmann give results opposed to some of the above conclusions, but furnish experimental proof for others. He found that in human beings, doses of 40 to 60 Cc. of a 10 per cent, or 40 to 50 Cc. of a 15 per cent, alcoholic solution, caused a rise in blood pressure. This reached its maximum 20 to 30 minutes after the ingestion of the 164 DISEASES CAUSED BY ORGANIC AGENTS alcohol, and then gradually diiniiiishcd until, after 60 to 75 minutes, it had entirely di.sapj)eared. This rise amounts usually to 15 mm. Hg. In some individuals, however, it was as much as 30 mm., but in others it amounted to only 5 mm. and in still other ])atients did not occur at all. Doses of 60 to SO Cc. of a 20 per cent, solution or 50 to 60 Cc. of a 30 per cent, so- lution of alcohol caused at first a slight rise followed by a fall of blood pressure. A dose of 50 Cc. of a 50 per cent, solution of alcohol produced from the beginning a fall of arterial pressure, but this was not more than 10 mm. Hg. and 60 minutes after the pressure had risen to the ordinary height. These results could only be obtained in individuals who were complete abstainers or practically so. It was also noted that, after the rising blood pressure had reached its maximum, it was ])ossible to keep it at this level by the administration of a second similar dose of alcohol. It was further found that the pressure could be kept up for four hours at the given height by administering alcohol at thirty-minute intervals and the blood pressure did not fall to its ordinary level until an hour after the last dose. During these experiments the frequency of the pulse remained practically constant, increasing only after large dosage with a fall of blood pressure. The size of the pulse was noticeably increased both to the palpating finger and in sphygmographic tracing; in the latter, the pulse excursion became greater and the dicrotic notch more noticeable. The rise of blood pressure seems dua to stimulation of the vasomotor centre followed by contraction of the vessels of the splanchnic area, which overcompensates the peripheral dilatation. Large toxic doses of alcohol gradually lower the reflex excitability of the vasocon- strictor centres, dilating the arteries and capillaries of the splanchnic and peripheral areas, lowering the blood pressure, and acting directly on the heart muscle as a powerful depressant, weakening first the auricular and then the ventricular systole, causing more or less distension of both cavities and gradual diminution in the output of blood. The action of alcohol, therefore, on the circulation, after moderate doses, is a change in the distribution of the blood and perhaps an increase in the power of the heart's action without increasing the pulse frequency. In large doses, it paralyzes both the control of the vessels and the heart muscle. Dilatation of the skin capillaries gives a sensation of warmth and there is increased radiation of heat from the body, but the temperature is seldom reduced more than 1° or 2° F. That very large doses of alcohol may cause a fall of 5° to 9° F. or even more, was exemplified in a patient whose temy)erature on admission was 90° and remained between 90° and 92° for fifteen hours; it then rose slowly to normal, reaching this point thirty-six hours after admission. The lowest temperature Avhich has come under the writer's observation, was in a woman found comatose from alcohol, when the temperature of the air was about 6° above zero. After she had been in the hospital for three hours, wrapped in blankets, her rectal temperature was 80° F. The temperature reached normal twelve hours after admission. Such temperatures as these, in drunkards exposed to cold, are unusual, but by no means unique. Shafer gives records of temperatures in drunkards after such exposure, of 79.5°, 86.6° and 83.1° F., the patients dying, while others, with temperatures of 72.2°, 76.4°, 82.2° and 86° F., recovered after a few days. ALCOHOL 165 The respiration is directly stimulated by moderate doses — according to Binz — more in fasting and fatigued individuals, than after a meal or in non-fatigued persons. This direct stimulating action on respir- ation is not accepted by all, alcohol being often classed as an indirect respiratory stimulant. In large toxic doses there is a paralyzing efi'ect on the respiratory centres, and the breathing becomes stertorous and slow. In studying the effects of alcohol on the digestion, we find that it stimu- lates the flow of saliva and also the concentration and amylolytic power of human mixed saliva. This is purely a local reaction of short duration, ceasing when the alcohol is swallowed. Alcoholic fluids, when intro- duced directly into the stomach, do not stimulate the salivary flow. Upon gastric secretions, alcohol has a marked effect, increasing very greatly the flow of gastric juice and its content of acid and total solids, giving a juice of strong proteolytic action. Furthermore, this action is exerted, not only by the presence of alcohol in the stomach, but also indirectly through the influence of alcohol absorbed from the intestines. Any direct influence of alcohol on the pancreatic or intestinal secretions must be small, because of its rapid disappearance from the stomach by absorption. On the chemical processes of digestion, Chittenden has found that pure absolute alcohol has no very marked influence on the digestion of farinaceous foods by the saliva. The presence of 5 per cent, of absolute alcohol may lead to a slight increase in the digestive power of active saliva. Large quantities cause retardation of amylolytic action, but even 10 per cent, of absolute alcohol produces only slight retardation, hardly recognizable in the solvent action, but showing in the amount of reduced sugar formed. Whisky, brandy, wine, and malt liquors show a powerful inhibitory influence upon salivary digestion, out of proportion to their alcoholic content and due almost entirely to their acid properties. The influence of alcohol on the chemical action of gastric juice is nil when present from 1 to 2 per cent., and not until the digestive mixture contains from 5 to 10 per cent, of absolute alcohol is the action of the gastric juice materially interfered with. The malt liquors in small amounts are without inhibitory influence on the gastric juice, showing a tendency to slightly increase the rate of digestion. In larger amounts, they give rise to an inhibition of proteolysis, which is entirely unconnected with the small amounts of alcohol present, but directly traceable to the comparatively larger amount of extractives they contain. There seems but little chance that alcohol, when consumed in moderate amounts, influences digestion in the small intestine, it being too rapidly absorbed to have much effect. Pancreatic juice, how^ever, in its proteoly- tic action, is more sensitive to pure alcohol than gastric juice, 2 or 3 per cent, of absolute alcohol being sufficient to produce a distinct retardation of proteolysis. The acid substances contained in the spirituous liquors and wines have a more detrimental action on the proteid digestion of the pancreatic juice than the alcohol in these beverages. The extractives in the malt liquors likewise exert an inhibitory action upon the pancreatic proteolysis. The amylolytic ferment of the pancreatic juice, being similar to the salivary enzyme, is affected the same as in salivary digestion. Moderate doses of alcohol, taken not too frequently, would seem, as a sum total of their action, to favor an increase in the digestive processes, 166 DISEASES CAUSED BY ORGANIC AGENTS but after repeated consumption, the digestive processes are perverted and diminished. We know from the experiments of Atwater and Benedict, that after the absorption of alcohol, 98 per cent, of moderate doses is consumed in the body, the residue being excreted by the lungs and kidneys. It is used by the body for the needs of heat and muscular work, and in this way protects the body fats from consumjjtion. It can, and sometimes does, protect the protein of food or body tissue from consumption, but at other times, in small doses, especially in persons not accustomed to its use, it fails to do this, even increasing the protein disintegration. In large quantities it is positively toxic; retarding or even preventing metabolism, and protein metabolism in particular. It is evident that alcohol, up to a certain amount, in healthy persons furnishes the equivalent of energy of the iso- dynamic amount of fats and carbohydrates, and the total amount of nitrogen under these circumstances must remain the same. The form in which nitrogen is excreted in the urine is often materially changed under the influence of moderate doses of alcohol. From the experiments of Beebe, in healthy young men on a given diet and in a state of nitroge- nous equilibrium, when alcohol is given, the percentage of urea to the total nitrogen is diminished and the percentage of ammonia and uric acid are noticeably increased. The men used in these experiments were unaccustomed to alcohol and showed under its influence a slight increase in the total amount of nitrogen excreted. From the recent work of Folin, experiments on persons of low nitrogenous diet and on persons of high nitrogenous diet, show that the distribution of the nitro- gen in the urine among urea and the other nitrogenous constituents, de- pends on the absolute amount of total nitrogen excreted per diem, but after taking this into account, the experiments of Beebe show that the uric acid and ammonia are increased and the urea diminished under the influence of only moderate doses of alcohol. From some yet unpub- lished work, kindly furnished to me by F-wing and Wolf of Cornell Uni- versity, in the urine obtained from patients suffering from various degrees of alcoholism in Bellevue Hospital, New York, excreting from 10.3 to 17.4 grams of nitrogen in twenty-four hours, the urea nitrogen ranged from 64.7 to 84.1 per cent, of the total nitrogen. The percentage of the ammonia nitrogen to the total nitrogen ranged from 2.2 to 7.4 per cent, and the relative percentage of the amino acids to the total nitrogen from 4.8 to 14.4 per cent. Comparing this with the results given in Folin's work for normal individuals excreting over 10 grams of nitrogen, it is seen that in normal persons excreting from 14.8 to 18.2 grams, the percentage of urea was from 86.2 to 89.4 per cent, of the total nitrogen, the ammonia from 3.3 to 5 per cent, and the amino acids from 2.7 to 5.3 per cent. Comparing the above results, it seems fair to conclude that in some indi- viduals suffering from chronic alcoholism, the percentage distribution of the substances forming the total nitrogen in the urine is materially altered in the ratio of urea, ammonia and amino acids to the total nitrogen. In three patients suffering from alcoholism, who excreted less than 10 grams of nitrogen in twenty-four hours, the ratios of urea, ammonia and amino acids to the total nitrogen did not vary to any greater extent than was seen in Folin's experiments with five healthy individuals excret- ing an equally low total nitrogen. In some of the patients in whom the ALCOHOL 167 ratios mentioned deviated most from normal, postmortem examination showed the livers extensively diseased; whether this was a coincidence or not is uncertain. It is evident, however, that, although alcohol may be used by the body for energy, the metabolic changes are not similar, and it must be a question of some moment from whence the body draws its energy, whether it be [alcohol, fats or carbohydrates. It is evidently possible for the body to use alcohol as a food material but the changes in metabolic results show that while being consumed as a food, alcohol may simultaneously exert its drug or toxic action. As to whether alcohol is a source of heat when oxidized, Atwater found in his rest experiments, the heat given off from the body was equivalent to the total potential energy of the material oxidized. This was as true in the experiments in which alcohol made part of the diet as in those with ordinary food exclusively. Hence alcohol must have contributed its full quota of heat as did the starch or fat, and all its potential energy was converted into heat. The same principles apply in the work experi- ments and unless all the potential energy in the alcohol was converted into the energy of internal work in the rest experiments and into that of internal and external work in the work experiments, certainly an improbable hypothesis, part must have been transformed directly into heat in the body. The question whether the energy of alcohol is used for muscular work is not definitely settled. There is no evidence that there is a difference in the energy or heat derived from alcohol and from other nutrients, but there is no proof that such difference does not exist. It certainly seems, from these experiments, that probably such energy for muscular work is derived from the alcohol. It is Atwater's opinion that the utilizations of the energy of the whole ration are slightly less economi- cal with alcohol than with ordinary diet, especially when the subjects were at hard, muscular work. For it was noticed that there were indications that the subjects worked to a slightly better advantage with ordinary rations than with alcohol. The possibility here shown of alcohol in moderate doses furnishing energy for muscular work is a far different question from the possibility of alcohol as a part of the diet for muscular labor. General observations, and the results of practical tests on a large scale, show such beverages to be of doubtful value or even harmful. Alcohol apparently increases the power of fatigued muscles, although it does not restore to them the same amount of power as they possessed before they were fatigued, and this restoration of power is only temporary and of short duration. It also lessens the sensation of fatigue, acting in some measure through the nervous system. To non-fatigued muscles it gives only a temporary increase in the work done. Alcohol will thus enable a brief spurt to be made, but it will not give sustained muscular power and is followed by a depression of energy to below the normal. The action of alcohol on the brain is still a subject of dispute. Binz holds that alcohol first stimulates and then depresses; Schmiedeberg, Bunge, and others that the apparent stimulation of alcohol is a paralysis of the higher functions and that alcohol depresses from the beginning. Kraepelin claims to have proven from his experiments, that, in the early stages of its action, alcohol truly stimulates the motor functions of the brain, but that all reactions requiring nicety of judgment are dulled by even small doses. Kraeplin has also shown that small doses diminish the 168 DISEASES CAUSED BY ORGANIC AGENTS accuracy and ability to add numbers or to learn numbers by heart Smith has shown that this is especially noticeable when small doses of alcohol are taken daily, and that, when the alcohol is cut off, the ability to add and to memorize immediately returns. It is also noticeable that the tendency to erroneous judgments is increased, the subjects experimented upon believing that they had performed their reactions better under alcohol, when, as a matter of fact, the reactions were diminishetl in accuracy and rapidity. Alcohol in moderate doses does not increase the quantity or vigor of mental processes, and the flow of ideas with the feeling of mental richness is due to the removal of normal inhibitions. Alcohol clearly tends to lessen the power of clear and consecutive reasoning and decidedly lowers the acuteness of the senses. After large doses the judgment is lost, the powers of self-control and will are in abeyance, all idea of ])roportion is gone, the sense of responsibility and restraining impulse is destroyed, and finally, the motor power for speech and motion disappears and torpor and coma supervene. The result of the continued action of large doses is the permanent loss of these mental functions and the chronic alcoholic becomes an irresponsible animal. Pathological Effects. — Since Anstie classified alcoholism as a nervous disease, it has been generally so considered. As concerns the relation- ship of man to his environment, the effect of alcohol on the brain is a predominant manifestation, but for the individual, the effect of alcohol on the heart and circulation in acute poisoning, and on the heart and abdominal viscera in chronic poisoning, is often more important. All the viscera are aft'ected by chronic alcoholism, the cerebral symptoms dominating only because of the special function of the brain. Death from acute poisoning by alcohol is rare, and usually follows large doses in those unaccustomed to its use, or sometimes in children, who have accidentally swallowed a large amount of some concentrated alcoholic beverage. The lesions found at autopsy do not correspond to the severity of the symptoms There is an intense overwhelming of the functions of the various organs, which occurs so quickly that it leaves no corresponding anatomical change. Thus a young, healthy man who had been drinking heavily all day, after sitting quietly, attempted to walk across the ward and dropped dead; the autopsy showed no cause for death. Death may occur suddenly, as in this case, after several hours of drinking, or within half an hour, or coma may suddenly come on after several hours and be fatal. In such acute poisoning, if death follows soon, the body may resist decomposition for an unusual length of time. The stomach and tissues may even have a more or less well marked alcoholic odor. The stomach, oesophagus, and duodenum may be of a deep red color, with, at times, punctiform ecchymosis in the gastric mucous membrane. There is at times, but not constantly, a venous congestion in some of the viscera and the bladder is often greatly distended. There is frequently congestion and sometimes extravasation of blood or oedema in the brain and its membranes. There may be a serous effusion in the ventricles. In one young woman, thirty-two years of age, previously a total abstainer, who took enormous amounts of alcohol, dying after four days' poisoning, the brain showed acute encephalitis with marked cellular degeneration; the spinal cord showed degeneration in the posterior tracts and in the cells of the anterior horns. The peripheral nerves were normal ALCOHOL \m Microscopically, the nerve cells show two different lesions. One, as shown by the Goigi method, is the so-called moiiiliforni change, character- ized by the appearance of irregular swelling from varicosities in the course of the protoplasmic processes of some of the nerve cells, associated with partial loss of the delicate bud-like or spinous projections normally pres- ent in these processes. The second change is that of chromatolysis, and is shown by the disintegration of the small chromatin granules, known as the Nissl bodies, as brought out by the stain of that name. These changes are not in ratio to the severity of the symptoms and as Welch says, they do not represent any serious permanent damage to the nerve cells, but are rapidly recovered from after the disappearance of the causa- tive factor. They seem to be the only significant anatomical change produced by acute alcoholic intoxication. These changes are not general and occur only in a minority of the cells, but they have been found in the cells of the cerebral hemispheres, the cerebellum, medulla, the spinal cord and the sympathetic ganglia. In studying the lesions of chronic alcoholism, one is forcibly struck by the great variations in their intensity in the various organs of different individuals. Personal idiosyncrasy is as marked in the lesions produced by alcohol as it is in the susceptibiUty of different individuals to the same dose. In 1 person, the brain may show the greatest change, and in another, the heart and arteries seem chiefly affected; in others, in may be the liver, or the kidneys, which seem to have borne the brunt of the toxic action. In studying the age at which death occurs from various forms of chronic alcoholims, there is a noticeable difference between the sexes. Taking 541 deaths from alcoholism in Bellevue Hospital, New York, 318 men and 223 women, it is noticeable that the highest per- centage of the men died in the same quinquennial period in which there were the greatest admissions, while the greatest percentage of female deaths was ten years later than the period of greatest admissions; thus 20 per cent, occur in men between thirty-three and thirty-seven years of age, and 19 per cent, of the deaths in woman occur between thirty-eight and forty- two years of age. This is undoubtedly due to the prevalence of pneumonia at these ages. Between thirty-three and forty-two years of age, both sexes show practically the same percentage (men, 34.4, women 38.2). But there is a very great difference in the number of deaths before thirty-two years of age, the percentage in men being 17.2 and in women 31.4; that is, nearly twice as many young women die of alcoholism as young men. The fact that a large number of young pros- titutes are necessarily included, accounts for the larger number of young women dying from alcoholism. From the same causes, there are, both relatively and actually, more fat alcoholic women than men and the bodies of the great majority of both sexes are well nourished, and this is striking, when we consider for what long periods these patients subsist on alcohol alone, without other food; it also shows well the possible food action of alcohol. The fine, white, smooth skin of most chronic alcohoHcs is noticeable, due partly to accumulation of fat beneath the skin and partly to atrophy of the skin itself. To obtain an idea of the lesions in chronic alcoholism, the records of 125 cases are taken from the post- mortem reports of Bellevue Hospital, 90 of which were men and 35 women. These were not chosen because they showed certain lesions, but 170 DISEASES CAUSED BY ORGANIC AGENTS because the patients had given a definite history of alcohohc excesses. Many histories with pneumonia have purposely been rejected. In the heart, we find lesions resulting from direct poisoning and from associated conditions. Fatty degeneration of the muscle is the most com- mon lesion, brown, atro])hy combined with fatty degeneration is the second most common, brown atrophy alone the third, and fibroid myocarditis the fourth. There are often various combinations of the above lesions, and while fatty infiltration is said by most observers to be more common than fatty degeneration, the reverse held true, in my experience. That brown atrophy of the cardiac muscle is caused by alcohol seems to be true, for after excluding all cases in which carcinoma was present and in which there were any signs of healed or active tuberculosis, in the 125 cases, there remained 23 hearts from individuals under fifty-five years of age in which this degeneration was present. The secondary effect on the heart is shown through the circulatory system, and from disease of the coronary arteries we obtain fibroid myocarditis; and the enormous hy])ertrophied hearts of beer-drinkers are produced by the large amount of fluid passing through the bloodvessels. The arteriosclerosis produced by alcohol or secondary to the kidney lesions produced by it, is also a cause of the cardiac hypertrophy and later of the fibroid myocarditis. Sudden death not infrequently occurs in young alcoholics, who, possessing a heart with fatty degeneration, further poison it with alcohol, and when some sudden muscular action causes a sudden strain on the cardiac muscle, it fails, and death results. Alcoholic poison- ing is usually considered as a cause of arteriosclerosis and atheromatous degenerations. Lance reaux states that atheroma of the aorta and vessels is so rare in alcoholism that its presence almost excludes alcoholism. Certainly the experience in this country is widely different; it is charac- teristic of arteriosclerosis that lesions are unevenly distributed in the body, and the peripheral arteries may remain unaffected, while the aorta or central arteries may be extensively degenerated. Atheromatous degenera- tion is a frequent cause, in alcoholics, of aneurism, apoplexy, and embolism. Cabot, in studying the frequency with which arteriosclerosis may be made out in the radial arteries in alcoholics, comes to the con- clusion that it is not noticeably present in more than 6 per cent., but the atheromatous degeneration from alcohol is more commonly present in the aorta and large vessels of the neck and in the cerebral and viscereal arteries than in the peripheral. It is usually uniformly extensive in the aorta and vessels, although it is sometimes extensive in the aorta and but slight in the vessels of the neck, and in other cases, the reverse is true. The aorta and vessels may show very slight atheromatous changes and yet the coronary arteries be extensively calcified. In 53 men dying under fifty years of age, atheroma was extensive in 9, moderate in 26, slight in 14 and absent in 4. In 19 women atheroma was extensive in 6, moderate in 6, slight in 6 and absent in 1. The most common conditions found in the lungs are oedema, congestion, and the various forms of pneumonia, such as lobar, broncho- septic; and aspiration pneumonia is not infrequent, especially in those who have serous meningitis and inhale particles of food. It is also very common to find tuberculosis in various stages; the old'idea that alcohol is preventive of tuberculosis is proven to be unfounded and it is unquestionably true ALCOHOL ■ 171 that alcoholism reduces the resistance of the bofly and distinctly predis- poses to tuberculous infection. Puhnonary emboli from cardiac throm- bosis and embolism of the pulmonary arteries were also found in this series. The liver has always been considered as especially prone to show changes from chronic alcoholic poisoning with fatty degeneration and cirrhosis as the two special forms of degeneration. Rosenfeld has found that a fatty liver can be produced in dogs, if they be starved for six days and then fed on alcohol, and by this method, after more than four doses of 3J to 4 Cc. of 96 per cent, alcohol, the fatty content of the liver increases over the normal 10 per cent, in starving dogs to an average of 22.6 per cent. If sugar be given with the alcohol, fatty degeneration does not take place. This seems to indicate that the frequency of fatty degeneration in man may depend in some measure on the common abstinence from food among alcoholics. It is very noticeable clinically, that those who par- take of large amounts of malt liquors are especially prone to fatty degener- ation of the liver. In the 90 livers of men examined, fatty degeneration occurred in 37 per cent., and, of the 35 women examined, it occurred in 40 per cent. In combination with cirrhosis, brown atrophy and paren- chymatous degeneration, fatty degeneration was present in 43 per cent, of the men, and 34 per cent, of the women. That is, it was present in 80 per cent, of the livers examined of the men and 74 per cent, of the women. Fatty degeneration combined with cirrhosis was the second most common lesion, being seen in 31 per cent, of the men and 17 per cent, of the women. Animal experimentation has not yet proven that progressive cirrhosis of the liver is produced by alcohol, but clinically we find a well defined history of excessive alcoholic indulgence in the great majority of patients suffering from cirrhosis. The fact that it occurred in almost one-half of the men and over one-third of the women examined in the necropsies under con- sideration, would certainly indicate its alcoholic origin. The term cir- rhosis, here used, is meant to designate an increase in the connective tissue, whether the liver was larger or smaller than normal or of normal size and weight. The enlarged cirrhotic liver seems to be the most frequent, and the true biliary cirrhosis, the least frequent. Clinical experience in Bellevue Hos- pital, New York, suggests that the extreme degrees of cirrhosis do not occur so commonly as they did fifteen or twenty years ago. This is probably due to the greater use of malt liquors. Lancereaux believes that, in Paris, those who drink wine in excess are the most prone to suffer from cirrhosis of the liver. Whisky, gin, and rum are more likely to produce the atrophic form of cirrhosis and the contracted hob-nail liver. The exact process by which cirrhosis is produced is still a disputed point. Alcohol is a cellular poison, causing degeneration and death of cells, which may be followed by an increase in connective tissue and thus be the chief cause of cirrhosis, or since acute and chronic congestions are at times followed by an increased growth of the fibrous tissue, the cirrhosis may result from the chronic hyperaemia produced by the dilatation of the vessels and congestion result- ing from the incessant doses of alcohol. Rosenfeld expresses the view with considerable reserve, that cirrhosis of the liver is the result of very long continued alcoholic poisoning with doses which cause most men to succumb; this he believes would explain the infrequency of cirrhosis 172 DISEASES CAUSED BY ORGAXIC AGEXTS relative to the large numbers of alcoholics. In the reported cases of children sufferino; from cirrhosis of undoubted alcoholic origin, it is noticeable that the disease seems to follow more (]uickly and from smaller doses than in adults. In the Bellevuc Hospital necropsies it was present in some ilegr^ee in 48. S per cent, of the men and 34 per cent, of the women. It is a very striking fact that in not a single individual of the 125 examined was the liver reported normal. In the spleen, chronic congestion and fibrosis are the two most common pathological conditions. Chronic congestion was found in 30 per cent, of the men and 66 per cent, of the women, fibrosis in 25 per cent, of the men and 18 per cent, of the women. Acute congestion occurred next in fre- quency; other conditions found were brown atrophy, amyloid degener- ation, Inemachromatosis and brown atrophy. Perisplenitis is recorded in 4 patients. In 4 men and 1 w^oman the spleen was normal. In the ])ancreas, the great frequency with which chronic fibrosis occurs is very noticeable. In the seventy-four times in which the pancreas is mentioned in the men, chronic fibrosis occurred in 52 per cent, and in 29 women it occurred in 50 per cent. Fatty infiltration occurred in 16 per cent, of the men and in 14 per cent, of the women. The pancreas was mentioned as normal in 23 per cent, of the men and in 25 per cent, of the women. It was atrophic in 3 patients and hemorrhagic in 1 man and 1 woman. The adrenal bodies, in 70 men, showed fatty degenera- tion of the cortex in 34 per cent., and in 21 women this lesion was present in 57.5 per cent. These bodies were mentioned as normal in 58 per cent, of the men and in 38 per cent, of the women. There has been much discussion as to the effect of alcohol upon the kidneys. It has been frequently demonstrated, as Welch points out, that the urine, even after a single alcoholic excess, often contains abnormal elements, indicative of transient irritation or of slight inflammation. In animal experiments, von Kahlden has shown that in dogs there occurs a fatty degeneration and necrosis of the renal epithelium, hypereemia of the veins and capillaries with hemorrhages, and he considers that with longer duration of the experiments, chronic interstitial nephritis would appear as a result. Formad found in alcoholics, who died suddenly, a marked hyper- semia of the kidneys with noticeable enlargement in beer-drinkers. The enormous amount of fluid taken produces a functional hypertrophy. When arteriosclerosis has developed, the chronic forms of kidney disease necessarily follow. It has been very noticeable in the autopsy experience of the author that there are no records of normal kidneys; all examina- tions showed some lesions, chronic ones greatly predominating. Acute nephritis was mentioned in only 2 men and 1 woman. Acute inflammation grafted on chronic nephritis was present in 7 men and in 1 woman. Chronic parenchymatous nephritis, often with congestion, was the most common lesion, being present in 60 per cent, of the men and in 63 per cent, of the women. Chronic interstitial nephritis, at times with conges- tion, occurred in 39 per cent, of the men and 29 per cent, of the women. As these examinations were made on patients from twenty to over seventy years of age who had died from chronic alcoholism, it would seem to show that while the kidneys for years may escape, and personal idiosyn- crasies vary greatly the intensity of the lesions in various organs, sooner or later the kidneys are certain to become diseased. ALCOHOL 173 The stomach shows various forms of gastritis; chronic gastritis is one of the commonest lesions. An inflamed gastric mucosa, covered with ropy mucus, is common from acute alcoholism, and the acute sooner or later goes on into the chronic form. Chronic atrophic gastritis was present in 50 per cent, both of the men and the women examined. Hemorrhagic gastritis was present in 24 per cent, of the men and in 16 per cent, of the women. These two conditions were not infrequently combined. The mucosa of the intestines does not suffer so much as the gastric mucosa. The most common condition found is congestion, sometimes with oedema. In about 50 per cent, of the patients examined the intestinal mucosa was normal. The bladder is very apt to be over-distended in patients who have died suddenly or had unconsciousness before death. It may even be ruptured as was the case in two men in the service of the author. In about 25 per cent, of both sexes we found the lesions of either acute or chronic cystitis . That alcohol tends to produce sterility has long been known. In 5 among 12 women between twenty and thirty years of age, the ovaries were markedly atrophic, appearing like those a number of years after the menopause, and, in women between thirty-one and forty, they were atrophic in 5 among 8. Thus in half of 20 women under forty years* of age, they showed extensive atrophy. In the men, the testicles did not show gross evidences of atrophy, JDut, in the few examined microscop- ically, there was sclerosis. Lancereaux has proved this and Simonds observed that in 60 per cent, of chronic alcoholics on postmortem exam- ination, azoospermia was found. Broun and Garnier have confirmed by animal experimentation this atrophy of the testicles following alcoholic ingestion. It has long been recognized that alcohol has a special affinity for the higher nervous centres, and especially on those coming more into the clinical aspect of the disease. Inherited or acquired constitutional defects cause great variations in the effects of alcohol upon individual nervous systems and it is difficult to estimate the difference between the lesions caused by alcohol in previovisly normal persons and in those inheriting various defects. That a previously weakened nervous system will show earlier and more extensive lesions seems logical and is probably true, but the idiosyncrasies of normal persons to alcohol present wide variations. There seems no question that serious nervous diseases in persons of pre- viously normal constitutions are produced by alcohol. Some individuals will die of various somatic degenerations and still retain apparently nor- mal cerebral tissues, while, in others, the brain and spinal cord seem to suffer early, and disproportionately, compared with the heart and ab- dominal viscera. The lesions in the central nervous system seem to be brought about either from the degeneration of the cerebral arteries or from the direct action of alcohol on the nerve cells. In examinations of given brains, it is difficult, or often impossible, to differentiate how much the changes are due to one or other of these causes. Qi)dema and congestion of the membranes are usually present, especially the former, and this ordi- narily extends into the cerebral tissue itself and was mentioned as present in 72 per cent, of the 76 brains of the men and in 51 per cent, of the 29 brains of the women examined by us. Congestion of the cerebral tissue 174 DISEASES CAUSED BY ORGAXIC AGEXTS was found in 54 per cent, of thr men and in 14 per cent, of the women. Adhesions of the dura to the skull, with increase in the Pacchionian bodies, are common, and very frequently there is thickening, o])acity, and adhesions of the pia. Chronic meningitis was observed in 65 per cent, of the men and in 41 per cent, of the women and, combined with this, atrophy of the ccnvoiutions was found in 31 per cent, of the men and in 41 per cent, of th? women. Cerebral degeneration seems to be more common among women and corresponds with the clinical experience that women degenerate mentally from alcoholic excesses more quickly and more completely than men. Pachymeningitis is not uncommon and pachymeningitis hemorrhagica is not infrequently seen in alcoholics, probably from trauma acting on the diseased vessels. All inflammations in alcoholics seem to be prone to the hemorrhagic type and hemorrhagic meningitis was present in three men. The degeneration of the vessels produced miliary aneurysms and it is not uncommon to find recent cere- bral hemorrhages or encysted old hemorrhages or areas of cerebral soften- ing from cerebral embolism. Microscopical examination of the cerebral tissues shows an intense degree of atheromatous degeneration of the minute vessels which are enlarged, often tortuous, unevenly distended, usually by fusiform dilata- tions, and their tissues covered with nuclear proliferations. About these vessels the spider or glia cells are crowded in great abundance. These so- called scavenger cells form, with their branching processes, a thick con- nective tissue felting, densest just underneath the pia, converting the outer fourth of the cortex into a closely matted layer, much diminished from the normal thickness and often clearly mapped off from the layers beneath. Sometimes the cellular elements of the glia predominate, but in later cases many of the protoplasmic masses have disappeared, leaving a dense connective-tissue structure in which the remaining nuclei are thickly sprinkled. The perivascular spaces are often filled with lymphoid cells. The second and third layers of the cortex show but little change, but according to Bevan Lewis, a few of the low, pyramidal cells may be degenerated; the fifth layer of motor cells shows extensive fatty degener- ation and, with the spider cells beneath, is undergoing disintegration and absorption. The cells show a marked degeneration of their apical pro- cesses and, in many, these have disappeared. The axis cylinder shows a loss of medullary investment and is itself greatly swollen and often irregu- larly fusiform. The bodies of the motor cells are swollen, rounded, and constantly show an abnormal, coarsely defined boundary wall with pig- ment crowding against the cell body, wliich also shows vacuolization and often extensive chromatolysis. The white matter of the cortex shows equally extensive atheromatous changes in its vessels and in the fusiform and sacculated dilatations are seen deposits of htematoidin granules. Not infrequently the vessels are plugged and the diseased wall found ruptured with extra vasated blood and haematoidin crystals in the surround- ing areas. The changes found in the spinal cord are similar to those of the cerebral cortex. The vessels of the posterior and lateral columns are more involved than those of the anterior columns. The characteristic change is an obliterating endarteritis, the lumen of the vessel being en- croached upon to mch a degree that the intima is folded into ridges. At times the vessels are even occluded by this process. The pia of the cord ALCOHOL 175 often shows thickening and evidences of inflammation, an extension downward of chronic meningitis of the cerebral pia or a coincident chronic inflammation. The connective-tissue processes from the pia into the cord are thickened, the median raphe of the posterior columns and the peripheral zone of the cord being the areas of election for the sclerotic processes. The anterior and posterior nerve roots are sometimes involved. The degenerative processes may be unilateral or bilateral and the various segments of the cord show varying and irregular degrees of involvement. The paralysis produced by the peripheral neuritis was described by older writers, such as Magnus Huss, as due to lesions in the central nervous system. When the peripheral lesions were fully studied the local changes were deemed sufficient to account for all symptoms and the central nervous system was not considered as involved. The changes in the nerves were described as of two types: the first in which the degener- ation of the axis cylinder was primary, the second the interstitial type, in which hyperplasia of the endoneurium and perineurium were primary, pressure atrophy following in the axis cylinder process. The acceptation of the neuron theory has caused us to revert to the ideas of the older writers and realize that, in the vast majority, the neuritis of alcoholics is of central origin. In a series of cases of alcoholic neuritis occurring in Bellevue Hospital, Dr. Harlow Brooks, with whom the work of the author in the pathology of alcoholism has been done, has studied the central ner- vous systems and peripheral nerves. In one patient the peripheral nerves alone showed the degenerative changes ; the most diligent search with the Marchi method failed to show any corresponding changes in the cord. It is possible therefore that alcoholic neuritis may be due to involve- ment of the peripheral nerves alone, but we are led to believe that such are very exceptional. In some of the other cases there was marked degen- eration in the cortical cells of the cerebrum, especially in the motor areas, accompanied by degeneration of descending fibers in the internal capsule and in the descending columns of the spinal cord; not a true tract degener- ation but one of isolated and often widely separated fibers. In the spinal cord, extensive cytoplasmic degeneration was present in the ganglion cells of the anterior horn, the ventrolateral group being especially studied, and there were invariably isolated degenerated fibers in the anterior nerve roots. Degenerated fibers were found in the ascending tracts of the spinal cord, particularly in the severe cases, this being accounted for by alter- ations, at times very marked, in the ganglion cells of the posterior roots. In some cases ascending and descending degenerations were present in the same spinal cord. Similar results have been found by numerous other investigators. The special staining of nervous tissues by the Nissl and Marchi methods at first raised hopes that, in delirium tremens, some lesions would be found in the brain and spinal cord which would correspond to the clinical symptoms. But so far these hopes have not been entirely fulfilled. Al- though the Nissl cell changes were found in all cases of delirium and in chronic alcoholism, Marchi's degeneration change was not found in pathological amounts in all cases of delirium nor in the chronic alcoholism without delirium. The changes in the bloodvessels and connective tissue in delirium tremens seem to run parallel to the intensity of the chronic alcoholic processes. Apart from the tendency of the chronic arterio- 176 DISEASES CAUSED BY ORGANIC AGENTS sclerosis to cause hein()rrlia<2:cs, there is in (lelirium tremens a distinct tendency to minute, acute liemorrhages which are (Htt'usely scattereil and numerous in the cerebral cortex in the central and frontal convolutions, less frequent in the cerebellum and still less common in the sjjinal cord. They lie in the tissues, at times unaccompanied by a bloodvessel, and often there is a thin layer of red cells along a vessel. The place of predi- lection for these hemorrhages is the region of gray matter around the third ventricle and the aqueduct of Sylvius. They vary in size from minute areas to the size of a bean; a concomitant acute inflammatory process does not occur. These hemorrhages are very commonly observed in the regions of the nuclei of the oculomotorius and abducens nerves. Taking all the pathological changes into consideration, it cannot be said that delirium tremens presents a specific ])atho]ogy. The pathology of Korsakow's ])sychosis is a combination of what has already been described. This has the dura adherent to the skull, the thickened pia with its gray striations along the course of its vessels, the diffuse cerebral atrophy and increase of the connective tissue, the cellular degenerations shown by Nissl's staining and other changes produced by chronic alcoholism. There is the same tendency as in delirium tremens to small hemorrhages in the cortex, spinal cord, jieripheral nerves and especially in the regions of the nuclei of the third and fourth nerves. These may extend down into the fourth ventricle and involve the nuclei of the vagi. They occur only in jiatients succumbing in the early stages but in those who die later there is still evidence of previous hemorrhages. The spinal cord shows degenerations in the various tracts, and of the spinal neurons. The peripheral nerves show the various lesions of neuritis or stages of reconstruction. That alcoholism reduces the resistance to infectious diseases has long been known and is generally recognized. This increased liability to disease is undoubtedly true in the temperate and northern climates. In the tropics, however, while the statistics from the British army seem to prove the same for India, a recent article by Major Woodruff gives statis- tics for the American troops in the Philippines which go to show that the moderate and even excessive drinkers, after two years residence, were in far better health, and much more able to throw off disease than the total abstainers. In the temperate zones an attack of an infectious disease in a chronic alcoholic is exceedingly prone to cause delirium tremens and the prognosis under these circumstances is always grave. Barthelemy em- phasizes the fact that waiters and workers around saloons acquire an especially severe form of syphilis. Biirs clearly shows that in epidemics of cholera, the disease claims the majority of its victims among the alcoholics and, when they are attacked, the chances for recovery are relatively small. In pneumonia, the mortality among the alcoholics greatly exceeds the average. In Bellevue Hospital, New York, in 1904, there were 1,001 patients with lobar pneumonia; of these 667 gave a history of alcoholism. Among these the mortality was 50 per cent, and among the non-alcoholics 23.9 per cent. The moderate use of alcohol is a relative term; moderation for one is excess for another. Duclaux defines excess as any amount of alcohol, any effects from which, one remains conscious of, an hour after its ingestion. Many moderate drinkers use alcohol throughout a long life and show no ill ALCOHOL 177 effects from its use, while others find after a longer or shorter period that it has insidiously produced nephritis, gout, degeneration of the liver, or arteriosclerosis and that their viscera are permanently damaged. The results of chronic alcoholism unfortunately do not end with the individual; the children of alcoholics often come into the world as idiots or weak minded. Howe, in Massachusetts, found that 145 of .300 idiots were descendants of drunkards, and that among the poorest classes of the population, not one-quarter of the parents who had idiotic chil- dren could be considered as abstinent. Beech, in England, found in 430 idiots that 31.6 per cent, were children of alcoholics. Bourneville, in Paris, found that of 1,000 idiotic epileptics and weak minded children, 471 had a father who was alcoholic, 84 an alcoholic mother, and in 65 both parents were drunkards. Only in 209 of these cases were the parents not alcoholic. In Normandy, Dahl found from 50 to 60 per cent, of the idiot children had either an alcoholic father or mother. In Sweden, Lovens ascribes drunkenness in the parents as the cause of 25 per cent, of the idiots. It was noted that, in Norway, from 1825- 1835, following the free distillation of brandy, drunkenness enormously increased and simultaneously the number of idiots increased 150 per cent.; afterward, in the ten years from 1855-1865, when the consumption of brandy had greatly diminished, the number of idiots diminished 16 per cent, simultaneously with an increase in the population of 14 per cent. Bezzola, in Switzerland, studied 70 cases of pronounced idiocy and found that half of these idiots were generated during the wine harvest. New Year's week and the Carnival; that is, in the fourteen weeks in which the Swiss chiefly carouse, while the rest wei'e divided evenly over the remaining thirty-eight weeks in the year. The normal genera- tion curve of Switzerland showed on the other hand that during these same periods of feasting there was a noticeable diminution in the num- ber of children generated. Epilepsy in children frequently follows alcoholism in the parents. Spratling mentions that while alcoholism is not usually a direct cause of epilepsy in women, it is frequently an indirect cause through its pres- ence in the parents, nearly always in the father. Fere found, in France, that among 308 male epileptics, 118 were descendants of alcoholics and of 286 females, 130 were descendants of alcoholics. Kawalewsky, in Krakow, could prove drunkenness in 60 per cent, of the epileptics. Wartman found, in Germany, the same history in 130 of 452 epileptics. Blueler, in Switzerland, could prove drunkenness in the progenitors of 70 per cent, of his epileptics. Congenital deafness and dumbness do not seem to be produced by alcoholism in the parents in any large num- ber of the children showing these afflictions. Chronic hydrocephalus seems to be more frequently the consequence of alcoholism in the parents, for, in Berne, 23 of 38 children suffering from this disease had alcoholic parents; in Paris, 18 out of 23 had drunken parents. That alcoholism tends to the degeneration of the race, and after a few generations to extinction, has been abundantly shown. Legrain observed 215 alcoholic famiUes, in three generations of which 814 mem- bers were hereditarily tainted; 197 of these were alcoholic, 322 were weak minded or idiots, 161 stillborn, 37 prematurely born, 121 died shortly after birth, so that 496 were either mentally or physically degen- 12 178 DISEASES CAUSED BY ORGANIC AGENTS erated. That 174, or 21 per cent., were stillborn or died so shortly after birth that they showed inability to continue their existence, is a striking example of the effect of alcohol on the unborn child. Demme observed ten alcoholic families and comjjared them with ten non-alcoholic families; in the alcoholic families, among 57 children, 25 were stillborn or died in the first month of life, 22 were designated as sick, and 10 as healthy, while in the non-alcoholic families, 5 were stillborn or died early, 6 were sick, and 50 were healthy. Only 17.5 per cent, in the alcoholic families were healthy, while practically only 18 per cent, in the non-alcoholic families were not healthy. Of the 37 children in the |seven families in which either the grandparents or the mothers were alcoholic, only 2 children were normal. Sullivan found that from 120 female alcoholics there were 600 children, and of these 335 died under two years of age or were stillborn; in more than 60 per cent, of these cases the children died from convulsions. He found that 21 of these alcoholic women had sisters or daughters who were abstinent and who had children from temperate men; these 21 alcoholics had 125 children, of whom 55.2 per cent, died before the second year of life and the 28 non-alcoholic women had 138 children of whom 23.9 per cent, died before the second year of life. The mortality of children from alcoholic mothers is thus 2.5 times greater than from non-alcoholic mothers in these statistics. Ani- mal experiments shows the same relative mortality between alcoholic and non-alcoholic animals. INIorel draws attention to the fact that individuals who are given to alcoholism in their youth as well as the descendants of drunkards, are noticeable for their small stature and feeble, muscular development, presenting a type of infantilism. Lancereaux compares this condition Avith the descendants of the tuberculous and considers that infantilism is especially marked in the descendants of the tuberculous alcoholic; thus he believes that, pushed to its extreme limits, alcoholism creates a special race as it were, which can continue itself for a certain period with its physical infirmities and vicious tendencies, but happily it lacks the elements sufficient to reproduce itself for any length of time; with its descendants cursed with impotence and sterility, it is not slow to disappear. DELIRIUM TREMENS. Etiology. — Delirium tremens develops on the foundation of chronic alcoholism. Its occurrence does not run parallel to the amount of alco- hol taken, for idiosyncrasy is usually as strongly marked here as in all conditions in which alcohol comes in question. Many men who have never been intoxicated, but who have for years steadily taken alcohol will, after some severe accident, develop delirium tremens. Its occurrence as far as climate, age and sex are concerned, is the same as for chronic alcoholism, but it differs essentially in its seasons of greatest frequency and is dependent for its development on other causes, which are engrafted on the chronic alcoholism. It occurs more frequently in northern regions and in the great industrial centres. Where beer and wine are the predominating drinks, delirium tremens is less frequent than in the countries in which men drink spirits chiefly. It has been ALCOHOL 179 claimed that since the distilled liquors contain less fusel oil there are fewer numbers of delirious cases, but it is doubtful whether any such deduction is justifiable. The writer has often noticed that delirium tre- mens patients who had consumed only high grade whisky, seem to clear up quicker than those who had consumed a cheaper grade, but even in these cases the doubt always remains whether or not less ethyl alcohol has been consumed. When one realizes that a pint of cheap whisky may be purchased for ten cents, and that not infrequently, at least among the Bellevue Hospital patients, a pint is reckoned as a single drink, even careful calculations on the amount consumed may go astray. The time of year shows a distinct influence on the number of delirious cases. Bonhoeffer, in Breslau, says that the winter months, January, February, and March, show the lowest numbers ; from April on there is an increased frequency which reaches its highest point in July and August. The curve maintains almost the same rise through September, and falls rapidly in November and December. He quotes Nacke as having noticed essentially the same differences in Konigsberg. The occurrence of delirium tremens in Bellevue Hospital corresponds with the above statements in so far that sudden heat always shows an in- crease as seen in July, but there are more patients suffering from de- lirium tremens during the winter months than in the spring and fall, and the number during the cold months is equal to or even greater than during the hot months. This is due undoubtedly to the large number of pneumonia patients and to the greater number of accidents, such as fractures, in the cold months, but even after deducting these, the total remaining is as high among some of the cold months as during any of the hot months. These statements are based on the statistics of 1,066 cases of delirium tremens occurring between January, 1904, and July, 1905. It would seem therefore that the varying occurrence of delirium during various seasons of the year is largely affected by other well known accidental causes which do not seem to act in different places with even intensity. The previous duration of chronic alcoholism seems to have more influence, and it is said that the average is from six to ten years, although according to Jacobsohn it is never less than seven years. The age at which delirium tremens develops is the same as that in which chronic alcoholism is most common, that is, between thirty and fifty years. In children it is rare. Bonhoeffer quotes one of sixteen years of age, and the writer saw one boy of fifteen years. It occurs most frequently in men, doubtless because they are more ex- posed to various accidents, which tend to bring about an outbreak. By some it is claimed that the delirium in women is shorter and less severe than in men ; this does not correspond with the opinions of others, although in my experience the delirium in women is usually of a less violent type. It is impossible to say to what extent inherited or acquired mental degeneration influences the occurrence of delirium tremens in chronic alcoholics but that such defect of mental vigor is present in the majority, is beyond question. It seems certain, however, that suc- ceeding attacks of delirium tremens are more easily brought about than the primary one. Accidental causative factors producing delirium tremens in chronic alcoholics have long been recognized, such as acute infections^ trauma, ISO DISEASES CAUSED BY ORGAXIC AGEXTS hemorrhage, epileptic attacks, the sudden withch'awal of alcohol, sudden intensity of alcoholic excesses or mental shock. Bonhoefl'er, in 250 cases of delirium tremens, could prove in 70 per cent, a recent acute illness or delirium occurring as a complication of it. Undoubtedly the most common acute infection which brings about delirium tremens is pneumonia. Kriickenberg and Bonhoeffer found j)neumonia in every seventh delirious patient. Jacobsohn in 2S1 delirious patients, found pneumonia in the ratio of one to eight; in 1,0GG patients in Bellevue Hospital, pneumonia occurred in every fifth patient. Traumatism such as fracture of the ribs, legs, arras, and skull, very frequently caused an outbreak of delirium tremens, although the percentage in which these occurred is much less than the acute infections. In our experience it is a noticeable fact that severe dislocation at the shoulder or elbow is not so frequently followed by delirium tremens as fractures of the long bones. Bonhoeffer believes that injuries to the breathing appa- ratus are especially likely to be followed by an outbreak of delirium. Many others lay great stress on epilepsy as a causative factor in the outbreak of delirium tremens, but it is a question whether the epileptic seizure is not an expression of the same causative factor which later produces the delirium. An epileptic attack is given as the direct cause of the outbreak of the delirium in from 2.5 to 16 per cent. Among chronic alcoholics, epileptic attacks are very common and in the majority are not followed by an outbreak of delirium. It is difficult, therefore, to accept the view that these are the cause of delirium tremens, although one cannot deny that it is reasonable to suppose that the mental shock produced by them may at times be sufficient to accelerate the outbreak of an already developing dehrium. The sudden withdrawal of alcohol in uncared for patients, in whom no attempt is made to replace it by proper treatment, is undoubtedly at times the cause of an outbreak of delirium tremens. This is due to the sudden change of the condi- tions of life, for when individuals are properly treated, the sudden with- drawal of alcohol does not produce delirium. That delirium tremens is caused by some factor outside of chronic alcoholism seems undoubtedly true but the definite specific cause is unknown. Symptoms. — The outbreak of delirium tremens is never sudden; there are always premonitions. The patient becomes peevish, excitable and restless, loses sleep, and when he falls into slumber, is disturbed by dreams from which he starts in anxious fear. Beginning hallucinations appear which he recognizes as dreams, but although he knows they are unreal, they still disturb him. He often feels oppression around his heart which may increase to precordial pain; there is singing in his ears, which may develop into voices scolding, abusing or even threat- ening him; the dizziness increases; and tremor becomes more marked especially in the hands and tongue. This incubation period may extend over several days or, according to Kraft-Ebing, as long as twelve days. Where the delirium occurs in the course of pneumonia it appears generally on the third or fourth day, and, following an accident or fracture, usually on the second or third or may be delayed until the fifth or sixth day. The writer has seen it appear in twenty-four hours, following a severe stab wound in the abdomen. Many patients on the verge of an outbreak of delirium tremens will deny positively and firmly that they ALCOHOL 181 have drunk any alcohol; when this is in marked contrast to the phy- sical evidences of alcoholic indulgence it should always warn one of the imminence of a severe outbreak. Many patients, when they begin to have insomnia and disturbed dreams at night, realize their condition and come to the hospital for treatment. They still know that the hallucinations of sight or hearing are dreams and explain this carefully. Some are still able to focus their attention on other matters and avoid the hallucinations that appear when dropping to sleep. One patient explained to me that he would read most of the night in order to avoid the family of skunks that came and played about his legs. They are often free from hallucinations during the day time and, after a few nights of disturbed slumber, im- prove, and this abortive form of delirium tremens passes over. In other patients, after the premonitory symptoms, the intensity suddenly in- creases and they are brought to the hospital in a furious and active delirium. This is usually connected with their daily occupation and they show no fear of what they see but are furiously belligerent; their attention can easily be obtained and they will explain minutely what they see, and demand to have their orders executed and explain logically why they wish to have this done. These patients, after a hypnotic and a night's rest, will clear up absolutely and by next morning remember shamefacedly what they had done. The delirium usually does not return. The majority of patients, when the delirium is fully developed, appear severely ill with a disturbed and anxious countenance or their ex- pression may be one of indifference; the face is congested, often slightly cyanotic and covered with sweat; they are restless, wandering about, busily twisting and turning, listening to imaginary voices and sounds. If in bed, they frequently attempt to leave it, pull and pick at the bed clothes, jump up, attempt to rush from the room and frequently hurl themselves against the walls to escape imaginary objects or push against the walls to prevent their falling in and crushing them. They fail to notice objects in their way and are indifferent to severe injuries. The gait is uncertain from the muscular tremor, which is noticeable in their hands with every movement, and often extends into the tongue and the muscles of the face. Their speech is trembling and stammering, or they blurt out expressions in short, sharp sentences. Some hardly speak at all; others shriek out questions and answer them, angrily discussing something and frequently scolding and cursing imaginary bystanders. The pulse is full, bounding and increased in frequency in the young and vigorous individuals and in the elderly or weak it often increases in frequency but is soft and weak. The respirations are increased, the tongue is usually coated, depending however on the condition of the stomach, for when the digestion remains good it is often clean, bright red and glazed; the temperature as a rule is near normal. By speaking sharply to the patient, his attention may be arrested for a moment and he may answer correctly the question put to him. It is evident that ordinarily the ideas of his personality and past remain clear; it is equally true that he has false ideas regard- ing his environment, the purpose for which he is in the hospital, the length of time that he has been there, and the individuals who are around him. 182 DISEASES CAUSED BY ORGANIC AGENTS Hallucinations of sight predominate and it is usually an occupation delirium; for example, one market man had the entire field of vision filled with blue potatoes wiiieh rained incessantly down upon him; an hostler saw innumerable niunbers of wagon-wheels rolling at him; the deck hand on a steam-boat begged me that he might go to bed as the room was rapidly filling with steam-boats that were bearing down upon him; the circus man saw elephants jutting out into the room, which crowded him, although they did not terrify him; the teamster usually drives horses and it is often a noticeable fact that as long as the horses obey his orders, he is not terrified, but if the horses back against his orders and he is unable to control them, there is instant terror inspired and the intensity of this is often a fair criterion of the severity of the delirium. The animal or menagerie dehrium is common and the pa- tients may see well known animals, or fantastic beasts and various horrid forms of monsters, or there may be disgusting insects, crabs and snakes of various forms or the animals they see may be of various abnormal colors, red and blue predominating, such as "pink giraffes that crossed a purple bridge and nibbled at his feet." These animals or imaginary monsters are not seen singly but usually in vast numbers. At times the hallucinations are pleasant and the room is filled with beautiful pictures; angels are seen talking to them, or God appears, talks to them, and commands them to go forth as his messenger. Some- times the visions take on a sexual type. Various paresthesias of the skin cause hallucinations of worms or spiders crawling on them. Specks on the walls or on the bedclothes, may be mistaken for various animals or vermin. Scratches, furuncles or injuries and the like may be mis- taken for the bites of animals or for Avounds given in attempts to murder them. The hallucinations of hearing consist of various noises, as the ringing of bells, crying of children, shrieks of people in distress, and volleys of musketry, or they are cursed and jeered at as traitors, mur- derers and thieves, or they hear their family outside the door conspiring to kill them or whispering and making plans to come in and mutilate them, often the mutilations taking the sexual characteristics. Rarely there are hallucinations of smell, and they imagine that the house is on fire, that smoke is coming up around their bed, or that sulphur fumes or other ill-smelling gases are being injected through the key-hole. The hallucinations of taste are also rare, but they may imagine that their food is covered with disgusting substances or that poison is being placed in it. The imperative monotone hallucinations are absent, although there is often rhythmical character to the aural hallucinations given by the ticking of a clock or dripping of water from the faucet, producing reflex ideas of speech hallucinations, usually of a scolding nature. Hypo- chondriacal illusions from sensations in the intestines, stomach, bladder, etc., do not occur; when these are present they give good cause for the suspicion of other mental diseases. Muscle and temperature sense are also normal. The mental processes in delirium tremens are of a peculiar nature; there is no diminution in general in the sharpness of perception of the sense organs; the ability to recognize objects seems intact. Some authors however believe that these patients are unable to obtain any sharp, clear impressions and explain the misinterpretation of noises, etc., as due ALCOHOL 183 to disturbances of apprehension; these b(;come very apparent when the patients attempt to read, when instead of correct sentences there is a senseless series of words and sound associations which is especially noticeable when the type is small and indistinct; sometimes there is no relation between the reading and the subject matter. Bonhoeffer's explanation that the inability to read accurately is due to disturbances of attention seems nearer the truth. He believes that the paraphasia and paralexia are closely related to the processes of physiological in- attention. The power of attention under special conditions in delirium tremens can for a short space of time attain the sharpness of that in healthy persons, but the ability to hold the attention is quite different. The more complicated the mental work, the greater necessarily are the demands on the attention and the greater the tendency to paralexia. With a sharp strain on the attention for the purpose of holding fast this maximum accuracy of any sensory region, a transitory normal value is attained but there appears an increased tendency to hallucinations in the sensory regions. If the attention is held at a middle level but still so strongly taxed that the patient must talk with, and give answers to the examiner, the hallucinations become rarer as with all hallucina- tory mental diseases. The disturbance then records itself in a tendency to mix up words and ideas similar to the physiological inattention. There exists in delirium tremens a persistent tendency to sink to a still lower level of attention. Closely allied to changes in the ability of fixing the attention, is the train of thought by which stimuli through the various sense organs bring about the final conception of the object. Simple pictures pre- sented to a delirious patient, or familiar sounds, may be often correctly recognized and designated, but in severe cases often these are mis- understood and cause hallucinations. At times the misinterpretation of pictures would lead one to believe that lack of color perception played a certain role. It is very characteristic for the misinterpretations to influence and lead to illusions through internal rather than through external similarity, as, for instance, the patient, looking at a picture of a bird, declares that it is a bird's nest. The final conception of the object lacks intensity and the ideas which come into consciousness are those which belong to associated related ideas. These patients are particularly susceptible to suggestion; this, however, extends only to the regions of sense from which the hallucinations come and it is there- fore strongest in the optic and in the auditory senses but often fails with touch, and seems to completely fail in the regions of smell and taste. Suggestion can also affect the hallucinations concerning their external environment, especially as to occurrences in the recent past, but has no effect whatever upon the events of their early life. These patients have no idea of the passage of time and the duration of their illness is usually wrongly given; the day, the week, the year, are ordi- narily misstated. The power of retention is much diminished and memory of objects seen is defective, this being strongest at the height of the delirium but also clearly apparent when the delirium has nearly ceased. The power to combine thoughts is distinctly in abeyance; this is clearly seen when one permits a patient to read, for he Avill read spontaneously the greatest nonsense without exerting the slightest critical faculty. 184 DISEASES CAUSED BY ORGANIC AGENTS One cf the most marked ])eciilianties is the misconception of place and environment and, uj) to a certain degree, of time; they have entirely lost their orientation. They are able to remember and (lescribe clearly the contents of their own room; one can sometimes make them clearly appreciate the objects which compose their ]:)resent environment, and yet they will be absolutely unable to a})preciate that they are not in their own room and in a hospital. Their occupation, former life, and all ideas that relate to their ])ersonality, are unaffected. Ideas of gran- deur do not occur in true delirium tremens; if they appear, it is the complication of some other psychosis. The emotional attitude of the patient depends largely upon the character of the hallucinations and illusions; they may be happy or fearful, they are more often anxious and fearful, and these may rajiidly replace each other from time to time. The feeling of anxiety is almost never absent from the beginning of delirium tremens; it is first seen as an oppression in the eldest or as an external restlessness; this feeling of anxiety or terror seems to be particularly prominent in patients with dyspnoea. During the height of the delirium the anxiety often diminishes and gives place to a eu- phoria, so that the patient becomes indifferent even to the hallucina- tions which previously terrified him, and he may even be amused at the external phantasies that are being worked out and played before him. The motor impulses are in most patients very pronounced. As many patients show occupation hallucinations in some degree, so their movements usually correspond with these. The impulse to speak often corresponds with these movements, but frequently patients will be busily moving about for hours, or lying in bed actively busy in many ways, without saying a word. The tremor from which the disease really takes its name is apart from the motor impulse just described and differs from the ordinary tremor in chronic alcoholism only in its intensity and in the greater distribution. It may be so marked in delirium tremens that the pa- tients totter and are unable to hold themselves erect, or, when lying in bed and suddenly spoken to, it may assume such convulsive intensity as to throw them off the bed. It persists even when the patients are at rest, although by movement there is a great intention increase. The tongue trembles strongly when thrust out and this often causes intense tremor in the muscles of the face. The eye muscles remain free from tremor and the head as a rule only takes part slightly. In slight de- grees it can be controlled when the fingers are held closely together, but becomes distinctly a]iparent when they are stretched wide apart. In convalescents, after the tremor has disappeared, it can be felt in the interossei muscles when these are taken between the index finger and the thumb. The speech often shows a distinct ataxia; besides trembling of the voice, there is often also a stumbling over syllables and words, and mispronunciation, which is as apparent in voluntary speech as it is in reading aloud. The handwriting shows some disturb- ance; besides the tremor, words and syllables are left out and an in- ability to follow straight lines with the tumbling of words above or below each other is seen. Sometimes in the morning tremor of drunk- ards, a glass of alcohol Avill steady the hand, so that the handwriting becomes clearer. ALCOHOL 185 There is a great tendency to sweating and often the slightest exertion brings on a profuse perspiration. The tendon reflexes are as a rule not changed. The sleeplessness continues throughout the entire extent of the delirium and ceases as the delirious period comes to an end. As has been said, the temperature usually rests near the normal line during the deUrium; it is however, in some cases raised, usually not above 101°, except in patients in whom the motor impulses are very intense and there is a consequent incessant muscular movement. Under these conditions temperatures of 103° and 104° are not uncommon; tempera- tures of 105° from these causes are of serious prognostic significance. Magnan describes febrile delirium tremens as a special form of the disease but it would seem that he has classified as a special group the patients in whom the most intense motor symptoms are evident, and it would seem that they differ from the other forms of delirium tremens only in the intensity of the delirium or of the motor impulses produced by the vividness of their hallucinations. They differ only in degree, and not in kind, from other cases of delirium tremens. During the summer months, in periods of great heat in New York, it is noticeable that this form of febrile delirium is most common when the motor ex- citement is very intense. The patient may pass into a condition of heat stroke, the temperature may rise to 108° F., and the patient die. During the delirium the pulse runs from 80 to 110 when the heart muscle is in fair condition. In patients showing much emotion or in those showing intense motor activity, the pulse is correspondingly in- creased. Its quality is usually soft, and according to Kriickenberg, often dicrotic. Constipation is the rule. Several German observers lay great stress upon the frequency of albumen in the urine of delirium tremens patients, with no other signs of nephritis, which disappears after the delirium has ceased. This albumin appears in about half the cases in the beginning of the delirium, and in others on the second and third day, it is transitory and may cease a day or so before the delirium or it may last a day or two after the cessation, but as a rule, is small in amount. Leipmann found albumoses in about 15 percent, of the delirious patients, and toward the end of the delirium, they are found in addition to the albumin. Microscopically the urine contains few formed contents, a few round epithelial cells and rarely hyaline casts. Bonhoeffer quotes Elsholz as having found in the examination of the blood an increase in the polynuclear leukocytes and a dimin- ishing of the mononuclear but no leukocytosis. In cases of severe de- lirium the eosinophiles were absent. The duration of an attack in mild cases is two or three days; it averages probably three to five days and may continue for eight or ten days. The cessation of the delirium usually follows a deep sleep which may last un- interruptedly for twelve to thirty hours. Some authors describe this sleep as coming on in the midst of the delirium but it is usually preceded by a period of weariness and relative quiet. When the patient awakens from the critical sleep he is sensible, the hallucinations have gone and his orientation is usually complete; his mental condition however is not fully recovered; the power of retention is diminished and the ability to combine thoughts is distinctly diminished for a few days. The memory of the recent illness is never complete but it is accurate for the essentials ; it is very rare 186 DISEASES CAUSED BY ORGANIC AGENTS that complete forgetfulness occurs. As to the duration of his illness, the patient rarely has an accurate idea, deeming the time shorter than it really was. In general the emotional and fantastic occurrences are better re- membered than the ordinary ones hut, after four or five days, even these lose their distinctness. Often for several days therapeutic measures, which were necessary during the stage of delirium, are remembered and still misunderstood as forms of persecution. In old alcoholics, who have had previous attacks of delirium, there is at times a certain appreciation of the disease during the entire delirium and they also show a corresponding clearness as to its occurrences. On the other hand these same patients are very prone to consider hallucinations as realities and retain these mis- apprehensions for a long period. In not a few patients there is a recru- descence of the deliriiuii for a few nights, while remaining free of it during the day; any unusual excitement producing mental exhaustion may often during the day time bring back some of the hallucinations. Meningeal Symptoms, Serous Meningitis, "Wet Brain." — In all forms of chronic alcoholism, but especially following acute and chronic delirium, a condition develops which has rarely been noted and Dana is the only one who has deemed it worthy of mention. This is the alco- holic meningitis or serous meningitis, the so-called "wet brain." It occurs with relatively equal frequency in men and women. There is no true inflammatory process and the condition is called a menin- gitis from the excessive amount of fluid, but this is a transudate, and meningitis is a misnomer. The most probable cause seems to be the degeneration of the vessels, the paralysis of vasomotor control and the weakened condition of the heart. It usually follows an attack of delirium tremens, though it may develop in any chronic alcoholic after a debauch, without previous delirium. When it follows delirium tremens, the patient, after a few days of delirium, sinks sloAvly into a semi-coma. The delirium becomes of a low, muttering type, and the patient retains sufficient con- sciousness to have the delusions and hallucinations of sight and hearing. He is roused with difficulty, though he will still take food. The pulse is rapid, the temperature remains normal or is slightly raised, but seldom over a degree. The pupils are usually diminished in size. The skin is hyperaesthetic and pressure on the muscles of the arms and legs and over the abdomen, causes pain. Conjunctivitis and keratitis often develop. In some patients the condition slowly progresses for several days, in others the effusion increases rapidly, and they sink into a more profound coma from which they cannot be roused. The arms and legs become stiff, the reflexes are all exaggerated, the neck is stiff, slightly retracted, and attempts to move it cause pain. The abdomen is retracted and the skin and muscles are still hyperaesthetic. The lids are closed; the pupils are contracted and react slowly if at all. The tongue is dry and brown, and there is usually incon- tinence of faeces and urine. The pulse is frequent and feeble, and the extremities are cold. He may continue in this condition for several days and gradually fade out, or improvement may slowly begin, the mind be- come clearer, the neck less rigid, the hjqjeraesthesia diminish, and recovery slowly take place. Often three or four weeks are required before the patient is really convalescent. Pneumonia, especially inhalation pneu- monia, is apt to develop; the temperature may rise to 101°-104°F., and the patient dies. In 709 cases of delirium in Bellevue Hospital, New ALCOHOL 187 York, this condition developed in 108 instances (15 per cent.); of these, 37 recovered and 71 died — a mortahty of G5.7 per cent. The prognosis is alv^ays grave when the coma and rigidity have become w^ell developed. Dana gives the stiffness of the neck as a useful prognostic criterion; if the patient has not a stiff neck he will recover, but when it comes on, the patient dies. Prognosis. — The prognosis of delirium tremens depends greatly upon whether it is complicated by trauma or infectious diseases, especially pneumonia. Bonhoeffer gives 122 deaths, or a mortality of about 11 per cent, out of 1,077 cases; of these, 40 per cent, were caused by pneu- monia, 17 per cent, by other acute pulmonary diseases, 4 per cent, by acute intestinal affections, 5 per cent, by burns and injuries of the body, 2 per cent, by erysipelas, while of the 32 per cent, remaining, autopsy showed no acute somatic affections, but a considerable number had clinical evidences of cardiac collapse and anatomically friable yellow- colored heart muscle. In his own uncomplicated cases, this author had scarcely a 1 per cent, death-rate. In 709 cases of delirium occurring in Bellevue Hospital, there were 143 deaths or about 20 per cent. Of these, 61 died of pneumonia, about 36 per cent. There were 125 cases of pneu- monia in these 709 patients, and after deducting these in the 584 remain- ing, the death-rate was about 14 per cent. Of the 125 cases of pneumonia, 64 recovered, leaving a mortality of 48.8 per cent. In uncomplicated attacks in young individuals the prognosis is fairly good. In the begin- ning of any attack of delirium tremens a guarded prognosis should be given. If the delirium develops into a severe form and the motor symptoms are very intense, the prognosis is correspondingly grave. The so-called moderate drinkers, who develop delirium tremens after trauma, have a bad prognosis, — in the experience of the writer about 50 per cent. die. In true delirium tremens, as differentiated from acute alcoholic hallucinosis, the tendency to suicide is unusual. The changing character of the delirium prevents the fulfilment of any transitory morbid train of thought. The premonitory stage of delirium tremens, when there is great intensity of painful emotions, anxiety and unrest, is the time in which the tendency to suicide is most apt to develop. It is difficult in these early stages, to say whether the patient is developing true delirium tremens or an acute alcoholic hallucinosis, so that the statement that in true delirium tremens suicide is rare, remains true. Treatment. — We must realize that there is no specific and treat it symptomatically. Most of these patients have been subsisting, often for long periods, on alcohol, with little or no food. We must also realize that the danger is not in the delirium but in the diseased condition of the heart muscle and vessels and that the gastric mucosa is in such a condition that substances given by mouth may remain unabsorbed for hours, and then suddenly be absorbed and the system be overwhelmed by the summa- tion of accumulated doses. This has always seemed to the writer the reason of the increased death-rate under the old digitalis treatment. Many drugs have been vaunted as causing sleep and cutting short the delirmm, but in a disease in which the critical cessation comes on with sleep, it is really impossible to say whether the sleep was coincident with the crisis or whether there was really any cause and effect in the adminis- tration of the given hypnotic. The question whether alcohol should be 188 DISEASES CAUSED BY ORGANIC AGEXTS withdrawn at once or continiuHl is still a mooted point. It is the writer's belief, after trying both methods, basing- his judgment on the treatment of several thousand patients by eaeh, that aleohol should be absolutely withdrawn in all cases. First and foremost, all these patients must be treated from the standpoint of those having a degenerated heart muscle and they therefore should be stimulated with strychnine (gr. uo-ao, gm. 0.001-0.002) every four hours or oftener or by caffeine or camphor, and these are best given hypodermically. Strong coffee or tea can be given in mild cases instead of the pure caffeine. The ])atient should be given a purgative such as compound cathartic pills, com])ound licorice powder, or calomel. In young, vigorous adults, without any appreciable change in their arteries, who have recently been drinking, an emetic such as copper or zinc sulphate is often an advantage. These should never be given in elderly persons or in those who appear old for their age. In mild and abortive attacks a dose of a dram of paraldehyde, repeated if necessary in an hour, is all that is necessary to cause sleep from which the patients frequently awaken either clear-headed or with their delirium lessened. In the severer cases, the paraldehyde may be given in dram doses, at hour intervals, even up to three doses. Other hypnotics, such as sulphonal, trional, etc., have in the hands of the writer usually failed utterly except in the mildest cases. Opium should be resorted to only as a last resort and is especially contra-indicated with pronounced arterio- sclerosis. Hyoscine, (gr. 125, gm. 0.0005) and morphine (gr. |-f, gm. 0.01-0.015) hypodermically, should only be given to young and vigorous individuals in whom the motor symptoms are especially marked. Hyo- scine alone, tends to increase the delirium, especially in women. Often in the severest cases a mixture of hyoscine, gr. yX)~o (S^- 0-0006) with apomorphine, gr. -^-^ (gm. 0.006) and strychnine, gr. -gL (gm. 0.002) will quiet them and give at least a few hours rest. Bromides are insufhcient and in the hands of the writer have been practically useless. Chloral is one of the best drugs when properly administered; small doses are useless and Lancereaux claims that they even tend to excite these patients. When the heart is properly stimulated chloral hydrate does not have any deleterious effects. Lancereaux recommends thirty to sixty grain doses (gm. 2-4); the combination of chloral and morphine is especially advan- tageous in that smaller doses of each can be given and the mixture be more effective than either singly. The mixture of morphine, gr. J (gm. 0.008), chloral, gr. 15-30 (gm. 1-2) with tincture of hyoscyamus, 5ss (2 Cc.) tincture of ginger, npx (Cc. 0.6), and tincture of capsicum rrpiii (Cc. 0.2), and water to oss (Cc. 15) is very effective and can be repeated at the end of an hour. These hypnotics, while causing sleep, do not neces- sarily cut short the delirium, but after a sleep of some hours, the delirium is often quieter and there is the further advantage of rest for the heart from the cessation of motor excitement. Of late years the writer has used ergot hypodermically in Livingston's solution, which is as follows: One dram of the solid extract of ergot is dissolved in an ounce of sterile water and three drops of chloroform and three grains of chloretone are added, and the solution filtered; this is sterile and should be given straight into the muscles in the gluteal region or in the deltoid. It should never be given subcutaneously; if carelessly given, it will produce painful spots. The administration of thirty drops of this solution, hypodermically. ALCOHOL 189 every two to four hours, reduces the dilated bloodvessels, lessens the various congestions, and brings about a better equilibrium of the circula- tion. After it, there is a distinct tendency to a quieter delirium and less need of restraint; it reduces the tremor, less hypnotic is required, and it diminishes the tendency to "wet brain." The writcT has never seen symptoms of ergotism although thirty minims of this solution were given every two hours for ten days or longer. As soon as patients awake they miust be given food, best in the form of milk or milk and eggs. This should be given regularly every two or three hours during the delirium but if asleep they should not be awakened for any reason. The treatment for the "wet brain" condition should be begun as soon as it is suspected. Strychnine, gr. eo to 3^0, and ergot, thirty minims, both hypodermically, should be given every two hours, and caffeine and camphor are also of use. The patient should be carefully fed every two hours with milk, broth, and eggs, and thorough purging is advisable. Alcohol seems to increase the effusion and should not be given. During convalescence, however, a little alcohol in the form of egg-nog two or three times a day for a few days is often of benefit. Bonhoeffer recommends that delirious patients should be placed for several hours in a warm bath at 95° to 97° F., and that an attendant should sit beside them so that when they attempt to get out of the bath, their attention can be diverted. He also recommends that one or two attendants should sit beside the delirious patients and keep them in bed, which is excellent treatment where there are many attendants and few patients, but where the reverse is true in a large, active service, restraint is often necessary. There is no question that these patients should be con- fined to bed through the entire delirious stage, as in the wilder delirium it is often necessary to restrain them by a sheet tied around their ankles and then tied to the foot of the bed, and by another sheet which goes from the bed up over one shoulder, doAvn through the axilla, across the back to the opposite axilla, out across the shoulder, up to the bed; the wrists, when necessary, can be restrained by a muslin bandage wrapped around over cotton wool which thus prevents abrasions and holds them firmly; some- times a folded sheet stretched across is sufficient to hold them in bed. The hot, stiff, canvass jacket is essentially bad, as it rigidly binds the pa- tient and prevents the radiation of heat. The question of the isolation of these patients and the permitting them to wander about in a padded room is often brought up ; young vigorous persons can be so treated for a few hours, provided the tremor is not too great and the delirium not so violent that they will do themselves injury. We have, moreover, always to con- sider sudden collapse, and the degree of cardiac degeneration cannot be accurately judged, so that on the whole, it would seem better to keep all patients in bed during their delirium and not to isolate them. In hospitals, the patients, although in open wards, are but little dis- turbed by their fellows, especially during their delirium, because they are too much occupied with their own hallucinations to pay attention to the disturbances caused by others. During convalescence, stomachics such as capsicum, nux vomica, and ginger are useful ; often a mixture of nux vomica, cinchona, and gentian is an excellent tonic. In the febrile cases of delirium tremens a cold bath is often necessary; the patients are placed on a rubber blanket in bed, and 190 DISEASES CAUSED BY ORGANIC AGENTS cold water is slapped forcibly upon them from a whisk broom; the impact of the water takes the place of the physical rubbing in the cold bath. Warm packs have been recommended, but often the resistance made by the patient, and the excitement produced, do more harm than good. Usually eight or ten days after the patient has recovered from his delirium he is fit to go out, and in hospitals his treatment here ceases. If possible, they should go to some place where they may live in the open air with good food and have moderate outdoor exercise. Total abstinence from alcohol is their only hope for future health; for this reason it is inadvisable to give any medicine with alcohol in it. Tonics should be in solid form containing no alcohol. ACUTE HALLUCINOSIS. Acute hallucinosis of drunkards is sometimes called acute alcoholic hallucinosis, acute paranoia, or acute persecutory insanity. It is closely allied to delirium tremens, and there are cases which seem more like connecting links than belonging clearly to either one. The patients suffering from this form of alcoholic psychosis are usually younger than in delirium tremens and belong to the better educated classes, while delirium tremens is most common among those who perform manual labor. The tendency of this form of alcoholic psychosis to develop as a concomitant symptom of trauma, pneumonia, and other acute diseases, is not so great as delirium tremens. Acute gastric disturbances are the most commonly observed physical ailments connected with it and it frequently follows fright and intense anger. Patients have been known in whom one attack of delirium took the form of delirium tremens and another the form of acute hallucinosis. Symptoms. — These patients show a predominance of the acoustic type of hallucination, although optic and tactile hallucinations are not infrequently present, but not as prominently as in delirium tremens. There is, in the beginning, the same irritability, easily excited condition, restlessness and undefined dread as in delirium tremens, but they often show a peculiar sensitiveness to ordinary noises; they are sleepless, their dreams are bad, and they start in their sleep, terrified by an unknown something. This unstable condition may persist for days and then become somewhat better, and a further debauch cause all the symptoms to return and go on rapidly into a full development of the complete psychosis. They are often troubled, at first, with noises in the ears, which develop into the hallucinations of singing, music, shooting, scream- ing, etc. ; finally they are persistently followed by definite voices, which hold their attention constantly at high tension and compel their undi- vided attention. Frequently they are brought into the hospital by the police because they have fled from the persecution of these voices, or they go to their rooms and refuse to come out or allow any one to approach. In this early stage, suicide is very common, especially in those in whom the terror is highly developed. The voices are sharply localized, they accompany the patient from behind, creep up at him out of the floor, come to him from a hole in the wall, or seem to be persistently telephoning to him. When he strives to sleep, they come up out of the pillow, from under the bed, and they follow his every movement. These voices have a. ALCOHOL 191 definite character; they may be the voice of a man, woman, or child, or the clearly recognized voice of some friend, or they may be unmistakably not human, or the voices may seem human and speak in a foreign tongue. The rhythmical character of the hallucinations is quite common and sometimes the patient hears constant repetitions of the last word spoken to him, or the last thought which he has had. As he goes into the street the auditory hallucinations, as in delirium tremens, take on the abusive character, and he hears himself called by name with various epithets added, or accused of various criminal acts. Not infrequently, the patient hears every thought as it occurs to him, spoken out aloud, and he declares that he knows the very spot of the tongue out of which his thoughts are loudly spoken; frequently he hears every movement he makes commented upon by the voices. Optic hallucinations are present but take a subordinate position; they frequently occur at night and often are the outlandish, terrifying, mixed- up pictures seen in delirium tremens. The sense of touch is less often involved and hallucinations of taste and smell are absent. These patients are not usually disturbed by sensations from the internal viscera; some- times, however, they seem to form an unimportant part of the hallucina- tions. When these last sensory regions give predominant hallucinations, there is always a strong suspicion that we are not dealing with a pure alcoholic psychosis, but with a more serious condition. Frequently there is a suspiciously disturbing misconception of all acts that are performed by others in his presence; he believes that people moving in the street are running together to discuss him; he is suspicious of the patients in the hospital, believes that the motions made by the nurse in handing him his food prove that he is about to be poisoned and misinterprets all therapeutic measures. The idea of persecution does not go further back than the recent past; his persecutory system is superficial, changes during the disease, and often develops suddenly; ideas of grandeur are sometimes present. Consciousness is not clouded, and they retain their power to combine thought and their powers of retention. Disturbances in the process of thought, as in delirium tremens, are not present. Most authors seem to believe that their orientation for place, as a rule, remains intact. In the patients who show a type of the disease tending toward the clinical picture of delirium tremens, there is sometimes disorientation especially in the beginning of the attack. Tremor of the hands and tongue, and gastritis, are usually present; the symptoms of neuritis are not uncommon, and other disturbances of chronic alcoholism, such as a tendency to perspire freely, etc., are common, although they are usually less marked than in delirium tremens, perhaps because this psychosis more often occurs in younger individuals. Bonhoeffer states that the albuminuria seen in delirium tremens was not found by him in these cases. The duration of this disease varies from a few days to weeks. Rarely does it continue more than two months, accordi ng to Bonhoeffer. As the patients improve, there are periods in which they seem to be free from hallucinations, Finally the voices in their ears are recognized as such and no longer produce the hallucinations. The various erroneous impressions improve coincidently with the disappearance of the voices. Wernicke believes, however, that these patients go though a paranoiac stage in some hallu- 192 DISEASES CAUSED BY ORGANIC AGENTS cinations in wliich their systematized illusions persist; however this may be, this stage is evidently of short duration, beeause the accurate appreci- ation of their psychic condition often occurs \\\\\\ an astonishing rapidity. They remember their hallucinations and are often proud to write a descrij)tion of them. Sometimes these patients go from these acute hallucinatory stages into a condition of chronic delirium. There are no known pathological lesions characteristic of this psychosis. Prognosis. — The prognosis as to life, if they are put into an institution, is good, but if they go through the early stages uncared for, the danger of suicide is great. The liability to death from intercurrent disease is not great, and the more they tend in their clinical j)icture toward the transi- tion type of delirium tremens, the shorter seems to be the duration of their delirium. Ideas of grandeur seem to tend to a somewhat longer duration. As in delirium tremens the same patient may show repeated attacks of this ])sychosis following continued excesses of chronic alco- holism. If the paranoiac condition has been prominent, continued alcoholic indulgence is liable to produce permanent insanity. Diagnosis. — Bonhoeffer gives the following differential diagnosis be- tween the acute hallucinosis and delirium tremens: The acoustic region dominates in the hallucinations in hallucinosis, the optic and tactile in delirium tremens; in hallucinosis orientation is retained, in delirium tremens it is lost; in hallucinosis the morbid occurrences are systema- tized and the patient has the illusions concerning his relations with others; both these conditions are lacking in delirium tremens; the dis- turbances of retention and the disturbances of memory dependent thereon concerning time and succession, the confabulation, the disturbances of attention and the power to combine thought are lacking in hallu- cinosis or at least are scarcely apparent. In spite of these differences, transitional forms occur which are likely to cause errors in diagnosis. Treatment. — This is the same as for acute insanity; the tendency to suicide must never be forgotten and isolation is ever contra-indicated. They should be kept in bed during the delirium; hypnotics should be given to produce sleep as in delirium tremens; especial attention should be paid to their digestion and to frecjuent feeding; cathartics will usually be necessary. Bonhoeffer recommends frequent warm baths for these patients. One can often impress on them after their recovery, with much better hope of intelligent appreciation, the necessity of total abstinence from alcohol. We are dealing Avith patients, as a rule, more intelligent than those suffering from delirium tremens, and have therefore a better chance to make them appreciate their condition and the dangers of further indulgence; they are also often less injured by the lesions of chronic alcohoHsm. CHRONIC ALCOHOLISM. Many of the forms of chronic alcoholism are described under other diseases, such as cirrhosis of the liver, arteriosclerosis, etc., for here, as in all forms of alcoholism, the idiosyncrasies of the patient are important factors and the kind and amount of the alcohol used also modify the clinical picture. ALCOHOL 193 The amount of alcohol which, consumed daily, will produce the lesion.s and symptoms of chronic alcoholism varies with the individual; most men who partake of moderate doses dilute their alcohol with large amounts of water and the effect produced is less than when the fluids are taken in concentrated forms. Many men take moderate amounts of whisky through long years with apparently no serious effects; many others partake of moderate amounts with their meals and seem to be benefited, and not injured, thereby. It is a noticeable fact that the wine connoisseur rarely becomes a drunkard. As soon as an individual begins to take alcohol for the effect produced, he is in danger of continuing the practice and becoming more and more tolerant; he requires more to produce the desired effect and soon partakes of amounts that necessarily must injure the organism. When once the condition of chronic alcoholism is developed, the first symptoms are those of weakening of the will and blunting of the moral nature; the patients become untidy and slovenly in their personal habits; are careless in their ways of doing things; forgetful of their promises and engagements; lose their sense of responsibility to the community as citizens, and to care and provide for their families. They become more and more selfish and self-centred, increasingly incompetent through forgetfulness and carelessness, and to cover up their shortcomings are at first prone to make excuses which are followed by actual lies to escape the responsibility of their misdeeds. They lose their sense of shame and although, while the remnants of their better nature remain, they may promise to give up drinking, if they break this promise, they make excuses and seem to be shameless regarding it. They are irritable, touchy, and liable, from slight causes, to intense fits of anger during which they will cruelly punish their children for slight ofPenses; they may abusively scold their wives and families on the slightest pretext or brutally maltreat them. With the weakness of will there is a conceited self-complacency which causes them to declare that they can stop drinking at any time if they wish, and yet when pinned down to the necessity for so doing, they have a never-ending series of excuses to avoid doing it. There is a very characteristic suspicion in the minds of these patients of the faithlessness of their wives, which, according to Kraft-Ebing, is produced by a failing sexual desire and a rapidly occurring impotence. Usually this does not express itself further than in contemptible and vicious vituperations; it may cause, however, in fits of drunkenness, actual bodily harm and even murder of an innocent wife or of the children, as suspected accomplices of their mother. These evidences of mental degeneration may continue through years, and the patient finally sink into early senile dementia, for unfortunately a degenerated intellect does not necessarily produce death, and as long as the heart and arteries hold out, many degenerated alco- holics continue to live, a burden and nuisance to the community. They usually die before the alcoholic dementia is fully developed, because of their liability to trauma and intercurrent infectious diseases, or during an attack of delirium tremens or other psychosis, or from visceral de- generations, or cerebral hemorrhage. 13 194 DISEASES CAUSED BY ORG AX I C AGENTS DIPSOMANIA OR PERIODIC INEBRIETY. In some individuals alcoholism exhibits itself in the form of periodical crises, the dipsomania or periodic inebriety of some authors. These patients are often total abstainers between attacks and struggle against the desire when it comes over them. Some authors believe these attacks are related to periodic epileptic explosions. Thelat defines the chronic alcoholic as one who becomes drunk whenever the opportunity is offered, and the dipsomaniac as one who becomes drunk only when the attack seizes him. Often these attacks are preceded by mental depression, restlessness, irritability, headache, anorexia, sleeplessness and precordial anxiety, and the desire to drink becomes irresistible. They will drink until the attack is past or until forced to desist by restraint. Some patients will mix various disgusting substances in their beverages, hoping thus to stop the craving. The periodicity varies from weeks to months or even a year or more. In some men regular recurring tasks or business stresses bring them on; in some women the menstrual periods seem to be the cause of the outbreaks. In others the attacks develop without appar- ent exciting causes. In some patients if protected for some hours or days, the craving passes away and they are safe until the next attack. In the beginning many patients drink only to drunkenness, but later their debauch goes on until they are forced to cease under restraint. In the majority, the periods between attacks shorten until they finally develop into the characteristic condition of chronic alcoholism, with no periodicity to their incessant indulgence. During their debauch they may develop an attack of delirium tremens or other forms of alcoholic psychosis. ALCOHOLIC TRANCE, AUTOMATISM OR PATHOLOGICAL DRUNKENNESS. In psychopathic, hysterical, or epileptic patients, or following traumatic injuries to the skull, or after sunstroke, alcohol produces disturbances of consciousness which deviate greatly from the ordinary sequences. The same conditions are seen in those who have been injured through the excessive use of alcohol; one of the simplest expressions of this condition is that in which the patients, after much smaller amounts of alcohol than formerly, become drunk and are absolutely oblivious next day to every- thing that occurs. After the first or second drink of whisky they may seem to their friends simply to have been drinking and not more than usual under the influence of alcohol, or they may in slightly more pro- nounced cases, completely lose their orientation, misinterpret entirely their environment, and show an ugly disposition, which was foreign to them, with evidences of a high degree of emotional anxiety. More pro- nounced examples of alcoholic automatism are those in which the patient may start off on a prolonged debauch and at the end wake up in some far away city and all occurrences from the time he began until coming to himself be an absolute blank. The amnesia is usually complete; some- times there are faint recollections that he has been recently in certain places; for instance, one patient of the writer remembered taking a drink in Boston and ten days later, having gone through a five days' attack of ALCOHOL 195 delirium tremens in Bellevue Hospital, came to himself with complete amnesia of everything which had occurred during the ten days; another who was drinking and sociably chatting with a friend, with no intention of taking enough alcohol to disturb his sobriety, came to himself five days later while ascending the stairs of a station of an elevated road, and was unable to remember any occurrences of those five days except that he had been in some bath establishment. This man was not an alcoholic, and filled a responsible position, although some years previously he had drunk to excess. Other patients, after a single drink or during a debauch, have been known to start off on long journeys and come to themselves on board a railroad train or a steamer. Others have been known to conduct com- plicated business transactions shrewdly and successfully, to go into court and conduct successfully a long trial, ending with a prolonged charge to the jury, come home and write out a long legal document concerning the case with perfect clearness and conciseness, and yet when consciousness returned, the amnesia was complete. In some this will occur but once, in others it is of recurrent nature and may be preceded by restlessness and irritability, and after a single drink they regularly go into this state of disassociation of consciousness. In these conditions men have committed forgery, theft, and even murder, without any recollection of them when consciousness returns, and are stricken with a deep remorse when accused of wrong-doing and made to suffer for their crimes. Others in this condi- tion of pathological drunkenness will murder their children for trivial causes and show no remorse for the act; calmly deliver themselves up and discuss the whole occurrence with no more appreciation or mental disturbance at what they have done than if they had broken a piece of furniture or accidentally injured some animal. Many of these cases belong to medicolegal literature rather than to general medicine. There is no question as to the reality of the total amnesia in these cases, and the responsibility for their acts should be placed in the same category as those of the acutely insane. ABSINTHISM. Lancereaux described a special form of chronic alcoholism produced by excessive indulgence in absinthe, various liqueurs and aromatic essences. The substances in the absinthe of commerce he divides into two groups, the convulsive and the stupifying; in the first are absinthe, hyssop and sennel, and in the second annis, angelica, menthe and marjoram. Absinthe and annis produce the main symptoms. He divides the clinical manifestations into acute, chronic, and hereditary absinthism. The symp- toms in acute absinthism come on suddenly; the patient becomes agitated, screams, loses consciousness and falls; there is a tonic convulsion tending to opisthotonos, followed by a succession of clonic convulsions for twenty or thirty seconds. He then falls back heavily, lies still for a few moments and regains consciousness. He has no recollection of what has occurred and is astonished that people should be caring for him; this lucid interval is of short duration and is succeeded by similar convulsions lasting for ten or twelve hours. In others the tonic convulsions are followed by clonic convulsions, and the patient throws himself from side to side, grinding his 196 ■ DISEASES CAUSED BY ORGAXIC AGEXTS teeth, screaming and foaming at the mouth, trying to bite tliose around him, striking his chest, and tearing at it. These attacks are of short dura- tion and followed bv a period of calm; they end suddenly without cyano- sis or coma. A series of such convulsions leaves the ])atient weary and some\^•hat stupid: For a day or two he may feel the effect but at the end of this time he is entirely recovered. Acute [joisoning of this kind is usually recovered from, although death may occur during the attack. Chronic Absinthism. — The patient not only suffers from convulsive attacks, but also has neuritis and terrifying hallucinations. Chronic poisoning develops often from an indulgence of less than a year and from amounts of the licjueur which seem inadeciuate to account for the symptoms on the ground of the alcohol consumed. Women seem to suffer more frequently than men, and especially women below twenty-five years of age. These patients have morning vomiting and marked dizziness; there is marked irritability of the muscles; the eyes are fixed and brilliant; they sweat easily; tremor is marked; and there is extreme hyperalgesia of the body. There is marked hyperpesthesia of the skin over the exits of the spinal nerves, diminishing in intensity from below upward; the plantar reflexes are extremely active. Pressure on the abdominal wall is painful, and tickling or touching in the lightest way causes such agony that the patient screams with pain. The tenderest points are in the lower abdomen outside the recti muscles and out into the iliac fosste. This is accompa- nied, especially at night, by the most intense pain in the muscles of the legs. In cases of long duration the hyperalgesia is succeeded by analgesia, but the pain, on pressure over the abdomen, chest, or the spinal column, re- mains almost as intense as at the beginning. These patients are sleep- less or, when falling to sleep, are troubled with terrifying nightmares. Hallucinations of hearing are rare, but have a menacing character and are heard especially during the night; the mental ability, as in all alco- holics, shows weakness. One would judge that they lapsed rapidly into the chronic delirium and not infrequently died in this condition. Hereditary absinthism is shown in children whose parents are addicted to its use. These children seem to possess an unusually unstable nervous system and are especially prone to convulsions in infancy, and later to hysterical manifestations, and convulsive seizures. It has been noticed in Bellevue Hospital during the past few years that patients, who give a history of drinking absinthe, have shown attacks of convulsions and in the majority there has been marked hypersesthesia and hyperalgesia of the lower extremities; the extreme types as described above have not come under the writer's observation. KORSAKOW'S PSYCHOSIS. For many years there has been recognized among chronic alcoholics a condition of delirium combined with a polyneuritis; this was finally classed as a distinct and separate psychosis by Korsakow and is now gen- erally called KorsakoAv's psychosis or syndrome. Mentally there is loss of orientation and a marked defect in the power of retention of new im- pressions, and loss of memory for the recent past and also for events during various periods of the patient's whole life. There is a strong tendency to ALCOHOL 197 confabulation, and to fabrications of the most absurd character and even hallucinations, together with a polyneuritis. This usually occurs in the prime of life and is said by some authors to be more common among women than men, while the statistics of others show a preponderance of men over women. It usually follows excessive indulgence in alcohol for long periods, although it has also been described as occurring as a result of infectious diseases and following poisoning from lead and arsenic. In the majority of the patients the psychosis begins with the delirious stage and this may be so marked that at first a diagnosis of delirium tremens is made, but the critical sleep, so characteristic of delirium tremens, is absent and the delirium pursues a protracted course. Acute hallucinations fall into the background and the defects of mental retention with the lack of orien- tation of time and space, and the foolish babbling, become more pro- nounced. In other patients, and some claim this to be the usual course, there is a prodromal period during which there are signs of forgetfulness, mental aberrations and irritability; in some sleeplessness, and in others a stupor from which they are aroused with difficulty. The symptoms of neuritis may precede the delirium or not come on until after it. The length of this prodromal stage varies in different individuals. Bonhoeffer de- scribes a form which develops as a very slow progressive weakness of memory with a sudden exacerbation of disturbances of memory to a definite standpoint. When however the characteristic delirium is de- veloped, there is a distinct loss of memory for the recent past; events of their early life may be very clearly remembered, or up to a certain definite time. This amnesia may be complete or there may be curious lapses of memory in which the patient forgets some events and, without any appar- ent reason, remembers others which occurred during the same period. Many lose all orientation of time or space; especially is the time element defective; they cannot tell whether an event occurred a few moments or a week or several years ago. These gaps of memory are filled in with curious fabrications. This tendency to confabulate and indulge in pseudo- reminiscences is very characteristic of this psychosis. The sense of recognition is much at fault; the patient does not know those about him, or remember his friends or even his nearest relatives. The attention is easily obtained but kept with difficulty. In the early stages, hallucinations, usually of sight, occur only at night but as the disease progresses they become more intense and may be present during the day. Optic and tactile hallucinations are most common; these may or may not be terrifying and may assume the fantastic forms seen in acute alcoholic delirium. If the delirious stage comes on early and quickly, these hallucinations are then prominent. The emotional condition of the patients varies; some are excited, even simulating a condition of paresis; others are depressed, having the self-accusations seen in melancholia; they are often anxious and disturbed and, later in the disease, are apt to be irritable, quarrelsome, or simply indifferent; in some there is a tendency to be silly and funny; they are at times childish and easily provoked to whining and crying; but in very severe cases they are practically emotion- less. They are noticeably lacking in mental initiative and for this reason are very prone to soil themselves; here also weakness of the bodily muscles and the neuritis play a distinct part. They show a distinct power of combination of thought and, as far as the power of retention 198 DISEASES CAUSED BY ORGANIC AGENTS permits, can reason correctly, especially in some purely intellectual mat- ters. The symptoms of neuritis are those which accompany polyneuritis; they have the various annesthesias, paresthesias, or hyjieraesthesias; there is often an ataxic incoordination; their gait is frequently unstable and they walk with their feet far apart; the regular pains and sensitiveness to touch and muscular weakness are present; the ])atella reflexes are weak or absent; the joints are lax and the muscles soft; these neuritic symptoms are usually more pronounced in the lower extremities and when the paralysis becomes marked, an atrophy quickly follows; there may then be contractions and permanent deformities. Paralysis of the extensors is more frequent than of the flexors. In very severe cases the upper extremities are involved and one finds a radial, ulnar, or median paralysis. Some individual muscles may escape while others may be paralyzed. The sensory disturbances are variously distributed. One can seldom prove these in single nerves but can simply make out well-marked zones of analgesia and hyperaesthesia. Disturbances in the sense of position not infrequently occur; delayed reaction to pain has often been observed, ataxia of the upper extremities is often extremely marked. Severe tropic disturbances may occur. The cranial nerves may be affected. The vagi are not infrequently involved, causing cyanosis, tachycardia, and a peculiar dyspnoea whicla produces short-breathed speech. Double-sided paralysis of the recurrent laryngeal nerves has been observed, as also disturbances of swallowing and of move- ment of the tongue. Paralysis of the palate has been seen and paralysis of the external eye muscles, especially of the abducens, is especially frequent. Ptosis is rare; the inner eye muscles, however, functuate well or fairly well, but slow reaction to light has been several times observed; true nystagmus has also been noted and nystagmus-like twitchings are very frequently seen in the last stages of the disease. Wernicke has described a cerebral psychosis with paralysis of the eye muscles which runs an acute and fatal course; this he called polien- cephalitis hemorrhagica superior. This disturbance of the eye muscles went on to complete paralysis. Wernicke believed this to be a separate psychosis and held that it was characteristic for the clinical picture of the disease to have an associated ocular paralysis, a progressive course, and a rapidly fatal ending. Observations have since shown that patients with this group of symptoms do not always die, and several recoveries have been reported. Bonhoeffer, after fully reviewing the subject, concludes that poliencephalitis hemorrhagica superior is not a separate clinical entity but that the ophthalmoplegia is moderate in certain cases and is an vmusually predominating symptom of a general disease, and he further shows that it is nearly related, if not identical, with Korsakow's psychosis. The course of this psychosis is a protracted one; the first stage up to the full development of the mental symptoms continues for some weeks. The neuritis usually shows improvement before the mental symptoms, and in the course of several months may go on to full recovery, although in some there may be permanent atrophy and paralysis. The mental im- provement does not run parallel with that of the neuritis but requires a longer time. The powers of retention seem to be the first to improve; then the orientation improves sufficiently for the patients to recognize where they are, and they begin to realize who the persons are with whom they ALCOHOL 199 come in contact. The length of time during which this improvement occurs is a varying one; it may take months or years before complete orientation has been obtained. Some authors believe that complete restitution can occur; others deny it. Most observers are unwilling to commit themselves to a definite opinion in this regard. Even after ap- parent recovery, most patients show some weakness of retention and a forgetfulness which often prevents them taking up their former occu- pations. They are apt to have a distinct lack of initiative and show irritability and unstable emotions while, unless there is total abstinence from alcohol, they soon revert to their former condition. These patients are very apt to die in the delirious stage and in the severe attacks in which the mental symptoms are very pronounced, death is not often long delayed. There is great tendency to die of intercurrent diseases. The prognosis in all recent cases is doubtful and what is of especial importance, it depends upon the general condition of the patient and the state of his cardiac muscle. In the early stages the severer the delirium the worse the prog- nosis and when the neuritis extends to the cranial nerves it is especially unfavorable; thus, when the vagus is involved with tachycardia, dyspnoea and cyanosis, death very frequently occurs. The prognosis for final recovery, if they have passed the severe stages, should always be given with great reserve. Although they may recover a fair amount of physical vigor and of their former mentality, the chances are always in favor of more or less mental defect remaining. The treatment is in general symptomatic. In the early stages they are best cared for in some institution. In the early months, even in the milder cases, rest in bed is necessary. The neuritis should be treated as any other polyneuritis. The mental symptoms can only be treated through improvement in the general condition. During the severe de- lirious stages hypnotics may be necessary; in the later stages the milder hypnotics are sufficient when any are needed at all. When their mental condition improves and they are able to be about, it is best to give them light and easy tasks, which is better than attempts to improve the mental state by especial exercises of an intellectual character. When one may be certain that they will receive good care at home and can be reasonably assured of their total abstinence, the patients may be allowed to return to their families. In addition to the clinical forms of chronic alcoholism already described, there are other designations given to various mental states in which various symptoms predominate. Occasionally, in patients in whom excessive indulgence in alcohol, usually without food, has produced intense exhaus- tion with complete mental confusion, a state of amentia appears which simulates manic depressive insanity. Following an attack of delirium tremens or acute hallucinosis, some sink directly into a paranoic state or this less often develops primarily. The ideas of suspicion and jealousy greatly predominate. In most of these the delusions are predominantly sexual and early in the disease hypersesthesia sexualis is not infrequently present. They have the alcoholic emotional instability and may be dangerous. Since alcoholic excesses are at times a symptom of paresis, the diagnosis of this condition from the pseudoparesis of alcoholism may be difficult. The ideas of grandeur, the mental stupidity, with failure of memory and judgment of the paretic, are present with alcoholic hallu- 200 DISEASES CAUSED BY ORGAXIC AGENTS cinations and ideas of persecution and infidelity; though the develop- ment is gradual and the course ])rotracted, it is not progressive. Often the course is the final differentiation. If a chronic alcoholic survives long enough, the last stage of many of the above mental states is early senility and alcoholic dementia. This often occurs without any ])revious delusions or distinctly insane stages and is the final result of the cerebral arterio- sclerosis and atrophy of the cerebral tissues. TREATMENT OF CHRONIC ALCOHOLISM. It is not always jiossible to olitain an accurate history of the length of a debauch or its intensity. If one studies the tremors in connection with the condition of the tongue, in the experience of the writer a fairly good guess can be made which is sufficiently accurate to justify [one in acting on the conclusions thus drawn. If the tongue is not coated and there is no tremor, the patient has been drinking about three or four days; if the tongue is moderately coated and there is no tremor, it means the debauch has lasted about five or six days ; a heavily coated tongue and no tremor, about seven days; a moderately coated tongue and a slight tremor, about ten days; a heavily coated tongue and a marked tremor, about fourteen days; a moderately coated tongue with a very severe tremor, about three weeks; a fairly clean tongue and a very severe tremor, about a month; a bright red, glazed tongue and a severe tremor, from six weeks to three months. This is true of young men up to about forty-five years of age; after that the tremor comes on earlier and a two weeks' spree will give as much tremor in an elderly man as a month's spree in a young man. In women these rules are not accurate; the nervous system is affected more intensely and earlier, while gastritis comes on sooner. A w^eek or ten days' spree brings usually an intense tremor and women will inva- riably endeavor to hide how much and how long they have been drinking. The same treatment applies as for delirium tremens; if a young patient comes in the midst of his spree, an emetic is very efficient, but this should never be given in elderly persons or in those in whom we suspect the arteries may be atheromatous. Calomel (gr. v, gm. 0.3) with sodium bicarbonate (gr. 15, gm. 1) in single doses, or tw^o compound cathartic pills, should be given as soon as the stomach has quieted down. If the patient should be in the midst of the spree and has recently taken alcohol, one or two drams of paraldehyde with a half ounce of whisky wall often give him a restful sleep; this may be repeated in an hour if necessary but if he has not been drinking recently, paraldehyde alone should be given or the mixture of chloral, morphine, hyoscyamus, ginger and capsicum. Hypodermic injections of ergot are usually most efficient, lessen the tremors and take away the feeling of collapse and exhaustion which the withdrawal of alcohol produces. As in delirium tremens, the writer is firmly convinced that alcohol should be withdrawn im- mediately and absolutely; if they are collapsed a hypodermic of strychnine and doses of aromatic spirits of ammonia replace the alcohol. Further- more, the withdrawal takes away the idea that alcohol is necessary or that they need it in any w^ay, and this is an essential element to be thoroughly emphasized. When the patient awakes, stomachics, such as nux vomica. ALCOHOL 201 ginger and capsicum, should be given with his food. During the first few days, liquor ammonia acetatis, in half ounce doses, every three hours, is often helpful. Sometimes, in very nervous patients, antipyrine (gr.v, gm. 0.3) with the acetate of ammonia will help greatly. If the patient is fur- iously and "fighting drunk," either from acute intoxication or at the end of a long spree, a hypodermic injection of apomorphine (gr. I'o, gm. 0.006) will quickly transform the most pugnacious into a limp and docile object. He can then be put to bed and in a few minutes will drop off to sleep with no other medication. This rarely causes vomiting unless the stomach is full; if this does occur, it is of no disadvantage. This is often the best means of saving further struggles and the writer has never seen any harm come from it. If the patients have recovered from the debauch, the question arises as to the permanent cure; some may pull themselves together under excep- tional circumstances; these are undoubtedly those in whom the alcohol has not produced serious cerebral changes, but it can be said that they belong to the curiosities of medicine and it is not to be expected of any one who has formed the alcoholic habit. Institutional treatment, by which the patient may be assured that he will be protected against him- self, and cannot obtain any alcohol for a period of one or two years, where he can live out of doors and bring his body back into as healthy a state as possible with a chance for the brain to recover from the poison- ing of the alcohol, offers the surest means of cure. This may sometimes be done at home, if the patient can be controlled and carefully guarded, but the influence must be strong indeed and appeal intensely to his moral nature to affect him. Taken all in all, the influence of religion has proved most effective for this but unfortunately it is not applicable in many cases. Most alcoholics are very open to suggestion and in a small number of cases, hypnotism seems to have been tried with success, but this more often fails than succeeds. Suggestion does come in play in institutions where several patients are endeavoring together to break themselves of the habit; the concerted effort helps materially to strengthen the weak wills of many of them. These patients and their families are prone to turn to advertised quackery and nostrums to ob- tain a cure rather than to persuade the patient to put himself under regular restraint. The fact that legally in this country an alcoholic can not be restrained against his will often adds to the difficulty of doing anything that will really assist him. A treatment has been published byMcBride of Toronto, which has proved very successful in his hands. The writer has tried it in a few patients and so far the results have been all that could be desired. It is as follows: As soon as the patient is over the severe effects of his debauch or if he is steadily drinking without any drunken outbreak, he should be given, hypodermically, three times a day, atropine and strychnine, of each gr. iho (gm. 0.0006); these drugs should be gradually increased until the full physiological effect of the atropine is obtained and the patient is taking a thirtieth or even a twen- tieth of a grain of strychnine, three times a day; when the mouth is continually dry and the pupils dilated, the atropine should be reduced slightly and held at this dosage for four or five days; then both the strychnine and atropine should be gradually reduced, and finally the patient should be given the drug twice daily, then once a day, and then 202 DISEASES CAUSED BY ORGANIC AGENTS cut off entirely; the length of time required for this treatment is about a month or six weeks. Often the compound tincture of cinchona is added, especially in the morning when the craving for alcohol is the greatest. It is a noticeable fact that after a few days, usually in less than a week, the- desire for alcohol has ceased, and the thirst from the dryness of the mouth is easily satisfied \A'ith water. McBride reports that he has tried this for a number of years and the patients whom he thus treated ten or twelve years ago have remained abstinent; this has not been universally successful but in his hands it has succeeded in such a large majority that it is worthy of the most extensive trial and it has the special advantage that the patients need not be confined or absent from their homes or even daily work. CHAPTER X. OPIUM. MORPHINISM. COCAINE. By ALEXANDER LAMBERT, M.D. OPIUM. Historical. — There are many legends connected with the discovery of the effect of opium. Along the Nile its use dates back to very ancient times as the Egyptian hieroglyphics seem to show. Homer mentions the poppy as a garden plant; the ancient Greeks knew the means by which the narcotic properties could be obtained from the plant as appears from the writings of Dioscorides, and in some parts of India and Persia to-day the opium is obtained from the poppy by the same method that was described eighteen hundred years ago. Hippocrates is among the first in whose writings we find the drug recommended for internal use. The Egyptian priests used it as a nervous sedative, believing that the sleep produced gave opportunities for the soul to commune with the gods. The Arabian physicians were the first to study its value in disease and they seem to have made wide use of the drug. The Persians early recognized the opium habit, for they had a proverb that, although opium cured disease, it also produced a disease. Serturner, an apothecary in Germany, seems to have been the first to study scientifically the alkaloids of opium Derosne, in 1803, discovered narcotin which he called the salt of opium, believing it to be the active principle. Robequet showed this belief to be erroneous and gave the name narcotin to this alkaloid. In 1804, Seguin isolated a crystal- line body which has proven to be the narcotic principle but he did not seem to realize the importance of his discovery and, in 1817, Serturner again published the existence of a salt of opium, which he named mor- phium. Crothers says that, although opium has been used subcutaneously for a long time, morphia seems first to have been thus used in this country by Drs Isaac Taylor and Washington, in New York, in 1839, and its use abroad was not generalized until a syringe was introduced into the French army, in 1866, by Pravaz. The dangers of morphinism as a habit seem first to have been realized, in England, about 1864. Nausbaum in the same year drew attention, in Germany, to the injurious effects of its continued use. Since then the attention of the medical profession has been drawn more and more strongly to the increasing dangers of morphia and opium addiction Not infrequently have physicians, in their efforts to relieve pain, been unconsciously responsible for the spread of this habit, and it is only in recent years that the full realization of this danger has become widespread. The pernicious habit of giving a h}"podermic s}Tinge to patients, teaching them to use morphia to alleviate a passing pain, has been all too frequent, and has been the cause of many an unhappy addiction. 204 DISEASES CAUSED BY ORGANIC AGENTS Etiology. — The more highly cultivated and mentally developed a race becomes, the more intolerant is it of pain. This is especially trueof the male sex. The Eastern nations have long used opium, thus in India and China, opium, though a curse from its excessive use, seems to be more often used in moderation ^vithout ])roducing the same deleterious effects as in other races. This is not true of all Eastern races, for the Burmese rapidly deteriorate under its use. The great majority of morphia addictees are among the educated classes, especially those who deal continually with it, as druggists, physicians and professional nurses, and among these, men predominate. A large class are those who are neurotic from inheritance; their will and judgment are in unstable equilibrium and they are either dominated by a desire to gratify any momentary pleasure, or they seek comfort in anything that seems to stimulate and increase their mental vigor for the time being. They are often the children of alcoholic, tuber- culous, syphilitic, or neurotic individuals, and unfortunately the alcoholism in the parent need not be more than the so-called moderation. Many persons of unusual intellect, precocious in early life, are pushed beyond their strength, mature early, and break under the undue strain. These seek relief from exhaustion by means of drugs and alcohol. It is not un- common to find strong and vigorous men, after some severe shock or dis- appointment or after intense strain, given morphia to alleviate insomnia, soon becoming addicted to its use. Many patients, suffering from chronic and painful affections or incurable disease, become addicted to the use of morphia from the necessity of alleviating pain. Women suffering from disorders of the genital organs fall easy victims, and it is especially danger- ous to prescribe morphia for women at the climacteric period. Formerly many patients became addicted to morphia through the widespread custom of giving it to relieve pain following surgical operations, but the number of these- is enormously diminished since the danger has been recognized by surgeons. Among Western nations the opium habit is indulged in more by the taking of morphia by mouth or hypodermically, or by drinking laudanum or paregoric, than by the smoking of opium. Among Eastern nations the smoking of o])ium seems rather to predominate. Of late years codein and heroin addictions have been recorded. Compared with alcohol, opium may be said to be equally degrading and destructive of the moral side of the individual, but it does not leave behind it the same amount of organic lesions in the individual nor transform the individual into the same vicious, destructive, and abusive beast that alcohol does. ACUTE OPIUM POISONING. Symptoms. — The symptoms of acute opium poisoning require little detailed description; the infrequent, stertorous breathing, the livid cyan- otic appearance, the pin-point pupils, the cool, sweating skin, give a well- known and easily recognizable clinical picture. The respirations may simply be infrequent with a rythmical regularity or they may be in groups of three or four with many seconds between each group. Treatment. — The treatment is chiefly a struggle to keep up the work- ing of the paralyzed respiratory centre. The old method of walking a OPIUM. MORPHINISM. COCAINE 205 patient up and down, injecting large doses of atropine to stimulate the respiratory centre and slapping him with wet towels, has always seemcid to the writer ill-advised. The incessant walking up and down, stagger- ing forward and back half asleep, exhausts the patient thoroughly and tlie liability to give, what is for that patient, an overdose of atropine and thereby add its poisonous effects, appears to be a dangerous pro- cedure. One may see patients, brought to the hospital with their hearts very rapid from an overdose of atropine, die suddenly in collapse; they really died from the antidote and not from the opium. The slapping with wet towels soaks them with cold water and in the exhausted condi- tion there is a strong liability that pneumonia may follow. It seems wiser to save the strength of the patient and the energies of the attend- ants for the long and tedious period through which artificial respiration must be kept up. As soon as possible the stomach must be washed out with a solution of potassium permanganate (1 to 500); a certain amount of this should be left in the stomach; whether opium be taken by the mouth or as morphia, hypodermically, the morphia itself is excreted into the stomach cavity and is then reabsorbed. It has been proven experimentally on dogs that more than half of the morphia given sub- cutaneously can be recovered by simply washing out the stomach. Dr. Moor, of New York, has shown that permanganate of potassium prevents the toxic action of morphia. In opium or morphia poisoning it is there- fore wise to wash out the stomach at least every hour and leave a little of the permanganate solution in the stomach to destroy any of the alkaloid that may be excreted by the gastric mucosa. In the periods between washings a strong infusion of coffee should be injected into the bowel. Artificial respiration should be kept up until the patient is able, when left alone, to breathe eight or ten times a minute. This may mean many hours of hard and tedious exertion, but as long as the heart is beating, if respirations are kept up, there is a possibility of recovery. To relieve the cerebral venous congestion produced by opium, the injection of ergot hypodermically, as described under alcoholism, is most effective and satisfactory. It equalizes the circulation and relieves the congestion. OPIUM SMOKING. The smoking of opium is an ancient vice. It is claimed that this habit came from Egypt and Arabia to India, but this seems doubtful. At all events, it is mentioned by Barbosa as being found in India as early as 1511; from India it was introduced into China and is the chief method in this last country by which opium is used. In 1773, the East India Company first began the exportation of opium from India to China, following the Portuguese by a few years. Since 1860, the impor- tation of opium into China, and the cultivation of the poppy, have greatly increased. Opium is smoked from a special pipe, the stem of which is usually twenty-four inches long, generally made of bamboo, at the loAver third of which there is placed a bowl, usually of red clay, through which a minute hole runs down into the stem. Compared with the other forms of opium addiction, according to Kane, ismoking takes longer to form a real habit, works less physical and mental injury when once formed, and is easier to cure. A gradual rise in the 206 DISEASES CAUSED BY ORGANIC AGENTS amount used is necessary in order to get the desired effect; the early pleasurable symptoms soon disappear and the evil effects on mind and body are similar in many respects and the symptoms incident to abstinence are the same. In smoking opium, the morphia is not all consumed and a large amount remains in the ash. Amounts of opium arc smoked which, if taken by the stomach, would certainly produce death. Kane quotes the case of a man who broke the habit after consuming as a daily dose 594 grains. He gives the tabulated statement of the daily dose of 1,000 Chinese smokers; 046 varied between 16 and 128 grains; 250 from 160 to 320 grains; 104 from 480 to 1,600 grains. To obtain the desired effect 5 grains seem sufficient for a novice, while old smokers need as high as 290 grains. The average American seems to consume more than the average Chinaman to obtain the desired effect. This vice among Amer- icans is of relatively recent origin, having been first taken up in this country in 186S, in San Francisco; from that time it rapidly spread through the west and from there tothe east, until now, throughout the United States, it is by no means rare. Opium smoking is not confined to any one special class. It has among its addictees the wealthy of both sexes, the sporting man, the mechanic, and the dissolute. Neither all Chinamen nor all Amer- icans who smoke, do so to excess ; some, especially the former, do so but once a week, and persons are met with who smoke for months without forming any habit and without any apparent injury. The effect desired by the opium smoker is not that of slumber filled with fascinating dreams, but a condition of dreamy wakefulness in which the mind is lifted out of the petty annoyances and cares of life. Symptoms. — ;The effect of opium smoking on a novice is described by Kane, who tried it himself and experimented with two other men; the first effect was nausea and dizziness, accompanied by a pleasant sensation of exhilaration, followed by a quiet, easy contentment; this was after deeply inhaling four pipes; there was an increase in the force and fre- quency of the pulse from 80 to 110, hot flashes over the body and face, and after a few more pipes came a soft pulse, lessened in frequency, and a fall in temperature, giddiness, and slight nausea, with some staggering on rising or walking, profuse perspiration, ringing in the ears, and intense itching over the entire body. The profuse perspiration and nausea con- tinued, followed shortly by abundant and easy vomiting; there was also a feeling of uncertainty in putting down the feet in walking, sleepiness, heaviness of the eyelids, contraction of the pupils, dryness of the throat, and a fear of crossing the street if a wagon or car was approaching. The sexual appetite was increased. This was followed by intense sleepiness. The doze, however, lasted but a moment, the awakening being sudden ; there were no dreams. The nausea was a prominent and distressing symptom and, in his case, lasted for twenty-four hours as did also the itching. The pulse dropped below sixty, and once, after ten pipes were smoked fell as low as forty-one, and remained so for six hours. Some- times the novice does not feel at all sleepy and becomes very talkative even after the tenth pipe, and later, when desiring to sleep, although sleepy, he is unable to do so from intense fear that some catastrophe may occur. Among other novices the drowsiness may come on after four or five pipes, and they sink back into a heavy slumber, lasting for some hours. Twenty- four hours after smoking, the novice frequently feels languid, is without OPIUM. MORPHINISM. COCAINE 207 appetite, has an intense headache, and the itching continues. Old smokers do not, as is usually believed, smoke a few pipefuls and then fall into a heavy sleep; as experience grows into a habit, stupefaction is less speedy, and it may require many hours and many pipes before even the coveted excitation is reached, and the majority complain that they are sleeping less than usual and are troubled by distressing insomnia. If the smoker has gone to excess, sleep filled with horrible hallucinations or a condition of terrifying wakefulness may follow. The stupid, sleepy condition of the next day is removed by a further resort to the pipe. The habitual smokers, who do not use the drug to excess, claim that, unlike any other form of opium taking, a headache never follows. The effect of opium smoking is first seen upon the mind. The feel- ings of pleasant exhilaration and contented indifference are gradually more difficult to obtain and, after from three months to a year, they cease to occur although the amount of opium smoked be largely increased. If the addictee endeavors now to break it off, distressing symptoms show themselves so intensely that he is forced to continue. The continuance of the smoking brings with it a disinclination for con- tinued mental effort, a weakness of the Avill-power, a lack of decision. and a loss of memory. A certain indecision, manifested by mentaf per- plexity and impatience concerning the smallest actions, is often noticed after smoking. Dull mental hebetude often alternates with outbursts of violent anger, or there is a gloomy presentiment of impending evil only allayed when indulging in a pipe. During these periods of despon- dency, suicide, especially in women, is not uncommon. Neiiralgias, noticed in other forms of opium taking, are rare during opium smoking. Occasionally colic is complained of but this seems more due to intestinal disturbances than to a direct effect on the nervous system. Tremor of isolated muscles sometimes occurs, but a general tremor, most marked in the hands and tongue, is noticed when smoking is excessive. The Eupils^ as a rule, are evenly contracted. When the effect of the last dose as worn off, the pupils are often widely dilated, and conjunctivitis, with burning and excessive lachrymation, is common. All who have smoked for any length of time, complain that they are getting near- sighted. The pulse-rate is usually above normal, except that after excessive smoking it falls below the normal rate. The flushing of the face with profuse perspiration in a novice, is replaced, in the old smoker, by a sallow and deathly hue. When under the full effect of the opium, the respiratory rate is lower and prolonged smoking produces a chronic bronchitis with cough, and pharyngeal and laryngeal catarrh with loss of power in the vocal cords. In the alimentary tract there is gastritis and constipation, often accompanied by haemorrhoids and an obstinate pruritus. The constipation is at times succeeded by a violent diarrhoea, which may become chronic and last for months. The vomiting that attacks .the novice may be only slight, come on suddenly and unexpectedly, and consist in a simple and spasmodic emptying of the stomach; later there may be persistent and violent attacks in which finally nothing but blood-stained mucus can be raised. The itching of the skin varies with the individual; in some it is slight and in others intense, especially in the genital region, so that they often excoriate themselves The average specific gravity of the urine is low, 208 DISEASES CAUSED BY ORGANIC AGENTS from 1,004 to 1,010; the reaction is nsuully neutral; there is an increase in the earthy and alkahne phosphates, and in twenty examinations Kane found no albumen, sugar, nor casts. For the first few months of smok- ing, in both sexes there is an increased sexual desire ■which is especially marked in young. women, and opium smoking has been used as a means of seduction. After a few mouths there is a diminution of desire and impotence in the male. In the majority of women menstruation is not interfered with, although in some it is scant}' and irregular and there may be amenorrhoca. In this, oj)ium smoking differs materially from morphia addiction. Some women, who smoke excessively, habitually miscarry; in others it seems to have no effect whatever upon their preg- nancy, and the children of some oj)ium smokers, as far as can be learned, seem strong and healthy; this is again in opposition to the other methods of taking ()])ium. The symptoms of abstinence and the sudden cessation of opium smoking are the same in most respects as those which follow the with- drawal of other forms of ojiiun-"., but the smoker often suffers less severely and for a shorter time than the opium eater or the mf)rphia addictee. The respiratory tract and the eyes are affected out of proportion to the rest of the body. The first symjjtoms are gaping, yawning, sneezing, profuse discharge of tears and mucus from the eyes and nose, irregularity of the pupils, ringing in the ears, followed by extreme restlessness, intense pain in the joints, nausea, vomiting, and purging; the vomiting and purging may become almost constant. A peculiar dull, drawing, dry, and burning ache in the pharynx and larynx occurs, which is followed by distressing tearing pains in the muscles, especially in the calves of the legs and be- tween the shoulders. Chills, followed by flashes of heat, are felt along the spine and are followed by profuse perspiration. In some cases, if no opiate is used, the vomiting and diarrhoea continue and the restless- ness and flushed face give place to complete relaxation, a ghastly pallor with sunken eyes, collapse, and death; but in less severe cases or when proper remedies are used, the distressing or dangerous symptoms cease one by one. Sleeplessness persists for a long time; the bronchitis and catarrhal inflammations of the throat usually last for months; the pains in the legs and body gradually disappear; the sexual power returns; the ap])etite gradually improves and becomes ravenous; an increase in the weight is manifested; a return to natural buoyancy of mind begins, and the patient regains his health and strength. Under proper treatment these symptoms can be cut short and the sufferings much reduced, but it is rare for individuals by themselves to carry out a cure to a suc- cessful issue. When once cured, it is difficult to say what proportion relapse, but a single indulgence may be sufficient to start them again into the habit. Rarely, individuals are found, who once having broken the habit, return to it and smoke but one pipe a week and do so for years without apparent injury. OPIUM BY MOUTH. This is much more widespread in this country than is generally realized. Dr. A. P. Grinnell recently ascertained the amount of opium, paregoric, OPIUM. MORPHINISM. COCAINE 209 and laudanum, sold by the various druggists in a single month in sixty- nine towns in the State of Vermont. The figures show that the amount consumed would be sufficient to average a dose to every man, woman, and child, in the State of Vermont, every day in the year. By a dose is meant, 1 grain of opium, \ grain of morphia, ^ ounce of paregoric and 20 drops of laudanum. Probably the most of the opium takers are those suffering from rheumatism, neuralgias, migraine, hepatic or renal colic, dysmenor- rhoea or other troubles which at first caused only a temporary indulgence in the drug. Later, however, especially in elderly people, the habit is insidiously formed. Opium is often used at intervals for insomnia or to allay grief and mental suffering. It is given up when the strain is past, and taken up again for any reason that seems sufficient. Often in these cases the only symptoms seem to be a mental and physical restlessness and anorexia, with a disposition to sleep. The opium taker shows cer- tain differences from the individual taking morphia. There is more excitement and exaltation following morphia, while with opium there is more a feeling of quiet contentment, lasting over a long time. The morphinist, after the feeling of satisfaction has worn off, is more apt to dread the slavery of his habit, while the opium taker never seems fully conscious of the danger. The opium taker rarely consumes as much as the morphinist and the duration of his existence, after the habit is once formed, is usually much longer. He may indulge for a year or more without apparent injury, but the morphinist, in a relatively short time, shows evidences of his degeneration and succumbs quicker. Gradually the effects of the opium begin to show when used to ex- cess. There is a change in the disposition; they become irritable, peevisli, somnolent and show evident dishonesty in little matters, espe- cially concerning the use or the procuring of the drug. They are prone to develop a sallow parchment-like complexion, although in the early stages their faces may be flushed, with a tendency to cutaneous erup- tions, and this last condition of the skin is apt to persist; the hair tends to become gray early and they have an old, worn-out, exhausted, or cachectic appearance. There is often general feebleness of the mus- cular system with tremors, and this may be so pronounced as to resemble ataxia. The visions so vividly depicted by De Quincey do not seem to occur among western nations. Sometimes the imagination seems stimulated for a while, producing a dreamy, visionary state, but it is extremely doubtful if, under the influence of opium, the mind is capable of more intellectual vigor. No new thoughts arise, no new levels of intellectual abihty are reached, and there develops simply a dreamy selfishness, producing an inclination to live apart from others, and to shun companionship. There is a tendency to ignore, and to break, appointments and social engagements. If the opium taker is found in company, it is usually among those who are below him in intellectual and moral development. His self-respect is gone, he is careless of his appearance, indolent in his habits, and neglectful of the decencies of life. In the end he sleeps poorly, grows emaciated, his eye becomes lustreless, and he goes about shrinking and cringing. In the later stages cardiac degeneration is prone to occur with attacks of pseudo-angina pectoris or with precordial anxiety; constipation is common, and the general nutrition is much disturbed. They are prone to die suddenly 14 210 DISEASES CAUSED BY ORGANIC AGENTS from acute infections as erysipelas or pneumonia, or tend to go into melancholia or dementia. MORPHINISM. Indulgence in morphia is a vice of recent years; it has taken the place, especially in large cities, of the preparations of crude opium. The readiness and cheapness with which morphia can be obtained and the ease with which hypodermic syringes can be bought, have made this vice a widespread curse. Physicians, nurses, pharmacists, form, unfortunately, a large percentage of the morphia addictees. Rodet, in Paris, in 650 men addicted to moqohia, found 40 per cent, physicians, 3 per cent, students in medicine, 3 per cent, pharmacists, 15 per cent, idlers living on their incomes, 8 per cent, merchants, 7 per cent, officers in the army, 5 per cent, workmen, and the rest scattered through many occupations. In 350 women, 43 per cent, were without occupation, 14 per cent, were prostitutes, 13 per cent, were working women, 10 per cent, were wives of physicians, and the others were scattered through various employments. As regards age, Rodet found in 324 cases that between twenty-five and forty the greatest number (GO per cent.) oc- curred; below twenty-five, 11 per cent.; from forty to fifty, 13 per cent, and the remainder after sixty years of age. Rodet also tabulated the maximum daily dose of 569 addictees; 25 per cent, took from 50 centi- grams to a gram (7J to 15 grains) ; 8 per cent, took below 10 centi- grams, that is, less than 2 grains; 15 per cent, from 10 to 30 centigrams; 14 per cent, from 30 to 50 centigrams; 12 per cent, from 1 full gram to IJ grams; 10 per cent, from 1^ grams to 2 grams, and 9 per cent, from 2 to 3 grams; the proportion rapidly diminished above this amount, there being individuals on record, however, who took from 9 to 12 grams a day. In studying the duration of the habit, Rodet found that in 270 individuals, 41 per cent, showed a duration of from two to four years; on the other hand, there were individuals who had been addicted to the habit for ten, twenty, thirty, and even forty years. There are no pathological lesions which are characteristic of chronic morphia poisoning. Fatty degeneration of the heart muscle has been described and Schweneger has found hypertrophy of the left ventricle and dilatation of the right ventricle and pulmonary artery. Fatty de- generation of the liver is reported as occurring in a marked degree in those dying of chronic morphinism. These various lesions can not be considered as characteristic. The cause for which morphia is taken often modifies the habit which sooner or later is acquired; thus those who take it to soothe the agony of some chronic disease probably resist longest its baneful effects. Many who take it only to assuage pain, knowing full well the habit and its effects, often bear moderate pain without turning to morj^hia for aid and only use it when the pain be- comes almost unbearable. The dosage in these patients is increased only as the need demands, and often the same dose will suffice for many months or years. In the end, many of these show the symptoms of chronic morphinism, but French writers differentiate this class of pa- tients from those who take morphia for pleasure, in whom the habit OPIUM. MORPHINISM . COCAINE 211. rapidly grows, and the demand becomes more and more urgent with increase in the dosage. These authors designate the first class as mor- phinists and the second class as morphinomaniacs. The question may arise in the case of a patient suft'ering from a painful and incurable disease, whether a physician is justified in giving morphia, knowing that if once used it must be given for the remainder of the ])atient's life. People are often opposed to having it said that members of their family died with the morphia habit. In many cases it is simj>ly cruelty to refuse to give it, and, under certain circumstances, the formation of the habit in some sufferers is of absolutely no consequence. The hypodermic use of morphia is the most seductive form of the habit and the hardest to break; some patients seem to require the sen- sation of the needle thrust in order to be satisfied What is sought in most cases is the feeling of exaltation, strength, and mental vigor, with relief from pain or ennui, the drowning of sorrow, or the killing of the hopeless realization of despair and failure. Morphia does this as long as the desired effect lasts. The duration of this varies in different individuals and is longer in the beginning because the toleration for the drug is rapidly acquired and the time between doses must be con- tinually shortened or the dosage increased, and finally both of these means must be used to obtain the desired results. In many who take enormous doses it would seem that all the morphia does not act, but some must remain inert and be excreted without action. In the morphia addictee there are practically three stages which, al- though shading into each other, can still be recognized; exaltation, in- toxication and cachexia. The first is one of enjoyment, happiness, and satisfaction. When the effect has subsided it is followed by malaise, a feeling of restiveness, and painful anxiety, which a renewal of the dose takes away. The effects of a single dose will sometimes last for twenty- four hours, but this is soon reduced to twelve, then to six, then to three hours, then to minutes instead of hours, and finally, the exaltation ceases, and he must take the drug to quiet the intense craving and the pains of abstinence. When the period of intoxication is reached, a dryness of the mouth, nausea, and anorexia supervene. The habitu6 then notices that an injection taken just at meal time will give him the appetite which he lacks. The voice becomes hoarse, and singers can no longer use their voices. Digestive troubles appear; constipation is obstinate; there is a loss of sexual desire, and amenorrhoea in women. The memory begins to be treacherous; insomnia becomes marked; the patient passes his nights reading, although worn out with fatigue, and if he sleeps, it is not a refreshing slumber. In the daytime he is peevish from fatigue, ill-humored, and seems stupified and benumbed. He takes no interest in anything which does not pertain to himself, and his character is notice- ably changed. There is moral inertia, absence of will-power, and com- plete self-centred selfishness. The nights become more and more dreaded, and soon, if he sleeps at all, he wakes constantly from his nightmares, which become more terrifying, and always of a distressing nature. His hair begins to fall out, the teeth to decay, and the body to emaciate. The face is drawn and aged; the eyes are lustreless, and the breath foul. Even from this stage it is possible to recover If he goes on, the cachexia develops, emaciation becomes extreme, and the 212 DISEASES CAUSED BY ORGANIC AGENTS secretions arc })ractically suppressed; cedema of the legs aj)pears and the shghtest exertion causes oppression and a sense of constriction in the chest. The pulse becomes small and irregular. The heart's action is enfeebled; there is increased precordial dulness and the apex impulse is diminished. There is a diminution in the amount of urine and often a marked albuminuria. He is morose, sullen, and in a state of semi- stupor, gazing with dull, lacklustre eyes, scarcely conscious of his en- vironment. The mental degeneration is complete and a continual delirium may be present. The condition of his heart and kidneys is such that restitution to a normal condition is impossible. Death occurs if the morphia is cut ofi", and the drug invariably kills if it is continued. Considering the symptoms more in detail, memory is one of the faculties first affected and the amnesia is similar to the beginning senile dementia. Names are the first to go; the mor})hinist will relate occur- rences early in his life, but will forget what he has done during the past week. He will forget the familiar names of streets, the details of his profession; thus the physician forgets the dosage of medicines and the scientific terms with which he is familiar. Others will make such errors in their daily work that they lose their positions. Amnesia of the well marked stage of morphia intoxication is only equalled by the amnesia of paresis. The will power is enfeebled and the patients spend days in bed without sleeping and without stupor; their minds are perfectly clear but their power to do is gone. They perceive the motive of actions and reason sanely, but all motive and reasoning is insufficient to pro- duce effective volition. In some patients this is continuous and perma- nent; in others it seems to run in crises, lasting over two or three days. There is psychic asthenia. The sense of responsibility is wiped out and is replaced by the indifference of perfect egotism. Their character is modified and they are discontented grumblers, obstinately "ugly," often given to explosions of intense rage, quarrelling without cause, and even destructive and dangerous to those with whom they come in contact. They may become misanthropic, hypochondriacal, annoyed at trifles, and prone to seek solitude. Often the morphinists are individuals of more than average ability and intelligence, realizing fully their condition, and appreciating their progressive degeneration. It is for this reason that they resent criticism and accept reproaches about their habit with bad grace, because they are already filled with remorse. Morphinists will invariably lie about their vice, because in the early stages, they feel the disgrace and have enough moral sense left to endeavor to hide it. If, however, they have just taken their morphia or are assured of sufficient dosage to keep them comfortable, they do not necessarily lie about other matters. But when the craving for the drug is upon them, there is nothing to which they will not stoop to obtain it. Lying, thiev- ing, begging in the street, prostitution itself, are to them all justifiable means to obtain the drug and smother the irresistible craving. Contrary to what is often supposed, morphinists do not sleep well; they are subject to nocturnal hallucinations which render their nights times of dreaded fear and terror; thus they endeavor to keep them- selves awake by reading, and during the daytime, when overcome by fatigue, are prone to fall asleep whenever they remain quiet, sitting in a chair, no matter in what place or company. These hallucinations OPIUM. MORPHINISM. COCAINE 213 are extremely rare in the daytime. The hallucinations of sight are always terrifying, being composed of various animals, spectres, and of all sorts of revolting and gruesome combinations. Contrary to the hallucinations of alcoholism, those of morphinism are not occupation deliriums. The hallucinations of sight are much the most frequent; next those of hearing; those of taste and smell are rare, and those of general sensibility are exceptional, which last is also contrary to what occurs in alcoholism. The sense of taste itself is often dulled and sometimes even abolished. The sense of hearing is often noticeably diminished and the sight is affected, sometimes making walking difficult. Reading and writing become impossible because objects appear clouded and deformed, and when the endeavor is made to fix an object, it dances or trembles or approaches or retrogrades, and this, together with a fre- quent distinct photophobia, causes great distress. Ophthalmoscopic ex- amination does not seem to reveal any distinct lesion. There is at times contraction, and at times dilatation, of the pupils; an ansemia of the retina has been described; sometimes the arteries seem scarcely visible with the venous congestion. These visual disturbances disappear when the morphia is permanently withdrawn. The reflexes are very variable. Disturbances of the general sensibility are often marked and vary greatly; there are often pareesthesias and sometimes intense neuralgic pains. Others show marked anaesthesia, which may be confined to one side of the body. More often there is hypersesthesia, and the sole of the foot becomes so painful, that, when it is touched to the floor, it gives a sensation of burning, and the patient can only walk with short, jumping steps. Rodet considers this form of hypersesthesia as very characteristic of chronic morphinism. The tactile sensibility is usually diminished or abolished. The question often arises whether indulgence in morphine impels the individual to suicide. At times when, inadvertently, too large a dose is taken, the patient succumbs, but as long as he can obtain his drug, he is an individual without will, apathetic, and incapable of mak- ing sufficient exertion to commit suicide; if, however, the morphine be withdrawn or he can not obtain it, the condition entirely changes and the symptoms and mental condition of morphia abstinence are, in many ways, the reverse of this. Troubles of digestion are among those most noticed by the patients themselves; in the early stages there is nausea, vomiting, and anorexia, which do not persist for a very long time. There is often an intense thirst; the breath is very offensive and of a peculiar odor, often spoken of as being so characteristic as to designate the morphinist by those who are brought in contact with many of these patients. They are markedly constipated and this often alternates with attacks of diarrhoea; their stools are bloody and, during the period of constipation, may be as infrequent as once or twice a month. The teeth are subject to caries which attacks first the molars on their grinding surfaces; this extends to the bicuspids, then to the incisors, and last of all to the canines. This caries at times does not follow the above course but it is always painless, not accom- panied by any periostitis, and usually progresses with great rapidity. Its occurrence usually coincides with the falling out of the hair. The disturbances of nutrition appear in some patients after a few months and in others not until after some years. Emaciation is perhaps the 214 DISEASES CAUSED BY ORGANIC AGENTS the most striking and may go on to an extreme degree. Their faces become Hvid and often sallow, the expression set, and there are pre- mature wrinkles, which, with the faded, sallow look of the skin, often gives the look of premature old age. The tissues lose their viability, which accounts in a measure for the ease with which slight bruises cause ecchymosis, and the greater liability to the occurrence of abscesses, to which we will refer later. Often in the skin there are multiple cica- trices and small sjjots from the use of the needle; as many as G3,000 have been counted on one individual. The pulse of the chronic morphinist is slow and there is a fall in ar- terial tension with, in the last stages, distinct enfeeblement of the heart's action and diminution in the force of the apex beat. The number of respirations is slowed and, at times, they are shorter, so that every now and then a long deep inspiration seems necessary to give the required amount of air. Dyspnoea on exertion, even of the slightest kind, is quite common. In the beginning of morphia addiction, there is polyuria, which later is followed by a diminution of secretion below the normal. In many there is albuminuria which is ascribed by Levinstein to a special action of morj^hia on the medulla, to changes in the arterial pressure, or to a paralysis of the nerves which enter the kidney around the renal artery. The effects in the genito-urinary system are much the same as those described under opium. Most women become sterile, but in spite of the cessation of men- struation, conception may take place. Pregnancy may run its normal course, or the morphia may cause a miscarriage or premature birth. Children born of morphinist mothers may be well-formed and normally healthy. Happel, of Tennessee, reports that in his experience a large percentage of children born of morphinist mothers have congenital car- diac defects. They showed, as so often seen in children of morphinist mothers, fretfulness, irritability, restlessness, and colic, which could only be relieved by opium. If they are not given opium, the restlessness and crying increase and they may go into a collapse in a few hours or live a few days and die from marasmus. If opium be given, they may be tided over for some months or years and perhaps a successful and gradual breaking off be accomplished. Often the children of morphia addictees are idiotic or show a lack of mental and physical development. The accidents which may follow the injection of morphia are those of infection from the use of a dirty needle or of an infected solution. These abscesses usually appear at the point of injection, but sometimes at distant points, in a portion oi "^he skin which has not been perforated. They are usually small, rather indolent, and not always as painful as one would expect. They usually heal under proper treatment, although they may form indolent ulcers. The points of injection may be the starting point of erysipelas, cellulitis, or phlegmon. Kane reports cases of tetanus developing from the hypodermic injection of morphia. In many morphinists the scars of the abscesses are very numerous on their legs and arms and even over the body. Where the morphia has been injected directly into a vein, sometimes a sudden, intense narcotism fol- lows and the patient feels a peculiar tingling over the entire body. There is at times a feeling of great fulness and throbbing in the head and this may be accompanied by difficulty of respiration, swelling of the OPIUM. MORPHINISM. COCAINE 215 face, and loss of consciousness. Death has been reported as following quickly when morphia is suddenly injected into the circulation. Most addictees increase the dose so gradually that the accident of acute poison- ing and death from an overdose is comparatively rare. When, however, an endeavor has been made to reduce the amount taken and then for some reason a larger dose is desired, an amount, which formerly could be borne with impunity, is taken and death results. When once a person is thoroughly under the influence of the habit, a cessation of the use of the drug produces symptoms, both physical and mental, of such intensity that few are strong enough to resist the craving thus produced and, unaided, break off the habit. When the effects of the last injection begin to wear off, restlessness, malaise, yawn- ing, and sneezing appear; the craving increases and can only be entirely relieved by a further dose. The length of time, after the last dose, at which these symptoms will begin, depends on the individual. Following quickly on the malaise, the eyes begin to water and the eyelids droop. The eyes lose their lustre and vision is much disturbed. The face be- comes pale and an expression of intense distress is very noticeable. Hearing is diminished and there is a mental hebetude which prevents all intellectual work. There is a trembling of the hands and of the arm in supination and pronation, varying markedly from the alcoholic tremor. In this condition there is nothing that morphinists will not do, and no means that they will not employ, in order to obtain morphia. As enforced abstinence continues, the patient may develop epileptiform attacks or hysteria, or there may be, in neurotic individuals, a state of choreic jactitation. In extreme cases a form of mania may develop in which the patients pace the room, shrieking, crying, throwing them- selves about, using whatever instrument comes to hand to commit suicide, 'or they may attack their attendants. Hallucinations of sight and hearing may develop and these are always of a terrifying nature. This is most frequently seen in those who have taken alcohol with their morphia, but it not infrequently develops in those who have taken mor- phia alone. Often, before these mental disturbances are fully developed, the patients are overcome with a sensation of extreme weakness and forced to keep in bed. They are pale and haggard ; there is nausea and vomiting, and almost invariably a diarrhoea develops, which may become extremely profuse. This is often accompanied with intense abdominal pain and hyperesthesia of the skin so that the patient can scarcely sup- port the weight of the bedclothes; the body is often covered with a cold sweat, and there may be chills of great intensity. When morphia is cut off abruptly there is great danger of collapse. This may supervene on the second or third day and the patient shows in- creased weakness, appears pinched and haggard, while the pulse becomes small and then disappears. Or he may show a sudden high pulse tension, feebleness of the heart action, and suddenly, while wandering restlessly around the room, fall pulseless to the floor. Sometimes the fatal collapse may occur without warning while the patient is quietly talking or sitting in bed. Still another form of collapse may occur; the face becomes deep red, the eyes shine brilliantly, the pulse falls to forty and the patient loses consciousness after a feeling of intense agony. These collapses may last for fifteen or twenty minutes; they may recur three or four times in the 21G DISEASES CAUSED BY OEGAXIC AGENTS twenty-four hours, and the patient may recover or he may die in any of them unless morphia be given. Fortunately these attacks are rare when the drug is withdrawn grackially but they are fairly common when this is done abruptly. There are some few cases on record in which the fatal collapse occurred some time after the patient was convalescent and appar- ently hatl passed through the symj^toms of abstinence and was well on the road to recovery. Du.ring their periods of sutl'ering, the patients are apt to be afflicted with distressing insomnia and, if they sleep, it is only in fitful dozes. In a loliger or shorter time the symptoms gradually disappear and the patient can rest with some degree of comfort; the morbid craving has gone; the appetite returns and often becomes excessive; in women menstruation is reestablished, at first painfully, later normally. In both sexes the sexual desire returns, often painfully and excessively and then subsides. The patient goes into a rapid convalescence. When morphia is broken off, if it has been taken to quiet some neuralgia or to beniunb some unbearable sensation, these pains, although quiescent during the period of the adtliction, return in full force when the habit is broken. Treatment. — The question often arises, whether the patient should be sent to some retreat, or whether a successful issue can be followed out at home. If the home treatment is decided upon, the family must be made to realize that they are dealing with the most cunning and cleverly decep- tive kind of individual, who will stop at nothing, and who is probably con- cealing somewhere a supply of morphia. The suffering may be intense and will certainly be intentionally increased in order to obtain sympathy and to break off the treatment whenever it is possible. Too much stress cannot be laid upon the necessity of removing everything that can possi- bly be used for injury from the room in which the patient is to be. Even projecting hooks should bo taken away, and the patient must never for a single instant of time, day or night, be left unwatched. In retreats or hospitals, the sufferings can be reduced to a minimum and when it is possible the treatment should always be carried on in some such insti- tution. The question of the abrupt withdrawal or the slow method al- ways comes into consideration. Levinstein, who used the abrupt method, says that he does not believe that this should be done unless the patient is otherwise healthy and suffering only from the symptoms due to mor- phia. This in ifself shows the intensity of the strain and suffering that the abrupt method induces, and the danger of a collapse, which may be fatal, is most apt to occur in this method. The rapid method, by which the morphia is reduced to half the accustomed dose the first day and then half the next day and so in a few days is entirely withdrawn, is prac- ticable in the majority of cases. The slow method, by which the drug is very gradually withdrawn, is useful for the very weak patients or those who suffer from some chronic disease and have gradually become addicted to excessive use. But in patients who are not afflicted with any chronic disease, it is apt to be extremely tedious and trying, really prolongs the suffering, and may discourage the patient, the physician, and the family. The best method in the majority of cases, is to endeavor to find approx- imately how much morphia the patient has been accustomed to and cut it at least in half and give this amount in divided doses for the first twenty-four hours. It is very necessary to bring the digestive tract into as good a condition as possible, in the shortest space of time, which is best OPIUM. MORPHINISM. COCAINE 217 done by the use of castor oil, in half ounce doses, three times a day, for the first week or ten days. When the patients are very weak, it is advisable to give subcutaneous injections of strychnine (gr.so-n'o, gm. 0.001-0.002), at first every four hours. The best drug to equalize th(; circulation and to reduce the physical craving and suffering to a minimum, is the sub- cutaneous use of Livingston's solution of ergot as described under alco- holism. To allay the nervousness, warm baths are often very efficacious. Kane recommends that they be given at a temperature of 112° F., and the patient rubbed down quickly, placed in bed, and covered up warmly. To combat the insomnia, cold packs are often useful. A tonic of nux vomica and compound tincture of cinchona with capsicum, given three or four times a day, is of great assistance. Often in the first few days champagne or sherry is helpful, but this should not be prolonged, for these patients are as prone to take up other habits as they were originally to take to morphia. Chloral as a hypnotic has been condemned by most writers. Levinstein says that it tends to increase the excitement. Kane recom- mends bromides, given in large amounts of water, even in one hundred grain doses. The patient should be fed with koumyss and eggs as the most easily assimilated food. If accustomed to coffee and tea there is no reason why they should not be continued. After the patients are over the worst of their symptoms and convales- cence is established, they are by no means finished with their treatment. During the next six months the liability to relapse is very great and a single dose of opium or morphia will start them into their habit again. The cause for which they took the drug should be ascertained as accurately as possible and every endeavor made to change these conditions. They must fully realize that whatever mode of life brings the same temptations to them must be given up. Men may have to give up their profession and resort to some out-door existence and many professional men have suc- ceeded in permanently curing themselves by going into the country and taking up some form of farming, stock-raising or flower-culture. The most difficult to cure are physicians or pharmacists, whose business leads them into the handling of morphia. It is said that about 80 per cent, of these relapse, and the relapse is more difficult to treat. Even after years of freedom the danger has not ceased and the writer knows a patient, who after eleven years of abstinence, fell into the habit again because, during an attack of pleurisy, he was given morphia by a physician and this against his protest. A certain number can be cured and, although the percentage of relapses and failures is very great, each individual should be treated on the supposition, however apparently hopeless, that he may be the one in whom success is possible. COCAINE. At the time of the Spanish conquest of South America, the Indians of Bolivia, Peru, and Colombia, were found to be using the leaves of Erythroxylon Coca to sustain their strength during fatiguing journeys and to alleviate the sense of hunger and thirst. Coca was used in the religious rites of the Incas and was treated by them with great rever- ence, being employed in their sacrifices to the Sun, the high priest chew- 218 DISEASES CAUSED BY ORGANIC AGENTS ing the leaf during the ceremony. Before the arrival of the Spaniards it was sometimes used as a medium of exchange. Nicholas Monardes, a Spanish physician, published, at Seville, in 1565, a history of medical simples brought from the new world. He describes the use of coca among the South American Indians as being of three kinds; it was chewed and mixed with the powder of calcined shells of oysters and other shell fish; this paste, after being allowed to ferment, was formed into boluses or troches and allowed to dry; during long journeys these were sucked and, under their influence, hunger and thirst were alleviated and fatiguing journeys sustained; when eaten for i^roducing pleasure or intoxication, the coca was chewed by itself; and third, it was mixed w^ith tobacco and smoked. The Spaniards, not understanding the action of coca, regarded it with superstition and the Council of Bishops at Lima, in 1569, condemned its use on the ground that the belief enter- tained by the Indians, that chewing the coca gave them strength, was a delusion of the devil. During the last century many observers noted the extraordinary endurance of the Indians under its influence, but it was not until Roller, in 1884, discovered the local anaesthetic properties of cocaine when applied to the eye, that its use became generalized as a medicinal agent. At fjrst it was considered harmless, but before long it was evident that continued use brought with it a seductive addiction, which was broken up with difficulty and produced very rapid and destructive effects. The pure cocaine addictee is not as commonly met with as the mor- phinist or the alcoholist. The drug is usually taken to overcome the nervousness of an alcoholic debauch or the depression following mor- phine. It is not infrequently used to relieve the exhaustion following sexual and alcoholic excesses. Judging from the statistics of drug store sales, cocaine addictees seem to be most common among the very poor and among the wealthy. Cocaine is contained in certain quack nos- trums ^yhich are sold extensively in certain sections of the country by itinerant peddlers. In the Southern states, cocaine addiction is very common among the negroes, who speak of it as "tabs" because it is bought by them in tablet form. Snuffing the pow^der or a solution of cocaine is a common method of use. It is often taken hypodermically, and, when thus used in impure form, it sometimes causes a green dis- coloration, which remains permanent at the site of the injection in the skin. One woman who came under the care of the writer had, on her hips, thighs, and legs, so many of these little, round, green spots, about a centi- meter in diameter, that there was scarcely a square inch from her waist to her knees w^hich did not contain one of them. Patients suffering from neuralgia, local or general, physicians exhausted and ansemic, who have to be tided over some strain, neurotic and psychopathic individuals, the worn-out and failures of modern life, fall easy victims to the pleasing and soothing effects of this drug. Acute cocaine poisoning is seen following the injection of the drug to obtain its local anaesthetic effect in surgery. Death is reported as having occurred in forty seconds following twelve drops of a 4 per cent, solution given hypodermically to a girl of eleven years. Half a grain to one unaccustomed to its use seems often to be a border-fine dose. Such small doses as four drops of a 2 per cent, solution in OPIUM. MORPHINISM. COCAINE 219 the eye, produced in an old woman an intoxication which lasted for four days, and eight drops of a 10 per cent, solution in the eye of a girl of twelve produced violent sympton)s of poisoning, and even one drop of a 1 per cent, solution in the eye of a child fourteen years old has been followed by symptoms of active poisoning. It is evident that there is a strong, personal idiosyncrasy, and while such small doses have caused death, recovery has followed such large doses as twenty- two grains by the mouth, and ten grains hypodermically. In the mild cases of poisoning the ordinary symptoms are great restlessness and nervous excitement, with no feelings of pleasure or comfort, but rather those of anxiety and even terror, an increase in the frequency of the respirations, and often a distinctly accelerated pulse rate, with the patient pale, faint, and dizzy. In the more severe poisoning there has been nausea and vomiting, a rapid and imperceptible pulse, great nervous- ness and jactitation; the patient feels as if the heart would stop beating; intense perspiration and collapse with or without loss of consciousness is seen; the pupils are usually dilated; in some they have been reported as contracted, and, occasionally, the pulse has been slow and feeble with slow and infrequent respiration, or Cheyne-Stokes breathing with marked cyanosis. After large doses, convulsions are frequently present and are often of a violent epileptiform character. At times these are partial, with unilateral or bilateral cramps in the muscles, chiefly in the flexors; these muscular spasms may go on to general rigidity and opisthotonos may be produced. Consciousness is usually lost but sometimes there is mania with hallucinations and delusions which have frequently been, violent and even homicidal. The treatment of the poisoning is sympto- matic; the patient should be kept in a horizontal position and given aromatic spirits of ammonia, alcohol, camphor, or caffeine. If the poisonous effects are manifested in the respiration, oxygen or even artificial respiration should be used. Intravenous injections of nor- mal saline solution have proved helpful. If the drug has been taken by the mouth, the stomach should be washed out. After the patients have recovered from this acute poisoning, nervous disturbances, such as insomnia, vertigo, tingling in the limbs, and mental depression, may continue for some days. Chronic poisoning by cocaine is both periodic and continuous. The periodic form is characterized by the excessive use of the drug for sev- eral days or weeks, after which it is abandoned and there is a period during which there is no desire for it. During the free intervals the patient remembers distinctly the pleasurable mental impression which he obtained, declares that he has broken from its use and that he will not use it again, but as soon as the cause returns which formerly drove him to the use of the drug, he will invariably reason that there is no danger in using it for a short time, and quickly returns to its use. Soon the free periods become shorter, and those of addiction longer, and its use becomes continuous. Few indeed of the cocaine addictees remain periodic takers. These persons also show the peculiarity which is espe- cially marked in the addictee of cocaine, that in order to conceal its use, they will take other drugs such as alcohol, chloral, and morphine, and when they cannot obtain cocaine they will turn to any drug that will quiet the nervous system. Some patients become violently mania- 220 DISEASES CAUSED BY ORGANIC AGENTS cal, requiring several persons to restrain them and, when given the drug, almost instantly quiet down, with all symptoms of their mania gone. The main pleasurable action of the drug is the feeling of exhilaration and increased mental and nuiscular strength and with this there soon develop delusions of great strength and vigor, the patient feeling as if he had absolute self-possession; he shows great activity, talks freely and enjoys everything; each sense seems to be greatly heightened; there is an increased pleasure in taste, and the keenness of smell is heightened. Finally hallucinations of voices begin to appear; there are delusions of persecution and fears of personal injury; insomnia comes on with great muscular restlessness and agitation, which simulates the irregular spas- modic movements of chorea major. They show a profuse volubility, talking in a wide discursive manner over all subjects and in their writ- ing or speech there are no pauses, no dividing lines, no jnirjioseful con- nection but a steady, connected flow of words, involved and without point, without direction, and without end. The patient will endeavor to convey some idea or belief, and after the first few sentences the pur- pose is forgotten and he wanders on in great prolixity and diffuseness. Thus many cocainists are great letter-writers, and in some instances the letters have taken on an amatory type. This same prolix type, in other instances, has taken on a slanderous form, but there is a noticeable lack of bitter, sharp accusations and distinct charges; the meaning of the letters can only be made out by inference from the involved mass of words. Again, hallucinations of sight and hearing develop, and the patients see suspicious characters watching them and hear voices plot- ting to do them injury; they begin to take unusual precautions and are prone to carry revolvers and knives to defend themselves, and justify such procedure by the explanation that their lives have been, or are, in danger. In the early stages of cocainism, when the effect of the drug begins to w^ear off, the patients become morose, irritable, easily excited, and suspicious; there is insomnia and an impending sense of trouble and danger. In the later stages, the exaltation periods are brief and are followed by stupor and restlessness with evidences of great mental dis- turbance. The appetite fails; they are anaemic, and emaciate very rapidly; look sleepy and tired; the skin becomes flaccid and pale; the senses of sight, hearing, and smell, are seriously impaired, and there is a feeling of paraesthesia in the skin, giving a sensation as if vermin were crawling on it, which is a very significant symptom. Although there is increased sexual excitement, the sexual power is diminished. Kraepelin describes a definite psychosis wdiich may develop on the basis of chronic cocainism and which bears a close resemblance to alco- holic delusional insanity. It begins wdth a few days of irritability, anxiety, and restlessness, after which the hallucinations suddenly appear. Threatening voices are heard compelling the patients to act strangely; moving pictures are seen on the w^all, filled with large and small objects. Minute black specks, moving on a light surface, are very characteristic hallucinations, and may be mistaken for flies, mosquitoes, and other small objects. ParcTsthesias of the skin create the belief that they are under the influence of electricity, are being punctured with needles, or are poisoned. Most characteristic is the sensation of foreign bodies OPIUM. MORPHINISM. COCAINE 221 under the skin, particularly of the ends of the fingers and palms of the hands. The muscular twitchings are thought to be due to poison. Auditory hallucinations make them suspicious of their surroundings. They believe their thoughts are secretly being read or they are being spied upon through holes in the ceiling. The patients may try to kill their alleged tormentors or attempt suicide. They have characteristic delusions of infidelity which come on as an acute symptom. These are often obscene in character and they will accuse their wives of the grossest immorality. They are prone to react to these false ideas in a vindictive and aggressive manner. Consciousness remains clear and orientation is good except in rare instances when the excitement is very great or after the fresh injection of the drug. The emotional attitude of these patients is dejected, excitable, irritable, and even passionate; more rarely they are reserved and reticent concerning their delusions. Their actions are usually restless and unstable though some may appear orderly. Cocaine delusional insanity develops rapidly and may run its full course in a few weeks. The symptoms increase under the influence of a single dose. The delirious state soon disappears if the drug be completely withdrawn, but the delusions may remain for weeks or months. Morphinism and cocainism in the same individual often lead to a combination of symptoms, but morphinism, except with cocainism, seldom produces a rapid development of pronounced mental disturbance. The cocaine psychosis develops more rapidly, the symptoms are more severe than in the alcoholic delusional insanity, and the delusions of jealousy appear earlier and are an acute symptom. A single dose of cocaine produces an exacerbation of the symptoms, while in alcoholism it produces little or no effect. The sensation of objects under the skin is characteristic only of cocainism. Diagnosis. — The diagnosis of cocaine addiction is often very difficult. In some patients there is only an increased buoyancy of spirits and an increased desire for mental and physical exertion, but if their work be studied closely it will be seen that its character, and the judgment dis- played in doing it, are below the former excellence. These patients show defects of judgment and a diminished sense of ethical duties; they are also more prone to be reckless and aimless in their thoughts and work, and show a diminution of ambition and will-power. The powers of connected application are less, and often a noticeable symptom is periods of buoyancy varying with periods of beginning depression, and a disposition on the part of the patient to go off alone; and on his return the old buoyancy and confidence have returned. Thus the cocain- ist differs from the alcoholist, by his periods of secretive solitude, and from the morphinist, in the later stages, by his delusions of persecution. When cocaine is the main drug and alcohol and morphia are taken to relieve it, the periods of exaltation and delusions of persecution are very noticeable. If, however, cocaine is taken to relieve morphia or alcohol, the peculiar symptoms of cocaine are usually absent and there is simply a restlessness and insomnia. Morphine and alcohol, taken after cocaine, intensify the injury to the nervous system and both mania and dementia are apt to follow. Thus the combination of these drugs renders the prognosis graver and the danger to relapse greater. 222 DISEASES CAUSED BY ORGAXIC AGENTS Prognosis. — As regards the prognosis in the early stages, where cocaine is taken alone, if the proper treatment can be instituted, the habit seems to be more easily broken than that of morphia or alcohol and the chances of a permanent cure and restoration to health are also greater. If, however, the habit is well-established, the prognosis is unfavorable for complete recovery. The drug causes its destructive action more quickly and more intensely than alcohol or opium. Treatment. — In treating cocainism we must realize that there is no druo- which brings with it such a blissful sense of satisfaction and of relief from mental or physical pain, or gives such a sense of increased vigor and the ability to do all that the mind craves or hopes for. The effect thus produced is very intense and, although the patient may realize the danger of relapsing, the mental impression made under the influence of the drug is so strong that the tendency to relapse is very great. The amount taken by the cocainist varies and has been given as from thirty to forty grains a day by mouth or hypodermically; it also varies widely with the individual. The greatest amount which has come under my per- sonal observation was in a young woman who took twelve grains of mor- phine and sixty grains of cocaine a day, by the hypodermic method. The withdrawal of the drug should begin at once; sometimes this can be com- plete; at other times tapering-off must be allowed, especially in the patients in whom the symptoms of maniacal excitement follow its withdrawal. If morphinism and cocainism co-exist, cocaine should be withdrawn first. Substitutes should be used to lessen the irritability and the distressing symptoms caused by withdrawal. The best of these seem to be valerian, hyoscyamus, and vegetable narcotics of this type. Bromides are often useful in large doses for a short period. If there are symptoms of collapse, camphor, caffeine, or strychnine, must be used. Chloral, alcohol, and opium are unsafe. The conditions are usually those of starvation and cell poison- ing and, therefore, the digestion should be carefully watched, and often, in the beginning, continued doses of castor oil, such as a half ounce or an ounce three times a day, are necessary. The insomnia should be treated largely by food and prolonged warm baths. These patients should be sent to some asylum or retreat to be cared for until the acute symptoms have subsided. After a shorter or longer time, they may be sent back to the care of the family physician, but a long period is required with con- stant care and surveillance, and absolute change of surroundings and conditions of life. These patients are especially prone to refuse co- operation with the physician and, from fear or pride, conceal their real condition. The closest study of the causes and conditions which brought about their addiction must be made and it is only by the removal of these causes, and their prevention, that the patient will ever be broken of this habit. CHAPTER XL FOOD POISONS. By FREDERICK G. NOVY, M.D. Whenever a given article of food becomes a vehicle for an injurious agent it is for the time being, a poison. Such a food acquires its poison- ous property, in distinction from that which is always injurious. In the latter instance we are dealing with plants or animals in which the elab- oration of poisonous substances is a normal physiological process, as in certain mushrooms and fish. The poison of such may be said to be of endogenous origin, whereas in the former it is accidentally present, from an outside source, and is therefore exogenous. Poisonous metals, animal parasites, and bacteria, make up the three chief causes of unwholesome food. Accidental poisoning from metals in the food is the least common occurrence, so much so, that in nearly all ordinary intoxications the question of the presence of metals may be disregarded. Nevertheless, notable outbreaks of this nature have been known even in recent years. Thus, the famous "beer epidemic" of Manchester and other English cities, in 1900, was due to the accidental presence of arsenic. Other poisonings, caused by water which had taken up lead or zinc, are so well knoAvn as scarcely to need mention. The wide use of canned goods suggests the possibility of these becoming poisonous by the solution of tin or solder, but the small amounts of these in solution could only manifest an action after the prolonged and ex- clusive use of such foods, a condition which never obtains in ordinary life. The animal parasites, such as trichina and cysticercus, are also of relatively little importance, especially in comparison with the group of bacteria. The latter constitute the chief factor in poisonous foods. At times, food may be derived from diseased animals, and injurious effects may be directly due to the presence of the specific germ, and the poison- ing represents actually an infection. At other times, food may become accidentally contaminated with germs, such as typhoid bacilli, and may give rise to veritable epidemics. And lastly, food may be invaded by bacteria which are themselves unable to grow in the living body but form their poisonous products directly in the food. The more detailed consideration of these causes will be given in connection with each kind of food. POISONOUS FISH. The ill effects following the use of fish (Ichthyismus or Ichthyotoxismus) may be due to a number of causes, some of which are well understood while others are still far from being satisfactorily explained. Obviously, 223 224 DISEASES CAUSED BY ORGANIC AGENTS poisonings of this kind are relatively more frequent in countries in which fish form a large part of the diet, notably Russia, Japan, and the West Indies. The several causes may be grouped in the order of their impor- tance under four heads. First, the presence of normal or physiological poisons in the fish; second, the presence of bacteria or their products; third, invasion by animal parasites; and fourth, contamination with metallic or other poisons. 1. Physiological Poisons. — It is well recognized that there are many fish which are always poisonous, while others may become so during the spawning season. The consum])tion of such fish may lead to severe and even fatal intoxication. Thus, in Tokio alone, from 1885 to 1892, there were reported 993 cases of so-called fugu poisoning, of which 680 were fatal — a mortality of more than 68 per cent. At times even, notably in China and Japan, such fish are taken for suicidal purposes. The fugu poisoning of Japan and the East Indian Islands is due to various species of Tetrodon and Diodon The active agent, which resembles curara somewhat in its effects, is present in the ovaries and testicles. The earlier Japanese investigators designated this substance as fugin. The exact nature of the poison is not determined. The symptoms of fugu poisoning resemble those of curara. There is dyspnoea, cyanosis, dilatation of the pupils, relaxation of the sphincters, paralysis of speech, dizziness, saliva- tion, and vomiting. After the onset of the symptoms death may result in from one to two hours. While the organs of the several species of tetrodon are always poison- ous, there are other fish which become toxic only during the spawning season. Under these conditions the roe of different members of the stur- geon family, of the pike, and the barbel, have been known to cause pro- nounced and even fatal intoxications. The symptoms are those of an acute gastro-enteritis. As further illustrations of physiologically poisonous fish may be men- tioned the cod-fish (Gadus morrhua), Perca venenosa, and Sparus Maena which, eaten in the raw condition, have been known to cause grave in- toxications. 2. Bacterial Poisons. — As might be expected, intoxications arising from this cause are fairly common and may be met with under various conditions. Thus, the fish may be diseased^ and the infection be trans- mitted when the flesh is eaten raw. The fish when caught may be perfectly wholesome but, as a result of imperfect preservation, bacterial contamination may occur with the production of poisonous products. It is necessary, therefore, to consider these two types of infection sepa- rately, especially since a similar condition will be noted in connection with other foods. Epidemics among fish have been repeatedly observed in this and other countries, but it is only within recent years that they have been studied from the etiological standpoint. It is not within the scope of this article to consider suc"h outbreaks except in so far as they throw light upon the subject of poisonous fish. That the consumption of such diseased fish may cause intoxications, and even actual infections, may be theoretically conceded even if such occurrences are few in number. Fischel and Enoch, in 1892, isolated from a carp, which died during a fish epidemic, a spore-bearing bacillus (B. piscicidus) which was patho- FOOD POISONS 225 genie for mice and guinea-pigs. The toxin elaborated by this })acillus was readily destroyed by boiling. From diseased trout, Bataiilon, in 1894, isolated a bacillus closely related to Proteus vulgaris. It was ap- parently pathogenic for pike, crabs, and frogs. In the same year Emme- rich and Weibel studied another epidemic among trout in which they found a bacillus (B. salmonicida) differing from the preceding. Similar observations were made in 1893 by Charrin in connection with a barbel epidemic in the Rhone, and by Canestrini, who isolated from diseased eels a bacillus resembling that of cholera. This was pathogenic for fish and frogs, but not for mammals. One of the most interesting studies of fish infection is that of Sieber- Schoumow. Two outbreaks occurred among the fish in a palace reser- voir at St. Petersburg, in 1894, and on both occasions she isolated an organism which she named B. piscicidus agilis. This germ was found not only in the diseased fish but also in the water and on the bottom and walls of the reservoir. The bacillus was also found in a large num- ber of the fish on the market at the time, and also in the discharges of two cholera patients. An attempt at isolating the active poison failed, although the presence of cadaverin and other ptomains was demon- strated. During an epidemic in Lake Zurich, in 1898, Wyss isolated a liquefy- ing bacillus which he considered to be identical v/ith Sieber-Schoumow's bacillus and Proteus vulgaris. The organism was pathogenic for fish, mice, and guinea-pigs. The outbreaks mentioned above were not associated with any in- stances of poisoning in man, though it is reasonable to believe that, if the fish had been eaten in a raw or partially cooked condition, such results might have followed. In the first place, the pathogenic organism in the fish, as is readily conceivable, may cause a real infection in man. And again, it will be presently shown that poisonous fish may contain a soluble toxin which is readily destroyed by heat, and consequently, fish carrying ouch bacterial products would be dangerous only when consumed in the more or less raw condition. In this and in the preceding case an coc^ntial factor is that the food be eaten in a raw state, since cooking destroys bacteria and certain toxins. On the other hand, it is possible to have toxins which re- sist boiling, and consequently food infected with bacteria which produce toxins of this type might prove injurious even after thorough cooking. Thus, Sieber-Schoumow found that macerations made from infected fish, after boiling for half an hour, were still capable of causing fatal intoxica- tion. This and similar observations indicate the necessity of distinguish- ing between these three types of bacterial action. The observations of Arustamow, made in 1891, are usually taken to indicate the effects of diseased fish. He studied eleven cases of fish poisoning of which five ended fatally. These were caused by the con- sumption of four kinds of fish which were eaten in a raw, salted condition. The fish, though somewhat soft, were of good appearance and showed no sign of decomposition. The process of salting, however, was not very effectual, since the entire bodies were found to be permeated with li\ang bacteria. From the fish and the organs of the fatal cases he isolated four kinds of bacteria, of which two, however, were particularly studied. Dur- 15 226 DISEASES CAUSED BY ORGANIC AGENTS ing the past year these two organisms have been studied by Konstansoff, who arrived at the conchision that the bacillus obtained from the sahnon was an ordinary Proteus vulgaris, while that isolated from the sturgeon was a variety of the B. call. The studies of "Konstansoff* are particularly valuable, inasmuch as they throw new light upon the nature and origin of the fish poison. His material was a sturgeon which ])oisoncd two })coj)lc. The fish was of good appearance and showed nothing abnormal. All attempts at demon- strating the presence of bacteria, either in stained preparations or by the usual cultivation methods, failed; in other words, the material was sterile. This Avas due to the fact that the sturgeon was well salted, containing as much as 15.6 per cent, of sodium chloride. Experiments made with ten different organisms showed that when these were planted in broth containing 15 per cent, of salt, no growth took place, and, moreover, all died out (spores excepted) in from three to five days. When fish were injected with such cultures and then salted they were found to be prac- tically free from organisms after the twentieth day. In view of the fact that fish are not salted immediately after being caught but are kept for some time and even transported to a considerable distance, it is evi- dent that partial decomposition may set in, especially if the fish were infected or diseased when taken. The subsequent salting inhibits the further growth of such organisms and even destroys them, but the poison which they have already formed persists and can only be removed by boiling. An emulsion of the sturgeon was found to be highly toxic to small animals, especially when administered by injection. In rabbits the in- toxication lasted for several days and was marked by nervous phenomena, such as clonic contractions of the extremities. At autopsy the most noticeable feature was the rose color of the tissues and blood, a condition which has been observed in man after fish poisoning and is suggestive of the action of hydrocyanic acid. A suspension of the fish after passage through a filter paper and then through a Chamberland filter gave a fil- trate which Avas as toxic as the original liquid, but the solid residue after washing was found to be wholly inert. Attempts at extracting the poison by means of alcohol or ether failed. The above filtrate was rendered inert by boiling, and even an exposure of half an hour at 50° C. was suffi- cient to destroy its toxicity. This behavior to solvents and to heat clearly shows that the soluble poison is not of the nature of a ptomain but rather is a toxalbumin or more correctly a toxin, and, as such, approaches those of diphtheria and tetanus. Like the toxin of tetanus, the fish poison tends to accumulate in certain organs and tissues. Thus, in a poisoned rabbit the toxin was found localized especially in the muscles and to less extent in the nervous tissue and in the liver. From Konstansoft''s investigations of the conditions under which nor- mal fish give rise to this or a similar toxin, it is certain that bacteria are necessary. In ordinary putrid decomposition of fish various poisonous products are formed, some of which resemble the above toxin while others are of the nature of ptomains. It is generally recognized, since the work of Brieger, that highly poisonous products are to be found only ^Archives d. sciences biolog., 1904, 10, p. 475. FOOD POISONS 227 during the first days of putrefaction and that they disappear as this pro- gresses, giving rise to relatively non-poisonous ptomains. In other words, the products of the initial changes, which are hardly recognizable by the sense of smell or taste, are more dangerous than those of advanced de- composition. Konstansoff showed that a uniform distribution of bacteria in the fish, a condition which is best realized when the fish is diseased or septicsemic, insures a uniform production of toxin in the tissues. The salting of the fish at this stage arrests all further decomposition, but the toxin already elaborated remains unchanged and, as a result, such fish, when eaten raw, cause the well-known symptoms of intoxication. The symptoms observed in this type of poisoning, as well as the prop- erties of the toxin m vitro, resemble very closely those of B . hotulinus, which, as will be shown, produces the most severe type of meat poison- ing. The presence of this organism in fish has never been established, and until this is done it will be best to regard these two kinds of intoxica- tion as etiologically distinct. The ill effects after eating such raw fish appear in from ten to twenty-eight hours. The fatal result, when it supervenes, occurs only after several days, and at no time has it been observed within the first twenty-four hours. The quantity eaten has no necessary relation to the severity of the symptoms. Thus, a small amount may prove fatal, whereas a larger portion may be followed by recovery. This peculiarity is probably not due to idiosyncrasy or to an uneven distribution of the poison in the fish but depends rather upon the quantity of food in the stomach. The dilution caused by the presence of a large amount of other food, and the consequent retarded absorption, may favor the destruction of the poison by the digestive fiuids. S3nnptoms. — The symptoms are general weakness, dull pain in the abdomen, dyspnoea, mydriasis, impaired vision, diplopia and vertigo, complete dryness of the mouth and tongue, inability to swallow, and loss of speech. Vomiting and diarrhoea are absent and instead there is ob- stinate constipation and retention of urine. Vomiting is absent at first but may come on in the later stages. There is no rise in temperature and, on the contrary, there may be a fall of several degrees, especially before death. Another type of bacterial poisoning from fish presents an entirely different train of symptoms. It is of the nature of an acute gas- tritis and gastro-enteritis. Violent vomiting, excessive diarrhoea, dizzi- ness, tremor, prostration, and cardiac syncope are observed. Autopsy shows extensive follicular enteritis with necrosis, hypersemia of many or- gans, fatty degeneration of the liver, and toxic degeneration of the heart. These symptoms and changes were observed in recent fish poisoning at Zurich in which fourteen persons were affected, two of whom died within twelve hours. From the fish and from the spleen and blood of the de- ceased persons, an organism was isolated which was identified with B, enteritidis, which is an important cause of meat poisoning. This out- break therefore, unlike the above, is clearly an infection and intoxica- tion. In view of the fact that poisonous products are met with in the raw and imperfectly salted fish it is evident that like substances may develop in canned fish. Indeed, serious results have followed the use of canned salmon, as is reported by Ballard. In spite of the fact that the can was "blown" and the contents partially decomposed, they were consumed by 228 DISEASES CAUSED BY OliGANIC AGEXTS five persons. Three of these recovered, while one who ate the most be- came ill about ten hours after eating, and died in three days. Another who ate somewhat less died in five days. No organism could be obtained from the fatal cases, or from mice which died after being fed some of the salmon. This Avould indicate, as in Konstansoff's experiments, the presence of a soluble toxin. From some canned salmon which caused poisoning in a man,Vaughan isolated a micrococcus which was found to be highly toxic, especially when grown under anaerobic conditions. About twelve hours after eating this fish the patient began to suffer from nausea, vomiting, antl a griping pain in the abdomen; and six hours later he was found vomiting small quantities of mucus, colored with bile, at frequent intervals. The pulse was 140, the temperature 102° F., and the respiration shallow and ir- regular. A scarlatinous rash covered the entire body but disappeared in the course of the next day; the tenijierature remained above the nor- mal for four or five days, and eventually complete recovery followed. Summing up the observations which have been made thus far upon the role of bacteria in fish poisoning, it is evident that many bacteria, especially of the Colon and Proteus group, take part in the process. These may be present in diseased fish, or they may be introduced after the fish are caught. In either case, during the initial decomposition changes which are scarcely recognizable, there are formed poisonous pro- ducts, which in some instances are readily destroyed by heat while in others they are not aft'ccted. The ingestion of such fish is followed by a more or less severe intoxication, depending largely upon the kind of organism present, and at times by actual infection. Animal Parasites. — Under this head it is sufficient to mention the numerous infections with Bothriocephalus latus, directly traceable to the eating of fish infested with the larvae. Metallic and Other Poisons.— Poisoning from canned fish is some- times ascribed to the presence of tin and other metallic poisons which have been dissolved out by the acid or ammoniacal contents. It is knowm that appreciable amounts of tin can be obtained at times from canned goods, but that fact in itself is insufficient to explain the effects observed. In all such cases, decomposition of the contents by bacteria offers a more rational explanation. Some cases of poisoning have been ascribed to the food taken by the fish, such as poisonous medusae and corals, and decomposing proteids. Without doubt, fish may become infected by eating putrid food or by livmg in contaminated waters, but when this does occur the resulting poisoning properly belongs under the head of bacterial poisons. The symptoms w^hich have been noted in such cases, are either those of an acute gastro-enteritis or are of a nei'vous order, and correspond to those already given. POISONOUS SHELL-FISH. The conditions which render such food poisonous are much the same as those which have been given in connection with poisonous fish. Thus, there is always the possibility that the molluscs may be diseased at the time they are gathered, in which case the infection is transferred to the FOOD POISONS 229 consumer. The existence of such disease, however, has not been estab- lished as clearly as in the case of fish. A second condition is to be found when such food is })erfectly wholesome at first, but on keeping, as a result of even slight decomposition, becomes toxic. With this, as with other foods, the initial products of putrefaction are the most dangerous. For example, mussels which have been allowed to decompose for some days have been shown to be free from poisonous substances. It would appear that the first products of the cleavage of proteids and of leci- thins are especially poisonous, and that by the further action of bacteria these are then converted into less toxic, or even inert, bodies. The most important condition which bears upon the toxicity of molluscs is their habitat. It has been repeatedly demonstrated that when these are grown or kept in polluted waters, they acquire toxic and even infec- tious properties. On being transferred to fresh clean water, they soon lose their poisonous character. The fact that perfectly fresh mussels at times cause severe and even fatal intoxications, would seem to indicate that the elaboration of the poison may occur during the life of the animal. It is because of this that some writers consider such products to arise by tissue metabolism, and hence designate them as "leukomains." Others have expressed a belief in the existence of a distinct poisonous variety of mussel, while still others have held that the mussels had taken up poisonous food material or even metallic poisons. Such views are, however, no longer considered seriously, since the condition mentioned can be accounted for more easily by the known facts regarding the presence and action of bacteria. Molluscs living in polluted waters are known to take up large numbers of difl^erent kinds of bacteria which they may maintain in a viable state for a considerable length of time. Without doubt some of these organisms are able to act upon the host, and thus give rise to poisons, but the exact conditions under which these products are formed in the living mussel are as yet undetermined. Of far more importance than the occasional poisoning from shell-fish is the fact that these convey specific infections to man. It has been established beyond a doubt that oysters and other molluscs are a prolific source of infection. A marked instance is that afl^orded by the mayor- alty banquets which were held at Southampton and Winchester, in 1903. Of the 132 guests at the former 55 became ill, and all but one of these had eaten oysters; 11 developed typhoid fever. Of 134 guests at the latter place 62 became ill and 10 of these had typhoid fever. The evidence showed that the oysters had been gathered at the same place, from beds which were polluted with sewage. An examination made by Klein showed the presence of a germ belonging to the B. enteritidis group. The studies of Herdman and Boyce have served to call attention to the extreme contamination which may occur. Thus, from the cavities of oysters obtained from the neighborhood of a drain-pipe they obtained as many as 17,000 colonies, against 10 colonies which were present in oysters secured in open water. On placing oysters in water infected with typhoid bacilli it was found that these organisms were ingested and that they could be isolated from the cavities in some cases as long as fourteen days after the infection. Klein has found the typhoid bacilli to persist in oysters for from two to three weeks. At times, however, the 230 DISEASES CAUSED BY ORGANIC AGENTS oysters may clean themselves Avithin a week. This is facilitated to a marked degree by j^laciiig them in clean water which is constantly being renewed. The disappearance of typhoid and colon bacilli from infected oysters, Avhile in part the result of elimination, is probably largely due to destruction within the body of the mollusc. It is evident that, under favorable conditions, self purification of the oysters may be secured. In view of the above facts it is reasonable to believe that other infec- tions, such as cholera and amocbiasis, may in some localities be spread through the agency of contaminated molluscs. Positive evidence on this point is as yet wanting. Mussels. — Poisoning from the common mussel {Myiilus cdulis) is by no means a rare occurrence in England and on the Continent. The symptoms of intoxication are subject to considerable variation. In gen- eral three types are to be recognized. The first partakes of the character of a gastro-enteritis. The choleraic symptoms, such as nausea, vomiting, diarrhoea, do not appear until after the lapse of some hours. Death may result, but not as a rule. This type corresponds to similar forms of intoxication caused by meat, cheese, and other foods. A second type of intoxication presents essentially nervous symptoms, and is the most common form. It begins with a sensation of heat. Itch- ing appears, usually at first in the eyelids, but before long spreads over the face and may involve a large part of the body. A diffuse exudative erythema, or general urticaria, develops. Angina and dyspnoea are at times pronounced. In this form, recovery usually takes place after a few days. The third type is paralytic and suggests the action of a curara-like body. It is less frequent and more dangerous than the preceding forms. To a certain extent it may be compared with the intoxication caused by Konstansoff's fish toxin, or with that of Van Ermengem's B. hotulinus. It differs from these, however, in the rapidity of the onset of the symp- toms and in the fact that boiling does not destroy the poison. The apparently perfectly fresh mussel may cause a rapidly fatal intoxication, as has been noted in England in several instances. Thus, in one case, the symptoms came on almost immediately after eating boiled mussels and death occurred in fifteen minutes. In another case the mussels "vvere gathered from water knoAvn to be polluted, and, although they were washed and cooked thoroughly, in several changes of water, yet they poisoned two persons, one of whom died. Four hours after eating the meal they were seized with giddiness and were unable to stand or sit up. They showed mental excitement or delirium, closely simulating early alcoholism. There Avas numbness of the extremities, diminished sen- sation, and dilated pupils. The abdomen was distended and tympanitic; constipation was present. Dryness of the throat, constriction in the neck, difficulty in breathing and swallowing, and a tendency to syncope were prominent symptoms. The temperature was normal, and the pulse did not go over 80. One recovered in two days. One of the most conspicuous examples of mussel poisoning was at Wilhemshaven, in 1885, where a large number of dock laborers and their families were affected. According to Schmidtmann the symptoms developed shortly after the cooked mussels were eaten, or within a few hours, according to the amount consumed. They began with a feeling FOOD POISONS 231 of constriction in the neck, mouth, and Ups. The teeth were set on edge as if sour apples had been eaten. There was a pricking, burning sen- sation of the hands, and later of the feet. Giddiness followed but no headache; a feeling of lightness of the body, with a sensation of flying and general excitation similar to that of alcoholism, restlessness, some anxiety, with slight distress in the chest, were present. The pulse was hard and rapid (80-90) without any increase in temperature. The pupils became dilated and reactionless but there was no impaired vision. Speech became difficult, broken, and jerky, and the limbs heavy and stiff. The patients became di^zy, staggered and grasped spasmodically at ob- jects which they missed, and finally the legs were no longer able to support the body. Then came marked nausea and vomiting but no abdominal pain or diarrhoea; there was numbness of the hands and coldness of feet at first, gradually extending over the whole body, with a feeling of suffocation; in some cases abundant perspiration, followed by quiet, restful sleep. Death occurred in one case in one and three- quarter hours; in a second, in three and one-half hours; and in a third, in five hours, after eating the mussels. The • chemical examination of the poisonous mussels was made by Brieger, who succeeded in isolating several bases or ptomains, one of which (mytilotoxin) proved to be highly poisonous. The effect pro- duced by this in animals was the same as that which followed the ad- ministration of boiled extracts of the mussels. Therefore, intoxications of this type are due to a heat-resisting alkaloid, or ptomain, and in a sense are analogous to those caused by poisonous mushrooms. The production of the poison, however, is not a physiological one, as in the latter, but the result of the action of bacteria in the polluted water. Oysters. — The part played by oysters in the spread of typhoid fever and other infections has already been given, and there remains to be considered the acute intoxication to which they at times give rise. Gastro- intestinal disturbances of variable intensity have been repeatedly met with, and have been shown to be due to oysters derived from sewage- polluted beds. The intense poisoning, such as is given above under mussels,is fortunately not a common occurrence. A striking instance is reported by Brosch, in 1896, in which an officer died in twelve hours after eating some oysters which at the time were noted to possess a bad taste. The symptoms began in a few hours with headache, pains in the side, difficulty in swallowing, salivation, impaired vision, and retention of urine. The gait became staggering, deglutition impossible, and speech difficult and indistinct; paralysis of the right side of the face, including dilatation of the pupil and ptosis of the right eyelid, followed. Finally, cyanosis set in, salivation ceased, likewise respiration, while the heart continued to beat for about two minutes. The nature of the poison in this case was not established. Lobsters. — Similar intoxications have been induced by lobsters and crabs. Jaksch cites an instance where an entire company partook of lobsters without any ill effects, but the remnants, which were eaten next morning by a family, caused severe illness and two deaths, the early stage of decomposition clearly giving rise to poisonous products. An- other illustration is afforded by Georgii, where a number of young people ate a mayonnaise made from canned lobsters. The symjptoms 232 DISEASES CAUSED BY ORGANIC AGENTS were nausea, vomiting, much pain, severe headache, small rapid pulse, and a slightly sub-normal temperature. Urticaria, eye symptoms, or paralysiss, did not appear POISONOUS MEAT. The earliest recorded observations regarding poisonous meats were made on sausages, the wide use of which, especially in Germany, fre- quently led to extensive outbreaks. It became customary to speak of the "sausage poison," and the condition itself was designated as Botul- ism, or allantiasis. A better knowledge of the conditions leading to the production of poison in this food has resulted in a lessening of such occurrences, so that at the present time they are rather rare. The sau- sage is not the only meat food which may acquire poisonous properties. Every kind of meat is subject to the same changes, and if these are more frequent in the sausage it is merely because of the method of prep- aration and the conditions of keeping. The question of a physiologically poisonous meat, as in some fish, and the possible presence of metals can be passed by in view of their very infrequent, if not altogether doubtful, occurrence. Similarly, the ill effects from the eating of meat infected with animal parasites, such as trichina and cysticerci, need no special attention here. After eliminat- ing these, the entire phenomenon of poisonous meat resolves itself into the presence of bacteria and their products. The infection of meat may result in one of two ways : First, the animal may be perfectly healthy and, when slaughtered, yield flesh entirely wholesome and free from bacteria. Such meat can acquire poisonous properties only by the introduction of bacteria from without, by contact with unclean utensils, vessels and the like. The chopping-up of meat obviously favors the spreading of organisms through the mass. Under suitable temperature conditions, the bacteria thus introduced multiply sufficiently to give rise to poisonous products, and, as a result, what was wholesome meat in the beginning, may now be positively injurious. Obviously, under these conditions various species of bacteria may be met with, and among these may be some which are true saprophytes, such as Proteus vulgaris and B. hotulinus. The colon group is most frequently represented. A second source of infection arises when the animal is diseased at the time it is slaughtered. In such a case, a specific pathogenic organism is present, more or less widely distributed in the tissues or organs, and, for that reason, the fresh meat may be toxic, or, at all events, it readily becomes so on keeping. Poisoning from such a source may not only partake of the nature of an intoxication but may also develop into an actual infection. Abundant evidence has been brought forth during the past few years to show that many forms of gastro-enteritis are really food infections, and that poisonous meat plays a very important part in their etiology. Such facts have been adduced not only with reference to summer diarrhoeas but also in regard to paratyphoid infections. A large number of closely related organisms have been isolated from such poi- sonous meat, and, so far as known means of differentiation is concerned; they are not to be distinguished sharply from the B. paratyphosus. FOOD POISONS 233 With reference to the chemical products elaborated by the bacteria in either form of poisoning, very little is known, except in a general way. The old view that such intoxications were due to ptomains is no longer tenable, and such basic products necessarily play an insignificant or very secondary role. The real poisons are essentially of the same character as those of the pathogenic bacteria. They may be divided into two groups according to their behavior to heat. Thus, in the case of B. hotulinus, a soluble toxin is produced which is easily destroyed by boiling, and in this respect it resembles closely the toxin of tetanus. In the case of the B. enteritidis, the soluble products are not materially affected by boiling, and, hence, meat containing such may still be injurious even after it has been cooked. The presence of poisonous products in meat is not necessarily indicated by changes in taste or odor. In fact, in the majority of instances, such food is in an apparently perfect con- dition, and it would seem as if marked decomposition favored the de- struction of the poisons formed during the early stages of bacterial action. Notwithstanding that many different species of bacteria are concerned in the formation of such poisonous products, it is quite impossible to draw sharp differences clinically between the various intoxications. Two forms, however, are sharply contrasted. In the first the central nervous system is affected and the symptoms are therefore characteristic and well marked. Owing to the frequency of this type among the recorded cases of sausage poisoning. Van Ermengem designated it aa true botulismus. In the second form of intoxication, the symptoms are gastro-intestinal. They may be of a mild type and of short dura- tion, or of a more severe character merging into an actual infection. Such food poisonings, according to Trautmann, represent the highly acute, whereas paratyphoid fever represents the subacute, form of an infection etiologically due to one and the same factor. Botulismus. — ^This term, originally employed to designate all forms of poisoning caused by sausage, is here used in the sense given by Van Ermengem — namely, a specific intoxication due to B. hotulinus. This organism was first isolated by him, in 1895, from poisonous ham. Kemp- ner obtained it from the faeces of a hog (1897); and in 1900 it was found, a second time, in ham by Romer. More recently (1904) it was isolated from poisonous canned beans, by I^andmann. The presence of the or- ganism in faeces, as well as its close resemblance to the tetanus bacillus, would indicate that its natural habitat is in the soil, which readily ac- counts for its presence in the canned beans mentioned. On the other hand, the organism can hardly be said to have a widespread existence in nature, since in a large series of tests of soil, intestinal contents of animals, etc.. Van Ermengem obtained negative results. The outbreak studied by Van Ermengem^ occurred at EUezelles, in Belgium, in 1895, and affected fifty persons, of whom three died. Inquiry showed that the poisoning was due to eating one ham. The flesh of the hog at the time of slaughtering was eaten without any ill effects. Moreover, the other ham, although in a decidedly decomposed state, was eaten with like negative result. This non-poisonous ham was in the same cask as the other, which was, however, on the bottom, immersed 1 Zeitschr. /. Hygiene, 1897, 26, 1. 234 DISEASES CAUSED BY ORGAXIC AGEXTS in a weak brine. A layer of pieces of fat separated the two hams, the lower one being covered by the brine while the upper was not, and being thus exposed to the air, it underwent ordinary putrefaction. The poison- ous lower ham was obviously under anaerobic conditions, and the bac- terial changes which occurred were of a ditt'crent tyj)e from those in the one above. It was not putrid, but had a sharp odor like that of rancid butter, and though somewhat macerated it was otherwise of good appear- ance. The taste was said to be bad by those who partook of it. The symptoms Avhich followed the eating of the suspected ham were those of the typical sausage poisoning. The onset was rather late, the first symptoms coming on from twenty to twenty-four hours, and in some thirty-six hours, after the meal. Nausea, gastric pains, and vomit- ing were the effects first noted. In two instances there was diarrhcea, while in the others there was obstinate constipation, and retention of urine. Visual disturbances developed in from thirty-six to forty-eight hours in all cases. The patients complained of a fogging of the eyes and were soon unable to recognize persons about them. More or less marked diplopia came on. At the same time there was observed a marked dilatation of the pupils with complete loss of reaction to light, ptosis of both eyelids, and a peculiar stony stare. There was a sensation of burning thirst and strangling; the swallowing of solid food and even of liquids was difficult and led to choking attacks. The mucous mem- brane of the mouth, nose, and pharynx, Avas strongly reddened and covered with a thick viscid secretion which caused violent attacks of cough- ing, and even of suffocation. In some there was suppression of salivary secretion, and the mucous membrane was dry and shiny. The voice became dull, and complete aphonia was not infrequent. Extreme mus- cular weakness was general and persisted for weeks. Notwithstanding these severe symptoms the respiration and circulation were unimpaired. The pulse never rose above 90 and the temperature remained normal. Recovery was slow, extending over several weeks and even months. In the fatal cases collapse, dyspnoea, coma, or wild delirium, were observed shortly before death. Autopsy showed a marked hypersemia of the or- gans and fatty degeneration of the liver. The B. bohdinus was isolated from the spleen of one of the patients. The same organism was found in large numbers, thoiigh irregularly distributed, in the poisonous ham. It was also obtained from the or- gans of animals inoculated with suspensions of the latter. Van Ermen- gem showed that the organism was essentially a saprophyte and incapable of multiplying to any extent in the body. The symptoms, therefore, are not those of an infection but rather of an intoxication, due to the intro- duction of the toxin produced by the germ in the meat, or culture. The ham which produced such marked effects in man was also very poisonous to smaller animals. Rabbits were found to be particularly susceptible and . 5 Cc. was sufficient to cause death in from six to ten hours; while even 0.001 Cc. per kilogram weight was fatal. Assuming that man possessed the same susceptibility as the rabbit, the calculated fatal dose for a full-grown person was 0.03 mg. When this amount is compared with the fatal dose of a purified tetanus toxin, which Brieger and Fraenkel estimated to be 0.13 mg. for an average man, it will be seen that the toxin of B. botuhnus is not inferior to the latter. The toxin, FOOD POISONS 235 Or active poison, in the ham was soluble in water and could be readily filtered through porcelain. Like the toxins of diphtheria and tetanus, it is gradually destroyed by light and heat; on exjjosure of the solution at 70° C. for an hour, the toxicity was markedly weakened, and at 100° it was promptly destroyed. The toxin dialyzed rather slowly and re- sisted putrefaction. Acids appeared to have no effect, while, on the other hand, the addition of sodium hydrate destroyed it in a few minutes. The toxin is insoluble in alcohol and in ether; like that of tetanus, it is fixed by brain tissue; that is, a mixture of the two can be injected without causing ill effects. By injecting the toxin subcutaneously into goats, Kempner was able to produce active immunity. Moreover, the serum of the immunized goats possessed marked antitoxic properties, both as a preventive and as a curative agent. The experiments, how- ever, were limited to animals such as cats and guinea-pigs. Decomposed Meats.— While botulism as just described, stiictly speaking, is included under this head, still it seems best for the present to reserve this designation for the more common decompositions of meat which in the beginning was perfectly wholesome and did not come from a diseased animal. In the ordinary putrefaction of animal foods, poison- ous products are not necessarily formed, as is seen from the relative absence of ill effects after eating "high" game, cheese, and the like. The custom of eating fermented, in reality thoroughly putrid fish, described by Morner for Norway, holds true for many parts of the world. Actual poisoning from such decomposed foods is of very rare occurrence. The bacteria which have been noted in connection with such poison- ings are of the Proteus vulgaris and B. coli type. The part played by the Proteus in fish poisoning has been discussed. Levy, in 1894, iso- lated a Proteus vulgaris from the vomited matter, stools, and from an ice-chest in which the infected food was kept. A larger outbreak was studied by Wesenberg, in 1897, in which sixty-three persons were affected by eating the meat from a cow which was slaughtered on account of illness. From the more or less decayed meat he isolated Proteus vul- garis. Silberschmidt obtained from a poisonous sausage, in 1899, cul- tures of B. coli and Proteus vulgaris. The following year Pfuhl examined a "beef sausage" which apparently was responsible for the illness of eighty-one soldiers. From this material, cultures of Proteus mirabilis were obtained. Schumburg also obtained from a sausage a Proteus culture. The sausage itself was poisonous to rats and mice on feeding; so also was meat infected with the isolated culture. Obviously the decomposition of meat products may be induced by other kinds of bacteria. Thus in a recent instance in Michigan about fifteen persons became seriously ill from eating poorly cured bacon. An examination by the author showed that the meat was permeated by a large coccus which was highly toxicogenic to animals. Diseased Meat. — ^Under this head will be considered those intoxica- tions which are due to the eating of meat derived from a diseased animal. They constitute by far the most common form of meat poisoning and are characterized by more or less severe symptoms of gastro-enteritis. The causative agent may be said to be any one of a group of related organisms which show close affinity on the one hand for the colon bacillus, and on the other for the hog-cholera bacillus. In other words, these intoxica- 236 DISEASES CAUSED BY ORGAXIC AGENTS tions represent a group of closely allied diseases which it is difficult to differentiate one from another. The symptoms may come on at once, but are usually delayed for six to twelve hours. -Nausea, vomiting, colicky pains, profuse diarrhoea, and prostration are nearly always present. At times there is erythema and urticaria followed by des([uamation, especially of the palms and soles. Albuminuria and catarrhal pneumonia are also met with. The mortality is much less than that of botulism. Autopsy usually shows marked gastro-enteritis of a hemorrhagic nature, an enlarged spleen, and con- gested organs. Infections of this kind have followed the use of divers meats, especially beef, veal, pork, and horse-flesh. The use of chopped or minced meat, sausages, pork-pies and the like, is more often followed by poisoning than is the use of the whole meat, for the reason that the method of manipula- tion ensures the thorough dissemination of the organisms through the mass. In such cases the animals are often suffering from a septicsemia of puerperal or traumatic origin, or from intestinal infections. The ill effects usually follow the eating of raw or imjierfectly cooked food. In some instances, however, even when the food was thoroughly cooked intoxication resulted owing to the presence of poisonous products which were not destroyed by heat. The common impression that boiling will destroy the poisonous properties which a food may have acquired does not always hold good, as has already been shown under mussel poisoning. Although poisoning from meats was noticed at an early date and fre- quent attention called to it, an exact inquiry was possible only after the methods of bacteriological study had been perfected. The first attempt to work along the new lines was made by Gaffky and Paak, in 1885, in connection with poisoning caused by sausage made from horse-flesh. More than eighty persons developed gastro-enteritis and one death resulted. The evidence indicated that the horse was diseased. Moreover, the sausage w^as prepared in a most careless manner, since the unused portions were found to be in an advanced state of decomposition. Macer- ations of the sausage caused death when injected into mice, guinea-pigs, and rabbits, and from these they isolated a bacillus which was closely related to the colon bacillus. It differed from the latter in not producing indol and in not coagulating milk, in which respect it resembled Gartner's bacillus, if not identical with the latter. It was eventually named B. jriedehcrgensis by Kruse. The fact that the pure cultures when fed to animals, or w^hen injected, caused death, led Gaffky and Paak to consider it as the specific cause of the poisoning, although its presence in the persons afflicted was not demonstrated. Another colon-like organism, designated as B. viorbificans bovis, w^as isolated by Basenau, in 1893, from the meat of a cow w^hich was slaugh- tered while suffering from puerperal septicsemia. I^ater on, he cultivated this same organism from the flesh of animals having perforative peritonitis, puerperal paralysis, and chronic pyaemia. This bacillus, which is highly infectious to animals, has since been studied by other workers and shown to be related to the other bacilli causing intoxication. A similar and very interesting observation of Levy and Jacobsthal may be mentioned at this point. In an apparently normal cow the spleen was found to have a large abscess, and smaller ones were present in the liver. FOOD POISONS 237 They isolated from the pus a germ which the cultural and agglutination .tests showed to be the ty])hoid bacillus. This is of importance, showing as it does the possible origin of sporadic cases of the disease. The part played by meat in the causation of paratyphoid infections is at present well recognized. Of especial interest is the food epidemic which occurred in 1888, in Frankenhausen. The source of the infection was a cow which was slaughtered on account of a severe enteritis. All told, fifty-seven persons became ill from eating of the meat. Some of these ate it raw, while most of them had it boiled or roasted; three partook only of the broth. The symptoms were those of a severe gastro-enteritis followed by desquama- tion. Convalescence was long, in the severe cases lasting for two to four weeks. Only one person, who had eaten a large amount of the raw meat, died. He was nursed by his mother who later developed the same symp- toms, probably as a result of infection from the discharges. Gartner cultivated from the spleen of the fatal case, also from the flesh and intes- tines of the cow, an organism which he named B. enteritidis. This organism resembles the colon bacillus in many respects. On feeding, it proved pathogenic for mice, guinea-pigs, and a goat. On injection, it was more fatal to rabbits, pigeons, and a canary, but not to dogs, cats, chickens, and sparrows. The injection of cultures sterilized by heat produced the same effects as did the feeding of such cultures to the susceptible animals. This resistance of the toxin of B. enteritidis to boiling is a striking property, and suggests the like behavior of the products of the tubercle bacillus. The heat-resisting intracellular toxin of the colon bacillus studied by Vaughan, affords another illustration on this point. In the following year Gartner found a similar organism in another out- break of food poisoning at Cotta, near Dresden. The meat in this case came from a cow suffering from an inflamed udder. There were 136 ' persons affected, and of these 4 died; apparently all had partaken of the raw meat. Cultures were obtained from the cow and from the bodies of 2 of the dead persons, and, though they resembled the B. enteritidis morphologically, they differed in being non-poisonous. Moreover, the flesh of the cow lost its poisonous property when cooked. Gartner's bacillus attracted considerable attention and numerous workers have since then found the same or a very closely related organism. An apparently typical B. enteritidis was obtained by Van Ermengem in 1891 from the outbreak at Morseele, Belgium, in which 80 persons were affected, of whom 4 died. The flesh was derived from two calves which had a severe enteritis; one died and the other was slaughtered. As in Gartner's case, the meat was eaten in a boiled or roasted condition, though the isolation of the germ from the liver, spleen, and intestinal contents of one of the dead, would indicate that the heat was not sufficient to sterilize the food. An identical organism was obtained from the bone- marrow of one of the calves. Feeding or injection of the cultures in mice, rabbits, guinea-pigs, and calves, produced severe and fatal infection. A monkey developed typical cholera nostras, but recovered. Although there were minor cultural differences, Van Ermengem held that it was the same as the enteritidis bacillus of Gartner, a view which has been confirmed by the subsequent studies on agglutination. 238 DISEASES CAUSED BY ORGAXIC AGENTS In 1892, Pools and Dhont investigated a poisoning at Rotterdam, where 92 persons became ill after eating the flesh of an apparently normal cow. The bacillus isolated formed colonies which resembled those of the typhoid bacillus; like the latter it did not ferment lactose. The sterilized cultures were poiso.nous and the living ones were pathogenic for mice, rabbits, and guinea-pigs. A cow which received an intravenous injection of a culture was killed twenty minutes later, and some of the meat after being kept for three days at a low temperature was eaten by 53 persons. Of these, 15 had in a short time headache, colic, and diarrhoea. In the same year, Fischer obtained an apparently true B. enleriiidis from a food poisoning at Rumlieth. The same organism was also obtained by him from meat which caused poisoning at Haustedt in 1895. This was derived from an ox which was killed after suffering for two days with diar- rhoea and fever. Of more than 50 people who ate of the meat, chiefly in the boiled condition, 27 became ill with severe gastro-enteritis. Recovery took place in from three to eight days. The following year Fischer again met with B. enteritidis in the spleen of a cow which had an inflamed udder. The food poisoning which occurred at Breslau, in 1893, also furnished a related organism. The meat was derived from a cow which was slaughtered on account of a febrile diarrhoea, and, although condemned, was stolen and sold as chopped meat. As a result of eating the raw meat 80 persons became ill in from three to sixteen hours and, although none died, recovery was slow. Dizziness, vomiting, fever, and herpes, were noted. Kaensche isolated, from the meat and from infected mice, an organism {B. Breslaviensis) which was apparently identical with that found by Van Ermengem in the Morseele outbreak. The toxicity of the cultures was not affected by boiling. Johne, in 1894, isolated another enteritidis-like organism from a poisoning in Saxony. Scheef obtained apparently the same bacillus, in 1896, from sausage which affected about 150 people. An interesting case of poisoning at Ghent, in 1895, was studied by Van Ermengem. A sausage made of pork and beef was examined by an inspector, who, on account of its fresh appearance, pronounced it un- objectionable. He himself ate of the raw sausage and others followed the example. They all became sick and the inspector died in five days. The animals furnishing the meat were not known to be sick. Cultures made from the sausage and from the organs of the dead showed a bacillus which could not be distinguished from the B. cnieriiidis or from that of INIorseele or Breslau. At the same time Van Ermengem called attention to the similarity which existed between these organisms and that of the hog-cholera group, a fact which subsequent investigations have fully demonstrated. A further instance of poisoning from pork sausage occurred at Posen, in 1896, and cultures were obtained from a fatal case by Giinther. The bacillus differed from that of Gartner in minor points only. In the same year Silberschmidt studied a Swiss outbreak caused by pork which came from diseased animals. The bacillus isolated was related to B. enteritidis and of hog cholera, and for that reason he inclined to the view that the flesh of animals sick of hog cholera could cause food poisoning. Pouchet also, in 1879, described a hog-cholera bacillus as the cause of a poisoning which developed and involved forty-eight persons. FOOD POISONS 239 Since 1898 the agglutination test has been used in identifying the causa- tive organism in food poisonings. Thus, in an outbreak of gastro-enteritis at Aertryck, in Belgium, de Nobele isolated an organism which aggluti- nated with the serum of the sick persons even in a dilution of one to four hundred. The sera from other diseases and from normal persons had no agglutinating action on this bacillus. Unlike ty})hoid serum which re- tains its agglutinating action for a very long time, the sera of the poisoned persons lost their agglutinating power in a few weeks. Such sera also agglutinated typhoid bacilli more readily than does normal serum. The sera, however, agglutinated in greater dilution (Aertryck) than the typhoid or enteritidis bacilli. The same author, in 1899, studied another case of poisoning at Brugge, caused by pork sausage. The serum from the affected persons agglutinated the bacillus isolated from the meat in even as high a dilution as 1 to 500, but it had no effect on the Aertryck bacillus. The Gartner bacillus, however, was agglutinated by the sera, but not to the same extent as the bacillus isolated. Still more recently, de Nobele has succeeded in isolating essentially the same bacillus from the organs of persons who died at Brussels and Willebroek, after eating smoked horse-meat. In England, the first application of the agglutination test in the study of these organisms was made in 1898, by Durham, who had occasion to investigate four outbreaks of gastro-enteritis. In the first of these, at Hatton, 185 persons were affected but the cause was not traced to meat of diseased animals. From the liver of a fatal case he obtained a bacillus which was agglutinated by the sera of the sick in varying dilutions, in some even as high as 1 to 1000. The sera also agglutinated the typhoid bacillus in greater dilution than did normal serum. The Giinther bacillus, and one from a Vienna case of poisoning, were agglutinated to about the same extent, whereas the B. enteritidis was not clumped except by fairly concentrated sera. By making these tests upon different organisms, Durham was able to show that the epidemic was associated with, and probably due to, a variety of the B. enteritidis. In the three other out- breaks studied by him the organism was not isolated, but from the be- havior of the sera of the sick to various bacteria it was made clear that the cause was essentially the same, that is, a variety of the enteritidis bacillus. That a meat infection was responsible, was particularly shown at Chatterton where veal pies were the undoubted cause of the illness of 57 or more persons, 1 of whom died. In the Derby outbreak (1902), the cause was traced to the eating of pork pies. As at Chatterton, no complaint was made as to the taste or ap- pearance of the pies. Furthermore, the more severe cases resulted from the eating of pies which had been kept several days, showing that the organisms, at first probably present in small numbers, in the interval had multiplied appreciably. About 210 persons became ill in Derby and its neighborhood and at least 4 deaths occurred. From the organs and intestines of two of the cases Delepine isolated the B .enteritidis derhiensis. This was said to resemble more closely the bacillus of Gaffky and Paak than that of Gartner. The agglutination of this bacillus by the sera of the sick persons served to establish its causal relation to the epidemic. The evidence seemed to show that the hog was not sick and that the infection Was of excretal origin. 240 DISEASES CAUSED BY ORGAXIC AGENTS Another well studied case of food poisoning is that whicli occurred at Neunkirchen, in 1903. Over 30 persons developed a non-febrile gastro- enteritis and 3 died. Frwn the horse-fiesh whieh was used as food and from the organs of 2 of the fatal cases, Drigalski isolated a baeillus belonging to this same group. The serum of the sick rapidly agglutinated this bacillus and that of Gartner, and, to a less extent, typhoid and paratyphoid bacilli. On about the eighth day, all the sera reacted in a dilution of about 1 to 400 and one even in 1 to 4,000. Even the serum of a dog that ate the lungs of the horse and later developed j)rofuse diarrhoea, agglutinated the bacillus in 1 to 100. The sera of normal persons had no such effect. He confirmed de Nobele's observation regarding the rapid loss of the s])ecific agglutinating power. Thus, the maximum strength was reached in about ten tlays, while in about three weeks it had fallen to less than 1 to 100. The bacillus was shown to give rise to heat-resisting products; that is to say, boiled cultures proved fatal to animals. From a similar case of horse-meat poisoning at Diisseldorf, in 1901, in which 57 persons became sick and 1 died, Trautmann was able to isolate a bacillus. This was obtained only from the s]:)leen of the child. There was no reason to believe that the meat was derived from a sick horse, and, on the contrary, the evidence showed gross lack of cleanliness so that excretal contamination was quite probable. In the majority of the cases of food poisoning mentioned, the fact that the food was derived from diseased animals was established. In some instances, as where the food was thoroughly boiled, the ill effects were those of a plain intoxication due to poisonous heat-resisting products. In the majority of instances, however, the food was eaten raw or incompletely cooked, and, as a result, true infection with the specific bacillus occurred. The relation of the different organisms which have been isolated from such outbreaks is important. In general they may be said to belong to the colon-typhoid group. Culturally and morphologically they offer very slight or no means of differentiation. For that reason they have all come to be regarded as varieties of the B. enieritidis. With the introduction of the serum reaction it became possible to draw the lines more closely and to establish degrees of relationship, not only among the bacilli of this group but also with typhoid, paratyphoid, and hog-cholera bacilli. The serum of t}q3hoid fever agglutinates Gartner's bacillus almost as readily as the typhoid bacillus, which fact shows that a certain kinship exists between these organisms. On the other hand a typhoid serum of very high potency, obtained by artificial inmiunization, will distinguish with certainty between the two bacilli. Mention should be also made of the fact that the serum of animals immunized to the B. enieritidis agglu- tinates the typhoid bacillus though in less dilution than its own kind; moreover, it has no action whatever on the colon bacillus- Especial importance attaches to the relation of this and the paratyphoid group of bacilli. Schottmiiller's two types of the paratyphoid bacilli, designated by Kayser as A and B, present about the same variation with reference to the agglutination test as do the several iy\)QS, of bacteria from poisonous meat. Thus, the serum obtained with type B, as shown by Drigalski and by Trautmann, readily agglutinated the bacilli from the Aertryck, Breslau, Diisseldorf, Neunkirchen, and Posen epidemics, and had much less action on the Brugge, Ghent and Rumfleth bacilli repre- FOOD POISONS 241 sented by that of Gartner. It would appear that paratyphoid infec- tions are essentially the same in kind as the typical meat infections; and Trautmann, as a result of his agglutination tests, would recognize several varieties of the B. paratyphosus: a — enteritiditis, represented by Frankenhausen, Morseele, Plaustedt and Hamburg. b — Breslaviensis, represented by Breslau, Posen, Diisseldorf and Giessen. c — Hamburgensis, represented by Schottmiiller's type B. d — Strassburgensis, represented by Schottmiiller's type A. e — morbificans of Basenau. The probability of meat being the conveyor of the paratyphoid infection has been pointed out by Fischer. It is of interest to note that the several rat plague bacilli behave the same as the Aertryck and paratyphoid B organisms with reference to the agglutination test. The classification of Trautmann is practically the same, as concerns the meat bacteria, as that which de Nobele had worked out several years before. From the behavior of the different bacilli toward very active agglutinating sera he divided them into two groups: Bacillus enteritidis and Bacillus Aertryck. The latter might also be called the hog-cholera type, since the two organisms react in the same way to sera. It is of interest to note that Fischer arrived at much the same grouping of the bacteria studied by him. On the other hand, Drigalski recognized that wholly unequivocal results could not be obtained even by the biological method of identification. While classifying some of the bacteria the same as de Nobele and Fischer, he brought together the Gartner, Breslau, and Aertryck bacilli. The explanation of this error, if such it be, perhaps lies in the fact that he employed relatively weak sera for his tests. A more active serum would probably have shown differences, as in the case of very potent typhoid serum in its behavior to typhoid and enteritidis bacilli. The origin of his Gartner bacillus, on account of this discrepancy, may be open to question. POISONOUS MILK AND ITS PRODUCTS. Of all the articles of food, milk unquestionably is most subject to bacterial contamination, and, for that reason, it is a most prolific cause not only of acute poisonings but also of real infections. The fact that milk is used to a large extent in a raw state accounts for all such acci- dents. Certainly, instances of poisoning from boiled milk are wholly unknown. Injurious bacteria present in the milk may be derived from various sources. They may come directly from the diseased animal, as in tuber- culosis; or be introduced either by the addition of impure water, or of excretal and other infected matter. It is unnecessary to consider these conditions at length, since in a sense they do not come under the ordinary meaning of the term poisonous milk. And yet, even a passing mention must be given to the part played by milk in the transmission of several diseases — for example, diphtheria and scarlet fever. Similarly, several epidemics of typhoid fever have been traced directly to its use. Above 16 242 DISEASES CAUSED BY ORGANIC AGENTS all else, the milk bacteria are responsible for most of the gastro-intestinal disorders met with during the summer months, especially among in- fants; whereas the choleraic conditions observed among the older people can be traced with equal certainty to the use of other contaminated foods, particularly meats. Apart from the real infections which have been noted, acute intoxi- cations not infrequently occur. In such instances, the bacteria present give rise to active j)oisonous ])ro(lucts of which but little is known. The poisonous ptomain which Vaughan first obtained from cheese has been found in milk on several occasions. It must not be sii])posed that in every milk poisoning the active agent is tyrotoxicon, for such is clearly not the case. Milk may harbor a large number of different bacteria, and each of these will form its own characteristic toxin. Among the organisms which have been studied may be mentioned the virulent colon- like bacilli, the B. cnieriiidis and the B. cnicritidis sporognics of Klein. It Mill be seen that essentially the same organisms are found in toxic milk as are noted in poisonous meat. When such toxicogenic bacteria are once introduced into milk there is but one further condition neces- sary and that is a temperature suitable for their development. The warm weather of summer is therefore particularly favorable to the forma- tion of poisonous products in milk. The usual result of the growth of bacteria in milk is to cause it to sour. It is worthy of note that acute poisoning from sour milk is rather rare, while that from milk which shows no apparent change, in other words, one which has an alkaline or amphoteric reaction, is frequent. This is in accord with the known behavior of the enteritidis group of bacilli in milk which is not coagulated but rendered somewhat trans- parent. In much the same w^ay that chopped meats and sausages are partic- ularly prone to become poisonous, it is obvious that preparations made from milk, such as ice-cream, frozen custards, and cream puffs, may be- come injurious though the original milk was not. A few hours of keep- ing under favorable conditions of temperature may so force the growth of the few bacteria originally present that the final product may be decid- edly noxious. The popular notion that such intoxications are due to the presence of metals or of injurious flavoring extracts has no basis in fact. The one product of milk which is most prone to cause poisoning is cheese. In fact cheese poisoning or tyrotoxismus claimed the atten- tion of the early chemists as much as botulism or sausage poisoning. Various theories were propovmded, but no satisfactory explanation was possible without a recognition of the part played by bacteria. The acci- dental introduction of toxicogenic bacteria, and their subsequent growth under favorable conditions, readily account for the phenomena observed. Inasmuch as different bacteria may take part in such changes it follows that different poisonous products may be met with, depending upon the organism at work. Our knowledge of these bacteria is far from being as satisfactory as might be desired. It has been shown by Vaughan and McClymonds that nearly all cheese contains poison-producing bacteria. Thus, the cultures from forty-nine samples of cheese were found to be pathogenic for white rats, rabbits, and guinea-pigs. The colon group was particularly well represented. FOOD POISONS 243 The poisonous ptomain Tyrotoxicon, discovered by Vaughan, was the first definite product of this Idnd obtained from such cheese. More recently, Le Pierre obtained another basic substance, which, however, was not toxic. Without doubt other poisonous products are present, as in the case of other types of food poisoning and in real infections. The study of such toxins, as well as of the bacteria to which they owe their origin, belongs to the future. POISONOUS VEGETABLES. The highly nitrogenous animal products are particularly prone to undergo those alterations which render them dangerous to the con- sumer. Similar changes, however, may occur in vegetable products, though much less frequently, and, as a result, poisonous bacterial sub- stances of different kinds may result. It has been shown that the same organisms which cause meat to be poisonous may give rise to exactly the same effects when they are introduced into vegetable food. The richer such material is in nitrogen, the more likely is it to give rise to poison production, and, on the other hand, with a large amount of sugars or carbohydrates the formation of such products is retarded, if not suppressed. A well known illustration of this fact is afforded by the diphtheria bacillus, which produces a maximum of toxin when grown on sugar-free media. As a further instance may be mentioned the changes which occur in whey and in whey proteids. In the former, as in normal milk, bacterial action is evidenced by a typical fermentation in which the sugar present is the chief substance acted upon, and conse- quently no disagreeable decomposition products of proteids form. By contrast, however, a solution of the milk proteids alone- — or what is the same thing, a dialyzed whey — will undergo, under exactly the same conditions, a typical putrefaction. Not infrequently, the ill effects observed in connection with plant food are due to the presence of metallic poisons. The strong acidity of many vegetables may, in canned goods, cause an appreciable solution of tin, lead, and zinc. Ordinarily the amount of these metals thus brought into solution is small and rarely plays a part in the observed intoxica- tion. Criminal carelessness or ignorance is more often responsible for the presence of dangerous quantities of metals in foods. A third type of poisoning from vegetable foods is due to the presence of plants which are in and of themselves poisonous. Under this head will fall the 1'airly well known ergot, vetch and mushroom intoxications. These must be considered in the briefest manner possible. Ergot poisoning is practically unknown in this country, but in Europe is still occasionally met with, although not to the same extent as in former times. The condition is commonly designated as ergot ismus and its cause is a parasitic fungus, Claviceps purpurea, which develops in the flowers of rye and other grains. From ergot, Kobert was able to isolate at least three poisonous substances, sphacelinic acid, cornutin, and ergotinin. More recent investigations have made it probable that there are other substances present which constitute the real toxic agent. Thus, Jacoby obtained a non-nitrogenous resin, sphacelotoxin, w^hich he regards 244 DISEASES CAUSED BY ORGANIC AGENTS as the specific poison. The intoxication may have an acute or chronic course and in either type the symptoms may be nervous or convulsive, or else trophic or gangrenous in character. Vetch poisoning, or laiJtijrismvs, is a rather rare condition, met with in some parts of Europe, notably Austria and Italy, in northern Africa and in India. The vetch seed is used in the form of flour as a partial sub- stitute for that of wheat. The eating of bread prepared from it is fol- lowed by sudden and severe pains in the lumbar region, girdle sensation, motor paralyses of the lower extremities, tremor and fever. The nature of the poison is not known but it is probably of the nature of a toxal- bumose, of which ricin and abrin, the poisons of the castor bean and jequirity seed respectively, are well known examples. The ill effects from eating mushrooms are due to mistaking the poison- ous for the edible species. One species of the former contains the highly toxic alkaloid muscarin which, with other poisonous constituents, is responsible for the symptoms induced. A most unusual and severe form of poisoning from vegetable food occurred at Darmstadt, where of twenty-one persons who ate of a bean salad, eleven died. The canned beans when opened had a peculiar odor but showed no marked decomposition. The symptoms, as reported by Landmann, came on twenty-four to thirty-six hours after eating. Visual disturbances such as mydriasis, strabismus, and ptosis, were the first to appear. Then followed difficult deglutition and bilateral paralyses. The pulse became greatly increased, respiration superficial, and death re- sulted in from five to fourteen days from bulbar paralysis. In the non- fatal cases convalescence lasted through some weeks. The symptoms, together with the almost complete absence of gastro-intestinal irritation, led to the diagnosis of botulism, caused by. the toxin of the B. hotulinus. This was confirmed by the demonstration of the toxin and by the iso- lation of the suspected organism. Cultures made from the salad gave an anaerobic bacillus, apparently identical with the B. hoiulinus of Van Ermengem. The presence of B. hotulinus in meats is common enough, but this is the first time that the organism and this type of poisoning were observed in a vegetable food. Landmann endeavored to account for its presence by assuming that it was accidentally introduced with bits of meat into the can, as might easily happen about a kitchen. The fact remains that a highly nitrogenous vegetable, as the bean, may be acted upon by the same organism as is found in meats and that the resultant toxin may be fully as active as that formed in the latter. Another striking example, apparently due to infected oatmeal, is that reported by Ohlmacher.^ At the Ohio Hospital for Epileptics, in three days, 218 patients became ill and took to bed. The cause of the poison- ing was not positively determined, but, by exclusion and elimination, it was finally decided to be a certain batch of oatmeal, which presumably had been contaminated by the dust arising by the removal of a large section of plaster from the ceiling the night before. This ceiling had been exposed to clouds of dust from a dirt road, and to the steam and vapors in cooking. The surface of the plaster harbored B. coli and Pro- teus vulgaris and these organisms were believed to be responsible for ^Journ. Med. Research, 1902, 7, 411. FOOD POISONS 245 the poisoning. The symptoms appeared in from about six to eighteen hours. There was chilliness, especially up and down the spine, cold hands and feet; aching of the limbs, with severe headache and sense of pressure in the head; nausea, and vomiting in many cases — but not in all; pain in the abdomen, griping and cramps, and profuse watery diarrhoea. There was dizziness, a staggering gait, prostration and fever, the latter ranged from 100° to 105° F. and persisted for from four days to two weeks. The gastro-intestinal infection which clearly followed the original intoxication would very properly be termed paratyphoid. The disease known as pellagra, or maidismus, is an intoxication caused by the continued use of damaged Indian corn. It was formerly met with in northern Italy, southern Austria and in parts of Spain, not as occasional poisonings but as veritable endemics affecting many thousands of individuals. While there is no question as to the fact that the poisoning is due to the corn, the actual cause, notwithstanding the numerous inves- tigations which have been made, is by no means established. It is reason- able to believe that the specific toxic products are formed by the action of some bacterium on the maize which has been cut while immature and stored in a damp condition. EXAMINATION OF SUSPECTED FOOD. It has been customary to look to the chemist for the detection of the cause of a given poisoning. So far as a search for metallic poisons and vegetable alkaloids is necessary, the chemical methods must be used. When the action of bacteria can be excluded with reasonable certainity, a chemical examination should be given precedence, especially when the clinical symptoms point to definite substances, such as lead or arsenic. In the great majority of cases of food poisoning, a chemical examination is of no value and hence should not be undertaken, certainly not until all other methods of inquiry have failed. The reason for delaying such an examination is perfectly obvious, since the amount of the suspected food is usually small and would be completely used up for the chemical tests, if these are carried out in the beginning. In order to avoid secondary decomposition the suspected food should be placed on ice until delivered for examination. Chemical preservatives should never be added. As soon as possible, animal experiments and a search for parasitic organisms should be made. The former serve to demonstrate the fact that poisonous properties are actually present in the article suspected. The material should be fed to animals, and, if necessary, introduced into the stomach by means of a tube. In such feeding experiments, it is well to bear in mind that the action of the poison is more pronounced when the stomach is empty. Macerations of the material in sterile water should be injected into other animals, and in either case, if they die, the indication is that bacteria or their products are probably present. In that event the experiments should be repeated with macerations which have been passed through a Berkefeld or Pasteur filter; also with such after boiling, in order to demonstrate the presence of a soluble toxin, or of heat-resisting products. 246 DISEASES CAUSED BY ORGANIC AGENTS At the same time cultures should be made under aerobic and anaerobic conditions, and grown at the temperature of the room as well as that of the incubator. Litmus-colored sugar media should be employed if possible. The cultures thus obtained are to be compared with those isolated from the animals. Of special importance is the application of the agglutination test to the organisms thus isolated, for, if the serum of the poisoned person has a selective action on the germ found, it is con- clusive evidence of the relation of the latter to the outbreak. An exam- ination for animal parasites, such as trichina, should Tiot be omitted if pork is present in any form in the food under examination. Treatment. — The treatment in food poisoning must necessarily take into ct)nsi(leration the cause, for it is obvious that the metallic and physio- logical poisons, as well as the infections due to animal parasites, must be distinguished from the intoxications and infections due to bacteria. As in the infectious diseases, prophylactic measures are of primary impor- tance, since with proper inspection of food products much can be done to restrict the consumption of improperly preserved food or such as is derived from diseased animals. Thorough cooking, while it suffices to destroy bacteria, does not always, or even as a rule, destroy their chemical products and hence cannot be relied upon exclusively. In the severe intoxications with rapid onset, as those due to shell-fish, free lavage of the stomach should be used as early as possible and followed by a brisk cathartic, such as calomel, gr. ij (gm. 0.13), followed by a saline. Indeed, it is hardly necessary to emphasize the importance in all food poisonings of removing the toxic material by lavage, purgatives, and diuretics except in cases of collapse where stimulants may he required. In the very acute cases, where death occurs rapidly, there is little that can be done except to employ, symptomatic treatment. In the more pro- tracted cases, accompanied with paralyses due to the toxin of the Bacillus botulimis, artificial feeding may become necessary, and, if possible, the antitoxic^ serum for this form of poisoning should be employed, though the results are not very encouraging. As the more common food poisonings represent true bacterial infections of the intestinal tract, the use of antiseptics such as calomel, salol, and like agents is indicated. Opium or morphine may be used to check excessive diarrhoea except in threatened collapse, and the vomiting may be allayed by ice. A liquid diet consisting chiefly of sterile milk and albumen water is advisable. In the more strictly para-typhoid infections the diet and treatment is the same as in typhoid fever. CHAPTER XII. SNAKE VENOMS. By HIDEYO NOGUCHI, M. D. Classification of Poisonous Snakes.— The general division of the animal kingdom known as the class Reptilia contains as a subdivision the order Qphidia, comprising all forms of snakes. This is divided into two suborders, Ophidia colubridse and Ophidia viperidse. The suborder Colubridse contains, besides numerous poisonous snakes, a large number of harmless ones; both are alike in general appearance. All members of the suborder Viperidse are poisonous. The only distinction between the poisonous and non-poisonous snakes is the presence in the venom- ous species of poison-glands and of poison-fangs, with teeth especially adapted for injecting the poison. The poisonous Colubrines, Colubridse venenosa, can further be di- vided into two groups by the anatomical differences in their teeth. The first group is called Opistoglyphia and is characterized by the presence of one or more series of long, mature poison-fangs in the back of the mouth, while in the front, two smooth, non-grooved teeth are present in the upper jaw. This group contains three families; viz. — Dipsademorphinse, with the nostrils situated at the sides of the head and with a strongly built mouth. Elachistodontinse, with the rudimentary teeth situated on the os plattinum and os ptergoideum in the back part of the jaw. Nearly all snakes belonging to this division are poisonous, but their venom is so weak and the position of their poison-fangs so unfavorable, that they ate scarcely dangerous to human beings. Homalopsinse. The nostrils are valvular, and are situated on the upper part of the snout. The eyes are small, with vertical pupils. They are absolutely aquatic and viviparous. More than twenty different species inhabit the rivers and estuaries of the East Indies and of the northern part of Australia. Some of them resemble the Hydrophinse and swim far out into the sea. The second group, Proteroglyphia (with grooved teeth), is the most important among all the colubrines, as they are furnished with strong fangs, provided with a frontal groove passing along their entire length, situated in the anterior part of the upper jaw; the bases of the teeth are connected with the exits of the excretory ducts of the poison-:glands, which are often highly developed. To this group the following two families belong : Hydrophinse, sea-snakes, mth the flat, oar-like tail. The head is more or less compressed at the sides. The eyes as a rule are small and have round pupils; the nasal shield is on the edge of the upper lip, which has two notches. 247 248 DISEASES CAUSED BY ORGAXIC AGENTS. Elapin.T, land-snakes, with cvlindrical tail, smooth or wedge-shaped scales, and richly colored. Some of them, the Najas, when excited or sur- prised, can spread their necks until they assume a jiarachute shape; this expansion extends as far as the first ribs ; in that case the neck appears to be larger than the head. They are found throughout Asia, Africa, and North and South America; all snakes inhabiting Australia belong to this family. The suborder Viperid?e, comprising the viperine and crotaline snakes, is distinguished chiefly by the triangular head and a stout body with short tail. The facial bones are movable; the jaw is short and has a joint with the OS pterygoideus externus and bears on each side a strongly devel- oped poison-fang, behind which are a number of reserve teeth, destined to come forward and to take the place of the princijial fang, when the latter is broken or falls off at the time of shedding. The poison-fangs are not grooved as in the colubrines, but are traversed by a canal. Hence the Viperidre are also called Solenoglyphia (with tubular teeth). The upper end of the canal of the fang meets the exit of the duct of the poison-gland, while the lower opens near the point on the anterior surface of the teeth. The point of the fangs is extremely sharp. The other teeth in the mandi- bles are small, curved, and solid, and do not conduct the poison. Members of this suborder abound in Europe, America, Asia, and Africa, but not in Australia. This suborder is further divided into two families: Viperinte, vipers, which have a very broad head with a small shield and scales, with, however, no pit between nose and eyes. The pupil is vertical. Crotalinse, pit- vipers, which have a very broad head imperfectly covered with scales and are characterized by the presence of a deep depression or pit between the nostril and eye on each side of the head. Some of this family have, at the end of the tail, a series of flat horny rings graduated in size; the shaking of these rings, if the snake is excited, produces the sound from which the name of rattlesnake is derived. GeographicalDistribution of Poisonous Snakes.— The geographical distribution of the snakes in general is mainly of interest to the naturalist, but the possibility of a specific antiserum therapy makes it necessary to include a knowledge of the geographical distribution of poisonous snakes in a discussion of snake venom from the medical standpoint. America. — Colubridce. — Most of the colubrines of America belong to the family Elapidae, especially to the genus Elaps. Many are called by the general name of coral-snake, but the real coral-snake, Elaps corallinus, is found in the forests of Brazil, Venezuela, Columbia, Guiana, and Florida. They are alternately striped with about twenty-five black and bluish- white rings on a red background. The length does not exceed three feet. They live among the withered leaves in the woods. Their poison-fangs are small and are situated at the back of the jaw, rendering their bite less dangerous. The venom itself is very powerful. Elaps ful- vius, the harlequin snake, and Elaps eurycanthus abound in Arizona and the southern states ; they are found even at the height of 6,000 feet. They may be often fatal to man notwithstanding their small size. Viperidce. — The Vipera, true vipers, are not found in America, while the family Ciotalinse, pit-vipers, are very common. The Crotalinae are divided into three genera, Crotalus, Lachesis and Anceistrodon. They are large and very vicious, and their venom is very powerful. SNAKE VENOMS 249 The Crotalus. — This genus lives only in America, spreading over Brazil, Texas, North and South Carolina, Florida, California, and even as far north as New^ York. The majority of this genus are provided with horny rings at the end of the tail, which produce the well known rattling sound. Crotalus adamanteus, the diamond-back rattlesnake, is the most famous species and is found in Florida and the neighboring states. They often grow over seven feet long. Crotalus durissus abounds in the south- ern states of North America and in Mexico, while the Crotalus horridus is found in South America, chiefly in Brazil, where it is called by the name of Boiquira. Both of these last named are the real Crotalus and are far smaller than their allied species, C. adamanteus. The Lachesis. — The dangerous species belonging to this genus are, the fer de lance, Lachesis s. Bothrops lanceolatus, and the Jararaca of Brazil. They caused an annual loss of nearly two hundred human lives among the sugar planters in St. Martinique. The Surucucu, bush master, is also dreaded by the colonists in Brazil. The Lachesis atrox, so-called Laboria, abounds in Guiana, Brazil, Paraguay, Uruguay, Argen- tine Republic, and Buenos Aires. It has a short tail, the end of which is somewhat horny in nature, although there are no rings. The Ancistrodon. — This genus is represented by the following venom- ous species: Ancistrodon piscivorus, water moccasin, and A. con- tortrix, copper-head snake. The former species is found in the tropical as well as the temperate regions and is much feared by the rice planters of Florida. Its length is about three to four feet, and it has a powerful venom. The copper-head snake is much smaller than the water moccasin but its venom is equally poisonous. Europe. — There is in Europe only one poisonous genus, Vipera, which is represented by various species. Vipera berus is the most com- mon species and spreads over all northern Europe, mountainous regions of central Europe, northern Italy, Spain, and Portugal. The vipers of Europe are small and seldom exceed two feet in length. Asia. — The tropical regions of Asia have many dangerous snakes. The most dangerous among them is the famous cobra de capello, Naja tripudians. Among the Colubrines the following sea and land-snakes are found: Hydro'phinoB, Sea-snakes. — A large number of varieties are found on the coast, where they live in colonies. They are all poisonous and vi- cious, and do not come on land as a rule; when they are taken out of the water, their motion is very slow, although they swim swiftly. They float on the surface of the ocean and can dive very deeply, by virtue of the large capacity of their lungs. They give birth to living young. ElapinoB, land-snakes, comprise most of the dangerous varieties of India and Indo-China. The genera, Bungarus, Naja, and Callophis, are found there. Bungarus fasciatus and B. coeruleuse are very common, and they reach a length of about three to five feet. The back is compressed like a wedge. They are less dangerous than the Najas, as their fangs are smaller, Naja tripudians, cobra, is the best known venomous reptile, which has a pattern resembling a pair of spectacles across the back of the neck. It spreads all over the tropical zone of Asia, extending from the 250 DISEASES CAUSED BY ORGAXIC AGENTS southern part of the Caspian Sea to the southern part of China; and is most common in India, Burma, and the JMahiyan Archipelago. The Najas are oviparous and hiy about twenty, soft-shelled, elliptical eggs the size of a pigeon's egg. They are not afraid of man and will hunt for rats and birds after sunset, in the human habitation. They swim well and live near running water. The Callophis, Ilemibungarus, is small and measures only two feet in length. It is sluggish and nocturnal, and, while it has never been known to bite man, its poison is strong for animals. Viperinoe, Vipers. — In India and Burmah there is found a large, richly colored viper, Daboia russelli s. Echidna elegans, which attains the length of nearly six to seven feet. Lachesis, Trimcrcsurus. — It lives in northern India, Tibet, and also in the Philijipine Islands. In Japan, namely in the Riukiu Islands, there is another dangerous species, T. riukiuanus. Africa. — Colubridce. — Sepedon hsemachates and Sepedon rhombeatus are similar to the Naja and can spread their cervical ribs when excited. The latter species is found everywhere in equatorial and southern Africa. The natives believe that it can throw its venom more than three feet and if it should touch human eyes the sight would be destroyed. But in reality, it causes only a slight conjunctivitis. Closely allied to the above species there is the Naja haje, aspis or Egyptian cobra, which often reaches a length of six feet. This species is very common in Egypt and is used by the snake-charmers; it was once worshipped by the ancient Egyptians and its picture is to be seen in the old buildings. ViperincE. — This family is well represented. In the north of Africa, Vipera cerastes, horned viper, and V. ammodytes, while in equatorial districts the Bitis (Vipera) arietans, puff adder, are found. The last named reaches a length of about five feet, and springs into the air be- fore biting. According to the natives it can jump high enough to reach a rider on horseback. The Hottentots hunt this viper to get its head, from which they extract the poison, and after mixing it with certain plant juice, use the mixture for their arrow-heads. The Rhinoceros viper, Bitis gabonica, inhabits Gabon district and vicinity of the River Ogowe; it is brownish-red in color, sluggish, and does not bite man unless molested. Its poison is powerful. Cerastes, or horned viper, has two small, soft, horn-shaped growths near the anterior edge of the head. It is quick in motion and very dangerous for the bare-footed Arabians, who are often fatally bitten. The Sahara, Algeria, and Tripolis, is their home. Echis carinata, pyramid viper, invades the houses of the Egyptian villages. Australia. — Coluhridw. — The poisonous snakes of this continent belong to the Colubrines and are peculiar to this land. The more important ones are: Pseudechis, Denisonia, Hoplocephalus, and Acanthophis. The head of the Denisonia is square and has curved teeth situated on the elongated part of the upper jaw. The most common ones among them are Pseudechis por])hyriacus, black-snake, and Hoplocephalus curtus, tiger-snake. The black-snake can reach a length of five feet and its bite is very dangerous. Acanthophis antarctica s. cerastinus, SNAKE VENOMS 251 death-adder, is a short reptile with decorative pattern and abounds near Sydney. No viperine snakes are found in Austraha. Oceania. — The Sunda isles and Papuasia are rich in the poisonous snakes, which are similar in species to those found in Asia. The sea- snakes are quite abundant. Poison Organs. — The poison-fangs are hollow or grooved teeth, sup- plied with a canal, or furrow, running the entire length of the tooth. The fangs of the Pmteroglyphia (with grooved teeth) and of the Solen- oglyphia (with tubular teeth) are immovably attached to the upper max- illary bone, and completely covered with a broad prolongation of the gingival membrane; this, at the same time, hides the reserve fangs in their varying stages of development. These are two to six in number, and grow out in the place of the mature fangs, in case the latter are damaged or shed. The upper maxillary bone is quite movable and, when drawn backward, erects the fangs to a vertical position; when at rest they lie horizontally. At the same time, the contraction of special constrictor muscles squeezes the poison-glands, the excretory ducts of which open into the canal at the base of the fangs. The size and shape of the poison-fangs differ according to the species. Thus, the Viperinae have longer and sharper teeth with more pronounced curvature, which causes a deep wound. On the other hand, the fangs of the Elapinse, and especially of the Hydrophinse, are much shorter; the poison of the latter is, however, much more dangerous than that of the former. The fangs can attain, as in Bothrops and Crotalus, a length of 25 mm. The narrow, slit-like opening of the canal of the fangs on the Solenoglyphia is situated at the anterior end, — on the convex side, — of the tooth. These differences, together with the arrangement of the other numerous small teeth, enable one to determine the species. The poison-glands are similar in structure to the salivary glands, and occupy a wide space between the muscles below and behind the eyes, on both sides of the upper jaw. In the Naja the size of the gland reaches that of an almond. The gland is covered with a capsule : fibers from the masseter muscle pass into the interior of the gland, and, on constriction, force the poison out of the gland. The secreted venom accumulates in the acini, and in a sac formed by a dilatation of the mucous membrane of the duct. The walls of this sac, also, contain a thin layer of muscle fibers from the same muscle, which form a constrictor at the exit of the ducts. The non-poisonous snakes, as well as the poisonous ones, possess parotid and supralabial glands; the supralabial glands secrete a poison. The non-poisonous snakes have no fangs but the secretion of the venom seems to be indispensable to the function of digestion. The histological process of the secretion of venom from the gland cells can be divided into two phases, — the development of the cell nucleus, and the action of the cell protoplasm. So-called "venogen" granules, — uni- form, round granules, — are produced from the nuclear chromatin; this transformation can be followed by the varying staining reactions of the chromatin granules during the process. An exomosis of dissolved nuclear substance also occurs, forming stored, or "ergastoplasmic" venogen. The nuclear membrane takes an active part in the secretion of both these forms of venogen. The venogen granules and the stored venogen dis- 252 DISEASES CAUSED BY ORGANIC AGENTS appear during the physiological activity of the cell, the venogen granules (characterized by their affinity for Unna's blue, safranin, and fuchsin) being converted into the venom granules, which are eosinophilic. The act of striking consists in "I Indoxyl-glycuronic acid. [ Oxidation products. Skatol-sulphuric acid. + -Skatol— > Skatol-glycuronic acid. Oxidation products. Skatol-carboxylic acid. As salt. With sulphuric acid. Phenol-sulphuric acid. + Phenol-glycuronic acid. ->Phenol— » \ Hydrochinon-sulphuric acid. + Pyrocatechin-sulphuric acid. + Benzoic acid— ^Hippuric acid. p-Oxy-phenyl- proprionic acid- -^Cresol- f Cresol-sulphuric acid. + \ Cresol-glycuronic acid. + [ Benzoic acid^ Hippuric acid. I As salt. [ With sulphuric acid. + -> Benzoic acid — > Hippuric acid. Phenyl-alanine — > x — > x The crosses indicate the substances that are included in the method for the total setherial sulphates. Since we are not able at the present time to estimate or control the amounts of aromatic derivatives eliminated in other form that paired with sulphuric acid, it is obvious, not only that the estimation of indican must often be of no value, but also that the estimation of the conjugated sul- phates must often yield an uninterpretable result, and one that will permit of no inference as to the degree of intestinal putrefaction. Abnormal Products. — When proteins are subjected to putrefaction, a large number of alkaloid-like substances are formed, commonly termed ptomains. They include a large number of substances of the fatty series, amines, and members of the pyridin and the chinolin series. In addition there are a number of bases, some belonging to the pyridin group, others yielding reactions of chinolin, while still others resemble muscarin. Most of these ptomains are innocuous. None of them except 276 DISEASES CAUSED BY ORGANIC AGENTS the simple amines have ever been found in the urine or faeces of normal individuals or of those sufi'ering from any diseases except cholera, idio- pathic cystinuria (occasionally dysentery, enteritis, and obstruction), and true ptomain poisoning due to the ingestion of decomposed protein. Several years ago the writer made a systematic search for ptomains in the urine and faeces of patients with pernicious anaemia, gastric carcinoma, chronic gastro-intestinal disease, and subacute partial obstruction of the intestine, always with negative results. It is known from experimental work that time is required for the elaboration of ptomains, particularly the toxic ones; in general no poisonous bases are formed in less than ten days. That these relations are, however, only relative is shown by the fact that in some of the well-studied cases of ptomain poisoning due to the ingestion of decomposed food, the analytically incriminated foods have been but a few days old. We possess no information that in the so-called gastro-intestinal auto-intoxications (the ingestion of decomposed foods must be excluded) ptomains have ever been found. Since a cer- tain decomposition of food occurs within the alimentary tract and the degree of this decomposition may be increased under certain conditions, we are driven to the conclusion (a) that there is not time for these changes to proceed to the stage of ptomain formation, (b) the ptomains are decomposed in the system, or (c) the decomposition of protein in the intestine is different from that outside the body. The last conjecture may be dismissed. We are left to choose between the other possibilities: Either ptomains are not formed in the alimentary tract (apart from the known instances already mentioned) or they are formed and distoxi- cated. What evidence is there that ptomains are distoxicated ? In experimental work, ptomains are eliminated in the urine just as in idio- pathic cystinuria. The general concensus of opinion is that for the diagnosis of ptomain poisoning, the presence of the poison must be demonstrated. Such chemical demonstration has never been accom- plished for the class of cases under discussion. Of experirnental demon- stration, w'e have largely the measurement of the urotoxic co-efficient. But since the normal urotoxic co-efficient is valueless, deviations are of little import. The strict conclusion to be drawn from our present know- ledge is that the term "ptomain poisoning" should be confined to instances of intoxication due to the ingestion of decomposed food and accompanied by the elimination of the poison, and to instances of decom- position within the tract in which toxic ptomains may be isolated. All other usage is guess-work. The presence of cadaverin and putrescin would mean little, for, apart from their harmless roles in cystinuria, they are to be found in old digestion experiments, where they are derived by fermentation of lysinandornithin, and thus they do not neces- sarily indicate an abnormal bacterial decomposition. The neurinc group has been considered responsible for some of the symptoms of Addison's disease, though without chemical demonstration. There are several clinical symptom-complexes in which, though the term ptomain poisoning is improper, there are reasons of fact and anal- ogy that furnish some warrant for the use of the term gastro-intestinal auto-intoxication. What is needed in these domains is exact investiga- tions, — accurate clinical observation and objective chemical research. While there is a large element of an art in practical medicine, diagnosis AUTO-INTOXICATIONS 111 ought to be an objective science. There is an element of fashion, per- sonal or collective, in the manner in which the obscure conditions of disease are interpreted. The progress of the auto-intoxication propa- ganda, like that of every other uncontrolled movement in practical medi- cine, is like the development of gossip in common life: The first person suggests that it might be so, the second states that it is so. The serious aspect of the situation, which, if we may judge by the history of medicine, is ephemeral and in a sense self-corrective (a good illustration is afforded in the history of the diagnosis of malaria), lies in the fact that positive diagnosis, however fictitious, inhibits investigation. Tetany. — Under tetany we understand the full complex, excluding the atypical instances of peripheral or carpopedal spasm. The tetanies associated with extirpation of the thyroid, intestinal parasites, pregnancy and lactation, acute infections, exogenous intoxications, rachitis, and the so-called epidemic or occupational variety, can have no dependence upon the digestive tract. Typical tetany of the severe form occurring in adults in association with gastric dilatation is rare and very fatal. The dilated obstructed stomach furnishes a most favorable opportunity for the decomposition of food. To determine whether these processes have gone to the stage of the pro- duction of poisons, the gastric contents and urine have been investigated. Hyperchlorhydria cannot be incriminated. In a few instances unchar- acterized substances have been obtained from the gastric contents (method of Brieger) that were somewhat toxic to rabbits; in other cases the substances were innocuous. From the urine in a few cases, substances have been isolated that gave group reactions of ptomains but were not toxic on intravenous injection into rabbits. Up to the present, therefore, a ptomain poisoning has not been demonstrated for tetany. Tetanic seiz- ures are observed in dogs in whom the duodenum is cut across and the ends brought into external fistulae, so that the gastric contents leave the body; the results might be explained by the assumption that there is in the gastric secretion some substance, a constituent necessary to the inter- mediary metabolism, that should return to the circulation by intestinal resorption. The tetany of children, associated with gastro-intestinal symptoms and diseases, is often accompanied by acidosis, and an excess of ammonia and of aromatic bodies in the urine. The toxicity of properly prepared extracts from the urine or digestive contents has not been studied. The association with the acidosis is of slight moment, since this is very com- mon in children in subnutrition. The Alimentary Tract. — Commonly regarded as intoxications are certain gastro-intestinal attacks associated with cutaneous symptoms. The symptoms are pain, vomiting, often diarrhoea, fever, followed by a general erythema, urticaria, or possibly by other exanthemata. Desqua- mation may follow. The symptoms in many cases resemble closely intoxication with shell-fish in susceptible individuals, less closely the drug- exanthemata. These attacks tend to recur periodically. Recovery usually follows promptly after gastric lavage, irrigation of the colon, and free purgation. Ptomains have never been reported in the contents of the tract or urine. The writer is acquainted with one case in which a care- ful search was made with negative results. 278 DISEASES CAUSED BY ORGANIC AGENTS Not infrequently instances of severe violent disturbances of the alimentary tract are observed that bear all the external marks of an auto-uitoxication. Usually no adequate cause is to be determined, particularly no gross dietary indiscretion. The attacks consist of sudden vomiting, that may be uncontrollable, extreme pain, profuse diarrhoea in some cases, and in others spasms of the intestine, with mcteorism, vertigo, vasomotor dilata- tion, shock, local spasms, even convulsions and coma. It does not seem possible to consider these as indigestions or infections. If it is possible to exclude exogenous intoxication, the assum])tion of a gastro-intestinal auto-intoxication is justified, even though a chemical investigation (which has apparently never been attemjited) should fail to isolate any known poison. This reasoning does not hold for the marasmus of enterocolitis. One must here choose between a gastro-intestinal and a metabolic auto- intoxication, and there has been so little work done that a definite opinion is not now possible. The recurrent vomiting of children will be discussed under acetone acidosis. In connection with subacute, complete, or partial obstruction of the stomach or intestine, symptoms suggesting gastro-intestinal auto-intoxica- tion are usually noticed. There is fever, albuminuria, headache, insom- nia, a marked increase in the aromatic substances in the urine, sometimes exanthematous rashes, possibly severe nervous symptoms, \Ahich sub- side when the obstruction is relieved. The difference in the appearance of patients with gastric carcinoma, before and after gastro-enterostomy, is usually so striking that one is driven to question whether this can be explained by the conditions of nutrition, and is not due in part to the re- moval of conditions of decomposition in the stomach. Nevertheless the definite demonstration is wanting. In not a few instances of chronic ap- pendicitis, nervous symptoms have been prominent (even epileptic seiz- ures), which disappeared with the removal of the appendix. Admitting the facts, the assumption of agastro-intestinal auto-intoxication is hypothetical. Constipation. — The diagnosis of auto-intoxication rests largely upon an excess of indican or conjugated sulphates in the urine. The elimination of indican and of the aromatic sulphates bears, however, no constant re- lation to the presence or absence of constipation; nor does the degree of increase in the aromatic substances in the urine bear any relation to the intensity of the symptoms. As previously stated, indicanuria is not a sign of auto-intoxication, nor does it afford any index of the elimination of other and toxic substances. The urine and fseces of patients with constipation have been analyzed "v\'ithout success for ptomains. An illustration of the fictitious value of the ir.terpretation of the symptoms of constipation is afforded by the fact that they are at all times more pronounced in Avomen than in men, and particularly marked during the menstrual period, which is, in all probability, to beexplained as a mechanical result of thedistension on the pelvic organs. It is also noteworthy that many of the symptoms of constipation are to be observed in association with abdominal and pelvic diseases unaccompanied by constipation. A recent suggestion is that the evil results of constipation may be due to the non-secretion, by the intes- tinal mucosa, of toxic substances, whose elimination is assumed to be a function of the intestine. For this hypothesis there is no evidence. Nervous Dyspepsia. — This has been classed as a gastro-intestinal auto- intoxication. The absence of inflammatory lesions and abnormalities of AUTO-INTOXICATIONS . 279 digestion, apart from variations in the secretion of hydrochloric acid, makes a conception of the etiology of nervous dyspepsia obscure but there is no good evidence that an auto-intoxication is present. It will not do to say that, since we know of nothing else, it must be an auto-intoxication; if we do not know of anything else and there is no exact evidence of an intoxication, we simply do not know the cause at all. Nervous System. — For the etiology of a large number of diseases of the nervous system, (migraine, neuritis, epilepsy, myasthenia, melancholia, dementia paralytica, psychoses, and even periodic family paralysis) gastro-intestinal auto-intoxication has been invoked. The evidence com- prises analogies between these diseases and conditions in the nervous system due to known poisons, the occurrence of constipation and often of an excessive ehmination of aromatic substances, the occasional occur- rence of acetonuria, the apparent relation of attacks to dietetic errors, the finding in nerve cells of lesions resembling those produced by experi- mental intoxications, and in the results of the measurement of the toxicity of the urine and, in some cases, of the perspiration. A perusal of the liter- ature bearing upon the subject suggests that it is not the validity or natural probability of the findings above summarized that leads to the diagnosis, but rather a conviction of the insufficiency of the previously offered hypoth- esis. Of exact investigations there are none. The Anaemias. — These have long been regarded as diseases of intoxi- cation. The earlier theory of the gastro-intestinal origin of chlorosis is now generally recognized as disproved. For pernicious anaemia, however, a good case has been made out. The reasoning does not rest upon such indefinite facts as constipation or diarrhoea, Indicanuria, acetonuria. That a persistent haemolysis is at the bottom of pernicious anaemia is shown and this is one of our best studied effects of poisons, and, wuth the demonstra- tion of the occurrence of a severe and persistent haemolysis as the cardinal feature of the disease, a reasonable etiology is established. Earlier w^ork made it probable that the poison was absorbed from the alimentary tract; this has been supported by the experiments with toluylene-diamine, and the analogy with the anchylostoma anaemia. It is supported by the histological findings, which indicate that the haemolysis occurs in the portal system, and by the atrophy of the mucosa of the stomach and intestine, so often observed. Concerning the nature of the haemolytic agent we know nothing. A ptomain it certainly is not. Years ago, the writer searched the faeces and urine of a series of cases systematically for ptomains, w'ith negative results. For leukaemia, we have no exact knowledge. Asthma Dyspepticum. — Is there a dyspnoea of toxic gastro-intestinal origin? The experimental foundation for such a conception is to be found in the observation that in dogs with an Eck's fistula the ingestion of bouillon or meat is followed by acute dyspnoea. Children exhibit attacks of acute dyspnoea associated with alimentary disturbances and unaccom- panied by any lesions in the thoracic organs or kidneys. The condition, not confined to children, has not been extensively studied. A close con- nection exists between the diet and exacerbations in the attacks. No poi- sons have been isolated. Gastro-intestinal Albuminuria. — The kidneys are sensitive to poisons. In not a few instances of gastro-intestinal disturbances, albuminuria is observed, and it is common in poisoning by shell-fish and decomposed 280 DISEASES CAUSED BY ORGAXIC AGEXTS foods. There can be no strong objection to this chissification of the in- stances of albuminuria that occur in well-defined cases of gastro-intestinal diseases. But to go to the extent of the assunij)tion,\vithout exact evidence, that the so-called idiopathic, cyclic, and recurrent albuminuria rest upon an otherwise unmanifestcd gastro-intestinal auto-intoxication is surely unjustified. ABNORMALITIES IN THE PROCESSES OF OXIDATION. The relations of the existence, extent, and nature, of sub- and super- oxidation are intricate and, in part, undetermined. Upon a normal mixed diet, the body heat is largely maintained by the carbonous metabolism; on a protein diet, the protein metabolism will be so exaggerated as to supply the entire heat. The minimum is determined by the amount required to sustain the body temperature under proper conditions of control Avithout food and at complete rest of voluntary movements. Since the body is sparse in its metabolism when deprived of food, the figures under these circumstances will be below the real normal; but it is the nearest approximation we can secure, since otherwise the heat of digestion introduces a factor of disturbance. For normal adults the minimum heat values may be given as 14 calories per lb. (30 cal. per kilo) per day. Elderly individuals may require less, children will require more, emaciated convalescents may maintain a balance upon as little as 10 cal. per lb. (22 cal. per kilo). The average is probably higher, and there are notable individual variations. Less than 10 per cent, of this heat is derived from the combustion of body protein utilized in the daily metabolism. To produce the rest, nearly 17 oz. (500 gm.) of sugar or 8 oz. (225 gm.) of fat are burned. Under less experimental conditions of life than a fasting repose in a respiration chamber at constant temperature, these figures will be in- creased. On a usual diet, nearly twice as much protein would be dis- assimilated, so that a couple of hundred of calories a day would be there added. The heat dissipation will be somewhat increased under ordinary conditions. An increase in oxidation is observed following the ingestion of food, which is marked for protein, much less for carbohydrates and fats. This increase is notslight sincetheO-inputand theCOo-output afterameal may exceed the fasting figures by 30 per cent., and with forced protein feeding equal the entire fasting oxidation. The reasons for this fact, which has clinical bearings, are not entirely clear. Digestion is an exothermic process; but since the products must be reconverted, heat will be again absorbed. Peristalsis and the secretion of the digestive juices represent a certain slight heat production. The older idea, that this increase in oxi- dation represents an extravagance of luxury (in the sense that, like a spend- thrift, the body increases its outlay with its income), has been shown not to hold good. The cleavage, after resorption of the protein, into the nitrog- enous and the non-nitrogenous moieties, is held to account, in large part, for this increased oxidation. Apart from the obscurity of this explanation, it is not in harmony with the fact that the degree of this digestive increment of oxidation is apparently quite constant in percentage for a particular substance, and not dependent upon the quantity. This digestion-oxidation AUTO-INTOXICATIONS 281 is greater in the child than in the aged, low in the obese, and high in the convalescent. Muscular exercise produces a great increase in the processes of oxi- dation. In the respiration experiment, this is limited to the movements of respiration, circulation, and peristalsis. The respiratory movements fur- nish a considerable percentage of the heat production. Ordinary work increases the oxidation processes by 50 per cent., heavy work may double the oxidation of the resting, fnsting individual. Marked individual variations occur. Exercise of the untrained muscle increases oxidation more than in the trained muscle; exercise of the exhausted muscle espe- cially is accompanied by superoxidation. The velocity of contractions in the unit of time increases the oxidation disproportionately. The weight of the individual is, for obvious reasons, of great influence. Lastly, there is the factor of temperament and facility. Two men of the same stature and weight will not do the same muscular task with the same expenditure of energy. This is not entirely a matter of training ; some are, by nature and construction, economical of motion, others extravagant. Restlessness is a factor of influence. These considerations are of great importance; unless constant conditions can be secured, fair comparison between the sick and the well cannot be made. Under the incidental oxidations are classed those associated with func- tions that have a raison d'etre independent of the heat production, such as the protein and nuclein metabolisms. These are increased but slightly by exercise and to some extent by conditions in the diet. So long as the diet contains the normal quota of fat and carbohydrate, less than a sixth of the heat required for the body is derived from these incidental sources. There is a regulatory mechanism in the carbonous metabolism. When the other sources of heat are prominent the combustion of sugar and fat is reduced; that this is a limited adaptation is shown by the fact that the- heat production, apart from the incidental combustions, is not reduced to nil when the individual is placed in an atmosphere of the temperature of the body, and by the continuation of sugar combustion when, to a mixed diet, protein is added in quantities sufficient to supply the body heat. Under these circumstances sugar is still burned and the needless heat dis- sipated by physical means. There is evidence that at higher tempera- tures, as in the Russian bath, the processes of oxidation in the body are actually increased. In considering the relations of oxidation in disease, we are concerned with the total alone; it is not necessary to state that a particular oxidation may be increased or decreased in health and disease. Suboxidation. — Have we evidence of the existence of a state of general suboxidation? The metabolic heat production is derived from the move- ments of circulation, respiration and peristalsis, secretion, and the reac- tions of catabolism. The hypothesis of a retardation of metabolism means that these reactions would be accomplished with less consumption of material and production of heat than in the normal; and since the cir- culation and respiration act in part reciprocally to these, they would be reduced. The hypothesis of a retardation of metabolism means that the unit of protoplasm would have a lower level of metabohsm. The unit of protoplasm in the cold-blooded animals has a very low level of metabolism, and in the hibernating animal a much lower level than during the summer. The hypothesis of a retardation of metabolism is therefore tantamount to 282 DISEASES CAUSED BY ORGANIC AGENTS the predication that, as a diseased condition, the unit of human protopLasm can suffer a reduction in the plane of its metabohsm. That this is true to a certain extent is ilhistrated by the economy in metabohsm dispUayed in the chronica Uy underfed. The real question is whether such a reduction as is assumed in the hypothetical retardation of metabolism is compatible with the relations of heat dissipation and body temperature. A moderate suboxidation could occur without reduction in the body temperature. There are four directions of heat dissipation: Radiation from the skin, evaporation of persjjiration, respiration, and the heating of food and drink to the temperature of the body„ The respiratory loss cannot be reduced below the values for the resting individual. The cutaneous radiation and perspiration are subject to a greater degree of regulation, and, with these physical regidations enforced to the maximum, the body temperature of the resting individual could be maintained upon less than the minimum values given. On how much less we do not know. Since, however, tlip body temperature is normal in individuals suspected of having suboxi- dation, the argument is concerned with just this rubric. A reduction of the body temperature would not in itself indicate suboxidation. That such a state of suboxidation exists as an acute condition may be assumed, though no accurate studies of appropriate cases exist. In pro- longed surgical anaesthesia and drug narcosis, following extreme hemor- rhage, in shock, in asthenic infections, in terminal diabetic and cholsemic coma, such a condition probably exists. In these states the body tem- perature is low. This may be due in part to excessive heat dissipation, since many have extreme vasomotor dilatation. The renal functions are nearly abolished and analyses of the urine indicate a very low protein catabolism, far below that of starvation. The whole picture suggests prostration of all the vital functions, including that of systemic oxidation. The state is one adjacent to death and can be tolerated but a few hours. In connection with chronic diseases, the use of the expression may be controlled by investigations, and, though these are very onerous, enough cases have been carefully studied to enable us to form a tentative judg- ment in the matter. Nowadays we read and hear much of suboxidation. It is particularly unfortunate to mix magnitudes of undetermined defi- nition with purely fictitious terms. Suboxidation is the name of an objective condition, and subject to control as such. There are four groups of chronic diseases in which suboxidation has been considered ; obesity, the ana?mias, myxoedema and cachexia strum- ipriva, and the cachexia of malignant diseases. The facts to be deter- mined are: What is the condition of the nitrogenous and carbonous metabolism, how is the O-input and C02-output? Obesity. — Is there suboxidation in obesity? Prehminary to this question a consideration of the relations of the sexual functions to metab- olism is important. Castrated animals are more easily fattened than their normal fellows. In young animals this growth comprises a flesh- as well as a fat-mast. The question whether this rests upon a reduction in the oxidation processes is of great importance, because if it should be demonstrated that the plane of oxidation may be shifted by castration, the sexual glands would acquire a metabolic function allied to that of the thyroid. Castration in animals converts a nervous into a phlegmatic temperament, and we know as an experimental fact that the nervous AUTO-INTOXICATIONS 283 temperament is wasteful in movements, metabolism, and combustion. There is an actual loss of material attending the functions of the organs of reproduction, though we have no way of estimating it. The sum total of these influences is sufficient to account for changes of notable degree, though a measurement is impossible. In the end, therefore, the decision must be left to the metabolic experiment. Years ago investigations were believed to have shown that the oxygen consumed by castrated animals was nearly 20 per cent, less than the amount consumed by the controlled animals. The methods were faulty, the experiments brief and the results excessive; such a degree of suboxidation would lead to the development of the highest degree of obesity within a very short time. Recently the work has been repeated with longer periods of observation; a positive evidence of suboxidation has not been obtained. Castrated dogs of both sexes (and unsexed women) exhibit the same car- bonous and nitrogenous metabolism as the properly managed controls. In the current literature there is a general confusion of the indirect and the direct effects of castration on nutrition, metabolism, and combustion. Coming to the question of obesity, there are two groups of fat peoplethat present symptoms suggesting an abnormal metabolism: The excessively fat children, and those adults who leading active muscular lives, and, not being addicted to excesses in eating and drinking, become pathologically obese. There are two ways of investigating these cases: The method of metabolic and combustion experiment, and the method of prolonged observation on a known and controlled diet, with careful observation of the body weight. In the use of the method of metabolic experimentation, one must realize that much lower values will be secured than in thin indi- viduals, without affording any basis for induction. The unit of substance necessary for a body is related only to the mass of the metabolic tissues. The bones, apart from the marrow, are practically of no metabolic moment; but, since they remain constant with respect to obesity, need not be considered. Little energy is required for fatty tissue. When an indi- vidual weighing 160 lbs. (70 kilos), in good nutrition, adds fat up to 220 lbs. (100 kilos), his metabolic transformations will not increase in the ratio of 16 to 22; the stout man will have about the same metabolism that he had when thin, and the unit of calories of 0-input and C02-output per kilo weight will have decreased. To be of positive value the varia- tions must exceed these relations. There have been some twenty inves- tigations of the combustion-metabohsm of cases of obesity. The results of these have been negative, — no evidence has been obtained that there is any reduction in the processes of oxidation. The error in the method of prolonged observation is the difficulty of determining the relations of water to solids, and of excluding dropsy. There are a few reported cases in which obese subjects have maintained their weight on a diet of very low caloric value (as low as 1,000 cal.). It is unfortunate that such an individual has not been placed on a respiration experiment. Inves- tigations therefore tend to show that no such thing as suboxidation occurs in obesity. Myxoedema and Cachexia Strumipriva. — The evidence bearing upon suboxidation in these diseases may be grouped under four headings: (o). The direct combustion experiment. In one case of sporadic cretinism the values, though low, were within the normal, {b) The clinical symptoms. 284 DISEASES CAUSED BY ORGAXIC AGEXTS These suo;gest suboxidation. The patients incline to low body tempera- ture despite the faettliat, on account of the almost comi)lete abolition of perspiration, the heat dissi})ation seems below the normal. These facts, while sugg-estive, do not directly indicate the existence of suboxidation; they indicate that the subjects have lost in part the power of suddenly increasing their combustion to meet the demands imposed upon it. (c) The results of thyroid medication. These are striking, but they bear only in part upon this question. The administration of thyroid preparations in the healthy, and to a greater extent in the m}ocoedematous, results in a marked increase in the protein catabolism and to some increase in O-input and COj-output. The increase of the combustion may be as high as 15 or 20 per cent, {d ) The contrast between myxoedema and cachexia strumipriva, and exophthalmic goitre. Increase in the nitrog- enous and carbonous metabolism is the striking metabolic symptom of Graves's disease; it is relieved by extirpation of the thyroid. Myxoedema associated with atrophy of the thjToid and cachexia strumipriva due to total extirpation of the thyroid are relieved by thyroid medication. The inference is tempting, nevertheless the facts do not establish a suboxidation. The nitrogenous and not the carbonous metabolism is the prominent feature. It is possible that the influence upon the carbonous combustion may be entirely secondary to the disturbances in the protein metabolism. The fact that "on administration of thyroid preparations a certain exag- geration in combustion occurs, is not proof that, with the atrophy of that organ, the combustion would fall below the normal. The Anaemias. — The essential antemias were long held to be associated with suboxidation. It seemed natural to question whether an adequate quantity of oxygen could be transported by such small quantities of hsemogiobin. The experimental studies have given the answer in the negative. Under proper conditions of control, subjects with chlorosis exhibit a normal protein and carbonous metabolism, while cases of pernicious antemia and leukaemia display excesses in the protein metab- olism and normal, or supernormal, oxidation. The work of circulation and respiration is notably increased in these subjects. Cachexia and Marasmus. — One not infrequently meets with instances of these conditions that suggest suboxidation. The patients become emaciated to the last degree, the condition seems to become stationary and, for weeks, the patients remain in a scarcely more than hibernating exist- ence. The body temperature is low, the skin dry, the extremities cold, there is scarcely any digestion, and yet life is prolonged in a most remark- able manner. That their metabolism and combustions are low is not to be doubted, but it is questionable whether they are lower than in simple chronic subnutrition. It is established that individuals subjected to pro- longed subnutrition become, in a sense, inured thereto and exhibit a nitrogenous and carbonous metabolism notably lower than in acute starvation. There is nothing to indicate that in the conditions of ma- rasmus and cachexia the relations are different or more extreme than in simple chronic subnutrition, and, although the body under these circumstances operates very economically, we cannot speak of subox- idation. The hypothesis that diabetes, gout, the so-called lithfemic diathesis, the chronic arthritides, asthma, migraine, eczema and other diseases of un- A UTO-INTOXICA TIONS 285 known etiology are manifestations of a retardation of metabolism is devoid of foundation. Superoxidation, — ^Under this term we understand an increase in com- bustion in excess of the caloric demands of the body. Since the body habitually burns something more than is needed to supply heat on the minimal physical heat-dissipation, it is apparent that there is a physio- logical superoxidation that serves as a compensatory arrangement, superoxidation occurs in many diseases. There are oxidations in the pro- tein metaboUsm, but the chief reaction is hydrolytic cleavage; and oxi- dation of the products of the hydrolytic cleavage of protein can scarcely be conceived to be susceptible of an exaggeration in the direct sense. Thus, oxidation is a secondary process in the metabolism of protein, and as such is not susceptible of a primary exaggeration, though it might be subject to a primary retardation. Superoxidation affects directly the sugar metabolism. If the carbohydrate input be not sufficient, the fat combustion will become exaggerated so soon as the body glycogen has run low. If the fat ingestion be not sufficient to the oxidation, the body fat will be burned. Since we regard these combustions as of the nature of ferment reactions, the pathological exaggerations are naturally and logically to be ascribed either to an increased concentration of the sub- strate, or to an excess of the ferments. An important practical con- comitant to the superoxidation of sugar and fat is the more or less complete loss of the saving power of sugar and fat for the protein me- tabolism. Deficiency of Oxygen. — Asphyxiation is the result of lack of oxygen. Many exogenous intoxications act in part by preventing the utilization of oxygen; such are the nitrites, morphine, arsenious acid, carbon monoxide, cyanides, chloral, paraldehyde, veratrine. A marked degree of deficiency in oxygen cannot be borne for more than a short time. One hears a great deal of the deficiency of oxygen in the production of disease, but when the evidence is analyzed it is seen to be very scanty. In order to establish a lack of oxygen, one ought to possess gas analyses of the respiration or blood. Breathing an atmosphere low in oxygen is accompanied by a high respiratory quotient. In acute pneumothorax and cardiac dilatation, the body suffers from lack of oxygen ; the blood content of oxygen and carbon dioxide falls. This situation cannot be long maintained; if compensation be not rapidly established death occurs. In acute and massive hemor- rhage a deficiency occurs ; this cannot, however, be due to the reduction in the red corpuscles, for it is not possible to bleed an animal over 40 per cent, of its blood even if the fluid be replaced, and there is no deficiency of oxygenation in such a degree of ansemia per se. As a subacute condition, there is evidence that a certain degree of deficiency in oxygen occurs in severe cardiac and pulmonary diseases. In these diseases the efforts at compensation usually are practically success- ful; what so often kills is the exhaustion produced. In these one may observe an excess of protein catabolism and the appearance of lactic acid in the urine. In some instances of heart disease the blood contains more CO2 and less O than normal. A favorable tension of O and CO2 can be shown to exist in the alveoli of the lung, despite v\^hich the blood does not seem able to cast out the normal amount of CO2 or absorb the normal amount of O. Whether the fault lies in an alveolar induration or in a 286 DISEASES CAUSED BY ORGANIC AGENTS slowing of the circulation is not known. It does not lie in a deficiency of the respiratory movements. Just how the partial lack of oxygen affects the organism is not well known. The loss falls first on the protein metabolism, the intermediary products of which appear unoxidized in the urine. The protein catab- olism is exaggerated. The body attempts to make up for the deficiency by the utilization of intramolecular oxygen; to what extent this can com- pensate is not known. In animals under carefully selected conditions of experimentation , an acidosis may be produced. In the anannias, cachexia, and tuberculosis, in which a deficiency of oxygenation has been popularly supposed to exist, the consumptionof oxygen is either normal or excessive. It is possible that exercise would lead to a temporary relative deficiency of oxygen, but under conditions of rest there is no such deficiency. DISTOXIOATION. Under distoxication are grouped those acts of metabolism by means of which endogenous toxic substances are rendered innocuous. The known reactions of distoxication include conjugation, oxidation, and reduction. In the intestinal putrefaction of the products of protein digestion, a num- ber of aromatic bodies are formed. In the act of absorption they are subjected to alterations that render their slight, though undetermined, toxicity inert. Some of the products of the digestion of protein are quite toxic, yet in the liver this is nullified. If in the dog the portal blood be conducted directly to the vena cava, a severe intoxication is the result. The general application of the theory of distoxication lies in the propo- sition that the intermediary products of metabolism are more or less toxic and that in the completion of the processes of metabolism to end-products we have what in effect has the value of a distoxication. When also abnor- mal intermediary products of metabolism appear, they may be distoxi- cated. Thus cations are withdrawn from the tissues to combine with the anions in experimental acid poisoning, in the acetone acidosis, and in connection with an ash-free diet. When glycuronic acid is derived from glucose it is paired in the body. If leucin and tyrosin are formed by an abnormal intermediary protein metabolism, they will be oxidized to phenyl-oxy-acids; should the amount of the amido-acids be large, a certain rest will be eliminated unchanged. In an analogous sense we may speak of cystinuria and alkaptonuria as abnormalities of distoxication. Phar- macology is filled with references to chemical processes of distoxication. EUmination is obviously an indispensable adjunct to distoxication. Some substances that cannot be chemically distoxicated are harmless if promptly eliminated. The general tendency has been to concede the relative in- nocuousness of the end-products of metabolism and to refer auto-intoxi- cations rather to deviations in, or the non-completion of, the intermediary processes of metabolism. Under the different headings specific references will, whenever possible, be made to the chemical reactions concerned; we here merely state the point of view. A hypothesis is now current to some extent, by which distoxication is assumed to be a function of the thyroid, adrenal, and pituitary bodies. This is not assumed to the exclusion of an internal secretion but in , AUTO-INTOXICATIONS 287 addition thereto. In particular the thyroid body is held to distoxicatc the products of renal insufficiency. The hypothesis is not yet upon an exact basis, and, while it may in the future develop into a recognized theory, it does not occupy that plane to-day. RETENTION INTOXICATIONS. Under this we understand the retention of the normal end products through insufficient excretion. This leads to accumulation of these sub- stances, and the intoxications are due to their influence upon various tissues and functions. We ought to distinguish the retention of an excess of a normal substance from the accumulation of an abnormal substance. The demonstration of the etiological relations will be obviously much more easy in the second than in the first group. Jaundice. — It may be accepted that, with the exception of cholesterine, no specific organic constituent of bile is normally present in the tissues. The biliary constituents that may be held responsible for the toxic action of bile are the salts of the glyco- and tauro-cholic acids and the pigments. Glycocoll and taurin are products of protein hydrolysis ; the derivation, as well as the chemical nature, of cholic acid is not known. Since the liver is the seat of the final disintegration of haemoglobin, it has been assumed that the glycocoll and taurin are derived in part from the hydrolysis of the protein moiety in hsemoglobin. The pigments are derived from the haemoglobin. Following biliary obstruction, the formation of the acids seems to suffer a reduction, but the pigments continue to be formed in the usual quantities. The toxicity of bile lies largely in the biliary salts, although the pig- ments possess a certain toxicity, especially evident in the depression of the body temperature. Bile acts as a tissue poison, particularly to the renal, hepatic, and muscle-cells. There is further evidence that it exerts a hsemolytic action. Possibly this may be related to the hemorrhagic tendency so frequently noted in jaundice. The body temperature is reduced, the pulse and respiration retarded, — apparently on account of peripheral influences, since the effects occur following the local appli- cation of bile to the surface of the heart after section of the vagus in the curarized frog. There is dilatation of the peripheral capillaries. Large doses cause coma, convulsions, and paralyses. In jaundice we observe clinically, retardation of the pulse, somnolence, albuminuria, sometimes emaciation and cutaneous disturbances, occasionally hemorrhages, — directly corresponding to the experimental findings. In simple instances of jaundice the digestion is little impaired. The temperature of the body may be normal or slightly reduced. Usually there is little disturbance in the nitrogen metabohsm, nutrition, or body weight. In prolonged cases the functions of the liver may be greatly impaired, the glycogen of the muscles, as well as of the liver, may be practically absent, and the epithelial cells extensively degenerated. The exceptionally deleterious effects of disturbances of digestion in jaundiced indi"sdduals have led several authors to assume a reduction in the activity of the distoxication functions of the liver. Quite inconclusive is the relationship of hepatic coma to jaundice. Symptomatically the so-called cholsemia resembles experimental bihary 288 DISEASES CAUSED BY ORGAXIC AGENTS intoxication, but the same symptoms are as frequently seen in hepatic cirrhosis without jaundice. It is difficult to understand how many indi- viduals bear jaundice without marked toxic sym})toms. The common explanation that in one case the renal elimination of the bile is sufficient, in another insufficient, is not borne out by urinary observations. In all likelihood the cause, of hepatic coma is to be sought less in the toxic effects of the circulating bile than in a disturbance of the metabolic functions of the liver, just as in acute yellow atrophy, phosphorus poisoning, experi- mental ablation of the liver, and anastomosis of the portal vein and in- ferior cava. Under this interpretation the prolonged jaundice could lead to grave auto-intoxication through abolition of hepatic function. Auto intoxications by retention do not remain pure but tend to entrain second- ary metabolic auto-intoxication. Retention of Carbon Dioxide. — Is there an intoxication with meta- bolic carbon dioxide, connected with disturbances of the circulation and respiration ? There is the greatest discrepancy between the apparent sim- plicity and the actual complexity of the problem. The actual problem must be first defined, (a) The gas-exchange of the body has no necessary rela- tions to dyspnoea. Dyspnoea appears when the gas-exchange is decreased or exaggerated, but often exists independent of any alterations of the gas metabolism. The increased res])irations following muscular exertion are not due to the accumulation in the venous system of an excess of carbon dioxide, but to a stimulation of the respiratory centre by substances derived from the muscular metabolism. Not a few chemical substances cause dyspnoea. Many forms of auto-intoxication, in which the gas- exchange is not in the least concerned, give rise to dyspnoea; such are diabetic coma, uraemia, hepatic coma. Lastly, bacterial toxins cause dyspnoea, as seen in pneumonia, (b) Intoxication with carbon dioxide is not necessarily associated with cyanosis, since the fault may lie entirely within the internal respiration, (c) There is no necessary association between the gas-exchange and the carbon-dioxide content of the blood. It is possible for the O-input and the COa-output, the heat metabolism, to be normal, while the blood is surcharged with carbon dioxide and the cyanosis pronounced, (d) Lastly, deficiency of oxygen must be separated from an excess of carbon dioxide. This is often extremely difficult. In what diseases and under what circumstances is there an excess of carbon dioxide in the blood and tissues, and what degree of such excess may be properly said to cause auto-intoxication? Oxygen is carried in the blood in chemical combination with haemoglobin, in small part by physical absorption in the cells and plasma. The arterial plasma is saturated with oxygen. Arterial blood contains about 20 vol. per cent, of oxygen, venous blood some 8 to 10 vol. per cent. In death by suffocation the oxygen is decreased before the death of the animal to less than 1 vol. per cent. The relations of the carbon dioxide are less certain. It is present in arterial blood to the extent of 30 to 40 vol. per cent., in venous blood about 10 vol. per cent. more. Five-sixths of the gas is in the plasma. In asphyx- iated animals the concentration of CO2 in the venous blood rises but little above the maximum normal of 50 vol. percent.; this is comprehensible when we realize that most of the oxygen contained in the body is held in the tissues. The mode by which the COg is removed from the tissues and AUTO-INTOXICATIONS 289 transported in the blood to the lung is obscure. The most difficult ques- tion concerns the nature of the substances with which the CO2 is held combined in the plasma. Since the stay of the blood in the tissues and lungs is so very brief, association and dissociation must occur with great rapidity. Since the reaction of the blood is neutral, no process can be assumed that is chemically incompatable with this neutrality.^ The gas has been held to circulate as a bicarbonate, this being formed in the peripheral venous blood, and then during the passage through the lungs reduced to the carbonate, in which form it would circulate to the arterial periphery, there to combine with a fresh quantum of the gas to again form the bicarbonate. This conception cannot be maintained. When a weak solution of sodium bicarbonate, exposed to the atmosphere, attains an equilibrium, it contains about 93 per cent, of the bicarbonate and about 7 per cent, of the carbonate; it requires but slight partial pressure of CO2, as low a pressure as 10 mm. of Hg, to check the dissociation entirely. Now the CO2 in the arterial blood never falls below 25 mm. of Hg and the absorbed gas is equal in the arterial and venous bloods. In addition, a reduction of bicarbonate to carbonate would result in a pronounced alkaline reaction. The inadequacy of the carbonate hypothesis is further illustrated by the fact that, in grave condition of acidosis, the only cation available in the circulation would be ammonia. The role of carrier has also been ascribed to the phosphates. This is impossible, from the fact that the plasma contains but a trace of phosphate. The most recent view allies the CO2 with alkali-globulin combinations. It is known that the proteins combine with acids or alkalies to form bodies subject to hydroly- tic dissociation. The weakest acids and alkalies, however, are able to dis- place the proteins and CO2 is able to do so. The conception is that the proteins of the blood plasma are combined with cations and in the venous blood the CO2 drives out the protein, which then circulates alone until the removal of the CO2 in the lungs, when it reassociates with the cations. The existence of combinations of protein with hydrogen- and hydroxyl-ions has been experimentally demonstrated. If the so-called alkali-globulin be considered to be an ion-protein, it must be remarked that no one has been able to determine the existence of such combinations in the case of the proteins of blood plasma; and, although considerations in general physiology have made it possible to postulate the existence of such combinations, the present data will not permit us to assume them for the blood plasma. Such a cation-globulin would be subject to a high degree of hydrolytic dissociation, with the production of an alkaline reaction. In short, though the general relations indicate that factors of association and dissociation control the transportation and discharge of the CO2, the actual definition of these factors is not now possible. In asphyxiation the blood-content of CO2 is increased from one-fourth to one-third, the oxygen -content falls to a trace. Death is due to lack of ^ There is a confusing difference in terminology regarding the reaction of the blood. "Some use the term alkalinity in the sense of titration alkalinity to indicate that the blood will neutralize a certain amount of weak acid. Others employ the term in its strict sense, as developed by modern physical chemistry, to indicate an excess of hydroxyl ions (OH — )^" (Howell). The latter view re- gards the blood as neutral but there seems little doubt that the amount of alkali in the blood as determined by titration is of much importance in regard to the neutralization of acid products. — Editor, 19 290 DISEASES CAUSED BY ORGAXIC AGENTS oxygen and not to the excess of CO2. If an animal be placed in an atmosphere containing 20 percent, or more of O, 76 percent, of N, and 4 per cent, of CO2 (the quantity in expired air), death will occur after a period of narcosis and this represents true CO2 poisoning. If an animal be placed in an atmosphere too low in oxygen, death ^^•ill result after a lapse of time and the blood will contain less CO2, as well as less O, than normal. Do disturbances exist in disease which act to reduce the exj^iration of CO2 more than the inspiration of O, to the end of CO2 congestion in the blood ? What is the extent of such CO2 congestion ? The conditions are divided into two groups: those in which the respiratory surface is dimin- ished and those in which the action of the heart is disturbed. Recent studies in the physiology of combustion have taught us the extent of the powers of ada))tation and comjDcnsation residing in the organs of circu- lation and respiration. In all probability, until these limits are reached, until the unit of blood is not aerated in the unit of time, an auto-intoxica- tion is not to be apprehended. Of gas analyses, either experimental or clinical, we have few, but it is fairly certain that five conditions may be met with: (a) The O-input and C02-output and the content of the blood in the two gases are normal. This has been found in several cases of emphysema and of heart disease, and indicates a complete sufficiency of the efforts at compensation, (b) The O-input and C02-output are normal, but the CO2 content of the venous blood is excessive. This has been noted in experimental disturbances of respiration, and indicates that the efforts at compensation were successful only when the level of CO2 in the venous blood was raised, (c) The O- input is normal, the C02-output reduced, the CO2 in the venous blood not increased. This has been found in some experimental pneumonias. (d) The O-input and C02-output are reduced. The CO2 is increased and the O reduced in the blood. This has been found in several cases of heart disease, (e) The O-input is much reduced, the C02-output re- duced, the O in the blood much reduced, the CO2 not increased. This has been found in some instances of experimental pneumothorax. CO2 intoxication could appear in (6) and (d) alone; intoxication from deficiency in O could occur in (<:/) and (e). Cyanosis is a sign of lack of O rather than of congestion with CO2. Considering the marked powers of adaptation and compensation, what we most need are repeated gas analyses to show what degrees of reduction in O-input and COg-retention in the blood exist, and with what symptoms and signs they are associated. In the ordinary cases of the types under consideration, the combustions of the body are normal. This does not indicate that there is no CO2 con- gestion — the over-flow of a stream will be the same over a high as over a low dam. It docs, however, indicate that the input of O is adequate and the total combustion normal; if these subjects are intoxicated it must be from simple COj-rctention. In acute experimental dyspnoea the protein metabolism is abnormally increased, the result of deficient oxygenation. The urine contains glucose and lactic acid, the results of lack of oxygen. In all these there is less to suggest that the subjects are in a direct sense suffering from intoxication with CO2 than to indicate lack of O. CO2- retention is accompanied by an increase in the molecular and ionic con- centration of the blood serum — a fact that is not yet understood. It is not A UTO-INTOXIC'A TIONS 291 to be denied that there is an intoxication with CO2 in these diseases, but we should realize how scant is our information of the actual conditions and how indefinitely it points to such an intoxication. The data certainly furnish no warrant for such generalizations as those contained in the statement of von Jaksch, that to C02-i'etention is to be ascribed the cellular degenerations sometimes seen in this class of cases. That there is a possibility of serious disturbance of metabolism in an organism whose venous blood is overloaded with CO2 is made obvious by the following consideration. The combustions of the body are acts of fermentation. Accumulation of the reaction products retards the velocity of fermen- tation. If now the venous blood be so charged with CO 2 as to take up no further gas from the tissues, an excess of the gas would accumulate and exert a retarding influence upon the reactions of combustion. The COg- content of the tissues is known to be much higher than in blood. We do not know that in any circulatory or respiratory diseases the blood-content rises to the height of the tissue-content, or that the latter is increased. Whether the retention of the products of the respiratory metabolism can be considered toxic apart from the CO2 is not known. Our present knowledge is negative; other toxic substances have never been demon- strated in expired air. Retention of Perspiration. — The natural interpretation of the cause of death from extensive superficial injury to the skin, as in burns, rests upon the abolition of the cutaneous function. The chief symptoms are quite like shock. They are not due to the retention of the normal perspiration, as the sweat is almost free of toxic action. There is a widespread notion that toxic volatile substances exist in the perspiration, but this is unsup- ported by data. The amount of gas-exchange that occurs in the cutaneous functions of higher animals is almost nil. The retention of water could not account for the symptoms nor the salts and organic substances known to be eliminated through the skin in the quantities and time concerned. That the simple retention of perspiration cannot be the factor is shown b,^- the experiments in which nearly the entire bodies of men were covered for days with rubber plaster and collodion, without producing any symptoms or signs of illness whatever. That rabbits die after being coated with varnish has been explained as the consequence of the paralysis of the vaso- motor system, whereby the heat dissipation is exaggerated beyond the power of compensation. We are thus driven to the assumption that widespread lesions of the skin cause disturbances in metaboHsm, which, acting with the disturbances in the vasomotor system, lead to the rapid collapse. We have no idea of the nature of these assumed disturbances in metabolism. That toxic substances are at work is shown by the widespread heemolyses, the acute degenerations of parenchymatous and muscular cells, and the rapid onset of these lesions and of the clinical symptoms. The hypothesis that the coagulations occurring in different parts of the body are due to an excess of fibrin ferment has not been proved. A burn must have a certain super- ficial extent in order to be fatal, but this cannot be related to a similar fractional destruction or alteration of erythrocytes. A much more rational explanation would be that the erythrocytes are affected while circulating through the burned areas. Thromboses are prominent in the pulmonary vessels, and these have been held to lead to an acute venous congestion and 292 DISEASES CAUSED BY ORGAXIC AGENTS arterial anremia. Acute venous congestion and arterial anremia due to other causes, however, do not produce the symptom-complex observed in burns. Retention Intoxication of Intestinal Origin. — Under a strict inter- pretation of the term, we have no evidence that such a thing as a retention of the intestinal excretions exists. The fa?ces contain the undigested and unabsorbed residue of the food; the alimentary juices; bacteria and the products of their metabolism; the unabsorbed gases of the atmosphere, mostly nitrogen, and the gases of fermentation and putrefaction; the unabsorbed salts of the diet, and the salts eliminated from the tract and glands; and a small, though undetermined, quantity of metabolic products. The bulk of the fa?ces is water and bacteria. Of the nitrogen of normal fseces, that of the digestive juices may comprise as much as one-sixth. Now the alimentary tract is, from the metabolic point of view, outside the body. The only true retention intoxication would therefore be such as results from the non-secretion of salt and the juices of the tract and the oifferent glands. Non-secretion of the gastric juice occurs as a nervous abnormality, independent of any lesion; it is not accompanied by signs of auto-intoxication. Of the non-secretion of the succus entericus we know nothing. In all probability, however, it would result simply in starvation. Eliminations of excretions stand obviously upon a totally different footing as regards their relations to auto-intoxications than the eliminations of secretions of physiological function. Abolition of the one results in a damming back; abolition of the other simply in the cessation of the particular function associated with it, though this may entrain a secondary auto-intoxication. The digestive juices in the lower intestines, after their functions are completed, are themselves the prey of putrefactive bacteria, and from this time are apparently to be ranked with the unabsorbed pro- tein. A retention intoxication from non-elimination of salts, particularly of iron and lime, is inconceivable. Of an intoxication resting upon the non-elimination of metabolic products we have no knowledge. All of the so-called retention intoxications of the alimentary tract are, so far as we have reliable evidence, due to the action of bacteria. Some foods are primarily toxic, others are directly indigestible. These and the bacterial decompositions should not be classed as retention intoxications. Suppression of Urine. — Under this term we understand the non-secre- tion of urine. The hypothesis that ursemia is simply a retention intoxica- tion, the result of the non-secretion of the urine, is incompatable with a number of well-determined facts. The anuria of hysteria probably repre- sents a pure non-secretion of urine without notable qualitative changes. There is no reason to believe that the functions of metabolism are repressed or altered ; we are simply dealing with a total inactivity of a healthy kid- ney, an inhibition doubtless of nervous origin. The suppression may be complete; there are many carefvilly controlled cases in which the anuria persisted for a number of days, in a few cases for over a week. In this type there are no symptoms of intoxication, and when secretion is re- established the urine is normal and the organs exhibit no signs of disease. Attacks of anuria may be of reflex origin ; the presence of a calculus in one kidney or ureter may for days inhibit secretion by the other kidney. Here, too, no signs of intoxication are present. Another form of non-secretion without intoxication is seen in acute cardiac dropsy, in which there may AUTO-INTOXICATIONS 293 be almost complete suppression of urine. Naturally the kidneys will become diseased from the passive congestion, but for some time they remain practically intact, and the slight amount of urine secreted may present no pathological changes but a trace of albumin and a few casts. This may persist for weeks without any indication of ura-mia, and, when later cardiac compensation is reestablished, the kidneys will often be found practically free of disease. Following the defervescence of fever in the infectious diseases, a marked output of urine often occurs, result- ing in the elimination of enormous amounts of organic constituents, whose retention has caused no signs of uraemia. Thus we must concede, that, with healthy kidneys, complete suppression is usually without any signs or symptoms of intoxication. In renal disease there is no parallelism between urgemia and retention. There are periods of almost complete anuria in subacute nephritis without symptoms of uraemia. Often in subacute nephritis anuria and uraemia go together, but many exceptions occur. A nephritic or cardio-nephlritic patient, dropsical to the last degree but free of uraemia, may be freed of his dropsy only to develop uraemia. The hypothesis is advanced that the diuresis, purgation, or diaphoresis, have brought into the circulation the poisons that lay concentrated in the tissues. This explanation will not hold, for unless it be shown that there is some co-efficient of distribution to account for such localization of the urinary constituents, we cannot with our knowledge of the circulation and of the laws of diffusion believe in it. Certainly if that explanation be true, the treatment of the uraemic attack by purging and sweating is dangerous. One reads a great deal of the retention of particular constituents with elimination of the water. Obviously such a condition could be but transient for the electrolytes, because it would lead soon to a condition of hyperisotonicity that we know to be impossible The organic constituents could be much longer retained without disturbing the osmotic conditions to a notable degree. But such retention must be analytically demon- strated by investigations under controlled conditions. The present data fail to substantiate the claim. A general consideration against the theory of simple retention is that it lays upon the kidneys no blame but that of a stoppage of the elimination; it reduces nephritis simply to a plugging of a filtering membrane. Exper- ience with nephritis surely suggests that the disturbances are more than a simple reduction in the power of elimination. Our knowledge of the toxicity of the normal urine does not support the idea that a simple retention would lead to an intoxication. The toxicity of the urine depends upon the fact that the urine is a hyperisotonic solution rich in potassium salts. Even this toxicity will practically disappear if the rate of injection be so slow that the cells have an opportunity to accommodate themselves to the new conditions. As a matter of fact, the whole line of reasoning on the urotoxic co-efficient presupposes a function of distoxication on the part of the kidney, — which is inadmissible in the theory of retention intoxication. It must be insisted that the urotoxic co-efficient of Bou- chard, as determined by the intravenous injection of urine into animals, is worthless; not over ten per cent, of the toxicity thus developed is due to the organic constituents; the main toxicity of the urine is that of a hypertonic solution rich in potassium salts. 294 DISEASES CAUSED BY ORGANIC AGENTS From the wider theoretical ]ioint of view, one can understand how a retention of urine could lead to tlisturbances in metabolism. If the organic constituents were retained to a g-veater degree than the water, the result would be to. increase the concentration of those substances in the body. Now the processes leading to the formation of these urinary constituents may be assumed to be of the nature of ferment reactions. The obvious result of an increase in the concentration of the products of the reaction would be to retard the reaction, that is, to retard the rapidity of catab- olism, and, in addition, to afford opportunities for qualitative variations. This is, of course, a pure speculation, but it is one based upon sound theory. SALTS. ACIDS, AND ALKALIES. The proper study of the relations of acids, alkalies, ions, and salts, by physico-chemical methods is quite recent. That they must possess re- lations of the greatest importance in disease may be confidently assumed. Of direct data almost none are available. Indeed, little of our present knowledge has been derived from studies on higher organisms. In the investigation on the actions of ions and salts on even lower organisms there is much confusion and not a little contradiction. The time has not yet arrived to attempt a discussion of the relations of these factors to dis- ease. At present, our knowledge of the relations of salts, alkalies, and acids in endogenous intoxications is limited to acidosis. Acidosis. — Under this term we group the disturbances in metabolism that result from the predominance of acids in catabolism. There is in the carnivorous organism always some such predominance, but one easily compensated for. The chief sources of acid are the following: (a) The acids of carbohydrate fermentation in the alimentary tract, {b) The sulphuric and phosphoric acids derived from the catabolism of common protein and nuclein respectively, (c) Lactic acid, (d) The members of the acetone group, diacetic and beta-oxybutyric acids, derived from the fats, (e) Other acids formed in the body — glycuronic, oxalic, uric, aro- matic oxy-acids, carbamic acid, and carbon dioxide — are apparently never concerned in the production of an acidosis. For the neutralization of these acids we have the excess of alkali contained in the mixed diet and in drinking-water; when these are insufficient, the fixed cations of the body and the ammonia of the metabolism. Obviously an acidosis may be inaugurated either by a deficiency in alkali or an excess in acids. The result will be the same whether acid be ingested or formed within the body. Experimentally an acidosis may be produced by the use of an ash- and alkali-free diet. Under these circumstances the sulphuric and phosphoric acids must combine with fixed cations withdrawn from the tissues, and ammonia withdrawn from the urea metabolism. After a certain number of days, no matter how normal the diet in other respects, severe symptoms appear in the peripheral neuro-muscular and central nervous systems, followed by death. In simple starvation the degree of acidosis is not marked, since the protein catabolism is low. Acidosis could occur only very late in a protein-free diet, since here too the protein catabolism is low. The human body cannot maintain the daily catabolism of a hundred A V TO-IN TOXICA riONS 295 grams of protein in the absence of ingested cations, without the development of an acidosis within a fortnight. In a similar manner, if a mineral acid be administered in quantity equal to that daily formed in the average metabolism, an acid intoxication will develop after a few days. The acids of carbohydrate fermentation arc ran^ly of pathological importance; they are easily oxidized and are rarely formed in (quantities so large as to constitute a menace. There is, however, a possibility that these acids may be responsible for some of the attacks of acidosis seen in childhood. Lactic acid may be derived either from protein or carbohy- drate; its constitution is very similar to that of alanine, a derivative of protein hydrolysis. Lactic acid is an intermediary product in the oxida- tion of glucose. It may theoretically be derived from the oxy-acids of the fatty acid series. In disease, it seems usually to have been derived from protein and sugar. The lactic acid formed within the alimentary tract is, apparently not a cause of acidosis. Most important are the members of the acetone group, which are most often concerned in the production of an acidosis. The ill effects of acidosis are not clearly understood. There are several chemical possibilities, (a) Acidosis may act simply by virtue of acidity. Difficult as it is to explain how large quantities of acids may be held com- bined in the blood after .a prolonged period of cation withdrawal, the postulated acidity of the blood must be first proven, and this cannot be done by determining that the carbon dioxide is reduced. That the blood may become acid shortly before the death of an animal with sulphuric acid poisoning, has been demonstrated. In any event, an acid reaction of the blood could be only a terminal phenomenon. (6) Acidosis may act through cation withdrawal. The reserve of cations in the body is limited. It is a postulate of physiology that there are cation -protein complexes in protoplasm. To .wdiat extent these might be assumed to be broken up cannot be conjectured. Very soon the supply of fixed cations is greatly reduced or fails, and from thence ammonia alone remains to combine with the acids. Ammonia does from the very beginning combine with a portion of the acid. What we do not understand are the relations of the ammonia to the fixed cations in the neutralization of the anions; no regularity is apparent in the fluctuations clinically observed. How the cation "withdrawal results in symptoms is totally obscure. It may be said that the withdrawal of fixed cations leads to protoplasmic disintegrations, to the suspensions of functions, and that the withdrawal of the ammonia from the urea metabolism gives rise to disturbances in the protein catabolism; but from such statements we obtain no exact or definite ideas. If the withdrawal of the cations be the condition underlying the symptoms of intoxication, one does not under- stand those cases in which the symptoms appear suddenly without having been preceded by a period of cation withdrawal. That the adminis- tration of alkalies does not always result in amelioration is no argument for or against this factor. (c) The acids may possess a toxicity 'per se. A certain toxicity has been made probable for the salts of /?-oxybutyric and diacetic acids. Normally the body possesses the power of oxidizing large quantities of these acids. We do not know whether we are dealing with such an overflooding that even the normal powers of oxidation are insufficient, or whether the body 290 DISEASES CAUSED BY ORGANIC AGENTS has lost, in part, its power of oxidation; weighty reasons favor the hitter. 11,, (d) It is theoretically possible that the internal gas-exchange should be disturbed, at least in the severe intoxications; and investigations have shown that under these circumstances the oxidations of the body may fall to less than one-half. Nevertheless, it is doubtful if this be an essential feature of the situation. CHAPTER XIV. AUTO-INTOXICATIONS ASSOCIATED WITH PROTEIN, PU- RIN, CARBOHYDRATE AND FAT METABOLISM. By ALONZO ENGLEBERT TAYLOR, M. D. The digestion of protein is an act of hydrolysis; the end-products are amido-acids. It has been shown that animals may be maintained in nitrogen balance on a diet whose sole nitrogen is present in the form of amido-acids. Under exceptional circumstances, native protein may pass through the intestinal mucosa into the circulations (for example, gelatine, egg albumin, and foreign serum), and be eliminated by the urine. The higher albumoses are absorbable; secondary albuminoses and peptones are readily absorbed. In the dog's stomach ligated at the pylorus, protein will be absorbed without the appearance of more than traces of amido- acids. If such a stomach be deprived of its return-circulation, amido- acids will accumulate in large quantities. From nutrose the human stomach will form amido-acids within two hours. The processes of protein catabolism may be discussed under the four end-products, urea, ammonia, purin bases, and kreatinin. The purin metabolism is really separate from the common protein metabolism and will be considered by itself. Urea. — Protein catabolism is chemically very similar to protein diges- tion; qualitatively we know of few distinctions. In metabolism, as in digestion, the end-products of the hydrolysis are amido-acids, simple and complex. In the aseptic autolysis of organs and in the rapid degenerations of tissue, amido-acids are found in large quantities. It must be further assumed that the dynamic factor is a ferment accelerating a slow hydroly- sis that can be demonstrated to occur whenever cells (protein) and water are mixed. The products of protein hydrolysis are subject to a variety of reactions, — disamidation, oxidation, anhydration, and reduction. It is obviously possible that these secondary reactions might be disturbed or insufficient, but our knowledge of these, in so far as they concern the elaboration of the nitrogen, is confined to the steps by which urea is formed from amido-acids. The liver is the chief seat of urea formation. Perfusion of the liver with the vegetable salts of ammonia, in particular the lactate, carbamate and carbonate, with the monamido-acids that are formed in the hydrolysis of protein, or with the poly-amido-acids like arginine, will result in the formation of urea. Liver pulp is able to convert these several substances into urea. There can be little doubt that these reactions are fermenta- tive, and consist of disamiclation and oxidation. In connection with the Eck fistula and extirpations of the liver, the elimination of urea sinks to a trace, while the blood becomes flooded with ammonium salts. We do not know experimentally where the quantities of ammonia (some 12 gm.) 297 298 DISEASES CAUSED BY ORGANIC AGENTS could be secured to furnish the material for the entire urea output; of amido-acid the necessary (juantitv is easily ayailable. Some ammonia comes to the liver through the ])ortal vein, some is formed in the liver, and a certain amount of amido-substance is withdrawn from the muscles by the venous blood. On purely theoretical grounds it would seem that most of the material should come to the liver from the general system through the arterial blood and that it should come rather in the form of amido- acids than as salts of ammonia. The liver is not the sole seat of urea formation; the excretion of urea never disappears entirely after the extirpation of the liver or its exclusion from the portal circulation. We have, in the different tissues, hydrolytic and oxidizing ferments, and to a certain extent the reactions probably occur in all tissues. That the kidneys are prominent in the synthesis of urea is not demonstrated. Ammonia. — The ammonia of the urine was once supposed to bear a reciprocal relation to the urea. According to this idea, if the diet were rich in vegetable salts of the fixed alkalies or in ingested fixed alkali, the urine would contain little or no ammonia; if the diet were poor in fixed alkalies or their vegetable salts, the urine would contain a large amount of ammonia, this being withdrawn from the urea metabolism to combine with the sulphuric and phosphoric acids derived from the oxidation of protein and nuclein, respectively. When herbivora, whose natural urine is very poor in ammonia, are starved, their urine contains notable amounts of ammonia in combination with the sulphuric and phosphoric acids derived from their own flesh. Of the importance of this factor there is no doubt, but it is ■not even the sole factor. The formation of diacetic and /?-oxybvityric acids in the intermediary metabolism is associated with an excess of ammo- nuria and may, indeed, except in so far as the acids are reduced to acetone, be measured by it. Normal urine contains a trace of acetone but neither of the acids. The absorption from the alimentary tract of the acid products of fermentation is accompanied by the binding of ammonia, of small moment normally. It is furthermore certain that if the forma- tion of urea is to be regarded as the conversion of ammonium salts into urea under the influence of enzymic acceleration, a certain amount of ammonia must remain in the circulation for the simple reason that the reaction is an incomplete and reversible one. This ammonia circulating in the blood-plasma would naturally be eliminated by the kidneys. The elimination of ammonia is subject to rather marked fluctuations, even ■when the subjects are upon a constant diet. INIasked pathological aug- mentations are in all probability connected always with acetone acidosis. Kreatinin. — Blood and muscles contain small quantities of kreatinin and larger quantities of the parent substance, kreatin; the urine contains kreatinin alone; kreatinin of urine is identical with that of muscle. Kreatin on administration is eliminated in part unchanged, in part as kreatinin; a fraction however is lost in the metabolism. It is possible that it has been converted either into purin or into urea. The natural interpretation of these relations would be that kreatin is formed from some protein of muscle and then elsewhere converted into kreatinin. The amount of kreatin and kreatinin is greater in the exhausted than in the resting muscle, but this does not appear to show itself in the total nitrogen or kreatinin output. Kreatinin, on hydrolysis in an alkaline reaction, is INTOXICATIONS IN GENERAL 299 split into urea and methyl-glycocoU, and this has been regarded as one of the possible sources of urea. I'ossibly the amounts concerned are too small to be noted under the conditions of the experiments. Disturbances in the Protein Metabolism Dependent on the In- put. — A diet devoid of protein means nitrogen starvation. If carbohydrate and fat be present in excess of the quota required for the maintenance of the body heat, the nitrogen output (urea) will sink far below the output in starvation. Insufficiency of protein is unfortunately of frequent occur- rence. Whether any people live for any length of time upon a ration con- taining less than 1 oz. (30 gm.) for a body weight of 150 lbs. (05 kilos) — the lowest known experimental figures — is not known. The results lead, so far as we know, to no auto-intoxication. Subnutrition is of grave con- sequences to children, less harmful to the aged. The most prominent result is the lowering of the resistance, particularly to the infections (starvation may be shown in animals to be accompanied by a reduction in the antibacterial properties of the blood) ; i. e., the full employment of the powers of compensation with respect to the diet diminishes the further available powers of compensation. Pronounced weakness attends such a diet, but prompt recovery follows on return to a normal diet. Important is one metabolic sign which those underfed in protein share with the con- valescent, — the retention of nitrogen on a ration that would not be suffi- cient to maintain a balance in the same individual in health and good nutrition. The results of an excess of protein have not been fully investigated. A man of 160 lbs. (70 kilos) can digest probably not over 2.2 lbs. (1 kilo) of protein per day. When an individual in good nutrition is placed upon a heavy protein diet, the usual result is that catabolism is exaggerated, so that the output equals the input and the body is upon a nitrogen balance. In an individual of superior powers of digestion, under forced feeding with carbonous as well as nitrogenous food, an appreciable retention of nitrogen may occur. This is not permanent for the healthy adult ; it dis- appears after the forced feeding is suspended, the products being elimi- nated by the urine. Such a retention of nitrogen is very easy to attain in children, but here it is largely permanent, represents a true flesh-mast, and is proportional to the growth and not to the input. The same thing is true to some extent of convalescents; until they have regained their normal musculature and body weight, the retention is likely to be permanent. In the aged such a retention is scarcely attainable. This retention is in the form of protein. It is in part carried in the blood plasma, the protein content being increased over the normal. (No in- crease in plasma protein leads to albuminuria.) The protein of the blood plasma is not a constant but a fluctuating quantity, being lowered in sickness and subnutrition and raised in supernutrition. In part, however, the excess of protein is carried in the tissues, especially in the muscles, which seem to possess powers of compensation. The muscle cells shrink in sickness, as has been shown by measurements ; and chemical analyses have shown, under these circumstances, a reduction in the nitrogen and an increase in the water. Supernutrition will result in aii increase in the size of the muscle fiber, and an increase in the nitrogen and a reduction in the water. We have no knowledge that the retained nitrogen is carried in any other form than as protein. This retention simply indicates an excess in 300 DISEASES CAUSED DY ORGANIC AGENTS the individual's powers of digestion and absorption over the power of disassiniihition; when the input falls holow the level of catabolism, the excess will be gradually removed until the individual is restored to the natural balance. Does the excessive ingestion of protein lead to abnormalities in the metabolism, to auto-intoxication ? There is now current in the laity, and also among many physicians, the idea that the heavy consumption of pro- tein is harmful, indeed the cause of widespread disease. It is supposed to be responsible for gout, innumerable ill-defined diatheses, arterio- sclerosis, nephritis, a large number of skin diseases, and, by extreme vegetarians, for an intoxication sui generis. For all these claims there is no adequate basis. The excess of protein is hydrolyzed, the body dis- plays the greatest vigilance in keeping the system in a nitrogen balance; to accomplish this means an expenditure of energy, which might be conceived to lead to some disturbance of function. With an increased protein ration the protein residue in the intestine is increased, affording a greater substratum for putrefactive processes. The products of the excessive protein metabolism have all to be eliminated, and this imposes an increased task upon the kidneys. If the products of protein metabolism be toxic, this toxicity must be exaggerated under an excessive protein diet. These considerations make it apparent that the excessive ingestion of protein might tend to alterations in metabolism and elimination that would constitute auto-intoxication. The question is again one of fact. Large classes have, since time immemorial, been accustomed to an excess of protein food. We have little exact information that this has produced disease. We have no exact evidence that a moderate excess of protein is the sole and direct cause of any known disease. There are, however, individuals who under such conditions are not well, suffer from headache and insomnia, have little spontaneity and initiative, are sluggish and uncomfortable, possibly morose, and who are relieved by reduction in the protein of the diet. There is, apparently, for each person a certain excess of protein that cannot be tolerated without disturbances m the sen- sations of health. Excesses of protein are borne badly by infants. What is commonly regarded as auto-intoxication following the excessive use of meat is usually indigestion and not a disturbed metabolism. The limits of digestion of protein are often more narrow than those for starch or fats. Disturbances of Protein Metabolism Independent of the Input. - — The retention of protein is seen only under few conditions. In youth this is of obvious purpose and is proportional to the growth. Following illness, subnutrition, and starvation, the body retains protein until it has returned to the normal. Under forced feeding, the body retains protein so long as the forced feeding is maintained. There is a current idea that the metabo- lism of the protein is often incomplete. Following the cessation of fever in the infectious diseases, an increased elimination of urea may be observed. It is believed that during the fever the catabolic processes were incomplete and that following the defervescence they are completed and the excess of urea eliminated. This explanation, like the one defining the condition as simply a retention due to renal insufficiency, is not supported by experimental work. The phenomenon is probably to be explained by the breaking down of the excessive number of leukocytes and other cells, INTOXICATIONS IN GENERAL 301 thus corresponding to the observed increased output of purin bodies and phosphoric acid. Excess of Protein Metabolism. — This is seen particularly in six groups of sickness: fevers, infections, neoplasms, the essential anaemias, exophthalmic goitre, and intoxications. As a rule in exaggerated protein catabolism, the secondary reactions are sufficient, and the nitrogen ap- pears the form of the normal end-products. Sometimes, however, the in- termediary products, amido-acids, appear in the urine. In some cases of acute atrophy of the liver, the nitrogen output in the urine will be very low at a time when the circulation is flooded with amido-acids; under these circumstances, these, as well as the end-products, fail of elimination. Fever, per se, increases the disintegration of protein. The high tem- perature increases the cellular disintegration and causes some cellular degeneration, the products of which are thrown into the circulation and there act to produce an increase in the nitrogen output. All fermentative reactions are accelerated by increase of temperature within certain limits, and it is theoretically possible that the increased combustions in simple fever are the direct result of this. To the possible objection that an in- crease in the temperature over the normal could not be supposed to accelerate a physiological function, it must be replied that for every fer- ment in the human body the optimum temperature is a number of degrees higher than that of the body. The febrile infectious diseases, especially of acute type, are accompanied by very marked increases in the protein catabolism. The relations vary for different days and periods; but if the input and output for the entire course of the disease be obtained, the fact in most instances is striking. Individuals of lean constitution are affected less than large, well-nourished subjects. The loss is greatest during the earlier stages of the disease. Rarely there is no nitrogen deficit. As a rule, the exaggeration of the pro- tein catabolism is more marked in the fevers than is the increase in the combustion of sugar and fat ; in moderate fever the combustion of fat and sugar is often normal. The deficit may mean a loss of protein to the body, but by increasing the diet the deficit may be abolished (even in the child), though it is usually possible only to minimize the loss. To accomplish this, much greater quantities of sugar and fat are necessary than would be needed in the normal subject. In other words, the protein-saving power of sugar and fat is reduced. An increase of the ingested protein in the febrile subject is not followed by an increase in the nitrogen output, at least not to the same extent. Thus, while sugar has lost a part of its power of saving protein, protein in the diet has acquired a power of sparing protein in the metabolism, — ^^vhich is best explained by the assumption that there is, as in subnutrition, a protein-deficit in the circulation which the excess of ingested protein simply makes good. Subjects ^^dth moder- ately severe infections of acute course will commonly lose from 5 to 8 gm. of nitrogen daily; severe cases from 10 to 15 gm. ; in extreme cases the loss may be as high as 20 gm. The afrebile infections have not been well studied. In chronic cases of tuberculosis, malaria, and syphilis, without any measurable fever and despite good feeding, we often see rapid and extensive emaciation of the muscular system, which must be accompanied by a nitrogen deficit. In lesions of the nervous system, as transverse myelitis, we often obsen'e a 302 DISEASES CAUSED BY ORGAXIC AGEXTS rapid and extensive muscuLir wasting; the muscle cells degenerate under the absence of the normal troj)hic influences, and the protein deriveil from their protoplasm would be disintegrated just as. though it were an excess protein ingested. In exophthalmic goitre we have a striking illustration of metabolic exaggeration. Associated with an excessive or perverted functionation of the thyroid botlv, the protein catabolism is exaggerated. There is a deficit of nitrogen, antl strenuous forced feeding (up to 60 cal. per kilo per day) may not maintain the body weight. Despite increased heat dissi- pation, the body tem})erature is normal or even increased. The exag- geration of the protein catabolism, while marked, is less extreme than the increased combustion of the carbohydrates and fats. The exaggeration of ])rotein catabolism may represent simply an attempt at a compensation for the exaggerated carbonous metabolism, an aid in the heat production. Possibly the condition may resemble starvation; since the sugar and fats are so abnormally burned, their sparing power on the protein metabolism would be wanting, just as in subnutrition with a low carbohydrate ration It may be possible that the exaggeration of the protein and the greater exaggeration of the carbonous metabolism are the common results of one cause. The thyroid body is now believed to possess an internal secretion that acts as an accelerator of protoplasmic combustions, the administra- tion of thyroid preparations and an excessive activity of the thyroid body lead to further exaggerations in the combustions. In other words, the thyroid body is conceived to supply a substance that acts as a zymo- excitor to the fermentative reactions comprised in the protein and carbon- ous metabolisms. The exaggerations that are observed in association with the essential ancomias are not dependent upon the aneemias per se, but upon the con- ditions underlying them. Simply anaemia and chlorosis present a normal metabolism. In pernicious anaemia and in leukaemia, the protein metabo- lism may be for long periods notably exaggerated and accompanied by a loss of body protein. All cases do not exhibit it at all times; one may obtain normal values, or indeed a nitrogen retention and the accumulation of flesh, during some periods of the disease. In the anaemias the exag- geration of the protein metabolism is not accompanied by a notable in- crease in the combustion of sugar and fat. A study of these diseases has led to the assumption that they are of toxic origin, and with this the exaggeration of the protein disassimilation is in good accord. In the cachexia of malignant diseases there is a notable exaggeration of the protein catabolism. It may be absent during periods of very chronic progress, but during active groAvth a nitrogen deficit is present, and this does not seem to be easily controlled by the ingestion of a luxurious carbon ration. These cases incline also to an excessive combustion, and may indeed, exhibit marked superoxidation. The relations of the tumor mass might be of influence. The reproduction of neoplasmic cells requires protein and this, if extensive, might be expected to tend to a nitrogen re- tention. The neoplasmic cells, hoAvever, are short lived and frequently degenerate en bloc, and this would lead to a nitrogen deficit. Intoxications. — Poisoning with exogenous substances (phosphorus, arsenic, chloroform and others) is accompanied by an exaggeration of the protein catabolism. As a rule the secondary oxidations are sufficient to INTOXICATIONS IN GENERAL 303 convert the amido-acids into the normal end-products, but in many cases these are to be found in the urine, while in the liver and blood amido-acids may be found in quantities. The urine contains lar<^e amounts of am- monia combined, not with acids of the acetone group, but rather with lactic acid and mineral acids derived from the disintegrated protein. The combustion of sugar may be reduced during the last perio(Js of the intoxi- cation. The respiratory exchange has been determined to be normal. Glycogen disappears from the liver and to a large extent from the muscles. The limit of assimilation for sugars is reduced, but the injection of jjhlorid- zin will not provoke glycosuria. The liver retains the power to conjugate aromatic bodies, but has lost the power of oxidizing benzol. The kidney loses the power of forming hippuric acid from benzoic acid and glycocoll. The brunt of the intoxication falls upon the protein metabolism. The excessive hydrolysis of protein is associated with exaggerated autolysis of the cells, particularly of the liver. That this postulated exaggeration of the autolysis of the liver occurs, is shown by the experimental fact that the aseptic postmortem autolysis of the liver is much more rapid in the case of phosphorus poisoning than in the normal liver. In a word, phosphorus poisoning acts like a fermentation. Acute yellow atrophy of the liver and acute pancreatitis resemble, in their chemical details, phosphorus poison- ing, and we are justified in the assumption that the acts of intoxication are similar. Whether these be due to bacterial or endogenous ferments can- not be stated. The mechanisms by which these exaggerations of the protein metabo- lisms are carried out have not been investigated for the various conditions. The following considerations deserve mention: The Fever, Per Se. — This is able to exaggerate to some degree the catabolism of protein. The Leukocytosis. — Associated with this is an excessive cytolysis, the products of which would enter the circulating plasma and be there subject to the same hydrolysis as protein from the diet. How extensive this may be we do not know, but in certain diseases it should not be a negligible quantity. The Cellular Exudates. — These, in pneumonia and septic collections, are unquestionably of great importance. During the period of resorption, the subject of a croupous pneumonia may resolve and disintegrate a kilo or more of cellular material, and in such cases the highest figures are obtained. The disintegration of such exudative collections could account for the protein deficit only during the stage of resolution, not during the stage of formation. Noav since the phenomenon is present during the stage of formation, when a nitrogen retention might have been expected, it is obvious that during that period some other active agent was in operation. The mechanism of the exaggeration of protein catabolism is here also simply that of flooding the circulation with the protoplasmic protein, which is then hydrolyzed like any excess however derived. Closely allied is the absorption of transudates, whose protein is thus added to the circulation. These fluids also contain urea, so the figures seem more striking than they really are, because this urea only balances a previous retention. An important factor is the toxic cellular degenerations, the exaggeration of the normal autolysis. In poisoning by phloridzin, toluylene-diamine, 304 DISEASES CAUSED BY ORGAXIC AGENTS nitro-benzol, and potassium chlorate, in addition to those previously mentioned, we find extensive and very rapid celhilar degenerations. The writer has recently seen cases of extreme degeneration of the liver occur- ring within three days of a chloroform narcosis. Similar conditions are found in acute yellow atrophy of the liver and in acute pancreatitis. These degenerated cells become an excess in the circidation and are then hydrolyzed and burned like any other excess of protein. Furthermore, there exists, particularly in the muscles, an emaciation of the cells without degeneration. That these cellular emaciations and degenerations exag- gerate the protein metabolism by casting into the circulation an excess of protein is shown l^y the fact that it is not possible by the administration of any amount of carbohydrate to spare the nitrogenous output as much as in health. Lastly, it is possible that there may be some direct influence on the reactions of the hydrolysis of protein, some accelerating influence of the nature of a zymo-excitor. The hypothetical substance could be derived from the metabolism of the bacteria, or less probably from the necrobiotic cells. It is conceded that this is a pure hypothesis, but it is high time that hypotheses derived from general chemistry and physics should receive some attention in these matters and not be entirely excluded by mechani- cal or vitalistic speculations. It is clear that an exaggeration of the protein catabolism bears no constant relation to any abnormality in the processes of carbonous com- bustion, and in particular one may not infer from the existence of such an exaggeration that a suboxidation is present. The failure to understand this has been responsible for much confusion. Cystinuria. — Cystinuria is a hereditary abnormality of the protein metabolism. Cystin is derived from protein ; it has been recovered follow- ing the acid hydrolysis of kreatin, hair, serum albumin, and edestin ; it has been found in the liver and kidney and among the products of the diges- tion of fibrin with pancreatin. The most obvious chemical mechanism for the formation of cystin in the body would be to assume that cystein is a normal product of protein disintegration, that it is oxidized to cysteinic acid, and this then converted into taurin by the splitting off of carbon dioxide, probably as a fermentative reaction. Under the pathological conditions in cystinuria, the cystein instead of being converted into taurin is converted into cystin by the union of two molecules, a sort of condensation. The administration of cholic acid to the cystinuric produces no increase m the cystinuria. Cystinuria is usually accom.panied by the excretion of pentamethylen- diamine and tetramethylendiamine. Since these ptomains are usually found as the results of putrefaction, the first inference was that the cys- tinuria was of intestinal origin. Cystinuria has been observed unaccom- panied by ptomainuria; the ptomainuria occurs in cholera and other conditions independent of cystinuria. These diamines may be recovered from the products of the tryptic or peptic digestion of protein (due to the fermentation of lysin and ornithin) and there is no reason why they may not be of metabolic derivation. Instead of terming cystinuria a condition of intestinal origin, it were better in these cases to locate the origin of the diamines in the tissues. Cystinurics are deficient in the faculty of oxi- dizing amido-acids. INTOXICATIONS IN GENERAL 305 In proportion to the quantity of the cystin, the neutral sulphur is in- creased at the expense of the sulphuric aeia. The amounts that may he eliminated are sometimes quite large, more than a gram p(;r day. A synthetic cystin-uramino acid is known, that is possibly contained in the normal urine. Occasionally calculi form in the kidneys or bladder. There are no symptoms of auto-intoxication and no known sequelae except calculi. The condition is not affected by any constituents in the diet; in particular, meat does not seem to cause any noteworthy increase. Alkaptonuria. — Idiopathic alkaptonuria is a family disease, consisting in the elimination in the urine of two aromatic derivatives, trioxyphenyl- propionic and dioxyphenylacetic acids. It was first thought that these were formed from tyrosin in the alimentary tract and then absorbed; experimental studies are opposed to this, as is also the occurrence of the condition in the new-born infant in an alkaptonuric family. Tyrosin is formed in the intestine as an end-product of tryptic digestion. From it phenol and cresol are derived by bacterial action through a reaction of disamidation. Tyrosin is formed in the body as an intermediary product of protein metabolism. If the amount be excessive, as in extensive tissue autolyses, tyrosin appears in the urine; otherwise it is oxidized. A normal individual is able to oxidize notable amounts of ingested tyrosin, and the abnormality in alkaptonuria consists, then, in the inability of the body to oxidize the tyrosin derivatives beyond the stage of dioxyphenylacetic acid, which is eliminated unchanged. The reaction is one of fermenta- tive order; a ferment is known in plants that converts tyrosin into dioxy- phenylacetic acid. The inability to further oxidize dioxyphenylacetic acid is seen in occasional cases of hepatic cirrhosis, tuberculous peritonitis, and diabetes. The abnormality is unquestionably situated in the inter- mediary protein metabolism. This anomaly is usually the only metabolic abnormality present and the subjects are entirely well. Uraemia. — Uraemia is here classed, without adequate experimental or chemical evidence, as an auto-intoxication of the protein metabolism, simply because this is the direction of least resistance. The carbonous metabolism is known to be normal. That the condition is an auto-intoxi- cation is provisionally proven by the resemblances of the symptoms to well-known exogenous intoxications. As stated, uraemia cannot be regarded as a simple retention intoxication; it is likewise not possible to incriminate any known normal constituent of the urine. Urea. — That urea cannot be the cause of uraemia is shown by its com- parative innocuousness. A toxic action is obtained only by the injection of large quantities, and the withdrawal of water. The injection of urea is followed by a vasomotor dilatation of the vessels of the kidney, but this has no bearing on the conception of uraemia. Animals bear such treat- ment without the slightest apparent result. A case has been reported in which, on the day following an eight-day anuria, nearly 150 grams of urea were eliminated. There is no parallelism between the occurrence of uraemia and the urea content of the blood. There may be retention with- out uraemia, uraemia may set in without retention. There is no relation between uraemia and dropsy. In subacute nephritis there is usually some retention during periods of uraemic intoxication, but this is coincident. Ammonia. — The theory that ammonium salts are the cause of uraemia is disproved by the simple fact that no such amounts of ammonia are to be 20 306 DISEASES CAUSED BY ORGANIC AGENTS found in the blood or urine. If it were true, then in acctone-acidosis we would have ura-mia, since here we have the largest quantities of ammonia in the blood and urine, and it would be immaterial for the causation of an intoxication whether the ammonia were withdrawn from the urea metabo- lism to be combuied with the fatty acids, or originated in a fermentative decomposition of urea or in its non-formation. That the ammonia might be sujjposed to circulate as the hydroxide is out of the question. Uraemia cannot be produced by the injection of salts of ammonia. Kreatinin and Kreatin. — The extractives are not responsible for urirmia. They arc not retained ])rior to the attack. In animals under ether antesthesia, the ajiplication of kreatinin to the exposed cortex causes spasms and convulsions, but since these may be provoked by innumerable substances, the conclusion that kreatinin is the poison in uraemia is un- warranted. The idea that the extractives bring about a condition of eclamptic irritability is not in harmony with the fact that the electrical irritability of the cortex is not increased after ligation of the ureters. Kreatinin and kreatin are not increased in the urine or blood during uraemia. The Salts, — Equally unsatisfactory is the theory that the toxic agents lie in the salts, particularly of potassium. If the salts be injected slowly and not in hypertonic solution, the tissues will accommodate themselves to very large quantities. Now in nephritis the accumulation is slow and hypertonicity is never produced, water is always retained in proportion. The more recent studies of the actions of salts have given no support to the saline theory of uraemia. There is no constant retention of salts in uraemia, no constant or notable hypertonicity of the blood, and the injections of hypertonic solutions will not provoke uraemia in nephrectom- ized animals. In acute and subacute nephritis the occurrence of uraemia seems to run parallel to the impermeability of the kidneys; in chronic interstitial nephritis no such relation is observed. We are entirely ignorant of the nature of this diminution of secretory power. There is no constant relationship between uraemia and the histological lesions in the kidneys. We are thus led to the conclusion that the causation of uraemia is to be sought neither in the retention of the total urinary secretion nor in the retention and toxic action of any known constituent. Consequently, since the end-products of protein metabolism cannot be held responsible, we must look for the agent in the intermediary metabolism. Three possi- bilities suggest themselves: (a) The functions of the kidney include an act of catabolism in which some intermediary product is converted into an end-product; in nephritis this fmiction would be to a certain extent non-operative and an intoxi- cation would result. This avoids entirely the difficulty of explaining why no intoxication is produced in the functional anuria. The studies on the total protein metabolism in nephritis have given very irregular results, and it is possible that an intoxication from some intermediary product could occur without leading to a marked nitrogen retention. (6) A metabolic anomaly lies behind the kidney, associated with the renal lesions as cause, effect, or correlation. This is a hypothetical propo- sition; we possess, however, a suggestive analogy. The intoxication that follows the switching of the liver out of the circulation is in many respects INTOXICATIONS IN GENERAL 307 like ursemia. An intoxication may be due to the ainrnoiiium carbamate and other ammonium salts, but the injection of these salts will not yield the full symptom-complex. The Eck fistula is well borne if the animal be given a little protein; coma and death occur early if much protein be administered; behind the known alterations is some abnormality in the intermediary metabolism (not a simple acidosis), and therein lies the un- known toxic agent. If now the hepatic artery be ligated, death occurs within a few hours under most excessive acidosis (not the acetone group), for which the available ammonia is insufficient. The loss of the hepatic circulation entrains greater disturbance of metabolism and intoxication than does the loss of the portal circulation, with its concomitant approxi- mate abolition of the formation of urea. (c) The kidneys possess an internal secretion necessary for the inter- mediary protein metabolism, the absence of which is followed by meta- bolic disturbances ending in intoxication. This theory avoids the difficulty of explaining the non-occurrence of uraemia following prolonged total retention; it is not irreconcilable with the observations that in some diseases, like pernicious anaemia, no ureemic symptoms appear, although the kidneys present extensive degenerations, while on the other hand uraemia may appear in some renal intoxications, as in cantharides poison- ing, that are accompanied with trifling lesions. The experimental findings have, in general, tended to speak in favor of this hypothesis; after neph- rotomy, life is prolonged and central symptoms ameliorated by the injection of renal extracts. Pertinent in this connection is the question of specific nephrotoxication, and the facts may be stated thus: it is not possible in animals to produce autonephrotoxins or isonephrotoxins; the injection of the blood serum of an animal with nephritis (spontaneous, or due to the injection of hetero- nephrotoxic serum or of chromium) into another animal is followed by signs of transient nephritis; chronic nephritis or uraemia is not estab- lished. It is apparent that nothing has been learned as yet that could be applied to the problem of ursemic intoxication. But the toxicity of the serum of animals with renal lesions for the kidneys of healthy animals, warns us that the relation of the kidney to the circulating blood is to be considered no more closely than the relation of the blood to the kidney. Conceding that we possess as yet no qualitative demonstration of the theory that the cause of uraemia lies in the intermediary protein metabo- lism, are there quantitative variations ? It is known that peculiar fluctua- tions in the nitrogen occur in nephritis; periods of retention are followed by periods of deficit, and these without any regular relation to the dropsy or to the symptoms of uraemia. No one can work with the nitrogen metabolism of nephritis without being convinced that there is something wrong which is not expressed in the end results except in an incidental manner. The influence of various diets on the metabolism of nephritis is not known ; we have only superficial studies on the relations of different diets to albuminuria. The albuminuria is of no metabolic consequence to a nephritic w^ho has moderate powers of digestion An excess of uric acid is often found in the blood in nephritis, but normal values are obtained in the urine. There is no evidence for the theory that nephritis is accom- panied by a retention of purin base. Acidosis is not present in ursemia, nor is the urinary elimination of ammonia particularly high. 308 DISEASES CAUSED BY ORGAXIC AGENTS Overexertion. — AYithin recent years we have learned of the existence in human beings of a condition termed autotyj^hization, apparently of autotoxie origin, resembling the surmcttagr of animals. It is seen follow- ing ])rolonged and abnormally heavy exertion. Unlike the surnininrjc of animals, it seems to have no relations to the diet. The symj)toms are fever of irregular type, headache, muscular prostration, albuminuria, sometimes an elimination of lactic acid, j)robably a slight excess in the nitrogen elimination, and often cardiac dilatation. Possibly the conditions that have been described in foot-ball players following severe games are related to surmrnacjc. The theory that the condition is due to an excess or abnormality in the kreatinin metabolism has failetl of confirmation by urinary analysis. The symptoms and attendant circumstances suggest an auto-intoxication but we have no exact knowledge of it. The acid intoxi- cation that occurs in herbivora, following excessive exercise, is a different complex. AUTO-INTOXICATION ASSOCIATED WITH THE PURIN METABOLISM. Concerned in this metabolism are the substances derived from the purih nucleus; uric acid; and several bases, xanthin, hypoxanthin, ade- nine, guanin, and thi'ee vegeta.ble bases, caffeine, theobromine, and theoj)hyllin, all methyl xanthins. The purin input consists of the nucleins and the preformed purin bodies contained in the diet, and the bases con- tained in tea, coffee, and cocoa. The purin input may vary with the diet, from nothing to 15 grains (1 gm.) per day. The nuclein is hydrolysed in the alimentary tract and split into purin bases, a pyrimidin complex, a pentose and phosphoric acid; the purins thus derived join, in their absorption, the preformed ]3urin of the diet. Whether any purins are oxidized or destroyed in the intestinal tract is not known. After absorption the purin may be used in the synthesis of nuclein, oxidized or eliminated unchanged. Ingested uric acid is eliminated in part unchanged, in part as urea; xanthin, hypoxanthin, and adenine are eliminated in part un- changed, in part as uric acid; the methyl-purins (caffeine, theobromine and theophyllin) are eliminated as methyl-xanthin and are not oxidized to uric acid. In a certain sense, therefore, all these bodies may be termed intermediary products; to what extent conversions occur we do not know. Obviously therefore the purin output on an ordinary diet comprises an exogenous and an endogenous fraction. For the purposes of clinical experimentation the exogenous purin may be excluded by the employment of a milk diet. Is the purin output derived solely from the input and nuclein catabolism or is uric acid formed by synthesis ? In other words, does the endogenous purin proceed entirely from the nucleinic metabolism, or is purin other- wise formed ? The hypothesis that uric acid may be formed by oxidation without the nucleinic metabolism is old, but has never been confirmed in an exact manner. Recent investigations however have shown that hypoxanthin is formed during the period of exercise of muscle, an im- portant observation whose bearing on the practical problems is not yet definable. Purin may be derived from purin and nuclein in the diet, from urea and lactic acid, and from the catabolism of nuclein; purin INTOXICATIONS IN GENERAL 309 bases may be (;liminate(l as derived from each of these three sources; they may also be converted into uric acid. Uric acid may be derived from the purin and nuclein input, from the nuclein catabolism, and by synthesis; uric acid may be ehminated as derived from these sources and may also be converted into urea There is no parallelism between leukocytosis and uric-acid output. The circulating leukocytes are but a fraction of the total leukocytes, and the assumption of a regular cytolysis ])roportional to the total increase is unfounded. In pneumonia the uric-acid output is parallel with the resorption of the exudate, not with the circulating leukocytes. The excess of uric acid to be seen in some cases of nephritis cannot be explained on any theory of leukocytosis or lymphatic activity. The excess of uric acid in dogs with an Eck fistula, following cauterization of the liver, and in acute yellow atrophy of the liver and phosphorus poisoning, cannot be reduced to the lymphatic system. Leukocytosis and an increased output of uric acid are correlated results of a common cause, but the latter can occur without the former. Our knowledge of the nuclein content of different tissues alone renders very improbable any theory that rests the production of uric acid upon the cytolysis of circulating lymphatic cells alone or even on the cytolysis of the whole lymphatic system. The purin metabolism is concerned with the nuclein of the entire body and not specifically with that of the lymphatic system. Is the purin absorbed from the alimentary tract utilized for the synthesis of nuclein; is it combined with the pyrimidin derivative, pentose, and phosphoric acid, to form nucleinic acid ? This is a crucial question. In health the intensity of the purin metabolism is quite constant. If the ingested purin be utilized in the synthesis of nucleinic acid, less would be required from other sources. That the body can easily synthesize purin directly is shown by the formation of nucleinic acid in the hatching chick, by the regular functionation of the purin output on a milk diet, and by direct prolonged experiments on growing animals. If now exogenous purin be utilized in the synthesis of nuclein, the exogenous purin of a particular diet cannot be subtracted from the total purin output in order to arrive at a figure for the purin output of endogenous origin. Since the increase of a purin input is followed by an increase in the output, it follows either that the purin metabolism behaves like the common protein metabo- lism — an excess of the substrate results in an acceleration of the catabo- lism — or else the absorbed excess is simply eliminated directly. This question of the utilization of ingested purin has not been definitely decided. In the writer's opinion the present evidence indicates that exogenous purin is not utilized in the synthesis of nuclein; the purin and pyrimidin rings are synthesized de novo from protein, the pentose from hexose, and these then combined with phosphoric acid to form the nucleinic acid. In all probability the purin metabolism, though it concerns a group of structures, is subject to exaggerations whenever abnormal excesses of cytolysis occur. The seat of the oxidation of purin bases to uric acid is not single, although the liver is particularly active in this function. Birds and dogs when deprived of liver are still able to secrete uric acid. That the hin- phatic structures have the power of effecting this oxidation has been experimentally shown. The older theory that the kidneys were the chief 310 DISEASES CAUSED BY ORGAXIC AGENTS seat of this oxidation is now entirely discredited. Of the relative pre- ponderance of the liver and lymphatic system in tins function we know nothing. This reaction is to be regarded as a fermentative oxidation, and we are not surprised that it shoidd not be localized in one organ The synthesis of uric acid occurs in birds only in the liver, and the same has been made very probable for the mammalian organism The oxidation of uric acid to urea has not been brought into definite connection with any organ. The liver, kidney, and muscle of the dog and pig have the power of thus oxidizing uric acid. The oxidation of uric acid to urea is probably not a pronounced })henomenon. AYhen a large single dose of uric acid is ingested it is converted in part into urea, but it is not known to what extent such conversions occur in the course of metabolism. It is certain that the purin output represents the larger part of the j)urin metabolism, {. e., an end rather than an intermediary product. Now these facts, apart from the light they may throw upon this complex problem, demonstrate one point of practical importance in the inter- pretation of urinary analysis. Without the purin input being known the estimation of the uric-acid excretion is worth nothing as evidence of the state of the purin metabolism. But with the purin input known (or ex- cluded), the estimation of the ^iric acid alone, or of the total purin, cannot be used to determine whether the purin output be normal, increased, or decreased, the purin metabolism normal or abnormal. The following diagram illustrates the facts of the purin input, metabolism, and output: Fig. 4. INPUT METABOLISM ^1 ■Tnii.r' ^ PURIN SYNTHESIS BASES PURIN - \(^ ~x" ^ -^ ^ ,('1 NUCLEINE PURIN URIC ACID UREA NUCLEINE lBases — ^ ^—"^ ^^..'^ ■^^ ^^ MUSCLE URIC X ACID ^ ... When one realizes that the output of uric acid and nuclein is related to respectively three and four variables, it is apparent that by no simple estimation of the output of uric acid or the total purin can a conclusion be drawn of the magnitude of nuclein metabolism, unless we control the other variables, which we are not able to do. We possess to-day no analytical, or, for human organisms, experimental method of determining the magnitude of the purin metabolism or the relations of output to metabolism. There is no constant relation between the purin and protein metabo- lisms or between the purin output and the urea or nitrogen output. It is possible by an arbitrary modification of the diet with respect to the in- gestion of common protein and nuclein ic tissue to vary the ratio within very wide limits; the urea uric-acid ratio gives no information of either INTOXICATIONS IN GENERAL 311 metabolism, it is a dietary index solely. While a certain amount of purin may be converted into urea and a certain amount of urea may be utilized in the synthesis of uric acid, the amount of nitrogen concerned is too small to affect the total nitrogen, while the relations of these two processes to the purin total are not known. The purin metabolism is, however, not entirely independent of the general metabolism, since a luxurious non-purin diet will reduce (that is spare) the purin output to a slight extent. In star- vation the purin output is not reduced corresponding to the reduction in the urea. The nucleinic metabolism is an integral part of the daily life of the cellular nuclei; it is not notably reduced in starvation or replaceable by any other metabolism, and has no role in the caloric or energetic aspect of general metabolism. In general language we may say that the cells that elaborate protein, sugar, and fat, for the purposes of the general metabolism, wear out in these efforts a certain amount of nuclein in their own internal mechanisms. Exceedingly important are the questions that relate to the form in which the uric acid circulates in the blood, its solubility, and the influence of the reaction of the blood upon these relations. We do not know in what form uric acid and the bases circulate in the blood This is a physico-chemical problem and it has never been investigated as such with proper methods. It is difficult to understand how, in a complex fluid like the blood, contain- ing electrolytes, colloids, and many amphoteric substances and practically saturated with a gas of acid reaction, a substance like uric acid, which contains no carboxyl groups and has an extremely low co-efficient of solu- bility and constant of dissociation, should be combined with a cation like sodium to form an electrolyte. It is quite certain that uric acid cannot circulate to any extent in the form of the di-sodium urate (a pronouncedly alkaline salt) or of the mono-sodium urate (a feebly alkaline salt); the so-called hemi-urate is a fiction Facts that have been demonstrated in researches on the purins point to a different conception. It has been long known that no known method of direct precipitation will throw down all the uric acid and purin bases in an extract of a tissue or in blood. It is now known that some of the pyrimidin derivatives of nuclein combine to form with uric acid complexes that do not give the ion reactions of uric acid and are not precipitable by the metallic salts, and of these substances one, thymic acid, has been identified. It is most natural to consider whether it may not be in some such form that uric acid circulates. Blood serum will dissolve forty times as much uric acid as distilled water (1 to 1,000 as against 1 to 40,000). This uric acid does not yield the ion reactions of uric acid, and can be recovered only after boiling with an acid ; obviously some complex combination needs to be split by hydrolysis. The fact that uric acid will crystallize out from the blood serum about a suspended thread is not a proof that the serum is saturated. It has been shown experimentally that such a serum will dissolve more uric acid. Analyses of uric acid in the blood are approximate only. Abnormal amounts have been determined to exist in most cases of acute gout, in many cases of nephritis, arteriosclerosis, pneumonia in the stage of re- sorption, in conditions associated with the disintegration of cellular exudates, following a meal rich in nuclein, and most markedlyin leukaemia. Whenever an increased blood-content is accompanied by an increased output, it may be reasonably inferred that an exaggerated nuclein metabo- 312 DISEASES CAUSED BY ORGAXIC AGENTS lism or purin inj)iit exists, "Whenever an increased content is not accom- panied h\ an increased output, as in gout and nephritis, there remain two possibiHties, — if one assumes tiiat the chemical form in which the uric acid circuh^tes is the same as in the normal, — a decreased oxidation of uric acid or a retention throuti'h failure of renal elimination. As regards gout, there is no evidence that the gouty individual displays any abnormality in the assimilation of purin ; the ingested purin is quanti- tatively absorbed from the digestive tract, as shown by the nitrogen balance and by the elimination of phosphoric acid. In some diet experi- ments the elimination of purin following the ingestion of sweetbreads was normal; in others there seemed to be a retention, the jihosphoric acid was eliminated but not the ])urin. AYhether such a failure could indicate a lack of oxygenation or a retention cannot be now decided. We need to know in detail how the gouty react in a c[uantitative and cjualitative manner to variations in the j)urin input. The once current notion that gout is the direct result of an excessive purin input is devoid of any experimental basis. Does the uric acid in the blood in gout circulate in the same form as normally ? This has been denied by those who would explain the excess in the blood without resting it upon a simple retention. We have no data tending to show that the solubility of uric acid in the blood is decreased in gout. The hypothesis of the dej^endence of this solubility on the phos- phates is a vague speculation. There is some evidence that the uric acid in the blood in leukaemia circulates in part in a form different from the normal. Is there a diminished power of elimination of uric acid fcr se in gout ? When we recall that from the purin output alone, even with a controlled purin input, the magnitude of the nuclein metabolism cannot be estimated, W'e realize that a retention cannot be thus.determined. Conceding that many cases of gout have renal lesions and that many cases of renal sclero- sis have urate depositions, it is still not possible to maintain that the excess of uric acid in the blood is the simple result of retention due to renal disease. The fact that the gouty kidney can eliminate an excess of uric acid after the ingestion of thymus, argues neither for nor against the theory, since a diseased organ may respond to extraordinary stimuli. On the contrary, the fact that in chronic nephritis the ingestion of thymus is followed by an increase in the blood-content as well as in the elimination, does not prove that the fault lies in the kidney. The renal theory of gout can be assumed only by postulating an elective type of purin nephritis. In chronic gout and in the intervals between the attacks in acute cases, the purin output is normal. Prior to the onset of an acute attack of gout there is a diminution in the uric-acid output, followed by an increase; it has not been shown that this bears constant relations to variations in the blood- content of uric acid. It is scarcely possible to believe that the attack is dependent upon the diminution in the output; the cpian titles concerned are too small to be the direct etiological factor. The depositions cut no figure in the cjuantitative relation; whether the urate depositions are ever absorbed with such rapidity and to such an extent as to show in the output is doubtful. Resolution in acute cases seems an act of phagocytosis rather than of solution. The deposition of urates is not the direct result of an excess of uric acid in the blood; they are absent in conditions other than gout, particularly INTOXICATIONS IN GENERAL 313 leuksemla, in which an excess is present in the blood, and occur most often in chronic gout in which there is no evidence that the uric acid in the blood is increased. Nor is the deposition to be explained by the coincidental occurrence of an excess of uric acid in the blood and a lesion in the tissues. Gout would be very easy of experimental production if nothing but an excess of uric acid in the blood and a local lesion were required. The formation of tophi must rest upon some physico-chemical basis of pre- cipitation and crystallization. That necrosis cannot be the sole sub- stratum is certain. These various facts compel us to assume that the actual etiology lies deeper than quantitative variations in the uric acid; the determining moment lies earlier in the purin metabolism. That these earlier factors may have relations to retention is not denied, but the retention is a result and not in itself an etiological factor. In a certain sense, the uric acid must be considered as the innocent weapon of the disease. The idea that the uric acid is itself the toxic agent, that it by a local action as uric acid inaugurates the local lesion, or that the local lesion is simply the reaction of the tissue to a crystallization of uric acid as a physico-chemical fact is contrary to our best knowledge. That the purin bases are devoid of that marked toxicity that was some time ago ascribed to them is now known; they are not in gout increased at the expense of the uric acid. The hypotheses concerning the morbid physiology of gout most in harmony with our chemical and experimental data are two: Gout is a disease of the intermediary purin metabolism; gout is an auto-intoxication. The first may be formulated in several ways. It may be assumed that products are elaborated in the purin metabolism which cause local in- flammations. It may be assumed that the uric acid normally circulates in combination in some pyrimidin complex, very soluble and easy of elimi- nation, possibly by virtue of some dissociation in the kidneys; in gout this combination would be lacking or so altered that the uric acid would circulate in a form more resistent to excretion. Such alterations as are postulated in this theory may be demonstrated. Substances exist, as formaldehyde, that will pair with purin s and thus protect them from further oxidation. Thymic acid combines with uric acid to form a large and stable complex which has totally different chemical relations than uric acid. The disturbance could be localized either in the processes of assimi- lation of ingested nucleins or in the cellular purin metabolism. It is con- ceivable that the oxidation of the absorbed purin bases might be altered and their utilization in the synthesis of nuclein might be abnormal. This would reduce gout to a disturbance within the realm of the purin input. This is unlikely, since practically all of the known disturbances of metabo- lism have been shown to reside in the intermediary metabolism, not in the processes of digestion and assimilation. It may be assumed that the dis- turbance in the purin metabolism postulated for gout is resident in the cellular nucleinic metabolism. The most recent theory rests upon the assumption that the formation of uric acid by oxidation of the nucleinic purin is more or less lowered and that instead, uric acid is formed by synthesis. Since, imder these circum- stances, the thymic acid with which the uric acid is held to circulate would not be available, the uric acid would circulate in a less soluble and elimin- 314 DISEASES CAUSED BY ORGAXIC AGENTS able and more easily precipitable form. The abnormality in the piirin metabolism would thus be a sort of retardation; the meehanism whereby the synthetic formation of uric acid would be increased is entirely obscure. The hypothesis that gout is an auto-intoxication other than in the purin metabolism is derived more from generalization than from research. It is conceivable that gout may be associated with tlisturbances in the common ])rotein metabolism. It has been established that there is during the acute attack of gout a nitrogen deficit that cannot be explained by any possible deviation in the purin metabolism, and suggests a toxic exaggeration of the protein catabolism. Between attacks a nitrogen retention is often observed which may represent simply the recovery of protein lost during the attack or a retention of the end-products of protein catabolism. Gas- tro-intestinal auto-intoxication might be supposed to produce deviations in the assimilation of ingested purin, local lesions favorable to the depo- sition of uric acid, and also conditions in the circulation unfavorable to solution and excretion. It is obvious that in the end any theory of auto- intoxication extraneous to the purin metabolism becomes merged into the theory of deviations in the intermediary metabolism, and since data are as yet entirely wanting, it is more logical to presume that the primary dis- turbance lies not without but within the purin metabolism. Oxaluria. — Oxaluria has been quite generally considered to hold some relation to the purin metabolism. There is no relation between the amount of oxalic acid in the urine and the quantity of crystals of calcium oxalate in the urinary sediment. Oxalic acid is formed in the normal body in the entire absence of the acid from the diet. Of the oxalic acid contained in the diet the larger part is destroyed in the alimentary tract. In all probability oxalic acid is not oxidized in the body. Oxaluria is no more common in the gouty than in others, and there is no clinical evidence of any relationship between oxaluria and disturbances of the purin metabolism. In so far as the common protein metabolism is concerned, oxalic acid is formed from gelatine and kreatin; it is experimentally not to be derived from any excess of fat or carbohydrate in the diet. There is no experi- mental evidence that it is, in the body, derived from glycuronic acid or bears any relations to it. Oxalic acid is likewise easily obtained from the higher fatty acids, but there is no evidence that it is in any way associated with the normal fat metabolism or the abnormal acetone acidosis. Lastly, oxalic acid might be derived, from the oxidation of oxy-acids such as lactic acid. In this manner it might be derived from sugar. It is apparent that these facts shed no light upon the symptom-complex of oxaluria. That this symptom-complex possesses anything but a definite objective character is freely admitted. In any event there is no reason to incriminate the oxalic acid In the quantities concerned it is innocuous and the symptoms currently attributed to the condition bear no resem- blance to oxalic acid poisoning. That calculi form is a chemical acci- dent. The most that may be claimed would be that the elimination of an excess of oxalic acid accompanies a symptom-complex, and may be assumed to indicate an underlying disturbance in metabolism. In which metabolism the assumed abnormality lies is not conjecturable. INTOXICATIONS IN GENERAL 315 AUTO-INTOXICATION ASSOCIATED WITH THE CARBOHYDRATE METABOLISM. The digestion of the starches and the higher sugars is an act of hydroly- sis. Ordinarily all the sugar absorbed (apart from pentoses) is in the form of hexose. It is possible under normal circumstances for higher sugars to be absorbed unchanged; the power of the alimentary tract to invert disaccharides is limited; beyond a certain point the sugar is absorbed unchanged. This mellituria is a strictly alimentary type; the sugar appears in the urine unchanged. In the common form of alimentary mellituria, the sugar in the urine is glucose, no matter what sugar was ingested. Normally no mellituria follows the ingestion of starch; time is the controlling factor in alimentary mellituria; if absorption be heavy in the unit of time, it will produce hyperglycsemia. The normal individual will not exhibit mellituria following the ingestion of 5 ozs. (150 gms.) of glucose or levulose or nearly double that amount of saccharose or maltose; milk sugar is often less well tolerated. The absorbed sugars are converted into glycogen but not all hexoses with equal readiness. Those sugars that undergo alcoholic fermentation, glucose and levulose, are easily converted; galactose slowly. The glyco- lytic fermentation takes place in the blood and general tissues, as well as in the liver, and the ferment and the conditions of its activity are the same throughout. It is not definitely known whether the different hexoses that are formed in the digestion of sugar (d-glucose, d-levulose and d-galac- tose) are absorbed unchanged or whether they are converted into d-glucose during the passage through the intestinal mucosa. In the event of their absorption unchanged they must be either converted into d-glucose in the liver or the liver must possess the faculty of forming glycogen from the different hexoses. According to our present evidence d-glucose is the combustion form of sugar; it is this hexose alone that is formed from glycogen, and the body unquestionably possesses the power directly, and probably indirectly, of converting the different hexoses into d-glucose. This is of practical importance, since it explains why the use of galactose or fructose is rarely of benefit to the diabetic; instead of burning the sugars directly, the body converts them into d-glucose. That the body can not only form d-glucose from d-galactose, but also form the latter from the former is shown by the synthesis of d-galactose in the central nervous system and in the breast glands. Following the conversion of glycogen into glucose, the latter is utilized in combustion for the maintenance of the body temperature and the for- mation of fat. The reactions of the combustion of glucose are not defin- itely known. According to recent work, ferments that convert glucose into alcohol are present in all tissues; an intermediary stage in the re- action is lactic acid. Recent experimental work has made it probable that the combustion of sugar in the body follows in a general manner the following scheme: glucose— ^lactic acid -methyl alcohol -^acetic acid — ^methane— »formic acid-^carbon dioxide and water, carbon dioxide being set free also with the appearance of alcohol and methane, water being evolved with the appearance of acetic and formic acid. The particular importance of this scheme of oxidation lies in the fact that it makes ethyl alcohol a normal intermediary product in the sugar metab- 31G DISEASES CAUSED BY ORGAXIC AGEXTS olism. Tlic combustion of sugar is an act of fermentation. For the maximum acceleration of the reaction, substances derived from two sources are necessary, — the muscles and the pancreas. We may regard the muscular enzyme as primary, and the pancreatic substance (that seems to be associated with the mtegrity of the islands of Langerhans) as a zvmo-excitor. It has not been proven that this relation is the sole one associated with the burning of sugar in the body, n )r is the loss of the power of burning sugar always associated with lesions in the pancreas. Were this ])roven the })roblem of the intermediate carbohydrate metab- olism would be greatly simplified. The process by which fats are formed out of sugar is not known. However this conversion is effected, the function is directly associated with the catabolic power of the carbohy- drate metabolism, just as is the formation of glycogen. Normally the body sugar is derived entirely from the carbohydrates of the diet. Tilany ]:»roteins contain preformed carbohydrate, which is avail- able for the formation of glycogen ; but the quantities are not large. It is, however, probable that when the sugar of the body is reduced, the body can secure it from other sources. For this })urpose the protein and the fats are available and if they cover the caloric needs of the body little sugar need be derived at all. That an animal, fed on sugar free protein, may retain a little carbon while eliminating all the nitrogen is true, but this retention is slight and transient. Animals fed on a carbohydrate free diet may display a glycogen content that suggests a formation from the protein of the diet, but the figures are not conclusive. It is an error to assume that the facts and interpretations in diabetes may be applied to the normal individual, since sugar starvation and the inability to oxidize sugar are totally different things. While recent experimental work has made it quite certain that in the depancreatized dog, sugar can be formed from amido-acids derived from protein, it is an equally certain experi- mental fact that in the normal dog, sugar is formed only from carbo- hydrate. No known disturbances follow the absence of carbohydrate from the diet. The use of carbohydrate alone (plus the necessary protein) to furnish the heat of the body seems equally harmless. When one recalls that the limit of assimilation of cane-sugar is some 200 grams, it is obvious that were an individual to supply his whole heat by the use of sugar, he would at each meal approach the limit of assimilation. This may be avoided by the substitution of starch for sugar and such a ration is ade- quate to the greatest physical exertion. If more carbohydrate be ingested than is necessary for the maintenance of the body heat, the remainder is converted into fat. The combustion of carbohydrate is determined not by the input but by the demands for heat and energy; to a small extent, however, the ingestion of an excess of carbohydrate may be followed by an increase in combustion, just as in the protein metabolism. Important for the estimation of the carbohydrate metabolism is a reduction of the limit of assimilation. This may be lowered to less than one-half the normal whh no signs of ill-health. This reduction is usually confined to glucose and saccharose, not to levulose and lactose. An alimentary mellituria associated with a starch diet is always pathological, indeed probably always diabetic. The best interpretation of the reduction of the limit of assimilation is that the power of the liver to convert a unit INTOXICATIONS IN GENERAL 317 of sugar into glycogen in the unit of time is reduced. Whether an ab- sorption of sugar by the lacteal instead of the portal system accounts for alimentary glycosuria is not known. A lowering of the limit of assimi- lation is regularly seen in exophthalmic goitre and often in alcoholism, gout, arteriosclerosis, lead poisoning, organic diseases of the liver, obesity, and in some of the psychfjses and organic diseases of the nervous system. A curious susceptibility to levulose has been observed in some cases of hepatic disease. The condition may be mild or pronounced and may be associated with a reduction in the power to burn sugar, but is in itself not associated with hyperglycfemia, apart from the period following the ingestion of the sugar. Superoxidation.^ — An excessive combustion of sugar is a common phenomenon. Most prominent in Graves's disease, it is seen also in infec- tious diseases, in severe ansemia, in malignant neoplasms, and in cachexia due to other causes. It is usually not marked in the febrile infectious diseases; the supercombustion is less marked than the exaggeration of protein catabolism. Though such a superoxidation of sugar usually accompanies fever, it does not in itself need to produce fever. The excess of combustion has apparently two causes: an exaggeration in the fermen- tative acceleration and the lowering in the saving power of sugar for pro- tein. The excessive combustion of sugar is in itself unattended with any untoward results, the body seems able to carry the process to the end- products of water and carbon dioxide; that the body may not be able to control the heat dissipation can be no fault of the carbohydrate metabo- lism. Sub oxidation. — A lessened combustion of sugar as a quantitative abnormality is, apart from acute conditions such as shock, hemorrhage, etc., probably met with only in true diabetes. In no other condition is there evidence that the body burns fat or protein to maintain the heat as the consequence of an inability to burn sugar. Since the combustion of sugar is a fermentation, the only dynamic explanation for the loss of the faculty, since the concentration of the sugar is not lowered, is to assume the loss of the ferment or of some zymo-excitor, or the presence of some condition in the system inimical to the action of the ferment. Glycosuria. — Glycosuria may be associated with normal or hyper- glycsemia. An increase of sugar in the blood may be due to an increased formation or a decreased oxidation. Glycosuria with a normal blood- content is probably associated with some abnormality in the renal functions. We have evidence that all these forms exist clinically. That of the number of non-diabetic glycosurias many are best explained as results of renal disturbances is certain. Glycosuria due to an increased for- mation of sugar may be due either to an excessive input, to an inability of the body to convert the absorbed sugar into glycogen, or to what might be termed an instability in the storage of glycogen. Sugar is known to circu- late in complex combinations (possibly colloidal), in fact the least part of the circulating sugar exists in the simple state. It is pertinent to inquire whether abnormalities in these relations, independent of hyperglycsemia, might not lead to renal elimination. Glycosuria per se need have no consequence to the metabolism. W'hile it is current teaching that hvper- glycsemia per se exerts a deleterious action upon the tissues, many indi- viduals have persistent glycosuria without signs of disturbance in the 318 DISEASES CAUSED BY ORGANIC AGENTS carbohydrate or other metabohsms. It is, however, possible experi- nientaliy to show that cells are quite sensitive to higher concentrations of sugar. Diabetes. — In diabetes arc concerned several disturbances of interme- diary metabolism : loss of the power of burning sugar; loss of the power in the liver of converting sugar into glycogen; loss of the power of con- verting sugar into fat; loss of the power of burning fat completely and in the normal manner; and a loss of the normal tendency to remain upon a minimum plane of carbohydrate metabolism when on a carbohydrate free diet. The ordinary distinction between diabetes and glycosuria, — the persistence of sugar in the urine (L e., hyperglyca?mia) following the with- drawal of carbohydrate from the diet — is convenient but pathologically inexact, since cases pass from one to the other side. The loss of the function of oxidizing sugar is a gradient in which the successive lapses may be grouped about as follows, in the order of their severity: The loss of the power of assimilating starch — mellituria after starch ingestion; reduction in the limit of assimilation of sugar to the point when any sugar causes a glycosuria; reduction in the assimilation of starch to the point when any starch is followed by glycosuria; the jiartial loss of the power of burning sugar; the loss of the power of burning sugar during exercise; the loss of the power of burning more sugar during fever; the loss of the saving power of carbohydrates on the protein metab- olism; and the total loss of all power of burning sugar. The last is extremely rare. The cases in which sugar no longer spares protein and supports in part fever and muscular exercise are uncommon. The suc- cession of losses in function do not necessarily occur in the order given and a function once lost may be regained. In proportion to the loss in the power to burn sugar, the heat of the body must be maintained by the com- bustion of protein and fat in the diet or from the body. The inability to convert sugar into glycogen is rarely lost, the tissues are not devoid of glycogen. The power of prompt conversion of alimentary sugar is lost. The power of formmg fats from sugar is reduced, in severe instances entirely absent. The origin of the excessive glycsemia is a fundamental problem in diabetes. It is now generally held that the quantities of sugar eliminated in severe diabetes on a carbohydrate free diet cannot be explained on the basis of the preformed glycogen and glycosides, or the preformed car- bohydrate contained in protein. The sugar must be derived from the protein or the fat. Under fat is understood fatty acid; though glycerine can be converted into fat, the available quantity is too low to make it of moment. Within recent years the views with reference to the formation of sugar from protein have undergone a change. Formerly it was assumed that protein Avas separated into a nitrogenous and non-nitrogenous moiety; from the latter the glycogen was derived directly. Recent studies have shown that the end-products of protein catabolism are amido-acids, and that the carbon as well as the nitrogen of the protein is to be found in these products. Consequently, the formation of sugar from protein means the formation of sugar from amido-acids. The experimental formation of sugar from amido-acids is an open question. It must be pointed out that all the substances theoretically regarded as intermediary stages in the formation of sugar from amido-acids are fatty acids that could be easily INTOXICATIONS IN GENERAL 319 derived from the fats. The formation pf sugar from protein in the diabetic body has been recently made probable by the study of the utili- zation of leucin and phenylalanine in the depancreatized dog. The fallowing facis speak for the formation of sugar from protein : The elimination of sugar in diabetes is often parallel to the protein catabolisrn • the ratio of glucose to nitrogen is often about 3 to 1 which corresponds to the relations in the molecule of protein. The ingestion of pure protein (as casein) is often followed by a proportional rise in the glycosuria; reduction of the protein in the diet will often lead to a diminution in the glycosuria. The glycosuria goes hand in hand with nitrogen deficit, if the j)rotein in the diet be insufficient. When starved animals freed of glycogen by strychnine are infected with the colon bacillus, their bodies [)resent more glycogen than the controls and this is held to have been derived from the products of excessive protein catabolism. The respiratory quotient in diabetes is low. In favor of the origin of the sugar from the fats are the following facts: In many of the worst instances of diabetes, especially experimental, the ratio of glucose to nitrogen is far higher than the ratio in protein, as high as 8 or 10 to 1 ; the sugar could not be derived from the protein except upon the assumption that a remarkable nitrogen retention has occurred. In many instances of ordinary diabetes the regular ratio speaks against a derivation of the sugar from the protein alone. The greatest glycosuria is often associated with the most marked excesses of fat combustion as revealed by the acidosis. The digestion of fatty acids with liver pulp yields sugar. Against the origin from protein speaks the practical impossibility of showing experimentally that a healthy animal ever derives sugar from protein, but it is going too far to apply these results unreservedly to the diabetic. Directly opposed is the fact that when the fatty acids held to be intermediary between leucin and alanine (capronic and propionic acids) are administered to diabetics, they appear in the urine as acetone and not as sugar. Opposed to the origin of sugar from fat is the fact that one cannot increase the glycosuria by increasing the fat in the diet. The ingestion of lecithin does increase the glycosuria. Some of these interpretations rest upon misconceptions of general metabolic relations. That the ingestion of protein may increase the gly- cosuria, while the ingestion of fat does not, cannot speak directly in favor of the origin of sugar from protein instead of fat, because the disinte- gration of protein within the body is proportional to the input while the combustion of fat is not proportional to or dependent upon the input. The ratio of nitrogen to sugar cannot be employed in favor of the origin of sugar from protein when the ratio is low, or the origin from fat when the ratio is high, because in neither case are we able to fix the relations of nitrogen input, retention, and output. The only proper standpoint is that the source of the excessive sugar in diabetes, whether from the protein or the fat, is undetermined. From theoretical relations, the origin of the sugar from fat would be the more simple, as we would have sugar derived normally from fat and representing the intermediary product of fat on the route to combustion ; in diabetes the loss of the power of burning glucose with the continuation of the conversion of fat to sugar would account for the hyperglycsemia, leaving more or less entirely to the pro- tein catabolism the heating of the body. On the other hand, since it seemis 320 DISEASES CAUSED BY OBGAXIC AGEXTS quite certain that norinally sugar is not formed from protein, we need in the diabetic the postidation that accompanying the non-oxidation of sugar is an abnormal formation of sugar (that cannot be burned) from the intermediary products of protein metaboHsm — just the converse of a com- pensatory mechanism. The crucial experiment would be the demon- stration that the diabetic man or dog during the course of the disease elaborates upon a protein diet more sugar than could be accounted for l)y the glycogen and other carbohydrates and the body fats; this experiment has been several times attempted in dogs, with negative results The gas-exchange is normal in diabetes, except in the attacks of coma, where it is probably subnormal. The carbonous metabolism is always unbalanced. The respiratory quotient is very low and is not raised by the ingestion of carbohydrate. With good powers of digestion it is usually possible to obtain a nitrogen balance, except in the periods of deteriora- tion. It recjuires much more protein than normal to accomplish this and this greater amount of protein is directly proportional to the gravity of the case. For this condition, which is an important practical one, we have first the explanation that fat does not equal sugar in its power of sparing protein. But only in the mild cases is this explanation sufficient; a diabetic will commonly have a nitrogen deficit on a diet of fat and protein such as would fully suffice for a normal individual. Those who consider that in diabetes sugar is regularl}^ formed from protein, explain this on the ground that the diabetic does not utilize the n on -nitrogenous moiety of the protein consumed. Those who incline to the view that the diabetic forms sugar from fat explain the condition by the assumption that the body has lost in part the power of burning fats, of which the acetone acidosis is an evidence, and this leaves a deficit that must be made good by the utili- zation of more protein. In attacks of diabetic coma the nitrogen deficit is most marked, so marked in fact that an additional explanation is usually sought in a toxic exaggeration of the protein catabolism. To what the toxic symptoms of diabetes are due is known only in part. In all probability the intoxications come rather from the perverted pro- tem and fat metabolism than from the suboxidation of sugar. The coma is an acidosis, due to the perversion of the fat catabolism. While there is no direct evidence that hyperglycsemia per se exerts a toxic action, the fact remains that the general condition of the diabetic is made worse and his power of burning sugar still further reduced by the ingestion of car- bohydrate, while the maintenance of a strict diet will ameliorate the symptoms and tend to a recovery of the power of burning sugar. Some of the toxic symptoms, as the disturbances in nutrition of tissues, are not related to the acidosis, the toxicity of the acetone bodies or to the hyper- glycaemia, but seem to rest upon some deeper abnormality in the protein metabolism. The investigations on diabetes teach another lesson. We hear so much of suboxidation, it seems as though it were supposed that the body would suffer such a condition without any attempt at a regulation. Now all these alterations in the protein and fat metabolism in diabetes are in a general sense simply the regulatory mechanism that prevents a sub- oxidation. There is a great leeway in the direction of increase in the physical dissipation of heat, there is much less in the direction of reduction. W'hen one main combustion is cut out, practically the full normal function INTOXICATIONS IN GENERAL 321 of heat production is thrown upon some other metabolism. There is no evidence that the diabetic attempts tc; minimize the results of the kjss of the power of burning sugar by restricting the dissipation of heat as the myxoedematous seem to do. Yet this would be directly the most saving act the body could attempt. AUTO-INTOXICATION ASSOCIATED WITH THE FAT METABO- LISM. The digestion of fat is an act of simple hydrolysis, the fats being split into the fatty acids and glycerine Fat is carried in the circulation partly in emulsion, favored by the colloidal nature of the blood plasma, but largely in solution. The fat in solution in the blood is dialyzable and apparently enters tho cells in that form, there to be in part reconverted into insoluble fat. Since it is easier to picture chemical reactions in a homog- enous rather than in a heterogenous system, we may assume that the fat is utilized in the metabolism in this soluble state of unknown nature. The process of formation of fat from sugar is not known ; it seems likely that it is formed indirectly from fatty acids derived from the partial oxidation of sugar. The seat of the conversion is also unknown, though the liver is credited with the function. That fat is normally formed from protein is very unlikely. Fat is the most potential form of carbonous food and is able to supply the entire caloric demands of the body. Nevertheless fats do not equal carbohydrates in the power of saving protein. The reaction of the combustion of fat is not known. A direct com- bustion could occur, successive CH2 groups being split off and burned. It is, however, a question whether a different procedure be not the true one. A trace of acetone is present in normal urine, derived from the reduction of diacetic acid. Whenever the fat catabolism is exaggerated, the acetone is increased and diacetic and /?-oxybutyric acids may appear. We do not know whether these substances are normal intermediary products in the fat combustion or products of an abnormal reaction of oxidation . If the acetone group represents an abnormal qualitative variation, it could be compared to cystin in the purin metabolism; if an intermediary product, it may be compared to leucin and tyrosin. Acetone itself is not oxidized in the body It is derived from aceto-acetic acid by reduction, carbon dioxide being split off. The diacetic acid is derived from /?-oxybutyric acid by oxidation. If these acids are normal products in the oxidation of fats, the reduction of diacetic acid to acetone is an abnormal reaction. Nevertheless, the normal trace of acetone is increased in every condition accompanied by an exaggeration in the combustion of fat. Normally /?-oxybutyric and diacetic acids, when ingested, are oxidized, no apprecia- ble reduction of the diacetic acid to acetone occurs. It is known that the normal body could not oxidize the quantities of these acids that are to be met with in the diabetic If the combustion of fats proceeded directly these oxy-acids would not be formed. There is some evidence that nor- mally the body does not oxidize butyric acid to oxy-butyric acid, but instead splits it into two molecules of acetic acid and bums these directly. Since the normal urine contains a trace of acetone, it is apparent that w'e have here a condition common enough in the domain of organic reactions, 21 322 DISEASES CAUSED BY ORGAMC AGEXTS where a major reaction is accompanied by a minor side reaction. In the state of the acetone complex, something converts the side reaction into the main reaction in the (juantitative sense. Suboxidation. — Of a suboxidation of fat Ave have no knowledge. There is no call for any oxidation of body-fat so long as the sugar and protein of the diet are sufficient to the caloric needs of the body. When the calories of the diet are presented partly in the form of fat, the diet-fat and not the body-fat is utilized. Superoxidation. — A .superoxidation of fat occurs under all circum- stances associated with a superoxidation of sugar if the sugar of the diet be insufficient. Except in Graves's disease and rai)itlly advancing ma- lignant neoplasms, it is usually possible, if the powers of digestion are normal, to administer such an amount of sugar and fat as to leave the body-fat intact. The greatest exaggeration of the fat catabolism is seen in tliabetes. Here it is always associated with an excessive utilization of protein from the diet or body. It is often impossible in a diabetic by the administration of fat to hold the catabolism to the level of the normal. More fat is furthermore utilized than is apparent in the respiratory ex- change. Superoxidation of fat is always associated with the appearance of the acetone bodies in the urine. This supports the theory that these acids are normal intermediary jiroducts in the fat catabolism. Their appearance indicates either some limit to their oxidation or an abnormality in the last stages of the reactions. The interpretation of this would obviously be totally different, depending on whether one considers that the fats are burned as such or converted into sugar. The formation of the acetone substances bears no known constant relation to the total combustion of fat; apparently it represents but a small fraction, the larger part proceeding to the natural end-products. In grave terminal diabetic coma, however, but little of the fat combustion reaches the final stage; it seems largely diverted in the acetone direction (1 mol. fat- — 4 mol. /5-oxybutyric acid). This of course does not furnish much heat, and is one reason why the protein catabolism is so exaggerated in these comas, since it is then the only metabolism that can furnish heat for the body. The Acetone Complex. — ^Under this term we group the associated elimination of acetone, diacetic acid, and ^-oxybutyric acids in the urine. The term acetone complex is coined to differentiate the condition from the acidosis due to other acids. Except in the last stages of diabetic coma, the acids circulate and are eliminated as salts. The acetone bodies are derived from the fats and not from the carbohydrates or protein. Perfusion of the liver with phenyl-amido-acids will yield acetone, and there is no bar chemically to its derivation from lactic acid. Clinically, in all the different groups of the acetone complex, when the condition is severe the acids accompany the acetone, and this speaks directly against the origin of the acetone from the protein catabolism in these cases. The current conception of the acetone complex connects with it dis- turbances in the carbohydrate metabolism in the sense that a cessation of the carbohydrate metabolism comprises the essential condition for the elimination of acetone, diacetic, and /J-oxybutyric acids, the oxidation of the higher fatty acids to carbon dioxide and water being only then com- pleted; when a certain amount of carbohydrate is simultaneously burned. INTOXICATIONS IN GENERAL 323 There are instances of aeetonuria in which this does not hold, and in which there are many things tending to prove the contrary. In phloridzin diabetes the acetone comj)Iex does not appear so long as the animals are in nitrogen balance, but appears with the installation of a nitrogen deficit. If a phloridzin dog be starved, the acetonuria disappears with the gly- cosuria. There are instances of the acetone complex in which there are no signs to indicate any disturbance in the carbohydrate metabolism, or indeed any exaggeration in fat combustion. Cases occur in which we have no evidence that the protein, carbohydrate or fat metabolism exhibit any quantitative variations, and only the fat metabolism displays this qualita- tive variation. Acidosis from any cause is very easily developed in child- hood and often to an exaggerated degree under even trivial illness. The origin of the acetone complex in diabetes would be simplified if we believed in the normal conversion of fats into sugar; an interruption in the com- bustion of the sugar would necessarily entrain a disturbance in the intermediary fat metabolism. Acetone Complex Associated with a Low Carbohydrate Combustion. — Starvation. — A few days after the withdrawal of food, the acetone group appears in the urine. When the stored glycogen is burned up, the heat must be derived from protein and fat, and since the nitrogen out- put is restricted, the bulk of the heating falls to the burning of the fats. It persists so long as the starvation continues. A pure protein diet or a protein-fat diet has the same result. In febrile diseases the complex is common. The fever makes large demands on the carbohydrate metabolism, the hepatic glycogen dis- appears, and, as the input is under these circumstances usually diminished, an exaggerated burden falls on the combustion of fats. /?-oxy butyric acid is rare in the febrile acetonuria; diacetic acid is often present. In diabetes the body seems to have lost in large part the normal power of burning diacetic and /?-oxybutyric acids. In diabetes, as in the two previous con- ditions, the administration of sugar will lov/er the output of the acetone substances. In severe cases the administration of sugar will not lower the output of the acetone substances, but this may be done by the adminis- tration of alcohol or glycuronic acid. Instances of Acetone Complex in which there is no Evidence that the Carbohydrate Metabohsm is Deranged. — In the cachexia of carci- noma, in severe infections, in atrophy of the gastric mucosa, in severe cases of anaemia accompanied by a rapid loss of flesh, we may encounter the acetone complex, it is rarely marked, /?-oxybutyric acid is usually absent while diacetic acid is not always present. In these cases the individuals are ingesting carbohydrate, there is no mellituria, there are no signs that the carbohydrate metabolism is exaggerated or depressed, there is nothing to indicate that there is in the body either a diminution of the glycogen or a loss of the power to convert it into sugar, to burn sugar, or convert it into fat. In this group the fat catabolism is abnormally in- creased, body fat is being burned. Instances of the Acetone Complex without Quantitative Alterations in Any Metabolism, with Normal Qualitative Protein and Carbohy- drate Metabolism. — Here are to be classed those seizures associated with marked gastro-intestinal symptoms. The subjects are usually m good health, the onset is sudden, the symptoms of irritation of the alimentary 324 DISEASES CAUSED BY ORGAXIC AGENTS tract are marked. There is pronounced urinary acidosis; grave nervous symptoms may supervene, even death. IMost of them yield })romj)tly on lavage of the stomach and colon, free purgation, and symptomatic treat- ment. INIany resemble exactly toxic gastro-enteritis but others are ob- viously something more. Fatal cases have been reported. Here also must be grouped the cases of recurrent vomiting in children associated \\itli this comi)lex. There are in these no symptoms of gastro-intestinal lesion; the vomiting is reflex in all likelihood. Probably related are the cases of convulsive pscudo-ejiileptic seizures associated with acetonuria. These subjects are all on ordinary mixed diet, have no glycosuria or albu- minuria, and usually recover under symptomatic treatment. The admin- istration of sugar does not affect the acetonuria. That they are ever of gastro-intestinal origin, in the sense that the acetone bodies are formed in the alimentary tract and then absorbed, is entirely without evidence; it has never been shown that these substances can be formed by any ab- normality of fat digestion or bacterial fermentation. The only logical explanation, if one inclines to a gastro-intestinal etiology, is to assume that a hypothetical gastro-intestinal auto-intoxication inaugurates sec- ondarily a perversion of the intermediary fat metabolism. In this connection the writer can report a controlled experimental obser- vation. A healthy man was placed on an ash-free diet composed of washed egg albumin (75 gm.), olive oil (120 gm.) and cane-sugar (250 gm.). A nitrogen balance was promptly established; the urine was in every way normal. On the seventh day, following the onset of prodromal nervous symptoms, a marked elimination of acetone and diacetic acid set in, following which the experiment was discontinued. The complex disappeared within a few hours after the ingestion of salt. No weight was lost. Here, therefore, the acetone complex was the result of with- drawal of salts and cations, of an acid intoxication. There is no reason to suppose that there was any qualitative or quantitative abnormality in either the protein or carbohydrate metabolism or any exaggeration in the fat combustion. A person on a normal diet of protein, in nitrogen balance, on 250 gm. of sugar and free from glycosuria, cannot be con- sidered to have any abnormality in those metabolisms upon which to rest an association with the acetone complex. Instances of Acetone Complex Associated with Disturbances in the Protein Metabolism. — There are now quite a number of cases reported in which following anaesthesia the patients suddenly pass into a state of intoxication, often with jaundice, acetone acidosis, the elimination of leucin and ty rosin in the urine, coma and death, with the finding of extensive degeneration of the liver at autopsy. In many cases following operations, particularly in children, a transient acetonuria occurs without dangerous symptoms These cases present no signs of abnormality in the carbohydrate metabolism. Hemorrhage into the large body cavities seems to be followed by acetonuria. An interestmg group of conditions in which the acetone complex may occur is seen in diverse exogenous intoxications with phosphorus, phlorid- zin, etc. It is not possible to believe in advance that these poisons act alike in this regard, nor can it be urged that they bring about a cessation or reduction of the carbohydrate metabolism. Very interesting is the acetonuria commonly seen on withdrawing morphine from an habitue; INTOXICATIONS IN GENERAL 325 if the drug be resumed the complex disappears. The logical interpretation is that the deviation in the fat combustion resulting in the acetone complex may be brought about by several causes. How these operate to disturb the intermediary fat metabolism is unknown; but that many cases exist in which the phenomenon cannot be explained as associated with any known abnormality in the carbohydrate metabolism must be obvious. Mode of Action of Intoxication in the Acetone Complex. — The mode of intoxication may be referable to the substances themselves or to their behavior as acids. The term acidosis expresses the view that in their behavior as acids lies the chief harm. Acetone is but slightly toxic. The salts of diacetic and /?-oxybutyric acid have some toxicity, which is prob- bably greater in the diabetic because of the inability to oxidize them. When one considers the really enormous quantities of the substances that may be voided in a day, one must hesitate to say that there can be no direct intoxication from them. The general interpretation is that these acids act by withdrawal of cations. How this leads to a secondary intoxication is not known, but it does so in experimental acid intoxication. That the acids circulate as such cannot be true, except during the closing hours of life. The carbon dioxide of the blood in diabetic coma has been found reduced to less than one-half the normal. This cannot be neces- sarily attributed to any alteration in the reaction of the blood and it is probably the result of moribund suboxidation. The sudden onset of symptoms in the acute cases can scarcely be explained on the ground of simple acidosis, yet alkali treatment is here most effective. It is a note- worthy fact that the injection of sodium bicarbonate is follov/ed as a rule by recovery in the non-diabetic cases, as an exception in diabetes — although this does not in itself antagonize the contention that the intoxi- cation is simply an acidosis. It is possible that an acidosis may be brought about by the reversed process: not by formation of organic fatty acids with secondary with- drawal of ammonia from the urea metabolism, but by the non-function- ation of the urea metabolism, whereby large amounts of ammonia are not utilized and thus bind fatty acids that would otherwise have been oxi- dized. In some severe hepatic diseases, unassociated with disturbances in the carbonous metabolism, acidosis appears and the attempt has been made to refer it to the abolition of the hepatic functions. PART V. DISEASES DUE TO VEGETABLE PAEASITES OTHEK THAN BACTERIA. By JAMES HOMER WRIGHT, A. M., M. D., Hon. S. D. (Harv.) In this section are considered certain general and local diseases due to infection with fungi and certain branching filamentous microorganisms which are classed by some writers also among the fungi, but which may be regarded as representing intermediate forms between the bacteria and the fungi. Various local fungus diseases of the skin, such as favus, pityriasis versicolor, and erythrasma, known collectively as the derma- tomycoses, are not included. Concerning the relationship and classification of the parasitic and pathogenic fungi, there is much uncertainty and lack of agreement among authorities. The subject has been thoroughly covered by Plaut,* Busse,^ and Ricketts.^ The theory of the etiological relationship of yeast-like fungi, or so- called blastomycetes, to malignant tumors now requires no further con- sideration than the statement that the results of all the most trustworthy work of the past few years have brought nothing in the support of the theory but have tended thoroughly to discredit it. CHAPTER XV. ACTINOMYCOSIS. Actinomycosis is a suppurative process combined with growth of con- nective tissue and characterized by the presence in the lesions of vegeta- tions or colonies of a specific microorganism, Actinomyces bovis. The disease may be local or general, subacute or chronic. It should be dis- tinguished from so-called pseudotuberculosis or Streptothrix or Clado- thrix infections or atypical actinomycosis. Such processes are considered in Chapter XVI, under the name of Nocardiosis. Actinomycosis affects man and certain mammals, particularly cattle, in which it has been called "lump jaw," or "big jaw." The disease has ^Handb. d. Path. Mikroorganismen. KoUe u. Wassermann, 1903, I, 526. ^ Handb. d. Path. Mikroorganismen. Kolle u. Wassermann, 1903, I, 661. ^Journal of Medical Research, 1901, VI. •' ' ' 327 328 DISEASES DUE TO VEGETABLE PARASITES a wide geographical tlistribution and is probably much more common in man than is generally recognized According to Erving/ one hundred cases in man had been observed in America up to December, 1901. In cattle, bovine actinomycosis had long been known chiefly as a form of sarcoma of the jaw, when Bollinger, in 1877, first clearly showed that the disease was due to infection with a vegetable parasite, to which Harz gave the name of Actinomyces bovis on account of the radiate structure of its colonies or vegetations in the tissues. Shortly after this, J. Israel described cases in man, which we now know to be actinomycosis, and also described the characteristic microorganism, which he regarded as the infectious agent, but he did not recognize its identity with the micro- organism described by Bollinger. The identity of the human and bovine disease was first pointed out by Ponfik." Etiology. — The specific infectious agent exists in the lesions and in the pus in the form of small whitish, or yellowish, irregular shaped granules varying in diameter from a fraction of a mm. to 1 or 2 mm. Larger granules are usually made up of aggregations of smaller ones so that they present a mulberry-shape. The granules may be soft and easily crushed or hard, resistant, and even calcareous. The essential element of the granules is a branching filamentous microorganism and certain trans- formation and degeneration products thereof. Typically the granules present the following peculiarities of structure under the microscope. Over more or less of the periphery of the granule, are closely set, hyaline, refringent, club-shaped bodies of varying size and thickness arranged in a radiate manner, while elsewhere the periphery is occupied by filaments of the microorganism likewise closely set together and disposed in a radiate manner. All transitions between the filaments and the club-shaped bodies may be present. Beneath this peripheral layer of radiating club-shaped bodies and filaments is a dense network of branching interlacing fila- ments, while the central part of the granule may be occupied by necrotic and degenerate filaments and pus cells. The club-shaped bodies develop out of the peripheral filaments by the latter becoming invested with a sheath of hyaline refringent material which is usually thickest at or near the distal extremity of the filaments, and thus club-shaped bodies with filaments in the centre are produced. The "clubs" may attain a thickness many times that of the filaments, which may degenerate and disappear from within them. This sheath formation may extend to the deeper lying filaments in the granule and these, likewise, may degenerate and become invisible so that the granule may finally be transformed into a mass of hyaline refringent substance and necrotic material, invested at the periphery with closely set radiating club-shaped bodies but without a trace of the filamentous microorganism out of which it was originally formed. In the "clubs," degenerate changes may occur whereby they acquire a lamellated structure or assume a variety of shapes and appear- ances. Eventually the granule may be absorbed or become calcified. The "clubs," or rays, are usually better developed in the granules in bovine lesions than in human lesions. In the latter they may be absent or poorly developed and the granules may consist entirely or chiefly of filaments. Certain cases in which the granules were destitute of "clubs' * Bulletin of the Johns Hopkins Hospital, 1902, XIII, 261. ^ Berlin Klin., Wochenschr., 1879, 345. A CTINOM YCOSIS 329 have been erroneously regarded as not cases of genuine actinomycosis and have been called pseudo-actinomycosis. This name has also been applied to certain suppurative conditions in which masses of various bacteria have been observed. Harz' regarded the "clubs" as organs of fructification, and Bostroem^ and others regarded them as degeneration products of the microorganism. In general, the club formation is most marked in lesions in which there is considerable development of connective tissue and in which the progress of the disease is slow, with manifest resistance on the part of the tissue to the spread of the process; while in relatively rapidly progressive cases or those in which there is little evidence of resistance on the part of the tissue to the infection, "clubs" may be wanting on the granules. The writer^ has shown that blood serum and serous pleuritic fluids are capable of provoking club formation by filaments in artificial growths of the microorganism that had been immersed in these fluids. From these facts and observations it seems probable that the club formation is a protective device, adopted by the microorganism to protect for a time the main mass of the microorganism constituting the granule from the destructive action of the tissue cells and juices. Concerning the biology of the specific microorganism of actinomycosis, much confusion has existed for a long time and much that is erroneous has been written. Many workers have made culture experiments with the microorganism with very varying and often contradictory results. The subject has been further confused by classing with actinomycosis certain other suppurative processes due to infection with branching microorganisms which are widely difl^erent from the specific micro- organism of actinomycosis, and should be called Nocardia. The various branching microorganisms claimed to have been isolated in cultures from actinomycotic lesions, and to represent the microorgan- ism of the lesions, may be roughly divided into two groups. All of these at some stage in their developmental cycle occur in filamentous forms, without sheaths or septa, and of a thickness of a medium sized bacillus. They are distinguished from the bacteria by their peculiarity of truly branching, and may be regarded as occupying a position in the botanical kingdom between the bacteria, on the one hand, and the hyphomycetes or mould fungi, on the other. One group is represented by the micro- organisms described by Bostroem,* and a few others; the other group, by the microorganisms of Wolff and Israel,^ the writer,^ and many others. The first mentioned group grow readily on all culture media, both at the room temperature and in the incubator. Their chief characteristic is the formation in cultures of spherical, spore-like, reproductive elements out of the substance of their filaments. None of this group are known to be capable of producing in animals inoculated with them, lesions like actinomycosis and containing the characteristic granules. ^Jahresber. Thierarzneischule. Milnchen, 1877-1878; Deutsch Zeitschr. Thiermed., 1879, V, Suppl. heft., 125. ^Beitr. Path. Anat. u. allgem. Path., 1891, IX, 1. ^"The Biology of the Microorganism of Actinomycosis," The Samuel D. Gross Prize Essay, Journal of Medical Research, 1905, XIII, 349. *Beitzr. z. Path. Anat. u. z. Allgem. Path., 1891, IX, I. 5 Virchow. Arch., 1891, CXXVI, II. "^Loc. at. 330 DISEASES DUE TO VEGETABLE PARASITES The memoers of the other group do not grow on all the usual culture media and only feebly or not at all at room temperature. They do not form spore-like reproductive elements. Some of them have been shown to produce in animals inoculated with them, lesions essentially identical with those of typiciil actinomycosis although not of a jirogressive character. The subject of the biology of the microorganism of actinomycosis has recently been discussed by the writer, who concludes, from his own culture experiments and the analysis of the work of many others, that only one species of microorganism, Actinomyces bovis, represents the specific infectious agent of true actinomycosis in man and animals.. This microorganism has properties essentially like those of the second group above mentioned. The microorganisms of the first group, des- cribed by Bostroem and others, should not be considered as representing the micro5rganisms in the lesions, but are to be regarded as secondary invaders of the lesions or extraneous microorganisms accidentally infecting the cultures. Concerning the mode of entrance of actinomyces into the tissues, it is generally taught and believed that this microorganism is widely dis- tributed in the outer world on grains and vegetable material and that it is carried into the tissues by penetrating foreign bodies of this kind, upon which it has its normal habitat. This idea is based on the following considerations: The frequent occurrence of such foreign bodies in actinomycotic lesions; a history, in many cases, of the patient having taken uncooked grains or other vegetable material into the mouth; the occurrence of pulmonary actinomycosis in those who have breathed the dust of dried grains; the occurrence in the outer world, upon grains and grasses, of microorgan- isms with biological characters similar to, or identical with, those of the first group above mentioned — which Bostroem, Gasperini and others claim to have isolated from actinomycotic lesions; the almost exclusive origin of actinomycotic lesions in the tissues and structures associated with the respiratory or alimentary tracts. This widely accepted idea is erroneous, because Actinomyces bovis does not have the biological characters of this saprophytic group as- signed to it by Bostroem and a few others whose culture Avork is open to doubt, but has biological characters which would suggest that it does not have its normal habitat outside the body. The specific microorganism of actinomycosis probably exists normally among the abundant flora of the secretions of the alimentary tract, where it has not been recognized because it exists there in a form which is not characteristic and very un- like that which it assumes in the lesions; it may gain entrance to the tissues through wounds, made by penetrating foreign bodies or otherwise, or through lesions due to carious teeth, or may invade the lungs as do other bacteria of the mouth and pharynx; in the tissues, under certain conditions it develops into the characteristic colonies or granules and by further proliferation gives rise to the disease. The disease in and about the jaw is frequently associated with carious teeth. Besides the specific and characteristic microorganism, various bacteria are also present in the lesions in many, if not most, cases of actinomycosis, and it seems very probable that these play an important part in the pro- duction of the disease in these cases. ACTINOMYCOSIS 331 Contagiousness has not been shown for actinomycosis. The small amount of evidence tending to show that it is contagious will not stand critical examination and there is much direct evidence that it is not. Many experimenters have attempted to reproduce the disease by inoculating animals with material from actinomycotic lesions, but the results of most of them have been negative or ambiguous. Only a few report results that apparently constitute a true reproduction of the disease. In view of the low degree of virulence thus manifested by Actinomyces bovis in healthy experimental animals, it would seem that the occurrence of the natural disease must be due in large measure to thie existence of an individual susceptibility to the infection. Thus it is most frequent in individuals living under unfavorable hygienic conditions. Infection from drinking milk and eating the flesh of diseased animals has never been proved. It is claimed that more cases of the disease are found among persons living in cities and that it is more frequent in the months from August to January. It is more frequent in men than in women and in the middle decades of life. Special Pathology. — The essential effects produced in the tissues by actinomyees are suppuration and tissue destruction, combined, in most cases, with new formation of granulation and connective tissue. In some cases the new formation of connective tissue may be excessive in amount, and thus simulate a neoplasm. The granulation tissue usually contains many large cells filled with fat globules. Giant cells may also be present. The area of tissue affected by a given vegetation or colony of Actino- myces bovis is usually many times greater than the colony, the poisonous and irritative action of the parasite affecting a wide area of the surround- ing tissue. Almost any organ or part of the body may be the seat of the lesions. The extension of the actinomycotic process takes place both by continuity of the lesions and by metastases, the latter almost always occurring by way of the bloodvessels. In the lung the process may also be disseminated by way of the bronchi. The extension by continuity probably takes place by means of the separation from a colony of fila- ments and fragments of the microorganism, and the transportation of these in some unknown manner into the neighboring tissue, where they form new colonies and produce more foci of suppuration, tissue destruc- tion and inflammatory reaction on the part of the surrounding connective tissue. In this way large portions of an organ or region may become re- placed by granulation and connective tissue, enclosing pus cavities; or large abscesses may be formed having the characters of cold abscesses. The small abscesses enclosed in the granulation and connective tissue often communicate with one another and may form sinuses discharging pus and inflammatory products. The small abscesses, with their associated connective tissue, may become very numerous and closely set together so that a focal lesion may arise, having the gross appearance of a sponge-like mass of connective tissue saturated with pus. This is typically seen in actinomycosis of the liver. A wide extension by continuity over extensive areas and to distant portions of the body, and the formation of suppura- tive tracts and of sinuses, opening either on the skin or in mucous mem- branes, is a marked feature of the disease. Another marked feature is that the older lesions may heal by cicatrization and the dying out and 332 DISEASES DUE TO VEGETABLE PARASITES absorption of the inicroorgaiiism, so that it may happen that the starting point of an extensive process may be difHcult or impossible to find Com- plete healing nia}' occur spontaneously through the death and destruction of the microorganism in the lesions and by its extrusion from the body by the way of sinuses or fistuhe. Extension by metastasis takes place by the rupture of a focal lesion into a bloodvessel, thus discharging the parasite into the circulating blood, whereby the lesions may be widely disseminated throughout the body, affecting first the lungs, if a vein of the systemic system is involved, or the liver, if a vein in the portal system. Among many other possible localizations of metastatic lesions, the brain, the heart and the extremities may be mentioned. In the heart the lesions may take the form of tumor- like masses projecting into its cavities from the walls. In these embolic disseminated cases, the process may have the character of multiple subacute abscess formation and thus be essentially a subacute pysemia. Extension by the lymphatics and involvement of lymphatic glands is very exceptional, if it occurs at all. In extensive chronic cases amyloid infiltration ma}'^ occur. Carcinoma has been observed to develop in old lesions in a few cases. According to the point of origin or the principal location of the lesions, four forms of the diseases may be differentiated; viz., head and neck, thoracic, abdominal and cutaneous. Actinomycosis of the Head and Neck. — More than half of all the cases in man are of this form. It includes those in which are involved the struc- tures in relation with the buccal and pharyngeal cavities, the tongue, the soft parts and the skin of the face and neck, the bones of the skull and jaws, the larynx, the thyroid, the lachrymal ducts and the brain. In these cases there may be extension to the meninges and brain through the skull or down the prevertebral space to the mediastinum and more distant parts. With the exception of the localizations in the lachrymal duct and in the brain by metastasis, it seems probable that the process in nearly all, if not all, cases of this form of the disease originates in the tissues immediately about the buccal and pharyngeal cavities. Cases in which this mode of origin is not obvious may be explained by the healing of earlier lesions. So-called primary cutaneous actinomycosis of the head or neck is open to ciuestion as to its origin in the skin in these situations. Lesions in the brain are usually metastatic. Only one case of apparently primary actino- mycosis of the brain is known. The muscular, bony and other tissues may be extensively replaced by granulation and connective tissue enclosing suppurative foci, abscess cavities, and sinuses. The inflammatory tissue and infiltration may be excessive in amount, characteristically forming brawny indurations or sarcoma-like infiltrations and swellings in the parts affected. The skin over these may be oedematous, of a bluish or reddish color, and may pre- sent projecting folds or elevations with furrows between. Here and there points of suppuration, or the orifices of sinuses surrounded by red granu- lation tissue, may be apparent. In less extensive cases the inflammatory process may be insignificant and may heal spontaneously. Primary involvement of the jaw bones is rare. In the brain the lesions may be like abscesses or cystic cavities filled with a gelatinous grayish-yellow substance. ACTINOMYCOSIS 333 Thoracic Actinomycosis.— About 15 per cent, of all cases in man are of this form. In most cases the lungs are the seat of lesions which consist chiefly of abscess and cavity formation, usually combined with the growth of granulation and connective tissue at the expense of the pul- monary tissue, so that larger or smaller portions of the lungs may be trans- formed into fibrous tissue permeated with cavities and sinuses. The cavities, as a rule, are small. The inferior are more frecjuently affected than are the superior lobes. Lesions of the bronchi may be extensive. The rupture of a focal lesion into a bronchus often leads to dissemination of the process by way of the bronchial tree. The disease may originate in the bronchi, from the oesophagus, or from lesions involving the neck by extension downward into the mediastinum, or by extension upward from lesions in the abdomen, or by metastasis. From these situations the process may extend widely and involve the lungs and thoracic wall, pro- ducing retraction and deformity of the chest. The initial and intermediate lesions in the evolution of the process may be healed and be neither obvious nor demonstrable. Cases of so-called primary cutaneous actinomycosis of the thorax probably represent an extension from within outward. The extension of the process through the wall of the thorax and the production on the exterior of the body of swollen and indurated areas in which are the orifices of sinuses, are char- acteristic features of this form of actinomycosis. These sinuses may open in the epigastrium as well as on the thorax. In the pleural cavities an accumulation of serous fluids may occur, and empyema has been observed. The disease may extend from the medias- tinum to involve the pericardium and heart. As in the lung, the lesions consist essentially in extensive replacement of the natural structures of the parts by inflammatory tissue in which are abscesses and sinuses._ Abdominal Actinomycosis.— About 20 per cent, of all cases in man are of this form. Any organ or region of the abdominal portion of the body may be affected and the lesions are very varied in character. The process may arise by extension from the thorax, by metastases or by in- fection from the gastro-intestinal canal. It is probable that primary ac- tinomycosis of the abdomen is always due to infection from the stomach or intestines and that the starting point in these situations, when not de- monstrable, has been a lesion that has healed. Primary lesions in the intestine appear as ulcerative processes. The most frequent localization of the primary disease in the abdominal form is in the region of the csecum and vermiform appendix. From the intestine the disease usually extends— producing fibrous adhesions, sup- purative foci and abscesses between intestinal coils — to the abdominal wall, most frequently in the right anterior half. Here the muscular and other tissues become replaced by inflammatory connective tissue in which are abscesses, sinuses, and intestinal fistulse. The portions of the abdo- minal wall involved becomes brawny, and the amount of inflammatory connective tissue produced may give the appearance of a fibrous neo- plasm. The skin over the affected region may be red, oedematous, and contain fluctuating suppurative foci which by their rupture become the orifices of sinuses and fistulae. Peritoneal abscesses may rupture into the intestine or bladder. From the abdominal wall the process may travel further and produce extensive 334 DISEASES DUE TO VEGETABLE PARASITES suppurating necrotic tracts extending througli the crural ring or along the psoas muscle to the hip-joint. The process may also spread from the intestinal canal along the retroperitoneal tissues, producing exten- sive destruction of the nuiscles and bone in this region, and eventually involve the thorax, or extend down into the ischio-rectal fossa and per- forate the skin in the region of the anus. Any of the abdominal or pelvic organs may become involvetl by direct extension of the process. A frequent location of the lesions is in the liver, in which the foci may be single or multiple and are sometimes of large size. The lesions in the liver present the appearance of a sponge-work or honeycomb structure of con- nective tissue saturated with pus. They frequently arise from metastasis through the portal system as well as by direct extension. Cases of so-called primary actinomycosis of the liver have probably arisen by metastases from healed or unrecognized lesions involving the portal system of veins. Me- tastatic lesions in abdominal actinomycosis arising from foci outside of the abdomen most frequently occur in the spleen, kidneys, and abdominal wall. Cutaneous Actinomycosis. — This form includes those comparatively rare cases in Avhich the lesions are regarded as primary in the skin. As already suggested, some of these cases represent secondary invasion of the skin from deeper structures. The lesions are ulcerative or may have great resemblance to lupus and to certain forms of cutaneous syphilis. The pro- cess is essentially a local one and is outside of the scope of this article. Symptoms. — In a disease with such a great variety of localizations and of such varying extent, it is impossible within the scope of this article to give an adequate account of all its signs and symptoms. These in general are like those of a subacute or chronic inflammatory process, or of a ma- lignant neoplasm. In many cases the disease is far advanced and has extensively invaded important internal organs and regions before any symptoms are apparent. In cases involving the external soft parts, prominent signs are swellings and indurations of the infected region in which suppurative foci, often recurrent, may develop, break through the skin and become the orifices of recurrent sinuses and fistulse. The skin over the affected part may be cedematous, discolored, and warm, or the swelling may have no inflam- matory character and simulate a neoplasm. Fever and pain may or may not be present. In the frequent cases in which the disease affects the temporomaxillary region the prominent symptoms are trismus, pain, swelling, and limitation of motion of the jaws. Involvement of the skin of the neck is character- ized by ridge-like elevations, or folds with sulci between, associated with the orifices of sinuses. The lesions in the tongue are usually nodular or tumor-like. Lesions of the brain, spinal cord, or meninges may give rise to all the various signs and symptoms of meningitis, encephalitis, myelitis, cerebral thrombosis, and tumor. In those cases originating in any region of the body with extensive suppuration or with metastases, the symptoms are usually those of pyae- mia, with chills, sweats, fever, pain, vomiting, and diarrhoea. In such cases the primary process may not be obvious until the autopsy. In the thoracic form definite symptoms and signs are usually wanting until the disease is far advanced. If the lungs are extensively involved ACTINOMYCOSIS 335 there is cough with foetid, sometimes bloody, sputum, and signs of bron- chitis, pulmonary consolidation and cavity formation. These usually are in the inferior portions of the lungs. There is also cachexia, anaemia, fever of a variable type, and the habitus of pulmonary phthisis. The frequent involvement of the pleura and thoracic vv^all is a marked feature of this form of the disease and may give rise to the first symptoms. A prominent symptom of this localization is pain in the afi'ected region. Retraction of the thoracic wall, signs of pleuritis, progressive emaciation, weakness, diarrhoea, night sweats, and fever may be present. The pres- ence of an inflammatory swelling or a board-like induration in the wall of the thorax or epigastrium, with suppurative foci or sinuses in it, is very characteristic. Lesions of the oesophagus have been attended with pain on swallowing or pain behind the sternum. In primary abdominal actinomycosis the most conspicuous sign in the majority of cases is a deeply seated tumor-like mass or a hard infiltration, involving the abdominal wall, in the midst of which may be fluctuating foci or orifices or sinuses and intestinal fistulse. The skin over the affected part may be red to brown in color and may be the seat of ulcers. Usually the affected region has a board-like consistence and is only slightly pain- ful on pressure. The tumor-like masses are only slightly movable. The right half of the abdomen is most frequently involved, commonly in the ileo-csecal region. The left half is less frequently involved, while localiza- tion of the lesions about the umbilicus or in the lumbar or gluteal regions is rare. These local signs may or may not be preceded or accompanied by intestinal colic, vomiting, fever, diarrhoea, constipation, swelling of the abdomen, and pain referred to the ileo-csecal region or elsewhere. The clinical course of the disease may be acute, with much fever and pain, as in the disseminated embolic forms, or it may be subacute or chronic with little or no pain and fever. Any of the types may develop from one of the others. Fever may occur at any time. Thespleenmay be enlarged. In the chronic cases especially, there may be anaemia, diarrhoea, emaciation, weakness, oedema, and cachexia. Ascites rarely occurs. In cases in which the liver is extensively involved the organ is enlarged, but there may be little fever and but little pain referred to it. Pain in the lower ribs, jaundice, and constipation may be present. An abscess may be evident in the right hypochondrium, and there is the fever curve of sup- puration. Sometimes there is a painless tumor at the right costal border, with only moderate fever. Involvement of the urinary tract may pro- duce symptoms of cystitis and pyelonephritis. Diagnosis. — So closely does actinomycosis simulate various inflamma- tory conditions and tumor formations that the diagnosis is definitely established only by the demonstration of the characteristic microorgan- ism in the lesions, or in the pus aspirated or discharged from them. The characteristic granules are rather to be sought for in the pus or discharges from the lesions than in pieces of excised tissue, because the granules or vegetations commonly exist in little cavities or sinuses in the tissue, from which they readily escape and are lost, or in which they may be concealed and elude observation owing to the small size of the granule as com- pared with the mass of the lesion. 336 DISEASES DUE TO VEGETABLE PARASITES The pus, or the sputum, in cases of suspected pulmonary actinomycosis, should be spread out thinly on a glass surface and the granules sought for against a dark background. A careful examination may be necessary to find them. Suspected granules should be transferred to a slide, with a small amount of water, and gently flattened under a coverglass. Under the microscope with a low power objective a typical granule appears as a brownish refringent, more or less lobulated mass or masses showing radiate striated appearances at the periphery. More or less pus adheres to the granule so that the masses of the parasite are seen to be surrounded by pus cells. Under an objective of medium magnifying power the peripheral portions of the granule are seen to be composed of the charac- teristic refringcnt radiating club-shaped bodies or filaments closely j)acked together and the central portions are seen to be granular or hyaline. In some instances the clubs may not be present and filaments only may be apparent at the margin. Granules composed of conglomerates of various bacteria, such as may be observed in pus from inflammatory processes about the mouth, should not be mistaken for granules or colonies of actinomyces. Cases of this kind have been called pseudo-actinomycosis. The same name has been erroneously applied to genuine actinomycosis, because the granules failed to show the "clubs." If the granules do not show the "clubs," the demon- stration in smear preparations made from them of truly branched fila- ments, like those of actinomyces, is sufficient to justify the diagnosis of actinomycosis. This is best done by breaking up one or more of the gran- ules on a coverglass so as to form a smear preparation, staining it by Gram's method and examining it with an oil-immersion objective. In addition to longer and shorter irregularly staining filaments, often branched and occurring singly or in groups or in masses, coccus-like or bacillus-like forms may be seen. These are either products of disintegra- tion and generation of the filaments of actinomyces or are true micrococci and bacilli that have been growing in symbiosis with them. The coccus- like forms have been erroneously regarded by some writers as spore-like reproductive elements of actinomyces. The pus of closed suppurative foci is most favorable for the finding of the microorganism, and the first drops of pus or inflammatory fluid which issue from the focus are best to examine, for the granules are usually most numerous therein. They may be very few and difficult to find in the in- flammatory fluid that may be expressed later from the lesions. The secretions from open sinuses may be very poor in granules and, in sus- pected cases with sinus formation, it may be necessary to examine the secretion accumulated during some time before the granules are found. This may be conveniently done by plugging the sinuses with a wick. The existence of subacute or chronic indurated swellings, associated with recurrent suppurative foci or sinuses or fistuUie in any situation, is suggestive of actinomycosis. Actinomycosis of the neck and head may be confounded with any of the tumors or inflammatory conditions occurring in these parts, especially with sarcoma of the jaw. In every inflammatory process about the mouth or pharynx actinomycosis should be considered. Actinomycosis of the tongue may be confused with cancer and other conditions. Actinomycosis of the brain may be suspected only when cerebral symptoms occur in as- ACTINOMYCOSIS 337 sociation with a focus of known actinomycosis elsewhere. Actinomycosis of the thorax may simulate every inflammatory or neoplastic affection of that part of the body. In cases involving the lung without obvious lesions of the thoracic wall, the disease is most likely to be confused with pulmonary tuberculosis from whichit differs clinically practically only inthe morefrequent localiza- tions of the signs in the inferior lobes and in the less frequent occurrence of haemoptysis. In these cases the diagnosis can be made with certainty only by finding the characteristic granules or colonies of actinomyces in the sputum or in the pleural exudate. The sputum in all cases of chronic pulmonary disease in which tubercle bacilli cannot be found, should be examined for actinomyces. The granules usually sink to the bottom of the sputum receptacle. Any concretions in the sputum should be carefully examined. The early symptoms of the disease may be those of typhoid fever or influenza accompanied by pleuritis, and the persistent pulmonary symp- toms may be regarded as sequelae of these affections. In cases in which the thoracic wall or vertebral column is involved the disease may simu- late chiefly tuberculosis or secondary carcinoma of the spine, or sarcoma or cold abscess of the thoracic wall. Involvement of the oesophagus may simulate cancer of that organ. Abdominal actinomycosis may simulate a great variety of diseases and conditions, among which may be mentioned tumors, gumma, and phleg- mon of the abdominal wall, appendicitis, typhoid fever, carcinoma of the intestines, tuberculosis of the ileo-csecal lymph nodes, abscess of the liver, psoas abscess, perinephric abscess, and sarcoma of the iliac bone. If neither superficial suppurative foci, nor sinuses, nor fistulse exist, it is possible that the actinomyces granules might be found in the faeces or in the urine, if the bladder be involved in the process. Prognosis. — The prognosis in actinomycosis depends chiefly upon the extent and localization of the lesions. In nearly all cases the disease is chronic, lasting for months and years. Some cases recover spontane- ously but for the great majority treatment is necessary to make recovery possible. In cases affecting the head and neck the general prognosis is much better than in the other forms. Poncet and Berard^ state that three- fourths of these cases get well. Of the 49 cases analyzed by Leiblein,^ 3 died and 36 recovered. Of 52 cases treated by v. Baracz,^ 45 recovered and the fate of 7 was unknown. Heinzelmann^ has recently reported that of 39 cases treated surgically, 35 apparently were cured and 1, or possibly 2 had died of the disease. Of the 53 American cases analyzed by Erving^ 36 had recovered and 5 had died. When the disease involves the superior maxilla and the pharynx the prognosis is not as good as in the generality of the cases involving the head and neck. ^ Traite Clinique de I' Actinomycose humaine, Pseudo-Actinomycose et Botry- omycose, Paris, Masson et Cie, 1898. ^Beitr. z. klin. Chir., XXVIII, 198. ^Arch. f. klin. Chir., 1902, LXVIII, 1050 ^"Ucber Endresultate bei der Behandlung der Aktinomykose, "/nott^. Diss., Tubingen, 1903. ^Bulletin of the Johns Hopkins Hospital, 1902, XIII, 261, 22 338 DISEASES DUE TO VEGETABLE PARASITES Recurrences are not infrequent after operation or apparent cure, and a case should not be regardetl as cured until f\vo years have elapsed without recurrence. Thus Heinzehnann reports that out of 31 cases had suf- fered recurrence before a cure was effected. The prognosis in the thoracic form is bad. As in nearly all of the cases of the thoracic foitn the lung is involved, statistics bearing upon progno- sis in this form deal chiefly with pulmonary actinomycosis. Of 34 cases collected by Ilodenj^vl/ all died exce])t 2. Among 58 cases collected by Illich,- no recoveries are recorded. Of the 20 American cases collected by Erving, 15 died and but 2 recovered. Apparently only about half a dozen cases of pulmonary actinomycosis arc recorded in the literature in which a recovery is claimed. In most of these the permanency of the recovery is doubtful. In abdominal actinomycosis the prognosis is not good but it is better than in the thoracic form. It is especially bad if the retro-peritoneal tissues are involved. It is better if the process is localized in the anterior abdominal wall, is accessible to surgical treatment, and the visceral in- volvement is lacking or not extensive. Of 64 cases analyzed by Harz,^ 22 died and 22 recovered. Of 107 cases reported by Grill, ^ of which 77 were treated surgically, 22 recovered and 45 died. Lowe^ selected 67 cases in which the disease was localized about the ileo-ctrcal region and found that 12 recovered and 36 died. Of the 23 American cases analyzed by Erving, 10 died and 5 recovered. At least 1 case of spontaneous recovery is known. Treatment. — The weight of experier.ce in the treatment of actinomy- cosis is in favor of surgical means combined with the internal administra- tion of large doses of iodide of potassium continued over long periods of time. The favorable effect of this drug in many cases seems to be gener- ally admitted. It is said to cause more or less absorption of suppurative foci and to facilitate the discharge of the specific infectious agent from the tissues. It seems also to inhibit the development of new suppurative foci. Cures are claimed to have been effected by the use of this drug alone. It is said to act less favorably in pulmonary actinomycosis than in other forms. It must be given in the largest doses that can be borne. Favorable effects may not be apparent in the lesions until its administration has been con- tinued for a considerable length of time. Treatment with the .r-rays combined with the internal administration of large doses of potassium iodide has been highly recommended. Opinion is divided as to the character of the surgical treatment. Some advocate the radical excision of the diseased tissue when the character of the case admits of it. Others believe that wide opening and drainage of abscesses, sinuses, and fistulse, with or without thorough curetting, is sufficient. With the latter mode of treatment tamponades of iodide of potassium and of various antiseptics have been advocated, such as tinc- ture of iod ine, corrosive sublimate, sulphate of copper and nitrate of silver. ^New York Medical Record, 1890, XXXVIII, 653. ^ Beitr. zur Klinik der Aktinomycose, 1892, Wien. ^Centralbl. f. d. Grenzgeb. d. Med. u. Chir., 1900, III, 561. ^Beitr. z. klin. Chir., 1895, XIII, 551. ® "Statistischesund Klinisches zur Kentniss der Actinomycose des Wurmfort- satzes und des Coecums," Inaug. Diss.,Greifswald, 1904. ACTINOMYCOSIS 339 In localizations about the jaw, any carious teeth that seem to be in relation with the lesions should be extracted. For rectal actinomycosis, Poncet has recommended the thermocautery. Recurrence is frequent in cases treated by simple incision and drainage and it may occur even after the most radical procedure, so that repeated operation may be necessary before a cure is effected. As a pro]) hyl actio against recurrence a course of treatment with iodide of potassium has Ijcen advocated. This has also been advised as a preliminary to surgical treat- ment in cases with extensive lesions, as in abdominal actinomycosis, be- cause its effects on the lesions tend to make the suppurative foci more evident, and thus more easily found and evacuated by operation. The internal administration of arsenic and of sulphate of copper has also been advised in place of iodide of potassium. V. Baracz recommends in circumscribed lesions, especially those about the face and neck, where it is desirable to avoid cicatrices for cosmetic reasons, the parenchymatous injection of tincture of iodine, or of a 20 per cent, solution of nitrate of silver without extensive surgical interference, one cc. or sixteen minims of either of these to be injected into the lesions repeatedly every few days. One case of pulmonary actinomycosis is claimed to have recovered under treatment with oil of eucalyptus. Ac- cording to V. Baracz the surgical treatment of pulmonary actinomycosis has not given hopeful results. CHAPTER XVL NOCARDIOSIS, iNIYCETOMA, OIDIOiAIYCOSIS, BLASTOMY- COSIS, PULMONARY ASPERGILLOSIS, MYCOSIS MUCORINA. By J MIES HOMER WRIGHT, A. M., M.D., Hon. S. D. (Harv.) NOCARDIOSIS. Definition. — A considerable number of cases of inflammatory charac- ter, due to infection with branched filamentous microorganisms more or less similar to Actinomycosis bovis, are recorded in the literature and have been the source of much confusion. A few of these cases are infections with branched tubercle bacilli or are cases of pulmonary gan- grene associated with so-called branched bacilli, the pathogenic signifi- cance of which is doubtful; these need not be further considered here. Excluding a few cases, which are more or less probably genuine actinomycosis, in which the infecting microorganism had not developed the characteristic "clubs," and some cases that are very meagerly re- ported, there remains a considerable group of cases which either have been shown, or may at present be assumed, to be cases of infection with different species of a single genus of microorganisms the chief characters of which are described below. To the cases in this group the terms pseudotuber- culosis, or streptothrix, or cladothrix infection, or atypical actinomycosis have been applied. None of these names are satisfactory. Pseudotuber- culosis is too indefinite a term and carries no etiological suggestion with it. Streptothrix and cladothrix are generic terms that are untenable for the group of infecting microorganisms in question, for they are well recognized generic names for microorganisms quite different from these. Atypical actinomycosis is objectionable, because it leads to the confusion of these cases with actinomycosis and because it implies that the infection micro- organism is so closely related to Actinomyces bovis as to be classed in the same genus with it. This idea of the close relationship of the infecting microorganism in these cases to Actinomyces bovis is widely accepted, but the writer^ has shown that it is erroneous and that Actinomyces bovis differs so markedly from the microorganisms of this group that it should not be placed in the same genus with them. It has been pointed out that if the name Actinomyces be not used for these microorganisms then the only permissable generic term to apply to them, in accordance with the principles of botanical nomenclature, is Nocardia,^ and disease processes produced by them should be called ^Journal of Medical Research, 1905, XIII, 349. '^De Toni et Trevisan. Saccardo. Sylloge Fungorum, VIII, 927. 340 NOCARDIOSIS, MYCETOMA, ETC. 341 nocardiosis. In accordance with this view these cases are grouped to- gether under the name nocardiosis and the infecting microorganisms will Be called Nocardia in this article. The first description, although an imperfect one, of a nocardia is that of Cohn,^ who found it in a concretion in the lachrymal duct and gave it the untenable generic name of Streptothrix. Tho first extensive study of a case of nocardiosis was that of Eppinger,^ in 1891. Etiology. — The nocardia, the infecting microorganisms in nocard- iosis, have resemblances, on the one hand, to certain bacteria in the structure, thickness, and staining of their filaments, and, on the other hand, to the hyphomycetes or moulds in their branching, thread-like form and in the production of fine conidia or spore-like reproductive elements out of the substance of the filaments. They differ from the hyphomycetes in that their filaments are more slender and are not tubular structures with double contoured walls, protoplasmic contents, and transverse septa. They may be regarded as representing a further transition from the bacteria toward the lower fungi or hyphomycetes than does Actinomyces bovis, because they have this property of producing spore-like reproductive elements or conidia, a property not possessed by that microorganism. Most of the known species grow readily on the ordinary culture media, are aerobic and do not require the temperature of the body for their multiplication. They grow in dense masses on culture media, on which the younger colonies may appear as aggregations of filaments radiately arranged. They are widely distributed in the outer world, especially in the air and on grains and grasses as shown by the work of Doria,^ Berestneff,^ and others. The various species difl^er chiefly in the color and other appearances of their growths on artificial culture media. It is very probable that the nocardia, claimed to have been isolated from certain cases of inflammatory lesions as well as from certain cases of typical actinomycosis, gained entrance to the culture tubes by accident or were secondary invaders of the lesions. Among such nocardia are those microorganisms described by Rosenbach,^ Naunyn,^ Almquist,^ Bost- roem,^ Vincent,^ and others. No.cardia have been observed in the sputum of apparently healthy individuals. Infection seems to take place most frequently through the respiratory tract. In three cases it has occurred from wounds. Malnutrition and chronic disease seem to predispose the individual to this infection as to others. Including four animal cases, there are some twenty well authenti- cated cases^'' of infection with nocardia from which the microorganism ^Beitr. z. Biolog. d. Pflanzen, 1875, I, 141. ^Beitr. z. path. Anat., 1891, IX, 276. ^Ann. deir Inst. d'Igiene speriment. , della R. Univ. di Roma, 1892, II, 1G7. *Zeitschr. f. Hyg. u. Infectionskrankh., XXIV, 94. ^Archiv. f. Klin. Chir., 1887, XXXVI, 346. ^Mitth. a. d. Med. Klinik, I Konigsberg, Leipzig, 1888, 296. '' Zeitschr. f Hyg. u. Infektionskrankh., 1890, VIII. ^ Beitr. z. Path. Anat. u. z. allgem. Path., 1890, IX. ^Ann. de I'lnst., Pasteur, 1894, VIII. ^° Epp'mgev, Ref. Zeigler Beitr. z. path. Anat., 1890, IX. Dessy, La Settimana medica dello " Sperimentale," Firenze, March 28, 1896, 156. Aoyma and Miya- moto, Mii^/i. a. d.med. Facultat d. kaiserl., japanisch Univ. z. Tokio, 1902, IV, 231. MacCallum, Centralhl. f. Bakteriol., I Abt., 1902, XXXI, 529. Birt and Leishman, Jour. Hyg., 1902. TroUdeiner, Zeitschr. /. Thiermed., 1903, XVII, 342 DISEASES DUE TO VEGETABLE PARASITES has been isolated and studied in pure culture. In a smaller number of cases* regarded as nocardiosis, culture experiments have not been successful or -were not attempted. The nocardia isolated in the cultures have shown sufficient differences among themselves to be regarded as belonging to various species. Analysis of the better studied cases shows that the microorganisms from at least eleven of the human cases and from one case in a dog were suffi- ciently alike to be considered as probably belonging to the species first described by Eppinger, who gave it the specific name of "asteroides" and the untenable generic name of Cladothrix. This species is characterized by the reddisii color of its growths on culture metUa, by not liquefying the gelatin and by producing so-called pseudotuberculosis in animals inoculated with it. The lesions in these animals consist of foci of sup- puration surrounded in typical instances by more or less well developed granulation tissue. They may be very extensive and widely disseminated throughout the body. A marked peculiarity of most of the microor- ganisms concerned in nocardiosis is their resistance to decolorization by weak acids after being stained by fuchsin. The wide distribution of the nocardia in the outer world has already been referred to and it seems very probable, in view of the biological characters of those that have been isolated from pathogenic processes, that they likewise have a natural habitat outside of the body. Special Pathology. — The lesions ascribed to the action of nocardia are of varied character. There is no doubt that these microorganisms produce necrosis, suppuration, abscesses and granulation tissue formation as well as miliary focal lesions that are essentially suppurative foci sur- rounded by more or less granulation tissue, but it is not proven that fibrous or calcareous nodules, areas of caseation and tubercles identical in structure with those of tuberculosis, can be produced by them. The best evidence in favor of the idea that lesions, histologically identical with those of tuberculosis, may be produced by them is offered by Flexner; but the microorganism in his case was not studied in cultures, and it is therefore not certain that it was a nocardia. The filaments of the in- fecting microorganism in nocardiosis are scattered among the cells of the lesions or are loosely grouped together, and are not aggregated so as to 81. Horst, Zeischr. f Heilkunde, Abth. f. path. Anat., 1903, XXIV, 157. Tuttle, Med. & Surg., Rep. Presbyterian Hospital, N. Y., 1904, VI, 147. Mc- Donald. Scot. Med. & Surg. Jour., 1904, XIV, 305-321. Schabad, Zeitschr. f. Hyg., 1904, XL VII, 41. Stokes, Am. Jour. Med. Sci., 1904, CXXVIII, No. 5, 861. Memmo, Quoted by RuUman, Munch, med. Wochenschr., 1898, No. 29, 920. Berestneff, "Die Aktinomykose und ihre Erreger," (Russian), Inaug. Diss., Moskau, 1897. Scheele and Petruschky, Deutsch. med. Wochenschr. Vereins beilage, 1897, No. 17, 124. Sabrazes et Riviere, La Sem. Med., 1895, 383. Ferre and Farquet, La Sem. Med., 1895, 3.59. Nocard, Ann. de I'Inst. Pasteur, 1888, II. Kruse and Pasquale, Zeistche. f. Hyg., XVI. Terni, Ref. Centralbl. f. Bakteriol, 1896, XIX, 160. Ophtils, Jour. Med. Research, 1904, VI, 439. Mayer, Miinch. rmd. Wochenschr., 1901, No. 44. Saint Servin, La Sem. Med., 1895. ^Flexner, Jour. Uxper. Med., 1898, III. Warthin and Olney, Am. Jour. Med. Sci., 1903, Oct., 637. Buchholz, Zeitschr. f. Hyg., 1897, XXIV. Ohlmacher, Clevelav'' Med. Jour., 1902, 29. RuUman, Miinch. med. Wochenschr., 1898, No. 23, 920. Ucke, St. Petersburg med. Wochenschr., 1901, XVIII, 87. Rabe, Berlin Thier. Wochenschr., 1888, 65. Butterfiekl, Jour. Infect. Diseases, 1905, II. 421„ Musser and Gwyn, Trans. Assoc. American Physicians, 1901^ XVI, 208. NOCARDIOSIS, MYCETOMA, ETC. 343 form thecompact masses orradiate structures or granules that are charac- teristic of actinomycosis. The process in most of the cases has been situated in the lung or has originated there. In the lungs jjneumonia, abscesses, gangrene, in- durative processes, fibrous nodules, cavities, caseous pneumonia, miliary tubercles, and other lesions like those of tuberculosis, have been described. As has been already pointed out, it is uncertain whether these lesions, like those of tuberculosis, are due to nocardia rather than to the tubercle bacillus. In two cases the reporters considered tuberculosis to be coin- cident. Metastatic lesions have been observed in nine cases, among which the brain, myocardium, lung, kidney, peritoneum, lymphatic glands and subcutaneous tissue have been involved. The primary process was in the lung in five of these cases; in a bronchial gland in one or two; in the region of the knee-joint in one; and was unknown in one. In six cases there were one or more abscesses in the brain. In two cases there was empyema and pericarditis. One case was of the nature of a subacute purulent peritonitis. Conjunctivitis and subcutaneous abscess have also been ascribed to infection with nocardia. In the animal cases there was suppuration in various regions. Symptoms. — The symptoms, as far as has been ascertained from the reports, have been m general those of suppuration or inflammation and have varied with the location and extent of the process. The clinical course was either acute or chronic. In most of the pulmonary cases the signs and symptoms have been those of pulmonary tuberculosis or of pneumonia and abscess. Cough, fever, pain, and emaciation have been observed. In two cases there was haemoptysis. Signs of empyema were present in two cases, in one of which there was an inflammatory fluctuating tumor on the external aspect of the chest wall. In one of these cases also, signs of pericarditis were made out. In two cases there were multiple metastatic abscesses in the subcutaneous tissue with symptoms of pyaemia. In one of these infection with the bacillus of glanders was suspected. In a few cases the process has been essentially • of the character of a terminal infection. In three of the cases in which there was abscess for- mation in the brain, there were symptoms of tumor and abscess in two, while m one the diagnosis of tuberculous meningitis was made. In the case of subacute peritonitis which followed gastrotomy, the prominent symptom was diarrhoea. Diagnosis. — Nocardiosis may be confused with a variety of diseases, but especially with pulmonary tuberculosis and actinomycosis. In cases with multiple abscess formation in the subcutaneous tissue, the disease may simulate infection with the bacillus of glanders. The diagnosis depends upon finding the special microorganism in the sputum or in the lesions. It occurs typically in the form of branched filaments of the character above described, which resist decolorization by dilute acids after having been stained with fuchsin. Fragments of the nocardia may be mistaken for tubercle bacilli, especially for the rare branched forms of that microorganism. The nocardia may be distinguished from the tubercle bacillus by their longer filaments and more marked branching and also by their occurrence 344 DISEASES DUE TO VEGETABLE PARASITES in loose aggregations. A further distinction lies in the fact tliat most of tht nocardia after staining with fuchsin do not resist decolorization with acids as strongly as does the tubercle bacillus, and are decolorized by alcohol, whereas the tubercle bacillus is not. Probably the best way of finding nocardia in sinituin or pus is by the microscopic examination of smear pre])arations stained by Gabbet's method, for this does not employ alcohol ancl is not a very vigorous discolorizer. The nocardia are distinguished from the microorganism of actinomy- cosis in that they do not occur in the inflammatory fluids or lesions in man in the compact masses nor form the radiate club-bearing structures or granules so characteristic of actinomycosis. Moreover, the microor- ganism of actinomycosis does not resist decolorization by dilute acids after having been stained with fuchsin. Localization of the lesions about the mouth and jaws, so common in actinomycotis, is unknown in nocardiosis. Prognosis. — All of the cases in which the lung or brain was involved died except two, which got very much better or recovered. These two cases were among the less well authenticated ones. Treatment. — No specific is known and the treatment will vary Avith the character of the process and the situation of the lesions. In cases re- sembling pulmonary tuberculosis the treatment should be essentially the same as for that disease. Empyema and abscesses should be treated according to the usual surgical principles. MYCETOMA (MADURA FOOT). Definition. — Mycetoma is a chronic infectious process, most commonly affecting the foot, the prominent features of which are multiple sinuses and enlargement and distortion of the parts. Carter^ first assigned to the disease a separate identity and a special parasitic causation. He gave it the name Mycetoma. Etiology. — The affection is characterized by the presence, in the dis- eased tissue and in the discharges from sinuses, of peculiar granules usually not more than 1 mm. in diameter but sometimes larger. In certain cases these granules are of a black color, of irregular shape, hard, rather brittle, and, in general, resemble grains of gunpowder In other cases the granules are whitish, grayish or yellowish in color, of a soft or cheesy consistence, and have been compared to fish roe in appearance. A few cases are also recorded in which the granules were of a red color. According to the observations of Carter and others, the granules are composed of aggregations of vegetable parasites and their products. On account of their relation to the lesions the granules are ]:»resumed to be the infectious cause of the disease and not merely secondary invaders of the lesions. They have not been shown by experimental inoculation to be capable of producing the disease. On account of the fact that at least tw^o very different kinds of granules are foimd associated with the lesions, two varieties or forms of the disease are recognized: the "melanoid" or black variety, in which the granules are black, and the "ochroid" or pale veriety, in which the granules are white to yellow in color. ^A. V. Carter: On Mycetoma or the Fungus Disease of India, London, 1874. NOCARDIOSIS, MYCETOMA, ETC. 345 The ochroid granules, as shown by the studies of Kanthack^ and Bishop,^ are apparently identieal with the granules of actinomyees; and at the present time the ochroid or pale form of mycetoma must be regarded as actinomycosis of the part. Boyce^ and Vincent^ claim to have obtained cultures of the specific microorganism from two cases of this form of the disease, but their microorganisms are widely difl'erent from each other and neither of them was proved to be identical with the microorganisms in the lesions and not a secondary invader or a con- tamination of the cultures. The black or malanoid granules, on the other hand, as shown by the studies of Bristowe,^ Carter, Wright,** and others, are of entirely different character. They consist of a mass of hyaline refringent, brown-colored, brittle substance, forming a matrix in which are imbedded a tangle of fungus tubules or hyphte with doubly contoured walls and transverse septa. This fungus of the melanoid form of the disease has been isolated in cultures by the writer from a single case. This is very probably the only instance in which its cultivation has been accomplished, for Carter's claims that he had grown the fungus in cultures do not bear critical ex- amination. The writer obtained a growth of the fungus from about twenty-five out of approximately sixty-five of the black granules experi- mented with in this case. The mode of entrance of the parasite into the tissues is not known. The disease is endemic in certain districts in India, especially in Madura, and has been observed in Africa, Italy, and other tropical or subtropical countries. It seeins to be acquired in the country districts and not in towns. In America it is of very rare occurrence, only four undoubted cases having been reported, and three of these were of the pale variety of the disease, which, as has been pointed out above, is to be regarded as actinomycosis. Special Pathology. — The process consists essentially in abscess and sinus formation, associated with extensive development of granulation and connective tissue. The granules are found in the abscesses or sinuses and sometimes they may be found surrounded by epithelioid cells and giant cells. Giant cells may be frequent in the granulation tissue. The inflammatory tissue may very extensively replace the muscles and bones of the affected part, the tendons and fascia most resisting replacement. In advanced cases the granules may exist in sinus cavities in masses. The foot is most commonly affected, but occasionally the hand and, rarely, other parts. The internal organs are never involved. Symptoms. — The process usually begins as a firm nodular swelling in the sole of the foot, which is followed by others in the neighborhood or elsewhere. These break down and become the seat of the openings of sinuses which rarely heal. By extension of the process the foot increases in breadth and thickness and may attain a considerable bulk and weight, eventually becoming very burdensome to the patient. The toes become ^Journal of Pathology and Bacteriology , 1893, I, 140. ^Hyde, Senn and Bishop: Journal of Cutaneous and Genito-urinary Diseases, XIV, 1. 1896, ^Hyg. Rundschau, 1894, IV, 529. *Ann. de VInst. Pasteur, 1894, VIII, 129. ^Transactions of the Pathological Society, London, 1871. ^Journal of Experimental Medicine, 1898, III, 421. 846 DISEASES DUE TO VEGETABLE PARASITES more or less displaced and deformed. The orifices of sinuses may be obscured by masses of granulation tissue. The discharges from the sinuses are oily, mucopurulent and may have a very bad odor. They con- tain the characteristic granules above described. Severe pain is rare. In advanced cases the great weight of the foot prevents its use in walking, and atrophy of the leg muscles occurs. Diagnosis. — The disease may be mistaken for syphilis or for sarcoma. The diagnosis depends upon finding the granules and upon recognizing their characteristic structure. To cases of the pale or ochroid variety, what has been written upon the subject of the diagnosis of actinomycosis applies. The fungus elements in the black granules are best demonstrated by softening and bleaching the granules with liquor sodre chlorati and examining teased preparations of them under the microscope. In such preparations the fungus elements should be clearly visible as septate, tubular, cylindrical or spherical structures with doubly contoured walls. Prognosis. — The process is very chronic and may last for years. Spon- taneous recovery never occurs. Death may follow from secondary in- fection with pyogenic microorganisms or may be due to exhaustion incident to the burden of carrying about the greatly enlarged and heavy, diseased foot. Treatment. — The internal administration of iodide of potassium is said to have no favorable effect upon the process. The only effective treat- ment is excision of the lesions or amputation. OIDIOMYCOSIS. Definition. — A granulomatous and suppurative process affecting the skin and internal organs. It is called dermatitis coccidioides, protozoic dermatitis, blastomycetic dermatitis, psorospermiasis, coccidioidal granu- loma, blastomycosis, and saccharomycosis. Apparently about forty-five cases have been reported. It is probable that some cases of this disease now go unrecognized and are classed under tuberculosis. The first cases were described by Wernicke,^ Busse,^ and Gilchrist and Stokes.^ A good description of the cutaneous forms of the disease is given by F. H. Montgomery.* Etiology. — The disease is due to infection with certain fungi wdiich although showing various differences in biological characters among themselves may, according to Ricketts,^ be classed asspecies of thegenus Oidium. In the lesions the microorganisms appear chiefly as spherical bodies, each consisting of a protoplasmic mass enclosed in a doubly con- toured hyaline capsule, which may be provided wdth prickles or spines in some instances. The diameter of the bodies varies up to thirty microns or more. In the protoplasm, vacuoles, granules and various markings may be seen, but no nucleus is apparent. The mode of proliferation in the lesions in the majority of cases is by gemmation or budding. The ^Centralbl. f. Bakteriol, 1892, XII, 859. ^Centralbl. f. Bakteriol, 1894, XVI, 175. ^Bulletin of the Johns Hopkins Hospital, 1896, VII, 129. ^Journal of the Arfierican Medical Association, June 7, 1902. "Journal of Medical Research, 1901, VI. NOCARDIOSIS, MYCETOMA, ETC. 347 microorganisms in some cases have great rcscmljlance to yeast fungi or saccharomyces. Busse regarded the microorganism in his case as a yeast and called the })rocess sacchromycosis. In a minority of the known cases, proliferation of the microorganisms in the lesions is not by bud- ding but by a process which is regarded as one of sporulation, the pro- toplasm of the larger forms segmenting into many small spherical bodies Each of these small spherical bodies acquires a capsule and, being set free by the rupture of the capsule of the mother cell, develops into the adult parasite. Wernicke, and Rixford and Gilchrist/ first described cases with these sporulating forms in the lesions and they regarded tho microorganisms as protozoa; but, later, Ophiils and Moffitt^ showed that they are stages in the life-cycle of a mould fungus. The microorganisms may be few or very numerous in the lesions. In cultures the microorganisms show con- siderable variation in biological character. According to Ricketts, the microorganisms obtained from various cases may be divided into three groups according to their biological char- acters as shown in the cultures as follows: 1. Those growing chiefly as spherical or oval budding cells and re- sembling yeasts, but capable of producing mycelium. 2. Those forming submerged mycelium, which breaks up into chains of spores, while proliferation by budding is not a prominent feature. 3. Those producing mycelium with fruit-bearing aerial hyphse and also capable of multiplying by gemmation or budding. The microorganisms of the first and second groups are capable of producing fermentation, while those of the third group are not. In animals inoculated with cultures of some, but not all, of these micro- organisms, abscesses, granulomatous tumors and tubercle-like nodules widely disseminated have been produced. In these lesions in the animals the microorganisms exist in the same form as in the human lesions. Wolbach,^ working with a microorganism of the type which prolifer- ates in the tissues by sporulation, has studied carefully, in animals inocu- lated with pure cultures, the transformation of the hyphee of the cultures into the characteristic spherical bodies of the lesions. He finds that the spherical bodies arise by the segments of the hyphae enlarging and assum- ing a spherical shape, the wall of the segment thus becoming the capsule of the spherical body. In his experimental lesions, Wolbach has also ob- served pointed and club-shaped hyaline bodies radiately arranged con- tinuous with the capsules of the microorganisms. The conditions underlying infection in oidiomycosis are not yet known. There is no definite relation between the disease and the sex, age, occupa- tion, nativity, or habits of the patients. Most of the cases with so-called sporulating forms in the lesions have occurred in California. All of the cases except two have been observed in the United States. A few cases followed traumatism. Special Pathology. — The process usually consists in abscess forma- tion, combined with proliferation of the fixed cells of the infected region ; but it may be characterized by the formation of caseating aggregations of ^ Johns Hopkins Hospital Reports, 1896, I, 209. ^Philadelphia Medical Journal, June 30, 1900. ^Journal of Medical Research, 1904., XIII, 53. 348 DISEASES DUE TO VEGETABLE PARASITES epithelioid colls accompanied by giant cells, thus simulatino- the lesions of tuberculosis. The reaction on the part of the tissue in some cases may be comparatively slight and the lesions may consist chiefly of masses of the microcirganisms. jNIultinucleated giant cells containing the parasites are jjrominent features of the lesions. In the skin there is, in most cases, extensive hyperplasia of the rete mucosum, abscesses botli in the corium and in the rete, aiid tubercle-like aggregations of e])ithelial cells A\ith giant cells. The microscopical a})])earances may simulate scjuamous- cell carcinoma or verrucous tuberculosis and the microorganism may be present in comparativly small numbers. The lesions may be limited to the skin or may involve also the lungs and internal organs. The disease may take origin in the lungs. The face is most frequently the seat of cutaneous lesions, but the skin of almost any region of the body may be involved. The skin involvement may be very extensive. There is but little tend- ency to involve mucous membranes. In the skin the process begins usually as a papule or pustule and slowly enlarges during the course of months, producing an elevated area, which may be of large size, with rough, scabby surface and enclosing numbers of minute abscesses. Later, ulceration occurs, and ultimately there may be cicatrization and healing. In many cases the cutaneous lesions are multiple and they may be situated in wddely separated parts of the body. Involvement of the lungs, and of other organs and structures not cutaneous, has been observed in sixteen or more cases, ^ in six of which cutaneous lesions were absent. Among these cases in addition to the lungs and skin, the pleura, liver, kidneys, spleen, bones, suprarenals, testicles, peritoneum, meninges, and various lymphatic glands have been the seat of lesions. In the lungs the lesions have consisted of abscesses, miliary nodules, bronchopneumonia, and areas of consolidation. The meninges w^ere affected in two cases and the lesions were very similar to those of tuberculous meningitis, both grossly and microscopically. In the liver, spleen, kidneys, adrenals, testicles and lymphatic glands, the lesions have consisted of small nodules, abscesses, cheesy or necrotic areas or grayish-white infiltrations. When the process has involved the bones it has been suppurative and necrotic in character, sometimes simulating tuberculosis. Amyloid infiltration has been observed in two cases. Symptoms. — In most of the cases the disease is very chronic, lasting for years. The cutaneous lesions in most cases have periods of rapid pro- gression interrupted by periods of relative quiescence. There may be severe pain. In cases involving the lungs and other internal organs, the symptoms and signs are very similar to those of pulmonary tuberculosis. Prominent symptoms are cough, pain, profuse expectoration, and fever, highest at night. Sweating has been observed in these cases. Eventually there is emaciation and asthenia. Diagnosis.- — The cutaneous lesions are most likely to be confounded with verrucose tuberculosis but they may also resemble carcinoma, mycosis fungoides, as well as certain forms of syphilis of the skin. The diagnosis can only be made with certainty by finding the microorganism 'Otis and Evans, Journal American Medical Association, October 31, 1903, 1075; Cleary, Transactions of the Chicago Pathological Society, 1904, VI, 105. Ophiils Journal American Medical Association, October 28, 1905, p. 1291. References to other cases may be found in the papers already quoted. NOCARDIOSIS, MYCETOMA, ETC. 349 in the lesions. This is best done by examining the cont(;nts of tlie small abscesses or a fragment of the tissue with the microscope and finding the fungus cells. A drop of the pus mixed with water or a 30 per cent, sodium hydrate solution may be placed under a coverglass and examined directly with the microscope without staining. The cases in which the lungs are involved may be regarded as pulmonary tuberculosis. The diagnosis in such cases will depend upon the recognition of the nature of any co- existent cutaneous lesions, or it might be made by finding the fungus in the sputum. Diagnosis by means of the examination of the sputum has never been made. Prognosis. — When the disease is primary in the skin it is generally very chronic and may persist for ten years or longer Death from in- volvement of the lungs and other internal organs, in cases in which the skin has been primarily the seat of the lesions, has been observed in 4 cases. As far as is known the cases in which the lungs have been involved have terminated fatally. As regards prognosis there is a great difference between those cases in which the microorganism exists in the lesions in budding forms and those in which sporulating forms occur. Thus, of the 13 or 14 cases due to infection with the sporulating form, all came to autopsy except 4; while of the 30 odd cases due to infection with the budding forms, apparently but 4 died of oidiomycosis. When confined to the skin the disease yields to proper treatment, with a varying amount of cicatricial deformity. Spontaneous healing may occur, at least in some of the lesions. After the lungs and other viscera have become extensively involved the disease may terminate fatally within a few months. Treatment. — The internal administration of iodide of potassium has been employed with considerable success in the treatment of oidiomy- cosis. It should be given in large doses; 50 to 150 grains (3.75 to 10 gm.) have been given three times daily. This may be combined with treatment by the ic-ray, especially in the superficial cases. Simple local antiseptic treatment of the cutaneous lesions has not given good results. It is, how- ever, of value in relieving soreness and preventing secondary infections, as well as in cleansing the lesions. Total excision when the lesions are limited gives the best results. Thorough curetting followed by cauteri- zation has been advised. There is some evidence, however, that curetting may lead to the general dissemination of the process. Walker and Mont- gomery^ recommend the actual cautery or free excision, with deep dis- section and repairs by skin-grafts or plastic operations, in those cases in which the iodide of potassium fails to cure. They do not recommend curetting Sulphate of copper administered internally in doses of from one-fourth to one grain three times daily and applied externally as a wash in 1 per cent solution has been employed by Bevan.^ Addendum.— Closely allied to the microorganisms of oidiomycosis is the microorganism of parasitic stomatitis, or thrush, — the Oidium albi- cans. In a very few cases this oidium has invaded internal organs and has been found in abscesses in the brain, spleen, kidney, and lung. ^ Journal of the American Medical Association April 5, 1902, 867. '''Journal American Medical Association, November 11, 1905, 1492. 350 DISEASES DUE TO VEGETABLE PARASITES BLASTOMYCOSIS. The ycast-likc budding fungi, associated with some of the cases classed above under oidiomycosis, are called by some writers blastomycetes; and, therefore, such cases may be called blastomycosis. In addition to these cases, however, a considerable number of obser- vations of the occurrence of yeast-like fungi in a variety of pathological conditions both in man and animals arc on record. Of these, there are only two isolated cases in man that seem worthy of mention. They are of a very different character from the cases grouped under oidiomycosis and, therefore, may be considered under blastomycosis. One of these cases* presented myxomatous tumors beneath the skin in several places. Histo- logically, the tumors resembled myxo-sarcoma and contained the fungi in large numbers. In the other case^ sarcoma-like tumors involved the omentum and mesentery, and there was chylous ascites. In the ascitic fluid a yeast or blastomyces was found but in the tumors it was not satis- factorily demonstrated. In animals, several infectious processes are ascribed to blastomycetes. The most important of these is a suppiu'ative disease in horses, resembling farcy, characterized by chronic inflammation of lymphatics and lymphatic glands in Avhich there is proliferation and nodular thickening followed by purulent softening. The upper air passages are also involved in the process. PULMONARY ASPERGILLOSIS. Definition. — A destructive inflammatory process affecting the lungs, due to infection with one or more species of fungus of the genus Asper- gillus. The first observation of the occurrence of a fungus that was probably an aspergillus, in a human lung, was made by Bennett, in 1842; but the first scientific description of cases with an exact determination of the identity of the fungus Avas by Virchow, in 1856. Etiology. — The disease is due to infection with the spores of the mic- roorganism, and the species fumigatus is probably the only one concerned. The spores gain entrance to the lung through the respiratory tract. The Aspergillus fumigatus is a true fungus belonging to the family Peris- poreacea. In cultures it grows in the foi'm of a mould consisting of a thick felt-work of septate tubular hyph?e, a few micra in diameter, some of which grow upward into the air and produce masses of spores at their free ex- tremities. The spores are spherical, 2.5 or 3 5 micra in diameter and are easily transported through the air. The various species of aspergillus are common in the outer world and the spores are widely distributed on vegetable material of all kinds. The Aspergillus fumigatus has been found as a harmless parasite in the auditory canal, tympanum, nose, mouth, maxillary sinuses, throat, respiratory passages, eyes, and genitalia. Sometimes it is found in an inflammatory condition of the external auditory canal, but the inflam- matory process in these cases is probably due, in part at least, to the action 1 Curtis, Ann. d. I'lnst. Pasteur, 1896, X, 449. 2 Corselli and Frisco, Centralbl. /. Bakteriol., 1895, XVIII, 368. NOCARDIOSIS, MYCETOMA, ETC. 351 of pyogenic bacteria. It is said to be capable of causing keratosis, derma- titis, a peculiar affection of the nails, rhinitis, and pliaryngitis. In various birds, and in cattle, horses, and dogs, it may be the cause of an inflammatory process more or less resembling tuberculosis in which the lesions are situated chiefly in the lungs. In birds, the liver, the kid- neys, and the air sacs may also be infected and it may produce a pseudo- diphtheritic condition of the mouth and air passages. The intravenous inoculation of birds and various animals with spores may produce death within a few days. The lesions produced resemble grossly those of tuber- culosis. Histologically, they consist of foci of necrosis, enclosing the microorganisms, together with more or less infiltration with inflammatory cells. Infection may be produced experimentally by way of the respiratory tract in birds, and rabbits may be infected by feeding. Most of the cases of pulmonary aspergillosis in man may be regarded as instances of secondary infection in lungs already diseased by tuber- culosis or other processes, and some have been mere terminal infections. But little clinical importance was attached to pulmonary aspergillosis until the observations of Dieulafoy, Chantemesse, and Widal,^ published in 1890, and of Renon,^ published in 1897, gave good grounds for believ- ing that it could exist as a primary disease. These writers claimed that primary pulmonary aspergillosis was frequent among the so-called pigeon feeders and hair sorters of Paris. The pigeon feeders are accustomed to feed the pigeons from their own mouths with a mixture of millet and vetch seeds in water. They are supposed to acquire the disease either from these seeds or from aspergillosis in the birds. The hair sorters work in an atmosphere charged with the dust of rye flour, which they use in consider- able quantities to free the hair from grease. Birds kept in this atmosphere died in two or three days, from aspergillosis. The spores of the asper- gillus are in the rye flour used and they gain entrance to the lungs directly from the air. Important contributions to the subject have been made by Saxer.^ Good general articles upon the disease have been written by Rolleston* and Sticker.^ Special Pathology. — The essential effects produced upon the lung tissue by the Aspergillus fumigatus are necrosis and exudation of leuko- cytes. The typical appearances are areas of pneumonic consolidation, or necrosis with a colony of the fungus in the centre. Where the colony is in close relation with a bronchus and has had a good supply of oxygen, spores are produced which may be disseminated through the lung by way of the bronchi and give rise to further extension of the process. Eventually the necrotic tissue may be sequestrated and expectorated, thus giving rise to cavities with gangrenous walls. Usually bacteria do not take part in the necrotic process, and purulent liquefaction of the necrotic tissue does not occur. In typical cases there is little foetor as- sociated with the process. It would seem that the fungus inhibits the invasion of the putrefactive bacteria into the lesionso ^ Tenth International Medical Congress, Berlin, 1890. "^Etude sur I' Aspergillose chez les Animaux et chez I'Homme, Paris, 1897. ^ Pneumonomykosis Aspergillina, Jena, Germany, 1900. *Allbutt's System of Medicine, VI, 257. ^Nothuagel; Specielle Pathologic und Therapie, XIV, 2; I. Abth. 156. 352 DISEASES DUE TO VEGETABLE PARASITES The niicroorganisni may exist in the lesions in eolonies, ^vith a form suggestive of actinomyees; or the hypha^ may penetrate the diseased tissue more or less diffusely. The process in the lungs may become arrested and the fungus may disappear. In this case, extensive fibroid changes may result, or the lungs may become the seat of tuberculosis. INIetastatic lesions are not known to occur in aspergillosis. Symptoms. — The clinical course of the disease in the primary cases is either that of chronic pulmonary tuberculosis or of chronic bronchio- litis, cm})hysema, and chronic interstitial pneumonitis. In secondary cases symptoms referable to the infection with aspergillus may be ab- sent or of little importance. Diagnosis. — The diagnosis can only be made by finding fragments of the aspergillus or its spores in the sputum. Culturc^s may be necessary to establish the identity of the microorganism. The fragments of the microorganism uuiy be found imbedded in blood clots or in masses of necrotic tissue. The sputum may resemble that of pulmonary gangrene but the characteristic foetor of that process is absent. Tubercle bacilli may be found coincidently in the sputum. It is important that the sputum be fresh, for it may be secondarily in- vaded by spores of the aspergillus from the air. Microscopical exami- nation of the sputum for the fungus is facilitated by mixing a small amount of it with a 20 ])er cent, solution of sodium hydrate in order to dissolve the cells and tissue fragments and render the fungus elements more clearly visible. Prognosis. — When aspergillosis is engrafted upon a chronic disease of the lungs, it usually does not seem to contribute much to the death of the individual. In primary cases the prognosis is not so bad as in pulmonary tuberculosis, but it is to be borne in mind that even if the aspergillosis is arrested and disappears, the permanent injury to the lungs may lead to eventual death or may be followed by pulmonary tuberculosis. Cases with a clinical course resembling emphysema and chronic bronchiolitis seem to have a worse prognosis than those resembling pulmonary tuber- culosis. Treatment. — In the primary cases it is of the utmost importance that the patient avoid breathing in a dust laden atmosphere, or contact with dry grains and vegetable material. The main reliance should be placed upon fresh air, good food, and tonics. The internal administration of iodide of potassium or of arsenic has been advised. In the secondary form the treatment should be that of the underlying disease. MYCOSIS MUCORINA. There is only one case on record of general infection with fungi of the genus mucor. This was the case reported by Paltauf in which there was found at autopsy ulcerative enteritis, pneumonia, phlegmon of the phar- ynx, and multiple abscesses in the brain. In the lesions a mucor was found. The mucors are moulds, a typical example of which is the common bread mould. Their spores, when injected into the circulation of certain animals, produce effects similar to ihose produced by the spores of asper- gillus. PART VI. DISEASES CAUSED BY PROTOZOA. CHAPTER XVII. THE PROTOZOA. By GARY N. CALKINS, Ph. D. The progress made during the last few years in the study of pathogenic protozoa justifies us in expecting that discoveries and advances v\^ill ulti- mately place the subject of protozoan pathology upon a sound scientific basis. So few malignant forms have as yet been worked out, however, that we are still constrained to seek analogies in rather distantly related non-parasitic types. Fortunately we have here a wide realm of facts which have been accumulated during more than two hundred years of study upon these unicellular forms; facts which have been collected and grouped into biological laws which we believe are applicable to all forms, parasitic and pathogenic, as well as harmless types. The protozoa are unicellular animal organisms, which reproduce by division or spore-formation. They invariably have nuclear material, usually in the form of a definite nucleus, but occasionally scattered throughout the cell. They may live alone or associated with sister-cells in colonies of varied form, size, and complexity. They have two well- defined phases, one of vegetative activity, the other of quiescence; during the latter the organisms are protected by resistant secretions, termed cysts. Protozoa are organisms of a different type from the bacteria with which they are often compared. The difference is not entirely covered by the usual statement that bacteria are plants while protozoa are animals, for it is universally agreed that there is no hard and fast line between the two, but a distinction is rather to be sought in the life-cycle involving the alter- nation of sexual and asexual phases. The protozoa must be recognized as organisms of a higher grade than the bacteria, with more varied con- ditions of life, greater complexity of functions, and probably with a more variable vitality. Strictly speaking there is no one type of protozoa, the thousands of species which have been named and described being grouped by zoologists into four great divisions, sarcodina, mastigophora, infusoria and sporozoa. 23 353 354 DISEASES CAUSED BY PROTOZOA The sarcodina, including about 5,500 known and described species, are characterized by changeable protoplasmic j)rocesses, called ])seudopo- dia. The great majority are marine or salt -water forms antl have played an important part in the formation of the earth's crust through the deposi- tion of their calcareous or silicious shells and skeletons. The masiujo'phora, including those forms which move by one or a few undulating processes called flagella, are the closest protozoan allies to the bacteria, and also, through their colonial forms, to the metazoa. Numeri- cally they are much less important than the preceding class, having less than 500 species, but economically they are rapidly assuming a first im- portance, and diseases like trypanosomiasis in man and domestic animals, and syphilis, are due to flagellates. The injusoria arc characterized by numerous fine cilia, distinguished from flagella by their greater number, shorter length and sweej)ing stroke. The class comprises the most highly dift'erentiated types of protozoa and includes about 600 or 700 species, among which are several families of highly modified infusoria in which the cilia are replaced in the adult by suctorial tentacles (suctoria). So far as known, these higher types are never pathogenic. The sporozoa, finally, have no motile organs and are invariably para- sitic. Their name comes from the characteristic method of reproduction, by sporulation. This group, more than any of the others, has a practical interest inasmuch as a number of diseases in man, as well as in the lower animals, can be traced to them. It is not particularly rich in species, about 250 to 300 being known. Were we to select a single cause for the origin of the many variations of structure in protozoa, it might well be the adaptations brought about by the various methods of food-getting due to the varied conditions of life. Many, like amoeba and its allies, take only living food which is captured by the pseudopodia and digested in internal cavities termed gastric vacuoles; others, like some mastigophora and infusoria, capture their prey by whirlpool currents caused by flagella or cilia; some, like certain ciliates, capture it by specialized harpooning organs, the trichocysts; others, like certain flagellates and sporozoa, have no food-procuring organs, but (like bacteria) living in a nutrient medium, absorb it directly without gastric digestion; still others, like suctoria, procure it through special sucking tentacles, and others, finally, like the phytoflagellates, manufacture their food through the agency of chlorophyl. Although many protozoa are parasitic — one group, the sporozoa, in- variably so— they form a small minority in the total number of protozoa. Some of these parasites are comparatively harmless (gregarines) ; others, like the pebrine organisms of silk worms, or epithelial-cell parasites of various animals, are extremely harmful. The majority are restricted to a particular organ or tissue; i. c, are limited to a particular kind of food; thus the organisms of smallpox and of scarlet fever thrive in skin cells, the organisms of malaria and of trypanosomiasis, of Texas fever and east coast fever, etc., in the blood; coccidia, in epithelial cells, eimeria sala- mandree and cyclospora karyolytica, in cell nuclei, and myxosporidia and sarcosporidia in muscle cells. It is not improbable that this apparent selection is due to chemical or physical actions which the organisms have no power to control, any more than some free-living forms have power to THE PROTOZOA 355 control the selection of a certain kind of food from abundance of different kinds. For example, actinobolus radians, found in pond water, gives no reaction to the impact of hundreds of minute creatures bumping against it, until a particular form, halteria grandinella, approaches, when tri- chocyst-bearing tentacles are shot out, paralyzing the halteria, which is then swallowed. This may be explained as a chemical or physical action which neither organism apparently, has the power to regulate. The protozoa have the usual physiological animal activities; proteids are digested through the agency of a mineral acid, and undigested food is voided, in many cases through definite and permanent anal openings. The waste products of protoplasmic combustion are thrown oif in many cases by definite organs, the contractile vacuoles, although more often by osmosis. They respond in varying degrees to stimuli — some manifest- ing complex motor reactions, as definite in purpose apparently as any reflex action, others responding sluggishly. Finally, in self-reproduction, the protozoa are exceeded in rapidity only by bacteria, and every conceiva- ble mode of reproduction is met with from slow, equal, binary fission, to prolific multiple fragmentation The processes of reproduction are governed directly by the food supply, and indirectly by the condition of that complex of functional activities which will be spoken of subsequently as vitality, this varying with the different phases of the life-cycle. The ordinary methods of reproduction are simple or binary division, budding or gemmule-formation, and spore-formation. Methods of Reproduction. — Under proper physical and vital con- ditions, multiplication of the protozoa is very rapid. If certain salts are present, protozoa in a short time may develop in the purest drinking waters to such an extent that, owing to odor and taste, it is unfit for use. If prey is abundant, the same rapid multiplication will take place in all kinds of predatory forms, while parasitic forms are kept down only by the natural immunity of their hosts, by remedial measures, or by loss of their own vitality. The primary method of increase is that of all cells — simple division — but here, as in all other living things, the number of progeny varies with the difficulties in perpetuating the species. Thus in parasitic forms like sporozoa, simple division has been replaced by the far more prolific method of spore-formation, while the same end is attained in some types by budding or gemmation. 1. Binary Fission. — ^The process of division in a protozoon is not very different from that in a tissue cell. The nucleus is the first to divide, and then the cell body. Very often there is a complicated nuclear figure con- sisting of centrosomes, spindle-fibers and chromosomes, but more often the material of spindle fibers and centrosome is compressed into a single intranuclear body called the division-centre, about which the chromatin is massed. Nuclei of this type are called "centronuclei" or "amphi- nuclei" and these are probably the most typical of all protozoan nuclei. There are many modifications, especially in the primitive forms, the most important being the absence of nuclear membranes and the diffusion of the chromatin granules (chromidium) throughout the cell {e.g., tetramitus. Fig. 5). In such cases the granules are collected about the diAdsion cen- tre prior to division, and at this period the nuclear eleme-nts appear like a typical centronucleus. This "distributed" condition of the chromatin 356 DISEASES CAUSED BY PROTOZOA is also characteristic of the bacteria and possibly re])resents a phylogenetic stage which is jiresent at some period in the life-histoiy of every known protozoon. The division-centre frequently plays other roles in the cell — thus, in heliozoa it may be the centre of the radiating axial filaments which Fig. 5. ^ £ C ^ Division of Tetramitus Chilomonas Calkins. — The ordinary vegetative form (A) has nuclear material (c) scattered throughout the cell (distributed nucleus). When preparing for division these granules are grouped in the vicinity of the division centre {B s) which divides first (C) after which the chromatin granules are separated into two similar groups about the two parts of the division centre (D). support the pseudopodia, while in trypanosoma it becomes die "blepharo- plast" or main part of the "micronucleus/' and furnishes the substance of the vibratile flagellum. 2. Budding and Gemmation. — In many forms of protozoa, division is frequently asymmetrical, resulting in dissimilar products. Such division may be multiple, forming three or more smaller organisms, and is dis- tinguished from simple, binary fission by the terms budding or gem- mation. The budding area, as in the free-living heliozoon, acanthocystis, or in the fish parasite, myxidium, may be the entire periphery, or as in acineta it may be confined to a limited part of the surface. A further com- plication may be brought about by the insinking of the budding area into the body substance so that the buds are contained in a kind of brood sac. These are distinguished as ectogenous and endogenous budding; the latter is characteristic of the group myxosporidia to which some of the most malignant types of animal parasites belong. Here the localized budding areas are called "pansporoblasts" and, as in typical brood pouches,^ the spores are formed while the animal continues the ordinary vegetative life.* 3. Spore Formation.— In some free-living forms, reproduction by division takes place w'hile the animal is protected by a cyst. Thus in colpidium, an infusorian abounding in stagnant waters, the cell secretes a cyst, within which it divides twice consecutively, forming four daughter ^In some types the entire organism forms the pansporoblast, and these have been interpreted by Stempel and Minchin as representing the pansporoblast areas of adult organisms which, in the course of phylogenetic development, have become free and now develop directly into pansporoblasts. This is the type, for example, in the genera Thelohania, Pleistophora, and Gurleya. THE PROTOZOA 357 individuals. Except in point of numbers this process of reproduction differs in no wise from that known as spore formation, whereby tlie single cell divides either serially or at one time into hundreds of daughter individuals. Much confusion has arisen because of a mixed terminology, especially in the case of parasitic protozoa. Consistent terms seem to be sifting out, however, from the heterogeneous collection, and these, based apparently upon natural lines, will probably supplant all others. Schaudinn, whose genius has dominated all lines of protozoan investigation, suggested in Different stages of the Flagellate Tetramitus Rostratus Perty. ( Stein.) — Ordinary vege- tative individuals {A. B. from side and front) reproduce asexually by longitudinal division. They ultimately become plastic (C) and miscible, and two individuals upon meeting {D) fuse. The copula secretes a membrane, and its protoplasm fragments into hundreds of spores, (£) which qtiickly grow into the parent type. (F. G. H.) 1899 that a consistent terminology of spore-forms is offered by the words "sporoblast," "sporozoite," and "merozoite," and by the words "spo- ront" and "schizont" which designate the adult forms producing spo- rozoites and merozoites respectively. Merozoites and sporozoites indicate biological conditions which are traceable to the general vitality of the parent forms, conditions which 358 DISEASES CAUSED BY PROTOZOA appear not only in parasitic forms but apparently in all protozoa. After a certain niiinljer of reproductions by asexual nierozoitc formation, vitality is exhausted and conjugation, or the union of gametes, takes ])lace, renew- ing vitality and resulting in spores and sporozoites, produced when the vital- ity is at its maximum. The s})orozoites in turn develop into schizonts, completing the cycle. A simple illustration is afi'orded by the reproductive phases of certain mastigo])hora such as tetramitus or cercomonas (Fig. 6). Here in both cases the usual mode of reproduction is by simple longitudinal division, the daughter cells being equivalent to merozoites. After division has been repeated for many generations, the organisms lose their definite contour, become plastic, and two of them ujion meeting, fuse to form a fertilized cell, the copula. Within the copula wall, the pro- toplasm breaks up into hundreds of reproductive bodies equivalent to sporozoites, but to which the name "spore" has been applied for many years. Turning from these simple cases to the complicated but analogous re- production of sporozoa, we find that the same principle holds good, and "spore" products are formed after sexual union. Confusion has arisen because the asexual reproduction, Avhich in tetramitus takes place by binary fission, is replaced in sporozoa by the more prolific multiple division or spore-formation in the old sense. The reproductive elements, which are formed in this way, are termed merozoites to distinguish them from the reproductive bodies formed after conjugation, while the process by which they are formed is termed schizogony, and the producing adult, the schizont. After this asexual method has been repeated for a more or less definite period, merozoites are formed which develop into conjugating individuals termed gametes, which like tetramitus, may be similar to one another, or, unlike tetramitus, may be sexually differentiated. If the latter, the larger, yolk-stored cjviiescent forms are the macrogametes, the minute, actively motile, spermatozoa-like forms, are the microgametes. After union of the sexual elements, the encysted copula becomes either a single sporoblast, or it divides into from two to many parts, each one being a sporoblast. Each sporoblast may be separated from the others by a special sporocyst (as in coccidia), or the sporoblasts may be merely repro- ducing centres W"ithout special sporocysts (as in plasmodium and laver- ania), but in all cases the sporoblasts give rise to the ultimate reproductive bodies or sporozoites w^hich, usually protected by spore-capsules, are shielded from the exigencies of a more or less prolonged ectogenous cycle. Spores in the myxosporidia differ from those in other protozoa in having one or more specialized thread-holding capsules. These so-called "polar capsules" are sufficiently characteristic to distinguish the spores of myxosporidia from all other sporozoan reproductive bodies. The function of the thread is to assist the sporozoite in securing attachment to epithelial cells when taken into the digestive tract of a new host. The variations which occur in the different types of sporulation in sporozoa are legion; among these monocystis ascidife is noteworthy in having two adult organisms (sporonts) unite to form a common cyst (Fig. 7). Each divides into a number of amoeboid elements, the gametes, which fuse two by two (in the allied genus stylorhynchus the con- jugating gametes come from different cells and this is presumably true of monocystis). Each of the many copulas forms a single sporoblast and THE PROTOZOA 350 gives rise to eight sporozoites. Another variation is seen among the coccidia where in some cases, (adelea, cyclospora, etc.), the ultimate sexually differentiated gametes are represented by a long series of genera- tions of sexually differentiated merozoites. Fig. 7. Life Cycle of Monocystis Ascidise. (Siedlecki.) — The young sprozoites enter epithelial cells (A, B, C), and grow into adult gregarines which leave the cells (£)), and live as "sporonts" in the cavity of tlie intestine. Two sporonts unite {E), their nuclei divide repeatedly (F), until many daughter-nuclei are formed ((?). These become nuclei of amcsboid gametes (H), which move about inside of the cyst, and soon conjugate two by two (/), the nuclei fusing to form cleavage nuclei of the sporoblasts (J). The cleavage nuclei then divide thrice to form eight daughter-nuclei {K,L,M,N), which ultimately become nuclei of the sporozoites (0). The sporoblasts, meanwhile, secrete firm cysts within which the sporozoites are protected. The merozoites do not leave the host, but migrate to new localities where they repeat the process of development and sporulation, until they ultimately change into the sexually differentiated reproductive bodies; these, after fertilization, produce the cyst-protected sporozoites, which remain quiescent until carried into new hosts. Merozoites thus give rise to auto-infection of the host, and sporozoites to fresh infection of new hosts, most frequently by way of the digestive tract where they are carried with the food. The cysts are then dissolved off by the gastric fluids, and the liberated sporozoites make their way into the epithelial cells. In appearance they closely resemble the merozoites but can be usually dis- tinguished by minor differences such as general contour, presence of pig- ment, nuclear characteristics, or other features. In non-parasitic protozoa we meet with closely similar life-cycles haA^ng the same alternation of sexually and asexually produced spores. In 360 DISEASES CAUSED BY PROTOZOA marine foraminifera, for example (poljstomella, Fig. S), the alter- nation is shown by struetural differences in the atiult shells and in the reproductive elements. Shells that are formed by recently fertilized gametes (equivalent to developing sporozoites) have a small central Fig 8. D ■■ i\\M\ \ ' ' j I'.i.i Life cycle of Polystomella Crispa . J ^ O J O ___.-^_r- 1 1-1 ,■ z * s I , ^ H o T ^—r ._. . _ ^ : --. J [ 1 " V 1 , y s ^ , ^r...._.o » 1 fc; '";• n. :'"" < s — ■ .._„ « to > aj "~ d tj e U3 I- o H . C - 1 a — « °-2 - § ^ S? *- "" c. S -■^ !--£ s a.> ° S _, •« .- -5 13 . f- O " ^ 3| S o 2 3 S^ Si i^ ^ CS .S <^ >'. ■ S - £ ■£ "5 -3 =3 -r >> 1^ S H ^ H S 2-3 "^ S §. £ ^Z-^'ao M. i_ s OJ -ti o d .2^.5 ^-S ^3 tn - bB 2 ® ^ >>-S^ £ C § ° -3 ". =3 E= ^. -a i f "g -3 ^ .2 ^ C <" is -t ^ C3 O ^ S I' 2 a oj J, o ■" g, -^ _ o •= 8 c 'g *- T .2 oT a £ § & ^ c. fl o d .a -s ■- - -"^ ■, tJD 'i ^ .o ■< I C: K oj d ba, and Leydenia. ORDEU 2. Thccamocbida. — Shell-bearing amoeboid forms with lobose pseudopodia; no parasitic form. SUB-CLASS. Foraminifera. — Divided into 10 orders; the various genera are salt water forms for the most part, and are never para- sitic. (Sub-class Mycetozoa would be placed here were we to consider these forms as protozoa instead of fungi. Here are placed parasitic forms such as Plasmodiophora, Tetramyxa, Labyrin- thula and other parasites of plants.) CL.\ss II. Heliozoa. — The genera are confined mainly to fresh water and are never parasitic. They are sub-cl:vided into four orders according to the nature of the skeleton. CLASS III. Radiolaria. — Salt-water forms of protozoa, never parasitic. PHYLUM II. Mastigophora. — Protozoa with flagella. CLASS I. Flagellata. — Small forms with from one to several flagella; with a strong tendency to form colonies. ORDER 1. Monadida. — Minute forms with from one to three flagella. There is no definite mouth-opening and nutrition is holozoic, saprophytic, or parasitic. The parasites and commensals which belong to this order are species be- longing to the genera Cercomonas, Herpetomonas and Trypanosoma. ORDER 2. Choanoflagellida. — With collar-like processes surrounding the base of the flagellum; not parasitic. ORDER 3. Heteromastigida. — With two or more flagella of dissimilar length; the genus Bodo is parasitic. ORDER 4. Polymastigida. — The flagella are numerous and of similar or dissimilar size. Here are several ecto- and endo-para- sitic forms belonging to the genera: Costia, Tetramitus, Trichomonas, Monocercomonas, Hexamitus, Lamblia, Polymastix, Lophomonas, Trichonympha, Pyrsonym- pha and Joenia. ORDER 5. Euglenida. — No parasites. ORDER 6. Phytoflagellida. — Flagellates with coloring matter in the form of green, yellow, or brown chromatophores. Frequent- ly colonial. Here belong the most frequent sources of odors in drinking waters, the following genera being especially noteworthy: Dinobryon, Synura, and Uro- glena, all colonial forms, with yellow chromatophores. ORDER 7. Silicoflagellida. — A single genus of salt water mastigophora with latticed skeleton. Distephanus, parasitic on rad- iolaria. CLASS II. Dino flagellata. — Never parasitic. CLASS III. Cysto flagellata. — Two genera of characteristic form. One, Nocti- luca, is remarkable for the vivid phosphorescence which it causes. PHYLUM III. Infusoria. — Protozoa with cilia. In the sub-phylum ciliata these are present at all times; in the sub-phylum suctoria they are present only during the young or embryonic phases. THE PROTOZOA 369 ORDER 1. liololrichida. — The cilia arc di.stributed over the surface, und there is no specialized oral apparatus known as the "adoral zone" consisting of cilia fused into "nicmbran- elles." Here are found some parasites belonfrjng to the genera Ichthioplithirius, Butschlia, Anophrys, Isotricha, Dasytricha, Opalina. ORDER 2. Heterotrichida. — With cilia distributed over the general sur- face and, in addition, a specialized adoral zone in the mouth region. Here are several well-l^nown parasitic forms belonging to the genera Nyctotherus, lialantid- ium, Entodinium, Diplodinium, Ophryoscolex and (Jyc- loposthium. ORDER 3. Hypotrichida. — The cilia are limited to the ventral surface, and are frequently fused into specialized organs of motion and touch, the cirri. There are no strictly parasitic forms. ORDER 4. Peritrichida. — The cilia are greatly reduced, in some cases to the adoral zone, but additional rings may be present. Several ectoparasites belong here, especially the genera, Spirochona, Kentrochona, Lichnophora, Cyclochseta and Trichodina. SUB-CLASS. Suctoria. — Infusoria with suctorial tentacles in the place of cilia. They are frequently ectoparasites and the young of some genera., e.g., Spheerophrya are internal parasites in other infusoria. PHYLUM IV. Sporozoa. — Protozoa without motile organs; reproduction by sporulation; always parasites. CLASS I. Telosporidia. — Sporozoa in which the act of reproduction ends the individual's life, the entire protoplasm being used in forming spores. ORDER 1. Gregarinida. — The young stages alone are cell parasites, the adult organisms living in fluids within the cavities of animal hosts. There are no human parasites. ORDER 2. Coccidia. — Intra-cellular parasites, mainly in the epithelial cells of vertebrate and invertebrate hosts. Human para- sites have been traced mainly to the genus Coccidium. Here also we should place Cyclasterella scarlatinalis Mallory. ORDER 3. Hoemosporidia. — Sporozoa of small size living in the blood cor- puscles of vertebrates. Human parasites belong to the genera Laverania, Plasmodium, and Piroplasma. CLASS II. Neosporidia. — Sporozoa in which the entire cell is not used at one time in forming spores, the latter developing while or- dinary vegetative processes are carried on. ORDER 4. Myxosporidia. — Neosporidia with spores containing polar cap- sules and anchoring threads. Here belong several gen- era of note, in that serious epidemics of lower animals are caused by them, e. g., nosema — causing pebrine dis- ease in silkworms, Myxobolus, Myxidium, etc. ORDER 5. Sarcosporidia. — Neosporida in which the initial stages are passed in muscle-cells of vertebrates. Cysts are formed with double membranes in which kidney-shaped re- productive elements are produced. The one genus occasionally parasitic in man is Sarcocystis. This phylum is particularly rich in forms whose affinities are too obscure to permit of taxonomic position, and further work must be done before they can be accurately placed. There is strong evidence that future research will demon- strate the necessity of another class to hold these organisms, or perhaps, several classes. At the present time such forms can only be admitted as Sporozoa In- certceSedis, and as such we would include the genera Ophryocystis, Serum- sporidium, Lymphosporidium, Blanchardina, Cytoryctes and Neurorycetes. (It is probable from Williams' observations that Neurorytes, the cause of ra- bies, is a rhizopod and not a sporozoa; if so, Cytoryctes, which is closely related, must be placed there too.) 24 *• CHAPTER XVIII. MOSQUITOES. By L. O. HOWARD, Ph.D. Every person interested in liiunan health should have some knowledge of mosquitoes. The carriage of malaria by the different species of the genus Anopheles and the transference of yellow fever by Stegomyia calo- pws render it necessary that not only medical practitioners but also the laity should be thoroughly familiar with the characters which distinguish these mosquitoes in order that they may at once be recognized not only in the adult form but in all the stages of their existence. The important discoveries which have been made regarding the carriage of disease by mosquitoes render further discoveries of a similar nature not only possible but rather probable, and therefore information among the medical pro- fession regarding them should be widespread; or at least there should be convenient sources of information for the use of those who wish to go rather deeply into the subject, and which may be available in case of needed emergency investigation. It is for these reasons that considerable space is devoted here to the consideration of mosquitoes, their habits, life history, classification, and methods of control. So far as is known definitely, the larvse of all mosquitoes inhabit water, although they are true air-breathers — that is to say, they come to the sur- face of the water at longer or shorter intervals to breathe. '^ Mosquitoes are rapid breeders, and pass the pupal condition also in the water, but floating normally at the surface. Most species pass through several generations in the course of a summer, and many of them hibernate as adults hidden away under the bark of trees, in protected places like outbuildings, the under side of bridge culverts, in old boxes, and in the cellars and attics of houses. In the extreme southern states many species are active throughout the winter, and even as far north as Washington, mosquitoes in heated houses may bite in December and January. In localities where there are prolonged dry spells and where heavy rains are to be expected only at certain seasons of the year, adult mosquitoes of many species live through the dry spells and lay their eggs as soon as the rains come. This is especially the case in tropical regions where the year is Givided into wet and dry seasons. Certain species do not necessarily hibernate as adults or live through the dry seasons as adults. There are many species which may exist for a long time in the egg stage, the eggs being laid in places like small excavations, sure to be filled with water when heavy rains occur, and others hibernate in the larval state. Under normal summer conditions of temperate regions, when rains occur more or less frequently, the life of the average adult mosquito is *The larv£e of Culex dupreei and C. discolor offer the only known exceptions to this rule 370 MOSQUITOES 371 short, and in fact the term of the life of the adult seems to be dependent mainly upon the opportunity of propagation which is the main purpose of the adult. The adult male mosquito does not necessarily take nourish- ment. It will sip water or any liquid substance, like juices of fruits and even the honey of flowers. The adult female does not necessarily rely upon the blood of warm-blooded animals; they are plant feeders, and very few of the countless millions ever get an opportunity to taste the blood of a warm-blooded animal. They have been seen puncturing the heads of young fish and swarming about turtles when the latter are upon land. They also have been seen puncturing the chrysalis of a butterfly. The larvae, on the contrary, feed upon all sorts of minute organisms float- ing upon the surface, held in suspension in the water, or resting upon the bottom of pools. Many species are adapted successfully to resist extremely low tempera- tures. Arctic travelers speak of the abundance and voracity of Arctic mosquitoes. They occur in enormous swarms during the short summers of Alaska, Lapland and Greenland. Classification. — All mosquitoes belong to the order Diptera, or two- FlG. 11. wmmm Wing of a mosquito, sliowing scales. (Original.) winged flies, and to the family Culicidae. The species of the family Culi- eidse may at once be distinguished from all other dipterous insects by the fact that the wing veins and the body bear flattened scales. There are certain other insects which bear a close general resemblance to true mos- quitoes, such as certain crane-flies of the family Tipulidae, and especially of the genus Geranomyia in which the insect has a distinct mosquito-like form and a prolongation of the mouth-parts resembling the mosquito's proboscis, but when examined under a microscope or high power hand- lens the wing veins are seen to be naked — not clothed with scales or hairs. The family Culicidse has been divided into several sub-families, but for the purposes of this work it is only necessary to consider the sub-families Culicinse and Corethrinae, the former sub-family including all true biting mosquitoes and the latter those forms in which the proboscis is short and not formed for piercing. Certain authors have split up the biting mos- quitoes into several sub-families, and have even given some of them family rank. Such a classification seems premature and the families so created do not seem to have equal classificatory rank or to be founded upon as important morphological characters as the other accepted famihes in the order Diptera. Considering, therefore, all true biting mosqui- toes as belonging to the sub-family CuUcinse, the principal North Ameri- can genera will readily be distinguished by the following table, and the 372 DISEASES CAUSED BY PROTOZOA non-bitiiig mosquitoes of tlie sub-fumilj Coivthriiuii will receive no further consideration in tliis aeeount. Synoptic Table of the Principal Genera of the Biting Mosquitoes (Culicinse) of the United States. 1. Palpi in the male at least nearly as long as the proboscis; in the female less than one half as long 3 Palpi in both sexes at least almost as long as the proboscis 2 Palpi in Ijoth sexes less than one-half as long as the proboscis 7 2. Proboscis straight or nearly so, colors of body brown and yellow- ish Anopheles Proboscis very strongly curved, colors bluish or greenish. . . .Megarhinus 3. Legs bearing many nearly erect scales Psorophora Legs destitute of such scales 4 4. Back of head bearing many narrow scales 5 Back of head covered with broad, appressed scales Stegomyia 5. Feet black, the hind ones in part snow-white J anthinosoma Feet not marked like this 6 6. Scales in outer rows on sides of veins of wings very narrow, scarcely tapering at tlie base Culex Scales in outer rows on sides of veins in basal half of wings very narrow, many of those in apical half of wings rather broad and distinctly tapering at the base M elanoconion Scales of wings very broad, strongly tapering at the base. . Tceniorhynchus 7. Upper side of thorax with line of bluish scales Uranotcenia Upper side of thorax not marked in this way 8 8. With several bristles below the scutellum Wyeomyia Without such bristles Aedes Certain additional generic names are used in connection with American mosquitoes, especially Grabhamia and Theobaldia. Mr. D. W. Coquil- FiG. 12 Head and beak of a mosquito, showing antennae, palpi, proboscis. (Original.) lett, who is responsible for the preceding synoptic table, is not yet quite certain of the status of these two genera Certain generic names have also been proposed by Felt and by Dyar in which the genera are based upon MOSQUITOES 373 examinations of the genitalia of the male sex. While it is quite likely that these genera may be valid, more must be known about them bcd'ore they are introduced into a work of this character. It may also be statfid that just as this article is being completed a West Indian genus, Deinocerites, has been taken by Dyar at Miami, Florida. D. cancer, the sj;ecies cap- tured, breeds in brackish water at the bottom of crab holes near the sea.^ MOSQUITOES OF THE GENUS CULEX. None of the species of the genus Culex have been definitely and ac- ceptably shown to be responsible for the carriage of disease in temperate or subtropical regions, although the parasitic worms of the genus Filaria, are said to be carried and transmitted by Culex jatigans as well as by Stegomyia calopus and Anopheles. The claim that dengue fever is trans- mitted by a Culex does not seem as yet to have been fully substantiated. The species of this genus may be recognized by the more or less erect forked scales on the head and the slender elongate side scales of the wing veins. Although many genera have been split off from the genus Culex as it was understood as late as 1900, by Theobald and other writers, the genus still remains complex and is likely to be still further split up. Although the adults of the genus as at present understood have a com- paratively uniform structure and may not readily be divided generically by sound morphological characters, the larvee differ radically among them- selves, and many important points in the life history are so variable among the species as to render a prophecy as to future generic subdivision prob- ably sound. Many of the individual species which are accepted to-day have two or more distinct types of larvse from which are bred non-separ- able adults, which would seem to indicate the necessity for new species based on larval characters. The type of the genus has always been considered to be Culex pipiens of Linnaeus, an almost perfectly cosmopolitan form which breeds com- monly about houses in all parts of the civilized world and is, in temperate regions especially, the commonest inhabitant of rain water barrels. This species was long considered as perfectly typical of the genus not only in structure but in life-history; but the extended studies of other species have indicated remarkable differences in life-histories. The eggs of Culex pipiens are laid in an irregular raft-shaped mass on the surface of the water. The mass is usually shaped like a pointed ellipse, somewhat convex below and concave above, all the eggs standing on end and closely applied side by side in from six to thirteen longitudinal rows, and from three or four to forty eggs in a row. The number in each batch varies from two hundred to four hundred. Individual eggs are ^ Since this article was put in tyi^je there has been great activity in the splitting up of the old genera and the erection of new genera of mosquitoes, and a condition of staple equilibrium has not yet been readied. To print a full synopsis of these late views would far exceed the limits of this work, and the writer therefore re- fers readers who wish to carry the subject of classification further, to Technical Bulletin No. 11, Bureau of Entomology, U. S. Department of Agriculture, entitled "A Classification of the Mosquitoes of North and Middle America," by D. W. Coquillett, Washington, 1906, page 31, 1 figure, which will be sent free to appli- cants. 374 DISEASES CAUSED BY PROTOZOA .7 mm. long and .IG mm. in diameter at the base. The entire egg mass is about one-fourth of an inch in length. In summer weather the eggs hatch in from sixteen to twenty-four hours. The hirvjie issue from the under- side of the egg mass and are very active at birth. They come frequently to the surface to breathe, and during the first few hours of their life may Culex pipiens : egg-mass and enlarged eggs. (Author's illustration.) remain under the egg mass where they get air from the air film by which the mass is surrounded. The mouth of the larva, or "wriggler" as it is commonly termed, is furnished with tufts or filaments which are con- stantly in vibration. The head is large, the antennse long, the thorax somewhat swollen, and the abdomen slender. The sides of the body are furnished with stiff bristles. There is a long breathing-tube which issues Fig. 14. Culex pipiens: full-grown larva. (Author's illustration.) from the next to the last segment of the abdomen, and this tube is thrust through the surface film of the water every time the larva rises to breathe. The extremity of the tube is furnished with a spiracle and into it run the two main tracheae of the body. The true end of the body is furnished MOSQUITOES 375 with four jflat flaps which in young larvae probably function as air-gills. The specific gravity of the larva is somewhat greater than water, and it wriggles in ascending to the surface, but so slight is this difference in spe- cific gravity that the tension of the surface film of the water is sufficient to maintain it without exertion while breathing. In warm weather about seven days suffice for the growth of the larva? and they then transform to pupaj. In this stage the insect breathes through two breathing tubes, one issuing from either side of the thorax. These are trumpet-shaped. The pupa is lighter than water and main- tains its position at the surface without effort. It is active, and to escape its natural enemies may wriggle actively below the surface of the water. Immediately this exertion ceases, it rises rapidly to the top where it re- FiG. 15. Culex pipiens: adult male and details. (Author's illustration.) mains most of the time. In the pupal stage the insect remains, in mid- summer, about two days. A minimum generation of Culex pipiens will, therefore, occupy ten days — egg, sixteen to twenty-four hours, larva, seven days, and pupa, two days. In colder weather, however, the duration of this development may be indefinitely suspended. There is an indefi- nite number of generations each year, and the species will go on breeding so long as the temperature is favorable. The adult as a rule hibernates. In the neighborhood of two hundred species of the genus Culex have been described, and as before stated there is considerable variation in the habits and life-histories of the different forms. The common salt-marsh mosquito of the Atlantic coast, Culex sollici- tans, for example, according to the observations of Smith, does not lay its eggs in water or on the surface of water. The eggs must be dry, or not 376 DISEASES CAUSED BY PROTOZOA water covered, for at least twenty-four hours after they are laid. Other- wise they will not iiatch. They may remain dry for three months or longer without losing vitality, and if at any time, after they have been dry for a week or tvvo, they become covered with water they hatch at once. It seems also from these observations that not all of the eggs hatch the first time they are cpvered with water, the others hatching upon the second covering. Eggs are laid in every damp space on the salt marsh and the country immediately adjoining it. They are not laid in raft-shaped masses, but singly. Culex icEniorhynchufi, also a salt marsh mosquito, lays its eggs as does C. .s-oJIicitans. C. perturbaiis, on the contrary, lays a raft-shaped mass, as docs C. pipicufi. C. squamirjer has apparently but one generation each year, instead of many as with C. pipiens. C. piplens bites Fig. 16. Culex pipiens : adult female. (Author's illustration.) mainly at night, but C. soUicitans flies by day and bites when opportunity offers. The common woods mosquito, C. sylvestris, lays its eggs singly on the surface of the water, when they sink to the bottom, or they may be placed upon moist mud to hatch when the water comes. It appears to hibernate in the egg stage, although larvse have been found in pools late m the autumn after ice has formed. A species commonly found in woodland pools, C. canadensis, as with several others, hibernates in the egg stage and is one of the earliest mosquitoes to bite in the spring. The flight of the species of Culex seems to vary considerably. C. pipiens is not a strong flier, and is in no sense a migratory mosquito. It stays about houses and flies no further than is necessary to secure food and lay its eggs. C. soUici- tans, on the other hand, is said by Smith to fly for long distances inland MOSQUITOES 377 from the sea coast where it breeds. He finds swarms of this mosquito forty miles from the coast; and in none of his experiments has he been able to breed it from fresh water. It is perhaps worthy of note that what is apparently this species has been bred by Mrs. Hinds in Texas and by Dupree in Louisiana, from fresh water; but this is probably a case where we have adults which arc specifically indistinguishable but which may really be specifically distinct. C. territans, a rather common small species, lays its eggs in rafts smaller than those of C. pipiens. The larva is very remarkable, having an enormously long, slender air-tube. The head is very broad with prominent antennae which are black at the tip and have a tuft of long hairs near the end. It seems to prefer cold water rather than Fig. 17. Culex sollicitans: adult female. (Author's illustration.) warm, stagnant pools. C triseriatus lays its eggs singly or in patches at the edge just below the surface of the water where they adhere slightly and remain unhatched until spring. This species is probably single brooded. C. dupreei has a larva which seems to be truly aquatic and never comes to the surface of the water to breathe. The larva of C. discolor also apparently rises to the surface very seldom. No such extraordinary variation among species seems to occur with other genera of Culicidse, and the generalizations which may be made concerning the life-history of Anopheles are much more perfect. 378 DISEASES CAUSED BY PROTOZOA MOSQUITOES OF THE GENUS ANOPHELES. As indicated in the synoptic table, the principal structural difference between the adults of Anopheles and Culex is the presence of long jialpi in the female of Anopheles and of very short palpi in the female of Culex. AVith Anopheles the ])alpi in both sexes are about as long as the proboscis. The body colors arc brown and yellow, and the wings are usually spotted. jNlembcrs of the genus Anopheles may rather easily be recognized when at rest, since the body, head, and beak are held in practically the same plane, whereas there is a marked angle between the body and the head and beak in most other mosquitoes. It is the habit of most species of Anopheles, in resting upon a horizontal wall like a ceiling, to hold the body not parallel with the wall but at a distinct angle with it — sometimes approximating 80°. Frequently with some species, even when on a per- pendicular wall, this angle of rest is very obvious. As a rule the Anopheles mosquitoes bite only after nightfall, but an exception must be made in the case of A?iopheIes crucians which will bite durino- the day. This is a matter of importance, since it has heretofore been believed" that shelter from mosquitoes after nightfall obviates all dano-er from malaria. Even Anopheles punctipennis has been seen by Smith in the afternoon on porches, and Dyar has known it to bite by day. It has not been proven definitely that this species will carry malaria, and in fact its presence in large numbers in portions of New Jersey where malaria is unknown and yet where cases of malaria must frequently be brought, would indicate that in this species we have possibly an exception to the disease-bearing function of the genus. ^ The Anopheles mosquitoes do not seem to be strong fliers, and there are no instances on record known to the writer which prove a longer flight from breeding places than half a mile, which of course is an impor- tant point in the problem of the extermination of Anopheles by means of the abolition of breeding places or their treatment with insecticides. All the species of Anopheles, differing from many woodland and swamp mosquitoes, make every effort to enter houses. Hibernation is almost uniformly in the adult stage, and in regions where they breed abundantly, the cellars of houses, barns, and other outbuildings will be found to be favorite places of hibernation. They are often found thickly massed on the inner walls of outhouses, and have been seen during winter on the dark underside of shelves in cellar storerooms, so close together that their bodies touched, for a space of several feet. There are a few recorded instances of the hibernation of the European Anopheles hifurcatus in the larval condition, the most marked having been in Switzerland where the larvEe of this species were found in the vicinity of Lausanne hibernating beneath the ice in January, February and March. The life-histories of all the species are very similar, and the differences among the early stages of the different forms are slight; so that the full life-history of a single species may in a measure be considered typical of the genus. Anopheles maculipennis, one of the commonest forms in the 1 Since this was written, Dr. J.W. Dupree of Baton Rouge, La., has sent the writer a paper in which he states that he has discovered the malarial relation for this species. MOSQUITOES 379 United States, has a wide distribution, occurring also in Canada and throughout Europe. It has not as yet been found in Asia or other parts of the world, and it is quite possible that it was introduced from Europe into the United States; in fact, it is possible that malaria itself was so introduced, although the recorded prevalence of fevers among the early settlers of Jamestown and other portions of this country would antagonize this theory. Fig. 18. Anopheles maculipennis : adult male at left, female at right. (Author's illustration.) The eggs of this species are laid singly upon the surface of the water, and are usually found in little groups. Each egg is boat-shaped and one end is slightly deeper and fuller than the other. When first deposited they are white, but soon darken. The upper surface is marked by minute reticulations, and the under surface by much larger and more regular reticulations dividing it into hexagonal areas. The rim is thickened and regularly ribbed. Along the centre of each side the rim is much thickened and the ribbing is more marked, the thickening recalling the rounded float which runs along the edge of a life-boat. It is composed of air- chambers and keeps the egg with its flat surface uppermost. Nuttall and Shipley have called attention to the fact that when the egg is drawn, by capillary attraction, a little way up from the water upon a leaf or blade of grass, the blunt end always points downward, so that when the hatching takes place the larva emerges into the water and not into the air. Each female deposits from forty to a hundred eggs. In warm weather they hatch in from three to four days, the young larva issuing from a circular split near the blunt end. During the early part of its life the larva remains habitually at the sur- face of the water. Its breathing-tube is extremely short, and the body is 880 DISEASES CAUSED BY PROTOZOA held parallel with the surface and immediately below the surface film, so that portions of the head as well as its breathing-tul)e are ]M-actically out of the water. The head rotates upon the neck so that the larva can turn it around with the utmost ease and feetls habitually with the under side of the head toward the surface of the water. This is its customary feeding position. The long fringes of the mouth parts are constantly in rapid motion, causing a constant current toward the mouth-opening so that all particles floating on the surface of the Avater gradually converge toward the mouth at an increasingly rapid rate and finally enter the alimentary canal. Spores of alga> and minute particles of all kinds, organic and in- organic, floating u])on the surface of the water follow this course and Fig. 19. Anopheles maculipennis : eggs, greatly enlarged. (Author's illustration.) enter the mouth of the larva. Seen under the microscope, those objects which are dark in color may plainly be seen to pass through the head into the thorax. From the fact that it feeds upon these very light floating particles, the specific gravity of the body of the larva is nearly that of the water. It is much lighter than the larva of Culex, which feeds habitually upon particles held in suspension at a lower level, and the Anopheles larva maintains itself horizontally just below the surface film without apparent effort. The tension of the surface film itself seems to afford all needed support. The structural characters of the larva are very distinct and at once separate it from the larva of any other genus of mosquitoes. The head is small; the respiratory tube is extremely short; the body is furnished with very long, lateral, branching hairs, and upon the upper surface of each of five of the abdominal segments there is a pair of specialized pal- mate hairs each with a stalk and a conical bundle of fine hairs, the whole forming a little cup; and it is thought that it is by means of these five pairs of palmate hairs, which cling to the surface film, that the larva maintains its horizontal position just under the surface. The ninth abdominal seg- ment bears below a fan-shaped arrangement of long hairs. The larvae in moving on the surface swim tail foremost. As they approach full-growth, they descend frequently to the bottom of shallow pools, and, where this is covered with sand, may be seen mouthing over the slimy surface of the MOSQUITOES 381 sand grains. The duration of the larval stage is, in midsummer, from sixteen to twenty days. In the pupa] condition Anopheles differs less markedly from other mosquitoes than in the larval stage. In its resting position at the surface of the vi^ater it is less perpendicular than the pupa of Culex, the long axis of the body being horizontal. There is a marked difference in the shape of the two thoracic respiratory tubes, those of Anopheh^s b(;ing short and with a much less slender base. The pupal stage lasts, in midsummer from three to ten days. Fig. 20. Anopheles macuKpennis: full-grown larva, with head reversed, in feeding position. (Author's illustration.) The minimum duration of a generation in the summer time in the lati- tude of Washington is probably about twenty days or perhaps a little less. This period may be extended indefinitely by cooler weather. The female Anopheles will bite a number of times, and in laboratory experimental work it is usually found necessary to give a female Anoph- eles a full meal of blood before she can be induced to deposit her eggs, although Dupree has induced fertile oviposition without the meal of blood. After the first breeding, no further sanguinary diet seems to be necessary and adults may be kept alive for some time by feeding them upon bananas or other fruit. 382 DISEASES CAUSED BY PROTOZOA The genus is one of wide distribution, and tliis distribution corresponds fairly well with the distribution of malarial diseases, the range of Anoph- eles nioscjuitoes, however, being greater than the range of the disease since there are very many localities where Anopheles exist in numbers and Fig. 21. Anopheles larva at surface of water, showing resting and feeding position. (Author's illustration.) where malaria has not been introduced. Just as the disease itself is one of low altitudes, so the mosquitoes of this genus prevail in low-lying situa- tions. They are seldom found in numbers above an altitude of one thou- sand feet, although in the tropics they are found at a considerably higher Fig. 22. Mosquito pupa in resting positions at surface of water; Culex at left, Anopheles at right. (Author's illustration.) altitude. They have even been found in the City of Mexico at an altitude of nearly eight thousand feet, although they are comparatively scarce and malarial diseases are practically unknoAvn, as the writer is informed by health authorities resident in that city. No s]w>cies occurs in the far North, as is quite to be expected from their absence at considerable clevationSt MOSQUITOES 383 In the number of species the genus is a very extensive one, although its distinct forms are not so numerous as the species of the genus Culex. In the United States there are seven recognized species, which may be dis- tinguished by the following synoptic table: GENUS ANOPHELES. 1. With a yelloys^ish-white spot near three-fourths the length of the first margin of the wing 3 Without such a spot 2 2. Scales of the last vein and the palpi wholly black 5 Scales of the last vein white, marked with three black spots, palpi marked with white at bases of last four joints crucians Weid. 3. Hind feet wholly brown 4 Hind feet largely snow-white on the apical half; West Indies, Mexico, Central and South America: Last joint of hind feet wholly white argyritarsis Desv. Last joint black at base albipes Theob. 4. Scales of last vein white, those at each end black, scales of third vein black, those at the apex white punctipennis Say. Scales of last vein white, those toward the apex black, scales of third vein white and with two patches of black ones. . franciscanus McCrack. 5. Wings with several dark spots maculipennis Meig. Wings unspotted barberi Coq. Several other species have been attributed to the United States. Of these, Anopheles Jerruginosus of Wiedemann is probably a synonym of crucians; quadrimaculatus of Say is a synonym of maculipemiis of IMeigen ; and hiemalis of Fitch is a synonym of punctipennis of Say. A. nigripes Staeger, a European species with unspotted wings, is said to occur in northern Europe and North America, but the locality and collector are unknown to the writer. A. pictus of Loew was described from Asia ]\Ii- FiG. 23. Costal cell SiCbcostal cell First vein ' Marginal cell Costal vein | Axillary vein j Second vein I Third vein \ First submarglnal cell ' ' I ''- '- ' ^ ixillary cell I Sixth vein Piflh vein Diagram of mosquito wing, with names of veins and cells. (After Coquillett.) A-'-'Ulcell / Small cross-vein i Second siibjaarginal cell Hind cross-vein Fourth vein nor, and its occurrence in the North American fauna is very doubtful. A. walkeri of Theobald also has unspotted wings, and is said by Theobald to have been captured at Lake Simcoe, Ontario, in September. It is now supposed to be a synonym of the European A. bifurcatus. Probably the commonest and the most Avidely distributed of these species is Anopheles maculipennis. It is not a striking looking form, being 3S4 DISEASES CAUSED BY PROTOZOA of medium size and of general insignificant coloring. The wings have a slight yellowish cast, and bear four rather small dark spots. As pointed out in the synoptic table, the scales of the last wing-vein and the palpi are entirely black. Its Eiu'o])ean distribution has already been referred to, and in the United States it is widespread. It occurs abundantly about New York City and on Long Island. Felt records it as occurring about Albany, and through the central part of New York State it is a compara- Fiu. 24. Anopheles punctipennis : adult femalo. tively common species. In New Jersey, Smith finds that it occurs through- out the state, and, although in general it is less numerous than A . punc- tipennvi, it is on the whole more plentiful in the northern and hilly sec- tions of the state. It is found about Boston and in other parts of New England. It occurs in all of the Atlantic States to Florida, in all of the Gulf States, in Ohio, Wisconsin, Minnesota, Idaho, California, and south into Mexico. It also occurs in Canada. MOSQUITOES 385 Anopheles punctipennis is a much more distinctive looking species. The general effect of the wings is that they are greatly mottled, and there is a characteristic and distinctive yellow^ish-white marginal spot near the apical fourth of the v^^ings. It is of medium size and of dark brown color, and the beak and legs are unhanded. It is very widely distributed through- out the United States, and occurs also in Canada, but its distribution is northern rather than southern. It is found in the New England States, New York, the Atlantic Coast States certainly as far north as North Caro- lina and Louisiana, the Central States including Minnesota. It has been found as far north as St. John, New Brunswick, and as far southwest as Salvatierra, Mexico. It also occurs in California. Fig. 25. Anopheles crucians : adult female. Anopheles crucians, as compared with the preceding species, has rather a southern than a northern distribution It is at once distinguished from the other species by the white bases of the last four segments of the palpi, and by the white scales on the last wing-vein, which, however, is marked with three black spots, while the disk of the wing carries several black patches. As pointed out by Smith, this species flies and bites freely long 25 386 DISEASES CAUSED BY PROTOZOA before dusk and long after sunrise. lie finds it to be the most annoying indoor form at Cape ]\Iay and tliat its chief brcetUng phu-e in New Jersey is in the Cape marsh. The species also occurs rather abundantly on the south shore of Long Island. It extends down the Atlantic coast to Miami, Florida, and is also found in Cuba. It occurs in the Southern States west to Texas. Anopheles albipes is distinctly a tropical and sul)tro)iical form. It oc- curs throughout the West Indies and at various points in Central America as far south as Panama. It has been taken at Key West, Florida, and is reported to occur in India. It is a striking mosquito in general appear- ance, and is distinguished by its silvery-white hind tarsi, the last joint only being black at the base. Anopheles franciscanus is sufficiently characterized in the synoptic table, and is a western form occurring at various points in California. It has also been found at Laredo, Texas, and at Las Vegas, New Mexico. The American Anopheles with unspotted wings, A. barberi, is a rare species, and breeds in hollow trees in the woods. It was originally found at Plummers Island, ISIaryland, and has since been taken in Virginia and at St. Louis. Anopheles argyriiarsis is a form of tropical and subtropical distribution, as is A. albipes from which it may at once be distinguished by the absence of the black mark at the base of the last tarsal joint. It has practically the same distribution as A. albipes. It has been taken at New Orleans and may breed there, although the constant traffic between that port and Central America and W^est Indian points renders the introduction of the species very easy and its capture does not necessarily mean that it is es- tablished in Louisiana. Anopheles albipes and Anopheles argyriiarsis have been placed by Theobald in his genus Cellia, which is distinguished from Anopheles by the dense scaling of the wings, and by the presence of nearly erect clusters of scales along the sides of the abdomen. The habits and larval characteristics are, however, those of Anopheles, and there is little doubt, since they are the prevalent species of the Anopheles group in malarial localities in the West Indies and Central America, that they are malaria carriers. In fact this relation has been proven in the case of argyriiarsis by Lutz, and in the other by Low. THE GENUS STEGOMYIA. The genus Stegomyia was separated by Theobald from Culex, by the fact that the scales of the head and scutellum are all flat and broad, whereas in Culex the scales of the head are narrow and curved with up- right forked ones and flat lateral ones. Sixteen species were originally placed by him under this genus and eight were later described and trans- ferred to this genus, but certain of these have since been placed in other new genera. The genus itself may not prove to be a stable one. Surely the differing life-histories of some of the forms would indicate further separations. No generalization can be made regarding the disease-bear- ing possibilities of the genus, since only a single species, Stegomyia calo- pus, has been shown to carry a disease — yellow fever. MOSQUITOES 387 Stegomyia calopus has a wide distribution. In general terms Theobald considered it as ranging from 38° south to 38° north latitude, the belt extending around the world. It seems to have a general distribution throughout all eastern Australia, western Sumatra, all of Java and farther India, southern Japan, eastern Hindostan, the Seychelles, southern Africa, Mashonaland, Nigeria, the African west coast inchuhng Sene- gambia and Lagos, all of Spain, southern Italy, Palestine, east coast of South America from British Guiana to Rio de la Plata, all of the West Indies, Argentina, the coast regions of Central America on both the Pacific and Gulf of Mexico sides. It is also found at Guayaquil and Callao and will undoubtedly be found at other South American ports in the western coast as far south as Valparaiso. It it also found in the Fiji Islands, the Hawaiian Islands and the Philippine Islands. The Central American distribution of the species is of especial interest as bearing upon the possibilities of its occurrence at high elevations. It is stated above that it occurs upon both the east and west coasts of Central America. In Mexico, since the introduction of railroads running up from the coast, it has been extending its inland and upward range. It has now established itself at Orizaba on the Vera Cruz road at an elevation of 4,200 feet, and at Carasal on the Interoceanic Railroad at an elevation of 3,000 feet. It occurs abundantly inland in North INIexico, having followed up the valley of the Rio Grande, and occurs at all points on the railroad from Tampico to Monterey (altitude 1,630 feet). It has been found in the summer time at Saltillo, which is much higher than Monterey. In the United States it occurs and breeds continuously in practically all of the territory which has been marked as belonging to the Lower Austral life Zone. This territory includes the Atlantic coastal plain from the mouth of the Potomac River southward, and all of the Gulf States except the high regions of Georgia and Alabama about the southern end of the Appalachian chain. It also includes the valley of the Mississippi River for some little distance above its juncture with the Ohio River, the valley of the Ohio River to nearly the middle of the southern border of Indiana, the whole of Indian Territory, the eastern portion of Oklahoma, a small southeastern strip in Kansas, and all of the low-lying eastern and southern portions of Arkansas. The dry regions of western Texas do not furnish sufficient moisture to propagate many mosquitoes, but in the water supply of ranches in such dry regions, if once introduced, the yellow fever mos- quito will probably breed. Although found on the Pacific coast of Mexico, the yellow fever mosquito has not as yet been authoritatively recorded from California, although the coastal region from Point Vincent south to Point Loma offers conditions favorable for its development. Actual collections of mosquitoes were made during the season of 1904 through a large part of this Lower Austral territory, and the distribution of Stegomyia calopus was found to correspond rather exactly with the lines here laid down. The northward spread of this species is interrupted by severe winters. In summer time it is constantly being carried north on boats up the Missis- sippi and Ohio Rivers and by trains coming from the South. Thus it has been found breeding, in the summer time, at points considerably north of true Lower Austral territory. During the summer of 1904 it was found breeding at St. Louis but the severe winter weather precludes the possibility of the perfect establishment of the species at that point. 3SS DISEASES CAUSED BY PROTOZOA Siegomyia calopus is a rather small mosquito, which was formerly re- ferred to in literature as Cidcx Jasciaius and as Culcx i(r>ti(iius. Purists are now calling it Stecjomyia calopus jNIeigen, since fasciata seems to be a homonym. It is a very handsome species, dark in color, with silvery white bands on the legs, conspicuous silvery strijies ujwn its thorax, silvery bands on the palpi, and silvery spots on the sides of the thorax and abdomen. In the British West Indies it is known as the striped-legged mosquito and also as the day nios(|uitp. It bites and is active by day, but may also bite at night. It breeds only in fresh water and is essentially a domestic mos- quito — that is to say, it is seldom found far from human habitations; but about houses and in cities and towns it will breed in any chance accumu- lation of water. It is a long-lived mosquito, a point of importance when considering the interval between the stamping out of an epidemic and a new outbreak without the introduction of a new case from a distance. Guiteras and his assistants at Las Animas Hospital have kept an adult female alive for more than 150 days; and in the dry season with no oppor- tunity to oviposit such a length of life is probably of frequent occurrence. The length of flight has not definitely been determined. It does not seem I to be an especially strong flier, but its possibilities in this direction are of importance as determining tlie safe anchorage distance of vessels from infected ports. Adult mosquitoes have been found on board a war vessel recently arrived in port and anchored a mile from shore, under conditions that seem to show that the mosquitoes flew aboard, the vessel previously having been free, and the possibility of the carriage of the mosquitoes from shore on the persons of individuals in boats having apparently been eliminated. This is on the evidence (in lit.) of Surgeon A. H. Russel, U. S. N. The eggs are deposited singly, each egg on its side, and preferably in artificial collections of water, especially in rain-water barrels and similar receptacles. The eggs may be found singly or in groups of three or more arranged in parallel rows or bunched together. They are black in color, cylindrical in shape, with conical extremities, of which one is blunter than the other. Each egg is .6 mm. long and .16 mm. broad. The female may deposit from 35 to 114 eggs at a time, the average being about fifty. These eggs will withstand desiccation, and are very resistant to external influ- ences. Taylor has kept thoroughly dry eggs for three months, which hatched on being placed in water. Normally the eggs will hatch in from twelve hours to three days, depending upon the temperature of the water. The larva is similar to that of Culex pipiens, but it is more slender and the respiratory tube is shorter and is swollen in the middle somewhat resembling an olive in shape. The growth of the larva is very rapid, and in Cuba the minimum seems to be about sLx days. The larvae develop most rapidly in foul, stagnant water, and the development may be hastened by placing a certain amount of faecal matter in the water. The pupa is rather dark in color, with more elongate thorax and a stouter abdomen than Culex pipiens. The minimum duration of the pupal stage is two days, and the mimimum length of the early stages is therefore eight and a half days (egg twelve hours, larvse six days, pupa two days). MOSQUITOES 389 REMEDIES AGAINST MOSQUITOES. The very best remedy against mosquitoes is to abolish their breeding places, and in many instances this may readily be done with isolated country houses or suburban residences or in villages where the houses are as a rule well separated and surrounded by gardens. In such localities, barring the vicinity of extensive swamp lands, and outside the range of flight of the salt marsh mosquito, every property holder is practically responsible for his own mosquitoes. Every effort should be made to clear out or to abolish chance breeding places. Disused springs and wells should be cared for, and every possible receptacle for standing water should be abolished or filled in. Cesspools should be covered in such a way as to render mosquito access impossible or they should be treated occasionally with kerosene. About a country place or suburban house chance breeding places are apt to be very numerous. Tin cans and old bottles in a rainy summer will hold sufficient water to breed hundreds of mosquitoes. The water pans for pet animals or for chickens are also breeding places, as are the water troughs for horses. The roof gutters of the house where trees overhang are apt to be clogged to some slight extent and thus afford enough resting water to breed generations. Rain water barrels and tanks should be carefully screened. All depressions in the soil in which surface water may rest for even so short a period as a week in midsummer should be filled in. The banks of any little brooks or rivulets should be kept clean so as to allow no opportunity for standing water or any amount of aquatic vegetation. Ponds which cannot be drained should be treated with light fuel-oil, preferably by spraying. Where for one reason or another it is considered impracticable to use oil, such ponds should be stocked with fish. Gold-fish, silver-fish, sun-fish, top minnows, killifish, and various other minnows are capital mosquito destroyers. In localities near salt marshes or fresh water swamps, the difficulty is much greater. Even in such places, however, strictly local work will greatly reduce the mosquito supply, and large-scale work is by no means impracticable. The recent work of the State of New Jersey, as reported by its State Entomologist, Dr. John B, Smith, has shown that the diffi- culty of draining salt marshes is not very great, and that the filling in of large areas is perfectly practicable. Inland the drainage of most swamps is practicable. For example, very perfect results in swamp drainage are shown in the reclamation of the Potomac marshes near Washington. In many communities the work of mosquito extermination has been undertaken by organizations of public-spirited citizens, but with proper legislation and with the proper public spirit this should not be necessary. The health-law of every state should contain a clause which places waters or pools, in which mosquitoes breed, among the nuisances that may be abated by local boards of health, and they, after due notice to the owners of the places, should be empowered, in case the owners fail to do so, to undertake the work and to abate the nuisance, the cost being charged to the owners of the property. Such legislation is in effect in New Jersey and should be in other states. 390 DISEASES CAUSED BY PROTOZOA THE COLLECTION AND BREEDING OF MOSQUITOES. Adult mosquitoes may be captured in a small, soft net or more easily by placing over them when at rest a small inverted vial. They are readily stifled by tobacco smoke or by a drojj of chloroform, or may be killed in the ordinary cyanide collecting-bottle used by entomologists. A good collecting-bottle may be made by soaking a few rubber bands in chloro- form and placing them in the bottom of a vial with a layer of blotting paper over them. They will give off enough chloroform fumes for a month or more to kill mosquitoes and other delicate insects. For permanent preservation, mosquitoes may be gummed with white shellac to the tips of small cardboard triangles, and the triangles pinned with an insect pin through the base. In rearing mosquitoes the rearings should be isolated, except perhaps when they are made from eggs deposited at one time by a single deter- mined female. Even here it is well to isolate the larvae, since with certain species they destroy each other. Where larvag are collected in a pool, isola- tion is necessary since several species may inhabit the same pool at the same time. A single larva should be reared in a single receptacle. When the larva pupates, the cast larval skin thould be saved in a small bottle of formalin or alcohol or on a slide. When the adult emerges the pupal skin should be added, and the adult and skins should be numbered with the same number. Since one usually has an insufficient number of jars to isolate all or a large proportion of the larv?e in each culture, it is well first to put them in a shallow dish and isolate those that appear to be different. The rest should be left in a general culture and watched closely for the appearance of forms not noticed at first. Breed all of the larvae to adults, unless reasonably sure that the culture is composed entirely of one species, in which case the remaining larvae can be preserved in formalin or alcohol. Mosquito larvae need food, and if they are small the water must be re- newed, by preference from the original source with some of the bottom matter. Too much fresh matter will often kill the larvae, possibly by the over-development of bacteria. Isolated pupae should be put into clean water with no organic matter. The larvae should not be crowded after collection, and enough air space should be left at the top of the jar or vial to insert a cork if necessary. Anopheles larvae, being surface-feeders, need a broad, shallow pan, uncovered and preferably placed in a bright light. They cannot be bred successfully in small, deep vessels unless full-grown and nearly ready to pupate. These recommendations are based upon Dr. H. G. Dyar's extended exoerience in breeding mosquitoes, and in the study of their early stages. List of Works to be Consulted. 1900. Howard, L. O., Notes on the Mosquitoes of the United States: Giving some Account of their Structure and Biology, loith Remarks on Remedies. Bulletin No. 25, new series, Division of Entomology, U. S. Depart- ment of Agriculture, p. 70, fig. 22. MOSQUITOES 391 1901. Theobald, Fred. V., A Monograph of the Culicidce or Mosquitoefs; Mainly Compiled from the Collections Received at the British Museum from Various Parts of the World in Connection with the Investigation into the Cause of Malaria Conducted by the Colonial Office and the Royal Society; Printed by Order of the Trustees. Vol. I., p. 424, text fig. 151 ; Vol. IL, p. 391, text fig. 318; Vol. III., (1903), p. 359, text fig. 193, pis. XVI. 1901-1903. Nuttall, G. H. F., and Shipley, A. E., Studies in Relation to Malaria, II.; "The Structure and Biology of Anopheles," Journ. Hyqiene, Vol. I., pp. 45-74, 3 pis.; 269-276, fig. 1.; 451-484, 4 pis., 2 figs., 1901; Vol. II., pp. 58-84, 1902; Vol. III., pp. 166-201, 5 pis., 1903. 1901. Reed, Walter, and Carroll, James, The Prevention of Yellow Fever, re- printed from the Medical Record, Oct. 26, 1901, p. 34, fig. 10. 1901. Howard, L. O., Mosquitoes: How they Live; How they Carry Disease; How they are Classified; How they may be Destroyed, New York, Mc- Clure, Phillips & Co., p. 241, text fig. 50, pi. I. 1902. Giles, George M., A Handbook of the Gnats or Mosquitoes, giving Anatomy and Life-History of the Culicidce, together with Descriptions of all Species noticed up to the present date; second edition, rewritten and enlarged, London, John Bale, Sons & Danielsson, Ltd., p. 530, text fig. 51, pi. XVII. 1902. Ross, Ronald, Mosquito Brigades and How to Organize them, London, Geo. Philip & S^on, 32 Fleet Street, E. C, p. 98. 1902. Berkeley, William N., Laboratory Work with Mosquitoes, New York, Pediatrics Laboratory, 254 West 54th St., p. 112, fig. 61. 1902. North Shore Improvement Association, Report on Plans for the Exter- mination of Mosquitoes on the North Shore of Long Island between Hempstead Harbor and Cold Spring Harbor, New York, Styles & Cash, 77 Eight Av., p. 125, fig. 7. map. 1903. Taylor, John R., Observations on the Mosquitoes of Havana, Cuba, re- print from La Revista de Medicina Tropical, June, 1903, p. 27. 1904. Felt, Ephraim Porter, Mosquitoes or Culicidce of New York State, Bul- letin 79, New York State Museum, Albany, p. 243-400, text fig. 113, pi. LVII. 1904. Smith, John B., Report of the New Jersey State Agricultural Experiment Station upon the Mosquitoes occurring within the State, their Habits, Life-history, &c., Trenton, N. J., Mac Crellish & Quigley, state printers p. v.— 482, fig. 136. 1906. Dyar H. G. , Key to the Known Larvce of Mosquitoes of the United States., U. S. Department of Agriculture, Bureau of Entomology. Circular No. 72, p. 6, fig; 1. 1906. Coquillet, I). W, A Classification of the Mosquitoes of Middle and North America. U. S. Department of Agriculture, Bureau of Entomology, Technical Series, No. 11, p. 31, fig. 1. CHAPTER XIX. THE MALARIAL FEVERS. By CHARLES F. CRAIG, M. D. Synonyms. — ^^Vechselfiebcl■; intermittent and remittent fever; tertian, quartan, or aestivo-autumnal fever; paludal; climatic fever; swamp or marsh fevers; ague; paludal fever; hill fever; jungle fever; mountain fever (in some localities); coast fever; gnat fever; htemamoebiasis; Cameroon fever; febbre intermittente; paludisme; maladies palustres; fievre paludeenne. Definition. — By the term malarial fevers Ave mean a group of specific infectious fevers due to infection of the red blood corpuscles of man by closely related animal parasites belonging to the Sporozoa, genus PlaS' modium} These fevers occur epidemically or endemically and are accompanied by a sjTnptom complex which is more or less characteristic of each va- riety. Periodicity is one of the most marked clinical phenomena and is due to the growth and multiplication of the plasmodia. Clinically, these fevers may be divided into intermittent, remittent and continuous, but such a classification is unscientific as it does not indicate disease entities. All malarial infections are transmitted by mosquitoes of the genus Anoph- eles, and so far as is known at the present time, this is the only means of transmission. Historical. — It is very probable that the ancient Egyptians had some knowledge of what we now term the "malarial fevers," and Groff con- siders that certain inscriptions upon the temple at Denderah are proof of this assumption. Hippocrates and Celsus described very accurately the manifestations of the various forms. Hippocrates (406-377 B. C.) divided them into c[uotidian and tertian, and Celsus (first century, A. D.) further distinguished the pernicious forms. Morton^ was the first to associate these fevers Avith miasmatic condi- tions, clearly indicating his belief that they were due to noxious gases arising from low lands and swampy districts. ^The malarial parasites belong to the Sporozoa, sub-order Hoemosporidta, genus Plasmodium. The name Plasmodium was first given to these organisms by Marchiafava and Celli, and is very unfortunate from a biological standpoint. Grassi has suggested tiie name Hcemamoebce for the jjarasites, and this is a prei- erable term to Plasmodium, but the latter term will have to be retained because of the law of priority. The same objection may be raised to the name" malaria," which was derived from tlie Italian, meaning bad air, and applied to these fevers because of the supposed relation of miasmatic conditions to tlieir causation. In the light of our present knowledge the name is erroneous, but will have to be re- tained as it has Decome so firmly established in our nomenclature. ^ Pyretologia, London, 1692. 392 THE MALARIAL FEVERS 393 The introduction of cinchona into Europe by th(! Viceroy Del Cinchon in 1640 gave an impetus to the study of mahiria, as it thus became possible to distinguish malarial fevers from other infections by the therapeutic test. The terra "malarial" was not applied to these fevers until 1712, when Torti^ published a classical description of the pernicious malarial infec- tions and distinguished them by their yielding to cinchona. Meckel, in 1847, and Virchow, in 1848, first described the melantemia which is in- variably present in these infections, and it is probable that they actually saw, without recognizing them, the malarial parasites. It was not until 1880, however, that the etiological factor in the pro- duction of malaria was discovered. Laveran,^ a French Army Surgeon, stationed at Algeria, after careful study of the blood of many cases of malarial fever, announced the discovery of a parasite in the blood which he had no hesitation in claiming to be the veritable cause of the disease. At first his researches attracted little attention but they were soon con- firmed by many observers, and his claim to have discovered the actual cause of malaria abundantly verified. Although by Laveran's great discovery the diagnosis of malaria was placed upon a scientific basis, but little was known regarding the means of transmission of the parasites, and it remained for Ross, in 1897, to clearly demonstrate that the hsematozoa of birds were transmitted by a certain species of mosquito. Grassi and other investigators soon confirmed the investigations of Ptoss, and proved that all varieties of the malarial fevers are transmitted from man to man by mosquitoes of the genus Anopheles. Geographical Distribution. — There is no infectious disease which can compare with the malarial fevers in the extent of its geographical distri- bution. In the Eastern hemisphere malarial infections do not occur above 62° N. Latitude, while in the Western hemisphere they are very rarely found above 45° N. Latitude. They are most common and severe in Ioav- lying coast regions, mountainous countries being comparatively exempt. The deltas of large rivers, especially the rivers of tropical countries, are hot-beds of malarial disease, and this is also true of all bodies of water situated in such localities. As the equator is approached we meet less often with the benign forms of malarial infection, the prevailing types be- ing the severe and often fatal sestivo-autumnal infections. The most important malarial localities are the following: North America. — In North America, malaria occurs rarely above the forty-fifth parallel, but is often frequent and fatal in the Southern states and in the West Indies, especially in Cuba, as well as in Central America. In the New England and Middle Atlantic states the benign forms are present, but are comparatively rare. The severe forms prevail along the low regions of the southern coast line, and especially in the swampy regions of the Gulf states. These infections are common and severe along the Mississippi River and its southern branches, and they are present in many of the Western states, especially in the river valleys of California where severe and fatal sestivo-autumnal infections are not uncommon. The regions about thi Great Lakes are almost free from malaria except in certain localities about Lake Michigan. Canada is the only country in North America which appears to be almost entirely free from malaria. ^ Therapeutica specialis ad febres quasdam perniciosas. ^Bulletin de I'Academie de Medecine de Paris, seance de 23, Nov., 1880. 394 DISEASES CAUSED BY PROTOZOA South America — In South America, severe types of the disease are common, esj)ecially along the coast regions of Colombia, Venezuela, Guiana, Brazil, Ecuador, Peru and Chile The whole Atlantic coast line of Central America is severely infected with festivo-autumnal malaria, and in this region the most jiernicious forms are common. Europe. — jNIalarial fevers occur but rarely in England, Germany and France. In Germany they occur along the coast of the Baltic, especially in Prussia, and they are not imcommon in the swamps of Hanover and Westphalia, and along the Rhine; in France these infections occur along the Loire and Rhone on the west coast; in Spain the valleys of the Tago and Guadahpiiver are infected, and pernicious forms occur in all the countries bordering upon the INIediterranean ; in Greece, Crete, Italy, Sicily, and Turkey, malaria is endemic; in Italy, especially, occur the most malignant forms in the regions around the Roman Campagna and the Pontine marshes, as well as in the valley of the Po; in Russia malarial infections are present in the valley of the Volga, Dniester, and Dnieper, and they are also common in the regions bordering upon the Black and Caspian Seas. Asia. — India, Ceylon, portions of China and Arabia, and the Islands of the Malay Archipelago are infected with the malarial fevers. This is also true of Asia Minor and the valleys of almost all the great rivers, such as the Indus and Ganges. In Japan the benign infections are common, and even upon the lofty table lands near the Himalayas malarial infections are often met with. The Philijipine Islands, until very recently considered as comparatively free from malarial disease, have been proved to be badly infected, a large percentage of our soldiers returning from there showing infection with the tertian and a?stivo-autumnal parasites. Africa. — In Africa are some of the most dangerous lurking places of malarial infections, the worst areas being those along the west coast and the Senegal, Congo, and Niger Rivers, as well as the regions around the great lakes and the jungles and lake shores of Abyssinia. Madagascar, Re- union, and Mauritius Islands present the pernicious varieties of the disease. Around Delagoa Bay and along the east coast of Africa, sestivo- autumnal fever is prevalent. Lower Egypt, the Soudan, the Nile delta, Tripoli, Tunis and Algeria, all harbor these infections. The resume given indicates the most important localities in which malarial infections are endemic, but there are numerous districts in which a few sporadic cases occur at rare intervals, but which may at any time become endemic foci, provided certain species of mosquitoes belonging to the genus Anopheles are present, together with individuals harboring the parasites. A knowledge of the geographical distribution of malarial infections is, therefore, most important, as localities which are known to be infected can thus be avoided, and those who are residents of such locali- ties can take the proper precautions to avoid infection. THE MALARIAL PARASITES. Etiology — ^The history of the discovery of the parasites concerned in the etiology of the malarial fevers furnishes one of the most interest- ing chapters in the annals of medicine. The theory that these fevers THE MALARIAL FEVERS 395 might be due to parasitic infection is very ancient, dating as far back as 118 B. C, but little, however, was known concerning this subject until 1849, when J. K. Mitchell ^ suggested that certain spores occurring in marshy districts might be the etiological factor. In 18G0, Salisbury^ described certain small vegetable cells which he claimed to have found in the perspiration and urine of patients sufi'ering from malaria, and which he considered to be the causu, and for a time his views were widely ac- cepted. In 1879, Klebs end Tommasi Crudeli^ found in the soil of malarial districts, certain .:od-shaped bacteria which, when injected into animals in pure culture, were claimed by them to produce the symptoms of the disease. Their observations were never confirmed by careful observ- ers but for some time their views were accepted by a large proportion of the scientific world. The bacterial origin of the malarial infections was believed in for a considerable period of time, although in 1880 Laveran^ described certain parasites occurring in the blood which he considered as the cause of the disease. His observations were soon confirmed by Richard, Marchiafava and Celli, Golgi, Councilman, Abbot, Sternberg, Osier and Dock. In his original communication Laveran described three forms of the parasite. The first consisted of oval or crescentic bodies with hyaline protoplasm containing pigment, arranged either in clumps or in a wreath-like arrange- ment. This form was undoubtedly the crescentic form of the parasite causing sestivo-autumnal malaria. The second form described consisted of small hyaline bodies containing pigment; and from these bodies there arose occasionally long, thin, hyaline filaments which possessed the prop- erty of motion. This form was undoubtedly the flagellated form of the sestivo-autumnal parasite. The third form described by him consisted of spherical, slightly granular bodies, with motionless pigment, which were evidently degenerative forms of the two foregoing classes. Richard^ later described the intracorpuscular hyaline parasites and the segment- ing bodies. In 1885, Marciafava and Celli® described carefully the hya- line and intercorpuscular parasites, and proposed the term Plasmodium malarice for the organism. Biologically, this term is very inaccurate and should be abandoned, as the parasites belong to the sporozoa, but the name is so firmly fixed in our nomenclature that it will probably have to be retained. In the same year, Golgi^ proved that quartan fever depended upon a specific form of the malarial parasite, and shortly afterward he also differentiated and described the parasite causing tertian fever. To him we also owe the discovery that the malarial paroxysm always co- incides with the segmentation or sporulation of a group of parasites. Occurring every forty-eight hours, this segmentation produces tertian fever, while if it occurs every seventy-two hours quartan fever is the t}^e present. In 1885, Golgi also called attention to the probably distinct type of the crescentic and ovoid forms of the organism, and Councilman ^On the Cryptogamous Origin of Malarious and Epidemic Fevers, Philadel- phia, 1849. ^American Journal of the Medical Sciences, January, 1866. ^Arch. f. exp. Path. u. Pharmak., 1879, XI, 311. ^Gaz. Med. de Par., 1882, 252. ^ Fortschritte der Med., 1885, III, No. 24, 787. ''Arch, per le sciens, Med.^ X, 1886, 109-135. 39G DISEASES CAUSED BY PROTOZOA first called attention to the diagnostic value of the various forms which are observed in the l)lood. In 18S9, Goigi further added to his studies concerning the development of the crescents, showing that they arose from the small, cellular rings, and that this parasite was associated with fevers of remittent character. To him belongs the credit, therefore, of first clearly differentiating the Jiestivo-autumnal parasite. In the same year, Marchiafava and Celli added to Golgi's observations and gave a most accurate description of the a^stivo-autumnal plasmodium. Classification. — The classification of the jxirasites causing malaria has occuined the attention of zoologists for many years, and a great many difl'crent o{)inions have been advancetl reganling their exact position. At the present time it is conceded by all that they belong to the Sporozoa, and the classification of Schaudinn, adopted at ])rescnt by nearly all authori- ties, is the one which will be followed in this contribution. He places the organisms imder the sub-order Ilcemosporidia, and gives three varieties, as follows: Plasmodium vivax (tertian parasite), Plasmodium malarioe (quartan parasite), and Plasmodium immacidahim^ (i:estivo-autumnal parasite). The Italian authorities, together with nearly every investigator who has studied malaria in the tropics, have made a subdivision of the sestivo-auturanal parasite into two varieties, the quotidian and tertian. A large amount of labor has been expended in differentiating these varieties of the testivo-autumnal parasite, and it is undoubtedly true that they can be differentiated when the material is available for study. From personal experience, the writer is satisfied that the quotidian and tertian restivo- autumnal parasites can be as easily differentiated as the tertian and quartan. The malarial plasmodia are found in man within the red blood cor- puscles and are essentially parasites living upon and within these cells. In this situation they destroy the red corpuscles and produce the well- known anaemia peculiar to malarial fever, together with the pigmentation, or melantemia which is due to the destruction of the haemoglobin of the red cell. In describing these parasites in the light of our present knowledge, two life-cycles must be considered: first, the human cycle, schizogony or asexual cycle, occurring within the infected individual, and second, the mosquito cycle, sporogony, or sexual cycle, occurring within the in- fected mosquito. As has been stated, the only known method of trans- mission of malarial fevers is by the aid of certain mosc(uitoes belonging to the genus Anopheles. These fevers are not infectious from patient to patient except through the intermediation of certain mosquitoes. Plasmodium Vivax — (The Tertian Parasite) — (Schizogony, Human Cycle). — The tertian parasite, or Plasviodium vivax, appears first within the red cell in schizogony as a small actively amoeboid hyaline body, the schizont, of various shapes, the difference in outline being due to the rapidity and extent of the amoeboid movement. At first the outline of the organism is very indistinct and careful examination is needed to dis- tinguish it. As the organism grows older and becomes pigmented it is much more easily distinguished. The hyaline stage is quickly followed * The name "P. immaculatum" is not correct. Blanchard has shown that Grassi previously used the terms " immaculatum" and " prajcox " for parasites occurring m birds, which prevents their use for the human parasite. This makes Welch's term, " falciparum," the proper one. — ^Editor. PLATE J Fig. 1.— Tertian Malarial Plasmodium. 1. Hyaline form. 7. SegmentinK forms. 9. Kon-flagellalo form. (Macro- 2 Pigmented ring form. 8. I'laffellate form. (Microga- gameto.; 3 to 6. Pigmented forms. metocyte.) 10. Segmei>ting form after S*!'~ 0fi 34 36 <^ 5 * f 37 ..-^«*^^' / /38 y THE MALARIAL FEVERS '.i'Jl by the appearance of a few minute granules of nnldish-brown pigment situated within it and showing active movement. This movement is due to protoplasmic currents which are present within the parasite. In the beginning, occupying but a minute portion of the red cell, as it continues to grow, the parasite encroaches more and more upon the infected cor- puscle, until when full-grown it fills the entire cell. The growth of the parasite is gradual, covering forty-eight hours. The full-grown para- sites have a rather distinct outline and the red cells containing them are greatly swollen, sometimes to almost double the size of the normal red blood corpuscle. Toward the end of thirty-six hours the organism has approached nearly to its full growth, only a narrow rim of the red cell showing around it. Amoeboid motion has become almost entirely lost, the parasite being circular in shape, well defined, the pigment more or less motile and much increased in quantity, still however, finely granular in appearance and reddish-brown in color, At the end of forty-eight hours segmentation takes place, the pigment becomes collected at the centre or to one side of the organism in the form of a compact clump and fine radial divisions are noticed branching from the centre toward the periphery of the organism, thus dividing the parasite into small ovoid segments. As a rule, there are two rows of these segments, one row surrounding the centre, and another surrounding the first row, but very often the seg- ments are irregularly arranged, and they are always devoid of pigment. They vary in number from twelve to twenty-four, the average being about sixteen, and are known as merozoites. At the time that segmenta- tion occurs the infected red cell has apparently disappeared, being en- tirely destroyed by the invading parasite. The destruction of the red cell, which is complete at the time of segmentation, liberates the segments, or merozoites, which, are again capable of infecting new corpuscles, and thus the human life-cycle or schizogony continues. The pigment which is not present at the beginning of the life-cycle in the red blood corpuscle, gradually increases as the degeneration of the red cell continues, being derived from the destroyed hsemoglobin of the cell. In all the pigmented forms of the tertian parasite the pigment is generally motile, the move- ment being due to the protoplasmic currents which have been mentioned. In examining blood from tertian cases it will be noticed that a certain proportion of the full-grown parasites do not segment, and it is these which are intended to commence the life-cycle of the organism in the mosquito, which will be described later. Plasmodium Malarias — (The Quartan Parasite) — (Schizogony, Human Cycle). — Like the tertian parasite, the organism causing quartan malarial infection appears at first within the red corpuscle as a small actively amoe- boid hyaline body without pigment, the schizont. It will be noticed that the amoeboid motion is less marked than in the case of the tertian or- ganism. The quartan parasite rapidly becomes pigmented, the pigment being collected in larger granules than is the case in the tertian parasite, being less motile and arranged around the periphery of the organism, whereas in the tertian parasite the pigment is distributed throughout the protoplasm. The outline of the organism is also much more distinct than is the case in the tertian parasite during all stages of its gro^i;h. In- stead of the swollen decolorized red cell seen in the tertian infection, the infected corpuscle in quartan fever is normal in size and often sUghtly 398 DISEASES CAUSED BY PROTOZOA below normal, and darker green in color, instead of pale. This difference in the appearance of the infected red cell serves at once to distinguish the two varieties upon microscopic examination of the blood. The para- site slowly increases in size, and in doing so becomes less amoeboid. The pigment increases in quantity and becomes collected at the extreme per- iphery of the organism and is absolutely immotile. The granules of pig- ment are considerably larger than in the tertian parasite, darker in color, and at no stage of the growth of the organism do they collect in small clumps throughout the protoplasm, as is common in the tertian form. As growth increases the parasite tends more and more to fill the infected red cell, and when full-grown — that is, at the end of seventy-two hours, it almost fills the cell, a small greenish rim of hemoglobin still being visible around the organism. At this stage of its growth the parasite is very dis- tinctly outlined and is much more refractive than is the tertian variety; the pigment is absolutely motionless and collected around the periphery; the shape is circular and amoeboid motion has entirely ceased. At the end of seventy-two hours segmentation occurs, the pigment becoming collected at the centre or in a star-like arrangement distributed from the centre. Radial striations appear dividing the organism into from eight to twelve segments, or vierozoites. The segments are generally arranged in a perfectly symmetrical manner around the central pigment, giving the so-called daisy or "Marguerite" appearance to the parasite at this stage. When segmentation is complete, each merozoite becomes free in the blood plasma and, in the human life-cycle, again invades the red corpuscles, undergoing the changes which have been described. As in the tertian form, certain parasites do not undergo segmentation, and these are the ones intended to carry on the life-cycle in the mosquito. Plasmodium Falciparum — (^stivo-Autumnal Parasite) — Quotidian Form — (Schizogony, Human Cycle). — As has been stated, the writer be- lieves with Marchiafava and Bignami that there are two distinct varieties of the festivo-autumnal parasite, the quotidian and tertian. These are distinguishable microscopically and the symptoms produced by them are characteristic and easily differentiated clinically. In previous contri- butions^ the differential points between these tAvo varieties of the testivo- autumnal parasite and also the clinical phenomena which are produced by them have been described. The quotidian parasite appears at first in the infected red cell as a very minute ring-shaped or round hyaline body, the schizont, which upon close inspection shows very active amoeboid motion. The outline of the organ- ism at first is indistinct but gradually becomes more distinct and when full-grown it is very clear-cut and refractive. The round forms are per- fectly hyaline in apjjearance but the ring form, which is most common, consists of a narrow hyaline body enclosing a small area which shows the normal greenish-yellow color of the infected corpuscle. This appearance is considered by most authorities to be due to the fact that the centre of the parasite is much thinner than the periphery, thus allowing the normal color of the corpuscle to show through. Careful observation of these ring forms, however, will show that they often become perfectly hyaline ^The Philadelphia Medical Journal, April 7, 1900; also, Journal Am. Med. Association, Nov. 3, 1900, The ^stivo- Autumnal (Remittent) Malarial Fevers, Wm. Wood & Co., 1901; International Clinics, vol. Ill, 13th series, Oct., 1903. THE MALARIAL FEVERS 399 and in so doing the protoplasm of the organism flows in from the edge of the ring, thus tending to prove that no protoplasm existed in this greenish- colored area. The amoeboid motion is very active, but the organism has to be carefully watched in order to distinguish it. The infected red cor- puscle is generally smaller in size than the normal corpuscle and darker green in color. It is very apt to be crenated. In many instances double or triple infections of the corpuscle may be observed. In the peripheral blood the hyaline, round or ring-shaped organisms are those which are most commonly observed, although a certain number of pigmented forms are not uncommon. The pigmentation is never as marked as in the ter- tian or quartan parasite, the pigment consisting of a small, solid block, almost black in color, situated at some portion of the edge of the parasite or at the centre; it is never motile. Very rarely the pigment consists of fine granules, but these granules never number more than three or four. The segmenting forms are but very seldom observed in the peripheral blood, although blood from the spleen taken at the proper time in well marked cases presents numerous parasites undergoing this process. Segmentation occurs at the end of twenty-four hours. Just before segmentation the parasite occupies about one-fourth of the red blood cor- puscle, thus distinguishing it from the quartan and tertian varieties which fill the corpuscle. The pigment does not show any decided increase in amount and is absolutely immotile. At the time of segmentation this pigment becomes collected at the centre of the parasite and radial striations can be detected, starting from the centre and dividing it into from six to eight very minute round or oval segments, or merozoites. While in the tertian and quartan forms it is often impossible to distinguish the remains of the red corpuscle when segmentation occurs, in this variety it can be plainly seen that segmentation occurs within the infected red cell. The mero- zoites are liberated by the entire destruction of the red corpuscle; each merozoite is capable of again infecting the red cell and the human cycle is thus repeated. In this variety, as well as in the tertian form, peculiar bodies occur which are developed within the red blood corpuscle, but which do not undergo segmentation. These are the so-called crescents, which are so characteristic of sestivo-autumnal infections, and which will be described in considering the mosquito-cycle of this parasite. Plasmodium Falciparum — (iSstivo-Autumnal Parasite) — Tertian Form (Schizogony, Human Cycle). — Like the quotidian, the tertian testivo- autumnal parasite appears first within the infected red cell as a round hyaline ring or disk. The infected corpuscle is greenish in color, smaller than the normal corpuscle surrounding it and generally crenated. The young parasites are considerably larger than the quotidian parasite, occu- pying from one-fourth to one-third of the total area of the infected cell. The ring forms are irregular in outline, one portion of the ring being larger than the rest, giving it the so-called "signet-ring" appearance. The organism is very highly refractive and sharply outlined, appearing as though it had been cut into the corpuscle with a punch. Amoeboid motion is present, although it is less rapid than in the quotidian form, and only very rarely is more than a single parasite seen within one corpuscle. In the course of from twenty to twenty-four hours the hyaline forms become pigmented, the pigment occurring in the form of very fine, reddish-brown 400 DISEASES CAUSED BY PROTOZOA granules somewhat resembling those found in the tertian parasite. The pigment is in larger amount than in the quotidian parasite and is generally motile. As growth inereases anurboid motion becomes lost, and this is also true of the peculiar ring-shape which is so characteristic of this form of the parasite. At the time of segmentation, which occurs in forty-eight hours, the organism-occupies about one-half of the infected red cell. The pigment is collected at the centre and radial striations start from this point and divide the ])arasite into ten or fifteen segments, or merozoifes. In some instances as high as twenty-four merozo^tes have been counted. Segmentation occurs within the red blood corpuscles but its situation is not so easy to distinguish in this form as in the quotidian. The segment- ing forms occur but seldom in the peripheral blood, although they are very numerous in certain cases in blood collected from the s])leen. The young segments are liberated in the blood plasma and again infect the red cell; thus the human cycle is repeated. So far, wc have considered the human cycle of the malarial plasmodia, which consists, briefly, in the infection of the red blood corpuscles by the merozoites which are derived from the segmenting bodies. The mosquito- cycle, which is more complex, will now be considered. Development of the Malarial Plasmodia Within the Mosquito— (Sporogony, Sexual or Mosquito-Cycle). — Historical. — That malaria is transmitted by insects is by no means a modern conception. Nearly two thousand years ago, Varro and Columella mentioned the possibility that these diseases were transmitted in this way. In 1848, Nott^ considered the subject as already proven, but King,^ of Washington, in 1882, was the first to advocate it vigorously and give evidence in favor of this method of transmission. In 1884, Laveran^ considered the subject and suggested that this was probably the way that malarial disease was transmitted. In 1894, Manson^ elaborated the theory and stated it as his belief that malarial disease w^as transmitted probably by mosqui- toes In 1895, Ross,^ of the Indian Army Medical Service, studied the development of the parasites of sestivo-autumnal malaria in mosqui- toes, and proved that the crescents underw^ent definite changes wdthin the body of the insect. In 1896, Bignami® advocated the theory that the malarial diseases were transmitted by the inoculation of man by the bite of the mosquito, comparing this process of infection to the one already proved in the production of Texas cattle-fever by the tick. In 1897, Ross^ further elaborated his experiments and was able to observe the development of the crescentic form of the jestivo-autumnal parasite in the mosquito. A great advance wr.s made when MacCallum^ observed that the full-grown extracellular halteridium, a parasite causing avian malaria, consisted of two forms, one of which is flagellated and the oth^* ^New Orleans Medical and Surgical Journal, 1848, IV, 563, 601. ^ Transactions of the Philosophical Society of Washington, February 10, 1882. ^ Traite des Fihrcs Palustres. Paris, 1884, pp. 457-458. ^ British Medical Journal, December 8, 1894. ^Proceedings of South Indian Branch British Medical Association, December 1 1895. "Lancet, November 14 and 21, 1896. ^ British Medical Journal, December 18, 1897. 'Bulletin of Johns Hopkins Hospital, November 1897; also Journal of Ex- perimental Medicine, January, 1S9S THE MALARIAL FEVERS 401 non-flagellated. He observed that the flagella, breaking away from the flagellated form, penetrated the non-flagellated organisms, and after penetration a motile body resulted which moved about among the blood corpuscles, and which was capable of penetrating and destroying them. Later he observed the same phenomena in studying the iestivo-autumnai parasites, and considered that this process was one of fertihzation. In 1898, Bignami performed some inoculation experiments upon man with mosquitoes which had bitten individuals suft'ering from malaria, but these experiments were unsuccessful, due to the fact that he did not em- ploy the right species of mosquito. Later Bignami' was successful in producing an attack of sestivo-autumnal malaria in man by allowing mosquitoes which had bitten an infected individual to bite a patient who had never had malaria. In the same year, Bastianelli, Bignami, and Grassi^ were successful in producing a double tertian infection in man by the bites of infected Anoflieles. In February, 1899, they were, for the first time, successful in infecting the Anopheles maculipennis with quartan parasites, and traced the developmental stages of this organism in the mosquito. They were also successful in producing sestivo-autumnal malaria by the bites of infected mosquitoes. Description of Forms Occurring in the Mosquito Cycle. — As has al- ready been mentioned, in tertian and quartan infections there occur certain organisms which do not undergo segmentation. This is also true of the aestivo-autumnal infections, in which occurs a peculiar body known as the crescent, intended to continue the life-cycle of the parasite within the mosquito. Tertian and Quartan Forms. — In tertian and quartan infections, in blood which has been removed from the body for some time, there occur peculiar bodies known as flagellated organisms. It will be noticed that these bodies are of two kinds, which the writer designated in a previous contribution^ as active and passive flagellated organisms. The active flagellated organism, or the microgametocyte, is spherical in shape and filled with actively motile pigment. This pigment is in the form of small granules which are distributed throughout the protoplasm of the organism. It will be noticed that in such round bodies the pigment becomes more and more active, until finally three or more serpentine prolongations of the protoplasm appear at the circumference of the organism. These prolonga- tions of the protoplasm are,frQjiijy3jreeJo_foJir. timesjhe_^ of the parasite and are possessed of a very active lashing movement, antTare known as flagella, or microgametes. Together with this form of the organ- ism there occur round bodies in which the pigment is collected in larger clumps and generally arranged around the circumference in the form of a perfect ring, while there is no evidence of motility. These are the pas- sive flagellated organisms, or macrogametes, and never present the process of flagellation as seen in the microgametocyte, or active body. The flagella from the microgametocyte eventually become free in the blood plasma and sometimes can be seen attached to the bodies which have just been des- cribed , I.e., the macrogametes. This process, however, takes place in nature ^Lancet, December 3 and 10, 1898. ^R. Acad dei Lancei, vol. VII, Dec. 4, 1898. ^New York Medical Journal. December 23, 1889. 26 402 DISEASES CAUSED BY PROTOZOA in the middle intestine of tl;e mosquito. A distinct difference has been demonstrated in the structure of the female viacrogametes and the male microgametocijies. In the macrogamete the nucleus is of good size and situated at one side of the centre of the organism, containing little chro- matin. In the microgamcioci/ie the nucleus is always situated at the centre of the organism arid contains a large amount of chromatin. When the flagella, ov microgamctr.^-, develoj) from the microgcunciocgte, it has been demonstrated that the chromatin passes into them and forms an essential portion of their structun\ iEstivo-Autumnal Infections. — There occur in the blood in irstivo- autumnal infections peculiar forms of the parasite knoM'n as crescents. These forms are developed within the red blood corpuscle and are typi- cally crescentic in shape. They are very refractive, having a more or less granular protoplasm, and contain A\ithin them, generally at the centre, but sometimes at one or the other pole, a clump of i)igment arranged in the form of slender rods or minute dots. In the very young crescents the pig- ment is distributed throughout the protoplasm, but as the crescent matiu'cs it collects at the centre or at one end. The border of the crescent is sharply cut and is represented by a single or double line, having a pecu- liar greenish color. In most crescents, when full-grown, careful examina- tion Avill show a dim line upon the concave side of the organism, which has a peculiar greenish color. This represents the remainder of the red blood corpuscles in which the crescent was developed. In tertian ?estivo-autumnal infections the crescent is much more slender and has pointed extremities. It very seldom shoAvs a double outline; the protoplasm is finely granular and the pigment is large in amount and in the form of slender rods. In the quotidian a^stivo-autumnal infections the crescent is generally much shorter and plumper than in the tertian. Its extremities are rounded and it always presents a distinct double out- line. The protoplasm is less granular and the pigment is smaller in amount and in the form of dots. Normally in the mosquito, and also in the blood which has been removed for some time from the body, these crescents undergo a series of changes, first becoming oval in shape and finally round. The spherical bodies represent, in the jestivo-autumnal infections, the macrogametes and microgavietocytes of the tertian and quar- tan infections and undergo similar changes in the stomach or middle intestine of the mosquito; that is, the male elements, or microgametocytes, become flagellated, the flagella, or micro gametes, becoming free and fertilizing the female elements, or macrogametes. Cycle of Development. — Having considered the bodies w^hich enter into the mosquito-cycle, and which may be observed at times in human blood which has been removed from the body for a short time, we will now take up the cycle of development which these bodies undergo in the mosquito, bearing in mind that it is essentially the same in all varieties of the Plasmodia. The process of flagellation and the fertilization of the macro- gamete, the female orgamism, by the microgaviete, or flagellum, which occurs normally in the middle intestine of the mosquito after biting an infected individual, has been described. The result of this fertilization is known as the sporont. After a certain period of time the sporont becomes elongated and finally motile, and it is then known as the ookinete. The ookinete penetrates the wall of the middle intestine and eventually becomes situated on the outer THE MALARIAL FEVERS 403 side of the epithelium and the basement membrane of the intestine between the adipose tissue and the muscular wall. Here the organism becomes spherical in shape and forms a cyst known as the oocyst. At this stage the protoplasm is granular and reticular in appearance, the pigment is reduced in amount, and the entire organism is enclosed within a well-defined capsule. The oocyst is formed at about the third or fourth day after infec- tion of the mosquito. About the fifth or sixth day the oocyst enlarges and within it are formed spherical refractive bodies known as sporolAasts. At this stage the organism is increased so much in size that it projects from the intestinal wall. Besides the sporoblasts, the cyst contains some pigment and minute granules which resemble fat. At the end of a week the sporo- blasts have produced a large number of delicate filaments having pointed extremities and containing a small amount of nuclear chromatin. These filaments are the sporozoites. They are about 14/i in length and are arranged in a ray-like formation about a central mass which may con- tain pigment. At this stage the capsule of the cyst- is very distinct. The sporozoites are finally liberated by the rupture of the cyst and make their way to the tubules of the salivary glands. At this time the infected mos- quito, when biting a man, will inoculate the sporozoites, which, penetrat- ing the red blood cells, develop into merozoites, and the human cycle of the organism begins. The entire cycle of development in the mosquito is about fourteen days in duration. Briefly stated, the cycle of development of the malarial plasmodium in the mosquito may be summed up as follows : 1. Macrogamete, in tertian and quartan infections, the female spherical bodies, and in festivo-autumnal infections the female crescent. 2. Microgametocyte, in tertian and quartan infections the male spherical bodies and in sestivo-autumnal infections the male crescent. 3. Microgamete, the liberated flagellum of the microgametocyte. 4. Sporont, the result of the fertilization of the macrogamete by the microgamete. 5. OoJdnete, the motile stage of the sporont. 6. Oocyst, the cystic stage of the sporont. 7. Sporoblasts, developed within the oocyst. 8. Sporozoites, developed within the sporoblasts and liberated by the rupture of the oocyst, and which are introduced into man by the mosquito and are capable of beginning the human life-cycle by infecting the red blood corpuscles. It may be stated that this cycle of development has been demonstrated in the mosquito in all varieties of the malarial plasmodia, and that infec- tion of man by the mosquito has also been demonstrated with all varieties of the Plasmodia. The Malarial Mosquitoes.— The structure and habits of the mos- quitoes which transmit malaria have been considered in another portion of this work. It may not be amiss to give a list of those mosquitoes which have been proved to transmit malarial disease. Only one genus, so far as we know, is capable of transmitting malaria, the Anopheles. Of the fifty or more described species belonging to this genus, the foUoA^ing have been shown experimentally to transmit the disease; 404 DISEASES CAUSED BY PROTOZOA In Africa, the A. costalis, A. paludi^, A. junestus. In India, A. sinensis, A Rossii, A. culicifacis, A. Theobaldi, A. barbirostis. In Europe, .4. superpictus, A. maculipennis, A. bijurcaius. In America, .1. tnaculipennis , A. argijrotarsus. Staining Reactions of the Malarial Plasmodia. — Under the division of this suhjcc't dcahng- with diagnosis, the staining methods which are of greatest practical nse will be fully discussed. While the examination of the fresh blood is of the greatest imi)ortance in studying certain j^hases of the life-cycle of the malarial plasmodia, the staining reactions exhibited by these organisms illustrate more fully the exact morphological structure. It may be stated that the staining reactions are similar in all varieties, and that they prove that the organism is composed of a nucleus and proto- plasm. The chromatin is the only portion of the nucleus which takes the stain, and by Wright's method it stains a very brilliant red and lies, appar- ently, within a vesicular nucleus, the protoplasm of w^iich does not stain. Surrounding the nucleus in the young forms is a small amount of protoplasm which stains a delicate blue color, and imbedded in which is the pigment. In all the forms, as the parasite matures, the chromatin becomes distributed throughout the protoplasm, and in the full-grown parasites a distinct nucleus cannot be demonstrated, while the protoplasm stains uniformly throughout. As segmentation approaches, the pigment becomes collected more or less toward the centre of the organism, and the chromatin which has been distributed diffusely throughout the protoplasm collects into small clumps, forming a portion of the young segments. At the time of segmentation the chromatin is compactly collected in clumps lying within a minute unstained area, the vesicular portion of the nucleus, and surrounded by a small ring of protoplasm, staining very intensely. In the pestivo-autumnal infections the crescents are composed, as shown by the staining reactions, of a large amount of protoplasm and a compact clump of chromatin situated at the centre or at one pole of the crescent. The flagellated organisms stain similarly to the full-grown parasites with the exception that a narrow thread of chromatin can be detected within each flagellum. This chromatin gradually becomes col- lected toward the centre of the flagellum before it becomes free from the parent body, the remainder of the flagellum staining a uniform blue, the chromatin being bright red in color. There are many exceptions to this general rule regarding the staining properties of the plasmodia, but these are probably due to external factors. In all varieties of the malarial parasite the first stage seen within the red cell in stained specimens is ring-shaped, consisting of a small dot of chromatin surrounded by an unstained area, and this again surrounded by a small amount of protoplasm. Contributing Factors in Etiology.— While the malarial parasites, or hosmosporidia, are the direct cause of the malarial infections, and while the transmission of the disease depends entirely, so far as we at present know, upon moscjuitoes of the genus Anopheles, there are certain factors which enter indirectly into the etiology of the disease. These factors favor the development of the parasites within the body or indirectly aid in in- fection. Among them may be mentioned the following: Locality. — This subject has already been considered under the geo- graphical distribution of malaria but it has a decided influence upon the THE MALARIAL FEVERS 405 character of the infection. The mild tertian and quartan infections, especially the tertian, are of almost world-wide distribution, but the more severe sestivo-autumnal types are much more limited as regards locality, being very uncommon in northern latitudes and becoming more and more common as the tropics are approached. Climate. — As stated in the foregoing, climate has a decided influence as regards the distribution of certain types of malarial infection. These infections are most common and pernicious in tropical climates, so that heat may be considered as an essential predisposing cause of the malarial fevers. Even in temperate climates, the sestivo-autumnal fevers prevail mostly during the summer and autumn months, while in the tropics they prevail throughout the year. Thayer and Hewetson^ call attention to the seasonal variation of these diseases as observed in Baltimore. The smallest number of cases occurred during the months of December, Janu- ary and February; during the spring months the cases increased until May, and then decreased until July, when they again increased and reached the maximum in September. The observations of these author- ities have been borne out by those of numerous investigators, and there can be no doubt that the season has a most marked influence as regards the number of cases observed in any locality. This, of course, is probably due to the fact that mosquitoes, especially in temperate climates, are much more numerous during the spring, summer, and autumn months. Time of Day. — It has always been observed that there is much more danger of contracting malaria at night than during the day. In the light of our present knowledge that these diseases are due to inoculation by the bite of the mosquito, this fact is easily explained, for it is during the night that mosquitoes mostly bite. Altitude. — These diseases occur especially in low-lands along the coast and rivers of warm countries. This is a fact which has been observed since the very earliest study of malarial infections. Mountainous regions are generally free from malaria, although this is not always so, for in the Philippine Islands certain valleys are almost free from malaria, while the hills in the vicinity are notoriously infected. It has also been observed that persons living in the tropics and sleeping in the lower stories of houses are more apt to become infected with malaria than those in the upper stories. For a long time this was held to be due to low-lying noxious vapors which penetrated the lower floors but did not rise to the upper stories of dwell- ings. The true explanation is that, as a rule, mosquitoes do not fly to any great height. Moisture. — Marshes and low-lying damp regions are usually condu- cive to malaria, and moisture is a most important factor in the distribution of the disease. This is again explained by the fact that mosquitoes are most numerous and breed most abundantly in moist regions. Soil.— It was long ago observed that the sailors upon ships cruising in tropical regions did not contract malaria unless they went on shore, and it was supposed that the miasmatic gases arising from swamps and moist soil led to the production of the disease, and for a long time it was be- lieved that the upturning of the soil in certain regions led to an outbreak. Tropical jungles, low marshy islands, or lands covered with pools of stag- ^ Johns Hopkins Hospital Reports, Vol. V, 1895, pp. 5-215. 406 DISEASES CAUSED BY PROTOZOA nant water have always been regarded as conducive to nialariul infection. The fact remains, however, that the soil per se has nothing to do with the production of malarial disease except in so far as it favors the breeding of mosquitoes. A moist soil favors the spread of the disease as it brings about- the conditions favorable for the development of the mosquito larv;ie; this is also true of thosc-instances in which malarial epidemics have followed the upturning of soil in certain localities, thus favoring the formation of stagnant })ools in which the larv;ic of the mosquito develop. Rain. — Rain favors the production of malaria because it favors the breeding of the mosquito. Ailded to this, continued rainy weather, by diminishing the resisting powers of the individual, favors the development of the disease after he has become infected by the mosquito. Race. — According to Thayer and Hewetson, the negro is less liable to contract malaria than the white man. This subject has attracted the attention of a great many investigators, and it has been found that the native negro races acquire a more or less complete immunity in early life from malarial disease. A very large percentage of negro children in in- fected localities are found to harbor the malarial plasmodia, but this is not true of the adult. There is probably no racial immunity against malaria, but it is imdoubtedly true that an acquired immunity is present among many people Avho inhabit malarial regions. Age. — Children are more susceptible to malarial infection than adults, and, as has been suggested by INIarchiaf ava, this is probably due to the fact that mosquitoes bite children in preference to adults. Sex. — When equally exposed, both sexes have the same ratio of infec- tion, but, as a matter of fact, malaria is more common in men than in women, as the latter are not as often exposed to the bites of the mosc[uito. Occupation. — The occupation of man becomes a predisposing factor in the production of the disease in proportion to the chances that occupa- tion gives him of infection by the nioscpiito. Laborers working at ditch- ing, railway building, and other occupations wdiich necessitate the turning up of the soil and exposure to night air, and therefore to the bites of mos- quitoes, are especially liable to contract the malarial fevers. An instance of this was the terrific mortality from eestivo-autumnal malaria during the early work upon the Panama canal. There are numerous other factors which contribute to the production of malarial fevers, among which may be mentioned those which lower the individual's resisting powers, such as exposure, dissipation, over-eating, over-work, whether mental or physical, and, in short, anything which interferes with the normal physiological processes. There can be no doubt that an infection with a small number of malarial parasites is over- come, in a great many instances, by the healthy individual, but should the normal resisting poAvers be lowered such an infection would result in the symptoms of the disease. Cultivation. — No one, as yet, has been able to cultivate the malarial Plasmodia in artific?al media, outside of the human body. The only in- vestigator who has ever claimed to have done so is Coronado,^ but his experiments have been repeated by other observers, none of whom has been able to confirm them. While cultivation of these organisms has not ^Cronica Medici Suirurgica de la Habana, November, 1892. THE MALARIAL FEVERS 407 been successful, the sestivo-autumnal parasites have been kept ahve out- side of the human body for some (hiys. Sakharov was the first to perfcjrrn such experiments and he was able to keep the parasites alive in blood, obtained by leeches from the human subject, for a week. No reproduc- tive changes, however, were observed. Hamburger and Mitchell, as quoted by Thayer,^ performed similar experiments and were able to keep the pestivo-autumnal parasites alive for a period of eight days. Inoculation Experiments. — ^The malarial fevers may be transmitted by direct inoculation from man to man. It would be unprofitable here to detail the experiments which have been performed along this line, but the disease has been successfully reproduced in this way by Gerhardt, Mari- otti, Marchiafava, Celli, Bignami, Bastianelli, Baccelli, Sakharov, Elting, and many others. It has invariably been found that the type of parasite inhabiting the blood injected is found again in the blood of the individual infected, and is followed by the clinical symptoms of the variety of malaria produced by the type of parasite injected. Thus, for instance, the inocu- lation of blood from a patient suffering from tertian fever is always fol- lowed by tertian fever in the inoculated individual. Immunity. — ^Tliis may be considered under the following heads, racial, congenital, and acquired immunity. Natural immunity may occur, but it is undoubtedly rare. Racial Immunity. — Certain races of mankind have been considered immune to the malarial fevers. This statement, however, rests upon but very little proof, and cannot be substantiated by facts. While this is so, it is a well-recognized fact that some races are more resistant to malaria than others. For instances, the black races are more resistant in adult life, but the immunity which exists is possibly acquired. In other words, in those races which live in malarial localities the disease is acquired in very early life and a natural immunity is established so that the adult individuals are resistant to the infection. It may be stated as a fact that no people inhabiting the world are, as a race, immune to the malarial fevers. Congenital Immunity. — ^There exist people, living in the most malari- ous localities, who have never suffered from the disease. This immunity is, in all probability, congenital, and in a few instances has been proven to be a family characteristic. Acquired Immunity. — ^Long residence in malarious country may, if the individual survives, confer upon him a relative immunity to the disease. Repeated attacks of malaria will in time render the individual less liable to further attacks. We can explain this in only one way: that the malarial poison produces certain changes in the human organism which render it at least partially immune to future attacks. The histoi'y of acquired immunity is simply that of repeated attacks of malarial fever, each one a little less severe than the preceding, until at last a spontaneous permanent cure is affected. Such immunity may be lasting, but as a rule hardship, privation, ill-health, or removal to a new locality will destroy it. Pathology.- — Primarily, malarial infections exert the most marked eflfect upon the blood, as the plasmodia live at the expense of the red blood corpuscles, arid probably elaborate toxins which materially affect all the ele- ^Lectures on the Malarial Fevers, 1897, p. 27. 408 DISEASES CAUSED BY PROTOZOA ments of this fluid. In 1847, Meckel discovered granules of pigment in the blood, and ever .since then the condition of nielana'niia has been recognized as one of the nio.st characteri.stic features of malarial di.sea.se. It may be stated that the patholojiical changes which occur in the blood are the result of primaiT and .secondary causes, the i)rinuiry cause being the infec- tion of the retl cells by the parasites and the changes brought about by such infection; the secondary, the anaemic condition which is the inevi- table result of malarial infection. Changes in the form of tlie red corpuscles are alwavs present, as in tertian infections, where the cor])uscles are swollen and mu( h larger than normal, while in the a\stivo-autumnal infections they are smaller, the color is much darker and the corpuscles appear greenish or brassy in color. Many of the infected red corpuscles, especially in the a^stivo-autumnal infections, show a retraction of the ha?moglobin, small areas being thus rendered colorless. The infected red cells are gradually destroyed by the growth of the parasite within them, but even in those which are not infected a marked difference is noted in the color index and in the form. There occur in the blood macrophages, containing much pigment, and in the restivo-autumnal infections especially, numerous plasmodia. Together with these there occurs either free or within many of the leukocytes, brown, black, or brownish-yellow pigment, occurring as blocks, granules, rods, grains, and irregular clumps. The occurrence of this pigment is one of the most characteristic conditions found in the blood of malaria. The pigment occurs in two forms, melanin and h(Emosiderin. The first gives no reaction for iron, while the second does. As regard the origin of the two varieties Bignami has well said: "The melansemia, index of an acute infection, is derived only from the direct transformation of hfcmoglobin into melanin through the action of the parasites within the red blood corpuscles; the melanosis of the viscera, spleen, liver, bone-marrow, etc., index of a previous infection, has a double origin. In chief part it is derived from the melansemia; that is, from the deposition in the viscera of the black pigment {melanin) formed during the acute infection in the circulating blood; in part it has a local origin, that is, it is derived from the slow transformation of the blocks of yellow-colored pigment (JioBmosiderin) , which are deposited or formed in the spleen and in the other viscera from the enormous quantity of altered red blood corpuscles, which, in grave infections, die before the direct action of the parasites has transformed their haemoglobin into black pigment." Besides the occurrence of changes in the form and color of the red blood corpuscles, as well as the occurrence in the blood of pigmented leukocytes and j)igment, in all forms of malarial fever there is a reduction in both the red and white corpuscles. This reduction is very often more marked in tertian and quartan malaria than in restivo-autumnal and is due to the action of the parasites upon the corpuscles containing them, the action of the poisonous material elaborated and set free by the parasites, and to inhibited function of the blood-producing glands. Most valuable observations upon the reduction of the red cells have been made by Kelsch,^ who found that a reduction followed every ^Archives de physiologic, 1875, 690. THE MALARIAL FEVERS 409 paroxysm of the fever. This reduction may be very great; some cases have been observed in which only 500,000 red cells were present to the cubic millimeter. In ordinary cases, after the infection has persisted for a few days, it will be found that the red cells have fallen to 2,000,000, or slightly less, per cubic millimeter. This marked reduction, however, is not persistent, for in long-continued infections it will be found that after a certain amount of anaemia has been produced fhcro is no further fall, and even in most cases a slight gain over the lowest point reached during the acute infection. In the pernicious forms the red cells may fall to 1,000,000 or less per cubic millimeter within twenty-four hours, but if the patient has suffered from repeated attacks such a marked decrease is but seldom observed. The return to the normal number of red cells is generally rapid after the mild, and in some cases after severe infections which have been promptly stopped by treatment; but in cases which have been treated improperly or where many relapses have occurred a chronic and persistent anaemia is produced which is one of the most marked characteristics of chronic malarial infection. As regards the white corpuscles, it may be said in general that the re- duction in their number corresponds with that of the red cells. During the paroxysm there is often a leukocytosis, while between the paroxysms the leukocytes are markedly reduced in number. This is, in general, true of all forms of malarial fever, but in some cases of fatal pernicious malaria a leukocytosis is observed, which is a strong argument against the theory of Metchnikoflf that the leukocytes play the most important part in the spontaneous cure of these infections. Recently much attention has been paid to the relative increase in the mononuclear leukocytes as being of diagnostic importance in malarial infection. While probably in a major- ity of instances there is a considerable increase in this type of cell, it has not been the writer's experience that very much weight can be given in diagnosis to a mononuclear increase in malarial infection. Besides the reduction in the red and white corpuscles there is generally a marked reduction in the haemoglobin, especially in the sestivo-autumnal infections. This reduction may be very rapid, the haemoglobin falling from 10 to 40 per cent, within two or three days. But little weight can, however, be given to the reduction of the haemoglobin as regards the prog- nosis of individual cases. In some of the most pernicious forms of ma- laria there may be but a slight reduction in haemoglobin, while in many benign tertian infections there is often a very marked reduction. Summing up our knowledge as regards the changes in the blood in the malarial fevers, it may be briefly stated as follows: A marked reduction of the red cells both by parasitic infection and as the result of poisons elaborated by the parasites, as well as changes brought about by these poisons in the blood-forming glands; a corresponding reduction in the number of white cells, with, in most cases, a relative increase in the mono- nuclear leukocytes; a marked reduction in the haemoglobin, and the presence in the blood of more or less black and brownish-yellow pigment. The chief changes in the blood of patients who have suffered from re- peated attacks of malaria consist in a greater or less degree of anaemia, the red blood cells seldom numbering more than 3,000,000 per cubic millimeter, often not over 1,500,000, and a reduction in haemoglobin and the leukocytes. 410 DISEASES CAUSED BY PROTOZOA In severe cases nucleated red cells are sometimes seen and poikiloey- tosis is almost invariably present. In such cases the polymorphonuclear leukocytes are decreased while the mononuclear are increased. The Urine, — In many cases of benign tertian and quartan malarial infections there is but little change in the urine, but in the more severe jestivo-autumnal infections there is often a marked reduction in the amount tluring the ajn'rexial stage, while during the paroxysms the amount is increased. Pohjuria is often marked during the convalescence from tertian and cpiartan fevers but is not so common in the aestivo- autumnal infections. Sometimes the polyuria is very excessive. One patient observed by the writer, after a tertian oestivo-autumnal attack, passed from 20,000 to 25,000 Cc. of urine per day. The color of the urine is generally dark amber or reddish, as in other febrile diseases, and the acidiiij is increased when the urine is diminished in amount. The specific gravity is increased during the attack, but in cases showing polyuria it is generally very low, being from 1.005 to 1.010. The total solids are in- creased. The amount of urea excreted in twenty-four hours is increased, especially during the paroxysm, l^ut in cases showing polyuria the amount is generally decreased. The chlorides are not increased as a rule. Albu- min a])pears in a certain ]iro})ortion of very severe tertian and quartan infections and in the majority of jestivo-autumnal infections. In the latter class of cases hyaline and granular casts are often observed, and it can be stated as a rule that all fatal cases of malaria show albuminous urine containing casts prior to death. Personal observations suggest that indican is almost invariably increased in the urine of patients suffering from festivo-autumnal infections. The Viscera. — The pathological changes occurring in the viscera have been thoroughly studied by many observers, among whom may be men- tioned Bignami, Laveran, Councilman, Bastianelli, Dock, Thayer, Barker and Ewing. From the observations of these authorities, we have come to realize better the extensive pathological ravages of malarial in- fections. It should be understood that any of the malarial parasites may cause pernicious infections leading to the death of the patient, and the pathological changes produced by them do not differ markedly one from the other. A patient dead of malarial fever presents a peculiar brown or grajdsh hue of the slcin. The degree of emaciation depends upon the duration of the infection. Rigor mortis is moderate, and postmortem discoloration occurs early and may be very intense. As most cases of pernicious ma- laria die from cerebral complications, the brain presents most marked pathological lesions. Externally the bloodvessels are much congested, the entire organ appearing hyperffimic. Small capillary hemorrhages are often observed and oedema is the rule. In cases where no brain symptoms have been exhibited during life, the organ externally shows but little hyperemia. The changes in the brain consist in congestion of the capil- laries and the presence of minute hemorrhages within the substance of the organ. The congestion and hemorrhages are due to blocking of the capil- laries by malarial parasites, which may be observed in various stages of development within the red cells, together with an immense amount of pigment and numerous pigmented leukoc}^es. Very often the pigment is present in such large amount that the organ appears pigmented upon THE MALARIAL FEVERS 411 naked-eye Inspection. The parasites may be so numerous that there are hardly any uninvadcd corpuscles seen, or they may be few in number. Microscopically, it may be found that many of the capillaries in the severe infections are entirely filled with red cells containing parasites, and often thrombi are formed, composed of such corpuscles, together with pigment and pigmented leukocytes. Besides the infected blood corpuscles free parasites may be observed, as well as macrophages, free pigment, i)ig- mented leukocytes, and endothelial cells. To the observations of Mar- chiafava and Monti we are indebted for valuable information upon the changes taking place in the nerve cells as the result of eestivo-autumnal infection. The changes occur both in the protoplasm and nucleus of the nerve cell and lead to a complete degeneration and consequent destruc- tion of the diseased tissue. Guarnieri has contributed a valuable research regarding the changes occurring in the retina in pernicious malaria, finding that they consist in hemorrhages and congestion of the capillaries, thus leading to impair- ment of function. The changes in the lungs are not at all characteristic, varying con- siderably according to the stage of the disease, and being those usually found in severe fever. A microscopic examination of sections in certain cases shows congestion of the alveoli, which contain large numbers of pig- mented, parasite-laden, white cells, and infected red blood corpuscles. In those cases in which bronchopneumonia has occurred, the exudation in the alveoli is mostly composed of polymorphonuclear leukocytes, to- gether with numerous infected red blood corpuscles and pigment, although the free pigment is generally small in amount. A pneumonia complicating a fatal attack of malarial infection, is without doubt due to a double infec- tion by the diplococcus of pneumonia and the malarial plasmodium. No changes which are characteristic are observed in the heart muscle. There has been considerable discussion regarding the changes occurring in the stomach and intestine in pernicious malaria. In certain cases in which diarrhoea has been marked some time before death, the mucous membrane of these organs is more or less pigmented and there is marked hypersemia, and even necrosis and ulceration. The Peyer's patches, as well as the solitary glands, are often swollen. Upon microscopic examination, sections of the stomach and intestine show that the capil- laries of the mucous folds are often crowded with parasite-invaded cor- puscles and these may occlude the capillaries, resulting in necrosis and ulceration of the mucous membrane. The epithelial lining of the mucous membrane is often necrotic, and there may be present a general super- ficial necrosis of this portion of the membrane. The liver is generally enlarged and markedly pigmented and in some cases it is almost black in color. Upon section, the cut surface is often very much pigmented and generally greatly congested. Microscopically the most marked changes are found in the capillaries and liver cells. The capillaries show many very large phagocytes containing much pig- ment and sometimes infected red blood corpuscles, as well as malarial parasites. The epithelial cells are greatly swollen and may contain free pigment and degenerated organisms. Free pigment is often obsen^ed in large lumps within the liver capillaries, while the stellate cells of Kupfer present marked pigmentation. The liver cells are atrophied, undergoing 412 DISEASES CAUSED BY PROTOZOA fatty degeneration, necrosis and pigmentation. The })igmentation, how- ever, in the Hver cells, is not due to the malarial pigment but to })igment derived from degenerated red blood corpuscles and is not characteristic of malaria, as it occurs in many other diseases. One of the most char- acteristic and important changes occurring in the liver are areas of focal necrosis, which are believed by Flexner to be due to the presence of some circulating toxic substance. The organ A\liich i)resents probably the most marked changes in mala- rial infections is the spleen. It is aln.iost invariably enlarged, some- times enormously so. It is of a dark blue or almost black color externally, the capsule being smooth, while upon section the cut surface is of a choc- olate, slate or almost black color, the consistence being very greatly decreased. The INlalpighian corpuscles are almost invisible. Upon microscopic examination the capillaries are found greatly congested by multitudes of red blood corpuscles, most of them containing parasites. This is not always true, as there are numerous cases in which few infected red blood corpuscles are demonstrable in the spleen. The intense congestion of the capillaries pushes apart the cells of the splenic pulp, and in some cases large areas are destroyed by hemorrhagic exuda- tion. In the spleen the red cells contain parasites in all stages of devel- opment, but the pigmented forms and the segmenting bodies are most commonly observed, as well as the crescents in Eestivo-autumnal infec- tions. Besides the infected red blood corpuscles, sections of the spleen show an immense number of phagocytes. These leukocytes consist of small cells which resemble lymphocytes, and larger cells known as ma- crophages. The macrophages contain clumps of pigment, red blood corpuscles containing parasites, free parasites, degenerated red blood corpuscles, and even the small phagocytic cells which have been mentioned. The Malpighian bodies do not become pigmented but the fibrous trabecu- Ife always present marked pigmentation. The free pigment is present in the form of small rods or granules. Here, as in the liver, two forms of pigmentation occur, the dark brown or nearly black melanin, the malarial pigment, and the golden yellow pigment, or hsemosiderin, derived from degenerated red blood corpuscles. The kidneys in pernicious malaria present very marked lesions which have been studied especially by Ewing and Dock, who have contributed very valuable work upon this subject. The condition produced is gener- ally that of an acute nephritis, presenting all the typical lesions of this disease, together with the pecidiar lesions due to malarial infection. As in the liver and spleen, microscopically the most marked change is the great congestion of the capillaries of the Malpighian tufts and the inter- tubular capillaries. These vessels are filled with infected red blood cor- puscles, free pigment and pigmented leukocytes. There is also present a marked pigmentation of the endothelial and epithelial cells, as well as those linifig the tubules. Free parasites are often observed and may be seen occasionally within the glomerular capillaries. The epithelium of Bowman's capsule is undergoing marked proliferation and the capillary space may be entirely occluded. The epithelium of the tubules presents marked degenerative changes, consisting of fatty and albuminoid degen- eration and necrosis. The straight tubules often contain hyaline, epithe- lial or granular casts. It should be remembered that there is not a marked THE MALARIAL FEVJJRS 413 pathological condition of the kidneys [)resent in every case, but it is safe to say that most cases of pernicious malaria are accompanied by an acute parenchymatous nephritis presenting the peculiar lesi* iis which have been described. In certain cases the bone marrow presents very marked changes. Micro- scopically, unless the malarial infection has persisted for a long time, there is but little change. If weeks or months have elapsed, however, the color of the bone marrow changes from the normal yellow to red or dull black. The capillary vessels are found to contain numerous endo- corpuscular parasites in various stages of development, and in festivo- autumnal infections, crescentic bodies. They also contain numerous macrophages, and in the marrow-pulp are found free parasites in various stages of development, as well as macrophages, nucleated red blood cor- puscles, and pigmented medullary cells. In considering the pathology of malarial infections it should be remem- bered that all the changes described are not presented, as a rule, in every case. Some cases will present marked changes in the spleen and liver, while the brain and kidneys are but slightly affected, and in others all the chief viscera of the body will show marked lesions. The pathology of chronic malarial infections, or malarial cachexia, is characteristic. As has been stated, there is always a marked anaemia, the spleen is greatly enlarged, sometimes weighing ten or more pounds, and presents marked pig- mentation. The liver is also enlarged but not in proportion to the enlarge- ment of the spleen. This organ also appears pigmented. The kidneys are enlarged, and grayish in color, due to deposits of malarial pigment. This is also true of the brain cortex, and upon section of the brain there is marked congestion of the capillaries, which contain numerous infected red blood corpuscles, pigmented leukocytes and free pigment. The condition pres- ent is characterized by the marked pigmentation of all the viscera, to which the name melanosis may well apply. Pathology of Latent Malarial Infection. — The pathology of acute and chronic malarial infection having been considered, it remains to discuss the pathology of latent infections. By this term we mean those cases in which no symptoms of malaria are presented, but which have died from some other disease. During the last three years at the U. S. Anny General Hospital, Presidio of San Francisco, California, seven cases have been observed in which the autopsy showed latent malarial infection; during life no symptoms of such infection had been presented. In three of these the infection was tertian in character, and in four, sestivo-autumnal. The pathology of these cases is interesting in that during life they pre- sented no symptoms of malaria, and as showing the lesions produced before the disease could be diagnosed. The pathological lesions found were confined entirely to the spleen and liver. The spleen in the tertian infections was considerably enlarged and somewhat pigmented. INIicro- scopically the sections showed intense congestion of the sinuses, together with pigmentation, especially marked along the edges of the iMalpighian bodies and the fibrous trabeculse. Many of the cells of the splenic pulp were pigmented. In the splenic sinuses and in the capillaries there were numerous parasite-infected red cells and pigmented leukocytes, but such cells were not nearly as numerous as in acute infections. The parasites were characteristic of those occurring in the peripheral blood and were all 414 DISEASES CAUSED BY PROTOZOA in about tlic same stage of development in each case. While this was so, it hai)ponc(l that the patients (hod at such intervals that the entire human cvfle of the tertian ixvraslte could be worked out from an examination of sections of the spleen, and the chief point of importance in the pathology of latent infections, as observed in these cases, is that the entire human cycle of the parasite .can be followed in the s})leen when no parasites are demonstrable elsewhere in the body, thus proving conclusively that the seat of the initial malarial infection is in the spleen. The capillaries also contain numerous pigmented leukocytes and macroi)hages. The liver in the tertian infections did not differ in appearance from that of the normal organ, but upon section, the cai)illaries showed within them a few j)igmcnted leukocytes, some containing what appeared to be degenerated malarial organisms. No infected red cells were observed. In the tiestivo-autumnal infections the pathological lesions were the same and the life-cycle of the parasite could be traced from the earliest hyaline organism to the segmenting bodies, but no crescents could be demonstrated. The only explanation of this fact is that the parasites had not advanced as yet to the stage in which crescent formation was possible. The pathology of latent malarial infections can be summed up by saying that before demonstrable clinical symptoms of malaria are present the malarial plasmodia are undergoing their human life-cycle within the sjileen and can be demonstrated in this organ after death. The changes produced are the same in character as occur in acute infections, but of course not so marked in extent. It is obvious that puncture of the spleen as a diagnostic measure in these cases would result in the discovery of the malarial infection. SYMPTOMS. Incubation. — The incubation period of malaria has received a great deal of attention, but at the present time there is considerable confusion regarding it. Marchiafava and Bignami have contributed a valuable study of this subject, in which they found that the incubation period, from the time the patient was bitten by the mosquitoes until the first symptoms appeared, varied from nine to ten days. Osier states that in the irregular fevers the incubation period varies from three to five days, while in the regular it varies from ten to twelve. From inoculation experiments, Bas- tianelli and Bignami found that in ?estivo-autumnal infections the maxi- mum period of infection was five days, the minimum two, and the mean three days. Mannaberg in seven cases found the period of incubation to vary from three to fourteen days, while Marchiafava and Bignami found the maximum to be fourteen days and the minimum two. As re- gards the data obtained from inoculation experiments, it may be stated that the disease was inoculated in an unnatural manner, and that for this reason the data may be unreliable. In inoculation of blood containing only the forms of the parasite belonging to the human cycle it is reason- able to suppose that the period of incubation will be shorter than is the case when the mosquito transmits the sporozoites to man, and this has been proven experimentally, for Marchiafava and Bignami have found that in an individual stung by the mosquito which had sucked blood con- THE MALARIAL FEVERS 415 taining crescents, festivo-autumnal fever developed in from nine to twelve days, whereas in the inoculation experiments of all the authorities quoted the mean was six days. But though the period of incubation of these fevers is doubtless in the majority of cases from nine to twelve days, numerous instances do occur which show a much longer period of incu- bation, sometimes weeks or months. Sternberg quotes the instance of certain sailors who were infected while their ship lay for two days in port and developed the disease, one after forty-eight, and one after one hundred and four days after leaving the port. The period of incu- bation may be very much prolonged, and in authentic instances jjcrsonally observed the first symptoms of malaria did not appear until from seven to ten months after exposure. These were in the person of officers and en- listed men of the army serving in a tropical climate, exposed to eestivo- autumnal fever and who immediately afterward were stationed in localities in which there were no Anopheles mosquitoes and no endemic foci of malaria. As Osier says, "A patient may dwell for years in an infected region without having paroxysms, or indeed fever of any sort, and he may then come under observation for the first time with ansemia and a greatly enlarged spleen and liver." The explanation of these long periods of incubation is made clear by the theory advanced by Thayer; i. e., that the parasites multiply and un- dergo their life-cycle, but in such small numbers that they give rise to no observable clinical signs. Although many individuals in malarial localities do not present symp- toms of malaria for long periods of time, it is without doubt true that in the great majority of instances an individual exposed to infection will acquire the disease in from three weeks to two months. ' This was well illustrated in the case of our soldiers in Cuba, almost ninety-five per cent, of whom gave a history of being there from two to six weeks before the onset of malarial fever. One month was the most common period given by the men as intervening between landing in Cuba and the first chill. The length of the period of incubation will vary, of course, with the amount of the infecting agent, the physical condition of the infected in- dividual and his surroundings as regards exposure, heat and cold, in- sufficient nourishment, etc. Classification, — It is extremely difficult to classify the malarial fevers from a clinical standpoint. A division into intermittent, remittent and continuous fevers, while useful, is at best but a rough classification which does not signify disease entities and which is confusing in many ways. It may be stated that any malarial fever may be intermittent, remittent or continuous. For instance, while a single tertian infection is undoubtedly intermittent, we can conceive of a tertian infection in which several genera lions of parasites may mature at various times, giving rise to a remittent or even continuous temperature curve. The same is true of quartan, and especially of the eestivo-autumnal infections. It is also trvie that infection with one generation of any of the malarial plasmodia will always result in a typical intermittent fever. In other words, all malarial infections are intermittent in character and only become remittent or continuous when more than one generation of the plasmodium matures at different inter- vals of time. While the term remittent malaria is generally applied to infections due to the sestivo-autumnal parasites, the name is a misnomer, 416 DISEASES CAUSED BY PROTOZOA as the .Tstivo-autumnal infections are as truly intermittent as are the tertian and quartan. For this reason it seems better, in considering the symptomatology to classify the malarial fevers frona an etiological stand- point; /. (' , tt-rtian, (|iiartan and a^stivo-autumnal. Sjrmptoms of Tertian Malaria. — The i)aroxysms of fever in tertian malaria occur every forty-eight hours and are due to the segmentation of the tertian malarial piasmodium. The time of the paroxysm can be accurately judgetl by the stage of growth of the organism as seen in the peripheral "blood. The onset of the paroxysm always occurs during the segmentation of the organism, and c|uotidian paroxysms are caused by double infections with the tertian ]iarasite. This, the most connnon and mildest form of malarial fever, occurs both in tropical and tem])erate climates, and when uncomplicated, presents a typical temperature curve, showing in single infections a rise of tem- perature every second day, while infections with numerous groups of Fig. 26. Tertian Malarial Fever. tertian oro-anisms may give rise to a remittent or sub-continued fever. In cases which present quotidian paroxysms it is often possible to destroy one o-roup of parasites by small doses of quinine, and, when this is done, the regular tertian paroxysm will reappear .^ The paroxysm, when typical, is divided into three stages, chill, fever, and sweating. The 'prodromal symptoms are generally malaise, loss of appetite and more or less dull headache. After these symptoms have persisted for a few days the patient is seized with a severe chill, but althouo-h he feels extremely cold the temperature continues to rise and at the acme of the chill has reached 103°, 104°, or even 106° F. The chill is immediately followed by a pronounced sense of heat, and in a short period of time the patient will complain as bitterly of this as he previously had of the cold. During the stage of fever, delirium is often present, accompanied by severe headache. During the onset of the chill, nausea and vomiting are common, but they do not persist, as a rule, during the stage of fever. After the fever has lasted for a few hours, it rapidly declines to normal, accompanied by very severe sweating, the entire skin being bedewed with moisture, often so pronounced that the bed- clothing is saturated. THE MALARIAL FEVERS 417 The Cold Stage. — As has been mentioned, there are generally some prodromal symptoms of the approaching malarial chill, as evidenced by yawning, a general sense of discomfort, headache, and often nausea and vomiting. The feeling of cold usually commences at the feet and gradually progresses upward, although very often the first chilly sensations are felt along the spine. In this form of infection the chill is severe, the patient shaking very vigorously, but, it is not so severe as in the quartan infections. In certain mild cases the chill may be absent, the patient complaining only of chilly sensations. The facial expression of the patient during the chill is one of cyanosis, the lips being blue and the skin bluish-red in color. The extremities are cyanotic and the skin presents the well-known condition characterized as "goose flesh." The jDulse is rapid, generally rather diminished in volume and often irregular. Headache is very often intense. During the chill the temperature rises very rapidly, reaching 104° F. or more, but careful examination will demonstrate that it has begun to rise before the onset of the chill. The urine is increased in quantity and lowered in specific gravity. The duration of this stage varies from one quarter of an hour to two hours in the most severe cases. The Hot Stage. — At the commencement of the hot stage the patient complains of flushings of heat, rapidly succeeded by cold sensations. Soon the sensations of cold are entirely lost and the patient complains bitterly of the intense heat occasioned by this high temperature. The facial appearance is that of congestion, the conjunctiva being injected and the skin red, while the entire surface of the body is reddened and the con- gestion is especially marked in the hands. The pulse is full, bounding and often dicrotic. The respirations are often rapid and hurried, and there may be more or less cough, denoting congestion of the lungs. The head- ache increases and may become very intense and of a throbbing character. Epistaxis occurs in a small proportion of the cases. In the milder tertians there are no nervous symptoms present beyond a severe headache, but in the severe cases there may be marked delirium or a drowsy condition merging into a semicoma. This condition is almost always present in those rare cases of tertian infection which become pernicious. The chief symptoms complained of by the patient during the hot stage are the severe headache and the intense heat. The temperature may reach its extreme height during this stage but very often the height of the fever is reached at the end of the cold stage. It is not uncommon during the hot stage to observe cutaneous eruptions. Herpes is very frequently seen, especially on the lips, and urticaria and a general erythema not infrequently occur. These eruptions sometimes lead to a suspicion of some eruptive disease being the cause of the chill. Herpes of the penis may occur during the hot stage of the paroxysm The duration of this stage varies somewhat, but is generally from four to six hours. The Sweating Stage. — ^As the fever begins to decline, it will be noticed that the perspiration appears first on the forehead and face, and the patient at once begins to feel better, the decrease in the unpleasant symptoms being proportionate to the severity of the sweating. Com- mencing, as has been said, on the face, the perspiration rapidly involves the entire body and is often so severe that water may be seen trickling from the skin of the arms, thighs, and legs. The sweating stage lasts, as a rule from two to three hours, at the end of which time the temperature has 27 418 DISEASES CAUSED BY PROTOZOA declined to normal, all of the impleasant symptoms have disappeared, and the patient generally sleeps for some time. As a rule, the temperature goes somewhat below normal and the decline is accompanied by con- siderable weakness of the circulation, the pulse being slow and weak In very rare cases this stage may be accompanied by collapse, and m one case of pernicious tertian infection observed by the writer this collapse proved fatal. During the cold stage an excessive amount of urine is often voided, i)olyuria being a most fre(]uent symptom. The average duration of the entire tertian paroxysm is from eleven to fourteen hours, but it must be remembered that there are paroxysms so slight as to be hardly recognized, especially in chiklrcn, while, on the other hand, the length of the paroxysm may be prolonged to twenty-four hours. In children the onset of the malarial paroxysms is often accompanied by convulsions. Physical examination of the patient will generally show an enlarged spleeii, but this sign cannot be thoroughly relied upon except in those cases which have severe and re])eatcd infections. Albuminuria is present in a considerable proportion of the cases. Of over 1,000 cases of ter- tian infection personally observed nearly 400 showed albumin in the urine, and 86 showed the presence of a few^ granular and epithelial casts. Symptoms of Quartan Infections. — The quartan paroxysms occur every seventy-two hours, but here, again, we may have double infections in which the segmentation of the parasites occurs at irregular intervals, thus giving an irregular temperature curve which may be misleading from a diagnostic standpoint. It is not necessary to detail the symptoms occur- ring with quartan paroxysms, as they differ in no way from those occur- ring in tertian infections except that, as a rule, they are more severe and Fig. 27. Quartan malarial fever. these infections are more apt to become pernicious. There are the same stages of chill, fever, and sweating as are seen in the tertian infection. The nervous symptoms are very much more pronounced, the headache being more severe, and slight delirium being almost always present. The quartan paroxysm is not as prolonged as the tertian, seldom covers more than ten hours, and is due to the segmentation of the quartan parasites. THE MALARIAL FEVERS 419 Symptoms of -ffilstivo- Autumnal Infections.— Clinically, all sestivo- autumnal infections should be classed as severe infections, in contra- distinction to the quartan and tertian infections, which are usually considered as mild infections. It should be thoroughly understood, how- ever, that a quartan or tertian infection may become pernicious, although such instances are rare. The old idea that there is a malarial parasite peculiar to the pernicious infections is no longer tenable, for it is now recognized that any of the malarial parasites may induce pernicious symptoms, and that the parasites accompanying such infections do not diflFer in any respect from those accompanying the mildest infections. The sestivo-autumnal infections occur in temperate regions most frequently during the months of July, August, September, and October, but in the tropics they persist throughout the year, and are not character- ized by any marked seasonal prevalence. As has been stated, the writer believes that these infections are caused by two distinct varieties of the sestivo-autumnal parasite, one completing its cycle of development in the human body in twenty-four hours, and the other in forty-eight hours. Either of these parasites is capable of caus- ing pernicious infections, but personal observations suggest that the tertian sestivo-autumnal parasite is the one most commonly concerned. From personal observations embracing nearly 2,000 cases of sestivo- autumnal fever in which the parasites were demonstrated in the blood, 75 per cent, were due to the tertian sestivo-autumnal variety. The sestivo-autumnal infections have long been distinguished by the term remittent, it being supposed that in these infections the temperature curve, instead of presenting the marked intermittency observed in tertian and quartan infections, was remittent or irregular in character. This is, however, not always correct, for these infections, when uncomplicated or uninfluenced in any way by treatment, may be as truly intermittent as are the tertian and quartan infections. It is undeniable, however, that remittency and irregularities in the temperature curve are more common in the astivo-autumnal infections, but too much stress should not be laid upon this point in diagnosis. Symptoms of Tertian .ffistivo- Autumnal Fever. — Patients suffering from this variety of malarial infection will present, as a rule, the following symptoms : Prodromal. — The prodromal symptoms are loss of appetite, slight headache, evanescent pains in the back and legs, nervousness, increased urination, and a general feeling of malaise. As in the tertian and quartan infections, three stages may be distinguished. The Cold Stage. — This commences with yawning and the patient complains of headache, slight nausea, perhaps accompanied with vomit- ing, and often intense nervousness. In a majority of cases there are no distinct chills, but the patient complains of creeping sensations along the spinal column and slight flushings of cold especially noticeable along the posterior portion of the buttocks and thighs. At the same time the head- ache increases and there is generally profound mental depression. The mucous membranes are cyanosed and the extremities cold. There is severe pain in the legs and back, greatest, as a rule, in the lumbar region. The pulse is generally weak and increased in frequency and may be very irregular. The respirations are rapid and rather shallow, During this 420 DISEASES CAUSED BY PROTOZOA stage the temperature is elevated and may reach 103° F. or more. This portion of the attack doea not hist over half an hour in a majority of the cases. Hot Stage. — The patient next experiences a sense of heat which comes first as localized flushings, but soon becomes general. The facial expres- sion is that common to fever, the eyes being suffused and brilliant, the face red, and the skin hot ap.d dry. Headache is intense and there is present '. either great mental depression or nervous excitement. The pain in the back and limbs is often agonizing in character, and in some instances Fig. 2S. Tertian jestivo-autiunnal fever. there is severe pain over the abdomen. The temperature is elevated and the curve very characteristic. Nausea and vomiting are often present, vomiting being sometimes very severe. The urine is increased in quantity and is generally albuminous. Diarrhoea is a common complication. The pulse is rapid and dicrotic in character, the respiration rapid, and there may be severe dyspnoea. This stage lasts for several hours, often from sixteen to eighteen or twenty, and is succeeded by a stage of remission. During this time the symptoms gradually decline in severity and finally disappear, the temperature returns to normal, generally going a degree or degree and a half below normal. A slight sweating occurs but this is not nearly so marked as in the tertian and quartan paroxysms. The intermission may last only two or three hours when another paroxysm ensues. As a rule, attacks of this fever occur toward evening, extend throughout the next day, and subside during the first hours of the third day, the entire paroxysm thus lasting thirty-sLx hours or more and occur- ring every forty-eight hours. While the symptoms described are often more severe than they are in the tertian and quartan infections, there is nothing diagnostic about them except the temperature curve. In uncomplicated eases the behavior of the temperature is absolutely characteristic, and the temperature curve is one that is not met with in any other disease. This peculiarity of tertian festivo-autumnal infection Avas first pointed out by Marchiafava and Bignami, and the writer has confirmed their observations in every uncomplicated case of such infection. At the onset of the fever the tem- perature rises suddenly to 103° or 104° F. Following the sudden rise THE MALARIAL FEVERS 421 there occur slight oscillations which cover several hours, during which time the temperature falls from one-half to one degree. This period of oscillation is followed by a distinct fall or pseudo-crisis, the temperature dropping from one and one-half to two, or even three degrees. This fall of temperature is often considered by the physician as the true crisis of the paroxysm. On the contrary, however, the fever again rises to a point higher than before attained and then falls rapidly. This is the true crisis, as the temperature goes considerably below normal. This peculiar temperature curve can be divided into five stages: (1) the initial rise; (2) the period of slight remissions; (3) the pseudo-crisis; (4) the precritical stage; (5) the true crisis. Another point of value in diagnosis between this type of fever and the mild tertian and quartan types is the length of time during which the fever lasts. This varies, but generally the temperature remains elevated over twenty-four hours, and often from thirty-eight to forty; in other words, the paroxysm really covers two days, while the period of intermission is very short. While this peculiar temperature curve will be observed in a very large proportion of cases of tertian sestivo-autumnal malaria, there may be many deviations from it due to several factors, among the most important being improper medication; double infections, or infection with more than one variety of malarial parasite; anticipation of the attacks or retardation, which are especially common in the pernicious forms; and slight elevations of the temperature occurring between the paroxysms. The ordinary temperature chart which shows only the morning and evening temperature is worse than useless as a guide in studying this form of fever. The temperature should be taken at least every four hours and better every three. S3nnptoms of Quotidian -ffistivo-Autumnal Infections.— The quo- tidian infection, which depends for its etiology upon the quotidian form Fig. 29. DAY OF MONTH 16 17 18 19 20 21 22 TIME OF DAY E ^ i : a, ° E -- : E E ; ; E E I en E S : OT E E : a. E E _ o " s : O) E ^ ID "• i E 1 CT. i E I tn S E : 105° ^ 104° I 103° i 102° § 101° < 100° 1 99° H 98° 97° = = = = E = E = = = = ~ = = = = E = =i iF - - 7 H g E ti E E -7 =J~ = — 1 — : ^ = E E Or = = i i = .J = = = ^ 3 = = = = ■:i fp-- '. ' ,S' '" "" t \ " ! "" ■?= s E = i i = i i ;a = gp = = = = ;& = = = iE = m- ^ ^ K-m =. -A - ^.-1 \ " '■ ~ = k ^ = ^ ' -l\:- A i¥ ^P M^ = h \ .|-;:4-/;l ■ ! -_^zzz = h i = ri-l M4 : i: : -f'-y- ^.--d-h rw 1 1 1 ^ A^ - =1 ~4- -/- i 1 ^ 1 1 i ^ 1 1 ( 1 E = h^ ^ ^ J y = ^^ -^- -e-<-- ^ i = = m = ^ = = = U = i = 1 = = 1 = = 1 1 1 ^^4- i t Quotidian sestivo-autumnal fever. of the sestivo-autumnal parasite, varies but slightly in its symptomatology from the tertian, except that the paroxysms occur every twenty-four hours. As a rule, in the quotidian cases the chilly sensations are more severe and 422 DISEASES CAUSED BY PROTOZOA there is often a distinct chill. Sweatingis also more pronounced but is not so marked as in the simple tertian and quartan fevers. The temperature curve is entirely different. It consists in the abrupt rise of the temperature to 103° F. or more, succeeded by as abrupt a fall. The attack lasts as a rule only about eight or ten hours. The tem})erature curve seldom remains reg- ular for long at a timie, for the attacks tend to run into one another, thus giv- ing rise to a continuous fever. This is especially true of those cases of a pernicious type. The temperature curve in the quotidian form is not char- acteristic as it resembles very closely that of double tertian infection, and we must therefore dejiend upon the microscope in making our diagnosis. There is no greater proof of the value of a microscopic examination of the blood than is founcl in the ease with which the various forms of malarial fever may be diagnosed and differentiated by it, and such an examination is often instrumental in saving life. Pernicious Malarial Infections. — Any one of the malarial plasraodia may give rise to pernicious symptoms, but the vast majority of fatal cases of malarial fever are due to the R\stivo-autumnal parasites. The tertian sestivo-autumnal parasite is more often concerned in such infections than is the quotidian, but it should be remembered that tertian infections are very much more numerous than are the cjuotidian. It is very important in treatins: cases of jestivo-autumnal malaria to remember that there is always an element of danger in that they may at any time develop pernicious symptoms which may cause the death of the patient, and it should be distinctly understood that the pernicious forms of malaria depend for their etiology upon the same organisms as do the mildest forms. The great majority of pernicious attacks of malaria occur in northern latitudes in the summer and autumn and are rare, while in the tropics they occur throughout the year and are very common. The most pernicious attacks occur in patients who have suffered repeatedly from malarial paroxysms which have not been properly treated, and the pernicious symptoms often develop during such a paroxysm. The causes of the pernicious symptoms are not very clearly understood. Bastianelli and Bignami considered that the chief causes for the development of the pernicious symptoms rest in the localization of the parasites in the brain or in other important organs, and also in the number of parasites present. While these reasons undoubtedly have much to do with the development of pernicious symptoms, it is probable that the amount of toxins secreted by the parasites have much to do with the development of these symptoms, as well as the physical condition of the infected individual and his sur- roundings as regards climate, food, hardships, etc. The pernicious forms of malaria may be classified in two ways; i.e., from the character of the temperature curve, and from the most prominent symptoms which are present. Under the first classification we may have tertian, quartan, remittent or larval pernicious malaria. Under the second classification we may have comatose, delirious, tetanic, eclamptic, hemi- plegic, dysenteric, choleraic, algid, cardialgic, hemorrhagic, jrtiemnonic and bilious pernicious malaria fevers. Only a few of the most common varieties will be described and it should be remembered that these are not disease entities, but only take their name from the clinical symptoms which are present. THE MALARIAL FEVERS 423 The Comatose Form. — This is the most frequent form of pernicious malarial fever and occurs in two ways, cither as a sudden attack of coma or a gradually developing comatose condition during a paroxysm o'f fever. The sudden development of coma is rare and, unless at once recognized and treated, invariably fatal. In this form the patient, who may have suffei-ed from repeated attacks of malaria and who has not felt well for some time, is suddenly stricken with profound coma, falls to the ground and, in the fatal cases, does not again regain consciousness. This form is apt to be mistaken for apoplexy. The face is suffused, the pupils con- tracted, the pulse at first full and bounding, later soft, rapid and thready, the respirations hurried and sometimes stertorous. The temperature is irregular, seldom reaching 103° F., and is often subnormal. Death generally occurs within two days. The most common form of comatose malaria is that in which coma develops more or less gradually during an attack of the fever. The symptomatology of the attack is the same as in the ordinary paroxysm, but the nervous symptoms such as restlessness and delirium may be more marked. As a rule the patient is restless and mentally depressed. Following this there develops a tendency to somno- lence, which deepens into stupor and finally coma. Unconsciousness is complete, the patient lying perfectly quiet, or there may be restless move- ments of the arms and legs. The skin is often somewhat icteric in hue, and hot and dry; the pupils are generally equally contracted but may be unequal or equally dilated. The icteric hue, which is often present in the conjunctivfe, has led to a diagnosis of yellow fever in infected regions. The face may be cyanotic but in old infections it is generally pale. Slight spasms of the muscles of the face are not infrequent. The tongue is tremulous, dr}'-, and thickly coated, and slight hemorrhages into the skin are sometimes observed. There may be hemiplegia present or total paralysis. The respirations are slow and quiet, but may be irregular, rapid and stertorous. The pulse is generally slow and full and incom- pressible at first, but becomes rapid and weak as the paroxysm pro- gresses. The faeces and urine are passed involuntarily, and retention of urine may occur. In cases having a fatal termination the pulse becomes thready, rapid and intermittent; the respirations irregular, labored or shallow; the skin pale and bedewed with cold perspiration, and death occurs by collapse. In cases which recover, the temperature falls, accom- panied by perspiration, the consciousness is slowly regained, but in many of these cases the improvement is only apparent and the patient relapses in the course of a few hours into a second paroxysm, and perhaps into a third, which usually results fatally. Between the paroxysms the mental condition is one of torpor or great mental depression accompanied by severe headache. The duration of the coma is variable, lasting from a few hours to three or four days, but it generally does not persist longer than twenty-four to twenty-six hours. As regards the course of the temperature in this form of pernicious malaria, it may be stated that it is irregular. Some cases present high temperature throughout, between 103° and 104° F., while in others the temperature may remain slightly above normal, or even below normal. In fatal cases the fever if present, declines, as a rvile, some hours before death, but it may ascend. Manson cites temperatures of 101° and 112° F. In a fatal case observed by the writer the temperature never went above 424 DISEASES CAUSED BY PROTOZOA 101° F, until a few hours before death, wlien it rose to 103°, the entire attack hasting six days. In this case the disease was not recognized by the attending physician until a few hours before deatii, when a blood examination was asked for, and large numbers of (jiiotidian a^stivo- autumnal parasites were found. Besides the comatose form of pernicious malaria there are other cere- bral forms, among which may be mentioned the dcliriou.f form in which the patient has hallucinations, followed by violent excitement; the eclamp- tic form, which is common in children, in wliich the sym))toms are similar to those of cerebro-spinal meningitis, there being vomiting, fever, head- ache, pain in the back of the neck, convulsions, and coma; the hemiplcqic form characterized by hemiplegia; and the amaurotic form, in which, after the comatose symptoms have subsided, complete blindness may result. The Algid Form. — In certain regions of the Southern and INIiddle States, as well as in other localities, there occur pernicious forms of malaria known as algid forms. The symptoms develoj) after one or more paroxysms, or they may be the primary symptoms. The characteristic condition is one of profound collapse attended by profuse perspiration, the temperature at the same time being more or less elevated, although in many cases the temperature is subnormal. Patients suifering from this form of malarial infection present a characteristic countenance, the cheeks being drawn and pinched, the eyes sunken, the nostrils dilated and the skin bedewed with persjiiration. The entire body is cold and the skin cyanotic and bathed with cold sweat. The lips and finger nails are intensely cyanotic. The tongue is tremulous, dry, and coated with a dirty white fur. The pulse is rapid, thready, and easily compressible, and generally more or less intermittent; the heart somids are muffled and the second sound sometimes inaudible, and as death approaches the pulse becomes imperceptible; the respirations are irregular, superficial in character, and labored; the muscular weakness is extreme, while the mental condition of the patient is one of apathy to his surroundings and indifference as to his condition. These symptoins rarely last over a few hours, death generally resulting. This is one of the most pernicious types of malarial infection and one which is most resistent to treatment. Such cases have been described by Laveran, Thayer, Marchiafava, Bignami, Osier and Sternberg. In one case observed by the writer in the person of a volunteer soldier who contracted a?stivo-autumnal fever in Cuba, algid symptoms developed and death occurred after six hours, despite all therapeutic aid. He had suffered previously from several paroxysms and his blood showed large numbers of sestivo-autumnal parasites. The Choleraic Form. — In certain cases of pernicious .Tstivo-autumna 1 malaria, the patient presents symptoms which very closely simulate those of cholera. As has been mentioned, diarrhoea is by no means an infrequent s}Tnptom in attacks of pestivo-autumnal fever, but in these eases choleraic symptoms develop, the stools suddenly becoming watery, very profuse and numerous. The diarrhoea leads to profound collapse accompanied by the usual symptoms. Death is a common result in un- treated cases, but where therapeutic measures are applied promptly, recovery occurs in the majority of cases. The temperature is generally THE MALARIAL FEVERS 425 elevated in this form. The great importance of this variety of sestivo- autumnal fever consists in the HabiUty with which it may be mistaken for cholera in countries in which epidemics of cholera are common. Microscopic examination of the blood is the only absolutely correct method of arriving at a diagnosis in such cases. Closely allied to the choleraic form, so far as sym]jtoms pointing to the abdomen are concerned, is the gastralgic form which has been de- scribed by Laveran, Colin, and Hasj^el. Prominent symptoms are agon- izing pain in the epigastrium, the vomiting of matter tinged with blood, while a diarrhoea severe in character may also occur at the same time. This form is interesting from a surgical standpoint, as a diagnosis of appendicitis may be made. The Dysenteric Form. — A considerable proportion of patients suffering from ajstivo-autumnal infection present symptoms of dysentery, consisting in frequent mucoid and bloody stools, tenesmus, colicky pain in the ab- domen, progressive emaciation, etc. At the Army General Hospital, Presidio of San Francisco, California, a very large proportion of ajstivo- autumnal patients coming from the Philippine Islands presented dysenteric symptoms. In fact, sixty-five per cent, of the cases of unrec- ognized malarial fever observed there were diagnosed either as chronic diarrhoea or dysentery. This proves how commonly dysenteric symptoms in the tropics are due to malarial infection, and probably a cer- tain proportion of cases diagnosed as dysentery in tropical regions are in reality the dysenteric form of malarial infection. The proper administra- tion of quinine in these cases has always resulted in the disappearance of the symptoms, thus proving their malarial nature. The Bilious Form. — Certain cases of malarial infection present a symptom complex in which jaundice and the vomiting of bile-stained fluid are most prominent. These cases have long been known under the term of bilious remittent fever. The attack is generally characterized in the beginning by well-marked malarial paroxysms, but the temperature becomes more or less remittent or continuous. Marked jaundice appears and severe vomiting is present, the matter vomited being greatly bile-stained. Epistaxis is rather common, and haematemesis often occurs. Delirium may be present or there may be a condition of semi- coma, or even coma. The patient often complains of severe pain in the epigastrium and hiccough is one of the most common symptoms. The temperature curve in well-marked cases is generally remittent or almost continuous, somewhat resembling that of typhoid fever. If untreated, this form of the disease is almost invariably fatal, but if the proper thera- peutic measures are applied recovery is generally the result. The Irregular and Remittent Forms. — As has been stated, any of the malarial infections may become irregular or remittent in character as regards the temperature, but the sestivo-autumnal infections are especially prone to present peculiar irregularities in the fever, which in many cases are very confusing. A malarial fever may become continuous, irregular or remittent in various ways, the principal of which are the an- ticipation or retardation of the paroxysm, infection with one or more groups of parasites, and insufficient treatment by quinine. In these infections it is very seldom possible to demonstrate the complete life-cycle of the para- site in the blood, but in those cases which are caused by mixed infection 426 DISEASES CAUSED BY PROTOZOA with more than one variety of parasite the forms may be easily differen- tiated. It is these forms, especially the remittent or continuous types, which are so often confused with typhoid fever and septic-emia, especially where {i?stivo-autinnnal infections are infrecjuent. The remittent type is the one which is of the most importance, as cases of this kind are not .infrequently supposed to be typhoidal in character. The symptoms are very variable and inconstant. The prodromal symp- toms are generally weakness, malaise, more or less headache, loss of Fig. 30. Sub-coutinued ffistivo-autiminal malarial fever. appetite, etc. The attack may or may not begin with chills, but there are always slight chilly sensations. The patient's appearance is very sug- gestive of typhoid, the face being flushed, the eyes brilliant, the mucous membranes congested, and the skin hot and dry. There is severe head- ache and muscular pain, especially marked in the back and limbs. There is often marked nervousness, sleep being poor, and there may be slight delirium. The tongue is dry and coated and resembles markedly the tongue of typhoid, while nausea and vomiting are present and diarrhoea is common. The pulse is rapid and dicrotic in character, while the res- pirations are hurried and often very superficial. There is often tender- ness of the abdomen, and the spleen is generally more or less enlarged. In some cases the resemblance to typhoid is very remarkable, epistaxis, an eruption resembling the roseola of that disease, and tenderness and gurgling in the right iliac region being present. In fact, in many of these cases it is impossible to make a diagnosis between malaria and typhoid fever without the aid of the microscope. The temperature curve in these infections is very variable, but usually there are present more or less marked intermissions, thus serving to differ- entiate it from the fever of typhoid. In rare cases, how^ever, the curve cannot be distinguished from that of a mild typhoid fever, there being slight daily remissions but no marked intermissions. An examination of the blood, if carefully made and repeated if neces- sary, will invariably demonstrate the type of malarial parasite concerned, which is generally one of the sestivo-autumnal organisms. The duration of the remittent or sub-continued fevers may be several weeks, but as a rule spontaneous cure or death occurs within tlii-ee weeks. If properly treated, the symptoms are easily controlled within a week, although in THE MALARIAL FEVERS 427 very rare instances the parasites may be very resistant to quinine and per- sist for eight or ten days. Spontaneous recovery, which has been mentioned, is often oVjserved in the mild tertian and quartan infections and rarely in the tcstivo-autum- nal infections. The chief causes leading to spontaneous recovery in malaria are: 1. Production and excretion of certain substances bactericidal and antitoxic in nature, by certain leukocytes, especially the eosinophiles, v^rhich lead to the death of the malarial plasmodia. 2. Disintegration of the leukocytes and the liberation of certain anti- toxic and bactericidal substances having a similar action. 3. Phagocytosis; i. e., the engulfing and digestion of the plasmodia. It is probable that all of these processes occur simultaneously and aid in the destruction of the infection. Combined Infections. — ^Any of the varieties of malarial plasmodia may occur together, thus causing what is known as a combined infection. In such infections the temperature chart is apt to be irregular or remittent, but very often one type of parasite may so predominate in numbers that it will give to the infection the characteristic symptoms caused by the par- ticular organism concerned; thus we may have a combined infection with sestivo-autumnal and tertian parasites in which the sestivo-autumnai parasites are so much more numerous than the tertian that the case will present the symptoms of an sestivo-autumnal infection. As would be expected, some very peculiar temperature charts are presented in these combined infections, and the symptoms are often so anomalous that a diagnosis of malaria cannot be made without the aid of the microscope. Latent and Masked Infections. — In previous communications^ the writer has called attention to the importance of the occurrence of latent and masked malarial infections, especially in individuals who have resided in malarious localities. A latent malarial infection may be defined as one in which parasites can be demonstrated in the blood but in which there are no symptoms which would lead a clinician to suspect malaria, while a masked infection is one in which the symptoms are obscured by those of some accompanying disease, or in which they are atypical in character. At the U. S. Army General Hospital in San Francisco, California, out of 1,267 cases of malaria in which the parasites were demonstrated in the blood, 395, or 25 per cent., have shown either latent or masked infections. The sestivo-autumnal infections comprised 275 of the cases, thus showing that the sestivo-autumnal parasite is concerned most often in latent and masked malaria. Examinations of the blood in such cases have shown the parasites in all stages of development, but always in small numbers. Of the 395 cases, 277 were latent infections, or infections in which the malarial parasites could be demonstrated in the blood but which presented no clinical symptoms, while 118 were masked infections, most of them being in patients suffering from other diseases which masked the malarial symptoms. Of the masked infections, chronic dysentery, chronic diar- rhoea, pulmonary tuberculosis, and amoebic dysentery were the diseases which most often masked the malarial infection. Lobar pneumonia was simulated very closely in three cases by the malarial infection, and a ^Medical Record, Feb. 15, 1902, also American Medicine, Oct. 21, 1904. 428 DISEASES CAUSED BY PROTOZOA diagnosis of this ilisease was made ])i'cvi()us to an examination of tlie blood. The pathology of eertain fatal eases of latent and masked malarial in- fection demonstrates that the malarial j)arasitc may undergo its complete life-cycle in the s])leen without producing any symptoms of the disease. The remarkable ])ercentage of latent and masked infections, as shown in the cases studied at this hospital, proves the great importance of a routine examination of the blood in all patients coming from malarious localities. It is obvious that recognition of such infection is of the greatest importance, as in the latent infections we are thus able to cure the disease before any annoying symptoms are present, and in the masked cases we are able to remove the malarial element which may be of the greatest importance as regards the recovery of the patient. Not only is this so, but an examination of the blood in these cases will often prove of service, not only to the physician, but also to the surgeon, as certain malarial infections simulate very closely surgical conditions. The following case is of especial interest, as it demonstrates how closely malarial infection may simulate appendicitis. The patient was an officer of the U. S. Army who was transferred to the Army General Hospital with a diagnosis of suspected appendicitis, transfer being made with a view to operation if the diagnosis was verified. He gave a history of having intermittent attacks of malaria in the Philip- pines which did not necessitate admission to sick report. He had not been feeling well for some time, but on the day before admission to the hospital he had an attack of pain in the region of the ascending colon. Upon admission he complained of pain in this region, at times very severe; his tongue was coated; bowels regular; and his pulse and temperature about normal. A blood count was made and a slight leukocytosis was foimd. Physical examination showed no rigidity of the muscular wall, but he complained of pain in the right iliac region on pressure, and after careful examination, operation the next morning was determined upon. That evening he had a slight chill and his temperature rose to 104° F. An examination of the blood was made and numerous hyaline forms of the tertian pestivo-autumnal parasite were found. Quinine was promptly administered, which resulted in a prompt fall of temperature, and con- tinued administrations of it in a complete cure. In this case an operation would undoubtedly have been performed in the morning for a condition which was essentially malarial in character. Microscopic examination of the blood in these cases is our only means of diagnosing the disease. Complications and Sequelae. — The malarial fevers, like other disease processes, are apt to be complicated by, or associated with, other diseases, and are also apt to be followed by certain grave sequelae. While this is so, the conditions complicating malarial infection should not be con- fused with the infection itself; in other words, a typhoid fever compli- cating malaria should not be considered as being due to malarial infection; nor is a pneumonia which may complicate such infections, due to the malarial parasites. Boudin advocated the theory that the complications were due to malarial poison, but in the light of our present knowledge this theory is entirely untenable. Of the many diseases which may com- plicate the various forms of malaria, and especially the sestivo-autumnal THE MALARIAL FEVERS 429 infections (for these infections, being more severe in cliaracter than the tertian or quartan, are more apt to be accompanied by complications), the following may be mentioned: Of the diseases of the nervous system acute mania, severe hysteria, par- aplegia, hemiplegia and meningitis may be noted. The most serious disease of the respiratory system complicating malarial infections is lobar and lobular pneumonia. For a long time pneumonia complicating these fevers was held to be due to the malarial plasmodia, and while this is true in a very small number of cases, it should be remem- bered that true lobar or lobular pneumonia may occur coincidently with any of the malarial fevers.' Pneumonia may complicate the malarial infection at any time, and may develop suddenly or insidiously. The course of the disease is similar to that in a patient in whom no malarial infection is present, but the prognosis in pneumonias complicating the sestivo-autumnal infections is very grave, Ascoli placing the mortality as high as 60 to 78 per cent. The pneumonic symptoms may mask the malaria, or vice versa. Among the other respiratory complications may be mentioned pneumonic septicaemia and empyema. Acute bronchitis is very common in all varieties of malarial infection and in the sestivo-autumnal infections is observed in about 40 per cent, of the cases. Tuberculosis very often occurs in conjunction with malarial infections, and often the symptoms of the disease mask those of malaria. Pleurisy is somewhat rare. Diseases of the circulatory system not infrequently complicate malarial fevers. As would be expected, many cases of malaria present organic disease of the heart and in such cases the prognosis is often grave. Acute endocarditis is a rare complication, while functional disorders of the heart are very common. The most common disease of the genito-urinary system complicating malaria is nephritis. Some form of nephritis occurred in at least 4 per cent, of sestivo-autumnal infections and in about | per cent, of tertian infections personally observed. It is more frequently a sequel of malaria than a complication. Orchitis and epididymitis very commonly occur as complications, but a history of gonorrhoea can usually be obtained. It is doubtful if true malarial orchitis ever occurs. The most frequent and important disease of the g astro-intestinal tract complicating the malarial fevers is dysentery or some form of enteritis. Dysentery is especially frequent in patients returning from regions where both malaria and dysentery are endemic. Sixty-five per cent, of the patients with malarial parasites in the blood observed at the Army General Hospital, Presidio of San Francisco, suffered at some time from acute or chronic dysentery. Of these over 25 per cent, were suffering from amoebic dysentery. Dysentery complicating malaria is very apt to run an aggravated course, and the prognosis is much worse than where it occurs alone. Frequently the malarial forms are masked by the symptoms of dysentery. The administration of quinine in cases complicated by dysentery has always resulted in the removal of the malarial infection and the improve- ment of the dysenteric condition. In a certain proportion of patients suffering from dysentery, the disease is probably due to the localization of the malarial parasites within the capillaries of the intestines, for in no 430 DISEASES CAUSED BY PROTOZOA other way can vre explain the rapid recovery of many such patients after the administration of quinine. Typhoid fever occasionally occurs in conjunction with the malarial fevers. In nearly 5,000 cases of malaria personally observed the com- plication of the disease with typhoid has only occurred 8 times. Of these 8 cases, 5 were combined infections of typhoid and lestivo-autumnal malaria, 1 a combined infection with tertian malaria, and 1 with quartan. The latter case, which has been reported,' is rare, in that the quartan parasite was demonstrated in the blood in conijjination with typhoid. As a rule, the malarial attacks occur during convalescence from typhoid but may occur tluring any stage of the disease. ^Vhere malaria is complicated by tyj^hoid, or even vice versa, the symptoms do not vary markedly from those occurring in a single infection. The subject of combined infections of t}']5hoid and malaria has been very fully inves- tigated by Lyon,^ who has collected all the published cases, which, at the time the classification was completed, numbered 29 in all. Undoubtedly, this is far from being the actual number of such combined infections, as Lyon considered only as such infections cases in which the parasites of malaria were demonstrated in the blood at the same time that the Widal test was present. The discovery of such combined infections is of the greatest importance, as the malarial element in the case can be easily removed by the proper administration of quinine, and thus a source of injury to the patient eliminated. Among other complications may be mentioned erysipelas, acute rheu- matism, sciatica, various skin eruptions and variola. Sequelae. — The toxins elaborated during the development of the malarial plasmodia may give rise to certain conditions which develop coincident with or after the malarial infection itself has ceased, and these must be regarded as sequels of the disease. Among the most common are those occurring in the nervous system, the genito-winary system, the glandular system, and the blood. The most numerous complications occur in the nervous system, due to the blocking of the capillaries of the cortex of the brain by the malarial parasites and their products, or to the effect of certain toxins liberated by them. Local paralysis frequently occurs, due undoubtedly to the blocking of the capillaries of certain cortical regions, but these are generally evanescent in character. Various psychical disturbances are common and the memory is often defective after repeated malarial attacks. Melan- cholia, delusional insanity and mania may follow severe attacks of sestivo-autumnal malaria, and especially common is a condition of melancholia. Mania, melancholia and delusional insanity have been observed in soldiers returning from the tropics which were undoubtedly sequelfe of severe and repeated attacks of sestivo-autumnal malaria. INIultiple neuritis rarely occurs. One of the most common sequelse is neuralgia, but it should be remembered that many so-called malarial neuralgias have in reality no connection whatever with malarial in- fection. * Philadelphia Medical Journal, June 17, 1899 ^ The Johns Hopkins Hospital Reports, Vol. VIII, 1900. THE MALARIAL FEVERS 431 Among diseases of the genito-urinary system, albuminuria is of frequent occurrence during acute attacks of malaria and oftentimes persists for some time after the cessation of such attacks. Thayer and Hewetson found albuminuria in over 50 per cent, of their cases. Thayer found that it was most frequent in sestivo-autumnal infections, occurring in 58.3 per cent, of these infections, in contrast to 38.6 per cent, of tertian and quartan infections. Rem-Pici has contributed most extensively to our knowledge of the albuminurias occurring during and after malarial infections. From personal experience, albuminuria apparently occurs in about 50 per cent, of cases of sestivo-autumnal and in about 30 to 35 per cent, of cases of tertian and quartan malaria. Both acute and chronic nephritis may occur as sequelae of the malarial fevers. Kelsch and Keiner have contributed valuable data regarding the symptomatology and pathology of nephritis occurring after malarial infections. It may be stated that all forms may occur, the most common being acute glomerular and chronic parenchymatous and interstitial nephritis. Personal observations suggest that nephritis occurs in at least 3 per cent, of all cases of sestivo-autumnal infections, the most common form being chronic parenchymatous. It is rare in tertian and quartan infections, but is always found in fatal cases. Polyuria is a frequent sequela of the malarial fevers, especially the sestivo-autumnal variety, but as a rule the condition is transient, although it may be persistent. Glycosuria is a rare sequela of the malarial infec- tions. Among the sequelse occurring in the glandular system may be mentioned hypertrophy of the liver and rupture of the spleen. After repeated attacks of malaria, a condition which may be termed hypertrophic, malarial hepatitis may develop, the liver becoming greatly enlarged, while the perilobular tissue is increased in amount and the capillaries greatly dilated and congested. The condition does not, as a rule, cause any clinical symptoms. Many authorities have endeavored to prove that continued malarial infection will give rise to cirrhosis of the liver, but when present it is undoubtedly due to some other cause, as cirrhosis of the liver is no more common in malarial than in non-malarial districts. Rupture of the spleen is a rare sequela of malaria and is generally due to falls or blows, in which the greatly enlarged organ, rendered soft and pliable by the malarial infection, is ruptured. The writer has reported two cases of this character. The symptoms are sharp, lancinating pain in the left side and the usual symptoms of collapse due to hemorrhage. Death may occur in a few moments or after a day or more. The Blood. — In repeated and severe attacks of sestivo-autumnal malaria there is produced a post-malarial ansemia which may be very severe and persistent. In tertian and quartan infections, after complete recovery the regeneration of the red blood corpuscles is generally rapid, but in the sestivo-autumnal infections the anaemia may persist. Along with the ansemia there is a marked reduction in the haemoglobin, always in about the same ratio as the red blood corpuscles, while the leukocytes are reduced in number as a whole, but the large mononuclear forms increased. A pernicious type of ansemia, occurring as a sequela of the sestivo- autumnal infections, have been observed by the writer in 6 cases, all of 432 DISEASES CAUSED BY PROTOZOA which provotl fatal. The bUxJtl showed no nucleated red cells, the red cells numbering from 490,000 to 590,000 per cubic millimeter. The leukocytes were about normal in number, relatively, but the polymor- phonuclear leukocytes were increased. Poikilocytosis was not marked, but there were great differences in the size of the red cells. This form of severe ana^nia has been described by Bignami and Bastianelli, and is remarkable in that no nucleated red cells can be demonstrated, due, according to these authors, to the almost complete absence of regenerative power in the blood-forming organs. In certain instances the classical type of pernicious anaemia may occur as a sequela of the malarial in- fections, esi)ecially the a^stivo-autumnal variety. Malarial Cachexia. — In patients who have suffered from repeated attacks of malarial fever which have not been properly treated, there develops a peculiar condition, the most characteristic symptoms of which are a more or less severe aniemia and a greatly enlarged spleen. This so-called malarial cacliexia is most frequent in troi)ical regions in which the tiestivo-autumnal infections are endemic, and least frequent in locali- ties in which tertian infections are present. It is especially apt to develop after latent and masked infections which have gone untreated because un- recognized The ansemia which is present partakes of the character of a secondary anaemia, the red cells being reduced to 2,000,000 or less per cubic millimeter, while there is a marked increase in the large mono- nuclear leukocytes and a corresponding decrease in the haemoglobin. The spleen may be enormously enlarged, reaching as low as the crest of the ilium, but as a rule it does not extend more than four to eight cm. below the border of the ribs. It is firm and not painful on palpation. Patients suffering from malarial cachexia present a peculiar yellowish or grayish hue of the skin, while the mucous membranes are very pale, due to the antemia. There is a loss of appetite, diarrha^a, dyspnoea, emacia- tion, and a general condition of nervous exhaustion. The temperature may be normal, but generally shows a slight rise toward evening; it seldom reaches 102° F. The condition is especially freciuent in children living in tropical localities. The long-continued malarial infection renders these patients especially liable to acute infectious diseases and slight injuries are often attended by serious results, such as phlegmonous inflammation or hemorrhage. Marchiafava and ]3ignami state that it has never been their experience to observe in patients suffering from malarial cachexia, grave infections with many parasites in the blood, but that there are always a few parasites and very little melansemia. Thus it will be seen that malarial cachexia cannot always be determined by microscopic examination of the blood, as the parasites will not be present in any number except when there are acute symptoms, and even melanaemia may be almost absent. Diagnosis.— The diagnosis of the malarial fevers from clinical symp- toms alone is often difficult and sometimes impossible, especially in the sestivo-autumnal infections, but there are two methods of diagnosis which are all-sufficient and deserving of confidence; i. e., examination of the blood and the therapeutic test by quinine. Of these two methods the examination of the blood is the more valuable, for the therapeutic test by quinine may be misleading, as other fevers may decline under the ad- ministration of this drug. The mild tertian and quartan infections, if THE MALARIAL FEVERS 433 uncomplicated, can usually be easily diagnosed by the clinical symptoms alone, but where double infections occur, a diagnosis of malaria is often impossible from a clinical study of the symptoms, and in a^stivo- autumnal infections a diagnosis of malaria is generally impossible with- out an examination of the blood, as the symptoms are often so con- fusing and atypical that they are of little value. Examination of the Blood. — In most instances one examination of the blood will be sufficient, but if a negative result is obtained repeated examinations should be made at short intervals. If this is done, almost invariably, even in the most obscure sestivo-autumnal infections, the parasites will be discovered. Cases of malaria of this variety undoubtedly occur in which no parasites can be demonstrated in the peripheral blood, but not when the infection is severe enough to produce symptoms. The symptoms in sestivo-autumnal infections are often so obscure, or even so slight, that malaria is not suspected, and in many cases an exami- nation of the blood will show the presence of the malarial plasmodia before any clinical symptoms sufficiently severe to excite a suspicion that the infection existed. It follows, then, that an examination of the blood in all cases of disease occurring in malarious localities should be adopted as a routine measure. The blood may be examined either in the fresh state or in stained specimens. The desirability of the examination of the blood in the fresh condition rather than in permanent specimens, which have been hardened and stained, has been advised but since the development of Wright's modification of Romanowski's stain, the examination of speci- mens stained by this method is preferable, except in the hands of an expert, to the examination of the fresh blood. If fresh blood is to be examined, the patient's ear is carefully cleaned with alcohol, dried thoroughly, and a slight puncture made with a lancet or needle, and the first drop or two of blood allowed to flow away. A small drop is then taken on a slide which has been carefully cleaned and a coverglass placed over it. Specimens should be examined as soon as possible, but if carefully wrapped in paper can be carried for several hours without much danger of changes occurring which would obscure the Plasmodia. The ear is preferable to the finger, especially in the case of children, as there is less pain, and the patient cannot watch the operator during the procedure. The blood should be examined with a one-twelfth oil-immersion objective and a one inch eye-piece. At least half an hour should be spent on the specimen before it is pro- nounced negative. For the examination of certain stages in the life-cycle of the malarial plasmodia, the examination of fresh blood is essential, but with our improved methods of staining, better results in diagnosis will be arrived at by the majority of physicians if stained specimens are used. Examination of Stained Specimens.— -There have been numerous methods proposed for the staining of the malarial plasmodia, the most valuable of which have been Romanowski's and its many modifications, such as Jenner's and Wright's. In 1902,^ the writer described a method of staining which is simple and can be easily applied by the practicing physician. It is not as satisfactory in showing the finer struc- ^New York Medical Journal, September 13, 1902. 28 434 DISEASES CAUSED BY PROTOZOA ture of the organisms as is Wright's method, but from a diagnostic stand- point it is easier of appheation in that the solution can be much more easily made, and the process is not so involved. In consists in the em- ployment of t\yo solutions: Solution A, a saturated aqueous solution of methyl violet B (Griiblcr's). This solution should be prepared with distilled water and sliould be at least three weeks old. Solution B, a five per cent, solution of aqueous eosin (Griiblcr's). The method is as follows: Very thin blood smears are made upon perfectly clean coverglasses. These smears are hardened in absolute alcohol for five minutes, and are then carefully dried and stained with solution A for ten seconds; they are then thoroughly washed in water and stained with solution B for from three to five seconds. Specimens are then dried and mounted in Canada balsam. If the method is used as described the results are very satisfactory. The red blood corpuscles stain a beautiful dark blue while the parasites take a much lighter stain, the chromatin staining a deep red. The stain is especially useful in de- monstrating the crescentic forms. These stain a very dark violet, the chromatin being reddish in color. The protoplasm of the polymor- phonuclear leukocytes stains a dull pinkish violet, and the nucleus stains much less intensely. The granules of the eosinophiles stain dark red and the nucleus bright blue, while the protoplasm of the lymphoc}i;es, both large and small, stain crimson violet and the nucleus pale blue. Probably the most satisfactory of all staining methods for the malarial Plasmodia is the modification of Romanowski's stain described by Wright. While the method of preparing the staining solution is somewhat com- plicated, a careful following of the directions will result satisfactorily. Numerous commercial houses have Wright's stain for sale, but as a rule the stains purchased in this way are unsatisfactory and cannot be relied upon. It is much better for the physician to make his own stain. Dr. H. R. Oliver has recently modified Wright's method slightly, and the staining solution as prepared by him gives very excellent results. The following is the method of preparation: Add .5 gni. of soda bicarbonate to 100 Cc. of distilled water, dissolv- ing thoroughly, and then add one gram of methylene blue (Griibler's) and heat for one hoiu" in a sterilizer after the steam is up. After heating allow the mixture to cool. Make a 1 to 1000 solution of yellow eosin (Griiblcr's) and add this, stirring constantly, to the cooled methylene blue solution in the proportion of 500 Cc. of the eosin solution to 75 Cc. of the blue solution. This should be done, preferably, in a large porcelain dish. Let the mixture stand for a few minutes, and then filter through one small filter paper and save the residue. The residue, which is a crystalline, greenish-black powder, should be dried in a hot air oven and preserved. To make the staining solution, take .3 gm. of the residue and add 100 Cc. of pure methylic alcohol (Merck's) reagent. This should then be filtered, and to 80 Cc. of the filtrate add 20 Cc. of methylic alcohol. This is the stock solution ready for use. To stain, add a few drops of this solution to the preparation and let stand for two minutes, and then add enough distilled water to cause a slight metallic scum to form on the surface of the preparation. Specimens should then stand for two to ten minutes, be finally washed in running distilled water and mounted. THE MALARIAL FEVERS 435 By this method all varieties of malarial parasites stain as follows: The protoplasm stains a robin's-egg blue, the vesicular portion of the nucleus remains unstained, while the chromatin stains a dark cherry red. The very young forms of the plasmodia — that is, the ring forms — are very distinctive, appearing as a bright blue ring at some portion of which is situated a dark cherry red dot marking the chromatin of the nucleus, the red blood cell being stained a very light red or brownish-yellow. The only objection to the use of staining methods in the diagnosis of the malarial plasmodia is that certain other material, especially broken-down leukocytes or extraneous matter, may take the stain and be so situated within the red cell as to be mistaken for the organism. But to one who has once seen preparations stained by the methods described no mistake is possible in this direction. Particular care should be taken to make the blood smears very thin, and this is best done by the use of the method advocated by Cabot, which consists in using the ordinary ribbed rice cigarette paper, small pieces the width of the coverglass being cut parallel with the rib. The edge of the paper should then be passed quickly across the drop of the blood as is exudes from the ear, placed on the slide and drawn carefully along it. With practice, very even, thin smears can be obtained in this way. The Therapeutic Test. — As Osier has well said, any fever which resists the action of quinine properly administered for more than four to five days, is not malarial in character. This fact is used as a means of diag- nosis w^here for any reason an examination of the blood is impossible, but it must not be forgotten that quinine is capable of reducing the temperature in diseases other than malaria. In many instances, also, much harm may be done, especially in typhoid fever, which often resembles the continued sestivo-autumnal infections, and in which quinine is not only contra-in- dicated, but may be harmful. Differential Diagnosis of the Various Forms of Malarial Fever. — A differential diagnosis of the various types of malaria is most quickly and scientifically made by an examination of the blood. In this w^ay the entire life-cycle of the tertian and quartan plasmodia may be studied, and the various types of plasmodia easily differentiated. Where, however, an examination of the blood for any reason is impracticable, the clinical symptoms may be of service in distinguishing the various types; thus, a typical tertian or quartan infection is easily differentiated by the time of the occurrence of the paroxysm and the study of the temperature chart alone, but it is impossible to differentiate a double tertian infection from a quotidian sestivo-autumnal infection in this way, and it is obvious that mixed infections cannot be differentiated by the clinical symptoms only. The temperature chart occurring in uncomplicated cases of tertian sestivo- autumnal fever is so characteristic that a differentiation of this form from other malarial infections can be easily made, but in all forms of malarial infections, the diagnosis should rest chiefly upon the result of blood examinations. While it may not appear to be of great importance to be always able to differentiate the exact type of malarial infection that is present, it surely is so from a scientific standpoint, and is often so practi- cally. Grave mistakes have been made in considering a severe sestivo- autumnal infection as a mild tertian, and many lives have no doubt been lost by such mistakes in diagnosis. The sestivo-autumnal infections are 436 DISEASES CAUSED BY PROTOZOA apt at any time to Ijccoinc ])crnicious and unless prompt treatment is instituted death is liable to follow. It can be easily seen that such an infection mistaken for tertian malaria, and treated by the administration of small doses of quinine, migiit result fatally. While in uncom[)licated tertian and quartan malaria the examination of the blood may not be absolutely essential in making- a diagnosis, it is in the a\stivo-autumnal infection, and it is especially in those presenting anomalous symptoms that such an examination is of the greatest service. In these cases the presence in the blood of the small intracellular ring forms, or of the crescents, demonstrates tat once the character of the infection and enables us promptly to apj^ly the proper treatment. The differential diagnosis of the malarial fevers from other disease processes which may closely resemble them is only possible, in many instances, by the use of the microscope. This is especially true of the restivo-autumnal infections which so often present anomalous sym])toms resembling those of some other disease, that from a study of the clinical symptoms alone a diagnosis cannot be arrived at. There are a number of diseases with which malarial fevers, especially the irregular types, may be confused. Typhoid Fever. — Perhaps no other disease has been so often confused with malaria as has ty])hoid fever. This was well borne out during our war with Spain. Clinically, the confusion regarding these two diseases has much to justify it. It is probable that a typical tertian or cjuartan infection is never suspected to be typhoid, or vice versa, but in the more irregular a?stivo-autumnal infections this mistake has often been made. In regions in which testivo-autumnal malaria is endemic, or supposed to be, it is a very common mistake to regard patients suffering from typhoid fever as victims of this type of malaria. This is because many cases of sestivo-autumnal infection present typhoid symptoms and a clinical differentiation is impossible. The mistake of considering a typhoid in- fection, however, as malarial, after quinine has been administered for several days, is inexcusable, for experience has shown that there is no malarial fever which will resist the action of quinine, when properly administered, for a period of over six or eight days. Despite this fact, many patients with typhoid fever in malarious regions are drenched with quinine under the suspicion that they are cases of restivo-autumnal malaria. The differentiation of these two diseases depends upon the microscopic examination of the blood for the malarial plasmodia. Secondary to this is the therapeutic test by quinine. If parasites are present in the blood and the Widal test is negative, the diagnosis is at once established, and cases of combined infection are rare. The administration of quinine will remove the malarial element and the typhoid will pursue its ordinary course. During the decline of the temperature in typhoid cases a marked intermittent temperature may be observed which resembles very closely that of quotidian malarial infection. Chills also may occur at this time and a diagnosis of malaria is made. Unless supported by the finding of the malarial plasmodia in the blood, such a diagnosis is unjustifiable. Yellow Fever. — In regions in which yellow fever is endemic, the differ- entiation of malaria from this disease is often exceedingly difficult unless a blood examination be made. The so-called bilious remittent type of sestivo-autumnal malaria is especially apt to simulate yellow fever, there THE MALARIAL FEVERS 437 being present a yellow tint of the skin, severe vomiting, sometimes of dark material resembling "black vomit," while albumin appears in the urine. A patient presenting such a clinical picture in a yellow fever region is almost always thought to have yellow fever, and it is in these cases that an examination of the blood is of the greatest importance. Tuberculosis. — In many cases tuberculosis is complicated by a strep- tococcus infection, and the temperature chart closely resembles that found in quotidian malarial infections. There may also be daily chills or chilly sensations, and the patient presents the facies so often observed in long- continued malarial infection. An examination of the sputum will gener- ally result in the demonstration of the tubercle bacillus, while physical examination will shov. pulmonary lesions to be present. An examination of the blood, however, is essential, as not infrequently patients suffering from tuberculosis may contract malaria. Hepatic Abscess. — In regions where amoebic dysentery is endemic, certain cases suffering from hepatic abscess may present symptoms which closely simulate those of malarial fever; thus there may be daily chills and a temperature curve, which, while it is that of sepsis, very closely simulates that of some of the forms of sestivo-autumnal infection. The chief clinical points in favor of hepatic abscess are enlargement of the liver and tenderness over the hepatic region, while the spleen is not enlarged. In malaria, enlargement of the spleen is almost always present. A history of dysentery can generally be obtained in cases of hepatic abscess. Examination of the blood will decide if malaria be present, while a leu- kocytosis will point toward a hepatic abscess. Ulcerative Endocarditis. — The temperature chart in ulcerative endo- carditis often resembles that of quotidian malaria, and Dock has published a very interesting case of this character. Examination of the heart wall generally suffice to determine the natvire of such cases, and if not, an examination of the blood will decide the question. Cerebral Apoplexy. — The differential diagnosis between the comatose pernicious form of malaria and cerebral apoplexy is often extremely diffi- cult unless a blood examination be made. The main clinical points to be relied upon in arriving at a diagnosis of malaria are high fever, although this is not constant, the age of the patient, and the splenic enlargement. An examination of the blood will generally decide the question at once. Sunstroke. — Especially in tropical or sub-tropical regions, certain forms of pernicious malaria very closely resemble sunstroke. It should be remembered that in such regions the heat very often aggravates or brings on severe malarial paroxysms. It is therefore necessary to be sure in such cases whether or not a malarial infection be present and a microscopic examination of the blood is often our only means of arriving at a differ- ential diagnosis. Dysentery. — Malarial infections may occur with dysentery, and the removal of the malarial element in a certain proportion of such cases results in a rapid improvement of the dysenteric symptoms and their final disappearance. In view of the fact that malarial infection is capable of producing the clinical symptoms of dysentery, it is important that a dif- ferential diagnosis should be arrived at in regions where dysentery is endemic. An examination of the blood is therefore essential in every case of dysentery occurring in such regions. 438 DISEASES CAUSED BY PROTOZOA Among other disease processes which may be confused with malaria, may be mentioned: septicannia, pyaniiia, diseases of the gall bladder or ducts, acute suppurative processes in any of the viscera, pneumonia, and Weil's disease. In all of these a careful examination of the blood is sometimes our only method of arriving at a differential diagnosis. Prognosis, — The prognosis in cases of uncomplicated tertian and quartan malaria is good, but in the more severe a^stivo-autumnal infections prognosis should be guarded. Osier has called attention to the fact that while in temperate climates it is well known that the prognosis in malaria is most favorable, still the vital statistics in some of our large cities show a greater death-rate for malaria than for typhoid fever. Ke says^ : "In the United States census report of 1890, which covers the six preceding years, the deaths from malarial fever in New York and Brooklyn were more numerous than from typhoid fever. In both these cities it is notorious that a death from true malaria is a great rarity. No more than three or four cases occur each year in the entire hospital practice of the city of New York." Nothing could illustrate more forcibly the immense importance of a scientific diagnosis of malaria fevers by an examination of the blood than does this cjuotation. ^Yhile the prognosis, as stated, in uncomplicated cases of tertian and quartan malaria is good, fatal cases of both these forms of fever have occurred, especially the quartan' variety. As regards the prognosis of the sestivo-autumnal infections, certain factors have to be taken into con- sideration, such as locality, age, occupation, position in life, and physical condition. These factors apply with some force also to the prognosis of the simple intermittent fevers, but are especially important in the sestivo- autumnal infections. In the tropics the prognosis in sestivo-autumnal infections is much more grave than in temperate regions, and in certain local regions these fevers are much more fatal than in others. The prognosis is most grave at the extremes of life. It is more grave in the poor than in those who are well-to-do, in the case of individuals in ill health than in those who are well nourished and healthy. Complications which are so frequent in sestivo- autumnal infections also have much to do with the prognosis, among the most serious being the various forms of nephritis, tuberculosis, pneumonia, dysentery, and the infectious fevers. The prognosis in the pernicious varieties of sestivo-autumnal infection should always be guarded, espe- cially if the patient is seen after having suffered from several severe parox- ysms, although even then if treatment be vigorously instituted the patient may recover. However, the pernicious symptoms may last for several days and despite all treatment, death ensue. The prognosis is very grave in the cerebral forms, especially the comatose form. While a large number of such cases recover under proper treatment, a great majority of the fatal cases of malaria suffer from this form of sestivo-autumnal infection. In the algid form the prognosis is almost as grave as in the cerebral forms, and not a few go on to a fatal termination despite all treatment. The prognosis is very grave in the choleraic form and also the pneumonic. In the dysenteric form the prognosis is always grave, depending upon the fact that the dysenteric symptoms have often masked ^Article on "Malaria" in AUhutfs System of Medicine, THE MALARIAL FEVERS 439 those of malaria for a considerable time and treatment is not instituted until too late. In soldiers campaigning in tropical countries where pernicious forms of malaria are endemic, many deaths are often due to this cause, and the prognosis in such infections should also be very guarded. In malarial cachexia where a change of locality cannot be secured the prognosis is always grave, death resulting not so much from the malarial infection as from some complicating disease. While under proper treat- ment a great majority of cases of sestivo-autumnal infection recover, unless quinine be administered for a long period of time relajjses in- variably occur, and one of these may prove fatal. It may be stated as an axiom that the prognosis in tertian and quartan malaria is good but in the sestivo-autumnal infections is always grave, as at any time during their course pernicious symptoms may develop and prove rapidly fatal. Prophylaxis. — Pi-ophylaxis in malarial disease is of much greater importance at this time than ever before in the history of such infections. We now know the etiological factor concerned in the production of the malarial fevers and their method of transmission, and we also know that proper methods of prophylaxis have already resulted in the disappear- ance of the infection from numerous localities. The subject of prophylaxis may be divided mto general and personal methods, all of which are directed against the mosquito. If it were possible to destroy all mosquitoes of the genus Anopheles in malarious localities, it is undoubtedly true that malaria would soon disappear. All our theories, regarding the transmission of the disease by water or any other way than by the aid of the mosquito, have been disproved and wx now know that the prophylaxis of malaria consists in the destruction of this insect, or, if this is not possible, the protection of the individual from the bite of the infected insect. General Prophylaxis. — General prophylaxis may be considered under the following divisions : (1) destruction of the mosquito; (2) isola- tion of the patient; (3) use of quinine. 1. Destruction of the Mosquito. — The mosquito is most easily destroyed during the larval stage, and many substances have been experimented with in the hope of obtaining one which would prove efficacious, being at the same time cheap and easily obtained. Howard, in 1892, published the results of his work upon the destruction of the mosquito larvse by sprinkling a thin layer of kerosene upon the surface of the water in which they breed. This method is very efficacious, not only killing the larvse in the water, but the mosquitoes when in the act of depositing their eggs. The method is especially applicable to collections of water which cannot be drained and which are not very large in extent. The quantity of kerosene used is approximately one ounce to fifteen square feet of surface, and as a rule the application does not need to be renewed more than once a month. This method has been used largely throughout the world and has proved of great value. Of other substances which are capable of killing the larvse, may be mentioned sulphurous oxide, permanganate of potash with hydrochloric acid, sulphate of iron or copper, carburet of lime, corrosive sublimate, formaline, cresol, certain aniline dyes, and coal-tar. It is obvious that most of these substances cannot be used in practice, the only one really 440 DISEASES CAUSED BY PROTOZOA available being kerosene, but this agent cannot be employed in water which is used for drinking purposes unless in the case of large reservoirs where the water is drawn from the bottom. The introduction of certain fish into reservoirs from which water is used for tlrinking purposes, and in which mosquitoes breed, has been suggested instead of the use of petroleum, and has been tried in some localities with success. The fish principally used have been carp and the connnon stickle])ack. The most imiM)rtant of all methods of destroying the mosquito larvae is that by drainage of their breeding places, and this is a method which can be employed over very large areas of country in which malaria is endemic, and which ex])erimentally has proved to be of greatest service. In many regions in which the most virulent forms of malarial infection are endemic, drainage is feasible and can be carried out with but little trouble, although the expense is often a factor in the problem, and, as Celli says, "such methods for the destruction of the mosciuitoes, while experimentally soluble, will only be practically so when economic interests desire it." AVhere drainage is impossible the breeding places of the mosquito may be filled up with loam, and it is very important in malarious localities to fill up all areas of depression in the surface of the land that cannot be ade- quately drained. Swampy areas, if not too large, can thus be filled in, and one of the greatest sources of mosquitoes removed. Besides drainage and the filling up of areas which serve as breeding places for the mosquitoes, the formation of mosquito brigades, as sug- gested by Ross, is of the greatest service in limiting malarial infection. This consists essentially in detailing a certain number of men whose busi- ness it is to inspect the premises and destroy the larvae in the small breeding grounds which harbor the Anojiheles, such as domestic water receptacles, water butts, and tanks, the removal of small puddles in streets and yards, as well as empty tins, jars, broken bottles, or anything in which water collects, and in which the mosquitoes may breed. In the formation of such brigades the region to be covered is divided into portions, each portion being under the supervision of a certain number of men detailed for the purpose. Methods similar to this were pursued in Havana by Gorgas, resulting in the almost total disappearance of the yellow fever mosquito in that city. Garden wells, water barrels, and tanks, being prolific sources of mosquitoes, should be covered, preferably with wire moscjuito-netting, thus preventing the laying of eggs and the development of the larvae. If for any reason this is not possible, and the water is not used for drinking purposes, the surface should be sprinkled with kerosene oil. In the adult stage the mosquito can be destroyed by various odors, fumes or gases. Among the odors may be mentioned turpentine, menthol and camphor. Among the fumes, tobacco, chrysanthemum powder, pyrethrum powder and the fresh leaves of eucalyptus; while among the gases, sulphuric oxide is very efficacious. In using any of these agents, however, it is very necessary that the air of the room should be saturated, as otherwise the insect may be simply stunned, and revive when the fresh air is admitted. The most useful of these agents is pyrethrum powder, which can be burned in rooms infected with mosquitoes, and which is very fatal to them. THE MALARIAL FEVERS 441 2. Isolation of the Patient. — We have seen that the mosquito is neces- sary as an intermediate host in the Ufe-cycle of the malarial plasmodia, and that the mosquito is infected by biting an individual suffering from malarial disease. From this it is obvious that if v^e can place the infected individual in a position v^here the mosquitoes cannot obtain access to him the transmission of the infection will be impossible. Theoretically, if every patient suffering from malaria could be screened from mosquitoes the disease would entirely disappear, but practically, the disease is of such a character that even when no symptoms are present the parasites may be present in the blood and the mosquitoes may become infected. In fact, in Bestivo-autumnal infections the crescentic form of the organism, which really is the form intended to undergo its life-cycle in the mosquito, is frequently present in the blood when there are no symptoms of malaria, so that it is obvious that we cannot in this way entirely prevent malarial infection. Still, in the light of our present knowledge, the malarial fevers should be regarded as infectious and the patient should be isolated in a screened room. Not only is this isolation of importance to those sur- rounding the patient but also to himself, for if he is not protected from mosquitoes he is in constant danger of reinfection from the bites of the insects. Isolation of the patient is, therefore, of the greatest importance in the prophylaxis of malaria, and should be carried out, especially in regions where the more pernicious forms of the disease are endemic. Besides the isolation of the patient, Ross and Stephens have suggested as a method of general prophylaxis the segregation of certain classes of the population. This applies especially to Europeans living in the tropics. They suggest that the European quarter should not be built in the midst of the native villages in malarious localities, but should be situated at some distance and should be surrounded by the proper hygienic conditions, which it is impossible to obtain among a native population. 3. Use of Quinine. — ^The use of quinine as a general prophylactic measure, as suggested by Koch, is undoubtedly of value in malarial regions. As is well known, this drug destroys the malarial organisms, and if it were administered to all the natives of a malarial region it is probably true that malarial fever would gradually disappear. In other words, the malarial plasmodia present would be destroyed and thus the mosquitoes would not become infected upon biting the native population. Unfor- tunately, the cost of the drug precludes any general use of it in large localities, although theoretically the employment of it in general prophy- laxis would be indicated. Summing up, then, the methods of general prophylaxis which are most important are drainage and filling in of all depressed areas on the surface of the ground, the use of kerosene upon the surface of collections of water which cannot be drained, the formation of mosquito brigades for the purpose of cleaning or destroying the smaller breeding places of the mosquitoes, isolation of the patient, and the general use of quinine. Personal Prophylaxis. — By personal prophylaxis we mean measures which the individual himself may take in order to prevent infection, or, in other words, to prevent being bitten by the mosquitoes. The use of mosquito-netting is of the greatest importance in malarious localities and no one should neglect the use of this means of prevention. The screening of the houses is also indicated, and the screening should be done most 442 DISEASES CAUSED BY PROTOZOA carefully, every door and window being screened. If one is obliged to travel in malarial districts, the season of the year in which such fevers are less prevalent should be selected, if possible, and traveling should be done in the day-time. In selecting camp sites and sites for buildings, high, well-drained land should be chosen. The drinking-water should always be boiled, for although nuilaria is not transmitted in this way, the measure may prevent other diseases which would so deplete the system as to render it easily susceptible to nudarial infection. If mosquitoes are numerous it is better to sleep above the ground fioor. In tropical regions the use of punkas, or fans, as well as, where obtainable, electric fans, is serviceable in keeping away the mosquitoes. For the protection of the hands and face during the day, or when travelling at night, odorous substances may be employed, these being smeared on the skin and renewed when needed. Among the most useful are oil of ]iennyroyal, camphor, oil of eucalyptus, oil of anise, and kerosene. Pyrethrum powder should be burned before retiring, in rooms in which mosquitoes are present. Individuals in malarial localities should always sleep under a mosquito net. One of the most important aids in personal prophylaxis is the use of quinine. It is borne out by the experience of all who have resided for any length of time in regions where malaria is endemic, that quinine exhibited daily in small doses is of the greatest value in preventing infec- tion. The drug should be given in doses of from 5 to 6 grains (.30-. 35 gm.) every day, or in larger doses, 8 to 10 grains (.50-. 60 gm.), two or three times a week. In the vast majority of instances the prophylactic use of quinine will prevent malarial infection, but a few individuals, despite its use, succumb to the infection. Some indi\dduals cannot take cpiinine regularly without suffering from disturbances of digestion or of the ner- vous system, and in such instances some substitute for it may be used, such as thiocol, or methylene blue. Neither of these agents, however, is as useful as quinine. Treatment. — The treatment of malarial infection may be divided into hygienic and medicinal. While the medicinal is altogether the most important, hygienic measures should always be combined with it. For- tunately, in the malarial infections we have a specific which is invariably successful, when properly administered, in curing the disease. This specific is quinine, an alkaloid of cinchona, wdiich was introduced into Europe nearly 260 years ago, and had probably been used by the natives in South America for many years before it was discovered by Europeans. Perhaps no drug known to the therapeutist is as true a specific in any disease as is quinine in malaria. When properly administered it will invariably destroy the malarial plasraodia and thus cure malarial in- fection. There are rare instances in which quinine seems to be powerless to limit the course of malarial infection, but a careful examination will prove that if it is administered in the proper manner it is efficient in these cases as in others. Thus, certain individuals cannot absorb quinine through the stomach, but in such persons the hypodermic administration of it will result in a cure of the infection, and thus it is that the successful treat- ment of malaria by quinine depends almost entirely upon the proper administration of the drug. The mild intermittent malarial infections, such as the tertian and quartan, tend towards spontaneous recovery, which has already been THE MALARIAL FEVERS 443 discussed. In many instances of infection by the tertian and quartan Plasmodia, recovery may occur without the aid of medicinal measures, but it should be remembered that even these infections may become per- nicious, and even if they do not, the occurrence of repeated paroxysms of the fever results in a diminution of the vitality of the patient, as evidenced by the anremia which invariably accompanies such repeated attacks. Thus it is important that every malarial infection should be treated medic- inally and not left for nature to cure. Hygienic Treatment. — It is undoubtedly true that in all malarial infections, however mild, rest is most important, and the patient should be confined in bed until the active symptoms have disappeared. While this is not essential in some of the mildest tertian and quartan infections, it should always be followed out in cases of sestivo-autumnal infection. Treatment by quinine is always much more effective when the patient is confined to bed, recovery is always more rapid and permanent, and the danger of pernicious symptoms is also much lessened. The diet should be light, while there are any active symptoms of malarial infection present, consisting of milk, soups, custards, soft boiled eggs, etc. A light diet should be persisted in until the temperature has been normal for at least a day, and then a more liberal diet is indicated. The more nutritious such a diet is the better, as in many cases of malarial infection the debility and anaemia following the paroxysms is remarkable. It is a good plan in treating all malarial infections to secure a complete evacuation of the bowels coincident with or before the administration of quinine. The administration of calomel until the bowels move freely, not only serves to better the patient's condition, but also renders the action of quinine much more efficient. It hastens and favors the absorp- tion of the drug. In all cases of malarial infection the sick-room should be, if possible, in an upper story, well ventilated and thoroughly screened, thus limiting the chances of infection to others. Care should be taken that the room is not subject to draughts, and the patient should be guarded against any irrita- tion, as in the most severe malarial infections, such as the sestivo-autumnal, the nervous irritability is apt to be very great. Medicinal Treatment. — In the vast majority of malarial infections but one drug need be considered, that is, quinine, and by quinine any derivative of cinchona bark is meant. In considering the therapeu- tical uses of the derivatives of cinchona the following points should be discussed: (1) the action of quinine upon the malarial plasmodia; (2) the choice of preparations; (3) the time of administration; (4) the methods of administration; (5) the dosage; and (6) contra-indications to its administration. 1. The Action of Quinine Upon the Malarial Plasmodia. — Quinine exerts its beneficial action upon malarial infections by directly destroying the malarial plasmodia. Binz, in 1867, was the first to discover that the drug had a marked influence upon the parasites concerned in malaria, and his observations have been confirmed by every investigator who has studied the subject. Quinine causes a degeneration of the parasites, especially marked in the youngest organisms and most marked at the time of segmentation. Marchiafava and Bignami, from their careful study of the subject, conclude as follows: "Quinine acts upon the 444 DISEASES CAUSED BY PROTOZOA malarial parasites in that phase of their life-cyele in which they are nour- ished and developed. Wlien the nutritive activities cease by an arrest of the transformation of hannoglobin into black j)ignient, and the repro- dnetive phase begins, the quinine is inetl'ectnal in its action." In other words, the drug is most etfective from the time of segmenta- tion until pigmentation commences within the red blood corpuscles. Many observations upon the blood of patients, showing malarial parasites, to whom quinine has been administered, have shown that the chief changes consist in loss of ama^joid motion and a granular degen- eration of the endoglobular ])arasites. The red cell containing the para- site very often appears to be shrunken, as Avell as the parasite within it. The changes are most marketl in the tertian and quartan organisms, but the same changes occur in the a^stivo-autumnal varieties. In the latter, especially, the young unpigmented forms appear greatly shrunken, their protoplasm more or less granular, while amoeboid motion is entirely lost. A study of stained specimens of malarial parasites after cjuinine has been administered, demonstrates more clearly than do fresh specimens the effect of the drug. In all such specimens the intensity of the stain is greatly diminished, and this loss of intensity is confined almost entirely to the chromatin substance of the nucleus, while the protoplasm stains more nearly as it does in the healthy organism. These changes prove that quinine acts directly upon the parasites causing the disease and that it is thus a true specific in malaria. 2. Choice of Preparation, — Of the ten or more salts of quinine which have been used in the treatment of malarial fevers, but tw^o are really deserving of attention, in that they are of practical use. These are the sulphate and the dihydrochlorate or bimuriate of cjuinine. Of these two preparations, the dihydrochlorate is the more soluble, being dissolved in the proportion of 1 part to .96 parts of water, while the sulphate is only soluble in 1 to 9 parts of water. Of the two preparations, however, the sulphate is the more used, as it is the cheaper and can be procured most easily. Where it is desired to use the drug hypodermically or intra- venously, the hydrochlorate should always be used. 3. Time of Administration. — The time of administration of quinine in malaria has been the subject of much discussion, but it may be said that in the tertian and quartan infections the drug should be given during the decline in temperature in one large dose, while in the festivo-autumnal infections it should be administered in broken doses at equal intervals throughotit the day. This subject has been very thoroughly discussed by Dock,^ with whose conclusions the writer agrees. In tertian and quartan infections if the qtiinine is administered during the decline of the temperature, or at least, at the end of the apyrexia, in the vast majority the next paroxysm will be prevented, as the clrtig has thus been brought in contact with the youngest forms of the plasmodia, upon which it acts most vigorously. In all such cases the sulphate administered in solution dissolved in dilute sulphuric or hydrochloric acid is the most effective preparation. If given in this way, one drop of the acid should be used for each grain of quinine. If perchance, there should be double tertian or quartan infection, quinine administered at this time may not prevent ^Journal of the American Medical Association, July 29, 1899, THE MALARIAL FEVERS 445 the succeeding paroxysm, and if tliis occurs, a second dose should be given at the same time, when almost invariably the paroxysms will cease. Quinine should not be discontinued, however, in the mildest cases, even after the paroxysms have ceased, but should be administered in doses of from 5 to 10 grains (.30 to .00 gm.) for at least a week. Only in this way can the return of the paroxysms be prevented. In tertian and quartan infections the time of administration can be accurately determined by a study of the temperature chart, but this is not so in the more irregular sestivo-autumnal types. In these forms the period of intermission may not be indicated clearly in the temperature chart, and it is therefore necessary in order to combat the infection to give quinine in divided doses of from 5 to 10 grains (.30 to .00 gm.) at intervals of four to six hours until the temperature reaches normal. When this occurs, quinine may be administered in one large dose at bed-time or in smaller divided doses during the twenty-four hours. In pernicious and irregular forms of malarial fever, especially if caused by the sestivo- autumnal plasmodium, the administration of the drug cannot be delayed and it should be invariably given hypodermically. 4. Methods of Administration. — Quinine may be administered by the mouth, by the rectum, hypodermically and intravenously. If adminis- tered by the mouth it is best given in the form of solutions or capsules. Pills and tablets are very apt to be insoluble and therefore should not be administered. When possible, the drug should always be administered in solution, but on account of the bitter taste, which is very objectionable to some patients, capsules may be substituted instead of the solution. The rectal administration of quinine, in the form of enemata or supposi- tories, has been advocated by some authorities but is most unsatisfactory. Absorption is very slow, and rectal irritability is almost certain to occur. When the drug is given in this way the dose should be one-half again as large as when given by the mouth. In the pernicious forms of malarial fever quinine should be adminis- tered hypodermically, and this is also true in cases in which the drug can- not for certain reasons be administered by the mouth. The solution which is generally used is the following: Dihydrochlorate of quinine gr. Ixxv 5 gm. Distilled water add 5iiss 10 gm. In this solution 1 Cc, 15 m. contains grs. viiss(.5 gm.) of quinine. In giving hypodermic injections of quinine, the utmost care should be taken that the syringe be thoroughly sterilized and also the skin over the area m which the injection is made. The solution, also, should be sterile and freshly prepared. The best sites for the injection are the muscles of the back, gluteal region or the abdomen, the gluteal region being prefer- able. The injections should be made deeply into the muscles, and the wound made by the needle of the syringe covered with a small piece of cotton held in place by collodion. Despite the greatest care in gi^'ing hypodermic injections of this drug, much discomfort and pain is often caused, while if the operation has been carelessly done abscess forma- tion is apt to result. If proper antiseptic methods are followed this generally may be avoided, although a considerable amount of induration is apt to occur around the site of the puncture. 446 DISEASES CAUSED BY PROTOZOA Bacelli was the first to suggest the intravenous injection of quinine. Such a method of administration is indicated wherever the symptoms of Inalaria are so severe as to threaten grave peril to the patient, and should never be followed unless such symptoms are present. The solution used by him is made as follows: Hydroclilorate of quinine grs. xv 1. gm. Chloride of sodium grs. xii 75 gm. Distilled water add oiisa 10. Cc. The entire amount is to be injected into a vein, ])rcfcrably of the fore- arm, the most careful antiseptic measures being used to prevent infection. 5. The Dosage. — It is probably true that in the administration of qui- nine in malarial fevers too much of the drug is generally given. Very frequently quinine is administered in such large doses that a large pro- portion of it is simply wasted. In tertian and c^uartan infections a single dose of 15 grains (1 gm.) is amply sufficient to prevent the next paroxysm, while in the vast majority of a?stivo-autumnal infections 30 grains (2gm.) given in divided doses during the twenty-four hours will result in cure. When the drug is used hypodcrmically, a dose of 8 grains (.5 gm.) should be administered and repeated until about 24 grains (1.50 gm.) have been injected. In very severe infections more of the drug may be needed, but in my experience this amount is amply sufficient if administered promptly. When given intravenously, 15 grains (1 gm.) is sufficient. Suinniary of Treatment. — In tertian and quartan infections quinine should be administered, preferably in solution and by the mouth in single doses of from 15 to 30 grains (1 to 2 gm.) during the decline of the temperature, and these doses repeated, if necessary, upon the following day. For a period of at least a month the drug should be given in grad- ually decreasing doses, thus preventing a recurrence. In eestivo-autumnal infections, quinine should be given in doses of 5 grains (.32 gm.) every four hours until the active symptoms have disappeared, and every five or six hours afterward for a period of three days. During the next week the drug should be admini'^tered in doses of 15 grains (1 gm.) on every other day and for at least two months thereafter upon every sixth day. If the drug is thus administered a definite cure of such infections may be predicted. The too rapid abandonment of treatment is one of the most serious mistakes which is made in the use of quinine. Relapses are almost sure to occur unless the drug be administered for a period of sev- eral weeks after the disappearance of active symptoms, and only in this way can we be positive that a recurrence of the disease will not take place. Contra-indications to the Use of Quinine. — It has been the experience of most physicians that certain patients protest against the use of quinine, claiming that they are unable to take it. In most instances it is simply a matter of personal opinion, and if the physician be firm in insisting upon the use of the drug it will be found that such objections are generally the effect of imagination. However, in rare instances, the administration of quinine is contra-indicated, in that the drug produces such unpleasant and even dangerous symptoms that it cannot be safely used. Idiosyn- crasy to quinine undoubtedly exists in certain patients, and therefor^ THE MALARIAL FEVERS 447 some substitute for the drug has to be administered. Among these sub- stitutes, none of whieh are as eflieient as the drug itself, may be mentioned euchinin, an ethyl carbonate of quinine which is tasteless, and which may be given in about twice the dose of quinine, and methylene blue, which has been advocated by Ehrlich, and which may be useful in some cases, but is not nearly as effective as quinine. It is also not devoid of dangerous properties as it may produce severe diarrhoja, strangury, and albuminuria- It has been administered with good results in a few cases, in doses of from 8 to 15 grains (.5 to 1 gm.), during the twenty-four hours. For many years it has been supposed that the administration of quinine in large doses may result in hsematuria. A careful investigation of the literature bearing upon this subject should convince any one that it is untrustworthy, and that true cases of haematuria following the adminis- tration of quinine are so rare as to be of practically no importance. The belief that haematuria may be produced in this manner is one of the medi- cal superstitions which remain as a legacy to the profession, despite all scientific proof. Treatment of Special Symptoms. — A cathartic dose of calomel should be given in all malarial fevers before the administration of quinine. Dur- ing the acute stages symptomatic treatment should be adopted; thus, in the cold stage warm drinks, with the application of external heat in some form, are indicated; while in the warm stage, if the temperature reaches a dangerous point, baths of tepid or cold water should be given. Antipyretics, such as phenacetin, acetanilide, etc., should never be admin- istered during the paroxysm of malarial fever, as they never do any good and may do much harm. If the vomiting be exhausting, or nervous symptoms be very pronounced, the hypodermic injection of morphine is indicated. Should cardiac weakness be present, suitable stimulants should be administered, such as hypodermic injections of ether, brandy, or strychnia. In the pernicious forms of eestivo-autumnal infection, symptomatic treatment is of the greatest importance; thus, if algid symptoms develop, stimulants should be freely administered, external heat applied by means of hot water and warm blankets, and collapse should be treated by hypodermic injections of brandy, strychnine, and by transfusion. While the treatment of special symptoms during the malarial parox- ysms is important, it should be remembered that unless quinine be given, all other treatment is useless, and that the prompt and proper adminis- tration of this drug will alone, in many instances, cause the disappearance of all alarming symptoms. Treatment of Complications and Sequelae. — The treatment of the com- plications occurring with the malarial fevers and the sequelae following them does not require any discussion, it being the same as that pursued in all similar conditions. Treatment of Malarial Cachexia. — The treatment of chronic malarial poisoning is most unsatisfactory if the patient remains in the locality in which he contracted this infection. While various remedial measures may be pursued, such as the administration of quinine, arsenic, and tonics of various kinds, but little result will follow unless a change of climate is secured. All these patients should, if possible, have a change of climate to a high, dry altitude, which is non-malarious, 448 DISEASES CAUSED BY PROTOZOA and this will invaribly do more for the patient than any therapeutic meas- ure. In conclusion, the fact is emphasized that no substitute for quinine can equal it in treatment of malaria, and that in the worst cases the proper administration of this drug will result in prompt recovery, provided the patient be seen in time. There are one or two substitutes for the drug which may be used- in very rare instances where quinine is contra-indi- cated, but the writer believes with Osier, that, "the physician who at this day cannot treat malarial fever successfully with quinine, should abandon the practice of medicine," CHAPTER XX. BLACK-WATER FEVER. By J. W. W. STEPHENS, M.D. (Cantab.), D.P.H. Definition. — Black-water fever, or hsemoglobinuric fever; a disease occurring in tropical and subtropical countries, the chief symptom of which is the passing of haemoglobin in the urine. Distribution. — This is still imperfectly known. The number of cases recorded from any locality is unsatisfactory evidence as to the frequency in that locality,[forwe know of instances where cases have existed for years in a district and yet have been recorded only quite recently. We shall consider later the factors that determine its occurrence ; one may here be mentioned: viz., that as it is a disease affecting chiefly Europeans, at least in Africa, its occurrence in a particular region will depend, first, upon the presence of Europeans; and, secondly, whether such Europeans are subject to the conditions which give rise to it. Again we cannot say the disease is equally common in any two particular places ; for in one case we may have a single record only, in others many. Bearing in mind these limitations to our knowledge of its distribution we may, in giving the following list, note any peculiarities. In North America it has been recorded from Arkansas, Mississippi, Lou- isiana, Tennessee (?), Texas, Florida, Georgia, North Carolina, Alabama, South Carolina, Virginia. Among these records we find that it occurs mainly among white but occasionally also among colored persons. Al- though no doubt the statistical statements as to the mortality from ma- laria in the United States require to be accepted with caution, yet from the census returns it appears that these states are the most malarious in America. There are no exact data on record for judging of its frequency iji any particular state. In Central America it is recorded from Nicaragua, Costa Rica, and Venezuela. West Indies: Cuba, Martinique and Guadeloupe, French, British, and Dutch (?) Guiana, Trinidad, and British Honduras. In Martinique it was recorded by French naval surgeons before 1850; but the only record from British Honduras occurs in 1905. South America: The data here are very scanty, but it is recorded from Brazil and the Argentine Republic. Lutz in a personal communication says it occurs at S. Paolo, but it is rare there. Europe and Asia Minor: The countries in which it is best known are Italy, Sicily, Sardinia, and Greece. It occurs at Merv (Russia), in Tur- key, and, according to Marchoux, along the banks of the Danube and in the Caucasus. In Italy it is practically unknoT\m in the North; a few cases occur in the Campagna; but it is in the South and especially in Sic- ily that it prevails, and here, too, malaria is most intense; thus,whereas the 29 449 450 DISEASES CAUSED BY PROTOZOA mortality from malaria in North Italy is less than 1 in 10,000, in Sicily it is 7 to S per 10,000. It is apparently quite common in Greece, but we have no data as to its relation to malarial mortality there. It occurs in Pales- tine and with considerable severity in certain districts. It is not, however, known in Cyprus. Africa: Its distribution is fairly well known, as the disease has here been carefully studied. It is found along the coast-line from the Senegal to the Orange rivers. It is found in the countries drained by the Congo, the Niger, and the Zambesi, and recently a few cases have occurred also in the upper reaches of the Blue and White Nile; in Senegambia, Gambia, Sierra Leone, Gold Coast, Lagos, Nigeria, Cameroons, Damara-land on the west, and British, German and Portuguese East Africa on the east. It occurs in Uganda and British Central x\frica, but probably does not extend much further south than Delagoa Bay. In all these regions we may say that intense malaria is found. In Algeria it is by no means rare, but is miknown in Egypt, where malaria, at any rate among Europeans, is very micommon. In INIadagascar it has been described since 1851 by French naval surgeons. It is known also in Mauritius and Bourbon, but its occurrence in Zanzibar is doubtful. India: Over the greater part of India it appears to be unknown. Foci occur in the Jeypoi'e agency (Madras), in the Canara district (Bombay), and in the Duars (Bengal) the A\Titer saw more cases in a fortnight than in the same time in iVfrica. It also occurs in the Terai (Bengal) and in Assam. According to Marchoux it exists in Burma. Other Countries: It is recorded from Cochin China and Tonkin; also from Java (Tjilatjap), New Guinea (German), and single cases from British INIalaya and New Hebrides. Finally, it occurs in Formosa, but not in Japan. We believe that a consideration of these data, imperfect though they be, will show that the distribution of black-water fever and severe malaria is co-extensive. This holds good for the United States and for Italy, where the figures are probably fairly trustworthy. There is a further method of gauging malarial intensity which so far has been applied only in a few cases. Perhaps there is no more sensitive test of the malarial en- demicity of a district, or endemic index, as we may term it, than the number of young native children with parasites in their blood (or with enlarged spleens). In many native villages of Africa for instance, 90 to 100 per cent, of children (under ten years of age) are infected with parasites, whereas if we take a similar determination in a large town or its suburbs the index will rapidly fall to 20, or 10, or even 0. It is possible by this means to measure marked changes in the malarial endemicity of dis- tricts which in no other way could make themselves evident. By this means we believe it would be possible to compare the amount of malaria for instance in British Central Africa with that of Italy. W^e should at least get some definite numerical basis of comparison, far more accurate than we now possess. That malaria (and we are concerned with malaria here because we believe black-water fever to be malarial) is a deadly disease in the Congo and a tri\dal one in North Italy we can hardly doubt. On what this difi'erence depends we cannot certainly say. It very possibly may be due to climatic differences, whatever that im- plies. In the contrast between malaria in North Italy and Sicily we BLACK-WATER FEVER 451 have a striking fact; and it is necessary to emphasize these differences in considering the relationship of malaria to black-water fever, because one of the objections frequently urged against its malarial origin is the fact that the distribution of the two diseases is not the same. But neither is the distribution of mild and severe malaria the same, a point to be remem- bered in considering the etiology of the disease. In considering the dis- tribution of black-water, the circumstances under which a susceptible European population lives is important. For instance in many in- tensely malarious districts of Africa, segregated stations or cantonments have now been provided for the European residents. In other places Europeans still live under the evil conditions of infection which almost universally prevailed before a knowledge of the mosquito malaria cycle became well known. In such a segregated area malarial fever is reduced to a minimum, and black-water fever also disappears. If all Europeans were segregated from native dwellings, then we could conceivably get an intensely malarious region, as judged by the number of young children having parasites in their blood, without any black-water fever. For at least in the African negro, black-water is exceedingly rare, and if Europeans live away from natives instead of in their midst, as is too often still the case, then they will escape infection and consequently black- water fever. We have dwelt upon this point, because unless Europeans live under dangerous conditions black-water fever may be absent even in highly malarial districts. It has rather been assumed so far that black-water fever is malarial in origin. What are the facts ? Many hypotheses existwhich need not con- cern us. We may refer to one which if true would be a simple solution of all difficulties that arise about this problem. Black-water fever implies haemoglobin in the urine. Now, in cattle there is a well-known disease with haemoglobin in the urine as one of its chief symptoms. This disease is due to a parasite, piroplasma; consequently, ex hypothesi, black- water fever in man is due to piroplasma. If all problems could be solved as simply as this, research into the nature of disease could be conducted in a library. Unfortunately there is not a shred of fact to support this simple hypothesis which the weary investigator has only too often wished true. That black-water fever is not a piroplasmosis is proved by the fact that piroplasma does not exist in the blood and tissues of cases of black-water fever, though repeatedly sought for by competent observers; and there is no question of its having been over- looked, for it is a parasite recognized without any difficulty. What, then, leaving aside this hypothesis, are the facts for and against the malarial origin of this disease? First, there are arguments of a general nature but yet of much force. 1 . There is no case on record of any one having contracted black-water fever who has not previously suffered from malaria and generally much malaria. Now if black- water were a disease sui generis, this would be very difficult of explanation ; for were it, e. g., piroplasmosis, then we should ex- pect that an immigrant coming into a black-water district would at least occasionally contract black-water before he had contracted malaria; but this is contrary to the facts. 2. It is well known that in the tropics the disease is commonest among those who have suffered from repeated attacks of fever, even if these are 452 DISEASES CAUSED BY PROTOZOA only slight in nature; and the frequency of attack according to the length of life in the tropics confirms this. Recent statistics on this })oint confirm the old ones of Berenger-Feruud, according to whom, of Europeans there are attacked 5.4 per cent, in their first year, 22.5 per cent, in their second year, 42.5 jjer cent, in their third year, 20 per cent, in their fourth year, and 4.8 per cent, in their fifth year. These figures conform with the experi- ence of physicians practicing in the tropics at the present day, who well know that it is among the "old" residents that they see the cases. This peculiar distribution of black-water is strong evidence against the disease being due to any specific parasite, be it protozoon or bacterial. 3. Tropical Africa is admittedly one of the most malarial regions on the earth, and yet the mortality from malaria is slight when com- pared with that of black-water, as the following figures, compiled from the statistics relating to (icrmau troops in Africa over a period of years, show: Cases of malaria Deaths from malaria Cases of black-water fever Deaths from black-water fever G. E. Africa, April, 1897, to March, 1898 G. E. Africa, April, 1898, to March, 1899 G. E. Africa, April, 1899, to March, 1900 312 345 390 213 138 149 186 72 1 (?) 1 4 2 30 33 17 10 12 12 28 5 2 3 8 (or ? 11) 1 Cameroon, July, 1897, to June, 1898. . . Cameroon, July, 1899, to June, 1900... Cameroon, July, 1900, to June, 1901. . . Togo. 1899 to 1900 2 7 8 5 Total 1805 S (?7) 147 36 (?39) Thus malaria has a mortality of about 0.4 per cent., while that of black- w^ater fever is about 25 per cent., i. e., 60 times as great. We believe that the true explanation of these figures is that malaria is not a mild disease, but that its intensity is displayed in the form of black-water fever. 4. If black-water fever is malarial in origin, then those who protect themselves from malaria, either by careful personal prophylaxis (mos- quito nets, adequate clothing, etc.), or by the taking of quinine, should be less attacked by black-water than those who are unprotected. The fol- low^ing data of A. Plehn support this view: Attacks of malaria Interval between attacks in months Black-water cases Interval between the cases in months Deaths from black-water fever 287 70 2 5 31 6 18.5 74.0 10% about 0. The first row^ consists of those who did not submit themselves to a sys- tematic quinine prophylaxis, the second row^ of those who did, taking seven and one-half grains of quinine every fifth day. 5. Finally w^e come to the positive facts in favor of the malarial origin; and first as to the occurrence of malarial parasites in the blood of patients suffering from black-water. Here we may incidentally consider one of the BLACK-WATER FEVER 453 main arguments against the malarial origin; viz., that in the majority of cases of black-water, parasites are not found, or, if they are, in so small a number as to have no causative relationship. The first part of this state- ment is true, and the observer w^ho examines cases of black-water will be disappointed with the negative results of his examinations. The second proposition that the number of parasites, when they are found, bears no relationship to the severity of the symptoms, may or may not be true, but it is not necessarily so, for in malaria, at least in the tropics, we may get severe malaria with few or no parasites in the blood, and also the reverse condition: viz., a considerable number of parasites and yet practically no symptoms. But wc must consider the first part of this statement more closely, for it is only true as a general statement, and when analyzed care- fully it is found not to accord with the facts. The following table is com- piled from the records of observers who were well acquainted with the malarial parasite: AUTHOR DAY BEFORE HEMOGLOBINURIA DAY OP HEMOGLOBINURIA DAY AFTER ONSET No. of cases No. positive No. of cases No. positive No. Of cases No. positive A. Plehn 5 5 1 3 9 5 5 1 3 8 5 21 8 9 3 17 3 18 6 2 1 9 10 10 6 16 2 20 2 F. Plehn 3 Koch 1 Stephens and Christophers. . . . 5 Total 23 22 63 61.9 p 39 Br cent. 64 11 Thus when the blood is examined before the attack, parasites are found in 95.6 per cent, of cases, on the day of the hemoglobinuria in 61.9 per cent, of cases, and on the day after, when frequently the cases are first seen, in only 17.1 per cent, of cases. So that it appears that not only is black-water dependent on a malarial infection at some previous time, but that the rela- tionship is a very close one, depending upon the actual presence of para- sites immediately prior to the attack. To deny the significance of these parasites, as has been done, seems equivalent to denying the significance of parasites in an equivalent number of malaria cases, and to be contrary to common sense. One of the most striking characters of the blood ex- amination in these cases is the rapidity with which parasites disappear. Subsidiary evidence of malaria: In cases of true malaria it occasion- ally happens that parasites cannot be found in the blood, and perhaps this is most frequent during the pyrexial stages of the attacks. Again, in other cases parasites are so few in number that the argument that has been applied to black- water fever might equally well be apphed here: wz., that the number of parasites bears no relationship to the severity of the dis- ease. Another cause of the absence of parasites in malaria is the previous administration of quinine; though the fever may still persist, yet no par- asites can be found. In such cases we have means at our disposal by 454 DISEASES CAUSED BY PROTOZOA which we can still diagnose malaria even though parasites are absent. These arc two in luiniber: (1) the presence of pigmented large mononu- clear leukocytes; and (2) an increasein the percentage of large mononuclear leukocytes. The yalue of these is usually about 5 to 8 per cent., but in ma- laria the percentage is often markedly increased eyen up to 40 per cent., so that a value of 20 per cent., which is not uncommon, may be considered as fairly good evidence of malaria, especially as in such cases diligent search is almost always certain to detect pigmented leukocytes also. Christophers and the writer, in Africa, found that parasites were present only in 12.5 per cent., while by applying these two subsidiary tests evidence of malaria was found in 93.8 per cent, of cases; and it may be stated that care was taken to make adequate control observations among a number of persons selected as being liable to infection, but in these no such evidence of a malarial infection existed. If we sum up now the actual evidence on which a malarial origin of black-water is based, we find that, apart from general considerations, (1) parasites are found in (nearly) all cases, provided the examination is made early enough; (2) that when parasites are absent, as is generally the case when the patients are seen late, still we have subsidiary evidence of malaria in (a) the presence of pigmented leukocytes and (b) the increased percentage of large mononuclear leukocytes. That parasites when found rapidly disappear is a well-known fact, but we must first consider another factor in the etiology of black-water fever. Black-water is common in Sicily, and it was here that Tomaselli first put forward the view that hsemoglobinuria in malaria is a quinine intoxication. This view has been vehemently controverted, but its adherents have steadily increased and at the present day it is impossible to deny that quinine can at least occasionally produce hsemoglobinuria. Patients who have themselves known that quinine certainly did induce an attack of hsemoglobinuria, have volunteered to undergo the experiment in hospital, and the result has been precisely as they stated. Thus it may now be taken as conclusively proved that quinine can induce black-water fever. It does not follow that all cases of black-water are due to quinine, sometimes in small and sometimes in large doses; but although absolute proof is wanting, yet any one who has carefully investigated the histories of cases of black- water and has observed patients in a hospital, can hardly doubt that quinine is often and indeed most often the exciting cause. Thus one patient had a typical malignant tertian malaria with a characteristic tempera- ture chart and abundance of parasites. Quinine was administered, and after a doubtful interval hsemoglobinuria came on; then the parasites completely disappeared and were not found again till after death, in the spleen. Secondly, we have seen a patient admitted with black- water fever about midnight; the next day at noon the urine was clear; then quinine was given and the same afternoon black-water returned. Such cases are, when seen, very convincing; but it must be admitted that they are not as conclusive evidence of the quinine etiology as the experimental cases just mentioned. This quinine factor is probably one of the reasons why parasites disappear so rapidly; another probably is the actual destruction of red cells, which may affect especially those cells infected with parasites. Whatever be the cause, it is very necessary to examine for parasites as early as possible. If they are to be found, a few hours' delay may mean a BLACK-WATER FEVER 455 negative examination. With regard to this quinine factor, two recent ob- servations are worthy of note: {!) According to Marchoux, quinine is not excreted in the urine during the actual hsemoglobinuria, but reappears after this has ceased. This may imply that the retention of quinine is as- sociated with the hsemoglobinuria, but though probable we have no actual chemical evidence of the truth of this hypothesis. (2) Poch records a case where, as the result of quinine administration, no actual hsemoglobinuria occurred, but only a diminution in red cells of 340,000. There are also other observations on record where quinine repeatedly induced black- water, yet on other occasions only gave rise to albuminuria. There are of course many objections to the quinine view; viz.: (1) The multitudes of people who take quinine and yet do not suffer from black-water. (2) Quinine will, we assume, produce an attack one day, but if administered on a subsequent day no such result occurs. We consider, however, that against the positive experimental evidence such objections cannot count, and the discrepancy means that we are in the dark as to the conditions of blood which allow of this hsemolytic action of quinine. We indeed should expect that if quinine has destroyed the less-resistant cells, then a second administration would not have the same result, as the residual cells are more resistant; but these are speculations about the resistance of red cells of which but little is known. We may sum up the etiology of black- water somewhat in this way : it is not a disease per se, but rather a condition of blood in which quinine, other drugs, cold, or even exertion, may produce a sudden destruction of red cells. The condition is produced only by malaria and generally by repeated small attacks insufficiently combated by quinine. In such cases of chronic malaria {i. e., in those suffering from anaemia with repeated attacks of fever and repeated doses of qui- nine) black-water fever sooner or later almost certainly supervenes, at least in tropical climates. The two main factors in hsemoglobinuria are, then, malaria and quinine. While then we believe that the cause of black- water is known, yet it' must be admitted that much work remains to be done in analyzing more minutely the exact blood condition which predisposes to an attack, and why especially quinine at one time will produce haemolysis, and at another time will not. Morbid Anatomy.— Spleen.— Melanin may be found in cells of the splenic reticulum in macrophages and in large mononuclear leukocytes. Hsemosiderin (yellow ocherous pigment) also is present. As already stated, pigmented leukocytes may be found here while absent in the blood during life; the same also holds good for parasites. Liver. — Melanin occurs in endothelial cells and pigmented leukocytes in the capillaries : areas of necrotic liver-tissue are found laterally to the intralobular vein, and thrombi occur in the sublobular veins, and in these, pigmented leukocytes can be found. Kidneys. — The epithelium of the convoluted tubes shows degen- eration, and the lumen is filled with a granular mass; similar changes are found in the straight and collecting tubules. Melanin is not usually present. Red Marrow» — Melanin is found in the capillary endothelium and in large branch cells, and also in leukocytes. Brain. — Occasionally parasites occur here when absent elsewhere, but frequently no pigment can be found. 45G DISEASES CAUSED 7?r PROTOZOA Symptoms. — As a rule tlie attack begins witli a violent rigor; at the same time tlie temperature rapidly rises to 103° to 105° F. This is accom- panied or preceded by general pain in the limbs, lassitude, and loss of appetite and not uncommonly there is great depression of spirits. On the other hand, sometimes the first indication the patient has that he is really unwell, is the passing of black water. There may be practically no other objective sign. It has been attempted to separate these cases from the previous ones and to regartl them as true cases of cpiinine hicmoglobin- uria, but no sharp line can be drawn between such cases and the severe ones with intense initial rigor. When the attack has set in — which the patient may have regarded as only a more than usually severe attack of fever — the urine next passed is found to be more or less black. The attack is accompanied by severe vomiting, which increases in severity and duration; the vomited matter is eventually almost entirely dark-green bile, and the persistence of this symptom exhausts the patient and is frequently of l)ad significance. Jaimdice appears more or less early and eventually the body becomes of a light lemon-yellow color, though this may not be well marked in slight cases. The spleen and liver are usually enlarged and there may be considerable pain in these regions and over the kidneys. Tympanites is often a distressing symptom, and the epigastrium is painful on pressure. In severe cases hiccough troubles the patient much, and if there is a deficiency in the excretion of urine the prognosis is grave. Somnolence adds to the gravity and may progress into a fatal coma. The quantity of urine passed in mild cases is greater than normal, but a deficiency of urine is always unfavorable, for such cases may result in complete suppression. The passage of the urine is not uncom- monly slightly painful. In a case of medium severity, however, after the initial symptoms, the temperature may quickly fall and the urine become free from haemoglobin on the next day, still for some time retaining its "high" color. The fall of temperature is accompanied by sweating, and with an abatement of the other symptoms convalescence has already be- gun. In other cases, however, a relapse may occur with a rigor and a return of the hfemoglobinuria. Unusual complications are bloody diar- rhoea or effusions of blood through the ear or nose. Occasionally parotitis is seen. Thrombosis of the heart is, according to Plehn, the com- monest cause of death. The Blood. — The drop of blood is often evidently yellow and "thin" in character; it has lost its viscosity, so that often, excej)t by taking a large drop, it is difficult to procure satisfactory smears. If a drop of blood is allowed to clot in a small capillary tube, either hfemoglobinjemia or cholaemia may be found. Hfemoglobinsemia, ma}^, however, be absent even when the haemoglobinuria is increasing — a fact which possibly supports the view that the haemolysis really takes place for the most part in the kidneys. Microscopically, the blood does not show any appreciable evidence of the great destruction that may l)e going on ; at most the red cells may look ana-mic and have their central depressions enlarged ; but there is no deformity of the red cells, as has been stated by some, such an appearance being due simply to badly made films. A stained specimen, e.g., with the Romanowsky stain, may show two conditions — (l)poly- chromasia and (2) basophilia. These should be carefully looked for, as by some observers such a condition is supposed to indicate a further BLACK-WATER FEVER 457 tendency toward hfemolysis and to make administrtiion of quinine dangerous. Further, normoblasts occur. The red cells may fall as low as a million in severe cases, and there is a corresponding deficiency in haemoglobin. Parasites. — ^We have said that as a rule parasites will not be found, as cases of black-water fever are not uncommonly first seen some time after the onset of the symptoms ; but if examination is made early, parasites occur. In the absence of parasites careful search should be made through well-made films (most conveniently on the slide) for pigmented large mon- onuclear leukocytes. Occasionally they are plentiful, but as a rule careful search is required before they are found ; and yet when absent from the blood during life, they may be found in the spleen postmortem. Leukocytic Changes. — In malaria itself two conditions occur : first, there is a transient leukocytosis during the pyretic attack; and, secondly, a leukopenia, most marked during the apyrexia. In black-water, the leu- kocytosis appears to be more marked, possibly associated with the toxic condition, whatever be its cause. At this stage the poly nuclear leuko- cytes may reach 90 per cent., and it is not until the leukocytosis ceases that the increase in the percentage of mononuclear leukocytes can be appreciated. This, which is most marked when there is leukopenia, may exceed 20 per cent., and, taken with the finding of pigmented leuko- cytes, is good evidence of a malarial infection when parasites are absent. The hsemoglobinuria generally supervenes some hours, one to five or more, after the taking of quinine, so that it is necessary to examine the blood early, as quinine itself frequently produces a rapid disappear- ance of parasites. The Urine. — The urine is generally faintly alkaline in reaction, and the specific gravity less than normal. The color may vary from a very dark red to a brownish yellow, in which the spectroscope may be neces- sary to detect the haemoglobin. A character of the urine in severe cases is the large amount of sediment, which consists of a yellowish granular material, the granules varying in size from 1 to 7^ and appearing to consist of broken-down blood-cells. In the sediment a few reddish crys- tals of haematoidin occur. The darkness of the urine is not always a safe guide to the amount of haemoglobin present, and often a centrifugal- ized urine will, on examination with the spectroscope, prove to be free from blood-pigment. Blood corpuscles are rare; the condition is one of haemoglobinuria and not hsematuria. A spectroscopic examination of the urine, diluted if necessary, shows the .double band of oxyhaemo- globin or the bands of methaemoglobin. Urobilin is commonly present; it is best detected in the form of zinc-urobilin. Further research is re- quired both on the pigments and on the proteid constituents of the urine. The amount of albumin is often so great that, after boiling, the contents of the test-tube set solid and may be inverted without spilling. Bile-pig- ments are generally absent, but may appear with the onset of the fever, to be replaced later by oxyhsemoglobin. Diagnosis. — The disease, which may present the greatest difficulty in diagnosis, is perhaps yellow fever. But the points of distinction are many. The history of many previous attacks of malaria and of the administration of quinine, point to black-water. In mild cases of yellow fever we do not get a definite haemoglobinuria, but at most a slight albuminuria. Fre- 458 DISEASES CAUSED BY PROTOZOA quently from past attacks of malaria the spleen is enlarged; in yellow fever it is not. In yellow fever of greater severity there is the pronounced suf- fusion of the face, the dry tongue with red tip, and later the pronounced icterus and black vomit. In black-water fever also there is icterus, but the other features are wanting, and the black vomit of severe cases is lacking. In black-water, on the contrary, we get almost pure dark-green bile. Finally we have in yellow fever the characteristic relationship of the pulse to the temperature, ri3., that the pulse does not increase, but decreases in fre- quency with the increase in temperature. The presence of parasites does not exclude yellow fever, but in practice there should be but little difficulty in distinguishing between the two diseases. Postmortem the distinction is equally well marketl. In black-water fever the spleen and liver are usually enlarged, may be pigmented, and parasites may be found micro- scopically. In yellow fever the liver is only slightly if at all enlarged, and presents on section a characteristic box-wood color. In black-water fever the liver is commonly enlarged, and is also icteric, though the tint is not the same as that in yellow fever. Ecchymoses occur in the gall-bladder in yellow fever ; they have not been noted in black-water. The body presents flecks and true hemorrhages in yellow fever, the stomach and intestines show a considerable amount of hypersemia or hemorrhages, and the stomach often contains dark, slimy masses. Prognosis. — Mild attacks are generally recovered from rapidly. The mortality may be set down roughly as from 10 to 20 per cent. It is advis- able that the patient who has once suffered from black-water should not return to the tropics unless he makes up his mind that he will undertake strict prophylaxis against malaria, either by protecting himself scrupu- lously against mosquitoes, or by a strict quinine prophylaxis such as 5 grains every morning or 10 to 15 grains every tenth day. Treatment. — If the quinine view of black-water be correct the question arises as to how black-water fever is to be treated. Whether or not we be- lieve this view, the result of experience is undoubtedly against the admin- istration of quinine. As parasites rapidly disappear, it is not generally necessary in these cases to administer quinine. In all cases a careful blood examination should be made, and if parasites still persist with a con- tinuance of the fever, then the question must be carefully weighed as to whether quinine is to be given or not. If it can be avoided we should say it is better to abstain ; but if it is judged advisable from the continuance of the fever, then it should be commenced in quite small doses — one or two grains at a time. According to some there is less risk if it is administered subcutaneously, and if this dose is well borne, then it should be in- creased to five grains and from this upward. In some cases methylene blue may be tried, but this lacks the efficiency of quinine. Should the black-water return after quinine, a second attempt may be made, but it is dangerous, for in one of Koch's cases the result was always the same, and finally the symptoms became so aggravated that quinine had to be withheld. This, however, does not ahvays occur, and a second attempt may be successful : if not, there is no course open but to trust to the fever subsiding . The general treatment is, however, the most important matter. The bowels should be kept open by calomel, jalap, or enemata. Champagne is frequently necessary and is often retained when all food is rejected. BLACK-WATER FEVER 459 The thirst should be allayed with ice, if procurable, and nutrient enemata given if necessary. The vomiting is often very troublesome, and for this Hearsey uses morphia (gr. i, gm. 0.03) hypodermically. Hearsey treats his cases with a mixture containing bicarbonate of soda (grs. 10, gm. 0.6) and perchloride of mercury (gr. gJ^, gm. 0.002) in each dose, given every two hours. Acid drinks are at the same time prohibited. We do not con- sider that this treatment has the specific value that the author claims for it, but it may well be tried. Doering alleviates vomiting by the use of Carlsbad salts, a teaspoonful in water, repeating the dose if vomited. Injections, intravenous or subcutaneous, of normal saline solution, have been used with good effect by some. Vincent recommends calcium chlo- ride to prevent the susceptibility to black-water and also during the attack (4-6 gm. daily or 1-2 gm. injected subcutaneously in saline solution). Dannermann uses a decoction of a native African fever remedy, the leaves of Combretus Raimbanthius. (Decoct, fol. combreti 24 parts, water 1,500 parts, used as a tea during the day.) To promote diuresis potassium acetate is used. The symptoms arising from the kidney, heart, and nervous system, are those which require especial attention. General treatment and good nurs- ing especially are of the greatest importance, and to these must be at- tributed the successful treatment, and not to any specific value of the various remedies advocated. . CHAPTER XXL TRYPANOSOMIASIS. By COL. DAVID BRUCE, C. B., F. R. S., R. A. M.C. Introduction. — The group of diseases which comes under the term Trypanosomiasis attracted Uttle attention until a few years ago; now, it seems to be usurping the position of interest held during the last quarter of a century by the bacteria.^ Diseases caused by trypanosomes are found over a large area of the earth's surface, from South America, through Africa, Southern Europe, Persia to India, Burma, China, and the Philip • pines,^ and affect many kinds of animals, including man. These diseases are all caused by the presence in the blood and body-fluids of species of flagellated protozoa belonging to the genus Trypanosoma. A trypano- some consists of a single cell, and in its best known form is a sinuous worm-like creature, provided with a macronucleus and a micronucleus or blepharoplast, a long terminal fiagellum, and a narrow fin-like mem- brane, continuous with the fiagellum and running the whole length of the body. The end from which the fiagellum protrudes is usually called the anterior; the other end, near which as a rule is situated the micro- nucleus, the posterior. When alive this hsematozoon is extremely rapid in its movements, constantly dashing about and lashing the red blood corpuscles into motion with its fiagellum, and it swims equally well with either extremity in front. These parasites give rise to an extreme variety of diseases, sometimes so acute as to cause death in a few days, at other times so chronic as to take several years to kill. Some of the species, again, appear to live in the blood of their hosts without causing any perceptible disease, and especially is this so in those species which livj in fish, frogs, and other cold-blooded animals. As to how the trypanosome damages its host is not very clearly known at present, but the probability is that it gives rise to the presence of small quantities of toxins in the blood and so causes, in some animals, chronic inflammatory processes, or in others extensive and rapid destruction of the blood corpuscles. However the damage is done, trypanosomiasis is extremely fatal in man and the domestic animals, such as the horse, dog, and ox. Large native populations in Central Africa are being swept away at this moment by this plague, and great tracts of country are rendered uninhabitable for man and the domestic animals. In this paper a brief historical sketch and description of the more important try]5anosomes and the diseases they give rise to, with special reference to that species which affects man, are given. * Trypanosomes et Trypanosomiasis par A. Laveran et F. Mesnil, Masson et Cie, Paris, 1904, p. 419. 2 "Report on Trypanosomiasis," etc., by W. E. Musgrave and M. T. Clegg, Report of the Superintendent of Government Laboratories in the Philippine Islands, 1903, Bureau of Insular Affairs, War Department, United States. 460 TRYPANOSOMIASIS 461 TRYPANOSOMA LEWISI. The Rat Trypanosome. — The earlier discoveries of trypanosomes in the blood of fish and frogs, dating from the year 1841, may be passed over. They Mrere interesting to the zoologist, but having at that time no obvious bearing on the causation of disease, did not attract the attention of medical men. For about forty years little or no progress was made in the subject until Surgeon-Major T. R. Lewis,^ F. R.S., Royal Army Medical Corps, made an important observation by finding flagellated organisms in the blood of rats. This interesting discovery may be de- scribed in his own words. He says that having been directed to make certain enquiries regarding the nature of the sometimes designated "spirillum fever," which prevailed in Bombay during the early part of 1877, he had occasion to examine the blood of a considerable number of animals, and, in July of that year, detected spirillum-like organisms in the blood of healthy rats. In some instances these were so numerous that the blood, when examined under a high power, seemed to quiver with life. On careful focussing, it was ascertained that each organism consisted of a body portion, and of an extension of it in the form of a gradually tapering, long flagellum. They were found in two species of rats — Mus. decumanus and Mus. rujescens — and in 29 per cent, of the animals examined. Lewis naturally fell into the error, when Dr. Grif- fith Evans,^ the Chief of the Veterinary Department in Madras, discov- ered similar organisms in the blood of horses suffering from surra, of considering that the two parasites were identical. With better micro- scopes than Lewis possessed, it can now be seen that the morphology of the rat trypanosome differs much from that of surra. The only animal in the blood of which the former will live is the rat. This rat trypanosome is distributed, broadly speaking, all over the world ; and even in Uganda, in Central Africa, we found numbers of the common field rat harboring it. The rat trypanosome does not appear to give rise to any symptoms of dis- ease, although their numbers in the blood may be exceedingly numerous. TRYPANOSOMA EVANSI.^ Surra. — This trypanosome was discovered in 1880, as mentioned above, by Evans.* Surra is mainly an Indian disease, occurring in the Punjab and in Burma. The disease usually appears during the rainy season, and disappears gradually with the advent of the cold, dry weather. Places in which surra is reported to occur naturally, are mostly situated close to swamps or alongside rivers, and liable to inundation during the rains. The horse and mule are most susceptible to surra, the dog coming next, and these three always succumb to the disease. The camel is supposed ^ Lewis, "Flagellated Organisms in the Blood of Healthy Rats," Qwari.Journ. Micr. Sc, Vol. XIX, January, 1879, 109. ^ Evans, "On a Horse Disease in India Known as 'Surra,' Probably Due to a Hsematozoon," Vet. Journ., Vols. XIII and XIV, 1881-1882. ^ Steel, J. H., Report on his Investigation into an Obscure and Fatal Disease among Transport Mules in British Burma, 1885. *EvanSj G., Report on Surra, Published by the Punjab Government, 1880. 462 DISEASES CAUSED BY PROTOZOA to live for three years after becoming infected, while the ox generally recovers after some five or six months. Rogers^ states that surra is carried from sick to healthy animals by species of tabanus, and other ■writers have stated that stomoxys also acts as an infecting agent. Surra is very closely related to the next disease — nagana — and, in fact, is con- sidered by many to be identical. TRYPANOSOMA BRUCEI.^ Nagana or Tsetse-fly Disease. — As the writer of this article had the good fortune to discover this species of trypanosome in 1894, perhaps a few words of personal experience will not come amiss. In October, 1894, when serving in Natal, South Africa, the governor of that colony, the Hon. Sir Waiter Hely-Hutchinson, G.C. M.G., asked me to go to Zululand to report on a disease which was causing severe loss among the native cattle. The native name of the disease was nagana. At this time no suspicion that nagana and the tsetse-fly disease were identical was entertained. The writer at once proceeded to Zululand and after a month's travelling by ox- wagon from Eshowe, the capital of that country, arrived in the infected area. A small laboratory having been set up and some of the aft'ected cattle obtained from the surround- ing natives, examination by the ordinary bacteriological methods was begun. The animals were emaciated, with staring hair, some fever, and sometimes oedema of the subcutaneous tissues of the neck. Exam- ination of the blood and organs for bacteria by microscopic and cultural methods produced no result. At this time it was my custom, when start- ing on the study of a new disease, to make a careful daily examination of the blood of the living animal, enumerating the number of the red and white blood corpuscles and estimating the percentage of the various varie- ties of leukocytes. After a few days of this blood examination it was noted that there was sometimes to be seen a peculiar stained body, having something of the appearance of an artistic dolphin, lying among the red blood corpuscles. It must be remembered that the trypanosomes are usually found in very small numbers in cattle, so that it is only after a long search that a single one can be found. It was thought at first that this small, peculiarly shaped object was an accidental appearance due to the stain, but thinking that if the body was a parasite, it might show motion, several specimens of fresh blood were examined. A long search was rewarded by finding a very active body, wriggling and twisting about with great energy and dashing in and out among the red blood corpuscles. It was the first time the writer had seen a trypanosome, and, as then there was little or no literature on the subject of these parasites, it was difiicult to know how to place it. It seemed that it must be a filaria, but having 'Rogers. "The transmission of the Trypanosoma evansi by horse-flies, and other experiments pointing to the probable identity of Surra of India and Nagana or Tsetse-fly Disease of Africa." Proc. Roy. Soc, Vol. LXVIII, March 14, 1901. ^Bradford and Plimmer, "The Trypanosoma Brucei, the Organism found in Nagana or Tsetse-fly Disease," Quarterly Journal of Microscopical Science, Vol. XLV, 1902. TRYPANOSOMIASIS 463 compared the description and drawing of the rat trypanosome in Lewis's book/ with my parasite, it was concluded that it was a trypanosome. But there was no proof that the parasite was the cause of nagana; it occurred only in small numbers in the blood of the cattle, and the rat trypanosome lives as a harmless guest in healthy animals. Therefore, the blood of the infected cattle was inoculated into horses and dogs.^ The disease in the horse and dog is much more acute than in the ox. In a few days the blood, especially of the dog, was found to be teeming with thousands of trypanosomes. It, therefore, began to appear probable that this parasite might be the cause of nagana. At that time there was no suspicion that this disease among the native cattle, occurring in kraals situated many miles from the "Fly country," was the same disease as that known to travellers as the tsetse-fly disease. The work at this time was being done on the summit of a mountain called Ubombo, some 2,000 feet above the surrounding low country. The low country to the east of the mountain was known to be infected with the tsetse-fly, and having often read, in Livingstone's and other books of travel and hunting, about this disease, it was determined to take a few animals into this "Fly country" and see what the disease was like. Two young oxen, a horse, and several dogs, were taken into the heart of the " Fly country." After being there a fortnight the animals were brought back to the top of the mountain and examined in the usual way; their temperature taken, their blood examined, and any symptoms that might occur noted. It was found that the blood of these animals affected with the tsetse-fly dis- ease contained the same parasite as that found in nagana. In this way, after many experiments and many observations, it was forced upon me that the two diseases, nagana and tsetse-fly, were one and the same. It is a characteristic of this species of tsetse-fly, Glossina morsitans, that at rare intervals, probably due to long continued drought, it overspreads its usual bounds to a distance sometimes fifty or sixty miles, [and so sets up an epidemic among the native cattle in a previously healthy district. This was the case in 1894; the disease had overspread its natural bounds and given rise to a wide spreading epidemic among the cattle to a distance of sixty miles. When it was once established that the two diseases were the same, experi- ments were made to find out how the animals became infected, whether the fly was the carrier or a mere concomitant of the low lying unhealthy district, and, if a carrier, if it was the only carrier of the disease from sick to healthy animals. Horses taken down into the "Fly country," and not allowed to feed or drink there, took the disease. Bundles of grass and supplies of water, brought from the most deadly parts of the "Fly coun- try" to the top of Ubombo and there used as fodder for healthy horses, failed to convey the disease. Tsetse-flies, caught in the low country and kept in cages on the top of the mountain, when fed on affected animals were capable of giving rise to the disease in healthy animals up to forty- ^ Lewis, T. B., Physiological and Pathological Researches, Published by Lewis Memorial Committee, 1888. ''Bruce, D., Preliminary Report on the Tsetse-fly Disease or Xagana in Zulu- land, Durban, Natal, 1895, Further Report, Printed for the Royal Society by Harrison & Sons, London, 1896; Appendix to Further Report, Harrison & Sons, 1903. 464 DISEASES CAUSED BY PROTOZOA eight hours after feeding. Tsetse-fUes, brought up from the low country and placed straightway upon healthy animals, were also found to give rise to the disease The flies were never found to retain the power of infection for more than forty-eight hours after they had fed upon a sick animal, so that if wild tsetse-flies were brought up from the low country, kept with- out food for three days and then fed on a healthy dog, they never gave rise to the disease. ■ In this way it was proved that the tsetse-fly, and it alone, was the carrier of nagana Then the (juestion arose as to where the tsetse-Hies obtained the trypanosomes. The Hies lived among the wild animals, such as buffaloes, koodoos, and other species of antelopes, and, naturally, fed on them. It seemed that, in all ])robability, the reservoir of the disease Avas to be found in the wild animals. Therefore all the different species of wild animals obtainable were examined both by the injection of their blood into healthy susceptible animals, and also by direct microscopic examination of the blood itself. In this way it was discoveretl that many of the wild animals harbored this trypanosome in their blood. The ])arasites were never numerous, so that it was only after a long search that they could be discovered by the microscope alone. The wild animals did not seem to be affected by the trypanosome in any way; they showed no signs or symptoms of the disease, and it therefore ap- peared probable that the trypanosomes lived in their blood as harmless guests, just as the trypanosome of the rat lives in the blood of that animal. The flies were examined at various times after feeding, to see if there was any kind of metamorphosis taking place within the body cavity. But no such evidence could at any time be discovered. The trypanosomes can be found alive and wriggling vigorously in the oesophagus and stomach for about five days after feeding; as long, in fact, as the smallest quantity of blood remains imdigested. No living trypanosomes are ever found in the intestines or dro})pings, and the latter, on many occasions injected into healthy animals, failed in every instance to give rise to the disease. The fly then can only be regarded as a mechanical carrier of the trypanosome and not as the specific intermediate host. If this is so it seems strange that the tsetse-fly should be the only carrier of the disease. That this is so is evident from the fact that a huge experiment to prove this has been going on in nature in South Africa from time immemorial. Here and there are tracts of country called 'Tly belts." They are called "Fly belts" on ac- count of the presence of the tsetse-fly. Outside the fly zone there may be a tract of country differing little in physical characters from "Fly country," where many species of biting flies abound, but no tsetse. Here the wild animals carrying the trypanosome in their blood are also found. Horses and cattle remain quite healthy in such a country, consort- ing with wildebeeste and other antelope, and constantly exposed to the bites of tabanidiie, stomoxys, and other biting flies. During a stay of two years on the top of the Ubombo, within an hour's march of the "Fly coimtry," although healthy animals lived side by side with those affected with nagana, not a single case of natural infection took place, albeit there were many ordinary biting flies about. On the other hand, if a horse or dog was taken into a "Fly belt," even for a few hours, it almost certainly be- came infected. It seems then to be a fact almost beyond suspicion that the disease known as nagana or the tsetse-fly disease is carried by Glossina and by no other genus of biting flies in Africa, It is strange that some TRYPANOSOMIASIS 465 phenomenon similar to this should not have been brought out in regard to the Indian trypanosome disease. It is evident that surra has a peculiar distribution, and it seems probable that this will be found to depend upon the distribution of some species or genus of biting insect. Nagana affects a large variety of species of animals. With the excep- tion of the baboon, it is fatal to monkeys, horses, i lulco, donkeys, cattle, dogs, cats, rabbits, guinea-pigs, rats, mice, and other animals. It is a peculiar circumstance that man is one of the few animals immune to this disease. No case has yet been recorded of the occurrence of nagana in man, either among the natives living in the "Fly country," or in Euro- peans who live or go into the "Fly country" in search of game. Nagana has probably been studied more than any other trypanosome disease, due to the writer having sent to England, in 1898, dogs with the trypanosomes in their blood. Descendants of these trypanosomes have found their way to many laboratories, even in America. TRYPANOSOMA GAMBIENSE. HUMAN TRYPANOSOMIASIS. SLEEPING SICKNESS. Historical. — ^The Trypanosoma Gamhiense was first described by the late Dr. J. E. Dutton. The parasites occurred in the blood of an English- man who had been employed for six years as master of a government boat plying on the Gambia River, West Africa. He was admitted into the hos- pital, at Bathurst, on the 10th of May, 1901, under the care of Dr. R. M. Forde, Colonial Surgeon/ Dr. Forde examined his blood and saw actively moving worm -like bodies, which he was unable to identify; he, therefore, asked Dr. Dutton to assist him in the diagnosis. In the mean- time, the patient had been invalided to England, where he was for some time under treatment in a hospital in Liverpool. He returned to Bathurst in December, 1901, and on the 15th, Dr. Dutton examined his blood and saw the trypanosome, which he described and named. ^ At this time no suspicion existed that the so-called trypanosoma fever or Gambia fever had any relation to sleeping sickness. This discovery of trypanosomes in the blood of man awakened a great deal of interest, and Dr. Dutton, accompanied by Dr. J. L. Todd, was sent out to Senegambia to make further investigations. They arrived at Bathurst on the 2nd of September, 1902, and remained on the West Coast for nearly a year They examined 1,043 natives in the Gambia, and found the parasite in 6 cases only. They sum up their report by saying that, taking all the facts into con- sideration, they believe the disease, as it occurs in natives, to be a pecul- iarly mild one, and that it is at present impossible to recognize it clinically, and they suggest the possibility that the natives in this disease may bear the same relation to the Europeans as does the wild game of Central Africa to domestic animals in the tsetse-fly disease.^ ^ Forde, R. M., The Journal of Tropical Medicine, September 1, 1902. ^Dutton, J. E., "Trypanosome Occurring in the Blood of Man," Thompson- Yates Laboratory Reports, Vol. IV, pt. II, 1902. ^Button and Todd, First Report of the Expedition to Senegambia, JjiwerTpool School of Tropical Medicine, Memoir XI, 1902. 30 466 DISEASES CAUSED BY PROTOZOA In the beginning of 1903, Dr. C. J. Baker^ noted the presence of try- panosomes in throe cases in the blood of man in Entebbe, Uganda. Shortly before this Dr. Castellani,^ a member of the Commission sent out to Uganda by the Royal Society, London, for the purjiose of investi- gating sleeping sickness, had observed these ha^niatozoa in the cerebro- spinal fluid of 5 cases of sleeping sickness, and in 1 of these he had also seen them in the blood. This was the first time try{>anosomes had been seen in the blood of recognized cases of sleeping sickness. When the writer arrived in Uganda, on March 16, 1903, for the purpose of con- tinuing the investigation of this disease, Castellani described his findings, and, as was to be ex])ected after the work on nagana, the observation was very strildng, Castellani, who intended to leave immediately for England, consented to stay a week or two longer, in order that we might, pursue this particular point. He remained in Entebbe for three weeks, and during this time we examined 22 cases of sleeping sickness and found the trypanosomcs in 15, about 70 per cent. From this time the history of the Tri/panosoma Gamhiense is merged in that of sleeping sickness and most writers are now agreed that in all pro- bability the so-called trypanosoma fever or Gambia fever is merely the first, and sleeping sickness the last stage of human trypanosomiasis. This, however, being still a matter of dispute, will be discussed more fully later on. This then is a short account of the Trypanosoma Gamhiense from its discovery as a supposed harmless parasite in the blood of natives on the Gambia, to its aj^otheosis as the cause of the terribly fatal sleeping sickness. Human Trypanosomiasis or Sleeping Sickness. — The history of ■ the disease itself may be given in a few words. Human trypanosomiasis or sleeping sickness has been known for more than a hundred years on the West Coast of Africa, and has attracted a good deal of interest and curiosity on account of the peculiar symptoms of lethargy which developed and which gave rise to the name of sleeping sickness. The disease, al- though of an apparently infectious nature in its native haunts, was found to lose its power of spreading from man to man upon removal to a non- endemic area. Thus much interest was raised by the fact that slaves introduced to other countries from the West Coast often died of sleeping sickness, but the disease never spread to their neighbors — never became endemic. Different theories w^ere held as to its causation, some holding it to be a food intoxication, others blaming various kinds of bacteria. As an upholder of the former Ziemann^ may be cited ; of the latter, Battencourt* and Castellani.^ Another theory w^iich seemed plausible was that the disease Avas caused by Filaria perstans and found its advocate in Sir Patrick Manson.® All these speculations have been proved to be un- founded, by the discovery that the causal agent in this disease is really the Trypanosoma Gamhiense. * Baker, C. J., "Three cases of Trypanosoma in Man in Entebbe, Uganda." British Medical Journal, May 30, 1903, p. 1245. ^Castellani, "Presence of Trypanosoma in Sleeping Sickness," Royal Society, Reports of the Sleeping Sickness Commission, 1903. Harrison & Sons, London. ^Ziemann, H., Centralblatt j. Balder, Orig. Vol. XXXII, 1903. *Battencourt, A., Doenca do Somno, Lisbonne, 1901. ^Castellani, A., British Medical Journal, March 14, 1903, ^Manson, P., Tropical Diseases, 3d Edition, 1903- TRYPANOSOMIASIS 467 Etiology, — Geographical Distribution, — Human trypanosomiasis has been known foi the last hundred years on the West Coast of Africa, and the disease may be said to extend from the River Gambia to the River Congo. At the present time it does not seem to be a common disease on the Gambia. Dr. Forde, the Principal Medical Officer at Bathurst, reports that, on an average, he only sees about one case a year, and only 6 out of 1,043 natives showed trypanosonies in their blood at Leopold- ville. On the Congo, of 1,172 natives, 103 were afi'ected. These included healthy laborers, prisoners, out-patients and patients in hospital. Out of the 103 cases, 57 were recognized as sleeping sickness. These natives were examined for trypanosonies by microscopic examination of a drop of blood from the finger-tip. If we had examined the apparently healthy natives in this way in Uganda probably not more than 1 or 2 would have been detected. It is therefore probable that if a more thorough examina- tion of the blood had been made on the Congo a larger percentage of cases would have been found. If a map of Africa be examined it will be seen that the basin of the Congo extends more than half across the continent, and that one of the tributary rivers, the Aruwimi, rises near Lake Albert in the northwest of the Uganda Protectorate. At present, the distribution of the disease has not been mapped out completely in the Congo State, but when it is, undoubtedly it will be found to extend far inland. It is therefore not to be wondered at that the disease has crept still further eastward and invaded Uganda It first broke out in that part of the country lying to the north- east of the great lake, Victoria Nyanza, called Usoga. Dr. Moffat, the Principal Medical Officer in Uganda, is of opinion that the disease was introduced when Emin Pasha's Soudanese, with their wives and fol- lowers, numbering some ten thousand, were brought into and settled in Usoga. These natives were brought from the edge of the Congo territory, where in all probability sleeping sickness was endemic. It seems, then, quite probable that some of these natives introduced the disease into Usoga. Be that as it may, the sleeping sickness broke out in that part of the country, according to Dr. Hodges, about the year 1896. It was not re- cognized, however, till 1901, when the cases became numerous.- That this introduction of sleeping sickness from the Congo to Uganda should have taken place in recent years should be no matter for surprise. As Moffat remarks, the recent opening up of Equatorial Africa has led to inter-communication between countries and districts, which, in earlier days, were absolutely cut off from each other. Civilization gives the natives of Uganda peace, and at the same time introduces a disease^ which, during the last three years, has killed off a hundred thousand of the population. Race. — ^For a long time it was considered that this disease was confined to negroes. Unhappily, this is not so; several Europeans have now succumbed to the disease, as well as the natives of Persia and India. Christy states that the Nubian police in Uganda are practically immune, but this is obviously an error as several of these men were affected and under our observation in Entebbe. Occupation. — ^Whatever occupation leads a native to spend much time on the wooded shores of Victoria Nyanza or any river or lake -R^tliin the sleeping sickness area, is dangerous. Hence, fishermen, canoe-men and 468 DISEASES CAUSED BY PROTOZOA the inhal)itant.s generally of the lake shore are prone to suffer. These people are half naked and spenil nuieh of their time trading and gossiping on the shore, 30 to SO per cent, of them harboring the trypanosomes in their blood, and being constantly bitten by nnmerous tsetse-flies. Sex, age, food, health or ill-health, have naturally no effect; if the trypanosome is introduced under the skin of the youngest or the healthiest there is no reason to believe that it does not take root and multiply. Monthfi and Seasons. — As the climate in Central Africa is much the same all the year round it does not appear that the disease is more prev- alent at one season than at another Dcscripiion of the Causal Agent — tJte Trypanosoma Gamhiense. — ^When the blooil of a man suffering from human trypanosomiasis or slec])ing sickness is examined microscopically, a minute, wriggling, worm-like parasite may sometimes be seen among the red blood corpuscles. It must not be supposed that a casual examination of the blood is all that is required to demonstrate this body An ordinary blood preparation, taken from the ear or finger, would, in all probability, not show this para- site once in fifty times. As a rule the trypanosomes are so scanty in the peripheral blood that, in order to demonstrate them in every case, a quantity of blood must be examined. In Uganda we examined many cases of sleeping sickness and found the trypanosomes in the peripheral blood of all but one. At that time we had five workers and five micro- scopes. Ten cubic centimeters of blood were drawn off from a vein of the arm; this was run into test-tubes containing a small quantity of citrate of soda solution in order to prevent coagulation; the blood was then centrifugalized for a quarter of an hour, to throw out the red blood cor- puscles; the clear liquid was pipetted off and again centrifugalized for a quarter of an hour. Specimens were taken from the surface of the red blood corpuscles and examined by the five workers. As soon as the moderately clear fluid had been subjected to the fifteen minutes' centri- fuging, it was poured off, leaving a small quantity of sediment behind. This sediment was again made into five specimens and examined micro- scopically. The clear, supernatant fluid was for the third time centrifu- galized and the resulting small quantity of sediment again examined. As a rule, it was in the sediment obtained from the third process that we found the trypanosomes most frecjuently. It will be seen then that five microscopes were employed and frequently fifteen preparations would be examined before a parasite was discovered. In the specimens made from the first two preparations there are too many red blood corpuscles to give a good view ; it is only in the third, or perhaps not till the fourth, that the red blood corpuscles have been so completely removed as to leave a clear fluid only containing a few white blood corpuscles; in this fluid the active, living trypanosome is readily picked out under a low power. The best method of bringing out the various details in the trypanosome is by the use of one of the many Romanowsky staining methods. The method we used in Uganda was that known by the name of Leishman's stain. This is an exceedingly simple stain to use and good results are invariably obtained with little trouble. The following is a description of the method, in Leishman's own words, "I need not recapitulate the some- what complicated method by which the solid stain is prepared, as those TRYPANOSOMIASIS 469 who wish may refer to my original communication;^ but there are several points in the preparation of the solution which are of importance to those who have to make this up for thcjuselves. The solvent for the powdered stain is methyl alcohol and it is of the first importance that the right quality of methyl alcohol should be used for the purpose; namely, Merck's methyl alcohol ('pro analysi, acetone free'). Good results are not to be expected if less pure varieties are employed. The powdered stain is dissolved in this alcohol in the proportion of 0.15 per cent., and the following details must be observed in preparing the solution in order to obtain its maximum staining power. The powder should be ground in a clean mortar as finely as possible and the proper proportion of methyl alcohol measured into a convenient vessel; a little of the alcohol is then poured into the mortar, and the grinding continued for some time. After a few minutes' rest, to allow the undissolved particles to sink to the bot- tom, the upper part of the fluid is poured into a clean bottle, a fresh supply of the alcohol is added and again rubbed up with the remains of the powder. This process is repeated until the whole of the finely divided powder is in this way dissolved in the proper quantity of solvent. This procedure is rendered necessary by the slight solubility of the powder — .15 per cent being nearly a saturated solution — and, if not carried out, or if filtration through filter paper is employed, the resulting solution will be unduly weak and the results obtained with it inferior." "Thin, even films of blood are made upon perfectly clean coverglasses or slides and are allowed to dry in the air or by gentle heat. A few drops of the stain are poured upon the unfixed film and allowed to act for fifteen to thirty seconds, by which time the film will be fixed by the methyl alcohol — previous fixation by most of the methods in general use will prevent chromatin staining. Only enough stain should be used to cover the film with a shallow layer, and care must be taken by moving the slide or coverglass to prevent the stain drying upon any part of the film. At the end of this time double the quantity of distilled water — not more — is added to the stain, and the water and the alcoholic stain are at once thoroughly mixed by shaking, or with the help of a needle held parallel to the surface of the glass and passed backward and forward through the fluid. When the stain is thoroughly mixed with the water the mixture is left on the film for five minutes, by which time an iridescent scum will have formed on the surface and a fine flocculent precipitate will be seen to have formed. This period of five minutes is ample for all ordinary blood work, such as leukocytic counts and the demonstration of malaria para- sites, and the stain must now be gently washed off by pouring on the film a little distilled water. When ail the precipitate and stain is washed away a little of the water is allowed to rest on the film for half a minute, as this intensifies the brightness of the color-contrasts of the various cells, and advantage may be taken of this moment to glance at the film with the one-sixth inch lens to make sure that the Romanowsky staining is deep enough. The dense nuclei of the polynuclears or lymphocytes form the best index of the depth of staining, and should appear of a deep purplish- red or ruby color. If these are seen to be too light in tint, as may happen ^Leishman, Major W.B.,R. A.M. C, British Medical Journal, September 21. 1902. 470 DISEASES CAUSED BY PROTOZOA with old or bad films, the stain may be rc-applicd as before until the proper density of nuclear staining is attained." "Stain trypanosomes for ten to fifteen minutes, controlling the depth of staining by examination under a low power while the film is soaking in water. To bring out all tiie details of their structure rather deep staining is necessary, and the film may be allowed to soak in water for a little longer than usual. When treated thus, the macronucleus appears red, the micronucleus black, the fiagellum red, and the basophile granules black, while the protoplasm of the parasite is colored blue." Fia, 31. Fig. 31 represents the trypanosomes in the blood of sleeping sickness cases, magnified 2,000 diameters, and shows the macronucleus in the centre of the body, the micronucleus at the posterior end; the flagellum taking its origin from the micronucleus and, running along the margin of the undulating membrane, becomes free at the anterior extremity. A large vacuole is seen near the micronucleus and dots of chromatin are scattered through the protoplasm. Some writers profess to be able to recognize the various species of trypanosomes by their shape and general appearance. In this way Plimmer makes out that the trypanosome found in Gambia fever, or human trypanosomiasis, is different from that found in sleeping sickness. Without being too dogmatic on this point, the writer's opinion is that it must be very difficult to distinguish between such trypanosomes as T. evansi, T. brucei, and T. gambiense by micro- scopic examination alone. Koch, on the other hand, refuses to recog- nize more than one or two species and would group most of the trypanosomes under one specific name. TRYPANOSOMIASIS 471 To Find the Trypanosomes in the Cerebrospinal Fluid. — In the earlier stages of human trypanosomiasis, the trypanosomes are seldom, if ever, found in the cerebrospinal fluid. It is only when the symptoms of sleeping sickness have appeared that they are found with any frequency. In Uganda we examined 40 cases of sleeping sickness by drawing off a small quantity of cerebrospinal fluid and found the trypanosomes in every case. In all the cases the patient v/as chloroformed as the operation done without an anaesthetic gives rise, evidently, to a good deal of pain, and the native of Uganda was extremely nervous and easily frightened. They take chloroform very easily. Ten to fifteen cubic centimeters of the cerebro- spinal fluid are allowed to flow into a test-tube. It is needless to say that if any blood escapes with the cerebrospinal fluid the specimen ought to be rejected. The clear, transparent, water-like fluid is then centrifuged for twenty minutes to half an hour, and the sediment examined in the usual way under a low power. As might be expected, the trypanosomes are seen very readily in the fields of the microscope, there being no red blood corpuscles and few cells of any kind. The Trypanosomes Found in Enlarged Lymphatic Glands. — One of the earliest manifestations of this disease is an enlargement of the lymph- atic glands. It is quite true that among natives going about constantly with bare feet, and their naked limbs exposed to scratches and wounds of every description, it is the rule and not the exception for them to have en- larged femoral glands. But in human trypanosomiasis all the glands are enlarged — the cervical, axillary, inguinal, femoral, etc. Captain Greig, Indian Medical Service, and Lieutenant Gray, Royal Army Medical Corps, made the important observation that the trypanosomes can be demonstrated with great ease in the swollen lymphatic glands, where they seem to be in much greater numbers than in the blood or the cerebro- spinal fluid. Greig found that it was only necessary to draw off a drop of fluid by means of a small hypodermic syringe from one of the swollen cervical glands and to place this fluid under the microscope to find the trypanosomes at once or in a comparatively short time. This is a great advance on the older methods of examining the blood and cerebrospinal fluid. It is no exaggeration to say that it took on an average an hour to find the trypanosomes in the blood of a patient, even when there were five microscopes employed. Now, it appears from Greig's report that the cervical lymphatic glands can be examined and the trypanosomes found with great ease in a few minutes. In What Tissues of the Body can the Trypanosoma Gambiense he Found? — It seems that when the trypanosome is injected under the skin it makes its way by the lymphatic channels and is evidently at first blocked in the lymphatic glands; this causes the swelling of the glands, and, as mentioned above, the trypanosomes are found in much greater numbers in the juice of these glands than in any other of the fluids of the body. From the glands they evidently pass in small numbers into the general circulation, and with it to every part of the body. The liv- ing trypanosomes are never found in any of the cells of the tissues but are restricted to the fluids. There can be no doubt that in the first stages of the disease the trypanosomes are not found in the cerebrospinal fluid. In an examination of many apparently healthy natives who had trypano- somes in their blood, trypanosomes were not found in a single case by 472 DISEASES CAUSED BY PROTOZOA lumbar puncture. In the later stage, however, when the symptoms of sleeping sickness su})ervene, the trypanosomes can as a rule be readily fountl in every case of the disease in the cerebros{)inal fluid. Mode of Re product ion of the Trypanosoma Gamhiense. — As far as is known up to the present this trypauosome only reproduces itself within the human organism by longitudinal division. Other modes of repro- duction have been describetl jjy various authors, but these at the present time are not sufficiently definite to warrant acceptance. There can be no doubt that the number of trypanosomes varies greatly from time to time in the blood and fluids. Huge numbers of them must perish at times and their dead bodies become dissolved in the blood plasma. It is sup- posed by some that these dead trypanosomes contain a snuxll quantity of toxin which is thus set free in the blood and gives rise to the proliferation of the lymphatic elements, and to the chronic conditions afterwards found in the brain and tissues. Life History of Trypanosoma Gamhiense outside the Body. — It is evident that as the Trypanosoma Gamhiense is only found in the blood and lymphatic fluids of the body, it can only leave the body on the escape of these fluids. There is no evidence that the trypauosome escapes from the body by the intestinal or urinary tracts, or by the sweat, salivary or other secretions. When an animal dies of the disease all the parasites disappear rapidly from the tissues on account of commencing putrefaction. If blood is drawn off during life and kept aseptic it only retains its viru- lence for four days. Blood dried on threads sometimes retains its infec- tivity for twenty-four hours; at the end of forty-eight hours it is inert. If exposed to a temperature of 40° to 44° C. it is slowly killed; 45° C. is rapidly fatal. The curious observation has been made that trypanosomes, like some bacteria, can be frozen at the temperature of liquid air (-191° C.) for a quarter of an hour and still retain th-ir vitality. There is, therefore, no evidence that the trypauosome is capable of retaining its vitality in external nature under natural conditions for more than a few h urs. Under artificial conditions, however, Novy and IMacNeaP did a remarkable feat in growing various trypanosomes on artificial media. The culture medium they used was rdinary nutrient agar t which had been added defibrinated rabbit's blood. They first succeeded in growing the rat trypauosome in 1903. Later in the same year they also succeeded in cul- tivating Trypanosoma Brucei outside the body. These cultures are, how- ever, by no means so readily obtained as in the case of the rat trypauosome. In this way Trypanosoma Brucei has been grown artificially through twenty-three generations, and, so far as the writer knows, is still being grown. Up to the present no one has succeeded in the artificial cultivation of Trypanosoma Gamhiense, but this will probably be a question of time. It is to be ho]:)cd that the cultivation of the various trypanosomes will assist in the identification of species as at present their classification is rapidly ' MacNeal, " The life history of Trypanosoma Lewisi and Trypanosoma Brucei," Journal of Infectious Diseases, Vol. I, No. 4, November 5, 1904, pp. 517-543, Novy and MacNeal, "The cultivation of Trypanosoma Brucei," Journal of the American Medical Association, November 21, 1903. Journal of Infectious Dis- eases, Vol. I, No. 1, .January, 1904, p. 1; MacNeal, "An improved medium for cultivating Trypanosoma Brucei," Sixth Annual Report of The Michigan Academy of Science. TRYPANOSOMIASIS 473 becoming chaotic. But to return to the question of how the trypanosomes can leave the body of the host. The common way in nature is by the agency of biting flies. It will be interesting then to trace the history of the trypanosome in the interior of one of these flies — the tsetse-fly. A priori one would think that the trypanosomes on being taken into the stomach of the tsetse-fly would soon perish^ on account of the processes of digestion going on. The result of observation, however, shows that the follow- ing are the facts as far as have been ascertained: Immediately after feed- ing, the tube of the proboscis can be seen to be crammed full of red blood corpuscles, among which the trypanosomes can be seen actively wriggling. Up to forty-six hours one can see living trypanosomes and red blood cor- puscles in the proboscis. After one hundred and eighteen hours the para- sites are still numerous and actively moving about in what remains of the blood in the stomach. After one hundred and forty hours the stomach is empty and no appearance of trypanosomes can be seen. Motionless, apparently dead, trypanosomes are sometimes seen in the contents of the lower intestine, but the result of the injection of the droppings into sus- ceptible animals always remained negative. There was never any sign that the trypanosomes undergo any metamorphosis in the stomach of the fly, such as occur in malaria. In regard to this life of the trypanosome in the stomach of the tsetse-fly, there is some evidence that multiplication may take place, as division forms are seen. In the opinion of the writer, if this takes place, it can only be to a slight extent, and it seems more reason- able to believe that no such multiplication takes place. It seems strange that although the trypanosome remains actively alive for some five days in the fly, we have never been able to infect an animal by means of the bite of the fly for a longer period than two days after feeding. This may be due to the fact that the trypanosome rapidly loses its virulence in vitro, and it is probable that this also takes place in the interior of the fly. How does the Trypanosoma Gambiense Gain Entrance to the Human Organism? — It is difficult to imagine that a deUcate blood parasite, in^ capable of living for any length of time outside the body, can pass from man to man in food, water, or dust, as so many other infectious agents do. When the question came to be asked in Uganda, the old work on nagana in Zululand came to the writer's aid, and a tsetse-fly was at once suspected of being the carrier. At this time it was hardly known that tsetse- flies were found in Uganda, but a short walk along the lake shore soon dis- posed of that objection. A species of tsetse-fly, afterward identified by Austen as the Glossina palpalis, was found to be exceedingly abundant. For months, a few native lads employed to catch these flies, brought three or four hundred daily to the laboratory. This Glossina palpalis is very similar to the Zululand species, except that the markings on the upper surface of the abdominal segment are less distinct. Full descriptions of these flies are given in Austen's "Monograph,"^ from which the two accompanying figures are taken, the first showing Glossina palpalis with artificially outspread wings, the other, Glossina longipennis, s\lO^\\ng the 1 Bruce, D., Tsetse-fly Disease or Nagana in Zululand, Further Report, 1896, Harrison & Sons, St. Martin's Lane, London. ^Austen, Monograph of the Tsetse-Flies, Sold by Longmans & Co., 37, Soho Square, London, B. Quaritch, 15, Piccadilly, London, W. 474 DISEASES CAUSED BY PROTOZOA wings crossed like the blade of a pair of scissors, tlie usual attitude as- sumed by this genus. In Uganda, experiments were made to find out if this fly (Glossina pal- falis) was capable of carrying infection from the affected to the healthy. Tsetse-flies contained in small muslin-sided cages were fed on slee))ing sickness patients and then, after a certain time had elapsed, on healthy monkeys. We secured the same results as were previously obtained in Fig. 32. Giussina palpatis, Rob. ( XSJ). nagana. Flies fed on healthy monkeys, eight, twelve, twenty-four, and forty-eight hours, after having fed on a native suffering from trypano- somiasis, invariably transmitted the disease. After three days the flies failed to transmit it. But this is not the only proof that these flies can carry the infective agent. On the lake shore there was a large native population among whom we had found about one-third to be harboring trypanosomes in their blood. The tsetse-flies caught on this lake shore, brought to the laboratory in cages,- and placed straightway on healthy monkeys, gave them the disease in every instance, and furnished a start- ling proof of the danger of loitering along the lake shore among these in- fected flies. It is true that the white man runs much less danger than the half-naked native. He is clothed as a rule from head to foot, and resents the presence of a biting fly, whereas the natives lie almost naked in the shade of the dense woods which line the shore of the lake and are little affected by the presence of the tsetse-flies. After these experiments it was held to be proved that the Glossina palpalis could convey the trypano- some from the sick to the healthy. Are other Species of Tseise-Flies besides Glossina palpalis Capable of Carryinrj the Infection? — Probably this question must be answered in the TRYPANOSOMIASIS 475 affirmative, as Wiggins, experimenting in British East Africa with Try- panosoma Gambiense and species of tsetse-flies other than palpalis-, succeeded in infecting healthy from affected animals, and Greig and Gray in Uganda found that Glossina palpalis could convey the trypanosoma of a disease, probably nagana, which occurred among cattle, as well as that of sleeping sickness. Do Flies other than the Glossina also Carry the Injection? — The an- swer to this is, in the writer's opinion, in the negative. Nuttall states that he tried for a long time in England to convey the Trypanosoma Brucei by means of the genus of biting flies called stomoxys. In no case did he succeed. Greig in Uganda also tried the same experiment and failed. In regard to the Trypanosoma Brucei and nagana, there can be little doubt that it is carried by Glossina and Glossina alone, and the distribution of nagana corresponds with the distribution of the tsetse-fly. So in regard to human trypanosomiasis in Uganda, if the Trypanosoma Fia. 33. A Tsetse fly {Glossina longipennis, Corti, from Somaliland) in resting attitude, stowing position of wings. ( X 34.) Gambiense is only carried by the Glossina then the distribution of the fly and the disease should correspond. We set ours?lves to work out this problem. Collections of all sorts of biting flies were made from all parts of Uganda, and at the same time the distribution of sleeping sickness was carefully enquired into. In the course of a few months several hun- dred collections of biting flies were examined. These were divided into two categories, those containing tsetse-flies, and ihoz^ containing other kinds of biting flies but no tsetse. Two maps were taken, one to represent the distribution of Glossina palpalis, the other sleeping s'ckness. On one, over every locality where a tsetse-fly was Cound, a red dot was placed, and over every spot where other biting flies but no tsetse were found, a black dot was placed. In the same way on ':he other map red dots represented where sleeping sickness cases were found, black dots where no sleeping sickness cases were found. When these maps were completed it could be seen at a glance that the distribution of Glossina palpalis and sleeping 476 DISEASES CAUSED BY PROTOZOA sickness coincided, and therefore we came to the conchision that human trypanosomiasis is conveyed from the sick to the heahhy by the Glossina palpali.s and by it alone. Austen wrote an account of the biting flies sent to him by us from Uganda, and it can be seen from it that there is no scarcity of genera and si)ccics in that country. Di.'iirihution of ilic Glo.s.sina Pal palls in Uganda. — When it became evident that the Glossina palpal is was the only carrier of this infection from the sick to the healthy, it was necessary to enquire somewhat closely into its habitat and habits. The results of this showed that this tsetse-fly palpalis is only found on the shore of the lake where there is forest. This forest is thick jungle ^xith high trees and dense undergrowth. The fly is never found on open sandy beaches backed by grass plains, even although there may be some scrub near the water's edge. It was never found in the grass of the grassy plains, even although the grass was long and tangled. It was not found by us in banana plantations, and not at any time far from the lake shore. ]\Iost of the rivers in Uganda are mere swamps, and up these valleys the fly does not penetrate. The fly is found along the Nile, almost as far north as Gondokoro on the border of the Soudan. It also occurs round Albert Nyanza. In Usoga the fly is seen to occur inland, but what the physical characters of this province are which would account for this have not been learned. Probably, rivers with open water-ways run into this country. It is evidently of the highest importance that the exact distribution of this genus should be made out, as the spread of sleeping sickness to the Albert Nyanza and down the Nile may interfere seriously with the opening up of Upper Egypt. Animals to which Trypanosoma Gambiense is Pathogenic. — Trypano- soma Gamhiense, like Trypanosoma Brucei, is pathogenic to many species of animals. It is on the whole much more chronic in its action than the latter, the duration of the illness it gives rise to being counted usually by months or even by years. It is curious that Trypanosoma Gamhiense should include man in its attack, as well as the other animals, whereas Trypanosoma Brucei, although as a rule much more rapidly fatal and acute in the lower animals, has never been recorded as having attacked man. Within the limits of this paper it is impossible to enter fully into the course of this disease in the lower animals, but a list of the principle species affected and a short account may be useful: — Monkeys. — The monkeys we used for inoculation in Uganda were Macacus rhesus and a Cercopithecus, (sp ?). In both species Trypanosoma Gamhiense gives rise to a chronic and fatal disease resembling human trypanosomiasis. The trypanosomes first appeared in the blood from about the tenth to the twentieth clay, were found in smaller or larger numbers every time the blood was examined, and the animals died after an illness lasting from four to twelve months. From our experience the disease is always fatal in monkeys. On postmortem examination, the same appearances are found as in man, except that in the fairly rapid cases there is not the characteristic small celled infiltration round the small vessels of the brain which is found constantly in man. In chronic cases, however, this meningo-encephalitis is just as marked in the monkey as in man. Dogs and Cats. — In Uganda the dogs made unsatisfactory experi- mental animals, as most of them died of ankylostomiasis before the ex- TRYPANOSOMIASIS 477 periment was finished. Other writers state that dogs die about two months after inoculation, and cats seem to be affected in much the same way as dogs. , , i- Guinea-pigs. — These animals are also susceptible, but m them the dis- ease pursues an extremely chronic course. In Uganda in two guinea-pigs which were inoculated more than once, the trypanosomcs only ai)peared in the blood after twelve and fifteen months respectively. According to Thomas the disease is sometimes fatal.^ It is probable that sooner or later all the animals die of the infection but this cannot be affirmed at present. Rabbits.— Incnhation period, according to Laveran and Mesnil, five to fifteen days. Duration from fifty to one hundred and twenty-eight days, iiafo.— Incubation period four to forty-seven days. Duration from forty-five to three hundred and eighty-eight days (average 85). Mice.— Incubation period one to thirty-seven days. Duration from eleven to fourteen days. Goats.— One of the goats in Uganda showed Trypanosoma Gambiense in the blood about fifteen months after infection. Sheep, horses, asses and cattle, are also very refractory, the trypanosomes appear- ing but rarely in the blood, although the blood may be virulent if injected into susceptible animals. Effect of Trypanosoma Gambiense on Man — Symptoms— 1st Stage — Trypanosomiasis. — When the Trypanosoma Gambiense gains entrance to the human organism it begins to multiply and appears in the blood. How long it is before it appears in the general circulation, is, of course, unknown, but in the monkey it usually appears about twenty days after inoculation. The course of the disease is so slow and insidious that months and even years may elapse before any marked signs manifest themselves. As an example of this, in Uganda in March, 1903, we had five natives in Entebbe under constant supervision. In January, 1905, after a period of nearly two years. Captain Greig informed the writer that 2 of these men died of pneumonia in April and May, 1904, respec- tively. Of the others, 1 appears to be undoubtedly in an early stage of sleeping sickness; he has gradually developed the characteristic signs of the malady and trypanosomes are now always found in his cerebrospinal fluid. The remaining two present some of the features of the disease, but are still able to do their work and have not yet shown trypanosomes in the cerebrospinal fluid. Again in June, 1903, 80 apparently healthy natives from the sleeping sickness area were examined and trypanosomes found in the blood of 23.^ Captain Greig now reports that 4 have died of undoubted sleeping sickness, 2 died from pneumonia, 5 are now in an early stage of the disease. No information could be gained concerning 6, and the remainder do not show any symptoms of sleeping sickness. Dr. Wiggins also relates the case of an "Askari" or native poHceman, sta- tioned at Fort Ternan in British East Africa for two and a half years before he developed the disease. All these facts go to show that the first stage of this disease, when the trypanosomes are found in the blood but not in the cerebrospinal fluid, 1 Thomas and Linton, A Comparison of the Trypanosomes of Uganda and the Congo Free State, Liverpool School of Tropical Medicine, Memoir XIII, p. 75, 1904. 2 Bruce, Nabarro and Greig, " Further Report on Sleeping Sickness in Uganda," Royal Society, No. IV, Report of the Sleeping SicJiness Commission, Harrison & Sons, St. Martin's Lane, London, 1903. 478 DISEASES CAUSED BY PROTOZOA may be of a very variable duration. If one may be bold enough to put this into definite figures, it may be said that this so-called stage of trypano- soma fever, this first stage of human trypanosomiasis, may last from three months to three years or more. During this time the native is going about at his ordinary vocation. He says he feels perfectly fit and strong. But there is one outward mark which proclaims the disease and that is the presence of enlarged lymphatic glands. This is a disputed point, but in my oi)inion this enlargement of the lymphatic glands must be looked on as a constant and early feature of the disease. It is not that enlargement of the inguinal or femoral glands should be taken as a sign of human trypanosomiasis; there must be a polyadenitis, and as a matter of routine, the postcervical glands should be examined first. Every case of sleeping sickness examined by us in Uganda showed this glandular enlargement, and according to Greig and Gray,^ the trypanosomes are readily dem- onstrated on examining the gland juice. Later it was found that the early cases of trypanosomiasis, the so-called trypanosoma or Gambia fever, also, in every case, presented enlargement of the lymphatic glands, and in these active trypanosomes could readily be found. The natives them- selves are alive to the fact, that, when the glands in the neck enlarge, they will, sooner or later, pass into the stage of sleeping sickness, and their custom is then to eat up their live stock, goats, chickens, etc. This en- largement of the cervical glands was used in Uganda to guage the inci- dence of the disease in a sleeping sickness area. The result was that in about three-fourths of the po]:)ulation of the islands of Sesse and Kome this symptom was present. As to whether there is any other symptom which can be depended upon to point to the first stage of this disease, is a question which, in my opinion, must be answered in the negative. Some writers state that there is fever from time to time of an irregular type, but if the charts of the men we kept under observation in Uganda be examined it will be seen that they kept absolutely normal for several months. The jBrst stage of this disease may be dismissed then by saying that the blood and lymphatics contain the trypanosomes, and that there is a general en- largement of the lymphatic glands of the body. 2nd Stage — Sleeping Sickness. — Naturally, in a disease so insidious as this it is impossible to say with absolute accuracy when the first stage merges into the second. But a time comes when a slight change in the man's demeanor becomes evident; when he is less inclined to exert him- self; he lies about more during the day, and at last his intimates see that he has the first symptoms of the disease. When these are well advanced the expression of the face is sad, heavy, dull-eyed and apathetic, as is well shown in Plate IV, Fig. 1. The body, however, is well nourished, and this is the rule, even up to the time of death, if the patients are well nursed and fed. Complaints of headache or indefinite pains in other parts of the body are often made. The pulse is rapid, shallow and weak, and the heart sounds faint and distant. The breathing usually presents nothing abnormal. The lymphatic glands are generally enlarged, and vary from the size of a pea to that of a bean. There is nothing abnormal about the skin; it may be at times harsh and rough, but usually is smooth * Greig and Gray, " Continuation Report of Sleeping Sickness in Uganda," Reports of Sleeping Sickness Commission, No. V, Royal Society, Harrison & Sons, St. Martin's Lane, London, 1905. PLATE IV FiG. 1 Sleeping Sickness. Second Stage. FIG. 2 Sleeping Sickness. Shortly before Death. TRYPANOSOMIASIS 479 and sleek, and any eruption is quite the exception. The gait is weak, un- certain and shuffling. There is little strength in the hand grip and the hands when held out are tremulous. Tremors of the tongue are, as a rule, well marked. The voice is weak, indistinct, and monotonous. At this time the temperature is usually irregular, often normal in the morning and rising to 101° or 102° F. in the evenings. During this time the patients in hospital are usually up a great part of the day, sitting in the open air, and to the casual observer show little or no signs of disease. The symptoms gradually increase until after weeks or months the patient is unable to walk, speak or feed himself. He is then altogether confined to his bed, lying in an absolutely lethargic condition all day long. It is at this time that the sick are often neglected by their friends and become much ema- ciated. The urine and fpeces are passed involuntarily. During the last two or three weeks the temperature sinks six or seven degrees below the normal, and, the condition gradually deepening, the patient dies in a state of coma. Plate IV, Fig. 2, represents a case of the emaciated type taken a few days before death. Principal Symptoms in Detail. — Nervous System. — The dull, heavy, listless, expressionless, emotionless physiognomy is a marked feature of this disease. Often when a patient is being examined he stares at a fixed point in a vacant way with eyes wide open. The intelligence and memory seem, as a rule, to remain fairly good. On two or three occasions we meet with cases showing mental excitement, laughing and jabbering all day in a meaningless way. In regard to sleep the usual history is that the pa- tients sleep well at night and a good deal during the day. The condition however, can hardly be called sleep. It is rather a vacant, day-dreaming, apathetic condition in which the patient remains for hours, often with eyes open, staring unmeaningly at the wall. They can easily be roused from this state by touching or speaking to them. The speech is peculiar: weak, slow, tremulous and indistinct, sometimes faint and high-pitched, like a whimpering child. When asked a question some little time elapses before the patient answers; he gives, as it were, a sigh, gathers his wits together, and answers with an evident effort. There is nothing, as a rule, noteworthy about the eyes. There is frequently {marked tremor of the tongue, lips, and hands, but the tongue alone may be affected. The mus- cular nutrition is usually good, but power is diminished as evinced by the grip. Sensibility to touch, temperature, and pain is normal and the mus- cular sense is little impaired. In regard to the reflexes, as a rule there is no abnormality. Sometimes, in the early stages, the knee-, elbow-, and wrist-jerks are increased; but in advanced cases the knee-jerks are often diminished and ankle clonus is in rare cases present to a slight extent. Alimentary System. — There is little or nothing to be noted here. The appetite is usually good, even in fairly advanced cases. The tongue is moist, flabby, and furred. Inspection of the abdomen seldom reveals any- thing. There is, as a rule, no enlargement of the liver and the spleen is rarely palpable. The bowels tend to be constipated and aperients are often required. When the patient is bed-ridden, unless care is taken, the colon becomes full of hard scybala. Circulatory System.— This is more important from a diagnostic point of view, as the heart and pulse tend to become affected early in the dis- 480 DISEASES CAUSED BY PROTOZOA ease. In regard to the heart no patient at any time made any complaint as to pain or palpitation. On examining tlie cardiac area the apex beat was found usually either very weak or imperceptible, but nothing else abnormal could, as a rule, be made out. On auscultation the heart sounds arc weak but regular, antl there is, in the great majority of cases, no bruit. The pulse is usually accelerated. It has a rate, as a rule, of from about ninety to one hundretl, with a low tension, a small size, easily compres- sible and regular rhythm. Respiraturtj System. — In all the cases of sleeping sickness examined by us in Uganda, the lungs presented nothing abnormal. The breathing is naturally somewhat increased in frequency when there is fever, and there is some congestion of the bases in the last few days of life. Pneu- monia seems to supervene more frequently in sleeping sickness cases than among the healthy. Dr. Cooke, Kampala, observes that the mortality among the natives from pneumonia has greatly risen since the occurrence of the sleeping sickness epidemic. Urinary System. — There is also, as a rule, nothing noteworthy to be found in this system. Cutaneous System. — Sometimes the skin is harsh and rough, and the papilhe prominent, especially over the legs and arms, but in the great majority of cases there is nothing abnormal. In one case we noticed an oedematous swelling over the shin, but, as a rule, swelling, puffiness and eruptions are conspicuous by their absence. Lymphatic System. — In every case the superficial lymphatic glands are slightly enlarged, varying, as a rule, from the size of a pea to a bean. The}^ are fairly soft and painless, but in a few cases in the last stages they become inflamed, tender, and break down. This is probably due to a terminal bacterial invasion and not to the trypanosomes. This poly- adenitis is considered to be one of the most characteristic signs of this disease and is only found among natives inhabiting the sleeping sickness area. It may then be accepted as the most marked symptom of the disease. Hcemopoietic System. — Antemia is not a feature of sleeping sickness; in uncomplicated cases no diminution of the number of the red blood corpuscles, or percentage of haemoglobin, takes place. Greig and Gray state that "toward the end in a certain proportion of cases the number of red cells, the percentage of haemoglobin and the specific gravity, rise. These cases did not present any signs of cyanosis." Low and Castellani, on the other hand, say that anaemia in varying amount is constant, the average number of the red blood corpuscles per cubic millimeter being 3,500,000 or thereabout, and that the haemoglobin is generally reduced proportionately. In regard to the leukocytes Greig and Gray state that a lymphocytosis occurs in all cases. They write that "enlargement of lymphatic glands being a constant feature in sleeping sickness, it is a matter of importance to determine whether the lymphocytes in the blood show an increase in numbers. This point is of interest, further, because the most constant lesion found in the nervous system of sleeping sickness cases is an accumu- lation of cells of this nature in the perivascular lymph spaces." Greig and Gray also made the interesting observation that all the cells found in the cerebrospinal fluid were lymphocytes and that they increased in TRYPANOSOMIASIS 481 number from 23 per Cc. in the early stage, to 730 per Ce. in the fully developed disease. The total number of leukocytes per Ccm. remains fairly normal, lying, as a rule, between 7,000 and 10,000, sometimes rising to 15,000 and 20,000. Greig and Gray's averages work out for the red blood corpuscles at 4,707,000, white blood corpuscles 11,000, eosinophiles 5 per cent., polynuclears 39 per cent., large mononuclears 12 per cent., and lymphocytes 38 per cent. Needless to say, among natives who all suffer more or less from helminthiasis there is often found a varying eosinophilia. The Temperature Curve. — There is nothing very marked about the temperature curve in human trypanosomiasis. In the early stage, when the trypanosomes are found in the blood and before symptoms of sleep- ing sickness appear, the temperature remains normal. The cases under observation in Entebbe remained without any rise of temperature for six or seven months, and it is impossible to say how long they harbored the parasite before coming under observation. When symptoms of sleeping sickness appear, the temperature, as a rule, becomes irregular, rising to 101° F. or 102° F. in the evening and sinking to normal or slightly below normal in the morning. But it must be admitted that cases occur with the temperature fairly normal throughout the disease, although there is always a certain irregularity. High temperatures may be said never to occur — 103° F. being a rare exception, and these are probably often due to an attack of malaria. There is one characteristic about the curve which is fairly constant : about a fortnight before death the tem- perature runs rapidly down 94°, 93°, and 92° F., and remains so until death. When the temperature becomes subnormal morning and evening, the patient will probably die within a fortnight. To recapitulate then, the few cases of human trypanosomiasis we have been able to follow, up to the present, show a normal temperature for six or seven months. During this time the trypanosomes are constantly found in the blood. Then the temperature becomes slightly irregular, the patient becomes heavier and duller in his demeanor, the trypanosomes begin to appear in the cerebrospinal fluid, and the stage of sleeping sickness may be said to be entered. The temperature remains irregular with two or three degrees of fever in the evening, until a fortnight before death when it becomes subnormal, running down to 93° and 92° F. Special Pathology. — There is little of special interest to be noted at the postmortem examination of an uncomplicated case of human trypanoso- miasis. The body is usually well nourished, but may be extremely erna- ciated. There are usually bed-sores present, or at least commencing bed-sores. The effect of the long chronic disease renders the heart muscle flabby and the Hver fatty. The lungs and kidneys present nothing abnormal, except the congestion incident to a failing circulation. In a malarious region, naturally, the spleen is usually somewhat enlarged, pigmented and tough. Of course, the patient may die of some inter- current malady, such as pneumonia, which is common enough, and the signs of the disease will be present. But it may be safely said that, except for the constant presence of general enlargement of the lymphatic glands, there is nothing in the naked-eye appearances to proclaim human trypano- somiasis. The lymphatic glands, both superficial and deep, are enlarged. The superficial usually vary in size from a pea to a large bean, and the 31 482 DISEASES CAUSED BY PROTOZOA deep run somewhat larger. Sometimes they increase very much in size, and on section are found to be caseous or to contain collections of pus. This is probably due to some terminal bacterial invasion and not to the trypanosomes. But A\hen one comes to examine the brain there is a divergence from the normal and a pathological picture which is fairly regular. On removing the calvarium, as a rule, a good deal of fluid es- capes. The dura mater is not adherent, and, usually, presents nothing abnormal. On reflecting it the convolutions on the surface of the brain are found to be flattened, and the sulci filled with opaque-looking sub- arachnoid fluid, giving a ground-glass ajipearance. The vessels on the surface are injected. On section the brain appears normal, but the lateral ventricles are dilated and contain an excess of fluid. This is all that can be seen on exposing the surface of the brain of an ordinary un- complicated case of sleeping sickness, but which, in my opinion, constitute an appearance fairly characteristic of sleeping sickness. A certain per- centage of the cases present much more acute signs of disease. These are the cases in which a terminal bacterial infection has taken place, and the brain may then present all the appearances of acute or purulent meningitis. Microscopic Examination of the Tissues. — It is to Mott we owe our knowledge of the pathological histology of sleeping sickness. He states that a definite characteristic appearance is found in sections of the brain, which is found in no other disease. He is able to pick out with certainty from a number of sections of brains of various nervous disorders, such as tabes and general paralysis, those cut from sleeping sickness cases. This is a condition of meningo-encephalomyelitis. Throughout the whole central system, but especially in the medulla, and at the base of the brain, Fig. 34. sections show the pia arachnoid to be infiltrated with mononuclear leuko- cytes; the inflammation can be traced along the bloodvessels and septa into the substance of the nervous system. The perivascular lymphatics around both large and small vessels are crowded with these lymphocytes. TRYPANOSOMIASIS 483 Fig. 34 is taken from his paper and shows this collection of lympho- cytes in the perivascular spaces. But this lymphocytic accumulation in the perivascular spaces of the brain and spinal cord is not restricted to the nervous system, but is found all over the body. We have seen that there is an increase of the lymphocytes in the blood and that the lymphatic glands are enlarged and show a proliferation of these cells. In sliort, throughout the body and especially in those tissues and organs rich in lymphatics, such as the intestine, this proliferation and accumulation can be seen. Human trypanosomiasis is essentially then a disease of the lymphatic system, and the irritation and proliferation of the lymphocytes is probably due to a toxin secreted by, or contained in, the bodies of the trypanosomes. The characteristic symptoms of the disease are no doubt due to the accumulation of these lymphocytes in the perivascular spaces of the brain, compressing the arteries and so interfering with the normal nutrition of the brain cells. The progressive weakness of the body, the tremulous condition of the muscles, the feeble rapid pulse, the weak voice, and uncertain gait, the rise of temperature, would all be accounted for by this obstruction or interference with the circulation, giving rise to degenerative changes in the nerve cells, and proliferation of the neuroglia. Terminal Bacterial Invasion. — Some writers are of the opinion that the bacteria, chiefly cocci, found frequently in the tissues of sleeping sickness cases after death, may be an important etiological factor in the disease. It is necessary then to say a few words on this subject. The Portuguese Commission described a diplo-streptococcus which they found in the cerebrospinal fluid after death, and during life by lumbar puncture. Castellani in 39 cases grew streptococci from the blood of the heart in 32 and from fluid taken from the lateral ventricles in 30. During life, he found his streptococcus very rarely and only in the last stages of the dis- ease. He examined the cerebrospinal fluid obtained by lumbar puncture in 28 patients ; in 5 he had positive results, but only when the examination was made a few hours before death, with the exception of 1 case in which he found it several days before death. Greig and Gray also made a number of observations by making cultures from the glands, blood, and cerebrospinal fluid. They say that "the result of these obser- vations showed that a number remained cases of pure trypanosoma infection to the end; the cultures made from the glands, blood, and cerebrospinal fluid remained sterile. On the other hand, in a propor- tion of cases, an invasion, chiefly by diplo-streptococcus, did occur but, by the results of the examination at different stages of the disease, it was possible to locate it to the final stage, when the patient was practically moribund. These cases at this stage of the disease have invariably numerous foci of suppuration on the hands and feet due to jiggers; also there is frequently before death a purulent discharge from the gums ; and their vitality and resisting power is a negative quantity." The writer's opinion of the role played by the diplo-streptococcus has always been that it is merely a terminal infection in the last days, when the patient is practically dead. At the same time it must sometimes hasten the end, and the cases of pneumonia, acute and purulent meningitis, which are often met with at autopsy of cases of sleeping sickness are due to bacterial inva- sions of the pneumococcus, the diplo-streptococcus, and other organisms. In nagana there is also frequently found a streptococcal terminal infection. 484 DISEASES CAUSED BY PROTOZOA The writer docs not believe that the di]:)lo-streptococciis plays any more important part, and it may be relegatetl to the lumber room to join the Filaria Perstans, Strongyloides, Ankylostoma, and the various bacteria wliich have been described at various times as the cause of sleeping sickness. Diagnosis. — From the description of the disease given above, it will be seen that it is no easy matter to diagnose human trypanosomiasis in the early stages. If a case were met with in America or England a history of the patient having lived in Africa in the endemic area within the last four to five years would give a clue: then, in all probability, at the time the patient sought medical advice the temperature would be found to be irregular, with an evening rise of one or two degrees; the pulse also would most likely be suspicious, being quicker than usual and with low tension. The examination of the blood Avould show a lymphocytic leukocytosis, which would help to exclude some other diseases; and, lastly, a drop of gland juice, removed by a hypodermic needle from a cervical gland, would show Trypanosoma Gnmhiense, and so definitely settle the diag- nosis. In more advanced cases the peculiar apathetic physiognomy, the pulse, the temperature curve, the tremors of the tongue and hands, the peculiar speech and weak shuffling gait, ought to form a picture which cannot be mistaken for any other disease. But the one unmistakable mark of the disease is the presence of the Trypanosoma Gambiense in the lymphatic glands, blood, or cerebrospinal fluid, and no medical man should rest content with a diagnosis which does not include the demon- stration of the parasite. Prognosis. — Every case of human trypanosomiasis which shows symp- toms of sleeping sickness dies sooner or later. It is an absolutely fatal disease. The question has arisen as to whether any of the natives with trypanosomes in their blood are able to kill the parasite off before organic changes in the tissues have been set up, and so establish an immunity. This question cannot yet be answered with certainty. Greig and Gray remark on this point, "In following the after history of cases of trypan o- soma fever we have arrived at these conclusions: (1) that many of them terminate fatally as sleeping sickness cases, which may be regarded as the usual mode of termination; (2) that a certain number die of intercur- rent affections; e.g., pneumonia; (3) that a certain proportion remain well for long periods, indicating that a tolerance toward the parasite has been obtained. It may be said that some of the cases may become in time sufficiently immune to destroy the parasite. The evidence collected so far suggests that this is the case." The writer agrees with Greig and Gray in everything except the last sentence but it is debatable as to whether the evidence does any such thing. It is of course, a very impor- tant point, but we must wait for more knowledge. Of the 5 cases of human trypanosomiasis in natives^ kept under observation since March, 1903, 2 have died of pneumonia, 1 shows undoubted symptoms of sleeping sickness, and the remaining 2 premonitory symptoms. Another case, a European brought under observation at the same time, came to me at the beginning of 1905 with swollen glands, trypanosomes in his blood, ^ Bruce and Nabarro, "Progress Report on Sleeping Sickness in Uganda," Royal Society, No. I. Report of the Sleeping Sickness Commission, 1903, Harrison & Sons, St. Martin's Lane, London. TRYPANOSOMIASIS 485 complaining of want of energy, and, in my opinion, in an early stage of sleeping sickness. He died afterward of undoubted sleeping sickness. Of the 23 healthy natives with trypanosomes in their l)lood in 1903, Greig reports at the end of 1904, that "it has been ascertained that since that date 3 have died of undoubted sleeping sickness; 1 ran away from his shamba and was reported to have died of sleeping sickness; 2 died from pneumonia (1 was almost certainly in an early stage of sleeping sickness) ; 5 are now in an early stage of sleeping sickness; no information has been obtained in 6 cases. The remainder, 6, do not as yet present definite signs of sleeping sickness." There is still time for these 6 to develop symp- toms. The incubation period may, as stated above, be three years or more. The evidence rather goes to show that all cases of human try- panosomiasis go on to sleeping sickness and death. Further knowledge is required before the question can be answered dogmatically. Treatment. — It may be stated at the outset, that up to the present, medi- cal treatment has failed to do more than prolong life. Arsenic has more influence on the trypanosome than any other drug. Horses, donkeys, and cattle suffering from nagana received 12 to 20 grains of arsenic daily. The result was, that in a few days, the parasite disappeared al- together from the blood, and remained out of it for a long time — from one to five or six months. In every case, however, sooner or later, the hsema- tozoa crept back into the blood, increased in numbers, and finally killed the animal. In no case was a cure effected. In the most successful case death was delayed for nearly a year. In human trypanosomiasis the same thing seems to occur. The writer has no experience of arsenic in human trypanosomiasis. Low and Castellani say that "iron, arsenic, and quinine, especially in cases complicated with malaria, produced a distinct but temporary improvement." Manson^ treated his case with arsenic in various forms, both by the mouth and hypodermically; also with methylene blue. The patient died after two years, of sleeping sick- ness. The Liverpool School of Tropical Medicine states that a "variety of drugs have been used with more or less success; up to the present arsenic and trypanroth, an aniline dye introduced by Ehrlich and Shiga, appear to be most useful; the parasite disappears for a time from the blood, and the life of the animal is prolonged, iDut with neither of the drugs is a cure obtained." Greig and Gray report several experiments with arsenic. They gave 10, 15 and 20 milligrams of arsenious acid daily. They write that "the effect of arsenic on the trypanosomes in the blood of patients in the early stage of the disease has been observed. The action is somewhat remarkable. The parasite disappears first from the periph- eral blood and, at a later date, from the lymphatic glands. After an interval of varying length the parasites will reappear in the blood temporarily and then again disappear, but have not so far returned to the glands. This reappearance of the trypanosomes in the blood and their final disappearance suggests that arsenic acts in two ways: (1) by ac- tually destroying the trypanosomes, and; (2) the trypanosomes so de- stroyed actively immunize the individual, the effect of this not being apparent till later." As none of these cases have been under observa- tion for more than five months it is, in the writer's opinion, too early to ^Manson, "Sleeping Sickness and Trypanosomiasis in a European," British Medical Journal, December 5, 1903. 486 DISEASES CAUSED BY PROTOZOA generalize; in nagana, it will be remembered, the parasite sooner or later reappeared in the blood and caused the death of the animal. Greig and Gray are also experimenting with trvjxxnroth. Concerning the latter drug Laveran and jNIesnil state that they liave had no success with it in the case of rats infected with Trypanosoma Gambicn.sr. In some of the trypano- some diseases, such as nagana and surra, every conceivable drug has been tried. All the sera have likewise been used. Toxins and cultures of liv- ing bacteria of many pathogenic organisms, as well as blood parasites, have also been found useless. In short, everything likely to effect a cure by interfering with the well-being of the trypanosome has been tried, but not a single case of recovery has occurred. At present, then, there is no reason- able hope of a curative agent being found, and preventive treatment seems equally unreachable. Laveran^ in a later note records the results of his observations on the action of arsenic and tryjianroth on the Tri/panosovia Gamhirnsc in rats and dogs. The method which Laveran adopts for the administration of the drugs is to inject the infected animal with arsenious acid and after an interval of forty-eight hours with trypanroth. He thinlvs that this treatment carried out three times at intervals of eight days is sufficient to cure the disease in rats. Two rats infected with Trypano- soma Gambiense on October 17, 1904, and treated in this way were, in his opinion, cured, the trypanosomes having been absent from the blood for ninety-one days. For dogs he considers that a dose of 1.5 mg. of arsenic per kilo should not be exceeded. For a dog of ten to twelve kilos, he recommends a dose of 14 to 16 milligrams and 30 to 40 centigrams of trypanroth. Plimmer tells us that his rats infected with the trypano- some of sleeping sickness lived for a year without showing any symptoms of disease and without the trypanosomes appearing in their blood. It is evident then that w^e must wait longer before any results of treatment can be accepted. That a substance could be found with the power of destroy- ing the Trypanosovia GaviJnense in the tissues of man is "a consummation devoutly to be hoped." Prof. P. Ehrlich is investigating the subject with a view to this and the members of the Sleeping Sickness Commission now in Uganda are testing these drugs on cases of human trypanosomiasis in the earliest stage. Some years must probably elapse before the result of these experiments can become known, but they will be looked forward to with great interest. Prophylaxis. — Since we have found that at present there is no cure for this disease, we must consider what means may be devised for its pre- vention. There are three factors to be considered; the human host, the parasite, and the tsetse-fly. If this were a disease affecting a species of the lower animals it is evident that the slaughter of all those with parasites in their blood would in all probability nip an epidemic in the bud. The neglect to take promptly this stamping out measure led to disaster in Mauritius and the Pliilippines, when surra was introduced into these islands. But we are dealing with man. We have seen that the disease only spreads by means of the tsetse-fly, and in its absence there can be no infection. Is it possible to destroy these flies ? They are found in great numbers all round the lake shore, where there is dense forest. There does not seem at present any means by wdiich such insects could be got * Comptes rendus des seances de I'Academie des Sciences, CXIV, p. 287, Stance du 30 Janvier, 1905. TRYPANOSOMIASIS 487 rid of. The dense jungle can hardly be entered except by the infrequent native paths. The vegetation is too green and damp to burn. It is possi- ble that, if the life-history of the fly were more fully known, some way of getting at it might be devised. At present the destruction of the carrier as a means of prevention must be reckoned impossible. If the Baganda were an intelligent, civilized race it might be possible to get them to migrate out of the sleeping sickness area, and this is what the intelligent among them do, but the great mass of them are half-naked, ignorant savages, who would rather die than desert their shambas. Again, if any big scheme of migration was attempted, it would be important that the dis- trict selected should be first carefully examined for any species of tsetse- fly. We have found that the trypanosomes can be carried by more than one species. It would, therefore, be dangerous to allow of any move- ment of natives from the sleeping sickness area into, let us say, the eastern parts of British East Africa, where more than one species of tsetse is found. But from what we have learned of the etiology of the disease the method of escaping from it is easy in the extreme. Just as no one would expose his horses or cattle to the danger of passing through a nagana "Fly belt," if he could possibly help it, so no one should expose himself to the danger of living in a sleeping sickness area. If it is neces- sary to have a settlement near the lake shore much can be done to render it habitable by cutting down the jungle in the vicinity and bringing the ground, if possible, under cultivation. CHAPTER XXII. AMGEBIC DYSENTERY. By RICHARD P. STRONG, M. D. Synon5nilS. — Amoebic colitis, amoebic enteritis, amoebiasis. Definition. — An infectious disease characterized by a variable mode of onset, a course of great irregularity, intestinal disturbances consisting chiefly of intermittent attacks of diarrhoea and constipation, abdominal pain, and the presence of amoebjie, and sometimes of mucus and blood in the dejecta. Besides man, in the tropics smaller monkeys and orang- outangs are attacked. Historical Note. — ^^Vhile dysentery probably existed in the earliest times, since in the most ancient writing upon medicine, the papyrus Ebers, references are made to it and even in the time of Hippocrates it was regarded as an independent malady, the suggestion of the existence and the first step toward the differentiation of a variety of amoebic origin may be said to date back not earlier than 1859, in which year Lambl called attention to the presence of rhizopoda in the intestinal mucus of a child who had died from enteritis. This was confirmed in 1875 by Losch, who found amoebae in the de- jecta during life and in the intestinal lesions at autopsy of a case of chronic dysentery. Losch gave a careful description of the parasite, which he named Amoeba coli, and was able by rectal injections of the faeces which contained living amoebae, to produce dysentery and ulcera- tions in the lower portion of the large intestine of a dog. Lewis and Cunningham, in 1870 and 1881, on the other hand, found these organisms in cholera stools, as well as in those of individuals suffering from other diseases, and even in the dejecta of healthy persons. They inclined to the belief that they bore no causal relation to intestinal disease. Grassi, Sonsino, Normand, Perroncito, Calandruccio, Blanchard, Koch, and others, likewise observed amoebae in the stools of those suffering with intestinal disturbances, but Grassi and Perroncito also ascribed no pathogenic properties to these parasites. Koch, however, demonstrated amoebae in sections of the intestine of those who had died of ulcerative dysentery. The question of the significance of amoebae in intestinal disease was uncertain until 1886, when Kartulis published the results of his investi- gations upon over 150 cases of Egyptian dysentery. Amoebae were found in the stools of every one of these. In 30 control patients suffering with other diseases he found no amoebae. Kartulis thoroughly convinced himself that this parasite was the cause of tropical dysentery and reported in his later papers his study of over 500 cases. He also in 1887 found the parasite in cases of dysenteric abscess of the liver. Halava in the same year, in Prague, found amoebae in 60 instances of partly endemic AMCEBIC DYSENTERY 489 and partly sporadic forms of the disease. He experimented upon animals, injecting faeces containing amoebtE into the rectum, and obtained positive results with both dogs and cats. In Baltimore in 1890, Osier discovered amoebae in the contents of a liver abscess and in the stools of a patient who was suffering with chronic dysentery, which he had contracted in Panama. Other cases in which amoebae were found in the stools were then reported in the United States by Musser, Stengel, and Dock. In 1891 Councilman and Lafleur pub- lished a complete study of 15 cases from Osier's wards. They de- scribed histological peculiarities by which this form of flux differs from other types, and concluded that amoebic dysentery should be regarded etiologically, clinically and anatomically as a distinct disease. It is to their important monograph that we owe much of our present knowledge. In 1894, Kruse and Pasquale by their extensive studies in Egypt did much towards confirming our belief in the existence of amoebic dysentery as a separate disease with a specific etiology; and Harris, in 1898, by his investigations also added important data in the differentiation of the malady in America. In 1900, the writer showed that the prevailing dysenteries of the Philippine Islands could be divided into two distinct forms, one of which owed its origin to a variety of amoeba (Amoeba dysen- teriae), and the other to a species of bacterium (Bacillus dysenterise). Leonard Rogers, in 1902 and 1903, increased our knowledge of the dis- ease as a separate infection in India, where its existence had previously been frequently denied, and showed clearly its association in that country with liver abscess. These investigations have convinced many of us of the existence of a separate form of dysentery of amoebic origin, and from them and from other experimental studies it seems that we are justified in regarding it as a distinct form of intestinal disease to be distinguished from other varieties of dysentery. However, there is still much objection to this, and it is opposed by a number of authors who have had a wide personal experience in tropical intestinal affections. Etiology. — Distribution and General Prevalence. — While the disease is widely prevalent and occurs sporadically in many subtropical and tem- perate countries, in tropical ones it finds its endemic home and is indeed the usual form of dysentery encountered. It is particularly prevalent in the Philippine Islands, India, and Egypt, and not uncommon in South America, particularly in Brazil, and in the Southern United States; sporadic cases are found from time to time in New England, and an occasional case is encountered in the Eastern, Central, and Western States. In the Eastern Hemisphere sporadic cases have occurred, par- ticularly in Russia, Germany, Austria, Italy, and Greece. In temperate climates the disease is rarely epidemic, but occasional outbreaks of moderate size have occurred, such as reported by Jager, in the German Army, in 1901, in East Prussia. Relative Incidence in the Philippine Islands. — In 1899-1900 an epidemic of bacillary dysentery occurred in the Philippine Islands, and in a series of 147 fatal cases of both this and of the amoebic form of the disease, 67 per cent, belonged to the latter variety. Of the dysentery cases in Manila during the past two years, over 80 per cent, have been amoebic. 490 DISEASES CAUSED BY PROTOZOA and nearly 90 per cent, of our fatal cases of dysentery have shown at necropsy lesions of this form. The disease is by far the most prevalent one in the Philippine Islands among white people. At the Government Civil Hospital in Manila the records kindly furnished by Dr. G. B. Cook, for the summer months of the year 190-1, show that over 30 per cent, of all the wliitc ])atients admitted had amoebic dysentery. Meteorological conditions have considerable influence upon the prev- alence of the disease. In the Philijipine Islands by far the greatest number of cases is recognized between June and September, the largest number appearing after the hea.vy rains have begun. During the year 1904, after the great flood in INIanila in July, the disease became almost epidemic, and the number of cases enormously increased. Harris states that the onset of the malady in the United States is almost invariably in the simimer months, ]\Iay, Juno, July, and August. Laflcur called attention to the fact that the disease is observed most frequently in dis- tricts approaching the sea-level, namely, the shores of the Chesapeake Bay, the Gulf of Mexico, and the Mississippi Valley. This is true also in the Philippine Islands, where near the sea coast and in the low lands the disease is very prevalent, while in the mountains, particularly in Benguet, Luzon, which has an altitude of over 4,000 feet and in which place many of the springs which funiish drinking water contain plentiful numbers of amnebne undistinguishable from those observed in the water- supply of INIanila, the disease, although occasionally encoimtered, is very rare. Sex. — All observers agree that the disease is much more prevalent in males. Harris states that it seems to occur in males about three times as frequently as in females. In Futcher's series of 119 cases at the Johns Hopkins Hospital, there were 108 males and 11 females. In the Philip- pine Islands the disease occurs also more frequently in males. In the Government Civil Hospital of 401 cases, the ratio of males to females is as 4.1 to 1. In 200 personal cases only 23 have been in females. Undoubtedly in the tropics men are more frequently exposed to infec- tion than women on account of their more active life. Age. — In Futcher's series the greatest number of cases occurred be- tween the ages of twenty-one and thirty years. Of the writer's, 149 among 200 were in the third and fourth decade; only 4 cases occurred in the second. The disease is common in children under ten years of age. Futcher calls attention to 11 such cases. Musgrave has encountered 21 with 1 death in a series of 100, and the writer met with 18. Harris reports 4 cases out of 35, and many other observers have also encountered the disease in young children. Race. — In the Philippine Islands the white race is much more sus- ceptible than the Malay. The natives, by reason of their mode of life and condition of their drinking water, are constantly exposed to infection, yet they do not suft'er nearly so often from it as Americans and Europeans, At the Government Civil Plospital the ratio of white to native patients has been as 2.5 to 1, while the ratio of amoebic dysentery in the two races has been as 9 to 1. Futcher and Harris found that in the United States blacks were somewhat less frequently attacked than whites. Unhygienic Influences. — Harris states that amoebic dysentery is an affection |)reemincntly of the poor, and is almost always associated with AMCEBIC DYSENTERY 491 filth, bad hygienic surroundings and lack of proper food. This, however, does not hold good in the tropics, and in the Phihppine Islands all classes are likely to be attacked who do not take continuous and extraordinary precautions in regard to their drinking water. Susceptibility, however, seems to depend considerably in some cases upon the general physical condition of the individual, although sometimes apparently perfectly healthy and robust persons are attacked. The Amoebss of the Human Intestine. — ^These organisms are classed under the rhizopoda of the protozoa. They are unicellular para- sites possessing an endosarc and ectosarc which can readily be distinguished when the organism is in motion. The endosarc is granular, and usually encloses several vacuoles of variable size. The ectosarc is clear and more hyaline in appearance. When seen in the faeces they frequently contain red blood corpuscles, the larger forms sometimes enclosing as many as twenty. Pigment granules and bacteria have also been observed in the endosarc. The parasite moves by means of pseudopodia; blunt processes con- sisting of the ectosarc are first protruded and into these protrusions the protoplasm of the endosarc appears to flow. The organism is capable of changing not only its shape but also its position and so moves about. It possesses a nucleus which may sometimes be observed in the living forms but which can be more clearly seen in colored preparations. It is usually placed eccentrically in the endosarc and contains a nucleolus. The most satisfactory stain for bringing out the structure of the parasite, in preparations from the stools, has been shown by Woolley to be Bor- rell's blue. In tissues the thionin stain is more satisfactory for differen- tiation, and for distinguishing the amoebae from mast cells. Musgrave recommends Wright's modification of Romanowski's method as most satisfactory for staining permanent preparations of the parasite from cultures, the technique employed being the same as recommended by Wright in staining blood films. The amoebae multiply by binary fission and by sporulation. The diameter of the organisms found in the human stools has been variously estimated at from 10 to 50/i. While they may vary greatly in size in different cases, in the same one they are usually of a fairly uniform diameter. Sometimes in stools that have remained standing for some time, the amoebae become encysted. They then appear to be surrounded by a coating of two layers, and it is sometimes almost im- possible to differentiate them morphologically from other substances. The outer layer of the cyst frequently presents a warty appearance. Biological Properties. — It is doubtful if amoebae have been grown artificially in pure culture free from bacteria, though numerous attempts have been made to accomplish this since the reported successful results of Kartulis in 1885. He used a straw decoction as a medium, and thought that he had obtained a pure growth of the parasites from an abscess of the liver which was free from bacteria. In 1895, Celli and Fiocca claimed to have obtained, after great difficulty, amoebae in pure cultures upon an alkaline media containing fucus crispus. However, the organism did not reproduce in transplants. In 1898, Tsujitani reported the pure devel- opment of encysted cultures of amoebae. He took old cultures of a favor- able symbiotic organism, heated them for an hour at 60° C, and then 492 DISEASES CAUSED BY PROTOZOA plated to see if all the organisms were dead. These dead cultures were then inoculated with encysted amcebfe and development occurred, though not so luxuriantly as with living bacteria. However, while the parasites have not been successfully cultivated free from microcirganisnis, single species have been grown with pure cultures of bacteria by numy workers. INIusgrave recommends for the cultivation of ama4)iTj with bacteria, a medium composed of agar 20 grams, sodium chloride and extract of beef each .3 to .5 grams, prei)ared as ordinary bacterial agar and with a final reaction of 1 per cent, alkaline to phenolphthalcin. The cultivation of amoebae from the stools, accord- ing to him, is frequently more difficult than of those found in water. It is necessary that the proper bacteria should be present in the culture in order to obtain a growth of the protozoa. He was unable to cultivate amccbie which contained red blood cells, as these seemed not to reproduce. Lesage recommends for cultivation ordinary gelatin that has been thor- oughly washed with distilled water, and then sterilized. Behavior Towards Physical Conditions and Chemical Substances. — AVhilc most observers have remarked that ama^biie usually lose their motility in the stools at or below 75° F., Musgrave and Clegg have not found this to be the case either in the stools or in cultures. Craig asserts that a freezing temperature kills amoebfe almost instantly. Tuttle goes so far as to say that the behavior of amoebjE found in dysentery differs greatly from that of those found in fresh water when exposed to heat or cold, and that it is this alone which positively distinguishes the two. The latter remain motile at high or low degrees, while the former are viable only at temperatures near that of the body. He states that a tem- perature of 70° F. is fatal to the motility and life of the dysenteric amcebfe. However, Kruse and Pasquale found by employing a dysenteric stool containing amoebse which had first been frozen and then subsequently thawed and injected into the rectum of a cat, that a typical dysentery followed and that at necropsy the mucosa of the large intestine was swollen and reddened and covered with mucus in which living amoebse were found. Harris found that these organisms were not killed in any reasonable length of time by lowering the temperature of the fluid in which they were contained to 0° C. Musgrave, moreover, has shown that extreme cold sometimes does not destroy this parasite. An encysted culture of an amoeba isolated from a dysenteric stool was placed in cold storage at - 12° C, for forty-five days ; at the end of this time a transplant gave a fresh growth of the amoebae. The same experiment was repeated with another strain of the organism isolated from a dysenteric stool and with one isolated from water, but with neither of these did any growth result. A temperature of 60° C. maintained for one hour usually suffices to kill encysted cultures, though considerable variation has been noted in the temperature necessary to destroy different strains. The action of various chemical substances upon amoebae has received attention for a long time. Harris found that amoebae (in the stools) were not seemingly affected by saturated solutions of quinine sulphate or boric acid, though 1 to 300 solution of quinine bisulphate invariably killed them within ten minutes. They were destroyed by weak solutions of hydrogen dioxide, potassium permanganate, toluidine blue, and dilute acids, Rogers found in scrapings from the walls of amoebic liver abscesses AMCEBIC DYSENTERY 493 that a solution of quinine, 1 to 1,000, failed to kill the parasite even after several hours. On the other hand, 1 to .500 solution stcjf)[jed all move- ment of the amoebfe in from five to fifteen miiiut(;s. In order to test if such a strength would be effective when applied to the living wall of an abscess, a piece of such tissue which was full of active amu;ba; was placed in a solution of 1 to 500 sulphate of quinine in normal salt solution, and scrapings examined every five minutes. In none of them were any living parasites found. In very thick walled abscesses, 1 to 100 solution of quinine was more satisfactory than 1 to 500. Tuttle found that 1 to 10,000 bichloride of mercury and 1 to 100 nitrate of silver solutions check the motility but do not destroy the parasite except after prolonged contact. Saline solutions and 5 per cent, of the 15-volume peroxide of hydrogen in water also did not seem to destroy the amcebEe at body temperature. However, in the hands of this observer all of these substances when used at a temperature below 70° F. proved fatal to the motility and life of the parasite. Musgrave and Clegg found that when a slant culture of amoebae with bacteria was treated with a 1 to 2,500 solution of quinine hydrochlorate, the parasites quickly encysted and in from five to eight minutes many had broken up and disappeared. Ten minutes later cultures were made but no development of amoebae occurred in the fresh inoculations, al- though the bacteria grew out well. In another experiment, performed in the same manner but with another amoeba, a slight growth was ob- served. Acetozone, 1 per cent, acid to phenolphthalein, in solutions of 1 to 5,000 and 1 to 2,000, always killed the amoeba in cultures. Thomas found that in cultures of amoebse in symbiosis with cholera spirilla, boric acid, eucalyptol, ichthyol, oil of cassia, and infusion of quassia, had slight if any effect on the amoebae. Tannic acid, 1 to 100, sulphate of copper, 1 to 2,000, permanganate of potassium, 1 to 4,000, and sul- phate of quinine, 1 to 1,000, had a distinct moderate effect on the growth of the parasite and spirilla within thirty minutes. Alphozone, 1 to 1,000, permanganate of potassium, 1 to 2,000, sulphate of quinine, 1 to 500, nitrate of silver, 1 to 2,000, argyrol, 1 to 500, and protargol, 1 to 500, exercised a very marked effect on the growth of the cultures within thirty minutes, and, with the silver salts and alphozone, the action was plainly due to the destruction or inhibition of the growth of the symbiotic cholera spirillum. Thymol, 1 to 2,500, applied for fifteen minutes had the most marked effect, in some instances destroying the amoebse, while exercising only a moderate effect on the cholera spirilla. In regard to special physiological processes of dysenteric amoebse, little is known. We are aware that certain definite secretions occur in the protoplasmic body, some of which evidently go to make up the mantle which forms about the parasite in encystation. It has been supposed by some that the engulfing of certain substances in the protoplasm — red blood corpuscles, bacteria, granular material, etc., — occurred for the purpose of nourishment. Some have thought that the pigment masses which amoebse sometimes contain are the remnants of partially digested red cells. This may be true, but no proteolytic enzymes have as yet been isolated, though Mouton has obtained a proteolytic ferment, resemb- ling trypsin, from cultures of an amoeba isolated from garden earth, and grown in symbiosis with Bacillus coli communis. 494 DISEASES CAUSED BY PliOTOZOA Distribution of Amoebae in the Body. — Besides the intestine and neighboring tissues, the iibdoniinal cavity, abscess of the Uver, lung, and pleura, anuvbie have been found hi the followhig pathological conditions: in aschic Huid in cases of abdominal tumor; in necrosis of the jaw-bone; in abscess of the mouth; and in disturbances of the bladder and urine. Celli and Fiocca reported their cultivation from the larynx and lungs in cases of tuberculosis, and Gross and Sternberg found them in tartar scraped from the teeth. Frequently when present in the bladder a sinus leading into the rectum (as has been true in several of our cases) is found, or one has previously existed, but this is not always the case. Classification. — Some observers have believed that more than one species of anueb;e occur at times in the intestine of man, and some have considered that not all are pathogenic but that some are harmless sapro- phytes. Kartulis, in reply to Grassi's communication, in which it was stated that amoebre had been found in the stools of healthy persons, asserted that these organisms were not of the same variety as those which he had found in dysenteric cases in Egypt. However, he did not definitely prove this assertion. Councilman and Lafleur, believing on account of the number of observers who had found amoebte in the stools of healthy persons that there might be more than one species encountered in the human hitestine, proposed the name amwha dijsenteriop for the pathogenic variety, and reserved the one of amoeba coli for the non-pathogenic organ- ism of the normal intestine. Quincke and Roos, in 1893, believed that they could distinguish three varieties of amoeba. (1) Amoeba coli Losch, or amoeba coli felis, which measured from 20 to 25« in diameter, possessed a finely granular plasma and a spherical nucleus, and contained blood corpuscles in the endosarc. Its cysts were spherical and presented a double contour. It was found in the stools of human amoebic enteritis, and upon injection into cats was pathogenic for these animals. (2) Amoeba coli mitis was somewhat larger than (1), (40/i); its protoplasm was coarsely granular and con- tained vacuoles. The nucleus did not have such a sharp contour and its motility was less. Included red blood corpuscles were never seen. This variety was also obtained from the stools in human intestinal disturbance but was found to be non-pathogenic for cats. (3) Amoeba intestini vulgaris was found in the stools of a healthy man. It was morphologically similar to the second and not pathogenic for cats; but since it was found in a healthy individual, the authors considered it a third species. Kruse and Pasquale, after numerous inoculation experiments per- formed on animals, distinguished two varieties of amoebae found in the human intestine. They adopted the name of amoeba dysenteric (Council- man and Lafleur) for the pathogenic variety, and amoeba coli for the harmless one occurring in the stools of healthy persons. The latter they observed in their own stools when no symptoms of disease were present. Celli and Fiocca have described six different varieties of amoebae found in the human stools. (1) Amoeba lobosa var. guttula measured from 2 to 4/z in diameter, the smallest forms from 1 to 2/i. It possessed a hyaline ectoplasm and blunt motile pseudopodia. (2) Amoeba lobosa var. oblonga was double the size of the former variety and contained one or two non-contracting vacuoles. Its pseudopodia were short and AMCEBIC DYSENTERY 495 compact and oblong in shape. (3) Amoeba spinosa (n. sp.). This variety was found in the healthy and dysenteric stf)ols of man and also in the intestine of guinea-pigs and frogs. It had little motility. It measured from 6 to 10/i in size. There was little ectoplasm and the entoplasm contained from 1 to 7 non-contracting vacuoles. Cystic forms were observed. (4) Amoeba diaphana (n.sp.) was also found in the dysenteric intestine. The ecto- and entoplasm was very difficult to dis- tinguish. It showed very active motility and measured from 0.5 to 2/x in diameter. (5) Amoeba vermicularis (Weisse) was found in the dysen- teric intestine, and also in the vagina of healthy women and of those suffering from carcinoma. It varied from 4 to Q/j. in length and was 1/i in breadth. No differentiation between ecto- and entoplasm could be made out and it contained no vacuoles. (6) Amoeba reticularis (n. sp.). The form of this species was very constantly oval; the pseudopodia were angular and their movements slow; the organism measured from 2 to 4fi in diameter. There was no visible nucleus. The protoplasm was hyaline and homogeneous. Celli and Fiocca regarded none of these species as the cause of dysentery. In the earlier work in Manila it was thought that at least two varieties of amoebae found in the human stools could be distinguished— amoeba dysenteriae and amoeba coli. This differentiation was based primarily upon the pathogenic action, as with one species found in the stools of dysenteric patients typical lesions could be produced in cats, and with another, from the fgeces of persons with apparently no intestinal disturb- ance, we did not succeed in obtaining any lesions. With still a third amoeba which developed in cultures of straw infusions, no pathological changes were produced upon injection into animals. Having observed these differences, other points of differentiation were sought for. The most striking of these was that in the dysenteric amoeba the distinction between endosarc and ectosarc could be readily made out, and that in the harmless one, the protoplasm of the ectosarc was not nearly so refractive. The nucleus of the former was eccentrically placed and could best be made out in stained preparations, while in the latter it was small and compact. The only other differences noted were that the amoebae found in the stools of apparently healthy individuals were never seen to contain red blood corpuscles, and they also seemed generally somewhat smaller than the dysenteric amoeba, since in a large number of measure- ments their diameter was usually less than 25/i, and in the dysenteric stools the amoeba sometimes measured as high as from 35 to 50/i in diameter. Shiga later described amoeba dysenteriae as from three to five times as large as amoeba coli. However, the size of the parasites cannot longer be regarded as an aid in the separation of the species, since a number of competent observers have reported very small amoebae as the only parasites present in undoubted amoebic dysentery. Moreover, the size of the organism may greatly change in cultivation and very small amoebae may become large. Further observations suggest that animal experiments are often misleading, as one frequently encoimters failures when undoubtedly employing the dysenteric species; and unless large series of inoculations are performed with each organism, the results are likely to be doubtful or misleading. Since pure cultures of amoebae can- not be obtained except in the contents of sterile liver abscesses in which 496 DISEASES CAUSED BY PROTOZOA other toxic material is probably present, many observers decline to accept the pathogenesis of an ama^ba as a point in differentiation. However, Sehaudinn^ has described additional details, particularly in encystation and reproduction, by which these organisms may be definitely separated. Schaudinn believed that und jr the name of amoeba coli, various authors have referred to .two entirely distinct organisms which differ so much in their manner of development and reproduction that they could even be placed in dift'erent genera. One of these forms lives commonly in the intestine of healthy man but can also exist in the dysenteric intestine with the second species. The latter he foimd only in cases of dysentery of tropical origin and with it he produced ulceration in the large intes- tine of cats by feeding the encysted forms. He points out that the harm- less amoeba is the one which has been carefully studied and described by Casagrandi and Barbagallo, who also demonstrated its non-pathogen- icity. From the description given by these authors, Schaudinn was able to recognize that he was encountering the same amoeba, and he has been able to confirm their work entirely. Yet he was unable to say, from the published descriptions, whether the species which Losch and other observers have described under the name amoeba coli was the same as that which Casagrandi and Barbagallo had studied. These latter authors named the form they encountered entamoeba hominis, believing that it was the same form which Losch had described. Schaudinn pointed out that since it was necessary to establish a new genus and their description was the first accurate one of the organism, the name of "entamoeba" should stand, but as they supposed they had the same form as Losch the name "coli" should be substituted for "hominis." Schaudinn infected himself on two occasions by ingesting the cysts of this harmless amoeba. In both cases the artificial infection was controlled by the examination of his stools for two months. Young cats were also infected for the purpose of the study of cyst formation. With reference to the structure of this harmless amoeba (entamoeba coli), he emphasizes that during rest the characteristic differentiation between ectoplasm and entoplasm does not exist and that it is only in the formation of pseudopodia that the hyaline appearance of the former is noted. The nucleus is vesicular, spherical, and provided with a thick, dense, nuclear membrane. The nucleolus consisting of plastin and chro- matin occupies its centre, while the remaining granular chromatin is distributed in the achromatin network. The multiplication takes place either by simple division or through spore formation (schizogony). In the former case the nucleus become contracted in the centre, assuming a dumb-bell shape, and parts amitotically. Then the entire cell divides after the separation of the daughter nuclei. In reproduction by schizog- ony the chromatic substance of the nucleus separates into eight parts, which after dissolution of the nuclear membrane become distributed in the protoplasm as daughter nuclei. The soft protoplasm then divides into eight young amoebse. Schaudinn recommended the half fluid stools as most favorable for the study of the encystation of this organism. He stated that there are few objects so favorable for nuclear study in the living cell as these cysts, ^ Arbeiten aus dem Kaiserlichen Gesundheitsamte, Bd. 19, 1903. AM(EBIC DYSENTERY 497 whose plasma is entirely clear of all foreign bodies, and, with proper artificial light, the nucleus appears as sharp and plain as in a stained preparation. Already in the resting state, if they do not contain many foreign bodies, the nucleus can always be clearly recognized. In encysta- tion the foreign bodies are cast out of the plasma, which becomes entirely clear and transparent, and the nucleus then can be even more clearly seen. Entamoeba histolytica (n. sp.); this was found by Schaudinn in the stools of those suffering with dysentery contracted in the tropics. It is different from the harmless form; the plainly developed ectoplasm is more strongly refractive and hyaline than in entamoeba coli. In the latter form the hyaline pseudopodial plasma in contrast to the remaining plasma is not well differentiated and is much less refractive than in ent- amoeba histolytica, in which there is always a plainly developed ecto- plasm existing as a plasma zone and possessing a stronger refraction than the entoplasm. Jiirgens had already called attention to the glassy hyaline appearance of the ectoplasm in the dysenteric amoeba, and this property, Schaudinn stated, is most important in the living amoeba and to it may be attributed special phenomena. The harmless entamoeba coli with their soft pseudopodia cannot enter into the healthy mucosa of the intestine but the dysenteric amoeba is able, by means of its stiff hyaline ectoplasm, to penetrate between the epithelial cells and to sep- arate them from one another. Schaudinn, in freshly cut sections of the intestine of infected cats, watched for an hour the process by which this protozoon separates the epithelial cells from one another. The nucleus of entamoeba histolytica is very difficult to recognize in fresh specimens. Its shape changes very easily and it often becomes stretched out. Its position is always eccentric. The parasite multiplies by division and budding. Under unfavorable conditions for the organ- ism, spores are formed. The usual method of reproduction is as follows : The nucleus expels some chromatin into the protoplasm and finally itself degenerates. In the encystation in vivo it is, under the eye of the observer, later expelled and cut off. Small spherical bodies possessing a diameter of from 3 to 1 p., and presumably containing some of the particles of chromatin, become formed in the cyst. The plasma then appears at the periphery protruded and bulged out and these buds are cut off finally in the form- of balls which show a concentrically arranged filamentous structure. They soon secrete an opaque membrane and all further process of development becomes invisible. The rest of the amoeba dies. The small round forms Schaudinn believed bring forth in the course of time a new infection, and this he showed by his experi- ments on animals. While he observed spore formation he never saw the eight nuclear cysts in the development of entamoeba histolytica. On one occasion when he did find these cysts in an infection with entamoeba histolytica he was able to prove later that a double infection with both amoebse existed. Craig points out that since Councilman and Lafleur accurately de- scribed the amoeba dysenterise, the name "histolytica" should be dropped and this species should be known as entamoeba dysenterise. However, Schaudinn was the first to call attention to the essential differences by which these two organisms might be separated from a zoological stand- 32 498 DISEASES CAUSED BY PROTOZOA point, for Lafleiir in his later paper stated that no definite morphological differences had been found between the ama^ba occurring in the stools of healthy persons and in patients suffering with dysentery. Lesage gives the same characteristic distinctions for entamoeba histolyt- ica that Schiiudinn had mentioned. Upon staining these amoebie in cultures by Laveran's method, the protoplasm colored itself lightly and uniformly except at one point near the periphery where it (the nucleus) stained more deeply. In the cysts the surrounding membrane did not stain and there was a clear space between it and the protoplasm. The latter during development was sometimes seen to be almost separated into three portions, each of which enclosed a lightly stained nucleus. Craig in his most recent work also confirms Schaudinn's observations. He says in addition that the ama'ba dysenterire is larger, and that when stained a diagnosis can be made by observing that the ectoplasm colors much more intensely than the entoplasm, w'hile in entamoeba coli the opposite is true. The latter form is not actively motile in the stools and a vacuole is seldom seen. Occurrence of Amoebae in Healthy Persons. — The presence of amoebre in the stools of apparently healthy individuals has inclined many authors to believe that all amoebjie are without etiological or pathological significance. Among the more striking of these observations in recent times may be mentioned: Schuberg, in 1893, found amoebje in the stools of 10 out of 20 healthy persons to whom a dose of Carlsbad salts had been given. Kruse and Pasquale, in 1894, when perfectly healthy, observed amoebse in their own fjeces and in those of 38 persons either healthy or suffering with diseases other than dysentery. Upon some of these, fresh autopsies were performed and the intestine carefully examined. In 1899, the writer examined with Musgrave in the Philippine Islands, persons who had no dysentery nor any history of the disease and found amoebae in the faeces in 4 per cent. A dose of Rochelle salts had been given by the mouth previously. Schaudinn recently found amoebae which he considered harmless in the stools of 34 of 68 healthy people in East Prussia, in one-fifth of the cases examined in Berlin, and in 256 out of 385 in Austria. Schaudinn twice infected himself with this amoeba and controlled his faeces before the infection for two months in order to be sure that his stools were free from these parasites. After infection he suffered from no intestinal disturbance. Craig in 1905, examined 200 patients not suffering wdth dysentery and found amoebae in 65. However, in other regions observers who have sought at random in the stools of healthy individuals for these parasites have failed to find them. Notable among these investigations may be mentioned those of Dock in the United States and of Zorn in Munich. There are periods in the course of amoebic dysentery, particularly in the earlier stages, in w^hich symptoms are entirely lacking. Hence when amoebae are found in the stools of healthy individuals we cannot say that they are not suffering wqth an early or latent form of the disease, or that the malady does not exist in its incubation period, unless we follow them over long periods of time in which no disease develops. The writer had opportunity, among private patients, to study some instances. One occurred in a chemist of our laboratory w^ho in August asked that an examination be made of his faeces, as he had a slight attack of diarrhoea AMCEBIC DYSENTERY 409 the day before. An unusually rich infection with amoebae was found and he promised to undergo the usual local treatment but next day as he felt perfectly well, the diarrhoea having entirely ceased, he remon- strated against beginning it. However, he did take enemata for about a week, but subsequently did not pursue any further treatment. His stools were many times examined and always infection with amnebse was demonstrated, the last being on December 10th. Two examinations made towards the end of January showed that the amoebae had dis- appeared. During the period from August to December he was without a single manifestation of disease. The stools were formed and appar- ently normal. He has been perfectly well since. It would appear that there are some individuals, apparently perfectly healthy, who harbor amoebae in large numbers for long periods without any unfavorable symptoms. It is not necessary to suppose that lesions are always present, although in some, lesions may exist which we cannot always be aware of during life; and the questions arise, are these instances of natural resistance or immunity against the parasite, or are they instances in which the parasites are unable to exert any harmful action until the proper symbiotic bacteria appear in the intestine and are only awaiting this moment to become pathogenic, or are they cases in which the organisms are still incapable of producing any injury until through some mechanical disturbance a small erosion in the mucosa occurs, or are they instances of infection with an amoeba harmless to man ? With our present knowledge some of these questions are very difficult to answer. Some incline to the belief that all amoebae are pathogenic and maintain that in every case in which infection is found, even though there be no symptoms, local treatment should be instituted and pursued until the amoebae disappear. Musgrave quotes his recent experiences in sup- port of this. He found in the examination of the stools of 300 prisoners in Manila that 101 were infected with amoebae; 61 of these in whom the parasites were found were suffering with dysentery, but the other 40 stated they had no diarrhoea. During the next two months 8 of the 40 cases died of intercurrent disease, and satisfactory evidence of amoebic in- fection was present in all. Three and a half months later all of the remaining 32 cases (with the exception of 2 discharged from the prison) had amoebae in their stools and were suffering with dysentery. How- ever, this does not disprove the existence of a harmless amoeba or the presence of such an organism in the intestines of his patients in con- nection with the dysenteric amoeba. Since Schaudinn has shown us that zoologically two distinct species of amoeba exist in human stools, it is necessary that careful studies be made of each of these species, that the cases in Avhich they are present singly and conjointly be separated and carefully observed. Natural immunity should be considered in this study. The writer has undertaken this differentiation in cases of amoebic infection, but is not prepared at this time to speak with cer- tainty as to the entire non-pathogenesis of the so-called entamoeba coli. Theoretically it would seem not unlikely that should erosions in the mucosa occur, the amoebae might, by their mechanical movements and wanderings and by carrying adherent intestinal bacteria with them into the broken epithelial layers, aid m continuing the existing lesions. There are, theoretically, from the description which Schaudinn has given, obAious 500 DISEASES CAUSED BY PROTOZOA reasons for sup])osing tliat entamcL^ba histolytica is the more harmful organism for man; but it seems that any classification into pathogenic and non-pathogenic amoebix; based alone upon the differences in the movements and character of the ectoplasm should be accepted with caution. Before coming to any more definite conclusion about the relative pathogenic'ty of entamoeba histolytica and entama^ba coli, a more careful investigation should be made of the secretory products of these jxxrasites and a search made for their enzymes, soluble and endo- toxins, etc. We know nothing yet of the relative virulence of amoebae or whether their pathogenesis under certain conditions may be increased by long periods of existence in the hmnan intestine. Occurrence of Amoebse in the Stools of Those Suffering with Other Diseases than Dysentery. — Another argument advanced against the etiological significance of amo-bre in dysentery, and brought forward as recently as 1902 by Duncan, is the fact that these organisms have been found in the intestines of those suffering with other diseases, such as chronic diarrhoea, cholera, intestinal tuberculosis, typhoid fever, hirmorrhoids, etc. In many of the reported cases the htT?morrhoids might probably be regarded as a complication, and the chronic diarrhoea as stages of pathogenic amoebic infection. But it should also be borne in mind that in some of these the entamoeba coli may have been the form of protozoon present. Lafleur mentions a case of malignant dis- ease of the stomach in which the light fluid movements contained many active amcebtie but no ulceration of the bowel existed, and Kruse and Pasquale found no lesion at autopsy in some of their patients in whom amoebae were present. In the tropics, where amoebic dysentery is so common and frequently a chronic disease of long standing, concomitant occurrence with typhoid fever, cholera, or tuberculosis, is not so very uncommon. In the writer's series of 100 fatal cases of amoebic dysentery in soldiers there were 4 cases of concomitant infection with typhoid fever, in 1 of which death occurred from a perforation in the ileum. The third case of cholera, at the begin- ning of the great Manila epidemic in 1902, was one of double infection with amoebic dysentery and this disease, and during the outbreak a number of others were found. The Non-occurrence of Amoebse in the Stools of Dysenteric Patients. — Many observers have advanced the argument that since amoebae are not found in the faeces or in the intestines of those suffering with tropical epidemic, or sporadic dysentery, these organisms are not the cause of the disease. Shiga in Japan, Flexner and the writer in the Philippines, and Leonard Rogers in India, have shown that tropical dysentery consists of at least two forms, one due to a species of anKcba and the other to a species of bacterium. These conclusions have been confirmed also for temperate climates by a number of observers in the United States and in Europe. In addition to these forms there is a third catarrhal dysen- tery, which is seen occasionally in the tropics and has a varied etiology. It is occasionally indistinguishable clinically from amoebic dysentery. Inoculation Experiments. — Several methods have been chiefly em- ployed. (1) The direct injection into the rectum of faeces containing the parasites. In this manner positive results have been obtained in cats and dogs. It is to be noted that in these experiments not all the AMCEBIC DYSENTERY 501 inoculated animals became infected, and that single experiments and those in which unsuitable material is employed are Ukely to fail. How- ever, there is no doubt that lesions may be produced in the large intestine in cats by this method, though there are often many difficulties. (2) By feeding encysted forms of amoebae. Casagrandi and Barbagallo, Caland- ruccio, and Schaudinn, fed themselves encysted amoebae, produced infec- tion and reobtained the amoebae from their stools. They had no symptoms of disease following the infection. They also infected cats by feeding encysted cultures of this parasite but obtained no symptoms of disease. Upon feeding the cysts of entamoeba histolytica to cats, Schaudinn ob- tained dysentery and ulceration of the large intestine in which were found numerous amoebse. Quincke and Roos fed stools containing encysted amoebse to two cats and obtained infection and amoebic ulceration, which they observed at autopsy. Musgrave fed encysted amoebse in cultures with bacteria to monkeys and obtained, in a small percentage of the cases, dysentery and ulcerations in which amoebse were found. The bacteria which were fed with the amoebse were not recovered from the stools, showing that it was not these microorganisms that had produced the disease. Against these experiments, in which bacteria together with the amoebse were employed, being used as an argument in favor of the pathogenesis of the parasites, objection was naturally urged. Therefore attempts were made to employ material in which amoebse were present without micro- organisms. Kartulis, and Kruse and Pasquale, used the contents of sterile liver abscesses and produced dysentery and ulcerations in the intestines of cats by rectal injections. They, however, stated that while the lesions in their most successful experiments bore in many points a striking resemblance to those seen in man, they were not identical. In 1899, the writer obtained dysentery and perfectly typical amoebic ulcera- tions in the large intestine of cats by the injection into the rectum of portions of the contents of a liver abscess which contained living amoebse but was otherwise sterile. These lesions were perfectly typical of the lesions seen in man. Many of the ulcers showed a distinct undermining of the mucosa and a round-cell infiltration of the submucosa with numerous amoebse at the base of the ulcers. Some of these specimens are now in the Army Medical Museum in Washington. These experiments are suggestive of the pathogenesis of this species of amoeba. It is possible that toxic substances may be introduced with the amoebse in the pus of these liver abscesses, and it might be argued that these cause erosions of the mucosa. However, a chemical substance alone could hardly produce the typical anatomical lesions of the disease which are so peculiar to amoebic infection alone and which no one has pro- duced without amoebse. Probably as much as could be expected has been gained from experiments on animals. Before leaving the subject it is interesting to note that both the lower monkeys and orang-outangs contract the disease naturally. At one time as many as four or five of our laboratory animals have suffered with naturally acquired infection. One of our imported orang-outangs recently died of a natural. infection of the disease. Source of Amogbse and Mode of Infection. — In Manila the greatest source of infection is the water-supply. Amoebse were frequently culti- 502 DISEASES CAUSED BY PROTOZOA vated from it in large numbers in 1902, but no attempt was made to demonstrate their patiiogenicity. In 1904, INIusgrave injeeted directly into the exposed civcum of a monkey, by a hypoilerniic syringe, an old culture of ixn amoeba growing with bacteria that had been isolated from the city water-supply. A month later violent diarrhaa developed, and amoebre, some of which enclosed red blood cells, were present in the stools. The animal was killed and small ulcerations were found in the large intestine. However, it must be stated that with cultures of this same amoeba he was unable in a few experiments to infect cats by rectal injection. From a practical standpoint it is demonstrated daily that it is very easy to live in jNIanila and avoid infection with amoeba^, provided one avoids infected drinking water. Those who never drink local water but use only the better imported bottled aerated waters are not attacked with amoebic dysentery. Open reservoirs and tanks containing drinking water may be polluted by the excreta of infected monkeys. Lettuce leaves contaminated with amoebas may be one source of infection. It is very probable that not all of the amoebne found in our water- supply are pathogenic, and it is also probable that those who ingest the pathogenic form do not all suffer with the disease amoebic dysentery. Dilute acids quickly kill the amoeba, and it is probable that many of those ingested are destroyed in the stomach. Natural and, in the natives, accjuired immunity from constant exposure to the disease may also exist, and probably in these cases the disease results only when the system is overwhelmed with very large numbers of the parasites or when it is weakened by other disease. Other Organisms Encountered in Amoebic Dysentery. — Other protozoal organisms common in the intestine in amoebic dysentery are the trichomonas, Cercomonas intestinalis, and Megastoma entericum. These, when present in this disease in very large numbers, probably by their rapid mechanical movements, act as an irritant . to the already inflamed mucosa. Other animal parasites which are found not infre- quently in the intestine of those who suffer with amoebic dysentery in the tropics are the Tpenia saginata, Ascaris lumbricoides, the Tricocephalus trichuris, Uncinaria duodenale, Strongyloides intestinalis, and Oxyuris vermicularis. In Egypt the ova of Bilharzia hasmatobia may be also present in the stools. When these parasites are present the cases may be regarded as a multiple infection. Schaudinn has stated that certain species of bacteria found in dysentery apparently exert a distinctly harm- ful influence upon entamoeba coli and monads which may be present in the intestine at the same time. This, however, is not true of Bacillus dysenterise and the dysenteric amoeba, since in some cases we find both of these parasites producing lesions side by side in the large intestine. Bacteriology. — Kruse and Pasquale investigated the organisms found in 14 cases of the disease and isolated streptococci. Staphylococcus pyogenes, typhoid-like bacilli, Bacillus pyocyaneus, and Bacillus clavatus. None of these was present so constantly or in such numbers as to suggest a specific relation to the disease. Of 6 cases in which pure cultures of Bacillus pyocyaneus. Bacillus clavatus, the streptococcus, or typhoid-like bacilli, were introduced into the rectum of cats, in 5 the results were negative; in the sixth, where the streptococcus was employed, there was AMCEBIC DYSENTERY 503 no dysentery, but a catarrh of the whole intestinal tract and a general septicaemia. In 26 fatal cases in plate cultures from the large intestine several varieties of the colon bacillus were the only organisms found constantly present. We were unable to produce dysentery or any lesions in cats by rectal injection of cultures of the varieties of the colon bacillus encoun- tered. In 7G fatal cases cultures were made from tlie solid organs. The bacteria encountered were streptococci and staphylococci, Diplococcus pneumoniae, colon bacilli, the typhoid bacillus, and Bacillus aerogenes capsulatus. The most striking fact demonstrated by these examinations was that 5 per cent, of the cases succumbed from a general terminal infection with the Staphylococcus and Streptococcus pyogenes. Pathology. — The Large Intestine. — The large intestine is chiefly involved. The most striking feature in chronic cases is the great thicken- ing of its walls. This may be confined to the submucosa or involve all the coats. It is always more marked in the submucosa and is due to a general oedema and localized areas of thickening. The other characteristic lesions consist chiefly of hemorrhagic catarrh, of raised hemispherical areas of infiltration protruding above the level of the surrounding mucosa, and of at least three forms of ulceration . Frequently a diphtheritic process is added to the amoebic one. The lesions may affect the whole large intestine or a portion only, as the csecum, the hepatic or sigmoid flexure or the rectum. Generally in fatal cases the large bowel is affected through- out. In some the intestine is riddled with ulcers; in others a moderate number is scattered through it. There appears to be no particular portion of the large intestine that is definitely predisposed to the infection. We may consider the lesions from the beginning of the pathological process. The amoebae insert themselves either between the cells of the normal mucosa, along the interglandular substance, or into small erosions which may exist in the intestine from other causes. They next generally work their way through the muscularis mucosae by the lymph channels and finally enter the submucosa. Here migration and reproduction take place and infiltration with round cells and oedema results. The mucosa becomes bulged out and small pin-head-sized dots appear on the interior of the bowel. Should a small capillary hemorrhage result in these areas, as frequently happens, the nourishment of the overlying epithelial cells becomes disturbed, and these, perhaps partly by digestion, become gradually disintegrated, softened, and cast off. The oedematous sub- mucosa is then exposed, which may appear yellowish from infiltration with round cells or yellowish red if the blood cells still remain in this area. Thus the earliest erosion is formed and becoming exposed to the faecal material and bacteria in the intestine, an increased number of cells accumulate, and if pus cocci are present more or less true suppura- tion occurs. The process is limited in extent by the surrounding tissue, which is well supplied with blood and hence red margins to the erosions or ulce- rations exist. The amoebae on the surface die or are cast off into the lumen of the intestine but others migrate deeper and laterally into the submucosa. Should no hemorrhage occur early beneath the small bulg- ings of the mucosa, the areas increase in size through the oedema and round-celled infiltration; hence the diameter of these erosions and small 504 DISEASES CAUSED BY PROTOZOA ulcerations when first seen depends upon how long the overlying mucosa remains intact before becoming necrotic, disintegrated, and cast off. They therefore generally vary in size from 2 or 3 mm. to about 2 cm. In some cases the nodular projections are intact and raised above the surface of the mucosa, and on incising tUeni they may be observed to contain a pale-yellow or grayish-yellow viscid material. The earliest lesions are obviously rarely seen at hunum autopsies, but may be studied in infected cats which have been killed a day or two after inoculation. In many of the ulcerations that have originated from nodules which reached 1 or 2 cm. or more in size before opening, we may see evidences of the primary nodular formation from the fact that the margins are raised and thickened and in many cases undermined. IMoreover some of the ulcers have a distinct crater-like appearance, with a small opening in the centre, which may be pin-head in size or so large as to freely expose the cavity. About the edges of many of these ulcers there exists a dark- purplish or reddish ring of congestion. The mucosa between the ulcers in early cases may appear perfectly normal, but in later ones a desquam- ative or hemorrhagic catarrh may be present. Whether this is due to certain soluble products of the amoebte acting upon the surface of the mucosa, or to their mechanical movements upon it, or to some other process, we do not know. The ulcerations increase in size, probably owing to the combined action of both amoebfe and bacteria. The floors and edges become softened, necrotic, and covered with a mucous exudate. In the earlier stages the ulcers are round or oval and placed with their long diameters transversely to the lumen of the intestine. Later they may become irregular in outline. The diameter of the large ones probably depends chiefly upon how laterally the amoebae have spread out in the submucosa, and their depth mainly upon the depth the amoebae have penetrated into it before the overlying mucosa was cast off. In the former case the shallow ulcerations of several centimeters in diameter with irregular margins are formed, whose edges are usually reddened and surrounded by apparently healthy mucosa and whose floors are usually necrotic and covered with a yellowish or greenish more or less muco- purulent exudate. From either of these two types of ulcer the more serious lesions usually develop, so that extensive surface ulcerations whose floors are formed usually of submucosa result, or deeper ones with smaller diameters whose bases consist of submucosa, muscular coat, or even peritoneum. It is in the ulcerations of moderate depth, owing to the burrowing of the amoebae in the submucosa beneath the mucosa, that the characteristic vmdermining of the borders of the ulcers results. This becomes particularly marked owing to the fact that the musculans mucosae is not infiltrated and destroyed to the same extent as the sub- mucosa and hence holds up the mucous membrane. In the more exten- sive ulcerations, necrosis and undermining of the muscular tissue also take place, whereby frequent sinuses are formed beneath the mucous membrane, and portions are dissected out and cast off into the lumen of the intestine as sloughs. A third form of ulceration sometimes seen is that in which the lesion extends only partially through the mucosa and results from a gradual disintegration of the epithelial cells and not by necrosis and sloughing of the underlying tissues. The bloodvessels of the mucosa are likely PLATE V Colon in Amoebic Dysentery. PLATE VI Colon in Amoebic Dysentery. AMCEBIC DYSENTERY 505 here to be more dilated and filled with blood. These ulcers may develop both laterally in the mucosa and in depth into the submucosa; but there is not in either case the characteristic undermining that is observed in ulcerations of the other type, though the round-celled infiltration in the vicinity is frequently even more extensive. When these surface ulcers extend only into the mucous membrane, amoebae are rarely found in them, but are sometimes encountered at their margins lying in or between the glands. It seems probable that this form of necrosis and ulceration is a direct extension into the mucosa of the process which begins as a hemorrhagic catarrh. It may be due to the 'action of soluble toxic pro- ducts of the amcebse aided later by the intestinal bacteria. A somewhat similar process is observed in the liver, which consists of an extensive necrosis of areas of liver tissue which contain no amoebae and which are situated in the vicinity of the abscess. Complete breaking down and softening seems to occur only when the amoebee actually come in contact with the cells, and this may be due to the action of an intracellular toxin. The amoebae wandering in the submucosa and carrying with them adherent bacteria cause continuous disturbance. The parasites them- selves seem to be responsible chiefly for the oedema and round-celled infiltration, and softening and breaking down of the tissues. The bac- teria cause additional leukocytic infiltration and necrosis. The action of the latter is manifested chiefly in the more superficial ulcerations where the amoebae may be scanty upon the surface. The parasites in addition cause early infiltration with round cells of the walls of the capillaries and veins, which condition is followed by softening and complete dis- organization of these structures. It is in this way that much blood appears in the stools. The amoebae may even penetrate the walls of the veins, and are frequently found inside these vessels, some of which they may have entered directly or been carried from the capillaries through the lumen of the vessel. In this way the veins may become thrombosed. The arteries in the neighborhood of the ulcer also frequently show thrombi, and in the chronic process evidences of endarteritis are found. The slow inflammatory process in the submucosa consisting of oedema, infiltration, and finally of proliferation of the fixed connective tissue cells, leads to great thickening in the bowel wall and hypertrophy of the vessels. In certain cases the tissues seem little able to resist the infection, and large gangrenous ulcers result whose walls are soft and whose bases are formed of blackish or greenish sloughing tissue in which numerous cocci, bacilli, and sometimes amoebae, are found. These changes are certainly not produced entirely by amoebae, but are probably due chiefly to the bacteria which are present. Another process which is sometimes seen in cases of this disease is the diphtheritic one. It is also certainly partially if not entirely caused by the action of bacteria. When Bacillus dysenteriae is present the origin of the pseudomembrane is easily ex- plained. Obviously the ulcerations in different cases and even in the same case may vary greatly in appearance in the active stage, according to the extent and manner of progression of the lesions, but they can usually be classified under one of the types which have been described. The process of healing may best be studied in patients who have been under treatment for some time with the intestinal disturbance and pro- 506 DISEASES CAUSED BY PROTOZOA grossing favorably but death has resiUtcd suddenly from some compli- cation. The ulcers may then be found with bases which are distinctly depressed and have a grayish or grayish-yellow color. Their margins, however, are raised above the bases, and are clear cut but are not usually swollen above the surroinuling mucosa. AVhen well advanced toward healing they are no longer softened. The surfaces of the ulcers are bathed in a serous fluid or covered with mucus. Healing takes place by the formation of fibrous connective tissue in the floors and by a gradual covering over with cpitheliiun. If the lesions have been extensive old pigmented scars result. Peritonitis. — As has been pointed out, the amoebtie may wander freely through the submucosa and into the circular muscular coat, Avhere they are frequently found along the intermuscular septa and between the muscle fibers, which they have evidently separated. The fibers them- selves become swollen, granular, indistinct, and may appear without nuclei. They finally become infiltrated, break up, and disappear. The parasites also destroy the bloodvessels in this layer; the blood-supply is then cut off and more extensive sloughs are formed. They may next push along the intermuscular septa through the longitudinal muscle and produce the same changes. Should they approach the serosa similar changes to those seen in the submucosa take place in the subperitoneal coat. In case many bacteria, particularly the pus cocci, now ihd their way into the tissue, deep sloughing gangrenous lesions are formed and per- foration with general peritonitis frequently occurs. In other cases when few bacteria are present this may take place from violent peristalsis after adhesions are formed. However, in the latter instance, particularly when the floor of the ulcer is composed of muscular tissue and does not extend completely down to the serosa, the peritoneal coat, owing to the action of the amoebae, becomes greatly thickened, not only from the cedema and infiltration but by the formation of considerable fibrin. This also occurs on the peritoneal surface, and so the intestine later becomes adherent to loops of the small bowel or to the omentum or ab- dominal wall and the adhesions so commonly found at autopsy in the chronic cases are formed. Occasionally general peritonitis will occur with no visible perforation, the amcebre having penetrated the muscular coat and serosa and set up an inflammatory exudate which consists of an opaque gelatinous fibrinous fluid in which the amoebpe may be found. It will be noted that one of the most striking points in the pathology of the infection is the absence of the usual products of purulent inflam- mation. Polymorphonuclear leukocytes are found in relatively small numbers in the tissues, and are never aggregated together in large groups unless many bacteria are present. Microscopic study shows that the submucosa is very cedematous. Its interstices are widened and the lymph channels engorged. The fixed connective tissue cells are swollen, stain poorly, and often show fatty degeneration. In places where extensive necrosis has resulted the elastic tissue fibers remain last and stain well. In these areas much amorphous granular material is present and the cells lose their nuclei and stain poorly. In addition there may be a general liquefaction of the tissues. Extensive round-cell infiltration exists in the submucosa where but few ■lK::ii^iiH ^^H fil ^BIpy...M^ rfP ..■ ^-m- ■ ■r ^^^^^rrl II II w III — m H^Hl^yL'^ ^IHHHIIi^l H^^B^V ^'-Xj ^^l^jf^SjBwfl HiSaP^Hflifl H^B^H 'JvRll^lfl^HR^^HHHll^^^^^H^HS^^^^^I ^■4 p^H9H||^^^H| ^m 9^BI»H^l^^i^^^^^^l Wl'.ij^li I^HH^^^MI ^^ >' ^Ml ^^^^^m|BBH|^ ^s^h^H ^^^HKj^|^nHH|^^fl^^BH^^B^HHn|^ "^'^«' '^^aH^^l ^^^w^^Hi°«^MRiiH^^^^^^^Bi^^^^^^^^li^H99BHHB^i v'^ '^^Si^^k^9^^^| AM(EBIC DYSENTERY 507 polymorphonuclear leukocytes are usually seen. Plasma cells are present at times in considerable numbers, and eosinophiles are in some cases also fairly numerous. At the margins of the ulcers many of the epithelial cells show parenchymatous or mucoid degeneration. The mast cells are usually diminished in these areas. One may also observe that the ulcerations do not as a rule begin in the follicles, but these may become secondarily affected. The amoebre arc found in large numbers in the lymph spaces, in which case the endothelial cells in the neighborhood are prohferated and there is sometimes a fibrinous exudate inside the vessel. The parasites are also present in the ulcers, being most numerous in the submucosa along their bases and sides, in the zone of oedema and round-cell infiltration which borders the necrotic portion of the lesion. Bacteria are always most numerous in the upper necrotic layers of the ulcer, and when the pus cocci are present purulent inflammation fre- quently results. In these areas amoebae are seldom found. Bacteria are also found, usually in small numbers, with the amoebae in the deeper lesions. Small Intestine. — Involvement of the lower end of the ileum some- times follows from an extension of the process upward from the caecum. The mucosa just above the valve is frequently hyperaemic and occasion- ally hemorrhagic. In only one of the writer's autopsy series did it show amoebic ulceration, though several other cases complicated with typhoid fever showed typhoid ulceration of the Peyers' patches. Lymphatic Glands. — The mesocolic glands are frequently swollen, particularly where the lesions are extensive and extend deeply into the muscular coats. They may occasionally be hyperaemic or oedematous but are very rarely hemorrhagic, and in this respect offer a strong con- trast to the condition of the lymphatics in bacillary dysentery. Micro- scopic examination shows that the lymph sinuses are more or less dilated, and there may be some proliferation of the connective tissue cells and a few plasma cells present. In rare cases necrosis may take place and bacteria may be present. The bloodvessels are usually normal. The small round cells are frequently increased in number. The Kidneys. — ^The chronic cases sometimes show evidence of par- enchymatous nephritis, which is rarely of extreme grade. The cells of the tubules are more or less granular and stain poorly, and albumin is sometimes found in the glomerular spaces. Occasionally the cells of the convoluted tubules and the glomerular epithelium are fatty, and in places desquamated. The s-pleen and the lieart muscle are usually normal, and the lungs show no special changes peculiar to the disease except abscess of the right lower lobe, which, together with the lesions of the liver, will be discussed under the subject of hepatopulmonic abscess. Musgrave has recently seen two cases of general infection with amoebae. Sjnnptoms. — General Characteristics, Clinical Forms, Mode of On- set, Course, Duration and Termination. — The symptoms may vary so widely that in order to discuss the subject intelligently the cases may be grouped for convenience under the following divisions: (a) Mild cases and those of moderate intensity, (h) Cases with acute onset, (c) Ad- vanced and chronic forms. This division is purely an arbitrary one since no sharp lines of dis- tinction can be drawn and the cases may pass from one to the other. 508 DISEASES CAUSED BY PROTOZOA Moreover instances may occur which can be better considered partially under more than one of these divisions. While individual cases may vary widely there are some features which are very common in at least the majority. These are the irregular course, marked by periods of intermission and exacerbation, the appearance of mucus in the stools, and the tendency to chronieity. A phenomenon that is peculiar to the malady is the frequent occurrence of the amrpbic liver abscess. (a) Mild Cases and Those of Moderate Intensity. — Usually the pa- tients are not able to tell exactly when they began to realize that they were not in good health. There may be complaint of some lassitude, of becoming easily tired, or of continuous slight headache; more or less indefinite abdominal discomfort and dyspepsia may be present. Slight intestinal disturbances consisting of moderate diarrhoea or of constipation may appear. Such symptoms may occur singly or in various combina- tions. These represent patients who, frecjuently in the tropics among the well-to-do people, consult the physicians for such minor ailments as have been mentioned and generally have no idea of the real trouble. Such vague symptoms may continue for months, and one may doubt whether they are all dependent upon the intestinal infection. Occasion- ally the abdominal pains become severer, or there may be an outbreak of diarrhoea which causes the physician to examine the stools, when amoebffi, sometimes mucus and even red blood cells, are found. A great many of these infections remain undiscovered for a long time. Such have been described under the name of latent or masked forms of the disease. Robust men may have the disease for a month or two without being aware that they are suffering from a serious malady. Indeed some may go to autopsy with advanced intestinal lesions in whom the symptoms have not been sufficiently prominent to attract attention. They may never advance beyond this latent stage; either under some simple treat- ment by the mouth, or even without treatment, the patient may overcome the infection and the parasites disappear from the stools. In by far the greater number, however, some of the symptoms sooner or later increase in severity, and in the event of recovery not taking place they may pass gradually into either those of moderate intensity or those with acute onset. The two symptoms most likely to attract attention are diarrhoea and abdominal pain. In those patients who are constipated the latter may be the first symptom; or indigestion and gradual loss of weight may be equally prominent. Palpation of the abdomen sometimes reveals tenderness, but this is by no means constant. As the lesions in the large bowel increase, the symptoms of intestinal disturbance usually become more marked, abdominal soreness appears, and the stools become more frequent and contain mucus and even blood. If they are properly treated the disease does not usually progress to the chronic stage, and this particularly is why the name "dysentery" is not an entirely apt one for the malady and why "amoebic colitis" would perhaps answer better. Musgrave has proposed the term Amcebiasis to cover all grades of the infection. Even if treatment is not instituted a small proportion of this group may entirely recover, frequently after several recrudescences of more or less active diarrhoea; but the majority pass gradually to the chronic form, or occasionally acute symptoms develop. Sometimes the abdom- AMCEBIC DYSENTERY 509 inal manifestations may be so insignificant as entirely to escape notice, or the appearance of a liver abscess first attracts attention. (6) Cases with Acute Onset. — Obviously it is not correct to consider all of these as acute cases. Some are really acute almost from the begin- ning, but others may have existed for some time as latent, mild, or moderately severe infections. The symptoms are frequently not in accord with the lesions; ulcerations may exist and become well marked before there is a sudden outbreak of the diarrhoea. Very abrupt onset may occur from the formation throughout the large intestine, but par- ticularly in its lower portion, of very numerous small and superficial ulcerations, or from secondary infection with streptococci or Bacillus dysenteriee. Cases with diphtheritic or gangrenous lesions may be classified clinically under this division, and in the latter instance portions of sloughing tissue may be passed in the stools. At the onset there may be from 15 to 50 or more bloody mucous movements in twenty-four hours. Colicky pains in the abdomen with tenesmus develop; fever, nausea, and vomiting may appear; great exhaustion sets in; the heart action becomes feeble and either death results, or the condition tem- porarily improves and gradually assumes the chronic form. It is in this form that wild delirium may develop before death. (c) Advanced and Chronic Cases. — In the advanced stages of the dis- ease the symptoms become well developed. The movements become more frequent and usually contain much mucus and frequently blood. Their number may vary from 2 or 3 in the morning to 10 or 15 or more during the day. There is aching in the back, and at times sudden and intense desire to defecate. As the disease becomes chronic, loss of weight is progressive, and finally marked emaciation may result. The patient becomes anaemic and the muscles soft; the tongue is pale and moist at first, later slightly furred, or sometimes heavily coated. There is more or less anorexia; indigestion and flatulence are common. The pulse and respirations may be slightly increased. The temperature is normal or subnormal in the morning and slightly elevated in the after- noon. As the malady progresses the anaemia becomes more marked, the skin dry and dull yellow in color, and the face drawn. The emacia- tion in some cases becomes very extreme; the abdomen becomes sunken, bed-sores may appear, and death follows from exhaustion or terminal infections. Another type of the chronic form is that in which there is nothing more than an intermittent diarrhoea often alternating with con- stipation, and accompanied, usually, by slow but gradual loss of flesh. These patients sometimes remain in this condition for several years. Occasionally the parasites disappear and the more serious lesions heal, but the bowel never assumes again its normal condition. Where the destruction of tissue has been extreme, cicatrices form and a chronic catarrh always exists. The course of amoebic dysentery is very variable and is not self-limited. The grave cases with acute onset may terminate fatally within a week or ten days in spite of all treatment. The mild and moderately severe ones may continue for many months before alarming symptoms appear. The occurrence of complications may terminate the infection in death or completely alter its course. If proper treatment is instituted many of the mild and moderately severe cases recover entirely, and the para- 510 DISEASES CAUSED BY PROTOZOA sites disappear in a month or six weeks Some of the chronic ones are completely restored to health in from three to six months. Occasionally amoeba? persist after all symptoms antl sometimes the lesions themselves have disappeared. Complete recovery is sometimes donbtful owing to the fact that after many weeks of a{)parent cure patients may develop more acute symptoms; sometimes these represent fresh infection, but usually they are merely evidences of the outbreak of the original disease. Cases of this nature, unless treatment is pursued until complete recovery results, are apt to sutler with so-called relapses every few weeks or months until some grave com})lication develops and carries them off. Patients who do not recover under continuous local treatment for six or eight months are likely either to die within a year or linger on as incurable. Rarely does an attack end in spontaneous recovery after the dysentery has existed for a year. Death may occur from the gravity of the intestinal lesions, from ex- haustion in protracted cases, from severe complications, from a terminal infection, from intercurrent diseases, or from severe intestinal hemor- rhage. The severity of the intestinal lesions and abscess of the liver are the most frequent causes of death. Analysis of the Symptoms. — Gastro-intestinal. — Of these, diarrhoea is the most important, usually being intermittent in character, coming on abruptly, and subsiding in like manner. Between the attacks the stools may become formed. The intermissions of the diarrhoea may last several weeks or even months, or this symptom may be absent through- out the entire course of the infection. The character of the diarrhoea usually depends, first, upon the ulceration, whereby increased peri- stalsis results, probably owing to the nerves being eroded and exposed; second, upon the impaired power of absorption of water by the intestine, due in part to the marked oedema. Ulcers of the intestine can exist without any diarrhoea, as is particularly likely when they are superficial and in the ceecum or the adjacent portion of the ascending colon. When the ulcers are very numerous throughout the intestine, or well developed in the descending colon and rectum, diarrhoea is practically always present. In mild cases the movements may not exceed 3 or 4 in twenty- four hours, but in the gangrenous and diphtheritic forms the diarrhoea becomes excessive and the movements sometimes number 50 or more in this time. In fatal cases before death they may diminish to 2 or 3. This has been explained as due to the gradual loss of expulsive power caused by the destruction of the muscular coat and nerves situated in the ulcer- ated areas, and the general oedema of the bowel wall. The Fseces. — The stools vary greatly in different stages of the infection and in different cases. Valuable information may be obtained from them of the condition of the lesions in the intestine and of the progress of the disease. At times they are liquid, at times pultaceous, and again well formed. In color they may be brownish, greenish, reddish, grayish or variegated. In those cases with gradual onset they are likely at first to be merely more or less watery and of normal color. As the lesions develop, mucus begins to appear. In the cases with marked intestinal catarrh and extensive ulceration it is always more abundant. The mucus may be finely di\nded, shreddy and mixed throughout the stool, or it may appear in large masses. The latter condition is particularly likely to AMCEBIC DYSENTERY 511 exist when the faeces are well formed, when small portions of blood- stained mucus may be observed over the surface of different portions of the stool. At times the movements may consist almost entirely of viscid masses of blood-stained mucus. Blood may be present so that the color of the whole mass is modified, or as clotted masses in portions of the stool, or mixed with mucus. It is sometimes in such small amounts as to be apparent only upon micro- scopic examination; or the stool may consist entirely of blood mixed with mucus. It is probable that the amount of blood is partially depend- ent upon the rapidity with which the lesions are forming as well as upon their position and extent. The presence of considerable blood in the stool makes the diagnosis of ulceration very probable; but we cannot conclude in its absence that ulcerations do not exist. When the ulcer- ations are high up in the csecum the blood is apt to be altered and brownish or even blackish in color. Pus cells are found chiefly after ulceration is well developed and in the diphtheritic form of the disease. In the chronic cases it is not unusual to find large numbers of polymorphonuclear leukocytes. These are to be distinguished from the small round cells so abundant where a well- developed catarrhal condition exists and where epithelial cells are also numerous. When pus is found in considerable amount it is an almost certain indication of extensive ulceration. The pus is frequently found only in small amounts. Shreds of Tissue. — As ulceration advances and becomes more chronic the amount of blood grows less; the stools become more copious and again more watery ; fragments of tissue are frequently seen in the early stages of the chronic cases. In advanced and particularly in gangrenous cases large sloughs and sometimes complete moulds of the intestine are cast off. These are of a grayish or brownish color and have a very offensive odor. The reaction of the stools is generally alkaline, sometimes neutral, and occasionally acid. In instances of recovery the mucus is the last abnormal elem^ent to disappear from the faeces. It usually persists for a long period and in many cases where chronic catarrh remains it never disappears. Microscopic examination reveals the amoebae in addition to those elements which have been described. These may be very plentiful or scarce, the number depending upon several factors. If there are only a few ulcers in the large intestine the mucus and faeces that have come in contact with these lesions are likely to contain the parasites in the largest number, and they will probably be scanty elsewhere. If the stool is liquid the organisms will be more or less evenly diffused throughout. The gravity of the lesion is not always indicated by the number of amoebae found. With very advanced lesions where the parasites are burrowing deep in the submucosa there may not be as many as in more acute con- ditions. In some instances blood can only be recognized microscopically. Numerous epithelial cells, small round cells, pus cells, eosinophiles, and a fair number of Charcot-Leyden crystals, are also frequently found. The bacteria are usually increased in number beyond those seen in normal stools. Abdominal Pain. — ^This is very variable and occurs more acutely in the gangrenous cases and where perforation is imminent. It may be 512 DISEASES CAUSED BY PROTOZOA colicky in character and very severe; localized over a particular ulcer, or exist over the abdomen generally. In chronic cases a tlull aching pain with occasional sharp exacerbations may be present. When this is con- stant, limited to a fixed point, and increased by external pressure, it is suggestive of the site of ulceration, though the most extensive ulceration may exist without any pain whatever. Pain which is produced only by external palpation and pressure suggests areas of circumscribed peri- tonitis. Very excessive {niin on pressure is usually present when the serosa itself is involved. If widespread or extensive ulcerations are present, pain on pressure may be elicited along the whole course of the large intestine. Cramp-like and aching pains frequently occur before and after evacuation of the bowel. A feeling of abdominal heaviness is not an uncommon symptom and is frequently accompanied by disten- sion and flatulence. Tenesmus is not nearly so marked or frequent a symptom in uncomplicated amoebic dysentery as in the bacillary form. It is most evident in the grave cases and in the gangrenous and diphtheritic forms, where the sigmoid flexure and rectum are involved. In the remain- ing cases it depends chiefly upon the extent of the ulceration in the rectum. A burning sensation in the anus after defecation is frequently present. Nausea and vomiting of severe grade are somewhat rare symptoms. They may occur early in the cases with acute onset. In moderate form they are most commonly encountered in the chronic ones. Nausea sometimes develops in all classes of cases as a result of the large and high intestinal enemas administered for treatment. Loss of appetite is a common symptom and is almost absolute in the acute cases. In the moderately severe ones it may not be apparent, but it becomes very evident again in the chronic cases. Hiccough is seen in the grave forms shortly before death and when the peritoneum is involved. The tongue shows nothing that is characteristic. In instances of very long standing it is likely to become fissured and to show small hemorrhages and erosions along its sides and tip. Anaemia of a secondary type is present in all the cases of long standing and is progressive with the disease. It is dependent chiefly upon the loss of blood from the intestinal lesions and the gastro-intestinal disturb- ances. It is possible that it may be in part of toxic origin due to absorp- tion. The reduction in haemoglobin is usually greater than that of the number of the red cells ; the hsemoglobin varies generally from 50 to 80 per cent. Futcher's average for the red cells in 38 cases was 4,802,000. In the tropics, in the advanced and chronic cases, the red blood cells some- times are not over 2,500,000. There is frequently a slight leukocytosis, and if a marked one exists it is the polymorphonuclear cells which are increased. The eosinophiles are not increased in cases uncomplicated with other intestinal parasites. Skin. — The skin is normal in the mild and moderately severe cases. In the chronic ones it becomes dry and sometimes glazed, and assumes a sallow, dirty yellow appearance when the mucous membranes show distinct pallor. Fever. — The temperature is likely to be elevated in the cases with acute onset; it is generally higher in the diphtheritic form, and par- ticularly when complicated witla Bacillus dysenterise. In the mild and moderately severe types there is usually little or no fever. In the chronic AMCEBIC DYSENTERY 513 ones the temperature is frequently subnormal for a portion of the day with afternoon rises to 100° to 102° F. At other times it may be subnor- mal or normal for a period of a week or more. In cases where there are many streptococci in the stools and advanced lesions of the intestine, it may become septic with daily rises to 103° to 104° F. Fever becomes an important symptom in perforation and in abscess of the liver and lung, when it is sometimes accompanied by rigors and sweating. The pulse and respiration are apt to be increased if fever is present. The pulse is frequently rapid in the grave cases with acute onset, and may become thready and rise to 120 to 140 or more. Usually in cases of moderate severity it is not over 100, and in the mild and chronic cases- it may be normal. The respirations are increased particularly in abscess of the liver and lung. Urine. — Moderate albuminuria accompanied with a few hyaline casts is occasionally seen in chronic cases. The urine is then usually some- what reduced in amount. Harris noted that in the severe forms the chlorides are often diminished and that in the most severe instances they may be entirely absent. Retention sometimes occurs when acute symp- toms of dysentery are present. Complications.— Abscess of the Liver. — This is the most frequent and one of the most serious complications. In 119 cases reported by Futcher it occurred in 22 per cent.; in a series of 100 cases examined at autopsy by Musgrave and the writer in 23 per cent.; in 74 by Craig, 33 per cent.; in 57 by Kruse and Pasquale, 11 per cent.; in 95 by Harris, 15 per cent. It is much more common in males than in females. Futcher reports 3 cases in the latter sex. The writer has not seen a case in a woman in the Philippine Islands, and but 1 in a native of these islands. However, Major E. C. Carter states that he has seen 1 case in a woman here and 3 cases in Filipinos. Rogers has shown that it is not uncom- mon in the natives of India. Harris and others state that this complication always arises during the acute period but observations show that it may develop at any time, and certainly not uncommonly after all symptoms of dysentery have ceased, or indeed, sometimes before any intestinal ones have developed. One patient here first showed symptoms of abscess of the liver after five months local treatment for amoebic dysentery. Futcher's statistics show that it may appear at other times than in the very acute stage. However, in the majority the abscess became evident in the first month after the onset of the dysentery. The most common seat of the abscess is in the upper and posterior portion of the right lobe. Out of 639 cases of abscess in amoebic dysentery collected by Rouis, 70.8 per cent, were situated in the right lobe and 13.3 per cent, in the left lobe. There may be single or multiple large abscesses or very numerous small ones scattered throughout. In Futcher's series out of 18 cases, 10 were single. In the writer's series, 13 were single and 10 multiple. In Craig's, 9 were single and 15 multiple; and in Rogers's, 21 single and 11 multiple. The number of abscesses is obviously an important factor from a surgical standpoint. For a long time alcohol has been believed to predispose to liver abscess and play an important part in its etiology. In 12 cases among private patients, 8 were alcoholics. In these islands at least, malaria is generally 33 514 DISEASES CAUSED BY PROTOZOA not a predisposing factor. Kartulis has reported 6 cases of liver abscess with amoebic appendicitis. In 3 the intestinal lesions were most marked in the crecnm and appendix. In 1 the appendix was most extensively diseased while in the c;vcum only 3 small ulcers existed. He snggcsts that the portal of entry of infection may sometimes be through lesions in the appendix. The amoebcx; are supposed to reach the liver by two paths. The more common is certainly through the portal vein. Amoeba are frequently found in the veins of the submucosa and in the portal capillaries. The other method of transmission is through the peritoneal cavity. Council- man and Lafleur, and Rogers all sup[)ort this theory and think that infec- tion occurs in many cases in this manner. The parasites are supposed to migrate through the intestinal wall and then invade the liver from its surface. Lafleur has cited an instance with peritonitis present in which amoebje were found over the peritoneal surface of the intestines and liver. This would certainly seem to be one mode of infection. In one of the writer's cases an amoebic abscess occurred beneath the right rectus muscle, the infection apparently having entered through the parietal peri- toneum. In another the abscess was less than a centimeter in diameter, solitary, and occurred just beneath the surface of the right lobe of the liver. Bacteriology. — In addition to amoebae the abscesses are usually infected with bacteria. In 27 cases reported by Futcher and examined bacterio- logically, 15 contained bacteria; of the writer's 23 cases bacteria were found in 13, and in 37 of Rogers's they were present in 16. In the larger abscesses the bacteria may have died out, but a proportion of even the earlier abscesses seem to be entirely sterile. The organisms most fre- quently found are the Staphylococcus and the Streptococcus pyogenes and the colon bacillus; the Micrococcus lanceolatus and the Bacillus pyocyaneus have occasionally been reported. It is obvious why bac- terial infection occurs so frequently, as these organisms have the same opportunity for entering the liver as the amoebre and frequently adhere to them. Undoubtedly the pus cocci exert an injurious influence upon the he]:)atic tissue, but there can be little doubt that the amoebae play a most important part in the formation of the abscess. This is demon- strated by the very different character of the amoebic and the pure bac- terial variety. The contents of the former vary somewhat. In the smaller abscesses they consist of thick, glairy, yellowish masses of mucus which are not fluid. In the large abscesses the contents are more liquid, frequently like thick gruel, and yellowish, grayish-red, brownish-red, or at times greenish in color. Frequently shreds of necrotic liver tissue are mixed with the fluid portions. INIicroscopically one is struck usually with the absence or presence in small numbers only, of polymorphonuclear leukocytes. The contents consist mainly of fine or more coarsely granular material containing fragments of cells, many swollen and fatty degen- erated liver cells, red blood corpuscles, fat globules, and amoebae. The latter are sometimes difficult to find in the pus, but can almost invariably be obtained in scrapings made from the abscess wall, though sometimes repeated examinations are necessary to detect them. Special Patholor/ij. — The liver may be of normal size, but is frequently enlarged. The tissue often shows advanced fatty degeneration or chronic PLATE VIII FIG. 1 Large Single Amoebic Liver Abscess. FIG. 2 Hepatopulmonary Amoebic Abscess AMCEBIC DYSENTERY 515 passive congestion, or, sometimes, it is acutely congested. There are areas of localized peritonitis where the abscesses reach the surface of the liver, and the overlying tissues may then be bound by adhesions to it. The size of the abscesses may vary from several millimeters in diameter to that of a man's head. In one of the writer's cases a single abscess occupied the entire right lobe, only a shell of liver tissue remain- ing. The liver and abscess weighed 3,700 grams. Very frequently several abscesses about the size of an orange are encountered. A some- what rarer condition is that in which very numerous small abscesses are scattered throughout both lobes of the liver. "When the contents are evacuated the walls of the small ones generally show a sharp contour. Those of the larger ones have an uneven and ragged necrotic appearance. The liver tissue along the margin of the abscess is softened and infiltrated. The older abscesses usually have walls composed of a dense layer of fibrous connective tissue. A microscopic study of the periphery of the small abscesses shows that the interlobular areas are always the first to become disintegrated, and to this is due the irregular contour, the periportal areas persisting until detached by the interlobular necrotic processes. The edge of the abscess consists of a necrotic area of liver cells where the amoebse, together with leukocytes, blood corpuscles, and fibrin filaments, are frequently found. The capillaries are dilated, filled with blood, and frequently contain the parasites. The latter show no indication of attempting to penetrate beyond the necrotic zone. Outside this layer is a zone in which great activity of the connective tissue cells is observed and in which the liver cells are frequently compressed and atrophied; mononuclear small cells are usually abundant. Finally this layer is usually surrounded by a zone of more marked hypersemia where small hemorrhages are frequently found. In these latter areas thrombi may occur in the branches of the portal veins, where amcebse and bac- teria may both be found. Councilman and Lafleur, in addition to the abscess formation, have also described a widespread necrosis of the cells situated round the central veins of the lobules and scattered throughout the liver. They suggest that this is due to soluble chemical products of the amoebse. A striking point also observed in the hepatic lesions is the absence of leukocytic infiltration, which usually accompanies suppu- ration of bacterial origin. (Plate VIII, Fig. 1.) Diagnosis and Symptoms. — Liver abscess is frequently overlooked, and this is not strange, for sometimes its development takes place so insidiously that perforation may be the first indication. If the onset is more acute the diagnosis is simplified. Pain is very common at some time. It is commonly dull and aching but may become sharp and lan- cinating. Its situation varies greatly, being almost as frequent in the vicinity of the right scapula and shoulder as over the liver itself. In the former case the pain is, according to Futcher, reflex through the phrenic nerve which receives large branches from the fourth cervical. The pain may occur over the hypochondrium or epigastrium. When not present spontaneously it may be elicited upon pressure over the liver. However, pain is not constant, and is frequently absent. Fever is usually present at some time, but is often not sufficient to attract attention. Occasionally it is continuous and not over 100° to 102° F. In other cases it is remittent; or it may be septic in type and intermittent and rise in the evening tQ 516 DISEASES CAUSED BY PROTOZOA 104° F. Chills and sweats may then occur, and the symptoms simulate those of malaria. Lafleur calls attention to sweating as an important symptom, and states that it is independent of the temperature. The pulse may be Uttle increased, but in the cases Avith high fever it may be 1-10 or more Blood. — niere is usually a leukocytosis from 15,000 to 40,000 in which the polymorphonuclear cells are increased. However the leukocyte count may be normal. The conjunctiva? are sometimes slightly tinged with yellow, but marked jaundice is rare. Persistent vomiting may occur. The skin frequently assumes a sallow color; and the face may become pale and yellow. The facies may suggest the diagnosis. In certain cases emaciation occurs rapidly; in others the flesh is well retained. The appetite usually dis- appears and the tongue becomes coated. Physical examination may show enlargement of the liver which may even cause bulging on the right side; pain may be elicited on pressure. Occasionally a swelling may be observed over the sixth and seventh ribs. Percussion and auscultation frequently give no information of the condition. If the abscess is large, percussion may reveal an increase in hepatic dulness. A friction rub may be heard over the liver when the peritoneum is involved. In the diagnosis of liver abscess there is not a single symptom that is constant, and proof that the liver is involved may be very doubtful. The general condition and appearance of the patient, with the progress of the case, rather than any single symptom, often suggest the diagnosis, which may sometimes be confirmed by aspiration. Spontaneous rupture of amoebic abscess frequently occurs if the patient lives long enough and is not operated upon. This is most often into the lower lobe of the right lung. Rupture into the abdominal cavity causing general peritonitis is also frequent. The abscess may perforate into the pleura, pericardium, stomach, colon, small intestine, bladder, vena cava, kidney, and through the skin in the lumbar or right hypochondriac region. Kartulis has reported brain abscess in 3 per cent, of his liver abscess cases. Amoebpe were found in the vicinity of the necrotic areas. Jiirgens had 2 cases of thrombosis of the femoral vein, in 1 of which amputation of the leg was necessary. Abscess of the spleen may occur. Abscess of the Lung. — Preceding this, the respirations are usually increased in number and are often painful and shallow. Before perfora- tion occurs the physical signs of pleurisy are usually present. Cough and expectoration then appear, and are generally constant. The cough in the early stage is hacking and accompanied by pain over the liver. AVhen the abscess discharges into the pleui'al cavity or into a bronchus, the dyspnoea becomes less marked. Sooner or later the characteristic anchovy-sauce-like sputum appears, in w^hich can be found amoebte with red blood corpuscles, leukocytes, altered liver cells, alveolar epithelium, elastic tissue fibers, Charcot-Leyden, tyrosin and hsematoidin crystals, and various bacteria. Small cheesy particles consisting of granular material and oil drops are also encountered. (Plate VIII, Fig. 2.) Special Pathology. — In abscess of the lung the diaphragm is adherent to the liver and usually to the base of the lung. If the latter is not the case, a layer of pus separates the lung from the diaphragm. Abscesses AMCEBIC DYSENTERY 517 are never metastatic, and the lower right lobe is always the one affected. The diaphragm may or may not be visibly perforated. On opening the lung abscess it may be found filled with viscid yellowish-gray or yellowish- red partially fluid material; or, if perforation into a bronchus or the pleural cavity has occurred, it may be empty. The walls of the abscess are frequently more uneven than those of the liver abscess; in places, however, they may be smooth and formed of dense connective tissue. Sections of the older abscesses show usually three zones; first a necrotic one containing fragmented nuclei, degenerated cells, and amcebse; second, a layer composed of connective tissue fibers, epithelial cells, elastic fibers, sometimes distinct groups of air cells, and occasionally amoebae; and third, a layer of small round-cell infiltration in which fibrin and some proliferation of the connective tissue fibers is also visible between the air cells. The walls of the bronchi are thickened and infiltrated with numerous round cells. The bronchi contain either purulent or serous fluid. Hepatopulmonary abscess is a somewhat rare condition. Harris reports it 3 times in 95 patients, and Futcher 9 times out of 119 with 3 cases in which the liver abscess ruptured into the pleural cavity. In the writer's series of 100 fatal cases, hepatopulmonary abscess occurred but once with 2 cases of empyema. Perforation of the liver abscess into the lung does not always occur. The extension may result through the diaphragm without visible perforation. When rupture into a bronchus takes place, the condition may last from six to eight weeks and terminate in death or recovery, or persist for a year. The mortality is usually very high. Peritonitis. — A local peritonitis may result from extension of the ulceration in the bowel or from an abscess in the liver. Patches of fibrous adhesions are of very frequent occurrence; in chronic cases it is the rule to find old localized areas of chronic adhesive peritonitis. These are very difficult to diagnose during life. They may cause abdominal sore- ness and pain. Peritonitis, which generally proves fatal, may follow perforation of a liver abscess or an intestinal ulcer. Perforation. — Perforation of the intestine results generally from the giving way of the base of a deep sloughing ulcer and is most frequent in the grave and gangrenous cases. The opening is usually a large one. The perforation occurs frequently in the csecum, and the condition has sometimes been mistaken for one in which the appendix is involved. Perforation of the large bowel with general peritonitis occurred in 19 of the writer's 100 autopsies. In 2 other cases it occurred after the ulcer was thoroughly walled off from the peritoneal cavity. In Futcher's series, perforation occurred only in 3 and in Craig's in 4 cases. In the writer's series of 200 clinical cases it occurred but 3 times. It is almost invariably fatal. In one of the Johns Hopkins series the patient was operated upon three hours after the perforation occurred, but died. Death may occur in a few hours from shock, or later from the resulting acute general peritonitis. Perforation sometimes happens after adhesions have formed, when a pericsecal or pericolic abscess may result. It may take place retroperitoneally into the psoas muscle and may even open externally. Appendicitis. — ^This complication occurred in 7 of my ICO fatal cases. In one a chronic appendicitis existed in connection with a pericsecal SIS DISEASES CAUSED BY PROTOZOA amoebic abscess In 4 of the G, death resuhcd from general peri- tonitis following perforation of the caecum or colon. All showed extensive general intestinal lesions and the involvement of the appendix merely followed extension from the caecum. A definite diagnosis of the appen- dicular affection during life is very difficult since the caecum in addition is usually extensively diseased. The process is not very acute as a rule. It consists of the formation of ulcerations in the walls of the appendix. In only one of the Avritcr's cases was the appendix perforated at its tip. Intestinal Hemorrhage. — Intestinal hemorrhage in which large amounts of pure blood are passed from the rectum is a rare complication. Councilman and Lafleur report but 1 case in which 125 Cc. of blood were passed. Death was apparently due to the bleeding. In 1902, the writer called attention to severe intestinal hemorrhage as a fatal complication and reported 2 cases in both of which liver abscess was present and in which death was due to severe multi})le hemorrhages. It was suggested that these large hemorrhages might perhaps bear some relation to the con- dition of the liver. Shortly afterward Haasler reported from China 3 more instances of intestinal hemorrhages, in 2 of which death took place from bleeding. In both of these cases liver abscess also existed. Since this time the writer has seen 2 more fatal cases from multiple hemorrhages, both with liver abscess, and therefore a connection between intestinal hemorrhage and the hepatic condition is suggested. While it is probable that fatal intestinal hemorrhage in amoebic dysentery may occur independ- ently of liver abscess, the cases mentioned suggest that when hemor- rhage occurs in patients with liver abscess it is likely to be very severe, and the bleeding is likely to recur. Futcher reports intestinal hemor- rhage in 3 of his series. Why is severe intestinal hemorrhage not more frequent in amoebic dysentery? One should consider the following points: the thrombosed condition of the bloodvessels in the zone of in- filtration and the oedema which surrounds the ulcers, the infiltration of the walls of the arteries and the more or less marked evidence of endar- teritis as the progress is rapid or slow. In chronic cases one may see at times the arteries entirely occluded by this process. The frequent occurrence of small amounts of blood in the stools may be explained from the fact that the walls of the veins are early infiltrated with round cells, followed by softening and complete disorganization, also from the fact that amoebae may penetrate the walls of a vein. How- ever, thrombosis of the veins is not infrequent. Sequelae, — In old chronic cases with extensive ulceration large cica- trices frec^uently form. When a long-continued catarrhal condition has been present a general atrophy of the mucosa may take place. In these instances we sometimes find a clinical condition closely resembling sprue or psilosis. The small intestine, owing to the inanition, ansemia, etc., may also become secondarily involved and its mucosa atrophied. The stools then are copious, liquid (at least never formed), pale in color, and usually frothy. The chronic gastric catarrh and enteritis, wdiich fre- quently develop wath a sore and fissvired tongue and often an inflamed oesophagus, complete the picture. This condition was observed in 3 very chronic patients who finally overcame the amoebic infection. Diagnosis. — This is not difficult by microscopic examination; but there are other forms of dysentery which clinically it may be impossible AMCEBIC DYSENTERY 519 to distinguish from the amoebic variety, and any one who attempts to make a diagnosis from the cUnical manifestations alone will make fre- quent mistakes. The occurrence of amoebic liver abscess always con- firms the diagnosis, but sometimes the.symptoms to which it gives rise are the first ones to attract attention to the intestinal disease. The examina- tion of the stools should be made as soon as possible after they are passed, and the specimens should be collected free from urine. Many observers recommend in cold climates that a warm bedpan be used and that the microscopic slide be gently warmed. This is not necessary in tropical countries. These precautions are necessary because the amoeba; frequently die in stools that have stood for any length of time or that contain urine, and their motility is often quickly impaired by cold. The amoebai must be found Hving and motile. In this condition they are easily recognized and cannot be mistaken for other bodies. After movement ceases and death or encystment results, it is frequently impossible to distinguish them from other substances. It is necessary to emphasize that the amoebae must be motile, for upon the presence of such forms depends the diag- nosis of the disease. Usually the examination of several specimens from one stool reveals the parasite, but sometimes the study of several upon different occasions is necessary. If bloody mucus or small pieces of necrotic tissue are present, these should be examined first, for if they come from the neighborhood of an ulcer they usually contain very large numbers of amoebae. If the movements are not liquid a dose of Rochelle salts should be given and the fluid portion of the stool examined. Another very convenient method of securing material for examination is by the passage of the rectal tube. When the stools are fluid considerable amounts may be obtained, or small portions of mucus will be found in the lumen of the tube. Since Schaudinn insisted upon the harmlessness of entamoeba coli for man it is important to distinguish between this and entamoeba histo- lytica. For differentiation Lesage has recommended the addition of a dilute watery solution of iodine to the fluid stools. This brings about in a few minutes encystation by which the amoebae may be distinguished from one another. However until we know more about entamoeba coli, in any instance in which symptoms of intestinal disturbance exist and amoebae are found, the diagnosis of amoebic coKtis had best be made and the proper treatment instituted; for, m an intestine with erosions, probably the entamoeba coli may cause additional disturbance from its mechanical movements, even if it is not capable of producing any othei pathological efl^ect. If, however, one chooses to attempt the separation of the two forms by their pathogenic action, extensive animal experi- ments, preferably upon cats, must be performed with the parasites found in the stools. Infection with other disease may co-exist, and in cases with acute onset it will be important and advisable to make plate cultivations of the bacteria from the stool and search for Bacillus dysen- teriae, as well as test the agglutinative and bactericidal reaction of the patient's blood serum with this organism. The diagnosis of liver abscess should be made only after a careful consideration of all the existing symptoms. The general condition of the patient and his faeces together with the progress should be taken into account. The blood should be examined to exclude malaria and for a 520 DISEASES CAUSED BY PROTOZOA leukocytosis, but it must be remembered that the leukocyte count may occasionally be almost normal. If no intestinal disturbance exists, an additional clue may be obtained from the history or by finding the amoe- ba^ in the stools. An absolute diagnosis can frequently only be made by the finding of ama>ba^ in the abscess. This may sometimes be done by asjiiration before spontaneous evacuation or operation. This should be done with a needle having a sufficiently larg? caliber to transmit the thick pus. The puncture may be made through the skin, the point of entrance being over the suspected area; but the surgeon must be at hand to operate if necessary. The method may fail and if unsuccessful should be repeated. ^Vhen pus is obtained it may contain no amoebie, but the absence of large nund)ers of leukocytes and the presence of much granular material will suggest that the origin is ama'bic. The diagnosis of amoebic he])atoi)ulmonary abscess may be definitely made when the patient suddenly begins to expectorate quantities of reddish brown anchovy-sauce-like sputum containing liver cells, haema- toidin crystals, and amcebre. The latter are always present, though sometimes a prolonged and repeated search is necessary to find them. Prognosis. — There is no doubt of the gravity of the disease and when well advanced before proper treatment is instituted the final outlook is often doubtful. The sym})toms in the majority of cases yield to treat- ment in a short time and the patient may feel quite well. It is in this con- dition (when he falls into the hands of those not thoroughly familiar with the malady) that he is frequently discharged only to return sooner or later with a recurrence. This may happen a number of times, and among this class of patients the mortality is always high. In untreated patients who are exposed to hardships, the death-rate is very great. Out of 78 collected cases (Harris) in the United States there were 30 deaths. In the Johns Hopkins series of 119, 28 terminated fatally; however in both of these series it seems probable that many were well advanced before treatment was instituted, since patients in America do not as a rule enter hospitals in the earlier stages of the disease vmless the symptoms are severe. One might expect a somewhat different outcome if treatment were instituted early. In the writer's series of 200 treated cases, which included all stages of the disease and from which accurate data were obtained, there have been 12 deaths and 4 are chronic invalids; the remainder have recovered. Tuttle has recently reported 73 cases in the United States with 70 recov- eries. In children the prognosis is almost always good. Amberg and INIusgrave each rejiort 1 death. Adding together these cases we have 44 cases in children with 2 deaths, a mortality of 4.5 per cent. In the un- complicated cases, those with acute onset, including the gangrenous form, usually have the gravest outlook. The writer cannot agree with Lafleur that a mild onset is no indication of a favorable course, for when local treatment is instituted early these cases usually progress favorably. In liver abscess the outlook is always very grave. Futcher reports 19 deaths out of 27 cases; 17 of these were operated upon but only 5 recovered. In the writer's clinical series of 200, abscess of the liver Occurred in 12, 3 of whom recovered after operation. The prognosis when hepatopulmonary abscess exists is perhaps even graver. Immunity. — While in many instances there seems to be a natural resistance to the disease, it would appear doubtful if there is any acfjuired AMCEBIC DYSENTERY 521 immunity against it. The apparent natural resistance may depend upon the fact that the parasites are killed before reaching the large intestine, or that they do not find favorable conditions for life and reproduction. The amoebse, after the development of the disease, may disai)pear from the stools independently of treatment, but this may be brought about by unfavorable conditions in the intestine rather than by any acquired immunity. Our knowledge of immunity in amoebic dysentery amounts to almost nothing. Perhaps further light may be thrown ujion it from the study of the secretory products of the parasites, their enzymes, endo and soluble products, etc., as well as by the application of other methods which have been employed in the study of immunity in bacterial diseases. Work of this nature has already been commenced in the laboratory in Manila. Treatment. — Prophylactic. — Since the disease is only acquired by the ingestion of the amoebee in food or drink, it is a preventable one, and may be avoided even when the malady exists endemically. Drinking water is the most usual medium, and hence only that which has been sterilized is safe to use. A reliable bottled imported aerated water is the safest to use in localities where the general water-supply is infected. Salads and uncooked fruits are sometimes a possible means of conveyance and should be avoided unless prepared with great care, particularly since they also may be a source of infection with other intestinal parasites. General, Dietetic, and Symptomatic. — Patients with acute onset or acute exacerbations of the disease should be confined to bed. In the most severe forms when very frequent bloody mucous stools are being passed, the diet should at first consist of nothing but rice or albumin water. Later milk may be added. Rest is most essential, and for this hypodermic injections of morphia sulphate (gr. \, gm. 0.016) may be given every three or four hours. Its use should be pushed if necessary. Local treatment in this stage is contra-indicated. The essential point is to secure rest for the patient and for the acutely inflamed bowel. If this can be accomplished the condition usually improves. As the symptoms begin to abate, Dover's powder (gr. 10, gm. 0.6) may be substituted for the morphia. This should be continued until the acute symptoms have subsided, when local treatment may be commenced. If the patient be seen before the symptoms are very acute a saline purge may be given, but if the severe symptoms have set in this is contra-indicated. In the mild attacks and those of very moderate severity it has become the custom in Manila not to confine the patient to the house but to allow him to be about and to enjoy a liberal diet. There is no doubt that this is frequently a mistake, but as the majority of these do not feel ill, they also feel that they are unable to remain away from their work and take the advised rest. Many of them it is true are better off when not confined to bed for the reason that they are likely to retain their strength better when up; but rest at home is usually advisable, though an occasional drive in the afternoon is often beneficial for its general effect. Where any intestinal irritation exists the diet should be restricted. Fresh milk, when obtainable, should be chiefly employed. It may be necessary to peptonize it, and this should be done if curds appear in the stools. If it is not well borne, other liquid nourishment may be substi- tuted. It is of course advisable to feed the patient frequently and in 522 DISEASES CAUSED BY PROTOZOA small quantities. As the symptoms improve, other licjuids and soft food may be gradually added. Not until the stools appear perfectly normal should general diet be permitted. Any lesions of the intestine will cer- tainly be more disadvantageously affected by solid than by li(juid food. Nausea and vomiting are frequently very annoying symptoms. They may result from the treatment or be one of the results of the disease itself. The vomiting Avhile annoying is very rarely persistent or con- tinued. The alkaline carbonated waters will sometimes give relief, and strychnine sul[)hute nuiy be employed in tonic doses. Pepsin, hydrochloric acid, and pancreatin arc rarely of benefit. In some, sodium bicarbonate in combiiuition with bismuth gives the best results. The use of bismuth is not contra-indicated in the treatment of amoebic dysentery. Some writers have thought that it may interfere with the local treatment. This may be true where it is allowed to accumulate in the bowel. It occasionally is of service when diarrhoea persists, for by its use in one-dnim doses every three or four hours constipation may be produced and a condition of the intestine brought about in which the amoeba^ die out. Just why the parasites cease to multi})ly and to exist it is difficult to say. Obviously one must not be led away with the idea that because the diarrhoea has stopped the lesions are healed and the parasites have disappeared. Repeated examination of the stools must be made to ascertain' if the amoebse have really died out. Ipecac and opium may sometimes bring about the same results. In cases where bismuth is employed, a saline cathartic followed by a high rectal enema should be given at least once or twice a week. In some instances of the disease an acute attack of diarrhoea has brought the patient for treatment. They have been confined to bed for a few days, several doses of Dover's powder administered, and local treatment instituted. The parasites may never be found in the stools after the first week, though numerous in the first examination. The symptoms will subside during this time and a recurrence does not take place. In other cases with identical treatment the parasites may persist for weeks or months. Certainly the destruction of the parasites in the former instance is not brought about by the direct action of the medicine administered by the mouth, nor is their early disappearance probably always dependent upon the direct action of the quinine administered in the enemata. The only explanation is that in one instance conditions in the intestine unfavorable to the life and propagation of the amcebse are brought about, and in the other we fail to produce them. Abdominal pain may be very troublesome. It may be relieved by turpentine stupes and hot fomentations; or, if severe, opium may be administered. When ulcers exist in the rectum and there is much tenes- mus, local treatment with argyi'ol or some other astringent or antiseptic substance may be applied through the speculum after the administration of a small enema containing cocaine or morphia. Enemas of starch and opium sometimes have a very soothing effect. If the anaemia is advanced some iron preparation is necessary; and when there is much lassitude and anorexia, a course of strychnine and alcohol in modera- tion is often of value. A change of climate is frequently beneficial during convalescence, and patients who after a long time seem to make no pro- gress in the tropics are often improved by a bracing cool atmosphere. AMCEBIC DYSENTERY 523 Curative Treatment. — During the writer's first year in the PhiHppine Islands he employed ipecac, and saw it used extensively, but concluded that it is not in any sense curative, and that, probably, the subsidence of the acute symptoms which sometimes takes place after its use is due more to the effect of the opium which is administered. Intestinal antiseptics by the mouth have practically no effect upon the parasites in the large intestine, or over the course of the disease. Calomel in divided doses has many advocates. It may be employed with good results when the usual symptoms indicating its use appear; but has no definite influence upon the parasites in the intestine. When the patients have no stool except after the enema, or in cases with constipation, either small doses of calomel or a saline purge should be administered at least once a week. The administration of quinine by the mouth on account of the effect it may have upon the amoebae in the tissues has been advo- cated, but its use in enemata seems to be equally, if not more, advanta- geous. Local treatment by rectal injections and irrigations is by far the most efficacious. After employing many substances, the writer concluded that quinine solutions give the best results. A reservoir of a capacity of two liters is advisable, which during use should be placed at a height of four to five feet above the patient. The rectal tube should be at least three or four feet in length, and not so soft as to fold too easily, or too stiff as to be apt to injure the bowel in introduction. It should be covered with vaseline before use and introduced if possible its whole length. The fluid should be allowed to enter slowly and the hips should be ele- vated. The solution may be 1 to 5,000 or 1 to 1,000 to begin with, and after a few days should be increased to 1 to 500 and used continuously at this strength. The amount injected should usually be about two liters; some patients will be able to take more and some less. The enema should be retained if possible fifteen minutes, and at least five minutes. Difficulty may be encountered in giving these large injections, and in passing the rectal tube its whole length. The attending phy- sician should, for a few days, either administer the enemas himself or have a trained assistant do so. The writer has never seen an accident result from this treatment. It is sometimes necessary when the rectum is very irritable to introduce a cocaine suppository first; or the irriga- tions may be suspended for a day or two. Harris recommends hydrogen peroxide in preference to quinine, and nitrate of silver solution 30 grains to the quart, corrosive sublimate 1 to 3,000, benzoyl-acetyl-peroxide (acetozone), and disuccinyl peroxide (alphozone) 1 to 2,000; slightly acid solutions have also been recom- mended. Recently Tuttle has obtained very favorable results with ice- water, particularly when the temperature is below 45° F. Harris reported in his first paper that not in a single instance did improvement follow injections of ice-water. One or two enemas daily are usually sufficient. In certain cases in robust individuals as many as three may be employed. A greater number than this will probably always do more harm than good. It is prob- able that the mere flushing out and cleaning of the colon plays an im portant role in the treatment, and many recover when saline solutions or ordinary water enemas are employed. It is obvious that this washing 524 DISEASES CAUSED BY PROTOZOA out must not be performed too often or the general condition of the patient may suffer, and the mucosa itself be injured and healing delayed. There are a number of cases in which the parasites persist even after all symptoms have disappeared and we are not able to rid the patient of them by any known means. Every physician who carefully and repeatedly examines the stools of his patients before discontinuing the local treatment will hnd this to be the case. Still, in other instances the parasites appear to persist, chiefly owing to their burrowing in the sub- mucosa where we are not able to reach them by local treatment. In those cases in which the lesions have healed and the parasites still persist, the time to discontinue treatment is important. If it is decided to inter- rupt the treatment, the enemas should be gradually reduced to one or two a week before their complete withdrawal, and the stools carefully watched for blood cells or other evidences of intestinal disturbance. Of course the prolonged local treatment for several months usually brings about a catarrhal condition of the large intestine which may exist for a long time or never disappear. In patients with suspected lesions in the coecum which do not yield to treatment by the rectum, colostomy has been recommended, or the appendix has been drawn out and amputated and the irrigations given directly through the Cfecum. The writer has seen only one advanced case treated by this method. The patient was not apparently benefited by it and succumbed about a month later. Treatment of the Complications.— Abscess of the liver should be opened and drained as soon as the diagnosis is made, unless it has already perforated into the lung and is being freely discharged through a bronchus. If the abscess is opened it should be frequently irrigated with quinine solution. If it is not found or no operation is performed the medical treatment indicated is the usual one for septicaemia. Per- foration of the bowel also demands surgical aid if the condition of the patient warrants it; there is practically very little hope of recovery, since in those cases which perforate the remainder of the bowel is so extensively diseased that the patient usually succumbs from the gravity of the lesions, or asthenia, if not from the general peritonitis. Morphia should be administered for the pain. Local peritonitis without perfora- tion requires rest and the application to the abdomen of ice or hot fomen- tations, with opiates by the mouth. For serious hemorrhage, morphia should be given and ice applied locally to the abdomen. Ice-cold or hot enemas containing tannin, silver nitrate, or calcium chloride, may be tried in extreme cases. Stimulants and subcutaneous or intravenous injections of salt solution should be employed when their use is indicated. PART VII. THE Z00-P4BASITIC DISEASES OF MAN. (EXCLUSIVE OF PROTOZOAN INFECTIONS). CHAPTER XXIII. GENERAL DISCUSSION. By CHARLES WARDELL STILES, Ph.D., D.Sc. Nature and Kinds of Animal Parasites.— A parasite is ar.y or- ganism which lives in or upon any other organism, called the host, and generally belonging to a widely distinct species, at whose expense it derives Its nourishment and habitation. Thus the prime ideas m parasitism are food and association. 1 Food.— No distinct line can be drawn between a parasite and a predaceous animal, although, as a rule, the parasite attacks organisms which are larger, stronger, and more intelligent than itseli, and does not immediately kill and devour its host, while the predaceous animal attacks animals which are smaller, weaker and less intelligent than itselt, and it kills and devours its prey. 2. Association.— Association of animals is one of the most common biological phenomena, and may occur between individuals of the same species or between individuals of different species. In the former case we usually have to deal with an association such as pairing (birds), or colonization (bees), resulting in a propagation and protection of the species, and a higher specialization of structure, but rarely with parasitism. _ in the latter case, however, when organisms of different species associate together, we rarely have to do with partnership for the purpose of propaga- tion (hybrids), but usually with a case of parasitism, involving a speciali- zation but degradation in structure. Such association may present an instance of — , . (a) Mutualism, when the partnership results in benefat to both parties, as in the case of the sponge growing on the back of a crab, or m the case of some of the bacteria in the mouth; or (6) Commensalism, when the association results in a benefat to one party (the messmate), but neither benefit nor injury to the other (the host), as in the case of the non-Tp&thogemc Entamoeba coh (not E. hzstolyt^ ica) in man; or ^„^ 526 THE ZOO-PARASITIC DISEASES OF MAN ((•) True para-siti^'im, \\\\cu the as.socialioii results in a benefit to the parasite, but an injury to tlie host, as in the patiiogenie Entamoeba kisto- lijika, or triehintv, hook-worms or the tapeworms in man. A parasite may visit its host only at intervals to take up temporary residence and to obtain food; such animals (mosquitoes, bed-bugs, etc.), are called temporary parasites. Others are more or less stationary with their hosts, and are therefore called .stationar;/ parasites; of these, we mav have periodical i)arasites, wiiich spend a given jK'riotl of their life with their hosts (as bots under the skin, or Strongijhrides .stercoral i.s in the intes- tine of man), or we may have permanent parasites, such as trichinte, in which the entire life-cycle is parasitic. Some parasites, as the pinworm, eelworm and hookworm, require only one host to complete their life-cycle; others, such as the large tapeworms, recpiire two hosts — an mtermcdiate host in which the larval stage lives, and a definite or final host which harbors the sexual stage. All cases thus far cited are examples of simple parasitism, but we may have parasites which are parasitic in or upon other parasites, a phenom- enon known as lii/perparasitism, aiul important from an agricultural point of view. We may further have ectoparasites (as lice), which live upon animals, and enduparasites (as tapeworms), which live in animals. The term cntozoa refers primarily to the cndoparasites, and helminthes refers especi- ally to the parasitic Avorms, while hehninthology is that part of zoology wiiich deals with worms, especially the parasitic forms, and helminthiasis denotes an infection with parasitic worms. Chance parasites, or pseudoparasites, are animals which are usually free-living but are, by chance, living as parasites (as the vinegar eel in the human bladder, mosquito larvre, and Gamviarus pulex in the stomach), or parasitic animals which by chance are not in their normal host (as Fasci- ola hepatica in man). Spurious parasites are objects which are described as parasites or mistaken for such, but which in reality are creations of the imagination (Furia injernalis, Vermis umhilicalis) , or half-digested food {Diacanthos pohjcephalus; Striatula; banana cells mistaken for tapeworm segments, etc.), or objects introduced into the body by hysterical patients in order to confuse the physician (frogs, earthworms — Spiroptera hominis is a par- asite, Ascaris capsidaria of fish, introduced by a girl into her vagina to confuse her physician, etc.). Frequency.^ — As a general rule, the smaller a parasite is, the more individuals there may be in a patient; compare, for instance, Tcenia saqinata, Ascaris lumhricoides, Oxyuris vermicularis, Entamoeba coli, Lamblia duodenalis. There is no species of animal, and no race or class of man known to be free from parasites. We may, however, lay down certain general rules covering the frequency of infection : — 1. Certain parasites are more common among people of careless per- sonal habits than among those of more careful personal habits; thus, as a rule, dwarf tapeworms, eelworms, and pinworms are more common in ^See also, Stiles and Garrison, 1906 a, pp. 1-77, "A Statistical Study of the Prevalence of Intestinal Worms in Man." Bulletin 28, Hygienic Laboratory U. S. Public Health and Marine Hospital Service, Washington. GENERAL DIHCU^HION 527 children than in adults, and whipworms are more common in negroes than in whites. 2. Certain parasites (eelworms) are said to be more common among people who — as in villages — drink unfiltered water than in townspeople who have a filtered water-supply. The difference in frequency is influ- enced, however, by the disposal of faeces by a better sewage system in cities than in villages. 3. Certain parasites (trichinse, pork tapeworms) arc likely to })e more common among people who (as East Prussians and Saxons) cat raw or rare pork than among people who (as South Germans, French, Americans) eat their pork well cooked. 4. Certain parasites (hydatids) are more common among pco[)le who (as in Iceland) keep large numbers of dogs and live more intimately with them, than among people who keep fewer dogs in proportion to the population. 5. In general, animal parasitism increases from temperate to tropical climates. 6. All intestinal and some hepatic parasites decrease hand in hand with the increase of care exercised in a proper system of latrines or sewers. Age and Sex of Patient. — Some parasites (eelworms, pinworms) are more common among children, while other species (large tapeworms and hydatids) are more common among adults of from twenty to forty years of age; some parasites (large tapeworms, hydatids, head-lice) are more common among women than among men, while other species (lung-flukes, pubic-lice) are more common among men. Fertility of Parasites. — Most parasites are exceedingly fertile, some of them almost representing egg-machines. This fertility is: 1. A natural result of their environment, since they live in the midst of their food, which their hosts provide for them; hence energy which might otherwise be expended in seeking necessary food, may here be turned to growth and reproduction ; thus it is estimated that the fat tape- worm (Tcenia sagtnata) increases at the rate of thirteen segments per day, growing 3 cm. per day for the first month and averaging 14 cm. per day for the second month, and producing 150,000,000 eggs per year. 2. Subject to natural selection, for the life-cycles are often very com- plex, hence in such cases the chances that any one egg has of reaching sexual maturity are very small, so that individuals which are only slightly fertile would probably not be represented by many generations. 3. In accordance with the general biological law (not without excep- tions) that the smaller an animal, the more fertile it is ; we should there- fore naturally expect a pinworm to be more fertile than a cow. Resistance of Parasites. — Some parasites, especially in their egg and encysted stages, are exceedingly resistant to external influences: the Persian argas may live five years without food ; Cysticercus cellulosoe may live four weeks or so after its host is dead ; trichinse may live for months after their host (hog) is slaughtered; eggs with thick shells (eelworms, whipworms, Taenia) are more resistant than eggs with thin shells (hook- worms, pinworms, dwarf tapeworm). Seasonal Periodicity. — Some parasites show a decided seasonal perio- dicity : hookworms have a better chance to develop in warm, moist months than in cold or hot dry seasons; and in general this obtains for vronns 528 THE ZOO-PARASITIC DISEASES OF iMAN Avhieh do not require an intermediate host. For certain worms (as treni' atodes) which do require an internietliate host (as snails) tiie seasonal periodicity depends upon the seasonal activity of this host, and this ac- tivity may de])entl ui)on various factors, such as moisture and warmth. Origin of Parasites. — Parasites, like other animals, have two origins: namely: 1. The ontogeuiitc origin, or origin of the individual Contrary to ideas held some decades ago, it is now known that there is no such ])henom- enon as a spontaneous generation of parasites, but it is known, on the contrary, that every animal parasite proceeds from some former genera- tion of parasites and that it came into being either through sexual or non- sexual reproduction. 2. The 'phijlogcnciic origin, or origin of the species. To assume that all parasites Avere created in the beginning as they exist to-day, would be to stamp Adam as a most remarkable helminthological museum, suffering from many parasitic diseases, of which any one of several could have been fatal. The zoologist holds that parasites have gradually evolved from free-living animals, that numerous connecting links between the two exist and that this process of evolution is still going on. Heredity of Parasites. — From the strict embryological point of view, it would be impossible to fulfil the condition necessary to demonstrate the heredity of any infectious disease in man, and when we speak of the hered- ity of these maladies in the higher animals it should be recalled that we are using the term "heredity" rather loosely. No parasitic disease is known to be hereditary in man, though we know of several diseases in lower animals (as in insects and ticks) which are hereditary in a stricter sense of the term; namely, the sexual products are infected before fer- tilization occurs. Influence of Parasites upon their Hosts. — Views regarding the inju- rious effects of parasites have passed from extreme to extreme, some authors going so far as to attribute to some parasites injurious actions Avhich they surely do not have, and others going so far in the opposite direction as to see in the parasites a supposed advantage or even a neces- sity to the host. Let us recall, however, that the injury done may vary with the species, size, location, and number of the parasites, and with the condition and age of the host. This injury may be accomplished in various ways: (1) Nourishment is taken which should go to the host, (2) blood is taken by the parasite as food ; (3) mechanical pressure irritates or causes atrophy of organs or parts of organs; (4) natural channels may be ob- structed; (5) the wandering of the parasite may cause irritation; (6) substances may be excreted which have a toxic influence, and which may change the natural condition of body fluids (blood); (7) injury to the intestinal mucosa or to the skin may form points of entrance for bacterial and protozoan infections. Such injury does not, as a rule, go on increasing indefinitely in any geo- metrical progression because of succeeding generations of parasites, for the general rule obtains (with a few exceptions, as in infections with cer- tain protozoa and with the vinegar eel) that for every adult animal para- site fmind in the human body a separate embryo or larva must enter. Thus, hookworms do not multiply generation after generation in the intestine, GENERAL DISCUSSION 529 but the eggs must leave the patient and the resulting larvae reenter the body in order to become adult. Greneric and Specific Infections. — In the following discussion, refer- ence will be repeatedly made to infections as being identical or distinct generically or specifically. These terms are used in their zoological sense, to express more accurately the relation which the diseases of man bear to those of animals. Thus, it has been reported that Trjonia .solium occurs in both man and dog. If this statement were correct, the dog would be a very important factor, from a public health point of view, in spreading Tcenia solium and cysticercosis. The reported presence of this parasite in dogs is however based upon an error of identification, for there is a tapeworm belonging to the genus Tcenia which does occur in dogs but which belongs to a species {Tcenia hydatigena) specifically distinct from, but quite closely (generically) related to, Twnia solium. Hence, man and dogs, in this instance, have infections which are generically identical, since both parasites belong to the same genus, but .specifically distinct, since the two worms represent distinct species ( T. solium and T. hydati- gena). On the other hand there is a specifically identical tapeworm- infection {Dipylidium caninum) which is common to dogs and cats and which may occur in man. Diagnosis of Parasitic Diseases. — ^The general rule may be laid down that the best method of diagnosing most parasitic diseases is by a micro- scopic examination : examine sputum for suspected parasitic diseases of the lungs; joeces for suspected parasitic infections of the intestine and liver; urine for suspected parasites of the kidney or bladder; blood, fcBces, and urine, for suspected parasitic diseases of the circulatory system; blood and muscle for suspected infections of the muscle; blood for suspected infections of the lymphatic system. In some cases a diag- nosis may be made by a gross examination of the faeces. In some para- sitic diseases, diagnosis may be safely made upon symptoms, especially if the patient is within the infected area of a given malady. It will be necessary to discuss further the question of diagnosis in connection with the different infections, but the technique of fsecal examinations can best be given here In gross examinations of the stools (for pinworms or expelled hook- worms, etc.), the fseces should be shaken up well with warm water and allowed to settle; pour off any floating material and wash the stool in this manner several times; the worms will thus be concentrated. For microscopic examination of fseces, take a small portion of faecal matter on the end of a match or toothpick, using a separate one for each stool; smear this in a drop of water on a slide; the large 2X3 slide is more convenient than the ordinary 1X3; cover with an ordinary coverglass, avoiding unnecessary pressure, and examine ten such preparations. For eggs with thick shells (whipworms, large tapeworms, flukes), use a strong illumination; for worms Avith thin shells (hookworms, pinworms, etc.), use a more moderate illumination; examine first with medium magnification (8 mm. or J-inch focal length), later wdth higher power. To make permanent mounts of eggs, preserve the material in alcohol; then transfer to 95 parts alcohol plus 5 parts of glycerine; allow the alcohol to evaporate slowly, and when evaporated to glycerine, mount the material in glycerine-jelly, 34 530 THE ZOO-PARASITIC DISEASES OF MAN Treatment. — The general rule may be laid down that for verminous infections of the brain, bones, muscles, eye, lungs, liver, kidneys, spleen, blood and lymphatics, there is no satisfactory specific medicinal treat- ment, although some of these cases may be treated surgically. Intestinal, bladder, and some skin infections by parasites may be treated medicinally. For further details, see under the different parasites. Prevention. — S(3 far as most verminous ])arasites in temperate climates are concerned, ordinary habits of cleanliness — such us are found in the educated American, English, and French families; ordinary care in preparing food — as followed by good housekeepers; ordinary methods of meat inspection — as carried on by the federal government; a pioper disposal of alvine discharges — as in sewers, or properly constructed privies; and a recognition of the fact that the dog is not a human being, are in themselves sufficient to prevent serious trouble (in form of epi- demics) from most parasites in Australia, Canada, England, and the United States. In warm countries protection against mosquitoes will reduce certain verminous affections (filariasis). Personal Rules of Hygiene. — (1) The use of spring, boiled or filtered water will decrease certain protozoan, fluke and roundworni infections; (2) proper care of meat (protection from flies) and thorough cooking will protect against certain dipterous larvfe, certain tapeworms and trichinosis ; (3) avoidance of depraved tastes for insects will aid in protecting against certain tapeworms; (4) keeping the hands and nails clean, especially after handling dogs, will aid in protecting against a certain tapeworm and hydatid disease; (5) personal cleanliness after defecation will aid in protecting against auto-infection with pin worms and Cysticercus celhdosoe; (6) wearing shoes in infected areas will help to protect against hookworm infection and the burrowing flea. Public Rules of Hygiene. — (1) If ^sewage is used for fertilizing, it is best to grow^ upon the land so fertilized, only such vegetables as are sub- jected to cooking before eating; (2) properly dispose of all fseces, espe- cially in schools, asylums, hospitals; (3) interdict nuisances, especially in warmer climates, and upon plantations, in mines and in digging tunnels and canals; (4) meat inspection in the local slaughter houses (the federal inspection covers only the abattoirs engaging in interstate trade) ; (5) segregate local slaughter houses and place them under the supervision of a competent veterinarian, who might well be a member of the local board of health; (6) keep swine in a less swane-like manner, — especially see that the privy is not near the pig-pen ; (7) swine-offal and swill should be first cooked in case they are fed to hogs ; (8) destroy all ownerless dogs and keep dogs away from slaughter houses — the dog pound is an institution of practical hygienic importance. CLASSIFICATION OP ANIMAL PARASITES. Contrary to early ideas, the parasites do not represent a group of ani- mals closely related to each other systematically, but rather several diverse groups, more or less widely separated but with somewhat similar biological habits. For the details of classification the reader is referred to Avorks on systematic zoology; for the purpose of this article, we may divide the animal parasites as follows; GENERAL DISCUSSION 531 1. Unicellular animals, as the parasites of malaria Protozoa. Pluricellular animals; metazoa 2 2. Body more or less flattened dorsoventrally 4 Body ordinarily round in transverse section 3 3. Body never annulated; never provided with legs; no jaws present. . . 5 Body annulated, or at least provided with mouth parts; usually breathe through a tracheal system; adults with jointed legs 7 4. Intestine, but no anus, present; one or two suckers present; body not segmented; parasitic in liver, lungs, blood, intestine, occasionally elsewhere; flukes Trematoda, p. 535 Intestine absent; two or four suckers on head; body of adults segmen- ted; adults (tapeworms) parasitic in intestine; larvaj (bladder worms) parasitic elsewhere Cestoda, p. 557 Intestine and anus present; ventral sucker on posterior end; body annulated like an earthworm; parasitic in upper air-passages, or externally; leeches, bloodsuckers Hirudinei, p. 626 5. Intestine absent; armed rostellum present; very rare in man, in intes- tine; thorn-headed worms Acanthocephali, p. 604 Intestine present; no armed rostellum 6 6. Intestine rudimentary in adult; rare, accidental parasites in intestine of man; hair snakes or horse-hair worms Gordiacea, p. 604 Intestine present; parasitic in intestine, muscles, lymphatics, etc.; very common and important; roundworms Nematoda, p. 582 7- Six legs present in adult ; wings present in most species; larva annula- ted much like an earthworm ; breathe through trachea; adults ecto- parasites; occasionally larva is parasitic under skin, or in wounds, or an accidental parasite in the intestine; insects Insecta, p. 632 Eight legs present in adult, six legs in larva; head and abdomen coa- lesced; ectoparasites; some burrow under the skin or live in the hair follicles; acarines Acarina, p. 626 Four claws around the mouth; larva encysted in various organs; adult occasionally parasitic in nasal passages; tongueworms Linguatulidce, p. 632 Numerous legs present; occasionally accidental parasites in nasal passage or intestine; thousand-leggers Myriapoda, p. 632 Organ distribution of parasites, according to their more common habitat. More or Less General. — Trematoda: Paragonimus, p. 536; Schistosoma eggs, p. 550. Cestode larvae: Taenia solium, p. 574: \ Echinococcus, p. 576; Spar- ganum, p. 581. Arachnida: Linguatula, p. 632; Porocephalus , p. 632. Intestinal Tract. — Trematoda: Fasciolopsis, p. 549; Heterophyes, p. 549; GastrodiscuSjTp. 549; Cladorchis, p. 549. Adult cestoda: Taenia, p. 558; Hymeno- lepis, p. 564; Davainea, p. 566; Dipylidium, p. 567; Dibothriocephalus, p. 567; Dip- logonoporus, p. 569. Nematoda: Ascaris, p. 596; Oxyuris, p. 599; Trichostrongylu^, p. 602; Agchylostoma, p. 584; Necator, p. 583; Uncino.ria, p. 583; Physaloptera, p. 602; Strongyloides, p. 595; Trichuris, p. 602; Trichinella, p. 605. Gordiacea, p. 604. Acanthocephali: Gigantorhynchus, -p. 604. Insecta, p. 632. Liver. — Trematoda: Fasciola, p. 543; Opisthorchis, p. 540; Dicrocoelium, p. 545. Cestoda: Echinococcus, p. 576. Lungs. — ^Trematoda: Paragonimus, p. 536. Nematoda: Metastrongylus, p. 610. Uro-genital System. — Nematoda: Anguillula, p. 624; Leptodera, p. 624; Dioctophyme, p. 624. Lymphatic System. — Nematoda: Filaria, p. 613. Blood. — Trematoda: Schistosoma, p. 550. Nematoda: Filaria, larvae, p. 613. Muscles. — Nematoda: Trichinella, p. 605. Subcutaneous. — Nematoda: Dracunculus, p. 611; Filaria, p. 613; AgdmofUa- ria, p. 623; Rhabditis, p. 611; Gnathostoma, p. 611. Insecta, p, 632. Ectoparasites. — ^Acarina, p. 626. Insecta, p. 632. 532 THE ZOO-PARASITIC DISEASES OF MAN NOMENCLATURE AND TERMINOLOGY. To the biologist, nomcncJaiurc deals with the 7iamcs used to designate systematic units, such as families {Tccniidcc), genera {Tocnia), species {Tocnia saginata), etc. As systematic zoologists are obliged to use thou- sands upon thousands of such names, it is advisable that these should be removed, so far as possible, from the influence of individual or national tastes and prejudices; and, in order to make them international in char- acter, Latin has been adopted as the basis for all technical names (as opposed to vernacular names). The acceptance or rejection of names and the method of writing them are governed by "codes of nomencla- ture," which may in a certain sense be compared with the medical "code of ethics." For the zoologists, the International Congress has adopted an "International Code," ^ (1905) prepared by a permanent international commission of fifteen members. This code is based primarily upon the rules proposed by Linnpeus, in 1751, modified to meet the advances in science. In order that no revolutionary principle may be suddenly intro- duced, the rules of the Congress provide that no proposition for chang- ing the code can be adopted unless submitted to the Commission at least one year prior to the tri-annual meeting of the Congress. The chief points in the code are: (1) The "law of priority," which provides that the valid name for any genus or species is its oldest available name; i. e., available under the code; thus, Ascaris, 1758, is an older name than Fusaria, 1800, for the eelworm. (2) The "rule of homonyms," which provides (a) that when two generically distinct animals have received the same generic name, this name is available only for the earlier genus (thus, when Trichina was proposed for a genus of worms by Owen in 1835, it was already in use for a genus of insects, 1832, hence the name cannot be adopted for the worm) ; and (h) that when two species in any given genus have received the same specific name, it is available only in its earlier use (thus. Taenia murina, 1845 — ITymenoIepis nana, 1852, — is antedated by Toejiia murina Gmelin, 1790 — Cysticerciis fasciolaris — hence murina, 1845, is not available as name for the dwarf tapeworm, and nana, 1852, its oldest synonym, becomes valid). (3) No name can be changed because of its inappropriateness or for any subjective reason, as names are not definitions, hence the introduction of Amoeba dysenterice ioT Amoeba coli was not permissible under the code. Physicians are urged to acquaint themselves with the code, before they publish or change zoological names, as it is often difficult to understand whether or not a physician is using a new name in a zoological sense, and further because names are too frequently proposed contrary to zoological customs. The question is frequently asked, why zoologists do not adopt, for the parasites, the names already known to physicians. The answer is simple: (1) The animals known in medicine form an almost insignificant frac- tion of one per mille of the animals with which we have to deal, and it would be a very dangerous precedent to make exceptions for this group; ^See Stiles, 190.5, pp 1-50, the "International Code of Zoological Nomencla- ture as applied to Medicine." Bulletin 24, Hygienic Laboratory U. 8 Public Health and Marine Hospital Service, Washington GENERAL DISCUSSION 533 (2) when physicians discover that two diseases have been confused under one name, or one disease has been given two or ten names, they do not hesitate to straighten out the terminology, yet the terms used by physi- cians go only into the thousands, while the names in zoology run into the millions, hence zoologists must be even more rigid than physicians in respect to technical names. Would any physician to-day, for instance, claim that trichinosis should be called typhoid, on the ground that before 1860 the two diseases were confused ? (3) Advance in microscopic tech- nique and instruments has made as great changes in zoology as it has in medicine, and zoologists are adapting their nomenclature to the changes in classification rendered necessary by the new discoveries. We do not, to-day, speak of Toenia lata and Bothriocephalus latus for the simple rea- son that the species in question is now known to belong neither to Toenia nor to Bothriocephalus. Terminology, in distinction to nomenclature, deals with the technical terms of parts, organs, functions, conditions, etc. No recognized code of rules governs the names of the muscles of the body or the names of dis- eases. A man adopts a technical term because it has been taught to him, or he changes it, if a better name occurs to him, and, finally, men adopt the names best known to them. Thus, terminology is largely subjective and such incongruities occur as using a term like "spotted fever" for two or three different diseases; while in the United States "typhus" refers to one disease, in Germany it is frequently used for another malady (typhoid). For parasitic diseases, we may distinguish three different kinds of terms in particular: (1) Latin terms based upon the zoological generic names (as distomatosis, tcBniasis, trichinosis, acariasis, etc.); (2) vernacular terms based upon some symptom, geographical locality, etc., (itch, Egyptian haematuria); (3) vernacular terms based upon a vernacular name of ^the parasite (hookworm disease) . For international use, Latin terms are by all means preferable, as they do not need to be translated, but for current use vernacular terms are often very convenient. Bibliography.— In a short article of this kind it is impossible to give a full bibliography, for which the reader is referred to Huber's Bihlio- graphie der klinischen H ehninthologie (1895, 1898, 1899-1900), or Stiles and Hassall's Index Catalogue of Medical and Veterinary Zoology (Bull. 39, TJ . S. Bureau of Animal Industry) and Looss (1905). For annual reviews of literature on parasites, see especially Zoological Record and Archiv fiir Naturgeschichte. For current literature, with original articles, reviews, and current bibliographies, see especially, ^ re A- ives de Parasitologic, Centralblatt fur Bakteriologie, Parasitenkunde und Infektionskrankheiten, Zoologischer Anzeiger, and Zoologisches Central- blatt. The current zoological references can be purchased in card form from the Concilium Bibliographicum, Zurich. The most extensive card catalogue on the subject is the combined index in the Zoological Divis- ions of the U. S. Public Health and Marine Hospital Service and the U. S. Bureau of Animal Industry. Determination of Specimens. — Specimens of animal parasites of man are determined for physicians, free of charge, by the Di\asion of Zoology, Hygienic Laboratory, U. S. Public Health and Marine Hospi- tal Service, Washington, D. C. Such material should be forwarded in alcohol (about 50 to 70 per cent.). 534 THE ZOO-PARASITIC DISEASES OF MAN Government Publications.— For U.S. government publications on animal parasites, applieatic^i should be made to the "Keeper of Public Documents, Washington, D. C," or (either directly or through a Sena- tor or Congressman) to the Chief of the Bureau by which the document was issued. CHAPTER XXIV. DISTOMATOSIS-TREMATODE OR FLUKE INFECTIONS.^ By CHARLES WARDELL STILES, Ph. D., D. Sc. Terminology. — The general term distomatosis or distomiasis is based upon Distoma which has been used by many authors as the collective genus for the trematodes, more especially for the so-called digenetic forms. As a generic name for these parasites Distoma is not valid and the species which have been included in this genus are now distributed over a large number of well defined genera. Upon the names of these more re- stricted genera, Latin terms have been based to designate infections with species of the respective genera (as fascioliasis, opisthorchiasis, parago- nimiasis). The word "distomatosis" has been combined with the name of the organ affected (as pulmonary distomatosis) ; while for some of the diseases, there are well-known vernacular terms (liver-fluke disease, liver rot, etc.). DifEerent Kinds of Trematode Diseases in Man. — In man there are four difi^erent clinical classes of trematode diseases which may be regarded as typical, in the sense that in these four instances the infection of man by certain trematodes is more or less normal in the life-cycle of the parasite under consideration. These cases are: L A pulmonary distomatosis, with cerebral or other infection as secondary; 2. An hepatic distomatosis, with splenic or intestinal infection as secondary; 3. An intestinal distomatosis; and 4. A venal distomatosis. In addition we find recorded rare instances of 5. An ophthalmic distomatosis, which may be an accidental secondary form of hepatic distomatosis. All of the parasites in question, with the exception of the blood-flukes, are hermaphrodites, and possess an oral or an oral and a ventral sucker, a mouth, and two blind intestinal caeca. The life-cycle is quite com- plicated and may involve two or more generations which live outside of man. The parasites may require an intermediate host or in some cases indications are not lacking that direct infection may perhaps occur. * For more detailed zoological descriptions, in English, of these parasites, see Stiles, 1904, pp. 1-66, figs. 1-48; " Illustrated Key to the Trematode Parasites of Man." Bulletin 17, Hygienic Laboratory, U. S. Public Health and Marine Hos- pital Service, Washington. For the most recent general discussion of trem- atodes, in English, see Ward, 1903, pp. 860-873; for keys (in English) to the numerous new genera of trematodes, see Pratt, 1900 and 1902. 535 536 THE ZOO-PARASITIC DISEASES OF MAN PULMONARY DISTOMATO SIS. —LUNG-FLUKE DISEASE. Paragonimiasis or Parasitic Haemoptysis.^— Geographical Distri- bution. — The Asiatic rc^non, ])articularly Jai)an and China, appears to be the special home of this disease in man, ahliough a generically related if not specifically identical infection occurs also as an endemic disease in hogs in the United States. It is reported also for the Phili]i]nnes, For- mosa and Korea and occasionally imported cases are found in various other places. Zoological Distribution. — It is difficult at present to determine the original host of this disease but it is known to occur more or less frequently in man, cats, tigers, dogs, swine; and Looss (1905)_says it occurs in cattle. Generically identical but supposedly specifically distinct infections occur in the Brazilian otter and the Indian ichneumon. Pulmonary distoma- tosis is occasionally found in cattle as an accidental manifestation of fascioliasis, and lung infection with other genera of flukes is exceedingly common in snakes, toads, and frogs. The Parasite. — Paragonimus ivestermaniv' (Kerbert, 1878) is a plump, depressed, oval, or pyriform, pinkish to reddish-brown (live specimens), spinose fluke 7.5 to IG mm. long by 4 to 8 mm. broad by 2 to 5 mm. thick; with branched testicles and ovary but unbranched intestinal cseca; eggs yellow, 77 to 102.5 by 40 to 75/( with distinct operculum but con- taining no miracidium when discharged. The adult parasites are found in cysts, one to three together, in the lungs, especially in upper lobes, occasionally in the pleura, liver, abdominal cavity, brain, orbit, lower eyelid, cervical glands, scrotum and various other parts of the body. Source of Infection. — Unknown. The eggs develop a ciliated mira- cidium (embryo) in water in four to eight weeks; this probably enters some snail. The infecting stage probably enters man with contaminated food or water; Katsurada thinks it may pass directly from the mouth to the bronchi, or if swallowed, from the stomach up the oesophagus and down into the lungs, or perhajjs from the stomach through the stomach wall to the mesenterium and from there by the lymphatics to the final point of rest. Frequency. — ]\Iore frequent in mountainous localities (Katsurada); chiefly in peasants, more common in males than in females (88.57 per cent, to 11.4.3 per cent, in 481 collated cases) and between the ages of sixt:;en and thirty years; in some localities 20 to 73 per cent, of the lung- fluko patients give a history of other cases in the same family (Katsur- ada), while in other places the family history is reported as negative. It is stated that in certain parts of Formosa, 15 per cent, of the in- habitants are aft'ected; in one Japanese village nearly all the inhabitants * For a more detailed discussion in English, with bibliography, see Stiles and Hassall, 1900, pp. 560-611. 2 Synonyms. — Distoma westermanii Kerbert, 1878; Distoma nngeri Cobbold, 1880; Distoma pulmonis Kiyona, Suga, and Yamagate, 1881; Distoma md- monnle Balz, 1883; Distoma jmlmonum (Bselz) Tomono Hidekata, 1883; Dis- tomum cerebrale Yamagiwa, 1890. In the lists of synonyms given in this paper, only the more common or the newer names are mentioned; for full lists of synonyms the reader is referred to the special literature on the various species. DISTOMATOSIS-TREMATODE OR FLUKE INFECTIONS 537 harbor the parasite (BjcIz). In a hospital in Okayama, 0.4 per cent, of the 20,793 patients from 1891 to 1897 showed infection (Inouye). Various Japanese physicians report that from 2 to 14 per cent, of their patients suffering from res{)iratory troubles harbor this fluke. Inouye (1903) has collected 19 cases of brain infection. Frequency doubt- less varies with occupation leading to exposure to infection. In Okayama, 7 of 130 dogs examined showed infection. From 2 to 28, perhaps more, parasites occur in each patient. Duration. — The longevity of the individual parasite is not established but cases are reported with histories extending over ten, twenty and even thirty years, these prolonged cases probably being due to repeated in- fections. Symptoms. — ^The symptoms vary according to the location and number of the parasites present. (a) Lung Infection, Parasitic HoBmoptysis. — This is the usual and un- complicated (primary) form of the disease and represents the typical paragonimiasis or pulmonary distomatosis as found in man. The onset may be so gradual that the beginning can not be recognized with certainty. The only constant and specific characteristic is the presence of the eggs in the sputum; it is estimated that as many as 12,000 ova may be ex- pectorated daily. The sputum is yellow to red or rusty brown, due to the presence of the microscopic eggs, and has a peculiar odor, partially due to blood; poor in water and rich in mucus, it varies from a small amount to 100 Cc. daily; blood is common but not constant, being present in points, strings, or larger amounts; while severe hemorrhages are not common, Bselz reports a case with a loss of a pound of blood within a few hours; the amount of blood, which is always arterial (Taylor), increases after violent exertion, irregularities in diet, use of alcohol, brain strain, excesfe in venery, tobacco smoking and in cold weather; intense ansemia may result; the sputum is often discharged in spirals, resembling Cursch- mann's asthma spirals, and contains eggs, blood, pus, mucus threads, alveolar and bronchial cells, numerous Charcot's crystals; Taylor and Mimachi have each observed an expelled worm. There may be hoarse- ness or a chronic cough, usually light, rarely so severe as to disturb sleep and most urgent in the morning upon rising. As the disease progresses the periods of cough and haemoptysis become more frequent and prolonged, tending more or less toward permanency and the amount of expectoration increases from a slight quantity at the onset to a much greater quantity later — as much as 10 to 12 ounces in a few hours. All symptoms increase after physical exertion. Physical examination does not usually reveal anything abnormal except in severe cases; Inouye (1903) reports retractio thoracis as among the most com- mon changes noticed, with contraction of the infrascapular portion; as the patient fails, auscultation shows diminished respiratory murmur, the breath sounds being vesicular but rarely weak, occasionally bronchial in character with dry or moist rales. Scheube observed repeatedly that one side, probably the infected, expands less than the other. Inouye reports unilateral or bilateral signs appreciable on percussion in 86 per cent, of 92 patients examined; only 1 of these had tuberculosis. The temperature is normal or but slightly elevated even in severe cases. The patient may become exhausted by cough and hemorrhage; he also 538 THE ZOO-PARASITIC DISEASES OF MAN becomes deeply anaemic, and suffers from dyspna^i on slight exertion. Slight oedema often occurs. There is a sensation in the chest variously described as of oppression or of heat or of mere irritation. Occasionally there are wandering pains in the chest, "most probably neuralgic." Inouye reports chest pains in 37 per cent, of 92 cases examined; in 28 of these (82 per cent.) retractio thoracis was present ; the pains were due to fresh ' or old pleurisy. After rest in bed all symptoms may abate except the cough and expectoration and months may pass before a relapse occurs. Gradually the constitution becomes under- mined, convalescence becomes less complete, periods of rest become shorter, those of prostration longer and more severe, oedema and anaemia increase and at last the exhausted patient dies. The lethaJltij of the uncomplicated form of the disease does not seem to be established but it doubtless varies with the intensity of the infection. {h) Brain Injeciion. — If the worms or their eggs gain access to the brain, a cerebral distomatosis develops, resulting in epileptiform attacks ( Jackson- ian or cortical epilepsy). It does not appear to be established in ^\hat percentage of cases tins complication appears but it is an extremely serious and fatal form; Inouye (1903) reports that of 92 patients with paragonimiasis, 3 showed brain symptoms (headache, dizziness, weak memory), 2 epilepsy, and 1 epilepsy and left hemiplegia; he has collected, in all, 19 cases; of these, 8 showed general spasms, 4 dextral, 2 sinistral spasms, 5 had hemiplegia, 5 spasm w^ith weakness of the same side, other symptoms (paresis of right arm, color ring, etc.) being less frequent. The epileptic attacks may at first be a month or so apart but they gradually increase in frequency and severity until death. (c) Infection in Eyelid. — Several cases have been reported in which the parasite lodged in the eyeUd, forming a tumor which resulted in obstruction to the sight and to movement of the eye. {d) Liver Injection. — A purely accidental hepatic distomatosis may occur in connection with pulmonary distomatosis, in that eggs of the lung- fluke may be found in the liver. Such occurrence, however, can hardly result in a typical hepatic distomatosis and it is possibly an open question whether some of these cases were not due to the newly recognized Japan- ese blood-fluke (see p. 550). (f) Injection oj Oilier Organs. — Cysts of lung-fluke eggs may also occur in the mesentery, omentum, etc., but thus far such lesions do not appear to have produced any serious symptoms. Pathology. — (a) Lung Injection. — Occasionally deep, more commonly superficially in the lung, or directly under the pleura, are found roundish or flat cysts about as large as the end of the little finger, and containing from one to three parasites or in some cases only caseous contents. Kat- surada (1900) is of the opinion that these cysts represent dilated bronchi, although he does not deny that cavities in the lung tissue may form inde- pendently of the bronchi ; the lumen communicates with the neighboring bronchi by one large or numerous small openings and the different cysts may communicate with each other by means of direct or long irregular tubes; the septa between the tunnels may break down and a considerable cavity be thus formed (Manson) ; the wall of the cyst is rather stout, grayish-white, about 1 mm. thick; the inner surface is usually smooth, and the lumen may contain a reddish or brownish-green slimy fluid. DISTOMATOSIS-TREMATODE OR FLUKE INFECTIONS 539 Fig. 35, Katsurada (1900) states that at first the changes are a more or less intense bronchitis and peribronchitis of a catarrhal, hemorrhagic or more puru- lent character. When the worms settle in the bronchi, the walls undergo an inflammatory infiltration, a richly vascularized granulation with con- nective tissue forms, and the original structure of the bronchi becomes lost. The bronchitis is caused not only by the worms but also by their eggs. An adhesive pleuritis may develop. (b) Brain Injection. — Yamagiwa reports disseminated circumscribed foci of trematode eggs, usually also with giant cells, in the cortical sub- stance of the occipital, parietal and central lobes of the brain; surrounded by connective tissue and round-cell infiltration; thickening of the wall of the bloodvessels, especially of the adventitia, and obliteration of some of the branches; associated with lesions in the lungs containing eggs of the same parasite and giant cells. (c) Liver Infection. — Yamagiwa reports cirrhosis of the liver resulting from emboli of eggs in the portal area (or perhaps co-existence of these fluke-egg emboli with cirrhosis due to other causes). See also p. 538. {d) Injection oj Other Organs. — Cysts containing these fluke-eggs, and fibrous nodules have been found in the mediastinum, diaphragm, mesen- terium, and walls of the intestine; Otani is said to have found abscesses in the cervical and inguinal regions caused by trematodes. Eggs have been noticed in the contents of the intestine but these may have resulted from swallowed sputa. Clinical Diagnosis. — This disease was long con- fused with tuberculosis from which it may be readily distinguished by microscopic examination of the unstained sputum to find the characteristic egg- Treatment. — No specific treatment is known. Inhalations have proved unsatisfactory. By send- ing the patient to an uninfected locality further infection is avoided and with the lapse of time (the length of which is not known) the parasites may finally die and become disintegrated or may be coughed up. Surgical interference has been sug- gested for cases in which the parasite can be definitely located. Prevention. — (1) Destruction of infected spu- tum; destruction of cats and dogs showing the same disease; destruction of the lungs of swine showing the same infection. (2) Use of filtered or boiled drinking-water; thorough washing of vegetables; thorough cook- ing of snails when these are used for food. These latter precautions are based upon analogy, as nothing positive can be stated in this line until the life-history of the parasite is known. Pulmonary Distomatosis Due to Fasciola Gigantica. — One case of pulmonary distomatosis in man has been reported as due to Fasciola gigantica. This was doubtless a case of chance parasitism, as man is not known to be a normal host for Fasciola and as the liver, not the lungs, is the normal organ in which Fasciola occurs. The parasite in question is common in Africa in the liver of buffalo, cattle, sheep and goats; it was Egg of lung-fluke showing ovic cell, yelk cells and operculum. X 100. (Kat- surada.) 540 THE ZOO-PARASITIC DISEASES OF MAN originally dcscnbcd for the girafl'e; it is similar to /•'. hepaiica in structure, but much narrower, measuring 25 to 75 mm. long by 3 to 12 mm. broad; eggs 145 to 190 by 75 to 90^<. HEPATIC DISTOMATOSIS.— LIVER-FLUKE DISEASE. At least six different species of liver-flukes, representing three different genera {Opifiilwrchi.'i, Dicrocccliuin and Fasciola), have been found in connection with hepatic distomatosis. Infections with Opistit orchis are common to man, dogs and cats, and are much more frequent in man than are infections with Dicroccclium and Fasciola, which man has in common with certain food animals, particularly cattle and sheep. Of the six specific infections in question, one (an Asiatic disease) is much more important than all the rest combined. Source of Infection. — For only two of these infections, namely for the fascioliasis, due to Fasciola hepaiica, and opisthorchiasis, due to Opis- thorchis jcUncus, is the source of infection known (see pp. 541, 546) ; for all of the others, this is a matter of speculation based upon analogy and circumstantial evidence. Clinical Diagnosis. — This is identical for all six infections. Make a microscopic examination of the unstained ffcces for eggs ; also of the sputum and urine, as the ova in pulmonary and venal distomatosis may be dis- charged per anuni; hence, finding eggs in the fseces, without excluding pulmonary and venal distomatosis, may lead to error. Treatment. — There is no specific treatment know-n for any form of hepatic distomatosis; remove the patient to a non-infected area or, if he be kept at home, avoid further infection and give good nourishing food. Prevention. — The same general principles apply to all six infections. Opisthorchiasis. The term opisthorchiasis has been introduced by Looss (1905) to designate infection with flukes belonging to the genus Opisthorchis, a group characterized chiefly by the position of the testicles near the posterior extremity of the body. In man w^e may distinguish at present three distinct infections by species of this genus; in order of importance these are the Asiatic, the European and the Indian species. Asiatic Opisthorchiasis or Japanese Liver-Fluke Disease — Geo- graphical Distribution. — This infection is endemic in Asia, more es- pecially in Japan and China, but it is also found in the Philippines, India, Formosa, INIauritius, Annam, Tonkin and Korea, and imported cases are occasionally reported for other parts of the world. About twenty imported cases have been recorded in the United States. Zoological Distribution. — So far as can be judged at present, man must be considered one of the normal hosts of this parasite, but cats and dogs also appear to be normal hosts. Generically identical but specifically distinct infections are found in quite a number of other animals. DISTOMATOSIS-TREMATODE OR FLUKE INFECTIONS 541 The Parasite. — The Asiatic liver-fluke disease is caused by Opisihor- chis sinensis,^ an elongate, lanceolate, non-spinose trernatode, 9.7 to 20 mm. long by 2 to 5 mm. broad. Its chief anatomical characteristic is the branched condition of the testicles. Eggs, 24 to 30 by 15 to 17.5/^, exceptionally 35 by 19, 20 by 15.7, or 22.5 by 15/i; the eggs are somewhat thicker than those of 0. jelmcus, dark brown, with sharply defined operculum, occasionally with small knob at posterior end and containing a ciliated miracidium at oviposition. The adult worm inhabits particularly the gall-ducts but may be found in the gall-bladder and in the pancreatic duct and (probably in the act of wandering) also in the duo- denum and stomach. Katsurada (1900) found it in the pancreas in 9 out of 67 infections. Source of Infection. — ^The life-history of species of the genus Ojyis- i/iorcAi? is unknown (except 0. felineus, contracted from eating raw fish), hence the source of infection can not be definitely stated but the micro- scopic anatomy of the embryo shows that at least part of its life is spent in water; it probably enters some snail. The probabilities are that infec- tion of man takes place either directly from water by swallowing the free cercaria or indirectly through eating some water-animal (snail or fish) or through food contaminated by infected water. Frequency. — According to Taylor, some native practitioners in the infected villages estimate that 1 in 7 or 1 in 5 of the entire local popula- tion is infected, irrespective of age, sex or physical condition, and where one member of a family is infected several members are likely to harbor the worm. Katsurada (1900) recognized 654 cases of infection in 1,075 persons examined (namely 60.8 per cent.) in three villages engaged chiefly in rice culture and in a region abounding in canals with dirty water. It is also said that in Japan, in certain littoral regions where the water is poor, 20 per cent, of the inhabitants are infected, \vhile in localities a few miles distant and with better w^ater the parasite is com- paratively rare. In some patients only a few parasites are present while in others large numbers are found. Thus Katsurada (1900) reports that of 72 cadavers examined, 4 contained from 2,216 to 4,361 worms each, and Blanchard (1901) reports 1 infection with over 10,000 parasites. Duration. — Cases of infection of two to five years standing seem to be common, but the longevity of the individual parasite does not seem to be determined. Symptoms. — To a certain extent these depend upon the number of parasites present, so that light infections may escape attention unless a chance microscopic examination is made. Usually there is at first in- creased, exceptionally decreased, appetite. In heavy infections, one of the first and most pronounced symptoms is the enlargement and tenderness of the liver, preceded, attended, or followed by diarrhoea; the stools be- come irregular; the diarrhoea is at first irregular and intermittent, the attacks becoming more and more frequent and prolonged, until after two to five years there may be hardly any interval between them; the stools ^Synonyms. — Distoma sinense Cobbold, 1875; Distomum spathulatum Leuck- art, 1876 (not Creplin, 1849; for spatulatum Rudolphi, 1819); Distomum spatu- latum Cobbold, 1879 (not Rudolphi, 1819); Distoma japonicum R. Blanchard, 1886 or 1888; Opisthorchis sinensis (Cobbold, 1875) R. Blanchard, 1895; Di- crocoelium sinense (Cobbold) Moniez, 1896. 542 THE ZOO-PARASITIC DISEASES OF MAN may be light, or dark and bloody and may roach twelve per day; in some cases blood is present only at irregular intervals, in others the bloody diarrhoea becomes almost constant. The liver continues to increase in size, in some cases reaching the navel, though at times it apparently diminishes temporarily; there may be tenderness over the hepatic region or more or less dull pain and pressure may result in excruciating agony; jaundice, sometimes intermittent, is a frecjucnt symptom; there is gener- ally a dark ashen discoloration of the skin. The temperature may be normal or may increase to 100° F. After a time anasarca, likewise inter- mittent, appears and affects the legs especially. Night blindness is likely to occur. Epistaxis is rather conniion. Ascites often occurs, may in- crease for a time, then gradually tliminish, to appear again and again. The patient is reduced by diarrhoea, becomes emaciated and grows antiemic and weak, but the appetite is usually preserved. It frequently happens that the patient is reduced so low that life is despaired of, yet he may gradually rally and apparently become almost well (Taylor, 1884). Later, however, relapse occurs and the same process is repeated again and again, ground being lost each time, until at length, worn out and ex- hausted, the patient dies after many years of illness. In some cases enlargement of the spleen is noticed and occasionally a chronic gastro- intestinal catarrh is reported. In prolonged cases the liver becomes smaller. Lethality. — Of 1,495 cases, compiled for the province of Okayama, Katsurada (1900) reports 238 as fatal (16 per cent.). Pathology. — As the parasites are situated chiefly in the liver, we naturally expect this to be the chief seat of the lesions; in fresh cases it is enlarged, sometimes hyperperaic, in prolonged cases normal or decreased in size and of more or less cirrhotic appearance. The superficial gall-ducts are prominent, white, opaque, and irregularly thickened; worms may be pressed out singly or in bunches in the thick, slimy, yellow to dark brown bile. The lesions are particularly of two kinds, involving the biliary canals and the hepatic parenchyma. When the worms enter the bile canals they obstruct the lumen more or less completely; the first result is a bile stasis with resulting dilatation of the canals; the latter acquire considerable dimensions, while both epithelial and subepithelial layers undergo pro- lound modifications. Opinion has been expressed that these changes are due to mechanical causes; without doubt these are important but the parasites seem to do other damage than acting simply as foreign bodies, for in case of infection with Fasciola hepatica, Railliet has shown that the parasites suck blood from the capillaries in the walls of the canals. The lining of the ducts shows catarrhal irritation; the discharged mucus con- tributes to the occlusion of the canals; the glands undergo considerable hypertrophy which increases progressively and develops an extended adenoma; the newly-formed bile canaliculr are numerous at the side of the chief canal with which they communicate; in sections nodules of several millimeters in thickness may be found which contain sections of a number of canals. The connective-tissue layer of the canals undergoes very active proliferation and may attain an enormous thickness, its outer layer show- ing more or less small cell infiltration; it pushes before it the epithelium and thus contributes to the obliteration of the canal; it also compresses the hepatic tissue at the expense of which it lodges and which then under- DISTOMATOSIS-TEEMATODE OR FLUKE INFECTIONS 543 goes secondary lesions A cirrhosis develops which, with time, acquires considerable proportions. The hepatic tissue undergoes granular and fatty degenerations and, little by little, atrophies. The lesions have a marked influence on the general nutrition; the arrest of bile causes digestive trouble; compression of the branches of the portal vein causes stasis toward its origin from which ascites results (Blanchard, 1901c); Kat- surada (1900) reports ascites in 15 out of 76 cases as a result of the parasitic interstitial hepatitis or of the stasis in the portal vein. Of the 76 cases reported by Katsurada, 2 had gall-stones in the gall- bladder (compare also a similar instance reported by Kirch ner for infection with Dicroccelium lanceatum) and 2 showed primary malig- nant growths in the liver, 1 of which was carcinoma; the parasites had caused a hepatitis in the course of which carcinomatous growth developed from the epithelium of the newly-formed gall-ducts. The gall-bladder may be greatly enlarged. The spleen was enlarged in 6 of the 15 cases in which ascites was present, but in 1 case this organ was con- siderably reduced in size. In especially severe cases Katsurada fre- quently found catarrhal changes in the stomach and intestine. Of 76 cases, 9 (11.8 per cent.) either showed or gave a history of icterus; of the 15 cases with ascites, icterus was present in 7 (46.6 per cent.). Clinical Diagnosis. — Microscopic examination of pm^ 35, unstained faeces to find the egg of the parasite is necessary. When in an infected locality a case of enlargement of the liver and bloody diarrhoea is seen, careful examination of the faeces is usually rewarded by finding the eggs. Treatment. ^ — No specific treatment is known. Whether any severe cases ever fully recover is not stated but it seems, a 'priori, that a change of locality to uninfected districts, thus preventing further infection of the patient, should be attended by at least a pro- longation of life. Taylor (1884) says' that it is doubt- Egg of Asiatic liver- ful whether recovery takes place after one becomes a larged. (Katsur- victim of this disease, by which he probably does not ^ refer to the light infections. Katsurada (1900) suggests the advisability of laparotomy in some cases, in order to press the parasites out of the gall-ducts into the intestines. Prevention. — (1) Destruction of all cats and dogs affected with this parasite, and disinfection, by heat or by drying, of all faeces from infected persons. (2) Until the life-history of the parasite is known, the pre- cautions mentioned under Prevention (2), p. 539. Siberian Opisthorchiasis or Siberian Liver-fluke Disease. — Geo- graphical Distribution. — The parasite in question is reported for France, Germany, Holland, Italy and Russia, but cases in man are known only for Prussia (Germany) and Siberia. The reported presence of this parasite in the United States is based upon a misdetermination (QpistJiorchis pseudofehneus) . Zoological Distribution. — The cat, and possiby the dog, the fox (Vulpes vulpes), and the glutton {Gulo horealis) form the natural hosts for this in- fection ; it is not yet thoroughly established whether man is a natural or a chance host for the parasite though indications point to the latter condition. 544 THE ZOO-PARASITIC DISEASES OF MAN The Parasite. — This particular infection is caused by the European cat-fluke {Oph'thurchlfi fclincu.s), a lanceohite, non-spinose \vorm, measur- ing from 8 to 15, rarely to 18 mm. long by 1.25 to 2.5 mm. broad; the testicles are lobate, but not branched; eggs oval, yellow-brown, 26 to 30 by 11 to 15;/, one side slightly flatter than the other; with sharply defined operculum on the more acute pole and containing a ciliated miracidium at oviposition. The adult parasites inhabit the gall-ducts but nre occasionally found in the pancreas and duodenum. Source of Infection — The embryo does not hatch in water but it hatches in snails belonging to the genus Limnwa, although it does not develop further in this host. From circumstantial evidence suspicion has fallen upon raw fish as a source of infection and Askanazy (1906) has traced the infection to the dace (Lcucu'cus rutilus) and the ide or orf {Idus idufi). Frequency. — This is an exceedingly common parasite of cats in some parts of Europe. Winogradoff (1892) reports 8 cases of infection (6.45 per cent.) in man in 124 autopsies at Tomsk, Siberia; Askanazy (1900b) reports 5 cases (all males) from Heydekrug district, Prussia; and Kurimoto (1900) and Kholodovsky are authority for 1 case in St. Peters- burg, Russia, in a patient who had been in Siberia. Thus, recent literatui'e shows that this is by no means a rare parasite in man. In the cases reported for man, there were several to a thousand (Askanazy, 1901) parasites present. Winogradoff has reported an additional case of infection with a small spinose fluke which he supposed was a young 0. felineus. Braun has, however, pointed out that this might perhaps be a Metorchis truncatus, a small spinose fluke which occurs in the dog, cat, fox, glutton, and seal. Duration. — Unknown. In one case probably nearly three years. Symptoms. — The cases that have been found have not all been care- fully studied from a clinical point of view. In general, approximately the same clinical picture can be expected which is found in corresponding in- fections with the Asiatic fluke, for the worms are very closely related and the lesions more or less identical. According to Askanazy (1900b), Winogradoff reported icterus in 5 of his cases, decreased liver in 5 cases, enlarged liver in 2 cases, ascites in 3 cases. In Askanazy's third case he reported (1901) icterus and bilirubinuria in a cachectic man with a very large, hard growth in the liver, enlargement of the gall-bladder and colic-like pains. Lethality. — In none of the cases reported is the parasite given as the direct cause of death. Pathology. — In general this is similar to that of Asiatic opisthorchiasis, except that no such severe infections have been studied. Askanazy (1900b) summarizes the pathology as cholangitis catarrhalis and peri- cholangitis fibrosa or as Virchow described it in fascioliasis, as a chronic choleportitis and fibrous periportitis. Bossuat (1902) summarizes the condition as an irritation of the Avails of the biliary canals, a thickening with pisiform dilatations, followed by a veritable cirrhosis. In two of the cases studied by Askanazy, he reports (1901) carcinoma (c/. above, p. 543) of the liver which he believes was indirectly caused by the parasites. The free eggs in the ducts were surrounded by eosinophile pus cells (Askau- DISTOMATOSIS-TREMATODE OR FLUKE INFECTIONS 545 azy, 1900b). The pancreatic duct showed the same changes as the gall- ducts. Charcot's crystals were present in the f'ajces. Clinical Diagnosis and Treatment. — See p. 543. Prevention. — See p. 543. In view of the fact that fishes form the in- termediate host, it will be well to avoid eating raw fish. This avoidance also recommends itself on general principles in connection with the pre- vention of infection with the broad Russian tapeworm. Indian Opisthorchiasis or Indian Liver-Fluke Disease — Geo- graphical Distribution. — Thus far reported only for Calcutta, India, unless Winogradoff 's ninth case (which Braun thinks may perhaps have been due to Metorchis trmicatus) belongs here (?). Ijima reports a spinose fluke for cats in Japan which might perhaps be identical with this species.^ Zoological Distribution. — Man and dogs. It is not yet known whether these are the normal or merely chance hosts for this infection. The view that this parasite occurs in the North American red fox {Canis fulvus) is based upon an error of identification. The Parasite. — The Indian liver-fluke, Opisthorchis noverca Braun, 1903, is a lanceolate, spinose fluke, 9 to 12.5 mm. long by 2.5 mm. broad, which lives in the gall-ducts. Eggs oval, 34 by 19 to 21//. Symptoms. — ^In general, these are probably the same as for other species of this genus, see p. 541. Source of Infection, Duration, Lethality, and Prevention. — Unknown. Frequency. — Only two cases (McConnell, 1876 and 1878) known. LANCET FLUKE INFECTION. Geographical Distribution. — This infection seems to be primarily one of Continental Europe. Its exact distribution can not be stated, as there has been considerable confusion in the determinations of infections with this and other lanceolate parasites. Aside from Europe, it is reported also for Northern Africa, Siberia, Turkestan, and North and South America. American specimens have never been seen by the writer. Zoological Distribution. — The same confusion noticed in connection with the geographical distribution also exists in reference to the hosts. Apparently cattle and sheep are the normal hosts for this disease, which is also reported for the goat, deer (Hirsch), horse, ass, hog, hare, rabbit, and man. Certainly many and possibly all of the reported occurrences of this infection in carnivorous animals (dogs and cats) are based upon errors of identification, as pointed out by Braun (1893e and f). The Parasite. — -The lancet fluke (Dicroccelium lanceatum Stiles and Hassall, 1896) is a non-spinose, lanceolate trematode, 4 to 9 mm. long by 2 to 2.4 mm broad, characterized by the anterior position of the testicles, which are between the acetabulum and the ovary, and by the posterior position of the uterus. Eggs, dark brown, thick-shelled, 38 to 45 by 20 to 30/<, with a distinct operculum and containing a ciliated miracidium when oviposited; the embryo is provided with two dark spots in posterior portion. ^Looss, 1905, p. 91. 35 546 THE ZOO-PARASITIC DISEASES OF MAN Source of Infection. — Unknown. Embryos hatch in tlie intestine of slugs (Arionidie) but not in water; they do not, liowever, develop further in these mollusks. Frequency. — While the parasite is quite common in cattle and sheep, only 7 cases of its occurrence in man have been reported. It is doubt- less purely an accidental parasite for man. Duration. — Unknown. Symptoms, Lethality, and Pathology. — Probably not serious, as only light infections are likely to occur in man. Kirchner reports 1 case with gall-stones. It seems not impossible that Mehlis's case, in which a woman vomited 50 si)ocimens of this parasite and 9 of Fasciola hepatica, re- sulted from eating infected liver which was not thoroughly cooked. Clinical Diagnosis, Treatment, and Prevention. — See p. 543. FASCIOLIASIS— INFECTION WITH FASCIOLA. Fascioliasis is, properly speaking, distomatosis caused by species of the genus Fasciola. While the liver is the normal habitat for these worms, it occasionally happens that fascicles infest other parts of the body. In man fascioliasis is probably always due either (1) to a purely chance infection by the larva? which then develop in the liver or, in rare cases, some other part of the body, as the lungs (p. 539), the eye (p. 556), or the veins {Hexathyridium venarum), etc.; or (2) to acci- dental infection -with the adult worm, due, as Khouri (1904) has recently shown, to eating raw liver containing these parasites. Geographical Distribution. — The common liver-fluke is reported with a very wide distribution but as the parasites on different continents are studied more carefully it is found that the infections alleged to be due to this species are specifically distinct, although generically identical. On account of these changes in ideas regarding classification this entire sub- ject must be restudied. Europe is to be considered the type locality of Fasciola hepatica and the same parasite seems to occur in North America and Australia. It is also reported for Asia, Africa and South America. Zoological Distribution. — ^This infection is reported from more animals than are probably actually infected with it but its normal hosts seem to be cattle, goats and sheep; it is also reported for many other animals. The Parasite. — Fasciola hepatica^ Linnaeus, 1758, is a flat, leaf-like, spinose worm measuring 18 to 30 mm. (reported to 51 mm.) long by 4 to 13 mm. broad; the intestine, testicles, ovary, and vitellogene glands are profusely branched. Eggs, yellow-brow^n, oval, 130 to 145 by 70 to 90/i, with distinct operculum, not containing embryo when oviposited. Source of Infection. — Snails of the genus Limnoea (L. truncatula, L. oahuensis, L. rubella) form the intermediate host, and infection takes place normally by swallowing the encysted cercaria. Frequency. — While this infection is rather common in cattle and sheep, especially those pasturing in marshy districts, it seems to be purely ac- cidental in man. Not every case reported as Fasciola hepatica is to be accepted as such. One source of error is to mistake single segments of 'SYNOivrYMS. — Distoma hepaticum. (Linnaeus) Abildgaard; Fasciola humana Gmelin, 1790; Hexathyridium venarum Treutler, 1793. DISTOMATOSIS-TREMATODE OR FLUKE INFECTIONS 547 tapeworms for liver-flukes; the writer has seen several cases in which this had been done. Blanchard has carefully collated the authentic cases reported for man and Moniez has added several to Blanchard's list. The parasite has been reported for the liver by several observers. One recent case for Poi-to Rico is known to the writer; but while the parasite is a Fasciola, he believes that it represents a new species. Cases have been reported for the blood and in subcutaneous tumors. Besides these cases, attention may be directed to the fact that the eating of raw liver infected with F. hepatica may be a much more serious matter than has heretofore been supposed and may cause in man a condition which, in certain localities at least, is apparently more common than is the presence of the common liver-fluke in the human liver. Halzoun. — According to Khouri (1904), there exists in northern Liban, Syria, a disease known as " halzoun,"^ which he attributes to Fasciola hepat- ica c ntracted through eating raw goat-liver infested with the parasite. His experiments upon rabbits, as well as clinical observations, indicate that the parasites attach themselves to the pharyngeal mucosa where they gorge themselves with blood after the manner of leeches ; Khouri thinks that the parasites may secrete a substance which acts as a vasodilator. After gorging themselves with blood the flukes loosen their hold, reach the stomach, or are expelled with the vomit. There are two sets of symp- toms; namely, congestive (a more or less intense cedematous congestion of the buccopharyngeal mucosa, of the larynx, nasal fossae, tonsils, Eustachian tube, ear, conjunctivae, and lips) and mechanical (dyspnoea, dysphagia, aphonia) resulting from the first phenomena. The mechani- cal symptoms are proportional to the .severity of the congestive conditions; they are less constant but of more serious prognostic import. The symp- toms appear a few minutes to an hour after eating the suspected liver and are localized in the cephalic region of the body; vomiting may result in expelling one or several worms and the severity of the attack varies with the number of worms present. Subjective Symptoms. — ^After eating the infected raw liver, the patient experiences an itching sensation deep in his throat; soon he feels more or less malaise; the itching increases, extending to the ears and becoming painful; a buzzing in the ears follows and a sensation of auricular tension exasperates the patient. Two or three hours after onset the itching lessens; deglutition and dysphagia become painful; dysphonia develops and may extend to complete aphonia. The most alarming symptom is the dyspnoea, varying to orthopnoea in severe cases or asphyxia in fatal cases. The patient complains of a sensation of suffocation or of violent constriction of the throat, and of headache, usually frontal, which is some- times extreme. Objective Symptoms. — The aspect of the patient is typical; the face is congested, the lips thick, cyanotic and livid; an abundant saliva flows; the eyes are highly congested and there may be lachrymation; the conjunctivse are injected and cedematous; photophobia and exoph- thalmia are common; the sight remains normal. The nose is large, red and shining; the pituitary mucosa is of an intense red- violet color, thickened, sometimes closing the nasal passages; usually it secretes a ^A-ra.t>ian word for spiral or snail, 548 THE ZOO-PARASITIC DISEASES OF MAN yellowish, ropy mucus, sometimes very abundant. In severe cases the neck is swollen and cedematous; palpation shows a variable submaxillary and cervical adenopathy and a diii'use pufhness; the oedema invades the cervical cellular tissue, in serious cases extending to the clavicle. Ex- amination of the throat shows congestion and a more or less intense oedema of the pharyngeal mucosa, of the palate and especially of the uvula and tonsils; "the latter are considerably enlarged and, in severe cases, may meet in the median line, leading rapidly to asphyxia. Laryngo- scopic examination shows an unusually narrowed superior larynx, of red- violet color, the vocal cords are slightly cedematous, but the opening of the glottis is not seriously restricted. There is rather an intense reddening of the external auditory canal and especially of the tympanum. Somatic Symptoms. — The tem{)erature usually remains normal but the pulse increases with the dyspnoea. Examination of the lungs and urine is negative. Forms. — Besides the common form, described in the foregoing, one may distinguish light, grave, and fatal cases. In the light cases, dysphonia and distinct dyspnoea are not observed; the duration is short, varying from a few hours to two or three days. In the grave form the symptoms reach their maximum; the incubation is only five to twenty-five minutes; after ten to eighteen hours, the pharyngolaryngeal symptoms are intense ; if the symptoms do not ameliorate by the end of thirty-six hours, to continue for four or five days in benign form, death is inevitable; usually this attack lasts five to eight days. In the fatal form the symptoms develop very rapidly. Complications. — As complications may be found: abscess, especially in the external auditory canal and in the mastoid region, which may be treated surgically, suppurative otitis media, followed by perforation of the tympanum, and peripheral facial paralysis which disappears after eight or ten days. Duration. — Attacks vary in length from a few hours to ten days. Most patients recover, death being exceptional. Diagnosis. — As a rule this is not difficult but some cases may be con- fused temporarily with diphtheria, oedema of the glottis, cardiac or pul- monary dyspnoea and acute iodism. Treatment. — Vomiting dislodges and expels the parasite, and should be encouraged; it is more effective if the stomach is well filled. Prevention. — ^Avoid eating raw liver. INTESTINAL DISTOMATOSIS. The entire subject of intestinal distomatosis in man is one which needs a careful restudy. Undoubtedly the infections are much more common than is ordinarily assumed but we cannot as yet say for which infections man forms a normal, and for which an accidental host. Geographical Distribution. — So far as the writer has records, intestinal distomatosis in man is reported only of Asiatic and African origin. Zoological Distribution. — Similar infections, some of them generically identical with those found in man, are exceedingly common in other a,nimals but of the infections which occur in man, only one {Heterophyes DISTOMATOSIS-TREMATODE OR FLUKE INFECTION,'^ 549 heterophyes) is known to occur in other animals (cats, dogs and a fox). The Parasites. — Intestinal distomatosis in man may be caused by the following flukes: Fasciolopsis Buslcii (Lankester, 1857). — This is the largest and perhaps the most important of the intestinal flukes of man; thus far it is known only for Asia (India, Assam, Siam, China, Straits Settlements, Sumatra), but Moore and Terril (1905) have reported one imported case in the United States. It measures 27 to 37 mm. (or even 75 mm., after Busk) long by 5.5 to 12 or 14 mm. broad, and 1.5 to 2 mm. thick. While not unlike the com- mon liver-fluke (Fasciola hepatica) in superficial appearance, it can be easily distinguished from that form by its very large acetabulum and by its simple intestine. The eggs measure 120 to 130 by 77 to 80/^ with very delicate operculum. The life-history and source of infection are unknown. Infection with this parasite is reported as being accompanied by in- digestion, nausea, headache and severe diarrhoea with bloody stools. It is said to be expelled by thymol or with calomel. Fasciolopsis Rathouisi (Poirier, 1887). — This trematode has been re- ported but once (Asia) and in this case it does not seem to have been definitely established whether the worm was in the intestine or in the liver. The patient is said to have had "severe body pains." The parasite measures 25 mm. long by 16 mm. broad; eggs ovoid, 150 by 80//. The life-history and source of infection are unknown. Heterophyes Heterophyes (Siebold, 1852). — This is a minute trema- tode, 1 to 1.7 mm. long by 0.3 to 0.7 mm. broad, found in the middle third of the small intestine of man, dogs, and cats in Egypt and reported once for Japan. Its chief anatomical characteristic is the presence of a sucker-like disk surrounding the genital pore; the acetabulum is much larger than the oral sucker. The eggs are light brown, thick-shelled, oval, 20 to 30 by 15 to 17/x with distinct operculum, and containing ciliated miracidium when oviposited. The life-cycle and source of infection are unknown. It seems to be entirely harmless in man (Looss). Gastrodiscus Hominis (Lewis and McConnell, 1876). — This fluke, originally described as Amphistoma hominis, occurs in the caecum and colon of man in India and has also been reported for East Indian immi- grants in British Guiana. Braun is of the opinion that it is undoubtedly only a chance parasite in man and that its normal host is some Indian mammal Indications are, however, not lacking that it is a more common parasite in man than has been supposed. It measures 5 to 8 mm. long by 3 to 4 mm. broad and when fresh is of a reddish color; the body is divided into an anterior, rather slender conical portion and a posterior flattened, ventrally concave disk with small ventral acetabulum at the posterior end. The eggs measure 150 by 72/x and possess an operculum at the narrower end; the miracidium is not formed before oviposition. The life-history and source of infection are not known. Its medical importance is not established. Cladorchis Watsoni (Conyngham, 1904) Shipley, 1905. — This is an 8 to 10 mm. long amphistome reported once from the small intestine of a negro boy from Adamawa, German West Africa. 550 THE ZOO-PARASiriC DISEASES OF MAN VENAL DISTOMATOSIS^BILHARZIOSIS^— BLOOD-FLUKE INFECTION. Geographical Distribution. — Africa, Asia, Panama, Cuba and Porto Rico ; probably more art of our American fauna. Zoological Distribution. — The adult tapeworm occurs in the upper half of the small intestine, but never close to the stomach, of dogs, wolves, jackals, Canis dingn, and it can develop in cats. The larval stage occurs in quite a number of domesticated animals, as sheep, cattle, hogs, and ^ also in certain wild animals, be- ing reported in all from twenty- seven species of mammals. From the public health point of view it is especially the dog, sheep, cattle, and swine which come into consideration. Man is prob- ably an accidental though not a rare host. The Parasite. — It is at present an open question upon which there may be a legitimate differ- ence of opinion, whether one, two, or three distinct species or varieties of echinococcus should be recognized. Most zoologists admit only one species, com- monly known as Taenia echino- coccus (Zeder, 1803) Siebold, 1853, but the writer agrees with Weinland that it is well to place this in a distinct genus; if this is done the correct name of the species is Echinococcus granu- losus'- (Batsch, 1786) Zeder, 1803. This is one of the smallest tapeworms known. It is composed of a head with 28 to 50 hooks, a short neck, and 3 or 4 segments ; the first segment is immature, the second is mature, the last segment is gravid and it composes about ^ (2. mm.) of the total length (2.5 to 5 mm.) of the worm. The larval stage of this worm is the largest larval cestode known, and is the Eckinococcus"^ or Echinococcus hydatid of medical and zoological authors. Hooks of hydatid tapeworm : a, from a hydatid; h, three weeks after feeding to a dog; c, from an adult; d, combined figures of a-c, showing the gradual changes in form. X600. (Leuckart. ) * Generic Synonyms. — Echinococcus Rudolphi, 1802; Acephalocystis Lsennec, 1804. Specific Synonyms. — Adult: Tcenia nana van Beneden, 1861, (not Siebold, 1853); Tania echinococcus (Zeder, 1803) Siebold, 1853; Echinococctjer echin- ococcus (Zeder) Weinland, 1861. ^ E polymorphus Diesing, 1850; E. unilocularis Huber, 1896; E. cysticus Huber, 1891. T^NIASIS—CESTODE INFECTION 577 This may assume a number of different variations in growth, as will be described below. One of the peculiar extreme forms, the multilocular echinococcus, is recognized by some authors as a distinct parasite but most writers deny Fig. 54. Diagram of an Echinococcus hydatid: cu, tliick external cuticle; pa, parenchym (germinal) layer; c, d, e, development of the heads according to Leuckart; f , g, h, i,k, development of the heads according to Moniez; I, fully developed brood capsule with heads; to, the brood capsule has ruptured, and the heads hang in the lumen of the hydatid; n, liberated head floating in the hydatid; o, p, q, r, s, mode of formation of secondary exogenous daughter-cyst; t, daughter-cyst, with one endogenous and one exogenous granddaughter-cyst u, v, x, formation of exogenous cyst, after Kuhn and Davaine; y, z, formation of endogenous daughter-cysts, after Naunyn and Leuckart; y, at the expense of a head; z, from a brood capsule: evag., con- stricted portion of the mother-cyst. (R. Blanchard slightly modified.) its right to distinct rank. It would seem to the writer that the present evidence, based largely upon geographical distribution and the larva, more than the adult stage, entitles it to rank as a sub-species, possibly as a species. If recognized as of sub-specific rank the correct name is Echinococcus granu- losus multilocularis-^ if recognized as a distinct species the correct name is * Synonyms. — Echinoccoccus multilocularis; E. alveolaris; E. muUilocularis exulcerans Huber, 1896; E. osteoklastes Huber, 1896. 37 578 THE ZOO-PARASITIC DISEASES OF MAN Echinococcus multilocularis. The finer points of distinction between the adult of this form and the typical form call for further investigation; the larval form or multilocular echinococcus is the "Gallcrtkrebs," "alveo- lar colloid," or "colloid cancer," usually found in the liver and reported, in man, especially for Kussia, Bavaria, Switzerland, Wtirtemberg, Aus- tria, the Alps, and Baden. Von Ledenfeld (18SG) states that an echinococcus tapeworm occurs in the dingo in Australia and may attain 10 to 30 mm. in length. The writer has not examined these worms, but unless confusion has here occurred with some other sj^ecies, he would incline to the view that this parasite represented a distinct species. Life-Cycle of the Parasite and Source of Infection. — The gravid, ter- minal segment of the tapeworm is discharged in the faeces of the dog, and the egg, which is said not to be very resistant, gains access to the inter- mediate host (sheep, cattle, hogs, man, etc.) through contaminated food or drinking water, or in the case of man, possibly also from hands soiled while petting dogs. Upon arriving in the stomach, the oncosphere (six- hooked embryo) escapes from the shell and, by means of its hooks, bores its way to various parts of the body, especially to the liver. Here it comes to rest and increasing gradually in size it presents a thick outer cuticle and an inner parenchymatic layer surrounding a cavity containing fluid. An outer connective-tissue cyst is furnished by the host. This simple form is known as an Accphalocystis Ljennec, 1804. Brood capsules arise from the parenchymatic layer and hang into the cavity; heads form in these brood capsules. If this stage is fed to dogs each head develops into a tapeworm. The growth of the hydatid need not stop at the stage last mentioned but daughter-cysts and even granddaughter-cysts may form and fall into the cavity of the mother-cyst; this variation represents the endogenous echinococcus,^ and is the more common variation as it occurs in man; it may attain 10 to 15 kilograms (22 to 33 pounds) in weight; the daughter-cysts may be numerous, "twenty-five to fifty" or up to "thousands." In still other cases the daughter-cysts pass outside of the mother-cyst into the surrounding tissue, thus giving rise to the exogenous echinococcus,^ a rather infrequent variation in man, but more common in ruminants, pigs and the horse. It occurs in the omentum, peritoneum, kidneys, mammary gland, and brain, exceptionally in the liver, but it never attains the enormous size sometimes seen in the endogenous variation. Frequency. — We are hardly able at present to give even approximate statistics covering the frequency of echinococcus infection in the United States. The writer recalls one abattoir (in Kansas City), where this infection in hogs was estimated several years ago at 1 per cent. This would indicate that in certain rural localities, indigenous cases have probably occurred in man which have escaped attention. Several years ago a former assistant (H. O. Somer) of the Avriter collated 100 cases in man for the United States and 12 cases for Canada, but as 33 of the United States cases were reported for New York alone, these statistics ^E. altricipariens Kuchenmeister, 1855; E. hominis (Zeder, 1800) Rudolphi. 1810. Echinococcus endogena (Kuhn, 1830); E. hydatidosus Leuckart, 1863. "^Echinococcus granulosus (Batsch, 1786) Rudolphi, 1805; E. veterinorum Rudolphi, 1810; E. exogena (Kuhn, 1830); E. scolecipariens Kiichenmeister, 1855f TJENIARIS—CESTODE INFECTION 579 must surely cover only a percentage of the cases which have actually occurred; they further show quite a percentage as having been found in foreigners, and as probably many, if not most of these latter brought their infection with them to this country, the figures can hardly be taken as representing American conditions. We may expect more cases in rural and village districts in which the "country slaughterhouse" flourishes. In Manitoba, the infection has been common among the Ice- landers. Of the English-speaking countries, Australia has presented the highest figures; the province of Victoria, for instance, is said to have 3 per 1,000 mortality from hydatids and 1 case of echinococcus for every 175 hospital patients, while 1.61 to 2.73 per cent. mortaUty is said to occur in South Australia. The estimate of 400 deaths per year for England is very difficult to accept, especially in view of the comparatively few articles on this disease in the current English medical journals, but Huber quotes Murchison as reporting about 1.5 per cent, infection in his postmortem examinations. In certain parts of Continental Europe, echinococcus dis- ease is not uncommon; thus Madelung reports for Rostock 1 case per 1,056 inhabitants; from 1861 to 1883, Rostock also showed 25 post- mortem cases in 1,026 autopsies, or 2.43 per cent.; and the slaughter- house statistics for entire Germany give an average of 10.39 percent, for cattle, 9.83 per cent, for sheep, and 6.47 per cent, for hogs. Iceland is recognized as the classical echinococcus land, but some of the estimates published must be taken with reserve. The more conservative statistics give the infection as from 1 in 43 to 1 in 63 of the inhabi- tants and Krabbe reports it for 25 per cent, of the dogs. Hydatids seem to be more common in females than in males, but some statistics give them as more common in males, and according to Meisser, they occur more commonly in patients from twenty-one to thirty years of age (about 30.8 per cent, of the cases collected), than from thirty-one to forty years (about 24.6 per cent.), forty-one to fifty years (about 15.2 per cent.), eleven to twenty years (about 13.2 per cent.), fifty7one to sixty years (6.2 per cent.), to ten years (4.8 per cent.), sixty-one to seventy years (2.8 per cent.), and seventy-one to eighty years (1.4 per cent.). The parasite is most commonly located in the liver. Thus, of 1,806 organ-infections, the following organs were the most frequently affected: liver (1,011), lung (147) and kidney (126); the parasite can, however, develop in any portion of the body. Duration. — The growth of the echinococcus is very slow; according to Leuckart's experiments on swine, it takes five months for the cyst to reach a diameter of 15 to 20 mm. If scolices are fed to dogs, the development of the adult worm is also slow; about ten to twelve weeks may be required for the worm to reach the gravid stage. How long an hydatid cyst might live in man is an open question; it has been stated that 50 per cent, of the infections are fatal within five years, but as many cases are doubtless not diagnosed, statistics on this point are naturally always open to some question. Authority exists for cases in man of two to eight years duration and even longer Symptoms. — ^The symptoms of echinococcus disease are practically those of a slowly growing tumor, which may attain 10 to 20 kilograms (22 to 44 pounds) in weight and which causes different symptoms according to its location. In some cases the worm may die, the parasite 5S0 THE ZOO-PARASITIC DISEASES OF MA^ then collapses and the cyst becomes gelatinous and thick; the heads, or at least the hooks, may be found in tlie altered, thick, opaque contents. In some cases the cyst may suj)purate. The hydatids are occasionally discharged through various channels (bile-ducts, lungs, in urine, etc.). Urticaria may develop upon the ru])ture or puncture of the cyst admitting the echinococcus fluid into the body cavity, but it is said to occur also in case of ap|)arently uninjured cysts. Diagnosis. — In many, but not all cases, the so-called hydatid thrill or fremitus is felt on percussion, resembling the quivering of jelly. Deeply seated echinococci give an elastic feeling, superficial parasites a fluctua- tion. Positive diagnosis may be made microscoj)ically by finding the hooks or heatls in case of discharge, or in the aspirated fluid; and ])re- sumptive diagnosis may be made by finding sugar in the aspirated fluid. The multilocular echinococcus is usually in the liver and accompanied by a chronic icterus. Treatment. — Numerous methods of medicinal treatment have been proposed for hydatitl disease, all having one attribute in common, namely, apparent uselessness. Echinococcus infection is a surgical disease and in our present knowledge of the malady only surgical interference is capable of curing it. For the technique of operation, the reader is referred to works on surgery. Several authors refer to "boldly incising the cyst, " but attention may be directed to the fact that by o]:)ening the external cyst (namely the surrounding cyst which is furnished by the host) very cau- tiously, the inner cyst (namely the parasite itself) can be taken out entire; to do this the external cyst should be raised at a convenient point leaving a small space between it and the inner cyst. To gain experience in this operation it is well to practice on several echinococcus livers of hogs or other animals from a slaughter house; judging from the observations of the writer on the killing floors of our large abattoirs, such experimental material is not difficult to obtain. Strictly aseptic tapping has been fol- lowed by recovery. In the event of suppuration the condition is treated as one of abscess. Prevention. — Since this disease is transmitted from dogs to man, and since dogs obtain their infection more particularly from eating the in- fected organs of slaughtered sheep, cattle, and hogs, it is clear that any plan of prevention should follow two lines: First and most important, dogs should be kept away from slaughter houses in order to prevent them from eating the organs rejected on account of hydatid infection; the rule that no dog which enters a slaughter house or its refuse yard should ever be allowed to leave would, if carried out, save many lives and much valuable live stock, but it is difficult of practical application. Secondly, whatever our affection may be for "Old Dog Tray," we should recall that he is a dog and not a human being; in his place he is useful, but out of his place he may be a very dangerous friend. So far as can be judged from the federal meat inspection, hydatid disease is much more common than is generally supposed. As stated above, the writer recalls one abattoir where the infection among the hogs was estimated at 1 per cent. ; with this percentage it seems positive that in some sections of the country the parasite has developed to such an extent that local boards of health should institute measures for its control by placing the local slaughter houses under sanitary supervision. TJUNIASIS—CESTODE INFECTION 581 Sparganum Mansoni (Cobbold, 18S2) is a larval hothriocephalide tapeworm reported 10 times^ in the Japanese. It measures 8 to 36 cm. in length by 0.1 to 12 mm. in breadth, and 0.5 to 1.75 mm. in thickness; it is flat and unsegmented and as yet no stage with genital organs has been found. It occurs in the subperitoneal connective tissue and body cavity of man in Amoy and Japan. Sonsino reports it for the jackal in Egypt. Daniels found this or a similar parasite in British Guiana. Of the Jap- anese cases, 7 of the patients were males, 2 were females, 1 unstated. By age: 1 case occurred in a patient nine years old, 3 cases between eleven and twenty, 3 between twenty-one and thirty, 1 between thirty- one and forty, 1 between forty-one and fifty, 1 unstated. The parasite was lodged in the region of the eye in 3 cases; it escaped from the urethra in 4 cases; was in the connective tissi^e of abdominal region in 1 case and in the pleural cavity in 1 case. A single parasite was reported in 9 cases, 12 parasites in 1 case. Looss (1905) suggests that the escape of the worm through the urethra indicates that the definite host is an aquatic animal and he thinks the regular intermediate host may possibly be one of the large ruminants. Surgical treatment should be used in superficial swellings, while in urethral cases the worm should be extracted while the patient is in a warm bath, the parasite being slowly drawn out or wound around a stick under water. It might perhaps be well to give the parasite a hypoder- mic injection of morphine shortly before pulling it out. Sparganum proliferum^ (Ijima, 1905) is a peculiar larval Japanese cestode reported but once. It occurred in the subcutaneous tissue, especially of the leg, and produced acne-like swelling and a condition somewhat similar to elephantiasis. The worms measure 1 to 12 mm. long by 2.5 mm. in breadth, and possess the peculiarity of reproducing by budding. Adults and life history are unknown. 1 For compilation of cases to date, see Stiles and Tayler, 1902, pp. 47-56, figs. 30-36. 2 Synonyms. — Plerocercoides prolifer Ijima, 1905; Plerocercus prolifer Ijima, 1905. CHAPTER XXVI. ROUNDWORM INFECTION— NEMATHELMINTHES. By CHARLES WARDELL STILES, Ph. D. D. Sc. The roundworms are divided into three orders (see key, p. 531), namely the Nematoda, the Gordiacea and the Acanthoccphali. Of these, the nematodes are by far the most important, while the horse-hair worms and the thorn-headed worms are of secondary importance in human medicine. For practical reasons they will be arranged in this article according to the part of the body they inhabit instead of according to their zoological arrangement. Systematically the nematodes parasitic in man are classified as follows : Family Anguillulidge : genera Anguillula, p. 624; Anguillulina, p. 602; Leptodera, p. 624; Rhabditis, p. 611. " Angiostomidse : genus Strongyloides, p. 595. " Gnathostomidse : genus Gnathostoma, p. 611. '' Filariidse: genera Filaria, p. 613; Dracunculus, p. 611; Agamofilaria, p. 623. " Trichinellidffi: genera Trichinella, p. 605; Trichuris, p. 603. " Strongylidae : genem Metastrongylus, p. 610; Trichostrongylus, p. 602; Uncinaria, p. 583 ; Agchylostoma, p. 584; Necator, p. 583; Dioctophyme, p. 624; Physaloptera, p. 602. " Ascaridse: genera Ascaris, p. 597; Toxocara, p. 597; Oxyuris, p. 600. INTESTINAL ROUNDWORMS. Uncinariasis^ or Hookworm Disease.— Geographical Distribution. — Uncinariasis encircles the globe in the tropical and subtropical belt, diminishing in frequency in the temperate climates, but occurring locally in mines as far north as England, Holland, and Germany in Europe; in North America the endemic infection stops about at the Potomac River. Zoological Distribution. — Generically identical, but specifically distinct infections occur in dogs, cats, foxes, and various other animals. The infection of cats, which was supposed to be specifically identical with the Old World hookworm of man, has proved to be distinct and the infection of the chimpanzee, supposed to be identical with the New World hook- worm of man, is also probably distinct. ^Synonyms. — Anchylostomiasis; ankylostomiasis; brick-makers' anaemia; dirt eating (in part); dochmiosis; Egyptian chlorosis; geophagia (in part), malarial anaemia (in part); malnutrition (in part); miners' anaemia; miners' cachexia; negro consumption; St. Gothard tunnel disease; tropical chlorosis; tunnel anaemia; tunnel disease. 6S2 RO UNDWORM INFECTION— NEMA TIIELMINTHES 583 The Parasites. — Hookworm disease in man is known to be due to two distinct species of parasites belonging to the subfamily Uncinariinse/ namely, the Old World hookworm and the New World hookworm. The New World hookworm, Necator americanus^ (Stiles, 1902) or Fig. 58. Fia. 67. JuiSffll. Fig. 55. Fia. 56 tcm.t. «R Fig. 55. — New World male hookworm. Natural size. (Stiles.) Fig. 56. — New World female hookworm. Natural size. (Stiles.) Fig. 57. — The same, enlarged to show the position of the anus (a) and the vulva («). (Stiles.) Fig. 58. — Dorsal view of anterior end of New World hookworm: b.c, buccal cavity; c. p., cer- vical papillse; d.w.<., dorsal median tooth, projecting prominently into the buccal cavity; d.sm.l., small dorsal semilunar lip; c, oesophagus; m.m. margin of mouth, the prominent oval opening 'seen upon high focus; p. p. papillae; v. sm. I., large ventral semilunar lips homol- ogous with the ventral hooks of A. duodenale Greatly enlarged. (Stiles.) 1 As this group of worms is more carefully studied, it becomes apparent that the old genus Uncinaria {ty-pe vulpis =criniformis) must be divided into at least four smaller groups: Uncinaria (type vulpis), Agchylostoma (type duodenale) , Neca- tor (type americanus), Bunostomum (type trigonocephalum), and probably into several additional units. Opinion will probably differ for some time to come as to whether these units represent genera or subgenera, but evidence is accumula- ting to the effect that they should be given generic rank. Changes in the generic nomenclature in consequence of such division, are of course unavoidable, in the same way that a new terminology had to be used when (1860) trichinosis was differentiated from typhoid fever. No changes, however, in the specific nomenclature of the two forms {americanus and duodenale) found in man can be foreseen. ■* Synonyms. — Uncinaria americana Stiles, 1902; Ankylostomum ameri- canum (Stiles) Linstow, 1903 (exclusive of form in the chimpanzee) ; Unci- naria (Necator) americana (Stiles) ; Necator americanus (Stiles) ; Uncinaria hominis Ashford, King and Gutierrez, 1904, in part. 584 THE ZOO-PARASITIC DISEASES OF MAN Fig. 59. Uncinaria americana Stiles, 1902, is the common hookworm of the American continent and adjacent islands but it has been introduced into Italy, and doubtless also into Spain. It has been reported recently also for Africa, China, and Guam. This cylindrical worm is 7 to 11 mm. long and jiossesses a dorsal and a ventral j^air of lips at the mouth, a prominent dorsomedian buccal tooth, and four buccal lancets ; in the male, the dorsal ray of the bursa divides at the base and each branch possesses two tips. In the female the vulva is in the anterior half of the body. The eggs are thin-shelled, G4 to 72^ long by 36 to 40;^ broad; they are oval with somewhat bluntly rounded poles. The Old World hookworm, Agchylos- ioma duodcnalc^ Dubini, 1843, or Unci- naria duodenalis (Dubini, 1843) Railliet, 1885, is the common hookworm for Europe, Asia, Africa, and Australia, but it has also been introduced to some ex- tent into the Americas. This parasite measures 8 to 18 mm. in length and possesses in its mouth 2 pairs of strong, curved, ventral teeth and 1 pair of knob- like dorsal teeth; the dorsomedian tooth of the buccal capsule is nil or practically so; a pair of ventral lancets is present in the buccal cavity. In the male, the dorsal ray of the bursa is divided two-thirds its length from the base and each branch is subdivided into three tips. In the female, the vulva is in the caudal half of the body. The eggs measure 52 to 61 /x long by 32 to 38 /x broad; they are oval Avith very bluntly rounded poles. Both parasites inhabit the small intes- tine, especially the jejunum and ileum but also duodenum and occasionally the stomach. Source of Infection, — The eggs are oviposited in the intestine of the patient; they do not develop until after they escape with the faeces; then they develop within twenty-four hours or more, according to co,nditions of heat, moisture and amount of oxygen, a rhabditiform embryo which undergoes ecdysis (shedding of skin) after about forty-eight to seventy- two hours; a second ecdysis which occurs within about five to nine days changes the worm to the infecting stage — the so-called "encysted larva"; from this point the worm takes no more food until it reaches man. In- fection takes place in two different ways: (1) It has been experi- mentally demonstrated, first by Looss, that the hookworm larva? may pass through the skin, reach the circulatory system, pass with the blood Four eggs of the New World hook- worm, in the 1, 2, and 4-cell stages. The egg showing 3 cells is a lateral view of a 4-cell stage. These eggs are found in the faeces of patients and give a positive diagnosis of in- fection. Greatly enlarged. (Stiles.) * Synonyms. — Agchylostoma duodenale Dubini, 1843; Ancylostoma duodenale (Dubini) Creplin, 1845; Dochmius duodenalis (Dubini) Leuckart, 1876; Anchi- lostoma duodenale (Dubini) Bozzolo, 1879; Uncinaria duodenalis (Dubini) Rail- liet, 1885; Ankylostoma duodenale (Dubini); Ankylostomuyn duodenale (Dubini); Uncinaria hominis Ashford, King, and Gutierrez, 1904, in part. RO UNDWORM INFECTION— NEMA TIIELMINTIIES 585 through the heart to the hings, from the lungs to the air passages, up to the larynx, down the oesophagus to the stomach and then to the small intestine. Looss's theory of skin infection first met with oj)position, incredulity, or reserve from various sides, but it now stands on the firm foundation of experimental proof and has been accef)ted not only by helminthologists who first preserved a noncommittal position toward it, but Fig. 00. V.p. Or. oes. - c. g. \ 7 — d. p. Dorsal view of the Old World hookworm: c. 3. opening of cephalic gland; v. I. ventral lancet; d. p. V. p. dorsal and ventral papillae: note also the four teeth. Greatly enlarged. (Looss.) also by men who at first directly opposed it. Strange and incredible as the view is, it is now not only established as a possible method of infection but evidence is rapidly accumulating to the effect that it is a common, if not the most common, method by which hookworms gain access to the system. (2) A second method of infection is through the mouth, either Fig. 61. Six stages in the embryonic development of Old World hookworm; fresh faces. X 336. (Looss.) e f a-c. are the stages found in with contaminated food or water or from earth containing the hookworm larvae and clinging to the hand. Since Looss' skin infection theory has been proved, the idea of infection through the mouth has lost many sup- porters, and numerous arguments are submitted to prove that it is of exceptional occurrence. That the time may perhaps come when the skin infection will be generally accepted as the most important method, may 586 THE ZOO-PARASITIC DISEASES OF MAN be readily admitted, but it does not seem to the writer that the time is now here when we would be justified in looking upon infection by the mouth as a curiosity or as a method which can be practically ignored. The skin- infection, as demonstrated by Looss, is a most brilliant proof of the correctness of an old-fashioned popular view which obtained regarding infection with certain parasites, a view which was practically abandoned as being too complicated and improbable, when the mouth offered such a simple, probable, and, in some cases, demonstrated entrance for intestinal worms. And it would be wise for us now not to be carried away with these new brilliant discoveries and this demonstration of the correctness of an old-fashioned idea to such an extent that we fall into error of forgetting that worms can and do enter the system by the mouth and that, given the proper conditions, there is no reason at present evident why the hook- worm should not be taken into the body in this way. The view advanced by several authors that the free embryos may de- velop into free adults, the progeny of which become parasitic, is not in harmony with what is otherwise known of this group of worms. Frequency. — Uncinariasis is a malady the spread of which is incon- sistent with a proper sewage system, cold weather or dry conditions. Accordingly, in general terms, it is more common in moist localities than in dry, more common in warm countries than in cold and more common in rural districts than in cities. Although it is one of the worst scourges of the tropics, even here its frequency may be decreased by a proper disposal of faeces, for fortunately the specific infections in man are not known for other animals. It is more common among people who come into direct contact with damp earth, as farmers, miners, tunnel-diggers and people who go bare- footed, than it is among persons of other occupations and those who wear shoes. Most authors report that it is more common among men than among women and children, but this view is not in harmony with the writer's experience, for he has found it more common and more severe in children and in women than in adult males. It is not difficult to harmonize these divergent statements. Physicians reporting for mining districts Avould, in general, find more cases among the miners, namely among men, for the infection here occurs chiefly "underground," while the homes in many mining districts are provided with sewage or with proper privies and the miners' families are thus more or less protected from infection. Further, most authors have reported upon cases which came to them for diagnosis and treatment, while in the investigations of the writer he went to the families in order to find the cases; hence the conditions covered by his repo ts represent more exactly the natural conditions in the rural districts visited. Again, in rural districts containing more children and women than adult males, as found in the localities in question, under conditions favorable to infection there would naturally be more cases among the chil- dren and women; furthermore the children and women were following a life more conducive to infection, namely staying near the house, in the area of concentrated infection, more than were the men, and infection would therefore be expected to be more common among the former. Ashford, King, and Gutierrez (1904) in their splendid "Report on Anemia in Porto Rico" found more cases (1,027 of 5,490) between the ROUNDWORM INFECTION— NEMATHELMINTHES 587 ages of five and nine years than at any other five-year period; of the same 5,490 patients, 3,259 or 59.34 per cent, were males, and 2,231 or 40.66 per cent, were females. The percentages relative to sex will naturally vary according to customs and proportion of sexes in different countries. In the districts which were visited by the writer, uncinariasis was pre- eminently a disease of the piney wood and sand localities, occurring less in clay regions. However this distribution was not confirmed by Ashford, King, and Gutierrez in Porto Rico. Some of the physicians in the South have confirmed the author's findings in this respect while others have ob- tained different results. The explanation of the different findings is not clear at present. There is evidently some factor in the case which has thus far escaped attention and which will doubtless harmonize the diver- gent reports. Possibly Nicholson and Rankin (1904) have given the correct clue when they state that it is not so much a question of the sandy nature of the soil as it is a question of fiiie soil which by its ability to hold moisture offers the most favorable conditions for development. Further, the trees would naturally protect the young worms, to some extent, against the drying effects of the sun. A certain seasonal periodicity is shown in so far that infection decreases in cold and very dry seasons, but increases in warm and moist seasons. Uncinariasis is more common and more severe among the poor than among the well-to-do, and more common among people who live under conditions of filth than among those who live under better hygienic conditions. As for statistics, some physicians in Southern Florida estimate that 90 per cent, of the rural population in that district harbor the parasite to a greater or lesser degree, and Ashford, King, and Gutierrez estimate that about 90 per cent, of the rural population of Porto Rico are infected. In some German mines, 30 to 80 per cent, of the miners have been found infected. So far as known the infection is rare in American mines. Symptoms. — Cases may be divided into light, medium, and se'ye?'^ infec- tions. Under the light infections may be included those patients who show eggs in the faeces upon microscopic examination, but who do not ex- hibit any or sufficiently marked symptoms to attract special attention. These cases are numerous and are important in that they are capable of keeping a region infected and thus giving rise to severe cases; hence from a prophylactic standpoint, they should always be treated when found. Under medium cases may be included those persons who show a definite ansemia, while other symptoms, mentioned below, develop to an extent which attract sufficient attention to bring the patient under medical treat-^ ment; a physician in the infected district should immediately suspect un- cinariasis, but the Northern physician might not be so promptly led to this diagnosis. Under severe cases may be classified the typical dirt- eaters who present a clinical picture which even the laity in the South recognize on sight. A fourth class, very severe cases, may be recognized if desired, to include those patients in whom death may occur at any moment. It is needless to say that these four phases grade imperceptibly from the lightest to the most severe. The division suggested is a compromise be- tween the classification proposed by the writer in 1902 and that used by Ashford, King, and Gutierrez (1904) and is here adopted from a practical standpoint in prophylaxis in order to lay stress upon that large number 588 THE ZOO-PARASITIC DISEASES OF MAN of cases in which eggs may be present but nu special syinptoiiis noticed; these cases must be constantly kept in mind in any scheme for eradica- tion of the disease, and are likely to be overlooked or ignored unless special attention is directed to them. Thus, of 16 medical students examined by the writer in one of the Southern medical colleges, 4 showed infec- tion but only 1 of these exhibited even slight symptoms; and Nicholson and Rankin (1904) have recently shown that there are numerous cases of infection in North Carolina which were not even suspected until the microscopic examination Mas made. If these light cases were submit- ted to physical examination for enlistment in the army or navy, probably most of the men -would be accepted as sound, unless some other defect were found. General Development. — If infection occurs before ])uberty it is likely to retard devel()j)ment both ]>hysical and mental. A boy or girl of twelve to fourteen years may appear to be eight to ten and one of eighteen to twenty-two may not appear to be over twelve to sixteen. Skin. — The skin may be waxy wdiite to dirty yellow, tallow or tan, the color being a general superficial, but not in all cases exact, indication of the degree of antemia. It becomes dry and parchment-like, perspiration being more or less completely suppressed. Petechise may be observed in older cases. Pruritis may be noticed more or less frequently. Atrophy of the skin is seen in chronic cases. Ground Itch. — As Bently (1902a) pointed out, it is very common to find a history of ground itch in hookworm districts. Of 4,741 Porto Rican patients questioned by Ashford, King, and Gutierrez on this point, 4,654 or over 98 per cent, gave a history of "mazamorro," as the dermatitis is called by the natives. "New Sump bunches" is the corresponding condition in the Cornwall miners as reported by Boycott and Haldane. Claude Smith and other observers in our Southern States report a similar condition as common. The present evidence is that this rapidly develop- ing condition (characterized by a few itching papules to a severe dermi- titis, found more particularly in bare-footed people, between the toes especially and on the sides and top of the foot, and in some cases on the buttocks or other portions of the body) is the initial symptom of uncinari- asis, due to the penetration of the larvse into the skin, and doubtless ac- companied in many cases with some bacterial infection. The writer is not aware that any dermatologist has as yet made any special study of ground itch and until this is done it will be wise to leave the question open as to whether all cases of this affection are due to uncinariasis, especiaWy since Strongyloides larvae, also, may enter the skin. Sufficient evidence has however been presented by the supporters of the ground itch theory to compel its recognition as a very general symptom of hook- worm disease. Hair. — While the hair on the head may be normally developed, there may be a marked scarcity or absence of hair on the pubes, in the armpits, and on other parts of the body, in patients who become infected before puberty. (Edema. — (Edema of the face, feet, ankles, leg, scrotum, or entire body may be present. According to the Porto Rican (1904) statistics it was most frequently found in patients showing a haemoglobin of 20 to 49 per cent. ROUNDWORM INFECTION— NEMATHELMINTIIES 5S9 Wounds and Ulcers. — In a number of cases, it is noticed that even slight lesions of the skin heal slowly. Head. — The face may show an anxious, stupid expression. The con- junctivae may be chalky-white. The puj)ils have a decided tendency to dilatation; the patient may show a blank stare; night-blindness is re- ported in a number of cases. The visible mucous membranes vary from a natural color to a white, corresponding more or less to the degree of anaemia. The tongue may show two purplish smears, one on each sicJe of the median lines; pigmented spots and a partial denudation of the epi- thelium may be observed. Neck. — Cervical pulsation, especially in severe cases, is very evident, often being visible from six to twelve feet from the patient. Thorax. — In emaciated cases the ribs are of course very prominent. Abdomen. — A more or less prominent abdomen is rather common, known among the laity as "jDot-belly," "butter-milk belly" or "shad- belly," and ascites may develop. Digestive System. — Appetite: This may be light to ravenous; in late stages there may be complete anorexia. There is further a marked ten- dency to the development of abnormal appetite for sour articles as lemons or pickles, or for salt, coffee, and buttermilk, or a perverted appetite for resin, charcoal, chalk, tobacco ashes, dried mortar, mud, clay, sand, gravel, shells, rotten wood, cloth, garments (the writer met one boy who had eaten three coats, thread by thread, within one year!), paper, tobacco pipes, and even mice and young rats. Salivation is frequent. Flatulence and heartburn are common. Nausea is frequently reported. Vomiting may occur. Pain and tenderness in the epigastrium are men- tioned by nearly all observers; Ashford, King, and Gutierrez (1904) give it as "the most constant, most suggestive, and most clearly marked of all the symptoms of the digestive tract." It may be brought into promi- nence by pressing on the right hypochondrium. Constipation is common, but diarrhoea may be present. The statements by authors relative to the faeces are very contradictory. Ashford, King, and Gutierrez found blood macroscopically in only 6 cases and blood and mucus in 5 cases, out of over 22,000 faecal examinations, statistics which are far below the condi- tions observed in the Southern Atlantic States by the writer. Leich- tenstern has suggested that the blood is more likely to appear during the period of. copulation of the worms. Whatever the conditions are which have determined the divergent observations, evidence shows that in some cases blood may be absent, in other cases present, either macroscopic- ally or microscopically, in the stools. Circulatory System. — Heart: The apex beat is pronounced in the slight grades of the disease; in moderate grades it is often displaced downward and to the left; in marked grades, a notable phenomenon is the great reduction in the force of the apex beat, which is replaced by a wavy, indefinite pulsation in the epigastrium, or a tumultuous heaving of the whole pericardium and in these cases cyanosis, chiefly in the lips, is likely to be noticed; a presystolic thrill is not infrequent in moderate cases, more common in marked cases; in moderate cases, hypertrophy, especially of the left ventricle, causes an enlargement of the heart area, the murmurs are best heard in the third intercostal space; in moderate cases, hsemic murmurs are almost always present (Ashford, King, and 590 THE ZOO-PARASITIC DISEASES OF MAN Gutierrez). Palpitation occurs early and is very prominent and con- stant. Dyspnoea is very common, especially in the later stages. The pulse varies from SO to 132, without any necessary relation to the tem- perature; in the later stages it becomes dicrotic, then weak and com- pressible, finally thready, irregular and intermittent. Blood. — The anannia is the most pronounced symptom and has been taken as basis for a number of the vernacular names of the disease (miner's ant^mia, brick-maker's anjvmia, etc.); it is natural that recent authors have conducted special studies on the blood. Ashfo'-d, King, and Gutierrez (1904) especially have made a faithful study of the blood contlitions. In one series of 540 jjcrsons, compared as to race, they found the average ha'moglobin at over 45 per cent, in whites, over 44 per cent, in mulattoes, and over 49 per cent, in negroes. In a series of 577 persons compared, in reference to sex, the males showed an average of 41 per cent, hc-emoglobin, females 48 per cent. As extremes, 8 per cent, and 101 per cent, are reported, while special selected cases ranged from 9 to 65 per cent., with an average of 24.38 per cent. Of one series of 579 cases, the haemoglobin upon later examination during treatment showed an increase in 371 cases from 1 to 71 percent., average 21.34 per cent.; 45 cases lost from 1 to 16 per cent., average 5.04 per cent.; 7 cases neither gained nor lost; a weekly increase of 20 to 30 per cent, was not rare. During the disease, the htemoglobin falls before the red cell count and may reach as low as 30 per cent, before much change in the reds is no- ticed; under treatment the reds usually increase more rapidly than the hfemoglobin. The red cells vary from 754,000 to normal according to conditions ; of 61 special cases, the average was 2,406,416; as the disease pro- gresses, the cells become polychromatophilic and show poikilocytosis; under treatment the red cells increase very rapidly, reaching or exceeding normal sometime before the haemoglobin. In 42 treated cases with a final average of 100 per cent, haemoglobin, the red cells averaged 5,624,197. Leukocytosis was not met with in Porto Rico; the majority of cases showed 5,000 to 10,000 leukocytes, and in chronic cases of long standing leukopenia was often found; the average white count of 61 cases was 8,009 on admission; during treatment 42 cases increased to 9,041 whites, 16 cases to 7,533 whites, and 3 fatal cases in- creased to 14,133. The eosinophil es present special interest: very severe chronic cases with poor resisting power and exhausted blood- making organs have little or no eosinophilia; a rise in eosinophiles is of good prognostic import; if very severe cases, presenting little or no eosinophilia, show a fall in the eosinophile count, the prognosis is not generally good; in general, good resistance to the toxin of hookworms is expressed by eosinophilia; the "special" cases gave an average of 10.8 per cent, before treatment, and 13.2 per cent, after treatment. In 29 cases, before treatment, the differential leukocyte count averaged as follows: eosinophiles, 17.1 per cent.; polymorphonuclears, 54.5 per cent.; small lymphocytes, 16.3 per cent.; large lymphocytes, 8.6 percent.; other leukoc\ies, 3.5 per cent. Respiratory System. — The respiratory symptoms are not character- istic. Patients may complain of difficulty in breathing, especially after exertion. ROUNDWORM INFECTION— N EM ATHELMINTHES 591 Temperature. — This may be normal, subnormal, or reach 100° to 102° F. Fever at the onset is said to be a fairly constant symptom in Porto Rico. Nervous System. — ^The effect of uncinariasis upon the mental condition is marked; the infected children, of school age, are greatly handicapped by it in their studies; in severe cases, there is a noticeable delay in answer- ing even simple questions and some of the patients are more or less stupid. Mental lassitude, headache and dizziness are frequently noticed; the patients may be more timid and emotional than normal; the patellar reflex is diminished or suppressed; tingling and formication are common; either insomnia or somnolence may be marked; dizziness is common, especially upon rising suddenly to the feet; joint-pains are also very frequent. Muscular System. — ^The muscles are soft and flabby, and the patient is naturally weak; he tires easily, is obliged to rest after slight exertion and a feeling of lassitude is experienced which, in absence of severe symptoms, may seem unexplained ; as a result, persons who are not acquainted with the true condition attribute it in the less evident cases to laziness, and there is no doubt but that much of the alleged laziness in infected dis- tricts is simply the natural lassitude connected with uncinariasis. A person with a haemoglobin of 30 to 60 per cent, and a subnormal blood count as a result of hookworm infection cannot be expected to be vigorous, any more than a person with this condition of the blood as a result of other infection. Urinary System. — The urine varies from 1,010 to 1,015 in specific grav- ity, is pale, neutral or alkaline, rarely acid, and is increased in amount. Genital System. — In case of infection before puberty, delayed develop- ment may be very marked. Menstruation is delayed several years beyond the normal and may be more or less irregular, or absent, especially in summer. Abortions and miscarriages are frequent. Sterility and impo- tence are common. Lethality. — The writer cannot state the average lethality of untreated cases in the United States, but Ashford, King, and Gutierrez (1904, p. 88) after a most careful study of the subject, express the astounding — yet probably correct — opinion that 30 per cent, of the deaths in Porto Rico are due to uncinariasis! The Porto Rico Commission treated 5,490 cases, with the following results: cured, 2,244 cases, or 40.8 per cent.; practically cured, 377 cases, or 6.8 per cent.; improved, 1,727 cases, or 31.4 per cent.; result not recorded, 522 cases; never returned, 224 cases, and ceased to return, 283 cases, total 18 per cent. ; unimproved, 86 cases; died, 27 cases, or 0.5 per cent. Sandwith (1894, pp. 16-17) states that of the patients nominally under his care, 89.5 per cent, were cured or greatly relieved, 2.5 per cent, were not relieved, 8 per cent. died. Pathology. — Aside from the anaemic conditions, attention may be directed to the intestinal tract. The stomach is usually dilated and exhib- its a chronic catarrh. The small intestines, especially the jejunum and ileum, show a diffuse catarrh of variable severity, and the bites made by the worms; hemorrhages may be present or absent; there may be large spots of hemorrhagic infiltration with a worm hanging from its centre; there is a chronic interstitial inflammation; Ashford, King, and Gutierrez report the intestinal wall as very much thinned but several authors report 592 THE ZOO-PARASITIC DISEASES OF MAX it as very much thickened; constrictions have been reported in South American hterature. The parasites injure in different ways, but evidence seems to be accu- mulating in support of the view that it is their toxic effect which is the most serious. Loeb and Allen J. Smith have shown that hookworms produce a substance which inhibits the coagulation of the blood. Economic Importance. — A person who has not been in an uncinariasis district and who has not seen the extent of the cases, the way the people live, or rather exist, how they attempt to work, how little they accomplisl compared with what they might do if they were healthy, how the mental faculties arc tlullctl, how backward the children are, how exhausted the laborers become and what a change takes {)lace in them during and after treatment, may find it difficult to grasp the full economic importance of this malady. As stated by the writer in 1902, it was "exceedingly difficult to escape the conclusion that in uncinariasis, caused by Uncinaria amencana, we have a pathological basis as one of the most important factors in the inferior mental, physical and financial condition of the poorer classes of the white population of the rural sand and piney wood districts visited. This sounds like an extreme statement but it is based upon extreme facts." Since this statement was published many southern physicians have either stated or written that they are of the same opin- ion. The economic importance of the malady in Porto Rico, as depicted by the Porto Rican Commission must be accepted as not being exagger- ated; and as observations in the United States multiply, what once seemed an extreme opinion is now rapidly becoming a very conservative view. The importance of the disease in the cotton mills is not to be under- estimated. The typical cotton mill "anaemic," of whom the writer has seen a number in different parts of the South, is a diagram of medium uncinariasis. From a purely financial point of view, it would pay the cotton mills to compel all candidates for positions to submit to micro- scopic examination for diagnosis, and, if infected, also to treatment, before they are given employment. Whether the American coal mines will experience a repetition of the sad and expensive history European mines have had from hookworm disease, will depend primarily upon the sanitary regulations they enforce. Diagnosis. — In severe cases, a diagnosis upon symptoms can be made with a very high probability of correctness by anyone who is familiar with the disease. A positive diagnosis may be made in either of two ways: (1) Examine the fpeces microscopically to find the eggs^; or (2) give an anthelmintic experimentally and examine the stools for the adult worms. Blotti7ig-paper Test. — For persons who have no microscope a very simple test may be made with filter-, blotting- or ordinary newspaper. Fold an ounce or so of faeces in the paper and allow it to stand for several hours, then unwrap and examine for a blood stain. ^Recently, Bass, (1906) has suggested a new method for concentrating the eggs. He shakes thoroughly a portion of ixcal matter in a test tube, or similar receptacle, filled nearly to the top with a nine-tenths saturated solution of salt in water. As the specific gravity of the eggs is less than that of the salt water, they float to the top. This procedure has been tested by the writer several times and the observations confirmed. The method takes more time, however, than does the ordinary examination of slides, but in some cases may be morQ satisfactory. ROUNDWORM INFECTION— NEMATIIELMINTHES 593 Several authors who have criticized this test, seein not to have under- stood why it was suggested and have objected that it is open to error. Certainly it is open to error, the same as are numerous other tests, but in not a few cases it is an additional link in the evidence-chain, exactly as the anaemia, the dirt-eating, the red cell count, etc., and for the "country physician" who probably owns no microscope, and who is perhaps fifty miles away from any one who does, it forms an additional clue. The writer has found it useful u})on a number of occasions, even when a microscope was at hand, but it is self-understood that a] rough test of this kind is not to be given much weight when a better test can be made, neither is a negative result with it to be accepted as final. Treatment. — The usual drug used in uncinariasis is either thymol or male fern and recently beta-naphthol is springing into popularity. Thymol. — ^As the parasites are more or less protected by the mucus in the intestine, this should be removed by administering magnesium or sodium sulphate, or other purge, the evening before the anthelmintic is taken. Early the next morning, say at eight o'clock, give (adult dose) 2 grams (30 grains) of finely powdered thymol in capsules; at ten o'clock, re- peat this dose; at noon, administer another dose of salts. The size of the dose should be modified according to the age or the condition of the pa- tient. Ashford, King, and Gutierrez, on the basis of an experience with 12,330 doses, state that in general 0.5 gram (7.5 grains) may be given with good results to children under five years; 1 gram (15 grains) between five and ten years; 2 grams (30 grains) between ten and fifteen years; 3 grams (45 grains) between fifteen and twenty years; 4 grams (60 grains) between twenty and sixty years ; 2 or 3 grams (30 to 45 grains) above sixty years; and in common with other clinicians they warn that certain conditions as great debility, very old age, pregnancy, advanced cardiac or other organic disease, a tendency to vomit, anasarca, chronic diarrhoea and dysentery are unfavorable to the administration of thymol. This medication is carried on one day per week until the patient is cured. It is in the interest of safety not to allow or give by mouth any alcohol, oil or other solvents of thymol on the day of treatment. If stimulants are necessary, they may be given hypodermically. Many authors warn about the ill effects of thymol. The Porto Rican Commission, after administering 12,330 doses seems to incline to the view that these warnings have been exaggerated and states that, "under certain precautions," they "came to know that thymol was an exceedingly in- oft'ensive drug." Still, they warn of certain ill effects in some cases (especially with chronic enterocolitis, oedematous patients, etc.), and while they state that they had no deaths directly attributable to thymol, it might perhaps be legitimately recalled that of 4,482 persons treated at Utuado, 224 patients, or nearly 5 per cent., never returned to the clinic after their first medication. Whether a history of any of these 224 cases would have modified the conclusions reached is not altogether clear, but so far as known (even with the unusually efficient check on deaths occurring on the island) none of these patients died. The Porto Rican Commission is entirely in harmony with the excep- tion taken by the writer to the apparently prevailing opinion of English writers that large doses of thymol must necessarily be given. If a patient jannot stand a large dose, smaller doses will expel a few worms and thus 38 594 THE ZOO-PARASITIC DISEASES OF MAN enable him gradually to reach a condition in which the dose may be increased. Of 4,630 Porto Rican patients treated with thymol, the worms were entirely expelled in 3,630 cases: 1 treatment was required in 1,518 cases; 2 treatments in 1,166 cases; 3 treatments in 518 cases; 4 treatments in 247 cases; 5 treatments in 104 cases; 6, in 47 cases; 7, in 19 cases; 8, in 6 cases; 9, in 3 cases; 10, in 1 case; and 11, in 1 case. The number of doses varied, of course, with the severity of the case. Beta-napJitJiol. — Beiitlcy (1904) abandoned thymol two years ago in favor of beta-naphthol. This he has now used in several thousand cases with excellent results. The Porto Rican Connnission^ used it with success in several cases. The drug is used in the same way as thymol, but with doses one-half as large (total of 2 grams — 30 grains, instead of 4 grams — 60 grains). Extract of Male Fern. — This drug has been used successfully in thou- sands of cases of hookworm disease. With thymol producing less serious effects than male fern, the former drug should, however, be shown preference. If it fails, male fern can be used. The dose is 4 to 8 Cc. (about 1 to 2 fluid drams) followed by salts or calomel and salts. Eucalyptus Oil and Chlorojorm. — In severe cases, especially when the patients are weak, Phillips (1905) favors the following formula: Euca- lyptus oil 2. to 2.5 Cc, chloroform 3. to 3.5 Cc. and castor oil 40. Cc. This is divided into two or three doses, according to the age and con- dition of the patient, and these are given twenty to thirty minutes apart, beginning early in the morning, fasting; should any depression occur after the first dose, the later doses are omitted. Particular stress is laid on the inclusion of chloroform in the formula, as three cases in which positive diagnoses had been made, were unaffected when chlo- roform water was, in error, substituted. The writer has used this treatment on only one occasion and then unsuccessfully (as the patient was severely nauseated) and accordingly, is not in a position to form a valid judgment on this formula. Prevention. — Since the fseces of hookworm patients represent the po- tential infection in concentrated form, it is clear that a proper disposal of the discharges is the great factor in preventing hookworm disease. Build proper privies and insist upon their being used ; in mines, adopt the pail system. This one line of prevention, if carried out, is sufficient to blot hookworm disease out of existence, for fortunately w^e do not have to deal with any specifically identical infections in any of the domesticated animals. Numerous other preventive measures have been advanced, but while good in themselves, they fail to reach the source of the evil. The propo- sition to wear shoes and thus prevent ground itch is of course a very good one, but financial considerations inhibit its universal adoption; if the infected fseces are properly disposed of, ground itch will prac- tically disappear even if shoes are not worn. The proposition to drink boiled or filtered water is an excellent one, but of impracticable general ^According to their most recent results (1905), it is not quite so efficient as thymol; it is more necessary to thoroughly clean the intestine before using it; its systemic effects are however less marked, although its effects on diseased kidneys seem to be more marked. RO UNDWORM INFECTION— NEMA TIIELMINTHES 595 Fig. 62. (Es Nerv. application among the poor; but if the fjieces are disposed of, the danger of infecting the water is removed. To keep the hands clean is of course an excellent plan, but unfortunately one of limited application. The great principle is to prevent the dirt from becoming "dirty"; clean dirt is not dangerous. Strongyloidosis.* — Infection with Strongyloides stercoral^. — €reo- graphical Distribution. — The distribution of this infection is much more general than was formerly supposed; it seems to be especially a tropical and subtropical species, but as such probably encircles the earth. American cases have been found, locally, as far north as Baltimore and im- ported cases even further north. European cases have been found as far north as Belgium, England, Germany, and Holland, and the in- fection is also reported for Siberia. In Asia it is known for China, India, and Japan. In Africa it is known for Egypt. In South America it extends into Brazil. In general it follows the distribution of hookworms in man, and is very common in Porto Rico. Zoological Distribution. — Strong (1901) re- ports this parasite for monkeys as well as man, and he was able to transmit the disease to mon- keys by feeding infected human excreta to them. The Parasite. — I. (a) The parasitic (intes- tinal) adults are parthenogenetic females, measuring 2.2 to 3 mm. long by 34 to 70// broad, with an oesophagus about one-fourth as long as the body; a double uterus is present, each horn containing a moderate number (3 or 6) of segmenting eggs (50 to 59 by 30 to Mjj.) which escape through the vulva, situated in the posterior third of the body. These eggs are deposited in the intestinal lumen of the host or in galleries in the intestinal mucosa made by the females, and developed into — (b) Rhabditiform embryos, 200 to 240 jjl long by 12 /< broad, which may grow to 450 to 600 p. long by 16 to 20 [i in diameter by the time they are discharged with the faeces. The buccal Cavity is short, relatively broad, and without thickened chitinous lining. These embryos then develop within two or three days into — II. (c) Free-living dioecious adults. The males measure 0.7 mm. long; the tail is curved ventrally to form a hook; spicules curved, 38 /z long. The females measure 1 mm. long; vulva slightly posterior of equator of the body. Each female develops 30 to 40 eggs which may or may not segment in the uterus, these eggs develop forming the — Gen. Larva of Strongyloides atercor- alis as found in fresh faeces; Nerv. , nervous systems ; (Es., oesophagus; Int., intestines; Gai., genital primordium; An. anus. X228. (Looss.) 1 Synonyms. — Anguilluliasis, Rhabdonemiasis. and Thayer (1901). See especially Strong. (1901) 596 THE ZOO-PARASITIC DISEASES OF MAN {(l) Free livinr/ ritahditiform embryos, which measure 220^t long; when they attain 550/j. in length, they moult and at the same time change to — (e) Filariforvi cmbri/o.s, possessing an elongate cylindrical oesophagus about halt' as long as the body. This is the infecting stage, which enters man by the mouth or through the skin, reaches tlie duodenum and upper part of the jejunum anddevclopsdirectlyto(«) the part henogenetic females. llic complete life-cycle (a-b-c-d-e-a) is thus an alternation of a dioe- cious with a ])arthen()genetic generation (alloiogenesis) and is the cycle reported more commonly in tropical and subtropical cases. In other cases, notably in the temperate zone, an abridged cycle consisting of a-b-e-a may occur; in other words there is, in these instances, a tendency to a more completely parasitic life by the omission of tiie free-living dioe- cious generation. Source of Infection. — Infection takes place in either of two ways, pas- sively by means of contaminated food or drinking water or actively tlirough tlie skin. Frequency. — Extensive statistics of a satisfactory nature are not acces- sible. In general, the infection increases in frequency from cooler to warmer climates. In Washington, D. C, several cases have been known (probably none contracted within the city); the writer believes the infection is much more common in this country than is generally supposed. Powell found it in 75 per cent, of the cases of amemia in India (Manson). Duration. — The longevity of the individual worm is not established. Cases of infection are known of several years standing, due perhaps to reinfection. Ward (1903) suggests that the very heavy infections occasion- ally reported possibly point to an endless chain multiplication by means of the ablireviated cycle (a-b-e-a) inside the intestine. Symptoms and Pathology. — Here again, as in so many other cases of parasitism, the literature contains extreme statements, that the parasite is utterly harmless and that it is exceedingly injurious. A number of authors, however, see in this parasite a worm which may indeed in some cases be apparently harmless, but which, when present in large numbers, may cause "clinically, an intermittent diarrhoea with intestinal disturbances, and pathologically, a catarrh of the small intestine" (Strong). Clinical Diagnosis. — The only possible method of diagnosis is by means of microscopic examination of the f feces for the rhabditiform embryo (h) (see p. 595). In this connection see also p. 602. In violent purging, eggs, strung together end on end and surrounded by a delicate tube, may appear in the stools. Treatment.— Repeated doses of thymol (see p. 593) as used in hook- worm infection are usually advised for strongyloidosis also, but owing to the fact that the parasites may burrow, treatment is not always satisfactory. Ascariasis— Eelworm Infection.— Geographical Distribution. — Cos- mopolitan, more in rural districts than in cities. Zoological Distribution.— In many medical works including some recent editions, the authors maintain that the common eelworm of man occurs in certain domesticated animals, such as the pig, horse, cattle, etc. This view is not in harmony with the present zoological classification which recognizes these infections as generically identical but specifically distinct. ROUNDWORM INFECTION— NEMATHELMINTHES 597 The Parasite. — Ascaris lumhricoides Linnaeus, 1758, i.s, in general terms, about as large as an ordinary lead pencil but tapering toward both ends; the male measures 15 to 17, even 25 em. in length by about 3 mm. in diameter; the female is somewhat larger, 20 to 40 cm. in length by 5 mm. in diameter, and is oviparous. The worms are grayish to red- dish-yellow in color; the anterior end is provided with three lips. The egg is 50 to 75 by 30 to 55/j!, ' ' ' unsegmented when oviposited, and provided with a thick mammillate covering, frequently tinged yellow when found in the fax-es. The parasites live in the small intestine. Development is direct, without intermediate host. Toxocara canis (Werner, 1782), the canine eel- worm, is an exceedingly common intestinal para- site of dogs and cats, and 8 cases have been reported for man, the worms having been vomi- ted in most of these instances. It measures 40 to 90 (male) and 120 to 200 (female) mm. in Egg of the common ascaris length by about 1 mm. in diameter, and is easily {Ascaris iumbricoides}oi recognizable from its arrow-shaped head ; the eggs ^^^ w'th°superfic Jho- are nearly globular, 68 to 72//, with a thinner shell ^us. Greatly enlarged. than that of A. lumhricoides. Development is (Stiles.) direct, without an intermediate host. {f Ascaris) maritima Leuckart, 1876, has been reported for man but once in Greenland. One immature specimen wsiS vomited by a child and was doubtless an accidental parasite, possibly swallowed with the entrails of some food animal. {f Ascaris) texana Smith and Goeth, 1904, has been described as a new eelworm for man in Texas; it measured 58 to 60 mm. in length and is said to possess intermediate lips; uterine eggs segmented, 60 by 40/i. Through the kindness of the describer, Allen J. Smith, the writer was enabled to examine the original specimens ; the structures described as intermediate lips do not correspond to the intermediate lips so far as he is familiar with them in other species of Ascaris, but as the material was poor the writer refrains from expressing any definite opinion regarding this species, which is still sub judice. Source of Infection. — ^The egg escapes in the faeces and slowly (in one to several months, according to conditions) develops an embryo; no inter- mediate host is required, at least for Ascaris lumhricoides and Toxocara canis; but when the developed eggs are swallowed, either in contam- inated food or water, or from hands soiled with dirt containing the eggs, the embryo develops directly to the adult stage. Drinking water and fruits, especially, are blamed for carrying the parasite to man. Some years ago the writer bred common house-flies in a dish con- taining eggs of the eelworm of hogs, a parasite very closely allied to that of man, and later found the eggs in the intestine of the adult flies. It would seem therefore, that flies, by breeding in privies, might act as dis- seminators of the lumbricoid worm of man. Frequency. — The eelworm is one of the most common parasites of man; it may occur at any age, from about eight months to eighty-five years, but is usually more frequent in childhood (from five to ten years) 598 THE ZOO-PARASlTIC DISEASES OF MAN and youth than in adult age, anil more conunon in women than in men. Autopsy statistics for Germany pubHshed by Heller and jMuller, give the following combined results: males, 220 cases in 2,275 autopsies, or 9.67 per cent.; females, 194 cases in 1,440 autopsies, or 13.41 per cent.; children, 101 cases in 584 autopsies, or 17.29 per cent. It was present in 0.49 per cent, of 3,457 persons examined under direction of the writer. In Porto Rico, Guam, and the Philippines, it is excessively common. Usually only from 2 to G individuals are present in one patient, but infections with 30, 40, 100, 140, and 300 to GOO worms are recorded, while P'auconncau-Dufresne (ISSOa) re])orts the case of a boy of twelve years who passed (chiefly by vomiting) more than 5,000 worms within less than three years, GOO being passed on one day! In general terms, Ascaris lumhricoides is more common in warmer than in temperate and colder climates, and more common in the rural districts than in the cjties. Authors attribute its greater frequency in rural patients to the use of unfiltered water, but other factors seem to be of more impor- tance: in cities with a sewage system the infectious material is carried away, while in country districts the boxprivy affords greater possibilities for the spread of infection. Duration. — The worm matures and oviposits in about a month after infection, but definite details as to the longevity of the individual parasites are lacking. Symptoms. — Very frequently no symptoms are noticed. In other cases they are more or less indefinite, practically all of the symptoms reported for tseniasis and oxyuriasis (see pp. 5G9, 601) being recorded for ascaria- sis also. For instance, among those recorded may be mentioned the following: irritation of the skin, urticaria, pallid appearance, alternate pallor and redness of the face, jaundice, dark rings around the eyes, unequal or dilated pupils, flashes before the eyes, mydriasis, amblyopia, amaurosis, strabismus, disturbances in sight and hearing, inflammation of the eye, itching of and picking at the nose, grinding of the teeth, bad taste and offensive breath, dry cough, hiccough, aphonia, anorexia, irreg- ular or capricious appetite, dirt-eating, eructations, sensibility of stomach on pressure, nausea, vomiting, gastrorrhagia, vague abdominal pain, borborygmi, colicy pains, cramps, irregular bowels, diarrhoea, constipa- tion, intestinal obstruction, meteorism, itching at the anus, muscular pains, progressive emaciation, headache, vertigo, fretfulness, fainting- spells, chorea, convulsions, epilepsy, catalepsy, ecstasy, hysterical con- ditions, eclampsia, neuralgia, paralysis, psychoses, tetanoid states, pseudo- meningitis, palpitations and irregular action of the heart, syncope, etc. While many physicians recognize the elements of danger which smoulder in an infection with ascaris, others sometimes view eelworms with little more than a passing curiosity. Hundreds of cases of ascariasis, recognized or unrecognized, may pass through a physician's hands without any fatal results being noticed. Still, the occasional danger connected with eelworms is deserving of attention. If a light infection of ascariasis is present, the chances are very great that nothing serious will result from it; but unfortunately these worms have a habit of wandering, especially in febrile conditions, and medical' literature shows that it is these wander- ings, even in light infections, which present the most dangerous aspect of the disease. The escape of erratic eelworms by the mouth or nose is ROUNDWORM INFECTION— NEMATHELMINTHES 599 not very rare. If during this wandering the worm happens to come into contact with an ulcer, perforation into the abdominal cavity or the lungs may result; or the worm may enter the Eustachian tube and escape by the external ear; in some cases it enters the lachrymal duct; or it may turn at the larynx and pass a greater or less distance down the trachea and bronchi, in some cases causing suffocation, in others abscess or gangrene of the lungs; about 40 cases are recorded in which ascarids have entered the air passages. About 90 cases are recorded in which the eel worms have wandered into the bile ducts, 9 cases into the pancreatic duct, and some 20 cases into the urinary passages. In some cases the worms pass into the abdominal cavity, either piercing the intestinal wall or working their way through an ulcer. Blanchard has compiled 81 cases in which eel- worms have escaped through the body- wall; 29 cases through the umbilicus, 30 through the groin, 10 at unstated points of the abdomen, 2 by the hypochondrium, 2 by the lumbar region, 2 by an inguinal abscess, 1 each by the sacral, pubic, perineal region, and abscess of the thigh, inferior por- tion of thorax and linea alba. Davaine points out that, corresponding to hernia, ascarids escape by the umbilicus more frequently in children than in adults, and by the groin more frequently in adults than in children. In view of the foregoing brief account of erratic ascarids, in not a few cases fatal, it is seen that it is at least worth while, from a prophylactic standpoint, to treat all cases of ascaris infection which are found, even independently of the question as to whether any moderate or serious local or perhaps reflex symptoms are traced to the presence of the worms in the patient under consideration.. That heavy ascarid infections, such as are found in unhygienic tropical countries, may be of considerable clinical importance is evident. Manson states that in China he treated his young patients twice a year with santonin as a matter of routine. Diagnosis. — It is possible to make a diagnosis independently of symp- toms, either by a microscopic examination of the fgeces to find the char- acteristic eggs, or by recognition of worms passed by the anus, mouth, or nose. Treatment. — Santonin is the classical drug for ascariasis. It is given in powder or troches, dose 0.01 gram per day {\ grain) for each year of the child's age, 0.06 to 0.3 gram (1 to 5 grains) for an adult. It is best given with an equal or greater amount of calomel, every morning two or three days in succession; then repeat the medication every three or four days as long as eggs are found in the fseces or until no further worms are expelled. In treating children it is well to forewarn the mothers of the possible effects of santonin upon the patient. Among other drugs used for the expulsion of eelworms may be men- tioned: oil of chenopodium, 0.13 to 0.666 Cc. (2 to 10 minims) on a lump of sugar or in emulsion, before meals for two days, followed by a purge (calomel). Fluid extract of senna, with equal parts of fluid extract of spigelia, 2 to 4 Cc. (| to 1 dram) of the mixture, three times daily until purgation occurs. Thymol (see p. 593) may be used. Serious intestina;l obstruction by ascarids should be treated as obstruction from any other cause. Ox3niriasis. — Pinworm Infection. — Geographical Distribution. — Cosmopolitan. 600 THE ZOO-PARASITIC DISEASES OF MAN Zoological Distribution. — The pinwonn o^ man is not known to occur in any other animal; gencrically identical but specifically distinct infec- tions are, however, known for a number of mammals. The Parasite. — Oxyuris (Oxyurias) vermicularis^ (Linnseus, 1758), known as the pinworm, seatworm, also mawworm, is a small, white, roundworm measuring 3 to 5 mm. (male) to 10 mm. (female) in length, 0.10 to 0.6 mm. in diameter; the male has but one spicule; the female is proviiled with a relatively long, sharply pointed tail; the vulva is in the latter half of the anterior third of the body; two uteri are present filled with numerous eggs, in which an embryo is developed before oviposition; these eggs are 50 to 52 by 16 to 24/(, with thin shell, and with dorsal surface much more convex than the ventral. The earlier stages of the parasite live in the small intestine, where the worms copulate. The males are not long-lived. The fertilized females wander to the csecum, and later when gravid to the colon. It has been maintained t. , r., „ that the normal location for pin worms is the vermi- Embryo of the common „ ^• • i i i i i • pinworm {Oxyuris I oHU appendix; it cauiiot be doubtcd that pmworms vermicuiaTis)oi man, do enter the appendix, for Heller, for instance, re- in the eggshell, as ported 36 males in 1 case; 19 males and 19 females fiiuckLtT'' ^'''''" ^" another; 30 males and 9 females in another; 46 males and 27 females in another; but it hardly seems proved tliat the appendix is the normal habitat for these para- sites. The statement occasionally found in medical works to the effect that the embryo escapes from eggs oviposited in the rectum and develops there into an adult is possibly traceable to VLx (1860); but this view cannot be accepted. Source of Infection. — Pinworms have a pronounced tendency to wander out of the anus, and when the female is crushed by scratching with the fingers to relieve the irritation, a person naturally infects his fingers, especially under the finger-nails, with the embryo-containing eggs; from the fingers to the mouth or nose is but a short distance, and auto-in- fection thus occurs. Or the embryos in the bedclothes may easily soil the hands of a bed-fellow, a companion, or a nurse, and thus be transmitted to a second person. Or the eggs (free in the fpeces or in the body of the discharged female worms) may be transmitted to people by means of con- taminated food, as uncooked fruit, vegetables, etc. No intermediate host is necessary. Theoretically it seems perfectly possible that flies may oc- casionally, if not frequently, play an accidental role in the dissemination of the eggs. Frequency. — ^This parasite is one of the most common of the intestinal worms, varying in different autopsy statistics from to over 57 per cent. It is more frequent in children (from three to ten years) and women, but has been observed in babes of five weeks up to men of eighty years. It was found in 1.3 per cent, of 3,457 persons examined under the writer's direction at the Hygienic Laboratory at Washington. Heller reports it in the proportion of 33.8 per cent, for children, 21.1 per cent, for 'Synoxyms. — Ascaris vermicularis Linnceus, 1758; Oxyuris vermicularis (Lin- naeus) Bromscr, 1819; Trichina cystica Salisbury, 1858; Filaria cystica (Salis- bury) Railiiet, 1893, in part only (not F. cystica Rudolphi, 1819). ROUNDWORM INFECTION— NEMATIIELMINTIIES GOl women, and 18.8 per cent, for men, in 611 autopsies at Kiel, Germany; one prominent German helmintliologist has stated that he beheves there are few persons who have not harbored this worm at one time or another in their lives. Further, infections are reported as more common in the spring than at other seasons of the year. The number of specimens of pinworms in one person varies from a comparatively few individuals to such heavy infections that the mucosa of the large intestine may be covered with them. Duration. — While the longevity of the males appears to be rather limited, that of the individual female is not established. Cases of infec- tion of ten to fifteen years and even much longer are recorded, but these are doubtless due to repeated auto-infection. Symptoms. — Doubtless many cases of light infection pass unnoticed, and in case the person is of clean personal habits, the infection dies out. In heavy infections, however, there may be marked irritation of the in- testinal mucosa, resulting in a catarrhal condition and a diarrhoea; there may be foul breath, nausea, vomiting, abdominal pain, tenesmus, deep rings around the eyes; further, one may find headache, restlessness, sleeplessness, itching at the nose, vertigo, unequal pupils, chorea, and even convulsions. One of the most constant symptoms is an intense itch- ing and burning at the anus, due to the wandering of the female, espe- cially shortly after the patient retires; the anus appears red, irritated, sometimes bloody; reaching the perineum the worms may pass to the vagina if the skin is moist, and may here cause hypersemia, increased secre- tion of mucus, and sometimes hypersesthesia and leukorrhoea; sexual excitement may result. Wandering pinworms have been found in the vagina, uterus, and even in the abdominal cavity. Diagnosis. — ^While symptoms may indicate pinworm infection, a posi- tive diagnosis may be made several different ways : the adult worms may be found in the stools, occasionally in considerable numbers; or they may be found in the crotch, especially if the child is examined during the rest- less period after retiring; a microscopic examination of scrapings around the anus (taken with a clean dull knife or a microscopic slide or other suitable object), or the cleanings from the finger-nails may reveal the characteristic eggs ; finally, the eggs may be discovered by a micro- scopic examination of the ffeces. Opinions are divided regarding the value of the microscopic examina- tion of the fseces; some authors consider that the eggs are not found free in the stools, while others state that they are common. The writer's experience is that the eggs may be found in fsecal examinations even in some cases in which pinworm infection is not even suspected; but that a negative examination is not of much value. Treatment. — Treatment should take into consideration two distinct points : namely, not only the removal of the gravid female pinworms from the rectum, but also the removal of the younger worms from the small intestine. A failure to consider this latter point doubtless explains not a few cases of treatment which have not met with the success the practi- tioner expected. Still, the emphatic statement so often met with, that persistence is an essential factor in favorable results, is often justified. For removing the younger pinworms from the small intestine, several drugs may be used, as santonin and calomel (of each 0.05 to 0.1 gram — f to IJ grains) given several days in succession, or large potions of an 602 THE ZOO-PARASITIC DISEASES OF MAN infusion of gentian, or active saline cathartics repeated several days in succession, or thymol or beta-naphthol. Ungar gives immediately after a laxative, four doses per day of naphthalin (0.1 to 0.4 gram — 2 to 6 grains) according to age, for two or three days in succession between meals. To expel the gravid females from the rectum, rectal injections are used. An infusion of quassia seems to be one of the most popular remedies. Other commonly used enemata are: lime-water, salt and water, iced water, salt and milk (highly s{)oken of), cold water, aloes, diluted vinegar (which should be sterilized before using, otherwise the patient may be- come infected with vinegar-eels), perchloride of iron, glycerine, benzine (20 drops to a pint of warm water), finely chopped garlic with water (which has stood for twelve hours and is then strained through linen). Diluted carbolic enemata are advised by a number of authors, but they do not seem to have any special advantage over the other drugs and have in some cases decidedly poisonous effects. The injections are given with the buttocks elevated, or in the knee-chest position, at first every evening, then every two or three or four evenings, until all evidence of worms has disappeared. If too large an injection is given to be retained this washes out a number of worms; but it should be followed by a smaller injection, two to four ounces, or an amount which can be conveniently held. Ointments of various kinds may be applied in the evenings to the anus and perineum to relieve the itching. Physaloptera caucasica Linstow, 1902, has been reported but once for the intestine, in Caucasus. (Length 14 [male] to 27 [female] mm., breadth 0.71 to 1.14 mm. Eggs 57 by 39/^.) Trichostrongylus Looss, 1905. — Three small nematode worms (r. vitrinus, T. probohcrus, and T. instahilis^) have been reported for man in Egypt, and one of them {T. instahilis) for man in Japan. They do not seem to be important parasites, so far as our present knowledge indicates, and further their normal habitat seems to be other animals (sheep, antelope, dromedary, baboon) rather than man. They measure 4 to 6 or 7 mm. in length. Their eggs might be mistaken for hook- worm eggs, but are in general somewhat larger, 73 to 90// long and are oviposited in the 8 to 32 cell stage. Anguillulina putrefaciens (Kuhn, 1879).— Small nematodes of vari- ous sorts frequently gain access to the stomach by being swallowed accidentally with food (vegetables, vinegar, water, etc.), and are likely to appear either in the vomit or in the ffeces. As an example of this sort reference may be made to Ang^dllulina putrefacieyis reported by Botkin (1883) as Trichina contorta, in the vomit. The worms gained access to the stomach in onions and caused vomiting. Trichocephaliasis. — ^Whipworm Infection.— Geographical Distribu- tion. — Probably cosmopolitan. Zoological Distribution. — The whipworm of man is also said to occur in various apes and lemurs; generically identical but specifically distinct infections are more or less common in dogs, cattle, sheep, and a number of other animals. * Synonyms. — Strongylus instahilis Railliet, 1893a; *S. subtilis Looss, 1895; Trichostrongylus subtilis (Looss, 1895) Looss, 1905; Tr. instahilis (Railliet, 1893) Looss, 1905. See also StUes, 1902, 41-42, figs. 14-21. ROUNDWORM INFECTION— NEMATHELMINTHES 603 The Parasite. — Trichuris trichiura^ (Linnicus, 1701), tlie whipworm, has the general form of a whip, the posterior swollen fjody representing the handle, and the lash representing the slender filiform anterior portion. The male measures 40 to 45 mm., the female 45 to 50 mm. in length. The parasites inhabit the caecum, but are occasionally ^^^ ^^ found in the vermiform appendix and in the colon, rarely in the small intestine. They produce numerous characteristic eggs, 50 to 54 by 21 to 23/i, of a yellowish to dark-brown color, with unsegmented protoplasm and with a peculiar light spot at each pole resembling apertures. Source of Infection. — The eggs develop after being discharged in the faeces, and with the contained em- bryo are swallowed in drinking-water or contaminated food. An intermediate host is not necessary. Frequency. — This is one of the most common para- -, £ • • £ i? 1 it: 1 Egg of whipworm. sites ot man, varymg m frequency from less than 1 ^^qq (Looss.) per cent, up to 90 per cent, of persons examined in different parts of the world. In general terms it is more common in warmer than in colder climates. In Washington, according to examina- tions made under the writer's direction in the Hygienic Laboratory, and in the Bureau of Animal Industry, it is twice as common in colored as in white children; it was present in 7.69 per cent, of 3,457 persons exam- ined by the Zoological Division of the Public Health and Marine Hos- pital Service; it may vary greatly in frequency in different wards of the same asylum; in the United States Government Hospital for the Insane 10.8 per cent, of 500 white male patients were infected, the highest per- centage being 38.98 in soldiers returned from the Philippines. It is most frequent in children from three to ten years of age. Duration. — ^The length of life of the individual parasite is not estab- lished. Symptomatology and Pathology. — ^The medical opinions expressed regarding this worm have been too frequently characterized by extreme statements, varying from the view that it is of no medical importance whatever, to the view that is the cause of very serious disease. That, in the vast majority of cases, it is of scarcely any appreciable importance, and that its presence can not be recognized symptomatically may be con- servatively admitted. But that severe infections do not produce injury is not in accordance either with probability or with recorded observations. According to some observers, the worm simply lies loose on the intestinal mucosa; but other equally competent observers report finding it with its head burrowed in the epithelium. Askanazy reports haemoglobin in the worm's intestine, and several cases of severe anfemia have been recorded within recent years which were, apparently justly, attributed to heavy infections with whipworms. Within the past few years Guiart, of Paris, has been defending the view that the wounds made by whipworms form the point of entrance for the typhoid bacillus; he thus attributes to whipworms a role in t}'phoid somewhat similar to the role played by fleas in plague. Examinations ^Synonyms. — Trichuris Biittner, 1761; Ascaris trichiura Ijinn&us, 1771; Trir- chocephalus hominis Schrank, 1788; Trichocephalus dispar Rudolphi, 1801. 604 THE ZOO-PARASITIC DISEASES OF MAN made at Washington do not boar ont this hypothesis for this locality. Of 200 typhoid patients examined by the author (1907), 92.5 per cent, failed to show any intestinal worms, and the whipworm infection found was only very slightly above that of the normal ])opulation. Whipworms are supposed by some authors to be the initial cause of some cases of appendicitis. Clinical Diagnosis.— The only method of recognizing whipworm infec- tion is by microscopic examination of the fivces for the characteristic eggs. Treatment.— Medical writers agree that treatment is unsatisfactory. Thymol is recommended by some,"^ but in laboratory experiments on the dog, Pfender and the writer have found it worthless in whij)worm infec- tions. In the literature on hookworm disease, frequent mention is found of the expulsion of whipworm by male fern administered in treating uncinariasis. Hemmeter (1902) advises irrigation of the colon with benzine (1 dram of benzine to 1 quart of warm water) and at the same time internal administration of benzine. Prevention. — A proper disposal of the alvine discharges is of first importance. Personal cleanliness, the use of proper drinking water, and the disuse of surface-water for drinking purposes, will also contribute largely to prevention. Infection with Gordiacea. — A number of different horse-hair worms are reported as accidental intestinal parasites in the intestine of man. They are, however, rare and their effect temporary. Six cases are known for North America; in 4 of these, the parasite was Paragordius varius. Infection with Thorn-headed Worms (AcanthocephaU).— The thorn-headed worms differ from the nematodes in two chief characters; namely, in the absence of an intestine and in the presence of a retrac- tile rostellum armed with hooks. An intermediate host (insects of various kinds) is required for their life-cycle. This group of parasites is of very little known importance in human medicine, but of greater import- ance in comparative medicine. Three species have been recorded as intestinal parasites of man, namely: Gigcmtorhynchus gigas^ (Goeze, 1782), 10 to 50 cm. long; eggs 80 to 100/i long, with three shells; very common in hogs; May-beetles and June-bugs are the intermediate host; alleged to occur in man in South Russia. Gigantorhynchus monilijormis^ (Bremser, 1819), 4 to 8 cm. long; eggs 85 by 45/^; occurs in rats and certain other rodents; a beetle (Blaps mucronafa) is the intermediate host; raised in man experimentally by Grassi and Callandrucio (1888c). According to Magalhaes, the large roach {Peripkmata amcricana) may also serve as intermediate host. Echinorhynchus hominis (Lambl, 1859), a doubtful species, 5.6 mm. long, reported but once. ' Dr. Stitt, IT. S. Navy, has recently expeled over 300 whipworms from one patient by using thymol. This result is much more encouraging than any simi- lar case known to the writer. 2 Synonyms. — Tcenia hirudinacea Pallas, 1781; Echinorhynchus gigas Goeze, 1782. 'Synonyms. — Echinorhynchus moniliformis Bremser, 1819. ROUNDWORM INFECTION— NEMATHELMINTHES 605 In all these infections the diagnosis should be made by microscopic examination of the faeces to find the eggs. Treatment is the same as for There are two other organisms (each reported but once) which have been interpreted as thorn-headed worms in man, but the cases are such that opinions differ as to whether they represent protozoa or worms m one instance, and worms or arachnida in the other. INTESTINAL AND MUSCULAR ROUNDWORMS. Trichinosis or Trichiniasis.— Infection with Trichinella spiralis-} Geographical Distribution.— Trichinte are practically cosmopohtan, because of the wandering of rats; but trichinosis as a recognizable disease in man is practically limited to persons who indulge in the mis-custom ("Unsitte") of eating raw or rare pork. _ _ Zoological Distribution.— From a practical, hygienic point of view, the zooloo-ical distribution of trichinosis extends to man, hogs, wild boars, rats docvs, and cats. It is also reported for several other animals, such as the fox, etc., and has been transferred experimentally to several rodents (rabbits, hares, etc.) and other animals (sheep, cattle, etc.), but these ex- ceptional infections or infections in animals not used tor food do not enter largely into any scheme of prophylaxis. , , . , • The Parasite.— Three stages of the parasite should be clearly held in mind: , . . . , (a) The adults live in the duodenum and jejunum; the males measure 1 4 to 1.6 mm. in length by 40/i in diameter, while the females are 3 to 4 mm long by 60/i thick; they are circular on cross section and appear as minute thread-like objects; the oesophagus is supported by a single rotv of cells known as the cell-body; the male is without spicules; the female is viviparous, the vulva being situated about one-fifth the length of the body from the mouth. The males die shortly after copulation._ ihe females may remain for a few weeks in the lumen of the intestine, or they bore into the lymphatic spaces of the intestine where they hve about five to seven weeks and deposit their numerous young, about 1,500 or more per female, namely, the — i i c • (b) Embryos, which measure about 90 to 100/x m length by bp. in breadth; these wander, either with the lymph, or with the blood less frequently actively, to the striated muscles. They begm to reach the muscle about the tenth day after infection; they enter the muscle fibers and there develop into the — . . , ^ n (c) Encysted Larvae.— The cysts vary somewhat m size, but are usually about 400 by 250/i. These encysted larvae may remain alive in the mus- cles for years, cases being reported for as long periods as twenty to thirty-one years. The encysted worm (the "fleshworm ) is the infect- ing stage, found in the hog; upon being swallowed m raw or rare pork the cyst is destroyed, the larvse pass from the stomach to the small 1 While the more commonly known name Trichirm spiralis^ is not available for this parasite, it is not quite certain whether its correct name is Trwhmella spiralis or Trichinus spiralis. 606 THE ZOO-PARASITIC DISEASES OF MAN intestine and develop within about two days or less to the adults; the latter copulate and may have embryos in the uterus within less than a week after infeetion. Source of Infection. — Leaving out of consideration the rare exceptions, and considering only the usual methods, it may be said that (a) man obtains trichinosis from eating pork; (b) hogs become infected from eating (1) uncooked swill containing scraps of pork, (2) swine offal at country slaughter houses, and (3) rats; (c) rats obtain their infection by eatino- (1) each other, (2) scraps of jiork in houses or at meat-shops and, (3) swine offal at country slaughter houses. Thus, rats alone, swine alone, or rats and swine together, may keep up an endless-chain infection, while the infection which reaches man terminates with the death of the individual. Accordingly, man must be viewed as a more or less accidental host for the disease, while the rat, because of its cannibalistic habits, pre- sents, theoretically, ideal conditions to serve as a normal host for this parasite. Duration. — As a clinical combination of symptoms, trichinosis may last from a fcAV days to several months, but usually it runs its course in about two or threeto five or seven weeks; convalescence is slow and may require ten to seventeen weeks, while cases are recorded where the pa- tients have not fully recovered from the effects for years. As an infec- tion, on the other hand, it is reported as having lasted for five to twelve years in man and eleven to twenty-four years in the hog;^ that is, cases are reported in which it is maintained that the encysted parasites have re- tained their vitality for these periods. Symptoms. — Incubation may last from several hours to several weeks, according to the amount of infection, and according to whether a large number of parasites are ingested at one time, or whether consecutive in- fections of a smaller number of worms have occurred. Some infections are so light as to be entirely overlooked; other light cases, which might escape proper diagnosis, are recognized because of their contemporaneous occurrence with severe cases in the same family or among people trading with the same butcher. The more severe typical cases present Rup- precht's three more or less well-defined periods, corresponding to the three stages of the parasite and their respective location: 1. Period of Ingression. — The adidt parasites are in the lumen or the tissues of the intestinal tract, hence the gastro-intestinal symptoms pre- dominate; but in some cases these may be absent or very slight. Within a few hours to two days or so, there is a more or less heavy feeling in the stomach, with eructations; nausea develops, and the patient may vomit once or several times, or in some cases persistently for some days; the appetite is diminished, constipation, or more generally diarrhoea occurs, often with colic; the stools are at first faecaloid, but become looser even to an almost watery consistency; this diarrhoea may continue for some weeks or may give place to a more or less obstinate constipation. Mus- cular pains may develop early, even before the muscular tissue is invaded by the parasites; recurrent abdominal pains, especially at night and as frequently as six attacks within twenty-four hours, may develop in the lit is not altogether clear to the writer that this record for the hog must be accepted as absohite, for repeated infections might have occurred during thes^ long periods. ROUNDWORM INFECTION—NEMATHELMINTHES 607 severest cases; the extremities become cold; the pulse small and inter- mittent. Toward the eighth day a temporary first cjedema of the eyelids and face may appear lasting for from two to five days. From the seventh or eighth day on, large numbers of wandering embryos are found in the peri- toneal, pleural, and pericardial cavities. 2. Period of Digression. — ^This begins on about the ninth or tenth or fourteenth day, rarely as late as the forty-second day (repeated small in- fections ?), and corresponds to the period during which the embryos are wanderhig and attacking the muscles; accordingly muscular symfjtoms (myositis) are the most prominent. The symptoms may be exceedingly light to severe. Certain muscles, particularly the biceps and gastrocne- mius, are more firm than usual, hard and very tender, especially when the patient extends the forearm or leg. Movement may cause excruciat- ing pain, and for relief the patient assumes a position of semiflexion. Mastication, speech, and movement of the eyes become painful; more or less complete aphonia may occur and the eyes become fixed; respira- tion becomes difficult, and respiratory troubles are likely to be severe, especially in the fourth and fifth weeks; there may be severe dyspnoea, accompanied by violent asthma. 3. Period of Regression. — All symptoms become exaggerated, and in addition the patient falls into an extreme cachexia; a second oedema de- velops about the twenty-fourth day, occurring in about 90 per cent, of the cases and attacking the head especially; hence the name, "disease of the big head," occasionally applied to trichinosis in Europe. The larval parasites encyst and the patient gradually recovers. It is hardly necessary to remark that this rather diagrammatic clinical picture may vary according to the amount and number of the infections, exactly in the same way that a double tertian or a double or triple quartan malaria, or consecutive malarial infections at different hours, modify the clinical picture of malaria. Early or late pruritus and formication may occur at certain points or over the entire body; cutaneous anaesthesia is rare. Profuse sweating is likely to occur, especially during the myositis. Stiffness of the muscles of the neck and back, extending to a distinct opisthotonos, has been re- corded. Thirst is increased. In females, anomalies occur in menstruation, and abortion is reported for some pregnant patients. The urine decreases in quantity with the second week, but toward the fifth or sixth week and in convalescence there is polyuria. There may be an abundant sediment but the presence of albumin is exceptional; the urine may be intensely red in color. As the nutrition is poor, extreme emaciation and anaemia may develop, and there may be oedema of the lungs and an obstinate bronchitis. The mental faculties are dulled, and the patient is indifferent to what occurs in his presence. In severe cases more marked nervous symptoms develop — extreme insomnia or somnolence, delirium, etc. Opisthotonos, due to stiffness of the muscles of the neck and back, may be noticed. Even in light cases moderate fever may be present; in severe cases it appears during the stage of ingression; the temperature rises after the beginning of the muscular symptoms, often reaching 104° F., or even 608 THE ZOO-PARASITIC DISEASES OF MAN 105.8° F., its duration (two or three to five or six weeks) depending upon the severity of the infection ; it may be remittent or intermittent. The puis'c follows the temperature; in high fever it may exceed 100 and be extremely feeble. The skin not infret|uently shows a miliary or roseolous eruption, more rarely herpes, and the oedema is frequently followed by extensive epider- mic desquamation. , Lethality. — The death-rate in different outbreaks varies between and 100 per cent. Of 1 1,820 cases in Germany which were collected by the writer for the years 1860-97, 831 were fatal, giving a death-rate of 5.6 Fig. CG. NOVEMBER 9 10 11 - 13 - 1 TEMP. 108° 107° 106° 105° 104° 103° 102° 101° 100° 99° aai. 2 00 M -i < 3 3 3 a -I. Ph ^ < < ?H 3 < < a 2 Ph ^, t5 Ph -1. si H :i5 h ^ H H g 3 ~ i M P n 8,? !• E. 1 ^ ■3 2 -a a. / / \ \ A " 3 ■\ ,/ V \ A ^, y\ / ' ''l V. / s t V 1/ \ \ a 1 ^ V / ^ \, / \ A V •* \ \/- J V^ _ _, ■r-i , 1 1 1 — — Temperature record in trichinosis. per cent. The death-rate is low before the second and after the seventh week, and highest from the fourth to the sLxth week, when the myo- sitis is at its maximum. Clinical Diagnosis. — In its severe form, trichinosis is a disease which occurs in groups of cases. In less extreme outbreaks cases may be mis- taken for typhoid fever and "muscular rheumatism." The possibility of trichinosis should always be held in mind in case of the occurrence of several typhoid-like attacks in the same family or neighborhood, or among friends (especially Germans from Saxony or Eastern Prussia), and following a celebration (wedding, birthday party, etc.) at which pork was served, or among families trading with the same butcher. When trichinosis is suspected make the following microscopic examinations : (a) Of the pork (if any has been left) to find encysted larvse; if these be found, chop the pork finely, wash thoroughly in water to remove the salt, and feed immediately to two or three rabbits, guinea-pigs, or white rats in order to determine whether the larva? are alive; never use wild rats or mice for this experiment ; kill one animal after two or three days and examine the contents of the upper half of the small intestine for the adult worms; kill the second animal after two weeks, the third after three weeks, and examine the muscular portion of the diaphram for the larvse. Even if live trichinae are found in the intestine of the first animal, an examination of the second and third experiment animals may show that the parasites were too weak to reproduce to any extent, hence the prognosis is favorable. ROUNDWORM INFECTION— NEMATIIELMINTII EH 609 {h) Upon the first suspicion of trichinosis, the patient's stools should be examined for discharged adult worms, especially if the diarrhcjca is severe; dilute the fsecal matter with warm water, using a rather tall, narrow gradu- ate, or similar dish ; shake well and allow the worms to settle to the bottom ; pour off any matter which floats; place the sediment in a shallow glass dish so that it will not be over one-twelfth of an inch deep, and, moving it gently over a dark background, by tipping the dish first to one side and then to the other, hunt for small hair-like objects which tend to cling to the glass (if the tipping is not too rapid) ; place these, if found, in a drop of water on a slide, cover with a coverslip, and examine under a low-power lens. (c) Examine the patient's blood for eosinophilia. The observations by Brown of the enormous increase in the eosinophiles has led to the recognition of many sporadic cases which otherwise would have been overlooked. {d) If in the third week or later and diagnosis is not established, but trichinosis is suspected, excise a minute piece of the patient's deltoid; tease this on a slide, add a drop of water, or water and glycerine, flatten gently by pressure on the coverglass, and examine under low power. Prognosis. — This is better in children than in adults, better in cases with severe diarrhoea in the early part of the disease, and good after the seventh week. If appetite, sleep, and respiration remain good, prognosis is good. Coma, delirium, and, in the last weeks, elevation of temperature and extreme dyspnoea, are bad prognostic signs. Some re- cover in a few weeks ; in others, recovery is tedious, requiring months or several years. Treatment. — If from the occurrence of a group of cases, or from a microscopic examination of meat, an early diagnosis is made, the stomach should be washed out immediately. In case of an early diagnosis, but at a time too late to recover the ingested undigested pork or the worms from the stomach, purge the patient with calomel, in order to remove as many of the worms as possible, for each female removed from the intestine means a reduction of the muscular infection by from 1,500 to several thousand worms. Calomel has in addition some anthelmintic property. Thymol or beta-naphthol might be administered with good effect. Un- fortunately the administration of anthelmintics has not been followed by very satisfactory results, the failure being due at least in part to the sub- epithelial position of the females. No drug is known to kill the para- sites in the muscles. After the parasites once leave the lumen of the intestine, all treatment must be symptomatic and supportive. Hot baths and morphine may be used to relieve pain; the profuse perspiration is relieved by atropine. Prevention. — The German school favors a microscopic examination of pork before it is placed on sale, but statistics (Stiles, 1901) show that this system is not only very expensive but also open to many practical sources of error. Frequent suggestions are made in American journals or text-books that we should introduce this microscopic inspection into the United States. There are, however, numerous difficulties (legal, financial, practical, and theoretical) in the way of carrying out such a plan. It would cost, in the aggregate, several million dollars per year, and that sum of money 39 610 THE ZOO-PARASITIC DISEASES OF MAN could be spent to much better advantage in fighting tuberculosis or some other serious disease. The federal government could inspect the meat only at the registered abattoirs, and a system which has shown such poor results in Germany would certainly not appeal strongly to national, state, and local legislative bodies when the heavy a])propriation was de- manded. To inspect tlie ])()rk in s])arsely settled portions of this country is an impracticable proposition. Further, experience has shown that the microscopic inspection gi^■es a false sense of security, antl even in (ier- many the authorities have repeatedly felt it necessary to warn the public not to trust to the inspection, but to protect against the disease by thoroughly cooking the pork. If a Saxon or an East-Prussian desires, upon coming to this country, to bring with him his mis-custom ("Unsitte") of eating raw or rare pork, let him see that his pork is inspected at his own expense; but let us carefully study the German statistics .before we increase directly or indirectly the taxes of the other people (who do not care to eat raw jiork) in this country by supporting an uncertain hygienic measure in order that a few immigrants may please their palates with a meal of raw pork. If pork is thoroughly cooked or thoroughly cured, there is no danger of contracting trichinosis; and since cooking and curing are methods which appeal to American and English tastes, we can well urge these upon hygienic groiuids also. An extermination of rats would result in a de- crease of trichinosis. Pseudotrichinas. — Various parasites have been mistaken for trichinse. Thus, a sarcosporidium {Sarcocijstis miesclieriana) , which is exceedingly common in pork, has been repeatedly mistaken for trichinae, but the fleshworm is usually wound in a spiral and enclosed in a much thicker cyst, while the Sarcocijstis is more elongate, slender, straight, and with content that appears granular under the microscope; under high power magnification, these granule-like bodies are seen to be more or less crescentic in form, somewhat similar to the crescents of sestivo-autumnal malaria. The worms described as Trichina affinis, T. agilissima, T. anguillce, T. cystica (see p. 600), T. cyprinorum, T. inflexa, T. lacertw, and T . microscopica, from various animals, are not trichinae. Various strongyles also have been recorded as trichinae. A very interesting case of pseudotrichinosis is presented in Rhabditis terricola (R. corntoaUi-Pelodera setigcra). This nematode was found in an exhumed cadaver of an English cadet, from the ship Cornwall, and was mistaken for a trichina; on the basis of this erroneous zoological determination, the outbreak of disease which had occurred was pronounced trichinosis and attributed to American pork. PULMONARY ROUNDWORMS. Metastrongylus apri (GmeUn, 1790) is a 12 to 50 mm. long thread- worm, which is rather common in the lungs of hogs. It has been reported by Diesing (lS51a, 317) once for the lungs of man; Chatin (1888b) states that it also occurs in the stomach of man, but such cases are probably due to eating hogs' lungs containing the worms. Rainey's (1855) case of Filaria trachealis in the trachea and larynx of a human subject may ROUNDWORM INFECTION— NEMATIIELMINTIIEB 611 possibly belong under M. apri. The eggs of M. apri measure 50 to 100 by 37 to 72/x, and contain an embryo at oviposition. SUBCUTANEOUS ROUNDWORMS. Gnathostoma siamense (Levinsen, 1889) is a very remarkable nematode which has been collected on two occasions, from three sim- ilarly affected patients in Siam. It attains 9 mm. in length by 1 mm. in breadth; head globular, with 8 circles of simple spines; mouth with two lips; anterior third of body with scale-like, tridentate spines, which become smaller and more simple the farther they are from the head. The brief description by Levinsen is based upon a female parasite collected from a Siamese in a superficial nodule on the side of the chest. Rhabditis niellyi (Blanchard, 1885) is at present a nominal species which can scarcely be classified even generically with any degree of cer- tainty. It is known only as a rhabditiform larva, 333/i long by 13/^ broad, which was found by Nielly (1882) in cutaneous papules, chiefly on the limbs, in a boy at Brest; small worms were also found for a time in the blood, but examination of the faeces, urine, and sputum was negative. Authors have compared this case with craw-craw, and have explained the infection upon the assumption that the boy might have swallowed eggs in drinking water of poor quality; that the embryo then escaped and reached the blood and skin. Possibly an equally plausible explanation would be to assume a direct cutaneous infection after the manner of uncinariasis. Dracunculosis^ or Guinea-worm Infection. — Geographical Distri- bution. — This is essentially an Old-World infection, being found in India, Persia, Turkestan, Arabia, and certain parts of Africa. It was intro- duced into South America by the slaves, but does not appear to have flour- ished there to any great extent. Occasional imported cases are reported in other parts of the world, several being recorded for the United States (Francis, 1901a, and others). Zoological Distribution. — This parasite is reported not only for man but also for cattle, horses, dogs, and several wild animals. Manson has suggested that possibly some of these cases represent specifically distinct infections. The Parasite. — The Guinea- worm or Medina- worm, Dracunculus medinensis (Linnaeus, 1758), is a white to yellowish parasite, 50 to 80 or more cm. long by 0.5 to 1.7 mm. in diameter; its anterior end is bluntly rounded, with a small terminal mouth and 6 papillae. A vulva has not been discovered, the genital organs probably discharging through the oesophagus. The intestine is rather reduced and no anus is present in adult specimens. The uterus is enormovisly developed and filled with sharp-tailed embryos 0.5 to 0.75 mm. long by 0.17 mm. in maximum diameter. The male is not positively known. Source of Infection. — ^The embryos escape, apparently through organs prolapsed through the mouth of the adult worm, and may live in clear water for six days, in muddy water or moist earth two to three weeks; if ^Synonyms. — Dracontiasis; Guinea-worm disease. 612 THE ZOO-PARASITIC DISEASES OF il/A.V Fig. 67. Nerv. slowly dried, they resuscitate in water. They may enter small crustaceans {Ci/ciops bicuspi'dafus, etc.), and within about three weeks develop to 1 mm. in ieno-th, casting the skin two or three times, losing the long tail, acquiring a cylindrical shape, and developing a trijiartite arrangement on the tip of the tail. They are then supposed to be swallowed in the drinking water. Accord- ing to Plehn's experiments, a direct develop- ment without intermediate host is not ex- cluded. It was formerly believed that the worm entered through the skin, and, as this mode of infection is now demonstrated for certain other worms, doubtless the possi- bility of this method will again be considered in connection with this species. The further history, to the gravid condition, has not been followed, but probably the worms soon leave the intestinal canal and reach the connective tissue; after copulation the male probably dies, while the gravid female, about eleven and one-half to fourteen months after infection, wanders to the sub- cutaneous tissue. Frequency. — It is not uniformly distrib- uted throughout the general area of infec- tion but is especially common in some districts. In parts of Deccan, at certain seasons of the year, about 50 per cent, of the population is infected ; in some parts of the western coast of Africa nearly every negro has one or more specimens (Manson). Symptoms. — The gravid parasite pro- duces very painful, superficial, furuncle-like swellings, chiefly on the feet and legs (about 85 per cent, of the cases), and occasionally on other parts of the body, as the back, neck, head, wrist, scrotum, penis, etc. A small blister forms and elevates the epidermis; the blister ruptures, disclosing a superficial ulcer about three-fourths of an inch in diameter, at the centre of which there is a small opening about two millimeters in diameter, from which the head sometimes protrudes. There may be fever, chill, nausea, and vomiting. The swelling may last two or three weeks; then the worm is extruded and the wound heals; or premature death of the parasite may give rise to an abscess; or the worm may become calcified and be felt for years as a hard knot. Treatment. — Emily's (1894a) treatment consists in injecting bichlor- ide of mercury (1 to 1000) into the protruding worm, which can then be easily removed twenty-four hours later; or if the worm itself is not visible, An. Gl. Embryo of the Guinea -worm. Nerv., nervous system; CEs., CBSophagus ; /ni., intestine; Gen., genital primordium; An. 67., anal papillae of glandular nature X 190. (Looss.) ROUNDWORM INFECTION—NEMATHELMINTHES 613 a few drops of the solution are injected as near the coil as possible; the parasite may then be wound out, or cut out. Another method is to protect the infected part from injury and douch it frequently with water; when this is done the uterus gradually empties and the worm may be extracted or it may come out of its own accord. Traction should not be used so long as the parasite discharges embryos, a point which may be deter- mined by microscopic examination of the fluid issuing from the opening. The old method of extraction is to pass a coil of the parasite through the cleft end of a small stick and to wind it out of the wound ver7j slowly, making only one or two turns of the stick daily. The objection to this method is that the worm sometimes breaks, the embryos escape into the surrounding tissue; violent inflammation ensues, with fever, abscess, and sloughing, and weeks or months may elapse before the patient recovers; death may occur from septic infection. Prevention.— Upon the theory that the infection takes place through the drinking water, only filtered or sterilized water, or water of unques- tionable origin should be taken when traveling in an infected region. FILARIASIS. Infections with Threadworms of the Genus Filaria.^— The genus Filaria Miiller, 1787, includes long, slender, filiform threadworms with curved or spiral tail. The male is smaller than the female, has 2 unequal spicules, 4 preanal papillse, and a varying number of postanal papillse; in the females the vulva is near the anterior end. The adults are parasitic, especially in the connective tissue, lymphatics, and body cavities; the embryo or larva frequently inhabits the blood, and in several species for which the life-history is known, insects such as mosquitoes form the inter- mediate host. Quite a number of species of this genus are reported as parasitic in man, but not all of them are described with sufficient accuracy to permit a positive zoological determination. In medical literature the chief interest has centered around the so-called Filaria sanguinis hominis. As a matter of fact, the name Filaria sanguinis hominis, as used in literature, means but little more to zoologists than does the expression "the tadpoles of Virginia." We know that Filaria sanguinis hominis is intended to designate a young stage of a threadworm in the blood of man, the same as we know that "the tadpoles of Virginia" is intended to designate young stages of frogs found in Virginia. In recent years Filaria sanguinis hominis is becoming confined more and more to one species, namely, to Filaria hancrofti; but as a scientific name it should be eliminated from medical literature. The various young filarise described for the blood of man may be tabulated as follows : KEY TO THE FILARIA LARVAE FOUND IN HUMAN BLOOD. Sheath present: — Periodicity absent; sheath very close; tail constricted, then sharply pointed; body 292 to 330by 65/(; type locality, Manila P.I. ; F. philippinensis, p. 624. ^For the most recent zoological summary of the species reported for man, see Penel, 1905, Les filaires du sang de I'homme. Paris. 614 THE ZOO-PARASiTIC DISEASES OF MAM Periodicity present: — Nocturnal periodicity (?); tail truncated; 131by5.3«; type locality, Bombay;' F. poiLiclli, p. 624. Nocturnal periodicity; — • Tail sharply pointed; 317by7.5^u; type locality, Australia; (F . nocturtia) F. bancrojti, p. 615. Tail truncated; 164 by 8//; type locality, Japan; F. taniguchii, p. 622. Diurnal periodicity; 317 by 7«; type locality, West Africa; {F. diuma) F. loa; p. 620. Sheath absent; no periodicity: — Tail sharply pointed: — 210 by OIL] type locality, West Indies; F. demarquayi, p. 622. 215 by 5,h; type locality, British Guiana; F. ozzardi, p. 622. Tail blunt, truncated: — 195 by 4.5/(; type locality. West Africa; F. perstans, p. 622. 220 to 240 by 8 to 12^«; type locality. West Africa; F. gigas, p. 624. So far as can be discovered, none of these young worms does any appre- ciable injury in the blood, and of the adult worms only one, namely, Filaria bancrofti, can at present be viewed as serious; while a second THE FOLLOWING IS A LIST OP THE FILARIA REPORTED FOR MAN. ADULT WORM. LARVA^ KNOWN AS TYPE LOCALITY AND GENERAL DIS- TRIBUTION. Filaria bancrofti Cobbold F. loa (Cobbold) F. perstans Manson F. ozzardi Manson F. demarquayi Manson F. volvulus Leuckart Filaria nocturna Manson F. diuma Manson F. perstans Manson F. ozzardi Manson F. demarquayi Manson Australia; tropics. West Africa; In- dia. West Africa. British Guiana. West Indies. Gold Coast; West F. magalhaesi Blanchard Africa. Rio de Janeiro. F. taniguchii Penel F. equina (Abildgaard) F. taniguchii Japan. Europe ; rather cosmopolitan. Pennsylvania; probably cosmo- politan. Europe. F. immitis Leidy F. lentis Diesing F. conjunctivae Addario Italy; Hungary. West Virginia. F. restiformis Leidy F. hominis oris Leidy Pennsylvania. Italy. Kilimara, East F. labialis Pane F. kilimarce Kolb F. romanorum orientalis Sarcani Africa. Roumania. [Unknown] Unknown] Unknown] F. gigas Prout F. powelli Penel F. philippinensis Ashburn and Craig Sierra Leone; West Africa. Bombay. Manila, P. I. ' The custom of giving to the larva a special name is not admissible under the International Code of Zoological nomenclature. Were we to give the egg of a mosquito one name, its larva a second, its pupa a third, and the adult a fourth, no end of confusion would result. A species is entitled to only one valid name. RO UNDWORM INFECTION— NEMA THELMINTHES 615 Fig. 68. Nerv. species, F. loa, Is more or less troublesome. We are hardly justified at present in assuming that all the other species are entirely without effect upon their hosts, but just what their effect is has not been shown, and whatever it may be, the indications are that at least in cases of light in- fection, that effect is of secondary importance when compared with /''. bancrofti. It is especially by the personal influence of Sir Patrick Manson that our knowledge of the filariae of man has been advanced, and any article written upon the subject must necessarily be based, to no little degree, upon his work. Infection with Filaria Bancrofti. — Geo- graphical Distribution. — Australia is the type locality for this parasite, but it may be designated in general terms as a tropical and subtropical infection of Asia, Africa, and America. It is especially common on the west coast of Africa, in South China, certain parts of India, Samoa, Friendly Islands, West Indies, etc. In the United States cases are occasionally found in the Southern States; Mobile (Anderson); Charleston, S. C. (Guiteras and others); occasional cases are found further n rth. Zoological Distribution. — ^The ad t worm is thus far known only for man. The L.rva occurs in a number of mosquitoes (Ano- pheles, Culex and Panoplites). The Parasite.^ — Bancroft's filaria^ (Filaria bancrofti Cobbold, 1877) is a whitish or brownish ( ?) transversely striated worm, 44 to 95 mm. long by 0.1 to 0.26 mm. in diame- ter; male with two spicules, 0.2 and 0.6 mm, long, anogenital pore 138/^ from tail, preanal papillae uncertain, but apparently 3 pairs of postanal papillae; vulva of the female 0.66 to 0.75 (or 1.2 to 1.3 mm.) from head, anus 225/z from tip of tail. Vivipa- rous. The larvse, 300 to 340 ^« long, by 6.6 to 8.5 or 11// in diam.eter, are found in the circulating blood and are provided with a sheath and sharply pointed tail ; they show a more or less marked periodicity in that they are much more numerous in the peripheral circulation during the night; but if sleep is reversed to day-time, the periodicity also is reversed. Mosquitoes, while biting patients, swallow these larvse, which then undergo development in the muscles, and finally, after fourteen to seventeen days, or, by lower Larva of Filaria bancrofti in the blood of man, in Egypt. Nerv., nervous system; Ex., excretory; An.., anus. X514. (Looss.) ^ Synonyms. — Filaria sanguinis hominis Lancet, Lond , 1872, Aug. 31, p. 310; larva; type locality, Calcutta (Lewis). F. dermathemica da Silva Araujo (1875) ; type locality, Bahia. F. bancrofti Cobbold, 1877g, July 14; adult; type locality, Australia. F. wuchereria Magalhaes, 1877, and F. wuchereria da Silva Lima, 1877; type locality, Brazil. Wuchereria filaria Silva Araujo, 1877. F. nocturna Manson, 1891; larva. 616 THE ZOO-PARASITIC DISEASES OF MAN temperature, up to thirty-five or forty-one days from time of infection, the worms reach a stage in which they are transmitted to man during the bite of the mosquito. Nothing is known of the biology of the worm from the time it enters man up to the aduU stage. The aduH worms occur alone or as several coiled together, chiefly in the lymphatics, but also occasionally in the fluids in swollen organs. There is no satisfactory explanation, as yet, of the periodicity shown by the larva. Source of Infection. — While it was formerly assumed that infection took place through tiie tirin king- water, this view may now be definitely abandoned and the mosquito bite regarded as the only known or probable source of infection. Frequency. — The frequency of the infection in man varies with the exposure to the infected mosquitoes, and this of course varies with the habits of the community, combined with proximity of mosquito-breeding places. In some places the infection is rare; in others it increases to 5, 10, 20, 50, or more per cent, of the inhabitants. Duration. — Nothing positive is known regarding the longevity of the adult or larva, but apparently neither is very short lived. Symptoms.— That numerous cases of infection show no appreciable symptoms is well established, but that in other cases the worms produced serious results must be admitted, especially if the adult parasites are present in large numbers or unfortunately located. According to Manson, Filaria bancrofti may produce the following conditions; abscess, lymph- angitis, varicose groin-glands, varicose axillary glands, lymph scrotum, cutaneous and deep lymphatic varix, orchitis, chyluria, elephantiasis of the leg, scrotum, vulva, arm, mamma, etc., chylous dropsy of the tunica vaginalis, chylous ascites, and chylous diarrhoea. In not all of these cases is the exact method by which the parasites act fully understood, and the relation of the parasites to elephantiasis is based chiefly upon circum- stantial evidence. In general, the adult parasites, or, Manson believes, in some cases, "their immature products of conception," cause two principal types of filariasis, one characterized by a varicosity of the lymphatics, the other by a more or less solid oedema. The frequency of these various manifestations does not seem to be uniform in filarial patients in different geographical areas, but the reason for this variation is not at present clear.^ Filarial Abscess. — These may be present in various affected organs and may contain the dead adult worms. They may discharge or be opened, if in the thorax or abdomen they may be serious. According to Manson, deep-seated pain in the thorax or abdomen, with inflammatory processes followed by hectic fever and a diminution in the number of or disappear- ance of filaria larvje in the peripheral blood, suggest filarial abscess and indicate exploration, and, if feasible, operation. Lymphangitis — ijlep^ianioid Fever. — This is common in all forms of filariasis due to F. bancrofti; it may or may not be followed by more severe conditions, as elephantiasis, lymph scrotum, varicose glands, etc. It ^Is it possible that local conditions, incident to the geographical distribution, have resulted in differentiating F. bancrofti into several subspecies, each with special tendency to a given clinical manifestation. Or have we in man even a larger number of distinct species of Filaria than have yet been described? ROUNDWORM INFECTION— NEMATIIELMINTIIES 617 usually appears on the extremities, but may be confined to other parts of the body (groin-glands, testis, spermatic cord, or abdominal lymphatics). The attack continues for several (usually two) days, then may recur after weeks, months, or years. It begins with a severe and prolonged chill (rigor), followed by high fever, 105.8° F.; is accompanied by headache, loss of appetite, frequently vomiting, and even delirium; it ends with profuse perspiration. At the onset of lymphangitis of the extremities, the painful cord-like swelling of the lymphatic trunks and of their glands, with a red, congested streak in the overlying skin, is visible; abscess or gangrene may develop; finally the tension is relieved by lymphous dis- charge and the swelling partially subsides, but the skin and subcutaneous tissue do not return to quite their normal condition, some permanent thickening remaining. Elephantoid fever has been repeatedly mistaken for malaria, but a differential diagnosis should not be difficult. The filaria embryos are not always found in the blood. In treatment, elevate the affected part, compelling absolute rest; give a milk diet; use mild laxa- tives, cooling lotions or warm fomentations, opium to relieve pain, and scarify the swollen area if necessary to relieve tension. Varicose Groin-glands, H elmintlioma Elasticum. — These frequently accompany lymph scrotum but may occur with other filarial manifes- tations; the affection may be unilateral or bilateral. They are soft, doughy, obscurely lobulate, and stationary in position ; but the skin may be readily moved over them. They may be easily mistaken for hernia. If the patient lies with raised pelvis the swelling slowly disappears; but if he stands erect the swelling slowly returns while the hand is pressing against the saphenous or inguinal openings. The contents are white to red, chylous, rapidly coagulable fluid, and usually contain filaria larvae. This condition is frequently mistaken for hernia, but the swellings are not tympanitic on percussion ; upon pressure they disappear slowly, and there is no gurgling; there is little or no impulse on coughing. Manson empha- sizes the fact that chronic swellings about the groin, cords, testes, and scrotum in patients from the tropics should always be regarded as of possible filarial origin. They are best left alone unless they result in an incapacitating discomfort, when they may be removed. Operation is not, however, always satisfactory, as it may be follow^ed by lymphorrhagia, excessive dilatation of some other part of the lymphatic area, chyluria, or by elephantiasis. Upon Manson's advice, Godlee, in order to prevent lymph stasis, drained the lymphatics of the region operated on into the vena spermatica and v. saphena, obtaining good results. Superficial or Deep Lymph Varices. — These are not rare, and may be superficial on the abdomen, legs, or other parts of body; or they may be more deeply located. If they rupture, lymphorrhagia results. They may appear and disappear within a few hours, and indicate lymphatic ob- struction. Lymph Scrotum. — ^This is frequently accompanied by varicose groin and femoral glands. The skin is silky to the touch, but presents lymphatic varices which may open and discharge milky to bloody, rapidly coagu- lating lymph, usually containing filarial larvae, which are also present in the blood. Elephantoid fever probably results from external mechanical irritation; the scrotum may become thickened, and elephantiasis may develop. In treatment, support and protect the scrotum, which should be 618 THE ZOO-PARASITIC DISEASES OF MAN' kept clean and powdered; but otherwise leave it alone unless inflam- mation be frequent, debilitating lymphorrhagia be present, or elephantiasis develops. If operation is decided upon, excise all the diseased tissue, obtaining flaps from the thigh if necessary. The patient should be warned of the possible occurrence of chyluria or of elephantiasis of the leg as a result of this surgicjil interference. Chyluria ; Hannaioclu/hiria. — This is very common, but intermittent; it may appear without warning or may be preceded by pains in the back, pelvis, and groin; the first symptoms may be retention of urine due to chylous coagulation in the bladder; the color of the discharge varies from a milky-white to a blood tinge, not only in different cases but also in the same case. It is rarely continuous; attacks occur usually lasting weeks or months or up to two years (Sheube), with more or less i)rolonged inter- vals. ^Yhile not directly dangerous, the continued drain upon the system may result in anannia, debility, depression, and incapacity for active life. Attacks are favored by pregnancy, childbirth, running, and other violent exertions which lead to rupture of a lymphatic varix in the bladder-wall. Treatment consists in absolute rest in bed, with elevated pelvis, a light saline purge, vesical irrigation, and restriction of food (especially fats) and fluids. Various drugs (gallic acid, benzoic acid, salol, chromic acid, gly- cerine, tincture of perchloride of iron, methylene blue, quinine, ichthyol, etc.) have gained some reputation, but INIanson is of the opinion that they have no effect whatever. P^ilarial larvae may be numerous in the urine. Orchitis. — This occurs as an acute manifestation accompanied by head- ache and vomiting and disappears as rapidly as it appears. It is preceded by elephantoid fever; there is a very rapid and very painful inflammation of the testes, which are much swollen; the swelling may also involve the epididymis, spermatic cord, and entire scrotum. Afterward, the fluid in the tunica vaginalis may not be entirely absorbed but may lead to chy- locele. Filarife are often present in the blood. Manson suggests the pos- sibility that the "malarial orchitis" of certain authors may in reality be a filarial orchitis. Chylocele. — This manifestation is more or less common, either alone or more frequently with or as a result of varicose lymph glands, lymph scrotum, etc. In the morning it is always soft and it is never so tense as common hydrocele. Numerous filarial larvse are present in the milky, reddish, quickly coagulating content. Treatment is identical with that of ordinary hydrocele. Elephantiasis. — The recurring attacks of elephantoid or erysipelatoid fever, with resulting and accumulative thickening of the affected part, gradually give rise to an elephantiasis, which, according to Manson, is the most frequent manifestation of this filarial infection. Occasionally, how- ever, progressive elephantiasis may occur after only one or several attacks of elephantoid fever. It is estimated that in 95 per cent, of the cases, the elephantiasis occurs in the legs, either alone or viiih elephantiasis of the scrotum or arms. Elephantiasis of the scrotum is also common, while that of the arms, mammae, vulva, and limited areas of the skin (peduncu- lated elephantoid tumors), is more rare. In only a proportion of the cases are the filarise found in the blood or in the fluid of the diseased organ. ROUNDWORM INFECTION— NEMATHELMINTIIES 619 The skin is rough and coarse, the hair is coarse and sparse, and the nails thick and deformed. The part pits but sHghtly or not at all on pres- sure, and does not glide over the underlying tissues. The skin is dense, fibrous, and enormously hypertrophied; the connective tissue is hyper- trophied and "blubbery" from its infiltration v^^ith lymph; bloodvessels are large; the lymphatics are dilated and the lymphatic glands enlarged. As even slight injury to the affected part may induce a recurrence of the elephantoid attacks, care must be taken to protect it. Violent exercise, exposure to the hot sun, etc., should be avoided. Massage, elevation of the affected part to drain out the lymph, and elastic bandaging, are to be encouraged. Absolute rest in the recurrent attacks of fever should be insisted upon; unfortunately permanent recovery never occurs. In extreme cases of elephantiasis of the leg, good results are sometimes obtained by excising a longitudinal strip 3 to 4 inches in breadth by 12 or more inches in length; during the febrile attacks, tension may be relieved by punctures with a lancet under aseptic conditions. Elephantiasis of the scrotum frequently develops to tumors of 10, 15, 20, 40, or 50 pounds; Manson gives 224 pounds as the largest case on record. These enormous growths are unsightly and inconvenient, but not as a rule directly dangerous. Occasionally they endanger life by becoming gangrenous or by abscess formation. They may develop either rapidly, in tv/o or three years, or very slowly. Upon reaching such a size that they are unsightly or inconvenient, surgical interference is indicated. The reader must be referred to works on surgery or to special papers on this subject for the full technique of operation. In brief, the scrotum is drained by ;3uspension, and the position of the testes determined, also of hernia, if present; the lines of intended separation are marked and should extend only through sound tissue, since otherwise disease is very likely to occur in the scar or flaps. Perineal, pubic, and connecting cuts are made; elastic webbing is used to expel the blood; a figure-of-eight is made with rubber cord around the neck of the tumor above the guiding incisions and over the pelvis; the testes and cord are dissected out; the prepuce channel is dissected up to the pubic incision; the penis is released; the perineal and pubic incisions are deepened and the neck of the tumor is cut close to the perineum. The bloodvessels are ligated; the redundant tunica vaginalis excised; the rubber cord removed; and the flaps brought together in a T- or Y-line, the penis emerging at the point of union. The mortality of the operation should not exceed 5 per cent. For elephantiasis of the arm, massage and elastic bandaging are used. A number of authors doubt whether elephantiasis is due to Filaria bancrofti. The general weight of circumstantial evidence seems however to indicate that at least some cases are due to this cause, while other cases which might formerly have been attributed to this worm may perhaps be due to other causes — as streptococcus infection. Brault, for instance, recognizes a bacterial (streptococcus) and a filarial elephantiasis. Diagnosis in General. — An attempt should always be made to find the larval filaria in the blood, urine, or chylous accumulation. There are chances for error in connection with the examination of the urine, and probably all those cases in which eggs are reported for the urine should be definitely rejected. Trichina cystica Salisbury, for instance, which 620 THE ZOO-PARASITIC DISEASES OF MAN nearly all authors have identified with Filaria bancrofti, is doubtless Ox- yuris vermicularis; vinegar eels (Anguillula aceti) have also been mis- taken for filarite. Blood. — The lymphocytes increase to 24 or 40 per cent. ; the eosinophiles to S or IS per cent. Treatment in General. — It is quite generally admitted that treatment to exterminate the larv;e in the blood is not only rather unsuccessful but also unnecessary. Authors have claimed, however, that they may be reduced in numbers with thymol, ichthyol, etc. The writer takes excep- tion to the view that such treatment is undesirable, if found to be practicable, as such eradication of the larvre would naturally be an im- portant point gained in jirevention. Anthelmintic treatment, directed against the adult, is in our present knowledge not only useless, but appar- ently imdcsirablc, as the dead worm is viewed as more dangerous than the live ]>arasitc. With Manson, the symptomatic treatment is generally admitted as consisting in rest, lowering the tension of the lymphatics by saline purga- tives, by appropriate food, and limitation of fluids ingested. Several drugs (potassium iodide, gallic acid, methylene blue, ichthyol, etc.) have gained a temporary reputation, but the conclusion drawn is that their adminis- tration accidentally coincided with the time of spontaneous remission. The necessity for asepsis in operation is so self-evident that it need not be emphasized here. Manson advises postponement of operation as long as convenient, but some authors are less conservative on this point. General Prognosis. — While filariasis is generally admitted to be a dis- ease which cannot be absolutely cured, the prognosis in uncomplicated cases is reported as good. Even in severe infections life may not be in danger. Prevention. — Every person who shows the filaria larvae m the blood, independently of the fact whether any pronounced symptoms are present, should, because of the danger of spreading the infection by mosquitoes, be considered a danger both to himself and to the persons in his neigh- borhood. This danger can be checked by compelling him to sleep under a mosquito-bar. Thus, the rule for prevention is : protect the mosquitoes from the patient, protect the patient himself and others from mosquitoes, and destroy mosquitoes. Infection with the Loa. — Geographical Distribution.— This infection is known particularly for the west coast of Africa, but imported cases are reported for other localities, chiefly in slaves or in missionaries who have visited western Africa. Ward (1906) has recently collected all of the recorded cases and has published several new cases for North America. Zoological Distribution. — The loa is positively known only for man, but Blanchard states that according to Plehn (1898) the natives say that it also occurs in sheep and goats. The Parasite. — Filaria (Loa) loa'- (Cobbold, 1864) is a filiform, colorless to yellowish-white threadworm, 16 to 57 mm. long by 0.3 to 0.57 mm. in 'Synonyms. — Filaria oculi Gervais and van Beneden, 1859; Dracunculus oculi (Gervais and van Beneden, 1859) Diesing, 1860; Dracunculus loa CohholA, 1864; Filaria subconjunctivalis Guyon, 1864; Filaria diurna Manson, 1891; F. san- guinis hominis major Manson, 1891* Filaria sanguinis diurna Fagge and Pye Smith, 1902; F, bourgii Brumpt. ROUNDWORM INFECTION— NEMATHELMINTHES 021 diameter; the cuticle is not striated but is provided with numerous wart- like structures, not known for any other Filaria found in man; male with lateral caudal alaj; 3 pairs of preanal pedunculated pajoillte, decreas- ing in size from the anterior to the posterior, and two or possibly three pairs of smaller postanal papillae; spicules unequal, 113 and 176/7. long; vulva of female 2.35 to 2.4 mm. from head; viviparous. The larva (F. diurna) circulates in the peripheral blood during the day, disappearing at night, and is indistinguishable morphologically from that of F. ban- crofti. Life-history unknown. Manson's view that F. diurna represents the larva of F. loa is not accepted by all authors, and in fact he, himself, merely suggested it as a possibility. The point raised by several authors that not all loa patients show F. diurna in the blood examinations, is not a very strong argument against the hypothesis, for it is perfectly possible that they were not examined at a time when the parasites were laying their young. In September, 1904, through the kindness of Sir Patrick Manson, the writer saw in London a lady who had been in West Africa and had just come to him to have a loa extracted; she also had F. diwma and gave a history of Calabar swelling. Other recent observations seem to raise Manson's hypothesis practically to a certainty. Source of Infection. — This is not yet determined. There is a popular impression that infection occurs through the drinking-water, but analogy would point to some insect as intermediate host. Manson suspects that mangrove flies (Chrysops dimidiatus) play this role; experiments on certain mosquitoes {Anopheles costalis and A. funestus) have been neg- ative. Duration. — Filaria loa is apparently rather long-lived; it has been seen in persons who had been away from the infectious locality for from four to ten or eleven years. Symptoms. — This parasite inhabits the connective tissue all over the body, which it traverses freely; recent observations indicate that it is quite superficial; it is seen especially around the eye in the subcutaneous fascia about the orbit, between the conjunctivae and bulbus; it travels over the nose, in the fingers, penis, etc. It disappears from the surface in two or three days and reappears after some days, weeks, or months. Its appearance is favored by warmth and retarded by cold. The loa causes an itching, creeping, prickling sensation, with occasional oedematous swellings and in some cases lachrymation or considerable pain; it may determine a more or less intense conjunctivitis and disturbances in vision. Several authors have associated with loa infections the so-called "Cala- bar swellings"; these appear suddenly on various parts of the body as elevations about half the size of a goose-egg, or 40 to 60 mm. in diameter; they wander slowly, about 20 to 30 mm. per day, then disappear in about three days to reappear after some months or years ; they are painless, but slightly irritating; do not pit on pressure, and feel "somewhat hot both objectively and subjectively"; they may occur on any part of the body, but, according to one patient, are caused by rubbing or scratching to relieve the irritation produced by the worm. Treatment. — When the loa approaches the surface it can readily be seen beneath thin skin; for instance, in the eyelid or over the bridge of the 622 THE ZOO-PARASITIC DISEASES OF MAN nose. It is then secured by means of forceps, an incision is made, and a second pair of forceps used directly on the worm; the first pair of forceps is then released and the worm drawn out with the second pair. Manson relates that the natives extract the parasite by means of a sharp thorn, or drive it into the deeper tissue by (lrop])ing a grain of salt into the con- junctival sac. He suggests the injection of bichloride of mercury (1 to 1,000) when the worni appears in parts of the body other than near the eye. Filaria taniguchii Penel, 1905, is reported as Go g ,-(0.-Hi-oo •* a> 00 r-i ■* 00 CO --H o g d ^^rtco'co'co CJ + + + + + J 1 + 1 + •8uun uj «■ ^t^tocoo-^^c^t^oo g COCOrtTjO g rji'-^'-^dcod^'racid •S30aBJ UJ 2 Tto-*i^t^iOTt CCH> t> 00 CI rti O '^ O g d ^ 'r-i •pooj UJ 2 c^ CI c) "O CM CD rt cq ^ o g 000000OiOl>rtOrtl> g icio'io'cq'odddddd CO •S 00'-iC0C>OOCDO03 5- 00.-IXOIOCDC01CC) O OSOlOiOCDiOCDCOOCO ^ cq cq ci 00 CO m' 'o v. 00 u2ioo'0-<}cqico-*"»''*r;'^co.CO— '0'00-*t^coa''-i05wO > £'3 C! o o Eh" a. _^ D 2 < a H 3 QJ C CO (M T-00'000 • • • • • • • • 00 3 a O oojc-ir^cnos 00 g"s a CO oo!co!M'oai ^ y s ^ rH .-H rH ^ g — - G 2 Oi COCOl^,-Hrt . • • ■ ■-H C > S •ril ioo5Nodi>coodtDodc> • ■ • ■ ■* rr 00 00t^00I>'©ffltDiOO'O . . • ■ 00 6 ^1 C) '^ lO _^ ^* D h a tH -^ . y 3 o c £'5 « 05 ■*00-- t£ tC tl ilj M U M M M tt ht tS M tO « CCGCCCCCCCCCCC 33333333333033 rnClCO^'OOt^OOOO'-HIMCO^ The actual extent of proteid katabolism during starvation is indicated by these data from experiments by Munk and by Van Hoogenhuyze and Verploegh. GENERAL CONSIDERATIONS OF METABOLISM 669 profound metabolic changes give evidence of themselves in the sudden and rapid increase in nitrogen output. So far as has been exp(!rimentally ob- served the oxidative processes maintained during hunger do not decrease in extent below the values noted in the same individual under comparable conditions when food is not denied. This is apparently true not only in periods of rest, but likewise during work. The essential difference be- tween the starving man and one in good nutritive condition (but tempo- rarily without food) lies in the earlier onset of fatigue in the former. That is, "the muscles of the man are still capable of accomplishing practically as much in a single contraction during starvation as before; but they become exhausted more speedily. An important factor in this lapid fa- tigue is found in the extreme irritabihty and slight working capacity of the heart.'' The metabolism of the elements other than nitrogen during prolonged starvation has not been extensively studied in man except in a few instances. The output of sulphur appears to run closely parallel to that of nitrogen, indicating a common source of the two elements in the dis- integration of proteid. The elimination of phosphorus has been found to be increased both absolutely and relatively with respect to nitrogen. If the phosphorus excreted in starvation is likewise derived from pro- teids it should obviously bear the same relation to the nitrogen excreted as the two bear to each other in the body. This has not usually been the case. In addition to the high output of phosphorus, an increased elimination of calcium and magnesium, too great to be attributed to the disintegration of muscle tissue, has also been found. These facts, taken together, leave little doubt, that the bones, which are so rich in phosphates of the alkali earths, suffer loss. Since the chlorides of the urine are primarily derived from the chlorides (chiefly NaCl) taken with the food, a rapid fall in the output of chlorides during starvation is naturally to be expected, and has repeatedly been ob- served. The writers have seen it sink to a small fraction of a gram in the early days of starvation in man, and continue at that level throughout a five-day hunger period. The excretion of potassium considerably ex- ceeds that of sodium, quite the reverse of ordinary conditions. This observation adds another to the many evidences, during starvation, of the disintegration of the tissue elements (structures) in which potassium salts greatly preponderate. So far as published experiments indicate, the formationof the f ffices does not cease during prolonged starvation, although the quantities are greatly diminished. The composition of the "hunger faeces," viz., the relatively high content of nitrogen (6 to 8 per cent.), fat, and inorganic salts, recalls the fseces discharged after an easily digestible diet, free from cellulose. This close resemblance has contributed largely to the prevailing \dew that the fseces are not to be considered as the undigested residue from food to any great extent under satisfactory conditions of diet, but rather as con- sisting in large part of secretory products from the alimentary tract. We cannot attempt to follow the fate of the many other katabolic products arising during hunger, nor designate the specific changes produced in individual organs. One is impressed, however, by the slight extent of the variations from the normal which are met vAih. The differences between fasting and normal individuals are quantitative 670 NUTRITION rather than qualitative, at least during the earlier stages of starvation. Experiments of Abderhalden and otliers have demonstrated that the chemical make-up of the tissues -svliich remain unused in a starving animal is not noticeably altered. The proportions of nitrogenous decom- position products obtainable are entirely comparable with those yielded by a well-fed animal of the same species. It is interesting to note that the fat content of the blOotl may be foimd notably higher during the early days of starvation. This corresponds with what might be expected if fat is transported during hunger from its storehouses in the body to the places where the oxitlations take place. With reference to the actual nutritive condition of the cells and their metabolic ca{)acity in hunger, experiments by Schondorlf (1893) have given some evidence. He perfused the hind extremities of well-nourished and starving dogs with the blood of starving and normal animals, and esti- mated the metabolic power of the surviving body cells by the percentages of urea found in the blood. It was found that even when normal blood was perfused through the "hunger" limb, the proportion of katabohc products was smaller than that yielded by the well-nourished muscles. We may reasonably conclude from this that the metabolic activities of the cells are dependent upon their inherent nutritive conditions, as well as upon the character of the blood which supplies them. The extent to which indi- vidual organs may be impaired is seen in the case of milk secretion during hunger. Barbera (1900) saw the daily yield decrease under these con- ditions to one-seventh of its original volume in the course of fourteen days, all the constituents being involved in the change, although the yield of fat diminished most slowly. Lusk (1901) had a similar experience with a goat in which the output of milk could be diminished to far greater extent by a few days' starvation. Closely related to the conditions pertaining in complete inanition or "acute" starvation, are those found in the more chronic forms of deficient nutrition ("Unterernahrung") or malnutrition. Unfortunately we have few accurate experimental data on this subject — one highly important for the physician, within w^hose province it distinctly falls. The cases in which deficient nutrition may arise are nvmierous, and in all we have to deal with physiological conditions not markedly different from those discussed under complete hunger. It is possible that the organism adapts itself to the deficiency in intake by a more economical utilization of its resources, so that the body can maintain its nutritive equilibrium with a smaller expenditure of energy. Accurate data are not yet available in this direction, while evidence to the contrary is not wanting. Von Noorden believes that even after prolonged deficient nutrition an intake of 30 large calories per kilo of body-weight is required to maintain equi- librium. Practical experience, however, has shown that under poor nutritive conditions, persons may make gains on diets Avhich are barely sufficient for the well-nourished individual. A careful study of this subject is important ; for in conditions (such as gastric ulcer) where larger quantities of food cannot be consumed without danger, a knowl- edge of body needs, as demonstrated by actual experience, becomes invaluable. In connection with the phenomena of metabolism pecuhar to starva- tion, it is perhaps appropriate to mention the marked retention of GENERAL CONSIDERATIONS OF METABOLISM 671 ingested materials which characterize what has been termed "re-alimen- tation"; that is, the return , to normal conditions when food ingestion is resumed. In accordance with the general protection which the body aifords in starvation to the organs most important for its survival, it has been noted that even prolonged starvation does not destroy the neuro- secretory apparatus. When food is again given, the digestive changes go on as usual. The glycogen content of the liver is rapidly reestablished and a decided gain is noted in the balance-sheet of intake and output of materials. This is especially true in the case of the inorganic salts as well as the nitrogenous intake. At present no extensive data appli- cable to inan are available on this subject. An interesting illustration of the extent to which nitrogen may be retained is afforded by observa- tions of Fr. Miiller on a patient whose body-weight had fallen to 31 kilos during insufficient nutrition following stenosis of the oesophagus. After four days of absolute starvation with a daily loss of 4.28 grams of nitrogen, it became possible to increase the intake of food. During the following twenty-six days of feeding, the nitrogen balance was as given below : Daily intake of nitrogen. Daily intake of food. Daily output of nitrogen in urine and faeces. Nitrogen retention per day. 5 days 7 days 8 days 6 days Grams. 7.60 8.99 11.77 13.67 Calories (large). 765 881 1000 1100 Grams. 5.91 7.04 8.18 8.83 Grams. 1.69 1.95 3.59 4.84 26 days 42. 03 29.96 With every gain in proteid intake, a proportionately larger retention of nitrogen was noted. This is characteristic of convalescence from wasting disease, in which the katabolic processes preponderate. A similar retention of nitrogen is not readily brought about in the well- nourished organism in which nitrogenous equilibrium tends to be es- tablished very speedily. Metabolism During Feeding-.— Observations during conditions of starvation might, perhaps, be expected to furnish a satisfactory basis upon which to estimate the actual nutritive needs of the organism. In hunger, where one group of factors — ^the intake— can be entirely elimi- nated, it might appear that we are dealing with the simplest state of metabolic changes possible and that the data obtained would be broadly applicable. This, however, is only partly the case. For example, the relative quantities of proteid or fat decomposed per day in a starving indi- vidual are not necessarily indicative of the most advantageous utiliza- tion of materials, as the organism is compelled to employ the resources which are most easily available. It becomes important, therefore, to learn how the metabolic processes are modified when food substances are ingested. 672 NUTRITIoy Influence of Proteids on Metabolism. — The unique importance of proteids in nutrition, owing to their content of nitrogen, has ah'cady been mentioned. Since the body is unable to utihze other tyj)es of nitrogenous compounds in the entire absence of true proteids, except perhaps the immediate decomposition products of the latter, prolonged proteid hunger becomes as serious in its consequences as does the comj^lete absence of food. Under suitable conditions a carnivorous animal like the dog can be kept in nutritive equilibrium on an exclusive meat diet. To accomplish this the animal must eat three to four times as much proteid as is decomposed during hunger. It has thus far been imj)ossible to maintain similar equilibrium in man on an exclusive ])roteid diet. The failure to do so is associated, in part at least, with the inability to digest properly the enormous quantities of i)r()teid requisite. It will be recalled that the net available energy of the proteids is smaller than their heat of combustion woukl indicate, owing to the incompletely oxidized products which are liberated from them. The digestive work which they entail is also not inconsiderable. The fundamental observations noted show that every increase in the amount of proteid fed tends to increase the katabolism of proteid. By virtue of the tendency of the body to adapt its nitrogenous katabolism to the proteid intake, it becomes possible to attain nitrogenous equilibrium with widely varying quantities of proteid. In all of these cases it is understood that the total intake of food must be sufficient to cover the demands of the body for energy. In the fasting condition the latter may amount, in the case of a man of average body weight, to somewhat over 2,000 calories per day, or 30 large calories per kilo of body weight. When food is taken, and no external work of any consequence is performed, the metabolism of energy is slightly in- creased over the fasting figure, perhaps to 32 to 33 large calories per kilo per day; while under conditions of muscular activity the demand for energy may be increased under extraordinary circumstances to 100 large calories per kilo per day or over. Provided that these nutritive demands are satisfied, the absolute quantity of proteid required to prevent a loss of body proteid will depend somewhat on the proportion of non-proteid foods ingested and absorbed. A determination of the maximum quantity of proteid which can be utilized is scarcely feasible in the case of man, since it is practically im- possible to exceed 200 grams in the intake without eliciting unpleasant symptoms. While it is true that most experiments in this direction have been carried out with meat as the chief source of the proteid, and that the extractive substances (such as lactic-acid salts, creatin, potassium salts, etc.) cannot be regarded as physiologically inert and non-toxic, yet there is no reason to believe that larger quantities of pure proteids of animal or vegetable origin could be consumed with relish for any length of time. Finally, certain considerations make it unlikely that a nutritive equilibrium could ever be established in man on an exclusive proteid diet. While an increase of the proteids in the diet tends to augment proteid katabolism and leads to a greater elimination of nitrogen in proportion to the supply of proteids offered, an increase in the fat or carbohydrate constituents of the food tends to diminish proteid katabolism, although the latter cannot be completely stopped under any combination of diets. GENERAL CONSIDERATIONS OF METABOLISM 673 An animal which receives a nitrogcn-frec diet of either fat or carbohy- drate or both, will not succumb as soon as a starving animal. Neverthe- less, the continued nitrogen losses during nitrogen (or proteid) hunger lead to a fatal result as inevitably as does complete inanition. More recent experimental work has, however, shown that in proteid starvation the loss of body proteid may become far smaller than the earlier investi- gators found. The essential feature in maintaining a lower plane of proteid metaboKsm in these cases consists in the administration of suffi- cient non-proteid nutrients to cover more nearly the demands of the organism for energy. This is well illustrated in experiments made by Fohn on man. On a diet consisting of 400 grams of pure arrow-root starch and 300 cc. of cream containing 15 to 25 per cent, of fat, together with a few grams of salt, the daily output of nitrogen was reduced to between three and four grams in all the individuals under observation over a period of several days. This effect appears to be common to both fats and carbohydrates, although in different degree. Effects of Non-Nitrogenous Nutrients on Proteid Metabolism. — The effect of carbohydrate and fat on the metabolism of proteids under con- ditions in which the total nutritive demands are more nearly satisfied is deserving of closer attention. Although these non-nitrogenous nutrients cannot check the katabolism of body proteid in proteid hunger, they are capable of exerting a definite and important influence in diminishing the extent of proteid katabolism. This is usually spoken of as the proieid- sparing action of fats and carbohydrates. Most of the data in demon- stration of this have been collected from experiments on animals. The following experiment by von Noorden and Dieters illustrates the proteid- sparing action of carbohydrates in man. The daily nitrogen intake dur- ing a period of four days amounted to 12.6 grams, with a daily output, in the urine, of 10.4 grams of nitrogen. When, on the fifth day, 200 grams of cane-sugar were added to the diet the urinary nitrogen fell to 9 grams. According to this, 1.4 grams of nitrogen (equivalent to 13 per cent, of the previous output) had been spared in the form of proteid. Similar pro- teid-sparing effects have been obtained with fat. The experience of all observers agrees in indicating the superiority of carbohydrates over fats in this respect. Voit found an average decrease in proteid metabolism of about 7 per cent, with fats and about 9 per cent, with carbohydrates. A comparison which Kayser instituted upon himself is interesting: with an intake of (in round numbers) 132 grams of proteid, 70 grams of fat and 340 grams of carbohydrate, having a fuel value of 2,600 large calor- ies, he was able to maintain nitrogenous equilibrium. The replacement of carbohydrate in the food by an "isodynamic" amount of fat (140 grams) caused an increase in the output of urinary nitrogen and a con- sequent negative balance, in contrast with the preceding slight gain. It should be noted, however, that possible differences in the relative avail- ability of the supposedly "isodynamic" quantities of fat and carbohy- drate have not been drawn into consideration by most investigators. The methods of estimating the protective power which the different foodstuffs exert upon tissue constituents, other than proteids, are indirect and too complicated to be referred to here. Marked differences in the role of the fats and carbohydrates of the food in sparing body -fat have not been made out. The preceding discussion of the relations of metab- 43 674 NUTRITION olism to the food suj)ply lias iiulicatetl the "flexibiUty in the anhiuil organism as regards the nature of the material consumed in its vital processes," Armsby has well summarized the range of choice by the organism and the mutual replacement of nutrients. "The amount of proteid material necessarily required for the metabolism of the mature animal, we have seen to be relatively small. Aside from this minimum, the metabolic activities of the body may be supported, now at the expense of the body-fat, now by the body ])roteids, and again by the proteid,", the fats, or the carl)t)liydrates of the food. AYhatever may 1k> true econoni- ically, physiologically the welfare of the matiwe animal is not con- ditioned upon any fixed relation between the classes of nutrients in its food supply, apart from the minimum requirement for proteids. The possibility of a mutual reiilacement of the several classes of nutrients in the food follows almost necessarily from the power of the organism to utilize them all indifferently (in a quahtative sense at least)." It is appropriate to consider the influence exerted upon metabolism by a number of substances which cannot properly be classed among the typical, foodstuffs, but nevertheless may enter to an important extent into the make-up of the diet. Among the nitrogenous compounds, gelatin stands foremost. Although closely related to the true proteids, gelatin is sufficiently characteristic and peculiar in its chemical make-u}) to be classed in the groupof albuminoids (proteoids,scleroproteins). Chemically it differs from proteids in the absence of the tyrosin- and tryptophan- yielding groups, the small content of sulphur-containing radicals, and the peculiar quantitative distribution of its constituent organic complexes. Experiments both on man and on animals have demonstrated the failure of gelatin to prevent loss of body proteid when it is the sole nitrogenous compound fed. It can, however, replace proteid to a very large extent, and it acts conspicuously in sparing both proteid and fat in the body. In the absence of other forms of nitrogenous substances, animals fed on gelatin with non-nitrogenous nutrients succumb within a few weeks. Careful experiments by Murlin, in Lusk's laboratory, have suggested the following conclusions: A mixed diet, more than covering the energy requirement of the organism, and containing two-thirds of the starvation minimum of nitrogen in the form of gelatin, and one-third in the form of proteid, will maintain nitrogenous equilibrium for a few days at least. In other words, the proteid requirement under the combined sparing action of gelatin, fat, and carbohydrate falls to one-third the starvation requirement. Experimental data obtained on animals by C. Voit and by I. Munk show that 100 grams of gelatin will protect about the same quantity of proteid as is spared by 200 grams of carbohydrate. Body- fat, likewise, can be protected by gelatin feeding. As might be expected, the gelatigenous tissues (tendons and cartilage) exert a similar proteid- and fat-sparing action to the extent to which they are digested and con- verted into gelatin in the alimentary tract. The influence of other nitrogenous compounds, such as proteoses, peptones, amino-acids, and amides, upon proteid metabolism, has not been studied in man. Undoubtedly these substances, especially the im- mediate derivatives of the proteids, can replace the latter to a certain extent; but under ordinary circumstances they are unim]5ortant. Among the non-nitrogenous ingesta, cellulose, owing to its indigestibility, plays GENERAL CONSIDERATIONS OF METABOLISM 675 little if any part, further than to increase the nitrogenous waste leav- ing the body when large portions of indigestible foods are fed. The few data available on the action of pentoses — the five-carbon sugars like arabinose, xylose, and rhamnose — upon proteid metaboHsm dis- close no marked effects. The fatty acids have been found to exert a proteid-sparing influence quite comparable with that of the fats from which they are derived; while the remaining component of the latter, the glycerin, appears to be negligible in this regard when equivalent doses are used. Alcohol. — Among the substances which may influence proteid metabo- lism, alcohol deserves mention because of its widespread use. The views regarding its value as a food and its influence on metabolism are somewhat divergent, and some of the testimony has not always been free from bias. That it is in large measure burned in the body seems reason- ably certain, at least as far as this applies to moderate quantities. We must, however, distinguish carefully between large doses which have an un- mistakable toxic action, and smaller doses in which the alcohol appears to exert a protective action on proteid and fat. Neubauer has observed that in severe diabetes administration of alcohol may check the output of acetone much as carbohydrates do. In careful metabohsm experi- ments by Atwater and Benedict, results with ordinary diet were compared with those in which part of the fats and carbohydrates of the food were replaced by the isodynamic amount, about 72 grams (2 J ounces), of absolute alcohol. This is about as much as would be suppHed in a bottle of claret, or 6 ounces of whisky, or 5 ounces of brandy. The quantities of alcohol eliminated by the lungs, skin, and kidneys, varied from 0.7 to 2.7 grams, and averaged 1.3 grams per day. Over 98 per cent, of the ingested alcohol was oxidized in the body, and one gram of alcohol was calculated to be isodynamic with 1.73 grams carbohydrate or 0.78 gram of fats of ordinary food materials. The proportions of food and of the several kinds of nutrients made available for use in the body were practically the same in the experiments with and those with- out alcohol in the diet. The potential energy of the alcohol was trans- formed into kinetic energy in the body as completely as that of ordinary nutrients. The efficiency of alcohol in the protection of body fat from consumption was very evident. The losses of fat were no larger and the gains no smaller with alcohol in the diet than with the corresponding diet without alcohol. In this respect there was no indication of any considerable difference between the alcohol and the nearly isodynamic amounts of fats and carbohydrates which it replaced. The efficiency of alcohol in protecting body protein was evident, but not fully equal in this respect to the isodynamic amounts of the ordinary nutrients, the result depending somewhat on the extent to which the individual was accustomed to the use of alcohol. We may repeat with Atwater and Benedict, "that there is a very essential diiference between the trans- formation of the potential energy of the alcohol into the kinetic energy of heat, or of either internal or external muscular work, and the useful- ness or harmfulness of alcohol as a part of ordinary diet." It would be a mistake, however, to assume that alcohol can be rated as a true non-nitrogenous food in the sense in which fats and carbo- hydrates are foods. For experiments have shown that alcohol prior to 676 NUTRITION its combustion in the body exerts a noticeable influence upon the meta- bolic processes in the liver, and possibly in other organs, whereby a marked effect is produced upon the output of uric acid. In other words, alcohol, and especially alcoholic drinks, when taken with purin-contain- ing foodstuffs, exert a direct influence upon the metabolism of those compounds which give rise to exogenous uric acid, increasing largely the amount of uric" acid excreted (Beebc). Whisky, for example, may be given with impunity when the patient — as in typhoid fever — is on a light or ])urin-free diet, without materially influencing the ])roduction or output of uric acid; but when the alcoholic fluid is taken with a hearty meat diet, or with any diet containing free or combined purin com- pounds, the system is at once liable to show the eft'ects of the excess of uric acid. In this respect alcohol behaves quite differently from an ordinary non-nitrogenous food. The literature abounds in studies regarding the influence of a large variety of substances, both organic and inorganic, upon metabolism. Some of these, like the drugs, cannot be considered here; others, like tea, coft'ee, and various dietary accessories, exert no profound action on the organism in moderate dietetic quantities. In recent years food pre- servatives, such as borax and boric acid, sulphites, benzoic and salic3'lic acids, formaldehyde and fluorides, have received special consideration in view of their increasing and widespread use. At the present time it would be unprofitable to generalize from these studies. Role of Inorganic Salts.— The inorganic constituents of the diet possess a significance in no degree commensurate with their lack of energy- yielding qualities. The elements which they include are essentially sodium, potassium, calcium, magnesium, iron, phosphorus, sulphur, chlorine, and silicon — which are distributed in widely varying propor- tions in different parts of the body, about S3 per cent, belonging to the skeleton and the remaining 17 per cent, to the soft parts. The quan- titative relationship is shown in the following table summarized from Soldner's analyses of the bodies of infants: Grams per Kilogram of Body Weight. K,0 1.87 AlA 0.03 SO, 0.54 Na.0 2.04 Fe..d.; 0.22 CI 1.76 CaO 10.12 Mn.A 0.007 SiO., 0.02 MgO 0.38 PA 10.01 COj' 0.14 That a growing organism must be supplied with the inorganic con- stituents necessary for the proper development and organization of the tissues is self-evident. It is interesting to note that in milk, nature has supplied the infant with an admirable diet in resjject to the needs for inorganic constituents. Milk is richer in calcium, so essential to the development of the skeleton, than any other common dietary article except the egg, which in turn is the storehouse of materials furnished to those young which have an extra-uterine development. The splendid adaptation to the relative needs of growing young, which Bunge has called attention to in the case of the milk of diff'erent species, is well worthy of careful study. His investigations have shown that the rapidity of growth of man and the domestic animals during lactation is propor- GENERAL CONSWERATIONS OF METABOLISM 677 tional to the composition of the milk. As regards calcium and phos- phorus, two elements especially concerned, this feature is striking. Time in which the body-weight of the new-born animal was doubled (in days). One hundred parts of milk contain Proteid. Ash. Calcium. Phosphoric acid. Man. . 180 Horse 60 Cow. . . 47 Goat 19 Pig... 18 Sheep 10 Dog. 8 Cat 7 1.6 2.0 3.5 4.3 5.9 6.5 7.1 9.5 0.2 0.4 0.7 0.8 6!9 1.3 0.328 1.24 1.60 2.10 2.72 4.53 0. 473 1.31 1.97 3.22 4! 12' 4.93 The effects of a lack of certain of the inorganic salts in the diet have long been familiar in the case of the adult, as well as the growing young. A deficiency of calcium giving rise to rachitic conditions in the child has its analogue in the osteoporosis of the adult. We have taken occasion to refer to these facts, because they illustrate the important role of inor- ganic compounds in the metabolism of growth and direct attention to similar functions of these compounds in adult life. In health, the adult is continually losing inorganic salts, not only so long as they are contrib- uted to the body with the diet, but equally well when there is a deficiency of them in the intake. Experimental observation shows that with ade- quate nutrition there is, in the full-grown individual, a tendency toward "salt equilibrium." The latter condition is apparently subject to far more extensive fluctuations than is the case with the organic foodstuffs; but it is as yet impossible to frame any general laws bearing on the in- direct influences of the inorganic food constituents on the metabolism of the energy-yielding compounds. There is here a broad field for fruit- ful research. Sufficient facts are at hand to indicate the promising character of such studies. For example, lack of sodium chloride m the food soon leads to deficient secretion of hydrochloric acid in the gastric juice. Animals fed for long periods of time on foods deficient in cal- cium, but rich in organic nutrients, are extremely susceptible to intoxi- cation with organic acids, like lactic or oxalic acid. Since the latter may be formed at times in the intermediary metabolism of carbohydrates, in certain perversions of metabolism their toxic action may be traced directly to the lack of neutrahzing or "antitodal" (disintoxi eating) inor- ganic bases in the diet. The profound osmotic effects which the inorganic salts of the body fluids are concerned in; the phenomena of saline diuresis and accelera- tion of lymph-flow; the imique types of salt glycosuria; the marked effects on the muscular and nervous structures; and the peculiar antagon- istic relations of differentiations such as sodium, potassium, and calcium, leave no doubt of the importance of the inorganic foods in modif}-ing metabolic processes. At present we can scarcely go beyond the realm of interesting speculations. We need further to be instructed not only regarding the quantitative needs of the animal body in the case of the individual elements, but also regarding the forms (or types of compoimds) 678 NUTRITION in which these are best rendered available. Many of the elements exist in nature in organic combinations, conspicuous in the case of cer- tain foods. The determination of the nutritive requirements of the body for these inorganic compounds properly belongs to the subject of dietetics. One of the difHcultics in arriving at a correct understanding of the metab- olism of the inorganic salts has arisen from a lack of knowledge regard- ing the channels by which they leave the body. Iron furnishes a good illustration of some of the errors formerly encountered. The failure to recognize the intestinal epithelium as a factor concerned in the removal of iron naturally allowed a false interpretation to be placed on the occur- rence of this clement in the faeces. To the earlier observers, iron in the stools was a direct indication of lack of iron-absorption, particularly in view of the extremely scanty elimination of ferric salts usually noted in the urine during the same period. But the establishment of the fact that the gut may be directly concerned in the excretion as well as in the absorption of iron compounds, made possible a new interpretation of the earlier observations. Iron might be present in the alimentary canal, either owing to failure to be absorbed, or ecpially well because it had been discharged into this channel, through the epithelial walls. It became necessary to follow the paths of elimination when the introduction of this element directly into the alimentary canal w^as avoided. Since it has been found that iron may be introduced subcutaneously or even directly into the blood current, without producing any marked increase in the output through the urine, while the faeces may contain noticeable quantities, the significance of the intestine with reference to the elimi- nation of such elements becomes apparent. The part which the inorganic salts may play is thus manifold and difficult of interpretation. No energy is set free in their oxidation; yet they may exert most subtle influences, if such examples as the assumed profound physiological function of the iodine present to the extent of a few milligrams in the thyroid glands are to be trusted. So far as can be judged at present, Liebig was cjuite correct in pointing out that the inorganic salts are not an accidental contamination of living matter, but rather of fundamental importance. Work and Metabolism. — Among the influences which affect metab- olism, muscle-work is perhaps of even greater significance than the food intake. The effects are immediate and the extent of the change produced is far greater than the mere measure of the work done would seemingly indicate; for the most part, the skeletal (voluntary) muscles outrank the non-striated (involuntary) ones in the extent to which they participate in these effects. When a muscle contracts, heat is liberated, and work is done. The relative distribution of the energy between these two effects varies somewhat with the conditions under which the contrac- tion is carried out. Within certain limits, as Fick demonstrated, the working capacity increases with the demand made upon the muscle. For example, a muscle which under slight stimulation transformed 6 per cent, of the energy used into work done, performed work up to 29 per cent, of the total used when its most vigorous efforts were called out. GENERAL CONSIDERATIONS OF METABOLISM 679 The law of the conservation of energy, which we have seen to hold for the body, teaches that the various manifestations of energy, such as heat, work, etc., can be expressed in common terms; and the relation between heat and mechanical work is shown in the equation, 1 large calorie = 425 kilogrammeters. On this basis, the potential energy of the foodstuffs can be expressed in terms of the maximum work which they can afford, approximately as follows: 1 gram of proteid yields 1,700 kilogrammeters. 1 gram of fat yields 4,000 kilogrammeters. 1 gram of carbohydrate yields 1,700 kilogrammeters. Actually, however, much larger quantities of the foodstuffs must be katab- olized to yield mechanical work in this amount; roughly, about one- fifth to one-quarter of the total energy is thus convertible. The extent to which metabolism may be increased by work under normal conditions is best illustrated by actual figures. In experiments covering forty-nine days on healthy adults, the average total energy given off per day during rest, with food, was 2,262 large calories; during work in the same in- dividuals, over sixty-six days, the daily average was 4,676 large calories. Of this twofold increase (2,400 calories), 450 calories were equivalent to the extra muscular work done. Rubner has calculated the total metab- olism of a large number of individuals, on the basis of an average body weight of 70 kilos, and expressed the results in heat units (kilocalories), thus: During rest 2,303 calories =32.9 calories per kilo. Slight bodily work "1 2,442 calories =34.9 calories per kilo = 6% increase, (physicians, etc.) j ' s^ /u ^1:soYSers,°ete ) "^"'^ } ^'^^^ ''^^°"^' =^^ "^ '^^°"^' P^' ^^"^ = ^4% increase. ( firh' ' i tp 1 I 3,362 calories =48.0 calories per kilo = 45% increase, Cminers'^etc ") I 4,790 calories =68.4 calories per kilo = 108% increase. The influence of muscular work on metabolism is speedily made evident by an increased consumption of oxygen and output of carbon dioxide. The relation between the oxygen inspired and the carbon dioxide expired, i. e., ~ is known as the respiratory quotient; normally this is less than 1 . Not all of the oxygen reappears again in the eliminated carbon dioxide, since some of it is used in the oxidation of other elements to form water, sulphuric acid, and other bodies. In the combustion of pure carbon, one volume of oxygen yields one volume of carbon dioxide. The ratio -^ in this case is unity. In the body, however, the magnitude of the respiratory quotient depends on the nature of the katabolized substances. For the combustion of carbohydrates it is approximately 1; in the katabolism of proteids it is about t^b; and for fats the ratio falls to To. The respiratory quotient will accordingly vary in accordance -^^th the relations here expressed, and may afford important information re- garding the nature of the katabolic processes. Experience has sho\\Ti that the consumption of oxygen by the tissues is independent, within wide 680 NUTRITION limits, of the oxygen supply, but varies directly with the demands of the tissues. In view of this, the extent of oxygen consum})tion may be taken as a measure of the action of different influences on the rate of metab- olism. Studies have been made on the effects of walking, marching, swimming, mountain climbing, etc., upon respiratory metabolism. Zuntz and Katzenstein have estimated the intensity of the metabolic changes which work brings about in man. Expressed in the consumption of oxygen per minute, in contrast with the conditions prevailing during rest, they found: During rest 263 cc, walking on level 763 cc, walking up hill 1,253 cc. These arerjuite comi)arable with the observations made by Zuntz and Schumburg on soldiers at rest, and marching with and without accoutrements. The total change in the daily excretion of car- bon dioxide resulting from work is shown in experiments on a man of twenty-three years of age. During the periods of ordinary work, the heat equivalent of the external muscular work amounted to about 11 per cent, of the total energy metabolized. D-ULY Elimination of Carbon Dioxide in the Same Individual. (From experiments by Atwater and Benedict.) Rest, without food 676 grams Rest, with food 812 grams Work, with carbohydrate in diet 1,820 grams Work, with fat in diet 1,665 grams Extra severe work, with fat in diet. . . 3,073 grams Higley and Bowen have made a study of the immediate changes in the excretion of carbon dioxide incidental to muscular work in bicycling. The results agree with those of previous workers in indicating a uniform output of carbon dioxide during uniform work. The changes which give rise to this katabolic product in the muscle may be pictured as beginning instantly with the commencement of the work. Since the gas must first diffuse into the blood and then be carried to the lungs, there should be a latent period of a little more than half the time required for a complete circuit of the blood before the first waste product formed during work can be exhaled. A variation of several seconds may reason- ably be expected, dependent upon the rapidity of the circulation. The latent period of increase in the output of carbon dioxide from the lungs in case of beginning work is nearly twenty seconds, the increase reaching its maximum in about two minutes. Upon cessation of work, the output decreases again to the normal amount in about the time occupied by its increase and after a like latent period. In view of the rapid adjustment of the carbon dioxide output to the muscular metabolism occurring, it might be expected that the extra elimination during work would be confined almost entirely to the day time when the work is done. This is actually the case; and during the night periods it is only a little larger in the work experiments than in the rest experiments. The proportions of carbon dioxide, water, and heat, eliminated during the different periods of the day in the same individual at rest and at work, with and without food, are shown on page 681 (Atwater and Benedict). It is well known that a given amount of mechanical work is not always done at the same cost of materials metabolized. Training and fatigue GENERAL CONSIDERATIONS OF METABOLISM 681 ^ ^ 1 V.2 c coo o> OiO ,^ o I'd g ■-irti lO -^O) ■* o coh-' '6 -t d -*' d coco t> t-H IM o fe Oh ^ jj M >. . c OCO CO i-HO t^ o Worl C'b'h diet Per ce 05C-I d -^ d CO co' o d < COCO t^ i-H < C-l o W •t^ "i t^OO lo iMco >o o -M'^ a> oo r-^ r~tt^ 00 o oiod t^ •*(» im' d (NCS lO IN.-H •* o Ph '"' ^\ -^ . M a IC* 05 03C^I rH o co(> O OiM 05 o fa ^"^ 00 "O Tj( .^^ d d 0)(>) lO C-) CO -*C0 r^ o ■*oo d-H CO t~05 rH OV o 00 o d K CO-* 00 r-t o ^ '"' Rest. Food. er cent. .' d N(M >0 (N(M •* o PL| "^ +i OCO a> OIO ,_^ o ■*r-l lO TjHCTl •* o i^co O Tt*-* d d OlIM lO (MIM ■* o ^ -t! i>co O COI> o o 10.-H t^ 00-* CO o O " 00 00 d co' d CO d coco l> rt IM o fa Ph '"' ^ H Work. C'b'hy, diet. Per cen ,-,iO O OIUO ■* o r-lt> 00 (MOO o >< 00 00 d T)i'o6 co' d O Q S coco t- rt l> Tt ,-nO o o f^fa S3 PL, coio a C^IOO o o O oo'od o TtJod CO d (NIN u- (N.-I •* o ^•. -t^ -g.C rH 03 'o Eh 3 T3 PPL, iSdn 1 682 NUTRITION are important factors in considering the expenditure which a given mus- cular task calls for. In general, the trained and untired muscle is the more economical; that is, it transforms less material in doing a given amount of work than docs the untrained or fatigued muscle. Other circumstances, among which are atmospheric conditions (oppressive heat, humidity, etc.), the relative strain on specific muscular parts, the absolute amount of work to be done, as well as personal factors — all influence the capacity for work and the relative expenditure of energy. The importance of an adequate knowledge of the factoVs which influence the capacity for work has been cmj)hasized by the study of Zuntz and Schumburg on soldiers during marching. Apj^arently minor considera- tions, such as comfortable or uncomfortable adjustment of the knap- sack, irritation of the skin, improper clothing, and overweighting, may be sufficient to occasion an increased expenditure of energy entirely dis- proportionate to the work done. Again, in bicycling, the influence of the speed on the energy utilized per kilo of body weight and 1,000 meters distance covered were found by Leo Zuntz to vary as follows: At a speed of 60 meters per min., 40 . 3 cal. = 552 cal. per kilo, per 1,000 meters. At a speed of 100 meters per min., 47 . 2 cal. = 647 cal. per kilo, per 1,000 meters. At a speed of 143 meters per min., 78 . 5 cal. = 1,075 cal. per kilo, per 1,000 meters. The increased expenditure of energy which is called forth by those exertions which ordinarily pass unnoticed may be not inconsiderable. The mere maintaining of the body in an upright position calls for a con- sumption of 10 to 20 per cent, more oxygen than is used in quiet repose. The varied activity of the hands and arms makes corresponding demands on the energy supply. Wolpert has estimated the increase of CO2 output in people engaged in various occupations over the quantities observed for the same individuals at rest, as follows: In a seamstress the increase was 13 per cent. In a bookkeeper the increase was 17 per cent. In a tailor the increase was 22 per cent. In a shoemaker the increase was 47 per cent. These differences are obviously attributable to the different degree to which the hands and arms are employed, the general (sitting) posture being maintained in each case. In sleep we have the extreme contrast to muscular activity in work; and although the consumption of oxygen and the output of carbon dioxide, for example, fall to about three-fourths of the figure quoted in the waking state, it is scarcely less than what can be attained by complete relaxation during waking hours. Johansson ob- served an hourly CO2 elimination of 22 grams during sleep; of 31 grams during waking rest. In general, we may say that there is an increase of about 40 to 45 per cent, in carbon dioxide output during waking rest over absolute relaxation; a figure which illustrates the physiological significance of repose in therapeutics. With a patient reduced to a minimum of strength and store of surplus energy, rest (in the sense of complete relaxation) can well be advised as an important protective measure, on the basis of sound physiological evidence. In addition to external muscular work, we may also call attention to another form of activity parity muscular, which is associated with diges- GENERAL CONSIDERATIONS OF METABOLISM 683 tion. The following figures, calculated from experiments made in Zuntz's laboratory, indicate the relation of the digestive work accomplished to the heightened metabolism, in terms of the percentage increase in carbon dioxide excreted and oxygen consumed (in daily averages) : Heat value of the Increase in carbon Increase in oxygen food absorbed. dioxide produced. consumed. Calories. Per cent. Per cent. 2,233 16.3 12.2 The same facts may be expressed from another standpoint, by noting that in rest the amount of energy expended when fasting is only about 10 per cent, less than with food. We have reserved any discussion of the influence of muscular work upon nitrogenous metabolism for this place, because it bears directly upon the question of the source of the energy transformed in this condi- tion of bodily activity. Is work done at the expense of proteids, fats, carbohydrates, or two or more of these body constituents? With respect to the proteids, the problem admits of a ready experimental answer. If an individual is maintained in nitrogenous equilibrium upon an adequate mixed diet, the effect of muscular activity ought to manifest itself in a distortion of the nitrogen balance if proteids are katabolized to supply energy for work. It seems obvious that if an individual is fed over long periods on a ration largely or exclusively composed of proteids, the source of muscular work must be found in increased proteid katabolism. Similarly when the supply of non-nitrogenous food is inadequate to fur- nish all the energy needed, the conclusion is inevitable that nitrogenous compounds will be disintegrated to supply the demands. In accordance with this, it has been observed that animals fed over long periods of time on lean meat alone are capable of performing severe muscular labor. Although the nitrogenous excretion has been observed to be increased under such conditions, the proteid katabolized was too small to account for the energy expended in the work; such experiments, how- ever, give no sufficient reason for concluding that the body performs work preferably at the expense of proteid material. What do observa- tions made under other conditions of diet teach? It may be profitable to review the history of physiological views on the sources of muscular energy. Liebig early assumed that proteids are decomposed in the body to yield the energy of mechanical work — a view which is, in a certain sense, still shared by Pfliiger. Observations by Pettenkofer and Voit soon made such a position appear untenable; for they failed to find the increase in urea excretion which might have been expected during increased muscular exertion. Further, the experi- ments made it clear that the non-nitrogenous nutrients must be the sources of the energy available under these conditions The classic experiment of Fick and Wislicenus (1866) w^as, perhaps, the first satis= factory attempt to compare the energy expended during work T^dth that rendered available by the proteid disintegrated. They calculated that the quantity of proteids katabolized during an ascent of the Swiss Faul- horn (6^500 feet), and measured by the urea excreted, was insufficient 684 NUTRITION to account for more than a .small fraction of the energy required to raise their bodies to the height of the mountain, not to mention the energy expended in the work of the internal organs and muscular movements not directly involved in the ascent. Contrary to these results, various investigators have found more or less increase in proteid metaholism after muscular work. In those in- stances, it has usually been found that the diet selected was insufficient for the demands made upon the body. Where the food suj)ply has been in excess of the amount required for maintenance, any material increase in the nitrogen excretion as the result of the work done has usually been overlooked. As an illustration of conditions where daily losses of nitrogen amounting to 5 to 8 grams were noted during severe muscular work, we may quote the observations of Atwater and Sherman on bicycle riders in six-day races. Analyses of food, urine and fteces are summarized below, in terms of daily averages: Rider. Nitrogen. Equivalent LOSS OF BODY PROTEIN. In food. In fspces. In urine. Loss. Miller Albert Pilkington.. . . Grams. 29.4 29. 1 36.0 Grams. 1.8 2.5 2.2 Grams. 30.2 33.7 38.9 Grams. 8.6 7.1 5.1 Grams. 53.8 44.4 31.9 The exertion in these races Avas very severe, the riders averaging eighteen and a half to twenty hours of work and a distance of over 300 miles a day. There was, unquestionably, a deficiency of non-nitrogen- ous nutrients in the diet which was evidently poorly selected and inade- quate, and it is quite conceivable that equally severe and prolonged exertion might be undergone without increased metabolism of nitrogen, provided the supply of non-nitrogenous fuel material Avas abundant. In the studies of Zuntz and Schum})urg on soldiers during marching, an increased elimination of nitrogen was observed on the marching days and the rest days immediately succeeding them. It was noted that the increased katabolism of proteid would account for not more than 6 to 7 per cent, of the extra work accomplished; furthermore, the increase in nitrogenous waste was in no way proportional to the absolute amount of work done, but was essentially influenced by the severe heat and other oppressive atmospheric conditions. Further, there was no change in the distribution of the nitrogen in the various types of urinary constituents during work. One feature during work deserves mention, namely, the noticeable increase in nitrogen eliminated in the perspiration. Under conditions of profuse sweating during active exer- tion, the daily output through this channel may, according to Benedict, become as high as 0.22 gram per hour — a quantity by no means negli- gible in accurate balance experiments. The increase in the excretion of nitrogenous waste during extreme activity may reasonably be attributed to a decomposition of tissue pro- toplasm, incited perhaps by fatigue or deficient respiration in individual GENERAL CONSIDERATIONS OF METABOLISM 685 groups of muscles, as Speck has maintained. In many experiments made in this country, under the auspices of the Department of Agriculture, no similar influence has been found; and no evidence whatever has been obtained to indicate that proteids are the sole source of energy in mus- cular work. Armsby has well summarized the evidence now available: "1. The non-nitrogenous ingredients of the food or of the tissues are the chief source of muscular energy. In by far the greater number, if not all, of the experiments upon this subject the amount of protcid metab- olized, as measured by the nitrogen excretion, was insufficient to fur- nish energy equivalent to the work done, the deficiency being in many cases very great. This statement, it will be observed, does not assert that the proteids are not concerned in the production of this energy. We may regard it as very probable that the non-nitrogenous matter metab- olized has first entered into the structure of the muscular protoplasm, which, as we know, consists largely of proteids; but in a contraction it is largely, if not wholly, the non-nitrogenous groups contained in the protoplasm which are metabolized rather than the nitrogenous groups. "2. With insufficient food there may be a considerable increase in the proteid metabolism, as a result of muscular exertion, especially when pushed to exhaustion. "3. This increase is far from sufficient to supply energy for the work actually done, is not proportional to it, and seems dependent to a con- siderable degree upon accompanying conditions. "4. With sufficient food the increase of the total proteid metabolism consequent upon muscular exertion is at the most slight and possibly equal to zero. "5. In some cases a storage of proteids has been observed to result from the performance of work." It would be a mistake to conclude that the proteids of the body play no part in the work of its muscles. The muscle protoplasm is built up of both nitrogenous and non-nitrogenous components; and while the readjustments which take place during the contractile processes involve a destruction of the non-nitrogenous constituents, perhaps in the form of sugar or glycogen, both components appear to be requisite for the proper maintenance of an active working apparatus. It is thus quite conceivable that with an inappropriate proteid supply muscular power might be impaired seriously, even though the liberation of energy in the actual contractile changes goes on at the expense of the carbohydrate groups of the protoplasm. We may picture the latter as a labile substance when the easily detached non-nitrogenous groups are joined to it. Mus- cular activity would accordingly involve a change in the stabiUty of the protoplasm, which in turn would resume its original condition of irritability by becoming regenerated through the addition of fresh carbo- hydrate groups. Several experimental observations are more easily inter- preted from this point of view. For example, it becomes evident that proteid alone will not accomplish the regeneration of the contractile substance in a satisfactory degree, although in its disintegration it may furnish a considerable proportion of non-nitrogenous groups — the so- called "carbon moiety" of the proteid molecule. Again, if the proteids form a semi-passive agent, as it were, in the development of muscular power, it is plain why the muscles may be more capable of retaining pro- 686 NUTRITION teid when they are active, than is the case with inactive or less ^^go^ously working musck>s. Herein hes the expUmation of the phenomena of muscular hypertrophy; and experiments have indicated a greater ten- dency for the body to gain proteid during hght work and abundant diet, than is observed in a less active condition. We have here indicated the distinction between "putting on flesh" (growth of muscle), and storing up foodstuifs. The bearing of this reciprocal relation between exercise and muscular growth and its connection with the metabolism of muscle, is not without })hysiological imjiortance. We must distinguish between the development of a well-organized muscular system calling for a liberal proteid supply, and the nuiintenance and working demands of such organs — i. e., between the construction of the machine and its energy requirement. Finally, the participation of the body proteids may apparently be provoked by unfavorable conditions for muscular work, to some of which reference has already been made and among which oxygen starvation is a conspicuous example. Thus, in the muscular exertion of dyspnoea the increased proteid decomposition seems to be attributable to local conditions in the muscles involved. The katabolic processes in these organs are qualitatively altered and fatigue products are more speedily formed. That proteids are not the only components affected in this perverted function, is seen by the disturbances evoked in the carbo- hydrate constituents of the muscles, whereby such compounds as lactic acid may arise in considerable quantities. At present, it is practically impossible to ascertain with certainty what choice, if any, the body exercises between fats and carbohydrates in the decomposition of non-nitrogenous compoimds in muscular work; nor can we say that the fats are transformed into sugar or glycogen before they become available for the immediate work of the contractile tissues. The more recent studies upon isolated muscles, especially the heart, are very suggestive. These show that such organs can maintain active con- tractions for many hours, when they are supplied by perfusion with an oxygen-laden isotonic solution of inorganic salts and dextrose. Blood serum or proteid solutions are not more effective than solutions of com- mon salt — all of which are decidedly inferior in sustaining power to Ringer's solution with sugar. It would seem from this that the sugar solution is effective not so much in washing away fatigue products — the muscle waste — as in supplying a nutrient group. Otherv;ise, we should expect equally efi'ective results from simple saline perfusion. Within the body as a whole, it is not so easy to analyze the function of the individual non-nitrogenous nutrients in muscular work. To be sure, numerous ergographic experiments seem to demonstrate the effective use of carbohydrates ; but the results afforded are not very trustworthy. We have seen that the respiratory quotient varies for the different kinds of materials consumed in the body. A review of the literature suggests that when the body is well supplied with carbohydrates the respiratory quotient remains high during work, indicating a large utilization of carbo- hydrates. The latter are thus readily used when they are available for the cells of the body; and accordingly the store of glycogen in the mus- cles is seen to diminish with severe work. On the other hand, metab- olism experiments on man fail to indicate any difference in the way the body utilizes the kinetic energy arising from oxidation of the different GENERAL CONSIDERATIONS OF METABOLISM 687 nutrients Atwater and Benedict have tested the relative efficiency of fats and carbohydrates by ascertaining whether it costs more energy to do the same work with fats than with isodynamic amounts of carbo- hydrates. In directly comparable work experiments a somewhat higher efficiency for the carbohydrate than for the fat -diet was observed. In other experiments not so comparable, less pronounced differences appeared. The general conclusion of the investigators is "that in these experiments the fats were slightly inferior to isodynamic amounts of carbohydrates as a part of a ration for muscular work. But while the natural inference is that calorie for calorie the carbohydrates were slightly superior to the fats as sources of muscular energy, the difference observed was very small and may have been due to some individual peculiarity of the subject with which the more directly comparable experiments were made, rather than to any inherent capacity of the materials to yield energy for external muscular work." Regarding the immediate sources of muscular energy and the character of the substances actually metab- olized in the muscles, these experiments give no answer; nor is the solution apparent in the lack of more extensive information respecting the intermediary changes in metabolism. Other Influences on Metabolism. — Regarding other influences which may be brought to bear upon metabolism aside from the intake of food and muscular exertion, the time has not yet come for any comprehensive summary. The influence of growth deserves careful investigation, and a study of the nutritive changes in the young is certain to afford an abundance of practical suggestions. The available data indicate a fairly good absorption of the foodstuffs in young infants, the figures for the total available energy varying from 90 to 96 per cent, of the total intake. Sugar absorption appears to be by far the most perfect. Oppenheimer first called attention to the fact that the gain in weight of infants is directly proportional to the quantity (or calories) of milk ingested. Thus two different children during the second month of their lives gained 191.2 and 201.1 gm. for each kilogram of milk given; in the third month, 120.3 and 138.5 gm.; in the fourth month, 102.6 and 103.3 gm. It is noteworthy that the appetite determines the regular ingestion of sufficient energy for the life processes, plus a small but fixed extra per- centage necessary for growth. Lusk has formulated a law of growth, that in the development of the normal young of the same age and species, a definite percentage of the energy content of the food is retained for growth irrespective of the size of the individual. According to Heubner, vigorous growth in 'infants demands an intake of energy amounting to 100 to 120 large calories. That growth itself is attended with an active chemical exchange is shown by studies on the respiration of the embryo, in which the gas metabolism has been found to be as active as that of adults. The metabolism of the young appears to be somewhat more iactive than that of the adult, as far as can be judged from the data on page 688 which the authors have compiled from various sources. Although it appears as if the metabolic processes are less extensive in old age, it must be remembered that the activity of the individual is greatly diminished, and our conclusions are based upon the dietetic habits of the old rather than on actual metabolism experiments. It 688 NUTRITION seems doubtful if any specific influence of old age aside from diminished muscular exertion can be demonstrated. Age of Subject. CO2 output per kilogram, and per hour. Urea output per kilogram, and per day. 35 years. 20 years. 15 years. 9-13 years. 3- 7 years. Grama. 0.51 0.53 0.00 0.90 1 . 20 Grama. 0.5 0.5 0.5 0.6 0.7 There is no evidence that the psychical processes, as exemplified in nervous excitement, specifically influence metabolism. During sexual changes modifying influences are doubtless at work, but they lack ex- perimental verification. More conspicuous than the preceding are the effects which external climatic and hygienic conditions impose upon metabolism. The explana- tion for many of these undoubted effects is not yet forthcoming. In some cases, problems of temperature regulation seem to be concerned; for the temperature, relative humidity of the air, and its rate of move- ment modify the "physical" regulation of the body temperature so long as an excess of heat is produced in metabolism. But below the so-called "critical temperature" (about 37° C. for naked man, according to Rub- ner, and 15° C. in ordinary clothing) the incidental heat production no longer suffices to maintain the normal temperature of the body, and addi- tional body material must be oxidized for this special purpose. Under ordinary circumstances this is avoided by the devices used to keep our immediate surroundings above the point where a "chemical" or meta- bohc regulation of temperature is called into play. Herein lies the in- direct influence of cloihing on metabolism. Materials which prevent radiation and conduction of heat, as well as modes of dress which fail in a cold environment to conserve the heat produced by the body, exert an influence on the chemical changes going on in the organism concerned. We are accustomed to dress ourselves in such a manner as to make the loss of heat equivalent to that which the naked body would undergo at about 33° C. The cold hath, rapidly removing heat from the body, stimulates katabolism. From calorimetric observations, Rubner has calculated the effects of an hour's bath at various temperatures in terms of additioyial fat katabolized, as follows: Bath at 15° C Katabolism of fat = 52 grams. Bath at 20° C Katabolism of fat =37 grams. Bath at 25° C Katabolism of fat = 22 grams. Bath at 30° C Katabolism of fat = 9 grams. Bath at 35° C Katabolism of fat = 0.7 grams. Lately, the action of high and low altitudes has received considerable attention in connection with climatotherapy. It appears that both moun- tain- and sea-air may exert a stimulating influence upon metabolism in those unaccustomed to the climatic condition selected. This is made evident in the increased consumption of oxygen and output of carbon GENERAL CONSIDERATIONS OF METABOLISM 689 dioxide at rest without food. It has become quite certain that other climatic factors than the diminished barometric pressure are eifective in the case of mountain experiences and similar subtle influences appear to come into evidence at the seashore. Doubtless the direct insolation plays some part in the action of climate at high altitudes; in illustration of this we quote from Rubner the observation that at Davos, on sunshiny days without winds, one can remain quietly seated in the open air at — 1° C. without wearing heavy clothes. The vacuum thermometer indi- cating the degree of insolation may rise to +43° C. at the same time. It is not impossible that increase in the radio-activity of the air in mountain regions may exert a physiological influence. In saying this, however, we are still within the realm of conjecture. FATE OF THE INGE ST A AND ORIGIN OF THE EXCRETA. No review of this subject would be complete without some considera- tion of the changes which the digested compounds experience in becom- ing incorporated with the tissues and fluids or transformed into materials for the purposes of movement and vitality and finally altered into pro- ducts ready for excretion. This intermediary metabolism still remains a most obscure chapter; and the progress of physiological chemistry has helped to make the subject more complex. Thus, in speaking of the albuminous substances we are now prepared to distinguish between the various members of a great group of organic compounds related in many chemical and physical features and yet sufficiently different in structure and physiological behavior to demand a special interpretation for their roles in metabolism in many instances. In this way, for example, a familiarity with the specific metabolism of the nucleoproteids, with their phosphorus, carbohydrate, purin, and pyrimidin complexes, has been obtained; and little by little the independent origin of the different nitrogenous excretives has been unraveled. The source of the katabolites, urea, uric acid, and oxalic acid, has been traced to different members of the proteid family; whereas at one time they were attributed to a common source which was assumed to give rise to diverse end-products by obscure variations in the metabolic processes of the organism, now yielding one, now another of them. Similarly, the physiologist is able at present to distinguish between the metabolic fate of proteids which convey phosphorus to the organism and those which do not; or, looking from another point of view, to refer eliminated phosphorus to a variety of possible origins — the phosphates ingested, or the phosphorus of gland nucleoproteids, lecithins, or disintegrating leukocytes, as the circum- stances may direct. In this way he aims to obtain a deeper insight into the chain of events which constitute intermediary metabolism — what Foster has termed the "gaps and guesses" of nutrition. There is so much which is uncertain and the subject of controversy that we shall aim to recount briefly only such facts and theories as have received more general acceptance, or are, in our opinion, deserving of special recognition. Metabolism of Carbohydrates.— Carbohydrates apparently experi- ence the best utilization of all the types of foodstuffs commonly ingested. In the healthy infant, which receives these nutrients in the form of milk- 44 690 NUTRITION sugar, no trace of sugar ordinarily escapes with the stools, and in the adult the record is scarcely less satisfactory for the digestible carbohy- drates. They are, of course, not all absorbed in the form in which they are ingested. Experimental evidence indicates that the monosaccharides (hexoses and pentoses) are the "physiological" sugars and that the digestible carbohydrates are converted into this form before they are absorbed and utilized. The ]>ossibility of functional adaptations of the digestive glands to the materia-ls upon which their secretions are required to act has been suggested in recent years. The experimental evidence thus far presented is, however, unconvincing. To what extent, if at all, such functional adaptations may involve an inter-relation between the diet and certain nutritive factors important in practical experience re- mains to be learned. AYhen soluble carbohydrates enter the circulation without intervention of the alimentary digestive processes they are only retained in part, de- pending on the nature of the compound introduced. The monosaccha- rides, dextrose and levulose in particular, are not excreted at once; but such carbohydrates as cane-sugar, milk-sugar, glycogen, or dextrins, re- appear to a considerable extent in the urine when they enter the blood as such. Maltose (malt-sugar) appears to afford an exception in this respect, presumably owing to the presence of a maltase, or maltose- inverting enzyme in the blood itself. Dextrose may be introduced into the circulation by a variety of channels and is in every case largely re- tained unless the quantity and rate of introduction are excessive. Under ordinary circumstances in man, the monosaccharide products of diges- tion are carried in the portal blood-stream to the liver, and doubtless go to form the glycogen store of this and other tissues. So far as is known, the glycogen from different sources is chemically the same. Aside from glycogen, another important carbohydrate constituent of the body is the blood-sugar. This has repeatedly been identified as dex- trose. Whether it exists there in the free state or in combination with other organic groups like the lecithins, or both, has not been answered to the satisfaction of all physiologists. The most recent experimental evidence speaks against the idea of a combination. Two facts deserve emphasis in considering the intermediary metabolism of the carbohy- drates; namely, the relatively wide distribution and noteworthy quantities of glycogen which may be present in the body at one time, and the appar- ent constancy of the sugar-content of the blood. It seems to be demon- strated that there is no pronounced diminution of the percentage oi sugar in the blood during starvation, although it is doubtless continually being requisitioned for the needs of the functioning tissues. Neither does work or rest detectably affect the sugar-content of the circulation as a whole; and any condition in which hyper- or hypoglycfemia arises partakes at once of the nature of disease. It is therefore apparent that some regulatory mechanism must be at work in the organism serving to maintain the constant level of the blood-sugar content. We ask ourselves: How is this constancy maintained? How, on the one hand, is the surplus which the digestive processes furnish retnined; and how, despite continued utilization, is the blood replenished with dextrose ? Under ordinary circumstances of health, the blood contains about 1 per mille of dextrose. Whenever sugar tends to increase to GENERAL CONSIDERATIONS OF METABOLISM 691 any considerable extent beyond this and excecKls tlie limit of about 3 per mille, dextrose is eliminated by the kidneys. Indeed, it is not unlikely that the intestine may act as an excretory organ at times when the sugar- content of the blood becomes physiologically excessive and the kidneys are insufficient. These processes are normally not called into play; for the excess of carbohydrate is taken care of and retained in the organ- ism or immediately burned up. But when this fails to be effected com- pletely, an excretion of sugar may follow the intake of relatively large quantities of carbohydrate, giving rise to the condition spoken of as "aUmentary glycosuria." The failure to retain or destroy the sugar intake may be a relative one in this case and depend upon the quantity poured into the circulation at one time; thus, 100 grams of dextrose ingested in a single dose can ordinarily be retained by a healthy individual, and the failure in this respect is generally regarded as an approach to a pathological condition. When, however, the monosaccharide sugar is retained in the organism it is not always burned at once. There can be no question regarding the increase of glycogen in the liver following the introduction of some carbohydrates at least. Whatever discussion the glycogenic function of the liver has aroused has been directed at the theory of glycogen deposi- tion. The anhydride theory assumes a chemical re-arrangement and alteration of the sugar molecule when it reaches the liver, together with a polymerization by which the relatively insoluble glycogen is retained in the hepatic cells, ready to be dispensed in ways which will be consid- ered later. A few physiologists have believed that the glycogen is not derived from the carbohydrates ingested; the latter are supposed to be burned up directly, thus sparing the glycogen which they believe is formed from proteid. This is the spariiig theory. Neither of these theories is satisfactory in explaining the facts of experiment. Nor can the newer metabolic theory be said to answer all objections. According to this view, the food-sugars are not converted directly into glycogen, but are first synthesized into the living protoplasm from which in turn glycogen is split off — secreted as it were. The most important feature of such a theory lies in the necessity for proteid in the construction of a glycogen-yielding protoplasm. It makes clear why more glycogen is apparently stored when both proteid and sugar are furnished, and how hexose sugars, with such different configurations as dextrose, levulose, and galactose afford, can yield a carbohydrate of constant chemical structure. The function of glycogen-formation thus becomes a property of the living protoplasm-constructing cell, and the deposition of gly- cogen in so many tissues of the body as well as in such vegetable cells as yeast can more readily be understood. Again, the metabolic theory of glycogen-formation makes it somewhat easier to appreciate how substances like glycerin or even inorganic salts like ammonium carbonate cause an increase of glycogen in the liver. These compounds afford both glycogen and urea, by inciting a katab- olism of the liver protoplasm, which results in the liberation of carbo- hydrate on the one hand, and nitrogenous groups on the other. The glycerin or ammonium salt accordingly need not be considered as directly entering into the glycogen-yielding process and itself participating in its construction. The metabolic theory also lends probability to the power 692 » NUTRITION of many, if not all, cellular tissues to produce glycogen as well as the liver, so that the muscles need not be assumed to owe their store to the supply transmitted from the liver. The living protoplasm can rebuild glycogen in any organ; and we can understand how starving animals can in part renew the glycogcn-content of their tissues, and why even in prolonged hunger, as Pfliiger has shown, the tissues may still contain a noticeable ]iroportion of the carbohydrate. Pfliiger, to be sure, is un- willing to admit the formation of glycogen from proteid, and assumes in the case of the starving organism that the glycogen is only slowly used up. Is it not more likely that the proteids incorporated in the indefinite substance called protoplasm may take part, as indicated above, in the re- newal of the glycogen in the cell ? And with the necessity of both nitrog- enous and non-nitrogenous groups admitted for protoplasmic anabolism, it becomes clear that with the lack of cHher of these constructive materials glycogen can be manufactured only at the expense of ready formed proto- plasm, involving in turn increased katabolism of nitrogenous material. We might expect in this event that proteid and carbohydrate katabolism should run parallel, or, in case of a failure to use the carbohydrate, its excretion in quantities strictly proportional to the nitrogenous waste — as it is observed in certain pathological conditions — could more easily be understood. For no conclusive evidence of a direct conversion of food proteid into carbohydrate has yet been advanced. Whatever our view regarding the origin of glycogen may be, whether we admit its formation from proteid or sugar alone or from both, directly or indirectly, or even from fat — for which there is much less evidence — the important role of glycogen as a carbohydrate reserve in the body must generally be admitted. Returning to a consideration of the fate of the ingested carbohydrates in metabolism, we have followed them until, in pathological conditions, they are excreted unused and unchanged or disappear from the circulating media. There remains the second inquiry: How is the sugar-content of the blood maintained and the losses to the tissues made good ? Without discussing this point we incline to the view that it arises from glycogen, notably in the liver. The blood-sugar rapidly sinks in quantity when the liver is cut out of the circulation; and it becomes difficult, if not impos- sible, to produce any typical hyperglycsemia by experimental means, when the glycogen-content of the liver has previously been greatly reduced. In the conversion of glycogen into sugar, enzymes are doubtless concerned to an important extent. Soluble ferments capable of inducing such changes are known to exist, and there is no good ground for denying that the processes which can be observed postmortem in the liver go on during life, though perhaps at a greatly altered rate. A reaction of this type is, furthermore, quite in accord with prevailing views regarding the importance of enzyrnes for the chemical organization of living cells. And in attributing the vital process of sugar-formation to enzyme activity, it is unnecessary to postu- late any extra-cellular secretion of the active agent; the modem view merely attempts to define more precisely the character of the chemical reaction involved by classifying it with those transformations known as enzymatic. The relation of the nervous system to these manifold pro- cesses is at present ill-defined and only partly understood, although its physiological bearing must be manifest. Finally, it seems likely that glycogen is not used directly, but is previously transformed into sugar. GENERAL CONSIDERATIONS OF METABOLISM 693 To be of use to the organism in furnishing energy, the carbohydrate must be burned up. From the standpoint of energy transformations it makes little difference whether it is consumed rai)idly and at once, or whether the decomposition goes on more slowly and in successive stages, as is the case in the living organism. To the physiologist, however, these intermediary processes are of no little concern; and for the physician they attain due significance in the light which appreciation of them throws upon many obscure pathological states. Experimentally, glycolysis, or sugar destruction, has been found to be characteristic of various tissues as well as of the blood. Undoubtedly, such destructive changes go on in the muscle during activity; but whether the glycolytic power of the muscular tissue is reinforced by contributions from other organs, such as an internal secretion of the pancreas, and whether the chemical reaction involved de- pends on the presence or absence of sufficient oxygen, cannot be foretold at the present moment. Some investigators believe that the process of car- bohydrate utilization in the body is comparable with typical fermentation changes as exhibited in the destruction of sugar by yeast or its zymase; for others the intermediation of oxygen in this internal respiration seems more important. Regarding the nature of the products actually formed, little is definitely known at present; carbon dioxide is undoubtedly pro- duced and various organic acids appear to arise in an intermediate stage. Perhaps we have in this the explanation of the tendency of an active tissue to become more acid when the circulation and oxygen supply are deficient. We regard it as extremely probable that the paralactic acid found in the animal organism has its origin in carbohydrates. Ordinarily it is further burned up; but when there is a lack of oxygen we have to deal with an incomplete combustion of the lactic acid derived by cleavage from sugar, without denying the possibility of a similar production from proteids. In accordance with this view, a considerable excretion of lactic acid and sugar is found in poisoning with carbon monoxide, in which an oxygen deficiency is always manifested; and simultaneously with the formation of lactic acid a decrease in the glycogen reserve is noted. Another evi- dence of the inter-relationship between lactic acid and carbohydrate katabolism has been offered in cases of phosphorus poisoning. Here the urine contains paralactic acid; but when artificial diabetes is produced by means of phlorizin during phosphorus poisoning, the lactic acid dis- appears from the blood and urine with the appearance of the sugar pro- duced by the phlorizin. According to Mandel and Lusk, this indicates that "lactic acid produced from the cleavage and denitrogenization of pro- teid, whether this occurs in the intestinal wall or in the liver or elsewhere, is first synthesized to dextrose within the organism (liver) before further distribution to the tissues. In the case of simple phosphorus poisoning this distribution of dextrose takes place with resultant anaerobic cleavage, leading to a second production of lactic acid." Following the view of Hoppe-Seyler, the formation of lactic acid from carbohydrates and its elimination may be regarded as an abnormal process, occurring only under the imperfect physiological conditions attending an insuflScient supply of oxygen. Another compound which doubtless owes its origin to the intermediary metabolism of the carbohydrates is glycuronic acid CHO. HCOH. HCOH. HCOH. HCOH. COOH. 694 XUTRITIO.y This is readily obtained in the urine paired with camphor, thymol, menthol, and a large number of other compounds when the latter or related antecedents are introduced into the body. Conjup;ated g'lycuro- nates are found in traces in the blood and liver; and the normal urine is said to contain very small cjuantities in combination with phenol, cresol, indoxyl and sk-atoxyl. The possibility of a formation of glycuronic acid from proteids cannot be denied at present and the problem is asso- ciated with the broader question of sugar formation from proteids. But the available evidence points to carbohydrates as the chief, if not the only, source of this agent with ^\•hich toxic compounds become conjugated and excreted in less harmful forms. Animals which have been starved sufficiently long to diminish to a minimum their carbohydrate reserve (gly- cogen) yield little, if any, glycuronate after ingestion of camphor. Re- versely, the toxic action of some of the conjugated compounds can be greatly diminished by feeding carbohydrates which yield glycogen or dex- trose in metabolism. The glycuronic acid conjugation appears to take place in the liver, and the primary significance of its formation, therefore, probably lies in its anti- toxic action. This is a well-known function of metabolic products of the proteids as we see it exemplified in the formation of ethereal sulphates. In cases such as profound cocaine intoxication, where dyspnoeic conditions arise, glycuronates have been found in increased c[uantity in the urine. P. Mayer believes that, normally, the oxidation of dextrose in the body proceeds through the stage of glycuronic acid, and that Avhen further katab- olism is checked the imperfectly oxidized carbohydrate is eliminated in part in this form. Corresponding with this view, a simultaneous elimina- tion of both glycuronates and sugar is observed under pathological con- ditions in which circulatory and respiratory disturbances play a part. A further step in the oxidative degradation of sugar is oxalic acid, which may likewise escape unburned under certain conditions. It is not uncommon to find oxaluria and glycuronic acid elimination associated in diabetes. Considering the preceding facts, it would appear as if carbohydrates may undergo fermentative decompositions in the body, or be decomposed through a succession of oxidative changes. Under conditions of imper- fect oxidation one or more of these ijitennediate 'products may escape from the body. Glycosuria is thus only one evidence of a defective interme- diary metabolism of the sugars. Glycuronic acid, saccharic acid, oxalic acid, lactic acid, and, perhaps, other organic acids primarily associated with diabetes are referable to the same source. Such a view may at any rate serve toward the construction of a tentative theory of intermediary carbohydrate metabolism . Reference may be made to other less frequent anomalies of carbo- nydrate metabolism, such as pentosuria, levulosuria, lactosuria, and galactosuria. The excretion of lactose (milk-sugar), during and after pregnancy, is a temporary disturbance referable to an escape of the carbohydrates from the active mammary glands into the circulation. When these glands are extirpated, lactosuria is never observed. The excretion of levulose has been frequently reported and seems to occur in conjunction with dextrose elimination in many diabetics. The fact that dextrose can be converted in part into levulose in alkaline media makes this less difficult of interpretation. Galactose has been found in the GENERAL CONSIDERATIONS OF METABOLISM 695 urine of Infants suffering with gastro-intestinal disorders. (Langstein and Steinitz.) It represents an unutilized inversion product of milk- sugar absorbed from the intestine of milk-fed individuals. In explana- tion of the phenomena of pentosuria little can be said at present. The ordinary diet of man contains pentosans, which yield five-carbon sugars (C5H10O5), such as xylose and arabinose, on hydrolysis. When pentoses are fed they are in part oxidized. It is unlikely, however, that the sugar eliminated in chronic pentosuria is derived from the food, since the elimination continues even during starvation. The nucleoproteids such as are found in the pancreas also yield pentose; but the latter is 1-xylose, whereas the urine pentose appears to be r-arabinose. Ordinarily, there is no interference with the oxidation of the hexoses in pentosuria ; and the condition may persist for years without exhibiting any other untoward symptoms. For the present, pentosuria is of interest chiefly as an illustration of a curious and unexplained anomaly of carbohydrate metab- olism. Metabolism of Fats. — In presenting a review of the present knowledge regarding the metabolism of fats, we shall be obliged to touch upon many topics Avhicli are still the subject of controversy. The views expressed are not to be interpreted too rigidly, for dogmatic statements should not be expected in a department of study which is at present being pursued by many investigators. An adult man can digest 300 grams of fat per day, provided that it is offered in suitable form. What becomes of this after it leaves the alimentary tract ? Furthermore we may inquire whether the tissue fat is derived directly from the ingesta or synthesized in indirect ways, and what are the chemical processes which inaugurate these transformations? At the outset, the radical changes which prevalent ideas of fat digestion and absorption have experienced should be mentioned. A few years ago it was thought that fats were absorbed in the form of an emulsion, the un- dissolved and finely divided particles passing through the epithelial cells in some mysterious manner. This view has been altered more recently; for we have learned of the more extensive distribution of lipolytic enzymes in the alimentary tract, the process of fat cleavage apparently having a beginning in the stomach itself. Fatty acids and soluble soaps are formed in not inconsiderable quantities in the digestive tube. Furthermore, bile affords a medium for the solution of large quantities of free fatty acids at the temperature of the body. It is difficult to obtain indisputable e^^- dence of the absorption of unchanged fat, except by histological methods which are perhaps not wholly reliable. Certainly other insoluble sub- stances (such as fluid paraffin) are not absorbed even when they are finely emulsified, but are recovered in toto in the faeces. While it is perhaps too soon to say that fats must be completely transformed by digestive change to soluble forms before they can be absorbed, it seems certain that such a preliminary cleavage or saponification does take place to a degree not for- merly appreciated. Once beyond the lumen of the gut, the fragments are again synthesized to neutral fats. Foreign esters of the fatty acids reappear as glyceryl esters. There is some evidence that the Ij^Tuphatic tissue-elements are concerned in these synthetic transformations. When fats reach the blood-stream through the lymph channels, they are exposed to a peculiar metamorphosis which is still little understood. The 696 NUTRITION suspended particles of the minute emulsion of the blood-fats may become changed into soluble and diffusible substance. Perhaps it is in this inter- mediary soluble form that fats arc transported to the tissues, as we know carbohydrates to be. Regarding the nature of the processes a few defi- nite statements may be ventured. The transformation is inaugurated by some constituent element of the erythrocytes which is destroyed by high temperatures; thus the change partakes of the nature of an enzyme reac- tion. It does not go on in the absence of oxygen, yet the chemical change certainly is not one of complete oxidation. The resultant product, unlike the original fat, is insoluble in ether and soluble in water. Neither is this fat metamorphosis a lipolytic change of the usual digestive type, compar- able with the cleavage produced by ordinary lipases. The latter appear to be almost completely wanting in the blood; the various body tissues are, on the other hand, supplied with more or less lipolytic power, so that we may postulate a widespread distribution of lipase in the animal body. The reversible action of fat-splitting enzymes, i. e., the capacity of the same enzyme solution to synthesize neutral fats from fatty acids and alcohols, as well as to effect a corresponding cleavage of neutral fats, has directed attention to the probable important role of lipases in the tissue metab- olism of fats. It is not unlikely, therefore, that the reserve supply of tissue fats is in some way transformed into more soluble forms by enzymes pre- cisely as the storage glycogen may be, and thus transported from the tissue cells; while the deposition of transported fat components is perhaps accomplished by a synthesis in which enzymes are likewise effective agents. Other esters are similarly attacked by tissue lipases. Enough has been said to indicate the actual occurrence of synthetic, lipolytic, and solvent enzymes for the fats. Connstein has offered the following tenta- tive description of the immediate fate of food-fats. When ingested in the form of an emulsion, they may be in part hydrolyzed in the stomach; otherwise the lipolysis begins in the intestine. The cleavage products are absorbed and incidentally resynthesized to neutral fat, wdiich reaches the blood through the chyle. In the circulation, the fat is transformed into an (at present unknown) soluble and diffusible modification which can readily pass through the capillaries, and thus gain direct access to the tissues themselves where a regeneration of fat goes on. AVhen the fat depots in the tissues are drawn upon, lipolysis again takes place. Before accepting this it remains to be seen whether the emulsified particles of fat cannot pass through the walls of the capillary vessels in other than water soluble forms. The possible fat-dissolving power of the lipoids (lecithins, etc.) present in all cells is not to be overlooked in this connection. The inadequacy of our present knowledge in only too patent. The fat which enters the circulation is not imlikely in part involved very soon in the combustions continually going on. \Yhere this katabolic change occurs can only be surmised; the liver is suggested, although the evidence is somewhat indirect. In greater part, the fat is undoubtedly first deposited, the most important depots being the subcutaneous connec- tive tissue, the liver, and the folds of the peritoneum. The panniculus adiposus is of foremost importance in fat deposition, the other storage places being utilized prominently only when the former has already been well taxed. The liver may become the seat of transitory or temporary storage. There exists in the liver a kind of antagonistic relation between GENERAL CONSIDERATIONS OF METABOLISM 697 glycogen and fat, as the result of which fat fails to accumulate in the liver so long as glycogen is abundantly formed there and the other fat depots are available. Thus it happens, as Rosenfeld has pointed out, that the livers of fattened pigs are frequently poor in fat, owing to their richness in glyco- gen; whereas those animals like fishes, which live on diets poor in carbo- hydrates (glycogen-formers) store up enormous quantities of fat in their hepatic cells. In man, with whom a mixed diet is customary, fatty liver is normally not observed for reasons just advanced. Lusk has pictured conditions when, owing to diabetes, or activity of the mammary gland in utilizing dextrose to form milk-sugar, the cells affected become "sugar- hungry cells, " which attract fat in greater quantity than they can burn it (fat infiltration). The preceding remarks involve the assumption that tissue-fats may owe their origin directly to the food-fat, and lead to the broad question of fat- formation in the animal body. Such an assumption is more easily made in the case of fats because they are believed to undergo less radical changes in the process of digestion than do carbohydrates or proteids, and the re- synthesis occurs in the passage through the absorbing cells. Kassowitz has modified the point of view somewhat by regarding the chyle-fat as a pro- duct of the internal secretion of the intestinal epithelial cells. From his standpoint the make-up of the circulating fat which is able to gain its way to the fat depots is dependent upon the protoplasmic activity of these living cells, a view which implies a somewhat indirect deposition of the fat in- gested. Such distinctions, however, are verbal rather than real. The im- portant facts are, firstly, that when foreign fats possessing recognizable chemical and physical characteristics are fed, the constituent fatty-acid group which lends peculiar character to them can be detected in the tissue- fats. The subject has attained importance in agriculture where the quality of the fat in animals is a matter of serious commercial moment. In the second place, it is noteworthy that despite variations in the char- acter of the fat fed, there is an inherent tendency to maintain a typical con- stancy for the species and the particular depot under consideration. Mutton-fat differs from the fat of cattle even under somewhat similar conditions of diet; and in the same animal the fat has not the same com- position in different parts of the body. These facts mean that various factors are at work in determining the make-up of the adipose tissue, and especially suggest other sources for body-fat besides the fat in- gested. Among these, carbohydrates are without question the most important. The feeding of a diet rich in carbohydrate is a familiar method of fattening animals. It does not, however, afford rigorous proof of the origin of the fat produced, since every dietary of this sort usually contains an abundance of proteid. In the formation of milk-fat we have a specific illustration of the relation of carbohydrates to fat formation. Jordan fed a cow during ninety-five days on a ration frOm w^hich the fats had been nearly all extracted, and the animal continued to secrete milk similar to that produced when she was fed on the same kinds of grain and hay in their normal condition. The yield of milk-fat during the ninety- five days was 62.9 pounds. The food-fat eaten during this time was 11.6 pounds, of which only 5.7 were absorbed; consequently at least 52.7 pounds of the milk-fat must have had some source other than the food-fat. 698 NUTRITION Tlic milk-fat in tlic above experiment could not have come from pre- viously stored body-fat. This is supported by three considerations: (1) The cow's botly could have contained scarcely more than GO pounds of fat at the beginning of the experiment; (2) she gained 47 pounds in Aveight during this jieriod of time with no increase of body nitrogen, and Avas judged to be a much fatter cow at the end; (3) the formation of this quantity of milk-fat from the body-fat would have caused a marked con- dition of emaciation, which, because of an increase in the body weight, would have required the improbable increase in the body of 104 pounds of water and intestinal contents. During fifty-nine consecutive days, 38.8 ])ounds of milk-fat were secreted and the urine nitrogen was ecpiivalent to 33.3 pounds of protein. According to any acce])ted method of interpreta- tion, not over 17 pomids of fat could have l)een produced from this amount of assimilated protein. From these considerations, it is concluded that the milk-fat was produced in part at least from carbohydrates, as we know to be the case with body-fat. The determination of the place where the conversion of carbohydrate to fat occurs is not easy. One is tempted to refer it to those places where carbohydrates accumulate, viz., the liver and muscles. But it is not less likely to be ])erfected in those locations where fat is deposited — in the cells of the subcutaneous adipose tissue, for example. With reference to proteids as fat -forming elements, it is impossible to make any conclusive statement at present; the evidence is by no means convincing and there is a growing tendency to regard such a process as un^ likely, if not impossible. In this respect, the theory of fat -formation has been seriously modified in recent years, as the outcome of the controversy between the adherents of Voit and of Pfliiger. Even pathological fat- formation, typically described as "fatty degeneration " is now for the most part explained as a "fatty infiltration," i.e., the introduction of fat trans- ported from fat-depots to the "degenerated" tissue. Corresponding with this view, Rosenfeld and others have removed from "fatty" livers of dogs previously fed abundantly on some recognizable foreign fat and then poisoned with phosphorus, the characteristic foreign fat fed. The "de- generation" fat is in these cases not manufactured from the cell proto- plasm, but transported and infiltrated. Accordingly, further, the total fat-content of animals poisoned with phosphorus, which induces the typi- cal symptoms of so-called fatty degeneration of the liver, is not increased, although its distribution between the various tissues is changed. Recent studies on the distribution of fat in pathological conditions, have shown that the impressions gained by mere microscopic examinations may be utterly misleading, as the fats are frequently incorpoi'ated very intimately in the tissues. In attempting to offer an explanation of the fatty metamorphosis in cells subject to toxic influences, we quote from Rosenfeld, the champion of the infiltration theory : When the proteid content of the cell is attacked by any noxious agency, certain molecules of the protoplasm are thrown out of function. In order to maintain its vitality, the cell now obtains its energy in the oxidation of all the carbohydrates which it controls (hence the liver soon becomes glycogen -free) or when this is impossible the proteid content is enriched by importation of proteid. Accordingly it is observed that in many intoxications, as with phosphorus and alcohol, the proteid content GENERAL CONSIDERATIONS OF METABOLISM 699 of the liver is increased. But when these various sparing agents are no longer available in sufficient quantity, the cell seeks tlie last help by at- tempting to recoup its losses with fat abstracted from the circulating l^lood which is in turn replenished from the fat -storage depots. With this infil- tration of fat into the cell, the latter may succeed in maintaining itself and its energy transformation until the toxic efiects have disap|)earcd; if not, the infiltration is succeeded by a true degeneration and the cell dies. Referring to the peculiar aspect of fat-metabolism afforded in the for- mation of milk-fat, we have already noted that the latter may, in the absence of an abundant fat-supply, be formed from carbohydrates. Under usual conditions, the fat of the milk is partly derived from the body-fat, but chiefly from the fat of the food. The fat is probably not transmitted directly from the blood, but is modified in the secreting cells of the mam- mary gland. If for any reason the quality of the milk is changed, there is always a tendency to return to the normal. The composition of the Vjutter- fat is modified within narrow limits by the fat of the food ; but the per- centage of butter-fat in milk is very little influenced by foods containing a large percentage of oil, or even by albuminous foods. Breeding rather than feeding seems to play the important part in determining the quantity and quality of the milk; the fact that foreign fats do pass into the milk is, however, not to be overlooked and corresponds with the newer findings regarding the ready transportation of fat in the body from one depot to another. There is also some evidence in the case of the sebace- ous glands tending to show an alteration in the make-up of their fatty secretion, depending upon the character of the fat fed. During embryonic growth, a consumption, rather than synthesis or deposition of fat, occurs in so far as can be judged from experiments on species which have an extra-uterine development. Thus a marked loss of fat is noted in the chick embryo during the process of development. The fresh egg containing 5.4 grams of fat may show a diminution to 2.7 grams or less. In connection with fats, reference may be made to a group of compounds widely distributed in the body in all types of tissues and resembling fats in various ways. The lecithins, cholesterin and its esters, kephalins, and cerebrins, may be considered briefly under the general term of "lipoids" or fat -like compounds, which differ widely among themselves, but possess the general physical properties and solubilities of fats. They are especially prominent in the nervous tissues, and their behavior toward the vola- tile anaesthetics is made the basis of the Meyer-Overton theory of narcosis. Of the metabolism of these substances, little can be said. Lecithins dis- appear from the cells far less readily than do the ordinary fats ; their con- tent is far more constant so that they appear to be an integral part of the protoplasm. In the disintegration of nervous structures, decomposition products of lecithin (cholin, glycerylphosphoric acid) appear to be liber- ated, as well as in certain autolytic changes For the present, it is scarcely profitable to do more than point out the possible physiological significance of the lipoids in the work of the cells. Regarding their origin little is known. Of the stages through which fats pass in their katabolism to the end- products, water and carbon dioxide, very little has been ascertained. As in the metabolism of carbohydrates, pathology has shed some Hght. In 700 NUTRITION severe diabetes, where carbohydrates are not burned up, fats are drawn upon. In this condition, as also in inanition, the "acetone bodies" may be eUminated in considerable quantity. This is not true under ordinary conditions on a mixed diet. Tlie compounds formed in the intermediary metabolism of fats under these conditions of imperfect combustion are acetone, aceto-acctic acid and ;5-oxybutyric acid. Formerly, these compounds were attributed to the proteids; but at present, they are generally associated with metabolism of the fats, and presumably represent products of the incomplete oxidation of higher fatty acids. In health, and on the customary mixed diets, only a few milligrams of acetone are excreted daily. In hunger, the quantity may increase to over a gram per day. Carbohydrates (and perhaps alcohol) check this production at once, but not proteids or fats. In diabetes, we have the extreme case in which figures somewhat as follows have been observed: Acetone, 15 grams; aceto-acetic acid, 26 grams; /3-oxybutyric acid, 102 grams per day. It may be, as Fr. Mtiller has suggested, that the normal metabolism of fats, i. e., oxidation of the higher fatty acids to carbon dioxide and water, goes on perfectly only when a certain pro- portion of sugar is simultaneously burned up, in the failure of which oxybutyric and aceto-acetic acids arise as intermediary products which cannot' be completely burned up. Whether the chemical abnormality hinges on the formation of these compounds or on the inability to oxi- dize them is uncertain. Accordingly, it is at present impossible to say whether they represent intermediary stages in the normal combustion of fats or not. Corpulence is scarcely to be regarded as a pathological manifestation of fat metabolism. Direct observations have failed to indicate any dimin- ished capacity of the organism to burn the deposited fats. AVe have rather to deal with a disproportionate relation between intake of food and food utilization. Whatever apparent diminution in energy trans- formation may occur is attributable primarily to the relative muscular inactivity of corpulent individuals. A small daily excess may lead to a considerable accumulation of body-fat. Finally, all influences which diminish the combustion processes in the body favor corpulence; these include lack of muscular exertion, sleep, and conservation of body-heat. Some idea of the quantities of fat which may be retained in corpulency is afforded by observations of Meyer and Falta. In a person of 111 kilo- grams body weight, the thoracic and abdominal cavities furnished 9 kilograms of fat-tissue, the subcutaneous tissue 27 kilograms. These 36 kilograms corresponded to 30.2 kilograms of pure fat. The muscles were estimated to contain an additional 13 kilograms, so that the entire body yielded 51 kilograms of fat or 38 per cent, of the total weight. Metabolism of Proteids. — The characteristic products of proteid katabolism are found in predominant quantity in the urine, although the fseces and sweat also contain part of the nitrogenous waste. In addi- tion to urea, creatin, creatinin, uric acid and other purin derivatives, hippuric acid, and ammonium salts, a few others occur in quantities which are normally very small but may be largely increased when metab- oUsm is disordered. The sulphuric and phosphoric acids ehminated in combination with various bases are also for the most part referable in origin to the proteids which contain sulphur and phosphorus. The GENERAL CONSIDERATIONS OF METABOLISM 701 chemical nature of the nitrogenous metaboHc products which escape with the stools is scarcely known; the small portions lost with the sweat are allied closely to those found in the urine. In following the transformations of proteids in the organism, it is necessary to bear in mind that they represent a great group of foodstuffs varied in physical characters and chemical behavior, yet essentially allied in structure in so far as they yield similar decomposition products. The latter are generally comparable, whether produced by hydrolysis with acids or by cleavage with proteolytic enzymes. The simpler types of proteid subjected to such decomposition yield leucin, glycocoll, a-amino- valerianic acid, alanin, aspartic acid, glutamic acid, serin, cystin, tyrosin, phenylalanin, pyrroHdin carbonic acid (prolin), oxypyrrolidin carbonic acid, lysin, arginin, histidin, tryptophan, and ammonia. The individual groups of proteids differ in the proportions of these different derivatives and future investigation will doubtless afford addi- tions. From the chemical standpoint, it will be noted that the products thus far obtained are for the most part amino-acids or similar com- pounds, a preponderance of NHg groups in some of them giving a de- cidedly basic character to the molecule. The conspicuous feature of the H I structure of all these derivatives is the presence of the group — C-NH2, I COOH and Fischer has shown that such groups are prone to form continuous syntheses in which the carboxyl group of one becomes united with the amino group of another. This explains the characteristic cleavage of the proteids into a-amino acids and their corresponding behavior toward enzymes as well as their characteristic deportment like acids and bases simultaneously. The sulphur is largely, if not entirely, grouped in the form represented in the cleavage product, cystin; and this throws light upon the origin of the cystin which is excreted in the rare metabolic dis- turbance connected with cystinuria. Many proteids apparently contain a carbohydrate group; but the typical carbohydrate derivatives obtained from the compound proteids like the mucoids are now recognized as amino-sugars, of which glycosamine is the most common. Other pro- teids, like the vitellin of egg-yolk and casein of milk, contain phosphorus in radicals not yet recognized by the chemist. This element plays an important part in nutrition, and the phosphorized proteids may thus become responsible in no small degree for the phosphates eliminated. In nucleoproteids, the presence of the nucleic-acid group introduces a new series of complexes which have a significant role. The cleavage products of the nucleic acids include — 1. Phosphoric acid: 2. Pyrimidin derivatives: NH— CO NH— CO NH=C.NHo II II II' CO CH CO C.CH, CO CH I II I II I 11 NH— CH NH— dn NH— CH Uracil Thymin Cytosin 702 NUTRITION 3. Purin derivatives: N=C.NH, HN-CO HN— CO HN— CO C C— NH, OC C— NH liC C— NH R,N— C C— NH I CH I I CH II II CH II II CH C— N/- -HN— C— N/- N— C— N/- N— C— N/- Adenin Xanthin Hypoxanthin Guanin 4. Pentoses CJIjoO,;. 5. Levulinic Acid. The ferruginous protcids like the haemoglobins, as well as the albumin- oids (scleroproteins) gelatine, elastin, etc., — all otter specific ditt'erences. The reader is referred to the text-books of physiological chemistry for a detailed stuily of their chemical i)eculiarities. Enough has been indi- cated to make clear the possibility of very different nitrogenous trans- formations, in accord with the varying complexity and chemical make-up of the specific proteids attacked. In following the ingested proteids we are at once confronted with the question as to how far they are altered by the digestive changes in the alimentary canal before absorption. In respect to this, the views of physiologists have been altered most distinctly in recent years. So long as proteoses and peptones were recognized as the essential end-prod- ucts of digestive proteolysis, attention was particularly directed to the fate of these products in absorption. Inasmuch as they were found to disappear quickly in contact with the intestinal mucosa, while the blood stream beyond was apparently free from them, it was naturally concluded that they "are regenerated to native proteid in their passage through the living intestinal wall. Such a view has, however, been rendered unten- able by the discovery that proteids can be and presumably are broken down far more completely in the process of digestion than was formerly assumed; and furthermore, it has been found that the disappearance of peptones in contact with the intestinal mucosa is in reality due to a diges- tive cleavage to non-proteid nitrogenous derivatives through the agency of the enzyme erepsin. Whether proteids are ordinarily completely dis- integrated' in the process of digestion into compounds which no longer give the typical proteid (biuret) reactions before absorption occurs, or whether even the more complex derivatives such as peptones normally traverse the intestinal wall, cannot be decided conclusively from the evi- dence at hand. It seems unlikely that the proteid derivatives circulate in the blood stream in anything more than traces; otherwise, they would not have escaped detection so often. Tentatively, we may picture the digestive change as occurring in accord with the following scheme, which represents the results of recent experimental observations (Abderhalden) : Native Proteid, Peptone. Polypeptid. Tyrosin, Leucin, Glutaminic Acid, Aspartic Acid, Trj'ptophan, etc. Histidin, Arginin, ProHn, Lysin. GENERAL CONSIDERATIONS OF METABOLISM 703 The polypcptids represent intermediate products, and the controversial features of the question centre in the extent to which digestive cleavage actually occurs in the gut. The determination of the fate of the proteid products — ^whatever they may be — after they leave the lumen of the digestive tube is attended with even greater difficulties. In the absence of convincing proof of the proteid "fragments" in the portal blood, it has been natural to assume a "regeneration" of the proteid in the intestinal structures. At the present time, however, the occurrence of proteoses and further disintegration products of proteids in the blood, especially after meals, is not at all unlikely. It is less difli(,-ult to a])pre- ciate how a few types of circulating proteids can be constructed from the ultimate cleavage products of the proteids than from such different complexes as must exist in the diverse proteids of the food. In other words, it is easier to understand how flesh-, or milk-, or wheat-proteids can give rise to the same serum albumin or muscle globulin if they are first broken down to simple fragments which enter into the composition of all the proteids, though in varying proportions. From the teleological stand- point, however, it is not apparent why a complete break-down of pro- teids should occur, only to be followed by immediate resynthesis. It is more reasonable to assume a cleavage into larger nuclei only, which might serve equally well in the anabolic disposition of the nitrogenous materials. The unsolved problems which have arisen in the study of this first step in proteid assimilation have been thus broadly presented because it is impossible at present to form anything like a satisfactory hypothesis of changes which actually take place. It is by no means certain that only "regenerated" proteid reaches the blood current from the intestinal sources; and it may be found that the quantities of cleavage products absorbed at ordinary intervals escape detection by the methods now available. The increase of ammonia nitrogen in the portal blood during digestion implies an increase in the non-proteid nitrogen of the blood, but the failure to demonstrate it may be ascribed to unfavorable condi- tions or inaccurate technique. The constancy of composition of the systemic blood in respect to its proteids is as striking as is its fixed sugar- content; and the intervention of the liver in some regulatory or regenera- tive function is at once brought to mind. Nor are we better instructed with regard to the further intermediary metabolism of the nitrogenous compounds. We have pointed out the conspicuous behavior of the proteids in their failure, under ordinary conditions of diet and health, to be retained. The elimination of nitrogen begins to increase almost immediately after a meal rich in proteids. Experiments by Sherman and Hawk illustrate the character of this response. When lean beef sufficient to furnish about 64 grams of extra proteid was taken with breakfast, the nitrogen in the urine began to rise in the first three hours and reached a maximum between the sixth and ninth hours, after which it declined at first rapidly and then more slowly. The increased excretion of sulphates was proportional to that of the nitrogen and followed the same general course. It is interesting to note further that the increased heat of combustion of the urine was but little greater than would correspond to an amount of urea equivalent to the extra nitrogen eliminated. The other constituents of the urine 704 NUTRITION were therefore but little affected, and a moderate gain or loss of body nitrogen did not seem to affect the changes noted. Faita has observed that after the ingestion of equal quantities of nitro- gen in the form of different proteid substances such as egg albumin, casein, gelatin, etc., the rate at which nitrogenous equilibrium is again established varies with the materials used. It is not improbable that these differences in rapidity of katabolism are ascribable to an unlike resistance of the proteids to the alimentary digestive processes, which accordingly alters tlicir rate of absorption. Theories of Proteid Metabolism. — In any attempt at a theory of pro- teid katabolism, certain fundamental observations must be borne in mind; namely, that this process never stops in the animal body, and that the adult organism has the capacity of rapidly adapting its proteid katabolism to the extent of proteid supply. According to Voit, a dis- tinction must be drawn between the organized, or tissue proteid, which constitutes an essential part of the living bioplasm, and the circulat- ing proteid representing the variable store of rapidly metabolized pro- teid transported in the blood and lymph stream and temporarily located in the interstices of the tissues and independent of the living substance. The organized proteid is replenished only to a slight degree by the proteid intake, since only a small part of this living bioplasm undergoes destruction under ordinary circumstances. The circulating proteid, on the other hand, is readily disintegrated to the extent that it is not drawn upon for tissue construction and its nitrogenous groups are speedily eliminated. Such a distinction becomes plausible in consider- ation of the rapid metamorphosis of proteid when a large supply is taken in, the assumption of a previous incorporation mto some organic structure and immediate degradation being rendered unnecessary thereby. As Hammarsten has expressed it: The tissue elements constitute an apparatus of relatively stable nature which has the power of taking proteids from the fluid bathing the tissues and appropriating them, while their own proteids, the tissue proteids, are ordinarily katabolized to only a small extent. By an increased supply of proteids, the activity of the cells and their ability to decompose nutritive proteids is also increased to a certain degree. When nitrogenous equilibrium is obtained after an increased supply of proteids, it denotes that the decomposing power of the cells for proteids has increased, so that the same quan- tity of proteids is metabolized as is supplied to the body. If proteid metabolism is decreased by the simultaneous administration of other non-nitrogenous foods, a part of the circulating proteids may have time to become fixed and organized by the tissues, and in this way the mass of flesh of the body increases. During starvation, or w'ith a lack of pro- teids in the food, the reverse takes place; for a part of the tissue proteids is converted into circulating proteids which are metabolized, and in this case the flesh of the body decreases. The most essential part of Voit's theory is the supposition that the food proteid of the cells is more easily destroyed than the organized or true protoplasmic proteid. Pfluger contends that it is only organized proteid which can undergo metabolic transformation — that the circulating proteid must be con- structed into tissue proteid or bioplasm before it can take part in the oxidation or katabolism characteristic for proteids. It is the state of GENERAL CONSIDERATIONS OF METABOLISM 705 nutrition of the body cells, rather than the circulating proteid which determines the extent of proteid katabolism, a view which is in a way merely a modification of the older theory of Liebig. The theory of Voit owed its formulation to the inadequacy of the older views of Liebig, which assumed that proteid katabolism must be proportional to muscular activity. Voit beUeves that the living substance is scarcely, if at all, disintegrated in such cases when the nutritive condi- tions are satisfactory. The greater part of the excreted nitrogen is ac- cordingly derived from destroyed food proteid. The ra])idity with which metabolic changes in proteids occur in the body, and the large amount of such metabolism which may take place when excess of proteid is taken with the food, renders unlikely the previous construction of the latter into living matter. Pfliiger's contention regarding the importance of the muscle cell is based upon the experiments of Schondorff, who observed that the extent of urea formation in the muscles and livers of dogs depends upon the nutritive condition of these cells rather than upon the character of the blood circulating through them. The experi- mental data are, however, by no means convincing and have lately re- ceived adverse criticism. Kassowitz has advanced a modified conception of proteid metabolism based upon his view that all true foodstuffs are constructed into proto- plasm prior to utilization. Carbohydrates and proteids together enter into the composition of the living material, which in turn can split off glycogen or nitrogenous residues no longer assimilable and accordingly excreted. This view differs essentially from Pfliiger's, in demanding non-nitrogenous as well as nitrogenous components for the constructive feature. Kassowitz remarks that if food proteid can be "organized" directly and alone, it is not easy to understand the difficulty in putting on flesh when large quantities of proteid are fed without any non-nitrog- enous foodstuffs, whereas this synthesis is accomplished far more effectu- ally with less proteid, when sugar is simultaneously available. According to him the excretion of nitrogen has a twofold source, namely, an "active" protoplasmic katabolism, inaugurated by nervous stimulation and affording little of the nitrogenous excretives; and an "inactive" destruction yielding certain reserve products, together with a large part of the nitrogenous fragments now in a form no longer capable of assimi- lation. There is, from this standpoint, no luxus consumption of proteid and no direct decomposition of surplus food proteid, but rather a luxus production of protoplasm which in turn suffers an "inactive" degrada- tion and eliminates its nitrogen. Thus it is that, in a full grown and well nourished organism, every increase in proteid supply is followed by a corresponding increase in nitrogen excretion. Such a view, following closely the standpoint of Pfliiger, involves much that is purely hypothetical, and touches closely upon the question as to what constitutes a true food. If we carry the contention of Kassowitz to its extreme, then no toxic substance can ever act as a true food; for toxic action implies protoplasmic destruction, whereas nutritive proper- ties involve some participation m the construction of the protoplasm. If the calories furnished by a substance like alcohol are merely converted into heat, which only serves to increase the useless excess already present • — if they can in no wise participate in the liberation of energy as mechan- 45 706 NUTRITION ical work because the alcohol is incapable of incorporation in the con- tractile protojilasma, the real food value of such a compound may be questioned. There are many substances, such as lactic acid, butyric acid, uric acid, etc., which are certainly oxidized in the body. We are not prepared to accept the view, however, that the result of their metab- olism is solely a liberation of waste heat; at any rate the question as to the nutritive value of compounds which unquestionably liberate energy in their transformations in the body seems debatable .still. Folin has recently made extensive and careful analyses of the urines of healthy persons living on diets in which the protcid intake was varied within wide limits. This range in the daily output in the same person is shown in the following table: July 13. July 20. Volume of urine 1170. cc. 385. cc. Total nitrogen 16.8 grams. 3.60 grams. Urea nitrogen 14 . 70 =87 . 5 per cent. 2 . 20 = 61 . 7 per cent Ammonia nitrogen 0.49=3.0 " " 0.42 = 11.3 " " Uric acid nitrogen 0.18=1.1 " " 0.09=2.5 " " Creatinin nitrogen 0.58=3.6 " " 0.60 = 17.2 " " Undetermined nitrogen 0.85= 4.9 " " 0.27= 7.3 " " Total SO3 3.64 " " 0.76 " " Inorganic SO., 3.27=90.0 " " 0.46=60.5 " " EtherealSOa 0.19=5.2 " " 0.10 = 13.2 " " NeutralSOg 0.18=4.8 " " 0.20=26.3 " " The diet during the period in which the urine of July 20 was collected consisted of pure starch and cream, so that the intake of proteid was minimal though the quantity of food was considerable. The striking feature is the pronounced change in the distribution of the urinary nitro- gen and sulphur, the characteristic end-products of proteid katabolism. For example, the relative proportion of nitrogen eliminated in the form of urea is greatly diminished in the absence of proteid feeding, w^hile the output of creatinin is absolutely unchanged, the relative quantity being greatly increased. In discussing the bearing of these facts, we shall quote freely from the papers of Folin. To explain such changes, it seems neces- sary to assume that proteid katabolism is of tAvo kinds, which are essen- tially independent and quite different. The one kind, extremely variable in quantity, yields chiefly urea and inorganic sulphates, no creatinin and probably no neutral sulphur. The other, the constant katabolism, is largely represented by creatinin and neutral sulphur, and to a less extent by uric acid and ethereal sulphates. The more the total katabolism is reduced, the more prominent become these representatives of the con- stant katabolism, the less prominent become the two chief representatives of the variable katabolism. If there are two distinct forms of proteid metabolism represented by two different sets of waste products, it becomes important to determine, if possible, the nature and significance of each. The fact that the crea- tinin elimination is not chminished, when practically no protein is furnished with the food, and that the elimination of some of the other constituents is only slightly reduced, shows why a certain amount of proteid must be furnished with the food if nitrogen equilibrium is to be maintained. It is clear that the metabolic processes resulting in the end-products which tend to be constant in quantity appear to be indis- GENERAL CONSIDERATIONS OF METABOLISM 707 pensable for the continuation of life; or those metabolic processes probably constitute an essential part of the activity which distinguishes living cells from dead ones. Folin, therefore, calls the proteid metab- olism vi^hich tends to be constant, tissue metabolism or endor/enous metabolism, and the other variable proteid metabolism, exogenous or intermediary metabolism. The endogenous metabolism sets a limit to the lowest level of nitrogen equilibrium attainable. Just where that level is fixed will depend on how much, if any, urea is derived from the same katabolic processes that produce the creatinin With reference to the remainder of the pro- teid involved, an extensive formation of Voit's "circulating proteid" followed by a second decomposition and elimination as urea seems almost, if not quite, as improbable as the corresponding formation and decomposition of Pfluger's organized protoplasm. Folin has therefore arrived at the following conclusion : The greater part of the protein fur- nished with standard diets represents exogenous metabolism and is not needed; or, to be more specific, its nitrogen is not needed. The organism has developed special facilities for getting rid of such excess of nitrogen so as to gain the use of the carbon moiety of the protein containing it. The first step in this process is the decomposition of proteid in the diges- tive tract into proteoses, amino-acids, ammonia, etc. The hydrolytic cleavages are carried further in the mucous membrane of the intestines, and are completed in the liver, each decomposition being such as to further the formation of urea. We have in these special hydrolytic decompositions, the result of which is to remove the unnecessary nitrogen, an explanation of why and how the animal organism tends to maintain nitrogen equilibrium even when excessive amounts of protein are furnished with the food. This excess is not stored up in the organism as such, because the actual need of nitrogen is so small that an excess is always furnished with the food. The ordinary food of the average man contains more nitrogen than the organism can use, and increasing the nitrogen still further will therefore necessarily only lead to an immediate increase in the elimination of urea, and does not increase the proteid katabolism involved in the creatinin formation any more than does an increased supply of fats and carbo- hydrates. Finally, the normal human organism can be made at almost any time to store up fats and carbohydrates. The katabolism of these products consists chiefly of oxidation, a decomposition which sets free large quan- tities of energy useful to the organism. The hydrolytic removal of nitro- gen from protein involves by comparison a very small transformation of energ} and yields a non-nitrogenous rest of great fuel value. The latter may be directly transported in part to the different tissues, and thus at once supply oxidative material where needed, but in all probability it is partly converted into fats, or at least into carbohydrates, and then be- comes subject to the laws governing the katabolism of these two groups of food products. It may be added, there is no urgent reason for assum- ing that the katabolism of the proteid nitrogenous derivatives is brought about by oxidations like those which decompose the fats and the carbo- hydrates; for such cleavages are more easily accomplished by hydro- lytic reactions than by oxidations. 708 NUTRITION The experience of the writers lends support to many features of the theory of proteid metabohsm outUned by FoUn. It makes intclUgible the ordinary absence of any demonstrable effect of physical work on nitrogen elimination, and indicates how excess of nitrogen furnished Mith the food is quickly converted under normal circumstances into urea and made harmless by elimination. Even in starvation it is presumably not the muscle proteid which is first attacked. Folin suggests the fol- lowing ex])lanation for this case: "All living protoplasm in the animal organism is suspended in a fluid very rich in protein, and on account of the habitual use of more nitrogenous food than the tissues can use as protein, the organism is ordinarily in possession of approximately the maximum amount of reserve protein in solution that it can advantage- ously retain. When the supply of food protein is stopped, the excess of reserve protein inside the organism is still sufficient to cause a rather large destruction of protein during the first day or two of protein starva- tion, and after that the protein katabolism is very small, provided suffi- cient non-nitrogenous food is available. But even then, and for many days thereafter, the protoplasm of the tissues has still an abundant supply of dissolved protein and the normal activity of such tissues as the muscles is not at all impaired or diminished. When 30 or 40 grams of nitrogen have been lost by an average-sized man during a week or more of absti- nence from nitrogenous food, the living muscle tissues are still well sup- plied with all the protein that they can use. That this is so, is indicated on the one hand by the unchanged creatinin elimination, and on the other by the fact that one experiences no feeling of unusual fatigue or of inability to do one's customary work. Because the organism at the end of such an experiment still has an abundance of available protein in the nutritive fluids, it is at once seemingly wasteful of nitrogen when return is made to nitrogenous food. This is why it only gradually, and only under the prolonged pressure of an excessive supply of food protein, again acquires its original maximum store of this reserve material." • If views such as this approach the truth, it is obvious that the prevail- ing ideas regarding the high proteid requirement of man are erroneous. We shall refer to this when treating of the dietetic needs of the body, in connection with the determination of the minimum proteid require- ment. Landergren has observed that nitrogen elimination may fall to a low level on a nitrogen-free diet, and that the extent of the endogenous output under these circumstances is conditioned by the presence of a certain amount of carbohydrate in the food. So long as the carbohydrate requirement can be satisfied, the output of nitrogen is minimal. In the absence of carbohydrate an additional quantity of proteid is destroyed, perhaps to furnish sugar for the blood, and this additional loss cannot be prevented by the feeding of fat. According to Landergren, a third or more of the proteid destruction in hunger is attributable to the demand of the organism for carbohydrate which is accordingly furnished from the carbon moiety of the proteids. In this way, the increased proteid destruction noted during complete inanition in contrast with specific nitrogen starvation is explained. The Proteids in Intermediary Metabolism. — If we follow more closely the history of the various nitrogenous urinary constituents we shall find that they represent quite distinct processes in intermediary metaboUsm. The GENERAL CONSIDERATIONS OF METABOLISM 709 urea output, in proportion to the total nitrogen elimination, may be greatly diminished in disease. The experiments of Folin make it yjrobable that even in health the urea fraction of the nitrogenous excretives may be very greatly reduced when the minimum proteid recjuirement of the organism is not overstepped. The theories bearing on the immediate origin of urea are numerous and cannot be examined here in detail. Urea. — It is well known that the liver has the power of forming urea from ammonium salts, and from simple amino-acids like glycocoll. The evi- dence is increasing to indicate a larger proportion of ammonia in the portal blood, especially at the height of digestion, than is found in the hepatic vein. Digestion thus furnishes many factors which may play a part in the synthesis of urea. Some of the tissues contain urea-forming enzymes. Thus arginase acts upon the proteolytic derivative arginin to form urea and ornithin and this mode of origin may explain the occur- rence of urea when the liver is completely excluded. That the liver is the chief organ involved in urea formation is suggested by the results found when it is completely excluded from the circulation. A greatly increased elimination of ammonia follows, with diminution in the output of urea; .the latter, however, never completely disappears, possibly owing to its production from proteolytic products like arginin in various parts of the body by the agency of urea-forming enzymes. Kossel has already found arginase in various tissues. There is no evidence of the direct formation of urea from proteids in the body, although Hofmeister has succeeded in forming it by oxidation with permanganate in the presence of ammonia at 40° C. from both nitrogenous and non-nitrogenous compounds. In certain diseases, especially such as seriously involve the functions of the liver, the proportion of urea nitrogen eliminated may diminish very markedly, falling even below 10 per cent, of the total output. In some instances this may be due to the small intake of proteid and corre- sponding diminution of exogenous proteid metabolism. But as the out- put of ammonia is almost always very large in these cases, amounting at times to 40 per cent, of the entire nitrogen output, it is more likely that the formation of acid products in intermediary metabolism — the condi- tion known as acidosis — may draw upon the ammonia for purposes of neutralization. For this reason, the elimination of ammonia is increased by administration of mineral acids; and under such conditions and in such diseases as in fevers and diabetes, where an increased formation of acid takes place, the quantity of ammonia in the urine is increased. The ammonia may be afforded by additional proteid katabolism and the destructive removal of fixed alkali thus prevented. The absolute quan- tity of ammonia eliminated ordinarily is small, — approximately one-half gram per day. Creatinin. — The current views regarding the significance of creatinin in the urine have experienced a marked change in recent times. The tra- ditional opinion is that creatinin in the urine is largely derived from the creatin of meat ingested. We have observed, however, that creatinin and creatin are not lacking in the urine of suckling animals, contrary to the statements of most writers. That the creatinin output is at once increased by ingestion of meat has received abundant confirmation. On the other hand, both Long and the authors have, in distinction from several other investigators, found creatinin abundant in the urine of vegetarians who 710 NUTRITION abstained for months from meat or other ereatin-eontainino; foods. Folin maintains that the absohite (|uantit_v of ereatinin eHminated in the urine on a meat-free diet is a constant quantity different for different individ- uals, but wholly independent of quantitative changes in the total amount of nitrogen eliminated. Creatinin in the urine would, on this assump- tion, become a measure of the extent of endogenous proteid metabolism under ai)propriate" conditions of diet. AYhether creatinin production is increased with excessive muscular work is as yet rather uncertain, as is the immediate antecedent of the creatinin. Lecithin has been suggested by Koch as a possible i)recursor, though the evidence is far from convinc- ing. The experience of the writers agrees in many ways with the essen- tial requirements of Folin's views. We have noted a production of creatinin in starvation in man, and have observed an elimination of this compound proportional, broadly speaking, to the body weight or bulk of the active tissues on diets practically creatin-free. The following sum- mary represents average figures drawn from protocols regarding endoge- nous creatinin obtained in our laboratory: Subject. Body weight. Creatinin. Creatinin per kilo. Kilos. Grams. Milligrams. A.C. 22 0.37 17 P. 27§ 0.44 16 E.H.R. 57 1.10 19 R.H.C. 57i 0.87 15 G.M.B. 6U 1.17 19 O.E.C. 62^ 1.46* 23* F.P.U. 65 1.21 19 L.B.M. 70 1.18 17 J.I. 90 1.87* 21* *These figures represent creatinin plus creatin. It is therefore not at all improbable that we may have in creatinin a most reliable index as to the extent of certain aspects of proteid metab- olism — the tissue metabolism. Purins. — In the case of uric acid and other purin derivatives, it is appar- ent from recent studies that there exists likewi-se a twofold source, viz., an exogenous source related to the foodstuffs and an endogenous one. No convincing e\ndence has yet been furnished of a synthetic formation of uric acid in man, although this is a familiar process in birds and reptiles where uric acid represents the chief end-product of nitrogenous metabolism. The exogenous sources of uric acid production are found in all those compounds which contain the purin nucleus in a form in which it can be attacked in the body. They include especially the nucleoproteids (nu- cleins) occurring abundantly in glandular tissues like liver, thymus, kid- ney, etc. To this may be added the free purin bases like hypoxanthin and xanthin which are present in tissue extracts, especially in the muscle. In smaller quantity, nucleic acid derivatives and purin compounds are found in vegetable foods. In all these cases, the purin group is either present preformed or is liberated by metabolic (enzymatic) changes and GENERAL CONSIDERATIONS OF METABOLISM 711 then oxidized further to uric acid, and in much smaller proportion appears in the form of other purin derivatives: xanthin, guanin, hypoxanthin, adenin, paraxanthin, heteroxanthin, etc. But even on a purin-free diet, or during starvation, uric acid continues to be eliminated in small, though noteworthy, amounts, and there is considerable evidence to show that this endogenous purin output is a fairly constant quantity for any individual, whatever the character of the (purin-free) diet. That the body is not entirely destitute of the power to form nucleoproteids, is seen in the construction of these compounds in the developing egg and in the growing infant nourished with milk, which is practically purin-free. In the purin metabolism of the adult, however, food purins are of fore- most importance and the synthetic processes, if they occur at all, are inconspicuous. In attempting to render account of the intermediary metabolism of the purins, it is apparent at once that we have to deal with a chemical transformation which, as in the case of creatinin, is quite independent of urea production and calls for a special interpretation. For many years it was believed that uric acid represented an intermediate stage in the katabolism of proteids to urea. It is indeed true that uric acid can readily be decomposed so as to yield urea and such a process doubtless occurs when uric acid is broken down in the body. Further than this the relation does not hold, since we have learned to recognize chemical differences in the nitrogenous foodstuffs, involving the presence of the purin group in some, and an entire absence of it in others. As an illus- tration of this, we may cite experiments of our own, in which 20 grams of nitrogen ingested largely in the form of sweetbread (thymus glands rich in nucleoproteid) afforded an output of nearly 2.0 grams of uric acid, whereas the same quantity of nitrogen taken in the form of the purin-free substances yielded only 0.3 gram of uric acid per day. The quantity of uric acid (and other purins) eliminated is not equivalent to the amount ingested, but represents only a fraction of it. Simultaneously with the tissue processes which result in the oxidative formation of uric acid, a destruction of the latter occurs; so that the quantity of uric acid actually excreted represents the equilibrium reached between the forma- tion and further oxidation of that compound. Recent studies make it probable that tissue enzymes cooperate in these changes in various ways. Nucleases may liberate the amino-purins, adenin, and guanin, from nucleoproteids or nucleic acids; amidases (adenase and guanase) trans- form these amino-purins to hypoxanthin and xanthin respectively; and axidases effect an oxidation of the latter to uric acid and even further. All of these reactions have been demonstrated with various tissue ex- tracts; and it is interesting to observe that whereas many tissues, like the liver, testes, etc., which are rich in nucleoproteids, yield adenin and guanin on direct hydrolysis with acids, after autolysis they afford hypo- xanthin and xanthin in place of the amino-purins. In addition to this, liver extracts are capable of oxidizing added xanthin and hypoxanthin to uric acid through intermediation of a special enzyme (xanthinoxy- dase), and to decompose the uric acid still further. A special influence on purin metabolism was at one time attributed to the spleen. Experi- ments by the writers have failed to substantiate such a view. In fact, there is no evidence that the spleen exerts any special influence on either 712 NUTRITION carbohydrate or proteid metabolism in general. The liver doubtless plays an important role in these reactions, especially in the destruction of the intermediary uric acid. Herein probably lies the explanation of the increased (or at least undiminished) output of vu'ic acid in organic disturbances of the liver, involving a complete or partial exclusion of its functions. Thus, too, we may believe that substances which disturb these functions, as alcohol, facilitate increased uric acid output by dimin- ishing the normal katabolic action. At any rate, the organism has the capacity, invested no doubt in difi'erent tissues, of converting food purins into uric acid which nuiy escape destruction and be excreted as such, or may be further oxidized. When the latter occurs, allantoin has been demonstrated as a characteristic product, rarely arising in man, however. It is not unlikely that oxalic acid represents a further intermediary stage. The relation between these compounds is shown below: HN— CO I I OC C— NH HN— CO OC CO HN— C— NH Uric Acid. / H.N CO HN— CH— NH Allantoin. NH, NH. Urea. COOH COOH Oxalic Acid. The purin bases which serve as antecedents of endogenous uric acid have been supposed to arise from the nucleoproteids of disintegrated cells, in particular the leukocytes. As a matter of fact, increased elimi- nation of uric acid has been observed in conditions attended with pro- nounced leukocyte destruction, enormous quantities (5 grams and over) ha\dng been reported in cases of leukgemia. If we may trust the obser- vations of Burian, however, the greater bulk of the endogenous purins is formed in the muscles, thus explaining in a way the relative constancy of the endogenous uric acid production in the same individual as well as the variations attributable to different personality, i.e., mass of active tissue. Amino-acids. — The hippuric acid CeHgCO.NH.CHaCOOH in human urine originates in part at least from aromatic substances derived from the diet, especially fruits and vegetables. Benzoic acid is speedily effective in bringing about the synthesis; and a small part may be formed indi- rectly tlirough putrefactive processes in the intestine. The place of syn- thesis ai)pears to be in the kidneys as well as other tissues. Theglycocoll required to conjugate with the aromatic radical is derived from proteids. In fasting animals repeatedly fed with benzoates, the amount of glycocoU eliminated through the urine as hippuric acid (benzoyl-glycocoll), com- pared with the total nitrogen metabolism, indicates that 4 grams of gly- cocoU may be derived from the metabolism of every 100 grams of body proteid. The glycocoll excretion runs parallel with the proteid destroyed. Feeding carbohydrates does not increase the formation of glycocoll; but the proportions formed after feeding gelatin and casein are between 3 and 4 per cent, of the proteid metabolized. The formation of glycocoll in the body is unquestioned; and the significance of the hippuric acid eliminated is therefore connected with the origin of the benzoic acid. Of the sulphur compounds in the urine, the ethereal sulphates represent veliicles of elimination for different conjugated groups. In indican, the GENERAL CONSIDERATIONS OF METABOLISM 713 organic radical is derived from indol formed by intestinal putrefaction from the tryptophan group in the proteids. In accordance with this view, Underhill has found that after feeding gelatin (which contains no tryptophan group) in place of ordinary proteids, the excretion of indican is greatly diminished. The ethereal sulphates also represent other organic radicals Kke phenyl and cresyl. The immediate source of all these com- ponents is not yet established. The inorganic sulphates appear to follow the fluctuations of urea, the neutral sulphur on the other hand showing a possible connection with some endogenous proteid katabolic process. Pathology has furnished several illustrations of perverted metabolism of proteids, which throw some light on the character of the normal inter- mediary changes. In alkaptonuria, the usual destruction of the aro- matic proteid cleavage products, tyrosin and phenylalanin, appears to be interfered with. IJnder conditions of health these compounds are completely burned in the body; but in the anomalous condition under consideration they leave the body as homogentisic or uroleucic acid. That the "alkapton" substances owe their origin to the aromatic group of the proteid molecule is evident from the proportionate relation between homogentisic acid and proteid destruction, and the fact that the quan- tity of the acid eliminated after a diet of some specific proteid substance is generally equivalent to the amount of tyrosin and phenylalanin yielded by it. Furthermore, feeding of tyrosin and phenylalanin to patients with alkaptonuria is followed by increased output of homogentisic acid, whereas in normal individuals these aromatic amino-acids are completely burned up. The experimental evidence gives no support to the idea of an abnormal production of homogentisic acid from proteids in this dis- ease; but rather that the katabolism of the aromatic complexes ordinarily proceeds through the stages above described, and in alkaptonuria meets with a condition where the final cleavage of the benzine ring represented in homogentisic acid is no longer possible Accordingly, the healthy in- dividual readily burns up ingested homogentisic acid, while in alkapto- nuria it is excreted unchanged. Cystinuria furnishes another pathological condition which consists in an inability to burn some of the amino-acids formed in intermediary metabolism, notably the sulphur-containing complex of the proteids represented by cystin. When this compound is fed to healthy individuals in quantities as large as 8 grams, it is completely oxidized and the sul- phur is eliminated in the form of sulphates and thiosulphates. It may in part be converted into taurin and enter into the composition of the bile as taurocholic acid. The relation of proteids to the production of bile salts thus becomes clear in the case of glycocholic and taurocholic acids, since the origin of glycocoll and taurin in the intermediary metab- olism of proteids is understood. Normally, urine is free from cystin even when the latter is fed; but when cystin is given to cystinuric patients it may be in part excreted again. There is at present some divergence of opinion on this point. It is further claimed that cystin is not the only amino-acid which is not burned in cystinuria; in some cases it has been reported that ingested tyrosin and aspartic acid are excreted unchanged. The diamino-acids take a peculiar position in the metabolism of some of the cystinuric in- dividuals. They are partly split up with liberation of carbon dioxide 714 NUTRITION and reappear as diamines. It is likely that this change is attributable to the action of intestinal bacteria, so that the diamines are absorbed as such from the intestine and eliminated unchanged. This seems the more probable because the diamines here concerned, putrescin and cadaverin, have been produced experimentally by the action of bacteria upon the diamino-acids, arginin and lysin, and the diamines are found in the fjeces as well as the urine in cystinuria. Arginin is doubtless first converted into urea and ornithin, which in turn is transformed into putrescin and carbon dioxide. The interesting cases of cystinuria and diaminuria fre- quently found combined in the same individual, give further evidence of stages through which proteids presumably may pass in their normal katabolism, and at which tlie decompositions may be arrested in patho- logical conditions. Further evidence of the formation of cystin as a normal intermediary stage in proteid katabolism has been afforded by a type of experimental cystinuria made known by Baumann. Dogs fed with brombenzol excrete the so-called mercapturic acid, which readily yields bromphenyl cystein, the halogen benzol compound apparently protecting the cystin radical from oxidation. Doubtless there are vary- ing degrees of incapacity for the katabolism of proteids in different patients, just as we have different degrees of inability to burn sugar in diabetics. Additional evidence regarding the occurrence of the characteristic proteolytic derivatives as stages in intermediary metabolism is gradually accumulating. Aside from the typical conditions described above, there are other pathological states in which unoxidized amino-acids are excreted in complete analogy with the ideas we have put forward regarding elimination of the intermediary products of carbohydrate katabolism, exemplified in glycuronic acid and oxalic acid. Thus, in acute yellow atrophy of the liver, in phosphorus poisoning, in gout, pneumonia, and leukffimia, tyrosin, leucin, glycocoll, etc., have been isolated from the urine, from which they are absent in health even when introduced as such into the organism. The conditions met with in these cases may be classed as jjerversions or disturhances in the metabolism of the amino-acids. We have seen that nucleoproteids follow transformations in metabo- lism somewhat distinct from those of the simpler proteids, the character- istic differences being associated with the purin complexes in particular. It is not unnatural, therefore, that perversions of 'puriji metabolism should occur. The phenomena of gout have long been associated with such disturbances, and the discussion of the pathology of this condi- tion has been prominently connected with the behavior of uric acid in the body, though with somewhat questionable justification at times. It would be unprofitable to review the enormous literature on this sub- ject here; yet it is impossible to make any concise statements which are at all adequate or undebatable. Certain features connected with purin metabolism in gout deserve mention. The particular attention which has been directed to uric acid in this connection has arisen pri- marily from the fact that urate depositions unquestionably are found in the tissues and joints. The cause for this is quite uncertain. It is true that the blood in gout has been found to be richer than usual in dissolved uric acid; but it is by no means saturated with purin compounds, and from this point of view no apparent] occasion for a deposition exists. GENERAL CONSIDERATIONS OF METABOLISM 715 Certain it is that both in experimental gout (produced by meat feeding to animals) and in human gout the liver is frequently involved. The important influence of this organ has been noted especially by the writers in studying the fate of uric acid injected intravenously. In animals, allantoin is produced in this way; the quantity is far greater, however, after injection directly into the portal circulation than into a systemic vein. Acute attacks of gout are accompanied by marked variations in the elimination of uric acid, a retention or deposition of the latter being fol- lowed by a sweeping out, as it were, of accumulated urates. In many cases, the rate of uric acid elimination after a meal containing meat is greatly altered in comparison with the healthy individual. Questions of solubility may be concerned herein. Enough has been said, we think, to indicate that in gout it is not so much a disturbance in purin metab- olism as a perverted function of one or more organs and tissues which is of pathogenetic moment. Before leaving the subject of proteid metabolism, we must consider one aspect of the anabolism of proteid which frequently attains clinical importance. Can the organism build or store up proteid elements in the form of flesh (Fleischmast) , in distinction from fattening. As a contin- uous process this is impossible in view of the tendency toward nitrogen equilibrium which has already been explained. Otherwise the growth of muscle, for example, might be facilitated enormously. As a matter of fact, flesh formation, whether directly from circulating proteid, or indirectly from proteid cleavage fragments, can at times be accomplished. It seems to depend primarily upon the nutritive condition of the cells rather than upon any surplus of food. Proteid tissue anabolism may take place in the muscles as it is seen in hypertrophy induced by vigor- ous muscular work; it is characteristic of growth in the developing organism; and can also be induced in the adult organism after malnutri- tion or undernourishment. In all of these instances, nitrogen retention may accompany the regeneration of the protoplasm. Pathology of Nutrition. — In outlining the more important features in the metabolism of proteids, fats, and carbohydrates, numerous refer- ences have been made to pathological variations in the transformations which these compounds undergo. Thus, the bearing of gout and diabetes upon the metabolism of purins and carbohydrates has been pointed out; and some of the features of the abnormal katabolism of the proteids illustrated in the case of alkaptonuria, cystinuria, and diaminuria. In this section we propose to consider certain more general and unrelated phenomena which are of interest in the study of the pathology of nutrition. Autolysis and Intracellular Enzymes. — The recognition of the im- portance of enzymatic processes, and the increasing acquaintance with types of enzymes capable of transacting the work of the cells under physio- logical conditions, has directed attention to the possible significance of these enzymes in pathological processes. As certain functional acti%i- ties have long been associated with definite morphological structures, the integrity of which was conceived to be essential for their work, pathology has depended upon structural or vague "functional" altera- tions to account for the unusual or abnormal. But since proteolysis, lipolysis, glycolysis, oxidation, deamidization, are all referable to appro- 716 NUTRITION priate enz}Tnes, some of which seem to be regulated by corresponding anti-enzymes or activated by kinases, new features are introduced into the study of pathological manifestations. In a system of coo])erating and interdependent chemical reactions, it is quite conceivable that the impairment or omission of one link in the chain may throw the entire complex out of gear. The autolysis of certain tissues in disease is doubt- less associated with some such disturbance. Autolytic enzymes are widely distributed; and in phosphorus poisoning and acute yellow atrophy an intravital autolysis of the liver frequently leads to a softening of that organ, with fonnation of ty})ical products of proteolysis. In car- cinoma, in the lungs during pneumonia, in abscess formation, and espe- cially where a destruction of polynuclear leukocytes is accompanied by a liberation of autolytic enzymes, autolytic changes may take place. The proteolytic products are then further destroyed in the usual ways, or they may accumulate in the blood and be excreted as such. Autolysis seems to be the effective agent in the destruction or metabolism of all necrotic tissues. The occurrence of amino-acids, like leucin, tyrosin, and glycocoU in the urine, is perhaps attributable in some cases to undue autolysis which is checked in conditions of health. It is not unlikely that analogous changes take place in the degeneration of nervous tissue, by which cholin is liberated from lecithins. As further peculiar products of tissue self-digestion, bactericidal and antitoxic products may be men- tioned; and lately the lack of suitable glycolytic enzymes has been proclaimed as a possible cause of the imperfect utilization of sugars in diabetes. Acidosis. — This term is used to designate a pathological condition clearly pictured by Naunyn, in which acids arise in metabolism. It is not easy to determine in every case whether the acid owes its origin to abnormal formation, or to imperfect destruction of some compound ordinarily generated in intermediary metabolism and at once subjected to further decomposition. There are several w^ays in which these acid products may become a source of harm. They are likely to withdraw from the body bases in combination wuth which they are then eliminated as relatively harmless salts; and when the organism is overwhelmed with large quantities of these unneutralized organic acids, toxic symp- toms may be occasioned. The most interesting feature of the general condition of acidosis, w'hatever the mode of its generation, is the accom- panying increased elimination of ammonia. This, however, does not necessarily signify any increased production of ammonia in metabolism. Ammonia is the acid indicator of intermediary metabolism. When mineral acids are introduced into the body, or organic acids are formed by some unusual circumstance within it, they are at once neutralized by ammonia, the nitrogen elimination in other types of compounds being correspondingly diminished. The dangers of acid intoxication are thereby avoided, and the alkali content of the blood and tissues pro- tected from loss. This typical behavior of ammonia in intermediary nitrogen exchange is a valuable protective reaction for the organism; and, conversely, the elimination of proportionately large quantities of nitrogen, in the form of ammonium salts, is to be referred not to any increased katabolism resulting in ammonia production, but rather to acids which have neutraUzed it prior to its conversion into urea. Of GENERAL CONSIDERATIONS OF METABOLISM 717 possible conditions which might initiate such an excretion there are many. The intermediary production of lactic acid, /^-oxybutyric acid, aceto-acetic acid, glycuronic acid, oxalic acid, etc., .suggests the types of acid compounds which may be formed. It has already been sug- gested that a probable — perhaps the most plausible — theory of the origin of these compounds is one which refers them to arrested stages in normal katabolism. Hence they are wanting in the healthy organism. Mineral acids (phosphoric and sulphuric) may likewise arise in metabolism. As a rule, however, the quantity of these is far too small to account for the high ammonia output in many pathological conditions, and it is neces- sary to assume the production of a considerable portion of organic acids. There are even cases in which the production of acids is sufficiently large apparently to call forth a destruction of proteid in order to furnish suffi- cient ammonia for the acidosis presented. When the quantities of the chief bases, sodium, potassium, calcium, magnesium, and ammonium, and the chief acids, sulphuric, phosphoric, hydrochloric, and uric, eliminated in the urine, are compared or "bal- anced," any excess of the sum of the bases over the equivalent sum of the acids may at once be referred to the presence of unknown organic acids. In diabetes, where the carbohydrates are no longer burned up, the nutritive demands of the body draw upon the fat supply in corre- spondence with which the fat-content of the blood has actually been observed to be higher than usual. We have seen that /3-oxybutyric acid and its derivatives, aceto-acetic acid and acetone, may arise in the katab- olism of the fats. The diabetic patient in the advanced stages of the disease also loses his capacity to burn up^-oxybutyric acid in contrast with the normal individual in whom it is readily and completely oxidized. In the more extreme cases, other bases, calcium, magnesium, even potas- sium and sodium, may contribute to the "disintoxicating" or neutraliz- ing process, and the body may be robbed of its bases in addition to losses of proteid katabolized to yield ammonia. The lethal symptoms in dia- betic coma are those of an acid intoxication, while loss of alkali doubt- less plays a contributory role in the effects produced. A severe acid intoxication tends to diminish the alkalinity of the blood markedly, and the carbon-dioxide content has been found to be diminished to one-sixth or less. Furthermore, the physiological capacity for excretion by the kidneys is not infrequently seriously impaired, so that imperfect elimi- nation adds to the gravity of the situation. The complications of perverted intermediary metabolism are far- reaching. The situation in diabetes is, perhaps, somewhat extreme, yet sufficiently characteristic to portray the salient features of acidosis. It is well, perhaps, to emphasize the fact that the fundamental disturb- ance is a nutritive one. Organic acids left unburned deplete the store of available bases. They may unite with ammonia, which the organism can almost always furnish with liberality when the proteid of the diet is present in customary abundance, or which it can requisition by in- creased katabolism if need be. Or the acids may unite with other bases and induce a new series of nutritive difficulties; so that there are cases in which the extent of ammonia output is not a reliable measure of the degree of acidosis. In such instances the "balance" of acids and bases must be depended on for more reliable indications. 718 NUTRITION All grades of acid intoxication may be observed. Thus Herter be- lieves that small quantities of organic acids pass from the blood into the urine in cases of dilatation of the stomach and in some other dis- orders of digestion. The character of the pathological acid or acids has not been made out here with certainty. The evidence rests upon the observed excess of known bases over known acids in the urine. It is more likely that any organic acid formed in such gastric disturbance owes its origin to fermentative processes, than to some obscure meta- bolic disturl)ance caused by toxic protlucts absorbed from the gastro- intestinal tract. There are various forms of hepatic disease accompanied and even characterized by the chemical symptoms of acidosis. Cirrhosis, degen- eration following phosphorus poisoning, acute yellow atrophy, and chronic abnormality of the liver, differing in their pathogenesis, are all characterized by relatively high proportions of ammonia-nitrogen in the urine. The characteristic high ammonia elimination in liver affections may be associated with an inhibition of the urea-forming powers of the hepatic cells. Seldom is urea absent from the urine, however; and the low urea output may equally well be attributed, in the experience of the writers, to the small proteid intake of patients suffering from serious hepatic impairment. Furthermore, it has been found that even in ad- vanced stages of hepatic degeneration ammonia salts administered by mouth can still be converted to urea. The differences which the meta- bolic disturbances may exhibit under changed conditions are well illus- trated by the distinction between the phenomena of complete liver elimination in animals and those observed after production of the Eck fistula. When the liver is completeUj excluded from the circulation, am- monia is eliminated in abundance and urea decreases, as is true in Eck fistula cases; but the reaction of the urine becomes markedly acid, and it cannot be made alkaline even by administration of large doses of soda, although the ammonia output is thereby diminished. The marked acidosis is presumably attributable to other acids than those character- istic of diabetic derangement. In many cases of acidosis the factor appears to be lactic acid, to which we are inclined to add various amino-acids — leucin, tyrosin, alanin, glycocoU — lately isolated from the urine of patients with severe hepatic insufficiency. Much of the lactic acid doubtless is referable to carbo- hydrates; some of it may be derived indirectly from proteids. Perfusion of the glycogen-yielding livers of well-nourished animals with blood results in a production of lactic acid — a result not noted when glycogen- free livers from starving animals are used. But alanin, a proteid deriva- tive, likewise appears to form lactic acid under similar conditions. The relation between these compounds is very close. Contrasting these facts with the presvmiable origin of the pathological organic acids of diabetic urine from fats, it appears likely that acidosis as a condition can be brought about through imperfect intermediary metabolism of all the types of foodstuffs — fats, carbohydrates, and proteids. An interesting disturbance of metabolism closely related to the phe- nomena of typical acidosis has been disclosed in connection with imper- fect fat absorption from the intestine. When this is brought about by lack of bile secretion or pancreatic disease, the fatty acids liberated in GENERAL CONSIDERATIONS OF METABOLISM 719 the alimentary tract from ingested fats appear to be excreted in the faeces in increased quantity as soaps of calcium and magnesium. The diver- sion of these alkali earths into this channel of elimination occasions dimin- ished excretion of them in the urine. Indirectly, the formation of lime soaps leads to a deficiency of alkali and a compensatory elimination of ammonia — phenomena characteristic of acidosis in metabolism. It has been suggested that the high ammonia output of infants suffer- ing from gastro-intestinal disturbances may be directly attributable to disturbed absorption of fat with the chain of consequences just outlined. Obesity. — ^The physiology of fat formation and deposition in the body has already been considered. It is indeed difficult to say to what extent, if at all, corpulence represents a pathological condition; at any rate from a metabolic point of view the body is concerned here simply with an ex- aggeration of normal processes. When once a beginning has been made, the conditions thereby developed tend to perpetuate and aggravate the difficulties encountered. Thus with increase in weight and growing corpulence the body becomes less and less capable of active exertion, which in itself is conducive to further storage of fat. As the corpulence increases the muscles tend to be brought less into use, and the lack of exercise in turn tends to weaken them and render them still more unfit for work. The conservation of body warmth by the highly developed panniculus, the low metabolism of energy called forth by the attendant slothfulness, in addition to the abundant food intake in the corpulent, all contribute to protect the body fat. A cumulative effect thus induced can only be counteracted by a restricted intake and increased exercise, the latter being difficult because of the discomfort which it occasions. Alcohol plays a contributory part by affording a readily combustible compound which may speedily experience oxidation and protect the body-fat; and further, its pharmacological action is such as to contribute to the general indifference and inactivity characteristic of obesity. These factors will be seen to be strictly within the province of normal physiological behavior. It has often been asked whether other elements do not contribute to the development of obesity. A hereditary tendency cannot be denied. The common observation of absence of any tendency toward corpulence in^ many individuals who eat very heartily and culti- vate no unusual degree of muscular exertion leads one to ask whether the obese transform the potential energy of their foods more advanta- geously, or are subject to functionally diminished oxidative powers. Experiments have demonstrated conclusively that this is not the case. The oxygen consumption and carbon dioxide production of corpulent subjects is precisely comparable with that of non-corpulent individuals of the same weight. Even the supposedly "constitutional" obesity which is seen in castrated animals is referable to the lesser bodily activity. Finally, an influence on the part of the nervous system cannot be denied. As Miiller expresses it, a vigorous individual whose spirit enters into continuous excitement and activity is certain to set his muscles into action to a far greater extent than the phlegmatic person who moves only when compelled. Malnutrition and Related Conditions. — Ordinarily the disturbances noted are referable to variations in the quantitative relations of nutri- 720 NUTRITION tion. As soon as qualitative changes arise the term malnutrition is more appropriately applied to the distinctly morbid states, and here the phenomena of autolysis, acidosis, protoplasmic disintegration and re- tarded katabolism of specific molecular complexes are met with. As regards the relation of fever to metabolism, the etiological and clinical conditions arc too diverse to permit any general theory. Fevers are usually accompanied by a noteworthy increase in proteid katabolism which contributes not a little to the serious physical impairment so often brought about. Undoubtedly it is quite correct to attribute this to a sort of involuntary inanition, but we believe that this alone is insuffi- cient to account for all the disturbances of metabolism associated with fevers. Toxic ])roducts of bacterial or bodily origin undoubtedly may exert a direct action on tissue katabolism. In so-called "aseptic" fevers the glycogen-content of the body ai)pears to determine in no small meas- ure the possibility of the rise in temperature. That the processes of inter- mediary metabolism may suffer qualitative disturbances is suggested by experiments like those of INIandel on the purin bases in aseptic fevers. A pronounced coincidence between the temperature and the purin bases has been observed; the quantity of uric acid eliminated varies with the alloxuric bases; that is, the latter increase in amount as the quantity of uric acid diminishes, and vice versa. It is therefore not unlikely that a distinct relation between the fever and the appearance of certain pro- ducts of incomplete cell oxidation, as shown by the excretion of purin bases, exists. The supposition that these bodies are directly concerned in the production of fevers is strengthened by the fact that the administration of xanthin and caffeine produces a decided rise in body temperature in otherwise healthy individuals. Without attributing to the purin bases the sole cause of the febrile temperature in the "aseptic" cases, it may be safe to assume that if other substances are concerned they are of sim- ilar origin and nature, i. e., intermediary products of metabolism, the source of which is to be looked for in the circulating leukocytes and tissue cells. "We may assume that in a number of pathological conditions the ability of the cells of the organism to oxidize -certain substances is directly interfered with. Probably this applies to the so-called aseptic fevers as, for instance, rise of temperature after severe operations, anaes- thesia, convulsions, poisons, cachexias of various forms. In all these disturbances we may suppose that temporary or more permanent injuries to the cells inhibit their oxidation ability for a shorter or longer period; the consequences will necessarily be less complete oxidation of sub- stances to their proper end-products." (Mandel.) A further specific factor is the continued new formation and simulta- neous destruction of cells in inflamed areas. Wlaere exudates are formed in considerable quantity an unusual addition may be made to the "circu- lating" proteid of the body; in such cases the body metabolizes the excess of proteid just as when an excess of the latter is furnished in the form of food. To what degree the disturbed thermogenic functions influence katabolism in fever is not determined beyond dispute. A retention of chlorides accompanying the increased proteid decomposition has been re- ported in many infectious diseases, like pneumonia and typhoid, which are attended with fever. It is not unlikely, however, that in most of these cases the deficient salt intake is the contributing cause. A marked acido- GENERAL CONSIDERATIONS OF METABOLISM 721 sis, especially intense in infancy, frequently adds to the complications which metabolism experiences in fever. Indicanuria can scarcely be spoken of as a disturbance of intermediary metaboUsm, inasmuch as the primary cause usually lies in the preliminary putrefactive decomposition which the foodstuffs undergo before leaving the alimentary tract. The products of putrefaction, indol, skatol, phenol, and cresol, are synthesized in the liver to ethereal sulphates orglycuron- ates. The question as to whether the indol derivative indican cannot also arise in intermediary metabolism — in cases which are characterized by vigorous tissue decomposition as in certain types of cachexia, in carci- noma of the stomach, etc. — has been actively discussed. We agree with Jaffe in concluding that the experimental evidence for a direct meta- bolic origin of indican is not convincing. At present no positive source of urinary indican is laiown outside of bacterial processes. The patho- gnomic significance of indicanuria (indoxyluria) is therefore restricted to the domain of those diseases which are attended with bacterial activity, either within or without the alimentary tract. DIET AND DIETETICS. The subject of dietetics has for its consideration the nutritive demands of the body in health and disease, and the conditions and means whereby they may satisfactorily be fulfilled. The problems are manifold; for the needs of an organism vary with the conditions to which it is subjected, and the response of the individual has been modified in no small degree by uni- versal custom or personal tastes, as well as by his environment. The ideal diet for a healthy man is one which will maintain him in nutritive equilib- rium. The physician, however, not infrequently has occasion to depart from the limits here proposed, when he aims to accomplish beneficial effects by overfeeding or by an insufficient diet. The physiological demands of the body can be determined by direct ex- periment and expressed in somewhat general terms; as, for example, the total energy required to preserve the chemical integrity of the body and maintain its functions. The necessity for a mixed diet and the inade- quacy of a diet composed exclusively of proteids have been explained. It need scarcely be repeated that chemical composition is, of itself, no safe criterion of the food value of any nutrient. The digestibility and conse- quent availability of the nutrients bear directly upon their dietetic value, and these factors are influenced in no small measure by physical condi- tions. Herein lies the significance of the natural texture of the food substances, their preparation by cooking and mechanical processes, the palatability of the product, and tolerance of the organism for it. Up to the present time the statements regarding the dietetic needs of the body have been based very largely on the observed facts of consumption rather than upon actual trials. The statistical method has been applied, in order to learn the kinds and amounts of food materials consumed by persons in different localities, of different occupations, ages and sex, and under varying conditions. From such data dietary standards have been suggested, upon the general supposition that the body is best nourished when through long periods the food approximates the requirements thus 46 722 NUTRITION ■a\\\v.\ loiij ^ Oi o o in 10 o >o o o rtiO — C4 IMOO Tji CC' » 05 C-l lO U5"OiOOQO'0 0000'OiO O C-) '^ C O lO W C C") CC OC' 'O 05 Pi U PL, s H o W K E-i •sarBjp •)1'J Cl'OOiOOSi-lCJOOt^OiO •uiaioj^i 05'0MO OCO CO C005CS*-* Oi05 o sajBjp -Xi[oqai!3 Tt" — o ■*•:(< CO 'O Tji ^ CO oo •*co oM(^iioo-*oofocnoot~(N C0'*05'*!010i-li-IC0OM>C0'-l ^ ■<}< CO CO o:) w -ji cc CI lO o iM 00 •?t;j a .-1 ,-1 CO rH .-H .-I T (M C5 -^ QC ^ 0> CO '^ CO O i.O CI t>. CCOr-HiCOi-iOt^-^t^OOCO •uiajojj C-l C: CO CO lO O r~ Tjl lO lO •:(< O Cl COOO^'-'OCOOl'-HCO-tiCCO •saS'BJaA'e ui papnpu! saipnjs JO aaquiri^ rJ lis 132 125 175 15(i 7S 1(17 Carbohydrates. Grams. 500 550 240 457 523 551 541 020 5S4 7()1 4SS 092 Fats. Grams. 5(5 40 100 SI 79 54 03 ()4 SO 109 50 71 Fuel value. Calories (targe). 3000 3100 2324 3174 343G 3229 3235 3623 3G75 3400 5500 477G 2800 4200 *With fat and carbohydrate sufficient to furnish the total energy indicated. Obviously any attempt to determine the minimal proteid requirement on the basis of the nitrogen output in starvation may lead to error. For the energy requirements of the body must be met at any expense; and in the absence of other supply, tissue proteid may be destroyed far beyond the actual katabolism necessary when other suitable nutrients are fur- nished. The Ijlood sugar for example must be maintained under all cir- cumstances. Landergren has studied the extent of proteid katabolism in proteid starvation with and without an abundant diet of fat or carbohy- drate. His experiments indicate that a healthy man receiving an abun- danceof non-nitrogenous nutrients, but practically no proteids, katabolizes proteid represented by no more than 3 to 4 grams of nitrogen per day. In combined proteid and carbohydrate starvation, the katabolism of body proteid may exceed that just noted by 100 per cent., despite a large intake of energy in the form of fat. From this it would appear that a cer- tain minimum of carbohydrate, as well as proteid, is necessary for the maintenance of the sugar-content of the blood. As soon as stored carbo- hydrate (glycogen) is no longer available, sufficient proteid is destroyed to furnish the desired materials, the nitrogenous moiety being simultaneously eliminated as useless. If this is true, then there is a limit to the extent to which fats can replace carbohydrates in isodynamic amounts; and with this, experience corresponds. But with a certain as yet undefined mini- mum of carbohydrate given, fat and carbohydrates can replace each other in proteid-sparing effects; whereas in the absence of all carbohydrate, fats are proteid sparing in lesser degree. In starvation, according to Lander- gren, a third or more of the proteid decomposition is occasioned by the body's demand for carbohydrate — ^which the proteids alone can satisfy in this case. From what has just been stated it follows that the minimum proteid requirement of man can only be determined correctly when due regard is had for the appropriate supply of non-nitrogenous as well as proteid nutri- GENERAL CONSIDERATIONS OF METABOLISM 725 ents; and the condition of hunger fails to afford this opportunity. Trials have been made to attain nitrogen (proteid) equilibrium with diminished proteid intake. Not a few experiments have been unsatisfactory because the total nutritive demands of the body were not satisfied by exhibition of adequate quantities of fats and carbohydrates. It requires no argument to show that impairment of the body must sooner or later follow any con- tinued insufficiency in the total supply of energy in the form of food. Nevertheless, not a few experiments on record have indicated the possibil- ity of maintaining both nitrogenous and bodily equilibrium on an intake of proteid considerably smaller than that recognized in the so-called diet- ary standards. Usually this has been accomplished only when a fairly large amount of non-nitrogenous food was consumed. Kumagawa, weighing 48 kilos, maintained nitrogen equilibrium for some days on an intake including only 55 grams of proteid and a total fuel value of 2,480 large calories. The daily average nitrogen eUmination through the urine was 6 grams, through the freces 2 grams. The diet was purely vegetable. Breisacher, in experiments on himself extending over thirty days, found that an estimated intake of 2,600 calories in the daily diet sufficed to main- tain him in nutritive equilibrium with an average daily nitrogen excretion of about 8 grams. Peschel obtained a satisfactory nitrogen balance for a brief period with 7 grams of nitrogen daily in the food, 5.3 grams appearing in the urine and 1 .6 grams in the fseces. Likewise, Caspari and Glaessner in a five-days' experiment with two vegetarians noted no loss of nitrogen on intakes of 5.3 and 7.8 grams of nitrogen, and 2,700 and 4,560 calories respectively. More important are the experiments which Siven conducted on himself. With a body weight of 60 kilos, he was able, in trials extending through a month, to estabUsh nitrogenous equilibrium on 6.26 grams of nitrogen with comparatively low total intake of food, amount- ing to about 2,500 calories. Such data as these surely warrant the question. How far are w^e justified in assuming the necessity for the rich proteid diet called for by the Voit standard and those like it? It is repeatedly stated that an abundance of food is a necessity for the maintenance of physical vigor and muscular activity. This view is certainly reinforced by the customs and habits of mankind; but we may well query whether our dietetic habits will bear criticism, and in the light of modem scientific inquiry we may even express doubt as to whether a rich proteid diet adds anything to our muscular energy or bodily strength. The experiments hitherto reported have been continued only for brief periods; and recalling the marked resistance of the healthy body it would be amiss to draw any far-reaching conclusions from observations of this character. Further, attention must be given to the unfavorable effects which have been attributed to a low proteid diet fed to dogs for some time. Thus, Munk and Rosenheim both noted after six to eight weeks a loss of the power of absorption from the aUmentary tract, loss of body weight, strength, and vigor, followed by death. Jagerroos likewise observed that there was after some months a striking disturbance of the intestines on a low proteid intake, which was, however, eventually traced to a distinct infection and probably not connected with the diminished quantity of pro- teid in the diet. One is impressed, in the study of these animal experi- ments, with the abnormal if not unhygienic conditions under which the 726 K'UTRITIOX dogs were kept. The great monotony in the diet and restricted quar- ters to which they were subjected makes it higlily riuestiouable whether the diet of the aninuUs was responsible for their poor heaUh in the sense in which it lias usually been interpreted. In prolonged experiments over seven hundred days on man, Neunuuin has found 70 to 80 grams of proteid i)cr day to suffice for the nuiintenancc ration, even with moderate additional food intake of 90 grams of fat and 300 grams of carbohydrate. He inclines to the belief that nitrogenous equilibrium can be maintained on various nutritive planes. Vegetarians have lived for years on a diet relatively poor in proteids without observing any dis- agreeable effects. Jaffa's observations on the fruitarians and nutarians of California "showed in every case that though the diet luul a low protein and energy value, the subjects were a])parcntly in excellent health and had been so during the five to eight years they had been living in this manner. " In comparing the income and outgo of nitrogen, on a diet composed maiidy of nuts and fruits, it was observed in 2 subjects that 8 grams of nitro- gen were sufficient to bring about nitrogen equilibrium, while Avith 2 other subjects the nitrogen required daily for ecjuilibrium was about 10 grams. In harmony with Siven, Jaffa beheves that after the body has suf- fered a loss of nitrogen there is at once an effort to attain nitrogenous equilibrium, and that any gain of nitrogenous body material is a compara- tively slow progress. If this is true, it is obvious that the living substance of the tissue protoplasm must be slowly formed from the proteid of the diet. This, says Jaffa, should serve as a warning to anyone contem- plating any appreciable decrease in the proteid of the daily diet. A further statement made by Jaffa serves to illustrate the attitude taken by many physiologists on this question. "Even if it could be proved," he writes, "by a large number of experiments that nitrogen equihbrium can be maintained on a small amount of protein, it would still be a great question wdiether or not it would be wise to do so. There must certainly be a constant effort on the part of the human organism to attain this condition, and with a low protein supply it might be forced to do so under conditions of strain. In such a case the bad results might be slow in manifesting themselves, but might also be serious and lasting. It has also been suggested that when living at a fairly high protein level the body is more resistant to disease and other strains than when the protein level is low." While these suggestions merit careful considera- tion, it is equally evident that there is another side to the question. The elimination of the excess of nitrogen may become physiologically burden- some and uneconomical, if not positively harmful. Hence, we may well query on which side lies the greater danger without magnifying it on the one hand or suppressing efforts directed toward the true proteid minimum on the other. With the purpose of throwing light upon the question of the proteid minimum and ascertaining how far, if at all, the intake of proteid food can be diminished without deleterious effects, an extensive series of ex- periments on man has been conducted in the laboratory of the writers. Recognizing that the maintenance of nitrogen and body equilibrium on a lower proteid standard than that generally adopted would have little practical value and would not escape justifiable criticism uidess the period of trial was extended over a long time, arrangements were made GENERAL CONSIDERATIONS OF METABOLISM 727 to realize this as far as possil^le. The experiments were conducted upon three distinct types of mdividuals: (1) Professional men who while leading active lives were not engaged in very active muscular work. They represent the mental rather than the physical worker. (2) A detail of men from the Hospital Corps of the United States Army, as repre- sentatives of the moderate worker. These men, of different ages and tem- peraments, took vigorous systematic exercise in addition to the routine work connected with their daily life as members of the hospital corps. (3) A group of university students who were thoroughly trained athletes, and some of them with exceptional records in athletic events. The records of these observations have already been published in Chitt(;n- den's Physiological Economy in Nutrition from which the data here pre- sented are taken. With reference to the general conduct of the experiments it should be emphasized that monotony of diet was avoided as far as possible, in due recognition of the psychical influences liable to affect secretion and digestion, and of the danger which continued exhibition of an unvaried diet may bring, in the lack or disproportion of certain inorganic elements in the course of a long period. The cooperation of a large number of subjects under different conditions of life and activity and with widely varying tastes must tend to exclude personal idiosyncrasies and thereby minimize the chance of misleading conclusions. The professional group exercised a free choice in the character and quantities of the foodstuffs consumed. For the soldiers a dietary was specially arranged, the char- acter and quantity of food for each meal being prescribed with due regard to the satisfaction of their desires. Preliminary observations were made on these men with a dietary such as they were accustomed to, in the form of the ordinary army ration which has a high content of proteid. The diet was then modified very gradually by the introduction of various articles in place of meat, until finally for months the heavier proteid foods were greatly reduced in amount and replaced in a measure by carbohydrate foods. While vegetable foods eventually predominated, there was at no time a complete change to a vegetable or vegetarian diet. The student athletes likewise lived on a prescribed diet, with somewhat greater range of choice. There were no restrictions as to quantity of food in their case. The method of observation consisted in a daily collection and meas- urement of urine and faeces. The nitrogen output in the urine was accu- rately determined throughout the experiment, extending from six to nine months or longer. At intervals the daily loss of nitrogen in the faeces was determined. Finally the balance between income and outgo of nitrogen was exactly ascertained several times for periods of about a week. The total intake of food in terms of heat units was approxi- mately estimated without direct measurement. The statistics on this point are therefore of subordinate value. It may be noted that the body weight of some of the individuals gradually fell until a certain stationary "level" was reached, about which small daily fluctuations were observed. This was true of all who had any considerable accumu- lation of reserve fat. In the well-trained men of slender or athletic build these initiatory changes in weight were not so apparent, if they occurred at all. One of the writers (C), of 57 kilos body weight, showed an aver- 728 NUTRITION age daily nitrogen output of 5.7 grams in the urine for nearly nine consec- utive months. Nitrogen oc[uilibrium and body weight were maintained. The other writer (M), with u body weight of 70 kilos, established from an original weight of 76 kilos, likewise maintained health, strength and equilibrium with an average daily output of G.5 grams of nitrogen in the urine. A third subject (U), of 05 kilos body weight, maintained health without increasing the total fuel value of the food, with an average daily output of about 7.5 grams of nitrogen for many months. These figures imply a daily proteid metabolism equivalent to about 0.1 gram of nitro- gen per kilo of body weight, or half of that which custom and habit prescribe. It should be said that these limits could only be reached with main- tenance of nitrogen equilibrium, provided the total food supply was adecjuate. Our estimates indicate that the latter, far from being exces- sive, tended to fall below the ordinarily accepted standard of 3,000 large calories for a man of average body weight and moderate work. The adaptation to the new standards was gradual in each case. The results obtained with the soldiers, living on a prescribed diet and exposed to the strain of military duties, together with gymnastic work and training, confirm the conclusions arrived at with the professional group from which some data are quoted above. Once accustomed to a more sparing proteid diet, less rich in nitrogen, these subjects had no difficulty in maintaining body weight on the food provided, and when the conditions were satisfactorily adjusted nitrogen equilibrium could readily be preserved. The members of the soldier detail were able to live for five consecutive months with a proteid metabolism corresponding to about 8 grams of nitrogen per day without discomfort or loss of vigor. The athletes, as well as the physically less active men, likewise met their ordinary requirements for several months on an average daily pro- teid intake of about 60 grams. Moreover, careful dynamometer and other tests, made at regular intervals on the soldiers and athletes, indicated an increase in muscular strength while the men were on the restricted diet. The summary on page 729 of a balance experiment lasting one week will illustrate the general character of the nitrogen results obtained in all of the experiments. The subject was a vigorous athlete of 63 kilos body weight. It is interesting to compare the previous dietetic habits of some of our subjects in respect to the proteid intake. During two weeks, at the be- ginning of the experiment on the soldiers when the ordinary army ration was used, the daily output of urinary nitrogen not infrequently exceeded 20 grams and usually reached over 16 grams (equivalent to 100 to 125 grams of proteid). The subsequent record of these subjects is given on page 729. We believe that these experiments demonstrate the possibilities of a physiological economy corresponding to a saving of considerable proteid food. Aside from its possible economic or sociological importance this may not be without physiological significance. The results are presented as a contribution to the solution of a serious problem. If the data ob- tained in these experiments, representing a proteid requirement 50 per cent, lower than the figures usually quoted as necessary to maintain strength and health, approach with any degree of accuracy to the true GENERAL CONSIDERATIONS OF METABOLISM 729 Nitrogen Balance. Nitrogen taken in. Grams. May 18 8.119 May 19 9.482 May 20 10.560 May 21 8.992 May 22 9.025 May 23 8.393 May 24 7.284 Nitrogen Output. 61.855 53.04 61.855 grams nitrogen. Nitrogen balance for seven days = Nitrogen balance per day = Average nitrogen intake per day = Weight of fseces (dry). Grams. is 89 24 128 — contain 6.40% N. 8 . 192 grams nitrogen. 61.232 grams nitrogen. + 0.623 gram. + 0.089 gram. 8.83 grams. minimal requirement of the men under observation, we believe that the physiological needs of the body can be served for an indefinite period on a greatly lessened proteid metabolism. The fact that the greater part of the nitrogen contained in an ordinary diet, including 120 to 150 grams of proteid per day, is speedily eliminated lends favor to the view that it can satisfactorily be replaced by other foodstuffs. As Folin has said: "Nitrogen enough to provide liberally for the endogenous metab- olism and for the maintenance of a sufficient supply of reserve protein Name. Body weight. October, 1903. Body weight. April, 1904. Average daily urinary nitrogen. November-April. Metabolized nitrogen, per kilo of body weight.* Kilos. Kilos. Grams. Gram. Fritz 76.0 72.6 7.84 0.106 Oakman. . . 66.7 62.1 7.42 0.116 Morris 59.2 59.0 7.03 0.119 Broyles . . . 59.4 61.0 7.26 0.120 Henderson 71.3 71.0 8.91 0.125 Loewenthal 60.1 59.0 7.38 0.125 Cohn 65.0 62.6 8.05 0.126 Steltz 52.3 53.0 7.13 0.134 Sliney 61.3 60.6 8.39 0.138 Coffman . . . 59.1 58.0 8.17 0.140 Zooman . . . 54.0 55.0 8.25 0.150 * In this calculation the figures used for body weight are those of April, or where there is much difference the average of the October and April weights is used. 730 NUTRITION is shown to be nccessarv. But it ouglit noithor to be necessary nor advan- tageous for the organism to split oii' and remove hirgo quantities of nitrogen which it can neitiier use nor store up as reserve material." In considering the possible physiological advantages of some reduction in the proteid element of the standard diet, it will be recalled that many of the disorders of metabolism involve the imperfect katabolism of pro- teid, so that nitrogenous derivatives other than urea arc liable to arise. Lowered proteid intake, especially diminished meat consumption, means a decreased metabolism of the purins. This is illustrated in the obser- vations made in our dietary studies from which the following table is taken : AvKu.vciK Daily Ex(m{etion Throxtgh the Urine for Seven to Nine Months. PltOFESSIONAI. GrOTTP. Name. Body weight. Total nitrogen. Uric aoid. Uric acid per kilo of body weight. I'liosplioric acid I'jOr, Cliittenden.. . . Mendel Underliill Kilos. 57.0 70.0 05.0 05.0 01. 5 Grams. 5.09 0. 53 7.43 8.99 8.58 Gram. 0.392 0.419 0.51G 0. 380 0.305 Gram. 0.0008 0.0000 0. 0079 0,0059 0. 0059 Grams. 0.90 1.40 1.28 1.73 1.49 The diet in these cases was very deficient in purin compounds as a rule. But even among the other groups where meat was more freely eaten, although in small amounts, the daily output of uric acid rarely exceeded 500 milligrams. It is difficult to see anything other than an advantage in a diminished production of intermediary products of proteid disinte- gration — for example, amino-acids and uric acid — under conditions where they are not properly converted into their appropriate end-products. This involves no assumption of any harmfulness of the excess of ordinary nitrogenous excretives in health. In disease, however, many conditions suggest themselves in which the clinician may do well to consider the therapeutic value of the possibilities involved in the foregoing discussion. This applies particularly to disorders in w-hich the organs of proteid digestion (gastro-intestinal tract), metabolism (liver), and nitrogenous elimination (kidneys), are concerned. Furthermore, there is no lack of evidence that temporary proteid starvation is ordinarily not attended with any immediate deleterious effects, owing to a considerable proteid reserve in the body; so that the physician meeting with circumstances of disease complicated by the difficulties of the "mechanics" of nutrition, for example, may readily exchange the minimum temporary damage or loss occasioned by endogenous proteid katabolism in the absence of food, for permanent therapeutic gains. If we pass to the data available regarding the total food demand of the body, expressed in terms of energy katabolized daily, statistics of actual food consumption show a fairly wdde range between 1,500 and 4,000 large calories. These differences are conditioned in part by differ- ences in the individuals studied, as well as by the variable demand created by unlike degrees of bodily activity. More exact information GENERAL CONSIDERATIONS OE METABOLISM 731 may be expected from the increasing number of calorimetric observa- tions made directly on man. In general the latter show a utilization of about 30 large calories per kilo of body weight during rest and fasting, increasing somewhat when food is administered, and rising to over twice this amount when muscular work is done. In cases of extreme exertion during many hours of the day, the transformation of energy may increase to 130 large calories per kilo of body weight. Calculated for a man of 70 kilos, the figures range from 2,100 to 9,000 large calories, the latter representing an extreme, yet not unreached, figure. To what extent the more usual average metabolism of 3,000 calories per day represents the actual needs of the body of a 70 kilo man during moderate work cannot be conclusively determined at the present time. From such observations as we have been able to gather in our experiments of lowered proteid diet, we are inclined to the view that the customary standards for the total energy demands represent a high rather than a low limit; for such approximate valuations as we were able to give to the diets used in these experiments, and which are here mentioned with due reserva- tion in view of the lack of direct fuel value determinations, indicated a metabolism of energy not greatly, if at all, exceeding 40 calories* per kilo of body weight. Among the better classes, the nutritive demands are certainly more than satisfied by the customary dietaries. Whether man can five on different nutritive planes, as various physiologists have suggested, re- mains to be seen. Any complete answer to such a question must, of course, take into consideration many factors more general in application than is indicated by bodily equilibrium alone. Mental as well as bodily efficiency, health and vigor must remain unimpaired. Much has been written about the relation of diet to the development and characteristics of races; a review of the literature soon convinces one, however, that it is impossible to form an unprejudiced judgment from the conflicting data, or unconfirmed opinions. Scientific observation has not yet re- placed personal impressions to a sufficient degree in the study of this interesting question. Muscular activity increases the demand for nutriment; but whether it increases the need for proteid seems very doubtful. The final answer will depend upon a determination of endogenous proteid metabolism during work, measurable perhaps by the output of creatinin. It is not unlikely that the wear and tear of the contractile tissues will be found somewhat increased by maintained activity. With a surplus of proteid in the diet, however, this does not make itself manifest in any study of total nitrogen exchange. As a rule we eat to satisfy the demands of the appetite without considering the true physiological needs of the body, or whether the appetite is in any degree proportioned to these. Perhaps the unwitting use of an excessive diet is occasioned by the modern culinary methods which make food palatable and attractive; and the danger in this direction applies more particularly to inactive, well-to-do persons than to the poorer working classes with a larger nutritive demand. As to the relative participation of fats and carbohydrates in the satis- faction of the food requirements, it is well to recall the comparative food value of each. One hundred parts of fat are isodynamic with 230 parts of a carbohydrate, like starch. Each of these non-nitrogenous 732 NUTRITION nutrients is well utilized and the combinations are likewise rendered available in large degree. An excess of fat in the diet is liable to diminish the utilization of carbohydrate in the same ration. This doubtless ex- plains the apparent failure of the widely advertised oatmeal diet in dia- betes to cause sugar excretion. Very large quantities of fat (300 grams of butter or more) are prescribed with the oatmeal. The absorption of the latter is thereby doubtless greatly impaired and diminution of the glycosuria is attributal)le nut to a better utilization of oat carbohydrates, but presumably to the imperfect absorption of the carbohydrate, which precludes its reappearance as diabetic sugar. On the other hand, an excess of carbohydrate in the intestine, especially in the form of coarse vegetable food, may become a severe burden to the alimentary tract. The extent to which fats and carbohydrates replace each other is, we believe, largely a matter of convenience, cost and individual taste. In general, fats are expensive and accordingly are allowed to furnish the smaller part of the energy. Zuntz and Schumburg have lately advocated a considerable increase in the fat foods of the German army ration, call- ing attention to the large food value of fats and their ready assimilation without much digestive work. They likewise suggest increased employ- ment of sugar, the refreshing influence of which on the fatigued muscles has lately been announced. If it is remembered that one gram of fat is equivalent to 14 grams of milk, 9.8 grams of meat, 9.3 grams of potato, 30 to 40 grams of vegetables, it will be understood that fats may become a valuable adjuvant to the diet whenever a decrease in its bulk becomes desirable. Dietetic habits are frequently of moment in this connection. Individuals accustomed to concentrated diets may find a voluminous ration unattractive and even unendurable. In contrast with this, others find no satisfaction in any diet, however palatable or nutritive, unless it is sufficiently bulky. Only in this way can the feeling of hunger be dispelled. To thes/i creations of habit must be added certain idiosyncrasies which exL>bit themselves in an intolerance for certain substances. In many cases these are immediately attributable to digestive disturbances or other recognizable disease. Not infrequently they are of a more subtle character. We see an illustration in the appearance of urticaria in other- wise healthy persons after eating shell-fish, strawberries, etc., indicating a susceptibility to minute quantities of chemical substances insufficient to affect the average individual in a perceptible manner. Preparation of Food. — ^The preparation of food plays by no means a negligible part in its subsequent fate in nutrition and may contribute both to its digestibility and its palatability. The appearance, flavor, and odor, stimulate or modify the activity of the digestive glands through various channels, as has been shown so strikingly by Pawlow and his pupils. Food which is repulsive fails to provoke the proper digestive response, or at any rate calls it forth more slowly than an attractive meal does. Man has been called a "cooking" animal, and the practice of sub- jecting foods to heat is well nigh universal. The rationale of the various ways of treating foods by means of heat is too little understood. In many cases it softens the foodstufi's and transforms their texture. The connective tissue fibers of meats are converted into gelatin by boiUng, GENERAL CONSIDERATIONS OF METABOLISM 733 so that they dissolve more readily and allow the digestive juices to act more directly upon the muscular fibers themselves. This change like- wise facilitates the processes of mastication. Similarly, cooking changes the tough, firm make-up of many of the vegetables into soft and easily masticated tissue. In developing thereby a more pronounced flavor and odor, other factors of value are added. In vegetable foods the starch grains are ruptured and liberated in considerable proportion from the indigestible envelopes of cellulose which surround them. Further, the changes which starchy foods, like the cereals, undergo by dry heat are of value from the standpoint of lending flavor rather than because of any profound chemical changes effected. In the case of the legumes, peas, beans, etc., we have a good illustration of the importance of cook- ing for the proper utilization of such food materials. Finally, heat destroys many toxic substances or organisms present in micooked foods and thus protects the body from dangers lurking therein. A variety of substances classed as "food accessories" exert an influence quite independent of any direct nutritive value. Some, like the extractive substances of meat, etc., are not entirely devoid of fuel value; others, like some of the inorganic salts, are indispensable, despite the fact that they convey no energy to the organism; while another class still, includ- ing ordinary condiments such as pepper, mustard, and other spices, exert an indirect influence on nutrition. The latter class includes sub- stances which act directly upon sense organs exciting the sense of taste and thus inducing a reflex flow of the digestive secretions. In so far as they stimulate the appetite, they may create favorable conditions for incipient alimentary changes by the indirect effect upon the secretory glands concerned therein. Pawlow has said : "Appetit ist Saft. " The psychical effect of various factors in promoting, or — what is less famil- iarly recognized — in inhibiting indirectly the nutritive processes, is for the most part underestimated; for foodstuffs are not selected, in the ordinary course of events, with any due recognition of their real nutri- tive value, but rather in virtue of their palatability and the appeal which they make to the senses. Again, the group of substances represented by the extractives of meat as they are obtained in soups, etc., plays a part in stimulating the secretory glands. They are rapidly absorbed be- fore the foodstuffs proper are digested, and in the blood-stream they act directly as secretory stimulants, inducing a flow of gastric juice. The question as to the effect of such substances upon the intermediate pro- cesses of metabolism has not yet received the consideration which it merits. Heretofore they have usually been studied from the standpoint of their pharmacological action. Yet taking alcohol as an illustration, the more distinctly physiological aspects seem worthy of attention. Ob- servations in our laboratory have shown that it may noticeably alter the output of exogenous uric acid in man; and if other katabolic processes in the organism are similarly affected, the subsidiary changes induced in intermediary metabolism by such food accessories as alcohol may quite overshadow the influence which they exert in the preliminary digestive changes. It is impossible to say in what degree the demand for these accessories has been acquired by man; this much is e^ddent, that in all culture lands the advance of civilization has been attended by increasing attention to the factors here discussed. Whether these subsidiary articles 734 NUTRITION of diet, Including meat extractives, tea, coft'ee, cliocolate, alcohol, etc., ■which arc for the most part sources of little or no energy and not ])os- sessed of reparative power for the tissues of the body, are as necessary to us as the foodstuffs themselves is difficult to say. Common experience confirms their agreeable influence. The inorganic salts, mineral nutrients or inorganic foodstuffs, are es- sential owing to the' fact that a lack of them must inevitably lead to physi- ological difficulties as a result of their continued loss in the excretions. The conservative efforts of the body are frequently displayed in the marked retention of some of these elements; for example, of chlorine in fevers. But unless restitution is made the defect inevitably mani- fests itself sooner or later. From the quantitative point of view the demand for chlorine and sodium (sodium chloride) is most cons])icuous, and the search for this salt appears to be almost instinctive in both man and animals. The pathological symptoms Avhich lack of some of these elements, such as iron and calcium, develops, is familiar. Occasionally the difficulty presented apparently involves a deficient absorption or re- tention of the compounds. AVe are inclined to believe that an increasing familiarity with the distribution of inorganic salts and their elements in the natural foods will tend to lead to a substitution of dietetic methods of administration of these substances, in place of the therapeutic meas- ures (artificial lime salts, iron salts, etc.) now employed so extensively. A radical change in diet will call for some consideration of the new adap- tation of the inorganic foodstuffs accompanying it. Especially is this true for the growing organism. When the salts required by the latter are accurately known, a change from milk to some other form of diet may properly suggest the question whether the child will continue to obtain the necessary salts in sufficient quantities. Similar considerations apply to the convalescent period in invalids. The following table (from Bunge) indicates the range of variation in the constituents of the ash of the most important articles of diet, arranged according to the content of Ume. One Hundred Parts of Dried Substance Contain. CI Beef Wheat Potato Egg-white. . . Peas Human milk Yolk of egg. Cow's milk. . KoO Na.O CaO MgO Fe.Os P.Os l.CG 0.32 0.029 0.152 0.020 1.83 0.02 O.OG 0. 065 0.24 0.026 0.94 2.28 0.11 0.100 0. 19 0.042 0.04 1.44 1.45 0. 130 0.13 0.02G 0.20 1.13 0.03 0. 137 0.22 024 0.99 0. 58 0.17 0. 243 0.05 0.003 0. 35 0.27 0.17 0. 380 0.00 0.040 1.90 1.C7 1.05 1.51 0.20 0.003 l.SO 0.28 (?) 0.13 1.32 (?) 0.32 0.35 1.60 The marked differences in the distribution of important elements among these familiar dietetic articles is clearly shown. Thus, the poverty of cow's milk in iron and the relative abundance of lime are conspicuous. The total quantity of mineral ingredients included in the ordinary diet of the adult and their distribution has been compiled by Gautier, as shown in the table on page 735. To the 17.43 grams of inorganic substances here accounted for, should be added 7 or 8 grams of common salt which are daily contributed directly to the food, making a total of 25 grams of inorganic compounds. It is GENERAL CONSIDERATIONS OF METABOLISM 735 estimated that we excrete somewhat more than this ({uantity by tlie various channels of eUmination. The shght gain is attributable to the sulphuric and phosphoric acids derived from the oxidation of organic compounds of sulphur and phosphorus ingested. It will also be noted Inouganic Salts in an Aveijage Day's Ration. Food. Bread and pastry Meats Milk Eggs Fresh fruits Fresh vegetables. Dried vegetables. Potatoes Cheese Sugar. Butter Wine Drinking-water. . Total Weight. Inorganic Salts. Grams. Grams. 435 3.15 266 3.40 150 1.05 30 0.03 90 0.45 200 4.15 40 1.20 100 1.20 12 0.80 40 0.00 28 0.00 650 1.65 1,000 0.35 17.43 in the preceding table that the preponderance of the ingested inorganic compounds is associated with foods of vegetable origin; this applies in particular to specific elements: Potassium, magnesium and phos- phates. Composition of Foods in Their Relation to Nutrition.— Broadly speaking, it is customary to refer to the nutritive value of the various foods in daily use on the basis of their general composition ; that is to say, the content of nitrogen or protein (N X 6.25), fats (ether extract), non-nitrogenous constituents (digestible carbohydrates and insoluble cellulose), inorganic components and their heat of combustion. In dis- cussing proteid metabohsm it has already been pointed out that the nitrogenous compounds are by no means equivalent or identical in their physiological role, and the peculiar position of the purin-containing foods was emphasized. Up to the present time, relatively few data have been obtained with respect to the purin-content of foods in common use. The great divergence in the distribution of purin derivatives is made manifest in the figures compiled by Walker Hall, as shown in the table on page 736. From this summary it is easy to arrange a dietary practically free from purin-containing foods and yet adapted to physiological require- ments. For this diet cereals, milk, butter, eggs, certain green vegetables, sugars, etc., form the basis; and the output of urinary purins soon falls to the endogenous level thereon. In illustration of this we quote from Rockwood a diet experiment in which two subjects subsisted for nearly two weeks on a ration consisting of milk, 1,350 cc; prepared cereal, 35 grams; sugar, 20 grams; crackers, 250 grams; cheese, 30 grams; eggs, 96 grams; apples, 90 grams; wheat bread, 50 grams; butter, 15 736 NUTRITION PuRiN Content of Common Foods. Food. Fish: Cod... Plaice. Halibut Salmon Meats : Tripe Mutton Veal Pork Beef, ribs. . . Beefsteak . . . Liver Sweetbread. . Chicken Cereals: Bread, white Rice Oatmeal. . . . Vegetables: Pea meal. . . . Beans Potatoes .... Onions Cabbage. . . . Lettuce Asparagus . . . Beers Wines Milk Average percentage Purin bodies of purin nitrogen. (ii-rams per kilo). 0.023 0.582 0.032 0.795 0.041 1.020 0.046 1.165 0.023 0.582 0.038 0.965 0.046 1 . 162 0.048 1.212 0.045 1.137 0.083 2.066 0.110 2.752 0.402 10 . 063 0.051 1.295 none none 0.021 6.530 0.015 0.390 0.025 0.637 trace trace 0.003 0.090 none none 0.009 0.215 0.005 0.125 none minute trace minute trace grams; confectionery, 100 grams; during this period the average daily outputs of nitrogen and uric acid in the urine were respectively: A. B. Nitrogen 11 . 580 grams 11 . 390 grams Uric acid . 305 grams . 340 grams The widespread and increasing use of cereal preparations of all sorts, which has come into vogue in recent years, may make it worth while to consider briefly to what extent some of the claims advanced have justi- fication in truth. A comparison of animal foods with those of vegetable origin as sources of proteid and energy is afforded by the following figures (Milner) : Proteid, Energy per gram, per cent. calories (large). Oat preparations 16 . 1 4 . 423 Wheat preparations 12.1 4 . 032 Corn preparations 8.6 3.894 Rice preparations 8.3 3.907 Beef, lean round 19.5 1 . 795 Beef, fat round 16 . 1 3 . 104 Bread, white 9.2 2 . 885 Bread, graham 8.9 2.872 Cheese, full cream 25.9 4.674 Potatoes 2.2 0.892 GENERAL CONSIDERATIONS OF METABOLISM 737 Milner has summarized the essential features with respect to modem cereal preparations, especially the ready-to-eat products, "breakfast foods," etc., in these words: "The difference between the various cereal preparations is principally one of process of manufacture. Some con- tain the whole of the grain, whereas with others the bran and germ have been removed in their preparation. Some are entirely uncooked, some are partially cooked, and some are wholly cooked and ready to eat as purchased. Among the latter are the so-called 'predigested' or 'malted' preparations. "The composition of the different products depends upon that of the grain from which they are made, and the extent to which the bran and germ have been removed in the manufacture. In general, the pre- pared product from any grain has much the same composition as that of flour or meal from the same grain. Different brands of similar nature when made from the same grain do not differ in average composition any more widely than different lots of the same brand. "Different prepared products from the same grain show no marked differences in respect to the amounts of nutrients that may be actually digested. The differences in actual nutritive value of the products from the same grain are therefore on the average so small that they may be disregarded in choosing between them. However, the oat preparations contain noticeably larger proportions of nutrients and energy than those of other grains, and as they are when properly cooked no less thoroughly digested the actual nutritive value of the oat preparations appears to be greater than that of the preparations from other grains. "The nutritive value of the 'malted' or so-called 'predigested' prepara- tions is no greater than that of other preparations from the same grains. In some instances the attempts to convert insoluble starch into more soluble material by the use of malt have been to a small degree success- ful, and to that extent the preparations have been rendered more easily digestible; but just as much and even more is accomplished by thorough cooking. In most of the malted preparations the quantity of starch actually converted is, however, very small and in some cases none has been changed. "The thoroughness of cooking has quite as much influence upon the actual food value of the preparations as the small differences in com- position. If the cereals are not thoroughly cooked some of the nutritive material will escape the action of the digestive juices." Practical dietetics has long had to contend with a conflict of opinions regarding the true nutritive value of many familiar food materials. The errors are associated with exaggerated or incorrect ideas regarding the food value of specific dietary articles; and a prejudice against food materials of certain origin has been fostered in the absence of accurate scientific testimony. These statements apply to the medical profession as well as to the laity, who cannot always be expected to arrive at sound deductions on the problems of nutrition. Current notions regarding the relative value of different kinds of bread furnish an illustration of what has been said here. Wheat or rye flour is used most extensively, though some kinds of bread are prepared from barley or maize. The oat, on the other hand, will not yield a light porous bread. Further differences 47 738 NUTRITION are brought about by the choice of leavening agent used in preparing the dough. In the manufacture of the commonly used "patent" wheat flour by the modern process of milling, the bran and aleurone layers, together Vsiih the germ, are removed by preliminary treatment and the remainder of the kernel is then ground. The bran, if included, would make the flour coarse; and the germ is removed because it contains oil, which acts upon the other constituents of the flour so that the bread in baking is darkened in color. The portions removed by the {)rocesses of refining are characterized especially by their richness in nitrogenous materials and inorganic salts. There has been much controversy regarding the nutritive value of the bran; and it has been claimed that valuable parts of the wheat are left in the waste cortical portions. To avoid this loss Graham flour is prepared by grinding the whole of the wheat kernel; and since no bolting or sorting process is introduced the product is in reality a wheat meal. As an intermediate product between the coarse Graham flour and the finest products, the so-called "whole wheat" or "entire wheat" flour has arisen. In this the attempt is made, with varying success, to remove only the woody part of the bran, leaving the aleurone layer and the germ with their nitrogenous and other ingredients and removing the irritating parts of the bran. Experimental observations now recorded in large numbers indicate how unreliable chemical analysis alone may be in determining the rela- tive nutritive value of the different grades of bread made from many kinds of flour. Actual trials on man show that wheat bread is more completely utilized than rye bread. Bread prepared from wheat flour is absorbed from the alimentary tract in larger or smaller amount ac- cording to the fineness of the flour used, the finest behaving most favor- ably in this respect. In cases where the flour is prepared from the whole grain there is always a considerably larger residue of unutilized food. The determining features are undoubtedly found in the varying physical peculiarities of the types of bread produced. That from fine wheat flour is far more porous than what is made from whole or crushed grains, and is thus more readily exposed to the digestive changes. Judging from the relatively large residuum of undigested material left after ingestion of the coarser kinds of bread, especially those containing considerable bran, the compounds included therein are protected from the digestive juices by their environment of cellulose and other indigestible substance and thus fail to contribute the food value which their composition alone dis- closes. From digestion trials with breads Woods and Merrill conclude that "in general, the digestibility of the ration, whether simply bread and milk with a little butter and sugar, or a more varied diet, was de- creased when the change was made from white bread to entire-wheat bread, and still further decreased when either was replaced by Graham bread, the remainder of the diet being, of course, the same in all three cases. The differences are sufficient to indicate that, even though the Graham flour contains the most and the white flour the least total pro- tein of the three, the body would obtain more protein and energy from a pound of entire wheat than from a pound of Graham flour and still more from a poimd of white flour than from either of the others. On GENERAL CONSIDERATIONS OF METABOLISM 739 the other hand, it does not follow that a larger amount of digestible nu- trients or available energy may not be obtained from 100 pounds of wheat when milled as Graham flour or entire-wheat flour than when ground into patent flour, because 100 pounds of cleaned and screened wheat will yield 100 pounds of Graham flour, about 85 pounds of entire-wheat flour, and only a little over 72 pounds of standard patent flour. This, however, is a question of pecuniary economy." They give as the amount of unabsorbable nitrogen for fine wheat bread, from 10 to 13 per cent.; for whole-wheat bread about 13 per cent.; and for Graham bread 23 to 24 per cent, of the food nitrogen. On purely physiological grounds there is no justification for the exten- sive consumption of the coarser forms of bread among the masses of America and Europe. To many persons the taste of the coarse grades of bread is very agreeable. The bran is undoubtedly utilized to a small extent; but the justification for the therapeutic use of coarse breads is referable almost entirely to the more vigorous intestinal movements which they induce by virtue of a greater proportion of indigestible materials acting as irritants. Experience accumulated in comparing the availability of proteids ob- tained from vegetable sources with those furnished by animal tissues has led to the inquiry whether these different types of proteids exhibit inherent differences in real digestibility. Not a few writers have assumed this to be the case. But observations made in our own laboratory, as well as by others, give no support to this view. Oat proteid, for exaihple, isolated and purified was found no less readily utilized than that from lean meat or milk; and this corresponds with similar experience with other vegetable proteids. When, however, they are still mixed with the materials naturally associated with them, vegetable proteids are not ordinarily utilized to the same extent as those of animal origin. In distinction from cereals and legumes, "vegetables," such as cab- bage, beets, etc., are of little value as sources of proteid or fat, although the carbohydrates which they contain appear to be quite well digested and absorbed. Bryant and Milner conclude from their studies that "the chief value of many vegetables, however, is perhaps aside from the nu- trients or energy they furnish; they add a pleasing variety and palatabil- ity to the diet, supply organic acids and mineral salts, and give the food a bulkiness that seems to be of importance in its mechanical action in maintaining a healthy activity of the alimentary tract. Possibly the result of these conditions is a favorable influence upon the digestion of other food eaten with the vegetable; at least such an effect was suggested by the results of some of the experiments. For instance, in the studies with potatoes and with apple sauce added to the basal ration the digestibility of the total ration including such material was noticeably higher than that of the basal ration alone." Some of the fallacies frequently met with regarding these vegetable products are well illustrated in certain popular prejudices with respect to mushrooms, or edible fungi. They are generally regarded as con- stituting a very nutritious and sustaining diet; and this supposition has given rise to the extravagant statement that "a hearty meal on mush- rooms alone would be about as reasonable as a dinner on nothing but beefsteak and might be expected to be followed by similar ill conse- 740 NUTRITION quences." Studies made in our laboratory, however, have indicated that the expression "vegetable beefsteak" is scarcely aj^propriate when applied to mushrooms in a strictly chemical sense. These fungi form no exception to the ordinary classes of fresh vegetable foods; indeed, they take a decidedly inferior rank in comparison with many. As dietetic accessories they may play an important part; but they cannot be ranked with the essential foods. In this connection we may note the variable content of cellulose in some of the common articles of diet. Cellulose Content of Common Vegetable Foods (Lohrisch). Per cent. Spinach, as served . 36 Head lettuce, uncooked 0.48 Kohlrabi, uncooked . 73 Carrots, uncooked 0.74 Cabbage, uncooked 0.79 Cucumber, as served 0.11 Potato, dried 1 . 22 Potato, boiled 0.25 Potato, raw 0.21 Lentils, uncooked 3 . 39 Oatmeal, dry 0.24 Rye bread 0.15 Graham bread . 94 Rademann's cellulose bread, dried 3.24 Cacao powder, dry 2 . 29 Agar-agar, dry . 62 Systems of Diet. — From early times various systems of diet and die- tetic cures have found favor and received vigorous advocacy from approv- ing followers. Most familiar is vegetarianism, a system of living which teaches that the food of man should be derived directly from the plant world. Considered in the light of its history, however, vegetarianism involves something more than a mere dietetic program. It teaches that the use of animal foods is morally wrong as well as erroneous with respect to the processes of nutrition. But in view of the widespread advocacy of this exclusive regime, it may be worth while to consider the physio- logical aspects which the system presents. At the outset, it should be noted that a diversity of views has entered into the so-called vegetarian doctrines. The most radical reformers have abstained not alone from all food of animal origin but also from tubers and underground roots, eating only vegetables and fruits grown in the sunlight; others again reject cereals and live on fruits, nuts, and milk; while the most conser- vative exclude only fish, flesh, and fowl from their diet. Among the latter groups may be arranged the so-called fruitarians, who abstain from all food obtained by infliction of pain. Among the more strictly scientific arguments advanced against the use of animal foods are those relating to the dangers of disease lurking in them. This applies chiefiy to the flesh of animals; such foods as eggs, milk, and butter, all derived from animals, are not ordi'^arily excluded from the modern vegetarian dietary, but rather contnoute thereto in considerable measure. It must be admitted that meat may be the carrier of harmful organisms, ptomaines, etc.; but this fact affords no funda- GENERAL CONSIDERATIONS OF METABOLISM 741 mental source of objection to animal foods, since the dangers here alluded to are avoidable, and vegetable foods themselves are by no means free from similar objections. The high content of "extractive" substances — creatin, purin bodies, inorganic salts — in meat is also referred to as an undesirable feature of any ordinary animal diet. We have seen that these play a pecuUar role in metabolism, failing in part to yield any energy to the organism, and again becoming partially oxidized to compounds like uric acid, which may have a significance in certain pathological conditions. On the basis of the facts now available, no serious objections against the small quantities of the meat bases daily ingested in an average dietary can be formulated for the healthy individual. A])parently they belong to the same category as many other food accessories such as tea, coffee, and alcohol, and are open to similar criticism. The supposed influence of meat extract in increasing the nutritive value of vegetable foods has not been substantiated. The substances which lend peculiar character to meat act in the same stimulating and refreshing manner that tea and coffee undoubtedly do, and from this standpoint must be looked upon merely as pleasant adjuncts to the food. Bunge writes: "That some or- ganic constituent of meat-extract may produce an effect on the muscular or nervous system must be admitted to be remotely possible; at pres- ent it is in no way proved. We know, with regard to bouillon, abso- lutely no more than that it tastes and smells agreeably. This fact, however, suffices to explain all the 'enlivening' and 'strengthening' virtues which common experience attributes to extract of meat and bouillon, and to recommend them as valuable and pleasant accessories of our food." We are inclined to believe that rational objections against a meat diet are applicable with respect to quantitative aspects rather than to the chemical make-up of such dietaries. In other words, it is the abuse of meat in modern dietaries which should be charged with any dangers attaching to the employment of this animal food; and the disadvantages of an excessive proteid diet apply with far less force to vegetarian re- gimes, owing to the proportionate nitrogen deficiency of the ordinary foods included in them. An appeal to the characteristics of races or peoples accustomed to fixed types of diet is frequently made in support of the superiority or undesirability of different nutritive habits. Mental and physical pecu- liarities of classes living largely on rice or other cereals are contrasted with those of fish- and flesh-devouring tribes. It is widely believed that meat eating tends to develop a degree of aggressiveness and related traits of character, in distinction from the more pacific features of those nations accustomed to the extensive use of cereals in place of meats. This seems somewhat exaggerated; and to us it appears doubtful if temperaments or physical stamina are so directly controlled by dietetic habits. It is questionable, for example, whether Gautier is justified in contending that by depriving him of meat it is easier to debilitate an EngHshman or a Dutchman than a Spaniard or Itahan. The diverse dietetic customs of individuals and races have become established pri- marily by virtue of their pecuHar environments, and the physiological features have developed only in a secondary way. In the case of carniv- orous animals, the very traits which are referred to the flesh diet are 742 NUTRITION necessarily established in animals which must gain their food by preying upon others. Analogy may be most misleading in science. A final argument in supj)ort of the vegetarian diet is based upon the supposed structural adaptation of the alimentary canal to such a regime. In reply it may be pointed out that a mixed diet is admirably utilized in man in the light of experimental e^^dence, There are no convincing physiological or anatomical grounds for recommending an exclusive diet of either animal or vegetable origin. The disadvantages attaching to the exclusive use of foodstuffs offering a large content of indigestible and unutilizable residues in the gastro-intcstinal tract has frequently been urged against the vegetarian. Fruits and vegetables are extremely bulky in proportion to the available nutrients in them, and may entail considerable alimentary waste. In fairness, a sharp distinction must be drawn between vegetable diet and vegetarian diet; and with progress in the processes of commercial food preparation many improvements in adapting plant products for dietetic uses have been introduced. The palatability and nutritive value of cereals and nuts in particular have been enhanced by technical processes, so that many of the newer food products promise to compete actively for popular favor with animal foods. If we attempt to separate fact from fancy in an estimate of the nutri- tive significance and possibilities of vegetarian diet, there can be no question regarding the actual possibility of sustaining life with foods drawn exclusively from plant sources. Careful studies of the metabolism of indi\dduals living largely or entirely on such dietaries are available in sufficient numbers to demonstrate with scientific accuracy what famil- iar observations have long indicated. Nor can there be any question as to the possibility of sustained and vigorous muscular exertion by per- sons accustomed to a vegetarian regime. This is no more than might be expected, since it has been demonstrated that the essential source of energy liberated in muscular work is to be found in non-nitrogenous foods, the preponderance of which specially characterizes the vegetarian diet. There is, however, no evidence that the vegetarian utilizes his food better or works more economically. Wliere advantage accrues it is referable in greatest measure to the moderation in diet which the so- called vegetarian regime tends to encourage. The appetite is stimulated to a lesser degree than by meats and meat products, and this fact taken in conjunction with the usual more bulky character of vegetable foods diminishes greatly the tendency toward overeating. The practice of temperance in matters of diet may be facilitated by the introduction of vegetarian methods, thus contributing therapeutic possibilities applicable in the treatment of metabolic disorders related to overnutrition or similar perversions — gout, plethora, obesity, etc. There are idiosyncrasies in which vegetable as well as animal foods meet with difficulties in the way of practical use. One is inclined to emphasize the desirability of using common sense in the application of dietetic rules, remembering that man is well adapted by nature and experience to subsist on a variety of foods. On matters of diet every man should be a law unto himself, using judg- ment and knowledge to the best of his ability, reinforced by his own per- sonal experiences. Vegetarianism may have its virtues, as too great indulgence in flesh foods may have its serious side; but there would seem GENERAL CONSIDERATIONS OF METABOLISM 743 to be no sound physiological reason for the complete exclusion of any one class of foodstuffs, under ordinary conditions of life. Diet "Fads" and "Cures." — Aside from the l^roader systems of diet already considered and many dietetic "fads" which have been exploited in a popular way, a goodly number of diet-cures, involving either exten- sive use or omission of certain types of food materials, have received the advocacy of the medical profession at times and thus found their way into the literature of nutrition. In illustration of some of the types here referred to, we quote actual dietaries which amply represent the characteristic features. Dietary of a Fruitarian. — ^The subject was a man aged sixty-three years, weighing 124 pounds. He had lived upon a fruitarian diet for up- ward of twenty years, and, while he had at times used cooked vegetables and cereals, he believed that a diet of ripe and sweet fruits with nuts agreed with him best. During the experimental period of twenty days the subject walked from 4 to 8 miles a day, besides working a little at gardening. His average daily food intake, consisting almost exclusively of fresh fruits and nuts, contained proteids, 40 grams; fat, 54 grams; starch, sugar, etc., 286 grams; crude fiber, 25 grams; with a total fuel value of 1,700 large calories. The articles of diet used were cottage cheese, honey, apples, bananas, cantaloupe, four varieties of grapes, scarlet haws, pears, pomegranates, persimmons, oranges, straw- berries, watermelon, dried figs, olive oil, almonds, and peanut butter. Though the data fall far below the tentative dietary standards, the individual was apparently able to satisfy his nutritive demands (Jaffa). Dietary of a Vegetarian. — I. The subject, accustomed to only light exercise, was a healthy man, aged thirty-eight years, weighing 61 kilos, who was under observation in our laboratory for many months, during which he abstained from meat, fish, and eggs. His average daily output of nitrogen in the urine was 8.5 grams. A typical day's ration, selected from a period in which he was actually in nitrogen equilibrium, is the following: Breakfast. — Oatmeal, 237 grams; butter, 10 grams; sugar, 35 grams; milk, 60 grams; coffee, 210 grams. Lunch. — Macaroni, 142 grams; cheese, 10 grams; bread, 71 grams; sweet potatoes, 119 grams; milk, 250 grams. Dinner. — Bread, 80 grams; butter, 20 grams; mashed potato, 176 grams; string beans, 77 grams; apple pie, 82 grams; milk, 250 grams. Total nitrogen in the food 10 .0 grams. Total nitrogen in the urine 8.5 grams. The estimated fuel value of food was over 2,000 calories. II. Another individual of medium stature, observed by Caspari and Glaessner, after he had been accustomed to a diet entirely composed of plant products for many years, maintained nutritive equilibrium upon rations like the following: 744 NUTRITION Nitrogen, Fat, Fuel value, grams. grams. calories. 20 grams, coffee . 34 82 46 grams, sugar 182 330 grams, dates 1 . 49 927 113 grams, nuts 3.09 64.9 782 154 grams, oil 154.0 1,457 1,005 grams, potatoes 3.02 988 30 grams, carrots . 33 .... 136 Total 8.27 218.9 4,554 This case is of interest in view of the extensive introduction of fat into the dietary and the complete exchision of butter, milk, cheese, or eggs. The food utilization was not as good as in case of subject I, living almost entirely on cooked, rather than raw products. Dietary in "Proteid-Fat" Cures. — The chmination of carbohydrates from the dietary, with substitution of fats and proteids, has been recom- mended by clinicians for the dietetic treatment of certain maladies, prin- cipally diabetes and obesity. Without discussing here the disadvantages of such a selection as is usually made, with its preponderance of meat, we quote a typical recommendation by F. A. Hoffman: Morning. — Milk, 200 grams; cream, 50 grams; two eggs; butter; meat, 100 grams. Noon. — Meat, 200 grams; with peas or green vegetables. Afternoon. — Milk, 200 grams; cream, 50 grams. Evening. — Four eggs; ham. The total fuel value is estimated at 2,200 large calories, and an increase in the proteid content is made possible by addition of preparations of pure proteid such as "plasmon" and "nutrose." Many of the dietaries now advised in tuberculosis resemble the above in various ways, with eggs added in larger quantity. In numerous instances, the phthisical patient is not noticeably injured thereby; nevertheless, it is doubtless wise to sound a warning of possible danger in this high proteid nutrition in such cases. Dietary in "Hypernutrition" Cures. — As illustration of a typical dietary recommended in the "rest cure" introduced into medical practice by Weir Mitchell, the following maximal intake continued for four weeks has been adopted by Burkart. It should be remembered that the patients are inactive for the most part during the period of treatment. Quantity, Proteid, Fat, Carbohydrate, Calories. grams. grams. grams. grams. Milk . . . 2.064 70.4 75.0 101.0 1,296.0 Meat 352 59.8 7.0 502.2 Eggs 212 26.7 487.6 White bread 30 2.0 2i.6 79.5 Zwieback 325 18.0 8.6 1.0 180.0 42.0 3.0 852.0 Potatoes 200 199.4 Vegetable 100 Butter 20 ie.e 50.0 145.3 Sweets 100 3.0 0.5 15.0 80.0 195.5 99.1 412.6 3,642.0 GENERAL CONSIDERATIONS OP METABOLISM 745 To the preceding list may be added such further extreme types of dieting as are represented in the so-called milk-cure, whey-cure, grape- cure, etc., in which a moderate diet is used containing a large propor- tion of the foods suggested by the names applied. Whatever theraj^eutic value they have is doubtless associated with a degree of moderation in eating which they induce, as well as with minor influences such as the mild diuretic and laxative effects incidental to the grape regime. Artificial Food Preparations. — Modern times have witnessed the in- troduction of an almost endless number of food products prepared on a commercial scale by modifying the natural foods in various ways. The prevailing preferences and methods have been altered from time to time, in accordance with the changing attitude toward the products of the period. A few years ago the use of various types of " predigested " foods was hailed as an important advance in feeding methods. This was especially true of numerous albumose (proteose) and peptone prepara- tions, which found their way into practice. The early favorable reception which these products received has, however, not been continued. Experi- ment has shown that they can, under appropriate conditions, replace true proteids in the diet without apparent disadvantage during brief periods of observation, and with maintenance of nitrogenous equilibrium. But in view of the manifold provision in the alimentary tract for the proper and complete digestion of proteid compounds, the unpalatable character of most of these predigested materials and the unfavorable symptoms (diarrhoeas, etc.) which larger doses of concentrated soluble foods may induce, their popularity has gone. In place of them a variety of native proteids, some of them in the form of soluble salts, like the casein de- rivatives, has been brought into prominence. Similar considerations apply to the carbohydrate and fat foods, all of them being combined with alcoholic fluids to form widely used stimulant or "tonic" prepara- tions. It is true that most of these are readily assimilated; yet it can scarcely be questioned that any therapeutic value which they may exhibit is attributable to their nutritive properties in minor degree only. Too frequently the "food-tonic" habit is induced in ways both irrational and unadvised. At present the field for artificial food preparations is more generally restricted to infant nutrition. Artificial Nutrition. — The cases in which ordinary methods of nutri- tion cannot be applied because of some temporary or permanent dis- ability of the ordinary paths of alimentation are sufficiently familiar to the physician. Artificial modes of nourishment in such instances have long been practiced in the form of feeding through a stomach tube, or of rectal feeding. It is in this latter process that the modern soluble food preparations promise to be of some value. Views regarding the ideal composition of nutritive enemata are somewhat at variance. The practice, however, is sufficiently well established to assure its usefulness. Subcutaneous injection of soluble foodstuffs has lately been advocated, especially by v. Leube in the use of fats. This author claims to have achieved a satisfactory absorption of liquid fats from under the skin, olive oil being employed. It is doubtful whether any satisfactory utiliza- tion occurs in this way. For proteids the experience on record is unfavorable, as might be expected, if a more complete break-down is essen- tial to their proper metabolism. In the case of carbohydrates studies 746 NUTRITION in our laboratory have shown that compounds like glycogen, dextrin, inulin, and isolichenin are absorbed from beneath the skin, but excreted again in part unchanged in the urine, owing presunuibly to the lack of appropriate digestive enzymes to convert them into "physiological" sugars during their passage into and through the circulation. The variable fate of diifercnt sugars has been previously noted and although over 50 grams of dextrose can be introduced subcutaneously in man with- out excretion of the sugar, the practical difficulties encountered in infus- ing any considerable quantities of nutriment in this way are at present almost insuperable. The increasing scientific and intelligent interest in the subject of nutri- tion is full of promise for the future, v. Leyden has well said: "The healthy and orderly conduct of our daily life is intimately associated with three important factors: nutrition, work, sleep. A measured par- ticipation in these closely interdependent things will preserve health, prolong life, and perfect the valuable habits of regularity, moderation, and self-control. Nutrition should therefore be looked upon as an im- portant function — as a duty of man toward himself." PART IX. CONSTITUTIONAL DISEASES. CHAPTER XXIX. DIABETES MELLITUS. By THOMAS B. FUTCHER, M. B. Definition, — ^A disorder of carbohydrate and fat metabolism charac- terized usually by progressive loss in weight, thirst and polyuria, and by the persistent excretion of glucose in the urine while the individual is on a diet containing only moderate amounts of carbohydrates, or, in certain instances, even when no carbohydrates are ingested. Historical. — Salomon and Hirsch have given the best historical ac- counts of the disease. Hippocrates made no reference to it in his writings. Celsus, in the first century, described a disease characterized by polyuria, wasting, and bodily weakness. Aretaeus (circa 150 A. D.) was the first to use the term diabetes (Sta/Jiyriys, a syphon). He noted the thirst, diuresis, and the striking emaciation. The writings of Galen indicate that he was familiar with the main symptoms of the disease. The ancient Hindoo physicians of India are credited with having been familiar with the sweet taste of diabetic urine. This characteristic is said by Hirsch to have been described in the Ayur Veda of Susruta, written in the sixth century. In a Cingalese treatise of the fifteenth century, diabetic urine is referred to as "modu mehe" or honey urine. Notwithstanding these references to the sweetness of the urine, the credit for pointing out this characteristic is universally attributed to Thomas Willis, who described it in his " Pharma- ceutice Rationahs," published first in 1674. On page 71 of Pordage's translation of this treatise, which appears in the 1684 edition of this author's complete works, the following statement occurs: — "But as to what several Authors say, that the Drink is little or nothing changed, there is no truth in their suggestion; because in all People (that I ever happened to know, and I believe it to be so in all) their Urin was very different not only from the Drink that they took in, but also from any other humors that are usually generated in our Bodies, being exceedingly sweet, as if there had been Sugar and Honey in it." It was not until 1776, a century later, that Matthew Dobson, of Liverpool, demonstrated that the urine contained saccharine matter, by evaporating down two quarts of diabetic urine and obtaining a cake of sugar weighing 2 oz., 2 dr., 2 scr. 747 748 CONSTITUTIOXAL DISEASES He noted that tlie urine lost its sweet taste when it fermented, and also stated that the blood serum was sweet. Rollo's atlvocacy, in 1797, of a meat diet in the treatment of diabetes, marks an epoch in its history. He was also the first to give a detailed and intelligent account of the disease. In 1849, Claude Bernard demon- strated that, in animals, puncture of a point in the floor of the fourth ven- tricle near the tip of the calamus scriptorius and between the nuclei of the pneumogastric and auditory nerves, causes a transitory glycosuria. In 1857, he discovered the glycogenic function of the liver. A great ad- vance in our knowledge of the disease was furnished, in 1889, by Min- kowski and V. jNIcring, who demonstrated that conijilctc extirpation of the ])ancreas in various animals regularly caused a ))ermanent diabetes. In 1900, Opie and others pointed out the association between degeneration of the islands of Langerhans of the pancreas and the existence of glyco- suria. The investigations of Otto Cohnheim, published in 1903 and 1904, and jiurporting to show that the carbohydrates of the system are normally burnt up by the interaction of glycolytic bodies formed in the ])ancreas and muscles, promise, if eventually confirmed, to go far toward elucidating many hitherto obscure points in the metabolism in diabetes mellitus. Etiology. — I. Predisposing Factors. — Although diabetes is not a very common disease, a study of its inridcnce seems to indicate that it is on the increase in the United States, even allowing for the greater accuracy in diagnosis, and in the reporting of deaths in recent years. The United States Census for 1850 gave 0.9; for 1860, 1.2; for 1870, 2.1; for 1880, 2.8; for 1890, 5.5; and for 1900, 9.3 deaths from diabetes per 100,000 population. In the census year 1900, there were 4,672 deaths from the disease in the United States, of which 2,650 were in males and 2,022 in females. In this year the ratio of deaths from diabetes to the total number of deaths was 1 to 222. Statistics recently published by Tyson gave the ratio of deaths in Philadelphia, for 1900, as 1 to 402. In 1870, the ratio was less than half this, namely 1 to 850, thus indicating a marked increase in the prevalence of the disease. In Greater New York City, the death- rate from diabetes in 1900 was 10.3, and in 1902, 12.96, per 100,000 popu • lation. In Baltimore, the death-rate from the disease in 1900 was 8. .3, and in 1903, 6.5, per 100,000. The incidence of diabetes in Baltimore is further indicated by the fact that in the seventeen years since the opening of the Johns Hopldns Hospital, ending May 15, 1906, there were 259 cases under treatment in the medical wards and medical section of the dispensary, out of a total of 106,000 medical patients. Of these, 159 were in-patients in the medical wards among 19,685 medical admissions or 0.8 per cent, of the total. The more recent statistics are opposed to the view that diabetes is much less frequent in the United States than m Europe. The report of the Registrar General for England and Wales, for 1900, gave 8.6, and for 1903, 8.5, deaths from diabetes per 100,000 population, while the rate in the United States for 1900 was 9.3. Accord- ing to Saundby, writing in 1897, the death-rate from the disease per 100, 000 population varies considerably for the different European cities and countries. In Paris the death-rate is 14; in Malta, 13; in Copenhagen, 7; in Vienna, 4; in Norway, 2; in Prussia, 2; and in Italy, 1.5. Race. — The statement that diabetes is very uncommon in the colored race does not seem to be altogether borne out by facts. In the Johns DIABETES MELLITUS 749 Hopkins Hospital series of 259 cases, there were 26 in negroes, or 10.03 per cent. Among the 159 ward cases, tliere were 143 whites and 16 colored patients, or a ratio of 9 to 1. The ratio of white to colored admissions in the medical wards during this period has been about 4 to 1. Thus, 1 out of every 10 cases of diabetes occurred in the colored race, while 1 out of every 5 medical admissions was a colored patient. Expressed in terms of susceptibility, it would appear then that in Baltimore the white population is only twice more liable to the disease than the colored. The Urn'ted States Census report for 1900, on the other hand, gave only 48 deaths from the disease in the colored race out of a total of 4,672 deaths from diabetes. Of these 28 were in males and 20 in females. All authorities agree that the Hebrew race is particularly susceptible. Frerichs states that of his 400 cases, 102 were Jews. Wallach clearly demonstrated its greater frequency among the Hebrews of Frankfurt. From 1872 to 1890 there were 171 deaths from diabetes in that city. The proportion of deaths from diabetes to the deaths from all causes was six times greater amongst the Jews than amongst the rest of the inhabitants. The factors occasioning this greater susceptibility in Hebrews are not well understood. It has been variously ascribed to greater instability of the nervous system, fondness for sweets, and over-eating and sedentary habits amongst the better classes, particularly. Diabetes is very common among the educa- ted and commercial classes in India, and Rose and Sen have shown that it is the Hindoos who chiefly suffer. The disease is said to be very un- common in China and Japan. Heredity, undoubtedly, is a factor in many cases. Several brothers and sisters may be affected. While one or other parent may have the disease, they often escape, and an uncle, aunt or cousin may suffer from it. Rich- ard Morton, who termed the disease hydrops ad matulam, or dropsy of the chamber-pot (Phthisiologia, 1689), records a family in which four children were affected, one of whom recovered on a milk diet and diascor- dium. Pleasants found only 6 cases, or 5 . 3 per cent, with a family history of diabetes, in the first 112 diabetics in Osier's clinic at the Johns Hopkins Hospital, and reported a family in which two brothers, two sisters, an uncle, and a grand-uncle had the disease. Of particular value is the series reported by Fitz and Joslin in which especial inquiry was made and in which heredity was found to play a role in 23.8 per cent. Naunyn ob- tained a family history of diabetes in 35 out of 201 private cases and in only 7 of 157 hospital cases. Obesity is often a feature in these hereditary cases. The possibility of one person contracting the disease from another by injection, was first suggested by Schmidt, in 1890. Amongst 2,320 cases, he recorded 26 instances in which the disease appeared in apparently healthy persons, living in intimate association with diabetics. These were chiefly married females who contracted diabetes after nursing husbands suffering from the disease. These are the cases of so-called "conjugal diabetes." Oppier and Kiilz, in 1896, reported 47 married couples amongst 3,489 diabetic patients or 1 to 93 . 3, or 1 . 08 per cent. Senator, in the same year, stated that amongst 770 of his cases of diabetes, there were 9 instances, or 1 . 19 per cent., in which a man and wife suffered from the disease. For several years the writer has had a husband and wife, both diabetic, under his care. The wife was shown to be diabetic in 750 CONSTITUTIONAL DISEASES 1899, and sugar was first detected in tlic husband's urine in 1902. Both patients are rather obese. When one chniinates the influence of heredity, worry, obesity, and dietetic conditions in these cases, Httle evidence remains to support the hypotiiesis that diabetes can actually be contracted by one individual from another. No age is exempt from the disease, but most authors agree that the largest number of cases occin* in the sixth decade, that is, between fifty and sixty years of age. The incitlencc as to decades in the Johns Hopkins Hospital series of 259 cases is shown in the following analysis: — 1-10 11-20 21-30 31-40 41-50 51-60 61-70 71-80 4 14 25 43 68 75 25 5 It will be seen that the largest number of cases — 75, or 28.9 per cent. — occurred in the sixth decade. These figures agree closely with those of Frerichs, Scegen, and Pavy, all of whom found the largest number of cases in the sixth decade, their percentages being 26, 30, and 30.7 respect- ively. Wegeli, in an analysis of 102 cases in children under sixteen years, found the age distribution to be as follows: under one year, 3; one to five years, 26; five to ten years, 31; ten to sixteen years, 42. Stern mentions a case in which a child was apparently born with glycos- uria, and in which recovery took place in eight months. Diabetes is decidedly more common in the male sex. The proportion of males to females affected is about four to three. In our series of 259 cases there were 151 males and 108 females. Of the 4,672 deaths from the disease in the United States in 1900, 2,650 were in males and 2,022 in females. This disproportion is not so marked in childhood and extreme old age, when the figures are more nearly equal. The incidence of the disease in the two sexes in the colored race is indicated by the United States Census figures for 1900. Out of 48 fatal cases in negroes for that year, 28 were in males and 20 in females, practically the same ratio as in whites. Statistics at the Johns Hopkins Hospital, on the contrary, show a striking preponderance of the disease in females in the proportion of two to one. Of the 26 cases in the wards and the out-patient department, 17 were in females and 9 in males. In spite of the fact tliat the disease is often seen in its severest form among the poorer classes, it is undoubtedly more common in those of good social jposiiion. Not infrequently the onset of the disease is preceded by a history of fright, severe nervous strain, mental worry, and irritation. Obesity plays a very important role. Diabetes occurs very frequently in persons who become very stout during middle life. Frerichs had 59 cases of obesity among 400 diabetic patients, or 15 per cent. It occurred in 30 per cent, of Seegen's and in 45 per cent, of Bouchard's cases. Women are liable to become stout at the climacteric period, and are particularly prone to become diabetic at this time. Diabetes occurring in fat individuals is termed "lipogenous diabetes." When diabetes occurs in obese persons of middle age it is usually of a mild type, and the progno- sis is more favorable, the glycosuria disappearing on a rigid diet. The obesity usually precedes the glycosuria by several years. The fat diabetic is more commonly met with in private than in hospital practice. Occasion- ally obesity develops rapidly in young persons before the twentieth year. DIABETES MELLITUS 751 These subjects may also develop diabetes, which is always of a grave type and rapidly leads to a fatal termination. Universally admitted as this connection between obesity and glycosuria is, the nature of the relationship between fat and carbohydrate exchange is not at all well understood. Von Noorden is of the opinion that the obesity is an early symptom of the diabetic condition, and that it develops long before glucose makes its appearance in the urine. Owing to the belief that the obesity is caused by the diabetic condition, he has given it the name " diabetogenous obesity." He believes that in every case of true diabetes, not only the oxidation of carbohydrates, but also their con- version into fat, is restricted. He says that it is conceivable that there are cases in which at first the power to burn up the sugar in the organism is alone interfered with, while the conversion of carbohydrates into fat still goes on. Under these circumstances the working or muscle-cells of the body are richly bathed in a nutritive sugar solution; nevertheless they are starved because they cannot, or at least can only with difficulty, seize upon the sugar molecule, owing to deficient powers of oxidation. As a consequence there occurs a sort of tissue-hunger, which excites reflexly a sharper appetite and leads to the ingestion of a greater quantity of food. The latter results directly in an increased deposit of fat. According to von Noorden, such persons are diabetic, only they do not excrete sugar externally through the urine, but into the easily accessible layer of adipose tissue. We might suppose that the prolonged excessive use of carbohydrate food would favor the development of diabetes. There seems no satisfac- tory evidence favoring this view, however. Cantani stated that the majority of his Italian patients subsisted largely on farinaceous food. He believed the diet was an important etiological factor. In Ceylon, also, where diabetes is common, large quantities of saccharine food are taken. The Chinese, on the other hand, rarely suffer from diabetes, although their diet consists chiefly of carbohydrates. The metabolic disturbances underlying gout seem to favor the occur- rence of diabetes. Grube, of Neuenahr, found that 16 out of 177 diabetic patients suffered from gout, and 23 had gouty parents (hereditary alter- nating gout). This proportion is probably unduly high owing to the fact that the waters at Neuenahr are especially recommended for the mild cases of diabetes occurring in gouty patients. Von Noorden says that the connection between the two diseases may manifest itself in various ways. The patient may suffer from typical attacks of gout in middle life, and later the attacks cease and glycosuria appears. On the other hand, cases are observed in which attacks of gout alternate with glycos- uria (diabetes alternans). In a third group, gouty symptoms and glycos- uria are present at the same time. In all these cases the diabetes is of a mild type and is compatible with a long life. In occasional instances, diabetes may be traced to a syphilitic infection. The cases are undoubtedly rare. Feinberg reported 3 cases of diabetes and 1 of glycosuria which he attributed to a syphilitic infection. Where syphilis plays a part, the lesion is most probably a local one, and most likely to be situated in the region of the medulla. Nutritional changes in the brain and pancreas from syphilitic arterial disease must be con- sidered as a possible cause for the diabetic manifestations. 752 CONSTITUTIOXAL DISEASES In certain cases the diabetic symptoms have begun shortly after one of the infectious diieases. Cases have followed typhoid fever, scarlet fever, cholera, diphtheria, and rheumatic fever. There seems no satis- factory evidence sui)porting the view that malaria is a contributory cause. Williamson thought influenza jilayed a part in G out of 100 cases in which special in(|uirv was made into the previous history. In rare instances diabetes appears to be induced by prrgnanci/. The disease may manifest itself only during the pregnant period, being absent in the intervals. It is an occasional accompaniment of Ba.tedoios disease. JNIore often a transitory glycosuria occurs. Lowered tolerance to car- bohydrates in this disease has been demonstrated by numerous observers. Falkcnberg has reported cases in which glycosuria has followed extirpa- tion of the thyroid. Marie, Fraenkel, Striunpell, and others, have observed it in acrovicgali/. A transitory glycosuria occasionally supervenes after attacks of gall-stone colic. It may occur after the administration of a general ana\stlietic, and in other forms of narcosis. Asphyxia, occasioned by carbon monoxide or carbon dioxide poisoning, may cause a glycosuria, or even a true diabetes. In this connection also may be mentioned the glycosurias following the administration of certain drugs, such as amyl- nitrite, strychnine, curare, and methyldcljihinin. Glycosuria in Lesions of the Central Nervous System. — Although isolated observations had previously called attention to an association between certain lesions of the nervous system, and glycosuria or diabetes, it was Claude Bernard, who, in 1849, first demonstrated this relation by his celebrated "piqiire" experiment. He showed that by puncturing a point in the floor of the fourth ventricle, situated between the centres for the pncumogastric and auditory nerves, a hyperglyca?mia, polyuria, and a transitory glycosuria occurred, lasting six hours in the rabbit, and about forty-eight in the dog. Although this experiment has not been confirmed in man, it is not surprising that certain injuries to the central nervous system cause sugar to appear in the urine. Thus glycosuria or a true diabetes may follow severe trauma. Ebstein obtained a history of external injury in 6 out of 116, and Williamson in 6 out of 100 cases of diabetes. Ebstein collected 50 cases of traumatic diabetes from his own clinic and from the literature. In one-half of these, the head was the seat of the injury. Glycosuria is more liable to follow trauma in this situation. In other cases, injuries to the neck, liver, kidney region, and pubes, have been followed by it. Ebstein thinks that individual predisposition is a large factor in determining the occurrence of diabetes in these cases. Glycos- uria may also develop in the course of a traumatic neurosis. Glycosuria or a true diabetes may occur in organic lesions of the brain, without Bernard's "diabetic centre" being necessarily involved. Glycos- uria is not infrequent after cereJjral hemorrhage. It rarely appears earlier than two hours after the apoplexy, and usually clears up within six days. Naunyn knows of only one instance where the glycosuria has passed over into a true diabetes — a case reported by Meyer. A true diabetes may be occasioned by a tumor of the pons, medulla, or cerebellum. Osier cites a case, seen with Reiss at the Friedrichshain, Berlin, of a woman with anomalous cerebral symptoms and diabetes, in whom at postmortem a cysticercxis in the fourth ventricle was foimd. Ebstein reported 4 cases in which there was a coincident occurrence of ejrilepsy and diabetes, but DIABETES MELLITUS 753 attributes the two diseases to the same cause. Similar observations have been made by Naunyn, Jacobi, and Lallier. Naunyn observed a case in chronic encephalomalacia. Observers agree in the comparative frequency of glycosuria, or a mild diabetes, in general paresis. Bond reports having found it in 10 per cent., and Strauss in 9 per cent, of their cases. Glycos- uria is an occasional accompaniment of tabes dorsalis and multiple scler- osis. Tumors of the vagus and involvement of the nerve secondary to a caseated lymph-gland have been associated with a glycosuria. The latter is sometimes seen in severe cases of sciatica, but in this connection it must be remembered that neuralgias are not uncommon in diabetes. Isolated instances of disease of the abdominal sympathetic ganglia accompanied by glycosuria have been reported. Experimental Pancreatic Diabetes. — Since Thomas Cawley, in 1788, recorded a case of diabetes in which the pancreas was atrophied and con- tained calculi, changes in the gland have been from time to time reported by clinicians and pathologists in this disease. In 1877, Lancereaux, on the strength of numerous clinical observations, described a special form of diabetes under the name of diabete pancreatique ou diabete maigre, in which emaciation was the striking feature, in contradistinction to diabete gras, in which the subject remains well nourished, and in which the pan- creas was not thought to be involved. A great advance in our knowledge of the relationship between the pancreatic functions and diabetes resulted from the publication by Minkowski and von Mering, in 1889, of the results obtained from the extirpation of the pancreas in animals. These results have since been amply confirmed. Our knowledge concerning experi- mental pancreatic diabetes may be briefly summarized as follows: The complete extirpation of the pancreas in dogs, cats, pigs, carnivorous birds, frogs, and turtles, is regularly followed by a permanent glycosuria; and in dogs, particularly, the train of symptoms is almost identical with those of severe diabetes in man, and in a comparatively short time ter- minates in death of the animal. This result is not due to cessation of the flow of pancreatic juice into the intestinal canal, because diabetes does not follow when the duct is ligatured or when the juice escapes externally through a cutaneous fistula. When about one-tenth of the gland is left behind with power to functionate, the glycosuria is slight and occurs only when carbohydrates are ingested. When more than one-tenth of the gland is left behind in a functionating condition, diabetes does not result. That the diabetes is not a result of injury of the sympathetic nervous system, as some have claimed, is shown by the fact that when the pancreas is only partially extirpated, and the remaining portion, with the vessel intact, is transplanted into the abdominal wall, diabetes does not occur. If later this engrafted portion be removed diabetes quickly supervenes. It should be emphasized here that in experimental pancreatic diabetes the deposition of the glycogen in the liver and muscles is interfered with. The animals may be given abundance of starchy material wih- out more than traces of glycogen being found in these organs. There is always a hyperglycsemia, however, the amount of sugar in the circu- lating blood reaching as high as 0.5 per cent, within twenty-four hours. Minkowski and von Mering formulated the following hj^otheses : either some substance which has an inhibitory action on sugar conversion col- lects in the blood after extirpation of the pancreas, or else, after this oper- 48 75i CONSTITUTIONAL DISEASES ation, some substance is wanting or function abolished which, under nor- mal conditions, serves to facilitate the conversion of carbohydrate bodies, Lepine, of Lyons, in 1892, was the first to advance the view that dia- betes in man, and after extirpation of the pancreas in animals, is due to the failure of the pancreas to j^roduce a "glycolytic ferment," which occurs as an internal secretion. This hyjxithesis was based on the following ex- periments: When. a quantity of blood of a normal dog is divided into two equal parts, one of which is heated to 54° C, and both then placed in a thermostat at 39° C, it is found that the amount of sugar in the vmheated specimen is much less than in the other. That is, the ferment is destroyed in the latter, and glycolysis does not occur. When the blood of a pan- creatized dog, or of a human diabetic, was treated in the same way, the difference in the amount of sugar in the heated and unheated blood was much less, indicating the absence of the glycolytic ferment. These very suggestive exj)eriments were not subsequently confirmed by the work of such investigators as ]\Iinkowski, Ivraus, and Seegen. Diabetes and Organic Diseases of the Pancreas. — It is not surprising, considering the foregoing experimental results, that pancreatic lesions in man are often followed by diabetes. Lesions of no other single organ so frequently give rise to the disease, and evidence is steadily accumu- lating to lead us to believe that many cases of diabetes, apparently unac- companied by any organic lesion, are actually due to pancreatic disease made out only on microscopic examination. Most of the published sta- tistics, showing the percentage of cases of diabetes with involvement of the pancreas, are altogether unreliable in the light of recent knowledge, owing to the fact that microscopic examinations were in the majority of instances omitted. According to Naunyn, a pancreatic calculus has been the most frequent lesion. Others would consider atrophy of the gland, chronic interstitial pancreatitis, the commonest pathological change. In the case of a calculus, it must be remembered that there is always an asso- ciated pancreatitis. Diabetes may occur when cancer involves the whole or greater part of the gland. It is an interesting fact that diabetes is absent in many of these cases. Hansemann, and Bard and Pic attribute the absence of the glycosuria to the assumption of the pancreatic function of the cancer-cells. It is surprising that glycosuria does not occur oftener in acute hemorrhagic pancreatitis with complete destruction of the gland. Seitz collected 100 such cases, in not a single one of which did glycosuria occur. This may be accounted for by the early death in most of these cases. Benda and Stadelmann reported a case with glycosuria. Sugar in the urine occasionally occurs in patients with pancreatic cysts. The Association Between Diabetes and Lesions of the Islands of Lan- geraans. — The year 1900 marks a new epoch in our knowledge of the etiology of diabetes. In that year Opie^ published from Welch's labor- atory a pathological study on interstitial pancreatitis in which he for the first time demonstrated a connection between disease of the islands of Langerhans and diabetes. His results were published more in detail in the following year.^ These groups of cells were first described by Langerhans, in 1869. They are composed of columns of cells having no ^The Journal of the Boston Society of Medical Sciences, Vol. IV, p. 251, June, 1900. 'The Journal of Experimental Medicine, 1901, pp. 398-428 and pp. 527-540. DIABETES MELLITUS 755 communication with the ducts of the gland, but being in intimate relation with a rich capillary network. They are about the size of a kidney glo- merulus, measuring 0.2 mm. in diameter. The islands are situated for the most part in the centres of the ordinary gland acini, and arc quite dis- tinct, structurally and functionally, from them. They are distributed throughout the whole gland, but are more numerous in the tail than in the body or head. In tissues treated two or three days with Miiller's fluid they appear, under low magnification, as conspicuous points of a bright- yellow color. With high magnification, they are found to be composed of small, irregular, polygonal cells having a round nucleus and homogeneous protoplasm. Opie described two forms of chronic interstitial pancreatitis — an interlobular and an interacinar type. In the former, the development of fibrous tissue is most conspicuous between the lobules, while that within the lobules and between the acini is much less marked. In the latter, on the other hand, the interlobular connective tissue is not specially increased, whereas the connective tissue between the individual acini is markedly augmented. Here, also, the connective tissue may invade the individual acini when, as would be expected from their situation, the islands of Langerhans are likely to be involved. In his first series Opie reported 11 cases of the interlobular and 3 of the interacinar type. Of the 11 cases only 1 was accompanied by diabetes. In this case, the connective tissue had invaded the individual acini and had caused atrophy of the islands of Langerhans. Of the 3 cases of interacinar pancreatitis, 2 had diabetes, and the islands were extensively destroyed. In the third case it was thought that the absence of diabetes was due to the patient having died of typhoid fever before the islands had had time to become extensively involved. The most suggestive case of all was a girl, aged seventeen, who had suffered from diabetes for two years. The autopsy revealed no gross lesions to account for the disease. The pancreas, macroscopic- ally, looked perfectly normal. On microscopic examination, however, it was found that the islands of Langerhans were completely destroyed throughout the whole gland, with practically no involvement of the ordinary secreting cells of the pancreas. In stained sections, the islands stood out conspicuously as red areas of hyaline degeneration — granular atrophy of Hansemann — a few nuclei still being seen, without any of the original island-cells being visible. Later, Opie observed 2 cases of diabetes with identical changes. This hyaline degeneration of the islands appears to be the characteristic lesion in cases of pancreatic diabetes in which they are not destroyed secondarily to an interstitial pancreatitis. Ssobolew, working independently, published, in 1901, practically identi- cal observations on the relationship between disease of the islands and diabetes. In view of the intimate association, in his series, between involvement of the islands of Langerhans and diabetes, Opie was led to conclude that there was a very intimate connection between the functions of these islands and carbohydrate metabolism. Laguesse and Schafer had previously suggested that the islands furnish an internal secretion in the same manner that the thyroid and adrenal glands do. Owing to the small size of the islands, and the almost utter impossibility of isolating them from the rest of the gland substance, it has been practically impos- sible to produce experimental evidence favoring this view, although 756 CONSTITUTIOXAL DISEASES Ssobolew claims to have done so. Occurring as ductless glands, and being surrounded by a rich capillary network, it is extremely probable that these islands secrete some substance — we may call it a "glycolytic ferment" after Lepine — which enters the circulating blood, and which is necessary for the })ro])er combustion of the carbohydrates in the system. Opie's observations have been confirmed by numerous observers, among them, by Joslin in this country, and in Gernuiny by Sauerbeck,^ who has published the best review of oiu' knowledge on the islands since Opie's comnnmication. Sauerbeck fui'uished a very important contribution to the subject by finding that ligature of the pancreatic duct in rabbits is eventually followed by diabetes, contrary to the view previously held. Until about the thirtieth day after the operation the islands of Langerhans are well preserved. On or about this day, however, they begin to dis- appear and their disappearance is marked by the simultaneous occurrence of sugar in the urine. The theory that pancreatic diabetes is dependent upon disease of the islands of Langerhans, while generally accepted, has certain strong opponents, among them Hansemann of Berlin. There is every reason to believe, however, that very many of the cases of diabetes in which at autopsy no gross lesion is observable, will be shown to reveal degenerative changes in the islands of Langerhans when examined microscopically. Although it is probable that all cases of diabetes are not due to organic changes in these islands, we must keep in mind the possibility of a func- tional distvu'bance in the cases where organic changes are not demonstra- able. It is quite likely that many of the cases of the so-called endogenous diabetes — that is, those without any attributable exciting cause, and without evident pathological lesions — are due to organic or functional disease of the islands of Langerhans. The recent work of Otto Cohnheim on the combustion of carbohydrates, to be referred to later, tends to support this view. At this point also must be mentioned the interesting group of cases of "bronze diabetes," occurring as a late manifestation of the remarkable affection known as hcemoehromatosis. The latter condition is character- ized by a peculiar pigmentation of the skin and viscera, associated with a form of hypertrophic cirrhosis of the liver and extensive sclerotic changes in the pancreas, and accompanied in the late stages by a persistent glycos- uria. Hanot and Chauffard first described these cases, in 1882, and, in 1886, Hanot suggested the name diabete bronze for this type of diabetes, and, as he considered the liver changes secondary to the diabetic condition, he gave the name cirrhose pigmentaire diabetique to this form of cirrhosis. The true nature of the affection was first revealed in 1889 by von Reck- linghausen, who described the disease under the name of hsemochromato- sis. He showed that the pigmentation of the skin and viscera is due to the deposition of an iron-containing pigment, hemosiderin, and a non-iron- containing pigment, htemofusein, in the tissues. According to the latest conception of the disease, hsemochromatosis is to be considered as a primary affection of the blood in which the red cells ^re made more vulnerable, causing them to disintegrate more readily and to give up their hsemoglobin. The hsemosiderin possesses a brown color , 1 Ergebnisse der Allgemeinen Pathologie und Pathologischen Anatomic, Achter jatrgang, II, Abteilung, 1902. Published in 1904. DIABETES MELLITUS 757 and is deposited mainly in the cells of the liver, pancreas, lymphatic and sweat glands. The hsemofuscin, on the other hand, is finer, of an ochre- yellow color, and is present in the smooth muscle fibers of the stomach, intestines, blood- and lymph vessels, and occasionally in those of the urinary bladder, ureter and vas deferens. Iless and Zurhelle have recently made very careful studies of two cases of "bronze diabetes," that is, two cases of hsemochromatosis which had advanced to the diabetic stage. As a result of their chemical and histological studies they incline to the view that the cirrhosis of the liver and the formation and deposition of the pigment are dependent upon some common cause. They hold that some toxic substance, possibly alcohol, causes disturbances in metabolism which bring about the above changes. A lipeemia, which was present in one of their cases, is explained in the same way. Their investigations also go to show that a sharp distinction between hsemosiderin and hBemo- fuscin cannot be made. They claim to have found them side by side in the same cell with gradual transitions from one into the other. The hsemoglobin of the blood is in all likelihood their common source. As a result of the local deposition of the pigment in the liver and pancreas, a chronic interstitial inflammation occurs, producing in the case of the liver, a hypertrophic pigmentary cirrhosis, and, in the case of the pancreas, an interstitial pancreatitis of a pigmentary type. In the early stages or early years of this affection sugar does not appear in the urine, and it is only when the changes in the pancreas become so advanced that pre- sumably the islands of Langerhans are largely or completely destroyed that diabetes develops. Whenever hsemochromatosis, either with or without diabetes, is suspected, the correctness of the diagnosis intra vitam will be made much more probable by removal of portions of the pigmented skin and the finding of iron-containing pigment in the cells of the sweat glands, by the potassium ferrocyanide test, and of the ochre- yellow haemofuscin in the muscle fibers of any bloodvessels that may be present. Naunyn, Grube, Laache, and Fleiner, have drawn attention to the frequency in the association between arteriosclerosis and diabetes. Nutri- tional changes in the pancreas, due to sclerosis of the pancreatic arteries, has been suggested as the assignable cause. Fleiner reported a case of diabetes in a patient with general arteriosclerosis in which there was a diffuse interstitial pancreatitis with marked thickening and obliteration of the branches of the pancreatic artery. Diabetes and Organic Diseases of the Liver. — When one considers what an important part the liver plays in carbohydrate metabolism — being the great glycogen reservoir — it would be natural to expect that organic lesions of the liver would frequently be the cause of diabetes. Clinical experience, however, teaches us that the most extensive disease of the liver, such as carcinoma and cirrhosis, may occur without even a glycosuria occurring. Naunyn seems to be the strongest advocate of what he terms a "liver diabetes," that is, where the diabetes is due to the organic change in this gland. He describes personal observations of cases of diabetes attributed to cirrhosis of the liver and to the liver disturbances accom- panying gall-stones. He also draws attention to the frequency with which he has met the glycosuria in individuals with enlarged livers, caused by passive engorgement secondary to. cardiac disease. There does 758 CONSTITUTIOXAL DISEASES not seem to be sufficient evidence at the present time to justify the opinion that a true "hver diabetes" exists. Until a larger number of cases of diabetes with organic disease of the liver and without microscopic evi- dence of disease of the islands of Langerhans are reported, we must sup- port this contention. Renal Diabetes. — The only cases known to be definitely of renal origin are those of "phloridzin diabetes," experimentally produced by the ad- ministration of phloriilzin. The latter is a glycoside obtained from the bark of the trunk and root of a])ple, pear, ])lum, and cherry trees. In 1886, von Mering discovered that when phloridzin is administered by mouth or subcutaneously in man or animals, a temporary glycosuria results. The amount of sugar may reach 18 per cent, in dogs. The glycosuria continues in animals fed on nitrogenous diet, or in men when fasting, indicating that the sugar is in part manufactured from proteids. An important fact is that no hyperglycjemia exists. That the glycosuria results from the phloridzin causing certain changes in the renal cells rendering them more permeable to glucose, is indicated by the fact that there is no increase of glucose in the blood; by failure of a hyperglycsemia to occur after ligaturing the ureters or excising the kidneys; and by the observation of Zuntz, who found that when phloridzin is injected into one renal artery, glucose is excreted by the corresponding kidney immediately, while it does not appear in the urine of the opposite kidney until half an hour later, that is, until after it reaches that kidney through the general circulation. Considerable doubt exists as to whether, clinically, the "renal diabetes" of Jacobi actually occurs. The instances of diabetes occurring in the course of chronic nephritis are usually cited in support of the view that a renal diabetes actually exists. Klemperer records a very suggestive case in which a patient with chronic nephritis excreted . 35 per cent, of glucose. There was no accompanying hyperglycsemia, nor did the latter occur even after the individual was fed on bread and glucose and excreted as much as 150 grams of sugar daily. In fact the blood showed a h^^oglycsemia. Naunyn reports 3 cases of diabetes in chronic nephritis, and inclines to the view that cases of renal diabetes occur, but admits that the question is still an open one. He cites the cases of glycosuria accompanying renal hemorrhages and chyluria, in support of the "renal diabetes" hypothesis. Adrenalin Glycosuria. — There is no clinical or pathological evidence showing that diabetes bears any intimate relationship to disease of the adrenal glands. In rare instances, glycosuria has been found in associa- tion with lesions of these glands. Experimentally, however, it has been shown that adrenalin, the active principle of the gland, has a powerful influence on carbohydrate metabolism. In 1901, F. Blum reported the results of his experiments in connection with adrenal diabetes. He found that the subcutaneous injection of an aqueous extract of the adrenal gland produced glycosuria in 22 out of 25 dogs experimented upon. This observation was later confirmed by Suelzer and Croftan. Herter, in 1902, published his experiments with adrenalin chloride. He used a 1 to 1,000 aqueous solution of adrenalin chloride in his research. Subcutaneous, intravenous, and intraperitoneal injections of the drug in dogs were almost invariably followed by glycosuria. Peritoneal injections, other things being equal, produced the most marked glycosuria, an excretion of 10 DIABETES MELLITUS 759 per cent, or more of sugar not being uncommon. The glycosuria lasts usually a little over twenty-four hours. In order to ascertain whether the more marked glycosuria following intraperitoneal injection was due to the direct action of the drug on the pancreatic gland, the pancreas was exposed in a number of normal dogs, and adrenalin chloride solution was applied directly to the presenting surface of the gland. It was shown that a marked glycosuria followed the application of very small quantities of adrenalin to the gland — quantities which, when applied locally to other parts of the body, gave rise either to no sugar excretion or only a trivial glycosuria. The problem now to determine was just how this glycosuria is produced. It was first shown that it was not due to vascular disturb- ances. Owing to adrenalin chloride being a very active reducing sub- stance, Herter thought that the glycosuria resulted from interference with oxidation within the pancreatic cells. Accordingly local applications to the pancreas of other reducing substances were made. Solutions of potassium cyanide constantly produced a glycosuria. Similar results were obtained with sulphurous acid, ammonium sulphide, sulphuretted hydrogen, illuminating-gas, carbon monoxide, and other reducing agents. Negative results were regularly obtained with non-reducing substances such as sodium chloride, sodium hydroxide, ferric chloride, hydrochloric acid, bromine water, etc. Herter concluded that adrenalin chloride and the other reducing sub- stances cause glycosuria by their power of removing oxygen from the pancreatic cells, thus interfering with their function. Histological exam- ination of the pancreatic gland at the height of the glycosuria showed no recognizable lesion. He did not think that the glycosuria was due to loss of function of the islands of Langerhans, although, later, he found that fatal doses of adrenalin produced marked granular degeneration of the cells composing the islands. Herter considered the experiments of clinical im- portance in that they probably threw considerable light on certain forms of human glycosuria. He suggests that the forms of glycosuria following conditions of asphyxia, as after epileptiform seizures and carbon monoxide poisoning, may be due to interference with oxidation in the pancreas. View that Diabetes is Produced by a Circulating Toxin. — In 1900, Hans Leo published the results of his experiments which led him to believe that diabetes was due to some unknown toxin. The urine from diabetic pa- tients was found to cause glycosuria in dogs when administered by mouth and subcutaneously. This result was obtained with fermented as well as with unfermented urine. Leo was unable to determine the true nature or source of this toxin. That it was not of the nature of a ferment he con- cluded from the fact that it was soluble in water and alcohol, was not precipitated by oxalic acid, and not destroyed by heat. No proof has since been advanced to support Leo's view. It is of interest to note that Hofmeister has produced a so-called "hun- ger-diabetes" in dogs by cutting off all food for several days. If a dog weighing two to three kilograms be then given 10 to 30 grams of starch, a glycosuria reaching 3.84 per cent, and a total excretion of 30 per cent, of the ingested starch results. So far as we know, an analogous condition does not occur in man; but Naunyn makes the suggestion that some of the glycosurias occurring in various cachetic diseases may be an expres- sion of a hunger diabetes. 760 CONSTITUTIONAL DISEASES II, Disturbances of Metabolism in Diabetes. — The immediate cause of diabetes is the development of a hyperglycivmia; that is, an excess of ghi- cose in the circulating blood. The explanation for the occurrence of this bypcrglvcaMuia is the prol)lem which has occupied the attention of so many investigators and one which is still in need of a solution. As the metabolic disturbances in diabetes have to do mainly with the warehousing of the carbohydrates, they will probably be best appre- ciated by first reviewing the fate of the carbohydrates in normal metab- olism. The hexoses mainly concern us in a discussion of both normal and pathological carbohydrate metabolism. The hexoses, in general terms, may be described as carbohydrates, the molecules of which contain the carbon atoms to the number of six or multiples thereof, and the hydrogen and oxygen atoms in the proportion in which they form water. They are classified according to the number of carbon atoms they contain, as fol- lows : 1. The monosaccharides, or cjlycoses, having the general formula CgHiz Og. These include grape-sugar, also called dextrose or glucose (dextro- rotatory) ; fruit-sugar or levulose (levo-rotatory) ; galactose and mannose (both dextro-rotatory) . All these ferment and reduce alkaline copper-sul- phate solutions. 2. The disaccharidcs, or saccharoses, possessing twelve atoms of carbon in the molecule, and having the formula C12H22O11. These are formed by the combination of two molecules of a monosaccharide with the loss of a molecule of water. They include cane-sugar or saccharose; milk-sugar or lactose; and maltose. With the exception of cane-sugar, all reduce alkaline copper-sulphate solutions. All are dextro-rotatory, but do not ferment wdthout being split up by dilute mineral acids, etc. 3. The polysaccharides, or amyloses: these are the anhydrides of a combination of many molecules of monosaccharides, and possess the gen- eral formula, (C6Hio05)n. They include starch, glycogen, and dextrin, (all dextro-rotatory); inulin (levo-rotatory) ; cellulose; and animal gum (inactive). They do not reduce alkaline copper-sulphate solutions and do not ferment w'ithout being previously split up. Normal Carbohydrate Metabolism. — The carbohydrates in the food undergo a series of changes during digestion, as a result of the action of the diastatic ferments in the saliva, pancreatic juice, and succus entericus. Possibly some changes also occur in the process of absorption. Starch, the most abundant article in our dietary, is eventually converted into maltose, or maltose and dextrin, after passing through a series of inter- mediate stages. The maltose and dextrin are further converted into dex- trose by the sugar-splitting enzymes of the intestinal mucous membrane. Cane-sugar, the sugar for ordinary sweetening purposes, is hydrolized into dextrose and levulose, and milk-sugar probably undergoes a similar change to dextrose and galactose, although of this we are not so certain. According to our present knowledge we may say that the carbohydrates of our food are eventually absorbed in the form mainly of dextrose (glu- cose) or dextrose and levulose. These sugars are absorbed directly into the portal capillaries and not into the lymphatics. As a result of car- bohydrate digestion the portal vein conveys to the liver a stream of sugars consisting mainly of dextrose, but also of smaller quantities of levulose DIABETES MELLITUS 761 ,and galactose, and there, by a jjrocess of dehydration, the liver-cells con- vert them into glycogen as follows: CJIigOg — H2(>=Q,HioC)5. After the ingestion of carbohydrates, the surplus that is not required for the imme- diate use of the economy is stored up in the liver as glycogen. According to the generally accepted view of {physiologists, this glycogen is recon- verted into glucose, probably by the action of a special enzyme produced by the liver-cells. This glucose reaches the general circulation by the hepatic veins, and is conveyed to the tissues, where it is oxidized, produc- ing heat and energy. This glycogenic function of the liver was first dem- onstrated by Claude Bernard, in 1857, and is generally accepted by modern physiologists, though it has been vigorously opposed in certain quarters. Pavy and his followers differ from most physiologists in their views concerning the method of absorption of carbohydrates. He thinks that in health a considerable portion of the carbohydrates ingested is converted by the villi of the intestinal mucous membrane into fat and carried thence by the lacteals to the blood. Another portion is split up, being incorporated with nitrogenous material and carried away in the form of proteid. These changes are affected by the same cells of the villi. Pavy thinks that only the carbohydrates not thus assimilated as fat or proteid-carbohydrate pass to the liver and are there converted into glycogen in the manner described. "The office of the liver," according to Pavy, "is thus supple- mentary to the assimilative work performed elsewhere. If the latter work is efficiently performed none is left for the liver to accoinplish. It is the sugar that is permitted to reach the portal vein that is taken up by the liver and it may happen that none reaches it in health." Glucose and glycogen are formed not alone from carbohydrates, but a certain amount is manufactured from ingested and sometimes from body proteid. Evidence favoring this view was advanced by Claude Bernard, who showed that the liver of an animal kept under conditions ordinaril^i favoring the disappearance of the glycogen, such as fasting, exercise, etc.,! still contains glycogen when fed on an exclusive proteid diet. Furthei? evidence is afforded by the fact that severe diabetics often excrete sugar when on a similar diet. According to Minkowski, 45 grams of carbohy- drate is formed out of every 100 grams of proteid decomposed in the body. The general belief, however, is that in normal metabolism carbohydrates are probably not manufactured from the ingested proteids. In the disordered metabolism of diabetes, on the other hand, both the proteids of the food and particularly the body proteids yield considerable quantities of glucose. The liver is capable of storing up glycogen to the extent of 14 per cent, of its own weight. The amount it contains depends on several factors. Pro- longed fasting, continuous physical exertion, and high temperature, rapidly deplete its supply of glycogen. The latter is greatest in amount on a diet rich in carbohydrates. The liver is not the only seat for the storage of glycogen, however. The other great reservoir is the muscular system; and it is estimated that the quantity in the muscles practically equals that stored in the liver. When conditions favor the depletion of the supply of glycogen it is found that the muscles give up their supply much less readily than does the liver. The source of the muscle glycogen is not definitely known, but presumably it is formed from the glucose brought to the muscles by the circulating blood. 762 CONSTITUTIOXAL DISEASES It has been clearly shown that the amount of glucose in the circulating blood normally varies within cjuite narrow limits, namely, between 0.1 and . 2 per cent. This is remarkable because we would expect that when carbohydrates are ingested in large quantities the blood would contain more glucose than when they are taken in smaller amounts. This is not the case, however, for the percentage of sugar in the circulating blood remains in normal individuals constantly within the narrow percentage limits mentioned above. This naturally leads us to consider the fate of the carbohydrates under conditions which may be considered as normal variations. (a) In Ordinary Nutniion. — In a healthy person, on a usual mixed diet and taking a moderate amount of exercise, the carbohydrates are always on hancl and are always in demand. By their combustion, pre- sumably for the most part in the muscles, they produce heat and energy. Owing to the fact that normally there is no loss of sugar in any of the excretions, excepting in the urine in the minutest traces, and owing to the interposition of the two carbohydrate reservoii's, the liver and muscles, the percentage of glucose in the circulating blood remains practically con- stant. After a meal the excess of carbohydrates is temporarily stored up in the liver as glycogen. (6) When the Supply of Carbohydrates is Insufficient and the Demand Excessive. — For a few hours or days under these conditions the glycogen in the liver and muscles is called upon, and makes up for the deficiency of the carbohydrate intake. In this way the percentage of glucose in the circulating blood is kept within normal limits. Eventually the glycogen is entirely used up, yet the blood contains the normal amount of glucose. This has been thought by some to be due to the conversion of the body- fat into glucose. This view has few adherents, how^ever, and the phenom- enon is more likely explained by the conversion of the body-proteids into glucose. (c) When Carbohydrates are Ingested in Excess of the Needs of the Body. — ^The fate here depends on circumstances. Within certain limits, the excess in carbohydrates can be stored up in the liver and muscles as glycogen. The limit of this storage capacity is eventually reached, for von Noorden states that the human organism is capable of storing up only about 300 grams of glycogen. Results will now vary according to whether the carbohydrates are ingested in moderate excess over a considerable interval, or in enormous quantities in a short period of time. In the former case the excess of carbohydrates is converted into fat which is deposited in the connective tissues, and no hyperglycsemia occurs. When, however, there is a sudden ingestion of an enormous amount of carbohy- drates, the liver and muscles cannot store it all up as glycogen, nor can the organism convert it all into fat. An excess of glucose accumulates in the circulating blood. When the blood contains more than 0.2 per cent, of glucose a hyperglyceemia exists, which always results in the appearance of glucose in the urine. The form of glycosuria produced in the manner just described is known as alimentary glycosuria. This may be considered a physiological pro- cess, and must not be confused with true diabetes. The quantity of sugar that can be ingested without its appearing in the urine is designated by Hofmeister as the assimilation limit. This varies in normal persons DIABETES MELLITUS 763 according to the individual and acconiing to the sugar ingested. Von Noorden states that the sugar that appears in the urine is the same as that ingested. This statement must be accepted with reservations. The glycosuria thus produced is known as glycosuria e saccharo. The assimila- tion limit for normal individuals on a fasting stomach is stated by von Noorden to be as follows: For milk-sugar, 120 grams; for cane-sugar, 150 to 200 grams; for fruit-sugar, 200 grams; for grape-sugar, 200 to 250 grams. When the sugars are taken after a light meal the limit is higher. It is well to emphasize here that, in a healthy person, sugar never appears in the urine after the ingestion of even enormous quantities of starch. Diges- tion and absorption take so much time that a sudden flooding of the blood with carbohydrates cannot take place. When a glycosuria does occur after the ingestion of starch it is called glycosuria e amylo. It should always lead the physician to suspect that a true diabetic condition exists, for it means that the assimilation limit, or power to warehouse carbohy- drates, is lowered. Manner in Which the Carbohydrates are Oxidized in the System. — ^We have until a recent date been almost entirely in the dark as to how and where the glucose of the blood is ultimately burnt up. At one time it was thought that it was oxidized in the lungs. Subsequently, the body tissues, particularly the muscles, have been held to be the seat where the carbohy- drates are oxidized, yielding energy and heat, and resulting in the produc- tion of carbonic acid and water. Lepine and Barral held that this "glycolysis" was affected through the agency of a glycolytic ferment pro- duced by the pancreas as an internal secretion. Arthus denied the exist- ence of such a ferment in the circulating blood, and held that the enzyme is merely a postmortem product resulting from the disintegration of the red blood corpuscles. Otto Cohnheim,^ in 1903 and 1904, published the results of experi- ments which, if ultimately confirmed, seem destined to solve the mystery of carbohydrate metabolism, and to throw much light on the etiology of diabetes rnellitus. By means of a specially constructed press, he obtained quantities of juice from the pancreas and muscles of cats and dogs. With each of these juices he first experimented separately. Each juice when added to a solution of glucose was inactive. When, however, muscle- juice and glucose-solution were mixed together, and then the juice of the pancreas added, there was a rapid, and eventually, a complete conversion of the glucose into carbonic acid and alcohol. Cohnheim holds that the ingested carbohydrates are burnt up in the muscles. He suggested two possible explanations for the remarkable results above noted. One is based on Ehrlich's side-chain theory. According to this view, the pan- creas and muscles provide complementary and intermediate bodies, both of which are necessary for normal carbohydrate metabolism. His second explanation is in accord with Pawlow's findings regarding the relationship between trypsinogen, the proteid enzyme of the pancreas, and proteid digestion. Pawlow found that trypsinogen itself was inactive on proteids, but when it came into contact with the "enterokinase" of the intestinal juice it was converted into trypsin and then caused rapid digestion of the proteids. Cohnheim believes that both the pancreas and the muscles pro- duce substances which are necessary for normal carbohydrate metabohsm. » Zeitschrift fiir Physiologische Chemie, Bd. XXXIX, p. 338, vmd Bd. XLII, p. 401. ;64 CONSTITUTIONAL DISEASES He at first thought that these substances were of the nature of enzymes oi ferments. According to this hyi)othesis, he held that the muscles jn-o- duced a proenzyme which reciuircs the action of a ferment, produced by the pancreas and contained in its internal secretion, before it can become active on carbohydrates. Cohnheim in his second communication gave the results of his experiments as to the nature of the glycolytic body pro- duced by the pancreas. He found that it withstands boiling, is soluble in water and 96 per cent, alcohol, but insoluble in ether For these reasons, he believes that the glycolytic agent of the pancreas is really not a ferment, but a body very closely allied in its characteristics to such other well- known constituents of internal secretions as adrenalin, iodothyrin, and secretin. An interesting feature is that an excess of this body hinders, and, when present in large quantities, absolutely prevents, carbohydrate com- bustion. The most active sugar destruction occurs when muscle and pancreas are mixed together in the proportion of 75 grams of the former to 0.8 grams of the latter. When more than 0.8 grams of pancreas is added the activity diminishes, and ceases when 2 grams is reached. Cohnheim suggests two explanations for this remarkable finding. The first is, that the pancreas produces two substances, one of which favors and the other hinders sugar combustion. For various reasons he sets this aside as a possible explanation. The second is based on the obser- vation of Neisser and Wechsberg, that the destruction of bacteria by a bacterial serum is due to the combined action of amboceptors and comple- ments, and that an excess of amboceptors destroys the bactericidal action of the serum. By analogy, he suggests that by adding an excess of pan- creas juice to a mixture of sugar solution and muscle juice, an over abundance of amboceptors is provided, thus destroying the glycolytic action of the two juices. Rahel-Hirsch, whose researches were published practically^ at the same time as Cohnheim 's, reached almost identical results. He found, further, that liver juice, preserved in toluol, itself caused an appreciable destruc- tion of glucose in solution, but that the destruction was much more marked after pancreas juice was added. Claus and Embden, in a pviblication which appeared early in 1905, stated that they failed to confirm Cohnheim 's results. They believed that the sugar destruction in Cohnheim 's and Kahel-Hirsch's experi- ments was dependent upon bacterial action and due to their failure to prevent bacterial growth in the added pancreas juice. Cohnheim claimed that their failure to confirm his results was due to defective chemical technicjue. In INIarch, 1906, he published his results of a reinvestigation of his former work, and states that they entirely confirmed his early experiments. His theory is an extremely suggestive one. According to his view, the sugar of the blood is burnt up in the muscles through the agency of a glycolytic substance which results from the interaction of bodies produced in the pancreas and muscles. The bearing of this con- ception on carbohydrate metabolism in diabetes will be considered under the theories as to the causation of diabetes. Having reviewed the main features of carbohydrate metabolism in health, it is now in order to see what variations occur in diabetes mellitus. Hyperglycemia, or excess of glucose in the blood, is the most constant and, striking evidence of disordered metabolism in the disease. Naunyn DIABETES MELLITUS 765 states that he knows of no case of diabetes in man without a hypergly- csemia, with the exception of Klemperer's case of diabetes in chronic nephritis, where the glucose in the blood was said to be subnormal. It will be recalled that this case was cited by Klemperer as evidence in favor of a "renal diabetes." In phloridzin diabetes, which is a true renal, diabetes, there is no hyperglycfemia, and often the glucose in the blood is decidedly below normal. The great problem is to ascertain why this hyperglycaemia occurs. Whereas the blood normally contains about 0.1 per cent, of glucose, with 0.2 per cent, as the maximum normal amount, in diabetes the glucose may reach O.G per cent, according to determina- tions made by Pavy and by Seegen. Naunyn found . 7 per cent, in one case. This is among the highest percentages recorded. Another very striking and almost constant metabolic disturbance in diabetes is the failure of the liver to store up glucose in the form of glyco- gen (zooamylon), a condition to which Naunyn has given the term "dyszooamylie." The amount of glycogen in the liver is usually reduced, or it may be entirely absent. Naunyn says that the evidence at hand is not sufficient to decide the question as to whether the deficiency of the liver in glycogen is due to failure of the liver-cells to convert glucose into glycogen, or mere failure of the liver-cells to store it up when received. This poverty in glycogen is also a striking feature in the experimental glycosuria follow- ing medullary puncture and extirpation of the pancreas. It is an interest- ing fact that a diabetic can store up glycogen in his liver from ingested levulose, whereas there is no conversion from ingested glucose. This failure of the liver-cells to store up glycogen is very closely related to the production of the hyperglycsemia. Why this power is lost is not yet understood. The fact that it occurs after extirpation of the pancreas in animals suggests the possibility that some ferment, contained in an inter- nal secretion of the pancreas, is necessary to enable the liver-cells to form glycogen from ingested carbohydrates. The metabolic disturbance in diabetes does not in itself cause an in- crease in the destruction of body proteids. The diabetic nearly always excretes a marked excess of nitrogen in the form of urea. This increase is due, however, in large part to the excessive ingestion of proteids, and must be considered physiological. The healthy individual would excrete proportionally large amounts of nitrogen if his diet were increased to the same extent. The condition becomes pathological only when the amount of nitrogen in the urine exceeds that taken in the food; in other words, when, in addition to the albumin in the food, that of the tissues also is decomposed. This occurs in diabetics when so much sugar is excreted that after the subtraction of its heat- value from the heat- value of the food, the latter is found to be insufficient. This waste of nitrogen is the greater the more the food value is depreciated by glycosuria. It is very large as long as the diabetic is left to himself to ingest the carbohy- drates which are useless to him, but becomes slight or ceases when the diet consists largely of proteids and fat. In the severe cases of diabetes with rapid emaciation there is often a marked increase in the excretion of nitrogen, owing to the consimiption of the body proteids. It is not alone the metabolism of the carbohydrates that is disturbed in diabetes. It is only in the last few years that students of this disease are awakening to the fact that there is also a marked disturbance in fat 766 CONSTITUTIOXAL DISEASES metabolism. There is now practically conclusive evidence that the power of the tissues to oxidize the fat of the food and body is markedly lowered. In the last five years evidence has gradually accumulatetl to show that /?-oxybutyric acid and its derivatives, diacctic acid and acetone, arise as a result of the incomplete oxidation of fat. This is the generally accepted view as to their origin at the present time. It will naturally be inferred that, in the regulation of the iliet of diabetics, we must not only consider the carbohydrates, but we must pay more attention to the prescribing of the amount and kind of fat than we have been accustomed to do here- tofore. Diabetes is sometimes considered among the auto-intoxications. We have no proof that an excess of glucose in the circulating blood is capable in itself of producing any toxic symptoms. Diabetic coma, the most serious complication of the disease, however, is definitely due to an acid auto-intoxication, as we shall sec later on. Theories of Diabetes MellitUS.— The results of researches published up to the present do not warrant any dogmatic statements as to the cause or causes of the hyperglycemia in diabetes. We can conceive of its being occasioned in at least two ways: (1) By over-production of glucose. (2) By under-consumption of glucose in the tissues. 1. Theory of Over-Production. — There is no evidence to show that the diabetic individual forms any more sugar from a certain amount of food than does a healthy person from the same amount of food. We have instances of over-production in those cases of glycosuria, or true diabetes, resulting from irritation or injury to the nervous system, of which the medullary puncture is a type. In these cases, however, the over-produc- tion of glucose is a temporary one, and results merely from an over- production of glucose from the stored-up glycogen in the liver. Two explanations are given for the h^'perglycjemia in these cases. One is that the injury to or disease of the nervous system causes a centripetal nerve- impulse to be sent out to the liver, causing its cells rapidly to part with their glycogen in the form of glucose. The other is that vasomotor disturbances are produced which result in increased vascularity of the liver. In this way a greater amount of some — as yet undetermined — ferment in the blood reaches the liver, causing a more rapid conversion of glycogen into glucose. Naunyn believes that the hyperglycemia is directly dependent on the fact that the liver and muscles of the diabetic are unable to store up glycogen in the same way that they do in health. The glucose derived from the ingested carbohydrates and proteids goes to the liver, and, instead of being there temporarily stored up as glycogen until required by the system, as occurs in health, it presumably passes directly into the blood after a meal, causing a hyperglyctemia and con- sequent glycosuria. This naturally does not necessarily mean an over- formation of glucose. Von Noorden denies the over-production of sugar, but advances no conclusive evidence to support his contention. 2. Theory of Under-Consumption and Deficient Oxidation. — In health, the glucose of the blood is consumed mainly in the tissue-cells, particularly those of the muscles. Normally arterial blood contains more glucose than venous blood, which is evidence in favor of the above con- tention. If the tissue cells of diabetic individuals fail to consume glucose we would expect to find less difference between the percentage of glucose DIABETES MELLITUS 767 in arterial and venous blood in diabetic than in healthy persons. Chau- veau and Kaufmann estimated the sugar in the blood of the crural artery and vein in healthy and in diabetic dogs. They found the difference to be the same in both animals, and conclude that the capacity for consuming sugar is not lost in diabetes. A healthy individual on a mixed diet gives out less carbonic acid than he receives of oxygen, the ratio being on an average 9 to 10. I^his is ex- pressed by the fraction 0.9, and is called the respiratory cjuotient. If there were an under-consumption of glucose in the tissues we would expect the quotient to be much reduced. Voit and Leo have shown that there is no such reduction. Von Noorden, who is a vigorous supporter of the under-consumption theory, lays great stress on an observation of Wein- trand and Laves, who found that the addition of small quantities of carbohydrates to the dietary of diabetics raises the respiratory quotient much less than in health. He considers that this is evidence that the glucose is not properly consumed in the tissues of diabetics. Another evidence in favor of under-consumption is that carbohydrates are not converted into fats as in health. Lactic and glycuronic acids are considered by most physiologists to be intermediate products in the combustion of glucose in the system. Gly- curonic acid, like glucose, is found in minute traces in normal urine. Mayer has found the glycuronic acid excretion considerably increased in diabetes, and as he has also found it increased in conditions of suboxida- tion he thinks he has demonstrated conclusively that diabetes is due to deficient oxidation in the tissues. The evidence so far provided does not warrant us in asserting definitely that diabetes results from over-production and not under-consumption of glucose or vice versa. In the opinion of the writer, however, the evidence points much more strongly toward the view that the hyperglycsemia is due rather to under-consumption of glucose from a lowering of the powers of the tissues to oxidize carbohydrates, than to an over-production of glucose. Pavy, it will be recalled, thinks that normally the ingested carbohy- drates are converted by the intestinal villi largely into fat and into a proteid-carbohydrate, and that only a smaller quantity reaches the liver as glucose. In diabetes he thinks that this function of the villi is largely abolished; and that consequently a much larger quantity of sugar reaches the liver and general circulation, resulting in a hyperglycsemia. Cantani holds that the sugar found in the diabetic individual is not ordinary glucose, but a paraglucose which the tissues are not capable of utilizing. Consequently it accumulates and a hyperglycsemia results. His view has not received substantiation. Theory Based on the View that a Normal Glycolytic Ferment or Body is Lacking in Diabetes. — Lepine was the first to advance the hypothesis that diabetes resulted from the failure of the pancreas to produce a glycolytic ferment which was necessary to the liver in order for it to perform its glyco- genic functions. The observations of Opie and Ssobolew on the relation- ship between disease of the islands of Langerhans of the pancreas and diabetes, and the recent important investigations of Otto Cohnheim and Rahel-Hirsch on the combustion of carbohydrates, have afforded evidence strongly supporting the view that the pancreas, pancreas and muscles. 768 CONSTITVriOXAL DISEASES or pancreas and liver, prodnce a glycolytic body "which is necessary for carbohydrate metabolism, the absence of which leads to failure in the combustion of glucose antl consequent hyperglycannia. Their work has already been given in detail, and only the essential points will be recalled here to elucidate the theory under discussion. Opie showed that in diseases of the pancreas accompanied by diabetes, the islands of Langerhans were practically always diseased and presumably ren- dered functionless. He also found that in certain cases of diabetes the pancreas macroscopically appeared normal, but microscopically revealed degeneration of the islands of Langerhans as the only patho- logical change. Cohnheim, in 1903, found that muscle juice of cats and dogs when added to a solution of glucose had no effect on the latter. When, however, the expressed juice of the pancreas was added to the mixture of muscle juice and glucose there was a ra])id breaking-up of the glucose into alcohol and carbonic acid. He concludetl that in normal animals a glycolytic ferment or body results from the interaction of substances produced by the pan- creas and muscles, and that this is necessary for the combustion of glucose. Opie's observations on the pancreas suggest very strongly that the pan- creatic part of the glycolytic body is produced by the islands of Langer- hans, and Ssobolew claims to have shown that this is the case. The work of these observers is extremely suggestive, and constitutes one of the most important contributions to our knowledge of the etiology of diabetes that has ever been made. It seems to afford an explanation for the development of diabetes after extirpation of the pancreas. Some ob- servers claim to have found no disease of the islands of Langerhans in certain cases of diabetes. In these cases two possibilities present them- selves. The islands may not be organically but functionally diseased. On the other hand the muscles may be at fault. The evidence thus afforded seems to justify us in strongly suspecting that in health the pancreas and muscles (and possibly other tissue-cells) pro- duce substances tohich, by their interactio7i on each other, yield a glycolytic body — call it a glycolytic ferment if tve will — ivhich is necessary for the proper combustion of the glucose in the body. This body may be necessary also for the normal glycogenic function of the liver to be carried on. Its absence would lead to an under-consumption of glucose with a resultant hyperglycaemia. It must not be forgotten that Cohnheim's results have not been confirmed by some of the workers who have repeated his experi- ments. Consequently, any explanation as to the etiology of diabetes based upon them is still in the hypothetical stage. If Cohnheim's work be correct it must necessarily add additional support to the view that the hyperglyctemia in diabetes is due rather to deficient consumption or lowered oxidation than to over-production of glucose. One seems justified in predicting that in the future it will be shown that a much larger percentage of cases of diabetes is due to pancreatic disease than was formerly believed. The recent advances in our knowledge of the physiology and pathology of the gland seem to warrant this pre- diction. It is quite probable that all cases of diabetes cannot definitely be attributed primarily to disordered metabolism — the cases of "pure" diabetes of Xaunyn — or to pathological lesions in the pancreas. A com- DIABETES MELLITUS 769 paratively small number are due primarily to functional or organic disease of the central nervous system, as noted in the consideration of the etiology. Pathology. — The etiology and pathology of diabetes mellitus are so clearly related that it is almost impossible to discuss one without the other. In the section on etiology those morbid lesions which were believed to be the cause rather than the result of the diabetes have already been con- sidered. Thus the organic lesions of the nervous system, liver, and pancreas which are so important in the etiology of diabetes, have been fully discussed. In order to prevent repetition, these will not be fully con- sidered here. The morbid changes not already considered, and, partic- ularly, those which are regarded as the result of the disease, will now be briefly considered. The blood always shows a hyperglycaemia. The only exceptions to this rule are the cases of phloridzin diabetes and the other rare instances of so-called "renal" diabetes which have been described by Kemperer and Naunyn. In these cases there is a hypoglycsemia. The blood is often concentrated. The specific gravity may be increased or diminished, according to the water content. In cases with marked polyuria, in which the watery constituents of the blood are depleted, the red cells may be 6,000,000 per cmm. or more. The latter react differently from those of normal blood with certain aniline dyes. Bremer found that smears of diabetic blood, heated for six to ten minutes at 135° C. and immersed for one to two minutes in a 1 per cent, aqueous solution of congo-red, remained unstained, while smears of normal blood take the red stain. The red cells of diabetic blood also stain differently with eosin and methy- lene blue. The leukocytes are usually normal in number, or increased only in proportion to the concentration. The writer has observed a leukocytosis of from 18,000 to 25,000 in diabetic coma. The leukocytes contain glycogen. The alkalinity is reduced, particularly in coma. This is occasioned by the presence of /?-oxybutyric and diacetic acids. Ace- tonsemia may occur. Lipcemia occasionally occurs. The fat may be de- tected in the form of numerous minute dancing granules in the serum in thick preparations of fresh blood. The separated serum has a decided milky appearance. Fraser, in 1903, reported a case in a diabetic with a fatal coma. The percentage of fat in the blood was 16.44 per cent. Fischer recorded a case with 18.12 per cent., the highest ever reported. According to Becquerel and Rodier, blood normally contains from 0.16 to 0.325 per cent, of fat. Exudates in the serous sacs may be turbid with fat. The lipajmia has been attributed to the over-ingestion of fats, to fatty degeneration of the viscera, and to deficient lipolysis. In Fraser's case, the appearance of the lipsemia was coincident with a marked reduction in the sugar of the blood, and he thinks that the fat may be derived from the glucose. The fat droplets take the characteristic stains with Sudan III and osmic acid. No characteristic changes are to be found in the gastro-intestinal tract. Frerichs frequently found a thick layer of a fungus growth in the mucous membrane of the fauces and oesophagus. Occasionally the stomach has been found dilated. Swelling, redness, and ecchymoses of the gastric mucosa, have been noted. Tuberculous ulceration of the intestine may occur where there is pulmonary tuberculosis. 49 770 CONSTITUTIONAL DISEASES The heart may be hypertro[)hiod, but this is rare. The myocardium is often pale and soft. In old-standino- cases, advanced fatty degeneration of the muscle-fibers is common. Pericarditis and endocarditis rarely occur. Arteriosclerosis is rather common. Of the pulmonary lesions, tuberculosis is probably the most common. The tissues of the diabetic seem to furnish a specially good medium for the growth of the tubercle bacillus. Acute bronchopneumonia and lobar pneumonia may occur, and either may terminate in gangrene. The writer has seen one case of bronchopneumonia terminate in abscess formation. Ch'ohe, Kiihne, and Ehrlich, have shown the cells of the pneumonic exudate to be rich in glycogen. A chronic non-tuberculous interstitial ])neumonia has been described. So-called fatty emboli of the pulmonary arteries occur in coma, but are of no pathological significance. The liver is usually somewhat enlarged, and fatty degeneration is com- mon. The form of cirrhosis designated by Hanot as cirrhose jncjvien- iaire diahetique, which is one of the lesions of htemochromatosis in which diabetes may develop as a late manifestation, has already been described. Poverty of the liver in glycogen is a striking feature. The jxmcreatic lesions have been described. There are no changes in the gland that are regarded as secondary to the disease. The kidneys are often enlarged. The most characteristic change is a hyaline degeneration of the epithelial cells of Henle's loop, described by Armanni and sometimes spoken of as the lesion of Armanni. The affected cells present a swollen, transparent appearance, as if transformed into large hyaline vesicles. The nuclei stain well and are pushed to the periphery. Cantanniand others have confirmed Armanni's observations. Ehrlich and Frerichs have described a glycogenic degeneration of the same cells as are involved in Armanni's lesion. The degeneration can be demonstrated macroscopically by treating the kidney section with Lu- gol's solution, the affected portion taking on a red color. Straus holds that the hyaline changes described by Armanni and the glycogenic changes described by Ehrlich and Frerichs, are really of the same nature. In some cases he has demonstrated the hyaline changes without finding glycogen present. In such cases, he thinks that the glycogen has been present at one time, but has disappeared before death, leaving only the hyaline changes. Ebstein has described a necrosis of the renal epithelial cells, similar to the coagulation necrosis of Weigert in other diseases. Interstitial and parenchymatous nephritis may occur, but there is no reason to believe that diabetes is the cause of the nephritis in these cases. A cystitis occasionally occurs. It has been attributed to irritation by the saccharine urine, but it is more likely due to bacterial infection. Of the lesions of the nervous system not already described, Saundby states that congestion and oedema, and thickening of the membranes of the brain, may occur. Williamson, Sandmeyer, and Kalmus, have des- cribed a degeneration of the posterior columns of the cord similar to the sclerosis of these tracts in tabes dorsalis. Williamson states that the lesion is best seen with the naked eye, when the affected portions appear much paler than does the healthy white matter. These changes are attributed to the action of some toxic agent. The peripheral nerves, particularly those of the lower extremities, may be the seat of an inter- stitial inflammation, with secondary degeneration of the axis cylinders of DIABETES MELLirUS 771 the nerve fibers. This neuritis may be the cause of definite cHnical symptoms. Symptoms. — Various writers have been disposed to recognize certain chnical types of the disease. Thus acute and chronic cases are described. The acute cases generally occur in children and young adults, the emacia- tion being marked and the course very rapid. The chronic cases usually occur in persons who develop the disease after the fortieth year, and in middle-aged and elderly obese individuals. The acute cases, however, may occur in the aged. Osier reports a man aged seventy-three years in whom the entire course of the disease was less than three weeks. There are the mild and the severe cases. According to Naunyn, if the glucose disappears with the patient on a non-carbohydrate diet, the case belongs to the former type. If, on the other hand, he continues to excrete glucose, the case is a severe one, for it means that sugar is being produced from the body proteids. Further, we have the fat or lipogenous (diabete gras) and the emaciated (diabete maigre) cases. Lancereaux believed the latter were caused by lesions of the pancreas. Exogenous and en- dogenous cases have been described. The former embrace the cases in which there is some external exciting cause. The latter, according to Striimpell and others, include those in which there is no apparent external etiological factor, or any evident organic lesion, but in which the disease is thought to be due to some developmental abnormality. We have also the neurotic cases due to injuries or functional disorders of the nervous system. There is no fundamental difference in any of these cases, and no satisfactory classification, along the lines indicated, seems possible. Although the disease is usually accompanied by a certain group of symptoms which especially characterize it, and which may be so abrupt in their onset that the patient can state the date of their appearance with considerable accuracy, yet these may for a long time remain in abeyance, and may even never become a prominent feature. Thus the polyuria, thirst, increased appetite, emaciation, and weakness, may not be suffi- ciently marked to attract the patient's attention. The first intimation of there being anything wrong may be a gradual failure in vision. An ocu- list is consulted who, finding a commencing or well-developed cataract or a retinitis, suspects diabetes, and orders an examination of the urine, which results in his suspicions being confirmed. On the other hand, the patient may consult the family physician for an obstinate general or localized pruritus as the first symptom, with the same results. Similarly, a furunculosis, a severe neuralgia, or impotence, may cause the patient to seek advice. Occasionally general weakness, nervousness, slight change in temperament, mental hebetude, and inability to apply himself to business, may antedate the characteristic symptoms. Too often, un- fortunately, the cause of such symptoms is not discovered sufficiently early, and the disease gets a firm foothold and has seriously impaired the general health before it is finally recognized. Polyuria is the symptom most frequently first complained of by the diabetic. In the acute cases, the patient asserts positively that the quan- tity of urine suddenly became greater, and that he is obHged to get up frequently at night to pass urine. The increase in the quantity of urine is referable to the hyperglycsemia. Owing to the increased quantity of glucose in the blood, the latter becomes hyperisotonic, and the fluids of the 772 COXSTITUTIOXAL DISEASES tissues arc absorbed into the circulation more rapidly than in the nornial individual, and consequently more water is secreted by the kidneys. The amount of urine may reach 10 to 20 liters (5 to 10 quarts) daily in the severest cases, although it is rare to see cases in which more than 10 liters is voided in the twenty-four hours. The amount of uriiie in the majority of cases ranges between 2 and 5 liters. The quantity usually bears a direct relationship to the percentage of sugar excreted. In certain cases it is well to remember that there may be no increase in the urine even when glycosuria is present. Thirst, or polydi})sia, may be extreme, and may be complained of as early as, but more often very soon aftt-r, the polyuria. It is indirectly traceable to the hyjierglycaniiia, and directly to the dessication of the tissues already described. It bears a definite relationshij) to the polyuria. Increased appetite (bulimia or polyphagia) is a frequent symptom, particularly in the very acute cases. In the milder forms, and in the advanced stages of the severe type, this symptom may be wanting. There may even be loss of desire for food. Notwithstanding the enormous amount of food eaten, ])rogressive emaciation is the rule, es])ecially in the young individual. The increased a]:)])ctite and the emaciation are largely dependent upon the same cause — the failure of the diabetic organism fully to utilize the carbohydrates of the food. The nutritive changes in diabetes are interesting and deserve some consideration. An individual doing light work requires about 40 calories for each kilo body-weight daily, although the recent work of Chittenden seems to indicate that this caloric requirement is too high. Thus a person of average weight would require food to yield 2,400 calories for his nutritive needs. Let us su})pose this individual to be suffering from diabetes and to be taking a mixed diet including proteids, fats, and carbohydrates, in the following proportions with their caloric ecjuivalents: 160 grams of albumin, yielding 656 calories; 110 grams of fat, yielding 1,023 calories; and 240 grams of carbohydrates, yielding 984 calories. This diet, therefore, would provide a total of 2,663 heat units, or 263 more than would be required by the individual were he perfectly healthy. Let us suppose, however, that he is excreting 140 grams of sugar daily. He would therefore lose each day nutritive material to the value of 140X4.1=574 calories. The food of this diabetic consequently would have the value of only 2,663 — 574 =2,089 calories. As the estimated nutritive need was 2,400, there Avas a daily deficit of 2,400 — 2,089=311 calories. The body, therefore, in order to meet the requirements of energy and heat production, must have consumed of its own substance to the value of 311 calories. The tissues drawn on for fuel material to make up for this caloric deficit are, of course, the albumin- ous and fatty. By estimating the amount of nitrogen in the food and in the urine and faeces, it is possible, accurately, to determine the exact proportion of body-fat and albumin consumed daily to make up for the caloric loss resulting from the failure of the organism to utilize all the ingested carbohydrates OAAing to a considerable quantity being eliminated in the urine as glucose. Tliis consumption of his own body-fat and albumin necessarily occasions a progressive loss in weight, and the hypothetical case illustrates how the emaciation is brought about. The latter will con- tinue unless the diet is so regulated as to prevent a loss of sugar in the urine. Von Noorden explains the polyphagia in the following way; DIABETES MELLITUS 773 "The sufferer from this disease whose diet is not regulated by medical advice, swallows great quantities of food, including much carbohydrate. The 'stomach hunger' is momentarily stilled, but quickly returns, for 'tissue hunger' is not satisfi(Ml. The inordinate appetite of the diabetic disappears only when the useless carbohydrates are cut off and their place sup})lied by albumin and fat. When this is done the emaciation of the patient comes to a halt, with relief of the polyphagia." The face is often of a deep red color. The skin of the entire body in the majority of cases is dry and harsh. This is due to the fact that the sweat, as is the case with nearly all the secretions, with the exception of the urine, is diminished in amount. The skin may be moist, however. In cases complicated by pulmonary tuberculosis, sweats may occur, and they have been known to alternate with polyuria. The nails are often brittle, and the hair thin and dry. There may be some irritability of temper. There is a strong tendency for the individual to become morose or even hypochondriacal. Some complain of extreme drowsiness during work- ing hours. The temperature in uncomplicated cases is usually subnormal. The pulse is generally increased in frequency, with the pulse-tension above normal. The mouth is dry, due to the thirst and to the diminished salivary secre- tio'ii. The saliva is less alkaline than in health, and that collected from Steno's duct is usually acid in reaction. Frerichs, von Noorden, and Mosler, found the saliva almost without exception free from sugar. Fre- richs demonstrated sugar in one out of nine cases. The tongue is usually dry and red, and often has a glossy appearance resembling that in psori- asis linguae. The digestion, notwithstanding the enormous quantities of food taken, is, as a rule, good. Obstinate constipation is the rule. The eye-sight, owing to the ocular complications, is often defective. Pain in the lumbar region is often an annoying symptom even early in the disease. Cramps in the calves of the legs occasionally cause much discomfort. Owing to the lowered vitality of the tissues, and owing to the latter being richer in sugar than normally and consec]uently being a better nutritive medium for the growth of organisms, wounds heal less readily and are much more liable to become infected. In patients with secondary lesions of the cord or peripheral nerves of the lower extremities a sensation of a "giving away" of the knees may be complained of. This occasionally occurs, however, even without nervous manifestations. Loss of sexual desire and power in men is common, and may be an early feature. It may reach the grade of actual impotence. Sexual power may return, according to Seegen, with improvement in the patient's other symptoms while under treatment. Occasionally increased sexual desire and power persist throughout the disease. In severe cases of diabetes in women the sexual desire is much impaired, but in mild cases in elderly women it is said to be often increased. Amenorrhoea is not uncommon, and may occur early in the disease. The Urine. — The amount of urine has been considered under polyuria. It is usually extremely pale and clear. The quantity and pallor generally bear a direct relationship to the percentage of sugar present. Occasion- ally one sees diabetic urine of quite deep color. In these cases there is little or no polyuria. It often has a suggestive greenish tint, and may, when shaken, have a syrupy consistency. It has a sweet taste, and in severe cases 774 CONSTITUTIONAL DISEASES with threatening coma, may have a sweetish, fruity odor, owing to the presence of acetone. The specific gravity usually ranges between 1,025 and 1,045. A jiale urine with a specific gravity above 1,025 should always lead one to suspect the presence of sugar. In rare instances diabetic urine with sugar demonstrable may have a specific gravit}^ of 1,015 or even lower. A specific gravity above 1,050 is rare. Naunyn has seen a case with 1,000. The highest si)ecific gravity recorded was in two cases re- ported by Bouchardat and Prout, in each of which it was 1,074. Very high specific gravities — 1,070 or over — always suggest fraud. The most characteristic feature is the presence of sugar and the diag- nosis is largely dependent upon this. This is almost invariably grape- sugar (glucose, dextrose). Normal urine contains glucose in quantities not demonstrable by the ordinary tests. In rare instances levulosuria may occur either with glycosuria or alone. Authentic cases have been reported by Seegen, Kiilz, and ]\Iay. Kiilz and Vogel have frequently noted pentosuria in human diabetes, and in experimental diabetes in animals, even after prolonged fasting, showing that the pentose originates in the animal body. The amount of sugar excreted varies considerably at different periods of the day. The period of minimum output is in the late night or early morning hours. According to Naunyn there are two periods of maximum output; one in the late morning hours, the other about six o'clock in the afternoon, occasionally lasting until midnight. The amount of sugar usually begins to increase about one and a half to two hours after a meal. The percentage of sugar should be determined from a sample of urine taken from the mixed twenty-four hour amount. Knowing the total amount of urine, it is then easy to calculate the total amount of sugar, in grams or grains, excreted daily. This is the only satisfactory way of following the progress from day to day or from week to week. Variations in the percentage of glucose excreted at different periods of the day are much less marked in the severe than in the mild cases, and in the former, the sugar of the night urine may exceed that of the day. In the latter, the variations are often quite marked and the urine of the early morning hours may be free from sugar. The percentage of glucose varies greatly. In the majority of cases it ranges about 3 per cent. In the severe cases it reaches 5 per cent, or over. It is very rare to meet with more than 8 or 9 per cent, although Naunyn reported a case with 11 per cent., and Higgins and Ogden a case of traumatic diabetes with 20 per cent, of glucose. The total output of sugar for the twenty-four hours may be only a few grams in the mild cases. In some cases the quantity of sugar may be enormous. It is not unusual to see cases with a daily excretion of 500 grams (15 oz.). Charcot reported a case with 1,100 grams (35 oz.), Lecorhe a case with 1,200 grams (38 oz.), and Dickinson, a case cited by Naunyn Avith the enormous output of 1,500 grams (48 oz.). Many factors influence the sugar output. Diet is the most important one. Carbohydrates cause a marked increase, whereas a diet consisting exclusively of proteids and fat will cause the sugar to disappear in mild cases and will reduce it to a minimum in the severe cases. Acute febrile diseases and septic infections often cause a marked reduction. It is not unusual in diabetes with pulmonary tuberculosis accompanied by high fever, to see the sugar almost entirely disappear in the terminal stages. DIABETES MELLITUS 775 The onset of coma manifestations with the appearance of /?-oxybutyric acid in the urine is not infrequently attended by a markerl reducticjn in the sugar excretion. The following are the most satisfactory tests for glucose : Fehling's Test. — Two separate solutions are necessary unless one uses the Haines or Purdy modification. The copper solution contains 34.65 grams of pure crystallized copper sulphate to the liter of distilled water. The alkaline solution is prepared by dissolving 173 grams of Rochelle salt in 350 cc. water, adding GOO cc. of a caustic-soda solution of a specific gravity of 1.12, and diluting with distilled water to 1 liter. For the qualitative sugar test, equal quantities of the two solutions are mixed together, then boiled, and the suspected urine, after being freed from albu- min, added a few drops at a time and then again heated. If glucose be present either the yellow hydroxide of copper or the red cuprous oxide will be precipitated. If reduction does not follow boiling, set aside for a while and a precipitation may occur on cooling, when only traces of sugar are present. Although the Fehling's test requires considerable experience in order to secure absolute accuracy as a quantitative method of determining the amount of sugar, it is probably the least expensive and most accurate of the methods available for the general practitioner where mere approxi- mate results are desired. This quantitative method is dependent upon the fact that 10 cc. of the copper sulphate solution is reduced by 0.05 grams of glucose. The determination is cai*ried out as follows: 10 cc. each of the copper and alkaline solutions are mixed in a small flask and 30 cc. of water added. If the urine has a specific gravity approximately of 1,030 the urine is diluted five times, if over 1,030, ten times. A graduated bu- rette is filled with the diluted urine. The Fehling's solution is boiled, and then the diluted urine is added at first about 1 cc. at a time and later in smaller quantity as the end reaction is approached. The solution is boiled after each addition of urine. The end reaction consists in the disappear- ance of the blue color immediately after boiling. The ability accurately to determine this point comes with experience. To determine whether the color has disappeared, allow the copper suboxide to settle a little below the meniscus formed by the surface of the liquid. If this layer is not blue on holding it on a level with the eye, the whole procedure is repeated add- ing 0.1 cc. less urine; if now, after the copper suboxide has settled, the supernatent liquid has a blue color, the titration is comjjleted. Three or four estimations should be made in order to accurately determine the end reaction. Once the amount of urine required to reduce the 0.05 grams of copper sulphate in the 10 cc. of Fehling's copper solution has been ascertained, the calculation of the percentage is easy. Let us take an example for illustration and suppose that the urine has been diluted ten times, and that 8.5 cc. of diluted urine Avas necessary to complete the end reaction. We therefore know that the 8.5 cc. of urine used contain 0.05 grams of sugar and the percentage is therefore (8.5 : 0.05 :: 100 : x) = 0.58. This would be the percentage if the urine had not been diluted. Since the urine was diluted ten times the percentage of sugar in the undiluted urine would therefore be 0.58 X 10 = 5.8. Trommer's test, in which a dilute copper sulphate solution and a solution of caustic soda or potash are used, while reliable in experienced 776 CONSTITUTIOXAL DISEASES hands, is subject to too many fallacies to be used by the general prac- titioner. Excess of uric acid or creatinin will give a similar reaction. Fermeniaiion Teni. — This is the most reliable single test we have. It is best carried out by using one of the fermentation tubes designed for bac- teriological purposes, or one of the special tubes such as Einhorn's saccharimeter (made especially for urinary work) by which also the per- centage of sugar can be roughly estimated. When yeast is added to diabetic urine and the mixture is kept at 22° to 28° C. for twenty-four hours, the sugar is decomposed and carbonic acid is given off. By measur- ing the gas given off from 10 cc. of diabetic urine (as is possible with Einhorn's saccharimeter), it is possible to determine the percentage of sugar. While this method is not absolutely accurate, for the purpose of following the progress from week to week it is sufficiently so for the general practitioner. As the yeast itself may cause a small evolution of gas, a control test with normal urine should always be made. The determination of the percentage of sugar by noting the reduction in the specific gravity after complete fermentation cannot be recommended. Bismuth Tcsi. — This is best performed with Nylander's modifica- tion of Almen's original solution. Nylander's solution is made by dissolv- ing 4 grams of Rochelle salt in 100 parts of 10 per cent, caustic soda solution and adding 2 grams of bismuth subnitrate and digesting in a water-bath until as much of the salt is dissolved as possible. To 10 cc. of urine add 1 cc. of Nylander's solution and boil two or three minutes. If glucose be present the urine becomes yellowish, yellowish-brown and finally black from a deposition of metallic bismuth. A simple modifica- tion is to render 10 cc. of suspected urine alkaline with caustic soda and then add a small amount of bismuth subnitrate and then boil (Botger's test). This on the whole is a delicate and reliable test. It shows 0.5 per mille of sugar. Combined glycuronic acid will cause a reduction and fallacies may result from the administration of chloral, salol, rhubarb, antipyrin, and turpentine. Polariscope Test. — Glucose is dextro-rotatory, so that urine containing it will rotate the rays of polarized light to the right. By measuring the degree of rotation, the percentage of urine can be accurately determined when above 0.2 per cent. For hospital and laboratory purposes, it is the quickest and most satisfactory quantitative test. Half-shadow and circular-shadow polariscopes are made especially for estimating the quantity of sugar. Albumin should first be removed. /9-oxybutyric acid is Ifevo-rotatory, and when present will neutralize some of the dextro- rotatory action of the glucose. Phcnylhydrazin Test. — This can be carried out by von Jaksch's simple method. To 8 to 10 cc. of urine in a test-tube add 2 knife-points of phenylhydrazin hydrochloride and 3 knife-points of sodium acetate, and if the salts do not dissolve on warming, add more water. Heat in a water-bath for one hour. Then cool by placing a test-tube in cold water. If sugar be present a yellow deposit of phenylglucosazone occurs which on microscopic examination is found to have a yellow color and to be arranged in sheaves and stars. Glycuronic acid and other substances yield similar crystals of an osazone. When any doubt arises, the crystals can be differentiated by determining their melting-points. Those yielded by glucose melt at 204° to 205° C. DIABETES MELLITUS 777 While there tire other tests for gUicose, those above described are the ones which give the best resuhs. Bremer showed that diabetic urine readily dissolved gentian violet powder, whereas normal urine fails to. He suggested this as a test. Unfortunately the urine in diabetes insipidus reacts in the same way. Precautions to Observe in Performing the Sugar Tests. — It is a safe rule never to rely on one qualitative test alone. The most reliable single test is the fermentation test. If there is a rapid reduction of the coijper sulphate in performing Fehling's test, one can be reasonably certain that the reducing agent is glucose. Where it is slow and slight, and, especially, if the precipi- tate be yellow rather than red, other reducing agents must be considered and eliminated. The other substances which reduce alkaline copper sul- phate solutions are conjugated glycuronic acid sometimes eliminated after the taking of certain drugs, alkapton (homogentisic acid), lactose, excess of uric acid, and kreatinin. The conjugate glycuronic acid also reduces bismuth, but is differentiated from glucose by being lievo-rotatory as voided, becoming dextro-rotatory when the glycuronic acid is split off by boiling with an acid. It does not ferment. Alkaptonuric urine is recog- nized by being negative with the bismuth, fermentation, and polariscope tests. Its special feature is its darkening on exposure to the air and on the addition of an alkali. I^actose, which is very frequently eliminated in the urine in the early days of lactation, and when there is retention of the milk in the breasts either from obstruction of the milk-ducts or from sore nip- ples, reduces copper sulphate and bismuth, and is dextro-rotatory, but does not ferment. Although excesses of uric acid and kreatinin may cause slight reductions of copper sulphate, there should be no difficulty in differ- entiating these from glucose if one takes the precaution to use one or more of the other tests, with which they are negative. It is a safe precaution to use at least both Fehling's and Nylander's bismuth solution as qualitative tests for sugar. The latter is a little more delicate and more reliable than the former. If a polariscope be available and the urine be found to be dextro-rotatory in action, there is little doubt about the reducing substance being glucose. When any doubt exists, the fermentation test, the most reliable of all, should be tried. Other Urinary Ingredients in Diabetes. — Mayer has shown that glycu- ronic acid, like sugar, is present in normal urine in minute traces, and that it is increased in diabetes. It is regarded as one of the intermedi- ary products of carbohydrate metabolism. It is recognized by the orcin test. Rosin and Alfthan demonstrated that the benzoyl esters are also increased. These normally do not exceed 2 to 3 grams daily. Edsall has found as high as 12.5 and 13.8 grams respectively in three cases of diabetes. Mayo Robson and Cammidge, have shown that in pancreatic disease glycerine is excreted in the urine. The glycerine results from the splitting up of the fat molecule in the areas of fat necrosis. Cammidge claims to have found it in one case of diabetes due to pancreatic disease. The de- tails of the test cannot be given here. Considerable doubt has been ex- pressed as to the value of this test and also as to whether the authors have properly interpreted their results. The urine of diabetics before and during coma symptoms very frequently, if not always, contains ^-oxybutyric acid and its derivative products, 778 CONSTITUTIONAL DISEASES diacetic acid and acetone. The tests for these substances may be briefly stated here. It is possible, by a process too long to be described here, to isolate ^-oxybuii/ric acid (C4II8O3) from the urine in crystalline form. On being boiled "with a mineral acid it is decomposed into o:-crotonic acid, the crystals of -which melt at 71 to 72° C, by which test it can be recognized. Its probable presence can be detected in two ways. Being a hvvo-rotator, its presence may be assumed if, after completely fermenting the urine, the urine rotates the rays of polarized light to the left. For the same reason its presence may be suspected if the percentage of sugar is found to be con- siderably higher by the Fehling's than by the polariscope method. This is due to the fact that dextro-rotatory power of the glucose is partially neutralized by the kevo-rotary power of the acid. Diacetic acid (C^IIeOg) is practically always present when the urine contains ^-oxybutyric acid, but the reverse is not always the case. The molecule of /9-oxybutyric acid by taking on an atom of oxygen splits up into diacetic acid and water. The former is now universally accepted to be the source of the latter. The urine must be fresh in testing for dia- cetic acid, for it readily breaks up into acetone and carbonic acid. It is recognized by Gerhardt's ferric chloride test. To 10 cc. of urine add a solution of ferric chloride until all the phosphates are precipitated as iron phosphate. Filter and continue to add ferric chloride to the filtrate. If diacetic acid be present, the urine now takes on a claret or Bordeaux-red color. Salicylic acid will give the same reaction. To differentiate them, boil a second portion of the urine for five minutes and follow the same procedure. If the Bordeaux-red color of the first test be due to diacetic acid, it fails to appear in the second, while it persists if due to salicylic acid, because the former is volatile and the latter is not. A third portion is treated with sulphuric acid and shaken with ether. The ether extract is decanted off and shaken with a very dilute watery solution of ferric chloride. If diacetic acid be present, the watery layer takes on a Bor- deaux-red color which disappears on heating. It is very unstable and quickly becomes broken up into acetone and carbon dioxide. This instability renders it impossible to quantitatively determine the amount of diacetic acid in the urine. The diacetic acid and acetone are estimated together and recorded in terms of total acetone. Acetone (CsHgO), when present in large quantities, may give the urine a fruity odor. It may be recognized by Legal 's sodiuni-nitroprusside test. To 10 cc. of urine add a few drops of a fresh solution of sodium nitro- prusside. Then add caustic potash or soda solution, and, if acetone be present, the urine assumes a ruby-red color. Creatinin gives the same color, but if glacial acetic acid be now added the color becomes carmine or purplish-red in the presence of acetone, but yellow and gradually green or blue in the presence of creatinin. This test is not so delicate as Lieben's iodoform test. Distil the urine and treat the distillate with caustic potash, and then add Lugol's solution. If acetone be present, the distillate becomes yellowish-white, owing to the formation of iodoform, which is recognized by its odor and by hexagonal or stellar crystals on microscopic examination. A very large percentage of diabetic urines will give a positive reaction with this test. For mere traces of acetone it is the most delicate of the various tests. Of the three substances just con- DIABETES MELLITUS 779 sidered it is the one most frequently found. There is no relationship between the quantity of these "acetone bodies," as the three are often called, and the amount of sugar excreted. The nitrogen output is greatly increased, chiefly in the form of urea. This is due largely to the greater amount of proteids ingested, but also in part to increased destruction of the body proteids in the more severe cases. Pettenkofer and Voit have shown that, even when fasting, a diabetic patient excreted about 8 per cent, more urea than a healthy person. Leo has shown that the addition of carbohydrates to the diet of a diabetic will occasionally diminish nitrogenous metabolism. An interesting feature is the extraordinary increase in the ammonia output in the severe cases, particularly when coma supervenes. According to Neubauer, the average amount of ammonia excreted in the urine by a normal individual on a mixed diet is about 0.7 grams daily. Part of the ammonia which should go to form urea is utilized in neutralizing the acids producing the acid intoxication. Naunyn reports having found an excretion of 5.8 grams of ammonia in a child weighing 48 pounds, and states that a daily excretion of 6 to 7 grams is not unusual in adult dia- betics. Although this amount is not often exceeded, Stadelmann records a case with an elimination of 11 grams. The amount of ammonia excretion can be taken as a safe measure of the grade of acid intoxication in diabetes. The uric acid excretion is usually increased, as has been shown by Naunyn, Riess, and others. Gaethgens, in a diabetic with fever, found the uric-acid excretion was 2.2 grams in the twenty-four hours. The increase is explained by the excessive proteids taken. It is very common to see diabetic urines with uric acid sediments. This precipitation is probably in part due to the diminished power of diabetic urine to retain uric acid in solution. Bischofswerder has shown that the total alloxuric bodies are also increased. Senator found the creatinin increased up to 2 grams daily. This is referable to the increased ingestion of meat and to the in- creased destruction of the muscular tissues of the body. Oxaluria often occurs, with an actual increase in the excretion of cal- cium oxalate. Teubaum has shown that the lime-salts are markedly increased in severe cases of diabetes, but not in the mild. The sodium chlor- ide is increased. The sulphates and phosphates are in excess, owing to the increased destruction of ingested and body proteid, with oxidation of the sulphur and phosphorus of the proteid molecule. A form of "phos- phatic diabetes " has been described by Tessier, Ralfe, and others, due to an excessive excretion of calcium phosphate. There is nervous irritabil- ity, deranged digestion, emaciation, and pain in the back. In severe cases there may be polyuria, and the spnptoms may simulate diabetes. The affection has really nothing to do with true diabetes, although it is said that traces of sugar have been found in some cases or have subsequently developed. Albuminuria is absent in the majority of cases of diabetes when they are first admitted to a general hospital. In private practice, w^here a larger proportion of mild diabetes in elderly persons is met with, it is more common. Five groups of cases of albuminuria may be recognized: (1) Cases of severe diabetes of considerable duration, with traces of albumin, but no other evidence of actual nephritis. (2) Those in dia- 780 COXSTITUTIOXAL DISEASES betics of advanced age, with indications of arterial changes. (3) Those in which, in addition to albuminuria, there are evidences of chronic neph- ritis, such as oedema, headaches, albuminuric retinitis, and cardiovascu- lar changes. (4) Cases of severe diabetes complicated bv diabetic coma. AVhen coma symptoms have definitely manifested themselves, albuminuria is practically always jnvsent. (5) Cases in which the albuminuria is due to a cystitis, or a balanitis in the male and vulvitis in the female. Naunyn and others state that diabetes mcllitus occasionally passes over into a true nephritis, with disappearance of the glycosuria. Casts are rare in diabetic urine except in those cases complicated by actual nephritis. There is one striking exception, however. Kiilz first pointed out that diabetic coma is accompanied by an abundant deposit of casts. A urine previously free from them and quite clear may suddenly become turbid, even on voiding, owing to the enormous number of casts present. In a very short time these settle to the very bottom of the glass as a grayish-white sediment. When pipetted off and examined micro- scopically, the field is foimd to be crowded with rather short hyaline and granular casts. The albuminuria and cylindruria of diabetic coma are probably evidences of a toxic nephritis. In cases of cystitis, balanitis, and vulvitis, pus-cells will be found in the urinary sediment. Diabetic urine, on standing, soon becomes turbid, owing to the growth of yeast-cells. This fact is of practical importance, as it indicates that sus- pected urine should be examined qualitatively and quantitatively as soon as possible after being voided, particularly in -v^-arm weather. The yeast causes fermentation of the sugar, and where the glycosuria is slight, it may cause a complete disappearance of the glucose, and in all cases will cause a reduction in the percentage of sugar on quantitative determination. The presence of yeast-cells in a urinary sediment should always arouse a suspicion of the existence of glucose. In balanitis in the male and vulvitis in the female, resulting from the constant irritation of the saccharine urine, there is often a fungus growth in the inflamed mucous surfaces, and fungus spores and mycelia may consequently be washed away in the urine dunng the act of voiding. These may be recognized in the urine on microscopic examination. Occasionally yeast-cells and fungi develop in the bladder and set up fermentation processes, with the evolution of gas, producing fneumaturia. This is a rare condition. Leube found that diabetic urine contains a sub- stance which gives all the reactions of glycogen. Lipuria has been de- scribed, the fat occurring in the form of a fine emulsion. Complications. — 1. The Skin. — Boils and carbuncles are very com- mon, so much so that when they exist one immediately thinks of diabetes as a cause. Their frequency is due to tke susceptibility of the tissues of the diabetic to infection. Boils are more common in the milder forms of the disease and in stout diabetics. Seegen says he has never seen boils in an advanced stage of the disease. The commonest seats are the neck, back, and buttocks. Cultures usually show staphylococci, and the Staphylococ- cus aureus or albus may occur in pure culture. Carbuncles are less com- mon but more serious. They are more likely to occur in the severe cases. The commonest situations are the back of the neck and between the shoulders. With the surrounding cellulitis the area involved may reach 20 cm. (8 in.) or more. They may precipitate an attack of coma. DIABETES MELLITUS 781 Owing to the irritation of the genitals hy the saeeharine urine, and to the growth of fungi (hyi)homyeetes) in the superficial layers of the skin, in- flammation of the prepuce and glans in the male, and vulvitis in the female, may occur. This may be attended by intolerable pruritiis pudendi, par- ticularly in women, in whom local boils or phlegmons of the genitals may develop. The general pruritus of diabetes is due in all probability to irritation of the sensory nerves by the sugar in the blood, just as pruritus in jaundice and uraemia is due to circulating toxins. Urticaria, pur- pura simplex, purpura hemorrhagica, dermatitis herpetiformis, gan- grcena diabetica bullosa serpiginosa (Koposi) may occur. (Edema of the feet, even without evident renal or cardiac affections, is not uncommon in advanced cachectic cases. A curious mottled cyanosis of the extremities is sometimes observed. In rare instances, the skin may be bronzed, con- stituting the so-called diabete bronze cases. The pigmentation is a symp- tom of the disease known as hsemochromatosis, in which glycosuria sometimes occurs in the late stages when the interstitial pancreatitis be- comes marked. Herpes zoster and perforating ulcer of the foot occasionally occur, and are expressions of a diabetic neuritis. A paronychia diabetica may occur. This may result in the loss of the nails. Williamson has observed three cases with bulbous fingers, due apparently to vasomotor changes. Spontaneous diabetic gangrene occurs usually in diabetics after fifty. The glycosuria is usually of a mild grade. It is commonest in the lower extremities, and generally begins with a bluish discoloration and then a blackening of the skin of the big or little toe. It is of a moist type and may subside, but usually extends gradually to involve the whole foot or leg until stopped by amputation. It may start in the heel. William Hunt analyzed 64 cases. In 50 the distribution Avas as follows: feet and legs, 37; thigh and buttock, 2; nape of the neck, 2; external genitals, 1; lungs, 3; fingers, 3; back, 1; eyes, 1. The artery supplying the affected area shows arteriosclerosis in the vast majority of cases. In many instances it is thrombosed, and Naunyn states that he has never failed to find obliteration of the pulse in the early stages of the complication. Phlebitis, particularly of the veins of the leg, occasionally occurs. It was present in 1 case in the Johns Hopkins Hospital series. Xanthoma diabeticorum occurs as a very rare complication. Up to 1892, Morris could find only 21 cases reported. The lesions consist of small nodules about the size of a pea, and having a yellowish or yellowish- red color They are slightly sensitive and occur mainly on the buttocks, forearms, and knees. The eyelids are much less likely to be involved than in the xanthoma multiplex accompanying chronic jaundice. The xanthomata appear rapidly and disappear quickly with relief of the glycosuria by diabetic treatment. They may recur several times. 2. Gastro-Intestinal. — An aphthous stomatitis due to the oidium albi- cans occasionally occurs. At autopsy the pharynx and oesophagus often show a diffuse growth of this fungus. Gingivitis with pyorrhoea alveolaris frequently develops. The teeth decay rapidly and tend to loosen and fall out. The latter is probably due to a trophoneurosis. Gastrectasia occa- sionally results from the enormous quantities of food and liquids taken. There may be actual gastric catarrh. Although moderate constipation is the rule, one occasionally meets with a case with obstinate diarrhoea. This 782 CONSTITUTIONAL DISEASES is referable to an intestinal catarrh. Stcatorrhoca, or fatty stools, may occur in pancreatic diabetes. Here fat digestion is interfered with, owing to changes in the pancreatic secretion, and the stools are of a puli)y con- sistence, of a dirty, dark-gray color, and of a greasy appearance. In these cases the movements are often very bulky, and at the end of defecation as much as a tablespoonful of almost pure fat may be passed. In a patient seen with A. D. Atkinson, of Baltimore, the autopsy revealed the presence of a large pancreatic calculus. INIicroscopically, large oil-globules and abundance of fatty acid and soap crystals are seen. 3. Pulmonary, — One of the commonest is pulmonary tuhcrndosis. Griesinger analyzed 250 cases of diabetes, and found ])ulm()nary tubercu- losis present in 42 per cent., and to be the cause of deatli in 39 percent. In 50 autopsies, Frerichs found the lungs tuberculous in 25. In 149 of Naunyn's "pure" diabetes cases, it was present in 25, or 17 per cent., w'hile in 113 cases, due to evident organic disease, there were 8, or 7 per cent. With the progress of the tuberculous process the glycosuria often diminishes, or may entirely disappear. Death may result from acute pneumonia, either lobar or lobular, A chronic interstitial pneumonia may occur. The pneimionia may be com- plicated by abscess of the lung. In 1 of the Johns Hopkins series there Avere multiple abscesses in the pneumonic area. Gangrene of the lung is not very uncommon, Naunyn saw 12 cases, all of which terminated fatally with one exception. He describes three forms — an acute, a sub- acute or chronic, and a form with numerous gangrenous foci complicating a chronic pneumonic process, with fibrous induration. 4. Renal, — These have been sufficiently dealt with in the accounts of the pathology and of the urine, 5. Nervous System, — Here only the nervous features directly refera- ble to the diabetes will be considered. It is of interest that glucose has been found in the fluid obtained by lumbar puncture. (a) Peripheral Neuritis. — This is the commonest nerve complication. The numbness, tingling, cramps, and neuralgias, are probably expressions of a mild neuritis. Sciatica is not uncommon, and other peripheral nerves, such as the inferior dental, may be affected. The neuritis may be multiple. Thus both ulnar nerves may be involved, causing muscular paralysis and anfesthesia of the skin. As expressions of the neuritis, must be mentioned jailing out of the nails, glossy fingers, herpes zoster, and perforating ulcer of the foot. The perforating ulcer closely resembles that of tabes. Williamson met 4 out of 140 cases. It occurs nearly always in men, and in appar- ently mild cases. The sole of the foot, in the region of the metatarso- phalangeal joint, is the commonest seat. The bone may be exposed or the joint opened. A corn may precede the ulcer. Attempts to remove the corn lead to infection, and the ulcer proceeds. On the other hand, trophic changes, due to the neuritis, constitute the chief etiological factor, and the ulcer may commence with superficial death of the skin. The ulceration is often painless. As the knee-jerks are often absent, the lesion may be mistaken for the perforating ulcer of tabes unless the urine is examined, A so-called diabetic tabes, resulting from a polyneuritis, has been de- scribed. This pseudotabes closely resembles true tabes dorsalis, and was first described by Fischer, in 1886. It is characterized by lightning DIABETES MELLITUS 783 pains in the legs, loss of knee-jerks, and loss of power of the extensors of the feet. There is a characteristic steppage gait similar to that seen in arsenical, alcoholic, and in other forms of ncuritic paralysis. A typical Argyll-Robertson pupil is rarely, if ever, present, although Charcot states that there may be atrophy of the optic nerve. (b) A diabetic paraplegia, probably due to a peripheral neuritis, with paralysis of the arms and legs, has been described. (c) Degeneration of the posterior columns has been described by Wil- liamson, Sandmeyer, and Kalmus. This lesion has been considered in the section on pathology. (d) Hemiplegia occasionally occurs. One would naturally expect to find some gross lesion to account for the paralysis, but cases have been reported in which careful search has failed to find any evidences of hemorrhage or thrombosis. The hemiplegia in these cases has been attributed to toxic causes, similar to the cases of hemiplegia in uraemia without manifest brain lesions. Careful microscopic examination of the brain is necessary in these cases before stating that there is no organic lesion, and a thrombosed vessel may explain the complication. In this connection the condition of the tendon re f exes may be considered. The knee-jerks are often absent, as first pointed out by Bouchard. Statis- tics differ as to the frequency with which the knee-jerks disappear. Griibe found them absent in only 13.5 per cent, of his cases, whereas Wil- liamson found them absent in 50 per cent of his series. Their disappear- ance is probably dependent on a peripheral neuritis, or changes in the posterior columns of the cord. The Achilles-reflex may disappear before the patellar, as in locomotor ataxia. The superficial reflexes — plantar, abdominal, and epigastric — are present in practically all cases. A patel- lar reflex may return after being lost. The condition of the reflexes bears no definite relationship to the prognosis, although the knee-jerks are more likely to be found absent in hospital than in private practice, the former cases being usually more severe than the latter. (e) Mental Complications. — In addition to the psychical symptoms al- ready described, a group of mental symptoms is occasionally met with closely resembling general paresis. Laudenheimer reviewed the relation- ship between diabetes and general paresis, and concludes that diabetes is not actually the cause of the latter. The mental symptom-complex is often improved under anti-diabetic treatment. It has already been pointed out that actual general paresis is quite frequently the cause of glycosuria. 6. Special Senses. — Of the ocular complications, cataract is the com- monest. Frerichs observed it in 19 cases out of 400 diabetics ; William- son, in 9 out of 100; and Seegen, in 4 per cent, of his cases. It occurs in the young as well as in the old. It is usually bilateral, and, in the young, of the soft variety, but in old diabetic patients it is indistinguishable from the non-diabetic variety. There is no satisfactory explanation of its cause. The view that it is due to abstraction of water is no longer gener- ally supported. Diabetic retinitis occurs, but is not so common as albumi- nuric retinitis. Williamson found it in 7 cases out of a 100 diabetics, but in some of these, renal disease could not be excluded as a cause. It was first described by Jaeger, in 1856. Hirschberg describes three types — • a retinitis hemorrhagica diabetica, a retinitis centralis punctata, and a 784 CONSTITUTIONAL DISEASES combined form. Rarely a diabetic iritis with hypopyon occurs. Diabetic amblyopia, due to a central scotoma, and optic neuritis, are rare com- plications. Dc Schwcinitz says that premature preslnjopia, with failure to accommodate, is a common and often an early symptom. Sudden amaurosis similar to that in ura^nia may occur. The vitreous may contain masses of cholesterin crystals. Such a case has recently come under the writer's observation. Ear complications are not common. Furuncles in the external auditory meatus, and acute otitis media occasionally occur. 7. Sexual Complications. — ^Most of the sexual symptoms have already been dealt with, but the relationship of diabetes to pregnancy will be considered here. INIatthews Duncan, Kleinwiichter, and Herman, have specially considered this subject. When diabetes develops during the child-bearing period, amenorrhoea usually results, and it is said that atro- phy of the uterus may occur. Conception is rare. According to Gaudard, 33 per cent, of pregnant diabetic women abort. Herman states that pre- mature delivery, due to intra-utcrine death of the foetus, has occurred in about two-thirds of the published cases of pregnancy wdth diabetes. A diabetic mother may bear a healthy child, however, and has never been known to bear a diabetic one. Usually the diabetes becomes aggravated after delivery. Pregnancy may go on to full term in certain instances with marked amelioration or complete disappearance of the diabetic features. Herman favors early delivery, for the reason that the chances are two to one that the child will die in idero, and that the earlier the pregnancy ends the more likely are the diabetic symptoms to ameliorate in the mother. 8. Diabetic Coma. — This is the most important and most serious of the complications of diabetes. It was first described by Kussmaul, in 1874. Three types of coma occur: (a) Typical dysp7ia;ic co}na, or l\ussTna.u\'s "air-hunger" type. This is the form that Kussmaul described, and is by far the most frequent of the three. He observed three cases of this type at his Freiburg clinic in the year 1874. As premonitory symptoms there may be lassitude, head- ache, epigastric pain, and occasional vomiting. The patient becomes restless and excited, and tosses about in bed. His speech becomes thick and eventually incoherent. He grows gradually duller, and eventually passes into deep coma. The pulse becomes small in volume, of low tension, and frequent, often reaching to between 120 and 140 per minute. A characteristic form of dyspnoea develops. It is inspiratory at first, but later expiration is also involved. When fully developed the respirations are full and voluminous; they are loud and can be heard a considerable dis- tance, although they are not stertorous as in apoplexy; they are quite regular and are usually not increased in frequency. The volume of the chest is greatly increased with each inspiration, and it is this apparent demand of the system for air that led Kussmaul to designate the phe- nomenon as "air-hunger." The temperature is usually subnormal. There may be some cyanosis. The breath often has a fruity odor (owing to the exhalation of acetone), which may pervade the whole room. The urine may also have an acetone odor. Traces of albumin and enormous num- bers of short hyaline and granular casts occur in the urine just before and during the coma. Death almost invariably results, and occurs within DIABETES MELLITUS 785 forty-eight to seventy-two hours after the onset of the coma. Frerichs and others recognize also the two following forms: (6) The So-called Alcoholic Form. — With headache and symptoms suggesting alcoholic intoxication; the speech becomes thick, the pulse rapid, and, without dyspnoea, coma su|)crvenes and the patient soon dies. (c) The Diabetic Collapfte. — The patient suddenly begins to suffer from drowsiness and great weakness. The extremites become cold; the hands, feet, and face, become livid; the pulse is small, thread-like, and 120 to 130 to the minute. The respirations are slightly quickened, b>ut are shallow and not dyspnoeic in character. Drowsiness develops, coma supervenes, and the patient dies in ten to twenty hours. There is no acetone odor to the breath nor acetone or diacetic acid in the urine. The collapse is be- lieved to be due to cardiac failure, probably induced by myocardial changes. Anomalous forms of coma occur due to renal disease, cerebral tumor, meningitis, and apoplexy. The coma in these cases is due to the accom- panying disease, and not to the diabetes. The true diabetic coma of Kussmaul, or the "air-hunger" type, is by all means the most frequent and most important, and the following considera- tions mainly concern this form. A large percentage of deaths in diabetes are due to coma, and it is almost invariably the cause in childern. An idea of its frequency can be gathered from the following statistics: Of Naunyn 's 44 fatal cases, 19 died in coma, 12 of which were of the dyspnoeic type. Frerichs reported 150 deaths from coma out of a total of 250 fatal cases; Taylor, 26 out of 43; Mackenzie, 19 out of 87; and Williamson, 28 out of 40. Certain factors tend to predispose to the development of coma. Among these are constipation, excessive fatigue, the onset of various complica- tions such as carbuncle and pneumonia, subjection to an operation, and sudden changes in diet. The complication is universally recognized now to be a manifestation of an acid auto-intoxication due to the abnormal circulation of /?-oxybu- ty ric acid in the blood. Previous to the establishment of this view, diabetic coma had been attributed successively to the action of acetone and diacetic acid. Both these substances, however, were shown to be innocu- ous when injected into animals. The chief developments in our knowl- edge of the actual cause of coma took place between 1880 and 1885. In 1880, Hallerworden found that the urine of many diabetics showed a remarkable increase in the ammonia output. As the urine in these cases was always markedly acid he thought there must also be a marked increase in the excretion of certain inorganic acids, eliminated as ammonium salts. Stadelmann, in 1883, proved the correctness of this hj^othesis. For a series of successive days, he estimated the total mineral acids and mineral bases, including the ammonia, in the urine of a healthy man and a diabetic, and compared them in terms of sodium. On comparison he found that in the normal individual the sum of the acid equivalents slightly exceeded that of the bases. In the diabetic, on the other hand, the bases were far in excess of the acids. He concluded, therefore, that in order to satisfy the great excess in bases, an inorganic acid must be ex- creted in large quantities. He succeeded in isolating an acid which proved to be a-crotonic acid (C4He03) but it was shown later that 50 786 CONSTITUTIOXAL DISEASES this acid was not excivtcd as such in the urine, but that it was a decom- position prothict of another acid which Minkowski isohited in pure form in 1884, and which he characterized as ,.9-oxybutyric (C^IIgOa). Indei)en- dently, and })racticalh' sinuiltaneously, Kiilz isolated the same acid from the urine of a diabetic patient. Stadehnann is given, and deserves, the credit for first suggesting that diabetic coma is due to an acid intoxication. The diabetic patient who was the subject of his first research died of typical dyspnoeic coma. ^Yalter had shown that when mineral acids were injected into animals, marked dyspntpa, frequent pulse, collapse, and death ensue, the symp- toms being very similar to those in diabetic coma. As Stadehnann had found an excess of acid in the blood of the patient, and was familiar with Walter's experimental work, he conchuled that diabetic coma resulted from an acid intoxication, and recommended that the coma symptoms should be treated by the administration of large doses of alkalis. His theory and suggestions as to practical treatment have been borne out by subsequent investigations. Without qualification we can, at present, say that the acid intoxication of diabetic coma, or "acidosis" as Naunyn calls it, is due to the action of /?-oxybutyric acid. By its action on the respiratory centre it causes the characteristic dyspnoea; and from its efl^ect on the brain in general, coma supervenes. The j(?-oxybutyric acid is eliminated in the urine not as such, but in combination with the bases, chiefly as sodium oxybutyrate. In severe cases the output is enormous, reaching to between 100 and 200 grams daily, and in a case reported by Kiilz, to 225 grams. For a considerable time the available bases of the tissues (sodium, potassium, etc.,) are sufficient to neutralize the acid; but when it is excreted for long periods these become used up, and then ammonia, derived from proteid destruction, is called on for purposes of neutralization. This accounts for the enormous output of ammonia, reaching to seven or eight grams in cases of threatened coma. We have already shown that diacetic acid and acetone are derivative products of /9-oxybutyric acid, and it is, there- fore, not surprising that we also find these substances in the urine. The acetone excretion in the urine may reach 10 grams or more daily. That an acetonaemia exists is indicated by the acetone odor of the breath in coma cases. The presence of diacetic acid in the urine in the vast per- centage of cases means that /?-oxybutyric is also present. Owing to the difficulty in performing the tests for /?-oxybutyric acid, clinically, we rely mainly on the ferric-chloride test for diacetic acid to indicate that an acid auto-intoxication exists. Acetone and diacetic acid are formed not alone from /?-oxybutyric acid. This is indicated by their sometimes being present in the urine without the latter. It is now generally recog- nized that acetone is practically always formed from fat. The presence of /?-oxybutyric acid or diacetic acid in the urine should always serve as a danger-signal of approaching coma. There are excep- tions to this rule, however, for one occasionally meets with cases in which a marked diacetic-acid reaction persists for months. Naunyn refers to a case in which there was an excretion of 100 grams of /3-oxybutyric acid lasting for months, and of another diabetic in whom it had been detected for years. These are exceptional cases, however. DIABETES MELLITUS 787 The source of the /?-oxybutyric acid in the system has now been defi- nitely settled. Until recently it had been attributed by nearly all investiga- tors to destruction of the body-proteids. Some comparatively recent researches of Geelmuyden, Magnus-Levy, and others, have shown con- clusively that the /3-oxybutyric acid and its two derivatives are produced as a result of the incomplete combustion of the fats of the body, as well as of those of the food. The latter suggests that it may also result from synthesis in the muscles or glands. It is particularly in the cases with this acid intoxication that we have the best proof that fat metabolism is also disturbed in this disease. Naunyn formerly supported the view that /?-oxybutyric acid is derived largely, if not entirely, from proteid. In the second edition of his work on diabetes, which appeared in 1906, he acknowledges that fat is undoubtedly a source of the "acetone bodies," as /?-oxybutyric acid and its two derivatives are termed. One gets the impression, however, that he has not altogether abandoned the view that proteids may also be a source. The relative amounts of acetone, diacetic acid and /?-oxybutyric acid excreted may vary markedly in different stages of the disease. The first to appear is acetone, then diacetic acid, and lastly ^5-oxybutyric acid. In advanced stages of the disease, /?-oxybutyric acid may be excreted in large amounts, acetone having practically disappeared from the urine. These changes are due to the gradual diminution of the powers of oxida- tion in the body. When it is possible to improve the body metabolism the acetone bodies disappear in the inverse order in which they make their appearance. As a general rule, the addition of moderate amounts of carbohydrates to the diet causes a diminution in the excretion of acetone, as well as of the /?-oxybutyric acid when it is present; their withdrawal causes an increase. While this is the rule in the mild cases, in the severest there are often exceptions. It seems to be quite certain that, when the capacity for oxi- dation in the body is not too much lowered, the presence of moderate amounts of carbohydrates in the food aids in the oxidation process and protects from destruction the fat which is believed to be the main source of the acetone bodies. The feeding of fats, however, seems to be a frequent cause for an increase in these bodies, as has been shown by Schwartz and others. Joslin has demonstrated that the extent of acetone excretion depends on the capability of the fat for absorption, hence on the character of the fat employed. It can readily be seen how important these con- siderations are and how directly they bear on the regulation of the diet when there are evidences of an acid intoxication in this disease. W^ith the development of coma manifestations and the appearance of ^-oxybutyric acid in the urine, the sugar excretion often markedly dimin- ishes, and the percentage of acid, which rarely reaches beyond 0.5 to 1 per cent., may exceed that of the sugar. Saunders and Hamilton found the pulmonary capillaries plugged with fat in certain cases of diabetes with coma. They advanced the view that diabetic coma was due to fat-embolism of the pulmonary arteries. This view is no longer held. Course and Prognosis. — In children and very young individuals, diabetes runs a very rapid course, and, almost invariably, death is caused by coma. Cases are recorded by Benson, Becker, Bohn, and Wallach, in 788 CONSTITUTIONAL DISEASES young individuals in which the disease ran its entire course to a fatal termination witliin five weeks. Generally speaking, the later in life the symptoms first manifest themselves, the better the {prognosis is. The majority of cases after middle life run a chronic course, and it is not very imcommon to see stout, elderly individuals in whom the disease has lasted ten to fifteen years. Cases without hereditary inffuences are the most favorable. Once the disease is well established, it is seldom, if ever, that a permanent cure is effected. Occasionally, however, one sees a glycosin-ia persisting for months or years in a very neurotic individual eventually entirely tlisapjiear. Naunyn cites cases of acute or subacute diabetes resulting from head-traunuis in which there has been a per- manent cure. The thought naturally arises, are these cases true diabetes, or are they instances of traumatic glycosuria ? It is always well to determine the power of the individual to warehouse carbohydrates. If an individual on a non-carbohydrate diet excretes no sugar, the case may be considered a mild one. If, on the other hand, sugar is excreted, it means that it is being manufactured from the body-proteids, and the case is a severe one. The tolerance of a diabetic to carbohydrates is determined by ascertaining the number of grams of starch tliat can be added to the diet without sugar appearing in the urine. The presence of /?-oxybutyric acid and diacetic acid in the urine is in the majority of instances of serious import, as they indicate the possibility of approaching coma. Once coma is well established, a fatal termination almost invariably results no matter how active the treatment may be.' Diagnosis. — There is usually no difficulty in arriving at a diagnosis if the precaution be taken to use two or three urinary tests, including fermentation, in any doubtful case. It is sometimes difficult to determine whether one is dealing with a true diabetes or a symptomatic glycosuria. Time is the main factor in arriving at a decision in these instances. The presence of conjugate glycuronic-acid compounds, homogentisic acid (alkaptonuria), lactose, excess of uric acid, or creatinin, may cause error in inexperienced hands. The differential tests have been considered in the section on the urine. In a few of the cases of alkaptonuria the con- dition has been mistaken at first for diabetes. This was true in the case reported by the writer. The mistake is due to the fact that the homo- gentisic acid which is eliminated in the urine reduced alkaline copper sulphate solutions. The characteristic which the urine possesses of darkening on standing or on the addition of an alkali should arouse one's suspicions. Alkaptonuric urine, further, is negative with the "bismuth, phenylhydrazine, fermentation, and polariscope tests. Bremer's blood- test may be of some value when a patient is seen for the first time with suspected coma symptoms and no urine is available. Deception may be practiced by the patient. Osier cites a case under his care of a young girl who had a urine with a specific gravity of 1065, and in which the sugar-reactions proved to be those of cane-sugar. The literature records one case in which a woman, after detection, bought cane-sugar and introduced it into her bladder! Pentosuria, although only nineteen cases have been recorded, is pro- bably more common than is generally supposed. Some of the cases have been mistaken for diabetes. Salkowski and Jastrowitz reported the first case Id 1892. The urine contained a copper reducing substance which was DIABETES MELLITUS 789 optically Inactive, did not ferment, and which from its osazone they identified as pentose. C. Janeway has recently reported two cases in brothers and states that there is a family predisposition to the disease. He describes three forms: (1) the alimentary pentosuria, due to the ingestion of large amounts of vegetables or fruits containing pentosanes; (2) rare cases occurring in severe diabetes in which the inability to burn carbohydrates extends to the pentoses; (3) chronic pentosuria occurring without reference to the pentoses of the food. The sugar excreted in this form is the optically inactive r-arabinose. Pentosuria is recognized as follows: Fehling's solution is reduced in an atypical way, the color remaining unchanged for a minute or so after boiling and then turning suddenly a green yellow or muddy orange color throughout. It gives the phenylhydrazine test, but is optically inactive and does not ferment. If doubt still remains the oricin test must be performed, in which the characteristic absorption bands of pentose are examined for with the spectroscope. Treatment. — Prophylactic measures should be taken in families in which there is a predisposition toward diabetes. Often there is also a tendency to obesity in these families. It is advisable to determine the ability of its individual members to warehouse carbohydrates. If glyco- suria results from administering 100 grams of glucose on an empty stom- ach, it maybe concluded that the assimilation for carbohydrates is lowered, for a normal person can take from 180 to 250 grams of glucose without sugar appearing in the urine. By restricting the carbohydrates in the members whose assimilation limit is shown to be lowered, von Noorden thinks that the possible development of diabetes in these individuals may be warded off. It may be well to emphasize at this point that, although certain general principles govern the treatment of diabetes as a disease, yet it is the duty of the practitioner to study each individual case separately, with special reference to his dietetic needs. It is only in this way that the disease can be intelligently treated. The patient should be weighed periodically, say every two weeks in private practice and twice weekly in hospital work, and a careful record kept. The patient's weight is the best single criterion we possess of the success of any line of treatment. This has especial refer- ence to the dietetic treatment. No matter what the condition of the urine may be with reference to the presence or absence of sugar, the patient on any line of treatment must be regarded as doing badly if his weight is progressively diminishing. It is much better for the mdividual to excrete moderate amounts of sugar and hold or increase his weight, than to be aglycosuric and steadily lose weight. It is important to keep this axiom always in mind, particularly in regulating the diet. It is not infrequent to find that a diabetic will lose weight when on a non-carbohy- drate diet and excreting no sugar or only small amounts, whereas he will begin to increase in weight if moderate amounts of carbohydrates be added, even though he excretes more sugar. This is probably explained by Leo's research, in Avhich he showed that the administration of a certain amount of carbohydrates to a diabetic spared proteid metab- olism. The treatment of diabetes may be considered under four headings — hygienic, dietetic, medicinal, and treatment of the complications. 790 CONSTITUTIONAL DISEASES Hygienic. — It is very important to look after the personal hygiene of the patient. Daily baths assist materially in kee])ing the skin functions active, and diminish the liability to furunculosis. By i)ersonal cleanliness the distressing pruritus pudcndi can be partially alleviated. To the thin diabetic, with a dry, harsh skin, the lukewarm bath is often soothing. The more robust patients can stand a cold bath. An occasional Turkish bath is useful in the obese cases, as it is a [)artial substitute for massage. Light woolen underwear should be worn. Moderate exercise should be taken, as a certain amount of nuiscular activity favors sugar combustion. Vio- lent physical exertion should be avoided in the severe cases, as it tends to induce coma. Massage is useful, as it tones up the muscular system and thus probably aids carbohydrate metabolism. All sources of worry and anxiety should be eliminated as much as possible. More or less obstinate constipation is the rule in diabetes, and it is of the utmost importance that this should be corrected, as persistent constipation in severe cases is held by many to favor the development of coma. Dietetic. — We have seen that the sjanptoms of diabetes are directly or indirectly dependent upon the hyperglycnemia, the grade of which is pretty accurately indicated by the amount of glucose excreted. Our object, therefore, should be to eliminate the hyperglycsemia if possible. This will be most quickly effected by cutting out of the dietary those constituents that are most readily converted by the digestive processes into grape-sugar — namely, the carbohydrates. When a diabetic patient comes under observation, it should be the physician's first duty to ascertain the patient's capacity to ware- house carbohydrates, or, in other words, to determine his tolerance for carbohydrates. This is done by placing the individual for at least five days on a diet absolutely free from starches and sugar; that is, on a pro- teid-fat diet. In so doing his weight must be taken into consideration and the diet so arranged that it Avill provide approximately forty calories for each kilo body-weight. This can, as a rule, be fairly readily done — and in hospital work should always be done — as the proteid and fat per- centage of the various foods is given in some of the standard works on dietetics. Knowing that 1 gram each of proteid and carbohydrates yields 4.1, and 1 gram of fat, 9.3 heat units, the caloric equivalent of the diet can be readily calculated. As the carbohydrates, which ordinarily provide the largest number of calories in our diet, are cut off, it will be seen that-the proteids and fats must be largely increased to make up for this deficit. Before arranging the non-carbohydrate diet, the individual likes and dislikes of the patient should be ascertained, so as to secure one that will be most palatable and one that will likely be entirely eaten each day during the test. The following may be used as a "standard" diet for the tolerance test, subject, to be sure, to variations according to the patient's age, weight, and likes or dislikes for certain forms of meats: Breakfast.— 7. SO A. M. 120 grams (5iv) of beefsteak or mutton-chops without bone; two boiled or poached eggs; 200 cc. (ovj) of tea or coffee. Lu7ich.— 12.30 P. M. SOO grams (ovj) cold roast-beef, mutton, or chicken; 60 grams (5ij) celery, fresh cucimibers, or tomatoes, with 5 cc. (3j) vinegar, 10 cc. (5ij) oil, pepper and salt to taste; 20 cc. (3v) whisky (if desired); 400 cc. (§xiij) of water or ApoHinaris water; 60. cc. (5ij) coffee. DIABETES MELLITUS 791 Dinner. — 6 p. m. 200 cc. (5vj) clear bouillon; 200 grams (5vj) roast beef; 60 grams (Sij) lettuce with 10 cc. (3ij) 'vinegar; 20 cc. (5iv) olive oil, or three tablespoonsful of some well-cooked green vegetable, as spin- ach; three sardines a I'huile; 20 cc. (3iv) cognac or whisky (if desired), with 400 cc. Apollinaris water. Slipper. — 9 p. M. 2 eggs, raw or cooked; 400 cc. Apollinaris or Seltzer water. With the four meals at least fifteen grams (about 5iv) of butter should be used in making the gravies and with the eggs. No milk or sugar m permitted with the tea or cofPee. Saccharin may be used to sweeten them. The time of taking lunch and dinner, of course, may be reversed. This daily diet should provide a person of 60 kilos (132 pounds) with a little over the requisite 2,400 calories for an individual of that weight. One precaution must be emphasized here. If the patient has been eating freely of starches these must be cut down slowly for two or three days before he is placed on the standard diet. Any sudden and radical change from one diet to another is liable to induce coma. As it has been found that a dog must fast five days before the glycogen of his liver has been all used up, it is well to keep the diabetic, on the above diet for at least five days; by so doing it practically eliminates the possibility that any sugar excretion at the end of that time is derived from the stored-up glycogen of the liver. While on this diet, the total amount of urine should be collected for each twenty-four hours, mixed, measured, and the sugar determinations made from a specimen of the twenty-four hour amount. The reduction in the sugar excretion is often very striking in the first twenty-four hours. If the patient becomes aglycosuric within the first five days the case may then be considered a mild form of the disease, and it is then desirable to ascertain how much starch can be added to his diet without sugar appear- ing in the urine; in other words, to determine his tolerance for carbo- hydrates. This is probably best done by allowing the patient a weighed quantity of plain white bread, which contains approximately about 55 per cent, of starch. For the first day 25 grams of bread may be allowed. If sugar fails to appear in the urine another 25 grams (a little less than Sj) may be added the next day and so on until glycosuria does develop. The formula for the tolerance is as follows: Tolerance = Standard diet+^ grams starch, x representing the number of grams of starch the patient can take without sugar appearing in the urine. If the patient continues to excrete sugar after being on the standard diet for five days, it indicates that he is suffering from a severe form of the disease. It further means that the tolerance for carbohydrates is entirely destroyed, and that the sugar eliminated in the urine is manufactured from his tissue-albumins. In the cases in which glycosuria persists after the patient has been on the non-carbohydrate diet for five days, Naunyn recommends that a "Hunger Tag," or hunger-day be instituted, during which time no food whatever is taken for twenty-four hours. In a certain percentage of these cases the patients will become aglycosuric as a result of the starvation-day. Naunyn's reason for establishing a hunger-day is to remove the hyperglycaemia even though it be for only twenty-four hours. By so doing he claims that the tolerance for starches is increased, and that it is then possible to give small quantities of starch without glycosuria 792 CONSTITUTIOXAL DISEASES occurring, and, which, without the hunger-day, would not be warehoused. This increased tolerance is believed to be due to the tissues securing a temporary rest from sugar formation. The writer's experience with the hunger-day is that it is useless to advise it if the percentage of sugar is 0.5 or over as when it is that high the sugar rarely entirely disappears. In the treatment of diabetes it is most advisable to put them on such a standartl diet at least every three months in order that their tolerance for carbohydrates may be increased. The foods the diabetic should be warned against taking, excepting with the permission of the j)hysician, are as follows: Bread of all sorts, wheaten, rye, and brown ; all farinaceous preparations such as rice, sago, tapioca, hominy, semolina, arrow-root, and vermicelli. Thick soups are to be avoided. Among meats, liver is about the only form to be prohibited, owing to the glycogen it contains. For the same reason, oysters are sometimes prohibited. All starchy vegetables: Potatoes, turnips, parsnips, squashes, vege- table marrow, beets, corn, peas, and artichokes. Beverages: Beer; the sweet wines and sweet aerated drinks. These are excluded owing to the sugar, and not to the alcohol, they contain. Fruits: Grapes, dates, figs, currants, raisins, dried prunes and plums, and other dried fruits rich in sugar, should be forbi(iden. Certain fruits such as peaches, apricots, stewed green gooseberries, may be permitted in mild cases. Some authorities on this disease are inclined to be rather more lenient in regard to fruits. It is well to remember that Isevulose (fruit-sugar) has been shown to be tolerated better by the diabetic patient than any other form of sugar. Sugar for sweetening purposes must be omitted. Without the physi- cian's permission, milk must not be taken. The following foods the diabetic may take unconditionally: Soups: Bouillon, ox-tail, and turde; broths; soups with marrow and eggs per- mitted. Fresh meats: All the muscular parts of the ox, calf, sheep, pig, deer, wild and domestic birds — roast or boiled — warm or cold, in their own gravy or in a mayonnaise sauce. Internal parts of animals: Tongue, heart, brain, sweetbreads, kidneys, marrow-bones, served with non-farinaceous sauces. Preserved meats : Dried or smoked meat, smoked or salt tongue, corned beef, American canned meats. Fresh fish: All kinds of fresh fish, boiled or broiled, prepared without breadcrusts or cracker-meal and served with any kind of non-farinaceous sauce, preferably melted butter. Preserved fisli: Dried fish, salt or smoked fish such as codfish, had- dock, herring, mackerel, flounders, salmon, sprats, eels, etc.; tinned fish, such as sardines in oil, anchovies, etc.; caviar. Eggs : Raw or cooked in any way, but without any admixture of flour. Fresh vegetables: Green lettuce, cress, spinach, cucumbers, onions, asparagus, cauliflower, red and white cabbage, French beans. The vege- tables, as far as they are suited to this method of preparation, are best cooked with meat or a solution of Liebig's Extract and salt, and cooked plentifully with butter. The addition of flour is not permissible. Preserved vegetables: Tinned asparagus, French beans, pickled cucum- bers, mixed pickles, sauerkraut, and olives. DIABETES MELLITUS 793 Spices: Salt, white and black pepper, Cayenne pepper, curry, cinna- mon, cloves, nutmeg, English mustard, and capers. Cheese- Neufchatel, Edam, Stracchino, old Camembert, Gorgonzola, and other fat and so-called crean cheeses. Beverages: All kinds of natural and carbonated waters, either clear or with lemon juice, or with rum, whisky, cognac, and cherry brandy. Light Moselle or Rhine wines, claret, dry sherry, or Burgundy, in amounts pre- scribed by the physician. Coffee, black or with cream, without sugar but sweetened with saccharin if desired. Tea, clear or with cream or rum. From this list it will be seen that the number of articles not containing starch the diabetic may choose from, is quite extensive, and permits him to vary his dietary from time to time. In making up the "standard diet" certain of the articles in the above list may be substituted for some of those in the diet outlined. Bread is the article of diet the cutting off of which the diebetic tolerates least well. Sooner or later a craving for it is inevitable. Various substi- tutes have from time to time been put on the market. The oldest of these and the one in most extensive use is gluten bread or biscuits made from gluten flour, first introduced by Bouchardat, in 1841. It is prepared by washing away the starch from wheat flour. The text-books on cooking give recipes for making bread and biscuits from this flour. Many firms claim to make pure gluten flour. Others are more conscientious, and state the percentage of starch their various preparations contain. It is easy to demonstrate that these gluten flours almost without exception contain starch, by adding a few drops of Lugol's solution. A blue, or even black, reaction is obtained, according to the amount of starch present. Another substitute is bread or biscuits made from aleuronat flour, advo- cated by Ebstein and prepared by Dr. Hundhausen of Hamm, West- phalia, Germany. It is a vegetable albumin prepared by a special process from wheat. It contains from 80 to 90 per cent, of albumin in the. dry substance and only 7 per cent, of carbohydrates. In making bread from it, a considerable percentage of starch has to be added. Flours prepared from the soya bean, almonds, cocoanuts, and Iceland moss, have had their advocates as substitutes for wheat flour. The writer's experience has been limited to the use of gluten and aleuronat bread, and it has taught him that patients eventually tire of them and they still crave white wheat bread. Owing to the expense and the un- reliability of most gluten flours, the writer has given up their use. It is much better to allow a diabetic to have daily a definite weighed quantity of white bread, the starch percentage of which we know to be about 55 per cent. It is well to have the bread thoroughly toasted. Well toasted graham bread may be used as a substitute with advantage. Starch, in the form of potato, is thought to be more easily assimilated than wheat starch, and the comparatively recent work of ^losse seems to bear this out. The observations at the Johns Hopkins Hospital tend to confirm this view. Mosse allowed his cases 1 to 1.5 kilos (2 to 3 pounds) of potatoes daily. He says that there is a marked amelioration of all the distressing symptoms under the potato treatment. It is best to bake the potatoes. Naunyn does not speak very enthusiastically of this special cure in his last edition. He thinks that when benefits result, it is 794 CONSTITUTIONAL DISEASES due mainly to the fact that the diet in the case heretofore has not been properly arranged so far as the allowance of carbohydrates is concerned. Von Noorden recently has atlvocated very strongly a specially prepared oatmeal, and has claimed remarkable results in eliminating the glycosuria. In the mild cases of diabetes (those that have become aglycosuric on the standard diet), the best course to pursue is to add to this standard diet weighed quantities "of woll-toasted white bread, the amount to vary with the tolerance of the individual. Occasionally, a roast potato may be sub- stituted for the bread. In these cases milk is.especially useful as it con- tains only between 4 and 5 per cent, of lactose which is very well assimi- lated by diabetics. A jiint or a pint and a half, accordingly, may be permitted daily. The monotony of the standard diet may be from time to time relieved by making substitutes from the list of unconditionally allowable foods given above. In the severe cases (those who fail to become aglycosuric on the standard diet) it, at first thought, would appear that the addition of carbohydrates would be contra-indicated as they would tend to increase the glycosuria, considering that the tolerance is ?^^7. Experience, however, shows that these do better, and are more likely to hold their weight if given very moderate cjuantities of starchy food. The danger of coma is increased by any long continuation of an exclusive proteid-fat diet. In both forms, a return to the strict diet, in order to increase the toler- ance, should be made at least every three months for a period of ten days. It is desirable at shorter intervals in the severe forms. No attempt should be made to restrict the water taken by the diabetic. No good will follow by doing so, as the thirst and polyuria are dependent on the hj^erglycjemia. Harm, on the other hand, is likely to ensue, as the increased thirst causes increased mental and physical distress. Apollin- aris and Seltzer water may be allowed, and the thirst may be quenched by drinking lemonade sweetened with saccharin instead of sugar. A drink made by dissolving a dram of cream of tartar in a pint of boiling water and flavoring with lemon peel and saccharin and then cooling, may be given freely for the same purpose. Alcohol, in the form of whisky, cognac, or rum, is to be recommended as it aids fat digestion, and tends to make up for the loss in heat-units resulting from the cutting off of carbohydrates. One gram of alcohol by its combustion yields 7.0 calories. Sawyer, of Cleveland, claims to have obtained marked benefit in diabetes by systematic gastric lavage. Medicinal. — Few diseases have had a greater number of drugs advoca- ted for their treatment; all of which goes to show that most of them are useless. In connection with no disease is quackery in and out of the profession more rampant. It is the duty of the practitioner, as much as possible, to discourage the patient from using the proprietary remedies so blatantly advertised in the daily press. These are all expensive and for the most part absolutely useless. Only a few drugs have proven of any service whatever. The most useful is opium and some of its alkaloids. Its use in diabetes dates from the latter part of the eighteenth and beginning of the nineteenth century and particularly since its strong recommendation by Pelham Warren, in 1812. It is claimed that it diminishes the thirst, appetite, amount of DIABETES MELLITUS 795 urine, excretion of sugar, and nervous irritability. As a consequence the weight increases and the general condition of the patient improves. Diabetic patients are unusually tolerant to opium and its alkaloids, and can take large doses without narcotism. By some, the crude opium, or the dried extract, are thought to give the best results. The patient may be started on half a grain of either, three times a day, and this may be increased until a total of from 4 to 6 grains daily are taken. Morphia, in increasing doses, has its advocates but the alkaloid now most extensively used in codeia. Half-grain doses of codeia sulphate after each meal may be administered at first, and increased until a total of 6 to 8 grains daily is reached. It is less constipating than the crude drug or morphia. There should be a gradual withdrawal of the opiates when the sugar is reduced to a minimum. Arsenic stands next to opium in its apparent efficacy. It may be given as Fowler's Solution, commencing with 3 minims and gradually in- creasing up to 10, three times daily. Leube gives one-third of a grain of arsenious acid three times daily. In diabetes with marked functional nervous manifestations, bromide of potassium or soda is often useful. It tends to allay the nervous irritability and to diminish the glyco- suria. The coal-tar products have been strongly advocated, and in neu- rotic cases antipyrine in 5 or 10 grain doses three times a day may prove useful. Potassium iodide should be given a thorough trial where strong suspicions of a luetic basis for the disease exist. Salicylates may be given where there are evidences of rheumatic arthritis. Uranium nitrate in recent years has been strongly advocated in certain quarters, but is un- certain in its effects. No attempt will be made to enumerate the multitude of other medicinal remedies that from time to time have been recommen- ded. Drugs play a very minor part in the treatment of diabetes. The writer rarely resorts to them, excepting for the relief of special symptoms or complications. Throughout the treatment, the urine should be regularly tested for the iron-chloride reaction for diacetic acid. If this be present, sodium bicarbonate in 2 to 3 gram (30 to 40 grain) doses, three times daily, should be administered. In this way the danger of coma may be averted. Here also, brief reference to treatment at mineral spas, and by alkahne mineral waters, may be made. Of the spas abroad, those of Carlsbad, Neuenahr, Vichy, Marienbad, and Contrexeville, are probably the best for mild diabetics, and, particularly, for those in whom there are gouty manifestations. No severe case should be recommended to run the risks of a long, fatiguing journey to reach these places. Only too often a fatal termination is hastened. Undoubtedly, many mild cases are benefited. How much benefit is actually attributable to the waters themselves is diflficult to determine. Undoubtedly, those that are mildly laxative, and those containing considerable quantities of carbonates and bicarbonates, thus tending to neutralize the abnormal acids of the blood, are helpful. There is no question, however, that the chief benefit is derived from the greater willingness of the patient to submit to a dietetic regimen, from the diversion and the freedom from business cares and worries. A bottle of Vichy or a couple of glasses of Carlsbad water daily may be taken with benefit in any part of the world. In the United States, mild cases may be benefited by a course at Saratoga Springs where the 796 CONSTITUTIOXAL DISEASES Hathorn water is probably the best, at Bedford Springs, Pennsylvania, and, possibly, at Poland Springs. Pancreatic preparations have been given a fair trial, but the results have been disa]ipointing. This must necessarily be the case until we possess some clinical test by which we can recognize the cases due to pancreatic disease. Cammidge thinks this may be possible by his recently devised test. Paftcrcatic juice and extract have failed to produce any material benefit. Williams, of Bristol, transplanted the pancreatic gland of a shee]> under the skin of the breast and abdomen of a diabetic. The patient tlied in three days of coma. Lepine advocated the use of pilo- carpine, hypodermically, to stimulate the secretion of the pancreas, but without any satisfactory results. The same investigator, believing that diabetes is due to the failure of the pancreas to produce a necessary glycolytic ferment, produced such a ferment from malt diastase and administered it to several diabetic patients with apparent satisfactory results. Pancreatic thei'apy, up to the present, may be said to have yielded no beneficial effects. The recent investigations of Otto Cohnheim suggest that a combination of pancreas and muscle-juice may offer better prospects of success in the future. Treatment of Complications. — (1) Diabetic Coma. — Certain factors predisposing to coma must be carefully guarded against. Obstinate con- stipation must be counteracted; prolonged restriction of a severe case to a diet entirely free from carbohydrates may tend to induce the complica- tion. Sudden and radical changes from a mixed diet containing con- siderable starch, to a rigid diet, or vice versa, may precipitate it. We have seen that the coma is due to an acid-intoxication, the toxic agent being /?-oxybutyric acid, derivative products of which are acetone and diacetie acid. Stadelmann, who first advanced the acid-intoxication theory, was also the first to recommend and use the alkaline treatment — the only one that has proved of any benefit. The existence of an "acidosis," indicated by the elimination of either /3-oxybutyric acid in the urine, or its product (diacetie acid), or an excess of ammonia, should at once be followed by the administration of sodium carbonate or sodium bicarbonate by mouth. The most serviceable clinical test for the "acidosis" is the ferric-chloride reaction for diacetie acid. If this be present, sodium bicarbonate, in 2 to 3 gram (30 to 45 grain) doses, three times a day, should be at once started. By so doing the acid-intoxication can be stopped, and the ferric- chloride reaction ceases to be obtained. The alkali neutralizes the acid in the circulating blood, and the tissue-bases (sodium, potassium, etc.), and the ammonia which is derived from the breaking down of the body- proteids are spared. In mild cases of acidosis, it is important to remember that the latter may be relieved by making moderate additions of carbo- hydrates to the diet if the latter has previously been very restricted. Although the presence of /3-oxybutyric acid, or diacetie acid, in the urine must always be considered a danger signal of possible impending coma, occasional cases are met with in which they are present for months with- out apparent harm. Naunyn states that when the ammonia excretion reaches 4 grams daily, he has never seen a case in which it was possible to ward off an eventful attack of fatal coma. W^hen actual symptoms of coma have set in, treatment is almost hope- less, and the rule that prevention is better than cure is nowhere better DIABETES MELLITUS 797 illustrated than in this dreaded complication. When coma symptoms do intervene, the most active treatment should be instituted, however. Carbohydrates should be added to the food if th(; j)atient is still able to swallow. We have already seen that acetone, diacetic acid, and [j-oxy- butyric acid are largely, if not entirely, derived from fat owing to the diminished power the tissues of the diabetic possess of properly oxidizing the fats of the food and tissues. The mildest grade of this defective power of oxidation manifests itself in the appearance alone of acetone in the urine; the medium grade with the appearance of acetone and diacetic acid; and the severest grade with the occurrence of both these, and an addition of /9-oxybutyric acid. As coma supervenes the amount of acetone diminishes and the quantity of /5-oxybutyric acid increases. The knowl- edge that the adniinistration of carbohydrates will diminish or clear up the acidosis when it has not reached too severe a grade is one of the important recent advances in the therapy of diabetes. The administered carbohydrate in some peculiar manner favors the more complete oxidation of the fats. In the severest cases of diabetes, even those with coma mani- festations, the organism never entirely loses its capacity to burn up carbohydrates. Milk is most valuable in these cases. From 500 to 1,000 cc. maybe given in the twenty-four hours. Of all carbohydrates Isevulose is most easily burnt up by the diabetic. Recently von Noorden has advocated the subcutaneous injections of 5 to 10 per cent, solutions of Isevulose in cases wdth threatened coma. Naunyn prefers its administration either by mouth or by enema. Realizing the origin of the acetone bodies, the importance of cutting down the fats in threatened coma becomes at once apparent. Those containing the lower fatty acids are most injurious. The fats permitted should be chiefly those of vegetables and meats, as these contain comparatively little of the lower fatty acids. Butter, if used, must be given in limited quantities and only after having been thoroughly washed with water to remove the above acids. It is probably better to entirely exclude butter in the threatened coma cases, as it has been shown to very materially increase the output of the /3-oxybutyric acid. Soduim carbonate, or bicarbonate, should be given by mouth, rectum, and intravenously, in enormous quantities. As much as 4 to 8 grams (1 to 2 drams) of sodium bicarbonate, every hour, by mouth, if deglutition is still possible, and double this quantity per rectum every two hours, should be administered. More effectual results will follow an intravenous alkaline injection. Enormous quantities of sodium carbonate have been introduced at one injection. Thus Minkowski gave 84, Lepine 44, Wolfe 30, and Rosenstein 20 grams at one operation. The temporary results are often striking. The respirations becomes quieter, and when the coma is not deep there may be temporary return to con- sciousness. As strong a solution of sodium carbonate as 3 to 5 per cent, has been used. In practically all these cases there is a recurrence of the coma in a few hours and death within twenty-four or forty-six. The custom at the Johns Hopkins Hospital has been to introduce a liter of a 2 per cent, solution of sodium bicarbonate in normal salt solution slowly into one of the median basilic veins, and to repeat the procedure on the opposite side in four or six hours. From 200 to 400 cc. of blood should be first removed. In a young girl of twelve, definite symptoms of com- mencing coma were, in this way, temporarily warded off, death resulting 798 CONSTITUTIOXAL DISEASES a week later from typical coma. Intravenous injections of Ringer's solution have been reeomnKMuled. Naunyn states that, once coma is well established, he does not think it possible permanently to relieve it. The grade of the acid-intoxication in these severe cases is indicated by the fact that, no matter how vigorously the alkalis are pushed, it is not possible to render the urine alkaline. Griihberger, in 1905, performed lumbar puncture in a coma case and found acetone and diacetic acid in the cerebrospinal fluid, although the urine was free from diacetic acid. Naunyn suggests that in these cases there may be a direct toxic action on the central nervous system and that the matter needs further inves- tigation. 2. Prvritus. — Frequent bathing of the genitalia, to prevent them from becoming saturated with the saccharine urine, is the best preventive. Bathing with soda solution, or 100 to 200 solution of carbolic acid, may give some relief. The best remedy is a solution of boric acid or of hyposul})hite of soda (30 grams or 1 ounce to the liter or quart of water), applied as a lotion. Ichthyol and lanolin ointment may give relief in some cases. Menthol ointment (grs. x to vaseline oj) sometimes gives relief. These are purely local measures and the symptom will yield when the glycosuria is relieved by the usual measures. 3. Gangrene and Carbuncle. — As temporary measures, the affected parts should be dressed with bichloride compresses. Early amputation and excision, respectively, are indicated. There is a certain risk of either the anresthetic or the operation itself precipitating coma, but this is much less than the danger from the complications, as both are liable in themselves to cause death by inducing coma. CHAPTER XXX. DIABETES INSIPIDUS. By THOMAS B. FUTCHER, M. B. Definition. — A chronic affection, characterized by the passage of large quantities of pale urine of low specific gravity, free from sugar, albumin, and casts, and usually accompanied by an insatiable thirst. Although Thomas Willis, in 1674, first recognized a difi'erence between a saccharine and a non-saccharine polyuria, it was Johann Peter Frank who, in 1794, first gave us a definition for diabetes insipidus when he described it as a long-continued, abnormally increased secretion of non- saccharine urine which is not caused by a diseased condition of the kid- neys. He distinguished two forms of diabetes, a diabetes insipidus, or spurious, and a diabetes mellitus, or verus. In 1838, Robert Willis proposed the following classification of the diabetes insipidus cases according to the urea secretion: Hydruria included those cases where there was poly- uria and a normal urea output; azoturia, those with polyuria and increased urea excretion; anazoturia, those with polyuria and diminished urea elimination. It is now well recognized that these do not represent distinct types of the affection. Incidence. — Diabetes insipidus is a rare disease. In the seventeen years ending May 15, 1906, since the opening of the Johns Hopkins Hos- pital, there were 8 cases out of 106,000 ward and dispensary medical patients, or . 007 per cent. Six of these were in-patients among 19,685 medical admissions, or 0.03 per cent. Among 113,600 patients treated at the Charite, Berlin, from 1877 to 1896, there were 55 cases, or . 048 percent. Eichorst observed 7 cases, or 0.02 per cent., among a total of 35,942 patients at the Zurich Hospital. Etiology. — The majority of cases occur in comparatively young per- sons. Of 85 cases collected by Strauss, 9 were under five years; 12, between five and ten years; 36, between ten and twenty-five years. In van der Heijden's series of 87 collected cases, there were 7 in the first, 19 in the second, 23 in the third, and 19 in the fourth, decade. A hereditary tendency has been noted in certain cases. The most remark- able instance of the influence of heredity is in the family reported by A. Weil. Of 91 members of four generations, 23 had persistent polyuria without any deterioration of health, namely, the great grandfather, his three children, seven grandchildren, and twelve great grandchildren. Of the 22 affected descendants of the original case, there were 1 1 males and 11 females. The cases were congenital and persisted throughout life. Lacombe, Pain, and Gee, have reported similar instances of heredity in this disease. Males are more liable to the affection than females. Cases have been reported to be due to the effects of exposure, drinking copiously of cold 799 800 CONSTITUTIOXAL DISEASES fluids, and a drinkin per- manent polyuria. The portion of the rabbit's brain just designated corresponds in the human brain with the area of the pons where the sixth and seventh cranial nerves make their exit from the brain. This throws some light on the cause for the existence of paralysis of the sixth nerve. DIABETES INSIPIDUS 801 occasionally seen in diabetes insijiidus. Kahlcr also found that destruc- tion of the inner part of the cerebellum with Dieter's nucleus and its caudal processes, causes, practically always, a permanent polyuria. From this experimental work it would appear that in dogs or rabbits a simple polyuria is most likely to result from the following lesions: (a) By injury of a point in the floor of the fourth ventricle a little anterior to Claude Bernard s "glycosuric" centre; (b) injuries to various portions of the middle lobe of the cerebellum, particularly the "lobus hydruricus et diabeticus" of Eckhard; (c) by lesions of the corpus trapezoides of the pons and the lateral part of the exposed portions of the medulla oblongata; (d) by cutting the greater splanchnic nerve in dogs. By analogy, we would expect that lesions in these situations in man would produce a simple polyuria, although positive conclusions must not be drawn. We can see how tumors occupying the medulla or the base of the brain, or a basilar meningitis of syphilitic or other origin, could be capable of producing symptoms of diabetes insipidus in the human subject. The immediate cause for the polyuria in the above experiments is not definitely settled. Although Eckhard claimed he had demonstrated special secretory nerves for the kidney, all the leading modern physiolo- gists deny the existence of such nerves, as they have never been demon- strated to enter the renal cells, and they believe the polyuria results from increased blood pressure. The possible effect on the urinary secretion of remote lesions of the nervous system was clearly stated by Ralfe in the following terms " It is interesting to trace the course of the nerves form- ing the renal plexus, as irritation from eccentric or distant sources may play a part in inhibiting the renal nerves. Thus the nerves forming the renal plexus are derived chiefly from the solar plexus; as the right vagus and greater and lesser splanchnics join the solar plexus, it is probable that branches of these nerves enter the kidney by way of the renal plexus. The splanchnics, also, send branches direct to the renal plexus, and the left vagus sends some fibers to the left kidney. They contain medullated and non-medullated fibers; and Krause has traced the latter as far as the apices of the papillae. Their mode of termination is unknown. Physiolog- ically, vasoconstrictor, vasodilator, and sensory nerves, have been ascertained. The connection through the vagus brings us into range with the medulla oblongata, and with many organs susceptible of tuber- cular or syphilitic growths, or of sudden shock, such as a chill. The solar plexus may propagate the effect of abdominal new-growths or aneurisms." We are now in a better position to understand the effect of the various lesions found in diabetes insipidus. According to Stoermer, traumatism to the brain is the cause in 30 per cent of the cases. Trauma of the soft parts has not the same effect. The only authentic exception is a case reported by Nothnagel in which the affection followed a kick on the abdomen. In traumatic injuries of the brain it does not seem essential that any special part of the brain be involved. The polyuria seems to result from the effects of the concussion the brain sustains. In 1865, Leyden reported a case following cerebral hemorrhage, and Ollivier subsequently drew attention to the comparative frequency of hemorrhage as a cause. Van der Heijden saw a case in chronic hydrocephalus. It has been observed in general paresis, and has followed the effects of otitis media. Cerebral tumors rank at the head of the list of gross brain lesions in the frequency 51 802 CONSTITUTIONAL DISEASES with which they are followed by diabetes insipidus. The nature of the tumor is a minor factor. It may be a gumma, a malignant growth, or a tuberculous focus. Diabetes insipidus is more likely to follow where the tumor involves the floor of the fourth ventricle, or the immediate vicinity. The writer has been impressed recently with the importance of cerebral syphilis as a cause of the affection, having recently reported 9 cases of diabetes insipidus, in 4 of which, from the history, symptoms, and the improvement under potassium iodide, it seemed without doubt that cerebral syphilis was the cause. In 1 of these the lesion was a gumma, and in the other 3, the symj)toms pointed toward there being a basilar syphilitic meningitis as a part of the syphilitic lesion. Polyuria and polydipsia have long been described as symptoms of cerebral syphilis. Fournier reported 6 cases in which these symptoms were present in association with various cerebral manifestations of the disease. Lancereaux, Oppenheim, and others, have noted the association. The lesion usually producing the polyuria is a basilar syphilitic meningitis. This was the form of lues in Buttersack's case, in which the disease was localized mainly in the inter- peduncular space. Polyuria was the initial symptom in his patient. Nonne states that it is not necessary, as was formerly held, that the lesion should involve the medulla oblongata or its vicinity. He asserts that all we can say is that polyuria and polydipsia are most liable to occur in syphilitic brain lesions which manifest themselves in the form of a diffuse basilar meningitis. One can appreciate how a basilar meningitis might cause a polyuria, when one recalls that, in experimental polyuria, it was shown that injuries to the middle lobe of the cerebellum, and to the super- ficial areas of the pons and medulla, caused a profuse flow of urine. Many of the cases of diabetes insipidus due to basilar syphilitic menin- gitis have been associated with a peculiar form of bilateral hemianopsia. Oppenheim considers an "oscillatory" form of hemianopsia or "hemian- opsia bitemporalis fugax" as being practically pathognomonic of this particular lesion. He has reported 3 such cases, in 1 of which polyuria and polydipsia were associated. Spanbock and Steinhaus state that in 50 collected cases of temporal hemianopsia, there was polyuria in 11. The hemianopsia comes and goes several times in the twenty-four hours, and such a history was obtained in 2 of the 4 cases of diabetes insipidus with cerebral lues reported by the writer. Hadra and Ralfe have reported cases accompanying aneurism of the carotid and of the abdominal aorta respectively. The affection has not infrequently been noted in affections of the abdominal viscera. In 1794, Frank observed a fatal case in a patient with chronic disease of the intes- tine. Schapiro reported 5 similar cases from Eichwald's clinic. Dick- inson recorded an instance in a patient with carcinoma of the liver with secondary metastases in the retroperitoneal lymph glands, which had involved branches of the solar plexus. Affections of the spinal cord have, in rare instances, been regarded as the cause of the disease. Schlesinger saw a case in a patient with tabes. In a case of Westphal's, it occurred in association with spastic spinal paralysis. F. Schultze saw a case in a patient with a dift'use tumor of the cord. Instances of persistent polyuria have been observed by Krauss in syringomyelia, and by Friedreich in hereditary ataxia. DIABETES INSIPIDUS 803 Diabetes insipidus has been known to follow the infectious fevers. Thus, it has been observed after typhoid, typhus, diphtheria, measles, and scarlet fever. In very rare instances, a diabetes mellitus may pass over into a diabe- tes insipidus. This is most likely to occur after traumatism to the brain, in which, at first, sugar accompanies the polyuria, but later disappears, leaving the characteristic urinary features of diabetes insipidus. Occa- sionally, however, diabetes insipidus may pass over into diabetes mellitus. In 1897, Senator reported such a case in a woman, aged forty-three years, who, since childhood, had voided daily from 12 to 15 liters of urine of a specific gravity of from 1,001 to 1,003, and who developed a mild glycos- uria. Three years before her death 0.3 per cent, of sugar was found in her urine. No organic lesions were detected at autopsy. Clinical Classification. — The disease may be divided clinically into two groups: (1) The primary or idiopathic cases. This group includes the cases in which there is no evident organic basis for the disease, and comprises a considerable percentage of the total. (2) The secondary or symptomatic cases. These include the cases in which there is evidence of organic disease of the nervous system or elsewhere, the lesion being con- sidered the cause of the polyuria. Symptoms. — The disease may begin abruptly, as after a severe fright. More commonly it develops slowly. Polyuria is the most constant and characteristic feature. The quantity of urine passed daily may be enor- mous. Trousseau had a patient, aged twenty-four years, who passed 43 liters in a day. The weight of the urine voided daily may almost equal that of the patient. Thus, Vierordt cites an instance of a child weighing 13.2 kilograms, voiding 12.3 kilograms of urine daily. The largest daily elimination in any of the writer's 9 cases was 16.5 liters. One passed 1,700 cc at a single voiding. The urine is usually almost colorless. It may have a bluish tint. The specific gravity generally ranges between 1,001 and 1,005. It may be much higher, if there is a marked excretion of urea. Thus Laparguois observed a case in which 6 liters of urine was passed daily with a specific gravity of 1,017. The urine is usually free from albumin, sugar, or casts. Occasionally, traces of albumin may appear in the late stages. In the early stages the output of urine may far exceed the intake of fluids. This is due to withdrawal of fluids from the tissues. The writer has noted this inequality in cases of long standing. Dickinson conducted experiments suggesting that this was in part due to absorption of the moisture of the air through the skin. The balance of opinion favors the view that a condition of "brady- uria" rather than "tachyuria" exists in this disease. In other words, when a copious draft of fluid is taken, an increase in the flow of urine is slower m making its appearance, and the total elimination is slower m a patient with diabetes insipidus than in a healthy individual. There is a slight increase in the urinary solids in the majority of cases. The urea may be markedly increased, but this is due to the food ingested, rather than to any increased tissue metabolism. The chlorides are some- times increased. Muscle-sugar, or inosite, has been frequently demon- strated in the urine. This is believed to result from the flushing out of the muscles by the enormous quantity of fluids ta^ken. 804 CONSTITUTIONAL DISEASES Thirst is practically a constant and often a distressing symptom. In many cases it is the first one complained of, as it first attracts the patient's attention. One patient of the writer said he "simply lived to drink," and described the infinite satisfaction it gave him to be able to take a whole pitcher of water at one draught. Trousseau's patient drank 50 liters in twenty-four hours. In experiments in which the fluids have been cut off, the patient, as in Strubell's case, has been known to drink his own urine. It is very difficult in many cases to determine, from the history or otherwise, whctiier one is dealing with a primary polyuria or a primary polydi}xsia. These can scarcely be considered independent diseases, how- ever. Nothnagel's case is usually cited as a typical instance of a primary polydipsia. A man, aged thirty-five, was kicked in the abdomen and fell, striking his head in the region of the right ear, against a stick of wood, but was not rendered imconscious. Half an hour later he began to have in- tense thirst and drank three liters of water, but it was not until about three hours afterward that the first urine was voided. Buttersack gives the following conditions as indicating a primary polydipsia in any partic- ular case: (1) There is normal sweat secretion. (2) The urine is less than the amount of fluids taken. (3) The polyuria ceases on cutting off the fluids. (4) The urine elimination and liquids taken run parallel. Stoermer states that in primary pohdipsia the blood is of normal concentration, while in primary polyuria it is increased. The appetite varies considerably in different cases. Often it is not increased, and may be diminished. On the other hand, it may be raven- ous, as in Trousseau's patient, who ate in the Paris restaurants, where the meals were a fixed price and the bread was not charged for. He de- voured so much of the latter that it was more profitable for the restaurant keepers to pay him to remain away. These bulimia cases are the ones in which there is such a marked increase in the urea output. Absence of sweating is the rule. The insensible perspiration is also diminished. Constipation is common. Cataract has been described. One of the writer's patients had bilateral plaques of xanthoma palpebrarum. As already stated, there may be recurring attacks of transitory bitemporal hsemianopsia in cases due to basilar syphilitic meningitis. Choked disk may be present. Paralysis of the sixth nerve is sometimes seen. Many of the cases due to cerebral disease have intense headaches. Some suffer early arid throughout the disease, with racking pains in the back and legs. In one of the waiter's cases there were several attacks of transitory left-sided hemiplegia, followed by an attack of longer duration, from wdiich it took Aveeks to recover. Impotence not infrequently occurs. Marked emaciation may develop in the secondary symptomatic cases. In the idiopathic cases, on the other hand, there may be no loss in weight. CEdema of the feet may occur in the last stages of the asthenic cases. In contrast to diabetes mellitus, the knee-jerks are likely to be exaggerated. Of 9 cases, they were exaggerated in 5, normal in 1 , diminished in 2, and not noted in 1. The results of researches show that metabolism is but little disturbed, notwithstanding the abnormal fluid exchanges. In some of the cases the blood is concentrated and the red cells may be between six and seven millions per cmm. The temperature is always subnormal, unless some complication intervenes. During febrile attacks the amount of urine may diminish considerably. The pulse is usually of small volume, DIABETES INSIPIDUS 805 and there Is said to be no increase in the blood pressure. Toward the end the exhaustion may be extreme. Death is sometimes preceded by an uncontrollable diarrhoea. Drowsiness eventually ensues, and death occurs with the patient in coma. The immediate cause in many cases is a low form of congestive pneumonia. Morbid Anatomy. — There are no lesions peculiar to the disease. The various morbid processes found at autopsy, and already given in the sec- tion on etiology, are primary rather than secondary. The kidneys are usually enlarged and hypersemic. The bladder is dilated, and its walls hypertrophied. Dilatation of the ureter and pelves of the kidneys is occasionally found. Theories as to Cause. — The essential cause for the polyuria has been the subject of much research, and is still far from being satisfactorily ex- plained. However it may be brought about, the determining factor seems to be a disturbance of the secretory function of the kidneys. Osier says that "it results from a vasomotor disturbance of the renal vessels, due either to local irritation, as in the case of an abdominal tumor, to cerebral disturbance in cases of brain lesion, or to functional irritation of the cen- tre in the medulla, giving rise to continuous renal congestion." Dietrich Gerhardt states that in the idiopathic forms "the disease is due to a disturbance of the secretory function of the kidneys and not to an increase in the thirst or to blood changes." Meyer, in a research published from Mliller's clinic in May, 1905, comes to the conclusion that in diabetes insipidus one has to do with a primary polyuria, which results from an incapacity of the kidneys to secrete a urine of normal concentration. In consequence of this functional incapacity of the kidneys, the diabetes in- sipidus patient, in order to eliminate the end-products of tissue metab- olism circulating in the blood, has to imbibe larger quantities of water than does the normal individual. Thus, the administration of sodium chloride to a patient with primary polyuria is not followed by the elimination of a urine of increased specific gravity, the quantity of urine being actually increased. In primary polydipsia on the other hand, ac- cording to Meyer, the power of the kidneys to secrete a more concen- trated urine is not destroyed. Thus, the administration of sodium chloride to such a patient is followed by an increase in the specific gravity, without any increase in the volume of the urine. Diagnosis. — There is no arbitrary line separating the physiological from the pathological polyurias, so far as the amount of urine is concerned. The chief distinguishing features of the polyuria of diabetes insipidus is its permanence, a physiological polyuria usually being transitory The greatest difficulty will arise in distinguishing the cases from those of chronic interstitial nephritis, where an abundant, pale urine is common. In the latter, the existence of albumin and a few casts, with certain cardio- vascular features, should not cause much difficulty. The hysterical poly- uria will usually be recognized by the existence of certain nervous and psychical symptoms. The polyuria, further, is likely to be intermittent in character. Some have included hysterical polyuria as a form of diabe- tes insipidus, but this hardly seems justifiable. The absence of sugar and the low specific gravity differentiate the affection from diabetes mellitus. Whether or not "primary polyuria" and "primary polydipsia" should be considered as two distinct affections is doubtful. The writer's feeling is 806 CONSTITUTIONAL DISEASES that they should not, as the clinical features in the two are practically identical. As stated, INIeyer holds that, in the former, the kidneys are incapable of secreting a more concentrated urine on the addition of sodium chloride, etc., to the diet, whereas this capacity is not destroyed in the latter. Prognosis. — Idiopathic diabetes insipidus is much the more benign of the two forms. There is usually no marked emaciation, and the cases have been known to last for fifty years. The prognosis is less favorable in the secondary or symptomatic cases. Emaciation is often rapid and an early fatal termination may ensue. The length of life depends largely on the seat and nature of the organic lesion causing the polyuria. Treatment. — This is on the whole most unsatisfactory. Once the polyuria is established, it is practically impossible permanently to relieve it. The long list of drugs recommended is ample evidence of their general inefficiency. Preparations of opium have been used with some benefit. The crude opium or extract, in half-grain doses, three times daily, and gradually increasing until a total of 4 to G grains daily are taken, may be tried. Codeia may be administered in the same way. The relief, pallia- tive rather than curative, is probably due to the lessening of the sense of thirst. The commonest drug administered is valerian. Either the powdered root, given at first in 5 grain doses, three times daily, and increased until the patient takes a total of 2 drams, or the valerianate of zinc in 15 grain doses, increased to 30 grains three times daily, may be tried. Preparations of ergot have a good reputation, and to a certain extent, justifiably so. Ten minims of the tincture or fluid extract, three times daily, may be tried, and it is not infrequently followed by an appreciable reduction in the amount of urine. The benefit is temporary and symptoms of ergotism must be guarded against. According to Erich Meyer, theocin seems to increase the functional activity of the kidneys. After its administration, the specific gravity is increased, and there is no increase in the amount of urine. It may be given in . 3 gram (5 grain) doses, three times daily. As it is probable that a larger percentage of cases are due to cerebral lues than is generally supposed by the profession, a luetic history should be carefully inquired for, and late syphilitic manifestations searched after. Where there are marked cerebral symptoms, potassium iodide and mercurial inunctions should be given a thorough trial. In the 4 of 9 cases in which syphilis was believed to be the cause of the disease, there was marked improvement in the cerebral manifestations, in the general health, and a striking increase in the weight, in all instances after a thorough course of luetic treatment. There was, however, no material diminution in the amount of the urine. These are the drugs which experience has shown to give the best results. The long list of other remedies that have been tried will not be enumer- ated. It is not advisable to greatly restrict the liquids. When a patient first comes under observation, it is wxU to reduce the fluids a pint a day, so long as there is a corresponding reduction in the amount of urine. When the reduction of urine ceases to follow the reduction in fluids, no further limitation of the latter should be made, as it means that the patient is abstracting fluids from his own tissues. For the thirst, the usual acidu- DIABETES INSIPIDUS 807 lated drinks may be tried. If the digestive powers are good, there is no occasion for any special Hmitation of the food. Strongly salted meats should be avoided, as they will tend to increase the thirst and, conse- quently, the polyuria. Meyer holds that meats in general should be restricted. They yield more products which are ordinarily excreted by the kidneys than do the other foodstuffs, and a diet liberal in meats would tend to aggravate the symptoms, since the patient would have to drink more freely of water in order to produce a solution of these products sufficiently dilute for the kidneys to be able to excrete them The tendency to constipation should be counteracted, and it is advisable to place the patient on a good general tonic. CHAPTER XXXI. GOUT. By THOMAS B. FUTCHER, M. B. Definition. — A nutritional disorder, characterized by disturbances in nitrogen metabolism, with an excess of uric acid in the circulating blood, and, usually, by an arthritis, the distinguishing feature of which is the deposition of sodium biurate in the peri-articular cartilages and tissues. Historical.— The writings of Hippocrates, who lived about 350 B.C., show that he was familiar with the symptoms of gout. Celsus and Galen also, had some knowledge of the affection. Aretseus, who wrote about the middle of the second century of the Christian era, classified the disease according to the part affected, and called it Podagra, Gonagra, and Chiragra, when the attack seized the foot, knee, and hand, respectively. He also mentions that a gouty patient has, during the interval between the acute attacks, even won in the Olympic games. These early writers were also familiar with the hereditary nature of the affection. The name gout (gutta, a drop) was introduced by Radulfe at the end of the thirteenth century. It owes its origin to the prevailing belief that the disease was due to the presence in the blood, of some peculiar humour which is thrown out, or, as it were, distilled into the joints, drop by drop. Thomas Syden- ham (1624-1689), Avho was himself a martyr to the affection, gave us an account of its clinical symptoms that has never been surpassed. In 1776, Scheele and Bergmann first discovered uric acid in vesical calculi and in human urine. The association between uric acid and gout dates from 1797, the year in which Wollaston demonstrated that the gouty deposits about the joints contained uric acid. Garrod, in 1848, by his well-known thread-test, demonstrated uric acid in the circulating blood of gouty indi- viduals. Incidence. — Gout is not so rare a disease in this country as the text- books would lead us to suppose. If physicians will recognize the fact that there is, probably, no such affection as chronic rheumatism, and that the vast majority of cases of chronic arthritis are either gout or arthritis deformans, it will be found that, with due regard to the points in the differential diagnosis, a great many more cases will be justly attributed to gout than has been the case in the past. In the first seventeen years since the opening of the Johns Hopkins Hospital, ending May 15, 1906, there have been 63 cases of gout among a total of 19,685 medical admissions, or 0. 32 per cent. A comparison between the number of gout admissions to the Johns Hopkins Hospital and those admitted to St. Bartholomew's Hospital, London, for fourteen years showed that the ratio was just 2 to 3. Considering that gout is more prevalent in Southern England than anywhere else in the world, it indicates that in the vicinity of Baltimore, 808 GOVT 809 at least, the disease is only one-third less frequent among hospital patients than in London. It must be remembered that the better classes, in which it is more common, do not usually seek hospital treatment. Etiology. — 1. Predisposing Causes. — (a) Heredity. — Hereditary pre- disposition is, undoubtedly, one of the most important factors and plays a part in from 50 to 75 per cent, of the cases. This is particularly true with the well-to-do class. Scudamore states that out of 523 gouty patients, 309, or 59 per cent., gave a history of the disease in the parents or grandparents. Garrod found that the predisposition was inherited in 50 per cent, of his hospital patients. In his private cases, however, he believed that the tendency was inherited in 75 per cent. In the Johns Hopkins Hospital series of 63 cases, there was a history of gout or "rheumatism" in 20, or 31 per cent. It would appear, therefore, that gout in the United States is acquired or "free-hold," rather than inherited or "copy-hold, " to use the classification of old Sir William Browne. It is an interesting feature that, althtDugh the women of gouty families may escape gouty manifestations, they are more likely to transmit the disease to their offspring than are the men. A grandson may inherit gout from a gouty grandfather through a mother who has never shown any manifest symptoms of the disease. Gout acquired from extrinsic causes may be transmitted to the offspring. (6) Age, Sex, and Race. — Although, in inherited gout, infants at the breast have shown manifestations of the disease, it is a rare affection in infancy and childhood. This is illustrated by Scudamore's statistics of 515 cases, in which only 4 occurred before the age of seventeen, the young- est being eight years old. There were but 13 in the first two decades. When gout appears in a very young person it is nearly always inherited. In our series of 63 cases, the ages on admission to the hospital, accord- ing to decades were as follows: One to ten, none; eleven to twenty, 2; twenty-one to thirty, 4; thirty-one to forty, 13; forty-one to fifty, 17; fifty-one to sixty, 18; sixty-one to seventy, 7; seventy-one to eighty, 2. Although this analysis shows the largest number of cases in the sixth decade, that is, between fifty-one and sixty years inclusive, general sta- tistics indicate that the initial attack makes its appearance most fre- quently in the fourth decade, namely, between the ages of thirty-one and forty. Males are much more liable to the disease than females. In fact it is rare in women until after the child-bearing period is over. Since the time of Hippocrates, the relative immunity in women has been attributed to the influence of the catamenia. Of 80 cases collected by a spe- cial commission of the French Academy, only 2 were in females. Of 124 cases admitted to St. Bartholomew's Hospital, in fourteen years, 24 were in women. In our series of 63 cases, there were only 2 in females. Gout in women is usually inherited. Their relative immunity is undoubtedly due, in large part, to their not being exposed to the exciting factors to the same extent that men are. The colored race does not escape. In the Johns Hopkins Hospital series there were 3 male negroes. Two came to autopsy and the biurate deposits were found in the joint cartilages, and in the third there were numerous tophi in the ears in which the sodium biurate crystals were demonstrated. 810 CONSTITUTIONAL DISEASES (c) Alcohol — It is probable that alcohol heads the list in importance among the predisposing causes. It is a curious fact that the fermented beverages, such as wines, particularly port and sherry, beer, ale, and por- ter, are much more injurious than the distilled liquors — whisky, brandy, rum, and gin. The quality of the alcohol seems to be, therefore, as im- portant as the quantity. In Scotland, where whisky is the prevailing drink, gout is much less prevalent than in Southern England, where beer is the ciiief beverage. Investigation has failed to explain this difference in the action of the alcohol. It is apparently not due to the greater acidity of the fermented beverages, nor to the greater percentage of sugar or salines containetl in them. Although the lighter beers of this country are considered less potent as an etiological factor than the heavier beers of England and Germany, the analysis of our series seems to show that beer is the chief etiological factor in the United States. A very important contribution to our knowledge as to how alcohol acts injuriously in disturbing uric acid metabolism, has recently been made by Beebee, in Chittenden's laboratory. It was found that if a patient be put on a diet containing a definite quantity of purin or nuclein containing food and while on this diet he is given alcohol, there is an immediate increase in the output of uric acid in the urine. The alcohol, however, did not produce this result when taken with a light diet, or with one free from purin compounds. In other w'ords, the alcohol only influences that portion of the uric acid which is derived from the ingested food, that is, the " exogenous " uric acid. Alcohol is well known to interfere with oxi- dative processes in the liver. Schittenhelm has shown that the liver and other organs contain an enzyme "oxidase," which has the power of oxidizing uric acid into urea and other products. It is quite probable that the increase of the uric acid in the blood and urine, after the ingestion of alcohol and purin-containing food, is due to the inhibitory action of the alcohol on this oxidase which normally oxidizes the uric acid into urea. The failure of the enzyme to effect this transformation, results in an ex- cess of uric acid in the blood and consequently also in the urine. This important work explains how a rich proteid diet, together with the con- sumption of alcoholic fluids, predisposes to the development of gout. (d) Food mid Exercise. — Gout undoubtedly is a penalty of high living. Rich, nitrogenous foods, particularly the red meats and game, have al- w^ays been held to be specially injurious. There is a growing tendency, however, to place less importance on the quality of the food and more on the quantity, and habits as regards to exercise. Overeating and the leading of a sedentary life are probably most important factors. Syden- ham stated the case clearly when he wrote: "Great eaters are liable to gout, and of these the costive more especially. Eating as they used to eat, when in full exercise, their digestion is naturally impaired. Even in these cases, simple gluttony and free use of food, although common in- centives, by no means so frequently pave the way for gout as reckless and inordinate drinking." Neither the quality of the food nor its quantity does so much harm as the fact that it is "unearned by muscular exertion, " as Ewart puts it. We must remember that gout is not confined to the rich, however. Osier says: "In England the combination of poor food, defect- ive hygiene, and the consumption of excessive malt liquors, makes 'the poor man's gout' a common affection." These were the conditions that GOUT 811 largely prevailed in our series, as 55 of the CO patients were treated in the public wards, and belonged to the poorer classes. (e) E^ect of Lead. — Musgrave, Iluxham, and Falconer (1772), had called attention to the association between lead poisoning and gout, but it remained for Garrod to show the importance of lead as an etiological fac- tor. He found that 33 per cent, of the gout patients that came under his care in hospital practice, had at some period of their lives suffered from lead poisoning, and had for the most part been plumbers or painters. Only 3 in our series showed positive evidences of lead poisoning. One had lead colic, and 2 had a blue line on the gums. Seven others, however, had occupations exposing them to possible lead infection. Of the 9 patients, 6 were painters, and 3 were tinners. Thus in 9 of the GO cases, or 15 per cent., lead was probably a contributory etiological factor. We do not know in just what way lead infection predisposes to gout. Garrod found that the blood of patients suffering from lead poisoning contained an excess of uric acid. He pointed out also that these patients were liable to develop chronic nephritis, and drew the conclusion that the increased amount of uric acid in the circulating blood resulted from a renal insufficiency. The majority of subsequent investigators have sup- ported this view. Sir Dyce Duckworth holds that the lead acts injuriously through its effects produced on the nervous centres. As will be seen later, Duckworth supports the nervous theory of the origin of gout. (/) Occupation and Physique. — As stated, those whose occupations bring them into constant contact with lead, such as painters, plumbers, and enamelers, and to a less extent, tinners, are specially liable to be attacked. Bartenders and employees in breweries, owing to the oppor- tunity for free indulgence in the use of malt liquors, are also very prone to the disease. It is a conspicuous fact that one rarely sees gout in a weakly, under- sized, and poorly nourished individual. Persons of large frame, good physique, and with a tendency to obesity, are the ones who usually manifest the disease, and seem particularly susceptible to the baneful influence of the predisposing factors already considered. (g) Traumatism is thought by many to be a contributory factor. The prevalence of the attacks in the big toe joints has been in part explained by the liability of this articulation to injury while walking or from pres- sure by an ill-fitting shoe. II. Metabolic Causes. — From the chemical standpoint, the etiology of gout is closely connected with nitrogen metabolism, and with the forma- tion and excretion of certain compounds of which nitrogen is a component. Since 1797, the year in which Wollaston demonstrated that the gouty de- posits about the joints contained uric acid, the vast majority of those who nave studied the disease have concluded that it is connected in some way with the formation and elimination of uric acid. There is a steadily growing conviction among the best students of this disease at the present day that uric acid plays little or no part in the actual etiology of gout. Although an excess of uric acid in the blood and of its salts in the tissues dominates the picture in well-marked cases, this excess of uric acid is held to play a secondary part and to be a mere weapon of the disease. There is no experimental proof showing that an excess of uric acid causes any special toxic symptoms. The growing belief is that gout is 812 CONSTITUTIONAL DISEASES really a disease of intermediary purin metabolism. This view receives added support from the very important recent discovery that certain tissue ferments play a most important role in the metabolism of the purin bodies. While it will seem hard for us to divorce our minds from the long prevailing uric acid theory of gout, the following considerations of purin metabolism indicate strongly that we shall probably have to do so. (a) Uric-Acid Metabolism under Normal Condiiions. — To better appre- ciate the metabolic disturbances in gout, it is important to understand, as fully as our present knowledge permits, the chemistry of uric acid and its closely allied compounds under physiological conditions. Uric acid has the empirical formula, C5H4N4O3 and the rational HN— CO II formula, OC C — NH The generally accepted view, at the I II UTi^-CO. HN-C-NH present time, is that it is derived partly from nuclein resulting from the disintegration of cell nuclei, and partly from the hypoxanthin, which is produced as a product of muscle metabolism. At least 4 other nitrog- enous compounds are known to be derived from nuclein. These are xanthin (C5H4N4O2), hypoxanthin (C5H4N4O), guanin (C5H5N5O) and adenin (C5H5N5). In addition to these, there are 5 other compounds closely allied to them in general structure. They are as follows : Hetero- xanthin (CeHgN^Os), paraxanthin (C7H8N4O2), episarkin (CiHeNgO), carnin (CyHgN^Og), and epiguanin (CeHyNgO). These 10 nitrogenous compounds were given the name alloxuric bodies, {alloxur korper) by Kossel and Kriiger, whereas the last 9 constitute the alloxuric, xanthin or nuclein bases. The term "alloxuric" was ap- plied to them because each was made up of a combination of an alloxan and urea nucleus. Emil Fischer has shown that there is a very intimate relationship between the various members of this group, and has demon- strated the remarkable fact that a number of them can be prepared synthetically. He found that they are all derived from a compound C5H4N4, which he termed "purin," having a carbon-nitrogen nucleus, the "purin nucleus," as a basis. Purin, according to Fischer, has the N=C II formula HC C — NH and the different purin bodies are derived II II ~:^CH N— C— N-^ therefrom by the substitution of the various hydrogen atoms by hydroxyl, amide, or alkyl groups. In order to designate the different positions of substitution, Fischer has proposed to number the 9 atoms of the purin IN— C6 I I nucleus in the following way: 2C C5 — N7s^^ I I >C8 3N— C4— N9^ GOUT 813 In studying the structural formula of uric acid given above, it will there- fore be seen that it is 2.6.8 trioxypurin. Xanthin, accordingly, is 2.6 dioxypurin; hypoxanthin is 6. oxypurin; adcnin is 6. amino purin; and guanin is 2. amino-6. oxypurin, etc. To summarize, thcrcifore, the allox- uric or purin bodies include uric acid, together with the alloxuric, purin, nuclein, or xanthin bases. The purin substances are supposed to be con- tained in the nucleic acid of the cell nuclei in the form of a loosely com- bined phosphorus-containing body — the nucleotin-phosphoric acid, as Schmiedeberg has termed it. The close relationship between uric acid and the xanthin or purin bases, and their common origin from nuclein, is shown by the following scheme: Nuclein . Albumin Nucleic acid Phosphoric acid Mother substance Uric acid alloxuric, purin, nuclein, or xanthin bases. Experimentally, this was clearly shown by Horbaczewski. He found that by adding some oxidizing substance, such as fresh blood, to macerated spleen pulp and then keeping the whole at a constant temperature of 45° C. for several hours, he obtained a certain amount of uric acid. If, on the other hand, no oxidizing agent was added, and only heat applied, he was unable to obtain any uric acid, but secured an identical amount of nuclein or xanthin bases, as indicated by the nitrogen content of each. In other words, it depended upon the facilities afforded for oxidation as to whether the product obtained would be uric acid or the nuclein or xanthin bases. The feeding of nuclein to man and dogs is followed by a marked increase in the uric-acid output. Horbaczewski, who advanced the erro- neous view that uric acid was derived mainly from nuclein of the disin- tegrated leukocytes, thinks that the increase in the uric acid after nuclein ingestion is not due to the ingested nuclein, but to the nuclein derived from the increased number of leukocytes occasioned by the nuclein administered. An amount of proteid not containing any purin or nuclein bases, but containing an identical quantity of nitrogen in some other form, does not produce a similar rise in the uric-acid excretion, as has been demonstrated by Schmoll and Kaufmann. The purin bodies from which uric acid is mainly, if not entirely, de- rived, come from two sources. Burian and Schur have designated them the "exogenous" and "endogenous" purins. The exogenous purins are those introduced with the ingested food, whereas the endogenous purins are those derived from the nucleins of the body and, according to recent investigations, chiefly from muscle metabolism. In the same manner, we speak of "exogenous" and "endogenous" uric acid, when it is derived from these respective sources. By the use of a purin-free diet (such as milk, eggs, butter, cheese, white bread, rice, sago, and fruits) it has been possible to estimate the quantity of nuclein derivatives or purin bodies which arise solely as a result of cellular processes. During the 814 CONSTITUTIONAL DISEASES year 1905, Burian demonstrated that the muscle purins, particularly hypo- xanthin, are the chief source of the endogenous uric acid. He finds that muscular exertion is always accompanied by a decided rise in the output of uric acid. The investigations of Burian and Schur show that the endog- enous purins excreted in the urine in twenty-four hours vary from 0.10 to 0.20 grams, expressed in terms of nitrogen, of which one-fiftieth to one- tenth is in the form of xanthin or purin bases and the rest as uric acid. On such a diet, Rockwood, working in Chittenden's laboratory, found that the daily output of uric acid in a normal individual ranges between 0.3 and 0.4 grams. He also confirmed the observations of Burian and Schur, that a given individual shows a certain degree of constancy in the daily excre- tion of uric acid. In other words, the elimination of endogenous uric acid is constant for each individual; that is, it is an individual factor dependent, probably in part, upon the weight of the individual or of the contained organs and tissues. The figures of Burian and Schur given above do not represent the entire amount of nuclein decomposed in the body. The remainder is transformed by specific enzymes of the liver and other organs (to be referred to later) and excreted as urea, or as bodies intermediate between the purin bodies on the one hand and uric acid and urea on the other. Allantoin is one of these intermediate bodies. Wiener holds that glycocoll is the only decomposition product of uric acid. Of the total purin bodies of the urine, nine-tenths is excreted as uric acid and one- tenth as the xanthin or purin bases. Seat of Formation of Uric Acid. — Until a very recent date, we have pos- sessed no definite knowledge as to the seat of formation of uric acid, nor in what organs the various purin bases were contained or oxidized into higher oxidation products. Garrod, Latham, and Luff, hold that the uric acid is formed in the kidneys. Zaleski, after extirpating the kidneys of snakes, and von Schroder, after removal of these organs in birds, have shown that there is an accumulation of uric acid in the blood and tissues of these animals. This goes to show that the kidneys of birds and snakes, at least, are not the only organs that produce uric acid. Hammarsten claims that we have, up to the present time, no direct jDroof that uric acid is formed in the kidneys and the general opinion is against the view that uric acid is formed in these organs. It is probable that uric acid originates in the system only as a result of oxidative processes. Experimentally, the synthetic formation of uric acid has been demonstrated. By passing ammonium lactate through the livers of geese, Kowaleski and Salaskin, in 1901, showed that it was syn- thetized into uric acid, as indicated by the great increase of the latter in the blood leaving the liver. There is no conclusive evidence, however, that a similar synthetic formation of uric acid occurs in the human sub- ject, although it is possible that it may occur. Physiologists and physiological chemists have demonstrated that many of the chemical transformations in the body, previously not understood, are really due to the action of specific ferments or enzymes. The very recent investigations of Jones, and his coworkers, Partridge and Winter- nitz, and of Schittenhelm, have clearly shown us that the various glands and tissues of the body contain specific ferments which are essential for the conversion of one xanthin base into another, and for the conversion of the xanthin bases into uric acid. It has also been ascertained that GOUT 815 certain glands contain only certain ones aniong the xanthin bases. Jones has found that when such glands as the thymus, suprarenal, spleen, etc., are subjected to autodigestion for several hours at body-temperature in the presence of an antiseptic, definite chemical changes occur. In the case of the thymus, large amounts of xanthin, and a small amount of hypoxanthin, together with uracil, are found in the fluid. With the supra- renal gland, large quantities of xanthin and a small quantity of hypo- xanthin, are found. In both of these glands, however, guanin and adenin are entirely lacking. By autodigesion of the spleen, on the other hand, guanin and hypoxanthin are formed abundantly, while adenin and xanthin are wanting. It will be seen that xanthin and hypoxanthin are the chief products of self-digestion of these glands. Quite different results are reached when the glands or their respective nucleoproteids are boiled with acids. When mineral acids are used as the hydrolyzing agent, then the above glandular tissues yield chiefly guanin and adenin. This differ- ence in the result by autolysis and by hydrolysis, with acids, is due to the fact that, in autolysis, the changes are induced by the presence of specific intracellular ferments which possess the power of acting upon certain parts of the purin bodies, transforming them into other related substances. Jones and Partridge have shown that, in self-digestion of the pancreas in an alkaline medium, large amounts of xanthin and hypoxanthin are found as end products of the autolysis. Guanin and adenin are also formed in all probability, but they are gradually converted into xanthin and hypoxanthin by intracellular enzymes. They found that if pure guanin is placed in a mixture containing finely divided pancreas, with chloroform to prevent putrefaction, and the mixture kept at 40° C.for some time, the guanin is slowly but completely converted into xanthin. The ferment that effects this transformation they have called guanase, and it is likewise present in the thymus and adrenals, but is absent from the spleen. Jones and Winternitz have found a similar intracellular enzyme which they term adenase, owing to the property it possesses of transforming adenin into hypoxanthin. It is found in the thymus, adrenals, pancreas, and liver. The two ferments are true hydrolyzing agents, the chemical reactions occurring being quite simple and as follows : Cs Hs Ns O+H2 0=C5 U, N, O2+NH3 Guanin Xanthin C5 H5 N5+H2 0=C5 H, N, O+NH3 Adenin Hypoxanthin It will be noted that there is not only a taking-on of water with the re- tention of the oxygen, under the influence of the enzyme, but there is also a giving-off of ammonia, bv which the change is made possible. As Chittenden has recently stated, these two enzymes are typical deamidiz- ing ferments, destroying the NHg group of the adenin and guanin. Schittenhelm has made the important discovery that it is possible to obtain from simple extracts of the spleen, liver, lungs, and muscles, an oxidizing ferment which is termed oxidase, and which possesses the power of transforming the purin bases quantitatively into uric acid. Thus xan- thin is converted into uric acid by the mere addition of an atom of oxygen, 816 CONSTITUTIONAL DISEASES and Burian has given to the ferment that brings this about the name of "xanthin oxidase." Schittenhchn failed to find it in the thymus, intes- tine, kidneys, or blood. It has for some considerable time been known that the nucleoproteids, nucleins, and nucleic acid, when fed, caused an increased excretion of uric acid, but it has not been heretofore understood how this is brought about. Recent investigations, however, have made this clear. It has been found that certain body cells contain an intracellular enzyme termed nuclease, which has the power of liberating the purin bases from their combination as a component part of tissue nucleoproteids. These liberated nuclein bases, such as guanin and adenin, are converted by the deamidizing enzymes, guanase and adenase, into xanthin and hyj)oxanthin respectively. Then, by the action of the oxidase just referred to, hypoxanthin is oxi- dized to xanthin, and xanthin to uric acid. It jnust be emphasized that these enzymes are not distributed indiscriminately throughout the body, but are confined to definite organs or tissues, as has been pointed out. It will thus be seen that we have four distinct enzymes — iiucleasc, gua?iase, adenase, and xanthin oxidase, or xanthase, which are responsible for the production of uric acid in the body. A further observation of great im- portance is that of Schittenhelm, in which he found that there is another tissue oxidase — contained, so far as is known at present, in the kidneys, liver, muscles, and perhaps, the bone-marrow — which has the power of oxidizing and destroying the uric acid, and converting it into urea and other bodies. This discovery has a direct relationship to the excess of uric acid in the blood in gout; for it is possible to conceive that this excess may be due as well to an inhibition of the action of this uric acid destroy- ing ferment as to an excessive activity of the ferments which lead to the production of uric acid. As pointed out in the section on the predis- posing causes for gout, it is possible that alcohol may act injuriously by inhibiting the activity of the uric acid destroying enzyme. For the above enzymes to perform their functions properly, there must be a proper relationship between the quantity of the purin bodies to be acted on, and the various ferments. Mendel has shown that, if the purin bodies be in excess, their thorough oxidation does not take place, and instead of their being largely oxidized to urea, an intermediate oxidation product — allantoin, is produced, and excreted in the urine in excess. The exogenous purins we take in our food are either in the form of the free bases adenin, guanin, hypoxanthin, and xanthin,or as combined purins and nucleoproteids. Of the free purin bases in the ordinary food stuffs it is the oxypurins, hypoxanthin, and xanthin, that the body has mainly to deal with, as they are contained in large amounts in meat broths and ex- tracts. They are, hoAvever, easily oxidized into uric acid, and excreted as such, or further oxidized into urea or other products by the special oxi- dase. When combined purins are introduced in the form of nucleins and nucleoproteids, adenin and guanin are liberated by the action of nuclease. The continuance, unchanged, of these two bodies, depends upon the pres- ence and action of the two enzymes, adenase and guanase. If these are present and active in normal degree, we can conceive of a rapid conversion into hypoxanthin and xanthin and then into uric acid. If the enzymes be deficient, then the adenin and guanin will circulate unaltered in the blood, for a time at least. Chittenden offers the suggestion that the pro- GOUT 817 longed circulation of these aminopurins may account for the renal changes in certain diseased conditions, presumably gout; for it has been shown that when adenin is administered to dogs and rabbits, it causes anatomical changes in the tubules of the kidneys, with deposits of spheroliths of uric acid and ammonium urate in the kidney substance. Since the division of uric acid into the exogenous and endogenous forms, it has been held, until a very recent date, that the endogenous uric acid resulted entirely, or almost entirely, from the nuclein derivatives derived from the destruction of the nuclein of the glandular and tissue cells. In 1905, Burian showed that this view is erroneous. He finds that only a very small amount of the endogenous uric acid has its origin in the nucleoproteids of disintegrating tissue cells or leukocytes, the larger part being derived from the purin-base hypoxanthin, which is continually being formed as a metabolic product of living muscle tissue. It is not possible to go fully into this important observation here. It is sufficient to say that Burian's work opens up a new chapter in purin metabolism, bearing on the production of endogenous uric acid. In the resting state, muscle is continually giving up to the blood a certain amount of uric acid formed at the expense of the hypoxanthin which originates within its own tissue. The oxidation of the hypoxanthin to uric acid is accomplished by the specific oxidase which the muscle itself contains. Burian points out, however, that this oxidase must be so located that the hypoxanthin is converted into uric acid just as it is passing from the mus- cle fibre into the blood or lymph, since muscle itself never contains any uric acid, only purin bases. He also believes that a certain amount of the uric acid is at once decomposed by the other oxidizing ferment which destroys this acid. The portion of the endogenous uric acid that results from the disin- tegration of the nuclei of body cells and leukocytes is also fully believed to be the result of the action of the specific ferments already described. It will thus be seen that these investigations have given an entirely new conception of the seat and method of formation of uric acid in the system. It seems justifiable to hope that this additional knowledge may soon lead to a better understanding of the disturbances of nitrogenous metabolism which appear to lie at the foundation of gout. Forvi in Which Uric Acid Circulates in the Blood. — This question re- quires elucidation. Uric acid is a dibasic acid, and as such may be represented by the formula H2(C5H2N403). It thus has two atoms of replacable hydrogen. It forms two groups of salts, and according to Bence- Jones and Sir William Roberts, three different salts. For purposes of illustration, sodium may be used as the replacing metal. The salts are as follows: (1) Neutral sodium urate, Na2C5H2N403. (2) Biurates, or acid sodium urate, or sodium biurate, NaHCgHaN^Og. (3) The quadriurates of Roberts, in which the sodium takes the place of one-fourth of the displaceable hydrogen of two molecules of uric acid loosely combined together, such as NaHC5H2N403,H2C5H2N403, the sodium quadriurate. The neutral urates are purely laboratory compounds, and under no circumstances occur in the human economy. The biurates are not believed to occur physiologically. They constitute the form in which uric acid is deposited about the joints, and in the tophi of gout patients. 52 818 COXSTITUTIOXAL DISEASES Free uric acid never occurs in the blootl or tissues, either under physio- logical or pathological conditions. Sir ^Yilliam Roberts holds that the uric acid circulates in the blood as the loosely combined, readily soluble, quadriurate. While accepted by a number of investigators, this view has met with considerable opposition. INIost of the present day physio- logical chemists claim that there is no such uric acid compound, and that it is impossible for it to exist in a medium such as that of the circula- ting blood. Opinions differ as to whether it is possible to demonstrate the presence of uric acid or its combinations in the blood of normal individuals. Garrod, Abeles, and Magnus-Levy, claim to have found it in minute traces; INIinkowski and Klemperer were unable to demon- strate uric acid in the blood of healthy persons. This diversity in results is thought to be due to the fact that, normally, the uric acid is in loose combination with some other purin product which consequently prevents its precipitation by the usual reagents. Minkowski holds that it is com- bined with the purin-base, nucleotin-phosphoric acid, and that it is in this form that uric acid circulates in the blood. Others think that it circulates in combination with one of the other pyrimidin derivatives of nuclein, namely, thymic acid. Daily Excretion of Uric Acid. — The amount of uric acid eliminated daily in the urine by the healthy adult of average weight, when on a mixed diet, ranges between 0.4 and 1 .0 grams. Hammarsten gives 0.7 grams as the average. Of the total purin or alloxuric bodies in the urine, nine- tenths exist as uric acid and one-tenth as the purin, alloxuric, xanthin, or nuclein bases. The ratio of uric acid to urea ranges in health between 1 to 50 and 1 to 70, and of uric acid nitrogen to total nitrogen, according to Minkowski, between 1 to 20 and 1 to 120. The form in which uric acid is eliminated in the urine has not been definitely ascertained, but Bunge and, later, Riidel suggested that it is here also excreted in loose combination with some other organic substance. They hold that this combination is easily broken up, and the uric acid is then set free. It may then either remain free or enter into combination with the sodium, potassium, or ammonium contained in the urine. (6) Uric Acid Metabolism in Gout. — There is undoubtedly marked dis- turbance of nitrogenous metabolism in gout. The total-nitrogen equilib- rium is disturbed. It has been definitely shown by the investigations of Vogel, Schmoll, and others, that a nitrogen retention occurs; that is, that the total nitrogen output is less than the nitrogen intake. Since the adoption of the classification of purins into the "endogenous" and "exogen- ous" varieties, too little time has elapsed and too few investigations have been published, to draw absolute conclusions as to how the metabolism of each is affected. The studies of Reach, Kaufmann, Vogt, and Chalmers Watson, show that in gout, the exogenous purins are more slowly excreted than in health, and that in some cases there is a distinct retention. Vogt gave rich purin-holding food to a gouty patient and to a healthy individual, and found that in the former there was a delayed excretion, and definite retention of the purin bodies. It can safely be concluded that exogenous purins, in part at least, lead to an excess of the nuclein derivatives in the blood-stream. There is no question but that the metabolism of the endogenous purins is also markedly disturbed in gout. This will probably be best shown by a consideration of the amount of uric acid excreted in GOUT 819 the urine as well as of that present in the circulating blood in this dis- ease. The Excretion of Uric Acid in Gout. — Garrod was the first to claim that there is a diminished excretion of uric acid in gout. He believed that this was true both of the acute attack as well as of chronic gout. Since the adoption of more reliable methods of quantitative analysis in recent years, Garrod 's results have not been confirmed in toto. P'rom the analysis of Ebstein, Pfeiffer, Luff, Camerer, Weintrand, Kaufmann and Mohr, Magnus-Levy, His, and others, Minkowski states that the following con- clusions may be drawn: (1) The daily excretion of uric acid, in the inter- vals between acute attacks, ranges within the same limits as does the excretion in healthy individuals. (2) Jn chronic gout, even in those cases in which there is niarked deposition of biurates in the tissues, a constant diminution in excretion of the uric acid has not been definitely proved. (3) Immediately preceding an attack there is regularly a diminution in the amount of uric acid eliminated in the urine, whereas, during and after the attack, the uric acid output is increased. The writer's analyses, made with Folin's modification of the Hopkins method for estimating uric acid, fully accords with the results stated in Section 3. They, however, differ materially from those given in Section 2 as the uric acid elimination has almost always been below the lower limit for normal, viz., 0.4 grams, in the intervals between the acute at- tacks in chronic tophaceous gout. To what are these variations in the uric acid excretion due ? Various possibilities present themselves. The diminution in the excretion of uric acid before the onset of an acute attack may be interpreted as meaning either a diminished uric acid production, or a temporary diminished capacity on the part of the kidneys to excrete uric acid The sudden deposition of uric acid salts about the joints and in the tissues affords a third possible explanation The increased uric acid output during an attack may be due to an increased uric acid production, or to the possi- bility that the previously retained uric acid is temporarily excreted in increased quantity. The variations in the excretion may further be explained on the supposition that at times a smaller, and at other times, a larger, part of the uric acid in the organism is metabolized into other waste products, such as urea. It may be possible to draw more definite conclusions as to the cause or causes of these variations in the uric acid elimination in gout after we consider the uric acid content and alkalinity of the blood in this disease. The Uric Acid in the Blood in Gout. — Practically all observers agree that there is a marked increase of the uric acid in the circulating blood. Garrod first demonstrated this excess by quantitative analysis and, also, by his well-known "thread- test." Klemperer, who was unable to demon- strate uric acid in normal blood, found in three cases of gout 0.067, 0.088, and . 0915 grams of uric acid in 1000 cc. of blood, during an acute attack. Magnus-Levy made 34 analyses in 17 cases of g^ut, and found the uric acid to range between 0.021 and 0. 10 grams in 1,000 cc. of blood. The same observer also sought to ascertain whether there was any regular difference in the amount of uric acid in the blood during an acute attack and in the intervals. Of 10 cases studied, the uric acid was the same during the acute attack as in the intervals in 5; greater in 2; and less in 3. 820 CONSTITUTIONAL DISEASES It cannot be said then that there is by any means a constant increase in the amount of uric acid in the blood during an acute attack over that present in the intervals. J' he Alkalinity of the Blood in Gout. — The methods of determining the degree of alkalinity of the blood are notoriously unreliable. Fokker and others, on the basis of recent work, deny that the blood of the normal individual is alkaline, claiuiing that it is neutral. However true this may be, (larrod based his theory of the production of gout largely on the belief that the alkalinity of the blood is diminished. He simply makes the state- ment that the alkalinity of the blood in gout is markedly diminished, and no reference is found in his writings to any quantitative determina- tions nor any intimation as to how he arrived at this conclusion. Recent investigations along this line, and by methods believed to be reliable, are conflicting in their results. Pfeiffer, Jeffries, and Drouin, claim to have found an increased alkalinity. Klempcrer, in 3 cases of acute febrile gout in which the alkalinity was determined by estimating the carbonic acid in the blood — the most reliable method — found a very slight diminu- tion, but not enough to account for the precipitation of the uric acid. In 16 cases in which Lowy's titration method was used, Magnus-Levy found no appreciable diminution in the alkalinity. In 11 cases he com- pared the degree of alkalinity during and between attacks. In 3 there was a diminution during the attack; in 2, an increase; and in 6, there was no difference. These results in general show that there is no constant diminution in the alkalinity of the blood in gout, nor is the alkalinity apparently diminished to a greater extent during the acute attack than in the intervals. Klemperer conducted a series of experiments which have a very impor- tant bearing on the alkalinity of the blood in healthy and in gouty individuals, as well as on the effect that a possible change in the alka- linity may have on the power of the plasma to hold uric acid in solution. He found that the blood of the gouty person is not a saturated solution of uric acid and that it is still capable of dissolving more of the acid. Whereas, 100 cc. of blood serum from 3 healthy persons was capable of dissolving 0.166, 0. 171 and 0. 174 grams of uric acid, the same amount of serum from 3 gouty patients was still capable of dissolving 0.126, 0.14, and 0.18 grams of the acid. The conclusion to be drawn from this observation is, that an over-loading of the blood with uric acid is not alone to be regarded as the cause for the deposition of the sodium biurate in the tissues. This is substantiated by the fact that in other diseases, such as leukaemia, there is a marked increase in the uric acid in the blood, yet biurate depositions in the tissues do not usually occur. There are apparently only 5 cases reported in the literature in which definite gouty manifestations have been found in association with leukaemia. This number is so small that the co-existence may well be considered acci- dental. Origin of the Excess of Uric Acid in the Blood. — Three possibilities present themselves. One can conceive of the increase being due to: (1) Diminished destruction or oxidation; (2) increased formation; (3) di- minished excretion by the kidneys. The evidence on this point has recently been analyzed by Wiener in his excellent review of uric acid in its relationship to gout. He claims that GOVT 821 there is no special evidence to point toward the excess being due to de- ficient oxidation. Klemperer has shown that the blood of the gouty individual still possesses the power in vitro of destroying uric acid, pre- sumably by oxidation. Wiener's analysis was published just previous to the appearance of the recent studies showing the important part that specific ferments play in the formation and destruction of uric acid. As already pointed out, the excess of uric acid in the blood in gout may eventually be shown to be due to a deficiency in the oxidase which nor- mally converts it into urea and other products. The knowledge that there is a special oxidase in the liver, kidneys, muscles and bone-marrow whose function is to further oxidize uric acid to urea and other products, renders it quite possible that the excess of uric acid in the blood may be due to influences which interfere with the oxidizing power of this particular oxidase. The diminished oxidation theory is the one receiving the best support at the present time, and is the one for which the writer thinks there is the most evidence. Although the increase in the uric acid in the blood and urine in leukse- mia and pneumonia is undoubtedly due to increased formation, resulting from increased nuclein destruction, the evidence is not nearly so con- vincing in the case of gout. We know that uric acid is formed partly by oxidative processes from the nucleins and partly by synthetic formation in the liver. There is no definite evidence of any increased nuclein de- struction in gout. There is no leukocytosis, excepting a slight temporary one during the acute febrile attacks; so an increase in the leukocytes with their increased disintegration cannot explain the increase of uric acid in the blood. We have no definite evidence to point toward an increased synthetic formation of uric acid in the liver. There are some points favoring the view that the excess of uric acid in the blood is due to diminished excretion by the kidneys. In support of it, is the prevalence of, and, according to Levison, the constant association of an interstitial nephritis in gout. Most authorities are inclined to con- sider the nephritis as a result of the gout. The influence of nephritis on uric acid excretion and its deposition about the joints is shown by Ord and Greenfield's statistics. Out of 96 cases of renal disease there were biurate deposits in the joints in 18. Levison claimed that it was always with contracted kidneys that this deposition occurred. This was sup- ported by the investigations of Luff, who found biurate deposits in the joints in 20 out of 26 cases of chronic interstitial nephritis. These obser- vations tend to show that in interstitial nephritis there is some condition produced, presumably a retention of uric acid, which favors the latter 's deposition in the joints. In support of the retention theory may be mentioned the researches of Hans Vogt and Reach, who found that the excretion of uric acid after the ingestion of nuclein or nuclein-containing food is much less marked in the gouty, than in the healthy, individual. Schreiber claims, contrary to Levison 's view, that interstitial nephritis is not always present in gout. In these cases without organic renal disease, Minkowski is inclined to support the older view of Garrod that it is possible that a functional disturbance of the kidney may occur which lessens its ability to excrete uric acid. He favors the retention theory as the cause of the excess of uric acid in the blood. He and His have advanced the view that the uric acid, in gouty individuals, circulates in 822 CONSTITUTIONAL DISEASES the blood in a (liffcrcnt organic combination from that in which it exists in the blood of healthy persons, and that consequently the kidneys are functionally incapable of eliminating it as in health, A very strong artrument against this retention theory is the fact that, even in cases with Avell-marketl nephritis, it is well known that the kidneys are capable of excreting uric acid in quantities considerably above the upper limit for normal for two or three days after the onset of an acute attack. Taking everything into consideration, the weight of evidence, in the writer's opinion, seems to favor the retention theory as the most plausible view to ex])lain the excess of uric acid in the circulating blood in this dis- ease. Subsequent investigations, however, may show that the excess is due to failure in the action of the special oxidase in the liver and other tissues whose function is to further oxidize uric acid. Theories of Gout. — Considering the number of these, only the more important ones can be considered and these merely briefly. Garrod held that in acute gout the alkalinity of the blood is lessened and the uric acid of the blood is increased owing to deficient power of elimination on the part of the kidney. The latter is due, usually, to organic disease but may result from a purely functional disturbance. He attrib- utes the deposition of sodium biurate in the tissue to the diminished alkalinity of the plasma, which is unable to hold the uric acid combination in solution. During an acute paroxysm there is an accumulation of the urates in the blood and the local inflammation is caused by their sudden deposition in crystalline form about the joints. This theory has had many supporters and in large part can be accepted, but, as we have already seen, any explanation based on the degree of alkalinity of the blood must be received with some skepticism. Sir William Roberts believed that uric acid normally circulates in the Blood in the form of a soluble quadriurate, which may be represented by the formula NaHCgHaN^Og, H2C5H2N4O3, which is sodium quadri- urate. The sodium atom may have its place taken by an atom of any of the univalent metals. In the gouty state, according to Roberts, either from deficient action of the kidneys, or from overproduction of urates, the quadriurate accumulates in the blood. The detained quadriurate, being very unstable and circulating in a medium rich in sodium carbonate, takes up an additional atom of the base, and is converted into the biurate as follows: 2 (NaHCsH^N.Og, H2C5H2N403)+Na2Co4=4NaHC5H2N4 O3+CO2+H2O. The biurate is very insoluble and less easily excreted by the kidneys. It consequently accumulates in the blood, and exists first in a gelatinous, and later in the almost insoluble, crystalline form. It is then that precipitation is imminent or actually takes place. This is apt to occur where the circulation is poor and the temperature low, and in regions in which the lymph contains a relatively high percentage of sodium chloride, as in the synovial sheaths. This theory has met with opposition from various quarters and partic- ularly on the part of Tunnicliffe and Rosenheim. Minkowski also holds that it is impossible for uric acid to circulate, even in normal blood, as the quadriurate, for in a medium so rich in carbonates and phosphates as is the blood, the quadriurate must necessarily be rapidly converted into the biurate. Minkowski thinks that uric acid normally circulates in the blood in organic combination with nucleotin-phosphoric acid. Others GOUT 823 believe that it is in combination with thymic acid, one of the nuclein derivatives. Ebstein holds that the local manifestations of gout are due to nutri- tive tissue disturbances which lead to necrosis. He found, after a study of many of the affected tissues in gout, that one change is common to them all, independently of the urate crystallization, and that is, a necrosis of the parts in which such deposition takes place. Ke believes that this necrosis is primary, and that it is as characteristic as the bi urate deposit. Both changes must co-exist in any tissue in order to constitute a true gouty lesion, and he has found such lesions in the kidneys, in hyaline and fibro- cartilage, and in tendons and connective tissue. He calls attention to the early stages of the necrotic process, in which he finds no deposition of the biurates, and consequently maintains that a nutritive tissue disturbance is the primary factor, and uratic deposition a secondary one, in the gouty process, the latter not occurring until death of the tissue takes place. Von Noorden supports Ebstein's views, and believes that the tissue necro- sis is due to the action of a special ferment. In 1784, Cullen advanced the theory that gout was primarily due to an affection of the nervous system. According to this view there is a basic arthritic stock — a diathetic habit, of which gout and rheumatism are two distinct branches. The chief advocate of the nervous theory at the present day is Sir Dyce Duckworth, who at first held that disease of a special tract in the cord was the cause of the tissue lesions in gout. Although he no longer insists that gout is due to a lesion of any particular column of the cord, he just as strongly insists that it is essentially of nervous origin. The influence of depressing conditions, mental and physical, in precipitating an attack of gout, points strongly to the part played by the nervous system in the etiology of the disease. The nervous theory has not received very general support. In recent years attention has been attracted to the xanthin or purin bases as a possible cause of gout. Kolisch found that although the uric acid excretion is diminished, yet the total output of the alloxuric or purin bodies was increased. He believed that the xanthin bases nor- mally are finally oxidized into uric acid in the kidneys, but that in gout the kidneys are diseased, and their power to oxidize the xanthin bases is con- sequently impaired. His results were obtained by methods shown later to be inaccurate, and Siilzer, Laquer, and Magnus-Levy, failed to confirm them. Whatever part the xanthin bases may subsequently be shown to play in the etiology of gout, up to the present they have not been shown to exert an important influence. Undoubtedly some of the xanthin bases are definitely toxic. Kolisch and Croftan have produced arterial and renal lesions by injecting hypoxanthin into animals. I. Walker Hall confirmed these results and also produced parenchymatous changes in the liver by long continued injections of hypoxanthin. Taylor has already in Chapter XIV considered gout from the standpoint of an auto-intoxication. It has been claimed by some that glycocoU is found quite frequently in the urine of gout patients, and it has been thought that it may be a factor in the causation of the disease. As yet, too little is known to express any definite opinion on this point. Its relationship to uric acid is well known. On heating the latter with concentrated mineral acids in sealed tubes to 170° C, it splits up into glycocoll, carbon dioxide, and ammonia. 824 CONSTITUTIONAL DISEASES Summary of Our Knowledge Concerning the Chemistry of Gout. — It will be seen from the foreregnancy is especially mentioned by Garrod and Fletcher^ as a cause of rickets in the oifsi)nno', and the same writers consider that want of fresh air and exercise during pregnancy has a similar result; they mention, also, multi[)le pregnancy, and pregnancy at an advanced age, or at an unduly early age, as factors. It is commonly stated that the last children born in a large family are more often affected with rickets than the earlier children, especially if the pregnancies have been not only numerous but in rapid succes- sion. In such cases it is sujjposed that exhaustion of the mother inter- feres with the nutrition of the infant in some way so that some months after birth rickets appears. Actual statistics hardly bear out tiiis sup|)osition. Baxter found that in consecutive cases of rickets, 1!) per cent, were first- born, 13.5 per cent, second-born, 19 per cent, third-born, 13.5 per cent, fifth-born, 8 per cent, sixth-born, 16 per cent, seventh-born, 2 per cent, ninth-born or later. Similar in its effect, presumably, is lactation during pregnancy, which some observers have thought to be a cause of rickets in the offspring. Whether any of these influences can be regarded as more than predis- posing, is doubtful. Rickets at birth is generally thought to be exceedingly rare, and when the disease makes its appearance some months after birth, there is always a possibility and often a probability that post-natal factors, ])articularly the feeding, played a larger part in producing the disease than any parental influence before birth. Syphilis. — Parrot's view that syphilis causes rickets is now generally discredited; but some still hold that syphilis strongly predisposes to rickets. INIonti states that he has never seen a case of inherited syphilis which did not develop rickets; Cheadle, on the other hand, says that many cases of congenital syphilis are not rickety. Undoubtedly, some of the most severe degrees of rickets are seen where this disease is associated with congenital syphilis, and it would seem that in such cases the osseous and perhaps the visceral lesions of rickets may be modified not only in degree but also in kind. In the skull, osteophytic change is more common and more marked when syphilis is associated with rickets although it may occur with rickets alone. Some have thought also that localized thinning of the cranial bones, craniotabes, is specially frequent when these two diseases are combined. Dietetic Causes. — What part, if any, is played by the factors already mentioned is uncertain; but there are strong grounds for believing that dietetic influences stand in a much more direct relation than any of the foregoing. Put briefly, the facts are these: Rickets is uncommon and in its severer degrees is exceedingly rare in infants who are having the breast milk only. It occurs almost invariably where the feeding has been such that the food constituents depart widely from the standard of human milk or include excess of carbohydrate whether in the form of sugar or starch. Rickets occurs in some of the lower ani- mals, and in these it has been shown to be preventable by simple dietetic measures. Several observers claim to have produced changes resem- bling rickets in animals by special methods of feeding. Rickets in chil- ^ British Medical Journal, September 21, 1895. ^Pathological Society Transactions, vol. xxxii, p. 360. RICKETS 869 dren is successfully treated by suitable feeding without other measures of any sort. As to the particular fault in the diet, some indication is obtained by a comparison of the methods of feeding in a series of rachitic children. These can be grouped thus in approximate order of frequency: (1) Starchy food; corn flour; potato; bread with more or less milk, fresh or condensed. (2) Condensed milk alone, often excessively diluted. (3) Proprietary foods, whether containing starch or not, and made with or without the addition of fresh milk. (4) Cow's milk diluted, with- out addition of cream. (5) Breast milk, with addition of starchy foods. (6) Breast milk only. Great importance has been attached to the early use or to excess of carbohydrate food, especially starch. Baxter found that 92 per cent, of the cases of rickets had had farinaceous food before the age of twelve months, 42 per cent, had had farinaceous food daily from their birth, 30 per cent, daily from the age of three months, 4 per cent, from the age of six months, and 16 per cent, from the age of nine months. He found, also, that in many, though not in all, the first onset of the disease and its degree of severity appeared to be distinctly related to the period at which the administration of starchy matter was begun and to the propor- . tion between this element in the dietary and the others with which it was associated. It is clear, however, from the occurrence of rickets in groups 2, 4 and 6, that the use of starchy food is not essential to its production. There is also some evidence that excess of sugar is not an essential factor, for in group 2 personal observations showed that rickets most often arose where excessive dilution of the condensed milk had been used so that the propor- tion of sugar was actually slightly below that present in human milk; and in group 6 it is very improbable that any notable and prolonged excess of sugar should occur; for the average proportion of sugar in human milk is remarkably constant. From the occurrence of rickets on a diet of condensed milk in watery dilution, it may be conjectured that the fault is one of defect rather than of excess, for all the constituents of milk in such feeding are usually pres- ent in unduly low proportion; moreover, compared with human milk this dilution of condensed milk will show a relatively greater defect of fat than of proteid, as can be seen from the following comparison: Condensed milk Human as often given milk. (.about 1 in 10). Proteid 2.0 ... 1.0 per cent. Fat 3.5 ... .9 per cent. Sugar 7.0 ... 5.4 per cent. Salts 2 ... .2 per cent. Water . 87.3 . . . 92.5 per cent. Analyses of human milk make it probable that deficiency of fat is commoner than deficiency of proteid. Where rickets occurs in an infant who has been fed only on cow's milk diluted, there has almost always been dilution sufficient to reduce the fat to half or less than half the proportion present in human milk, and this low proportion has been continued usually for many months. Such dilution reduces the proteid little if at 870 CONSTITUTIONAL DISEASES all below that found in human milk. When the proprietary foods are used, whether with fresh milk or without, analysis shows that there is almost invariably a deficient proportion of fat in the diet. All these facts suo;o;est that deficiency of fat in the food is an important factor. Failure of assimilation of fat may be as effectual as deficiency of fat- supply in causing fat-starvation. It seems likely that an infant, even when receiving an amj>le quantity of good breast milk, may fail to assimilate it properly if farinaceous food is being given at the same time. Whether starchy food or excess of sugar has any special influence in hindering the absorption of fat is uncertain, but there is no doubt tiiat by setting up dyspepsia and fermentation it can and does interfere with the absorption of any food-stuif, including fats. Similarly, any cause which weakens the infant's digestive ])owers, be it simple debility, as in a premature child or in one of twins, or a gastro-intestinal disorder, or disease such as syphilis or tuberculosis, may interfere with the absorption of food and so of the fat. Strong support has been given to this view by the observations of Bland Sutton upon animals in the Zoological Gardens in London. These have been described very fully by Cheadle,^ from whose account the following statements are quoted: "Young monkeys deprived of their mothers' milk and fed entirely upon vegetable food, chiefly fruits, became rickety. Two young bears fed exclusively upon rice, biscuits, and raw meat, of which latter they hardly ate, died of extreme rickets. For many years the lion whelps were weaned early and fed on raw flesh only; they invariably became rickety and died. When milk, pounded bones, and cod-liver oil, were added to the raw meat, they lost all signs of rickets and were successfully reared." Here evidently there had been no deficiency of proteid. The addition of pounded bone to the diet makes the experi- ment less conclusive than it might have been if fat only had been added; but a comparison with the results of addition of cod-liver oil only to the regimen of children makes it all but certain that the fat was the effective therapeutic agent. The value of cod-liver oil is in itself suggestive of the role of fat-starva- tion and from recent experience it would seem that any fat, animal or vegetable, jjrovided it is easily digested, is equally curative of rickets. It is noteworthy also that those who have advocated the use of phosphorus have almost always used it in an oily solution. Whilst, therefore, it seems possible that deficiency of proteid, and per- haps deficiency of certain salts, in the food may contribute in some degree to the j:)roduction of rickets, there is strong evidence that the chief, perhaps the only constant, fault is deficiency of fat assimilation, whether this deficiency be due to a low proportion of fat in the diet, or to faulty methods of feeding interfering with digestion and so with the absorption of fat. It must be added, however, that some experiments on pigs, by Herter, of New York, showed that prolonged fat-starvation, although it produced muscular weakness and drowsiness, did not produce the bone-changes of rickets (Freeman). Pathology. — Morbid Anatomy. — The most obvious change is the enlargement at the junction of epiphysis and diaphysis in the ribs and in the long bones, but to understand the changes here, it is necessary to have ^ Allhutfs System of Medicine, vol. iii, p. 131. RICKETS 871 some knowledge of the normal processes of growth in bone. At the ends of the long bones, for instance of the radius of an infant about nine months old, there arc between the cartilage of the epiphysis and the cancellous tissue of the diaphysis, two distinct zones of transition: the one nearer the cartilage is a thin, translucent, bluish-gray band about ^ to ^ of an inch (1 to 2 mm.) in thickness, and beyond this is a much narrower yel- lowish-white opaque zone which, toward the cartilage, has a sharply defined and perfectly regular limit, but toward the bone merges irregu- larly into the cancellous tissue: the former is the zone of proliferation, the latter is the zone of calcification. In rickets, the bluish-gray zone of proliferation is enlarged so that it may be more than twice the normal thickness, and instead of being an even band with sharply defined edges limiting it from the cartilage on the one side and the zone of calcification on the other, it is quite irregular, especially toward the zone of calcification, where, even with the naked eye, it can be seen that the two zones are mixed together, islets of calcifica- tion are seen amidst translucent cartilage, and irregular processes of cartilage extending into the region of calcification, and the whole is abnormally vascular so that to the naked eye, num^erous vessels are obvious, traversing these confused zones in all directions. Histologically, there is the same confusion ; the cartilage cells are more numerous than they should be, the arrangement of columns has lost its regularity; they are ill-formed and no longer parallel. Between them in many places are areas of calcification, sometimes even of fully formed laminated bone, lying amid cartilage cells and cartilaginous matrix in which are numerous vessels passing inward from the adjacent perios- teum or perichondrium. The cancellous tissue of the shaft has also an undue vascularity, and the absorption of this tissue which should proceed but slowly, keeping pace with the formation of new bone from the perios- teum without, proceeds in rickets too rapidly, so that the bone consisting of an imperfectly ossified layer without, is further weakened by the rare- faction and looseness of its cancellous tissue within. The subperiosteal formation of bone is also disturbed, the periosteum itself becomes thickened and the proliferating layer beneath, in which calcification should occur, is excessively vascular, and contains abundant cell elements, but is imperfectly calcified, and the production of true lam- inated bone is deficient, so that the bone here also is softer than normal and bending easily occurs. The bone thus formed may be of spongy character, a condition specially noticeable in the thickened areas of the parietal and frontal bones, where also the vascularity is sometimes so great that it can be observed clinically as a bluish discoloration seen through the tense scalp. Muscles. — It is stated that the muscles show microscopically some blurring of striation, and that there is excess of fat in the connective tissue between the muscle fibers. In severe cases, fatty degeneration of the muscle fibers themselves has been observed. Viscera. — The liver is sometimes enlarged, and the cause of this is not yet certain. The surface is smooth; the consistence is not appreciably altered. It is stated that the interstitial tissue is chiefly increased, that in the portal areas particularly, there is some overgrowth of connective tissue, and some increase of the liver cells (Dickinson). Jenner 872 CONSTITUTIONAL DISEASES described an "albuminoid" cliangv whifh, whilst givinp; to the liver some of the translucency of lardaccous disease, dill'ers in not yielding the iodine reaction. But the connection of such changes with rickets is quite uncertain. A much commoner change is fatty infiltration, but this certainly is not peculiar to rickets. The Spleen. — The s])]een is only occasionally found, at autopsy, to be enlarged, and then only to a slight degree. This, like the enlargement of the liver, has been attril)uted by some to overgrowth of the fibrous stroma, by others, to increase of the cell elements. According to recent observations, the first change is hyperplasia of the spleen-pulp; then overgrowth of the perivascular connective tissue and of the stroma in general, and ultimately in severe cases, replacement of the parenchyma by fibrous tissue, so that the INIalpighian corpuscles atrophy (Sarcinelli, Sasuchin). The Brain. — The brain has been described as hypertrophied, and it is suggested that this is due to increase of neuroglia, but this has not been established. It was formerly su])i)osed that hydrocephalus was a result of rickets. V. Starck states that in 113 autopsies on rickets, he found hydroce])halus 12 times. Such an experience must be very exceptional; probably any association bet\\een rickets and hydrocephalus is nothing more than a coincidence; but Stoeltzner, whilst denying any causal con- nection between rickets and progressive hydrocephalus, states that a slight dilatation of the ventricles, insufficient to produce any untoward symptoms clinically, is a characteristic feature in the morbid anatomy of rickets; the writer is unable to confirm this from his own experience. The lungs show no characteristic change, but there is almost always much collapse of alveoli, and more or less bronchitis and bronchopneu- monia. These may be regarded as epiphenomena; they show no peculiar- ities to distinguish their occurrence from that in any other diseases. Pathogeny. — Chemistry of Rickets. — The chemical pathology is at present entirely unknown. Of the several theories which have been put forward, none rests upon a satisfactory basis; experiments and observa- tions have been discordant and contradictory. The facts which have to be explained are not merely the softening and bending of bone, but the overgrowth of cartilage, the perversion of the whole process of bone for- mation, and in addition more general disturbance, especially in the nervous system, and also in the muscles and viscera. There is evidently some wide disturbance of metabolism. One of the few points upon Avhich there is agreement is deficiency of lime-salts in the bones: in the healthy child the bone yields about 63 to 65 per cent, of earthy salts, and 35 to 37 per cent, of organic matter; in rickets, according to Friedleben, the tibia yielded 37 to 48 per cent, earthy salts and 51 to 63 per cent, organic matter: other observations showed in rachitic bone, 20.89 percent, earthy salts, 79.1 per cent, organic matter (Boettger), 20.6 per cent, earthy salts, 79.4 per cent, organic matter (Marchand). Deficiency of lime in the food w'as found by Chossat (1842) to produce fragility of bones in pigeons, and recently Stoeltzner, by feed- ing puppies on lime-deficient food, produced softening of bones; but mere softening or fragility of bones is not rickets, and it has been shown both by Friedleben and by Stoeltzner that the changes produced in these experiments are not those characteristic of rickets. lilCKETS S73 Deficient absorption of lime-salts has also been suggested, but if this were so the lime-salts eliminated in the urine might be expected to be increased; some observers have found this to be the case, others have found no difference from normal urine. Cow's milk contains .15 per cent, of lime, whereas human milk contains only .02 per cent, of lime (Cautley); it is evident, therefore, that even when cow's milk is given greatly diluted, much more lime is supplied to the child than when breast milk is used: but rickets is very much commoner in children fed on cow's milk than in children who are being fed only on breast milk. The facts that lime-water has no therapeutic value in rickets, and that rickets is so common in districts where the water contains much lime, are also noteworthy, but it is possible that for the absorj^tion of lime, its administration in organic combination may be important. A relative deficiency of lime, rather than an absolute, has been sug- gested by Kassowitz, who points out that prolonged hypersemia of bone, which he produced by intermittent constriction of the limb of a growing animal, causes proliferation of cartilage and some absorption of bone; the formation of bone tissue is in excess, the supply of lime salts necessary for its perfect calcification is not correspondingly increased. This theory presupposes some irritant chemical or otherwise, which causes prolonged hypersemia and changes similar to those of chronic inflammation in the areas of bone-formation. No such irritant is known to exist in rickets, but the frequent association of gastro-intestinal disturbance with this disease has led some to suggest that this may be primary, while the rick- ets is the result of an intestinal toxaemia. Solution of lime salts by lactic acid circulating in the blood has also been suggested; according to this view, lime already deposited in the bone is dissolved out by the acid, or the acid in the blood prevents the deposit of lime salts. This theory is based on the fact that starchy food is liable to give rise to fermentation in the alimentary canal with the pro- duction of lactic acid, and that starchy food is known to be frequently associated with the presence of rickets. Lactic acid has been found in the urine in rickets. It has been stated that lime salts are found in excess in the urine; and finally Heitzmann claimed to have produced true rickets by administering lactic acid to animals in their food. Such a theory, how- ever, is untenable. It has been shown that the alkalinity of the blood is not diminished in rickets (Stoeltzner) — injections of lactic acid into ani- mals and also a repetition of Heitzmann's experiments, failed to produce rickets (Spellman). A diet of meat, which does not produce lactic acid, produced rickets in animals (Guerin). The addition to the diet of certain nutritive elements in which it is deficient, cures rickets without any diminu- tion of the farinaceous constituents (Cheadle). Lactic acid is often found in urine apart from rickets; in some cases of rickets there is no excess of lime in the urine (Zuelzer). Excess of carbonic acid in the blood has been held accountable (Wachsmuth) by keeping the lime salts in solution: the only clinical evidence adduced in support of this theory has been the occurrence of rickets in children living in ill- ventilated rooms; but rickets occurs both in children and in animals who spend a large part of their time in the open air. The disease is successfully treated without any change beyond dietetic measures and the administration of oils. Moreover, there is no 874 CONSTITUTIOXAL DISEASES proof that any such excess of carbonic acid as could interfere with deposit of Ume salts, exists in the blood in rickvts. Rickets has been attributed to deficiency of phosphoric acid in the diet, especially where calcium is deficient at the same time: on the other hand the administration of phos- phate of potash to dogs has been stated to produce rickets (Delcourt) and Wegner has stated that by administering phosphorus to animals, who at the same time were deprived of lime-containing food, he produced rachitic lesions. The same observer found that by injections of phosphorus near the epiphysis of growing animals, he produced a change in the bone of inHanunatory type. But none of these observations can be considered as established, and although AYcgner's conclusion that rickets is the result of the combined action of some irritant on growing bone and of a deficient supply of lime, may be correct, his experiments hardly prove it. Some experiments have recently been made by Frcund on the relation between fat in the diet and the absorption of phosphorus from the food. He found that when infants were fed upon a diet of cream diluted with water so as to contain more fat than the diet of other infants who were fed on milk diluted with water, the urine contained a much larger proportion of phosphates and from this fact and other results of his investigations, he concludes that when much fat is given in the food, there is a much greater absorption of phosphorus compounds from the intestine. Possibly this observation, taken in conjimction with an analysis of the ffeces in rickets quoted by Ritter, in which it appeared that a very high proportion of phosphorus compounds, especially calcium phosphate, were excreted in the freces, i. e., were not absorbed from the food in rickets, may serve to connect the clinical facts as regards the deficiency of fat in the ricket- producing diet, and the therapeutic value of fat, with the pathological fact of deficiency of calcium phosphate in the bones. The problem is obviously extremely complex and no mere chemical formula is likely to explain a condition which is intimately bound up with biological processes of which at present we know but little. Bacteriology. — There is little to be said in favor of an infective origin. Mircoli, on grounds of theory and experiment, has suggested that the bony changes are of the nature of an attenuated and chronic form of osteomyelitis, and that this is produced by streptococci and staphylococci, which reach the tissues from the alimentary canal. Morpurgo claims to have produced rickets by injecting a certain diplococcus into young rats. Spellman inoculated animals with pieces of bone from rachitic infants and also with the diarrhoeal stools of rachitic infants, but in 127 of these and other similar observations, only once foimd any rickets (Freeman). Up to the present it cannot be said that there is any proof that rickets is ever produced by bacterial infection. SjnnptoniS. — Rickets is a disorder of nutrition, and, as such, affects the whole organism. The bone changes are only part of a general disease. Much of the confusion as to the pathogeny and even the diagnosis has resulted horn the tendency to concentrate attention upon the osseous lesions to the exclusion of other features. A child may suffer severely and yet show so slight a degree of rachitic change in the bones that the disease might almost pass unnoticed if only the osseous system were considered. The stress may fall upon the nervous system in one case, RICKETS 875 upon the muscular in another, and perhaps even upon the blood and blood- forming tissues in a third. Before describing the symptoms in detail, an outline of a typical and well-marked case of rickets may be given. An infant aged about eighteen months is brought for inability to walk. He has been suckled entirely perhaps for six or seven months, and then has had condensed milk and occasionally bread or potato. For some months past, he has sweated profusely about the head and neck whenever he falls asleep. Dentition did not begin until he was nearly a year old, and even now ho has but three or four teeth. He has never walked, and sitting on the mother's lap there is a marked kyphosis especially in the upper lumbar region. He is pale and fretful; perhaps rather fat, but flabby; the head is unduly large, with a tendency to squareness; the anterior fontanelle is much more widely open than it should be at this age. The chest is ill shaped, the sternum a little prominent, and there is some transverse constriction below the level of the nipples. A row of knob-like eminences rfiark the junctions of the costal cartilages with the ribs on each side of the chest; the lower ribs are somewhat everted above the big abdomen, in which the liver can easily be felt, and the spleen is also just palpable. The muscles feel flabby and soft. Just above the ankle and the wrist, the bones seem thickened. There is little or no abnormal curvature of the bones. Such is a moderate degree of rickets; but there are many more in which the symptoms are altogether less marked, and perhaps delay of dentition and of closure of the fontanelle,with slight thickening at the costochondral functions (beading of the ribs), and possibly, but not necessarily, some enlargement of the radial epiphysis, are the only evidences of the disease. There are also cases, much less frequent, in which the symptoms are altogether more severe, the limbs are deformed by various bendings and distortions of the bones, the cranium is irregularly thickened or thinned, and the child perhaps shows severe nervous symptoms, convulsions, or laryngismus stridulus. Nutrition. — The child is often unduly fat especially in slight, or moder- ate degrees of rickets. This deposit of fat is apparently derived from carbohydrate food, for it is seen where the diet is greatly deficient in fat. It would seem also that this stored fat is unable to replace the functions of fat taken as such in the food. In severe rickets wasting of greater or less degree is common. Head Sweating. — This is often one of the earliest symptoms and may be so profuse that the pillow is soaked. It usually occurs when the child falls asleep; it is not present in all cases. Probably with this is associated a feeling of heat, for the infant at this stage is very apt to push the bed- clothes off at night and lies uncovered. Temperature. — This is normal in most cases even during the most active stage of the disease, so far as the writer's observations go; a rise of temperature is almost always due to some complication. Teeth. — Delayed dentition is one of the most constant symptoms. In 32 out of 42 consecutive cases, between nine months and three years old, this was present. Frequently no teeth have appeared at the end of the first year. Rarely their appearance is delayed beyond the age of eighteen months. There is a striking tendency to very early caries; even before the tooth is fully cut the enamel at the cutting edge is often com- 876 CONSTITUTIONAL DISEASES pletely destroyed. If dentition has begun before the onset of rickets, it is often arrested for several months. Muscular Weakness: Laxity of Ligaments. — Muscular weakness is a very common result in the active stage of the disease, and in the more severe cases is almost always well marked. It may be quite out of proportion to the osseous changes, and for this reason is liable to be mis- taken for some paralysis of nervous origin; it may be so great that a child of two or three years is unable to stand or even to sit up. The late acquirement of sitting, standing, and walking, is chiefly due to this weakness, though in part, no doubt, to laxity of ligaments, and to bone changes. The child who has already begun to stand often loses this power at the onset, so that he is said to have "gone off his legs." The stooping of the back, or kyphosis, which is common in rachitic children, would seem to depend chiefly upon weakness of the muscles of the back. It is possible that muscular weakness of the respiratory muscles plays some part in the tendency to ])ulmonary affections. The effects of muscular weakness are intensified by laxity of the ligaments, apparently as the result of some structural change which has not yet been determined, but which renders them soft and yielding. The child can often place his toes behind the ears without difficulty; and the head of the tibia shows an undue amount of lateral mobility, so that it can be loosely knocked against the condyles of the femur. Both these changes, the muscular and the ligamentous, contribute to some of the deformities, such as talipes valgus and planus, genu valgum and varum, and lateral curvature of the spine. Osseous Symptoms. — These are the outcome of the delayed and imperfect ossification, hyperplasia, and abnormal absorption of bone tissue. The most frequent manifestation is the so-called "rickety rosary," or beading of the ribs, a thickening at the costochondral junction which in a thin child can be seen and in others easily felt. These beads are usually largest and most readily felt on the fifth, sixth and seventh ribs, and in a mild case may be scarcely perceptible on other ribs. They are often seen postmortem to be more marked on the internal than on the external surface of the thorax (Fig. 69). The internal bead, however, is sometimes exaggerated by a displacement of the bony rib backward at the costochondral junction, so that, instead of joining the cartilage end to end, it joins it at an angle which projects on the inner aspect of the thorax (Fig. 70). In such cases the external beading may be obscured altogether, and the junction of rib and cartilage forms a depression externally, so that, clinically, beading may not be detected. The rickety rosary is one of the earliest symptoms and is often the only bone change to be found during life. It gradually dim.inishes after the fourth and fifth year and has usually disappeared before puberty. As a result of the backward displacement of the anterior portion of the rib, in some cases there is an exaggeration of the angle of the rib, poster- iorly, or actually a greenstick fracture at that situation; the projections formed thus are sometimes described as "posterior beading," but are obviously different in their pathology from the anterior "rickety rosary." Enlargement of epiphyses is a very common symptom. It is generally most marked at the lower end of the radius, where some thickening was present in 64 per cent, of the writer's cases. At the lower end of the femur RICKETS 877 and tibia it is also frequent. Other long bones show it less frequently. The ends of the phalanges of the fingers are oeeasionally affeeted giving a somewhat spindle-shaped appearance. Some thickening of the diaphy- sis of the phalanges has also been described (Koplik). Fig. 09. Anterior wall of thorax, internal surface showing extreme rickety deformity; sternum and cartilages project forward in front of the internal beading which is seen to consist partly oS a sharply angular junction between bony rib and cartilage. Owing to the softness of the bones, some degree of curvature in the limbs is common : 43 per cent, of the writer's patients showed curvature of the bones either in the upper or in the lower limbs, but in most of these the bending was slight in degree. The commonest deformity of this kind is a bending outward of the lower third of the tibia, — sometimes there is combined with this, or alone, a forward bend which may be slight or may be sharply angular in the lower third. (Fig. 71.) The femur is less often affected; it shows a general outward curve in children who are already able to stand or walk when the rickets affects them. In children who are being carried about on the nurse's arm, the curve in the femur is often anteroposterior with the convexity forw^ard. A much rarer result of rickets is the condition known as "coxa vara,'' in which the head of the femur is bent downward so that it is at the same level with, or even lower than, the great trochanter, while the neck of the femur is curved with the convexity forward and upward. Bending of the bones of the upper limbs takes place chiefly in children who spend much of their time crawling about or in the sitting position supporting the weight of the trunk partly upon the hands ; a favorite position is that showm in 878 CONSTITUTIOXAL DISEASES the illustration (Fig. 72), where the child sits tailor-wise and uses its hands as a prop. Both the humerus antl the bones of the forearm are usually curved outward in such cases. The clavicle, in severe cases, often shows a sharp angular bend forward Fin. 70. Anteroposterior section of costochon- dral junction to show rachitic disi)lace- ment. In the upper specimen the dis- placement is slight, in the lower, which was taken from the chest shown in Fig. 69, there is complete displacement. and uj)ward at the junction of the inner and middle third; and sometimes there is evident thickening here, the result of a greenstick fracture. All these deformities are the result partly of pressure from without, partly of the weight of the body, and partly of muscular traction upon the softened bones. Similar in their production are the rachitic deformities of the thorax and pelvis. The for- mer shows a lateral contraction so that the sternum and costal cartilage appear to project forward in front of the ribs, while the depres- sion at the junction of each rib and cartilage forms a furrow passing downward and out- ward and usually lost in a deeper transverse groove just below the level of the nipple, the so-called "Harrison's sulcus." This sulcus, which extends from the ensiform cartilage to the posterior axillary line, is commonly associated with eversion of the lower ribs over a dis- tended abdomen which increases the distorted apjiearance of the chest. The pigeon chest (pectus carijiatuvi) in which the ribs appear straightened as they pass from the posterior axilla to join the prominent sternum so that the cross-section of the thorax would be roughly triangular with the apex at the sternum, is often described among rachitic deformities. Neither pigeon chest, however, nor "Harrison's sulcus" are essentially rachitic. They are seen in any condition in which there is obstructed respiration. Photograph of a cast at the museum 'of the Hospital for Sick Children, Great Ormond Street, London, showing a common rhachitic curvature of tibia. RICKETS 879 Pelvic deformities hardly enter into the clinical picture of rickets in childhood, for they attract no attention at that age, although in the adult female they become of great importance. Rickets here, as in the rest of the bones, may arrest development so that the pelvis remains small and generally contracted. Often there is in addition flattening of the pelvis antero-posteriorly; it is shallow, and, occasionally, from traction of the muscles and the pressure transmitted from the spine and from the femora, more marked distortion takes place. Fig. 72. Common position of rickety child witli bending of forearm, showing also large head, large abdomen and deformed thorax with Harrison's sulcus. The bones in rickets become not only soft but brittle, so that fractures, usually of greenstick character, are apt to occur in severe cases with little evidence of traumatism, sometimes apparently from muscular traction alone. This tendency depends partly on absorption of cancellous tissue in the rickety bone, partly on deficient calcification, and partly perhaps upon some abnormal arrangement of the trabecuhe in the substance. As a result of the epiphyseal affection and of the sclerosis which may occur in the bones after the rachitic process has ceased to be active, per- manent stunting of growth occasionally takes place, so that the child may be undergrown or actually dwarfed for the rest of its life. Cranium. — One of the most constant symptoms is d Jay in the closure of the anterior fontanelle. Normally this should measure about f t" 1 inch (2 to 2.5 cm.) antero-posteriorly and transversely at the end of the 880 COXSTITVTIOXAL DISEASES first year and should close at or ;il)()ut the age of eighteen months. In rickets, it often measures 2 inches (5 cm.) in both directions at twelve months, and is frequently open as late as two and a half or three years; the writer found it o])en at four and one-half years. This delay of closure is not due to any general expansion of the skull such as occurs in hydro- cephalus, for it occurs equally where there is no enlargement of the head and where the head is, as often happens in rickets, unduly large; it indi- cates rather the general backwardness in bone formation which is one of the features of the disease and which may determine more extensive fail- ure of consolidation in the cranium so that the interparietal and the parietooccijntal sutures arc not firmly united for many months. The size of the head is conunouly above the normal; in 17 cases of rickets with an average age of 4.72 years, I.ucas^ found that the average circumference was 21.2 inches (54 cm.), whereas in 17 non-rachitic children with an average age of (3.05 years, the average circumference was 19.95 inches (50.5 cm.). The cause of this increase in size is uncertain; some- times the brain has been found above the average weight and in some cases there is considerable thickening of the bones of the skull, though hardly sufficient to account for the large size. ' The rachitic skull differs from the normal not only in size but also in shape. Two types may be recognized. In the one, the more frequent, the skull is flattened on the vertex and tending to squareness, the posterior segment especially is enlarged; in the other the head is narrow from side to side and elongated antero-posteriorly. The softening of the bones is sho^^•n in the skull by the deep grooves which are hollowed out on its surface by the veins of the scalp so that their course can easily be traced by running one's finger-nail along the groove. The relation of bossing of the skull and of craniotabes to rickets has been much disputed. Both have been attributed to syphilis by some, and to rickets by others. So far as personal observations go, both seem to occur in rickets apart from syphilis but to be aggravated when syphilis is added to rickets. Some have thought that the symmetrical bosses which occur on the frontal and parietal bones, giving rise to the "caput quacbxitum" or "hof-rross-bvn head," can be distinguished by their position from those of syphilis, which are said to be closer to the anterior fonta- nelle. However this may be, there are certainly two conditions, very different in appearance, which give rise to the local thickenings felt on the skull. In the one, the surface of the bone is smooth and the thickening is due to a very vascular increase of the cancellous tissue between the compact inner and outer tables; in the other, there is a deposit of vas- cular spongy bone on the outer surface of the skull, which has a roughened, worm-eaten appearance. Whether these represent difPerent stages of one and the same process or whether they indicate different processes is at present uncertain. The term "craniotabes" is used with varying significance. Some would apply it to a diffuse yielding of bone near the sutures, especially about the parietooccipital sutures, which is not uncommon in rachitic children under twelve months of age and is exceedingly common in infants during ^ Pathological Society Transactions, Vol. xxxii, p. 359. RICKETS 881 Fig. 7a. Posterior view of rachitic skull, show- ing characteristic areas of true craniotabes. the first two months of life. In early infancy this thinness of the bone is often associated with unusual separation of sutures and patency of the fontanelles, posterior and lateral as well as anterior. It is very doubtful whether such a condition should be taken as necessarily indicating rickets; certainly it is quite common during the first three or four months of life in breast-fed infants, particularly those of small size and generally feeble development, with no other evidence whatever of rickets. Much more significant are localized patches of thinning of the bone situated generally in the occipital or in the parietal bone (more commonly the latter) near to, but not actually adjoining, the parietooccipital suture, from which they are separated by an area of firm bone (Fig. 73). The patches are usually about J to 1 inch (1.5 to 2.5 cm.) in diameter, round or oval, and can be detected by taking the head between the palms of the hands so that the fingers rest on the posterior parietal and occipital region. On press- ing firmly with the fingers, the affected areas are felt to yield, bulging inward like a piece of thick parchment and rebounding when pressure is removed. In severe cases these areas run together, but even then the irregular and patchy distribution distinguishes them usually from the diffuse thinness mentioned above. This condition, unlike the diffuse thinness of the edge of the bone, is often found when the sutures are well closed and only the anterior fon- tanelle remains patent. It occurs often in the second year of life in chil- dren who have only developed rickets after the skull bones are already well ossified. It is an absorption of already formed bone, not a mere delay of development as the diffuse thinness with patent sutures prob- ably is in some cases. According to the meaning attached to craniotabes, its frequency has varied in statistics. According to some recent observations made by S. Fraser upon children under three years of age at the Children's Hospital, Great Ormond street, London, 29 per cent, of the rickety children showed craniotabes, but this series included many cases in which there was only yielding of the bones near the sutures. There can be no doubt that craniotabes occurs with rickets without syphilis. In the form of isolated patches it is associated particularly with laryngismus stridulus and tetany, the former of which, if not also the latter, when it occurs in childhood, occurs almost exclusively in the rachitic and has no connection with syphilis. Out of 21 cases of larjmgis- mus stridulus in which the writer noted this point, craniotabes was present in 7. According to Barlow and Lees, 47 per cent, of cases of cranio- tabes show evidence of syphilis; but many of their cases with sypliiUs had rickets. Nervous Symptoms. — Mental. — The rickety infant is often fretful and peevish, but perhaps more from the discomfort of prolonged ill-feed- ing than from any direct effect of the disease. In later childhood, rickets 56 882 CONSTITUNIONAL DISEASES has been described as a cause of precocity, and the large head has been supposed to allow a larger capacity for mental development. Thackeray has been quoted as an instance. The accuracy of these observations is very questionable; the child who is invalided by any chronic disease is likely to be much with its elders and to accpiire a precocious manner in consequence. The writer is quite unable from his own observation to afHrm any intellectual superiority in rachitic children. There is no evi- dence that they are inferior, although it was stated by Sir W. Jenner* that "Children, the subjects of extreme rickets, are almost always deficient in intellectual capacity and power." Convulsive conditions are the chief evidence of rickets affecting the nervous system: from about the sixth to the twenty-fourth month con- vulsions in infancy are most often due to it. The cortex is in some way rendered so unstable that trivial exciting causes, such as constipation or dentition, are sufficient to induce an attack. As part of this convulsive tendency must be reckoned laryngismus stridulus and tetany Avith their almost constant accompaniment — the so-called "facial irritability." In laryngismus stridulus, a spasm of the larynx suddenly closes the glottis so that the infant is for a few seconds unable to draw air into the chest: the face becomes livid, the infant looks terrified, and makes violent eft'orts to inspire. After a few seconds the spasm relaxes and a deep in- spiration is taken with a loud crowing noise. These attacks come on usually when the infant begins to cry or just as it wakes, or a sudden draught of cold air may start the attack. There may be many in the day, or only two or three in a week. If the spasm is prolonged many seconds, the infant becomes cyanosed and may pass into a general convulsion, or may die silently of asphyxia. These attacks occur most often between the ages of six and eighteen months ; they are rare after the age of two years. Of 35 cases, 32 showed definite rickets, 2 probable rickets; only 1 showed no bone manifestations of rickets. Tetany, a tonic spasm affecting chiefly the muscles of the forearm and hand, and leg and foot, is in young children almost always associated with rickets. The hand is generally slightly flexed at the wrist, the thumb is adducted so that its tip points to the interval between the ring- and the mid-finger, the rest of the fingers are semi-flexed at the metacarpopha- langeal and extended at the phalangeal joints, often with some tendency to overextension at these latter. The toes are crowded together in a position as far as possible resembling that of the fingers; the foot is some- times extended at the ankle. Apparently from some pressure on veins by the contracting muscles, oedema of the hands and feet is often seen with the tetany. The spasm of tetany is in some cases persistent for several hours or even for days; in others it is intermittent, lasting only a few minutes at a time and causing some cramp-like pain each time it recurs. It is most frequent at the age at which laryngismus stridulus is common, and is usually associated therewith. A latent form of tetany is not uncommon in rickety children; it is dem- onstrated by the method described by Trousseau : the upper arm is firmly grasped in such a way as to compress the vessels and nerves on the inner side of the arm, and after a period varying from thirty seconds to about two minutes, the hand assumes the characteristic position of tetany. ^Lectures on Rickets, Vol. iii, p. 416. RICKETS 883 Of 24 cases of tetany in young children, 22 showed definite rickets, 1 doubtful rickets, and 1 no bone manifestations of rickets. Twenty- three of these cases were associated with laryngismus stridulus. Facial irritability, Chvostek's sign, is also closely related and par- ticularly to the convulsive manifestations. On gentle tapping over superficial branches of motor nerves, a contraction of the corres[)onding muscles occurs. This was first described with regard to the face, but is to be seen in the limbs also. Of 35 cases of laryngismus stridulus, 33 showed this nerve irritability; and it is almost always present with tetany whether this is associated with laryngismus stridulus or not. Facial irritability is found in rickets also apart from laryngismus stridulus and tetany, and is then probably always an indication of a con- vulsive tendency. In some of these cases there is a history of preceding convulsions; in others, after the facial irritability has been observed, coiivulsions occur. It is therefore of practical value as indicating the need for such drugs as bromides, by which convulsions may be averted. This nerve irritability is probably most common in the face, but as the writer has notes of cases in which it was in the limbs only, the term facial irritability is not sufficiently conclusive. Head nodding with nystagmus (spasmus nutans) needs only to be mentioned here, for, although it is generally associated (Hadden, J. Thomson), the rickets ic regarded only as a predisposing cause. The pronounced nervous instability may show itself in other ways, — a rhythmic head-rolling upon the pillow so that the back of the head is rubbed almost bald, or a head-banging in which the child beats its head with its hands or against any object near, are both seen most often in rickety children, although the determining cause may be some peripheral irritation, dentition, or middle-ear catarrh. Hydrocephalus was regarded by Jenner as sometimes produced by rickets but this view is now generally discarded. The large head of rickets, especially when the square shape is less pronounced than usual, may simulate hydrocephalus, but is probably rarely, if ever, due to dis- tension of the ventricles. The association of zonular or lamellar cataract with rickets, and espe- cially with convulsions, has been noticed by several observers since David- son and Horner of Zurich first drew attention to it in 1865. Tenderness. — It is generally stated that there is some tenderness present not only in the bones but also in the muscles (Gee). Hilton Fagge described this as one of the characteristic features. If such a condition occurs at all, it must be quite exceptional. The rickety child is often fretful and nervous, resents, or is frightened by, any examination; but if there is definite tenderness, the presence of scurvy with the rickets should be suspected. Gastro-intestinal Symptoms.— The abdomen is usually distended so that the rachitic "pot-belly" has become a recognized term. The dis- tension is due to three causes, — flatulence arising from improper feed- ing; displacement downward of the liver and spleen by eversion of the lower ribs; diminished space in the small pelvis; probably to these may be added relaxation of the abdorninal muscles so that they afford less support than normal. 884 CONSTITUTIONAL DISEASES As a result of this distension, the recti muscles arc often separated so that there may be a gap of 1 inch (2.5 cm.) between them, where the abdominal wall is jmtt'ed out in a bulging ridge when the child lies on its back putting the abdominal wall on the stretch; but this is not peculiar to rickets; it occurs in young childern with chronic distension of the abdomen from any cause In the gastro-intestinal, as in the pulmonary mucosa, there is a special tendency to catarrh. The liver is often to be felt 1 inch (2.5 cm.) or more below the costal margin, but this is due in many cases, partly at least, to disi)lacement downward by eversion of the ribs. The si)leen, for the same reason, is often felt \ to 1 inch (1.5 to 2.5 cm.) below the costal margin; it is probably but seldom enlarged to any considerable extent, unless the condition known as splenic anicmia is to be regarded as a manifestation of rickets. Kiittner found the spleen enlarged in 44 out of GO cases; in 33 it was just palpable; in 9 it was two finger-breadths below the costal margin and in 2 there was great hypertrophy. Respiratory System. — The laryngeal spasm has already been de- scribed. Bronchitis is very frequent in rachitic children, and this ten- dency is favored, in severe cases, by the softness of the ribs and the weak- ness of the resj)iratory muscles. There is, in fact, a vicious circle. For the mechanical reasons mentioned, the lung is very imperfectly filled with air and the collapse thus induced favors the occurrence of bronchitis and hence further collapse. The movements of the diaphragm also must be rendered less extensive by the eversion of the lower ribs, and at the same time hampered by the abdominal distension. Circulatory Symptoms. — Antemia is common and sometimes very pro- found. In severe cases, the child may have a waxy complexion not unlike that of chlorosis and Hutchison has referred to cases in which the blood changes corresponded. In a rickety infant aged one year and seven months, the blood showed four million red corpuscles and only 20 per cent, haemoglobin; in another child, aged three years, with rickets, the red cells numbered five million, the hremoglobin was only 31 per cent. The leuko- cyte count shows nothing characteristic; some observations by Thursfield and Drysdnle^ gave the following results: Haemoglobin, 44 per cent.; red corpuscles, 4,364,000; white corpuscles, 11,000; polymorphonuclears, 49.2 per cent.; lymphocytes, 46.8 per cent„; large mononuclears, 3.3 per cent.; eosinophiles, .5 per cent.; myelocytes, 0; occasional nucleated red corpuscles. This would agree very nearly with the average proportions of the differential count for a healthy infant of about twelve months, except perhaps for a very slight increase of polymorphonuclear cells. A systolic bruit is frequently heard over the open anterior fontanelle, and was formerly thought to be of value in the diagnosis between a rachitic and a hydrocephalic head (Rilliet and Barthez). It is, however, as Osler^ has shown, frequent in infants and young children who are free from rickets; it is heard most commonly in the second year of life but may be heard as late as the sixth year. Complications. — Bronchitis has already been mentioned as extremely frequent. Bronchopneumonia is also common and is one of the chief ^Med-Chir. Society Transactions, 1904. ^Boston Medical and Surgical Journal, CIII, No. 2, p. 29. RICKETS 885 sources of danger to life, especially where there is much rachitic deformity of the chest. Gastro-intestinal catarrh and diarrhoea are common accompaniments and considerable dilatation of the stomach is sometimes evident both clinically and postmortem. Infantile scurvy is an occasional complication, but the association is to be regarded as a coincidence; there is no essential connection. Diagnosis. — ^The clinical picture of severe rickets is so striking that it can hardly be mistaken. The projecting rickety rosary, the large epiphy- ses, the large square head, the bent limbs, are characteristic enough; but in slight cases the difficulty is greater and it is clear from a comparison of various observers' statistics that there is no general agreement as to what constitutes evidence of rickets. For instance in Munich, at the same insti- tution, one observer found about 70 per cent, of the childern under two years to be rickety; another observer found that less than 5 per cent, of the children were rachitic. Beading of the ribs has often been accepted as evidence of rickets, but this is not necessarily so* it is common to find beading of the ribs in healthy infants just after birth, and Escher found on microscopic exami- nation that these showed none of the characteristic changes of rickets. Yielding of the skull bones on pressure, a diffuse thinness along the edge of the bones with some separation of sutures, has been taken as a proof of rickets, but this also is incorrect. A simple delay of development occurs quite apart from rickets and Fede and Finizzio concluded from a micro- scopic examination of the skull bones that the yielding of the skull in new- born infants was not necessarily due to rachitic change. It seems probable that there are other bone diseases which may cause softening of bones or deficiency of calcification, so that bending or fracture of bones results. Osteomalacia, or mollities ossium, in which at an age usually beyond puberty the bones show progressive softening so that they bend in all directions, is probably quite distinct in its pathology as it usually is in its course. Occasionally cases are seen in childhood with extreme softening and bending of bones and lacking the usual characteristics of rickets, such as the enlarged epiphyses and the large square head. Some of these cases are probably much nearer allied to the so-called osteomalacia of adults. It may be that in some cases a condition like the osteoporosis produced experimentally in puppies occurs in children also. The weakness of the limbs may be mistaken for infantile paralysis; the general distribution, the gradual onset, the retention of reflexes and the changes in the bones will usually suffice for the distinction. The kyphosis may be so marked as to suggest spinal caries; it is generally taught that the curve of rickets disappears when the child is held up supported under the armpits, whereas that of spinal caries re- mains. In long-standing cases, however, the kyphosis may not disappear thus, nor even when the child is made to lie on its face, and the diagnosis has to be made from the more general curving of the spine and from the association of the kyphosis with marked rickets elsewhere. The enlargement of the head is sometimes difficult to distinguish from that due to hydrocephalus. As a rule the flattening of the vertex and the square shape distinguish the rachitic head from the more globular hydro- 886 CONSTITUTIONAL DISEASES cephalic head; but there are cases in whieh, if the chihl is first seen after the fontanehe and sutures have closed, the diaynosis may be impossible; and it is only when symj)toms result from increasing tension in the ventri- cles that the (juestion may be settled. Course and Prognosis. — Rickets is readily amenable to treatment, and when once the disease has stopped, any recrudescence is very excep- tional. Probably, some of the cases described as late rickets are of this nature. The intensity and duration of the symjitoms vary chiefly accord- ing to the feeding; no doubt, in some cases as the child grows older and takes a more varied diet, which happens to include a sufficient proportion of the requisite constituents, the disease comes to a stand-still without special treatment. In others it progresses so rapidly that within a few months consiilerable softening and bending of bones occurs, nervous and respiratory symptoms become pronounced, and the child dies. When death results from rickets, the immediate cause is usually bronchitis or bronchopneumonia, convulsions, or laryngismus stridulus. Rickets is seldom seen in active progress after the age of three years, but the deformities produced may last for life. In their slighter degree however, some of these may disappear: the beading of the ribs is gradually lost in many cases and even considerable deformity of the chest may diminish greatly as the child becomes stronger and expands his lungs more thoroughly. Slight curvature of the legs may right itself if the child is kept off his feet for several months while suitable treatment is used. Treatment. — Prophylaxis. — Rickets is in large measure a preventable disease, and as it is due chiefly to faults of diet so its prevention depends almost entirely upon dietetic measures. The surest safeguard is the continuance of breast feeding alone for nine or ten months, and the use of fresh milk as the chief article of diet until the end of the second year. It is important to realize that breast feeding does not protect from rickets ^vhen other food is given at the same time. An infant suckled, and at the same time receiving farinaceous food, often develops a marked degree of rickets. Even when an infant has been suckled entirely for the first nine or ten months, this does not prevent the onset subsequently if the feeding is then unsuitable. It is probable that the liability becomes gradually less after the end of the first year; in other words, of the large number of cases seen in the second year, most have had their onset at some period within the first twelve months; but there are certainly some in which the disease began in the second year. For this reason the diet in the second year requires care as well as in the first. A common fault is to allow the child much farinaceous food to the neglect of milk. Milk should certainly be the staple diet until the child is two years old. There is no doubt that the early use of farinaceous food plays a large part, and it is the writer's belief that even the small proportion of starch present in barley-water has this tendency and should, therefore, be avoided during the earlier half of the first year. Few infants are the better for any starch addition to the diet before the age of nine months, and even then its introduction should be very gradual. It should be added first only to one meal daily, and when the infant is twelve months old should not be given in more than two meals. The rest should consist of milk to which raw meat juice may be added. The yolk of an egg, lightly boiled, RICKETS 887 may also be allowed at this age. Potatoes are to be avoided altogether until the age of eighteen months, and even then only very little, thoroughly mashed with milk, should be allowed. During the second year the child should not take less than one and one-half pints (about one liter) of milk daily. Where hand-feeding is inevitable, careful modification of fresh milk is necessary. It is not sufficient to order cow's milk diluted with water; the proportions must be properly adjusted. It is not uncommon to find marked degrees of rickets in children who have had no starch whatever but have been given equal parts of milk and water up to the age of nine or ten months, with no addition of cream. The fault in such cases is probably the deficiency of fat, and for this same reason rickets is a common result of many of the proprietary foods whether mixed with fresh milk or not and whether containing starch or not. It would seem that a propor- tion of fat under 2 per cent, for infants over the age of six months involves some risk, and that a proportion of fat under 1.5 per cent, given for several months at any period of infancy involves a high probability of rickets. The addition of cream to the diluted milk is an important pre- ventive measure, and if circumstances make this impracticable, the milk should be given as little diluted as possible. Where deficiency of fat is combined with the too early use of starch or with excess of carbohydrate, as in many of the proprietary foods, the risk is greatly increased. Other possible factors should also be considered: the child should be out in the open air three hours daily or more if possible, and the rooms in which he lives should be well ventilated and get plenty of sunlight. If rickets has already appeared, much may be done to prevent bending of the bones by adopting such measures as will avoid the pressure of the body or other weight upon the Hmbs. Standing and walking especially, should be forbidden until the remedies, dietetic or otherwise, which are employed have had time to diminish the softness of the bones and the laxity of the ligaments and muscles. This may take several weeks. The greater vigor of the child's movements, the disappearance of sweating, and the increased activity of dentition, afford some indication of the improvement; but in a general way it may be said that with a marked degree of rickets, if the child has already begun to stand before the symp- toms attract attention, he should be kept off his feet altogether for at least three months from the time when treatment is begun, and if standing has not yet been acquired the parents should be instructed not to encourage the child to attempt to stand. In severe rickets in the active stage of the disease even sitting should be discouraged, for apart from the kyphosis and lateral curvature of rickets, which are usually transitory, the occurrence of pelvic deformities is favored by the pressure from above and below incurred by the sitting position. In cases where much deformity of the chest has occurred, with sinking in of the ribs in the axillary region and prominence of the sternum and cartilages, the danger of bronchitis and bronchopneumonia is to be remembered, and every precaution taken to avoid these complications. Therapeutics. — The most important factor is the diet. In almost all cases this requires modification, generally in the diminution or discontin- uance of farinaceous food according to the age, and in increase of the fat. The latter presents difficulties chiefly amongst the poor who are unable to 8SS COXSTITUTIOXAL DISEASES 1 afford cream or who live under such contlitions that milk and cream undergo much bacterial contamination. Under such circumstances, the deficiency may be supplied by any oil or fat which is easily assimilated. Cod-liver oil is most conmionly used in England but other oils, such as cotton-seed oil and olive oil, have been used; and apparently it makes little difference how the fat is sup]:)lic(l provided it can be digested. There are many i)alatable emulsions of cod-liver oil, and any of these may be used, but it may be more convenient to use the plain oil. In either case the amount of oil given at each dose should not exceed 15 minims (.75 cc.) for an infant six months old; 20 minims (1.25 cc.) for an infant twelve months old; and 25 to 30 minims (1.5 to 2 cc.) for an infant of eighteen to twenty-four months; these doses should be given three times daily just after food. In some cases, one of the combinations of malt extract with cod-liver oil is taken better and may be more valuable, especially where some farinaceous food is being allowed, as the diastasic power of the malt assists the digestion of starch. A valuable method of administering fat is to add to the diet daily the yolk of one egg. This contains 20 to 30 per cent, of fat. It must be given very lightly boiled, otherwise it becomes indigestible. An infant of nine months can have half the yolk of 1 egg daily, at ten or eleven months the whole of the yolk can be given. After the age of twelve months, the egg can also be given in the form of custard. In some parts of Europe, especially in Vienna, but also in America by Jacobi, phosphorus has been strongly advocated. Opinions are, how- ever, much divided as to its value; some writers state that it is not only entirely without effect but that it produces gastro-intestinal disturbance and occasionally serious toxic symptoms. It seems probable that some, at least, of the benefit which has been attributed to phosphorus, may have been due to the oil in which it has almost invariably been given. It is usually dissolved in cod-liver oil or given in an emulsion with almond oil; aJo to iJo grain (.3 to .6 mg.) of phosphorus may be dissolved in 1 dram of cod-liver oil (3.5 cc), and half this quantity may be given two or three times a day. Jacobi recommends the elixir phosphori of the U. S. pharmacopoeia; of this, 6 to 15 minims (about 0.4 to 1 cc.) should be given three times daily. Various organic and other compounds of phosphorus have been used in rickets, particularly lecithin, preparations of hypophosphites in syrup, wheat phosphates, the soluble part of bran, and many patent prepara- tions containing phosphorus. The syrupus ferri phosphatis of the British pharmacopceia is used by many for rickety children over the age of twelve months; it is given in doses of | to 1 dram (1.75 to 3.5 cc). Glycerin extract of bone-marrow has given good results in some cases. Various organic remedies have been tried, but, in most observers' hands, have proved useless. Stoeltzner advocated the use of suprarenal extract; but subsequent observations by Honigsberger gave entirely negative results; the thymus and thyroid have also been tried, but the successes claimed for them have not been justified. The value of baths is perhaps hardly sufficiently recognized; the child should have a warm bath at about 85° F. every morning, and while sitting in the bath should be douched with w^ater at a slightly lower temperature, 75° to 80° F. If this is done with tact and the child gradually accustomed RICKETS 889 to It, there should be no dislike to it, and it seems to have an invigorating and tonic effect which may be of value especially in reducing the nervous instability. If convulsions have already occurred, or if a tendency to them is shown by the presence of laryngismus stridulus, tetany, or facial irritability, bromide should be given with cod-liver oil. Two to 4 grains (.13 to .26 gm.) of potassium bromide in 1 dram (3.5 cc.) of cod-liver oil emulsion, are given three times daily. Sometimes chloral | to 2 grains (.032 to .13 gm.) is more effectual than bromide, and may be given every four or six hours. Massage has also been advocated and is likely to be useful in maintain- ing the nutrition of the muscles while it is necessary to keep the child off his feet; but the massage must be extremely gentle and is less applicable to the infants under twelve months than to those who are older. The child must be kept off its feet during the active stage of rickets, and if fat and heavy and especially if the bones of the legs already show bending, this measure may be necessary for several months. Often the only way to ensure this is to apply long splints to the outer side of the legs, the splints being sufficiently long to project well beyond the sole of the foot. They should be removed when the child goes to bed so that it may kick its legs about freely and exercise its muscles as much as possible. CONGENITAL RICKETS. It seems certain that rickets may be present at birth, but until recently cases of achondroplasia were described as foetal or congenital rickets, and, as Ballantyne has shown, there are several types of bone disease which occur in utero, all of which have probably been described as rickets in the past. The relation of these to rickets is uncertain but they bear so little resemblance to postnatal rickets, that it seems wise at present to consider them as something altogether distinct, although, as Ballantyne suggests, it may be that rickets occurring during intra-uterine life, would be modified according to the period of development at which it occurred. As to the frequency of congenital rickets, there is a wide discrepancy in statistics. Feyerabend at Konigsberg, among 180 new-born infants, found 68.9 per cent, rickety. Schwarz in Vienna found that among 500 new-born infants, 80.6 per cent, showed rickets. Fede and Cacace, at Naples, among 500 new-born infants, found only 1 with clinical evi- dence of rickets, and in another series of 475 new-born infants, Fede and Finizzio found only 3 with rickets. Personal experience at the Children's Hospital, Great Ormond Street, suggests that within the first two months after birth rickets is excessively rare. The symptoms are those which have already been described as char< acteristic of postnatal rickets, but the frequency of fractures in the long bones is a notable feature of the congenital disease. Often 4 or 5 of the bones are broken and the fracture is often complete, not green- stick. Monti quotes Chaussier as having found in 1 case 42, in another 112 fractures. These are certainly not always produced during parturi- tion for they have been found already united or in process of uniting at 890 CONSTITUTIONAL DISEASES the time of birth (Notta). All degrees of curvature of bones are also found. It has been stated that the rachitic distortions of the thorax are lacking in this form, but this is ])erhaps doubtful, for H. Ashby has recorded a case in which the ty[)ical deformity of the rachitic chest was present at the age of fourteen days in association with several fractures in the limbs. There has been extensive failure of ossification of the skull in several of the recorded cases, a defect which some have described as craniotabes. It is very doubtful, however, whether such a condition bears any relation to the localized patches of craniotabes mentioned as characteristic of ordi- nary rickets where the thinning of the skull is probably due to absorption rather than to defect of formation of bone. Infants with congenital rickets are often of premature birth and apart from this are commonly feeble, so that the prognosis must be guarded. But so* far as the fractures are concerned, the outlook is good; they unite rapidly after birth. With suitable feeding the rickets rapidly improves and may even disappear entirely in a few months. Congenital rickets is no doubt dependent upon some deficiency in the mother's blood of the constituents requisite for bone formation, and it is an observed fact that in a considerable proportion of the cases the mother has been ill during pregnancy. That the mother's health may exercise some effect, especially upon bone formation, in the foetus, is suggested by some experiments on rabbits in which the inoculation of the parents with the toxins of diphtheria or tuberculosis resulted in deformities of the hind limbs in the offspring (Charrin and Gley). Treatment. — The treatment, apart from suitable fixation for the frac- tured bones, consists chiefly in careful feeding, at the breast if possible, otherwise with milk which has been carefully modified so as to contain a proper proportion of fat. LATE RICKETS. Rickets is occasionally seen as an active disease in the later period of childhood and in adolescence, and has then been described as late rickets, recrudescent rickets, or rachitis tarda. Probably the term recrudescent rickets most accurately describes the majority, for usually the patient has shown evidence of rickets within the first two years of life and then after years of quiescence the disease has again started into activity. ]\Iuch more rarely rickets makes its first appearance at this later period. Whether recrudescent or not, this late rickets is very rare; but it is said by some surgeons that adolescents at the period of rapid growth not infrequently show slight bending of bones, and this has by some been described as rickets. Apart however from the curvature of bones, such cases usually show no other evidence of rickets and it seems very doubtful whether a mere failure of the hardening process in bone to keep pace with the rapid growth of bone at this age should be considered evidence of rickets. There is no doubt that bending of bones resembling that seen in rickets may occur quite apart from the histological characters of rickets. Stoeltzner's experiments have already been mentioned. He produced bending of limbs in puppies by a special diet but microscopic examination showed that the changes were not those of rickets. RICKETS 891 Fia. 'J?. Late rickets has occurred most often between the age of nine and ff)ni- teen years, but it has begun as late as seventeen yeilrs. At what age; rickets should be described as late, has not been s(!ttled. Probably the disease beginning or recrudescing after the age of four years, might properly be described thus. Symptoms. — The symptoms are similar to those already described, but the onset has usually been with some pain in the limbs, more or less severe, especially in the legs. At the same time there has been weakness so that in some cases the patient has been unable to walk without assistance. The ribs become beaded and the epiphyses enlarged, as may be seen in the accompanying Fig. 74 of a boy aged nine and three-fourths years, in whom the symptoms of rickets, after remaining almost quiescent since his earUest years, became a(."tive again at the age of nine and one-half years. He was under the care of my colleagues, R. Hutchison and A. E. Garrod, at the Children's Hospital, Great Ormond Street. There was no enlargement of the head in this case, and this appears to be the rule; only 1 case has been recorded in which the head became enlarged during late rickets (James). The thorax has become distorted in some cases with deformity described as typically rachitic. The bending of the lower limbs is sufficient generally to cause a waddling awkward gait. With the ic-rays, the bones give a less marked shadow than normal, presumably from deficiency of calcification. Examination of the urine in one case (James) showed excessive excre- tion of lime (more than twice the nor- mal). The amount of phosphoric acid was fully up to the normal but hardly excessive. Irregular pyrexia was noted in one case (Cautley) during the progressive stage of the disease. Like rickets at an earlier age, the late form of the disease hinders growth and development, the establishment of puberty may be delayed, and the child remain undergrown. Hitherto no explanation of these cases of late rickets has been found. It has been stated in some cases that there was no obvious fault in the diet; in some cases a severe illness has preceded the onset of the symptoms. Prognosis. — Prognosis must be guarded, for the deformity is often considerable; the disease is, however, rarely fatal. There seems to be less 892 CONSTITUTIONAL DISEASES tendency to respiratory complications than in rickets during the first two years of life. Treatment.— The treatment which has been found most effectual is similar to that used in ordinary rickets, namely, the administration of cod-liver oil, to which some have added phos])horus. After the disease has become quiescent, operative measures may be required for the correction of deformities. CHAPTER XXXIV. SCURVY (SCORBUTUS). By ROBERT HUTCHISON, M. D., F. R. C. P. (Lond.) Scurvy may be defined as a general disorder of nutrition characterized by debility, mental apathy and anaemia, with sponginess of the gums, ulceration of the mouth, and a tendency to hemorrhages into the sub- cutaneous tissues and from mucous surfaces. History. — Good historical accounts of the disease have been given by Budd^ and by Hirsch.^ Scurvy does not seem to have been clearly recognized in Greek and Roman times though some passages in the writings of Hippocrates may perhaps refer to it, especially where he speaks of "a condition marked by foul breath, gums receding from the teeth, bleeding from the nose, and ulcers of the legs." The earliest description of the disease as we now know it does not occur until the year 1260, when a severe outbreak occurred amongst the troops of the Christian Army fighting in Egypt under Louis IX. ^ The historian of that campaign, himself a sufferer from the disease, describes clearly all the chief symp- toms — bleedings from the gums, black spots on the legs, epistaxis, debility, and a tendency to syncope. In later periods good descriptions of land scurvy are found in various writings of the sixteenth and seven- teenth centuries, notably in the history of the northern nations, by Olaus Magnus, and in the writings of the three physicians, Roussens, Ecthius and Wierus. It is noteworthy that these writers recommend the same remedies as are at present in use against the disease. From that time down to the present day accounts of scurvy are constantly met with, especially as occurring in besieged garrisons and among troops exposed to the privations of war, conditions in which, outbreaks still most fre- quently occur. The earliest report of the occurrence of scurvy on board ship is con- tained in the Narrative of the Voyage of Vasco de Gama Round the Cape in the Year 1497, in which about 100 of his men, out of a total of 160, died of the disorder. About this period, when long voyages became frequent and fresh food was unobtainable on board ship, scurvy developed into a terrible scourge of the sailor and the accounts of the voyages of most explorers abound with references to it. It prevailed, indeed, down to the year 1795 when, on the initiative of Sir Gilbert Blane, lime juice was introduced into the Navy, after which scurvy rapidly declined in that service though it is still met with occa- * Tweedie's System of Practical Medicine, 1840, v, p. 58. ^Handbuchder historisch-geographischen Pathologic, StuttgSiTt, 1883. 26 Aufl. Abth. ii, p. 354. ^Histoire de Louis IX par le Sieur Joinville, Trans., vol. i, p. 162. 893 894 ' CONSTITUTIONAL DISEASES sionally even now in ships of the Mercantile Marine. The rarity of the disease, however, is shown by the fact that in the last ten years only 22 cases have been treated in the Seamen's Hospital at Greenwich Etiology. — The true causation of scurvy is still rather obscure. It will be convenient to consider in order the different views which have been entertained. 1. That Scurvy is Due to a Deficiency of Potassium in the Blood. — This hypothesis was first put forward by Alfred Garrod.^ Guided presumably by the Ilippocratic axiom " curat ioncs naiuravi morhorum os tend lint" lie analyzed diets known to have antiscorbutic properties and found that they differ from those which tend to produce scurvy chiefly in containing larger (luantities of potassium. Proceeding further he found that potassium salts were diminished in amount in the blood and urine of patients suffering from scurvy, and putting the two facts together he formulated the above-stated hypothesis as to the causation of the disease. It was soon shown, however, that his view, in this simple form at least, was untenable, for, as Ralfe jiointcd out, beef-tea, though it contains a large quantity of salts of potash, has no antiscorbutic power and, further, the crucial test of administering nitrate of potassium to patients suffering from scurvy failed to show that it was possessed of any curative influence. Buzzard^ modified Garrod's hypothesis by suggesting that it is not potash as such but the form in which it is combined which is of impor- tance, and it was to the organic salts of potash that he attributed the anti- scorbutic power of fresh vigetables. "AH antiscorbutic juices," he says, "contain salts of citric, tartaric or malic acids, and we have no evidence of any substances which contain these materials in considerable quantity, and are yet deficient in the power of preventing scurvy. The mode by which they act is still involved in obscurity." Subsequent investigations have been directed to the clearing up of this obscurity and have led to the adoption of the following view: 2. That scurvy is caused by a diminution in the alkalinity of the blood, or, in other words, that it is to be regarded as an acid intoxication. This hypothesis was first put forward by Ralfe,^ who concluded from his analyses of the urine of patients with scurvy and that of healthy persons after the withdrawal of fresh vegetables from the diet : 1. That the primary change that occurs in scurvy is a chemical altera- tion in the quality of the blood. 2. That this chemical alteration as far as can be judged from inferences drawn from the analysis of urine in patients suffering from scurvy, and analysis of scorbutic and antiscorbutic diets, points to a diminution of the alkalinity of the blood. 3. That this diminution of alkalinity is produced in the first instance (physiologically) by an increase of acid salts (chiefly urates) in the blood, and finally (pathologically) by the withdrawal of salts having an alkaline reaction (chiefly alkaline carbonates). 4. That this diminution of the alkalinity of the blood finally produces the same results in scurvy patients as happens in animals when attempts are made to reduce the alkalinity of the body (either by injecting acid 1 Edinburgh Monthly Journal of Medicine, 1848, New Series, ii, p. 457. 2 Reynolds's System of Medicine, 1866, vol. i, p. 731. s "An Inquiry into the General Pathology of Scur\'y," Lanpet, 1877, ii, p. 81. SCURVY 895 into the blood or feeding with acid salts) ; namely, dissolution of the blood corpuscles, ecchymoses and blood stains on mucous surfaces, and fatty degeneration of the muscle of the heart, the muscles generally, and the secreting cells of the liver and kidney. This conception of the disease has been independently advocated by A. E. Wright, whose line of argument is as follows:^ "The scorbutic condition is a pathological condition which is induced by a dietary con- sisting of meat and cereals to the exclusion of green veg(;tables, tubers and fruits. Inasmuch as the foodstuffs which are excluded from the dietary in question are foodstuffs which contain an excess of bases over mineral acids, while the foodstuffs (meat and cereals) which remain are foodstuffs which contain a large excess of mineral acids over bases, it is obvious that the scorbutic condition is one which supervenes upon the ingestion of a considerable excess of mineral acids over bases. It would, in view of this consideration, seem probable that scurvy is a condition of acid intoxication very similar to the acid intoxication which can be experimentally produced in herbivora by the ingestion of a surplus of mineral acids. The theory that scurvy is essentially a condition of acid intoxication would appear to be in harmony with the circumstance that the rapidity with which the scorbutic condition supervenes depends apparently upon the degree to which the mineral acids are in excess in the dietary. The condition is apparently more rapidly superinduced by a dietary of corned meat (i. e., meat which has been rendered hyperacid by the removal, in the process of corning, of the alkaline salts of the blood and lymph) than by a dietary of fresh meat (z. e., meat which still contains these alkaline salts) Justification for the identification of scurvy with a condition of acid intoxication would appear to be afforded also by the consideration that the scorbutic condition is remedied or alleviated by the addition to the scorbutic dietary of any one of a whole series of different substances — tubers, green vegetables, decoctions of leaves and growing shoots, blood (used for this purpose by the Laps), fruits and fruit juices — substances which have apparently in common only the circumstance that they all contain an excess of bases over mineral acids." In confirmation of this view Wright found that there was a striking reduction in the alkalinity of the blood in a series of scurvy cases which he examined and that as the condition passed off the alkalinity rose again to normal. 3. The view that scurvy is caused by poisoning with ptomaines was first put forward by Torup, of Christiania, and has been investigated experimentally by Jackson and Vaughan Harley.^ They argue from the experience of Nansen in the Arctic regions that scurvy cannot be due to a diet devoid of fresh vegetable constituents and exposure to insani- tary surroundings, for Nansen was subjected to both these conditions and yet escaped the disease. They also advance evidence to show that the disease is not prevented by the consumption of lime juice but that it is associated with the eating of tinned or salted meat. They then describe experiments upon monkeys fed upon a diet of boiled rice or maize to which was added a proportion of tinned meat given either fresh or after being kept until it was slightly tainted. The monkeys which were fed on *"0n the Pathology and Therapeutics of Scurvy," Lancet, 1900, ii, p. 565. ^Lancet, 1900, i, p. 1184. 896 CONSTITUTIONAL DISEASES the tainted meat developed sponginess of the gums, and diarrhoea with blood and mucus in the stools. Interesting as these experiments are it would be rash to conclude that we have here an exact reproduction of the disease as it occurs in the human subject. It is to be noted, for instance, that in none of the animals was there any swelling or tenderness of the fimbs or appearance of puv})uric spots, and in any case the diet above described must be regarded as so abnormal for monkeys that it would be unwise to draw conclusions from its effects upon them as to the results which it might be expected to produce in the human subject. 4. The view has recently been gaining ground that scurvy is the result of a specific infection which takes place through the mouth. The earliest attempts to cultivate a microorganism from the cases of the disease were made by ^Nlurri,^ Contu,^ and Wieruszkij,^ but yielded no definite results. Babes, ^ however, was more successful and succeeded in reproducing some, at least, of the features of the disease in rabbits by injecting them with cultures taken from the gums of patients suffering from scurvy. He demonstrated, also, in the blood of his cases, a bacillus which he believed to be the cause of the disease. He describes it as being narrower, and considerably longer than the cholera bacillus, pointed at the ends, and not staining by Gram's method. It is probably always present in the mouth. Myer Coplans^ strongly supports the infective view of the origin of scurvy as the result of his experience of the disease in the Concentration Camps during the Boer War. He found that the disease prevailed directly as the habits of the occupants of the camps were filthy, and could trace no relation between its prevalence and the character of the diet; the disease might be present in one camp and not in another although the rations of the two were identical. Summing up all the evidence, it seems probable that whilst a deficiency of fresh vegetables, i. e., of organic salts of potash, plays a part in the production of the disease by reducing the alkalinity of the blood, yet this does not afford a complete explanation of the occurrence of all the symptoms, and it is not unlikely that upon the soil so prepared there is grafted some specific infection which finds access to the body by the mouth. Insanitary surroundings, overwork, mental depression, and exposure to cold and damp, facilitate the development of the disease by lowering the resistance of the patient. Morbid Anatomy. — The bodies of patients who have died of scurvy usually exhibit only a slight degree of rigor mortis, and putrefaction occurs early. The only constant morbid change found, however, is effusion of blood in various situations. These effusions, which may be diffuse or circumscribed, are met with both in the skin and subcutaneous tissues and under the periosteum of the bones and consist of altered blood which may have undergone partial clotting or even organization into fibrous tissue. Hemorrhages are also met with in the pleura and pericardium and though more rarely, in the peritoneum as well. There may also be ^Riv. Clin, di Bologna, 1881, 3s. i, p. 215. ^Raccoglitore Medico, 1881, xvi, p. 188. ^Wratsch, 1890, pp. 208 and 303. *Deut. Med. Wochensch, 1893, xix, p. 1035. ^Lancet, 1904, i, p. 1714. SCURVY 897 hemorrhagic effusion into the joints. The internal organs show no con- stant change but the heart muscle is soft and often degenerated. The lungs are oedematous, and may contain infarctions. The kidneys and liver rarely exhibit any signs of disease. The spleen is large, soft, and congested, and may also show infarcts on its surface. It is important to note that all accurate observations agree in showing that the bloodvessels exhibit no gross or microscopic changes. In the altered gums, Babes distinguishes five layers: (1) A surface layer, for the most part free from epithelium, moderately thick, pale, resembling a diphtheritic membrane with a few fragments of nuclei, and containing various bacteria, especially streptococci. (2) A structureless layer, about one millimeter thick, consisting of a felt-work of long fine bacteria. (3) Uni- and multi-nucleated round cells. (4) A layer of oedematous mucous membrane containing many bacilli resembling those in the second layer. In the walls of the vessels are numerous swollen spindle-cells. (5) Large and much dilated vessels with large spindle- cells in their walls. In the blood which fills the vessels are various cell masses, numerous multi-nucleated leukocytes, endothelial and mast cells but no bacteria. Symptoms. — Prodromal Symptoms. — Scurvy is usually a disease of insidious onset. The patient begins to suffer from loss of bodily vigor, and from an even more marked mental apathy and lassitude so that the slightest task becomes a burden. At the same time he looks ill. The face becomes pale, or sallow and drawn, the eyes sunken, lusterless and encircled by dark rings. At this period too, there may be some pitting of the ankles on pressure, and a tendency to diarrhoea whilst it may be observed that the least knock or injury tends to be followed by a bruise. He suffers also from pains of a rheumatic sort in the limbs and joints. To these symptoms there are soon added those characteristic of anaemia — • shortness of breath on exertion, palpitation, and a tendency to syncope. Such symptoms may precede by a few days or even weeks, the more characteristic signs of the disease. Amongst these the most striking though not necessarily always present, are the changes in the mouth. The gums begin to swell, especially around stumps or carious teeth, and as the process goes on the swelling may become so great as to amount to a veritable hypertrophy so that the teeth become buried in a mass of soft, fungous tissue of a bluish or purplish tint. Ulceration quickly follows along the margins, the process being accompanied by the discharge of a sanious fluid which imparts an odor of great foetor to the breath. Finally the teeth become loosened in their sockets and may fall out whilst necrosis of the alveolar edges ensues. Equally characteristic and constant are hemorrhages inio the skin and subcutaneous tissue which assume the form either of petechise or of ecchy- moses. The former occur as small red or purple spots resembling flea bites which appear first around the hair follicles of the lower extremities and impart, by the elevations which they produce, a slight feeling of roughness to the skin. They remain for about a week, and then gradu- ally fade into greenish spots which soon disappear; their disappearance being followed by a slight degree of desquamation. The production of the petechise is determined by the slight irritation caused by the friction of the clothes, and hence they are always to be found first on the outer 67 898 CONSTITUTIONAL DISEASES surface of the leg, and the outer and anterior aspects of the thigh. Here and there the petechia? may coalesce into Uirger areas or maculae. In severe cases the slightest pressure on the skin is sufficient to cause ulcera- tion, the ulcers having thick edges and bleeding surfaces from which a very offensive discharge is given off. Such ulcers may spread rapidly, and invade surrounding tissues, giving rise in some cases to dangerous, and even fatal hemorrhage. Ecchymoses, the other characteristic sur- face lesion of scurvy, are produced by hemorrhage into the subcutaneous or intermuscular tissue. They may occur spontaneously or as the result of injury, and vary greatly both in size and extent, being commonest in the lower extremities where they may form quite large swellings. The part affected by them is brawny, tender and pits on pressure, the indenta- tion persisting longer than it does in ordinary cedcma. The skin over them is red, shiny, and hot. Such effusions are common, also, in the popliteal space and in the bend of the elbow as well as in the loose tissue around the malleoli, and beneath the muscles of the jaw. In these situa- tions they form indurated swellings which fill up the natural hollows of the part, and greatly interfere with the movements of the adjacent joint. Where such effusions occur, as they sometimes do, over the shins, they are apt to be mistaken for syphilitic nodes. There is no marked tendency to bleeding from the internal organs in scurvy, but hemorrhages may take place from the mucous surfaces. Of such hemorrhages, epistaxis and bleeding from the mucous membrane of the mouth are commonest. Bleeding may also occur from the mucous membrane of the intestine when there is a co-existing diarrhoea. Hae- moptysis, haematemesis and haematuria are rare. Hemorrhagic effusion into the pleura and pericardium have also been described. Not uncom- monly hemorrhage occurs under the conjunctiva and may be so extensive as appreciably to raise the ocular layer, leaving the cornea at the bottom of a pit surrounded by swollen and red conjunctival membrane. As the disease progresses anaemia becomes a marked feature. The blood itself presents simply the characters of a secondary anaemia, and there is no leukocytosis unless secondary inflammatory complications exist. Special interest attaches to the chemical condition of the blood on which, however, but few observations have been made. If the views of Ralfe and of Wright as to the etiology of the disease are correct one would expect to find a diminution of alkalinity and of coagulability and Wright in a few cases has shown that diminution of coagulability is actually present. Barnardo, who had the opportunity of investigating this point during the Somaliland Campaign, found no constant relation between the degree of reduced alkalinity and the severity of the symptoms. Although he states that in all cases where the alkalinity is much reduced profound constitutional disturbance will soon manifest itself if it be not already present. Alimentary symptoms are often absent. Appetite is not necessarily impaired but dyspeptic symptoms may be present as the result of the imperfect diet which produces the disease. Constipation is the rule but the conditions under which scurvy is developed frequently favor the production of diarrhoea of a dysenteric t}qDe and when such a complication exists it may be attended by bloody discharges from the bowel. SCURVY 899 The urine at the outset is scanty, high-colored, turbid and occasionally albuminous but as improvement sets in it becomes more abundant and pale. The amount of free acid in it is diminished and so, it is alleged, are the potash salts. Of the complications of scurvy, gangrene of the lung is one of the most frequent and dangerous. It is marked by the usual expectoration of dark foetid matter, by rapid and difficult breathing with great depression, and usually ends fatally. Buzzard describes an affection of the chest in scurvy which may be mistaken for pneumonia. Faint rigors, followed by a certain amount of feverishness and accompanied by lancinating pain in one or both sides, usher in this condition. The pain is felt only in coughing and a very viscid mucus is expectorated. The dyspnoea increases, and a constric- tion as though from a cord bound tightly round the chest is described. Although it occasionally happens that these pulmonary symptoms are dependent upon true inflammation, they are much more commonly associated with the effusion of sanguineous fluid into the cavity of the pleura or into the substance of the lung itself, these structures sharing with every other organ that tendency to effusion which is the dominant feature of scurvy. When the lung is thus invaded the expectoration after a short time becomes dark and sanious, with all the horrible foetor which is ordinarily associated with gangrene of the lung, but which is here dependent upon decomposition of the bloody fluid poured into the lung substance. There are now cold sweats, increasing dyspnoea and anxiety, a small and frequent pulse, and death. In other cases there is no pain or cough but the breathing rapidly becomes short and labored and death occurs suddenly. Auscultatory signs in the lungs are usually wanting, but now and then there is localized dulness on percussion with bronchial breathing, or mucous rales are heard, sometimes also with gurgling sounds at certain parts of the chest. Night blindness is a condition sometimes met with in patients suffering from scurvy who have also been much exposed to bright light, and may occur quite early in the disease. It would appear to be merely the result of the ansemia and exhaustion which scurvy produces and is in no sense an essential part of the scorbutic process. Diagnosis.—If all the characteristic symptoms are present and if the disease arises simultaneously in a number of subjects in circumstances known to favor its development, the diagnosis of scurvy is easy. Diffi- culty only occurs when one has to deal with sporadic cases, such, for example, as the cases of land scurvy occasionally met with in badly fed individuals. The disease which perhaps most closely resembles it is purpura haemor- rhagica (morbus maculosus of Werlhof) but in this the affection of the gums is absent and the hemorrhages have not, as they have in scurvy, an inflammatory character. Mercurial cachexia, which in many points- closely simulates scurvy, is now but rarely seen and an inquiry into the history will usually lead to a correct conclusion. Acute lymphatic leukcemia, which is often marked like scurvy by ulcera- tion in the mouth, can be at once distinguished by an examination of the blood. 900 CONSTITUTIOXAL DISEASES Prognosis. — The prognosis of scurvy, exccjit in tlie severest cases, is favorable, provided suitable treatment can be adopted. It has often been noted that the outlook in this tlisease is by no means dependent upon the severity of the lesions in the skin, mouth, and muscles, but is in far closer relation to the state of the internal organs such as the lungs and heart. The supervention of complications and of intercurrent disease also exerts powerful influence upon the prognosis whilst a speedy and often un- expected fatal result may be brought about by severe hemorrhage or lieart failure. Even in eases which run a favorable course it may be weeks or even months before the patient is restored to his original vigor, and when recovery is comj)lete there may still be some results of the disease shown in cicatrices in the skin or })artial ankylosis of joints. Treatment. — The first point is to remove the patient if possible from the place in which the disease has developed and to bring him under more hygienic conditions. Cold and damp should especially be avoided and he should be placed in warm and dry surroundings. Of even greater imj)ortance is it to make a radical alteration in his diet. Whatever view may be held as to the causation of the disease all experience goes to show that the introduction into the diet of a sufficient quantity of fresh vegetable food has a powerfully curative effect. It would appear that there is no particular form of vegetable food which has a specific influence over the disease but that all are equally efficacious. The antiscorbutic power of fresh limes and lemons has been known since the seventeenth century and these fruits still constitute a favorite remedy. It is important that they should be fresh; lime juice which has been bottled for some time is apt to decompose into free citric acid and carbonates and loses much of its value. An objection to lime juice IS its rather acrid taste, on account of which it is sometimes found to be difficult to induce those who are exposed to the disease to take it regu- larly as a preventive. Lemonade made from fresh lemons is not open to this objection. Preserved vegetables, though useful, seem to have a feebler antiscor- butic power than fresh; sauerkraut appears to be more serviceable in preventing the disease than any other form of preserved vegetable and Captain Cook employed it successfully in some of his voyages. Infusions of malt are also powerfully antiscorbutic. Forster,^ who accompanied Cook in his second voyage, describes a severe outbreak of scurvy and its cure of infusion of malt without any other change in the diet; he adds, "The encomivuns on the efficacy of malt cannot be exaggerated." In some of the worst cases that he saw the patient took as much as 5 pints of the infusion in a day. The infusion should be fresh, for its good qualities are impaired if it is allowed to become damp and mouldy. Fresh meat juice has been found to be of value as an antiscorbutic owing, it is alleged, to the lactates which it contains. Milk is also service- able, 3 pints of it containing as much citric acid as 1 ounce of lime juice and instances are on record of outbreaks of scurvy which have been checked by its administration. Of beverages, French and Italian wines are stated to be antiscorbutic but opinions as to the power of cider in this resj)ect vary considerably. ^Notes from a Voyage Round the World, by George Forstcr, vol. i, 1777. SCURVY 901 Drugs are of far less use in scurvy than the measures above indicated. Wright, on hypothetical grounds, has recommended the administration of Rochelle salt in doses of 30 to 60 grains (gm. 2 to 4) thrice daily until the urine is alkaline, along with 20 grain (gm. 1.3) doses of crystallized calcium chloride to increase the coagulability of the blood. Barnardo speaks favorably of this treatment as the result of his experience in Somaliland. The administration of bitters — especially of quinine — and of iron to combat the anaemia is of help in restoring health, and special complica- tions may require the administration of appropriate remedies. In the treatment of diarrhoea, bael fruit is stated to be specially useful. Locally the conditions of the mouth will demand most attention. Anti- septic washes of permanganate or chlorate of potash or peroxide of hydrogen help to remove the foetor, whilst the spongy and ulcerated gums may be painted with a strong solution of nitrate of silver. Absorption of local effusions of blood may be promoted by gentle massage. The prophylactic treatment consists in attention to general hygienic conditions and in the provision of an abundant and varied dietary con- taining an adequate proportion of vegetables. In Nansen's Arctic ex- pedition, which lasted three years and during which scurvy was entirely avoided, the diet consisted of meat of various sorts in hermetically sealed tins, dried fish, potatoes both dried and tinned, all sorts of dried and pre- served vegetables and fruits, jam, marmalade, condensed milk, preserved butter and desiccated soups. Flour was carried to make fresh bread. Drinks consisted of tea, coffee and cocoa, beer and lemonade. Lime juice has long been used as a prophylactic but is apt to undergo decomposition when kept long in a barrel. Two ounces twice a week is recommended as a preventive dose. INFANTILE SCURVY. - That infantile scurvy is closely related to the adult form of the disease there can be little doubt, and as in the latter there is reason to believe that a deficiency of vegetable salts in the food plays an important part in its development. None the less the clinical manifestations of the two forms are very different, but the differences are probably to be explained by differences of diet and by the anatomical and physiological peculiari- ties of the infantile period of life. Historical. — As far back as the middle of the seventeenth century Glisson, in his Treatise on the Rickets,^ had already given a clear descrip- tion of scurvy occurring as a complication of rickets but the disease seems to have been lost sight of until two centuries later when Lloller^ described some cases under the title of "acute rickets" a term which was adopted by other continental writers on the subject, such as Bohn, and Hirschsprung. In 1873 Jalland^ described a case in a child of ten months and considered it as identical with the scurvy of adults. ^English Trans., 1651, p. 249. ^Konigsb. Med. Jahrhucher, 1859, i, p. 377. ^Med. Times and Gazette, 1873, i, p. 248. 902 COXSTITUTIOXAL DISEASES Anothei' case was published in 1870 by Thomas Smith wlio described it as one of "Hemorrhagic periostitis of several of the long bones with separation of the epiphyses,"^ but failed to recognize its scorbutic nature. To Cheadle belongs the credit of first clearly emphasizing the identity of such cases with the scurvy of adults, which he did in a paper on "Three Cases of Scurvy Supervening on Rickets in Young Children,"^ published in 1878. In 1881, Gee^ published a series of cases under the name of osteal or periosteal cachexia, but in 1882 Cheadle'* again insisted upon the identity of such cases with scurvy. A year later Barlow secured general recognition of the truth of Cheadle 's views by a paper entitled, "On Cases Described as 'Acute Rickets' Which are Probably a Combina- tion of Scurvy and Rickets, the Scurvy Being an Essential and the Rickets a Variable Element."^ This paper contained an exhaustive clinical and pathological account of the disease and has become a classical publication of the subject which on the Continent has secured for infantile scurvy the title of Barlow's Disease. The terms "acute rickets" and "scurvy rickets" are still sometimes used but all later observations tend to show that the rickety element is a mere complication and not an essential part of the process. The latest and most exhaustive account of infantile scurvy was written by Cheadle,^ but almost every day adds to the literature of the disease. Etiology. — Clinical observation shows that the vast majority of cases of scurvy arise in infants who are being fed on a diet which is deficient in fresh constituents. The diet which most commonly produces the disease seems to be one consisting of condensed milk with the addition of a tinned food, but a diet of sterilized milk alone is undoubtedly capable of giving rise to it, and so even may milk which has merely been boiled. Griffith,^ in summarizing the results of an investigation of 356 cases collected by a committee of the American Pediatric Society, with the addition of 18 cases of his own, concludes that in 60 per cent, a proprietary food had been used but often with the addition of sterilized milk. Nine per cent, had been fed on condensed milk and 19 per cent, on sterilized milk only.* Pasteurized milk seems much less apt to produce the disease. That the want of freshness in the food is not the only cause of the disease, how- ever, seems to be shown by the fact that 10 of the cases had been fed on the breast only and several of them on raw milk. It may be asked, What is it, in a diet deficient in fresh constituents, which tends to produce infantile scurvy ? That the fault is a negative and not a positive one, that is to say, due to the absence from the food of some constituent which it should contain rather than to the presence of some abnormal element, is shown by the fact elicited by some observations made * Transactions of the Pathological Soceity of London, xxvii, 1876, p. 219. 2 The Lancet, 1878, ii, p. 685. ^ St. Bartholomew's Hospital Reports, vol. xvii, p. 9. * The Lancet, 1882, ii, p. 48. ^ Trans. Royal Medical and Chirurgical Society, 1883, Ixvi, p. 159. ' AUbutt's System of Medicine. ' New York Medical Journal, 1901, Ixxiii, p. 317. * For additional evidence for the production of scurvy by sterilized milk, see Netter (Scorbut infantile et lait sterilis) Rev. des Maladies de VEnfance, xx, p. 543, 1902; Neumann, Deut. Med. Woch., 1902, xxviii, pp. 628, 647; and Ashby, Brit. Med. Journ., 1904, i, p. 479. SCURVY 903 by the writer^ that the mere addition of sterilized fruit juice to the diet without any other alteration, exercises an undoubtedly curative influence. The same was found to be true, though in a lesser degree, of the vegetable salts of potash when administered artifically. It would seem probable that a deficient supply of vegetable salts plays at least a large part in the causation of infantile scurvy just as it does in that of the adult form of the disease. Milk contains a considerable quantity of citrate of lime; and Corlette^ has pointed out that this salt is present in fresh milk in the amorphous and more soluble form, its solution being aided by the presence of phosphates, but that when milk is boiled the amorphous is converted into the crystallizable form of the salt, which is less soluble and separates out. The mere boiling and, a fortiori, the sterilization of milk causes it to become poorer in citrates than it ought to be, and to this he attributes the tendency for scurvy to develop when such milk is exclu- sively used. How it is that a deficiency of vegetable salts in the food leads to the hemorrhagic tendency characteristic of scurvy we do not know. It is not, apparently, by reducing the coagulability of the blood, for (as already pointed out) the coagulation time in cases of scurvy is not longer than the normal. It is more likely that the hemorrhages are in some way induced by a lowering of the alkalinity of the blood (according to the views of Ralfe and Wright as already stated in the section on Scurvy in the Adult), although no actual proof of the existence of a diminished alka- linity in cases of infantile scurvy has yet been obtained. In favor, too, of this hypothesis is the fact that the mere withdrawal from the diet of a tinned cereal food, where such is being given and which yields an acid ash, is often sufficient of itself to lead to a cure of the disease. There is therefore considerable reason to believe that a reduction of the alkalinity of the blood from a deficient supply of vegetable salts plays at least a large part in the production of infantile scurvy just as it does in the scurvy of adults. On the other hand there is much less reason to assume the existence of an infective element in the infantile form, for the infants who exhibit it are but rarely drawn from the poorer classes but, on the contrary, are more commonly the children of well-to-do parents and enjoy clean and comfortable surroundings. Morbid Anatomy. — ^The chief changes found after death, in infants who have died of infantile scurvy, are present in the neighborhood of the bones. If a section be made across a limb which has been the seat of swelling during life it will be found that the periosteum is thickened, highly vascular and separated from the subjacent bone by a layer of blood clot which may show various degrees of organization. There is, however, no sign of inflammation and as a rule no hard bone is formed in the perios- teum except in very old-standing cases. The muscles surrounding the bone may be infiltrated with blood or serum, which gives them a sodden appearance. The bone itself exhibits a considerable degree of rarefaction, the can- cellous tissue being unusually porous and the normal marrow replaced by a highly vascular connective tissue into which hemorrhages may have ^Goulstonian Lectures for 1904 on Some Disorders of the Blood and Blood-form.' ing Organs in Early Life. "^British Medical Journal, 1900, ii, p. 573. 904 COXSTITUTIOXAL DISEASES occurred. The changes characteristic of rickets may also be present in the bones. The rarefaction of the bone is apparently the result of delayed ossifica- tion and is the cause of the fractures which are not uncommonly met with in severe cases and which are usually situated a little above the epiphyseal line, although there may sometimes be separation at the line of the epij)hvseal cartilage itself. Hemorrhagic efl"usions may be met with elsewhere in addition to those around the bones, such as in the joints or in the serous cavities or sub- dural space. None of these, however, is characteristic of the disease. The internal organs exhibit no constant change. Symptoms. — Scurvy is commonest in infants of about eight to ten months old. In an analysis of 04 cases by Bovaird^ the youngest was six months old, the oldest two and a half years, the average age being twelve months. Fifty-four per cent, of the cases occurred between the ninth and thirteenth months. The children affected are usually well-nourished but often exhibit some degree of pallor. The invasion of the disease may be either gradual or abrupt. After a few days of fretfulness or after having exhibited for some time great tenderness Avhen handled, the more prom- inent symptoms appear. The most striking of these is tenderness of the legs, which causes the child to scream out when touched or even at the approach of the doctor. It can be observed that the child lies very still, usually on his back with one or both legs everted and motionless. Ex- amination in a well-marked case reveals some swelling of the bones, most commonly of the lower end of the femur or upper end of the tibia. The long bones of the upper extremities are much more rarely affected, the collective investigation in America yielding only 14 cases with swelling in the arms to 131 in which the legs Avere affected. At the site of these swellings the tenderness is extremely acute and the skin over them is often tense and glossy and may be slightly oedematous but there is no local heat. On gently handling the limb soft crepitus may be elicited, from fracture, or separation of the epiphysis. In some cases hemorrhage takes place into the orbit, giving rise to proptosis and ecchymosis of the eyelids. This symptom occurred in 49 out of 379 of the American cases. The proptosis may appear suddenly, often during a fit of crying, and in severe cases may even lead to ulceration of the cornea. Rarer sites of hemorrhage are round the ribs, clavicles, or bones of the skull. Sir Thomas Barlow has described a peculiar depression of the sternum en hloc which is present in severe cases and is apparently due to a loosening of the articulations between the sternum and ribs. Changes in the Gums. — These are not usually present unless some teeth have been cut, but even in the absence of the latter there may be a slight degree of injection and ecchymosis, especially over the sites of the incisors. Should any teeth have erupted, the gum around them is usually swollen and of a purplish color, but the change is rarely if ever so marked as in the scurvy of adults and does not often go on to ulceration. It is rare for the gums to appear normal after any teeth have appeared, but a few such cases have been observed. Other Symptoms. — Petechise and subcutaneous ecchymoses are rarely met with in infantile scurvy and hemorrhages from mucous surfaces, ^ Philadelphia Medical Journal, 1898, ii, p. 375. BCURVY 905 with the exception of the gums, are not common. Hsematuria, however, is met with not infrctjuently and a slight degree of it, at least, is probably much commoner than is generally believed. Sometimes indeed it is the only symptom present and in a few cases it apjiears to lead to nephritis^ or pyelitis. Fever is not a conspicuous feature of infantile scurvy, but where extensive hemorrhages have taken place there may be a rise of temperature which, however, rarely exceeds 101° or 102° F. Changes in the Blood. — There is usually a greater or less degree of anaemia present, especially in cases in which extensive subperiosteal hemorrhages have (occurred. The anaemia is usually of the chlorotic type, the haemoglobin being reduced out of proportion to the red cells, but where the hemorrhages have been specially severe the characters of a secondary anaemia may be exhibited as well, and the red cells are re- duced in number and some nucleated forms present. In the absence of complications no leukocytosis occurs. The chemical changes in the blood have not been fully investigated but in a series of cases examined by the writer no alteration in the coagulability could be discovered. Whether or not there is any reduction of alkalinity has not been determined. Association with Rickets. — ^The relation of scurvy to rickets has been much disputed. That the two conditions are not invariably associated is shown by an analysis of 40 fatal cases by Schoedel and Nauwerk^ in 18 of which the presence of rickets had been recognized during life, whilst it was found in 3 others after death. The frequent co-existence of rickets in cases of scurvy would seem indeed to be due merely to the fact that the kind of diet which produces the one disease is also that which tends to give rise to the other. Diagnosis. — The diagnosis of scurvy in a well-marked case is easy, provided the leading features of the disease are known to the observer. The screaming of the child on examination, the swelling and tenderness of the legs, and the condition of the gums leave no doubt as to the nature of the affection with which one has to deal. All cases, however, are not so pronounced in type. Not infrequently one encounters mild or incipient forms which it is easy to overlook. In these, tenderness when the child is handled or when he is put in his bath may be the only symptom. In other cases again, slight sponginess round the incisor teeth may alone be present or one may have to deal with an apparently causeless haematuria. In any case in which there is doubt two points will help. One is the nature of the feeding. If this has been of such a nature as is known to favor the development of the disease the diagnosis will be greatly strengthened The other point is the application of the therapeutic test. If the symp- toms present are really due to incipient scurvy then they will certainly disappear rapidly so soon as appropriate treatment is begun; if they fail to do this then one has to do with some other condition. The affections for which scurvy is most often mistaken are these: 1. Rheumatism. — ^Time and again the writer has had well-marked cases of infantile scurvy sent to him with a diagnosis of rheumatism and in one such case he has known the affected limb to be painted with iodine with the result of greatly aggravating the sufferings of the unfortunate child. The mistake should really never be made if it be remembered ^See Still, Lancet, 1904, ii, p. 441. '''Rev. des Maladies de VEnfance, 1902, xx, p. 543. 906 CONSTITUTIONAL DISEASES that below the age of one year rheumatism is practically never met with. An inquiry into the mode of feeding and a careful search for the other signs of scurvy will confirm the diagnosis, 2. Periostitis. — The distinction between scurvy and periostitis is often a matter of great difficulty, especially when the gum changes are absent. The presence of a marked degree of pyrexia is in favor of a diagnosis of periostitis, for in, scurvy, fever is usually absent or but trivial in amount. If the other signs of scurvy are present as well, the diagnosis will of course be clear but sometimes one may be obliged to fall back on the therapeutic test. 3. Infantile Paralysis. — When infantile paralysis sets in, as it some- times does, with a marked degree of hypersesthesia, it may simulate scurvy. It will be noted, however, that there is no swelling of the affected limb and that the other signs of scurvy are absent. 4. Epiphysitis. — Epiphysitis may simulate scurvy but the swelling in the latter extends along the shaft of the bone and is not confined to the neighborhood of the epiphysis. 5. The changes in the mouth may be mistaken for those of ordinary ulcerative siomaiiiis. In scurvy, however, the changes are confined to the gums whilst in stomatitis they extend to the lips and cheeks as well. The ulceration in the mouth which often occurs in acute leukaemia may also lead to a suspicion of scurvy. Here the examination of the blood will at once settle the diagnosis. 6. Cases which are characterized by hemorrhage into the orbit may be mistaken for sarcoma of the skull or for chloroma. In the former case there are usually signs of sarcoma elsewhere and in the latter the blood shows an excess of lymphocytes whilst in both the positive signs of scurvy are absent. 7. The hcematuria of scurvy is apt to be mistaken for renal hemorrhage from other causes, such as renal sarcoma. In a doubtful case of bleeding from the kidney it is therefore always well to try the effect of an antiscor- butic diet before proceeding to other measures. Prognosis, — The prognosis in infantile scurvy is quite favorable, pro- vided the disease be recognized in time and suitable treatment adopted. Nothing in therapeutics, indeed, is more striking than the rapidity with which such patients improve under a change of diet although some degree of thickening of the bones may persist for a long time. Death, when it occurs in the more severe cases, is usually the result of intercurrent diseases, of which bronchopneumonia and chronic liarrhoea are the most frequent, although sudden hemorrhage, cardiac failure, or exhaustion, may occasionally lead to a fatal issue. Treatment, ^ — This consists solely in altering the diet. Tinned foods and sterilized milk must at once be stopped and the child put upon a due allowance of unboiled milk. Fruit juice should be added, a few teaspoon- fuls of grape or orange juice sweetened with a little sug::.r being given daily. Baked potato is also useful, a little of the floury part under th:; skin being rubbed up v^ith the milk into a thin cream which is either added to the bottle or given separately (two teaspoonfuls three or four times a day). Raw meat juice is certainly of value. It may be gi\on in quantities of half an ounce daily. Drugs are of little service though the vegetable BCURVY 907 salts of potash certainly exert a certain curative influence. During the period of convalescence cod-liver oil and iron are helpful. Scorbutic infants should be handled carefully and the clothing should be so constructed that it can be easily taken off and on. If it is necessary to move the child about he should be placed on a pillow. The affected limb should be steadied by light splints or wrapped in wet towels, which, if allowed to dry in position, afford considerable support. In mild cases a casing of cotton wool secured by a light bandage will be sufficient pro- tection. INDEX. Abdomen, actinomycosis of, 333 Abscess, filarial,- 616 hepatic, diagnosis of, from mala- rial levers, 437 of liver in amoebic dysentery, 513 of lung in amoebic dysentery, 516 of spleen in amoebic dysentery, 516 Abnormalities in processes of oxidation, 280 Absinthism, 195 chronic, 196 Acanthocephah, 531, 582, 604 Acanthrotrias, 575 Acariasis, 533, 626, 631 demodectic, 630 parasite of, 630 symptoms of, 630 sarcoptic, 627 diagnosis of, 629 frequency of, 628 parasites of, 627 symptoms of, 628 treatment of, 629 Acarina, 531, 626 Acarus folliculorum, 630 Acephalocystis, 576, 578 "Acetone bodies," 700 complex, 322 action of intoxication in, 325 associated with low carbo- hydrate combustion, 323 in cachexia, 323 and carbohydrate metabolism, 322 not deranged, 323 with disturbances of protein metabolism, 324 in febrile diseases, 323 with normal qualitati^'e carbo- hydrate metabol- ism, 323 ■protein metabolism, 323 without quantitative altera- tions in metabolism, 323 in starvation, 323 in urine in diabetes mellitus, 778 Acid intoxication, in scurvy, 894 Acidosis, 294, 716 in childliood, 295 in diabetes mellitus, 786 treatment of, 796 explanation of, 295, 325 and lactic acid, 295 Acquired immunity, 44 Acromegaly, diabetes mellitus and, 752 Actinium rays, 63 Actinomyces bovis, 327, 330 Actinomycosis, 327 of abdomen, 333 of brain, 332 clubs in, 328, 336 cutaneous, 334 diagnosis of, 335 etiology of, 328 filaments in, 328 of head, 332 of lungs, 333 metastasis in, 332 of neck, 332 pathology of, 331 prognosis of, 337 recurrence of, 339 symptoms of, 334 of thorax, 333 treatment of, 338 Adiposity, 845. See Obesit3^ Adrenalin diabetes, 758 ^stivo-autumnal fever, 392. See Malarial fevers, parasites, quotidian form, 398 tertian form, 399 Agamodistomum ophthalmobium, 556 Agamofilaria, 582 georgiana, 623 oculi, 623 Agchylostoma, 582, 583 duodenale, 582 Ague, 392. See Malarial fevers. Air, 69 hunger in diabetic coma, 784 pathological effects of, 69 physiological effects of, 69 Albuminuria in diabetes mellitus, 779 gastro-intestinal, due to auto- intoxications, 279 in gout, 831 in malarial fe^er, 431 (909) 910 INDEX Albuminuria in obesity, 854 Alcohol in metabolism, 675 Alcoliolic trance, 194 Alcoholism, 157 ajje at death from, 109 arteriosclerosis in, 170 cardiac lesions in, 170 chronic, 192 symptoms of, 193 treatment of, 200 etiology of, 157 lieredity in, 159, 177 infantilism and, 178 infectious diseases and, 176 kidneys in, 172 liyer in, 171 neryous system in, 173 neuritis in, 175 pathological effects of, 168 pathology of, 100, 169 relation of age to, 159 of occupation to, 158 of season to, 160 stomach in, 173 tuberculosis and, 170 Algid form of malarial feyer, 424 Alimentary glycosuria. 762 tract, substances formed by bac- teria from normal food \vithin, 272 Alkaptonuria, metabolism in, 713 excess of protein, 305 Allantiasis, 232 Alloxuric bodies, 812 in urine in diabetes mellitus, 779 Alopecia from x-rays, 60 Amblyomma americanum, 627 dissimile, 627 Amentia in chronic alcoholism, 199 Amino-acids, metabolism of, 712 Ammonia, elimination of, 709 in acidosis, 716 relation of, to ursemia, 305 in urine in diabetes mellitus, 779 intoxications due to, 298 Amnesia in alcoholic trance, 194 in morphinism, 212 Amoeba coli, 495, 532 discoyery of, 488 forms of, 496 dysenteria;, 495, 532 AmoebEe of human intestine, 491 behayior of, toward chem- ical substance, 492 physical condi- tions, 492 biological properties of, 491 classification of, 494 cultiyation of, 491 distribution in body, 494 AmoebfB of human intestine, physio- logical processes of, 493 yarieties of, 494 inoculation experiments with, 500 methoil of reaching the liyer, 514 mode of infection with, 501 non-recurrence of, in stools of dysenteric patients, 500 recurrence of, in healthy persons, 498 in stools of patients with other diseases than dysentery, 500 recognition of, 519 source of, 501 Amoebiasis, 488. See Dysentery, amoe- bic. Amoebic colitis, 488. See Dysentery, ama?bic. dysentery. See Dysentery, amoe- bic, enteritis, 488. See Dysentery, amoebic. Amphimixis in inheritance, 45, 46 Amphinuclei, 355 Amphistoma hominis, 549 Amyl alcohol, 162 Anabolism, 639 Anaemia in amoebic dysentery, 512 brick-makers', 582 due to auto-intoxication, 279 in infantile scuryy, 905 in malarial feyers," 408, 431, 582 miners', 582 in rickets, 884 tunnel, 582 AnaBmias, essential, excess of protein metabolism in, 302 suboxidation in, 284 Anchilostoma duodenale, 584 Anchylostoma duodenale, 584 Anchylostomiasis, 584 Anders' dietary treatment of obesity, 860 Aneurism of abdominal aorta, diabetes insipidus and, 802 of carotid artery, diabetes insipidus and, 802 in gout, 832 Angina pectoris in gout, 832 in obesity, 855 Anguillula, 582 aceti, 024 Anguilluliasis, 595 Anguillulina, 582 putrefaciens, 002 Animal parasites, 525 age and, 527 bil)liography of, 533 classes of, 520 classification of, 530 definition of, 525 diagnosis of, 529 fertility of, 527 INDEX 911 Animal parasites in fish, 228 frequency of, 520 heredity and, 528 identification of, 533 infection with, f!;cncric, 529 specific, 529 influence on host, 528 origin of, 528 periodicity of, 527 prevention of, 530 resistance of, 527 sex and, 527 terminology of, 533 Ankylostoma duodenalc, 584 Ankylostomasis, 582 Ankylotoinum americanum, 583 Anomalies, gross, inheritance of, 26 probably of defect, inheritance of, 26 Anopheles, albipes, 386 argyritarsis, 386 barberi, 386 bifurcatus, 378 crucians, 378, 385 ferruginosus, 383 franciscanus, 386 heimalis, 383 life history of, 379 maculipennis, 378, 383 nigripes, 383 pictus, 383 punctipennis, 378, 385 quadrimaculatus, 383 species of, 383 walkeri, 383 Anthomyia canicularis, 637 Antivenin, 263 Anuria without intoxication, 292 Apoplexy, diagnosis of, from malarial fevers, 437 in gout, 832, 833 _ Appendicitis in amoebic dysentery, 517 diagnosis of, from malarial fever, 428 Appetite, loss of, in amoebic dysentery, 512 Argas miniatus, 627 persicus, 627 reflexus, 627 Argasidse, 626 Argopsylla gallinacea, 633 Argyria, 136 diagnosis of, 137 patiiology of, 136 prognosis of, 137 prophylaxis of, 138 symptoms of, 137 treatment of, 138 Arsenic, detection of, in urine, 122 eating, 117 immunity to, 118 poisoning, 114 ataxia in, 121 Arsenic poisoning, diagnosis of, 121 erythromelaigia in, 119 etiology of, 1 14 eye manifestations in, 120 from l)(;(!r, 1 16 clotiiing, 115 foods, 115 occupation, 116 wall paper, 114, 115 herpes in, 119 keratosis in, 119 medicinal, 114, 116 mode of entrance of, 118 nervous lesions in, 1 17 pain in, 120 paralysis in, 120 diagnosis of, 122 pathogenesis of, 118 pathology of, 117 pigmentation in, 119 prognosis of, 122 prophylaxis of, 122 sensory disturbances in, 120 skin lesions in, 119, 120 symptoms of, 119 treatment of, 123 susceptibility to, 118 Arteriosclerosis, diabetes mellitus and 757 in gout, 828, 832 in obesity, 852 Artificial nutrition, 745 Ascariasis, 596 diagnosis of, 599 distribution of, 596 frequency of, 597 infection in, 597 parasites in, 597 symptoms of, 598 treatment of, 599 Ascaris, 532, 582 capularia, 526 lumbricoides, 597 maritima, 597 texana, 597, 598 trichuria, 603 vermicularis, 600 Aspergillosis, pulmonary, 350 definition of, 350 diagnosis of, 352 etiology of, 350 pathology of, 351 prognosis of, 352 symptoms of, 352 treatment of, 352 Aspergillus, 350 Asphyxia, diabetes mellitus and, 752 Asthma, cardiac, in obesity, 854 dyspepticum due to auto-intoxi- cations, 279 in gout, 832 Atavism, 31 Atrophy of skin from x-rays, 59 912 IXDEX Auto-intoxications, 206 associated with carbohydrate metal)olisin, 815 with I'at metabolism, 321 with i>rotein metabolism, 297 - with purin metabolism, 30,S asthma dyspepticum, 279 chissilication of, 267 definition of, 26() diseases of the nervous system, 279 due to constipation, 27S to ner\ous dyspepsia, 278 from bacterial products, 273 cytolysis, 2GS excessiA-e protein inges- tion, 300 gastro-intestinal, 270 albuminuria, 279 ana-mias, 279 metabolisin and, 268 tetany, 277 Autolysis, 715 Automatism, 194 Autotyphization, 308 B Bacillus botulinus, 232, 233, 244 breslaviensis, 238 enteritidis, 227, 237, 240, 242 agglutination of, 239 friedebergensis, 236 morbificans bovis, 236 paratyphosus, 232, 240 piscicidus, 224 agilis, 225 Bacteria in milk, 241 in shell-fish, 229 Bacterial fish poisons, 224, 228 Bacteriology of rickets, 874 Banting's dietary treatment of obesity, 857 Basedow's diseases, diabetes mellitus and, 752 Bed-bugs, 635 extermination of, 636 Benzol deri\-atives, 274 Bernard's diabetic centre, 752 Big jaw, 327 Bile, toxicity of, 287 Billiarzia capensis, 550 disease, 550 ha-matobia, 550 Bilharziosis, 550 Bilious malarial fe^•er, 425 Biopliores in inheritance, 37, 38, 42, 43, 46 Black-water fever, 449 blood in, 456 15hick-water fe\-or. bone-marrow in, 455 lirain in, 455 (lelinition of, 449 tliagnosis of, 457 tlistribution of, 449 etiology of, 455 jauntlice in, 456 leukocytes in, 457 malarial fe\'er and, 450 origin of. 454 morl)id anatomy of, 455 prognosis of, 458 quinine anil, 454, 458 symptoms of, 456 treatment of, 458 urine in, 456 Blastomycetcs and malignant tumors, 327 Hlastomvcetic dermatitis, 346 r>lastomycosis, 346, 350 lilendi'd inlieritance, 29, 34 Hlepharoplast, 356 Blood in black-water fe\-er, 456 clotting components of venom, 255 deficiency of potassium in scurvy, 894 in diabetes mellitus, 769 dimiruition in alkalinit)^ of, in scurvy, 894 examination of, in malarial fe\ers, 433 fluke infection of, 550 African, 550 Asiatic, 550 in gout, 825 alkalinity of, 820, 822 in human trypanosomiasis, 480 in uncinariasis. 590 uric acid in, 817 in gout, 819 origin of excess of, 820 Blue line in lead poisoning, 99 Body, mechanical efficiency of, 662 Boils in diabetes mellitus, 780 Bone-marrow in black-water fever, 455 in malarial feAers, 413 Bones, curvature of, in rickets, 877 in lead poisonmg, 102 Boophilus annulatus, 626, 627 Bothriocephalus cordatus, 569 cristatus, 567 latus, 533 Botulismus, 233 symptoms of, 234 toxin in, 234 /?-oxybutyric acid in urine in diabetes mellitus, 777 amount of, 786 source of, 787 liradycardia in obesity, 852 Brain, actinomycosis of, 332 in black-water fever, 455 INDJ'JX 913 Brain, changes in, in rickets, (S72 in diabetes mellitus, 770 in malarial fevers 410 traumatism of, diabetes insipidus and, 801 Brass poisoning, 138 worker's ague, 139 Breads, composition of, 738 digestion of, 738 Broad tapeworm, 567 description of, 567 diagnosis of, 568 distribution of, 567 frequency of, 568 infection by, 568 features of, 568 prevention of, 568 Bronchitis, chronic, in gout, 828, 832 in rickets, 884 Bronchopneumonia in diabetes melli- tus, 770 in rickets, 885 Bronze diabetes, 756 Budding of protozoa, 356 Bunostumom, type trigonocephalum, 583 Burns, 77 conditions with, 291 electrical, 67 pathogenesis of, 78 pathology of, 78 treatment of, 78 x-ray, 59 Cachexia of malignant diseases, excess of protein metabolism in, 302 miners', 582 strumipriva, suboxidation in, 283 suboxidation in, 284 Caisson disease, 72 pathogenesis of, 73 pathology of, 73 prevention of, 75 prognosis of, 73 symptoms of, 73 treatment of, 74 Calabar swellings, 621 Cameroon fever, 392. See Malarial fevers. Cancer of liver, associated with flukes, 543 diabetes insipidus and, 802 from x-rays, 60 Caput quadratum, 880 Carbohydrate assimilation, 316 combustion, low acetone complex associated with, 323 influence of, on proteid metabolism, 673 metabolism, 315, 689 58 Carbohydrate metabolism, acetone complex not deranged in, 323 auto-Intoxication associated with, 315 normal ciualitative, acetone complex with, 323 starvation, 316 Carbon bisulphide; poisoning, 149 diagnosis of, 154 etiology of, 149 hysteria and, 154 industrial, 149 mode of entrance of, 151 motor disturbances in, 153 pathogenesis of, 151 pathology of, 150 prognosis of, 155 prophylaxis of, 155 psychoses in, 153 sensory disturbances in, 152 symptoms of, 151 treatment of, 155 tremor in, 152 dioxide, excretion of, 680, 682 retention of, 288 monoxide poisoning, 141 accidental, 143 acute coma in, 145 diagnosis of, 147 I by blood changes, 147 etiology of, 141 from furnaces, 142 house epidemics of, 145 industrial, 142 metabolism in, 693 mode of entrance of, 144 pathogenesis of, 144 pathology of, 144 polycytha?mia in, 147 prognosis of, 148 sequelae of, 145 in nervous system, 146 symptoms of, 145, 146 treatment of, 148 Carbuncles in diabetes mellitus, 780 treatment of, 798 Cardiac asthma in gout, 832, in obesity, 854 Cardiovascular lesions in gout, 828 system in lead poisoning, 100 Caries of spine, diagnosis of, from rick- ets, 886 Catabolism, exaggerations of, 266 Cataract in diabetes mellitus, 783 Catarrh, gastro-intestinal, in rickets, 885 Cayor worm, 637^ Cellular exudates, excess of protein metabolism in, 303 Centronuclei, 355 914 IXDEX Cerebellum, tumors of, (li;\l)etcs mcllitus antl, 752 Cerebral heniorrluige, dial)ctc's mollitus and, 752 symptoms of Icail poisoning;, 106 tumors, dialictos insipidus and, SOI Cerebrospinal fluiil, trypanosoma Gam- I)iensc in, 471 C(-stoda, 531. 557" Cestode infection, 557 Chalk-sfonos, S27, 829 Choose, poisonous, 242 Chemical ajionts, diseases due to, S3 properties of venoms, 252 Chemistry of rickets, S72 Che\iie-Stokes respiration in obesity, S54 Chicken mites, G31 CliigGier, G33 Chigol, (533 Chloroma, diagnosis of, from infantile scurvy, 900 Cholorosis, Egvptian, 582 tropical, 582 Choleraic malarial fe\'er, 424 Chromitlien, 364 Chromosomes in inheritance, 37 Chvostok's sign in rickets, 883 Chvloccle in filariasis, 618 Chyluria, fihxrial, 618 malarial, 618 Cimex lectularius, 635 Circumscriljod obesity, 855 Cladorchis watsoni, 549 Cladothrix, 342 Climatic fever, 392. See Malarial fevers. Clonorchis Looss, 1907, new name based on opit>iltorchis .sinensis endcnricus, for Japanese species sine7isis, for Chinese species Coast fever, 392. See Malarial fevers. Cocaine, effects of, 220 history of, 217 poisoning, 217 acute, 218 diagnosis of, 221 etiology of, 218 prognosis of, 222 treatment of, 222 psychosis, 221 Coccidioidal granuloma, 346 Coccidium Schubergi, life-cycle of, 365 Co-efficients of a^ailaljilitv of nutrients, 653 Coenurus, 559 Cold, effects of, 79, 80, 81 patliogenesis of, SO pathology of, 80 prognosis of, 80 treatment of, 80 Colic in lead poisoning, 101 treatment of, 112 Colica pictonum, 84 Coma, diabetic, 784 in gout, 833 Comatose malarial fever, 423 Combustion products, poisoning by, 141 diagnosis of, 147 etiology of, 141 mode of entrance of, ,144 jiathogenesis of, 144 jiathology of, 144 prognosis of, 148 symjitoms of, 1 15 treatment of, 148 Commensalism, 525 Compsomyia macellaria, 637 Conditions truly inherited, 25 ex-specie, 25 familial, 25, 26 racial, 25, 26 Congenital rickets, SS9 symptoms of, 890 treatment of, 890 syphilis, 23 Conjugal diabetes, 749 Conjuncti^■itis in gout, 831 Conorhinus sanguisuga, 635 Conservation of energy, 656, 658 Constipation and auto-intoxication, 278 in diabetes mellitus, 781 in gout, 831 in obesity, 853, 854 in scur\-y, 898 Constitutional diseases, 747 Consumption, negro, 582 Convulsions in riclcets, 882 Copper poisoning, 138 pigmentation in, 139 (brpulence, metaljolism of, 700 Corpulency, 845. See Obesity. Coxa vara, 877 Oaniotabes in rickets, 881 Cranium in riclcets, 879 Creatinin, metabolism of, 709 Crenocephalus canis, 634 Cross-breeding, 30 Ctenoccphalus canis, 634 Culex, discolor, 377 dupreei, 377 fasciatus, 388 fatigans, 373 life history of, 373 perturbans, 376 pipiens, 373 sollicitans, 375 squamiger, 376 sjdvestris, 376 ta?niatus, 388 ta?niorhynchus, 376 territans, 377 triseriatus, 377 Cutaneous eruj)tions in gout, 831 Cysticercosis, 560, 562, 574 INDEX 915 Cysticercosis, parasite in, 575 symptoms of, 575 Cysticercus acanthotrias, 575 bovis, 559, 560, 5()3, 575 cellulossc, 527, 530, 5G1, 503, 574, 575 fasciolaris, 532, 563 pisiformis, 563 racemosus, 575 tiBiiise mediocancllattc, 560 saginata;, 560 tenuicollis, 575 Cystinuria, metaljolism in, 304, 713 Cystitis in diabetes mellitus, 770 Cytolysis, acceleration of, 267 Davainea asiatica, 557, 566 madagascariensis, 557, 566 Degeneration and degenerates, 32 Delirium in gout, 833 tremens, 178 etiology of, 178 hallucinations in, 182 influence of season on, 179 trauma on, ISO mental processes in, 182 mortality in, 186, 187 nervous system in, 175 orientation in, 184 prognosis of, 187 symptoms of, 180 meningeal, 186 treatment of, 187 tremor in, 184 Demodex folliculorum, 630 hominis, 630 Dentition, delayed, in rickets, 875 Dermacentor electus, 627 occidentalis, 626, 627 reticulatus, 627 Dermanyssus gallinaj, 631 horundinis, 632 Dermatitis blastomycetic, 346 coccidioides, 346 protozoic, 346 a;-ray, 59 Dermatobia hominis, 637 Determinants in inheritance, 37 Diabetes in gout, 833 hunger, 759 insipidus, 799 age in, 799 classification of, 803 definition of, 799 diabetes mellitus and, 803 diagnosis of, 805 etiology of, 799 hemianopsia and, 802 heredity in, 799 Diabetes insipiflus, incidence of, 799 morbid anatomy of, 805 [prognosis o\, 805 symptoms of, 803 appetite, 804 polyuria, 803 thirst, 801 syphilis and, 802 theories as to cause of, 805 thirst in, 804 trauma and, 801 treatment of, 800 urine in, 803 mellitus, 747 acute, 771, 787 adrenalin, 758 age in, 750 albuminuria in, 779 alcohol in, 794 appetite in, 772 arteriosclerosis and, 757 blood in, 769 boils in, 780 bread in, substitute for, 793 carbuncle in, treatment of, 798 cataract in, 783 chronic, 771, 778 pancreatitis and, 755 complications of, 780 constipation in, 781 conjugal, 749 course of, 787 definition of, 747 diabetes insipidus and, 803 diagnosis of, 788 from alkaptonuria, 788 from glj'cosuria, 788 from pentosuria, 788 diet in, 790 potatoes in, 793 diseases of liver and, 757 of pancreas and, 754 disturbances of metabolism in, 760 emaciated, 771 endogenous, 771 etiology of, 748 predisposing factors, 748 exogenous, 771 experimental pancreatic, 753 fat, 771 gangrene in, 781 treatment of, 798 gastro-intestinal tract in, 769 glycolytic ferment and, 767 heart "in, 770 hemiplegia in, 783 hepatic lesions and, 757 hereditv and, 749 historj^'of, 747 incidence of, 748 islands of Langerhans in, 754 kidneys in, 770 916 IXDEX Diabetes mellitus, liprrmia in, 7G9 liver in, 770 nieiitiil changes in, 783 mild, 771 nervous system and, 752, 770 neurotic, 771, 782 nutrition in, 772 obesity an,d, 750 pancreatic lesions and, 754 paraplegia in, 783 pathology of, 769 phlebitis'in, 781 phloridzin, 758 posterior sclerosis in, 770 pregnancy in, 78-1 prognosis of, 787 pruritus in, 781 treatment of, 798 pseudo-tabes in, 782 pulmonary lesions in, 770 tulicrculosis in, 782 race and, 748 reflexes in, 783 renal, 758 retinitis in, 783 severe, 771 sex in, 750 symptoms of, 771 increased appetites, 772 polyuria, 771 thirst, 772 urine, 773 syphilis and, 751 theories of, 766 over-production, 766 under-consumption and deficient oxidation, 766 toxins and, 759 traumatic, 752, 788 treatment of, 789 dietetic, 790 hygienic, 790 medicinal, 794 milk in, 797 prophylactic, 789 urinary casts in, 780 urine in, 773 xanthoma in, 781 metabolism in, 318 phosphatic, 779 Diabetic coma, 784 alcoholic form, 785 collapse from, 785 dyspncric, 784 explanation of, 785 frequency of, 785 sugar excretion in, 787 treatment of, 796 alkalies in, 796 Diacanthos polycephalus, 526 Diacetic acid in urine in diabetes melli- tus, 778 Diarrhoea in diabetes mellitus, 781 Diarrhoen in gout, 833 in obesity, 853 in rickets, 885 in scurvy, 898 Diatheses, inheritance of, 27, 49 Dibothriocephalus cordatus, 557, 558 569 latus, 557, 558, 560, 562. 567, 570 Dibothrium latum, 567 I)icroC(eIium, 540 lanceolatum, 545 sinense, 541 Diet, 721 amount of, 723 of carliohydrate in, 731 of fat in, 731 of proteitl in, 724 animal, objections to, 741 characteristics and, 741 cures, 743 in dial)ctes mellitus, 790 fads, 743 fruitarian, 743 hypernutrition, 744 inorganic salts in, 734 proteid-fat, 744 required in, 723 in rickets, 886 in scurvy, 900, 902 statistics of, 722 systems of, 740 vegetal )les in, 739 vegetarian, 743 Dietetics, 721 Digestion, abnormal, products of, 271, 275 energy required for, 682 normal, products of, 271 Digestive tract, lead poisoning in, 100 juices, intoxication by absorption of, 270 Dilepis, 566 Dioctophyme, 582 renale, 624 Diplogonoporus grandis, 557, 569 Dipsomania, 194 Dipterous infection, 637 Dipylidium caninum, 529, 557, 567, 574, 634 Dirt eating, 582 Disintoxication, 286 Distoma (or distomum), 535 haematobium, 550 hepaticum, 546 japonicum, 541 pulmonale, 536 pulmonis, 536 pulmonum, 536 ringeri, 536 sinense, 541 spathulatum, 541 spatulatum, 541 INDEX 917 Distoma westermanii, 536 Distomatosis, 535 Distomiasis, 533, 535 cerebral, 538 hepatic, 535, 538, 540 intestinal, 535, 548 parasites in, 549 ophthalmic, 535, 556 pulmonary, 53G, 537, 538, 539 renal, 535, 550 blood in, 555 diagnosis of, 554 distribution of, 550 frequency of, 551 hajmaturia in, 551 infection in, 551 parasites of, 550 pathology of, 554 prevention of, 555 prognosis of, 553 symptoms of, 551 treatment of, 555 varieties of, 535 Diver's paralysis, 72. See Caisson disease. Dochmiosis, 582 Dochmius duodenalis, 584 Dominant inheritance, 35 Dracontiasis, 611 Dracunculosis, 611 distribution of, 611 frequency of, 612 infection in, 611 parasite of, 611 prevention of, 613 symptoms of, 612 treatment of, 612 Dracunculus, 582 loa, 620 medinensis, 611, 624 oculi, 620 Drunkenness, pathological, 194 Dwarf tapeworm, 564 description of, 564 distribution of, 564 frequency of, 564 infection by, 564 features of, 565 prevention of, 565 treatment of, 565 Dynamic replacement of nutrients, 662 Dysenteric malarial fever, 425 Dysentery, amoebic, 488 abscess of liver in, alcohol and, 513 appendicitis and, 514 bacteriology of, 514 brain abscess and, 516 diagnosis of, 515, 519 intestinal haemor- rhage and, 518 leukocytosis in, 516 Dysentery, amoebic, abscess of liver in, pathology of, 515 j)rognosis of, 520 rupture of, 516 symptoms of, 515 thrombosis and, 516 time of onset, 513 treatment of, 524 of lung in, diagnosis of, 520 occurrence 'of, 517 pathology of, 516 symptoms of, 516 amojbaj in f:cces of, 511 bacteriology of, 502 blood in stools of, 511 complications of, 513 course of, 509 definition of, 488 diagnosis of, 518 distribution of, 489 early lesions in, 503 etiology of, 489 gangrene in, 505 healing of ulcers in, 505 histological changes in, 506 immunity from, 520 intestinal adhesions in, 506 mild form of, 508 onset, acute, in, 509 organisms other than amoeba in, 502 pathology of, 503 intestines in, large, 503 small, 507 kidneys in, 507 lymphatic glands in, 507 peritonitis in, 506 prognosis of, 520 season and, 490 sequelae of, 518 sex and age in, 490 spontaneous recovery in, 508 symptoms of, 507 abdominal pain in, 511 anaemia in, 512 faeces in, 510 fever in, 512 gastro-intestinal, 510 hiccough, 512 loss of appetite, 512 nausea and vomiting, 512 pulse in, 513 respiration in, 513 skin in, 512 urine in, 513 synonyms of, 488 tenesmus in, 512 treatment of, 521 of complications, 524 curative, 523 dietetic, 521 general, 521 918 INDEX Dysentery, amoeliic, Iroatinont of, by irrifiatioiis, 523 prophvlactic, 521 results of, 520 symptomatic, 521 ulcers in, 504 Dyspepsia, nervous, auto-intoxical ions "and, 278 Dyspna\a in pout, 833 Dyszooamylie, 705 E Ebstein's dietary treatment of obesity, 858 Ecchymoses in scurvy, 898 Echinococcosis, 576 diapinosis of, 580 distril>ution of, 576 duration of, 579 frcriuency of, 578 parasite in, 576 prevention of, 580 symptoms of, 579 treatment of, 5S0 Echinococcus, 576 altricipariens, 571 alveolaris, 577 cysticus, 576 disease, 576 endogena, 578 exogena, 578 granulosus, 574, 576, 578 multilocularis, 577 hominus, 578 hydatidosus, 578 multilocularis, 577, 578 exulcerans, 577 osteoklastes, 577 polymorphus, 576 scolecipariens, 578 unilocularis, 576 veterinorum, 578 Echinococcifer echinococcus, 576 Echinorhj'nchus gigas, 601 hominis, 604 moniliiormis, 604 Ectoparasites, 526 Eczema in gout, 831 Eehvorm infection, 596 Electrical shock, consequences of, 65 Electricity, 64 accidents from, treatment of, 68 burns from, 67 death from, 65 eye lesions from, 66 injury from, 64 Elephantiasis in filariasis, 618 Elephantoid fever, 616 Emphysen:a in gout, 828, 832 Encephalomalacia, chronic, diabetes mellitus and, 753 Encephalopathy in load poisoning, 106 treatment of, 113 Endocarditis, ulcerative, diagnosis of, from malarial fe\ers, 437 Eiuloparasitt's, 526 Energy, l)alance of, 657 conservation of, 656, 658 metaljolism of, 650 methods of study of, 652 ([ualitative relations of, 651 quantitative relations of, 651 muscular, source of, 683 relation of carbohydrate to, 683 of fat to, 686 output of, 657 patns of discharge of, 660 psychical functions and, 050, 663 transformation of, 650 Entamceba coli, 525, 526 dysenteria*, 497 histolytica, 525, 526 Entozoa, 526 Enzjrmes, in carbohydrate metabolism, 692, 763 fat metaljolism and, 096 intracellular, 715 pathological processes and, 715 purin mctaliolism and, 711 uric acid and, SI 6 xanthin bases and, 814 Epilepsy, diabetes mellitus and, 752 Epiphysitis, diagnosis of, from infantile scurvy, 906 Epistaxis in scurvy, 898 Ergot poisoning, 243 Ergotismus, 243 Ethyl alcohol, effects of, 163 influence of, on body tempera- ture, 164 meta]:)olisni of, 166 poisoning, 163 death from, 168 pathology of, 168 subnormal temperature in, 164 Eustrongylus gigas, 624 Exclusive inheritance, 35 Excreta, origin of, 689 Exophthalmic goitre, excess of protein metaljolism in, 302 Eye lesions from electricity, 06 from .T-rays, 00 symptoms of lead poisoning, 107 Facial irritability in rickets, 883 F;eces in amoabic dj^sentery, 510 Fasciola, 540 INDEX 919 Fasciola gigantiea, .539 hepatica 510, 542, 54G, 547 huniana, 54 (J Fascioliasis, 535, 540, 54G symptoms of, 547 treatment of, 548 Fasciolopsis buskii, 549 complications in, 548 diagnosis of, 548 forms of, 548 frequency of, 546 infection in, 54G parasite of, 540 rathouisi, 549 Fat, absorption of, 695 changes of, in cells, 698 formation of, in boily, G97 from carbohydrate, 697 from proteid, 698 influence of, on proteid metabolism, 673 metabolism, 321, 695 auto-intoxication associated with, 321 suboxidation of, 322 superoxidation of, 322 tapeworm, 558 Fatness, 845. See Obesity. Feeding, metabolism during, 671 Fever, elephantoid, 616 of digestion, 271 excess of protein metabolism in, 303 Filaria, 582, 624 bancrofti, 613, 615, 616, 619, 620, 621, 624 bourgii, 620 conjunctivae, 614, 623 cystica, 600 demarquayi, 614, 622 dermathemica, 615 diurna, 614. 615, 620, 621 equina, 614, 623 faniguchi, 622 gigas, 614, 624 hominis oris, 614, 623 immitis, 614, 623 kilimariB, 614, 623 labialis, 614, 623 larvae of, 613 lentis, 614, 623 loa, 614, 615, 620, 621 magalhaesi, 614, 622 nocturna, 614, 615 oculi, 620 ozzardi, 614, 622 perstans, 614, 622 philippinensis, 613, 614, 624 powelli, 614, 624 restiformis, 614, 623 romanorum orientalis, 614, 624 sanguinis diurna, 620 hominis, 613, 615 Filaria sanguinis major, 620 subcoiijunctivalis, G20 tanigucliii, 614, 620 traclicalis, 610 varieties of, 613 volvulus, 622 wuchcreria, 615 Filariasis, 613 abscess in, 616 chylocele in, 6bS chyluria in, G18 diagnosis f>r, 619 distribution of, 615 elephantiasis in, 618 frequency of, 616 infection in, 616 loa infection, 620 distril)ution of, 620 parasite in, 620 symptoms of, 621 treatment of, 621 h^mpli scrotum in, 617 lymphangitis in, 616 orchitis in, 618 prevention of, 620 symptoms of, 616 treatment of, 620 varices in, 617 varicose glands in, 617 Fish, poisonous, 223 Fit of the gout, 829 Flagellate tetramitus rostratus Perty, stages of, 357 Fluke-worm infections, 535 Fleas, burrowing, 633 infection with, 633 jigger, 633 jumping, 633 Food accessories, 733 artificially prepared, 745 cellulose in, 740 cereal, composition of, 736 proteid content of, 736 changes in, by cooking, 732 composition of, in relation to nutri- tion, 735 normal, substances formed by bac- teria within alimentary tract, 272 poisons, 223 preparation of, 732 purin content of, 735 suspected, examination of, 245 Foodstuffs, available, 653 energy, potential, of, 679 Frost-bite, pathologj- and pathogenesis of, 80 prognosis of, 80 treatment of, SO Fruitarian, diet of, 743 Furia infenialis, 526 Fuscaria, 532 Fusel oil, 162 920 INDEX Gallstone colic, diabetes mellitus anci, 7o2 due to liver flukes, 543 Gamniarus pulex, 526 Galton's la^v, 35 Ganglia, sympathetic, dialietes melli- tus and, 753 Gangrene in amtebic dysentery, 505 dial)etic, 7S1 treatment of, 798 of huig in scurvy, 899 from x-rays, 60 Gastrodiscus hominis, 549 Gastro-intestinal albuminuria due to auto-intoxications, 279 anaemias, 279 asthma dyspepticum, 279 auto-intoxication, 270 tetany, 277 catarrh in rickets, 885 constipation, 278 diseases of nervous svstem, 279 nervous dyspepsia, 278 symptoms in amcebic dysen- tery, 510 tract in diabetes mellitus, 769 Gastrophilus, 637 Gelatin, influence of, on proteid metab- olism, 674 Gemmation of protozoa, 356 Generative organs, effects of rr-rays on, 60 Genito-urinary system^, lead poisoning in, 102 Geophagia, 582 Gigantorhynchus gigas, 604 moniliformis, 604 Glaucoma in gout, 833 Glossina palpalis, 473 distribution of, 476 Glucose, overproduction of, diabetes mellitus and. 766 under-consumption of, diabetes mellitus and, 766 Glvcerin in urine in diabetes mellitus, 777 Gh'ciphagus domesticus, 631 prunorum, 631 GycocoU and gout, 823 Glvcogen-formation, metabolic theorv of, 691 metaljolism of, 691 in urine in diabetes mellitus, 780 Glycolysis, 693 Gh'colytic ferment, diabetes mellitus and, 767 Glycosuria, 317 alimentary, 691, 762 e mnylo, 763 e saccharo, 763 Glycosuria in gout, 833 in obesitj', 854 Glycuronic acid, metabolism of, 693 in urine in diabetes mellitus, 777 Gnat fever, 392. See Malarial fevers. Gnathostomum, 582 siamensc, 611 Goitre, exoplitlialmic, excess of protein metal)olism in. 302 Gonliacea, 531, 582, 604 Gordius aquaticus, 623 Gout, 80S acute. 828 alimentarv tract in, 831 arthritis in, 826, 828, 829, 833 as aTi auto-intoxication, 314 biurate deposition in, 826, 834 blood in, 825, 829 alkalinity of, 820 calculi in, 831 chalk-stones in, 829 chemistrv of, 824 chronic, 829 complications of, 832 cardiovascular, 832 diabetes, 833 glvcosuria, 833 renal, 832 retrocedent, 833 definition of, 808 diabetes and, 751 diagnosis of, 833 etiology of, 809 metabolic causes, 811 uric acid, 812, 818 predisposing causes, 809 age, 809 alcohol, 810 exercise, 810 food, 810 hereditary, 809 lead, 811 occupation, 811 physique, 811 race, 809 sex, 809 traumatism, 811 glj^cosuria in, 833 heart in, 832 history of, 808 incidence of, 808 irregular, 830 local necrosis in, 823 lungs in, 832 metaboHsm in, 313, 811, 818 nephritis in, 827 nervous manifestations in, 831 theory of, 823 obesity and, 846 ocular changes in, 831 pathology of, 825 blood, 825 INDEX 921 Gout, pathology of, cardiovascular lesions, 828 joint changes, 82G kidneys, 827 respiratory system, 828 prognosis of, 835 purin bases, relation of, to, 823 metabohsm in, 714 relation to lead poisoning, 102 retrocedent, 833 skin in, 831 symptoms of, 828 acute, 828 chronic, 829 irregular, 830 alimentary disorders in, 831 cardiac manifestations in, 832 cutaneous eruptions in, 831 nervous manifestations in, 831 ocular manifestations in, 831 pulmonary features of, 832 urinary disturbances in, 831 urine in, 832 theories of, 822 tophi in, 827, 829, 833 treatment of, 836 alkalies and mineral waters,839 of complications, 844 dietetic, 837 hygienic, 836 local, 843 medicinal, 840 operative, 843 prophylactic, 836 uric acid oxidation, 843 solvents, 842 uraemia in, 832 uric acid elimination in, 715 relation of, to, 820 urinary disturbances in, 831 urine in, 832 Gouty diathesis, 830 kidney, 827 Groin-glands, varicose, 617 Ground itch, 588 Guinea-worm disease, 611 infection, 611 Gums, changes in, in infantile scurvy, 904 Gynsecophorus hsematobins, 550 HiEMAGGLUTiNATiVE principles of venoms, 257 IIff>mamnDbiasis, 392. Hee Malarial fever.s. Haimuto-chyluria, 618 Haematuria, bilharzian, 550 Egyptian, 550 endemic, 550 in gout, 831 in infantile scurvy, 905 HsDmenteria officinalis, 026 Hai'mochromatosis, 756 diagnosis of, 757 Hsemoglobinuric fever, 449. See Black-water fever. Hsemolytic principles of venoms, 257 Haemoptysis, parasitic, 536, 537 Hallucinosis, acute, 190 diagnosis, 192 hallucinations in, 190 prognosis of, 192 symptoms of, 190 treatment of, 192 Halteridium, 400 Halzoun, 547 Hamularia, 623 Harrison's sulcus, 878 Harvest bug, 631 mites, 631 Head, actinomycosis of, 332 nodding in rickets, 883 sweating in rickets, 875 Headache in gout, 831 Heart in diabetes mellitus, 770 Heat, efTect of, 76 exhaustion, 53 treatment of, 56 production in body, 663 influence of temperature on, 663 Heberden's nodes in gout, 830 Helminthes, 526 Helminthoma elasticum, 617 Hemiplegia in diabetes mellitus, 783 Hemorrhage, cerebral, diabetes mellitus _ and, 752 diabetes insipidus and, 801 intestinal, in amoebic dysentery, 518 into skin in scurvy, 897 Hemorrhagic principles of venom, 257 Hepatic abscess, diagnosis of, from malarial fevers, 437 Heredity in absinthism, 196 in alcoholism, 159 in morphinism, 214 in rickets, 867 Herpes zoster in diabetes mellitus, 781 in gout, 831 Heterophyes heterophyes, 548, 549 Hexathyridium venarum, 546 Hiccough in amoebic dysentery, 512 Higher alcohols, 162 Hill fever, 392. See Malarial fevers. Hirudinei, 531, 536 922 INDEX Histiogaster spermaticus, G31 Holothyrus coccinella, B31 Hook-worm disciisc, 582 Human trypanosomiasis, 4GG. See Trypanosomiasis, human. Hunger diabetes, 759 faeces, GOO metal)olism during, 664 Hyalonuna a^gyptiiini, G27 Hybridism, 31 Hydatid disease, 576 Hytlrocephalus, diabetes insipidus and 801 diagnosis of, from rickets, SSG in rickets, 8S3 Hymenolepis, 564 diminuta, 557, 566 flaropvmctata, 566 lanceolata, 557, 5G6 murina, 564 nana, 532, 557, 564 fraterna, 557, 564, 565 Hyperglyc;rmia in dial)etes, 764, 7GG Hypernutrition ciu'cs, diet in, 744 Hyperparasitism, 626 Hvpoderma, 637 bovis, 037 diana, 637 lineata, 637 IcHTHYis:\ius, 223 Ichthyotoxismus, 223 Illuminating gas poisoning, 141 diagnosis of, 147 etiology of, 141 mode of entrance of, 144 pathogenesis of, 144 pathology of, 144 prognosis of, 148 symptoms of, 145 treatment of, 148 Immunity, acquired, 44 Impressions, maternal, 19 paternal, 19 Indican, metabohsm of, 712, 721 Individual inheritance, 27 different forms of, 29 Inebriety, periodic, 194 Infantile paralysis, diagnosis of, from infantile .scurvy, 906 from rickets, 885 scurvy, 901. See Scurvy, infan- " tile. rickets and, 885 Infection of meat, 232 placental, of offspring, 23 through spermatozoa, 24 in utero, 24 Infections, specific, scurvy due to, 896 susceptibility to, 26 Infectious diseases, diabetes insipidus and, 803 diabetes mcUitvis and, 752 non-inheritance of, 22 Infusoria, 354 Ingesta, fate of, 689 Inheritance of acquired characters, 28 blended, 29, 34 diatheses, 27, 49 and disease, 17 dominant, 35 exclusive, 35 of functional modifications, 21 of gross anomalies, 26 indiviilual, 27 different forms of, 29 mosaic, 29, 35 nervous disturbances, 27 particulate, 29, 35 of probal)le anomalies of defect, 20 theories of, 35 physico-chemical, 39 of variations, 26 Inorganic salts, in metabolism, 676 lack of, 677 Insecta, 531, 632 Insects, parasitic, 632 Insolation. See Sunstroke. Intake, method of study of, 643 and output, comparison of, 645 Intermediary metabolism, 689 proteids in, 70S Intermittent fever, 392. See Malarial fevers. Intertrigo in obesity, 854 Intestinal and muscular roundworms, 605 putrefaction, 274 table of aromatic urinarj^ products of, 275 roundworms, 582 tcTniasis, 557 Intestine, human, amcoba of, 491 behaA'ior of, towartl chem- ical substance, 492 physical condi- tions, 492 Intestines, hemorrhage of, in ama>bic dysentery, 518 large, in amoebic dysentery, 503 perforation of, in amoebic dysen- tery, 517 small, in amoebic dysentery, 507 Intoxication by absorption of digestive juices, 270 action of acetone complex in, 325 protein metabolism, 302 retention, 287 carbon dioxide, 288 of intestinal origin, 282 jaundice, 287 perspiration, 291 INDEX 923 Intoxication retention, .suppression of urine, 292 Intracellular enzymes, 713 Iritis in gout, S33 Iron, excretion of, GTS Islands of Langerhans, diabetes melli- tus and, 754 Isodynamic replacement of nutrients, 661 Itch, Norwegian, 628, 629 sarcoptic, 627 Ixodes hexagonus, 627 ricinus, 627 Ixodiasis, 626 Ixodidai, 626 Ixodoidse, 626 Jaundice in black-water fever, 456 intoxication due to, 287 Jigger fleas, infection with, 633 Joints, changes in, in gout, 826 lead poisoning in, 102 Jumping fleas, infection with, 633 Jungle fever, 392. See Malarial fevers. Katabolism, 639 Kedani mite, 631 Kidney-worm, canine, 624 Kidneys in amoebic dysentery, 507 in black-water fever, 455 in diabetes mellitus, 770 in gout, 827 in malarial fevers, 412 Korsakow's psychosis, 196 neuritis in, 198 paralysis in, 198 pathology of, 196 symptoms in, 197 Kreatinin, intoxication due to, 298 relation of, to urcemia, 306 Lamblia duodenalis, 526 Lancet fluke infection, 545 parasite of, 545 Laryngismus stridulus in rickets, 882 Late rickets, 890 prognosis of, 892 symptoms of, 891 treatment of, 892 Lead poisoning, 84 accidental, 85, 91, 92 action of lead in, 96, 97 albuminuria in, 102 arteriosclerosis in, 101 arthralgia in, 102 Lead poisoning, basic granulation in, 98, 99, 109 blindness in, 107 Ijlood in, 98, 99, 100 l>lue line in, 99, 109 cachexia in, 98 in children, 107 colic in, 108 convulsions in, 108 paralysis in, 108 symptoms of, 108 chronic nephritis in, 102 colic in, 101 coma in, 106 delirium in, 106 diagnosis of, 108 from gastric carcinoma, 100 from uraemia, 109 disturbances of sensation in, 103 duration of exposure to, 93 encephalopathy in, 106 etiology of, 86 age in, 87 habits in, 88 heredity in, 86 occupation in, 88 period of year in, 87 previous diseases and previous attacks of saturnism in, 88 race in, 86 sex: in, 87 fever in, 100, 107 from bullets, 93 food, 92 water, 91 generalized paralysis in, 105 gout, relation to, 102 hallucinations in, 106 hemiplegia in, 106 hysteria in, 106 industrial, 85, 88 inheritance of, 44 lead in urine in, 109 medicinal, 93 metabolism in, 97 mode of entrance of, 95 muscular spasm in, 103 neuralgic pains in, 102 paralysis in, 103 of cranial nerves in, 105 pathogenesis of, 95 pathology of, 94 prognosis of, 109 prophj'laxis of, 110 cleanliness in, 110 regulations for, 110 symptoms of, 97 bones, 102 cardiovascular system, .101 924 INDEX Lead poisoning, symptoms of, cerel)ral, 106 digestive tract, 100 genito-urinarv system, 102 joints, 102 nervous system, 102 , ophthalmic, 107 respiratory tract, 101 treatment of, 110 potassium iodide in, 112 purgation in. 111 tremor in, 103 wrist -drop in, 103 Leeches, 626 Leptodera, 5S2 pellis, 624 Leptus americanus, 631 autumnahs, 631 irritans, 631 Leukaemia, acute hinphatic, diagnosis of, from scurvy, 899, 906 Leukocytes in black-water lever, 457 in malarial fevers, 409 Leukocytosis, excess of protein metab- olism in, 303 Leukomains, 229 Lice, infection with, 634 Life-cycle of protozoa, 361 malignant forms, 365 Light, pathological effects of, 52 physiological effects of, 51 Linguatula serrata, 632 Linguatulidse, 531, 632 Linnatis nilotica, 626 Lipsemia in diabetes mellitus, 769 Lipoids in metabolism, 699 Lipomatosis universalis, 845. See Obesity. Lipuria in diabetes mellitus, 780 Lithsemia, 830 Lithic-acid diathesis, 830 Liver, abscess of, in amoebic dysentery, 513 in black-water fever, 455 cancer of, diabetes insipidus and, 802 changes in, in rickets, 871 in dialaetes mellitus, 757, 770 fluke infection, 540 Asiatic, 540 diagnosis of, 543 frequency of, 541 infection in, 541 parasite of, 541 pathology of, 542 prevention of, 543 symptoms in, 541 treatment of, 543 Indian, 545 parasite of, 545 Siberian, 543 frequency of, 544 infection in, 544 Liver, fluke infection, Siliorian, para- site of, 544 pathology of, 544 pre\ention of, 545 symptoms of, 544 in malarial fevers, 411, 431 Loa, 620 Lobsters, poisoning l)y, 231 Lousiness, 634 Lump jaw, 327 Lung, aliscess of, in amoebic dysentery, 516 actinomj^cosis of, 333 conditions of, in scurvy, 899 fluke infection, 536 gangrene of, in scurvy, 899 Lymph scrotum in filariasis, 617 varices, 617 Lymphangitis, filarial, 616 Lvmphatic glands in amoebic dysen- tery, 507 trypanosoma Gambiense in, "471 leuktemia, acute, difTerentiation of, from scurvy, 899 M Macrogaiietes, 402 Madura foot. See Mj^cetoma. Malarial fevers, 392 age and, 406 albuminuria in, 431 altitude and, 405 ana?mia in, 408, 431 blood examination in, 433 bone-marrow in, 413 brain in, 410 cachexia in, 432 classification of, 415 climate and, 405 combined infections, 427 complications of, 428 definition of, 392 diagnosis of, 432 from appendicitis, 428 from cerebral apoplexy, 437 from dysentery, 437 from hepatic abscess, 437 from sunstroke, 437 from tuberculosis, 437 from typhoid fever^ 436 from ulcerative endocar- ditis, 437 from yellow fever, 436 dysentery and, 429 etiology of, 394 contributing factors in, 404 INDEX 925 Malarial fevers, geographical distribu- tion of, 393 history of, 392 immunity from, 407 incubation in, 414 inoculation of, 407 irregular and remittent forms, 425 kidneys in, 412 latent and masked infections, 427 pathology of, 413 leukocytes in, 409 liver in, 411, 431 locality and, 404 melantemia in, 408 moisture and, 405 nephritis in, 429, 431 occupation and, 406 parasites of, 394 pathology of, 407 pernicious, 421 algid form, 424 bilious form, 425 choleraic form, 424 comatose form, 423 dysenteric form, 425 irregular and remittent forms, 425 Plasmodia of, cycle of develop- ment of, 402 development of, within mosquito, 400 staining reactions of, 404 pneumonia in, 429 prognosis of, 438 prophylaxis of, 439 general, 439 destruction of mos- quito, 389, 439 isolation of patient, 441 use of quinine, 441 personal, 441 quartan, fever in, 418 quotidian sestivo-autumnal, fever in, 421, 422 race and, 406 remittent type, fever in, 426 sequela of, 430 sex and, 406 soil and, 405 spleen in, 412 rupture of, 431 spontaneous recovery in, 427 symptoms of, 414 sestivo-autumnal, 419 quartan, 418 quotidian ajstivo-autum- nal, 421 tertian, 416 eestivo-autumnal, 419 Malarial fevers, symptoms of, tertian, a!stivo-autum- nal, cold stage, 419 hot stage, 420 prodromal, 419 cold stage, 417 hot stage, 417 sweating stage, 417 synonyms of, 392 tertian anstivo-autumnal, fever in, 420 albuminuria in, 418 duration of paroxysm, 418 fever in, 416 therapeutic test in, 435 treatment of, 442 of complications and se- quelae, 447 hygienic, 443 of malarial cachexia, 447 medicinal, 443 of special symptoms of, 447 summary of, 446 typhoid fever and, 430 urine in, 410 mosquitoes, 403 parasites in black-water fever, 452, 457 Malignant diseases, cachexia of, excess of protein metabolism in, 302 Malleolar oedema in obesity, 853, 854 Malnutrition, 582 metabolism in, 719 Manganese poisoning, 138, 140 Marasmus, suboxidation in, 284 Marsh fever, 392. See Malarial fevers. Mastigophora, 354 Maternal impressions, 19 Meat decomposed, 235 diseased, 235 organisms in, 236 and paratyphoid infections, 232,241 poisonous, 232 Medulla, tumors of, diabetes mellitus and, 752 Melansemia in malarial fevers, 408 Mendel's law, 29, 30, 47, 48 Meningitis, serous, 186 Mercurial cachexia, differentiation of, from scurvy, 899 Mercury, mode of entrance of, 127 poisoning, 124 accidental, 126 convulsions in, 128 diagnosis of, 130 disturbance of speech in, 128 emotional disturbances in, 129 etiology of, 124 hysteria and, 129 industrial, 124, 125 medicinal, 126 926 INDEX Mercury poisoning, neuritis in, 129 pathology of, 12G prognosis of, 1.30 prophylaxis of, 130 symptoms of, 127 treatment of, 130 tremor in, 127 Mermis, 023 Merozoitos, 397, 398, 399, 403 Metabolism, G39 adaptation processes in, 660 in alkai)tonuna, 713 amino-aciils in, 712 anabolic, ()39 of carbohytlratcs, ()S9, 7(i(), 763 acetone complex not deranged in, 323 anomalies of, 694 auto-intoxication associated with, 315 in diabetes, 764 intermediate products of, 694 normal qualitati\e, acetone complex with, 323 variations of, 762 composition changes in, 642 in corpulence, 700, 719 in cystinuria, 713 definition of, 640 disturbances of, diabetes mellitus and, 760 of energ}', 650 enzymes in, 641 of fats, 695 auto-intoxication associated with, 321 in diabetes, 765 intermediate products of, 700 glycogen in, 691 in gout, 714, 811 influence of altitudes on, 688 of appetite on, 687 of climate on, 688 of clothing on, 688 of cold bath on, 688 of growth on, 687 of hygiene on, 688 of inorganic salts on, 676 of old age on, 687 of proteids on, 672 of sexual changes on, 688 of work on, 678 intake, 643 and output, comparison of, 645, 659 intermediary, 689 proteids in, 708 katabolic, 639 in lead poisoning, 97 of lipoids, 699 in malnutrition, 719 methods of study of, 642 modifications of, 664 Metabolism, modifications of, during feeding, 671 hunger, 664 nature of, (540 of nitrogen, 645 influence of work on, 683 output, 644 channels of, 644 of j)hosph()rus, (il7 ])roteid, 700 auto-intoxications associated witli, 297 in cachexia, 301 and cellular degeneration, 303 exudates, 303 in diabetes, 765 disturljances of, acetone com- plex associated with, 324 dependent on input, 299 independent of inj^ut, 300 effects of non-nitrogenous nu- trients on, 673 excess of, 301 exophthalmic goitre, 302 in i'e\er, 301 influence of alcohol on, 675. intoxications, 302 leukocytosis and, 303 normal qualitati\e, acetone complex with, 323 theories of, 704 purin, auto-intoxication associated with, 308 bodies in, 710 reactions of, 641 in re-alimentation, 671 in staryation, 665 sugars in, 690 of sulphur, 647 urea in, 709 uric acid, in gout, 818 under normal conditions, 812 waste heat in, 664 Metallic poisons in food, 228, 243 Metastrongylus apri, 610 Methyl alcohol poisoning, 161 treatment of, 162 toxicity of, 161 Metorchis truncatus, 544, 545 Microfilaria, 624 Microgametes, 401, 403 Microgametocyte, 401, 403 Micronucleus, 356 Migraine in gout, 831 Milk, poisonous, 241 Miner's disease, 143 Mites, chicken, 631 harvest, 631 kedani, 631 Monocystis ascidia>, life-cycle of, 359 Monoetomulum lentis, 556 INDEX 027 Monostomuluni lentis, 550 Morphinism, 210 cachexia in, 211 exaltation in, 211 hallucinations in, 212 incidence of, 210 intoxication in, 211 sj'mptoms of, 211 of withdrawal, 215 treatment of, 216 Mosaic inlieritance, 29, 35 Mosquitoes, 370 breeding of, 390 classification of, 371 collection of, 390 of genus anopheles, 378 culex, 373 stegomyia, 386 malarial, 403 remedies against, 389, 439 Mountain sickness, 71 pathology of, 72 Multiceps, 559 Multiple sclerosis, diabetes mellitus and, 753 Musca domestica, 637 vomitoria, 637 Muscles, changes in, in rickets, 871 swelling of, from x-rays, 60 Muscular weakness in rickets, 876 Mushroom poisoning, 244 Mussels, poisoning from, 230 Mutations, 32 Mutilations, non-inheritance of, 20 Mutualism, 525 Mycetoma, 344 definition of, 344 diagnosis of, 346 etiology of, 344 pathology of, 345 prognosis of, 346 symptoms of, 345 treatment of, 346 Mycosis mucorina, 352 Myiasis, 637 Myocarditis in gout, 832 Myriapoda infection, 632 Mytilus edulis, 230 Myxoedema, suboxidation in, 283 N Nagana, 462 Nausea in amoebic dysentery, 512 Necator, 582 americanus, 583 Neck, actinomycosis of, 332 Necrophagus sanguinarius, 632 Nemathelminthes, 582 divisions of, 582 Nematoda, 531, 582 Nematodes, urogenital, 624 Nephritis, gout and, 827, K',2 in malarial fevor, ■^12!), V.'A Nephrotoxication, 307 Nerve, vagus, tumors of, diabetes melli- tus and, 753 Nervous dyspepsia and auto-intoxica- tions, 278 system in diabetes meUitUH, 752 770 diseases of, due to auto-intoxi- cations, 279 lead poisoning in, 102 in rickets, 882 Neuralgias in gout, 831 Neuritis, optic, in dialjctes mellitus, 784 periplicral, in diabetes mellitus, 782 Neurotoxin of venom, 255 Nitrogen balance, 045 metabolism of, 645 output in urine in diabetes melli- tus, 779 retention of, 299 starvation, 299 Nocardia, 340 divisions of, 347 synonyms for, 340 Nocardiosis, 340 definition of, 340 diagnosis of, 343 etiology of, 341 granules in, 344 melanoid, 345 metastasis in, 343 ochroid, 345 pathology of, 342 prognosis of, 344 symptoms of, 343 treatment of, 344 Nomenclature, zoological, 532 Non-inheritance of mutilations, 20 of specific infectious diseases, 22 Nutrients, availability of, 653 co-efficients of, 053 energy values of, 654 isodynamic values of, 661 non-nitrogenous, effect of, on proteid metabolism, 673 replacement of, 660 dynamic, 662 isodynamic, 661 Nutrition, 639 artificial, 745 composition of food in relation to, 735 deficient, 670 pathology of, 715 acidosis, 716 autolysis, 715 intracellular enzymes, 715 malnutrition, 719 obesitv, 719 in rickets, "868, 875 Nutritive equilibrium, 645 928 INDEX Obesity, 845 albuminuria in, 854 ana>mic, 846, 853 cardiac astlima in, 854 circumscribed, 855 complications of, 854 definition of, 845 in diabetes, 750 diagnosis of, 855 diets in, 857 etiologj' of, 846 excitino;, 848 predisposing, 846 age, 847 enforced rest, 848 heredity, 846 occupation, 848 sex, 847 temperament, 848 exercise in, 861 gout and, 846 heart in, 852 histology of, 851 history of, 845 hydra^mic, 846 metabolism in, 719 modes of death from, 856 myxccdema and, 863 pathogenesis of, 850 pathology of, 849 blood, 850 heart, 849 plethoric, 846, 851 prognosis of, 855 sequela? of, 854 suboxidation in, 282 symptoms of, 851 anaemic form, 853 physical signs of, 854 plethoric form, 851 physical signs of, 852 synonyms of, 845 treatment of, 856 dietetic, 857 local, 863 mechanical, 861 medicinal, 862 prophylactic, 856 thyroid therapy in, 862 varieties of, 846 Ochromyia anthropophaga, 637 QEdema of feet in diabetes mellitus, 781 malleolar, in obesity, 853, 854 Oertel dietary treatment of obesity, 858 CEsophagostomum brumpti, parasite of cecum, Africa, 604 Oidiomycosis, 346 definition of, 346 diagnosis of, 348 etiology of, 346 pathology of, 347 Oidiomycosis, prognosis of, 349 sym])toms of, 348 treatment of, 349 Oidium albicans, 349 Oocyst, 403 Ookinete, 402 Opisthorchiasis, 535, 540 Asiatic, 540 Indian, 545 Siberian, 543 Opisthorcliis, 540 felineus, 540, 544 noverca, 545 pseudofelineus, 543 sinensis, 541 Opium, history of, 203 by moutli, 208 symptoms of, 209 poisoning, 203 acute, 204 treatment of, 204 etiology of, 204 smoking, 205 symptoms of, 206 Orchitis, 618 Ornithodoros megnini, 627 savignyi, 627 Ornithodows talaje, 627 tholozani, 627 turicata, 627 Osteomalacia, diagnosis of, from rick- ets, 885 Otitis inedia, acute, in diabetes mellitus, 784 Output of energy, 657 method of study of, 644 Oxaluria in dial:)etes mellitus, 779 in gout, 831 purin metaI)olism and, 314 Oxidation, alanormalities in processes of, 280 castration and, 283 exaggerations of, 266 muscular exercise and, 281 Oxygen, deficiency of, 285 Oxyuriasis, 599 , diagnosis of, 601 distriliution of, 599 frequency of, 600 infection in, 600 parasites of, 600 symptoms of, 601 treatment of, 601 Oxyurias, 600 Oxyuris, 582 yermicularis, 600, 620 Oj'sters, poisoning b}', 231 Paludal feyer, 392. fever. See Malarial INDEX 929 Paludisme, 392. See Malarial fevers. Pancreas, diseases oF, diabetes mellitus and, 754 Panophthalmitis, suppurative, in gout, 833 Pansporoblasts, 356 Paragordius varius, 604 Paragonimiasis, 535, 536, 537 diagnosis of, 539 frequency of, 536 infection in, 536 pathology of, 538 prevention of, 539 symptoms of, 537 treatment of, 539 Paragonimus westermanii, 536 Paralj'^sis, diver's, 72. See Caisson dis- ease, infantile, diagnosis of, from infan- tile scurvy, 906 from rickets, 885 in lead poisoning, 103, 104, 105 treatment of, 112 Paramcecium caudatum, life-cycle of, 362 Paraplegia, diabetic, 783 Parasites, age and sex of patient, 527 in black-water fever, 457 chance, 526 definition of, 525 distribution of, by organs, 531 fertility of, 527 frequency of, 526 heredity of, 528 influence of, 528 malarial, 394 sestivo-autumnal, human cvcle of, 398, 399 mosquito cycle of, 402 quotidian, from, 398 classification of, 396 crescents, 402 history of discovery of, 394 of mosquito cycle, 400 quartan, 397 human cycle of, 397 mosquito cycle of, 401 staining of, 433 tertian, 396, 399 human cycle of, 396 mosquito cycle of, 401 origin of, 528 periodical, 526 permanent, 526 pseudo-, 526 resistance of, 527 seasonal periodicity of, 527 spurious, 526 stationary, 526 temporary, 526 Parasitic diseases, diagnosis of, 529 prevention of, 530 treatment of, 530 59 Parasitism, simple, 526 spurious, 637 tru(!, 526 Paratyphoid fever and meat, 232, 241 Paresis, general, diabetes mellitus and, 753 Paronychia diabetica, 781 Parotitis in gout, 831 Particulate inheritance, 29, 35 Paternal impressions, 19 Pathological drunkenness, 194 effects of air, 69 of light, .52 of x-rays, 59 Pediculoides ventricosus, 631 . Pediculosis, 634 parasites in, 634 symptoms of, 635 treatment of, 635 Pediculus capitis, 634 cervicalis, 634 corporis, 634 humanus, 634 inguinalis, 634 pubis, 634 tabescentium, 634 vestimenti, 634 Pelagra, 245 Pelodera setigera, 610 Pelvis, deformities of, in rickets, 878 Pericarditis in gout, 828, 832 Periostitis, diagnosis of, from infantile scurvy, 906 Peritonitis in amoebic dysentery, 506 517 Pernicious malarial infections, 421 Perspiration, retention of, intoxication due to, 291 Pharyngitis in gout, 831 Phlebitis in gout, 832 Phloridzin diabetes, 758 Phora rufipes, 637 Phosphates in gout, 831 Phosphatic diabetes, 779 Phosphorus balance, 647 metabolism of, 647 poisoning, 131 accidental, 132 diagnosis of, 135 etiology of, 132 fragility of bones in, 133, 134 industrial, 131, 132 medicinal, 132 metabolic changes in, 133, 693 necrosis in, 134 pathology of, 133 acute, 133 prognosis of, 135 prophylaxis of, 135 symptoms of, 134 acute, 134 treatment of, 135 urine in acute, 134 930 INDEX Phthirius inguinalis, 634 Po pubis, 634 Physaloptera, 5S2 caucasica, 602 Physico-chemical tlicorv of inheritance, 39 Physiological effects of air, 69 of light, 51 fish poisons, 224 properties of venom, 252 Pigeon chest, cS78 Pinworm infection, 599 Piophila casei, 637 Placental infection of offspring, 23 Plasmodium falciparum, 398, 399 malaria^ 397 vivax, 396 Plerocercoides prolifer, 581 Plerocercus prolifer, 581 Plica palonica, 635 Plumb ism, 84 Pneumaturia in diabetes mellitus, 780 Pneumonia, lobar, in diabetes mellitus, 770 in malarial fever, 429 in scurvy, 899 Poisoning, alcohol, 157 etiology of, 157 pathology of, 160 treatment of, 200 arsenic, 114 _ diagnosis of, 121 etiology of, 114 mode of entrance of, 118 pathogenesis of, 118 pathology of, 117 prognosis of, 122 prophylaxis of, 122 symptoms of, 119 treatment of, 122 brass, 138 carbon monoxide, 141 diagnosis of, 147 etiology of, 141 mode of entrance of, 144 pathogenesis of, 144 pathology of, 144 prognosis of, 148 symptoms of, 145 treatment of, 148 cheese, 242 cocaine, 217 diagnosis of, 221 prognosis of, 222 treatment of, 222 combustion products, 141 diagnosis of, 147 etiology of, 141 mode of entrance of, 144 pathogenesis of, 144 pathology of, 144 prognosis of, 148 symptoms of, 145 isoning, combustion products, treat- ment of, 148 cojiper, 138 diseased meat, symptoms of, 236 by fish, svmptoms of, 227 fugu, 224 illuminating gas, 141 diagnosis of, 147 etiology of, 141 mode of entrance of, 144 pathogenesis of, 144 pathology of, 144 prognosis of, 148 symptoms of, 145 treatment of, 148 lead, 84 in children, 107 symptoms of, 108 diagnosis of, 108 etiology of, 86 mode of entrance of, 95 pathogenesis of, 95 pathology of, 94 prognosis of, 109 prophylaxis of, 110 symptoms of, 97 treatment of, 110 loljsters, 231 manganese, 138 meat, 232 mercury, 124 diagnosis of, 130 etiology of, 124 mode of entrance of, 127 pathology of, 126 prognosis of, 130 prophylaxis of, 130 symptoms of, 127 treatment of, 130 metallic from food, 228, 243 milk, 241 morphine, 210 treatment of, 216 mussel, 230 oatmeal, 244 opium, 203 acute, 204 etiology of, 204 oyster, 231 phosphorus, 131 diagnosis of, 135 etiology of, 132 pathology of, 133 prognosis of, 135 prophylaxis of, 135 symptoms of, 134 treatment of, 135 ptomain, scurvy due to, 895 silver, 136 diagnosis of, 137 pathology of, 136 prognosis of, 137 prophylaxis of, 138 INDEX 931 Poisoning, silver, symptoms of, \'.M treatment of, 13.S snake, 247 mortality from, 2()1 symptoms of, 2(jl treatment of, 2()2 specific, 203 tin, 138 vegetajile, 243 zinc, 138 Poisonous fish, 223 milk and its products, 241 shell-fish, 228 snakes, classification of, 247 geographical distribution of 248 _ Poison.^, bacterial, 224 food, 223 physiological, 224 Poliencephalitis hemorrhagica superior, 198 Polonium, 63 Polystomella crispa, life-cycle of, 360 Polyuria experimental, 800 Pons, tumor of, diabetes mellitus and, 752 Pork tapeworm, 561 Porocephalus moniliformis, 632 Pot-belly, rachitic, 884 Potassium in blood, deficiency of, scurvy due to, 894 Potential energy of foodstuffs, 653 Pregnancy, diabetes mellitus and, 752, 784 Presbyopia in diabetes mellitus, 784 Products of femtientation and putre- faction, 272 Proteid, circulating, 704 digestion of, 702 endogenous metabolism of, 707 exogenous metabolism of, 707 fat cures, diet in, 744 influence of, on metabolism, 672 metabolism of, 700 auto-intoxications associated with, 297 creatinin in, 709 disturbances of, acetone com- plex associated with, 324 dependent on input, 299 independent of input, 300 effects of non-nitrogenous nu- trients on, 673 excess of, 301 influence of alcohol on, 675 intoxications, 302 normal qualitative, acetone complex Avith, 323 theories of, 704 minimum requirement of, 724 experiments on, 726 reduced intake of, 730 I'rotnid tissue, 704 transfonna(,ioiis of, 701 veg(!table, availability of, 739 Proteus vulgaris, 232 Protozoa, 353 classification of, 368 divisions of, 353 infusoria, 354 mastigophora, 354 sarcodina, 354 sporozoa, 354 life-cycle of, 361 methods of reproduction of, 355 binary fission, 355 budding, 356 gemmation, 356 spore formation, 356 Protozoic dermatitis, 346 Pruritus in dial)etes mellitus, 781 treatment of, 798 in obesity, 854 Pseudotrichina,', 610 Psoriasis in gout, 831 Psorospermiasis, 346 Psychosis, Korsakow's, 196 Ptomain poisoning, scurvy due to, 895 Ptomains, 275 Pulex irritans, 633 penetrans, 633 Pulmonary aspergillosis, 350 definition of, 350 diagnosis of, 352 etiology of, 350 pathology of, 351 prognosis of, 352 symptoms of, 352 treatment of, 352 roundworms, 610 Purin bodies, intermediary metabolism of, 711 metabolism of, 710 in gout, 818 perversion of metabolism of, 714 metabolism, 308 auto-intoxication associated with, 308 in gout, 312 Purpura in diabetes mellitus, 781 differentiation of, from scurvy, 899 Q Quartan fever, 392. See Malarial fevers, parasite, 397 Quinine, action of, on malarial Plas- modia, 443 administration of, in malarial fever, 444, 445 choice of preparation of, in mala- rial fever, 444 932 INDEX Quinine, contra-indications to, 446 use of, in malarial Plas- modia, 446 dosage of, in malarial (ever, 446 Quotidian a'stivo-autunnial parasites, 39S Rachitic pot-belly, 884 Radium, 63 Rat try)ianosomc, 461 Re-alimentation, metabolism in, 671 Red bus, 631 Remittent fever, 392. See Malarial fexers. Renal diabetes, 758 Respiratory system, clianj^ies in, in gout, 82S tract, lead poisoninji; in, lUl Retention intoxications, 287 carbon dioxide, 288 of intestinal origin, 292 jaundice, 287 perspiration, 291 suppression of urine, 292 of lU'ine and metabolism, 294 Retinitis, diabetic, 783 hemorrhagic, in gout, 833 Reversion, 31 Rhalxlitis, 582 comwalli, 610 genitalis, 624 niellyi, 611 terricola, 610 Rhabdonemiasis, 595 Rheumatism, diagnosis of, from infan- tile scurvy, 905 Rhipicephalus sanguineus, 627 Ribs, bending of, in rickets, 876 Rickets, 864 bacteriology of, 874 l)lood in, 884 chemistry of, 872 complications of, 884 congenital, 889 symptoms of, 890 treatment of, 890 course of, 886 diagnosis of, 885 diet in, 886 epiphyses in, 876 etiologj' of, 866 age, 866 defective hj'giene, 867 dietetic, 868 heredity, 867 overcrowding, 867 season, 866 sex, 866 syphilis, 868 geographical distribution of, 864 history of, 864 Rickets, late, 890 prognosis of, 891 symptoms of, 891 treatment of, 892 lime-salts in, 872 liver in, 871, 884 mori)iil anatomy of, 870 nutrition in, 868 pathogeny of, 872 pathology of, 870 brain, 872 muscles, 871 spleen, 872 viscera, 871 prognosis of, 886 relation of, to infantile scurvy, 905 symptoms of, 874 * circulatory, 884 cranium, 879 gastro-intestinal, 883 head s^veating, 875 muscular \veakness, 876 nervous, 881 osseous, 876 respiratory, 884 teeth, 875 temperature, 875 tenderness, 883 treatment of, 886 prophylactic, 886 therapeutic, 887 Rickety rosary, 876 Roundworms, 582 intesthial, 582 and muscular, 605 pulmonary, 610 subcutaneous, 610 urogenital, 624 Saccharomycosis, 346 Salts, relation of, to unemia, 306 Sarcocystis, mischeriana, 610 Sarcodina, 354 Sarcoma of skull, diagnosis of, from infantile scurvy, 906 Sarcopsylla penetrans, 633 Sarcoptes minor cati, 628 scabiei, 627 anchcnitp, 628 cameli, 628 canis, 628 capne, 628 crustosa>, 628 equi, 628 leonis, 628 oris 628 suis, 628 vulpis, 628 worn bat i, 628 Sausage poison, 232 INDEX 933 Scabies, 627 crustosa, 629 Schistosoma catioi, 550 ha-matobium, 550 japonicum, 550 Schizont, 357, 396, 397, 398 Scleroderma I'rom ;c-rays, 60 Sclerosis, multiple, diabetes mellitus and, 753 Scoleciasis, 637 Scorbutus, 893. See Scurvy. Screwworm, 637 Scurvy, 893 diagnosis of, 899 from acute Ij^mphatic leukae- mia, 899 from mercurial cachexia, 899 from purpura hemorrhagica, 899 diet in, 900, 902 etiology of, 894 * history of, 893 infantile, 901 diagnosis of, 905 from acute leukaemia, 906 from epiphysitis, 906 from infantile paralysis, 906 from periostitis, 906 from renal hemorrhage, 906 frorn rheumatism, 905 from sarcoma of skull, 906 from ulcerative stoma- titis, 906 etiology of, 902 history of, 901 morbid anatomy of, 903 prognosis of, 906 rickets and, 885 symptoms of, 904 associated with rickets, 905 changes in blood, 905 in gums, 904 treatment of, 906 morbid anatomy of, 896 prognosis of, 900 symptoms of, 897 prodromal, 897 treatment of, 900 prophylactic, 901 Seat worm, 600 Serous meningitis, 186 treatment of, 189 Shell-fish, poisonous, 228 Shock, electrical, consequences of, 65 SiWer poisoning, 136 accidental, 136 diagnosis of, 137 industrial, 136 medicinal, 136 pathology of, 136 Silver poisoning, pigmentation in, 137 of gums in, 137 prognosis of, 137 prophylaxis of, 138 symptoms of, 137 treatment of, 138 Siriasis, 56 treatment of, 56 Skin in anxi^bic dysentery, 512 atrophy of, from x-rays, 59 hemorrhages into, in scurvy, 897 Skull, sarcoma of, diagnosis of, from infantile scurvy, 906 Sleeping sickness. See Trypanosomia- sis, human. Snakes, poisonous, blood-clotting com- ponent oF, 255 classification of, 247 geographical distribution of, 248 mortality from, 261 neurotoxin of, 255 poison organs of, 251 principles of, hajmagglutina- tive, 257 hsemolytic, 257 hemorrhagic, 257 properties of, chemical, 252 physiological, 252 symptoms of, 261 toxicity of, 259 treatment of, 262 specific, 263 Somatic tteniasis, 574 Sparganum mansoni, 574, 581 proliferum, 574, 581 Spinal caries, diagnosis of, from rickets, 886 cord, conditions of, diabetes insipi- dus and, 802 Spiroptera hominis, 526 Spleen, abscess of, in amoebic dysen- tery, 516 in black-water fe^'er, 455 changes in, in rickets, 872 in malarial fevers, 412 rupture of, in malarial fever, 431 Sporant, 357 Spore formation in protozoa, 356 Sporoblast, 357, 403 Sporont, 402 Sporozoa, 354 Sporozoites, 357, 403 Sports, 30, 32 Starvation, 323 creatinin in, 710 faeces in, 669 heat production in, 669 metabolism in, 665, 669 of cells in, 670 proteid, 666, 724 934 INDEX Stan'ation, nitrosjen output in, 007 Steatorrlura in diabetes niellitvis, 7S2 Stegomyia calopus, 373, 3S(i description of, 3SS distril)ution of, 38G Stomatitis, ulcerative diagnosis of, from infantile scurvy, 906 Striatula, 520 Strongyloitles, 582 stercoralis, 526, 595 Strongyloidosis, 595 diagnosis of, 596 distri!)ution of, 595 frequency of, 590 infection in, 590 parasite of, 595 symptoms of, 596 treatment of, 596 Strongvlus instabilis, 602 subtilis, 602 Subcutaneous roundworms, 611 Suboxidation, 2S1 in ana'uiias, 284 in cachexia, 284 strumipriva, 283 of fat, 322 in marasmus, 284 in mvxcedema, 283 in obesity, 282 of sugar, 317 Sugar, formation of, from protein, 318 from fats, 319 metabolism of, 690 suboxidation of, 317 superoxidation of, 317 Sulphur balance, 647 Sunburn, 52 Sunstroke, 53, 54 diagnosis of, 55 from malarial fe^'e^s, 437 pathogenesis of, 54 pathology of, 54 prognosis of, 55 prophylaxis of, 57 sequela' of, 54 symptoms of, 54 treatment of, 56 Sun-traumatism, 56 treatment of, 56 Superoxidation, 285 of fat, 322 acetonuria and, 322 of sugar, 317 Suppression of urine, intoxication due to, 292 Surra, 461 Swamp fever, 392. See Malarial fevers. Syphilis, cerebral, diabetes insipidus and, 802 congenital, 23 rickets and, 868 Tabes, diabetic, 753, 782 Ta:-nia, 532, 557, 559 africana, 557, 560 eanina, 557, cellulosa\ 561 ccenurus, 559 confusa, 557, 563, 564 cucumcrina, 567 dimimita, 561 echinococcus, 576 clliptica, 567 hinuliiiacca, 604 honiinis, 557, 561 hydatigena, 529, 561, 575 inermis, 559 lanccolata, 566 lata, 537, 567 medicocanellata, 559 hominis, 559 moniliformis, 527 nuiriana, 532, 564 nana, 564, 576 pisiformis, 563 saginata, 52(5, 527, 532, 557, 558, 559, 560, 561, 562, 570, 573, 575 description of, 559 diagnosis of, 560 distribution of, 558 frequency of, 560 infection, source of, 559 prevention of, 560 solium, 529, 557, 558, 559, 500, 561, 562, 570, 571, 573, 574, 575 description of, 561 distriljution of, 561 frequency of, 562 infection liy, features of, 562 larval, 574 source of, 562 pre^■ention of, 563 teniseformis, 563 vulgaris, 567 zittaviensis, 559 Tasniarhynchus, 559, 560, 561 Ta:niasis, 557 intestinal, 557 parasites of, 557 sj'mptoms of, 569 treatment of, 571 anthelmintic, 572 in children, 574 expulsion of worm, 574 preparatory, 572 somatic, 557, 574 forms of, 574 Trcniida?, 532 Tapeworm infection, 557 Telianychus molestissimus, 631 Temperature, effect of, 76 INDEX 935 Tendon reflexes in clial)etes rncUilus, 783 Terminology, parasitic, 532 Tertian a-stivo-autumnal parasite, 39!) fevers, 392. (See Malarial fevers. •parasite, 39G Tetany due to auto-intoxications, 277 in rickets, 882 Tetramitus chilomonas, 356 Tetranychus molestissimus, G31 Thorn-headed worm infection, G04 Thorax, actinomycosis of, 333 Thrombosis, venous, in gout, 832 Thyroid and metabolism, 302 Ticks, infection with, 626 Tin poisoning, 138, 139 Tongue-worm infection, 632 Toxicity of venoms, 259 Toxins in decomposed fish, 226 shell-fish, 229 in poisonous fish, 225 Toxocara canis, 597 Transformation of energy, 650 Traumatism of brain, diabetes insipidus and, 801 Trematode infections, 531, 535 Trichina, 532 affinis, 610 agilissima, 610 anguillffi, 610 contorta, 602 cyprinorum, 610 cystica, 600, 610, 619 inflexa, 610 lacerta;, 610 microscopica, 610 spiralis, 605 Trichinella, 582 spiralis, 605 Trichiniasis, 605 Trichinosis, 533, 605 diagnosis of, 608 distribution of, 605 duration of, 606 infection in, 606 lethality of, 608 parasite of, 605 prevention of, 609 symptoms of, 606 treatment" of, 609 Trichinus spiralis, 605 Trichocephaliasis, 602 diagnosis of, 604 distribution of, 602 frequency of, 603 infection in, 603 parasites of, 603 pathology of, 603 prevention of, 604 symptoms of, 603 treatment of, 604 Trichocephalus dispar, 602 hominis, 603 Trichostrongylus, 582, 602 instabilis, fl02 jtrohiiiurus, 602 subiilis, (i02 vitrinuK, 602 Triclniris, 582, (i03 tricliiura, 603 Tricoma, 635 Triodontopliorus deminutus, parasite of intest. as Mayotto, 595 Trombidium, 6.31 tlalsahanto, 631 Trypanosoma brucei, 462 evansi, 461 fever, 478 gambiense, 465, 468 in animals, 476 in cerebro-spinal fluid, 471 des«ription of, 468 effect of arsenic on, 485 on man, 477 life history of, outside of body, 472 in lymphatic glands, 471 in man, 477 method of leaving the Ijody, 473 mode of gaining entrance into human organism, 473 reproduction of, 472 staining of, 468 tissues of body in which found, 471 lewisi, 461 Trypanosome, description of, 460 rat, 461 Trypanosomiasis, 460 human, 466, 477 blood in, 480 diagnosis of, 484 etiology of, 467 fever in, 481 histological changes in, 482 history of, 466 pathology of, 481 prognosis of, 484 prophylaxis of, 486 symptoms of, 469 in alimentary sj^stem, 479 in circulatory system, 479 in cutaneous system, 480 in hsemopoietic system, 480 in lymphatic system, 480 in nervous system, 479 in respiratory system, 480 in urinary system, 480 temperature curve in, 481 terminal infection in, 483 treatment of, 485 Tsetse-fly disease, 462 Tuberculosis in diabetes mellitus, 770, 782 936 IXDEX Tuberculosis, diagnosis of, from malarial fevers, 437 Tumors, cerebral, diabetes insipitlus and, 801 Tunnel disease, St. Gothard, 5S2 Tydeus molestus, G31 Typhoid fever, diagnosis of, from malarial fevers, 436 Tyroglyphus fariua>," G31 Tyrotoxicon, 243 longior, G31 siro, 631 Tyrotoximus, 242 U Ulcer of foot, perforating, in diabetes mellitus, 7S1 Ulcerative endocarditis, ^liagnosis of, from malarial fevers, 437 stomatitis, diagnosis of, from in- fantile scurvy, 906 IHcers in amcebic dysentery, 504 Uncinaria, 582 americana, 583, 584 criniformis, 583 duodenalis, 584 hominis, 583, 584 vulpis, 583 Uncinariasis, 582 blood in, 590 bodily development in, 588 diagnosis of, 592 distribution of, 582 frequenc}' of, 586 infection in, 584 lethality of, 591 parasite in, 583 pathology of, 591 prevention of, 594 symptoms of, 587 treatment of, 593 Uraemia, explanation of, 306 nieta])olism in, 305 and retention, 293 Urea formation, 297 intoxications due to, 297 metabolism of, 709 relation of, to uraemia, 305 Urethritis in gout, 831 Uric acid in the blood, 311, 817 in gout, 819, 825 origin of, excess of, 820 diathesis, 830 elimination of, in gout, 312, 715 endogenous, 813, 817 excretion of, daily, 818 in gout, 819 exogenous, 813 metabolism of, and alcohol, 810 I'ric acid, metabolism of, in gout, SIS under normal conditions, 812 oxidation of, in gout, 824 precipitation of, as biurate, 822 pin-in bases, relation to, 813 relation of, to gout 820 seat of formation of, 814 sources of, 710 endogenous, 711 exogenous, 710 in urine in diabetes mellitus, 779 Urinary disturbances in gout, 831 Urine, ammonia of, intoxications due to, 298 in amoebic dysenterj^ 513 in black-water fe^•er, 456, 457 in diabetes mellitus, 773 acetone in, 778 alloxuric liodies in, 779 ammonia in, 779 /?-oxvbutvric acid in, 777,786" diacetic acid in, 778, 786 glycerin in, 777 glycogen in, 780 glj'curonic acid in, 777 lipuria in, 780 nitrogen output in, 779 oxaluria in, 779 sugar in, 774 bismuth test for, 776 Fehling's test for, 775 fermentation test for, 776 phenylhydrazin test for, 776 polariscope test for, 776 Trommer's test for, 775 uric acid in, 779 in diabetes mellitus, yeast-cells in, 780 in gout, 832 in malarial fevers, 410 in scurvy, 899 suppression of, intoxication due to, 292 TTrogenital nematodes, 624 Vagus nerve, tumors of, diabetes melli- tus and, 753 Vegetables, poisonous, 243 Vegetarian, diet of, 743 Vegetarianism, 740 Venom, action of, 255 chemicals on, 254 INDEX 937 Venom, action of heat on, 254 light on, 254 amount of, 252 constituents ol', 253 principles in, 255 secretion of, 251 toxicity of, 259 Vermis umbilicalis, 526 Vetch poisoning, 244 Viscera, changes in, in rickets, 871 in malarial fevers, 410 Vomiting in amoebic dysentery, 512 in gout, 833 W Water gas poisoning, 142 Wechselfieber, 392. See Malarial fevers. Weissmann's theory, 36 Whipvirorm infection, 602 Wet brain, 186 Wood alcohol, 161 Work, factors influencing energy re- quired, 680 influence of, on metabolism, 678 nitrogen metabolism, influence on, 683 Wrist-drop in lead poisoning, 103 Wuchereria filaria, 615 X-RAYS, 58 alopecia from, 60 atrophy (jf skin from, 59 cancer froiri, 60 dermatitis from, 59 effect of, on internal organs, espe- cially generative organs, 60 eye lesions from, 60 gangrene from, 60 general symptoms from, 60 lesions, pathogenesis of, 62 treatment of, 63 pathological efft^ct of, 59 scleroderma-like changes from, 60 swelling of muscles from, 60 Xanthoma diabeticorum, 781 Yeast-cells in urine in diabetes melli- tus, 780 Yellow fever, diagnosis of, from malarial fevers, 436 Zinc poisoning, 138 Zoo-parasitic diseases, 525 COLUMBIA UNIVERSITY 0032456107 DATE DUE Demco, Inc. 38-293