LIBRARY NEW YORK STATE VETERINARY COLLEGE ITHACA, N. Y. CORNELL UNIVERSITY LIBRARY 3 1924 104 226 240 The original of this book is in the Cornell University Library. There are no known copyright restrictions in the United States on the use of the text. http://www.archive.org/details/cu31924104226240 GENERAL PATHOLOGY BY DR. ERNST ZIEGLER PBOFESSOB OF PATHOLOGICAL ANATOMY AND OF GENERAL PATHOLOGY IN THE UNITEBSITT OF FREIBURG IN BREISGAU FROM THE ELEVENTH EEVISED GERMAN EDITION (GDSTAV FISHER, JENA, 1905) EEVISED BY DOUGLAS SYMMERS, M.D. DIEECTOB OF LABORATORIES, BELLEVUB AND ALLIED HOSPITALS, FOUMEELX PBOFESSOB OP PATHOLOGY IN THE UNIVEBSITY AND BELLETUE HOSPITAL MEDICAL COLLEGE lWITH 604 ILLUSTRATIONS IN BLACK AND IN COLORS NEW YORK WILLIAM WOOD AND COMPANY MDCCCCXXI Copyright, 1921, Br WILLIAM WOOD AND COMPANY. PREFACE. This revision is an attempt to present the subject of Pathology from the standpoint primarily of the needs of the medical student, while pre- serving the usefulness of the book as a convenient reference for the practitioner. Advantage has been taken of the fact that the book was to be reprinted to make almost numberless changes in the language of the translation, in order more simply and directly to express the views of the author, and to add a considerable amount of new subject matter, in addition to making certain needed alterations in portions of the old, including the subjects of acromegaly, Addison's disease, status lymph- aticus, eunuchoidism, autolytic, amyloid and Zenker's degenerations, ochronosis, hasmochromatosis, and bronzed diabetes, carotinasmia, lipo- matoses and the embryonal fat cells, ossifying myositis and multiple exostoses, the skin moles, malignant transformation of myomata, neuro- blastoma, polycystic kidneys, lymphosarcoma, pseudoleukemia, Hodgkin's disease, the multiple myeloblastomata, Martland:'s tumor of the bone marrow and Barrie's hsemorrhagic osteomyelitis, surgical tuberculosis of the intestine, Wilms' tumor, anthrax, ascariasis, oxyuris in the appendix, trichina embryos in the blood, juvenile gangrene, the effects of the so- called pandemic influenza, botulism, the reactions to arsphenamine, a somewhat drastic rearrangement of the chapter on thrombosis, etc. Some of these changes appear in small type while others have been interpolated in the original text. The general arrangement of the book has not been disturbed, although many of the old illustrations have been eliminated. In general, these have been replaced by photographic reproductions from the wards and laboratories of Bellevue Hospital ; for these I am indebted to Mr. William B. Morrison. In the same way, some of the older liter- ature has been omitted and in its place, wherever possible, references to works in English have been substituted as more easily reached and read. I am amply repaid for all the difficulties of the work by the conscious- ness that it should be helpful to the medical profession generally and especially to students of medicine, inasrnuch as the book, as written by Ziegler and as modified by my distinguished predecessor. Professor Warthin, was far too valuable to be abandoned for the lack of someone to bring it up to date. I wish especially to acknowledge my debt to my secretary. Miss Martha Wirth, without whose tireless support and inter- ested co-operation I could not well have completed the great amount of technical work involved in preparing this new edition. Douglas Symmers. The Pathological Laboratories, Bellevue Hospital, New York, October, 1920. AUTHOR'S PREFACE TO THE ELEVENTH EDITION. In the preparation of this new edition I have endeavored to utiHze as fully as possible the researches of the last several years, and, in so far as , these have given us new facts and represent actual advances in our knowl- edge of pathological processes, to incorporate them into the contents of the book. It has become almost impossible to review the great mass of literature concerning the pathogenic micro-organisms, their life history, and their effects upon the human organism; but I hope that the essential and established results of recent investigations have not escaped me, and that I have estimated them at their proper worth. I may merition with especial emphasis the researches of Schaudinn on the spirochsetas and the parasites of malaria ; also those of other authors on the trypanosomata, various pathogenic bacteria, the agglutinins, precipitins, cytolysins, and hsemolysins, as well as the numerous investigations and theoretic observa- tions that, based upon Ehrlich's side-chain theory, have been carried out concerning the toxic action of bacterial products and the formation of antitoxic and antibacterial substances. During recent years an immense amount of literature concerning tuberculosis has appeared ; but our previous views concerning its etiology and genesis have not been materially altered. Koch's view as to the difference between human and bovine tuberculosis is applicable only in so far as certain differences in the characteristics of the two strains of bacilli are concerned. For all these differences it is true that bovine tuberculosis is communicable to man, and the domestic animals may be- come infected from tuberculous human beings. Von Behring's publica- tion that infants may be easily infected through milk containing tubercle bacilli has only confirmed well-known views. The attempt of von Behring to refer all cases of tuberculosis to an intestinal infection occurring in infancy is doubtless an error, and is not likely to destroy the belief that tuberculosis is most frequently an air-borne infection and enters primarily through the lungs. The researches concerning the etiology, genesis, and morphology of neoplasms have likewise been numerous and extensive; nevertheless, any expectations of a great advance in our knowledge of the etiology of neo- plasms are doomed to disappointment. The attempts to establish a para- sitic etiology for tumors have entirely failed, and the extensive statistico that have been amassed concerning the distribution of carcinoma have led to results that can be regarded only as antagonistic to the parasitic theory. Of greater value have been the researches on the histogenesis of tumors ; yet I find in these essentially only a confirmation and a more thor- ough grounding of our older views. I cannot bring myself to the accept- ance of all the latest views, for example, the assumption that the prelimi- nary condition of tumor development is to be found in the isolation, disconnection, and misplacement of germinal anlage or of single cells iv AUTHOR'S PREFACE TO THE ELEVENTH EDITION. during embryonal or extrauterine life (Ribbert, Borrmann), or that the epithelial cells of a carcinoma can become transformed into connective- tissue cells (Krompecher). Significant advances in the theory of fatty degeneration and glycogen deposit are also to be noted;, and although many problems- must- still wait a solutioii, our knowledge 'concerning ' these processes has been greatly furthered through the labors of recent years. The long discussion over the significance of the cells appearing in the tissues during the course of inflammation has at last reached certain conclusions. The questions still unsettled are of minor importance. The arrangement of the book is left, on the whole, as in the last edition; but I have not simply inserted the new facts and views, many sections having been entirely recast to agree with the additions. The number of illustrations has been increased from 586 to 604. The bibli- ography has been given a careful revision and brought up to the autumn of this year. E. ZlEGLER. Freiburg im Breisgau, December, 1904. NoTE.r- Because of the difference in the size of the page it has been found necessary to reduce slightly some of tlie illustrations. In such cases the magnifica- tion or amplification has been changed to meet the amount of reduction. GENERAL PATHOLOGY. INTRODUCTION. Physiology is the science of normal life and teaches us concerning its activities. At the same time it shows us that vital functions are performed according to laws having their foundation in structure. Changes in organic structure, manifesting themselves as vital phenomena differing from those regarded as normal, form the basis of disease. The return to the normal is known as recovery or healing. Permanent cessation of all vital functions constitutes death. Tempo- rary interruption of the vital activities without loss of the possibility of return to the normal may be seen in the condition of apparent death or congelation, which may be followed, by either death or by return to Hfe (anabiosis). When pathological changes are present in the tissues, arising either before the appearance of symptoms or persisting after their cessation, so that at any time a new outbreak of the latter may take place, the disease is spoken of as latent. The science of disease is embraced by Pathology. There falls to it the determination of the causes and origin of pathological processes, these two divisions constituting etiology and pathogenesis. A second task lies in the investigation of the anatomical changes underlying the altera- tions of function ; and that branch of the science to which this is assigned is known as pathological anatomy. Since the finer organization of different tissues varies according to their functions, and since we cannot conceive of vital manifestations without a material substratum, it is reasonable to assume that pathological manifestations must likewise be the expression of material changes in the tissues concerned. Moreover, experience has taught us that in the case of any alteration of function in any tissue or organ, there may be demonstrated changes of structure, in part even macroscopically, while at other times they can be made out only with the aid of the microscope and by special histological methods. A third field belonging to pathology is concerned with the observa- tion and interpretation of the symptoms of disease as seen in the patient, and this branch is designated clinical pathology, pathological physi- ology, physiological or biological pathology. Its facts are ascertained by observation and examination of the patient, and through special physical and chemical methods. Successful application of the results obtained by the methods of clinical or biological pathology requires a knowledge of the pathological-anatomical changes present, as well as of their etiology and pathogenesis. As a furthc help to the interpre- tation of disease a knowledge of the chemical processes taking place in the living organism under the influence of the activity of cells is essential. This knowledge is specialized in the science of pathological chemistry. 1 1 2 INTRODUCTION. The many-sided domain of Patnology demands division into various branches according to special points of view. A knowledge of clinical pathology is best gained at the bedside or in the clinic. Likewise chemical pathology requires special theoretical and practical training. In this text-book General Pathology will be considered as including etiology, pathogenesis, and pathological anatomy. Chemical Pathology will be touched on only in so far as it is necessary to an understanding of the anatomical changes in diseased organs. CHAPTER I. The Extrinsic Causes of and the Congenital Foundations for Disease. 1. Deficient Supply of Food and Oxygen, Fatigue, Heat and Cold, Changes of Atmospheric Pressure, and Electrical Influences. § 1. From birth to death man is exposed to the influences of the world surrounding him, many of these influences being favorable to the exer- cise of his functions, while others are not. As long as the human organism is able to offset these influences, through independent changes of its relations to the world or through adaptation of its functions to external conditions, it will remain in health. If his regulating mechanism no longer suffices for successful opposition to unfavorable influences, and if he cannot escape these or change his conditions of life, man becomes ill or dies. For its preservation the body needs a certain amount of food, water, and oxygen; and though it may exist for a short time without these, an insufficient supply beyond a certain limit and after a certain time must lead to disease or death. Total deprivation or diminution in the supply of oxygen to the tissues may take place at any period of life, either because of lack of oxygen in the surrounding medium, or obstruction td the entrance of the oxygen into the lungs or blood, or inability on the part of the blood to take up sufficient. The foetus in utero may . be insufficiently supplied with oxygen as a result of diminished supply to the mother, premature separation or disease of the placenta, or compf.-^ssion of the cord, whereby the interchange of gases between maternal ana fa;tal blood is hindered. After birth an insufficient supply of oxygen may be due to hindrances to respiration, or the child may be so weak that its respiratory movements are insufficient to expand the lungs. When the supply of oxygen is completely shut ofl^, as may happen from the entrance of water or other fluid into the respiratory tract or from closure of the air-passages, the affected individual dies in a short time from choking or suffocation. Animals confined in closed chambers die as soon as the oxygen of the air reaches two or three per cent by volume, the normal volume percentage being 20.8 (CI. Bernard, P. Bert). If the supply of oxygen is not wholly shut ofif, but greatly diminished, as in carbon-monoxide poisoning, in which the firm combination of carbon monoxide with haemoglobin prevents the taking up of oxygen by the red blood-cells, death by suffocation may take place only after several days. In gradually increasing hindrances to the entrance of oxygen and resulting accumulation of carbonic acid in the blood, as in narrowing of the lumen of the larynx through inflammatory exudates, compression of the trachea, weakening or obstruction of respiration, etc., a condition of breathlessness, cyanosis, convulsions, and disturbances of consciousness is produced, which is termed asphyxia. 3 4 THE EXTRINSIC CAUSES OF DISEASE. If the taking up of oxygen is diminished in sHght degree but for a long time, as in the lessened number of red blood-cells in oligocythsemia, de- generative processes characterized by fatty changes may occur in various tissues and may lead not only to disease but to death. Total deprivation of food and water leads to rapid loss of body- weight, inasmuch as fat and albumin continue to be decomposed; death finally ensues. According to Lehmann, Miiller, Munk, Senator, and Zuntz, the total amount of oxidation in starvation does not fall below that of the same individual in the fasting state under the same conditions. In animals death occurs after the loss of about forty per cent of the body- weight, about one-half being due to the waste of muscle. The fat disappears most rapidly; even as much as ninety-three per cent may be lost. The other organs show diminution of substance in the following order: liver, spleen, testicles, muscles, blood, intestines, skin, kidneys, and lungs. The heart, nervous system, and bones show the least loss of weight; but destruction of bone-tissue does take place during starvation, as is shown by the increase of calcium and phosphoric acid in the urine, following ingestion of water. In the blood there is rapid diminution of the leucocytes (Luciani) ; the red blood-cells, on the other hand, may be relatively increased. The organs of animals dying from starvation show simple atrophy of the tissue-elements, particularly of the liver (Lukjanow). After total deprivation of food and water, death occurs in man in from seven to twelve days; exercise hastens the end, ingestion of water may delay it markedly, so that individuals have been enabled through the use of water to endure a period of abstinence from food for thirty days or longer, without suffering permanent harm. Life may be maintained for a long time on insufficient nourishment, but wasting of the body takes place which may lead to extreme emacia- tion, marasmus, or cachexia, and finally to death. The same thing hap- pens when the composition of the food is unsuitable and only a portion of the necessary elements is present, so that the body is starved either in albumin, fat, salts, or water. Dogs deprived of all nitrogenous food die in from thirty-one to thirty- four days (Magendie). When the food is abundant but poor in albumin, there occur after a time (in dogs after six weeks) loss of appetite and repugnance to proffered food, with impairment of digestion and assimilation (Munk). This is especially the case when the food is lacking in fat, less so when albumin or carbo- hydrates are wanting. If for experimental purposes an animal well supplied with food be totally deprived of water, there is rapid loss of weight followed in from eight to twelve days by death. The pathological changes found in the different organs are similar to those resulting from starvation. Literature. Lehman, Miiller, Munk, Senator, und Zuntz: Untersuchung an zwei huns-prnrlpn Menschen. Virch. Arch., 131 Bd., Supplement, 1893. Luciani: Das Hungern (iibersetzt von O. Frankel), Leipzig, 1890. Lukjanow: Verand. d. Zelkerne unt. d. Einfl. d. Hungerns. Arch Hpo «;,- k;^i vi.^und vii., 1897 u. 1898. ' *''• '"°'- Munk: Ueber die Folgen einer ausreichenden aber eiweissarmen Nahnir.™ Virch. Arch., 132 Bd., 1893. i^anrung. FATIGUE; HIGH TEMPERATURES. 5 § 2. An unusual demand on the functional activity of an organ for an extended period leads sooner or later to a state of exhaustion, which is due to the consumption of cell-substance, and to the formation of toxic products of metabolism, whereby the organ is incapacitated for extended activity. Most often the results of overwork are manifested in the muscles and nervous system by such symptoms as soreness and stiffness of the muscles, mental excitement, sleeplessness, loss of appe- tite, weakness, unnatural sweating, and sometimes elevation of tempera- ture. Overwork of the heart may cause death. This may occur either when the heart is for a short time taxed to the limit of its power or when for a longer period it works slightly under its maximum capacity. If the exhausted tissues are permitted to rest and are supplied with an abundance of nourishment, the loss of cell-material will be replaced, the abnormal products of metabolism removed, and the part restored to normal. If a tissue be frequently subjected to excessive functional de- mands, and if the periods of rest are too short to admit of complete restoration, there will ultimately result a condition of permanent func- tional insufficiency which may manifest itself by degeneration or atrophy. For example, a muscle through overwork may become atrophic, and a brain constantly stimulated without proper periods of rest may reach such a state of exhaustion that it is incapable of performing its normal functions. Through rest and proper nourishment such a brain may recover; but beyond a certain limit the functional insufficiency may be- come permanent and manifest itself in anatomical changes. Overwork of any organ is more quickly followed by fatigue and functional insufficiency if its nutrition is defective. Fatigue and insuffi- ciency of the heart are most frequently observed when the general nutri- tion is lowered, as in fever, or when there is deficient oxygenation of the blood, as in poorly compensated heart or pulmonary diseases. Finally, overwork and poor nourishment lower the resistance of the body to infection. When the functional demands on a muscle or gland are only mod- erately increased, and if the nutrition is maintained in proportion to the increase of labor, the tissue becomes hypertrophied, and is enabled to perform increased work permanently. Permanent diminution or cessation of activity causes in organs that normally perform a definite and constant function (muscles and glands) loss of tissue-substance (atrophy). § 3. High temperatures act, either by local destruction of tissue (burning) or by overheating of the entire body. The latter is possible only when the body is exposed to increased temperature for such a time that it cannot protect itself by increased heat-dispersion. In dry air of from 55-60° C. (131-140° F.) even profuse perspiration is no longer able to protect the body from overheating, and in a moist atmosphere the same is true at still lower temperatures. If the human body is subjected to high temperature, it becomes over- heated, and the condition known as heat-stroke results. The pulse-rate is increased, respiration is rapid and labored, the pupils _ dilate, and death may occur as in animals made the subject of experiment. _ The occurrence of heat-stroke is favored by heavy bodily labor, by inter- ference with heat-dispersion through impermeable clothing, or by lack of water in the body. 6 THE EXTRINSIC CAUSES OF DISEASE. The direct action of the rays of the sun on the head may cause cerebral and meningeal irritation, characterized by hyperaemia and in- flammatory exudation, and the resulting condition is known as sun-stroke or insolation. The local effects of heat on the skin, burns, are shown, according to the intensity of the heat and the time of its duration, either by hyper- aemia (burn of first degree), by the formation of a blister (second degree), by tissue-eschai' (third degree), or by carbonization (fourth degree). The heat produces local changes in the tissues, and kills them at a certain height or after a certain exposure. When a large part of the surface of the body, about one-third, is burned, the individual usually dies, even though the burn be only of slight degree and eschars are not formed. The anatomical findings in fatal cases of superficial burns would indicate, when death has not re- sulted quickly from shock, that the cause of death is to be sought in changes in the blood and in disturbances of the circulation. The blood- changes consist in the loss of a portion of its water and in destruction of the red cells, or in such injury to them as diminish their function and give rise to a deposit of the products of destruction of haemoglobin in the liver, spleen, and kidneys. The circulatory changes are characterized by a tendency on the part of the blood to stasis, hemorrhages, and intra- vascular coagulation, through which vessels of both the pulmonary and the systemic circulation may be obstructed, so that local tissue-degen- eration and necroses occur in certain organs, for example, in the kidneys, liver, mucosa of the stomach and intestine, bones, and soft parts. Low temperatures act in the same manner as high ones, in part by local injury and death of tissues, in part by refrigeration of the entire body. Severe and lasting lowering of temperature causes tissue death; after mild chilling there occur, as the result of tissue-degeneration, throm- bosis, hyperaemia, and exudations which are relatively rich in leucocytes. Short refrigeration at the freezing-point is sufficient to produce degener- ative changes followed by regenerative proliferation on the part of the uninjured cells. Epithelial thickenings may be produced (Fuerst) by repeated slight refrigerations (as well as by repeated slight increase of temperature). The tips of the extremities, nose, and ears are the most easily frozen. _ After repeated chillings of mild degree redness and swell- ing of the skin, associated with severe itching, often occur (chilblains, perniones). If the temperature of the entire body be markedly lowered, general paralysis results from diminished excitability of the tissues, the nervous system and heart being especially affected. The sensorium becomes dulled, the heart-beat and respiration grow weaker, and finally cease. If the body be warmed, before the excitability of the tissues is wholly lost by crystalization, the power of movement in the limbs is gradually restored, and after a time consciousness returns. In man, instances of complete recovery have been observed, even after refrigeration of the body to from 24-30° C. (75-86° R). Besides the more severe forms of local or general lowering of the tis- sue temperature there may occur mild, general or local chillings the so-called colds, as the result of which disease-phenomena may manifest themselves at the seat of chilling, and in distant parts. For example after wide-spread refrigeration of the skin there may occur diarrhcea' THE EFFECTS OF HIGH AND LOW TEMPERATURES. 7 catarrh of the respiratory tract, or disturbances in the kidneys; after local chilling of the skin, painful affections of the deep-seated muscles. The exact relation between these phenomena and refrigeration is un- known (the oft-repeated hypothesis that they are due to hypersemia of the internal organs caused by the chilling of the surface has not been proved), but there is no reason on this account to deny the existence of diseases caused by cold. Though many diseases formerly attributed to " catching cold " have been shown, to be of infectious origin, there yet remain a number of disease conditions for which we know no other eti- ology than that of refrigeration. Conditions in which the skin is hyper- semic and the perspiratory function active favor the taking of cold. Many individuals appear to possess a predisposition on the part of certain tis- sues to the effects of refrigeration ; in one person certain muscles, in an- other the mucous membranes may be affected. According to many writers, refrigeration of the body increases the susceptibility to infection, so that, for example, pathogenic bacteria which may be present in the cavities of the body may, after such refrigeration, be able to exert injurious influences upon the tissues. If rabbits are placed in well-ventilated incubators at a temperature of 36-40° C. (96.5-104° F.), the body temperature will rise to 39-40° C. (102.3-104° F.), the respiration and pulse being at the same time greatly increased in frequency. A very marked elevation of body temperature may lead in one to three days to death through paralysis of the nervous and muscular systems, the chief symptoms being increase of both respiratory and cardiac activity. If the increase of body tempera- ture is not greater than 2-3° C. (3-5° F.), the animals may, if properly nourished, live from ten to thirty days or even longer, but they will lose in weight and ulti- mately die, showing before death a gradually increasing diminution of hjemoglobin and of red blood-cells. Degenerative changes, particularly fatty degeneration, occur in the liver, kidneys, and heart muscle. According to Pfluger and others, all the vital processes may be brought to a standstill through refrigeration, without it being_ impossible for recovery to take place. Preyer also holds that the continuity of life may be wholly interrupted by refrigeration, and designates subjects who are thus "lifeless," but still capable of living, as anabiotic. Frogs are said to remain capable of life for many hours, even though the temperature be reduced to — 2.5° C, at w'hich point the heart is frozen. According to the investigations of Koch, such anabiosis of frozen animals is possible when only a portion of the water in the body is frozen and when the thawing process takes place slowly. In the case of rapid thawing, strong diffusion currents are set up between the water coming from the ice^:rystals and the concentrated albuminous solutions of the blood and the tissues ; and these currents exert a damaging effect. According to the investigations of /. Dewar (Proc. of the Royal Sac, London, 1900), the seeds of wheat, barley, mustard, peas, and pumpkins do not lose their germinative power when put into liquid hydrogen; that is, in a temperature of — 250°. Further, the protoplasm under these conditions is not changed by the cold. Not only do the heat-rays of the sun-light or the arc-light affect the human body, but their chemiccilly active violet and ultraviolet rays also have an important action upon tissues. According to Young, Beclard, Schnetzler, Godnew, and others (for literature see Sack, I.e.), the processes of growth and regeneration are carried on more rapidly under the influence of blue and violet rays than in ordinary con- ditions. According to Finsen, variola-lesions in the skin run a more favorable course when protected from the violet rays by means of red glass. According to the investigations of Maklakow the violet and ultraviolet rays of the arc-light can pro- duce a peculiar erythema of the skin, even when the heat-rays are excluded {Widmark). Finsen holds that "sunburn" is produced chiefly by the violet and ultraviolet rays. Bacteria in plate-cultures are killed within a short time by exposure to the ultraviolet rays of the arc-light. According to the investigations of Godnew, Finsen, Moller, and others, the violet and ultraviolet rays penetrate the skin, but are absorbed by the blood. Basing his views upon these facts, Finsen has treated skin diseases, especially lupus, vascular nasvi, acne, etc., with the ultraviolet rays of the 8 THE EXTRINSIC CAUSES OF DISEASE. sun and the arc-light. The heat-rays are excluded by means of quartz lenses and chambers of running water. A hollow lens of quartz through which water is ttowmg is pressed firmly against the affected area in order to exclude the blood, which absorbs the ultraviolet rays. According to investigations by Dreyer, confirmed by Neisser and Halberstaedter, infusoria, bacteria, and animal tissues when impregnated with erythrosin (solution of 1 :1,000-1 :4,000) become sensitized to red and yellow rays, so that these rays act upon them in the same manner as the violet and ultraviolet. Since the red and yellow rays possess a greater power of penetration into the tissues, a more marked and deeper effect of irradiation can be obtained by the previous treatment of the tissues with solutions of erythrosin. Roentgen-Rays, acting upon bhe skin for some time, cause at point of entrance and exit, degenerative changes affecting chiefly the epithelium, but also the connec- tive-tissue cells. These are followed by infiannmatory processes. Clinically these changes show themselves usually about fourteen days after exposure, and reach their acme after some weeks. The hair and finger-nails may be lost. If tissue- necrosis occurs, the healing of the resulting ulcer _ is slow and difficult. The Roentgen-rays have also been used with some success in the treatment of lupus and carcinoma of the skin. Exposures of 30 to 60 minutes are given, and repeated two or three times. After one or two weeks the cancer shows an inflammatory reaction. Healing takes place through the destruction of the tumor cells, which are especially ■susceptible to the action of the rays ; and the resulting ulcer heals through the formation of scar-tissue and regeneration of the epidermis. In the case of carci- noma of the mamma a certain amount of destruction of the neoplasm may be accomplished, but not to the extent of cure. Recent cases have been observed of cancer developing in skin frequently exposed to Roentgen-rays. According to investigations by Hehieke and Warthin, the experimental irradi- ation of rats, mice, guinea-pigs, rabbits, and dogs causes, even after fifteen-minute exposures, marked destruction of the lymphoid cells of the spleen, bone-marrow, and lymph-nodes. The disintegration of the lymphoid cells is evident almost imme- diately after the exposure, and persists for some hours. After single exposures regeneration is rapid, but after prolonged or repeated exposures the spleen may finally' become practically devoid of lymphoid cells. In exposures of this degree the death of the animal usually takes place within ten days, after it has exhibited marked symptoms of intoxication. Small animals may be rendered blind by pro- longed exposures. In the use of Roentgen-rays as a curative agent in leukaemia it has been shown that the size of the spleen may be greatly diminished, the white-cell count brought to normal and the general conditiion temporarily improved. Warthin has shown that this improvement is due wholly to the destructive action of the rays upon the white cells of the blood-cell-forming organs, and that the essential disease- process is not cured. He has also emphasized the dangers of intoxication arising from the products of proteid disintegration, and has shown the occurrence of extensive degeneration and calcification of the kidneys in cases so treated. His investigations show also that slight changes occur in the renal epithelium as the result of short exposures. Capps believes that a leukotoxin is produced in the seTa of animals exposed to the rays. Schoh, Seldin, Philipp, Halberstaedter, and others have demonstrated the production of azoospermia in man and animals by means of Roentgen irradiation. Numerous, cases of sterility in Roentgen-ray operators have been observed. Bardeen found that the death of spermatozoa is hastened by irradi- ation, and that spermatozoa injured by short exposures to Roentgen-rays but still capable of fertilization, may cause the development of monsters from ova 'fertilized by them. He concludes that nuclear material may be so influenced by exposures to the rays that after a latent period it may show marked abnormalities in develoc- ment. Foersterling warns against the dangers of irradiation in young children Edsall has reported an instance of death following Roentgen irradiation and the present tendency is to regard the rays as agents capable of producing serious damao-e to the animal organism. ° According to certain observers, the lymphocyte is an important agent in the defensive mechanism against tuberculosis. A number of investio-ators have attempted to show that exposure of guinea-pigs to massive doses of X-rav follow ing inoculation with urine and other fluids containing tubercle bacilli brings about a positive result more quickly than otherwise. Kellert, however, in a carefuUv trolled series of investigations has shown that when fluids containing no micro' organisms other than tubercle bacilli are injected, radiated guinea-pigs are found tn be no more susceptible to tuberculosis than the control animals If however th ROENTGEN RAYS. 9 injected fluids are contaminated by other micro-organisms, the radiated guinea-pigs are rendered more susceptible to secondary infection. (Journal of Medical Research, Vol. 39, 1918, p. 93.) Becquerel-Rays act similarly to the Roentgen. Tissue-degenerations and in- flamimations appear in the second or third week after the exposure and reach their acme in 20-30 days (Halkin, I.e.). Slowly healing ulcers may be formed. Some success has been claimed in the treatment of cancer of the skin and lupus. Accord- ing to Pfeiffer, Friedherger, and Scholtz the rays are bactericidal, and a portion of the active rays can penetrate the tissues to a depth of several millimetres. Roentgen- and Becquerel-rays are not, like light, heat, and electricity, special forms of undula- tions of the ether, but consist of extremely minute particles of matter, electrons, ■which are given off into space with great rapidity. In the case of the Roentgen-rays the projecting power is the electrical energy supplied to the Roentgen tube. The Becquerel-rays represent a property of certain bodies designated by Becquerel as radio-activity. In 1896 this investigator discovered that uranium and its salts give off rays that act upon photographic plates in the dark and are capable of penetrating bodies impervious to light. In 1898 Madame Curie succeeded in separating from pitchblende two radio-active bodies which were named radium and polonium. In 1899 a third radio-active body {actinium) was discovered by Curie and Debierne. Radium has been produced in a pure form and has been the most carefully studied. It is a new element, the salts of which are radio-active in the hig'hest degree and project electrons into space at a velocity of 160,000 kilometres per second, at the same time giving off heat-rays. The air about it becomes ionized, that is, becomes a conductor for electrical discharges. The action of radium upon the tissues is similar to that of Roentgen-rays. According to Hinstedt {Ann. der Physik, 1903), numerous springs, hot ones in particular, are radio-active, and it is not improbable that their special action is in part dependent upon this property. Literature. {Effects of High and Low Temperatures.) Bardeen: A Review of the Pathology of Superficial Burns, Johns Hopkins Hoap. Rep., vol. vii. Finsen: Ueber die Bedeutung d. chem. Strahlen des Lichtes f. Medizin, Leipzig, 1899. Fuerst: Verand. d. Epidermis durch leichte Warme- und Kalteeinwirkung. Beit. V. Ziegler, xxiv., 1898. Koch: Wirkung der Kalte und Ana'biose. Biol. Cent., 1890, u. xv., 189S. Neisser u. Halberstaedter: Lichtbehandlung nach Dreyer. D. med. Woch., 1904. Pfliiger: Die allgemeinen Lebenserscheinungen, Bonn, 1889. Prayer: Ueber Anabiose. Biol. Centralb., xi., 1891. Sack: Wesen d. Finsenschen Lichtbehandlung. Miinch. med. Wochenschr., 1902. {The Effects of Radio Activity.) Bardeen: The Action of Roentgen Rays upon Spermatozoa. Amer. Medicine, 1906. Capps: On the Production of a Leukotoxin by Roentgen Irradiation. Trans. Assoc, of Amer. Phys., 1906. Edsall: Dangers of Roentgen Irradiation. Jour. Amer. Med. Assoc, 1906. Halkin: Einfluss der Becqnerelstrahlen auf die Haut. A. f. Derm., 65 Bd., Heineke: Einwirk. d. Roentgenstrahlen auf inn. Organe. Miinch. med. Woch., 1904. Scholtz: Einfluss der Roentgenstrahlen auf die Haut. Arch. f. Derm., 59 Bd., 1902; Roentgenstrahlen. Eulenburg's Jahrb., ii., 1904; Wirk. d. Radmms. D. med. Woch., 1904. Warthin: The Effects of Roentgen Rays upon the Blood-formmg Organs. International Clinics, Jan., 1906; ibid. With Especial Reference to the Treatment of Leukemia. Physician and Surgeon, 1907 (Lit.); Action of Roentgen Rays upon the Kidney. Am. Jour, of Med. Sciences, 1907 (Lit.). 10 THE EXTRINSIC CAUSES OF DISEASE. § 4. Sudden lowering of atmospheric pressure, as in mountain- climbing and balloon ascents, may cause great exhaustion, with marked palpitation of the heart, unconsciousness, irregular breathing, and some- times vomiting, and bleeding from the gums and lips. These symptoms depend upon lack of oxygen (P. Bert), the capillaries of the lungs being unable to take up sufficient oxygen from the rarefied air. Kroenecker believes that they are to be referred to disturbances of the pulmonary circulation. According to the investigations of Schumburg and Zuntz, it appears that a given amount of labor calls for a greater amount of oxygen at an increased elevation than at a lower level. The symptoms of mountain-sickness appear at a lower elevation than those of balloon-sick- ness, owing to the demands made upon the muscles in the former case during the climbing. During the building of the Corner Grat Railway it was found that at a height of 2,700-3,000 metres the capacity of the laborers was diminished to a third. According to the researches of Egger, Miescher, and others, sojourn in high altitudes leads, after a short time, to increase in the number of red cells and a greater haemoglobin-content of the blood. Schaumann and Rosenquist hold that the same phenomenon may be observed in animals confined for some time in bell-jars at a lower atmos- pheric pressure. Other authors (Schumburg, Zuntz, Gottstein) oppose this view, and maintain that the phenomenon is due either to concen- tration" of the blood, from loss of water and to changes in the distribu- tion of the blood, or to changes in volume of the measuring-apparatus; they endeavor to explain the favorable effects which many individuals experience from a residence at high altitudes by certain stimulating influ- ences (greater exposure to sun's rays) which affect the nervous system and cause increased metabolism. According to Marti, intense and pro- longed irradiation of the body stimulates the formation of red blood-cells and to a lesser degree also that of the haemoglobin. A sojourn in diving-bells or caissons, such as are employed in build- ing operations beneath the water, in which the atmospheric pressure is increased, under certain conditions, as high as four atmospheres or even greater, causes a slight difficulty in breathing and a relatively unimpor- tant increase of the pulse-rate. If a change be made quickly from the compressed atmosphere to air of ordinary pressure, there may occur within an hour a condition of great fatigue, tightness of the chest, ring- ing of the ears, cramps in the muscles, pains in the joints and limbs, haemorrhages from the nose, ears, and lungs, dilatation of the pupils, and under certain conditions paralysis, coma, delirium, and even death after an interval of from one to twenty days (Caisson disease). The cause of these phenomena is probably to be found in the obstruction of blood- vessels of the spinal cord by bubbles of nitrogen that has been absorbed under high pressure (Hoche). According to experimental investigations of Heller, Mager, and von Schrotter, the blood, after rapid removal of pressure, contains free gas (almost exclusively nitrogen). In fatal cases associated with paralysis areas of degeneration (Nikiforoff) are found in the white columns of the spinal cord, in which individual nerve-fibres present marked changes in the form of swelling of the axis-cylinders and disintegration of the medullary sheaths, with the formation of vacu- oles in the place of the nerve-fibres that have been destroyed If the gray matter is involved, the ganglion-cdls may degenerate ELECTRIC CURRENTS. 11 Changes in the electrical condition of the atmosphere and in the mag- netic state of the earth have no demonstrable influence upon the human l)ody; op the other hand, electric discharges, as hghtning-stroke, may cause, in part, local lesions of the skin resembling burns, haem- orrhages in the skin, and burning of the hair, and, in part, lesions of the whole body. Under certain circumstances lightning-stroke causes lacera- tion of internal organs, as, for example, the heart and liver. The most frequent and important effect of lightning-stroke is paralysis of the nervous system, which gives rise to severe dyspnoea, which may be immediately fatal, or after a few minutes or hours, or may gradually pass away after several hours, days, or weeks. Only rarely do individual nerve-trunks remain permanently paralyzed. A transitory paralysis may occur when the electrical discharge has not passed through the body, but has descended in its neighborhood. In individuals who have been struck by lightning there may be found slight or severe burns of the skin corresponding to the points of entrance and exit of the current, and various injuries to the tissues in the course of its path through the body. The marks of the burn are for the greater part red, and form peculiar zigzag lines, the so-called lightning figures which soon disappear if the burns are not severe. The passage of powerful electric currents of high tension, such as are generated by dynamos, through the human body, as may happen when an individual is placed in a circuit or comes into contact with an uninsulated conductor, may give rise to severe disturbances or cause death. According to Kratter, the lower limit of danger occurs at a ten- sion of about five hundred volts. Alternating currents are more danger- ous than continuous ones of the same strength and tension. When the effects are not fatal, the injured person is suddenly rendered uncon- scious, this condition lasting for a few minutes or several hours, and for several days afterward vertigo, prostration, headache, and palpitation of the heart may persist (Kratter). At the points of contact more or less severe burns are produced. In fatal cases, death takes place suddenly or rarely after ten or thirty minutes. The autopsy findings, aside from the burns at the points of contact, are indicative of suffocation and hypervenosity of the blood, stasis within the thoracic vessels, and often small scattered haemorrhages due to the direct action of the current. The cause of death is paralysis of the centre governing respiration or the heart's action. Literature. (Effects of Changes of Atmospheric Pressure and of Solarization.) Egger: Veranderungen d. Blutes im Hochgebirge. Congr. f. inn. Med., Wies- baden, 1893; u. Arch, f. exp. Path., 39 Bd., 1897. Gottstein: Klimat. Einfliisse als Krankheitsursachen. Ergebn. d. allg. Path., iv., Wiesbaden, 1899; Vermehrung der rothen Blutkorp. im Hochgebirge. Miinch. med. Woch., 1899. Heller, Mager, Schrotter: Mitth. iiber Caissonarbeiter, Klin. Woch., 1895; Untersuch, iiber d. Wirkung rascher Veranderungen d. Luftdruckes. Pfliiger's Arch., 67 Bd., 1897; Luftdruckerkrankungen, Wien, 1900. Hoche: Luftdruckerkrankung d. Centralnervensystems. Berl. klin. Wochenschr., 1897. Kronecker: Die Bergkranheit. Deutsche Klinik, Bd. xi., 1903. 12 THE EXTRINSIC CAUSES OF DISEASE. Marti: Wirkung der Hautreize und Belichtung. Verh. d. Congr. f. inn. Med., Wiesbaden, 1897. ^ „, r- ui r Miescher: Bezieh. zwisch. Meereshohe u. Beschaftenh d. Blutes. Corrbl. f. schweiz. Aerzte, 1893. Nikiforoff: Veranderungen d. Riickenmarks in Folge schneller Herabsetzung des barometrischen Druckes. Beitr. v. Ziegler, xii., 1892. Schaumann u. Rosenqvist: Blutverand. im Hohenklima. Zeit. f. klin. Med., 35 Bd., 1898. Schumburg und Zunz: Einwirkung des Hochgebirges. Pfliiger's Arch., 63 Bd., 1896. (Effects of Lightning and Electrical Currents.) D'Arsonval: L'energie electrique. Path. gen. putil. par Bouchard, i., Paris, 1895. Kratter: Wirkung d. Blitzes. Vierteljahrsschr. f. ger. Med., 1891; Tod durch Elektricitat, Wien, 1896 (Lit.); Elektrische Verungliickungen. Eulenb. Jahrb.,vi., 1896 (Lit). Mills and Weisenburg: The Effects on the Nervous System of Electric Cur- rents of High Potential. Univ. of Penn. Med. Bull., 1903. 2. The Origin of Disease through Mechanical Influences. § 5. Traumatic influences of various kinds leading to concussion, bruising, and laceration of tissue are of frequent occurrence, and act through the tearing of tissue, through changes in tissue-organization not recognizable by the naked eye, through rupture of blood- and lymph- vessels, and through irritation and paralysis of nerves. The sequelae are represented by necrosis, disturbances of circulation, inflammation, and regenerative proliferations. Frequently repeated traumatism of slight degree, such as rubbing, may give rise to hypercsmia and inflammation, which may lead to hyperplastic growth of tissue. If large quantities of insoluble dtist particles are continuously taken into the lungs induration of the pulmonary tissue may develop. As a result of .prolonged pressure, atrophy of an organ or tissue may occur (corset-liver). After a single or after frequently repeated trauma, there may de- velop under conditions at present unknown to us, malignant new-forma- tions called tumors. Trauma may further pave the way for infection, in that the wound caused by the trauma is infected at the time of injury or is secondarily infected from without; or that micro-organisms pre- viously present in the body under conditions inhibiting their growth find in the injured tissues a suitable soil for proliferation. Traumatic influences affect, iirst of all, the external parts of the body; but it may happen, either with or without visible injury, that internal organs are injured, and the lacerations, necroses, and haem- orrhages thus produced, may be followed, not by inflammation and reparative tissue proliferation, but also by malignant neoplasms, and by infective processes. Mechanical lesions (also thermal, electrical, and corrosive) run a spe- cial course, if through local injury the nervous system becomes in- volved. Such involvement occurs either through the direct action of the trauma upon the central nervous system; or, by the stimulation of the sensory or sympathetic nerves, the central nervous system may be so affected that a number of additional nervous symptoms follow If direct concussion of the cranium is followed by paralysis of the cerebral function and unconsciousness, the condition is called commotio SHOCK; TRAUMATIC NEUROSES. 13 cerebri or cerebral concussion. This term is specially used when the trauma has produced no visible changes in the structure of the brain, or at least none of notable size. Excessive stimulation of the peripheral nerves may cause reflex in- hibition or paralysis, involving chiefly the functions of the heart and respiratory apparatus; the symptoms thus produced being collectively designated as shock. The most frequent causes of shock are injuries to the spinal column, abdominal contents, and scrotum, less frequently to the extremities and thorax. Further, shock may be caused by lightning- stroke, burns, corrosions of the skin; fear, and other strong emotions. Individuals whose nervous systems are in a certain condition of irrit- abiHty are specially liable to shock; conditions of narcosis and drunken- ness inhibit its occurrence. Shock is characterized chiefly by diminished energy on the part of the heart and irregular breathing, which lead to decrease in the inter- change of gases in the tissues and to lowering of the temperature (Roger). The consciousness is usually preserved, the skin and visible mucous membranes are pale, the pulse is small and markedly quickened, often irregular and intermittent. Further, the individual suffering from shock may be excited, groan, shriek, and exhibit fearful anxiety associated with dyspnoea {erethistic shock) ; or he may lie quiet, with sunken countenance, and evidences of great weakness of both sensory and motor functions {torpid shock). In severe cases death takes place from stoppage of the heart and of respiration. Shock, being due to the over-stimulation of the peripheral nerves, is allied etiologically to the phenomenon known as syncope ; but the last- named condition differs essentially irom shock in that its chief symptom is transitory loss of consciousness, while the functions of the heart and respiration show no marked disturbance. Syncope, furthermore, is usu- ally preceded by prodromal symptoms, such as dizziness, ringing in the ear, and darkening of the visual field, these being absent in shock. Not infrequently, following injury to some part of the body, there arises a more or less pronounced functional disturbance of the nervous system, which may often persist long after the local injury has healed, so that such disturbance is in no way dependent on anatomical changes in the peripheral or central nervous system, but must be regarded as a disturbance of psychical origin. Such conditions are term.ed traumatic or accident neuroses, and are characterized chiefly by subjective but in part by objective symptoms. To the first belong pains not definitely localized at the seat of injury, as headache, pain in the chest, backache; difficulty in movement, lassitude, inability to perform mental labor, dul- ness of perception, disturbances of sight, flashes before the eyes, dizzi- ness, restless sleep, loss of appetite, and disturbances of digestion. With these last symptoms are associated psychical depression of a hypochon- driacal or melancholic character, irregularly placed areas of cutaneous anaesthesia, enfeeblement of the senses of taste, hearing, and smell, motor paralysis, cramps, and hypersesthesia, concentric narrowing of the visual field, pareses, muscular spasms, tremors, acceleration of the pulse, and tendency to sweating. All of these phenomena depend essentially on psychical shattering of the perceptive life, a psychoneurosis. The condition may partake of 14 THE EXTRINSIC CAUSES OF DISEASE. the nature of hysteria, as characterized by disturbance of the normal relation between the mental and bodily processes; of hypochondria, as recognized by the spontaneous occurrence of abnormal sensations; and of neurasthenia, which reveals itsel^f by the production pf abnormal sensations through relatively slight stimulation. If the will no longer controls the motor centres, hysterical paralyses arise; if the normalcon- trol and inhibition of the will are lost, so that unreasonable will-stimuli are created and influence the muscles, hysterical twitchings, contractures, or convulsions take' place. If a nervous stimulus arising in the sensory tract fails to reach the consciousness, there follows hysterical anaesthesia ; if there arise in the consciousness the images of expected or f eared_ sen- sations, and if these images are intensified into actual subjective stimuli of consciousness, hysterical pains and neuralgias result (Striimpell). Rosenbach designates as kinetoses those diseases which arise when energetic and continuous movements of the body in one direction are changed into the oppo- site direction, so that a shifting of the internal organs results. In this class belong the pathological phenomena observed in seasickness, and in the conditions caused by see-sawing, whirling, movement in a vertical direction, and sudden stoppage of motion. As a result of the rapid change in direction of bodily motion, the molecules which are moving in the line of the primary direction are forced to move in the opposite direction, and, according to Rosenbach, such a change is sufficient to cause more or less important molecular disturbance. He explains the symptoms of sea- siclcness, as, for example, the abnormal secretion of the stomach, the increase of intestinal peristalsis, the vomiting, etc., as the results of purely mechanical influences on the tissues, and believes that the liver, intestine, brain, and nerve-plexuses are similarly affected through mechanical influences acting upon their protoplasm. On the other hand, Binz refers seasickness to an acute anaemia of the brain which causes the nausea and vomiting. A horizontal position and the administration of a water solution of chloral hydrate, which dilates the arteries of the head, have a favorable action upon the condition. Literature. {Effects of Trauma.') Roger: Choc nerveux. Arch, de phys., v., 1893, vi., 1894. Rosenbach: Die Seekrankheit, Wien, 1896; u. Eulenburg's Realencyklop.. xxii.. 1899. Striimpell: Traumat. Neurosen. Miinch. med. Woch., 1889: Verb d XII Congr. f. inn. Med., 1893. 3. The Origin of Disease through Intoxication. It is difficult to give an exact definition of poison and poisoning, since the action of the substances considered in this connection varies greatly according to the dose and attenuation, as well as the method of introduc- tion into the tissues of the body. The most powerful poisons when in- troduced in minute doses may not only be harmless, but may exert a beneficial or curative effect. On the other hand,' substances which are not usually classed with poisons, such as the non-corrosive sodium salts, when introduced into the body in large quantities or in concentrated solu- tions, may produce effects which must be regarded as of the nature of poisoning. Further, poisons in certain dilutions (phenol) may serve as food-material. § 6. By poisoning or intoxication is meant that impairment of health, caused hy the injury to a tissue, which certain substances, by virtue of their chem,ical nature, are able to produce under certain conditions. Such POISONS. 15 substances are termed poisons, and are derived partly from the mineral kingdom, partly from the vegetable, and partly from the animal king- dom. They may occur in a natural state or be produced artificially from inorganic or organic substances. Many of the most important poisons are products of plant or animal life, and are formed within the tissues of the plant or animal. Other poisons belonging in the same category are derived from the decomposition of food-stuffs brought about by the growth of certain lower forms of vegetable life. The most important poisons belonging to the mineral kingdom or which are produced from minerals are: metallic mercury, chlorine, bromine, iodine, sulphur, and various combinations of these substances, dift'erent combinations of arsenic, antimony, lead, barium, iron, copper, silver, zinc, potassium, sodium, chromium, etc. Of the poisons containing carbon, which are artificially produced, the most important are: chloroform, chloral hydrate, ether, alcohol, iodoform, carbon bisulphide, hydro- cyanic acid, potassium cyanide, oxalic acid, nitroglycerin, amyl nitrite, petroleum, carbolic acid, nitrobenzole, picric acid, and aniline. It may be observed in this connection that modern chemistry is constantly pro- ducing new substances, some of which are poisons. Of the poisons produced by plants of the higher order, those of chief importance are : the vegetable alkaloids, such as morphine, quinine, colchi- cine, atropine, hyoscyamine, veratrine, strychnine, curarine, solanine, nicotine, digitaline, santonin, aconitine, cocaine, coniine, muscarine, and ergotine, all of which in relatively small doses cause poisoning. The lower forms of plant life, especially bacteria, produce an extraordi- nary variety of both poisonous and non-poisonous substances, out of the food material in which they develop. Some of these substances are simi- lar to the vegetable alkaloids, others to the ferments, and are therefore designated toxic cadaveric alkaloids, toxic ptomdins, toxins, and toxen- zymes (compare § 11). It may happen that the blood, flesh, or any organ of a healthy animal acquires poisonous properties through the presence in it of products of bacterial growth. Examples of disease due to bacterial poisons in the food are botulismus, sausage, meat, fish, and cheese poisoning. These conditions are to be explained, in part by the growth of bacteria {B. botulinus) in the food and the formation of poisonous products, (§ 11) ; in part by the fact that germs were present in the tissues of the animal before death, and the animal having been slaugh- tered while diseased, the use of its flesh as food causes either symptoms of poisoning or of the same disease as that which affected the animal. Under certain conditions foods which are not spoiled may contain bac- teria, and these may develop in the intestine of the individual eating the food and cause poisoning through the production of toxins, or enzymes. According to Lombroso, the disease pellagra, which is of common occurrence in Italy, Roumania, and Greece, is caused by the eating of decomposed corn. The disease kakke or beri-beri, which is endemic in Japan, is regarded by Miura and Yamagiva as due to the extended use of rice which has been spoiled in drying. Among the animals which normally produce poisons within certain tissues of their bodies, the best known are : serpents, toads, salamanders, fish, mussels, oysters, scorpions, Spanish flies, and many stinging insects. Certain forms of sea-fish are poisonous at all times, others only at certain, periods, and observations have been made particularly of such fish found in Jap- 16 THE EXTRINSIC CAUSES OF DISEASE. anese waters. According to Saotschenko, the poison of many poisonous fishes is secreted by certain skin-glands found at the roots of the dorsal and caudal fins, and may be found also in the eggs of such fish. According to Remy, Miura, and Takesaki, the poison is secreted in the sexual glands alone in the case of the poison- ous fish belonging to the family Gymnodontes (tetrodons). According to Masso, there is found in the blood-serum of eels a toxic substance (ichthytoxin) which, when introduced into the small intestine of animals experimentally, causes symptoms of poisoning and may kill the animal. According to M. Wolff, the liver of mussels (Mytilus edulis) contains the poison ; its action, according to Schmidtmann, Virchow, Salkowski, and Brieger, is similar to that of curare. Brieger has also shown that from the poisonous mussels there can be obtained basic substances closely related to ptomains, the basic products of decomposition. To what extent the pro- duction of poisons in poisonous fishes and mollusks is to be ascribed to normal and to what extent to pathological processes cannot at present be decided. From the fact that the mussels and oysters are poisonous only in certain places where the water is impure, and as the starfish found in the same localities are similarly effected, it is probable that the poisonous action of these mollusks may in part be due to their contamination with bacteria or to the occurrence of certain diseased conditions. Tht .venom of serpents is formed exclusively in the poison-glands lying in the upper portion of the corner of the mouth. It is a green or yellowish fluid and its activity is not influenced by drying or by preservation in spirits. Snake venom, the poison of spiders and toads and of the blood of the eel and murana, ricin {obtained from the seed of the castor-oil bean), and ahrin {from the seed Abrus precatorius) show properties similar to those of the bacterial toxins (compare §11). Snake-poison and that of the blood of the eel have also a haemolytic action. § 7. Poisons may be divided according to their action into three groups: first, those producing local tissue-changes; second, those acting injuriously upon the blood; third, those affecting chiefly the nervous system and the heart without producing recognizable anatomical lesions. The poisons which cause marked local lesions injure the tissues with which they first come into contact. If such poisons are diflfused by means of the body-fluids, diverse organs and tissues may be injured ; but their action is usually limited to that organ in which they are stored up or through which they are excreted, especially the liver, intestine, and kidneys. The primary seat of injury is most often the mucosa of the upper portion of the intestinal tract and the respiratory passages, but in many cases the skin is first affected. Frequently poisons, which are employed for disinfecting, are brought into contact with wounds for the purpose of killing bacteria or preventing their growth, and in this way cause local changes or are absorbed and damage deeper tissues. The poisons belonging to this class are those which cause tissue- changes at the point of contact, similar to those of burns, and for this reason are designated caustics or corrosives. If the action of a caustic reaches its greatest degree of severity, the affected tissue is destroyed and converted into either a dry, hard eschar, or a moist, soft sloucrh If the action is of moderate intensity as the result of a less concentrated solution of the caustic agent, or of incomplete action of the chemical even when applied in strong solution or in substance, or because the tissue Itself is resistant as in the case of the skin, the changes produced are less severe, and are characterized by inflammation and haemorrhage Diverse changes are often found in the same organ, such as local 'slou?hine (necroses), haemorrhages, inflammations, and local hyperemia If the changes have existed for some time, the local eschars are surrounded bv an inflammatory zone, which in the case of certain caustics mav be of limited extent. ^ POISOXS. 17 The caustic poisons are : first, the corrosive acids, sulphuric, nitric, hydrochloric, phosphoric,_ oxalic, arsenic, arsenious, osmic, acetic, lactic, trichloracetic, carbolic, and salicylic; the corrosive combinations of the alkalies and alkaline earths, potas- sium and sodium hydroxide _ (watery solutions of KOH and NaOH), caustic ammonia (solution of NH3 in water), ammonium carbonate, caustic lime, and barium sulphate. In this class are also certain corrosive salts, chiefly of the heavy metals, such as salts of antimony (tartar emetic and antimony trichloride), salts of mercury (corrosive sublimate and red precipitate), nitrate of silver, zinc chloride, zinc sulphate, copper sulphate and copper acetate, aluminum acetate, potassium chromate and bichromate, and chloride of iron. The caustic poisons_ derived from animals are : cantharidin, from the beetle Lytta yesicatoria ; phrynin, the secretion from the cutaneous glands of the toad; the secretions from the poison-glands of snakes and scorpions; the secretion of the sting-gland of bees, wasps, and hornets; the secretion of the salivary glands of stinging-gnats, flies, and gad-fiies; and the secretion of the poison-glands of the maxillary palpse of spiders (tarantula) — all of which cause local necrosis, or haemoirhage and inflammation. Many of the higher plants produce in their blos- soms, seeds, stems, or roots substances which, when brought into contact with the tissues, cause irritation and inflammation, as, for example, daphne, different forms of Ranunculus, varieties of anemone Primula obconica (pubescent portion), marsh- marigold, different varieties of Calla, dragon-root, Croton tiglii (from the seeds of which croton-oil is obtained), buckthorn (Rhamnus cathartica), black elder (Rhamnus frangiJtla) . The nature of the local changes which these and similar substances produce is varied, and is dependent partly on the activity of the poison, and partly on the location and manner of application. The mineral acids, solutions of caustic potash "and mercuric chloride, when concentrated, cause marked tissue-eschars, associated with haemorrhagic inflammation, especially when taken into the stomach. Through the action of acids there is marked withdrawal of the alkaline constituents of the body fluids, leading to disturbances of respiration and circulation. The venom of snakes usually causes severe local inflammation and haemorrhages, which often extend beyond the region of the bite, and sometimes may cause widespread gangrene. There are snake-venoms, however, which produce only insignificant local changes, the general symptoms of poisoning being more prominent. The volatile or gaseous poisons affect chiefly the mucous membranes of the eye and respiratory tract {irrespirahle gases). To this class belong especially the. fumes of ammonia, chlorine, sulphurous acid, nitric oxide, nitric dioxide, nitric trioxide, osmic acid, formalin and mustard-oil. The action of these poisons is varied, often causing only transitory hypersemia, but being able also to give rise to tissue necrosis and inflammation. The irritation of the respiratory tract gives rise to coughing, and spasmodic narrowing of the glottis may interfere with breathing. To the local irritation and inflammation caused by these poisons at the seat of contact may be added effects upon internal organs. After the absorption of these 'poisons, those organs suffer most in which the poison is stored up or through which it is eliminated, though organs of varied structure may be affected, as well as those not concerned in the excretion of the poison. In the case of certain poisons, the changes at the point of entrance are slight and often not recognizable, the important anatomical lesions occurring in other tissues, to which the poison has been carried. Finally, a given poison may act as a nerve and heart poison, so that clinically the effects of this action are more prominent than the local lesion. In poisoning with corrosive sublimate, cell necrosis and the deposition of calcium take place in the secreting part of the kidneys, and there is also severe inflammation of, the colon. The salts of chromic acid, cantharidin, and many acids cause more or less marked degenerative, inflammatory or hajmorrhagic changes in the kidney and urinary passages. . . , . , . . , , , Phosphorus, arsenic, anttmony, produce tissue-degeneration, particularly fatty degeneration, and haemorrhages, in the kidneys, liver, heart, muscles, bone-marrow, and other organs, these changes being particularly marked in cases of phosphorus poisoning. The effects of arsenic are particularly important in view of the frequency with which arsphenamin and related compounds are administered in the modern treat- ment of syphilis. The method is by no means free from danger. The untoward reactions of the drug are classified by Blanton (American Journal of Syphilis, 1919) as follows: (a) Anaphylactoid reactions, which appear during the administration of the drug, last 15 to 30 minutes, and are characterized by sensations of burning in 2 18 THE EXTRINSIC CAUSES OF DISEASE. the mouth, flushing of the skin, injection of mucous membranes, facial oedema, nausea, vomiting, a sensation of suffocation, sometimes endmg m unconsciousness (b) Deferred reactions, which appear several hours after the admmistration of the drug, last from 12 to 24 hours, and are characterized by chills, headaches, vertigo, nausea, vomiting, diarrhea, generalized aches and pains and, occasionally, by skin eruptions, (c) Late reactions, which appear after 24 hours or even later. Frobably the majority of fatal cases fall into this group. Beginning with vomiting, diarrhea and fever, these patients rapidly develop headache, muscular twitchings,_ dilated pupils, disappearance of various reflexes and, after a brief illness, may die in coma. In fatal cases, Blanton and others have described widespread acute hemorrhagic encephalitis, (d) Herxheimer's reaction, characterized by intensification of the syphilitic rash, said to be due to the sudden liberation of endotoxin or to insufficient doses; the so-called neuro-recurrences, in which neuritis develops in the cranial nerves, particularly the auditory and optic, an effect which^ is probably due to awakening of pre-existing processes in these localities; morbilliform skin eruptions, jaundice, and albuminuria. Moreover, the intensive treatment of syphilis by a combination of arsphenamin and mercury compounds occasionally gives rise to necrotic lesions in the liver, simulating acute yellow atrophy, and to degenerative and necrotic lesions in the kidney, associated with calcification of the dead epithelial structures, comparable to that of bichloride of mercury poisoning. If an individual is exposed for long periods to the fumes of yellow phosphorous, there may take place an inflammation of the jaw bones leading to necrosis, but only when the occurrence of inflammatory changes is favored by other causes, such as decaying teeth. Formerly, this variety of necrosis constituted an important occupa- tional disease, particularly in match factories, but strict attention to dental hygiene among the workers has almost completely eliminated it. The long-continued use of silver nitrate may be followed by a deposit of black granules of silver in diverse tissues, the skin, kidneys, intestinal villi, and choroid plexus. In such circumstances the deposit of metallic silver in the skin gives a ghastly greyish hue to the complexion (,argyria). The venom of snakes possesses, in addition to its local effects, a paralyzing action on the nervous system and heart, and may cause death through paralysis of the respiratory centre. Soluble salts of lead whe,n ingested may cause irritation and inflammation of the intestine, with such symptoms as vomiting, diarrhoea, constipation, cramps in the stomach, associated with such nervous phenomena as anaesthesia, motor paralysis, convulsions, vertigo, and loss of consciousness. When ingested continuously for a long time, lead gives rise to ansemia (lores), general disturbances of nutrition, intes- tinal colic, pains in the limbs, anaesthesia, motor paralysis, cerebral disturbances, and kidney disease. These disturbances are without doubt dependent upon the distribu- tion and deposit of lead throughout the body, leading to anatomical lesions of varied nature. The active principles of ergot (Secale cornutum), sphacelinic acid and cornutin, when taken in large doses, or when repeatedly eaten in bread, cause itching, pain, and cramps in the limbs, followed by numbness and feeling of cold in the toes and finger tips, and finally there may occur more or less extensive gangrene of the parts (ergotism, " Kribbelkrankheit"). In cases of chronic poisoning, degenerations of the spinal cord take place {Tuczeh), The feeding of chickens with ergot causes gangrene of the comb through stasis and hyaline thrombosis in the blood-vessels. So characteristic is this change that it is employed as a test of the physiological activity of preparations of ergot intended for medicinal use. In animals fed for a long time with ergot degenerative changes are found in the central and peripheral nervous system, in the blood-corpuscles, and in the endothelium of the blood-vessels (Grigorjeff). § 8. The poisons which affect the blood chiefly, and are therefore termed blood-poisons, are partly gases and partly fixed substances. The latter are absorbed mainly from the intestine, but may also enter the body through wounds, or be injected directly into the blood-vessels. Some of the blood-poisons produce local lesions at the point of entrance- further there may be joined to the action on the bWod a direct effect upon the nervous system, which under certain conditions may cause death before the action on the blood is recognizable. Finally, it should be empha- POISONS. 19 sized that the blood-changes produced by the poison may cause numerous secondary changes m different organs, for instance, in the kidneys liver mtestme, and brain. ' Carbon monoxide, hydrocyanic acid, potassium cyanide, and hydrogen sulphide form combinations with haemoglobin giving rise to carbon-mon- oxide-hjEmoglobin, cyan-methsemoglobin, and sulphur-methsemoglobin, inhibiting or destroying the functional capacity of the red blood-cells. Ihey also produce an effect upon the nervous svstem which is most marked in the case of hydrocyanic acid and potassium cyanide. These poisons in small doses attack the central nervous system, producing death almost immediately through paralysis of the centres of respiration and circulation. Potassium chlorate, toluylendiamin,^ hydrasin, nitrohenzol, nitro- glycerin, amyl nitrite, picric acid, phallin (a poison obtained from the vmishroom, Agaricus phalloides), helvellic acid (poison oi'Helvella esculenta), arseniuretted hydrogen, and other substances cause haemolysis of red blood-cells and lead to the formation of methasmoglobin, that is, to an oxygen combination of haemoglobin, the oxygen content of which is the same as that of oxyhaemoglobin, but in which the oxygen is more firmly bound. Certain bacterial products, called bacterial hcemolysins, have a specific action on the red blood-cells, leading to the production of hsemoglo- binsemia. The best known are those occurring in infections with certain varieties of streptococci. When the blood of an animal is introduced into the blood stream of man or of an animal of another species, specific hcemolysins become active, that is, poisons which cause haemolysis of the foreign red blood- cells. Recognition of this fact is of the utmost importance in view of the frequency with which the transfusion of blood from one human being to another is now employed as a therapeutic measure. Carbon-monoxide poisoning most often results from the carbon monoxide in coal- or illuminating-gas, but may occur under other conditions, as in the case of vapors produced by gun-powder or gun-cotton. The effects of the inhalation of carbon monoxide result from the combination of the gas with the haemoglobin of the blood and the formation of carbon-monoxide-hasmoglobin. The amount of oxygen combined with the hsemoglobin is thereby decreased, and the taking up of oxygen is reduced, even when the respired air contains only 0.05 per cent, or even 0.02 per cent, of CO (Gruber). The red blood-cells themselves present no changes. A rapid supply of carbon monoxide to the nervous system may cause direct injury to the nerves, givmg riseto convulsions and later to paralysis {Geppert). In cases of long-continued poisoning the displacement of the oxygen from the greater por- tion of the red cells leads to asphyxia. If the affected individual does not die, there may result, in addition to the poisoning, severe disturbances of nutrition, occurring especially in the nervous system. The poisoning itself is characterized by headache, tinnitus aurium, vertigo, malaise, vomiting, fainting, convulsions, paralysis, and coma. The blood, as a result of the presence of carbon monoxide, becomes a bright violet or cherry-red color, so that the hjTseraemic skin and internal organs also appear bright red. In many individuals who recover from the jmmediate effects of carbon monoxide, death occurs within ten days or two weeks and, at autopsy, char- acteristic areas of softening are to be found in the lenticular nucleus on both sides. Hydrocyanic acid (CNH) is found in unstable combination in the leaves, bark, and seeds of many plants (bitter almonds, cherry- and peach-stones, apple-seeds, leaves of the laurel, bark of Prunus padus, tubers of many of the Euphorbiaceae, flaxseed, etc.). Potassium cyanide (CNK) is used in many of the technical arts. The action of both of these poisons on the blood leads to the formation of cyanmethsemoglobin, which gives the blood a bright red color and produces a bright red post-mortem lividity. 20 THE EXTRINSIC CAUSES OF DISEASE. Hydrogen sulphide (HiS) is a constituent of the gas of sewers and dung-pits. When inhaled in large amounts, it may cause sudden death from paralysis of the nervous system. When hydrogen sulphide is for some time brought into contact with blood containing oxygen (as is usually the case in decomposing cadavers), a sulphur-methssmoglobin is formed, which gives a greenish color to those tissues in which it is deposited. The poisons that dissolve the red blood-cells, with the formation of methaemo- globin, belong partly to the oxidizing substances (ozone, iodine, sodium hypochloride, chlorates, nitrites, and nitrates) ; partly to the reducing agents (nascent hydrogen, palladium hydride, pyrogallol, pyrocatechin, hydrochinon, and alloxanthin) ; and partly to substances which have neither a reducing nor oxidizing action (salts of aniline and toluidin, acetanilid). In the transformation of haemoglobin into methae- moglobin through oxidizing substances, oxyhemoglobin is present .as an intermediate body. The formation of methsamoglobin can occur either in the red blood-cells or in the haemoglobin which has escaped into the blood-plasma ; but the destruction of the blood-cells and the escape of haemoglobin into the plasma are not always followed by the formation of methaemoglobin. In the case of marked destruction of red cellS; as in poisoning from phallin, helvellic acid, arseniuretted hydrogen, only a portion of the haemoglobin is changed into methasmoglobin. Haemoglobin and oxyhaemoglobin have a red color, methaemoglobin a sepia-brown. Large doses of potassium chlorate {CIO2K) may cause death in a few hours through the destruction of red blood-cells and the action of the potassium, with the symptoms of vomiting, diarrhcea, dyspnoea, cyanosis, and cardiac insufficiency. The blood becomes chocolate-brown in color. In more protracted cases of poisoning through smaller doses, products of blood destruction .are found in the spleen, liver, bone-marrow, and kidneys ; and the urine may show a brown-red to black color (methaemoglobin). Delirium, numbness, coma, and convulsions occur during the course of the intoxication, showing that the central nervous system suffers severely. Pyrogallol (CeHiilOH]^) produces similar effects; hydrazin {H2N — NH^) and phenylhydrasin cause, in addition to haemolysis and the formation of methaemo- globin, multiple thromboses. In poisoning with toluylcndiamin (CeHalNHzliCHa) the chief action is the destruction of red blood-cells leading to deposits of iron- containing pigment in the spleen, liver, and bone-marrow. In cats methaemoglobin may be excreted through the urine (Biondi). In poisoning with picric acid (CHziNOs^sOH) there occurs, in addition to the blood changes and the formation of methaemoglobin, severe irritation of the central nervous system finding expression in violent convulsions. Small doses produce a yellowish discoloration of the skin and conjunctivae, simulating jaundice. According to Kobert, ricin derived from the seeds of the castor-bean, and abrin from the seeds of abrus precatorius, should be classed with the haemolytic-poisons, in that in the test-tube they cause agglutination of the red cells and the formation of a flocculent precipitate. In animals poisoned experimentally, local irritations, tissue-degenerations and inflammation, similar to those caused by certain bacterial toxins, are produced, as well as disturbances in the centres of the medulla oblongata, leading to cessation of respiration with progressive falling of blood-pressure! Tissue-degeneirations, inflammation, and haemorrhage are found, after longer action, at the point of application and in the intestine, where the poison is excreted! Degenerative changes are also found in lymphocytes, liver and kidney cells, and heart muscle. § 9. The last group of poisons, classed as nerve and heart poisons, is characterized chiefly by the fact that, in spite of the severity of symptoms, as shown in the form of irritations and paralyses, anatomical changes either cannot be recognized at all or are confined to structural changes in the protoplasm of individual nerve-cells, which are of similar character in the case of different poisons. This is especially the case when the poison is quickly fatal, while if the poisoning runs a pro- tracted course, or in the case of chronic poisoning from small doses ex- tending over months and years, there are often found marked anatonaical changes. POISONS; INFECTION. 21 Of the great number of poisons which act especially upon the ner- vous system and may cause death through its paralysis, the most im- portant are: chloroform, chloral hydrate, alcohol, ether, opium and its alkaloids, notably morphine; cocaine, atropine, hyoscyamine, daturine (stramonium-atropine), nicotine, coniine, cicutoxin, santonin, quinine, veratrine, colchicine, aconitine, strychnine, cytisin, curarine, and saman- darine (salamander-poison). Of the heart-poisons, digitalin, helleborin, muscarine, and phrynin (poison of toads) are of importance. Chloroform (CHCL), when applied to mucous membranes, causes local irri- tation and_ transitory inflammation. When conveyed to the blood by inhalation or by absorption from the intestinal tract, it gives rise, after a short period of stimu- lation, to diminished irritability of the cerebral gray and white matter. According to Bim, the protoplasm of the ganglion-cells suffers slight coagulation. Death may be caused by paralysis of the central nervous system, as well as by heart-failure; the latter, however, occurring more especially when the heart is weak or degen^ erated. Certain individuals show a special susceptibility to the action of chloro- form. The long-continued use of chloroform may cause degenerative changes in different organs, as the heart, kidneys, liver, muscles, and blood. Alcohol (CzHsOH), after transitory stimulation, has a depressing and paralyz- ing action on the brain, at the same time causing dilatation of the capillaries of the skin, so that in intoxicated individuals severe chilling may easily occur. Death may take place suddenly, with symptoms similar to those of apoplexy; more frequently there is a gradual loss of consciousness and of sensory perception, the respiration becomes slower, the pulse small, the face cyanotic; complete coma and gene;-al paralysis forming the closing sjtoptoms. The immoderate use of alcohol for months or years may cause degenerative atrophies of liver and kidneys associated with increase of connective tissue; further, sclerosis and atheroma of the arteries, degeneration of the brain, etc., are ascribed to the action of alcohol. At the present time it is impossible to say in what manner, how often, and to what extent these changes are dependent on the use of alcohol. Much is ascribed to the action of alcohol that is not in any way caused by it and is due wholly to the action of other injurious agents. It is certain, however, that drunkards suffer frequently from disturbances of digestion and circulation, catarrhal inflammations of pharynx, larynx, and bronchi, and of cerebral function ; and that the disease known as delirium tremens, which is characterized by general muscular tremors, obstinate insomnia, anxiety, and hallucinations, is to be ascribed to alcoholism. Opium and Morphine {CnHisNO^) depress the cerebral functions, Inducing sleep ; in individual cases there may be a preceding period of stimulation. Large doses lead to unconsciousness, paralysis of muscles, slowing and weakening of the heart's action, contraction of the pupils, slowing of intestinal peristalsis, diminu- tion in the exchange of gases in the blood dependent upon diminished excitability of the respiratory centre. There is no characteristic autopsy flnding; the blood is usually dark and fluid, as in any variety of asphyxia. 4. Origin of Disease through Infection or Parasitism. § 10. The entrance of living micro-organisms into the tissues, and their multiplication there with the production of pathological processes, is known as infection. Since these micro-organisms take their food from the tissues, they are to be regarded as parasites. The parasites causing the majority oi the infectious diseases are now known. In those diseases in which they are not yet discovered (small- pox, measles, scarlatina, etc.) the existence of a parasite may be assumed since the diseases in question are characterized by phenomena common to other infections. It may happen that a given disease spreads from one affected individual to other individuals, giving rise to pestilence or epidemic, which may sweep through a house or city or through the land or over many lands. The spread of disease sometimes occurs by direct 22 THE EXTRINSIC CAUSES OF DISEASE. passage from man to man, direct contagion (smallpox, gonorrhoea, syphilis, and leprosy) ; at other times, as if the causal agent of the dis- ease clung to certain regions as a so-called miasma (malaria) and in- fected the individuals who came into its neighborhood. The parasites that cause the infectious diseases belong, for the greater part to the schizomycetes or bacteria ; but certain of the higher plants, the mould-fungi (eumycetes), and the yeasts may also cause infectious diseases. Animal parasites are also represented by numerous species, belonging to the protozoa, to the worms, and to the arthropoda. It has been the custom to accord the animal parasites a special position, since many of them do not increase in the host in whom they live, but only pass through certain stages of development without causing symp- toms characteristic of the infectious diseases. Such a distinction does not hold good, since certain infectious diseases (malai'ia) are caused by animal parasites. Further, in the case of many of the animal parasites a definite increase takes place within the human organism. With the recognition that infectious diseases are caused by living microorganisms, the view was soon reached that contagious diseases must be caused by parasites that thrive only within the human or animal organisms; while miasmatic diseases arose from agents living in the outer world and which occasionally gain entrance into man or animals. In the first case the microorganisms are designated endogenous parasites, the second ectogenous. It was assumed in. regard to the miasmatic dis- eases that the microorganisms could increase either within the body or in the outer world ; but, in the latter place, only when they passed from the human or animal body into water, food, or earth. With certain limitations this view is still regarded as correct; but, according to later experiences, its original application is not always cor- rect, since many microorganisms that ordinarily increase only in living tissues as parasites require for their growth outside of the human body certain conditions of hfe that make their multiplication possible. The causal agents of measles, scarlatina, and of syphilis can develop only inside the human body; that of smallpox, within the body of man and cattle, and we have not yet succeeded in growing them in artificial media. Tubercle bacilli ordinarily develop only in the tissues of man and certain other vertebrates ; but they may be cultivated on artificial media at the temperature of the body, and be successfully inoculated into man and other susceptible animals. Staphylococci and streptococci, which pro- duce suppuration, anthrax bacilli, typhoid bacilli, cholera spirilla, and others grow easily in different solid and fluid media and can after artificial cultivation cause disease in man. But it should be noted that, even in the last-named cases, the bacteria concerned have not spontaneously in- creased in the outer world, so that, for example, water used for drink- ing becomes only the conveyor of the infective agent. Malaria, which is considered the chief type of so-called miasmatic disease, is produced by a microorganism, which, outside the human body, must pass through definite stages of development in certain mosquitoes' Through the taking up of blood from a malarial patient the infected mosquitoes (Anopheles) represent the malaria-producing miasm and man is infected through their bite, and not, as was originally supposed through mists arising from marshes. It is also possible to produce in- fection with malaria by the transfusion of blood from a malarial patient to a healthy individual. INFECTION. 23 The view that certain diseases are of parasitic origin is old, and found expression in the works of Kirchner (1602-1680), Lancisi (1654-1720), Linne (1707-1778), and others. It was left to recent times, however, to place the theory of the parasitic nature of the infectious diseases on a secure foundation. Though several decades ago Henle, Liebermeister and others asserted that the peculiarities of infectious diseases could be explaini '. only by the assumption of a contagium animatum, the establishment of this doctrine is due to the investigations of recent years. Climate is often held responsible for the origin of disease, and we are inclined to consider a region having a uniform temperature, much sun, and little wind as a healthy one, while one having marked variations of temperature, abundant precipita- tion, little sun, and much wind is regarded as unhealthy. This is true to a certain extent, in so far as invalids or individuals susceptible to the influences of weather are concerned, but a better criterion of the healthfulness of a region is the presence or absence 6i specific agents of disease, vegetable or animal parasites that may infect man. Such disease-producing agents may exist in affected members of the population of the region, in the drinking-water, in the earth, or in animals, etc. In the tropics malarial parasites play the most important role, their transmission to man being brought about through the agency of mosquitoes. Therefore, a beauti- ful region which seems to offer the best climate may be unhealthy ; while raw, cold, and inhospitable climates may be healthy because' of the absence in them of the causal agents of disease. § 11. The bacteria are small, unicellular micro-organisms, which appear in the form of minute spheres (cocci), and fine, straight, or curved rods (bacilli and spirilla), frequently uniting in peculiar com- binations. Many possess inotile organs in the form of flagella. Under special conditions some of them produce spores. From the standpoint of the physician bacteria may be divided into the non-pathogenic and the pathogenic. To the latter belong all those vthat are able to increase in the human and animal organism. But this classification is not altogether satisfactory, inasmuch as pathological con- ditions may be caused by bacteria that are not able to increase within living tissues. This rests on the fact that all bacteria, not only the pathogenic, but also the non-pathogenic, in their growth in nutritive media (albumin, peptone, gelatin), decompose these, and thereby often produce substances that are toxic for man and for the higher animals. The most important of the substances produced by the decomposition of proteids are the basic cadaveric alkaloids or ptomains, many of vi^hich are poisons for man. For example, the toxic products neuridin, cadaverin, putrescin, neurin, and methylguanidin, the last three of which are poisons, may be obtained in pure form from decomposing meat. If these enter with the food into the human body symptoms of intoxica- tion may be produced without the development of bacteria in living tissue. On the whole, their activity is not considered very great, and it is ques- tionable whether the artificially produced poisonous ptomains ever arise during the processes of decomposition. Besides the property of producing ptomains and other poisonous sub- stances (for example, hydrogen sulphide), which belongs to many dif- ferent bacteria, the pathogenic bacteria produce other specific poisons. The first of these to be considered are the toxins in the narrower sense, that is, poisonous substances which do not belong to the ptomains and are also not albuminous bodies (toxalbumins). They are products of secre- tion of the bacterial cells and can be separated by filtration from the bacteria. The most important representatives of such poisons are those produced by the bacilli of diphtheria and tetanus, both in cultures and in the human organism. The toxins are unstable bodies and quickly lose 24 THE EXTRINSIC CAUSES OF DISEASE. their activity through heating above 50° C, the effect of light, and through the action of acids and other chemical substances ; when dry they will stand 100° C. without injury. Their chemical structure is not known; they may be compared with the enzymes. When injected into susceptible animals, their action takes place after a period of incubation known as the period of latency. In the affected organism they cause the production of antitoxins, which render the toxin harmless in the organ- ism and also neutralize it in vitro. As a second form of specific poison there occur intracellular toxins or endotoxins, that is, poisons which cling to the bacterial cell and are separated from it only with difficulty. Even less is known of their nature than of the true toxins. Typhoid bacilli, cholera spirilla, and. pneumococci form such poisons, and it is assumed that they are released and become active after the destruction of the bacteria in the human organism (bacteriolysis ) . A third form of poison is found in the bacterial proteins, that is, the substance of the cell itself. They produce chiefly a local effect, find- ing expression in inflammatory reactions. It is probable that such reac- tion occurs in all bacterial infections in which the bacteria develop locally. If the bacteria concerned produce antitoxins the action of these is com- bined with that of the bacterial proteins. In individual cases it is often impossible to decide to what extent ptomains or specific bacterial toxins and proteins are concerned in the production of pathological conditions. The term toxin is often used to cover all of the poisonous substances produced by bacteria. Some pathogenic bacteria increase first in the outer world (for ex- ample, the tetanus bacillus), and only occasionally develop in the human or animal body ; other forms develop ordinarily only in the human or ani- mal organism (tubercle bacilli, glanders, leprosy, diphtheria, and in- fluenza bacilli) and need for their development outside of the body special nutritive media, or, indeed, they cannot be cultivated at all. Still others increase with energy in human and animal tissue, hut are also easily grown upon, nutritive media (streptococcus, staphylococcus, anthrax bacillus, typhoid bacillus, cholera spirillum), and are able to multiply under natural conditions in the outer world. The distribution of pathogenic bacteria from the affected indi- , vidual to the outer world takes place through coughing, sneezing, expec- toration, speaking, through intestinal and urinary discharges, secretions from wounds, sloughing of tissue, etc. \A'hen thrown into the air they may float for some time and be carried to a distance, but, sooner or later, become attached to some object. Through drying and sunlight many are quickly destroyed. Others remain alive for a period, often a long time, especially in the form of spores, and may be found in either a dry or moist state, in the water or earth. If they find the proper food-material and if the temperature is favorable they may multiply. From the place where they are thrown down, or from the objects to which^ they cling, or where they have undergone development, the bacteria may suffer a wider distribution. Strong currents of air' may carry them away, especially from the objects to which they cling, or in the dust of the room or of the street. Many of them are brought' to the human and animal organism through food and drink, through the air or through contamination of the fingers. INFECTION. 25 The avenues of entrance for bacteria are, in general, the mucous membranes of the intestinal canal, respiratory tract, the conjunctiva, the alveoli of the lungs, and open wounds. But it should be noted that many- bacteria are able to enter only through certain tissues, for example, the typhoid bacillus and the cholera spirillum gain entrance only from the intestine. Through recent wounds, both pathogenic and non-pathogenic bacteria are rapidly taken into the lymph and blood; while through wounds showing healthy, gi-anulating surfaces, the entrance of bacteria into the tissues is hindered. Pathogenic bacteria (pus cocci) not infre- quently enter through the skin, either by way of the hair-follicles or the sebaceous or sweat-glands. Under certain conditions (coitus, surgical operations, dribbling of urine, childbirth) infection may take its start from the mucous membranes of the uro-genital tract. Some infections are transmitted by insects, which have taken up bacteria from the blood or secretions of a diseased individual or animal, or, having become con- taminated externally, infect an open wound by scraping the bacteria from their legs, or by the introduction of germs into the skin or mucous mem- branes during the act of stinging or sucking. If meat containing bacteria be eaten, and if the animal while alive were affected by an infectious dis- ease to which man is susceptible, this particular disease may thus be transmitted. If toxic bacterial products enter in consideral amount into the in- testinal canal or wounds at the same time with bacteria, the symptoms of intoxication may be produced without infection, that is, without increase of the bacteria in the tissues. This may also happen when bacteria pro- ducing such poisons develop in the contents of the intestine, in wound- secretions or in necrotic tissue, and increase as saprophytes. Strictly speaking, we cannot regard this as an infection, but as an intoxication; although it is not always possible to draw a sharp line between intoxica- tion and infection, since bacteria originally developing as parasites not infrequently penetrate into the tissues and multiply. Intestinal intoxications dependent upon bacterial toxins occur when meat or fluids in a condition of bacterial decomposition has been eaten as food. To such intoxications belong the affections designated as meat-, sausage-, fish-, and cheese-poisoning, in which the poison is either taken as such into the intestinal canal, or is formed there. Likewise, vegetables in a condition of fermentation and decomposition, for example, cabbage, peas, beans, corn, rice, etc., may exert a harmful influence on the intestine or on the entire organism, especially when they have been eaten in large amounts or for a long period. If bacteria which have entered the body through one of the above- mentioned avenues are pathogenic, so that they give rise to infection, they may increase first at the point of entrance, in the intestinal mucous membrane, in a wound, in the skin, etc. The local effects of their growth depend on the individual characteristics of the bacteria, as well as on the peculiarities of the affected tissue. In general, the local action is characterized by tissue-degenerations, necrosis, inflammation, and new- formation of tissue, so that it is possible in many cases to determine the specific nature of the infection, that is, the species of bacteria causing it, from the character of the local changes. It is however, difficult or im- possible to determine in every case the mode of action of the multiplying bacteria ; in general, it may be said that the processes of chemical meta- morphosis excited by the multiplication of the bacteria produce certain 26 THE EXTRINSIC CAUSES OF DISEASE. changes in the tissue-cells, in that different substances of active chemical nature either kill the cells, or at least induce degenerative changes in them, or excite increased cell-activity. In the further development of the process the substances derived from dead and dissolving bacteria may also react on the surrounding tissue. In a sense, therefore, there occurs through the growth of bacteria a local intoxication, which is of greater significance than the znnthdrawal of nutritive material through the con- sumption by the bacteria of food substances. The latter is, however, not without significance, inasmuch as the chemical changes produced by the bacteria in the tissue juices often render these unfit for the nourishment of the tissue-cells. The participation of the body as a whole in a local bacterial infec- tion may be slight or absent, so that the disease remains a purely local affection (tuberculosis). In other cases the toxins and toxalbumins formed at the focus of infection are absorbed into the blood, and a gen- eral intoxication (toxincemia) is produced. In such diseases as tetanus and diphtheria the sytemic reactions to local poisoning are especially prominent. If healing does not take place at the primary seat of infection, the neighboring tissues may be involved by invasion of bacteria by con- tinuity. Often the bacteria gain entrance to the lymph- vessels or blood-channels (bactericemia) , and in this way are transported over the entire body. The result of this metastasis of bacteria is the produc- tion of a lymphogenous or haematogenous infection ; that is, secondary foci of disease identical in character with those at the primary seat of infection are formed at a distance. In certain diseases (tuberculosis, suppuration, plague) the number of metastases is usually great, so that many parts of the body (lymph-nodes, liver, lung, brain, muscles, bones, kidneys, etc.) contain diseased foci. In other infections metastasis of bacteria from the original focus to other organs does not occur (tetanus, diphtheria), or the transported bacteria cause changes of a milder type (typhoid fever). The entrance of bacteria into the blood constitutes the condition known as bacteriaemia. During transportation through the blood-vessels, there is usually no increase of the bacteria, the blood serving merely as a vehicle, multiplication occurring at those points where the bacteria come to rest. Nevertheless, in certain infections (anthrax) the bacteria increase enormously in the circulating blood. Through the obstruction of small blood-vessels by the multiplying bacteria, there may be added to the symptoms of intoxication local disturbances of circulation. The metastasis of bacteria or toxic substances, or both, from a local- ized seat of infection, and the production of secondary foci and symptoms of intoxication, gives rise to the condition termed sepsis. According to the predominant symptoms there may be distinguished septiccemia, pycBmia and lymphangoitis. Through the combination of both the latter with septicaemia, septicopyemia is produced. Originally the designation septicaemia was applied to those cases in which localized infection was associated with intoxication caused by bacterial poison without the spread of bacteria through the body. At the present time, septicaemia is used to designate the condition characterized by the entrance of bacteria and their poisons into the blood, a coincident toxinmnia and bactericemia; indeed, by many authors toxincemia is separated from septicaemia. ' INFECTION. 27 The. term pyaemia is employed to designate that condition in which the metastasis of pyogenic baoteria gives rise to the formiation of meta- static abscesses at the point of lodgment. In septicopyaemia the symptoms of toxinasmia and bacterisemia are combined with the formation of metastatic foci. Lymphangoitis is an inflammation of the lymph-vessels and their surroundings caused by transported bacteria. Sepsis is most frequently caused by the true pyogenic organisms, staphylococcus pyogenes aureus, and streptococcus pyogenes, but similar conditions occur in infection with the pneumococcus, typhoid bacillus, colon bacillus, plague bacillus, etc. If bacteria are deposited secondarily in the body-passages which are lined with mucous membrane, as in the respiratory or urogenital tract, they may multiply within these tracts and produce their characteristic pathological changes. Likewise, they may multiply within the large body-cavities, in the peritoneal, pleural, and subarachnoid spaces. In the case of infection occurring in a pregnant woman, several varieties of bacteria (anthrax, glanders, typhoid, the pyogenic bacteria), may be transmitted to the foetus. The description above given of the course of an infection may be taken as a general type, and many infections run such a course ; but there are many deviations from this scheme. In the first place, it not infrequently happens that in an infection which in general runs a typical course, the primary seat is not demonstrable, either because no changes occurred at the point of entrance, or because the changes produced have since disappeared. Such forms of infection are known as cryptogenic; they may be lymphogenous or haematogenous. It is typical of many infections that the primary localization of the cause of the disease is not recongnizable, so that general symptoms occur before local changes are demonstrable, and the tissue-changes occurring later have more the char- acter of a secondary localization of the poison of the disease. This occurs in a number of infectious diseases, the causes of which are un- known to us ; for example, in scarlet fever, smallpox, and measles ; yet in many infections whose causes are known we are not always able to discover at what point the first multiplications of the bacteria occurs. Thus we know that in relapsing fever the spirilla are found in the blood in large numbers at the time of the fever, but the place of their multipli- cation is unknown to us. Not infrequently a secondary infection may be joined to one already present. In many cases the association is accidental, in other cases the anatomical changes produced by the first infection cause a local predis- position to the new invasion. To the first group belong, for instance, croupous pneumonia occurring in an individual suffering from tubercu- losis of the kidney or bones; while infection with cocci causing suppur- ation and septic intoxication during the course of typhoid, influenza, diphtheria, scarlet fever, dysentery, ulcerating tuberculosis, etc., may be regarded as due to the production of local tissue-changes favoring the entrance of such bacteria. These secondary infections usually aggra- vate the sufferings of the patient in that a new disease is added to the one already present; but it 'may also happen that the microorganisms entering secondarily grow only as saprophytes in exudates or in tissues killed by the first infection. In certain infections, as, for example, in 28 THE EXTRINSIC CAUSES OF DISEASE. many purulent processes, the tissues may contain, even at an early stage, two or more varieties of bacteria — a mixed or double infection. The associated bacteria can persist in their association and in common excite pathological changes; but they may also become separated from each other, so that one microorganism gains a wider distribution than the other. It has been known for many years that during decomposition poisonous sub- stances are formed. As early as 1852 Beck observed that ammonia hydrothionate, which occurs in pus, possessed septic properties when injected into animals. Panum, in 1863, obtained from decomposing material a putrid poison, that is, a body not destroyed by boiling and evaporation, which possessed an action similar to that of snake-poison and the vegetable alkaloids and caused in dogs salivation, dilatation of the pupils, diarrhoea, fever, and severe prostration. Von Bergmann and Schmiedeherg obtained from decomposing yeast a crystalline body, sepsin, which in animals produced the symptoms of intoxication. Senator, Hiller, and Mikulicz extracted from decaying tissue-masses by means of glycerin a substance which likewise possessed a septic action. Billroth called this poisonous substance putre- factive symoid. Selmi endeavored to characterize all these substances more min- utely, and obtained from different constituents of cadavers extracts, partly soluble in ether, partly in water, which he recognized as fixed bases of alkaloid-like char- acter, and which he designated cadaveric alkaloids or ptomains. Gautier, Etard, Zuelzer, Sonnenschein, Bechamp, Schmiedeherg, Harnach, v. Nencki, Otto, Anger er, and others also found in decomposing tissues similar alkaloids, which in experi- ments on animals were partly inert, and partly toxic, producing in the latter case symptoms of poisoning similar to those of curare, morphine, and atropine. To von Nencki (1876) is due the honor of being the first to obtain a cadaveric alkaloid in pure form_ and to establish its formula ; this was accomplished in the case of col- lidin, obtained from decomposing glue and albumin, its platinum salt crystallizing in flat needles. Following v. Nencki, Etard, Gautier, and Baumann, and especially Brieger, studied ptomai'ns, the last named having obtained a large number of them in a_ pure state and determined their physiological action. For instance, Berger obtained from fibrin peptone a poison (peptotoxin) which in animals causes symptoms of paralysis and ultimately death. From decomposing, horse-flesh he extracted three substances crystallizing in needles, namely, neuridin, neurin, and cholin, the second of which is markedly poisonous, and, like muscarine, causes salivation, disturbances of circulation and respiration, contraction of the pupils, and clonic convulsions. From fish-flesh he obtained, besides neuridin, other poison- ous bodies: ethylendiamin, a substance similar in its action to muscarine, and a substance called gadinin. From decomposing glue and cheese he obtained the poison neurin, and from decomposed yeast dimethylamin. The majority of ptomains are not found in fresh tissues, and it is therefore probable that they are derived from the splitting of chemical combinations present m the tissues. Thus it is probable that cholin is formed from the s,plitting of lecithin, and by the further decomposition of cholin the poison neurin is formed Choiin and neuridm are, according to Brieger, demonstrable in the fresh human bram. After the poisonous nature of part of the ptomams had been made known through the researches mentioned above, there was developed the hvbothesis that the toxic symptoms observed m infectious diseases could be entirely or in a ?reat measure, ascribed to the action of the toxic ptomains. Through the investio^tions of recent years (Roux, Yersin, Buchner, Bnegcr, C. Fraenkel, Pfeiffer Ehrlich Wassermann, and others) it has been shown that besides the ptomaini there S specific bacterial poisons, which are characteristic for the given bacterial snerip. These were first regarded as active albumin bodies and were called toxalbumins Investigations of the poisons formed in diphtheria, tetanus, cholera tvofaoid fever pneumonia and tuberculosis have shown that the so-called toxalbumins are not albumm bodies, and have led to the differentiation of different poisonous substance^ as given in the text above. =uusLctin.c» The toxins, in the strict sense, may be comnared ^rrnrA\nr, +„ ti, • with the enzymes formed by the body cells (p^psin, tV^sin Xlin^ wh*;.^"^'"' duce hydrolytic splitting On the other ha„d,\he endotSs cl W S to he ll\{, may be compared with the expressed juice of yeast known as zyiSasI (i?McL" which is able, in the same way as the living protoplasm of the yeast-cell, to excke INFECTION. 29 alcoholic fermentation -in fluids containing sugar. Toxins and enzymes are mixed with albuminous substances which up to the present time have not been separated from them. This explains why they were earlier regarded as albuminous bodies. Brieger, who first characterized the toxic substances as toxalbumins, has himself prepared toxins that gave no albumin reaction. According to the views of Ehrlich, only those substances are poisons that possess a chemical affinity for some element of the body and through their union with this element cause an injurious action that may be recognized clinically (toxo- phorous affinity). A toxin or haptin is, according to him, a poison which possesses two specific atomic groups, a haptophore group which permits the union with the body cells through the haptophorous group of the latter, and a toxophore group which exerts the poisonous action. If in any poison the specific action of the toxophore group is lost, while the haptophore group remains, there arise toxoids or non-poisonous haptins which may anchor themselves to the body cells but are no longer poisons. Finally, there occur also primary bacterial products (in diph- theria), the toxons {Ehrlich), that is, poisons which have the same haptophore group as toxins but a less active toxophore group. Since the intracellular toxins, the endotoxins (typhoid bacilli, cholera spirilla, B. pyocyaneus, pus cocci), are stored in the bodies of the bacteria, the bacterial cell-substance is the most active. In old cultures the poisons pass into the fluid, but they probably no longer represent the primary endotoxin, but a modification. Cholera spirilla, typhoid bacilli, and pneumococci form endotoxins, which on the death of the 'bacteria are set free, and become active as such, or act in a modified form at the same time with the bacterial proteins. Anthrax and tubercle bacilli probably form no true toxins, but contain poisons of another kind whose action is combined with that of the bacterial proteins. The importance and the course of an infection depend, therefore, upon the character of the cells possessing receptors for the given toxin. In tetanus it is the nerve-cell ; in tuberculosis the connective-tissue cell. Diphtheria poison does not injure the skin of the mouse, while the one-hundredth or one-thousandth part of the same dose will produce tissue-necrosis in the guinea-pig {Ehrlich). Aggressins: When bacteria are grown in the pleural or peritoneal cavities, in pleural or peritoneal exudates, blood-serum, or even in distilled water, there is formed a substance which, when the non-toxic sterilized culture fluid is inoculated at the same time with a sublethal dose of the bacteria, neutralizes the protective powers of the body and permits the growth of the bacteria. These substances have been called aggressins, and are regarded by some as serving the bacterial organism in the same way that opsonins protect the animal body. {Bail: Arch. f. Hyg., 1905.) Literature. {Bacterial Infection and Intoxication.) Bolduan and Koopman: Immune Sera, John Wiley & Sons, New York, 1917. Flexner: The Pathology of Toxalbumins, Baltimore, 1897. Vaughan and Novy: The Cellular Toxins, 1902 (Lit.). Woodhead: Bacteria and their Products, London, 1891. § 12. The pathogenic moulds (eumycetes) and the budding fungi belong, as do the schizomycetes, to the non-chlorophyllaceous thallo- phytes. They occur in the human organism in the form of jointed or non-jointed and sometimes branching threads or hyphoc, and short oval cells, the so-called conidia. The eumycetes may be divided into the moulds, the fungus of thrush, and the cutaneous mould-fungi. At times they form fructification organs of peculiar structure. The single cells are larger than those of the schizomycetes. Outside the body the moulds develop as velvety films of dififerent colors, on the surface of many organic substances and fluids, from the carbon-compounds and salts of vrhlch. they derive their nourishment. The yeast-fungi are found chiefly in fluids con- taining sugar, and are the cause of alcoholic fermentation. 30 THE EXTRINSIC CAUSES OF DISEASE. The spores or conidia, which represent reproductive elements, are for the greater part formed in special organs of fructification, but may also be developed by a simple process of constriction of the ends of the. hyphffi, and pass into the air from the surface of the mould-film_. Like- wise, yeast-cells may be carried in the air, in the case of evaporation of a fermenting fluid and the conversion of its residue into dust. The moulds may, as do the bacteria, produce poisonous substances in the nutritive media in which they multiply, usually outside the human body, and when these are taken in with the food symptoms of intoxica- tion are produced. For example, the chronic disease, known as pellagra, which occurs particularly in Italy, Spain, southwestern portions of France, Roumania and certain Southern States, is characterized by gastro-intestinal disturbances, changes in the skin, spinal and cerebral disturbances, and marasmus, is, according to one view, the result of the eating of corn which has been spoiled through the growth of certain moulds. According to Ceni the active poisonous substances are pro- duced in the spores of the fungi. As parasitic agents causing disease the moulds and the yeasts cause, as a rule, local infections characterized by tissue degeneration and inflam- mation. The moulds develop in regions accessible from without, in the skin, the crypts of the tonsils, the ear, mouth, lungs, etc. They usually occur as saprophytes in cerumen, necrotic lung tissue, etc., but may also pene- trate living tissue. The thrush fungus occurs chiefly in the epithelium of the upper layer of the mucosa of the alimentary tract, but often penetrates into the con- nective tissue and causes inflammation. Hasmatogenous metastasis is rare. The cutaneous moulds multiply in the epithelium of the skin and give rise to such lesions as favus, herpes tonsurans, pityriasis versi- color, and erythrasma. The yeast fungi develop most frequently in the stomach, particularly after the ingestion of fermenting fruit juices. In glycosuria they may multiply in the urinary bladder and excite fermentation of its contents. Yeast-like budding fungi occur also in a granulomatous and suppurative process affecting the skin and internal organs (blastomycetic dermatitis, blastomycosis, sac- charomycosis, coccidioidal granuloma, etc.). The majority of the cases have oc- curred in America. The parasites involved cannot at present be definitely classified. By some writers (Ricketts) they are believed to belong to the genius Oidium (oidiomycosis). Blastomycetes are supposed to be the cause of a peculiar suppura- tive disease in horses. Literature. (Infection by Moulds and Yeasts.) Bestarelli: Stand der Pellagrafrage. Cent. f. Bakt, xxxiv., 1904 Buschka: Ueber Hefenmykosen. Klin. Vortr., No. 18, Leipzig- 1898 Busse: Pathogene Hefen und Schimmelpilze. Ergebn. d. allg Path v' 1900 Ceni u. Besta: Aspergilkis fumigatus und flavescens u. d. Bez z Peliaora ' Cent f. allg. Path., xiii., 1902. ' ' ° " Lombroso: 'Die Lehre von der Pellagra, Berlin, 1898. Ricketts: Oidiomycosis. Journal of Med. Research, 1901. Toulerton: Pathogen. Action of Blastomycetes. Journ. of Path vi 1RQ0 Harris, H. F.: Pellagra, The Macmillan Co., 1919. ' ' ®^- INFECTION BY ANIMAL PARASITES. 31 § 13. The production of disease by animal parasites is most fre- quently brought about by the introduction of mature parasites, larvae, or eggs into the intestinal tract through the medium of food and drink or by unclean fingers. This is particularly true of those parasites whose habitat is in the intestine or other tissues within the body; such para- sites are designated Entozoa. Parasites living in the outer tissues, as the skin, are termed Epizoa; they remain on the surface of the skin or penetrate into the deeper structures from without. The animal para- sites for the greater part produce local changes, but can also cause symp- toms of general disease, particularly when they increase in the body, or produce toxic substances. Many of the parasitic protozoa are harmless. Other forms, on the contrary, penetrate into living tissues, increase within the cells, and give rise to morbid changes, characterized by new-formations of tissue (coccidia-di'sease of the rabbit's liver, epithelioma contagiosum). Still other forms which are probably to be classed as Sporozoa, increase in the blood, and destroy the red cells. Others (trypanosomata) inhabit the blood-plasma. It is not impossible that such infectious diseases as small-pox are caused by parasites belonging to the Protozoa. The parasitic ■worms {Nematodes, Cestodes, Trematodes) occur in man, partly in the adult and fully developed sexual state, and partly in the larval state. Most of the adult worms are intestinal parasites, and obtain nourishment from the intestinal contents, rarely sucking the blood from the mucosa. Fully developed worms, however, are found in other reigions, as in the blood- and lymph-vessels, bile passages, lung, pelvis of the kidney, and in the skin. The eggs or fully developed larvae produced in the body by parasitic worms are either cast out with the dejecta or, by wandering through the blood or lymph, reach other organs, where they pass the first stage ,of their development. Here they remain, however, in a larval condition, and do not reach sexual ma- turity. The larvce are capable of further development only when they have been taken into a new host, or have been again eaten by the same host. Those worms which reach sexual maturity in the human body are taken in as larvae through the food a«d drink. Their first stage of de- velopment is passed in the majority of cases in animals whose flesh is used for food; in other cases in certain lower animals not used as food. Others develop in water or damp earth or even in the human intestine, so that the embryos or eggs, which pass of? with the dejecta, develop at once if they are again introduced into the intestinal tract of man. Worms which occur in man in the larval condition only (hydatids) develop from eggs which have come from sexually mature worms, in- habiting different animals. They are taken into the intestinal tract usu- ally in the food or drink, but under special conditions eggs capable of development may be contained in the dust of the air, and, being inhaled and finally reaching the intestinal tract, complete the first stage of de- velopment. The intestinal parasites in most instances produce only slight me- chanical irritation of the intestine. The presence of blood-sucking worms, on the other hand (notably Anchylostoma duodenale and Un- 32 THE EXTRINSIC CAUSES OF DISEASE. cinaria), are frequently productive of extremely severe anemia by the mechanical withdrawal of small quantities of blood for a prolonged period. Still other intestinal parasites manufacture poisons which are absorbed by the host. Thus Schaumann and others have demonstrated ha^molytic substances in the segments of Bothriocephalus latus, whose presence in the human body is sometimes associated with anemia of the pernicious type. Those parasites which enter the tissues may cause in the vicinity mild inflammation and proliferation, producing marked clinical symp- toms when the number of the parasites (trichina larva;) is great. Others are of pathological importance, in that they reach large size (echinococcus cysts) and compress the neighboring structures. A para- site situated in the muscles or subcutaneous tissue may cause slight symptoms, while one in the eye, medulla oblongata, heart, or blood-ves- sels may cause severe disturbances, and under certain conditions death. The parasitic arthropoda (Arachnida and Insects) come to the human body from the outer world, and from infected animals and human beings. They belong almost wholly to the Epizoa, which have their habitat in and on the skin and accessible mucous membranes (lice, bedbugs, fleas, mites) or occasionally take their nourishment from the skin (gnats, gad-flies, flies) ; a few multiply in the skin (itch-mite) ot on its surface (lice). Flies and gad-flies occasionally lay their eggs on the mucous membranes or in wounds, and from the eggs so laid larvas develop. The larva of an arachnoid {Pentastoma- denticidatum) is alone found in the internal organs. When these parasites penetrate into the tissues, they cause irritation and inflammation; the bite of insects that suck blood is also followed by inflammation in the neighborhood of the puncture. Attention has been directed to the fact that mosquitoes, stinging flies, gad-flies, bed-bugs, lice, etc., may be the conveyers of infection, in that bacteria or protozoa may be attached to their bodies, or that in the act of sucking blood of an infected m'an or animal they may take into their bodies bacteria or protozoa and convey them to other individuals. So far as experience goes, the danger of such conveyal is not great in the ma- jority of the infectious diseases, since the bacteria thus taken up die after a time. This method of conveyal is of great importance, however, in malaria, in that the Plasmodia taken from the blood of infected individ- uals by mosquitoes (anopheles) undergo development in the body of the mosquito and produce a new generation, which through the bite of the mosquito is transferred to another individual. Similar conditions exist in the case of the tsetse-fly disease and Texas fever of cattle, the latter being conveyed by ticks. Further, it is claimed by Manson, Sonsino, and others that the mfection of man with filaria is also brought about through the agency of mosquitoes. Of the parasitic protozoa there should be mentioned also the Amcsha dysenteries the cause of oneform of dysentery « man; the Trypanosoma evansi, the cause o^' surra; Jr. bruce^, th^ cause of the tsetse-fly disease or nagana; Tr. gamblmse the etiological agent m human trypanosomiasis or sleeping-sickness; and the Trichn- monas as a probable causal agent in catarrhal conditions of intettin. ^\. J : urinary tract. Supposed protozoan parasites have aho been de,rr bed ,= % ^ ^°', factors of ^allpox, scarlatina, tumors, etc., but convLcbg p'ooffare'ot at'hand. IMMUNITY, PREDISPOSITION, IDIOSYNCRASY. 33 Literature. (Origin of Disease through Animal Parasites.) Blanchard: Parasites animaux. Path, gen., ii., Paris, 1896. Braun: Die thierischen Parasiten des Menschen, Wiirzburg, 1893. Celli: Die Malaria, Berlin, 1900. Grassi: Die Malaria, Jena, 1901. Howard: Mosquitoes, New York, 1901. Huber: Bibliographie der klin. Helminthologie, Miinchen, 1891-1895. Laveran: Du paludisme et de son hematozoaire, Paris, 1904. Laveran et Mesnil: Trypanosomes et Trypanosomiasis, Paris, 1904. Leuckhart: Die therischen Parasiten des Menschen, 2 Aufl., 1879-1897. Liihe: Ergebnisse der neuren Sporozoenforchung. Cent. f. Bakt., xxvii. and xxviii., 1900. Nuttal: Die Mosquito-Malariatheorie. C. f. Bakt., xxv. and xxvi., 1899; die Rolle der Insecten, Arachnoiden u. Myriapoden als Trager bei der Ver- 'breitung von durch Bakterien u. thier. Parasiten verursachten Krankheiten. Hygien. Rundschau, ix., 1899, ref. Cent. f. Bakt., xxvi., 1899. Schneidemiihl: Die Protozoen als Krankheitserreger, Leipzig, 1898. II. Congenital and Inheritable Foundations for Disease. 1. Immunity, Predisposition, and Idiosyncrasy. § 14. Toward the injurious agents capable of producing disease different individuals show different powers of resistance. Such differ- ences are exhibited particularly in the case of the infections and poisons. When an individual is not susceptible to a given infection or poison, the property thus manifested is designated immunity and insuscepti- bility; but if an individual is easily infected by a pathogenic micro- organism, we assume that he possesses a predisposition to the disease caused by the microorganism in question. Hypersusceptibility to influ- ences having no effect on ordinary individuals is designated idiosyncrasy, and has particular reference to poisons, pollens, etc. Immunity and predisposition represent the opposite behavior of an organism to external injurious agents, but they cannot be sharply sep- arated from each other. In many cases immunity is not absolute but relative, so that an individual may be made ill through a given agent, for example, a pathogenic microorganism or poison, when the agent acts in its characteristic manner and strength. On the other hand predis- position may be so slight that disease arises only in extraordinary cir- cumstances. An absolute immunity or insusceptibility is possessed by man against many of the microorganisms pathogenic for animals, for example, against the bacteria of swine plague, swine erysipelas, and symptomatic anthrax. This may rest on the fact thatthe character of his tissue and tis- sue juices does not permit localization and multiplication of the causative bacteria, or that the poisons produced by the latter are not toxic for man. The human race is highly susceptible to 'smallpox, measles, and in- fluenza, so that many individuals acquire these diseases. In the case of scarlet fever, typhoid fever, diphtheria, the susceptibility seems less, but it is not possible to determine to what extent individuals who escape are not exposed to infection. 3 34 THE INTRINSIC CAUSES OF DISEASE. In many infectious diseases greater susceptibility is shown in child- hood than in old age; for example, in diphtheria, whooping-cough, and scarlet fever. There are also variations in the degree of susceptibility at different times ; for example, an individual may be exposed to measles without becoming infected, while at other times under apparently similar conditions he contracts the disease. In the case of many pathogenic organisms there appears to be neces- sary for the occurrence of infection a certain favoring condition or tem- porary increase of susceptibility. As evidence of this is the fact that in the human alimentary canal, especially in the mouth and throat, as well as in the respiratory tract, pathogenic organisms (streptococci, staphy- lococci, pneumococci), may be present without any indications of in- fection. It may also happen that cholera spirilla increase abundantly in the intestine without symptoms. Such occurrences may be explained by decrease or loss of virulence on the part of the bacteria, but this cannot be applied to all cases. In many instances it must be assumed that the harmlessness of the bacteria is due to the ability of the tissues to hinder their entrance into and their action on the deeper parts. In some cases this may depend on the structure and organization of the tissue, in other cases chemical sub- stances have a determining influence (see § 29). In favor of the first assumption is the' fact that tissue-lesions permit the entrance of bacteria, and promote infection. A wound, therefore, in, whatever way produced, forms a local predisposition, and the disease, in such cases, bears the character of a wound infection. Infections caused by pus-cocci, tetanus bacilli, glanders, and anthrax bacilli are of this character. Other causes leading to increased predisposition to infection are less easily recognized. It appears that severe chilling, " taking of cold," or hunger may have this effect ; also changes in tissues due to preceding infectious or non-infectious local or general diseases (see § 11, Sec- ondary Infections). In the case of intestinal infections (typhoid, chol- era), gastro-intcstinal disturbances, play a role. Not infrequently it is impossible to determine what causes have favored the production of an mfection at a given time. Predisposition or lessened resistance is not infrequently shown to injurious agent.s other than those of infectious nature. Certain indi- viduals are less able than others to withstand high temperatures, particu- larly if at the same time bodily labor is performed. Of soldiers on the march only a fraction may suffer from heat-stroke, although all are under the same conditions. The altitude at which different individuals become sensitive to the deficiency of oxygen, varies greatly. The effects of chloroform anaesthesia differ in different individuals. Many persons become exhausted through physical or mental labor at a time when in other individuals, under like conditions, no trace of exhaustion is dis- coverable; such influences operating daily in cases of special predispo- sition, may lead to disease. Occasionally individuals show a degree of sensitiveness to external influences, which is anomalous to that usually observed, so that symptoms of disease arise which ordinarily would not affect the majority of man- kind. Such sensitiveness is designated idiosyncrasy. It is exhibited particularly to certain chemical substances, in that articles of food or drink regarded as harmless act on such persons as poisons— eating of fresh fruit or sugar or salad produces nausea and vomiting. Others have IDIOSYNCRASY. 35 an aversion to dishes prepared from liver or kidneys, and become ill if they overcome this aversion and eat these foods. Still others, after eat- ing lobster, strawberries, raspberries, morels, or asparagus, are affected with urticaria, a symptom characterized by an eruption of itching wheals. Certain persons are unable to drink boiled milk without unpleasant re- sults. Alcohol, even in small doses, may cause marked excitation, or narcosis, or remarkable disturbances of the vaso-motor system. Doses of morphine or chloroform, which are borne by the majority without in- jury, may cause in certain individuals severe symptoms or even death. Some individuals show a high degree of sensitiveness, on the part of the mucous membranes of the respiratory tract, to the pollen of certain grasses, so that during the hay-harvest the inhalation of pollen gives rise to a catarrhal condition of the nose and conjunctiva, often of the larynx, trachea, and bronchi, which in severe cases may be associated with asthma and fever. These conditions are known as hay-fever, hay- asthma, or as pollen-diseases. According to the investigations of Dun- bar, pollen contains a substance that may be extracted, and which, when injected subcutaneously into those disposed to this disease, causes symp- toms of intoxication. Disinfecting fluids, such as corrosive sublimate or carbolic acid, in solutions which are ordinarily borne without discom- fort, may, when applied to the skin of certain individuals, cause not only local disturbances of sensation, but may excite dermatitis of wide- spread proportions. The importance of natural predisposition and immunity in the origin of in- fectious diseases has not only been made evident by the study of epidemics amotig men and animals, but has received confirmation by experimental investigation. If, for example, a mixture of bacteria be injected into an animal, only a part of these develop and produce tissue-changes; the others die. If the same mixture be in- jected into an animal of different species, the bacteria which develop are not the same as those in the first case. Further, bacteria which, when inoculated into a certain species of mouse, invariably cause death, may, when inoculated into a mouse of different species, be without effect. Mice are susceptible to anthrax, rats are nearly immune. The poison of the so-called septicaemia of rabbits kills rabbits and mice ; guinea-pigs and rats are immune to it, while sparrows and pigeons are susceptible. The spirilla of relapsing fever may be successfully inoculated only into apes. Gonorrhoea, syphilis, and leprosy cannot be successfully inoculated into any of the lower animals with the exception of apes. In the case of natural antitoxic immunity the toxins that enter the organism remain as perfectly harmless material in the body, and only relatively late are split in the process of metabolism. In such cases the avidity between the toxin and the body cells, their receptors respectively, may be wanting or slight. When not entirely wanting, an increase of the dose may produce intoxication. Immunity against small doses may arise through anchoring of the poison (for example, tetanus poison) to tissue elements changes in which do not produce symptoms of disease; or- antitoxins may be present which render the toxins inert. Nurslings and older children are more susceptible to certain infections than adults ; particularly in the case of whooping-cough, diphtheria, measles, scarlet fever and tuberculosis. In the intestine of nursing infants, bacilli,_ tubercle bacilli in particular, are easily taken into the lymph-vessels ; the skin of infants offers less resistance to the entrance of pus-cocci than that of older individuals. Young dogs may be infected with anthrax while old ones cannot. In this connection it should be noted that the slight susceptibility or the immunity of many adults is conferred by attacks of such diseases during childhood. In later life, haemorrhage into and softening of the brain, cardiac degenerations, cancerous growths, and the formation of gall-stones . are of frequent occurrence. The predisposition in old age to certain diseases depends in part on degenerative processes, associated with premature senility of the tissues ; in part on the fact that certain influences, which the years bring with them, gradually accumulate, so that 36 THE INTRINSIC CAUSES OF DISEASE. finally the changes which they produce become so prominent that they lead to func- tional disturbances and recognizable morbid conditions. Moreover, it is to be re- marked that many symptoms occurring in old age are those of secondary diseases, which become apparent after other tissue-changes have reached a certain degree. For example, senile hemorrhages, senile gangrene, degenerations of the brain and heart are dependent on disease-processes occurring in the arteries. The predisposition of the sexes to certain diseases depends, in the first place, on the structure and function of the sexual apparatus. Pregnancy and the puerperium offer a favorable field for many diseases, for example, infection. Differences of predisposition of different races are shown particularly in regard to malaria and dysentery, toward which the negro in general shows less suscepti- bility than the European. Malarial parasites may be present in the blood of the former without giving rise to symptoms of disease. 2. Inheritable Diseases Based on Congenital Defects. § 15. Among the morbid conditions arising from congenital defects and which appear spontaneously or are developed through external in- fluences, there may be distinguished several groups; one in which the body as a whole is involved ; another in which only part of the body is afl^ected ; and a third in which only a part of an organ presents changes of a pathological nature. There is no sharp dividing line between these groups. It is often impossible to determine what part congenital defects and what part extrinsic causes have taken in the production of such pathological conditions. Among the constitutional conditions arising from intrinsic causes are to be mentioned the development of dwarfs and giants. The first is marked by under-development of all parts of the body, both the skeleton and soft tissues, while the second is characterized by growth exceeding that of the ordinary individual. It cannot be doubted that both dwarfism and giantism are dependent on congenital defects in the fetal architecture, but it cannot always be told to what extent such abnormalities in bodily growth are traceable to foundational faults or to pathological influences exerted during the period of development, such, for example, as dis- ease of the thyroid gland, or of the pituitary. Another constitutional^ peculiarity is corpulence (obesity, adipositas, lipomatosis universalis), in which fat is deposited in excessive amount eithei; in tissues normally containing fat, or in regions which normally contain none, for example, beneath the endocardium or between the muscles'. The increased deposit of fat is to be referred to disproportion between the production or supply of fat, and its consumption, patholog- ical increase being at one time dependent on abnormal fat-production, at another on decreased consumption. Experience teaches that the energy with which metabolism goes on in the body varies at different periods of life, so that the normal amount of nourishment tends at one time to fatten, while at another time it does not. In the pathological condition termed obesity, which in part at least is attributable to a congenital tendency, the energy of destructive meta- morphosis is so altered that an abnormal amount of fat is deposited even when a moderate or decreased amount is supplied. ' Gout, like obesity, is a constitutional disease, which is partly depend- ent on congenital peculiarities, and at the same time is favored bv in- trinsic causes. The exact nature of the disease is not known Accord- mg to Garrod and Ebstein, the acute attacks of gout are caused by an accumulation of uric acid. On the other hand Pfeiffer holds that the essential feature of gout consists in the fact that the uric acid is pro- INTRINSIC CAUSES OF DISEASE. 37 duced in a form wh,'ch is soluble only with difficulty. According to von Noorden, the formation and deposit of uric acid is a secondary process, induced by the presence of a ferment having a local action, and is con- sequently not dependent on the amount of uric acid formed in other parts of the body. Pathological changes arising in single systems and organs on a congenital basis, may occur in any part of the body, and may involve an entire system or organ, or only part of one. In the skeleton there may occur abnormal development of single parts, as, for example, smallness of the extremities (micromelia) or of the head (microcephalus) in contrast to the size of the trunk; over- development of a bone or group of bones (macrocephalus, macrodactyl- ism, giant growth of a finger, entire foot, or of an extremity) ; malforma- tions of the extremities (cleft -hand, cleft- foot, etc.). Occasionally supernumerary bones, as carpal bones or phalanges, may develop, or atypical formations, such as bony outgrowths (exostoses, hyperostoses), which may extend over the skeleton to a greater or less extent, originat- ing either spontaneously or following traumatism. In the muscular system pathological bony formations are sometimes seen, notably in the condition known as myositis ossificans, which is apt to lead to progressive stiffness through the transformation of muscles into bony plates. In the vascular system there occur either gross anatomical changes, such as abnormal branching of the arteries or mal-development of the heart; or finer changes, which reveal themselves through hjemorrhages {hemophilia) the severity of which is out of all proportion to the in- jury, e. g., in such subjects the withdrawal of a tooth may be followed by long and almost uncontrollable loss of blood. During the development of the central nervous system changes may occur which manifest themselves as disturbance of function or as a special predisposition to disease. Others are distinguished by gross anatomical changes, such as abnormal smallness of the brain (micrencephalon) or of the spinal cord (micromyelia), defective development or absence of par- ticular parts (see chapter on malformations), misplacement of the gray matter (heterotopia), abnormal formation of cavities (syringomyelia), or abnormal formations of neuroglia. These may involve the functions of the sensory organs and the motor centres, and even the psychical processes. Such conditions as idiocy and epilepsy have their origin in congenital predisposition. The tendency to crime has been ascribed to congenital predisposition, and Lombroso, in particular, has endeavored to prove that the man who lives through and for crime, the Homo delinquens, is a congenital criminal — that is, a man who possesses other physical and psychical characters than the normal in that he presents well defined stigmata of degeneration. According to Lombroso, subnormal develop- ment of the anterior half of the cranium, associated with corresponding lack of development of the anterior portion of the cerebrum, in connec- tion with over-development of the posterior portion, produces feebler development of intelligence and of the moral sense, and favors the in- stinct-life. Benedikt goes so far as to maintain that the criminal pos- sesses a peculiar configuration of the cerebral convolutions, similar in type to those of beasts of prey. 38 THE INTRINSIC CAUSES OF DISEASE. The views of Lombroso and Benedikt have met with much opposition. There can be no doubt that there does exist a degenerate species of the human race, which is characterized by such anatomical peculiarities as make it possible to distinguish a class of Homo delinquens from that of Homo sapiens. All the somatic peculiarities regarded as characteristic of the criminal, for example, the beast-of-prey type of cerebral convolu- tions, slightly developed frontal brain, receding forehead, massiveness of the lower jaw, asymmetry of the cranium, marked prominence of the arcus superficiaHs and arcus frontalis, pathological conformations of the skull, etc. — while relatively frequent in criminals, are far from infre- quent in others. On the other, hand, it is not to be doubted that the tendency to crime is frequently dependent on a congenital predisposition having its seat in some irregularity in the organization of the central nervous system. In this respect the criminal resembles the insane in- dividual. Pathological cerebral functions may develop in individuals of morbid predisposition without the occurrence of external injury, either during the period of development and growth or later. On the other hand such influences as over-work, sorrow, care, contribute to mental illness. In these cases the inherited tendency consists in a predisposition to mental disease so that influences which would produce no recognizable efifects in a normal individual are sufficient to excite morbid phenomena. Since many influences, as diseases and infection, are adequate under certain conditions to produce mental disturbances in individuals who must be regarded as normal, it is difficult and often impossible to determine what part intrinsic and what part extrinsic causes have had. Among the congenital pathological conditions of the visual appa- ratus are dyschromatopsia and achromatopsia, congenital partial or total color-blindness, which are frequently spoken of as Daltonism, and are characterized by want of perception for certain colors (most frequently red and green) or for all the colors. In this category belongs a variety of degeneration of the retina, in which there occurs a peculiar spotted, black pigmentation, associated with diminution of central vision and light-perception, with narrowing of the visual field. Finally, certain forms of myopia_ and albinism (absence of pigment in the choroid), are to be considered in this connection. Of intrinsic conditions of the auditory apparatus deaf-mutism is of chief importance; this condition, in part at least, is dependent on dis- turbances of development. Further, certain malformations of the ex- ternal ear fall into this class. In the skin and subcutaneous connective tissue new-growths may develop on a congenital basis in the form of proliferations of connective tissue, at other times of epithelium. They often involve particular parts of the skin, as the nerves, blood-vessels, lymph-vessels, or the adipose tissue. When occurring as extensive thickenings of the skin and sub- cutaneous tissue, they constitute the foundations of the conditions known as fibromatous, neuromatous, hsemangiomatous, lymphangiomatous, and lipomatous elephantiasis. As circumscribed growths they are known as birth-marks, fleshy moles, lentigines, and freckles. The epithelial hyper- trophies give rise to those conditions designated fish-scale disease or ichthyosis, ichthyotic warts, and cutaneous horns. INHERITANCE OF DISEASE. 39 In addition to the pathological conditions which have been mentioned, there are malformations of the body (see chapter on malformations) or of internal organs which must be regarded as primary — i.e., which are not produced by injurious influences exerted on the developing foetus. Finally, many forms of tumors (see chapter on tumors) are to be placed in this class, particularly those which are found at birth or which develop during childhood. § 16. The origin of diseases in which extrinsic influences are either entirely absent during both intra- and extra-uterine life, or are of signifi- cance only as a source of irritation sufficient to excite into development pathological tendencies which are already present in the body ■ — may be explained in two ways : Either the pathological peculiarities of the indi- vidual concerned are inherited from the ancestors, or they are developed from the seed, i.e., from, the individual sexual nuclei that have copulated or from the segmentation nucleus resulting from their union. The inheritance of pathological qualities is clearly shown by clinical observations, inasmuch as many of the diseases due to intrinsic causes which are cited in § 15 also appear as inheritable characteristics in certain families. In some cases these characteristics are transmitted from the parents to the children, in other cases the grandchild may exhibit patho- logical peculiarities of the grandparents, the parents themselves remaining exempt; in other cases the pathological peculiarity may be manifested in the collateral branches, as from uncle to nephew. Dwarfishness and giantism are pathological peculiarities which frequently characterize cer- tain families. Six fingers, cleft-hand and cleft-foot, hare-lip, dextro- cardia, birth-marks, multiple exostoses, fibromatosis of the nerves, and multiple neurofibromata may appear in families for successive genera- tions. Haemophilia is an inheritable condition. It is ordinarily transmitted •through the daughter to a male grandchild, the daughter not showing the disease. There may occur, however, direct transmission of haemophilia from parents to children. Partial or total color-blindness also occurs as a family disease, especially affecting the male members, and like haemo- philia is transmitted through the female line, which does not suffer, to the male descendants. The typical pigment-degeneration of the retina, myopia, deaf-mutism, certain forms of progressive muscular atrophy, and polyuria (Weyl) are also inheritable. According to Gairdner and Garrod, in about ninety per cent of all cases of gout there is a family history of the disease. Of the pathological conditions of the nervous system many are in- heritable ; to these belong periodic and circular insanity, epilepsy, hysteria, and to a somewhat less extent melancholia, mania, and alcoholism. Pro- gressive paralysis, the deliriums, and conditions of nervous exhaustion are but slightly influenced by heredity (Kraepelin). Hagen estimates the number of hereditary insane at 28.9 per cent, Liedesdorf at 25 per cent, Tigges at over 40 per cent of all cases, while Forel holds that 69-85 per cent have hereditary taint. In the more severe forms of transmissible degeneration the patholog- ical condition itself is inherited. More frequently the predisposition is alone inherited and the morbid condition itself is developed later through the action of extrinsic influences on the central nervous system. The character of the disease in the descendants may be the same as in the 40 THE INTRINSIC CAUSES OF DISEASE. ancestors (identical heredity). More often the character of the disease is changed (transformational heredity), not infrequently in the sense that the severity of the condition increases from generation to generation (degenerative heredity). According to Morel, there may appear, for example, in the first gen- eration, nervous temperanient, moral depravity, excesses; in the second, a tendency to apoplexy, severe neuroses, alcoholism ; in the third, psychi- cal disturbances, suicidal tendency, intellectual incapacity; in the fourth, idiocy, malformations, and arrests of development. The occurrence of inheritable diseases is comparable to the well- known fact that in a family not only the peculiarities of race, but also of that particular family are inherited, and that often the qualities of either parent or of both recur in the children. As a hypothesis for the explanation of heredity, it is only necessary to assume that the peculiar quality under consideration represents not merely a somatic change accidentally acquired during the life of the ancestor, but rather a quality of the ancestor developed on a congenital basis. Diseases which in a normal individual arise only under the influence of some external in- jurious agency are never in a true sense inherited (compare § 17), but only those pathological conditions existing in the germ are to be regarded as examples of true inheritance. If a certain disease, as, for example, mental disease or myopia, is the product of a special inherited predisposi- tion plus the effect of injurious influences which have acted on the body during life, only that part can be transmitted which has its seat in some peculiar congenital arrangement, but not that caused by external in- fluences—the acquired condition cannot be inherited. In direct inheritance — i.e., in that form of inheritance in which parental qualities are transmitted to the child — the transmission of nor- mal as well as of pathological qualities is possible only when both sexual cells, in the condition in which they combine, contain the potential char- acteristics of both parents, in so far as these are transmissible. The product of the union of the sexual cells — the segmentation-cell — must, therefore, contain within itself both the paternal and maternal qualities. Since the sexual cells do not represent a product of the body developing during the course of life, but are rather to be regarded as independent structures, which at an early period of development are separated from the other parts of the body (that is, from the somatic cells) into special organs, where, protected and nourished by the body to which they belong, they lead an independent existence ; the only possible explanation for the phenomenon of inheritance is found in the hypothesis that the idividual sexual cells contain, from the time of their origin onward, the poten- tialities which appear in the body in which they dwell. Both the sexual cells and the body itself, therefore, inherit in general the same qualities from the ancestors. _ Since in the act of frutification only the nuclei of the sexual cells — that is, parts of the same — come to copulation, we are compelled to assume that the nuclei are the bearers of inheritable quali- ties, and the peculiarities of the individual arising from the combination of sexual nuclei have their foundation in the organization of the nuclei. The appearance in the descendants of normal or pathological char- acters belonging to the collateral relatives (uncle, great-aunt, or cousin), but which are not present in the parents, is known as collateral inheri- tance. This phenomenon is explained by the hypothesis that the sexual cells, in their origin, received characteristics which the bodies of the INHERITANCE OF DISEASE. 41 parents did not receive, or which, at least, did not undergo development or were submerged in the parental bodies, whereas in certain relatives they did develop and become manifest. _ The appearance in an individual of normal or pathological character- istics which were wanting in the parents, but were present in the grand- parents or great-grandparents, is known as atavistic inheritance. This phenomenon is explained by the hypothesis that given characteristics of the grandparents or great-grandparents were transmitted to the sexual cells of the son, or of the son and , grandson, without developing in the body of the first, while the quality thus remaining latent was re-awakened in the grandson or great-grandson. The attempt has been made to give to the atavistic mode of transmis- sion — which is of frequent occurrence and is usually confined to the immediate generations of ancestors — a wider significance in pathology. Thus it has been proposed to explain the occurrence of many newly aris- ing pathological conditions, which appear similar to certain somatic qualities possessed by remote animal species in the ancestry of man, as a reversion to the type of these ancestors. For example, microcephalus and micrencephalus have been explained as a reversion to the ape type; and Lombroso is inclined to regard the homo delinquens as an atavistic phenomenon. There can be no doubt that certain writers have gone too far in this respect and have mistaken certain acquired pathological for- mations or new germ-variations (compare § 17) for atavistic conditions. Aside from the question of reversion to the type of the nearest genera- tions of ancestors, atavism plays but an insignificant part in pathology, and it can really be employed only in the explanation of pathological formations in which the tissues show a certain fluctuation of behavior, so that not rarely formations arise which in phylogeny or ontogeny rep- resent stages of the then normal conditions. In this category belong, for example, the occurrence of certain forms of the ear, supernumerary ribs, nipples, or mammary glands, and the development of certain muscles which are 'found in the closely related mammals. It is held by many writers that in individual cases, acquired pathological conditions may, under certain circumstances, be transmitted to the descendants. Some even affirm hereditary transmission of deformities caused by injury. In support of their view they refer to the hereditary transmission of birth-marlcs, malformations of the fingers, myopia, mental diseases, predisposition to tuberculosis, etc., as examples which appeared in the first instance as acquired, and were then transmitted to the descendants. Further, they hold that they can point to observations on animals as giving evidence that injuries may cause deformities which are later transmitted to the offspring. An unprejudiced examination, however, of the material collected in support of this view shows that the hereditary transmission of acquired pathological character- istics does not occur. The alleged proofs are found in part to be based on inac- curate observations, in part on incorrect inferences drawn from accurate observa- tions. For example, the assumption that the occurrence of a birth-mark in a child in the same region of the skin as that in which the mother has a scar is proof of inherited deformity is wrong, inasmuch as birthmarks and scars represent two entirely different pathological processes. If, among the descendants of a man who suffered from some form of mental disease and who showed this disease only after a certain age, there appears an inheritable disease of the central nervous system, or if we note a similar occurrence in the case of myopia, we cannot conclude from such observations that the disease of the ancestor was an acquired condition. The term acquired, in the biological sense, can be applied only to that which in the course of the life of an individual arises exclusively from extrinsic influences, but not to a quality, the basis of which existed in the germ-cell, although this quality did not become manifest until excited by extrinsic influences. Should there appear in a 42 THE INTRINSIC CAUSES OF DISEASE. family inheritable mental diseases or hereditary myopia, the first case °f such diseases may have been due to some pathological alteration of the germ, although no manifestations of the disease occurred until some of the outside mfluences of life excited it to activity, and so rendered possible the recognition of the pathologi- cal condition. The pathological condition in this case cannot, therefore, be re- garded as acquired. , , . , As opposed to the theory of the inheritance of acquired pathological condi- tions is the consideration that the human race, which is exposed to so many in- jurious influences, and whose individual members suffer so frequently from disease and mutilations, would soon deteriorate and eventually perish were only a small part of the acquired diseases transmitted io descendants. Further, the reproduction of man and animal forms through germinal cells is in itself an argument against the transmission of qualities accidentally or incidentally acquired by the individual , Darwin represented the view that acquired characteristics could be transmitted to the descendants, and endeavored to make it intelligible on the theory that mole- cules from all the cells of the body contribute to the formation of the germ-cells, and that, consequently, alterations of the organism can be transmitted to the germ- cell. Nevertheless, there occur in the writings of Darwin statements which not only do not agree with this opinion, but contradict it. The act of fructification — that is, the first step leading to theproduction of a new individual — is accomplished by copulation of the sexual nuclei — that is, of the nuclei of the ovum and spermatozoon. According to the researches of the last decades, there can be no doubt that these nuclei are the bearers of the hereditary characteristics of the parents, and that the individuality of the copulating nuclei is inherent in the organization of the same. It is impossible to conceive in what man- ner processes taking place in the body cells can produce in the sexual nuclei, which lie within special cells in the sexual glands, such alterations of organization that they shall contain in potential form the acquired characteristics of the body and transmit them, after copulation has occurred, to the descend?.nts. At the present time the views with regard to the inheritance of disease generally accepted are that there is no true inheritance of infections and that gross struc- tural disturbances cannot be inherited. The only possible inheritance of conditions acquired by the parents is that of conditions acting both on the somatic tissues and germ-cells of the parents. Chemical and physical conditions acting within the body or from without may cause changes in the constitution of somatic and germ-cells. The occurrence of such changes in the germ-cells is clearly shown in the effects on the progeny of paternal or maternal alcholism, plumbism, and experimentally with abrin. It is a well-known fact that in the production of monsters there is often obtainable a history of some infection in one of the parents before conception took place. Bardeen's experiments regarding the changes in embryos arising from ova fertilized by spermatozoa that had been injured by Roentgen irradiation are very suggestive. Recently much discussion has been waged over the principles of heredity in- volved in Mendel's law, Galton's law, and De Vries' theory of mutations (see literature). Literature. {Inheritance of Pathological Conditions.) Bateson: Mendel's Principles of Heredity, London, 1902. Bulloch, Hemophila, Albutt and RoUeston's System of Medicine. Darwin, C. H.: Die Ehe zwischen Geschwisterkindern und ihre Folgen, Leip- zig, 1876. Galton: Natural Inheritance, London, 1889; Proc. Roy. Soc, 1897. Israel: Angeb. Spalten der Ohrlappchen. Virch. Arch., 119 Bd., 1890. Mayer: Spalthand u. Spaltfuss (durch 4 Generat. vererbt.). Beitr. v. Ziegler, xiii., 1898. Pearson: Law of Ancestral Heredity. Proc. Roy. Soc, 1898; Law of Re- version. Ibid., 1900. De Vries: Die Mutationstheorie, Jena, 1901. Ziegler: Konnen erworbene pathologische Eigenschaften verebt werden u wie emtstehen erbliche Krankheiten u. Missbildungen ? Beitr v Zieo-le'r i 1886; Die neuesten Arbeiten iiber Vererbungs- u. Abstammun^lehre u. ihre Bedeutung f. d. Pathologie, ib., iv., 1888. See also § IS and § 17. THEORIES OF INHERITANCE. 43 § 17. As has been explained in § 16, inherited diseases are such as have developed from intrinsic causes, that is, from certain peculiarities in the germ-cells; or at least are diseases in which the predisposition thereto is a congenital characteristic. Conversely, the statement may be made that all normal or pathological qualities in the germ-cells are in- heritable. The appearance of new pathological characteristics which are in- heritable may be dependent on the fact that as a result of the union of two sexual nuclei, one of which is the bearer of the transmissible qualities of the father, the other of those of the mother — variations are con- stantly arising, so that the child is never exactly like one parent ; but, in addition to the qualities which the parents offer, it possesses new quali- ties. Even if we assume that the sexual nuclei at times contain in poten- tial form exactly the same characteristics as those of the parents, the product resulting from the union of these nuclei would present a certain degree of variation. However, the differences between the children of such parents would be but slight. As a matter of fact, different products of the same parents may show an infinite variety, by reason of the fact that the germ-cells themselves contain a mixture of the transmissible characteristics of the paternal and maternal ancestors, and this mixture is never the same. In accord with this is the fact that the children of a certain family always present important differences in both physical and mental quali- ties. A marked resemblance occurs only in the case of twins arising from one egg — i.e., when the process of development of both children has started from the same act of copulation. The embryonal variations resulting from the mixture of two indi- vidually different hereditary tendencies find their expression in varied qualities of body and mind of the developing child. If these do not deviate in marked degree from the characteristics which other members of the family show, the conditions are regarded as normal and ordinarily receive no special attention. If, on the contrary, important differences are produced, the fact attracts attention; and, according to the value which it has for the individual concerned, is regarded at one time as something favorable, at another time as something unfavorable, some- thing pathological. When small, weak parents produce children who develop into large and strong individuals, or when the intellectual ca- pacity of the children surpasses that of the parents, the occurrence is re- garded as favorable. If, as happens, a genius suddenly appears in a family, without any evidence of extraordinary mental development in the ancestors, the phenomenon attracts attention and is regarded as a for- tunate event. But if, on the other hand, strong parents beget children who are weak or defective, or if they show a mental development in- ferior to that of their parents, or stunting of their mental faculties, the nezvly appearing variation is regarded as abnormal, pathological. The assumption seems warranted that of transmissible pathological conditions and predispositions, many, perhaps the majority, are refer- able to a variation of the germ based on the amphimixis.. For ex- ample, the group of hereditary pathological conditions and predispositions of the central nervous system, hereditary myopia, hsemophilia, pigmenta- tion of the retina, and polydactylism may arise in this manner. If such abnormal characteristics show themselves repeatedly in the children of parents who are themselves normal and have healthy ancestors, it may 44 THE INTRINSIC CAUSES OF DISEASE. be assumed that the germ-cells of the parents, though individually normal, have through their union given rise to pathological variation. This hypothesis becomes substantiated when one or both parents produce normal offspring through copulation with other individuals. Besides those variations which are the result of normal sexual repro- duction, it is probable that pathological germ-variations which lead to the development of transmissible pathological qualities may also arise through the action of injurious influences on the sexual nuclei or the segmentation nucleus; or that the union of the sexual nuclei has been disturbed. The injurious substance may be a body-product, or it may come from without, and at the same time produce its harmful effects. Consequently, in these cases we may speak of the germinal acquisition of a transmissible pathological characteristic through the action of an extrinsic injurious influence. This does not mean, however, as has been accepted by many, that the tissues of the body, under the influence of extrinsic harmful influences, suffer changes in themselves, and then transfer these changes to the germ-cells. It is to be believed, rather, that the harmful influence acts directly on the sexual nuclei or on the seg- mentation-nucleus, producing in these a change which later leads to pathological development in the individual developing from the im- pregnated tgg. It is a matter of no importance, so far as the nature of the resulting pathological variation is concerned, whether the somatic tissues also suffer changes, or what the character of these may be. If a transmissible pathological characteristic arise, it may, if it does not affect life or prevent reproduction, be transmitted, although this does not necessarily follow. The chances that a particular characteristic will be transmitted are greatest when both parents possess the same quality, as, for example, when both parents are affected with hereditary deaf-mutism or with near-sightedness. If the characteristic is wanting in one parent, there is produced most frequently a new germ-variation, in which the pathological characteristic fails entirely to manifest itself, and in following generations may completely disappear. If several descendants are begotten, the pathological characteristic, if it be not wholly lost, may show itself in only a few of the descendants, and in either modified or_ aggravated form. Not rarely it happens that the characteristic remains latent in one generation — that is, confined to the sexual cells, and appears again in the second. § 18. Besides the inheritable pathological conditions mentioned above, hereditary transmission of infectious diseases sometimes occurs. This is not a true, form of inheritance, but is more properly designated as postconceptional intra-uterine infection. If pathogenic micro-organisms enter the blood-stream of a pregnant woman they may be carried into the vessels of the maternal placenta, and may pass_ through the fcetal placenta into the body of the foetus. Such transmission has been demonstrated in many infections (staphylococcus, streptococcus, pneumococcus, typhoid fever, anthrax, smallpox, syphilis^ and others) through the presence of the micro-organisms or of charac- teristic changes in the tissues of the foetal organism. In certain cases for example, in anthrax, the path which they have taken may be demon- strated since the placenta shows characteristic pathological chano-es. It was once assumed that besides placental transmission there might also occur germinal transmission, that is, infection of the sexual cells before or durmg fructification. Further, it has been taken for THEORIES OF INHERITANCE. 45 granted, that, through infection of the fructifying spermatosome, infec- tion of the ovum without that of the maternal organism may occur, and such a mode of infection has been regarded as established, particularly in syphilis. Up to the present time, however, this mode of transmission has not been proved by unquestioned observations to occur in man and the mammals, and its occurrence even in syphilis has also been thrown into doubt (Matzenauer). According to our present knowledge we may say definitely that the transmission of infections through the placenta to the foetus in utero has been positively demonstrated and occurs in different infectious diseases. Infections of the ovum or of the sperm before or during fructification are indeed possible, but it has not yet been positively demonstrated in the case of man and the other mammals that a further development into a viable foetus is possible in the case of an ovum in which the agents of infection have produced characteristic changes. This is true not only in the case of acute infections, but also in such chronic ones as tuberculosis and syphilis. According to the views of Matzenauer, in no case of hereditary syphilis can maternal transmission be excluded ; and there are no clinical observations that speak for a pure paternal spermatic infection of syphilis. The fact that the mothers of children showing hereditary lues are immune toward syphilis (Colles' law) cannot be explained by the hypothesis that the mother has received syphilis toxins from the child syphilized from the father and in consequence has produced antitoxins {Finger), but can be explained only on the ground that she herself was infected with syphilis. That the mother often shows no syphilitic changes cannot be taken as an argument against the latter view, since syphilis may often be present with complete absence of symptoms. Literature. (Transmission of Infectious Diseases to the Fcetus.) Blumer: Congenital Typhoid. Jour. Amer. Med. Assn., xxxv. V. During: Hereditare Syphilis. Eulenb. encyklop. Jahrb., v. 1895 (Lit.). Eberth: Geht der Typhusorganismus auf den Fotus iiber? Fortschr. d. Med., vii., 1889. Finger: Die Vererbung der Syphilis, Wien, 1898 (Lit). Kockel u. Lungwitz: Placentartuberkulose beim Rirtd. Beit v. Ziegler, xvi., 1894. Latis: Uebergang des Milzbrandes von der Mutter auf den Fotus. Beit v. Ziegler, x., 1891. Lubarsch: Ueber die intrauterine Uebertragung pathogener Bakterien. Virch. Arch., 124 Bd., 1891. Malvoz: Transmission interplacentaire des microorganismes. Ann. de ITnst. Past, 1888 and 1889. Morse: Fcetal and Infantile Typhoid. Arch, of Fed., 1900. Schmorl u. Geipel: Tuberkulose der mensch. Placenta. Miinch. med. Woch., 1904. Warthin: Tuberculosis of the Placenta. Journal of Infectious Diseases, 1907. Warthin and Cowie: Tuberculosis of the Placenta. Journal of Infectious Dis- eases, 1904. CHAPTER II. The Spread and Generalization of Disease Through the Body. Autointoxications and Secondary Diseases. § 19. Primary local disease is accompanied by disturbance of func- tion of the affected part. If the causative agent passes into the lymph stream or blood without causing noticeable changes at the point of en- trance, while within the body it gives rise to solitary or multiple foci, the disease thus resulting is designated lymphogenous or haematogenous, as the case may be. Local diseases may remain confined to the organ originally affected; frequently they lead to secondary diseases of organs or to general disease. One method by which disease spreads through the body is by the process of metastasis, by means of which not only solitary, but innumer- able foci arise in different parts. Not infrequently dissemination of disease by the blood and lymph-channels (tuberculosis, suppuration, and malignant growths) may proceed to such an extent that the majority of the organs are thus secondarily involved. A second method occurs in which at the primary focus toxic pro- ducts are formed, and these, when taken into the lymph and blood, produce local changes due to the effects of poisoning. Such intoxica- tion is of common occurrence in the infectious diseases, and leads not only to secondary degeneration of organs, but even to general disease, as shown by constitutional reactions characterized by disturbances of metabolism and fever. A third form of the spread of disease through the body becomes possible by reason of the fact that the integrity and normal functional capacity of many organs are in great measure dependent on the func- tion of other organs ; and, further, on the fact that the organism needs, for the preservation of its normal condition, the perfect functional work- ing of its organs. _ There is, therefore, a large group of local and general diseases which arise as the result of the imperfect functional activity of individual organs. A fourth mode of origin of secondary diseases is through autointoxi- cation — that is, through poisoning of the organism by substances which arise in the body itself {metabolic poisons) . These substances may arise in the intestinal tract (enterogenous poisons), or in the tissues (histo- genous poisons) . The poisonous action of these products of metabolism lies partly in the fact that they are produced in increased amount or are retained in the body as a result of disease of certain glands- or because they are not transformed to non-poisonous bodies, as in normal circumstances. In conditions of disturbed metabolism poisons foreign to the normal body may be produced. 46 METASTASIS AND EMBOLISM. 47 A fifth method by which the body may be injured is through loss of function of those glands producing an internal secretion. In this category belong the thyroid, hypophysis, pancreas, adrenals, and sexual glands. Since in disease of the glands just named intoxication plays an. important role, this group of processes is closely connected with that of the fourth mode of generalization of disease. / I. Metastasis and Embolism and their Significance in the Etiology of Lymphogenous and Haematogenous Diseases. § 20. The transportation, through the blood or lymph-stream, of a disease-producing agent, and the production of disease at the point of deposit, is termed metastasis. This is one of the common modes of the spread of disease through the body. Ordinarily the term metastasis is applied to those cases in which the transportation of a given substance is followed by easily recognizable clinical and anatomical manifesta- tions of disease, especially those of inflammation or tumor-formation, so that we are accustomed to speak of metastatic inflammations and metas- tatic tumors. There is, however, no good reason for not including under metastasis those cases of transporta- tion of corpuscular elements through the lymph or blood stream in which the changes produced by the trans- portation are less striking, and are recognizable only through careful anatomical or microscopical investiga- tion. The term metastasis indicates that the substance deposited has arisen from some other place in the body, and we are accustomed to speak, of lymphogenous or haematogenous metastasis, depending on the mode of transmission. The significance of metastasis is dependent on the properties of the transported body. I nsoluble bland foreignbodies of sm all sk e may have little_effect on the tfssue; soluble and'chemically active sub- stances may, on the other hand, produce important tfesue changes. 'iJac- teria capable of reproduction may give rise to disease which corre- sponds to that produced at the primary focus of infection. Tumor-cells may develop a secondary tumor. The size of the transported body is of importance in haematogenous metastasis, in that small bodies may pass all the blood-vessels, even the capillaries, while larger ones are carried only through those vessels whose lumen is sufficiently large to admit them. When the latter obtain entrance to the arteries and are carried along by the blood-stream, they become lodged at those divisions of the vessels where the lumen is too small to admit them, and more or less com- pletely obstruct the lumen. This occurrence is designated embolism; the body blocking the vessel is the embolus (Fig 1). The effect of embolism is more or less complete obstruction of the vessel, partly through the presence of the embolus itself, partly through associated coagulation of the tlood. As a result of such obstruction there is in- «Zai^ Fig. 1. — Multiple emboli in the branches of the pulmonary artery, after thrombosis of the right auricle, a. Arterial branch; b, embolus; c, embolus with secondary thrombosis. 48 THE GENERALIZATION OF DISEASES. terference with the circulation, which may vary greatly in different cases ; behind the point of obstruction there may be established either complete or partial collateral circulation, in other cases such compen- sation may be wanting. When compensation is incomplete or absent, the tissue supplied by the obstructed vessel undergoes degeneration or dies. Both lymphogenous and hsematogenous metastasis usually occur in the direction of the normal current, but transportation in the opposite direction may take place — retrograde metastasis. .Such a change of current in the lymph-vessels occurs when the escape of lymph from the region involved is hindered through stoppage of the lymphatics, and the lymph is forced to seek other outlets. A similar condition may occur in circumscribed areas supplied by the peripheral blood-vessels. In this way clots arising in the right heart or in the large veins of the body may be trainsported to the peripheral veins, particularly under conditions in which backward waves of blood gradually force the clots into the smaller veins. According to the investigations of Arnold on dogs, for- eign bodies (wheaten grits), which were too large to pass the capillaries, when introduced into the jugular or crural veins, as well as into the longitudinal sinus of the dura mater, were carried by retrograde metas- tasis not only into the main trunks, but into the smallest branches of the veins of the liver, kidneys, heart, extremities, dura mater, pia mater, and orbit, and into the posterior bronchial veins. In the case of a defect in the septum of the heart, bodies circulating in the blood rnay pass directly from one side of the heart to the other, and thereby give rise to crossed or g^adoxical embolism. § 21. The substances which are transported in the process of metastasis may be divided into six groups, this classification being based partly on the origin and character of the transported body, and partly on the effects of its lodgment. In the first group are placed insoluble lifeless substances composed of small particles, which enter the body from without, and may be desig- nated collectively as dust. The majority of these substances enter the body, in the respired air, and pass from the lungs into other tissues. Others enter the tisues through accidental or intentional wounds (tattoo). Most frequently these substances are particles of soot, coal- and stone-dust, more rarely metal, porcelain, tobacco, hair or other kinds of dust. In tattooing of the skin, lampblack, india-ink, ultramarine, and similar granular pigments are used. The behavior of the tissues toward such substances will be treated of elsewhere ; it is only necessary to mention here that these forms of dust, sometimes in a free state, sometimes enclosed within cells are first deposited in the tissues nearest the point of entrance, later in the lymph- vessels and lyrnph nodes. In the latter location they may remain for a life-time ; but in cases of excessive deposit they may be carried beyond the lymph nodes, especially in those instances in which the nodes be- cause of the great deposit, undergo softening and give rise to inflamma- tion and proliferation of the tissues in the neighborhood Often as a result of such changes the affected nodes become conflueat with and break into neighboring veins This event is especially likely to happen at the hilum of the lungs whereby the contents of the node ultin^^telv sometimes slowly, at other times more rapidly, gain entrance to the vessel-lumen and are carried away by the blood-stream In the lungs METASTASIS AND EMBOLISM. 49 dust may be deposited directly in the vessel-walls and gradually pene- trate as far as the intima. Further, the particles from a broken-down lymph node can enter the lymph-stream, and, if not arrested by some other lymph node, may reach the blood-stream. It is also conceivable that softened lymph nodes may break directly into the thoracic duct. In fact, rupture of a tuberculous node into the receptaculum chyli is a recognized mode of origin for the rapid dissemination of tubercle bacilli through the body (acute miliary tuberculosis). As numerous experiments have shown, dust gaining entrance to a blood-vessel remains but a short time in the circulation. Large amounts artificially introduced into a vein disappear in a few hours from the circulating blood. The greater part collects in the capillaries of the liver, spleen, and bone-marrow, partly free and partly within leucocytes, in the former case adhering to the surface of the endothelium. After a short time the leucocytes containing the dust particles wander out from Fig. 2. — Fat-embolism of the lungs (Flemming's solution, safranin) Arteries filled with blackened masses of fat; b^ fat-droplets in capillaries; Cj veins; d, cells in the alveoli, x loo. the vessels and the dust collects in the tissues, where it is held for a long time, in wandering or in fixed cells, or free. It may remain here during the lifetime of the individual, or be carried in the lymphatics to other regions and deposited, particularly in the portal and cceliac lymph nodes. According to the researches of Kunkel and Siebel, still other cells containing dust-particles may reach the surface of the body-cavities, either through the lungs, the parenchyma of the tonsils, and probably also from the lymphoid tissue of the intestines, and in this way be discharged externally. From the liver the dust-particles may be discharged in the bile. According to observations made on inflamed organs, wandering leucocytes are able to take up a great number of the particles lying in the tissues and transport them from the lungs, intestinal tract, and other organs to the surface, and in this way clear the tissues. The second group is composed of portions of the body itself, namely, tissue-detritus, parenchyma cells, and dead, coagulated, and broken-up constituents of the blood. Of the elements arising from the destruction 4 so THE GENERALIZATION OF DISEASES. of tissue, fat-droplets (Fig. 2, a, b, and Fig. 3, a, b) often find their way into the circulation ; particularly when through trauma or some other pathological process, as, for example, haemorrhage, the tissues are de- stroyed. This occurs most frequently in cases of crushing, destruction, and violent agitation of fat-tissue, as may happen in the different panniculi adiposi and the bone-marrow; fat may also enter the circu- lating blood through destruction of liver-tissue. The parenchyma cells most frequently entering the circulation are liver-cells, syncytial placenta-cells, portions of chorionic villi, and bone-marrozv cells. Ordi- narily these are carried into the pulmonary arteries and capillaries, but through retrograde metastasis they may be carried into the veins, and through paradoxical embolism into the arteries and capillaries of the systemic circulation. Embolism of liver-cells and bone-marrow giant- cells is caused by traumatic and toxic injuries and haemorrhages of the affected tissues. Placental-cell emboli, in the form of syncytial giant- cells, have been observed in puer- peral eclampsia, but occur also in the course of normal pregnancies. Pulmonary emboli composed of small portions of the chorionic villi have been observed. In diseased conditions of the intima of the heart or blood-vessels, degenerated endothclimn, brokcn-dozi'n and de- generate masses of intima, portions of the vah'es, and material of similar nature may gain entrance to the blood-stream. Fragments of blood-corpuslcs may enter the cir- culation from haemorrhagic foci or may arise within the vessels them- selves, in degenerative changes produced in the blood through the in- fluence of the various harmful agents. Coagulated masses of blood enter the circulation when a thrombus — i. e., blood coagulated in the vessels (see Chapter IV) — ^breaks loose, either in toto or in fragments. The fate of the last-named substances is for the chief part dependent on their size and physical properties. All fragments of greater diameter than the lumen of the capillaries become lodged in the bifurcations of the arteries (Fig. 1, a, b) and usually occlude the same. This occurs most frequently in the case of dislodged thrombi or of fragments of such; on the other hand, fat-droplets usually pass into the capillaries, where part remain, while others pass through and become lodged in some other place. Smce the fat occasionally passes first into the veins of the body and thence to the heart, the fat-droplets collect especially in the capil- laries of the lungs (Fig. 2, b) ; but thev mav also pass throucrh the lungs mto the capillaries of the greater circulation, and are then^'found m the intertubular and glomerular capillaries of the kidneys fFio- 3 a b) and to some extent in the capillaries of other organs CapTllarv 'fat' embolism causes noticeable disturbances of the circulation only when of extensive occurrence; in this case it may lead to the production of oedema of the lungs. Furthermore, the fat disappears in the progress of metabo- lism, or is conveyed into the neighboring tissues. Fig. 3. — Fat-embolism of the kidney (Flera- ming's solution, safranin). a, Glomeruli with fat m the capillaries; b, fat-droplets in the in- tertubular capillaries. >: loo. METASTASIS AND EMBOLISM. 51 Parenchyma cells become lodged in the capillaries or smaller arteries in the case of arterial metastasis. The latter is especially true of liver- cells when entering the circulation en masse. At the place of lodgment their presence may lead to heaping-up of blood-plates and hyaline coagu- lation. The cells themselves do not multiply, but may remain unchanged for a time, according to Lubarsch, as long as three weeks. They then gradually die, the protoplasm dissolves, the nuclei swell or shrink, and finally lose their chromatin. The point of lodgment of loosened thrombi or fragments of thrombi depends on the path which they take, as well as on their size. Since thrombi may be formed in the systemic veins, right heart, and pulmonary arteries, as well as in the pulmonary veins, left heart, and systemic arteries (see Chapter IV.), it is possible for embolism to occur in any of the arteries of the greater or lesser circulation. Often emboli lodge at the bifurcation of arteries, forming the so-called riding or straddling emboli (Fig. 1, c). Through retrograde metastasis emboli may be carried from the venas cavse or larger veins into the smaller veins. Defects in the septum of the heart may lead to the production of para- doxical embolism. Small fragments of thrombi, dead red blood-cells or fragments of such, endothelial cells undergoing disintegration or fatty degeneration, etc., meet the same fate as dust-particles. They may remain free or be taken up by cells ; but are soon removed from the circulation and collect in the spleen, liver, and bone-marrow, where they undergo further changes and are destroyed. The products resulting from the destruc- tion of red blood-cells may persist for a long time in the organs named, as pigment deposits. The third group of substances producing metastases is composed of living cells, which, originating from proliferating tissue-foci and hav- ing gained entrance to the circulation through rupture into the blood- vessels, or having entered the lymphatics, are carried to other organs. This process may be observed in the case of tumors growing by infiltra- tion. The metastasis of living cells from a tumor leads through prolifera- tion of the transported cells to the production of metastatic secondary tumors, which in lymphogenous metastasis develop first in the lymph- vessels and lymph nodes, but in the event of direct rupture into the blood-vessels arise in that part of the vascular system to which the tumor-cells are carried by the blood. The metastasis usually occurs in the normal direction of the blood- and lymph-streams, but retrograde transportation may occur, so that a tumor which has broken into one of the systemic veins may give rise to metastases in the region drained by smaller branches of other systemic veins. Retrograde metastasis is not infrequently observed in the lymphatic system, when closure of the ef- ferent l5Tnph-channels has produced a change in the direction of the lymph-current. In the fourth group may be placed all those processes characterized by the entrance of vegetable or animal parasites into the circulation. If in such circumstances these organisms do not find conditions suit- able for their development, they are eliminated from the blood-stream and destroyed. But if they are able to reproduce themselves, they give rise to metastatic foci of infection, partly in the vascular system, but also extending thence into neighboring tissues. The secondary foci produced by bacterial invasion have in general the same character as that of the 52 THE GENERALIZATION OF DISEASES. primary. If an embolus contains organisms capable of producing tissue- necrosis, inflammation, and putrid decomposition, repetition of the same processes will occur at the place of lodgment. In the fifth group of metastatic processes may be classed those cases in which constituents of the human body having undergone solution are transported in the soluble state and deposited in a solid form; and also those in which extrinsic substances are taken up by the body in a soluble form and are deposited in the tissues in a solid state. Frequently bile-pigment enters the circulation within the liver, and permeates the tissues, giving to them a yellowish color (icterus). Not infrequently iron-containing derivatives arising from the destruction of red blood-cells in the circulation are carried to the spleen, bone-marrow, liver, and kidneys and form pathological deposits of iron (hsematogenous siderosis). Fat can be split from the fat depots in the form of soluble soaps and carried through the blood to different organs where it is taken up by the cells and changed into neutral fat. When preparations of silver are, for medicinal purposes, introduced into the body through the gastro-intestinal tract for long periods of time, there may occur a deposit of fine granules of silver in the connective tis- sue of the skin, in the glomeruli, medullary pyramids of the kidneys, intima of the large arteries, adventitia of the small arteries, in the neigh- borhood of mucous glands, connective tissue of the intestinal villi, in the choroid plexus of the cerebral ventricles, and in the serous membranes. Tissues showing such a deposit have a grayish, color. The fact that epithelial tissues and the brain are not affected shows that there is a selective action on the part of the tissues, and that this selective action differs essentially from that which is seen in the metastatic deposit of corpuscular elements. It may be assumed that the chemico- physical character and the functional activity of the tissues coming into contact with substances in solution exert a determining influence on the separation and precipitation of such substances. In a sixth group of metastatic processes may be classed the entrance of air into the circulation. If a large amount of air gains entrance to the right heart, an event which occurs especially in case of injury to the large veins lying in the neighborhood of the thoracic cavity, or more rarely from the opening of a vein, for example, in the stomach, through ulcerative processes, the air mingling with the blood forms a foamy mass, which the contractions of the heart are not able to drive onward. As a result the left heart receives little or no blood, the aortic pressure falls, and the individual quickly dies. Should the air enter the circulation in small amounts or intermittently, it may be carried by the blood-stream in the form of bubbles and circulate through the body. Larger amounts may lodge for a time in the vessels of the major or minor circulation, obstruct their lumen, and cause disturbances of the circulation, which give rise to functional disturbances of the brain and respiration. If these conditions do not cause death, the air is after a time absorbed. If the lung-tissue be ruptured through trauma or violent coughing, screaming, or vomiting, etc., air may be forced into the connective- tissue spaces and lymphatics, and may extend through these into all parts of the lungs, pleurae, and the mediastinum, as well as into the skin. The condition thus produced is termed emphysema of the skin of the subcutaneous tissue, of the mediastinum, etc. In certain circum- METAST.iSIS AND EMBOLISM. 53 stances the air may spread through a large area of the subcutaneous lymph-vessels and connective-tissue spaces, and the skin presents an inflated appearance and when pressed upon produces a crackling sound. According to ^iefce/ and i?'M«fee/, granules of cinnabar and indigo injected into the blood-stream of a frog are quickly taken up by leucocytes, and after one to two hours no free granules are to be found. After twenty-four hours the leucocytes containing pigment-granules have disappeared from the circulation, and lie clumped in the capillaries, the greatest number being found in the spleen, liver, bone-marrow, and lungs, while they occur in smaller numbers in the kidneys, and in still smaller numbers in the capillaries of the heart-muscle. Even after two hours free pigment and cells containing granules are found out- side the vessels, and after a few days they have almost wholly disappeared from the vessels. The granules lie partly in wandering-cells, partly in fixed ceils, and in the free cells of the splenic pulp (Ponfick) and bone-marrow. They may be found in these organs for weeks afterward (^Hoffmann, Langerhans). In both frogs and dogs some of the granule-containing cells find their way into the lumen of the alveoli and bronchioles and so pass out of the body. In the liver the pigment- particles adhere for a short time to the endothelium oif the capillaries and may be taken up by the endothelial cells (Browicz, Heinz) ; another part is found in leucocytes, which later wander out frorn the vessels into the tissues. Thence they are in part taken up into the lymphatics of the liver and ultimately reach the lymph- nodes. A part of the granules finally passes out with the bile, but by what course they reach the bile-vessels is not known. In dogs the pigment-granules also collect in the tonsils and are carried to the surface through the epithelium by the leucocytes » which have taken them up. According to the observations of Jadassohn (" Pigmentverschleppung aus der Haut," Arch. f. Derm., 24 Bd., 1892) and Schmorl ("Pigmentverschleppung aus der Tiaut," Centralbl. f. allg. Path., 4 Bd., 1893), both normal and pathological pigment may be transported from the skin to the lymph-nodes — in other words, pigment- metastasis takes place. According to Lewin (Arch. f. exp. Path., 40 Bd., 1897), if the outflow of urine from the bladder be hindered, small foreign bodies can pass into the kidney-pelves, and thence into the urinary tubules, lymph-vessels, and veins, and into the general circulation. Literature. {Metastasis of Dust.) Arnold, J.: Staubinhalation u. Staubmetastasen, Leipzig, 188S; Die Geschicke des eingeathmeten Metallstaubes im Korper. Beitr. v. Ziegler, viii., 1890. Browicz: Phagocytose der Lebergefassendothelien. A. f. mikr. Anat., 58 Bd., 1902. Buxton: Absorption from the Peritoneal Cavity. Journal of Medical Research, 1907. Heinz: Phagocytose der Lebergefassendothelien. A. f. mikr. Anat., S8 Bd., 1901. V. Kupffer: Sternzellen, der Leber. Miinch. med. Woch., 1899. MacCallum: Absorption from the Peritoneum. Johns Hopkins Hospital Bulle- tin, xiv., 1903. Ponfick: Ueber die Shicksale korniger Farbstoffe im Organismus. Virch Arch., 48 Bd., 1869. Siebel: Ue'ber das Schicksal von Fremdkorpern in der Blutbahn. Virch. Arch,, 104 Bd., 1886. Sulzer: Durchtritt corpuscul. Gebilde durch d. Zwerchfell. Virch. Arch., 143 Bd., 1896. (Embolism of Fat and of Parenchyma Cells.) Aschoff: Capillare Embolic von riesenkernhaltigen Zellen. Virch. Arch., 134 Bd., 1893. Beneke: Fettembolie. Beitr. v. Ziegler, xxu., 1897.' 54 THE GENERALIZATION OF DISEASES. CoUey: Fettembolie nach gewaltsamer Gelenkbeugung. Zeitschr. f. Chir., 36 Bd., 1893. Ebstein: Lipamie u. Fettembolie bei Diabetes. Virch. Arch., ISS Bd., 1899. Graham: Fat Embolism. Jour, of Med. Research, 1907. Hamilton: Lipsemia and Fat Embolism. Edinburgh Med. Journal, 1879. Hess: Beitr. z. d. Lehre v. d. traumatischen Lebterrupturen. Virch. Arch., 121 Bd., 1890. Jiirgens: Fettembolie u. Metastase v. Leberzellen. Tagebl. d. Naturf.-Vers. in Berlin. 1886. Klebs: Multiple Leberzellenthrombose. Beitrage v. Ziegler, iii., 1888. Leusden: Puerperale Eklampsie. Virch. Arch., 142 Bd., 189S. Lubarsch: Parenchymzellenembolie. Fortschr. d. Med., xi., 1893; Zur Lehre von den Geschwiilsten u. Infectionskrankheiten, Wiesbaden, 1899. Maximow: Parenchymzellenembolie. Virch. Arch., 151 Bd., 1898. Ribbert: Fettembolie. Correspbl. f. Schweizer Aerzte, 1894. Schmorl: Embol. Verschleppung v. Lebergewebe. Deut. Arch. f. klin. Med., 42 Bd., 1888; Organbefunde bei Eklampsie. Cent. f. allg. Path., ii.; Unters. lib. Puerperaleklampsie, Leipzig, 1893. Turner: Hepatic Cells in the Blood. Trans, of the Path. Soc. of London, 1884. Warthin: Pulmonary Emboli of Liver-cells and Bone-marrow Giant-cells. Med. ~ News, 1900. {Air Embolism.) Hare: Entrance of Air into Veins. Therapeutic Gaz., 1889; Amer. Tour, of * Med. Soc, 1902. Senn: Entrance of Air into Veins. Trans. Amer. Surg. Assn., 1885. Wolf: Luftembolie. Virch. Arch., 174 Bd., 1903. II. The Sequelae of Local Organic Disease. § 22. Secondary diseases occur with great frequency as phenomena associated with pathological changes in the blood and circulatory appar- atus. The circulatory apparatus and the blood bear intimate relations to all the body-tissues, and accordingly diminution in amount and patholog- ical alterations of the blood, as zvell as changes in the blood-vessels, often give rise to disease conditions. If the haemoglobin-content of the blood is decreased through diminution in the number of red blood-cells (oligocythaemia), or through a pathological condition of the same, or if the hemoglobin through the action of carbon monoxide is rendered in- capable of taking up the oxygen of the air, the body-tissues no longer receive a normal amount of oxygen; consequently if the degree of oxygenation falls below a certain point, disturbances of nutrition arise, and are most frequently exhibited in the form of fatty degeneration of the heart, icidneys, liver, and other viscera. Should an artery become narrowed or closed through thrombosis or embolism, or thickening of its walls, as in the disease known as arterio- sclerosis, there arise in the region supplied by the affected vessel a local deficiency of food and oxygen, local asphyxia, and later degenerative processes, which frequently end in death of the specific parenchymatous elements, at times also of the connective-tissue framework. In the brain and spinal cord the vessel-changes lead to ischaemic soft- ening, which frequently results in paralysis, and not rarely in death. In the heart diffuse fatty degeneration or local softening of the heart- muscle may occur, giving rise to disturbances of cardiac activity or even to complete insufficiency. In the kidneys the secreting parenchyma, to- THE SEQUELiE OF LOCAL DISEASES. 55 gether with a portion of the connective tissue, undergoes necrosis or atrophy ; and the loss of these substances gives rise to local or widespread contractions, which, according to their origin, are designated embolic or arteriosclerotic atrophies. In the stomach ischasmia of the mucous membrane gives rise to local ulcerations; in the liver and muscles to atrophic conditions. No tissue can withstand the harmful effects of long-continued anaemia, and con- sequently the narrowing and closure of arteries, through the formation of clots or changes in the vessel-walls, play an extremely important role in pathology; and are not only the causes of ancemic necrosis (see Chapter V.) and hoemorrhagic infarction (see Chapter IV.), but also of numerous progressive atrophies of organs. In the pathogenesis of the last named, arteriosclerosis has an especially important part, since in old age it is of common occurrence, and gives rise to tissue-degenerations in organs of widely different structure. The majority of the affected organs show areas of scar-tissue, in which the specific parenchyma has disappeared while the connective tissue has increased. The active participation of the vascular apparatus in all inflammatory processes (see Chapter VII.), the disturbance of circulation through alteration of the vessel-walls, the shifting and changes in the vascular channels which result from the closure of vessels by proliferation of en- dothelium and connective tissue, or through thrombosis, as well as from the formation of new vessels, make easily comprehensible the fact that in all chronic inflammations the specific cells dependent on regulated nutri- tion undergo degeneration and are frequently replaced by connective tissue of a lower grade than normal. Profuse watery discharge from the intestines may deprive the body of water. If, as a result of stenosis of the oesophagus or pylorus, food is prevented from entering the intestinal tract, or if the stomach and intes- tine are no longer able to digest food and to prepare it for assimilation, the organism as a whole becomes poorer in albumin and fat. If the heart is no longer able to propel with normal strength the blood coming to it, there arise in various organs changes due to venous stasis. If respiration is imperfect, the composition of the blood suffers. Collec- tion of fluid in the thoracic cavity causes compression of the lungs ; such mechanical interference may lead to atrophy. If a part of the lung has been rendered useless by chronic inflammation, the inspiratory enlarge- ment of the thorax affects only that portion of the lung which is capable of functionating, and this part becomes over-distended and finally atrophic. Disease of the parenchyma of the liver often gives rise to disturbances of the circulation of the blood through the organ, and stasis throughout the portal circulation with resulting ascites. Should the pancreas be de- stroyed or if it is no longer able to produce its ferments (proteolytic trypsin, amylolytic diastase, and the fat-splitting and emulsifying steap- sin) there results imperfect metabolism of albumin, carbohydrates, and fat. Hindrance to the outflow from the ureters reacts on the secretion of the kidneys and leads to atrophy. The loss of a large portion of the renal parenchyma is followed by increased blood-pressure in the aorta, in- creased action of the heart, and hypertrophy. Increased resistance in the pulmonary circulation due to diseased con- ditions of the lungs is often followed by dilatation and hypertrophy of 56 THE GENERALIZATION OF DISEASES. the right heart. Obstruction to the flow of blood through the aortic opening is followed by hypertrophy of the left ventricle. Stenosis and insufficiency of the mitral valve cause a stasis of blood backward through the lungs to the right heart. This may be compensated for through hypertrophy of the right ventricle, or the process of stagnation may ex- tend into the veins of the systemic circulation. An oblique position of the peluis leads to curvature of the spine. Stiffness and immovability of a joint cause atrophy of the muscles which normally control the movements of the joint, the atrophy being due to inactivity. Diseases of the nervous system .may give rise to functional dis- turbances and anatomical changes in any organ of the body — in glands, muscles, skin, bones, lung, heart, intestine, etc. Destruction of the ganglion-cells in the anterior horns of the spinal coird leads tO' atrophy of the corresponding peripheral nerves and muscles. Paralyzed extrem- ities become atrophic. Injury to certain portions of the medulla ob- longata, or the presence of tumors in the brain may be followed by or associated with withdrawal of the, glycogen of the liver into the blood- stream and the excretion of sugar in the urine. Stimulation of periph- eral nerves may produce abnormal reflex sensations and movements as well as circulatory disturbances in other parts of the body. Paralysis of both vagi or of their branches, or the recurrent laryngeal nerves, through inflammatory changes or pressure from enlarged lymph nodes, etc., may be followed by inflammation of the lungs, in that the accom- panying paralysis of the laryngeal muscles favors the entrance of for- eign bodies during inspiration. The so-called trophoneurotic diseases of the tissues are not mentioned above, for the reason that the trophic relations of the nervous system to indi- vidual tissues are not clear, and the views of different authors as to the depend- ence of the tissues on the nervous system vary greatly. Many authors ascribe to the trophic action of the nervous system a far-reaching influence. For example, muscular atrophy, glandular atrophy, atrophy of the bones and joints (in tabes-and syringomyelia), different patholog'ical conditions of the skin char- acterized by thinning, exfoliation of the epithelium, loss of hair, inflammation, etc., unilateral tissue-atrophies, necroses, hypertrophic proliferation of muscles, glands, skin, or bones, etc., are all referred to affections of the nerves. It cannot be doubted that both degenerative and hypertrophic tissue-changes and inflammation often occur as sequelae to disturbances of innervation, but these most probably are not the direct result of removal or change of nerve- influences, but are the results of increased or decreased functional activity of the tissue, or of injuries, inflammation, or disturbances of circulation, which have developed in connection with the disturbances of innervation for exam- ple, in connection with the loss of sensibility. Golz and Ewald, after completely destroying the thoracic and lumbar portions of the spinal cord of dogs were able to preserve uninjured the skin of the animals thus operated on; they are therefore, opposed to the theory of trophic centres and nerves. ' (Pfliiger's III. Autointoxications and Disturbances of Internal Secretion. § 23. Autointoxication may take place in a variety of ways. Pois- onous products of metabolism may fail of proper excretion. Secondly the physiological production of poisonous substances may be transcended to such an extent as to become pathological. Thirdly", it may happen that poisonous products of metabolism, which normally'are decomposed and rendered harmless, may escape destruction. Finally, it may happen that, as the result of pathological changes in, or interference with the AUTOINTOXICATION. 57 functional activity of certain organs, poisonous substances appear in the blood and are excreted in the urine. According to their origin poisons may be classed as enterogenous, arising in the intestine, and histo- genous, arising in the tissues. If injurious products arising from the decomposition of albumin are retained or are formed in excessive amounts in the intestinal canal, they may give rise not only to local changes, but to symptoms of general intoxication. For example, through the action of bacteria present in the intestines, sulphuretted hydrogen may be formed in such amount as to pass into the blood and impart its characteristic odor to the breath, and also to be found in the urine. Further, toxic substances which arise from the decomposition of albumin through the action of intes- tinal bacteria, when taken into the blood are able to produce symptoms of poisoning — vomiting, headache, vertigo, stupor, acceleration and weak- ening of the heart's action, etc. This is especially true of those cases in which there is faecal retention. If the function of the kidneys is disturbed to such a degree that sub- stances convertible into urea are excreted in sufficient quantity, symp- toms of intoxication manifest themselves. These are characterized by coma interrupted by convulsions and by disturbances of respiration — the symptoms collectively being designated uraemia. According to von Limbeck, the retained substances have a narcotic action, the first effects of which are dulling of sensibility and insomnia. It has not been de- termined whether the toxic effects are due to a single element or to a mixture of substances. Disturbed function of the intestines may render it difficult for the organism to rid itself of poisons, and in this way leads to autointoxication, copraemia. Likewise, excessive accumulation of carbonic acid in the blood, through interference with the exchange of gases in the lungs, may cause symptoms of poisoning. ^Vhen the excretion of bile is hindered or arrested, through altera- tions in the bile-passages or in the liver itself, the elements of the bile are taken into the blood, and the condition known as cholaemia is produced. Biliary salts and bile-pigment enter the blood, and give rise to lassitude, depression, inclination to sleep, slowing of the pulse, itching of the skin, a tendency to hemorrhage on slight provocation, and abnormal sensations of hearing and taste. The effects on the heart, muscles, and central ner- vous system are ascribed to the bile-salts. These also possess a lytic action on the red blood-cells. According to Bickel, ammonia- salts, leucin, and phenol must also be taken into consideration in the explana- tion of the symptoms. If the liver has undergone marked pathological changes, not only does the production of bile and the synthesis of urea suffer, but sub- stances brought to the Hver from the intestines and normally decomposed by this organ may pass through unchanged. Many believe that the severe symptoms (delirium, lethargy, coma), which occur in degenera- tions of the liver (icterus gravis) are to be referred in part to the pres- ence of such substances in the blood, and base their belief on the fact that under such conditions abnormal products of metabolism (ammonium carbonate) appear in the urine. In degenerations of the pancreas, large amounts of dextrose, acetone, and aceto-acetic acid (see § 25) may ap- pear in the blood and urine. The two last-named substances have a 58 THE GENERALIZATION OF DISEASES. toxic action, and many are disposed to ascribe such symptoms to dis- turbance of pancreatic function. Finally, after degeneration of the thyroid or adrenals (§§25 and 26), pathological symptoms arise which may be explained in part by the assumption that poisonous products of metabolism are no longer destroyed. In the constitutional disease known as gout, deposits of urates are associated with tissue-degeneration and inflammation. The condition of eclampsia is an autointoxication resulting from pregnancy, and is possibly due to poisons originating in the placenta. The term autointoxication is not used in the same sense by all writers. Many give to it a broader meaning than the one above, and even apply the term to certain intoxications caused by pathogenic bacteria. Such wideriing of the term appears to me inexpedient, in that the cause of the decomposition lies not in the body itself, but comes from without, so that intoxication is the result of a preceding infection. It seems to me to be more correct to apply the term autointoxication only to those forms of poisoning which are caused by products of metaboHsm, either under the influence of the body-cells or through the activity of bacteria constantly present in the intestine. As authorization for including the poisoning by products arising from intestinal decomposition among the autointoxications, I draw on the fact that the micro-organisms which cause this decomposition are constant inhabitants of the intestine, and, accord- ing to the investigations of Schottelius, are indispensable factors in the processes of nutrition of man and the higher vertebrates. The enterogenous autointoxica- tions, which are caused by these intestinal bacteria and which occur especially in childhood through retention of the intestinal contents (ileus) or in acute digestive disturbances are in their severe forms characterized by disturbance of heart-action, small and frequent pulse, cyanosis, coldness of the extremities, and lowering of the body temperature. They may owe their origin in part to reten- tion of intestinal contents, and in part to changes in the products of decompo- sition (formation of toxins) depending either on the character of the material taken into the intestines (deficiency of carbohydrates, particularly of sugar, favors the extension into the small intestine of processes of decomposition normally confined to the colon), or on a change in the virulence of the bacteria, or on deficient production of enzymes. It is not always possible in such cases to decide whether bacteria, foreign to the intestine, are not also concerned in the production of poisons. The appearance of cystin in the urine is to be regarded,^ according to the researches of Baumann and von Udranski, as evi- dence of intestinal decomposition resulting in the production of diamins.' The hypothesis that puerperal eclampsia is an autointoxication" is sup- ported by the majority oif writers. Clinically the formation of toxic substances during pregnancy may be recognized by the occurrence of nausea, vomiting, emotional depression, hemoglobinuria, albuminuria, and finally by convulsions and coma. The anatomical findings in women who have died of eclampsia are multiple thromboses in the smaller vessels and capillaries, and focal degenera- tions, usually associated with haemorrhages in the liver (hemorrhagic hepatitis) In the lungs there may also be found syncytial cells. The fibrin-content of the blood IS markedly raised. Should the child die (as takes place in about forty per cent of cases) corresponding changes may be found in its liver and blood. It was at firsit thought that the origin of the poison was in the maternal organism, and the cause was sought in alterations of proteid metabolism in which the disturbances of function were located in the kidneys or in the liver or the thyroid. Recently the view has been advanced that the intoxication is to be referred to products of the placenta (cytotoxins). Veil assumes a direct intoxication through placental elements which takes place when the olacental toxin can no longer be rendered inactive through the formation of antitoxin (syncytiolysm). On the. other h^nd Arcoli belilves that the mother produc s an excess of syncytiolysm and thereby poisons herself. Weichart thinks that there are formed through, syncytiolysis, that is, the solurion of the transported placental elements, albumin bodies (syncyt.otoxins) which are poisonous to he mother. At the present time it cannot be decided which one of these hypothe- ses corresponds most fully to the actual conditions. nypotne DISTURBANCES OF INTERNAL SECRETIONS. 59 § 24. If a gland produces an internal, secretion — that is, if it gives to the lymph or blood substances which are necessary for the perform- ance of the functions of other organs or of the body as a whole — ■ alteration or withdrawal of this secretion is succeeded by more or less grave disturbances. Such an internal secretion is ascribed to the pan- creas, thyroid, adrenals, pituitary, thymus, and the sexual glands. We are able to infer the influence exerted by these glands on metabolism and life from the disturbances which arise when the glands in question become diseased. Among the more important diseases belonging in this category are diabetes mellitus, exophthalmic goitre, the dystrophies of pituitary origin, eunuchoidism, myxcedema, cretinism, Addison's dis- ease, and the functional and anatomical changes occurring in the body after castration. Diabetes mellitus is a disease which is characterized by large amounts of grape-sugar in the urine (glycosuria), accompanied by great increase in the amount of urine secreted (polyuria), and often by acetone and the excretion of aceto-acetic acid and y3-oxybutyric acid. At the same time grape-sugar and these acids are found in the blood and lead to diminution of its alkalinity. When the acid-content of the blood is high, headache, delirium, fainting, and finally loss of consciousness (coma diabeticum) develop. Glycosuria may be caused by too great ingestion of sugar, so that part passes into the urine unchanged (alimentary glycosuria). Glycosuria may also follow injury to certain portions of the medulla oblongata (puncture of Bernard), or as the result of fracture of the skull with hemorrhage, epilepsy, severe psychical disturbances, tumors, parasites, or of certain forms of poisoning (carbon monoxide, curare, morphine, strychnine, amyl nitrite, nitrobenzol ) , in which the liver probably gives its glycogen to the blood more rapidly than normal, so that hyperglycaemia is produced. Finally, glycosuria may be due to inability on the part of the kidneys to hold back the small amounts of glucose normally found in the blood, a phenomenon which may be produced experimentally by the administra- tion of phloridzin (von Mering) or of caffeine sulphate (Jacobj). These alimentary, nervous, and toxic glycosurias are to be sharply distinguished from true diabetes.. In the latter the cause of the gly- cosuria is to be sought, not in an increased conveyance of sugar into the blood, or in a pathological excretion of the sugar normally contained in the blood, but rather in the fact that the diabetic patient is unable to decompose carbohydrates, notably dextrose, although the sugars which turn polarized light to the left (levulose and inulin) can be oxidized either wholly or at least in greater amounts than dextrose. In most cases the power to form fats from carbohydrates is also lessened, yet there are instances in which this function is unimpaired and the sugars are stored in the body in the form of fat (diabetogenous obesity). Accordng to the investigations of von Mering and Minkowski, which have been confirmed by others, this loss of power to oxidize the sugars brought to or formed in the body, or to store them as glycogen or fat. is to be ascribed to insufficiency of pancreatic function. This conclu- sion is drawn chiefly from the fact that after total extirpation of the pancreas in dogs, diabetes of severe character, usually fatal within a few weeks, is produced, this being characterized, as is diabetes in the human subject, by polyuria, polydipsia, hyperglycaemia, glycosuria, diminution 60 THE GENERALIZATION OF DISEASES. of the glycogen of the tissues, at times by marked destruction of albumin, emaciation, excretion of large amounts of acetone, aceto-acetic acid, ;8-oxybutyric acid, and ammonia, as well as by the occurrence of diabetic coma. In support of the view that there is a definite relation between disturbances of pancreatic function and diabetes, it has been found that in this disease in man the pancreas has exhibited demonstrable changes, of the nature of atrophy or degeneration. Thus it has been shown by Opie, and abundantly confirmed by others, that a large per- centage of all subjects dead of diabetes mellitus exhibit sclerotic or hyaline changes in the islands of Langerhans. In those instances where anatomical changes in the pancreas are not found we are forced to con- tent ourselves with the hypothesis that our methods of investigation are defective or that there is a variety of extra-pancreatic diabetes. An exact explanation of the relations between pancreatic disease and diabetes cannot be given, yet from the foregoing researches the hy- pothesis has been deduced that the pancreas produces an internal secre- tion which either gives the body the power to destroy glucose or in- creases this glycolytic capacity. Likewise, no explanation can be given for the increased destruction of the albumins and the accompanying abundant production of y8-oxybutyric acid, aceto-acetic acid, and acetone. Since these substances are not always found in experimental pancreatic diabetes, their formation probably does not stand in direct relation tO' the excretion of sugar, but is to be regarded as a complication of diabetes (Minkowski). Their occurrence in human diabetes, moreover, is not constant, and they are found in other diseases (intoxications, carcinoma, disturbances of digestion, pregnancy, starvation, ether narcosis, etc.). The occurrence of diabetes after total extirpation of the pancreas is evidence that this organ possesses a special function which is of the greatest importance in the normal consumption of sugar in the organism. Lepine is of the opinion that there is in the blood a glycolytic ferment, which is formed by the pancreas arid passed from this organ into the blood; and that the cause of the mellituria in diabetic patients and in dogs from which the pancreas has been removed is to be sought in decrease in the amount of this ferment. Accordirrg to Cohnheim, Rahel Hirsch, Arnheim, Blumenthal, and others the pancreas has the power, in a way not explained, of exciting to action the glycolytic ferments found in the different organs. The addition of pancreatic emulsion {Cohnheim) to the expressed juice of muscle increases its glycolytic capacity. At the present time it is impossible to offer a satisfactory explanation of the pathogenesis of pancreatic diabetes -Accord- ing to Stoklasa the anaerobic respiration of the animal organs is an alcoholic fer- mentation caused by enzymes which may be separated from the cells and obtained in the form of powder. They will produce an alcoholic fermentation as long as they are not subjected to the action of lactic acid and thereby inhibited In diabetes such an inhibition of the splitting of glucose into alcohol and carbonic acid occurs through the formation of lactic acid. If only a portion of the pancreas of a dog be removed, no diabetes occurs or at least the excretion of sugar is much less than after total extirpation (Minkow- ski). If in dogs from which the pancreas has been totally removed a portion of pancreas is transplanted subcutaneously, diabetes does not follow {Minkowski, W^dOM), but occurs if the transplanted piece be excised '"vo ., According to Minkowski, there is no direct communication between the secre- me7aboHsm°o"f sugar' ^'""'^' ^^' ^""''^"^ °* "^^ °^^^" concerned in the Poisoning with phloridzin produces, according to von Mering and Minkowski a marked glycosuria in most animals and in man, and the same symptoms as Zse seen in diafietes, may be Produced by continuous administratiorofThe poison Since m this case the cause of the pathological excretion of sugar lies in the Iddnevs and represents a flushmg-out of sugar from the organism, phloridzfn diabetes can- not be identified with the ordinary form of diabetes found in man -that is whh. CACHEXIA THYREOPRIVA. 61 pancreatic diabetes. In. dogs in which diabetes has been produced by the extirpation of the pancreas, phloridzin produces an increase in the amount of sugar excreted (Minkowski) . Literature. {Diabetes Mellitus.) V. Mering: Ueber experimentellen Diabetes. Verhandl. d. V. u. VI. Congr. f. inn. Med., Wiesbaden, 1886, 1887; Zeitschr. f. klin. Med., xiv., 1888, and xvi., 1889. V. Mering u. Minkowski: Diabetes mellitus nach Pankreasexstirpation. Arch. f. exper. Pathol., 26 Bd., 1890; Zeitschr. f. Biol., 29 Bd., 1892. Michael: Diabetes (Cysticercus im IV. Ventrikel). Deut. Arch. f. klin. Med., 44 Bd., 1889. Minkowski: Diabetes nach Pankreasextirpation. Arch. f. exp. Path., 31 Bd., 1893 (Lit.). Moritz u. Prausnitz: Phloridzindiabetes. Zeitschr. f. Biol., 27 Bd. V. Noorden: Pathologie des Stoffwechsels, Berlin, 1893 (Lit.). Op:e: The Relations of Diabetes Mellitus to Lesions of the Pancreas. Journ. of Exp. Med., vol. v., 1901. Sauerbeck: Die Langerhansschen Inseln d. Pankreas. Ergebn. d. a. P., viii., 1904. Seegen: La glycogenic animale, Paris, 1890; Der Diabetes mellitus, Berlin, 1893. Stoklasa: Die glykolytische Enzyma im tier. Gewebe. D. med. Woch., 1904. Tiroloix: Le diabete pancreatique, Paris, 1892. § 25. Cachexia thyreopriva is a disease caused by deficient or arrested function of the thyroid, resulting either from defective de- velopment or from pathological changes in the gland. Kocher was the first to observe that it followed extirpation of the thyroid, and his. re- sults have been substantiated by many others. Numerous clinical observations and experimental researches have confirmed the fact that the presence of thyroid tissue is essential to the integrity of the organ- ism, especially during its period of growth. The gland produces a sub- stance known as thyroiodine which is the active ingredient of the colloid and which probably neutralizes or destroys certain poisons and at the same time exerts a complementary action on intracellular metabolism. According to older experimental observations, total extirpation of the thyroid gland produces in man and in animals severe symptoms characterized by muscular twitchings, convulsions, and paralysis, so- called tetany. It is now known, however, that the production of tetany is due, not to removal of the thyroid itself, but of the parathyroid glands (para thyreopriva! tetany). If loss of the thyroid gland is at first well borne, there arise in man in the course of months or years peculiar disturbances of nutrition, be- ginning with weakness and heaviness of the limbs, feeling of coldness, pain and transient swelhng, loss of mental activity, leading to cachexia associated with anaemia, by pale sweUings of the skin, especially of the face, and diminution of mental powers, together with loss of muscular strength, these symptoms terminating in death. Removal of the thyroid gland in childhood causes disturbances of growth, the increase in length of the bones falling below the normal or ceasing altogether. Animals (rabbits and goats) that have had their thyroid glands removed soon after birth do not reach full growth and acquire an expression of stupidity. Disturbances of thyroid function, as well as total extirpation, lead 62 THE GENERALIZATION OF DISEASES. to pathological conditions of the body. Both clinical observations and experimental investigations show that the disease known as myxoedema (C3rd) is due to changes in the thyroid. Myxcedema is a condition in which the external appearance of the patient is indicative of thyreoprival cachexia, in that the same characteristic pale and elastic swellings of the skin of the face, are associated with similar changes in the skin of other •parts of the body. Further, there is loss of intellectual power, which finds expression in increasing diiificulty in thinking and acting, dullness of the tactile sense, retardation of muscular action, and a monotonous nasal voice. Finally, general weakness and pronounced symptoms of mental derangement occur, and death follows after gradually increasing cachexia associated with ansemia and coma. Cretinism is dependent on disturbances of thyroid function. In cretins there is always present some degenerative condition of the thyroid, the organ being either enlarged (goitre) and changed in structure (endemic cretinism), or imperfectly developed or absent (sporadic cretinism). The general appearance of cretins is similar to that of those individuals who as a result of thyroidectomy in early childhood have become stunted in development. The longitudinal growth of the long bones is below the normal, while the soft parts are well developed. Indi- vidual parts of the body are unequally developed ; the head is relatively large, the abdomen and neck are thick, the bridge of the nose is depressed, , while the nose itself is broad and stumpy ; the skin is pale, flabby, ! wrinkled, or puffed, as if oedematous, particularly over the face, and the belly is protuberant. The mental faculties are feeble, sometimes markedly so. The power of speech and of understanding may be absent, and only in the less-marked cases of cretinism are the subjects capable of work of any kind. The cause of endemic cretinism is unknown. The importance of the thyroid gland in nutrition and development has been placed beyond doubt by clinical observations and experimental investigations. As to the mode of action of the thyroid, there are, however, different opinions. If an animal, after thyroidectomy, is fed with the thyroid of some other animal — for instance, that of the sheep — the injurious effects usually observed after removal of the thyroid do not appear and occur only when the feeding is stopped. In man the administration of fresh thyroid tissue or of thyroid extracts exerts a healing influence on the thyreoprival cachexia and myxoedema ; and reports have been published of favorable results in the treatment in children suffering from cretin- like disturbances. According to the investigations of Baumann, the thyroid contains an iodine substance, thyroicdine or iodothyrin, which is present in greatest quantity in old individuals, and in the smallest quantity in young children. The normal thyroid is able to store the extremely small amounts of iodine brought to the body in vegetable foods or in drinking-water, and to convert it into thyroiodine. The internal administration of preparations of iodine leads to accumulation of iodine in the thyroid. According to Baumann, iodothyrin is the active element of the gland Its employment in the treatment of goitres, myxoedema, and strumiprival cachexia' etc has the same effect as feedmg with fresh thyroid tissue. It would appear that the organism requires iodine for its maintenance, and that the thyroid supplies it with the necessary combination. In regions where goitres are not commonly found (North Germany), the thyroid glands are, on the average, smaller (from 30-40 em ) and contain more iodine (on the average about 3^ mgm. instead of 2 mgtn ) than in regions where goitres are numerous (Switzerland, South Germanv) Whether lack of lodme m the food and drinkmg-water is the cause of the hvoertroohied condition of the thyroid m goitre or whether some injurious agent, perhaps some lower organism, interferes with the specific function .of the gland cannot be said Among domestic animals having a large amount of iodine in the thyroid are th.^ sheep, cow, and calf, while m hogs the iodine-content is small EXOPHTHALMIC GOITRE; ACROMEGALY. 63 Anatomical investigations have failed to throw definite light on the question of the internal secretion of the thyroid. It has been proved that the colloid pro- duced by the thyroid cells passes into the IjTnph-vessels. It is probable that iodothyrin is obtained in this colloid substance. During intra-uterine life the thyroid appears to be destitute of that function, which in later life is so important. Graves' disease, or exophthalmic goitre, which is characterized by goitre, exophthalmos, rapid heart, tremor and great excitability on the part of the patient, is dependent on disease of the thyroid characterized by hypersecretion (hyper- ihyreosis). According to Becbe the experimental feeding of thyroid glands pro- duces symptoms and metabolic changes similar to those of Graves' disease. Removal of a considerable portion of the gland will in many cases effect a cure; and recur- rence of the disease after operation is in most cases accompanied by recurrence of the tumor. Osicald has shown that the colloid of the glands from cases of exophthalmic goitre is, in the majority of cases, deficient in iodine. He believes that the symptoms are due to flooding of the body by altered secretion. Ewing Fig. -(Eellevue Hospital,) Acromegaly, sliowin,^ the enlar,& -ri^f^^mMP- ' ^^sfe? ^"" Fig. 8.- — A lardaceous clot from the cadaver. (Formalin, hematoxylin, and eosin.) x 500. light-yellow, elastic lumps and stringy masses having a smooth surface and not adherent to the vessel-wall, that are known as lardaceous or "chicken-fat" clots. These contain fibrin threads (Fig. 8) and scattered red and white blood-cells. Through the inclusion of red cells Fig. g. — Coagulated blood in a fresh ha;morrhagic infarct of the lung. (Muller's fluid; h,-ematoxylin and eosin.) a, Alveolar septa without nuclei, containing capillaries filled with dark bluish-violet, homogeneous thrombus-masses: b, septa containing nuclei; c, vein filled with red thrombus; d, di, alveoli filled with firm blood clots; e, alveoli filled with serous fluid, fibrin, and leucocytes. X 90. in these formations, they may present in places a red or reddish-black color ; if large numbers of leucocytes are present, they have a whitish color. JJlien blood is drazvn from an artery or vein into a foreign receptacle, coagulation will occur in a short time, as the result of adhesion to the 108 DISTURBANCES OF THE CIRCULATION. sides of the receptacle. The blood becomes changed into a soft coherent mass. When freshly drawn blood is beaten with a solid body, the surface of the latter becomes covered in a short time with fibrin. If in the body large quantities of blood pass into the tissues — for example, into the pericardium or lungs — coagulation may likewise occur, and the ex- travasated blood acquires a firm consistence (Fig. 9). Under certain conditions there may be formed in the heart or blood- vessels during life, firm deposits, which are similar to cruor or to the fibrin formed by whipping the blood. These formations are known as thrombi, and the process which leads to their formation is thrombosis. According to their color thrombi may be distinguished as red, or zvhite (yellow or grayish-white), and mixed. The pathogenesis of thrombosis centers in the chemistry of Jhe co- agulation of the blood. The substances necessary for coagulation are fibriiLogen, iibiin ferment (thrornbin) and calcmm salts. Fibrinogen and calcium salts are normally present in the blood. Thrombin, on the con- trary, is not present as such ; otherwise coagulation would occur. It is supposed that it first appears in an inactive form — prothrombin. Moro- witz and Fuld independently put forward an explanation to account for the activation of prothrombin, namely, that thrombokinase (the zymo- plastic substance of Schmidt) in the presence of calcium salts transforms prothrombin into thrombin, as a result of which fibrinogen is coagulated. As to the origin of prothrombin and thrombokinase there is some un- certainty ; prothrombin, however, is probably provided by the blood plate- lets and is either secreted by them or results from their disintegration. Thrombokinase, on the other hand, is derived from the blood platelets, the leucocytes, the vessel walls or from the tissues generally, the testis being a convenient source from which to obtain it for experimental pur- poses (Mellanby). The problem of thrombokinase is further compli- cated by the presence of coagulins in the vessel walls and tissues, extracts of which, as has long been known, produce coagulation of fibrinogen (Welch). The immediate cause of ante-mortem intravascular coagulation is to be sought in increase in the fibrinogenic substance of the blood, together with diminution in the ability of the walls of the vascular apparatus to inhibit coagulation. Coagulation may be brought about by disturbances of the circulation, particularly retardation of the current and the formation of eddies which drive the blood plates against the vessel wall, and by changes in the vessel walls themselves. Fig, 10. — Bundles and star-shaped clusters of fibrin threads within a blood-vessel. (Fibrin stain.) Prepa- ration taken from an inflamed tracheal mucous mem- brane. X 500. THROMBOSIS. 109 The formed elements which may enter into the composition of thrombi are blood platelets, fibrin, leucocytes and red corpuscles. The diversity in appearance and structure of thrombi is dependent on variations in tlie number, proportion and arrangement of their constituents. Histolog- ically, the intravascular clot is characterized by the formation of minute rods and threads which lie between the cellular elements as a delicate supporting meshwork or as stellate or fasicujar^groups arranged ai'^und centers. "THesel-ods and fibres are collectively known as fiiifin and the centers around which the groupings occur are composed practically ex- clusively of blood platelets. The granular material found in thrombi, to which the older observers attached relatively little importance and which they interpreted as collections of finely divided fibrin or as detritus derived from white corpuscles, is now known to be an essential factor in the process of thrombosis and consists of blood platelets. Bizzozero, in 1882, de- scribed a new element of the blood in the form of small homogeneous structures which he designated blood plates. He regarded them as identical with the haemato- blasts previously described by Hayem. As a result of ex- perimental investigations, Biz- zozero concluded that these bodies played an important role in the coagulation of the blood. This view has been amply substantiated and is now universally accepted. At one time the blood platelets were regarded as disintegra- tion products of the red cells. This view has been abandoned. Cole, for example, has produced a specific agglutinating serum for blood platelets and his experiments militate against a genetic relationship between platelets and red blood corpuscles. According to Wright, the platelets are frpgn ients of th e cytoplas m of th e bone marrow giant cells and occur only in those vertebrates m whose~marrow giant cells are found. The number of platelets increases or diminishes in proportion to the number of giant cells in the marrow. Platelets are a constituent of normal blood, but occur in great abundance only in pathological conditions. Following Eberth and Schimmelbusch, many observers explain the beginning of thrombosis by the accumulation of pre-existing platelets round a foreign body or on the damaged inner wall of the heart or vessels associated with slowing or irregularities in the blood current. Contact with the altered surface sets up immediate viscus metamorphosis of the platelets, as a result of which they adhere to one another or to the foreign body or vascular wall. For example, if, in a vessel whose circulation is Fig. II. — Section through a red thrombus formed in one of the veins of the thigh-muscles, after occlusion of the femoral vein. (Miiller's Huid; hcematoxylin.) a. Fibrin-threads; b, leucocytes and granular masses, x 250. 110 DISTURBANCES OF THE CIRCULATION. retarded, the intinia is injured by compression or crushing or by chemical irritants, blood platelets may be seen adhering to the injured portion and in a short time the spot is covered. Variable numbers of leucocytes now become imbedded in the mass together with red cells which drop out of circulation and are entangled in the thrombus. There are five outstanding varieties of thrombi: (a) red, (b) zuhitc, mixed or laminated, (c) agglutinative or hyaline, (d) Icucoeytic, (e) fibrinous. (a) The red thrombus is formed in conditions attended by marked slowing of the circulation and is composed of red and white cells in the same relative proportions as they exist in normal blood, together with a network of fibrin (Fig. 11). In fresh clots in small vessels, it not Fig. 12. — Section from a mixed thrombus rich in cells. (Muller's fluid, h:cmatoxylin.) a. Red blood-cells; b, granular masses; c, reticular fibrin containing many leucocytes; d, threads of fibrin in parallel arrangement. x 200. Fig. 13. — Section from a white thrombus con- taining but few cells. (Miiller's fluid; hsma- to.xylin.) a. Granular masses; b, fibrogranular fibrin formin.c; a net-like reticulum; c^ fibrin- threads in parallel arrangement, x 200. infrequently is possible to demonstrate the presence of bundles and star- shaped clusters of fibrin, which radiate from centers composed of blood platelets. In such cases, however, it is not always possible to determine to what extent the coagulation is intra-vital or to what extent it is post- mortem. Such coagulation, however, is most frequently observed in in- flammed tissues, and the conckision seems warranted that in these cir- cumstances it is a vital phenomenon. (b) White, mixed and laminated thrombi arise from the circulating blood in diseases of the vascular apparatus which are attended by gen- eral or local slowing or by irregularity of the blood stream, and are yellowish^ or of various^shades of red or of ahernating layers of red and white. Microscopic examination sliows them to consist of masses of platelets and thread-like collections of fibrin together with variable pro- portions of leucocytes, red cells and blood platelets. In mixed thrombi, fibrin and red blood cells are combined, often in alternate strata, and among these elements are greater or less numbers of leucocytes and blood platelets. THROMBOSIS. Ill (c) Agglutinative or hyaline thrombi: Agglutinative thrombi occur in the smaller vessels — capillaries, arterioles and venules — and are char- acterized histologically by the appearance of closely pacl'ced and poorly defined red blood-corpuscles which later become fused and transformed into a translucent hyaline substance. This variety of thrombosis has been observed in a number of conditions, among them, pneumonia, in the intestine in typhoid fever, and the stomach in carbolic acid poison- ing. They are particularly frequently encountered, however, in the smaller branches of the hepatic veins in eclampsia and are associated with hsemorrhagic and necrotic foci in the parenchyma (hasmorrhagic hepatitis ) . Ag-glutinative i^~ ©> Fig. 14. thrombi may be produced ex- perimentally by the injection of various micro-organisms, by ricin, ergot, freezing and hasmagglutinative sera. (d) Leucocytic thrombi: In certain inflammatory pr^o- cess^ intrJA^a scular plugs oc- cur which_are made upjvholly or predoininantl}' of -poly- nuclear leucopytes (\\^elch). Small vessels are sometimes plugged by lymphocytes in chronic lymphatic leukemia, in the walls of the appendix in conditions attended by exces- sive hyperplasia of^Jlie lym- phoid elements norfnally resi- dent in the submucosa, etc. (e) In certain inflamma- tory lesions, notably croupous pneumonia, vessels of small size are sometimes encount- ered in which the lumen is more or less completely filled with fibrillated or whorl-like clumps of fibrin. An occa- sional leucocyte or small col- lections of platelets may sometimes be observed. This form of thrombosis is of negligible importance. The formation of thrombi may be studied under the microscope, both in cold- blooded and warm-blooded animals; and observations made in this manner, espe- cially by Bizzozero, Eberth, Schhnmelbusch, and Lowit, have led to important results. , , . , , , , ,_ When the blood flows with normal velocity through a vessel, there may be seen under the microscope a broad, homogeneous red stream in the axis of the vessel (Fig. 14, a), while at the sides there lies a clear plasma-zone (h) free from red cells. This may be observed in the arteries and veins, but best in the veins, while in the capillaries, which are just large enough to permit the passage of the red cells, this difference between the axial stream and plasma-zone is not apparent. In the axial stream the different constituents of the blood are not recognizable; in the plasma-zone there appear, from time to time, white corpuscles (Fig. 14 d) , which roll slowly along the vessel-wall. Fig. 16. Fig. 14. — Rapidly flowing blood-stream. a, Axial stream: b, marginal zone with isolated leucocytes, d. (After Eberth and Schimmelbusch.) Fig. 15. — Moderately slow hlood-stream. a. Axial stream; b, peripheral zone with numerous leucocytes, d. (After Eberth and Schimmelbusch.) Fig. 16. — Markedly slow current. a, Axial stream: b peripheral stream with blood-plates; c, collection of blood-plate-: d, di, leucocytes. (After Kberth and Schimmelbusch.) 112 DISTURBANCES OF THE CIRCULATION. If the blood-stream becomes retarded to the degree that the red cells of the axial stream are indistinctly recognizable (Fig. IS, a), the white corpuscles which roll slowly in the plasma-zone, at times adhering to the vessel-wall, become con- stantly increased (Fig. IS, d), so that they finally lie in great numbers in this zone. If the current is still further retarded so that the red cells become plainly recognizable (Fig. 16, a), there appear in the peripheral plasma-zone, in addition to the colorless corpuscles {d), blood-plates {h), which increase in number with the retardation of the current, while the leucocytes again become diminished. When arrest of the blood-current occurs, there follows a distinct separation of the corpuscular elements in the lumen of the vessel. If, in the vessel in which the circulation is retarded, the intima is injured at a certain point by compression or crushing, or by means of chemical agents, as corrosive sublimate, nitrate of silver, or sodium chloride, and if the lesion of the wall does not lead to complete stoppage of the circulation, blood-plates may be seen adhering to the injured portion; and in a short time the injured spot is covered with many layers (Fig. 16, c). Often leucocytes (di) become embedded in this mass, and their number is the greater the more numerous they are in the plasma- zone. Under certain conditions they may partly cover the blood-plates. In case of great irregularity of the circulation or more severe changes in the vessel-wall, red cells may become adherent to the vessel-wall or to the colorless deposit already formed. Not infrequently portions of the thrombus-mass are torn loose and a new deposit of blood-plates occurs. The vessel may finally be closed as the result of continued deposit of the blood-elements. When at any point blood-plates in large numbers have become adherent to the vessel-wall, they become after a time adherent to one another and finally fused into a compact mass. Eberth designates the sticking together of the blood-plates con- glutination, their fusion as viscous metamorphosis. If we compare the observations made on warm-blooded animals by Bizzozero, Eberth, and Schimmelbusch, and more recently by Lowit and Gutschy, with the his- tological findings in thrombi occurring in the human subject, we are warranted in the conclusion that the formation of thrombi in the circulating blood of man occurs in the same way as that observed in the lower animals. Thrombosis is, therefore, directly dependent on two causes : HiRtiirhaT 7rpg p f \hf^ PTrfn l^ tinn^ p^y- ■t\c\^LSX^:i _retardatio p_ "f *h^ curr"^* and the form ation of e ddies which drive the blood-plates, against the vessel-wall; and lo cal changes m the ve sael-walls. It is also probable that thrombosis is favored by pathological changesintirenood. From the variety of conditions under which thrombosis in man occurs, we must assume that at one time one cause, at another time another, plays the chief part in the formation of the thrombus, or that all three may take an equal part. According to Arthus and Pages, the blood flowing from the veins becomes inca- pable of coagulating spontaneously if sodium oxalate, sodium fluoride, or soaps are added to it in such quantities that the mixture contains 0.07-0.1 per cent of the oxalate, or about 0.2 per cent of the fluoride, or 0.5 per cent of soap. These act by precipitating the calcium salts. If to blood, kept fluid by treatment with oxalic acid, one-tenth of its volume of a one-per-cent solution of calcium chloride is added, coagulation occurs in six to eight minutes, and the calcium salts pass into the combination of the fibrin-molecule. The fibrin-ferment can act on the fibrin- ogen only in the presence of calcium salts. Under the influence of the fibrin-fer- ment, and the presence of calcium salts, the fibrinogen undergoes a chemical change which results in the formation of a calcium-compound, fibrin. Hammarsten who holds that the presence of calcium is not necessary for the change of fibrinogen into fibrin, attempts to explain the observation of Arthus and Pages on the assumntion that the calcium salts are necessary factors for the conversion of prothrombin into thrombin. If blood be allowed to flow beneath a layer of oil, into a vessel coated with a film of vaselme, it will not coagulate (Fr?«nd) ; and from this it may be assumed that the cause of coagulation is to be found in the adhesion of the blood to a foreign body. A. Schmidt, in his work on the blood, published in 1892, in which he collects the results of many years of study on the coagulation of the blood regards the fibrin-ferment or thrombin ^s a cell-derivative, which arises from an inactive ante- ;\kh^^"^dTo"cef^dfr[va7iv^s """"AVvt '•^"'"" °} ^l^'^'A ^ymoplastic substances which are also cell-denvatives. He likewise regards the fibrnogenic substance or metaglobuhn, as a product of disintegration of cellular protoplasm. """^ ' °' VARIETIES OF THROMBI. 113 § 39. According to the cause of the injury to the vessel-wall there may be distinguished : traumatic, infectious, and thermic thrombi, as well as those produced by degenerative changes in tJif, wall, foreign bodies, and tumor proliferation. Thrombi occurring in individuals with poor circulation are designated marasmic or cachectic. Thrombi also may be classed according to their relation to the vessel- lumen. Thus thrombi attached to the wall of the heart (Fig. 17, a) or blood-vessel are known as parietal thrombi, those situated on the valves of the heart or veins (Fig. 18, d) are termed Valvular thrombi. In both cases the thrombi may consist only of delicate, membranous, translucent or hyaline deposits; but are often thick and firm and project into the lumen of the heart or vessels. Their surface often shows ribbed eleva- tions which are paler than the other portions. A thrombus completely closing the lumen of the vessel is called an ObJj iratin g thrombus (Fig. 18, a, b). The coagula first formed are designated primary or autoch- FlG. 17. — Polypoid heart thrombi firmly attached between the trabeculje of the left ventricle. a. Thrombus with smooth surface; b. thrombus with open cavity of degeneration. (Natural size.) thonous, those subsequently deposited on these as induced thrombi. Through growth by accretion a parietal thrombus may become changed to an obturating one. In this way it not infrequently happens that on an originally white or mixed thrombus a red one (Fig. 18, c) is formed; the thrombosis at the beginning occurring in circulating blood, while later, after closing of the vessel, the blood comes to a standstill and clots en masse. The reverse may occur — that is, on a thrombus originally red there may be deposited white or mixed coagula — when a red throm- bus obturating a vessel becomes smaller by contraction, and thus opens up a channel for the passage of blood. Thrombi may occur in any part of the vascular system. In the heart they are formed chiefly in the auricular appendages and in the intertra- becular spaces, or on any diseased spot (Fig. 17, a) in the heart-wall. They begin usually in the recesses between the trabeculae, but through continual accretions form large coagula which project above the surface in the form of polypoid masses (Fig. 17). They are sometimes more or less spherical in shape, with a broad base ; at other times club-shaped ; their surface is ofted ribbed. In rare cases large spherical or knobby thrombi may become loosened; and, if they cannot pass the ostium, lie 8 114 DISTURBANCES OF THE CIRCULATION. free in the corresponding chamber of the heart. Such free globular thrombi are sometimes seen in (the auricles in stenosis and insufficiency of the auriculo-ventricular orifices. After detachment they may in- crease in size through new deposits of fibrin. Masses of coagula which are deposited on inflamed valves are known as valvular polypi. Parietal and valvular polypi may reach such proportions as to fill a large part of the heart-chambers. In the arterial trunks thrombi may occur in a variety of places, par- ticularly behind constrictions and in dilatations. Occasionally in cachectic individuals with a degenerate intima, parietal, white, or mixed thrombi, adherent to the surface, are formed in the aorta. In the veins thrombi are occa- sionally formed in the pockets of the valves (Fig. 18, d), from which they may protrude and develop into ob- turating thrombi. Often a thrombus may grow from a smaller vein (a), where it was primary, into the lumen of a larger vein (b). Thus, a thrombus having its origin in a small vein of the lower extremity may grow into the inferior vena cava and even reach the heart. Of especial import- ance, because of the resulting local disturbances, are the obturating thrombi of the femoral veins, the renal veins, the sinus of the dura mater, the venae cavas, and the portal veins. Thrombosis in the small vessels is most frequently the result of dis- ease of the surrounding tissues, par- ticularly infectious, toxic, and necro- tic processes. The thrombi are, for the greater part, hyaline; in their composition the red blood-corpuscles have the chief share, fusing into a homogeneous mass. Nevertheless, it may be demonstrated occasionally, by means of proper technique (Weigert's staining method), that they also contain fibrin. Thrombi of smaller vessels occur also after burns of the skin (Klebs, Welti, Silber- mann) and often in cases of poisoning — for example, with corrosive sublimate (Kaufmann) — and are found especially in the smaller vessels of the lung. They frequently occur in hasmorrhagic infarcts (Fig. 9, a). Thrombi originating in the capillaries may involve the efl^erent veins, partly for the reason that through obturation of numerous capillaries the blood flows more slowly into the veins, partly for the reason that dis- integrating red cells and blood-plates pass into the veins in large num- bers. Fig. 1 8. — Thrombosis of femoral and saphenous veins, a, b. Obturating mixed and laminated thrombus; c, red throm- bus showing peripheral attachment; d. thrombus protruding from a valve. (Reduced one-fourth.) SEQUEL/E OF THROMBOSIS. 115 The first deposits in the formation of a parietal thrombus consist of dehcate, translucent, or whitish layers. The fully formed thrombus is a rather firm, dry mass, adherent to the inner surface of the vessel or heart, and in color and structure varying according to the conditions mentioned above. Thrombi, originally soft and moist, undergo in time a process of contraction, and become firmer and more dry. By means of contraction vessels closed by obturating thrombi may become partially opened for the passage of blood. In the event of marked contraction, the fibrin, blood-plates, and red cells become changed into a firm mass, which may remain in this condition for a long time, and finally undergo calcification. This may occur in both valvular heart-thrombi and thrombi located in the vessels. The chalky concretions formed in the veins are known as phleboliths; those occurring in the arteries as arterioliths. Contraction and calcification are relatively favorable sequelae of thrombosis. Much less favorable are the more frequent processes of de- generation occurring in thrombi, which are known as simple and as puriform softening. In simple softening the central portion of the thrombus becomes changed into a grayish-red, or gray, or grayish-white grumous mass, consisting of disintegrated and shrunken red corpuscles, pigment-granules, and colorless, granular debris. If the softening extends to the superficial layers, and if there is sufficient strength of blood-current in the neighborhood of the thrombus, the pro- ducts of disintegration may be swept into the circulation. If larger pieces become loosened and transported by the blood-stream emboli are produced (see Fig. 1, page 47). In puriform softening the thrombus breaks down into a yellow, or grayish-yellow, or reddish- yellow, grumous, creamy, and at times foul- smelling mass, consisting of pus-corpuscles and a large amount of finely-granular substance, composed of fatty and albuminous detritus and micrococci or other bacteria. The process of softening of a thrombus, associated with purulent in- filtration of the vessel-wall, is designated purulent thrombophlebitis or thrombo-arteritis accordingly as it involves a vein or an artery. The inflammation of the vessel- wall may take its start either in the softening thrombus or in the tissues adjacent to the vessel. In the laitter case softening of the thrombus is coincident with the inflammation of the vessel-wall or follows it. These processes occur most frequently in the neighborhood of purulent foci. The most favorable sequel of thrombosis is organization of the thrombus — that is, substitution of the thrombus by vascularized Fig. ig. — Remains of a thrombus of the right femoral vein occurring three years before death, a. Obliterated portion of the vein (the right common iliac artery wa*s also obliterated) ; &, c, d, connective-tissue cords in the lumina of the vein and its branches; e, fresh thrombus. (Natural size.) 116 DISTURBANCES OF THE CIRCULATION. connective tissue derived from the proliferating cells of the vessel-wall. The thrombus itself takes no part in the organization; it is a dead mass which excites proliferation of the surrounding tissues (Fig. 20, b, c, d). Fig. 20. — Obliteration of a pulmonary artery by connective tissue after embolic plugging of its lumen. (MuUer's fluid, hematoxylin, and eosin.) a. Artery wall; b^ connective tissue filling » the vessel-lumen; c, d, newly formed blood-vessels. X 45. The cicatricial tissue formed in the place of the thrombus contracts in the course of time. Cicatrices formed after ligation may thus be- come very small. Such a cicatrix in the continuity of a vessel may appear simply as a thickening of the vessel- wall, or there remain only threads and trabeculse (Fig. 19, b, c, d), which cross the lumen of the thrombosed vessel, so that the blood-stream can once more pass the affected spot. Not infrequently the connective-tissue strands crossing the vessel cause marked narrowing of the lumen ; or the vessel may become obliterated (Fig. 19, a), and converted for a greater or less distance into a fibrous cord. Pieces broken from a thrombus and carried into an artery and lodged ■ — that is, emboli — induce new de- posits of fibrin on their surface. Later they undergo the same changes as thrombi, and may soften, contract (Fig. 21, a), or become calcified. If the emboli are non-infective they are apt to be replaced by vascular con- nective tissue (Fig. 20, b, c). In many cases the new-formation of connective tissue leads to ob- literation of the artery (Fig. 20). In other cases in the place of the embolus there is developed only a ridge of connective tissue or a nodular Fig. 21. — Remains of embolic plugs in a branch of the pulmonary artery, a. Contracted embolus traversed by connec- tive-tissue threads; h, cords of connective- tissue crossing the orifices of branch vessels. (Natural size.) SEQUELS OF THROMBOSIS. 117 or flat thickening of the initima. In still other cases the lumen of the vessel is traversed by strands of connective tissue (Fig. 21, b), which either run separately or form a fine- or coarse-meshed network. ^'?."^-""=' <:^?^'^V Fig, 22. — Embolism of an intestinal artery, with suppurative arteritis, embolic aneurism, and periarterial, metastatic abscess. (Alcohol, fuchsin.) a, b, c, d, e, Layers of the intestinal wall; fj artery wall; g, embolus, surrounded by pus-corpuscles, lying in the dilated artery which is partly destroyed by suppuration; h, parietal thrombus; *, periarterial purulent infiltration of the sub- mucosa; k^ veins gorged with blood. X 27. If pyogenic organisms are present, as is the case when the emboli arise from a thrombus lying in a suppurating focus, a purulent process is produced (Fig. 22, i) at the site of lodgment (Fig. 22, g). Literature. {Blood plates, Coagulation of the Blood, and Thrombosis.) Arthus et Pages: Nouvelle theorie chimique de la coagulation du sang. Arch. de phys., ii., 1890. Bizzozero: Blutplattchen u. Blutgerinnung. Obi. f .d. med. Wiss., 1882, 1883; Virch. Arch., 90 Bd.; Arch, per le Sc. med., 1883; Arch. ital. de Biol., i., ii., iii., iv. and xvi. ; Festchr. f. Virchow. Internat. Beitr., i., 1891. Eberth u. Schimmelbusch: Die Thromliose nach Versuchen u. Leichenbefun- den, Stuttg., 1888; Dyskrasie u. Thrombose. Fortschr. d. Med., vi., 1888. Eisen: Blood-plates. Journ. of Morph., xv., 1899. Flexner: Agglutination Thrombi. Univ. of Penns. Med. Bull., 1902. Gutchy: Blutgerinnung und Thrombose. Beitr. v. Ziegler, xxxiv., 1903. Halliburton: The Coagulation of the Blood. British Med. Journ., 1893. Hammarsten: Lehrb. d. phys. Chemie, Wiesbaden, 1899. Hayem: Du sang et de ses alterations anatomiques, Paris, 1889. Lowit: Blutgerinnung. Sitzber. d. K. Akad. d. Wiss. in Wien, 89, 90 Bd., 1884; Blutplattchen u. Blutgerinnung. Fortschr. d. Med., iii., 188S; Die Beo- bachtung der Circulation am Warmbliiter. Arch. f. exp. Path., xxiii., 1887; Blutplattchen u. Thrombose. lb., xxiv., 1888; Studien zur Physiologic u. Pathologic des Blutes, Jena, 1892. 118 DISTURBANCES OF THE CIRCULATION. Morawitz: Blutgerinnung. D. Arch. f. klin. Med., 79 Bd., 1904; Vorstufen v. Fibrinfermente. Fol. haem., i., 1904. Osier: Trans. Ass. Am. Phy., 1887. Pearce: Experimental Production of Liver-Necroses by the Injection of Hemagglutinative Sera. Jour, of Med. Research, 1906. Schmidt, A.: Die Lehre v. d. fermentativen Gerinnungsercheinungen, Dorpat, 1877; Zur Blutlehre, Leipzig, 1892; Weitere Beitrage z. Blutlehre, Wies- baden, 189S. Welch: Thrombosis and Embolism, Allbutt & Rolleston's System of Medicine, 1899. (Lit.) Wright, A. E.: Contr. to the Study of the Coagulation of the Blood. Jourr. of Path., i., 1893. Fig. 23.— Congestive stasis in the vessels of the corium and papilla of the plantar surfac-p^ of the toes from a man dying of valvular disease, heart failure, and arterTo°clerosif(MXr'f fluid alum carmine.) Toes presented a deep violet color, and beginning gangrene! x 20 ^ ' § 40. Stasis or stagnation is characterized by retardation of the cir- culation without coagulation of the blood. The red blood-cells are so closely pressed together that the small vessels are filled or distended and the outlines of the individual cells cannot be distinguished (Fig '23), The condition is one of marked passive congestion. When the "blood entering a certain area finds its avenues of escape impeded the circu- lation m the small veins and capillaries, and even in the smallest affer- ent arterial branches, comes to a state of almost complete arrest Since from the arteries there come with every pulse-wave fresh masses of blood to the congested area, the capillaries and veins become distended STASIS; CEDEM'A. 119 and the pressure within these rises to the height of that at the point of divergence of the nearest permeable artery. In this way the red blood- cells become so closely packed that their contours are no longer dis- tinguishable, and the contents of the vessel form a homogeneous, scarlet- red column (Fig. 23). The red blood-cells, however, are not fused; as soon as the impediment to the outflow is removed and the circulation is restored, the corpuscles become once more separated from one another. Stasis may be caused by many influences which aifect the vessel-wall and the blood itself. Thus, heat and cold, acids and alkalies, concentrated solutions of sugar and salt, chloroform, alcohol, etc., cause stasis. These act by abstracting water from the blood, and by producing changes in the composition of the corpuscles, and vessel-walls ; as a result, the red cells become less mobile and the vessel-walls offer increased frictional resist- ance to the blood-stream, and at the same time permit the fluid portions of the blood to pass through more readily. IV. CEdema. § 41. The fluid which permeates the tissues is essentially a tran- sudate from the blood, though under certain conditions fluids contained in cells and fibres may also pass into the intervening spaces. The passage of fluid from the vessels is in part a process of filtration and in part a t; Vr'ii ' ' Fig. 24. — Stasis-oedema of the papillary bodies of the skin of the leg from a case of mitral stenosis. (K. Ziegler, 1. c). a, Lymphocytes; b, connective tissue fibrillse with cells; c, red blood- cells; dj blood-vessel, x 300. secretion, accomplished by means of a specific function of the capillary walls. The fluid secreted by the capillaries mingles with the products of metabolism in the tissues, and is taken up by the lymph-vessels, and through the thoracic duct is returned to the blood. 120 DISTURBANCES OF THE CIRCULATION. Increase in the transudation of the fluids of the blood causes more marked saturation of the tissues, which may be compensated for by absorption through the lymph-vessels. This compensation has, however, its limits; with increased transudation from the blood-vessels there is produced more or less permanent over-saturation of the tissues. The condition produced by collection of fluids in the tissues is known as dropsy, oedema, or hydrops. According to its extent there may be dis- tinguished general and localized hydrops. (Edema extending over the superficial portions of the body is known as anasarca. The transudate from the blood which constitutes oedema or hydrops is poorer in albumin than the plasma. The fluid collects at first in the tissue-spaces, pushing apart the tissue-elements (Fig. 24, b), but may soak \ into the tissue-elements themselves and cause swell- ing of cells and fibres, and, under certain conditions, the formation of so-called vacuoles (Fig. 25), due to the collection of droplets in the cells. This may be frequently demonstrated in the epithe- lium of the body-surfaces and of glands, but at times becomes evident in other tissue elements — for ex- ample, in connective-tissue cells and muscle-fibres (Figs. 25, 26). Moreover, it often happens in oede- matous tissues that cells be- come loosened from their basement-membrane, par- ticularly in the lungs and serous membranes and are mixed with the fluid. In cedema of the skin, the epidermis (Fig. 27) may be separated and lifted from the papillary bodies, while the fibrillse of the latter are pushed apart. Tissues which are the seat of oedema are swollen. The degree of swelling depends on the structure of the affected tissue. The skin and subcutaneous tissue are able to take into their lymph-spaces large quan- tities of fluid, so that an extremity may become enormously swollen. In this condition it is pale, doughy in consistence, and pits on pressure. On incision an abundance of clear fluid escapes. The lung behaves in a similar way. Owing to limited space it cannot become greatly distended, but it contains vast numbers of alveoli filled with air which, in the advent of cedema, is displaced by fluid, and this on pressure escapes from the cut surface, mingled with air-bubbles. (Edema of the kidney, which may become marked, is caused by re- tention m the dilated tubules of the water secreted by the glomeruli In the connective tissue between the tubules infiltration of fluid mav also occur. ^ Fig. 25. — Hydropic connective-tissue cells from the subcutaneous tissue of a case of chronic cedema due to stasis. (K. Ziegler, 1. c.) x 400. CEDEMA. 121 The amount of blood contained in cedematous tissues is variable, and their color varies accordingly. Body-cavities which are the seat of dropsical effusion contain at one time a large, at another time only a small amount of clear, usually light- yellow, rarely colorless, alkaline fluid, which at times contains a few fibrin flakes (see the chapter on Inflammation). Organs are compressed by the effusion; cavities are dilated. A collection of transuded fluid in the abdominal cavity is known as ascites. The albumin-content of tran- sudates is not the same in all the cavities and tissues, but According to Reuss, the albumin-content ; that of the pericardium, Fig. 26. — Longitudinal section of cedematous muscle-fibres from the calf muscles in a case of chronic cedema of the legs. (Flemming's solu- tion, safranin.) x 45. differs in pronounced degree, of transudations of the pleura is 22.5 pro 18.3; of the peritoneum, 11.1; of the subcutaneous connective-tissue, 5.8; of the membranes of the brain and spinal cord, 1.4. These facts may be taken as proof of the different constitution of the vessel-walls in the various tissues of the body. § 42. According to their etiology we may distinguish five varieties of oedema: cedema due to arterial congestion; oedema from stagnation of blood; oedema caused by hindrance to the outflow of the lymph; oedema l^iG. 27.-^Inflammatory cedema of the papillary bodies, with elevation of the epidermis from the papillary bodies by an inflammatory exudate, from a case of phlegmon of the thigh. (K. Ziegler, 1. c.) a, Coriiun; b, exudate consisting of fluid, fibrin and leucocytes, x 40. caused by disturbance of the capillary secretion due to changes in the capillary walls ; and oedema ex vacuo. The fourth is designated inflam- matory, hydrasmic or cachectic, or neuropathic oedema, according to the clinical features. CEdema due to arterial congestion occurs acutely in localized areas, in the skin and subcutaneous tissue, larynx, bronchi (asthma), nose, periosteum, and muscles (angio-neurotic cedema). In individuals show- 122 DISTURBANCES OF THE CIRCULATION. ing the tendency in marked degree, bullae may be formed in the skin. In angio-neurotic oedema toxic influences assume an important part. It not uncommonly happens, for example, that the ingestion of straw- berries, oysters, etc., is succeeded by oedema of the eye-lids of such an ■extent as to produce closure ; if the soft tissues of the larynx are involved symptoms of suffocation may arise and death may occur from occlusion of the glottis. Urticaria is a variety of angio-neurotic oedema. It is probable that the changes in question are of the nature of anaphylactic phenomena. CEdema due to stagnation of blood arises when, as a result of impediment to the outflow of blood, the pressure in the capillaries rises and the fluid of the blood seeks a lateral outlet, so that an increased amount escapes. The amount of escaped fluid is larger the greater the discrepancy between inflow and outflow ; it is therefore increased through coincident increase of the inflow. The escaping fluid is always poor in albumin, but with increased pressure in the veins the albumin-content is increased (Senator). The immediate result of increased transudation from the blood- vessels is increase in the lymph-flow, and this may be sufficient to carry off the fluid. If it does not suffice, the fluid collects in the tissue-spaces and oedema results. According to Landerer, this is favored by the fact that the elasticity of the tissues becomes diminished as the result of the long-continued increase of pressure to which they are subjected. Obstruction to the outflow of lymph, as experiments have shown, is not ordinarily followed by oedema. The lymph-vessels possess such extensive anastomoses that obstruction to the outflow does not readily occur. Even when all the lymph-channels of an extremity are obstructed, if the amount of lymph formed is normal no oedema results, inasmuch as the blood-vessels are able to take up the lymph. Only occlusion of the thoracic duct is likely to lead to stagnation of lymph and the production of oedema, particularly ascites, but even in this case collateral channels may be opened in sufficient numbers to carry off the lymph. Although lymphatic obstruction is not ordinarily sufficient in itself to produce oedema, it does increase oedema caused by concomitant transu- dation from the blood-vessels. Pathological changes in the walls of the capillaries and veins of such nature as to cause increase in the vascular secretion, and thus to give rise to oedema, may occur as the result of long-continued conges- tion and imperfect renewal of blood. Such changes occur, however, more frequently as the result of prolonged ischcemia, lack of oxygen, action of high or low temperatures, the development of tumors (especially in the serous mem'branes), infection, and intoxication. It is also probable that irritation or paralysis of the vasomotor nerves may lead to increase of vascular secretion. Just what changes the vessels suffer under these con- ditions we are not able to state, but it may be assumed that alteration of the endothelial cells and of the cement-substance renders the vessels more permeable. The oedemas so produced may be classed according to their cause as toxic, infectious, thermal, traumatic, ischaemic, neuropathic, etc. ; and such a classification has much to commend it. Hitherto the forms of oedema under consideration, with the exception of the neuro- pathic, have been arranged in two groups— namely, inflammatory and cachectic. CEDEMA. 123 Inflammatory oedema is to be referred to alteration of the vessel- -wall, and occurs as an independent affection, in the form of circumscribed or diffuse swelling or as hydropic effusions, and as a coincident pheno- menon in the neighborhood of inflammatory processes. In the latter case it is designated collateral oedema. Inflammatory is distinguished from stagnation-oedema by the fact that the transuded fluid is richer in albu- min and in the number of white blood-corpuscles, and in the fact that larger rnasses of coagula (Fig. 27, b) occur in it (see chapter on In- flammation). Its cause is to be sought in infectious and toxic, some- times in thermal and traumatic influences, at other times in temporary ischasmia. As to hydraemic or cachectic oedema, it was formerly believed that hydraemia — 'that is, diminution of the solid elements of the blood — as well as hydraemic plethora — that is, retention of water in the blood — could cause increased transudation from the vessels. It was supposed that the vessel-walls behaved as dead animal membranes, and allowed fluid poor in albumin to filter more easily than one rich in albumin. The vessel-wall is not, however, a lifeless membrane, but a living organ. Hydrasmia experimentally produced does not, according to Cohnheim, give rise to oedema. Even when hydraemic plethora is produced by filling of the blood-vessels with watered blood, and is followed by increased transudation, leading to oedema, the oedema so produced occurs only when the proportion of water becomes very high, and does not develop in the same regions where the so-called hydraemic oedema in man appears. We must therefore assume that the oedema of cachectic individuals, as well as that occurring in individuals suffering from impairment of renal function, depends on alteration of the vessel-wall, caused either by the hydrasmic character of the blood or by a poison or poisons in the blood. Probably other lesions through which the elasticity of the tissues is diminished are also concerned. Hydrcemia favors the occurrence of oedema, but is not the sole cause and certainly does not determine its localization. Cachectic oedema is allied to stagnation-oedema and to inflammatory oedema, in that at one time the circulatory disturbance is a prominent feature, at another time the vascular alteration. CEdema ex vacuo occurs chiefly in the brain and spinal cord, and arises when a portion of the brain or cord is lost and not replaced by other tissue. In atrophy of the brain or cord the subarachnoid spaces become enlarged, occasionally the ventricles. The fluid has the same albumin content as the normal cerebrospinal fluid. Local defects become filled by dilatation of the nearest subarachnoid spaces or of the ad- jacent portions of the ventricles, or through collection of fluid at the site of the defect itself. V. Haemorrhage and the Formation of Infarcts. § 43. By haemorrhage is understood the escape of all the constituents of the blood from the vessels {extravasation) into the tissues or on a free surface. It may be arterial, venous, or capillary, or from the heart. The blood which has escaped is termed an extravasate. For special forms of haemorrhage a variety of terms is used. If the haemorrhagic foci are small, and form more or less sharply outlined, punctate, red or 124 DISTURBANCES OF THE CIRCULATION. dark-red spots, they are called petechios; if larger and not sharply out- lined, they are known as ecchymoses, or suggillations. If the tissue is firmly infiltrated with escaped blood, but not torn or destroyed, the con- dition is spoken of as a hemorrhagic infarct. If the extravasated blood forms a large mass, it is known as a hematoma. The blood which escapes from the vessels into the tissues collects in the tissue spaces (Fig. 28). Large haemorrhages may completely conceal the structure of the tissue (Fig. 29, d). Delicate tissues, as those of the brain or spinal cord, may be destroyed by large haemorrhages. If the haemorrhage occurs on the free surface of an organ, the blood either escapes externally or is poured into a neighboring cavity. Haemorrhage from the nose is called epistaxis; vomiting of blood hcematemesis; bleeding from the lungs, hcemoptysis; from the uterus, Fig. 28. — ^Haemorrhage in the skin near the knee; from a man eighty-one years of age. hematoxylin, and eosin.) x 80. (Formalin, metrorrhagia and nienorrhagia (during the menses) ; haemorrhage from the urinary organs, hcematuria; from the sweat-glands, hccmatidrosis. A collection of blood in the uterine cavity is designated hcomatometra, in the pleural cavity hemothorax, in the tunic of the testicle hematocele, in the pericardium hemopericardimn, in the peritoneum hemoperitoneum, etc. Haemorrhages of the skin not caused by trauma are termed purpuric (Fig. 28). Collections of blood and fluid beneath the epidermis in place of the dissolved deeper epithelial layers are known as hemorrhagic blebs. Recent extravasations show the color of either arterial or venous blood. Later the extravasate shows alterations characterized particularly by color-changes. Suggillations of the skin become brown, then blue, and green, and finally yellow. In time the extravasate is absorbed (see Chapter V.), and during absorption tissue-proliferation often occurs. Large collections of blood may become organized into connective tissue or be encapsulated (see Chapter VII.). HEMORRHAGE. 125 Haemorrhage may occur from rupture of the heart or vessel-wall — that is, per rhexin or per diabrosin. This is the only form of cardiac and arterial haemorrhage. From the capillaries and veins haemor- rhage may also occur per diapedesin — that is, the red cells escape through the vessel-wall without the occurrence of a tear. Often such haemor- rhages are small and of slight extent; in other cases the process con- tinues for a longer time, and infiltration of the tissues reaches a significant degree. Haemorrhages by diapedesis are not always small, haemorrhages by rhexis not always large. Rupture Of a capillary or 1 i.' ■:aTlBW*3P d C- w^ C~ 'W'"'^^^l?;''^^^^^Sa^ 1 Fig. 29. — ^Traumatic cerebral haemorrhage. (Formalin, hamatoxylin, and eosin.) a. Normal brain substances; b, blood-vessel; c^ perivascular collection of blood; d, larger area of haemorrhage "with destruction of the brain substance, x 100. small vein does not give rise to a large haemorrhage ; on the other hand, haemorrhage through diapedesis can reach an important size. The causes of interruption of continuity of the heart and vessel- walls are traumatic injuries, increase of intravascular pressure, and diseased conditions of the heart and vessel-wall. Increase of pressure in the capillaries and smallest veins can lead to rupture without the aid of vascular changes, particularly in marked passive congestion. The heart, normal arteries, and normal veins of large size cannot be ruptured through increase of pressure alone, but abnormally thin-walled or diseased areas in the heart, arteries, or veins may be so ruptured. Newly formed vessels are easily torn. Diapedesis may be caused by increase of pressure in the capillaries and veins, as well as by increased permeability of the vessel-wall. If the outflow of the venous blood in a given area be obstructed, diapedesis of red cells from the capillaries and veins takes place as a result of in- creased pressure in the vessels. Diapedesis as a result of changes in the vessel-wall occurs particularly after mechanical, chemical, and thermal 126 DISTURBANCES OF THE CIRCULATION. injuries. Further, abnormal permeability of the vessel-walls is observed when for a long period the vessels have not been traversed by the blood- stream, and their nutrition has suffered in consequence. When an individual shows a special tendency to haemorrhage, the condition is designated hasraorrhagic diathesis. Two forms may be distinguished — congenital and acquired. Congenital haemorrhagic diathesis or haemophilia, depends most probably on abnormal constitution of the vessel-walls. The composition of the blood may also be pathological, so that a haemorrhage once started is not arrested, as usual, by coagulation of the blood. Acquired haemorrhagic diathesis occurs in those diseases known as scurvy, morbus maculosus Werlhofii, purpura simplex, purpura (peliosis) rhuematica, purpura hsemorrhagica, haemophilia, and melsena neonatorum (gastric and intestinal haemorrhages) ; in many infections — septicaemia, endocarditis, typhus fever, cholera, smallpox, plague, yellow fever; in intoxications, e. g., phosphorus poisoning, after snake-bites, etc. ; and, finally, in pernicious anaemia and leukaemia. Hemorrhages per rhe.vin cease when the extravascular pressure comes to equal the pressure in the bleeding vessel, or when narrowing of the vessel and coagulation and thrombosis close the rent. Hemorrhage by diapedesis ends with cessation of blood-supply to the bleeding vessel, or when the intravascular pressure is lowered and the vessel-wall restored to its normal state. The process of diapedesis may be observed in the frog's mesentery or web. If the efferent veins are ligated, the capillaries and veins are seen to be engorged with blood. After a certain time the red blood cells begin to pass from the capil- laries and veins (see Cohnheim, " AUgem. Path.," i, and Virch Arch., 41 Bd.). Arnold {Virch. Arch., 58, 62 u. 64 Bd.) believed that, at the place of exit of the corpuscular elements, spaces between the endothelial cells must exist, and these he designated stomata; later he found that the supposed openings consist of heap- ing-up of the cement-substance between the endothelial cells. Under pathological conditions the cement-substance gives way and allows the red blood-cells to pass through. § 44. The sudden closure of an artery by thrombosis, embolism, ligation, or other means, leads, as has already ieen stated (§ 39), to stoppage of the circulation beyond the point of obstruction, after the vessel has more or less completely emptied itself by contraction of its walls. At the same time there is an increase of pressure in the vessel from the point of obstruction back to the point of divergence of the nearest branch. If the branches of the artery beyond the point of obstruction have free communication with some unobstructed artery, the latter by becoming dilated may be able to supply a sufficient amount of blood to the affected area to restore the circulation. If the obstructed artery has no collateral connections through which it may draw its blood-supply, the portion of tissue deprived of blood remains anaemic and dies, giving rise to an anaemic infarct. Paren- chymatous organs — for example, the spleen and kidneys — ^present in in- farcted areas a cloudy, opaque, yellowish-white, often clay-colored appearance. (See § 48.) When the obstructed vessel possesses no collateral anastomoses, as in a terminal artery, but if, on the other hand, there is a scanty influx of blood from neighboring capillaries or veins, a haeinorrhagic infarct HEMORRHAGE. 127 may be formed. The capillaries of the area rendered anaemic by the obstruction become gradually filled with blood from the capillaries of the adjacent vascular area, and from the veins by retrograde flow. The blood flowing in from adjacent capillaries is under low pressure, which is not sufficient to drive the blood through the obstructed area into the veins. When conditions of pressure become such that a retrograde cur- rent sets in from the veins to the capillaries, restoration of the circulation becomes impossible. The imperfect circulation in the obstructed area, which, through coagulation of the blood in the veins and capillaries, is finally brought to a standstill, leads sooner or later to degeneration and necrosis of the vessel-wall, and to increased permeability. As a result, if the afflux of blood be continued, there occur in the stagnated area diapedesis of red Fig. 30. — Haemorrhagic infarct of the lung. (Hasmatoxylin and eosin.) Alveoli filled with blood; scattered pale nuclei in the alveolar septa and in the blood of the alveolar spaces, belonging partly to connective-tissue cells and partly to leucocytes. X 40. cells and infiltration of the tissue with extravasated blood, through which the obstructed area acquires a dark-red color and firmer consistence; a haemorrhagic infarct is thus formed (Fig. 30). Embolic hxemorrhagic infarcts occur in the lungs (Fig. 30), but are formed only when there exists passive^ congestio n ; if the pulmonary cir- culation is normal the disturbances produced by embolism are quickly compensated. In the systemic circulation embolic haemorrhages are con- fined almost entirely to the distribution of the superior mesenteric artery, whose branches, though not terminal, possess but few anastomoses. Anmnic infarcts occur especially in the spleen and kidneys. Around the periphery of the anaemic area there is always more or less haemorrhage, so that the' pale infarct is surrounded by a hwmorrhagic border or at least by hcrmorrhagic spots. In obstruction of the cerebral arteries or those of the extremities, or the central artery of the retina, punctate haemorrhages may occur. In the infarcted area the tissues are wholly or for the greater part dead, and the specific elements of the organ in 128 DISTURBANCES OF THE CIRCULATION. particular (Fig. 32, c, d) die quickly. After a time inflammation arises in the neighborhood of anaemic and hsemorrhagic infarcts, with the forma- tfon of a cellular (Fig. 32, /) or a cellular and fibrinous exudate ; this is followed 'by proliferation of fixed cells, and the dead area is gradually replaced by connective tissue (see Part II. of Chapter VII.). Literature. {Hemorrhagic Infarction.) Cohnheim: Untersuch. ub. d. embol. Processe, Berlin, 1872; Allgem. Pathol., Berlin, 1882. Welch: Hsemorrhagic Infarction. Trans. Assn. Amer. Phys., 1887. VI. Lymphorrhagia. § 45. Lymphorrhagia occurs when the continuity of a lymph-vessel is interrupted and lymph is poured into the neighboring tissue! Since the pressure in the lymph-vessels is low — that is, not greater than in the surrounding tissues — outflow of lymph can occur only when the injured vessel lies on the surface, or when a natural cavity is at hand into which the lymph can flow, or when, through the cause producing the rupture, an open space is formed in the tissues. For example, escape of lymph together with blood may take place from wounds, but the outflow is stopped by slight counterpressure. If, after the wounding of a lymphatic, the opening persists, there is formed a lymph-fistula, through which considerable quantities may be lost. Important and often dangerous is rupture of the thoracic duct, which sometimes occurs as the result of traumatism, and occasionally as a result of obstruction to the lymph-flow at some point in the lumen of the duct (after inflammation or by the invasion of tumors). The lymph is poured into the thoracic or abdominal cavity, giving rise respectively, to chylous hydrothorax or chylous ascites; in rare cases to chylo pericardium. It sometimes happens that the urine, as it comes from the bladder, has the appearance of a milk-white, or yellowish, or, through the admixture of blood, a red- dish emulsion; and contains albumin and finely-divided fat-droplets. This is known as chyluria. It occurs as an endemic disease in certain tropical regions (Brazil, India, the Antilles, Zanzibar, Egypt) where it is caused by a parasite, the Filaria Bancrofti, which inhabits the lymph-vessels of the abdominal cavity and there produces its embryos {Filaria sanguinis) ; these, during the repose of the patient in a horizontal position, swarm in great numbers in the blood, and are also found in the chylous urine. The connection between chyluria and the invasion of the lymph-vessels has not been satisfactorily demonstrated by anatomical investiga- tions ; ibut it is probable that the chyle-like fluid does not come from the blood through the kidneys ; but, as a result of obstruction in the lymph-circulation, chyle escapes from ruptured lymphatics of the bladder and mingles with the urine (Scheube, Grimm). In corroboration of this view is the fact that, at autopsy, the abdominal lymphatics exhibit marked dilatation (Havelburg), while the kidneys are but little changed ; and further, according to an observation made by Havelburg, . the urine obtained from- the ureter showed no admixture of chyle, though chyluria was present at the same time. The anatomical cause of the non-parasitic chyluria is still unknown. Literature. {Chylous Effusions in the Body-cavities; Chyluria.) Busey: Amer. Jour, of Med. Sciences, 1889. Edwards: Chylous and Adipose Ascites. Ref. Handb. 0)f Med. Sciences, 1901. Lothrop and Pratt: Amer. Jour, of Med. Sciences, 1900. CHAPTER V. Retrograde Disturbances of Nutrition and Infiltrations of tissues. § 46. Retrograde disturbances of nutrition are characterized in a general way by degeneration of the affected tissue and by diminution in size and disappearance of the individual tissue elements, the functional capacity being at the same time lowered. Tissue infiltrations are characterized by the deposit of pathological substances which have been formed in the body or introduced from with- out. The functional capacity of the part affected is diminished. In some cases, infiltration is merely a result of degeneration; in others it may itself constitute the chief feature in a degenerative process. Retrograde disturbances of nutrition may effect the body in its fully developed state or during its development and growth; in either case it may lead to abnormal smallness of a part or tissue. In the fully de- veloped body, diminution in size of an organ or tissue due to disappear- ance of individual tissue elements or to reduction in their size, is desig- nated atrophy. If, in the period of development, an organ or part totally fail of development or is represented by rudimentary structures, the con- dition is known as agenesia or aplasia. If the development of a part pro- ceed to a certain extent but still does not attain the normal, the condition is known as hypoplasia. The causes of tissue degenerations and associated atrophy are to be found in those injuries to which the tissues are exposed during life ; but atrophy may also depend on intrinsic conditions. The latter is exemplified by tissues which, in old age, reach their physiological limita- tions and become incapable of nourishing themselves. In certain tissues similar regressive changes occur earlier in life ; for example, in the ovary and thymus. As extrinsic harmful influences which may lead to degenerations should be considered all those agencies mentioned in Chapter I. Dis- turbances of circulation, lack of oxygen and food supply, and intoxica- tions play a very important role. In the majority' of cases degenerations are localized, so that we may speak of degenerations of special tissues or of special organs. Not infrequently the disturbances of nutrition are more general, so that the entire organism suffers. Thus the picture of a general disease may be produced by a degenerative or atrophic con- dition of the blood — that is, diminution in the number of red blood- cells (oligocythaemia), at times also deficiency of haemoglobin (chloro- sis), so that a permanent condition of insufficient blood-supply or a general anaemia is produced, the nutrition of the body being corre- spondingly impaired. As the result of diminished ingestion of food, or of disturbed me- tabolism, and of increased waste of the proteids and fats of the body, there may result a condition of general emaciation and weakness, often 9 129 130 THE RETROGRADE CHANGES. associated with anaemia, a wasting of the entire body, which is designated cachexia or marasmus. If under such circumstances it appears likely that certain substances are formed in the body, which, when taken up into the blood and tissue juices, cause contamination or alteration of' these, the condition may be spoken of as a dyscrasia. II. Death. § 47. All life comes sooner or later to an end — to death. When this occurs at an advanced age, without preceding symptoms of disease, it may be regarded as the normal termination. When death occurs pre- maturely — that is, at an age earlier than the average — and when' pre- ceded by symptoms of disease, it must be regarded as pathological. It is obviously impossible to draw any sharp line of separation between physiological and pathological death. An individual is dead when all his functions have ceased. Death is inevitable at that instant when one or more of the functions indispensable to life has ceased, though it is not necessary that at that moment all should have ceased. Indeed, it often happens, that after life is irretriev- ably lost, many organs are still capable of function, and it is only after a certain time that all the organs die. The life of the body passes by progressive cessation of the functions of its different organs into the state of death. Cessation of the functions of the heart, lungs, and nervous system results in immediate death of the entire organism. Cessation of the functions of the intestines, liver, or kidneys leads to death after a certain length of time, often measured by days. Destruction of the sexual glands does not endanger the life of the individual, and likewise man may spare one or more of his organs of special sense. The occurrence of death is usually determined by the last respiration and by stoppage of the heart. With cessation of respiration it is im- possible for any organ to remain alive after a certain short period. Stop- page of the heart likewise makes further nourishment of the tissues impossible, in consequence of which the central nervous system is unable to continue. After death the body may present a variety of appearances. The aspect of the visible portions is largely dependent on the distribution of the blood at the time of death. An abundant supply of blood in the skin gives it a blue-red color, anaemia gives it a pale color. Further, preceding disease may alter the external appear- ance of the body in different ways. Within a certain time after death various changes occur in the tissues of the body, which may be regarded as the absolute signs of death. In the first place the temperature of the body falls, sometimes rapidly, at other times slowly, until it reaches the temperature of the surrounding air. It must be borne in mind, how- ever, that the temperature at times does not begin to sink immediately after'death, but first rises somewhat. The rate of cooling of the body depends partly on the character of the body itself, and partly on the nature of its surroundings. The time required may vary from one to twenty-four hours. The coldness of the dead body is termed algor mortis. At the time of death the skin for the greater part becomes pale; but after six to twelve hours, sometimes earlier, bluish-red spots appear on the skin over the dependent parts of the body. These are known as death-spots or tivores mortis (post-mortem hypostasis), and are due to the accumulation of blood in the veins and capillaries. They are not found in those parts subjected to the weight of the body. Their number and size depend on the amount of blood in the skin at the time of death. Parts which have been cyanotic during life may retain this appear- DEATH; NECROSIS. 131 ance after death, especially the head, fingers, and toes. The color of post-mortem hypostasis is usually blue-red; the intensity of the color varies; in cases of poison- ing with carbon monoxide it is a bright red. The weight of the body causes flattening of those muscular parts upon which it rests. Sooner or later there occurs stiffening and contraction of the muscles, due to coagulation of the contractile substance {Brueke, Kiihne). This is known as cadaveric stiffening or rigor mortis. It usually comes on about four to twelve hours after death, but may occur almost immediately or as late as twelve to twenty- four hours. It begins usually in the muscles of the jaw, throat, and neck, and extends from them to the trunk and extremities. After twenty-four to forty- eight hours it usually vanishes, but under certain conditions may persist for several days. Rigor mortis affects also the smooth muscle fibres; contraction of these in the skin gives rise to the so-called goose-flesh of the cadaver. Decomposition of the cadaver begins with the disappearance of rigor mortis. Its occurrence is shown by the odor of putrefaction, by changes of color in the skin and mucous membranes, and changes in the consistence of the tissues. The commencement and progress of putrefaction depend partly on the nutrition and the nature of the disease preceding death, partly on the surroundings, especially the temperature. Not infrequently putrefaction may occur in dead areas even before death of the body as a whole. When putrefactive bacteria are present in the body, decomposition may begin immediately after death. An early sign of decomposition is greenish discoloration of the skin, appear- ing first over the abdomen. With the progress of putrefaction the unpleasant odor and discoloration increase; gases are formed in t^e intestine, later in the blood and tissues, which become soft and friable. Shortly after death the cornea becomes lustreless, and the eyeball loses its elasticity and shrinks, due to changes in the humors. If the lids are not closed, the uncovered portions of the eyeball show the results of drying. Whenever the skin has lost its epidermis the exposed tissues undergo desiccation. If the phenomena of life be reduced to a minimum, there may result a condi- tion of apparent death which may be mistaken for real death. Though post- mortem hypostasis, rigor mortis, and putrefaction are unmistakable evidences of death, these changes may not take place until some time after death, so that an interval is left during which it may be' doubtful whether death has actually oc- curred. To ascertain the true condition it must be determined by appropriate exam- ination whether the heart still beats, whether respiration still takes place, whether the blood still circulates, and whether the nerves and muscles retain their irri- tability. Conditions which simulate death occur under a variety of circumstances, for example, in cholera, in catalepsy, hysteria, -after excessive bodily exertion, violent concussion of the central nervous system, sever haemorrhage, suspension of respir- ation through hanging, • strarigulation, or drowning, in certain cases of poisoning, after lightning-stroke, prolonged exposure to cold, etc. The duration of this condition is usually short, but may occasionally be extended. III. Necrosis. § 48. Local death, or death of individual cells or groups of cells, is known as necrosis. As a result of necrosis the functions of the affected tissue are forever lost. Necrosis of a cell-group or of an entire organ is only rarely attended by immediately recognizable changes of structure. The slight histological changes which cells undergo during the process of death do not always permit us to determine the cessation of life; nor does the macroscopic appearance of visible portions of the body always inform us when a part has become necrotic. Necrosis is evident on anatomical investigation only when certain changes in structure have occurred, either coincidently with death or subsequently. Necrosis is shown by immediate histological changes only in a limited number of instances; in all other cases necrosis is followed 132 THE RETROGRADE CHANGES. by sucn changes after a longer or shorter interval. According to the nature of the tissue-changes it is possible to distinguish different varie- ties of necrosis. His.tologically, necrosis of a cell is shown first by disintegration and disappearance of the nucleus, the chromatin breaking up to form small clumps and granules which pass into the cytoplasm and are dissolved (karyorrhexis) . At other times the nucleus shows signs of shrinking,' and takes the stain more deeply than under normal conditions (pyknosis). In other cases the nucleus retains its form hut loses its staining power, and then dissolves and disappears (Fig. 31, c, d), so that in well-fixed and well-stained preparations no trace whatever can be found (karyolysis). Thus, in an anaemic infarct of the spleen or kidney the nuclei of the spleen and kidney cells are lost soon after the death of the tissue (Fig. 32, c, d, f, g). At the same time the affected area be- comes pale, cloudy, yellowish- white, or cream-colored; so that the presence of necrosis may be recognized by the naked eye. The protoplasm of dying cells sooner or later undergoes changes which, according to the mode of death, may begin before the cells die, or take place only after the cells are dead. The , kind of change is dependent on three factors: the nature of the cells themselves, the character of the destructive influence, and the amount and character of the fluids surrounding and in- filtrating the cells. Amoeboid cells usually assume a globular form after death. Cell-bodies, rich in protoplasm, often become, before or after death, markedly granular, less frequently homo-' geneous and himpy (Fig. 31, c, and Fig. 32, e). Through the taking-up of fluid the protoplasm or even the nucleus may become swollen _ and show drops of fluid (vacuoles) ; and this may lead to breaks in the continuity of the protoplasm {plasmoschisis). Not in- frequently as a result of plasmochisis portions of the cell may be ex- truded or cut off. The end of all these changes is disintegration of proto- plasm and nucleus into granular masses, the process often being accom- panied by the formation of fat. The injurious influences which give rise to necrosis may be divided into five groups. The first two include those which destroy the tissue directly — mechanical and chemical forces. A third group comprises those of thermal character. Elevation of the temperature of a tissue to 54°-68° C. for any length of time leads to its death. Higher temperatures act more quickly. Refrigeration to low temperatures likewise can be borne but a short time. A fourth group is caused by infection. A fifth group is caused by cessation of nourishment and Fig. 31. — Necrosis of the epithelium of the urinary tubules in icterus gravis. (Miiller's fluid, gentian violet.) a, Normal convoluted tubule; b, ascending portion of the loop; c, convoluted tubule with necrotic epithelium; d, convoluted tubule with only a part of its epithelium necrotic; e, normal stroma with blood-vessels, x 300. NECROSIS. 133 oxygen to the tissues, and is known as ischasmic necrosis or local asphyxia (Fig. 32). All those factors which affect the circulation in any part and lead to stoppage of the blood-supply- — -such as thrombosis, embolism, ligation, pressure' etc., may lead to necrosis of tissue. Not only permanent ces- sation of circulation, but also temporary stoppage lasting beyond a cer- tain time, leads to death of the affected tissue. Whether haemorrhage occurs in such cases is immaterial, and influences only the appearance FiG. 32. — From the edge of an anjemic infarct of the kidney. (Miiller's fluid, hjematoxylin, and eosin.) a, Normal kidney tissue; ai, normal kidney-tubules with stroma infiltrated with leucocytes; &, normal glomerulus; c, necrotic tissue without nuclei, showing granular coagula in the tubules; d, necrotic swollen glomerulus with few nuclei; e, tubules without nuclei in a stroma still con- taining nuclei; /, necrotic tissue with cellular, g, with hasmorrhagic infiltration, x so. of the part. Hcsmorrhagic infarction has, therefore, the same significance as ancemic necrosis associated with hamorrhage . When death follows quickly on the action of an injurious agent, it is spoken of as direct necrosis. When it occurs slowly and is pre- ceded by tissue-degenerations it is designated indirect necrosis or necrobiosis. Mechanical, chemical, thermal, and infectious agents may act coincidently, or separately, one after the other. When the tissue is damaged by any one of the group, the blood often suffers changes which lead to stasis and coagulation in the capillaries, as well as in the veins and arteries, and in this way the circulation is arrested. Whether injury will cause necrosis of tissue depends, not only on its nature and severity, but also on the condition of the tissue at the time of injury. A tissue whose vitality has been lowered as the re- sult of long-continued disturbances of circulation, changes in the composition of the blood, etc., dies more easily than the normal. In typhoid fever relatively slight pressure on the ti-ochanters, elbows, sacrum, heels, etc., may suffice to bring about necrosis of the skin and 134 THE RETROGRADE CHANGES. subcutaneous tissues. Such forms of necrosis are known as marasmic necrosis or marasmic gangrene, and as decubitus or decubital necrosis. The course of necrosis is dependent on the character of the affected tissue, its location, the manner of its death, and the cause of the necrosis. Further, the amount of lymph and blood in the tissue, the opportunity afforded for the access of air and putrefactive organisms, together with preceding tissue changes are of significance in deter- mining the character of the necrosis. As the result of necrosis of certain tissues, there always develops inflammation of greater or less intensity in the surrounding parts. (Fig. 32, /). This reactive inflammation is most marked when the necrotic area becomes gangrenous. The necrotic area becomes isolated or se- questrated; this process is spoken of as a sequestrating or limiting in- flammation, and the dead area thus shut off is called a sequestrum. A more detailed description of these inflammatory processes will be found in Chapter VII. Five chief sequelae of necrosis may be distinguished: 1. The dead tissue may be removed by absorption, or cast off, and its place taken by normal tissue {regeneration) . 2. The dead tissue is similarly removed, but instead of normal tissue being restored, the defect is filled wholly or in part by connective tissue, so-called cicatricial tissue. 3. The necrotic tissue is cast off or liquefied, the defect is not filled in and an ulcer remains. Should this heal without regeneration of the lost tissue there remains a scar. 4. The necrotic tissue is partly absorbed, but a portion remains as a sequestrated mass which not infrequently becomes calcified and sur- rounded by a connective-tissue capsule. 5. The fifth sequel of necrosis is cyst-formation. The necrotic area becomes encapsulated by connective tissue, the dead tissue becomes liquefied, and the space filled with fluid. This sequel of necrosis occurs most frequently in the brain. _ By many -writers there is recognized besides these forms of necrosis a special variety designated neuropathic necrosis, that is, necrosis resulting from a lesion of the central or peripheral nervous system. By some the cause of such necrosis is referred to a lesion of the trophic nerves, while others refer it to disturbances of circulation, pressure, and mechanical injury of anaesthetic and paralyzed por- tions of the body. According to observations made on men, as well as in experi- ments on animals, injuries and disturbances of circulation play the most important role in the production of this form of necrosis, and can never be wholly excluded. The time required to, kill tissue by shutting off the circulation varies with different tissues. Ganglion-cells, kidney epithelium, and liver-cells die quickly, while surface epithelium and connective tissue may live for hours. Epidermis under certain conditions may remain alive for a number of days, and still retain its power of proliferation (see Transplantation). § 49. According to the condition of the tissue, four chief forms of necrosis may be distinguished: coagulation-necrosis, caseation, lique- faction-necrosis, and gangrene. Coagulation-necrosis is characterized by coagulation, either extra- cellular, in the fluids about the cells ; or intracellular, leading to changes in the cells. Coagulation-necrosis with extracellular coagulation is exemplified by both intravascular (Figs. 10, 13) and extravascular coagulation of the blood, inasmuch as this phenomenon constitutes death of the blood ; and in fact destruction of cells does occur. Further, there may be considered as belonging to this class the various forms of coagulation which occur NECROSIS. 135 in inflammations, on the surface and in the interior of the tissues (see Chapter VII.) and which are characterized by the formation, in some cases, of stringy fitrin, in other cases by granular or hyahne masses of coagula. Intracellular coagulation occurs when dead cells are infiltrated with coagulable lymph. The cells lose their nuclei and present either a granu- lar (Fig. 31, c, d, and Fig. 32, c,d,e) or hyaline appearance. They remain in this condition for a time and then break down into granules and are dissolved. This phenomenon is most frequently observed in anaemic, toxic, and thermal necroses, for example, in anaemic infarcts of the kidney (Fig. 32) and of the spleen, also in many inflammations which are associated with infiltration of the tissues, due to exudation from the blood- vessels. In the necrosis of striped muscle, which is of frequent occurrence in typhoid fever and other infections, the contractile sub- stance acquires a waxy appearance and breaks up into hyaline lumps. The necrotic tissue of anaemic infarcts is yellowish-white, or cream- colored. Muscles containing many dead fibres in a state of hyaline coagu- lation are pale red, and of dull lustre, resembling fish-flesh. Inflamed tissues undergoing coagulation necrosis are cloudy, opaque, and grayish- white ; but the color may undergo marked changes through admixture of 4)lood or imbibition of bile, as in the intestine, for example. The structure of a tissue which is the seat of coagulation-necrosis, may still be recognized if only the more delicate parts have been de- stroyed. When all parts have been changed, the tissue may be con- verted into a structureless, hyaline, or granular mass, containing no nuclei or few. This change takes place often in the necrosis of inflamed tis- sues which are infiltrated with exudate. There frequently may be demon- strated in these necrotic areas intercellular stringy fibrin; occasionally in anaemic infarcts, but more often in inflammatory necroses. Caseation is a form of coagulation-necrosis, and is characterized by a cheesy appearance. The dead tissue resembles yellowish-white, hard cheese, or raw potato, or is white, soft, dry or moist, resembling thick cream. Typical caseation occurs most frequently in tubercles and represents the end of the retrogressive changes in this condition. It also occurs in syphilitic granulomata and in cellular tumors; inflammatory exudates may also become changed into cheesy masses. The process of caseation takes place gradually, and is to be re- garded as a form of necrobiosis. The cells are changed" successively into non-nucleated, homogenous or lumpy masses, which disintegrate and break up into granules. At the same time there often appears between the cells a delicate, thread-like or hyaline substance, sometimes forming a framework around the cells or at other times more lumpy or granular — the so-called "fibrinoid substance." Typical fibrin (Fig. 33, a) stain- ing deep blue with Weigert's fibrin stain is often present. It may be assumed that both represent coagulation-products of fluid which has escaped from the blood-vessels. Through progressive cleavage and disintegration of the dead cells, and of the fibrinoid substance and fibrin, the tissue is ultimately reduced to a finely granular mass, in which no traces of the original structure can be perceived. 136 THE RETROGRADE CHANGES. The cheesy metamorphosis of fibrino-cellular exudate, which is found especially in the lungs in the neighborhood of tubercles, is similarly brought about by disappearance of the nuclei, and the disintegration of cells and fibrin into a non-nucleated granular mass. The granules of the soft cheesy masses in tuberculous and non-tuber- culous foci are chiefly albumin particles, more rarely fat-droplets. The fate of such masses may be liquefaction and pultaceous softening, absorp- tion, desiccation or calcification. CoUiquation or liquefaction-necrosis is characterized by the fact that the necrotic parts become dissolved in the fluids of the tissues. The dissolution may be accomplished by swelling and liquefaction, or by <^^ Fig. 33. — Fibrin-containing tubercle from the lung. (Alcoliol, haamatoxylin, fibrin stain.) a, Fibrin; b, giant-cell; c^ cellular portion of the tubercle, x 300. breaking up of the tissue-elements, or by a combination of these processes. Thus, in burns of the second degree the cells of the epidermis, which have been killed by the heat, become dissolved in the fluid exuding from the papillae (Fig. 34, d, f). In the case of anaemic infarcts of the brain the necrotic brain-substance undergoes softening, and becomes con- verted into a mil17). For example, the trunk may be of normal size, while the extremities are short (Fig 37) ; or both the trunk and the extremities may be abnormally small, while the head is of normal size, and consequently appears relatively large for the body. When the vice of development affects individual parts of the skeleton, or is Fig 36. Fig. 36. — Skeleton of a female cretin, thirty-one years of age, ii8 cm. in height, ' with klmo- cephalic skull. The cartilage sutures of the diaphyses of the long bones and pelvic bones still show; as does also the frontal suture. The individual parts of the skeleton are. on the whole, in the proper proportion, the upper extremities alone being relatively short. Fig. 37. — Skeleton of a female dwarf of fifty-eight years of age, 117 cm. in height, with very short extremities, and long trunk. The cartilage sutures are still present; the articular ends of the bones are thick. more marked in certain parts than elsewhere, stunting results. For example, defective development of the cranium gives rise to microcephalus and micrencephalus ; defective development of the humerus results in shortening of the arm; and through hypoplasia of the lateral masses of the sacrum the transverse diameter of the pelvis becomes diminished. The central nervous system and the genito-urinary tract in particular sufifer stunting of development, although the intestines, heart, lungs, liver, ATROPHY. 141 etc., do not escape similar disturbances of growth. For example, the entire brain, or one of the hemispheres, may fail of development. The intestine may be represented by a thin canal or by a solid cord. The uterus not infrequently remains in an undeveloped state, and occasionally the entire generative apparatus may remain undeveloped throughout adult life. Marked hypoplasia of the kidney is not rare. The tissue composing hypoplastic organs or parts of organs, though of less bulk than normal, may present no other abnormalities of struc- ture. In certain cases hypoplasia may be associated with agenesia of individual parts. Thus, in hypoplasia of the ovary the development of Fig. 38. — (Bellevue Hospital.) Excessive atrophy of muscle tissues. ova and the ripening of follicles may fail ; in hypoplasia of the brain there may occur defective development of the ganglion-cells and nerve-fibres, at times portions of the brain may consist of membranous masses in which no ganglion-cells are present. In hypoplasia of the lung there may be complete failure of development of the alveoli, so that the lung consists entirely of bronchi embedded in connective tissue. § 52. Atrophy is diminution in the size of an organ due either to re- duction in size or disappearance of its individual elements. It may occur at any period of life, and is a common result of many pathological pro- cesses. Within certain limits it may be regarded as a physiological phe- nomenon, in that in old age there constantly occurs a retrograde change in all the organs, associated with diminution in size. Certain organs 142 THE RETROGRADE CHANGES. undergo atrophy with partial or total loss of functional power be- fore old age, for example, the thymus, which atrophies even before the end of the period of growth; and the ovary, a part of whose ova are discharged during the period of sexual activity, the remainder being de- stroyed. The lymphoid tissues suffer atrophy at a comparatively early age, the bones and muscles at a later date. Atrophy of an organ is characterized chiefly by diminution in size. In atrophic conditions of the muscles the affected portions of the body become smaller, and in marked cases the extremities appear as if con- sisting of skin and bones. When atrophy of an organ is uniform, its normal shape is preserved; but if the atrophy progresses more rapidly in certain parts than in others, the surface may show local depressions and cicatricial contractions, so that, for example, the liver or kidney, may present a knobbed or granular appearance. When tissues which are undergoing atrophy are prevented from contracting, as in the case of the bones and lungs, the external form is preserved. In bone, the medul- lary spaces and Haversian canals become enlarged, and a condition re- /TvT-n^*^; 39.— Section of an atrophic muscle, from a case of progressive muscular atrophy. (Muller s fluid, Bismarck brown.) a. Normal muscle-fibres; b, atrophic muscle-fibres; c, peri- mysium internum, the nuclei of which, at ci, seem to be increased in number, x 200. suits which is known as excentric atrophy or osteoporosis. In the lungs the alveoli become confluent into large air-spaces as the result of disap- pearance of the intervening walls. In atrophy of glands and muscles there frequently occurs a change of color, though this is of secondary importance. Either the normal pigment pi the organ is brought out more distinctly by atrophy, or asso- ciated with the atrophy there is a deposit of pigment {brown or pigment atrophy), or the change of color may be dependent on the blood-content of the atrophic tissue. The diminution in size of atrophic organs is the result of diminution in size and disappearance of the histological elements composing them. In the majority of organs, particularly glands, muscles,. and bones, the cells which perform the special function of the affected organ, are affected in atrophy to a greater degree than the connective-tissue frame- work. Indeed, it may be observed that the connective-tissue elements are preserved, or even increased in number, while the more highly special- ized elements have disappeared. Thus, in atrophic muscle the contractile substance within the sarcolemma may disappear to a great extent with- out the occurrence of any atrophy of the connective tissue between the muscle-bundles. The nuclei of lie connective tissue may even be in- creased in number. ATROPHY. 143 In atrophy of the kidney the epithelial cells of the tubules (Fig. 40, a) become smaller and may vanish so that the tubules collapse. Likewise, the epithelium of the glomeruli is lost and the capillaries are obliterated. The same thing occurs in simple atrophy of the liver, in that many of the cells of a lobule may disappear without any perceptible decrease of tlie supporting reticulum. Likewise tlie ganglion cells of the brain and spinal cord may atrophy without the neuroglia being diminished. Not infrequently the latter may become increased. In atrophy of bones the true bone-tissue becomes diminished. In atrophy of the bone-marrow the total mass of marrow-cells is diminished. The supporting cells may take up an increased amount of fat; but, on the other hand, the fat in the cells of the marrow may vanish, so that spaces filled with fluid are formed between the supporting cells. Atrophy may take place without any apparent change of structure in the tissue- elements (Fig. 39), the con- dition being reached through loss of volume of the indi- vidual parts. Both the cell- body and nucleus become smaller; the latter change may be observed particularly in the liver in starvation. This form is known as simple atrophy, and is to be distin- guished from the degenera- tive atrophies, in which the tissue-elements show changes in structure. Thus a cell may become granular, and undergo fragmentation, or may swell and liquefy, or there may be formed in the cell drops of fat or mucus ; all of these changes signifying degenerative conditions of the protoplasm. Degenerative changes can occur at the same time in the nuclei, as shown by fragmentation, distorted shape, clumping of chromatin or its diffusion into the protoplasm, swelling and liquefaction of the nucleus. These processes lead ultimately to disappearance of the nucleus and destruction of the cell. According to their genesis the several forms of atrophy may be classed as active or passive. In the former the cell is no longer able to make use of the food brought to it; in the latter the food is either not supplied in sufficient quantity or proper form, or substances are brought to the cells which impair their function. Active atrophy is part of the involution of old age, but occurs under pathological conditions, especi- ally in nerves, glands, and muscles whose function is in abeyance. The clinician prefers another classification of atrophy ; namely, senile atrophy, atrophy due to impaired nutrition, pressure atrophy, atrophy of disuse, and neuropathic atrophy. Senile atrophy is partly active, and partly passive, in that it is not simply the result of the diminishing vital energy of the cell, but also Fig. 40. — Senile atrophy o£ the kidney. (Alcohol, alum-carmine.) a, Normal urinary tubules; &, normal glomerulus; c, stroma with blood-vessels; dj atrophic and obliterated glomerulus; e, small artery, with thick- ened intima; /, atrophic and collapsed urinary tubules. X 200. 144 THE RETROGRADE CHANGES. depends on narrowing and obliteration of the vessels conveying nourish- ment to the cells. It may occur in all the organs, but is often more marked in one than in another, notably in the bones, kidneys, liver, brain, and heart, all of which may undergo marked loss oi volume. Atrophy due to impaired nutrition may result from insufficient supply of food to the body as a whole, or from extensive loss of fluids. In these cases the whole body is affected, though the fat, blood, muscles, and the abdominal organs suffer to a greater extent than the remaining tissues. Local atrophies may result from local disturbances of circula- tion, and are frequent sequelae of diseases of the arteries in which the vessel lumen is narrowed. Further, they are of frequent occurrence in or after inflammatory processes; in these cases the condition is not of the nature of simple atrophy, but of degenerative changes leading to the death of cells and tissues. Pressure-atrophy occurs when a tissue is subjected for a length of time to moderate pressure. It depends partly on direct injury to the tissues and partly on disturbance of the circulation. The most typical examples are atrop'hy of the liver caused by the pressure of the edge of the ribs on the organ due to tight-lacing ("corset-liver"), and the disappearance of bone following the pressure of an aneurism, tumor, or accumulation of fluid. Atrophy of disuse occurs in the muscles, glands, bones, ski'i, and other tissues. In muscles and glands the atrophy is active, the nutritive processes diminishing as the result of lessened functional activity. In the other tissues the atrophy is largely dependent on the lowering of nutri- tion of the disused parts, though a change in the power of assimilation of the cells cannot be excluded. When the inactivity occurs during the period of development the condition is to be regarded as hypoplasia, though no sharp line can be drawn between hypoplasia and atrophy, since in the former there may also be disappearance of structures which had undergone a certain degree of development. Neuropathic atrophy is a result of diseased conditions of the nervous system. For example, after destruction of the anterior horns or the motor roots of the spinal cord, there follows atrophy of the corresponding nerves and muscles. After injury of peripheral nerves the skin often becomes atrophic. According to many authors, disease of the nerve- trunks of one side of the face is followed by unilateral neuropathic facial atrophy, but by others (Mobius) the neuropathic nature of this condition is contested. Unilateral affections of the brain in fcetal life or during childhood may lead to atrophy of the opposite side of the body (con- genital and infantile hemiatrophy'). V. Cloudy Swelling and Hydropic Degeneration. The term cloudy swelling or parenchymatous or granular degenera- tion is applied to that form of cell-degeneration which is characterized histologically by swelHng and enlargement of the cells due to the for- mation in the protoplasm of free granules, which according to their microchemical properties (solubility in acetic acid, insolubility in alka- lies and ether) are to be regarded as albuminous bodies. The epithelial cells of the kidney and liver (Fig. 41), and the heart-muscle frequently show this degeneration, acquiring a cloudy appearance, as if covered with CLOUDY SWELLING. 145 dust, while at the same time their normal structure and form are lost. Thus, in cloudy swelling of the kidney-epithelium the rod-like markings of the protoplasm are lost (Fig. 42, a), as are the cell-processes projecting into the lumen of the tubules. The cells {b. c. d) are swollen, plump and granular. This change is to be regarded as a disorganisation of protoplasm following absorption of fluid, and leads to partial separation of the solid and liquid constituents of the protoplasm. At the same time the nucleus swells and undergoes disorganisation. Recovery is possible at a certain stage of the process, and the cells may be restored to normal. In other cases the cell-body is destroyed, breaking into granular fragments. Fatty degeneration often suc- ceeds cloudy swelling. Cloudy swelling may occur in the cells of any of the parenchymatous organs, as the liver, kidneys, or heart, during the course of infectious dis- eases, particularly scarlet fever, typhoid, smallpox, erysipelas, diphtheria, septicaemia, etc. The affected organs present a cloudy, often gray appear- ance ; in marked cases the organ may appear cooked, the blood-content is slight, the consistence doughy, and the details of structure are lost. _ Fig. 41. — Cloudy swell- tng of liver-cells (scrap- ing from the cut sur- face of the liver of a man_ dying of septi- cemia, examined in normal salt solution.) X 350. Fig. 42. — Cloudy swelling of kidney epithelium. (Chromic acid, ammonia, glycerin.) 4ij Normal epithelium; b, bee-inning cloudy swelling; c, advanced stage of cloudy swelling; d, desquamated degenerated epithelium, x 600. It is not improbable that autolytic processes (see paragraph 49) play a role in parenchymatous degeneration (Landsteiner). Orgler regards it as auto- lysis accompanied by increase of the water-content. The granules which be- come visible and show double refraction he regards as protagon, which, during autolysis, is either preserved because of its slight solubility or during the course of the process is precipitated in the form of granules. 10 146 THE RETROGRADE CHANGES. According to the investigations of Symmers (Jour. Exp. Med., 1907), the orocess of autolysis results in morphological changes, not only in certain fixed tissue cells, but in those of the blood. The changes are characterized mainly by solution of the hyaloplasm with er.posure of the spongioplastic network and retention of the cell mem'brane, giving the cell a finely reticulated appearance. The effects of autolysis are particularly noticeable in the liver, where it some- times occurs focally, at other times over a wide distribution. Extensive auto- lytic degeneration of the liver not infrequently is to be observed in the toxaemias of pregnancy and in patients dead of uraemia. § 54. Hydropic degeneration is that form frequently observed in cells of different kinds, whereby they become swollen through the im- bibition of fluid — it is an intracellular oedema. When epithelial cells undergo this change the contents appear clear, the granules of the protoplasm are pressed apart by the fluid, often crowded into a ring at the periphery ; the cells thus resem- ble plant-cells. Globules of clear Fig. 43. — Hydropic degeneration of muscle- fibres from the calf muscle in chronic oedema of the leg. (Flemming's solution, safranin.) X 45. Fig. 44. — Transverse section of a rauscle- bundle sliowing hydropic degeneration of its fibres. (Miiller's fluid, hasmatoxylin.) o,» Muscle-fibre with small drops of fluid; &, muscle-fibre with large drops, x 66. fluid may often be formed in the cells. The nucleus swells and becomes changed to a bladder-like structure containing clear fluid. In muscles showing hydropic degeneration clear droplets of fluid appear between the fibrillas, pushing the latter apart (Figs. 43 and 44, a, b). Through the abundant formation of such drops the muscle fibres may acquire in places a foamy appearance ( Fig. 43 ) . At first, the muscle fibres between these drops remain preserved, but finally undergo frag- mentation and liquefaction. Hydropic degeneration of cells may be the result of oedema (Figs. 43 and 44) ; it occurs in inflammatory foci (Fig. 34). and in tumor- cells. In inflammation tihe degenerative character of the process is more marked than in simple oedema; and complete liquefaotion of the cells may result. In oedema the cells, in spite of their hydropic condition, may remain alive for a long time. VI. Fat Deposit and Fatty Degeneration. § 55. Fat, in a form that can be demonstrated microscopically, is widely distributed through the human and animal organism. It ap- pears most prominently in the subcutaneous and subserous tissues and bone-marrow ; in these regions adipose tissue develops at a certain time during embryonal life or in childhood. Less prominent, and in part visible only on microscopic examination, is the fat present in various glands, in ganglion-cells, leucocytes, surface epithelium, duct epithe- lium, endothelium, etc. FATTY CHANGES. 147 The fat of adipose tissue occurs in the connective-tissue cells in which it is deposited in the form of droplets that often become con- fluent, so that the fully developed fat-cell appears as a spherule sur- rounded by a cell-membrane and containing a nucleus. In prepara- tions mounted in Canada balsam the fat-drop is represented by a clear vacuole (Fig. 46, c) the fat itself having been dissolved by the ether used in the process of preparation. Sudan III. and Scharlachroth stain fat a yellowish-red (Fig. 45), while treatment with osinic acid, which Fig. 45. — ^Adipose tissue from the panniculus of the heart. (Formalin, hasmatoxylin, and Sudan III.) a. Fat tissue; &, muscle; c^ muscle infiltrated with fat tissue, x 40. is reduced by the fat, causes the fat-drops to become blackened Fig. 48, 0- The fat contained in the special adipose tissues of the body is stored fat which the organism, in case of necessity, may use for its preservation, and it may be designated fat for consumption or tempo- rary fat. Its abundance may be regarded as an indication of the condition of nutrition ; when this is good the adipose tissues are well developed, in starvation and marasmus they may vanish entirely. There occurs atrophy of fat-tissue, in which the fat-cells contain only small droplets or no fat at all, in the latter case reverting to the type of ordinary connective-tissue cells. The atrophic fat-lobules often take on a pale yellow color through the formation of pigment in the cells (yellow atrophy of adipose-tissue) . Through the collection of fluid be- tween the atrophic fat-cells the fat-tissue (most frequently in the cardiac panniculus) becomes translucent, resembling myxomatous tissue (serous atrophy of adipose tissue). Hyperplasia of adipose tissue leads to the condition known as obesity, adipositas, or lipomatosis. It is dependent primarily on ex- cessive food-supply; but there are frequent exceptions to this rule, since 148 THE RETROGRADE CHANGES. in many people an increased formation of panniculus does not take place, no matter how rich the food-supply. Again, an abundant deposit of fat occurs in some individuals when the food-supply does not exceed the Fig. 46. — Lipomatosis of ihe calf muscles, associated with atrophy. (Miiller's fluid, carmine.) a. Transverse section of normal fibre; 01, of atrophic fibre; a2, transverse section of sarcolerama tube containing disintegrated contractile substance; b, connective tissue; c, fat-tissue. X 60. normal. In such cases the cause of the lipomatosis must be sought in inability on the part of the organism to destroy the fat brought to or arising in it. Fig. 47. — Spinal muscular atrophy with lipomatosis, in ascending atrophy of the anterior horns of the spinal cord. (Miiller's fluid, Bismarck brown.) Section from the calf muscle. a. Transverse section of atrophic muscle-fibres; b, perimysium; i.-, fat-tissue; d, artery; e, vein. X 60. In general lipomatosis the deposit of fat takes place first in the normal fat-depots, and later in places that normally contain no fat, for ex- ample, in the connective tissue of the muscles, in the myocardium, and LIPOMATOSIS. 149 beneath the endocardium. Local lipomatosis may occur in various regions of the body, for example, in an arm, the front of the neck, nape, etc., and leads to deformities of the affected regions resembling elephan- tiasis. When occurring in circumscribed masses or nodules the con- FiG. 48. — Skin with sweat glands, from the sole of the foot. (Osmic acid.) «, Thick gland coils with fine fat droplets; b, slender gland coils without fat droplets; c, fat drops lying about the gland coils. X 390. dition is classed with the fatty tumors known as lipomata (see Lipoma). Local lipomatosis occurs as a disease of muscles, particularly those of the calves of the legs (pseudo-hypertrophic muscular paralysis) (Fig. 46, c) through the development of adipose tissue in the perimysium Fig. 49. — Fatty liver from a case of pulmonary tuberculosis. (Flemming's solution, safranin.) a. Central portion of the liver-lobule; b, peripheral zone containing fat; c, periportal connective tissue. X 30. internum. At the same time they become weaker, since many of the muscle-fibres (Fig. 46, a, a-^, a^) disappear. Finally, in other cases adipose tissue may develop secondarily in places where other tissue has disappeared, for example, in muscles (Fig. 47, c) that have become 150 THE RETROGRADE CHANGES. atrophic as the result of disease of the anterior horn of the spinal cord or in lymph-nodes that in old age have lost the greater part of their lymphocytes. The fat of the glandular organs occurs ordinarily in small, even minute droplets, but in the case of great abundance of fat larger droplets may be formed. The sebaceous. Meibomian, and lachrymal glands, and adrenals are normally rich in fat. It occurs to a lesser extent in the testicles and ovaries; still less in the salivary glands, thyroid and sweat glands (Fig. 48, a). The kidneys have the least fat-content of any of the glands. During the period of functional ac- tivity (testicles and ovar- ies) and in advanced age the fat-content is, in general, somewhat increased. The fat-con- tent of glands is but slightly dependent on the general nutrition, so that it does not dis- appear during starvation (Traina). This glandu- lar fat may be desig- nated permanent or intrinsic fat. The liver holds a Fig. 50. — Fat-granule cells in an anjemic area of softening . 1 . . in the brain. (Marclii's fluid.) a. Fat-granule cells; b, blood- special position among vessels, x 280. the glands so far as fat is concerned. As do other glands it contains a certain number of fine fat- droplets which do not disappear during starvation. In addition there also occurs a temporary storage of fat which, beginning in the periphery of the lobule, extends toward the centre (Fig. 49, b) ; and, finally, the liver may become completely changed into cells containing fat, and the parenchyma acquires a straw-color. Fatty infiltration of the liver may result from excessive food-supply, but is more frequently observed in marasmic individuals, particularly in consumptives whose panniculus is atrophic. Inability on the part of the liver to destroy or to give off again the fat brought to it from the intestine or from the fat-depots appears to be the cause of this phe- nomenon. Muscle-fihres, surface epithelium, the epithelium of different gland- ducts, connective-tissue cells, vascular endothelium, leucocytes, etc., show a variable content of fat ; but without changes that can be regarded as degenerative in nature. In individual cases it is evident that the fat- content is dependent on an abundant supply from the intestine or of transportation from the fat-depots, especially in those cases in which the leucocytes or the vascular endothelium (particularly that in the liver) are rich in fat. In other cases there are functional states during which a rich supply of fat appears (muscles). All animal fats are mixtures of olein, palmitin and stearin, that is, com- binations of oleic acid (C18HMO2), stearic acid (CisHaeOj) and palmitic acid FATTY DEGENERATION. ^ \,'^,.P(Z ."^ ^I'si (CieHaaOz) 'with the trivalent alcohol glycerin (C8Hs[OH]3) to form neutral esters, the so-called triglycerides. Whether taken in as free fatty acids, as neutral fats, or as soaps, the process of absorption is always the same; they appear constantly in the form of neutral fats in the channels through which absorption takes place. In close relationship to the body-fats stand the l/cithins (combinations of each single molecule of glycerin-phosphoric acid with t wAanol ecules of fatty acid and the complex of an ammonium base, cholin), the;2r2SS2 and the cholesterins, sub- stances which occur in small amount in various tissues, but abundantly in the myelin of the brain and peripheral nerves. Cholesterin occurs also in the bile. The fat contained in the human organism is derived primarily from the food-fat taken up in the intestine. In the early weeks of life, when the intestine of the nursing infant is still abnormally permeable, the finest fat-droplets are taken up as such and carried through the lymph-stream into the blood. In later life the taking up of unchanged fat through the intestinal epithelium probably occurs to a. slight degree or not at all, that is, the fat is, for the greater part, split up in the intestinal canal, and through the combination of the fatty acids with the alkali present in the intestine there are formed soaps soluble in water, which are absorbed by t'he epithelium. Even in the intestinal epithelium these soaps are changed into spherules of neutral fat (just as absorbed peptone is again changed into albuminate). The glycerin necessary for this change is absorbed directly from the intestine, where it is present in a free state arising from the splitting of the neutral fats. In the entrance of the fat into the cells of the fat-depots the fat-molecule is again split up and then reconstructed in the cells. According to Arnold, the entrance of fait into the cells is associated in many cases with a certain activity of the plasmosomes, and is therefore connected with the cell-granules, which he regards as the morphological products of the function of the plasmosomes. In intracellular fat-formation, designated by him as granular fat-synthesis, which occurs in leucocytes and lymphocytes, also in endothelial, connective-tissue, cartilage, epithelial and gland cells, soap is taken into the cells in soluble form and undergoes granular change into fat. The fat-droplets appear at the site of the antecedent granules. In this manner there arise in part the so-called fat-granule cells, leucocytes and lymphocytes closely packed with fat-droplets, that occur in areas of necrosis and inflammation, particularly in the central nervous system (Fig. SO, a). According to Arnold the uniform size of the fat-droplets speaks in favor of such an origin. Such granule-cells may also be formed through phagocytosis ; that is, the amoeboid cells may take up through their protoplasmic movements fat-droplets lying free in the tissues (in softening of the brain and spinal cord they arise through disintegration of the medullary sheaths). In the event of such occurrence, chemical and morphological changes in the material taken up are not excluded. The carbohydrates form a second source of fat-formation in the organism, but the chemical processes attending the formation of fat from carbohydrates have not been determined. It is probable that the amount of fat so formed is rela- tively much less than the fat taken in as such from the food. It is st ill a ques- tion as to whether fat can be formed in the body from albumin. Smcemany' facts speak for the transformation in the animal body of~ce?tatn groups of the albumin-molecule into glycogen or grape-sugar, the theoretical possibility of the formation of fat from albumin cannot be denied (Kraus). Of the fats and lecithins present in the organism, those containing oleic /) acid aidne reduce osm ium tetraox i de to a black osmium hydroxide, so that treat- r' ment with osmic "aci3 or FlemmTng's solution does not show the presence of ' palmitin and stearin. On the other hand, Sudan III and Scharlach-roth (pon- ceau) stain all the fats. § 56. Fatty degeneration or fat-metamorphosis is that condition of the cells in which fat-droplets appear in the protoplasm in such manner as to indicate a change in the chemico-physical cell-structure. In a part of the cases this change may be inferred from the appearance of the cells, in that fragmentation, distintegration (Fig. 51, e, /), and separation of the cells from their substratum may be demonstrated. The views of Virchow were formerly accepted, that in lipomatosis there occurred a deposit of fat from the blood and tissue-juices; while 152 THE RETROGRADE CHANGES. fatty degeneration represented the formation of fat from the albuniin of degenerating cells. Recent investigations make the latter view doubt- ful Although the possibility of formation of fat from albumm cannot be denied, it has not yet been proved that this is the case in the so-called fatty degeneration of cells. . . , . ,. In many cases what we call fatty degeneration is the expression of a molecular physical rearrangement of the cells, a f at-metamorphosis, in which the fat contained in the cells in a form that cannot be recognized microscopically is separated out in the form of visible droplets. Therefore, an increase in the actual fat- content of the cell does not occur in fatty degeneration. Renal cells that on micro- scopical examination show no fat may, nevertheless, contain twenty per cent of fat. Should degeneration occur, so that the fat becomes visible in , /t> i: u the form of droplets, the total fat-content is not increased (Rosenfeld, Kraus). A process similar to that taking place in the body occurs during the autolysis of tissue preserved aseptically in the incubator, fat-droplets Fig. 51. — Fat-containing liver- cells, a and b. Fat-infiltration; c, d, e, f, fatty degeneration. X 400. Fig. 52. — ^Fatty degeneration of the heart-muscle. X 350. Fig. S3. — Anaemic and fatty necrosis of the myocardium 85 hours after the closure of a coronary artery. (Flemming's solution, safranin.) o^ Necrotic; b, fatty muscle fibres; c, con- nective tissue with leucocytes containing fat. x 300. becoming visible in such tissues (Hansen, Wentscher, Kraus, Miiller, and others). When fat as such is not present in the cells it may arise through chemical decomposition of lecithin, cerebrin, and protagons (myelin) contained in the cells. A second source of fat appearing in fatty degeneration is the fat brought to the affected cells by the blood and tissue-juices, arising either from the fat contained in the food or transported from the fat-depots in other tissues. For example, in phosphorus-poisoning transportation of fat from the panniculus to the liver takes place. It is probable that FATTY DEGENERATION. 153 Fig. 54. — Fatty degeneration, vacuolization, and dis- organization of tile heart-muscle in a patient dying from pneumonia and nephritis. (Flemming's, safranin.) a. Transverse section of normal, muscle-cell; b, muscle- cell in a state of fatty degeneration; muscle-cells with vacuoles; d, disorganized cell. X 400. the same thing occurs in other intoxications (arsenic, alcohol, chloro- form, oleum pulegii). In such cases increase in the fat-content of the affected organ must occur, but this is not always the re- sult of synthesis of fat, that is, the formation of higher fatty acids and glycerin and their combination, but is a taking-up of fat that, either as such or as soaps, has been given over to the blood. In the condition which we call fatty degeneration, the fat appears usually in the form of fine droplets (Figs. 52, 53, b, 54, b, and 55, b), but these may become con- fluent to form larger drops (Fig. 56), particularly during the disintegration of the cell (Fig. 51, /). The conditions under which the fat of fatty degeneration appears' make it pro'gable that the cells which are the seat of fatty metamorphosis are still living, but have been injured by external influences^ In anaemic infarcts of the spleen, kidneys, and heart, the fatty cells (Fig. 53, b) are found in thp zone of transition between the necrotic (a) and the living tissue ; that is, where the circulation of the blood and lymph is weak, but has not ceased. The appear- ance of fatty cells in glands (Fig. 51, c, d, e, f), in the endothelium of the blood- vessels, or the cells of the heart-muscle (Fig. 54, b) occurs in intoxications and infections as the result of cell-injury through toxic action. Chronic fatty de- generation of the heart- muscle (Fig. 55, b) is seen in valvular lesions, pul- monary emphysema, gen- eral anaemia; in the renal epithelium of consump- tives it occurs partly as the result of diminished supply of oxygen, and partly from the action of toxic substances. Experimental investigations have shown that long-continued elevation of the body r? Ililii'l'/: i' III I s& ^'f": % |lii '!-'l'i' '^Wk ''< '.^|''l ■ 1 A'/.JM ; ^ \ ' ' t 1 ?j ' ■ ' «'3 ■'^i', 'y m ■:\l' iM,l« m 'Wtt ^ !iilffii#igjs>«i^ifigl|l| Fig. 5S. — Marked fatty degeneration (chronic) of the heart-muscle. (Flemming's solution, safranin.) a, Nor- mal muscle; h, muscle which has undergone fatty de- generation. X 8o. 154 THE RETROGRADE CHANGES. temperature leads to fatty degeneration of different tissues (heart, kidneys, and liver). , vu ^u i j A mild grade of fatty degeneration cannot be seen with the naked eye The more severe forms give an opaque yellowish color to colorless tissues as for example, the intima of blood-vessels and the heart-valves, which 'frequently show patches of fatty metamorphosis. The cortex of a kidney in a state of fatty degeneration becomes grayish or yellowish. In the heart-muscle the yellowish discoloration of fatty degeneration, particularly when the change is localized in small foci (Fig. 55, b), yio. 56. Fatty degeneration of the renal epithelium, from a case of chronic pulmonary tuberculosis. (Formalin, hsematoxylin, Sudan III.) X 300. stands out prominently ("tiger-heart"). The change is best seen im- mediately beneath the endocardium covering the papillary muscles of the left ventricle. It is not always possible to decide whether the fat present corresponds to a physiological or pathological condition. We can no longer accept_ the view that fine droplets of fat in the cells signify a pathological condition, since most glands and other tissues, for exaniiple, muscle-fihres, contain fat-droplets un j adenomatous pclyp of the small in- DCCOme tatty. Or CVCU UndCrgO mUCOUS dc- r''EWHum°'with'"£r£Yalire^ generation. In the last event the entire (hematoxylin) drops of mucus tissuc Ultimately forms a hyaline mass, in within the cells; b, free mucus; c, i ■ i i , . j i^i r leucocytes in the epithelium, x 300. which Only Scattered hbrcs of connective tissue, or single cells or groups of cells are left to suggest the original tissue. The stringy, or gelatinous miaterial, which results from mucous de- generation, does not represent a single chemical substance; in it there Fig. 60. Fig. 61. Fig. 60. — Epithelial cells which have undergone mucous degeneration, from a cystadenoma of the ovary, a. Cells showing slight change; b, cells showing marked degree of mucous change. X 400. Fig. 61. — Mucous degeneration of the connective tissue of the aortic valves (osmic acid, glycerin), a. Fibrous tissue; b, myxomatous tissue. X 350. may be found different varieties of mucins as well as of pseudomucins. The mucins (submaxillary, intestinal, and tendon mucin) are nitrogenous substances resembling albumin. They dissolve or swell in water forming a mucoid fluid, from which they may be precipitated in 160 THE RETROGRADE CHANGES. a stringy form by means of alcohol or acetic acid; but differ from the true albumins in the fact that the precipitate is not redissolved in an excess of the acid. The precipitated mucins are soluble in neutral salt- solutions, caustic alkalies, and alkaline carbonates; and are gradually converted into alkali-albuminates in case of solution by the last named. All mucins contain nitrogen and sulphur; their content in carbon, oxygen, nitrogen, and sulphur varies in the different forms. Pseudomucin also dissolves in water, forming a gelatinous fluid, from which it may be precipitated in stringy masses by alcohol. The precipitate redissolves in water. Solutions of pseudomucin are not pre- cipitated by acetic acid. Pseudomucin is found particularly in ovarian cystomata, and is the cause of the gelatinous character of the cyst-contents. It is produced by the epithelium of these tumors (Fig. 60) ; and in its formation the same changes take place in the cells, as in the formation of mucin from epithelium. In all probability the mucous substance present in gelat- inous carcinomata is a body closely related to pseudomucin or metalbu- min — that is, there are different varieties of pseudomucin (Pfan- nenstiel), of which the two mentioned are examples. IX. Formation of Epithelial Colloid and Epithelial Hyaline Concretions. § 60. The epithelial formation of colloid is a process closely related to the epithelial production of mucus; it consists partly in secretion of colloid by gland-cells, and partly in conversion of cells into colloid. Fig. 62. Fig. 63. Fig. 62. — Colloid in enlarged thyroid gland. (Alcohol, hematoxylin.) o, Follicle filled with cells; b, follicle showing lumen; c, masses of colloid; d, capillary; e, connective-tissue septum with artery, x 60. Fig. 63. — Secretion of colloid in the thyroid. (After Bozzi.) a. Colloid; b, secreting cells with granules. Physiologically, colloid is found in the thyroid (Fig. 63), where it appears in the form of hyaline, rather firm, colorless, or faintly brown- ish, jelly-like masses, which fill the vesicles, but from these may extend into the lymph-vessels of the thyroid. Pathological collections of colloid occur both in residual thyroid tissue and in newly-formed glandular- tissue of pathological nature. The accumulation causes a more or less marked distention of the vesicles, and leads to enlargement of the gland, known as colloid goitre. uYALIN. 161 Fig. 64. — Dilated urinary tubules filled with colloid. (Miiller's fluid, hematoxylin, and eosin.) X Z50. The secretion of colloid is characterized by the formation of homo- geneous granules and spherules in that portion of the epithehal cells next to the lumen of the vesicle (Fig. 63). Some of the cells may be completely filled with these granules. In excessive and atypical forma- tion desquamated cells may become converted into hy- ' aline colloid. The colloid of the thy- roid is found on micro- scopical examination to be homogeneous; and because of its physical properties it may be designated epi- thelial hyalin. As a rule it incloses no cellular ele- ments, although degenerat- ing cells may be found in it. Alcohol and acetic acid cause no clouding, or pre- cipitation in. the form of threads, as happens in the case of mucin when so treated. By Van Gieson's method colloid is stained orange-red, while the connective tissue takes a fuchsin-red. It must be noted that the contents of the thyroid follicles, which are designated colloid, are not always of the same char- acter. At one time the substance is firm, at another soft or even fluid, or at least is readily soluble in water. In preparations fixed in alcohol granulation or cleav- age may be caused by contraction ; moreover, the stain- ing reactions are not always the same. The chemical nature of the thy- roid colloid is not fully known, and it is probable that the contents of the folli- cles are of variable composition. It is most probably an albuminoid body which is combined with iodothyrin, the active principle of the thyroid gland. Epithelial hyalin is also found in the glandular elements of the hypophysis cerebri, in the tubules of diseased kidneys (Fig. 64), in the prostate (Fig. 66, d), in cysts of the paro- varium (Fig. 65, d), in the glands of the stomach, and more rarely in other glands. In the last-named organs the hyalin occurs in the form of a uniformly homogeneous mass completely filling the gland-lumen, or as 11 I^° Fig. 65. — Colloid concretions in the cystic dilated tubules ot the parovarium. (Formalin, Van Gieson's stain.) a, b. Gland- tubules of the parovarium; c, cysts containing colloid concretions (d). X 80. 162 THE RETROGRADE CHANGES. hyaline, in part laminated concretions (Fig. 65, d, and 66, d) of more or less firm consistence. _ . _ _ It must not be assumed that the last-named formations are identical in their chemical composition with thyroid colloid. The only thing which they possess in common is this : they both represent transformed 'protoplasm of gland-cells — z. substance which is hyaline, possesses a certain firmness, and does not react to chemical reagents in the same manner as does mucin. These concretions may also undergo changes which necessitate, on their part, a different behavior toward micro- chemical reactions. This is particularly true of the prostatic concre- FiG. 66. — Section from a hypertrophic prostate with concretions. (Miiller's fluid, hasmatoxylin, and eosin.) o. Stroma; b, glands; c, dilated glands; d, concretions, x 45. tions, which not infrequently show, when treated with iodine, a reaction that has been taken as evidence that they are composed of amyloid ma- terial (see § 63). It may be proved, both in the case of prostatic con- cretions and of renal colloid, that they represent cell-material which has become changed into hyaline substance. In the case of renal colloid, however, it is only under special conditions that the participation in its formation of albumin derived from the glomeruli may be excluded. Colloid is a collective term which is applied to a variety of formations that pos- sess certain physical attributes in common. There is great difference of opinion among authors as to the application of the term. Under colloid degeneration, for example, von Recklinghausen places mucous, amyloid, and hyaline degenerations; including under the last-named epithelial colloid-formation, hyaline degeneration of connective tissue, as well as hyaline coagulation-necroses and hyaline thrombi. Marchand gives the term a more limited^ application, but includes under colloid certain forms of epithelial mucin-formation (particularly in tumors), and also hyaline formations in _ connective tissue. Inasmuch as colloid is not a chemical entity, andas its staining-reactions do not differentiate it from other hyaline sub- stances, Ziegler thought it expedient to apply the term only to those hyaline products of epithelium which do not possess the characteristics of mucin. He, therefore, also classified as colloid those epithelial concretions which on account of their reaction with iodine (brown or blue color when treated with dilute iodine solutions) have hitherto been regarded as amyloid bodies If objection is made to the classification of these formations as colloid, they may be placed under the CORNIFICATION. 163 heading of epithelial hyalin. {Ziegler's application of the term colloid has been respected in the present revision.) Hyaline spherules have been described by Russell and others, particularly in cancer cells, and, at one time, were regarded in certain quarters, as etiologically related to cancer. It is now generally believed that these so-called " fuchsin bodies " represent phagocytised and hyalinised red blood cells. They occur in a wide variety of conditions and are noticably frequent in the mucosa of the stomach in pernicious anemia. In certain infections, notably typhoid fever and influenza, the lower end of the rectus muscles not infrequently shows changes characterized by hyalinization, the areas appearing smooth, opaque and grayish pink in color. On microscopic ex- amination, it is found that the muscle fibres are swollen, opaque and glassy {Zen- ker's degeneration.) In the recently prevailing pandemic of influenza, this variety of degeneration was encountered in the rectus muscles in a considerable proportion of. all cases examined at autopsy. Rupture of the hyalinized muscle fibres occa- sionally occurred with the production of extensive hsemorrhage into the sheath and mechanical disintegration of the remaining muscle fibres. In still other cases, hyaline degeneration and haemorrhage were followed by secondary infection and abscess formation. Literature. {Colloid.) Pratt: Goitre. Ref. Handb. of Med. Sc, 1902. Russel: Characteristic Organism of Cancer. Brit. Med. Journ., ii., 1890. X. The Pathological Cornification of Epithelium. § 61. Cornification of surface epithelium is a physiological process, characterized by the fact that the cells in the outer strata of the prickle layer of the stratum germinativum undergo horny change. This corni- fication takes place first at the periphery of the cells and in the bridge- like processes binding the cells together, at the same time the inner por- tions of the cell and the nucleus shrink, so that the cells become changed into scales. This horny substance or keratin is a modified albuminoid body of homogeneous composition, and is capable of resisting digestion by the gastric or pancreatic juices. As accompaniments of cornification there appear in the cells of the prickle layer hyaline granules and spherules resembling colloid, which stain intensely with nuclear stains and are known as keratohyalin. In those areas of the skin possessing a thick horny layer, there is formed a stratum of keratohyalin-containing cells ; this is known as the stratum granulosum. In those places where the horny layer is thin, the stratum granulosum is imperfectly developed and exhibits breaks of continuity. Pathological cornification may occur as a wide-spread or localized increase of the horny layer, resulting in hypertrophy of the epidermis (see Chapter VI., § 76), or hyperkeratosis. This phenomenon may be primary — that is, due to causes inherent in the skin (ichthyosis, lichen pilaris) — or acquired as the result of external influences, mechanical lesions (callosities, corns), infections and inflammations. Further, there may occur disturbances in the process of cornification of the skin, so that certain pathological manifestations recognizable by the naked eye make their appearance, such as desquamation of the skin. Such changes are included under the term parakeratoses. They occur especially as sequelas or concomitant phenomena of infections of the epidermis, and of inflammations of the corium and papillary body, sometimes without any recognizable cause ; and in these cases either the process of cornifica- tion or of the formation of keratohyalin, or both, is disturbed. 164 THE RETROGRADE CHANGES. Finally, pathological cornification often occurs in regions where nor- mally it either does not occur at all or but to a slight extent. In the skin the cornification may extend to the ducts of the sebaceous glands and to the hair-follicles (ichthyosis) or to the sweat-glands (porokeratosis). Further, pathological cornification occurs not infrequently in the mucous membrane of the mouth, giving rise to white thickenings of the epithe- lium or to hair-like formations (hairy tongue). Horny change may be observed also in the mucous membrane of the middle ear, in the mastoid cells, in the descending urinary passages, and in these places it may lead to the formation of shining white scales {formation of cholesteatomata) . Cornification of cancer cells is very frequently seen, particularly in cancers of the skin, in which the horny scales are found usually in the form of round masses resembling onions or pearls. Similar homy prod- ucts are also found in cholesteatomata of the pia and brain. ' The pathological formation of horny substance in the mucous mem- branes or in tumors takes place either simply through cornification of the cell-membranes with contraction of the cell, or it may be combined with the formation of keratohyalin as in the case of typical cornification. The formation of keratohyalin and the cornification of epithelial cells often are irregularly distributed, particularly in cancers. XI. Amyloid Degeneration and the Amyloid Concretions. § 62. Amyloid degeneration is characterized primarily by the de- posit of an albuminoid substance (amyloid) in the connective tissues of blood vessels, so that the involved organ increases in bulk and ac- quires a glassy, homogeneous appearance. The degeneration may occur in almost all the organs of the body; but is especially frequent in the spleen, liver, kidneys, intestine, stomach, adrenals, pancreas, and lymph nodes. It is rarely observed in adipose tissue, thyroid gland, aorta, heart, muscles, ovaries, uterus, and urinary passages. Extensive deposits of amyloid may be recognized by the naked eye, as the affected parts present a translucent appearance resembling bacon (lardaceous degeneration). In the spleen the deposit of amyloid occurs first in the walls of the blood vessels of the lymphoid follicles, and the follicles finally are con- verted into homogeneous, translucent bodies (Fig. 67, b) resembling grains of boiled sago^ — -this form of amyloid spleen is known as sago spleen. When the amyloid change occurs throughout the spleen-pulp it may be recognized on the cut surface as more or less distinct spots or streaks. Ultimately the greater part of the substance of the spleen may be replaced by amyloid material. The spleen is thus enlarged, its con- sistence becomes hard, and the organ may finally be transformed into a bacon-like substance (lardaceous spleen). The liver, in well-marked amyloid degeneration, is increased in size and consistence. On section, the liver-tissue is found to be, replaced to a greater or less extent by translucent, lardaceous masses, between which the remaining liver cells appear brownish or yellowish from abundance of contained fat. The kidney, in cases of extensive amyloid change, is likewise enlarged and hardened, and on section shows hyaline, lardaceous spots and streaks of firm consistence. More often the kidney is normal in size or only slightly enlarged, but increased in consistence, while in the cortex the AMYLOID. 165 presence of amyloid material is revealed by minute waxy, translucent spots corresponding to infiltrated glomeruli. In order to bring these out it may be necessary to treat the tissue with iodine. In still other instances the amyloid is apparent only on microscopic examination. In th«^ intestine and lymph nodes the degeneration usually cannot be recognized without the aid of the microscope and chemical reagents; and the same is true in regard to the other organs which are more rarely affected, such as adipose tissue, heart-muscle, the great blood- vessels, the thyroid gland, etc. The substance which is deposited in amyloid degeneration forms Fig. 67. — Amyloid degeneration of the splenic follicles and neighboring tissue. (Muller's fluid, haematoxylin, and eosin.) Oj Transverse section of splenic artery; b, amyloid areas; c, pulp; d, trabeculae; x 30. shining, homogeneous masses, which exhibit a characteristic reaction with iodine as well as with various aniline dyes. Iodine dissolved in water, or better in a solution of potassium iodide, and poured over the affected tissue, stains the amyloid substance dark hrozvnish-red (mahog- any brown). In thin sections, under the microscope, the amyloid appears bright hr own-red (Fig. 68, b) while the remaining tissue is a straw- yellow color. In marked amyloid degeneration, when the tissues are of wooden hardness, the iodine reaction sometimes gives a blue or green color. Prep- arations which have been changed to mahogany brown through the action of iodi ne become still deeper brown~wfren treated with dilute sul- phuric acid or with a solution of zinc chloride, or they may become bright red, violet, blue, or green. This reaction is, however, imperfect in the majority 'of cases. Methyl violet stains amyloid ruby red (Fig. 69, a, b), while the nor- nial tissue takes a blue or dark blue-i/f6let. Because of the peculiar reaction with iodine, Virchow was led to re- gard the amyloid substance as a non-nitrogenous body related to cellu- 166 THE RETROGRADE CHANGES. lose or starch, inasmuch as cellulose when treated with iodine and con- centrated sulphuric acid becomes bright blue, and starch similarly treated gives an ultramarine color. Virchow accordingly gave the name amyloid to the newly discovered substance. Several years later Fried- reich and Kekule showed that amyloid is a nitrogenous body of albu- minous nature. According to the investigations of Krawkow amyloid is a firm combination of chondroitin-sulphuric acid with albumin. The reactions of amyloid enable __us to detect its presence in the tis- sues when it is present in such small amounts as to be otherwise invisible. In the microscopic examination of fresh preparations care should be Fig. 68. — Section from an amyloid liver, treated with iodine solution. X 35- taken to wash out the blood from the tissue, since the color resulting from the combination of blood and iodine may be deceptive. Amyloid is_ resistant to acids and alkalies. Alcohol and chromic acid do not affectit; it isalso resistant to putrefactive changes. Amyloid is deposited in the ground-substance of the connective tis- sue of blood-vessels, especially in the walls of the small vessels. Living cells are not affected. In the connective tissue the amyloid substance appears first between the fibrillse. Amyloid degeneration as a rule is associated with diseases which are of hopeless chronicity and are characterized by the long-continued drain of albuminous elements from the blood and, in many instances, by the destruction of bone and cartilage. The condition is by no means as common now as formerly, since iir.proved methods of treatment have tended to modify those diseases with which amyloid is most frequently associated. In 5,900 autopsies performed at Bellevue Hospital, amyloid degeneration occurred in 27 cases (0.5 per cent.) ; in 17 cases it was associated with ulcerative tuberculosis of the lungs, and in 10 of these AMYLOID. 167 there were tuberculous ulcers of the intestine; in 6 cases amyloid was associated with ulcerative syphilides ; in 2 cases with chronic suppiirative pyelonephrosis ; in one case with ulcerative carcinoma of the stomach; in another with chronic pyogenic osteomyelitis. The order of frequency with which the organs were involved was as follows : Spleen 23 times ; liver 18; kidney 17; adrenals 7; gut, lymph nodes and heart once each. In the acini of the liver the amyloid is found along the capillaries. The endothelium (Fig. 70, c) is covered on its outer side by a thick layer of a homogeneous, glassy substance, which may be broken up through numerous clefts into lumpy masses (c) of amyloid material. The liver- FlG. 69, — Amyloid degeneration ot the splenic follicles and pulp. (Alcohol, methyl violet, hydrochloric acid.) a. Follicle showing marked degeneration; bj pulp showing beginning degenera- tion. X 300. .: cells between the amyloid masses are either intact (a) or compressed (b), and atrophic, or may have disappeared. They often contain fat. The afferent blood-vessels of the liver, particularly the media of the arteries, may also show amyloid deposits. In the kidneys (Fig. 71) the amyloid is found particularly in the vessel- walls. The capillaries of the glomeruli (&) may be thickened and homogeneous; likewise the arteries (i), the veins, and the capillaries (k) of other parts of the renal parenchyma may show amyloid deposits. In the intestinal mucosa the deposit is also found in the walls of the blood- vessels. In fat-tissue, which is occasionally extensively involved, the amyloid substance is found in the vessel-walls, and in the connective tissue, and the membranous sheath of the fat-cells may be converted into a hyaline mass. In the spleen the connective-tissue trabeculas (Fig. 69, a, b) and vessel-walls are especially likely to be affected, and may suffer marked thickening. In striped muscle the perimysium internum and the sarco- lemma are involved. In glandular organs possessing a tunica propria, for example, the mucous glands and kidneys, this membrane may become greatly thickened. The effects of amyloid degeneration on the functions of the affected organ are indicated by the degenerative and atrophic alterations in the 168 THE RETROGRADE CHANGES. cells of the parenchyma. The connective tissue itself is permanently changed; the insoluble amyloid is never removed from it. The deposit of amyloid substance in the blood-vessels leads to marked thickening of their walls, and to narrowing or even obliteration of their lumina (Fig. 71, b), and in this way to permanent disturbance of circulation. The amyloid masses may compress neighboring epithelial structures (Fig. 70) and cause them to atrophy. Often there is asso- ciated fatty degeneration of the epithelium (Fig. 71, e^ /), particularly in the kidneys ; this change is not to be referred wholly to the disturbances of circulation caused by the amyloid deposit. It is more likely that the Fig. 70. — Amyloid degeneration of the liver. (Alcohol, Van Gieson's.) containing fat; b, compressed liver-cells; c, amyloid, x a. Liver-cells, 240. in part fatty degeneration, at least in part, is a pathological process running parallel with the amyloid disease, and caused by the same conditions pro- ducing the latter. Consequently, in some c^ses the amyloid change may be slight, while the fatty degeneration is marked. In the spleen and lymph nodes the lymphoid cells lying in the meshes of the thickened reticulum disappear as the result of atrophy. In muscles the contractile substance diminishes in proportion to the increase of the amyloid deposit in the intervening connective tissue. _ Amyloid deposit is usually a sequel of cachexia due to chronic ulcer- ative tuberculosis of different organs, chronic suppuration (for example, of thebones), syphilis or chronic dysentery. In the cachexia of carci- noma it is but rarely observed. In rare cases the degeneration occurs without being associated with any of the above-mentioned diseases. According to investigations by Czerny, Krawkow, Lubarsch, David- sohn, Maximow, Nowak, Petrone, and Schepilewsky amyloid may be produced experimentally in the spleen, liver, kidneys, and intestines of various animals, rabbits, chickens, doves, mice, and dogs, through the production of suppurations lasting several weeks. Amyloid may de- velop also in horses that are inoculated with diphtheria bacilli. Suppura- tive processes caused by staphylococci and oil of turpentine appear irt AMYLOID. 169 particular to favor the formation of amyloid. In a number of cases amy- loid was also successfully produced through injections of decomposed bouillon, dead cultures of staphylococci, rennet-ferment, and pancreatin (Schepilewsky), when the inflammation produced by these agencies ran a somewhat chronic course. Krawkow observed the beginning of amy- loid formation after three days, Nowak after eight days. The origin of the amyloid substance has not been definitely deter- mined. The results of experimental investigation vary greatly, the de- generation often being absent in chronic suppuration (particularly in dogs). It is probable that the blood brings to the tissues some substance Fig. 71. — Section of an amyloid kidney. (Miiller's fluid, osmic acid, methyl violet.) a, Nor- mal vascular loops; b, amyloid vascular loops; c, fatty glomerular epithelium; ci, fatty capsular epithelium; d, fat-drops lying against the outer surface of the capillary walls; e, fatty epitheliiim in situ; f, desquamated and fatty epithelium; g, hyaline coa^ula (cast); h, transverse section of a cast composed of fat-drops; i, amyloid artery; k, amyloid capillary; /, cellular infiltration of the connective tissue; w, round cells within the tubules. X 300. • which is changed into amyloid at the site of deposit. It has been many times shown that as the antecedent of amyloid there is found a hyaline substance in the tissues, which does not give the amyloid reactions. Similar observations have occasionally been made in man. The material from which amyloid arises is formed, perhaps, by disintegrating pus- cells or tissue-cells at the seat of the primary disease and thence enters the blood-stream. According to Krawhow,jh&:6 are found normally in the wall of the horse's aorta, in the ligamentum nuchae of cattle, in the stroma of the spleen of calves, and in the mucous memhrane of the stomach, combinations of chondroitin-sulphuric acid which are closely related to amyloid. According to Neuberg, amyloid proper is a basic albumin in the process of metamorphosis combined with chondroitin- sulphuric acid. From this last-named combination the basic albumin body may be easily differentiated chemically. 170 THE RETROGRADE CHANGES. Literature. (Amyloid.) Davidsohn: Exper. Erzeugung von Amyloid. Virch. Arch., ISO Bd., 1897; Erkennung zweier Stadien der Amyloidentartung. Ibid., ISS Bd., 1899. Edens: Histopathologie lok. u. allg. Amyloiddegeneration. B. v. Ziegler, xxxv., 1904. Krawkow: Exper. Erzeug. v. Amyloid. Cbl. f. allg. Path., 1895; Arch, de med. exip., 1896; Chemie der Amyloidsubstanz. Arch. f. exp. Path., 40 Bd., 1897. Wells: Chemical Pathology, 1920. § 63. The form of amyloid degeneration just considered is a disease, which usually appears as an affection of several organs, or, if confined to a single organ, as a change extending throughout the whole organ. There is, however, a form of amyloid disease appearing as a local infiltration of the tissues or in the form of free concretions. The local amyloid infiltrations occur in cellular granulations and in tissues showing chronic inflam- matory processes; and in scars. They are also found occasionally in turnors in which other retrograde changes have begun. In certain •cases only small deposits are found in the affected tissues, usually in the vessel-walls. In other cases larger nodules may be formed, and may acquire a wooden hardness. Here also the amyloid substance is deposited in the ground-substance of the tissue; but it has been claimed by some authors (Rahl- mann) that the cells of the tissue may acquire a hyaline appearance and give the amyloid reactions. Such local infiltrations of amyloid have been found in the inflamed conjunctiva, m syphilitic scars of the liver, tongue, and larynx in in- flamed lymph nodes, m the urinary bladder, ulcers of the leg 'and in tumors of the larynx and stomach. Tumor-like nodules of amyloid also occur in the conjuctiva, tongue, larynx, lymph nodes, and trachea tinder conditions in which it is impossible to establish any relationship between them and inflammatory processes, and where besides the hyaline masses there is but little normal connective tissue present. Accordincr to Burow Manasse, von Schrotter, Zahn, and others, such nodules may arise also from connective-tissue tumors. Free concretions or corpora amylacea occur most frequently in the tissues of the central nervous system, especially in the substance of the spinal cord, and m the ependyma of the ventricle. They are found rlso in the prostate. In the nervous system they appear as small (Fig 72r) dull-shmmg, mostly homogeneous bodies, more rarely consisting of a Fig. 72. — Corpora amylacea. u, Laminated prostatic concretions. x 200. b, Corpus amylaceum from an old hjemorrhagic infarct of the lung, with hsematoidin crystals in its nucleus. x 200. c, Corpora amylacea from the spinal cord, x 400. HYALINE DEGENERATION. 171 nucleus and an outer shell (Redlich) ; in the prostate they form larger (Fig. 72, a) bodies which usually show distinct stratification. Corpora- atnylacea have also been found in carcinomata (Wagner, Langhans), and have been repeatedly observed in the lung, where they occur in inflam- matory areas, haemorrhagic extravasations (&), and in emphysema. Corpora amylacea cannot be regarded as of the same nature as the progressive amyloidosis of connective tissue. Some of them, it is true, give characteristic amyloid reactions, and the corpora amylacea of the nervous system, in particular, become blue or brownish-violet when treated with iodine and sulphuric acid. But, in the case of these bodies, we have to do with formations which are dependent on local conditions for their origin; and are derived in part from epithelium, and in part from connective-tissue cells. They are, therefore, to be regarded as modified epithelial (§60), or connective-tissue hyahn (§65). The pros- tatic concretions are formed through the fusion of degenerating epi- thelial cells (epithelial colloid, § 60) ; similar bodies found in the lungs and in tumors are likewise composed of disintegrated cells, though in part of albumin derived from the blood. The corpora amylacea of the ner- vous system probably arise from fragments of swollen axis-cylinders to which, perhaps, remains of the medullary sheath still cling. Literature. (Local Formation of Amyloid and Amyloid Concretions.) Manasse: Tumorformiges Amyloid des Larynx. Virch. Arch., 159 Bd., 1900. Posner: Ueber Prostataconcretionen. Zeitsch. f. klin. Med., 16 Bd., 1889. Redlich: Die Amyloidkorperchen des Nervensystems. Jahrb. f. Psyoh., x., 1891. Tschistowitsch: Amyloidtumoren d. Retroperitonealdrusen. V. A., 176 Bd., 1904. XII. Hyaline Degeneration of Connective Tissue and the Hyaline Products of Connective-tissue cells. § 64. Under the head of hyaline degeneration of connective tissue may be grouped those changes in which the fibrous ground-substance acquires a hyaline character without giving the specific reactions of amy- loid (Fig. 73). The change may involve connective tissue, altered by chronic inflammation, as well as the newly formed connective tissue of inflammatory lesions and the stroma of tumors. Hyaline degenera- tion is found most often in the connective tissue of the thyroid (Fig. 73, b) ; the valvular endocardium; intima of the arteries; the entire wall of the smaller vessels, particularly of the brain and spinal cord; the lymph nodes (Fig. 75, a,b); glomeruli of the kidney ; the connective tissue and blood-vessels of tumors of the dura mater (psammoma), parotid, and submaxillary glands (angiosarcoma) ; the connective tissue of scars; the peripheral portions of tuberculous nodules; the connective tissue of chronically inflamed tendon-sheaths and bursas (Fig. 74, b). Hyaline degeneration of connective tissue possesses no specific stain- ing reactions, as does amyloid. Staining with Van Gieson's acid fuch- sin and picric acid gives to hyalin in the great majority of cases an in- tense fuchsin red; but this reaction is sometimes wanting. It is prob- able that the transformation of connective tissue known as hyaline repre- sents a variety of degenerative conditions. 172 THE RETROGRADE CHANGES. S-0 Fig. 73. — ^Hyaline degeneration of the connective tissue of a colloid goitre. (Alcohol, Van Gieson's.) a. Follicles containing colloid; 6, hyaline connective tissue; c, blood- vessel. X 300, In many cases (hyalinisation of the heart-valves or of the intima of arteries) the tissue appears on microscopic examination to be thick, homogeneous and poorly nucleated, and the condi- tion has been designated sclerosis. The gradual disappearance of the nuclei, the subsequent cal- cification or softening even to the point of complete disintegration (for ex- ample in sclerotic areas of the intima), the sequestra- tion of the altered tissue from the normal (for ex- ample, in the degenerated portions of the walls of bursse), all point to the fact that the process is de- generative in character., In other cases the ap- pearance of the hyaline tis- sue resembles closely that of amyloid degeneration, and there is associated with the hyaline change a pronounced increase of bulk, particularly in the small vessels of the central nervous system, of the spleen, renal glomeruli and lymph nodes, more rarely in the connective tissue itself. There oc- cur moreover, though rarely, certain forms of hyaline degeneration in- volving the heart (Fig. 76, b, c), serous mem- branes, intestinal wall, etc., with the formation of glassy masses, which in part give the amyloid reaction, and in part do not. In proliferations of the conjunctiva there frequently has been ob- served hyaline degeneration of the reticular ground-substance with nodular thickenings ; this material gives the amyloid reaction only in part. It m'ay therefore be assumed that there is a form of hya- line degeneration of connective tissue which is closely related to amyloid, and may become changed into the latter ; and that it arises through the deposit of a hyaline insoluble albuminous body probably derived from the blood. The preparation shown in Fig. 76, was taken from the heart of a woman of fifty-five years of age, the greater part of the heart-wal' presenting hyaline Fig. 74. — Hyaline degeneration of the connective tissue ot the wall of a tuberculous bursa. (Miiller's fluid, hsematoxylin, and eosin.) a. Fibrous connective tissue; fo, hyaline con- nective tissue. X 40. HYALINE DEGENERATION. 173 degeneration. In both endo- and pericardium there were numerous hyaline nodules and flattened masses. The muscle tissue was in part degenerated, as shown in the hgure. Associated with this condition there was extensive degeneration of the blood-vessels, particularly of the intestines, tongue, lungs, heart and urinary blad- FiG. 75. Fig. 76. (Alcohol cirmi^r-)'"! -feTf ^''°" ?* 'I'if blood-vessels of an atrophic axillary lymph-node. (.Alcohol, carmine.) a. Hyaline vessel with open lumen; b, obliterated vessel, x 200. l,«„'^/°' ,?*•— Hyaline degeneration of the connective tissue of the myocardium. (Alcohol, ™^?5= ^ t- '^^™'"^-) «' ^'°™3l connective tissue; b, hyaline connective tissue; c, hyaline masses; d, transverse section of normal muscle-cells, of atrophic (e). x 250. Ji » = ^^!^"?^^ 'TXi^iJi der. The peritoneum was also thickly covered with hyaline nodules. The fact that the small areas and the periphery of the larger ones gave no iodine-reaction, while the central portions of the larger areas did so, appears to point conclusively to a close relationship between hyaline degeneration and amyloid. A similar case has been described by Steinhaus. § 65. Hyaline products arise from certain spherical masses of con- nective-tissue cells arranged in concentric layers, which, in a manner similar to the cornification of epithelial cells, become changed into a hyaline substance containing no nuclei. These formations occur most frequently in the meninges, the choroid plexus, and the pineal gland, and in the new-growths arising in these regions. Through subsequent calcification they lead to the formation of laminated concretions (see § 66, Fig. 84). Another kind of hyalin possibly owes its origin to secretory activity of connective- tissue cells. This may be designated secretory connective-tissue hyalin, but it must be noted that the cells themselves may he converted into hyaline products. The variety of hyalin is perhaps oftenest observed as red-staining spherules lying free in the tubules of chronically inflamed kidneys. The fuchsinophile bodies of Russell were formerly included in the same category, but are now regarded as phagcx;ytised red corpuscles which have undergone hyaline transformation. Von Recklinghausen gives to the term hyalin a more comprehensive meaning than Ziegler. He includes under hyaline degeneration pathological changes which Ziegler placed under other heads. He defines hyalin as an albuminous body which stains intensely with eosin, carmine, picrocarmine, and acid fuchsin ; is homogeneous and strongly refractive; is but slightly changed by acids; and in its resistance to alcohol, water, ammonia, and acids resembles amyloid, but does not give the iodine reaction. As hyalin he includes epithelial colloid and the hyaline products of con- nective tissue cells, as well as hyaline degeneration of the ground substance of the Fig. 77. — Calcification of the media of the aorta, x 350. 174 THE RETROGRADE CHANGES. connective tissue, also hyaline thrombi, and the hyaline coagula of inflammatory exudates, and hyaline tissue-necroses. According to Von Recklinghausen all of these formations result from the fusion of the elements of neighboring cells. From their external appearance, all may be designated hyalin; but the following varieties must be recognized: epithelial hyalin (colloid, keratohyalin), connective-tissue hyalin (hyaline degeneration of the ground-substance of connective-tissue, hyaline pro- ducts of cells, and cells which have become hyaline), blood-hyalin (hyaline thrombi), exudative hyalin (hyaline coagula of exudates on mucous membranes, serous sur- faces, inflamed connective tissue, in the urinary tubules, tubercles, etc.), and hyaline tissue-necroses. In the case of connective-tissue hyalin a distinction must be made between the hyalin formed as a secretion in the cells (closely related to epithelial colloid, in its mode of origin), and hyaline degeneration of the ground- substance of connective, tissue. XIII. Petrifaction of Tissues and the Formation of Concretions and Calculi. § 66. It is of rather frequent occurrence for firm crystalline or amor- phous masses to be deposited in various parts of the body; and when the deposits are of such extent as to cause hardening of the affected tissue, the resulting condition is known as petrifaction, or when the deposit con- sists of lime-salts (particularly carbonates and phosphates) as calcifica- tion.. The deposit may occur, in the first place, in a tissue which forms an integral element of an organ,' and which bears its normal relation to the surrounding tissues. In other cases it takes place in portions of tissue which have been loosened from their surroundings ; or in insoluble sub- FiG. 78.— Calcification of fte media of the femoral artery. (Silver preparation.) a, Intima; b, media; c, adventitia. x 40. Stances which have become changed into a firm state; or, finally, in foreign bodies which have entered the body from without, and form the centres of a process of incrustation. In the first case there arise petrifactions of the tissues; in the sec- ond, free concretions and calculi. It is to be noted, however that un- der certain conditions free concretions may become firmly attached to the tissues of the organ in which they lie, by means of tissue-prolifera- tions extending into or surrounding them. On the other hand a calci- TISSUE PETRIFACTION. 175 fied portion of tissue may in the course of time gradually become loosened from its surroundings and ultimately form a free concretion. Deposit of lime salts occurs in the form of fine colorless gran- ules (Fig. 71^ which when treated with silver (von Kossa) take on a black color (formation of silver phosphate) (see Figs. 78, h, 80, and 81, B, b). When closely crowded they become confluent, and give rise to chalky foci (Fig. 78, b) that are usually not sharply circumscribed; they Fig. 7g. — Calcified vessels in the cerebellum. (Alcohol, hEematoxylin.) x lOo. may form also circumscribed spherical concretions (Fig. 79). In the blood-vessels calcification may begin either in the connective tissue, muscle-fibres, or in the elastic tissue. The cause of petrifaction is to be found in local tissue-changes, in that the deposit of lime-salts occurs in places where the tissue has al- ready died or is in process of degeneration. For example, lime salts may be deposited in pulmonary infarcts (Fig. 80), in thrombi, in ne- Fig. 8o. — Calcification of a necrotic lung in the periphery of a hemorrhagic infarct six weeks old. (Formalin, silver treatment.) x loo. erotic foci arising during the course of inflammations, in dead cells, particularly renal epithelium (Fig. 82, d, e), and liver-cells (von Kossa) that have been killed as the result of intoxications (mercuric chloride, lead, aloin, bismuth, copper salts, iodine, and iodoform). A frequent antecedent to the deposit of lime-salts is hyaline degeneration of con- nective tissue, often associated with a deposit of fat. This occurs in the thickened intima of the blood-vessels and heart-valves, in the media of the medium-sized arteries, particularly in the extremities, in inflamma- tory new-formations of connective tissue (for example, in the serous 176 THE RETROGRADE CHANGES. membranes), in the connective tissue of the kidney pyramids of old people (Fig. 81, A, B), and in degenerated thyroid glands. In dying adi- Fig. 8i. — Hyaline degeneration and calcification of the connective tissue of the kidney papillae. A, Stained with hematoxylin and eosin. B, Treated with silver nitrate, a. Collecting tubules; b, blood-vessel; c, connective tissue showing hyaline degeneration and calciiica.ion. x 300. pose tissue (fat necrosis in the neighborhood of the pancreas) chalky soap may be formed. The hyaline character of the degenerated connective tissue shows well both in staining with Van Gieson's and with simple hsematoxylin. With the latter stain the calcified connective tissue becomes a diffuse dark blue color (Fig. 81, A, c). The same staining reaction occurs in calcified necrotic cells (Fig. 82, d, e). This reaction holds good only for the de- posit of carbonates and phosphates, but not for the oxalates of lime. In rare cases there may occur a deposit of lime-salts in organs which show but slight changes — for ex- ample, in the lungs. Since in such cases there is destruction of bone — osteomalacia, caries, tumors, etc. — this deposit is regarded as metastatic in nature, due to the over-loading of the blood with lime salts. Even under these circumstances the im- mediate cause of the calcification is local, and is dependent on retro- gressive changes; the increased ab- sorption of bony structures is but a favoring factor. According to in- vestigations of Kockel and Kischensky the elastic lamellae of the small and medium-sized vessels in particular be- come calcified, but the elastic fibres and capillaries of the pulmonary interalveolar septa are also involved. Fig. 82. — Calcification of the epitllelium of the kidney-tubules following sublimate poisoning. (Alcohol, hematoxylin.) Patient died seven days after the poisoning, a. Normal tubules; b, tubule with desquamated epithelium; _c, tubule with de-quamated and necrotic epithelium possessing no nuclei; d, e. tubule with degenerated and calcified epithelium, x 300. CALCIFICATION. 177 The calcification may affect either small or large areas, and in the latter case causes hardening and white coloration of the tissues. Oc- casionally it appears in the form of sharply circumscribed spherical, or nodular (Figs. 83 and 84, a, b, c), or long spicule- (Fig. 84, d), or cactus-like formations, and there arise in consequence concretions in the tissue that occasionally may be recognized with the naked eye. Under physiological conditions such concretions are found in the form Fig. 83. Fig. 84. Fig. 83. — Calcareous concretions, o. Concretions from an inflamed omentum; b, calcareous masses from a tuberculous lymph-gland which had undergone caseation, x 200. Fig. 84. — Section from a psammoma of the dura mater, with concretions. (Alcohol, picric acid, hematoxylin, eosin.) _ a. Hyaline nucleated rpherule with enclosed calcareous granule; 6, calcareous concretion with hyaline non-nucleated capsule, embedded in fibrous connective tissue; c, calcareous concretion surrounded by hyaline connective tis'"ue: d, calcareous spicule in connective tissue; e, calcareous spicule containing three separate concretions, embedded in tlie connective tissue. X 175. of laminated chalky spherules in the pineal gland and choroid plexus, forming the so-called brain-sand (acervulus cerebri). As pathological formations they occur in different regions, in tumors of the meninges known as psammomata, in caseous masses or in indurated connective tissue (Fig. 83, a). The origin of these formations may best be studied in the psammomata and is to be referred to transformation of tissue cells (Fig. 84, a, b, c), or of fibrous connective tissue (d) into a hyaline mass tb.at at first may contain nuclei (a), and later loses them (b, e), and takes up lime-salts. Spherical concretions arise chiefly from hyaline masses formed from cells (a, b, c) ; spicules (d) arise through the calcification of hyaline connective tissue, but spherical concretions (e) may also arise in hyaline connective tissue. Formation of bone or ossification may follow the calcification of a tissue, either as the result of new tissue-formation, or of metaplastic development of osseous tissue. This has been observed in the media of calcified blood-vessels of the extremities and in the aorta, but may occur also in calcified lymph-nodes, in the neighborhood of calcified necrotic areas in the lungs, and in thickened serous membranes, etc. One of the most striking examples of the latter form of involvement is complete calcification and ossification of the tunica vaginalis testis. According to the investigations of Gierke, calcifying tissues (foetal bones, the enamel of the dentine, sand bodies of the choroid plexus, placental calcifications, 12 178 THE RETROGRADE CHANGES. calcified ganglion-cells) contain more or less iron, and there occur also iron-con- taining cell-necroses (epithelial casts in sublimaite poisoning) which stain like calcified tissue, but are not calcified. In other cases (fully developed bone in ex- trauterine life, calcified thrombi and calcified vessels) iron is not present. Klotz {Jour, of Exper. Med., 1905, 1906) suggests that the formation of cal- cium soaps is the first step in the formation of pathological masses of calcification, these soaps later undergoing transformation into the less soluble phosphate and carbonate. Wells {Jour, of Exper. Med., 1905) found but minute traces of calcium soaps in calcifying 'matter. It is therefore, probable that calcium-soap formation may be an important step in the process of pathological calcification, but is not an essential one. The especial affinity of calcium for cartilage, hyaline connective tissue, etc., cannot at present be explained. Literature. {Calcification of Tissues, and Formation of Concretions in the Tissues.) Buerger & Oppenheimer: Bone Formation in Sclerotic Arteries. Jour. Exp. Med'., 1908. Ernst: Ueber Psammome. Beitr. v. Ziegler, xi., 1892. Kaufmann: Die Sublimatintoxication, Berlin, 1888; Virch. Arch., 117 Bd., 1889. Kischensky: Kalkablagerungen in Lunge und Magen. C. f.a. P., xii., 1901. V. Kossa: Kiinstlich erzeugbare Verkalkungen. Beitr. v. Ziegler, xxix., 1901. Mallory: Calcareous Concretions in the Brain. Journ. of Path., ii., 1894. Virchow: Kalkmetastasen. Virch. Arch., 8 u.'9 Bd. For an excellent resume of Calcification and Ossification, see Gideon Wells, Arch, of Int. Medicine, 1911. § 67. The more common petrifactions consist of deposits of phos- phate of lime, sometimes of carbonate; with these magnesium salts may be mixed. Under special conditions there occur deposits of uric-acid salts; particularly in the disease known as gout, which is a disturbance of general nutrition characterized by the deposit of uric acid in the tissues. Gout is usually inherited, rarely acquired; it occurs frequently in certain regions, for example, in England and in North Germany; and is rare in other countries, as South Germany. Of the cause of the disease we have no positive knowledge. It is characterized by the deposit of uric-acid salts, chiefly sodium urate, with which small quantities of carbonate and phosphate of lime are sometimes associated. The deposit of these salts usually takes place during acute paroxysms characterized by pain and inflammation, but departures from a typical course may occur. The deposits are found in the kidneys, skin, subcutaneous tissue, tendon sheaths, tendons, ligaments, bursse, and articular cartilages, but. may finally involve almost all the organs. The metatarsophalangeal joint of the great toe is the favorite site of deposit, and often the first part affected. The deposits consist of clusters of slender needles (Fig. 85), in whose neighborhood the tissues are degenerate or necrotic ; from this it may be assumed that the urates entering the tissues in solution give rise to necrotic changes in the latter. The areas of necrosis and incrustation are at first of small size, but occasion inflammation and tissue-proliferation in their neighborhood. GOUT. 179 Fig. 85. — ^Deposits of needle-shaped crystals of sodium urate m the articular cartilage. (.After Lancereaux.) x 180. With the occurrence of other paroxysms the deposits become larger, so that nodules (the so-called tophi) are formed. These consist of white, plaster-like masses, and may form marked thickenings in the joints and tendons (Fig. 86). In the joints th'e articular cartilages appear as if sprinkled with plaster-of-Paris, but later the white masses may permeate the entire articular cartilage. In the kidneys necrosis and inflam- mation may lead to contraction and induration of the organ. The deposit affects chiefly the medullary pyramids, but is also found in the cortex. According to Garrod and Ebstein the acute paroxysms m gout depend on excessive accumulation of uric acid, either as the result of deficient excretion by the kidneys (Garrod) or of local changes (Ebstein). Accord- ing to PfeiflFer the gouty pre- disposition is due to the fact that the uric acid in the body- fluids is produced in a form which is soluble with diffi- culty, and is deposited in the tissues in such quantity as to cause localized necrosis. The symptoms of the gouty paroxysm ar-e supposed to depend on increased alkalinity of the body-fluids and as a re- sult there follows partial solution of the deposited uric acid, in the course of which pain and inflammation are produced. On the other hand, von Noorden regards the formation and deposit of uric acid as a secondary process, due to the local ac- tion of a special ferment, and quite independent of the amount and condition of the uric acid in other parts of the body. § 68. Free concretions are formed in various ducts „, ,, , j . n, i. ^ , . , r J Fig. 86. — Gouty nodes of the hand. and cavities which are linea Lancereaux.) (After 180 THE RETROGRADE CHANGES. Fig. 87.- •Faceted stones from the gall-bladder. Natural size. by epithelium, as in the intestines or in the ducts of glands pouring their secretions into the intestine, in the gall-bladder, urinary passages, and respiratory tract. The concretions formed in the blood-vessels and serous cavities might also be included in this group, although they are for the greater part united to the surrounding tissues. All free concretions possess an organic base or nucleus. Thus enteroliths which form in the in- testines have a nucleus of in- spissated faeces, or foreign bodies which have been swallowed, such as hairs {hezoar stones or agagropilce) , or indigestible por- tions of vegetable food, etc., in and about which phosphates (am- monium-magnesium and calcium phosphate), and carbonates are deposited. In the mouth in- crustations of the teeth, known as dental calculi or tartar, are formed by the deposit of lime-salts in masses of mucus, cell-detritus, and bacteria. In the same' way there are formed in the ducts of the salivary glands and pancreas oval or spherical faceted, or irregularly nodular concretions, through the calcareous impregnation of substances derived from the epithelium of the gland. Bronchial calculi are formed by the calcification of thickened secretion ; the stones found in veins and arteries (phleboliths and arterioliths) from the calci- fication of thrombi ; prostatic calculi through the calcifica- tion of the so-called amyloid concretions ; navel stones through the incrustation of desquamated epithelium, hairs, and other substances which enter the navel-de- pression. The biliary calculi or gall-stones found in the bile passages and gall-bladder are small granules, or larger spherical, oval, or faceted stones (Fig. 87), which on fracture appear to consist purely of crystalline masses. By proper methods it may be shown that these stones also possess a nitrogenous ground-substance. According to their composition gall-stones may be classed as choles- terin, cholesterin-pigment, bilirubin, biliverdin-calcium, and calcium carbonate stones. The first two varieties are the most common; they Fig. 88.- -Section through a small cholesterin stone after removal of the cholesterin. x 13. CALCULI. 181 present a rayed, crystalline, often laminated fracture ; and vary in color and mottling according to the amount of bile-pigment present. When no pigment is present they may be colorless and translucent. If the cholesterin be dissolved out of a stone, it will be found that Fig. 89. — (Bellevue Hospital.) Stones in left kidney; secondary distention and tortuosity of both ureters; gangrenous cystitis. the form of the stone is preserved, and a delicate yellowish mass remains. This, when cut into sections, is found to consist of a homogeneous substance (Fig. 88) with concentric stratification and radiating clefts or spaces which were formerly occupied by the crystal- 182 THE RETROGRADE CHANGES. line masses. A similar ground-substance may be demonstrated m other calculi after solution of their calcium salts. , , . , ,. , The majority of all gall-stones are the result of the mcrustation of an organic substratum, derived from the mucous membrane of the bihary passages and the gall-bladder, following injury produced by mfections, most commonly the typhoid and colon bacilli. Thus gall-stones may be brought about experimentally by injecting typhoid baciUi into the blood stream after mechanical injury of the mucosa of the gall-bladder, and living bacilli may be demonstrated in gall-stones long after the sub- sidence of typhoid fever. Inflammation of the bile-passages (angiocho- litis) leads to desquamation and destruction of the epithelium, and in the products derived from these changes bilirubin and cholestenn are deposited. When once_ a concretion is formed it in- creases in size through new products of cell-disintegra- tion which become en- crusted with cholesterin, pigment, and calcium. Ac- cording to Naunyn the original nucleus of the con- cretion undergoes a change, in that it separates into fluid, and into firm, gran- ular masses of pigment, calcium, and crystals of ■cholesterin which are de- posited on the outer crust, so that the stone contains a cavity filled with fluid. In the course of time this fluid may be replaced by cholesterin, as may the pig- ment and calcium in the re- maining portions of the stone. In addition calcium carbonate may be deposited. The cholesterin masses from which the concretions are formed are derived from the disintegration of epithelial cells; likewise, the lime- salts combining with bilirubin are furnished by the mucous membrane. The urinary calculi, gravel, and stones are also composed of an organic ground-substance in which various constituents of the urine be- come deposited. According to location we may distinguish calculi of the l.:, B product of cell-activity, and is >: ,-i-':^- formed from albuminous bodies. The different forms , Fi«- es— ^. and b, Pigmented ceils of the skin . . 1-1 from a case of Addison s disease with caseous tuber- of melanin, m which group culosls of both adrenals. (Alcohol, carmine.) a, +V10 i^irrrvi^^Tif c- n -p fln*^ ct-in nnA Pigmented epithelium cells from the deepest layer, ine pigments 01 rne SKin ana ;^ ^ section cut at right angles to the surface. choroid are placed are ac- ^' ^' Pigmented epithelial cells from a section made J. ^ jT . ' ,. ' . parallel to the surface. B, b. Epithelial cells con- COrdmg to the investigations talning no pigment; c. ci, nucleated pigmented con- rvf vnn Ni^nrti '^ipbpr Ahpl nective-tissue cells, the processes of which, in B, 01 von INenCKl, aieuer, /\Dei, p^^,, between the epithelial cells; d, pigmented cell- Davids, and Schmiedeberg, processes, x 350. nitrogenous bodies rich in sulphur, but vary greatly in composition. According to Schmiedeberg the differences in the several melanins depend on their mode of origin, inasmuch as these pigments represent the final product of a long series of metamorphoses of albumin. The albuminous bodies do not furnish the material for the building up of the final product (Schmiedeberg), but it is derived from sulphur-containing bodies formed by the cleavage of albumins, and from which certain carbon-containing groups have already been split off, so that there arise combinations which in propor- tion to their carbon-content are rich in sulphur ; from these the melanins are formed. Iron may be present in small amounts in melanotic pigment, but is usually absent and is not necessary to the production of melanin. In the case of abundant formation, melanin may be excreted in the urine. Lipochrome is the term applied to the coloring-matter of adipose tissue, corpora lutea, ganglion-cells (Rosin), of the greenish tumors known as chloromata (Krukenberg), and of the muscle cells of the heart in brown atrophy. It is greatly increased in the subcutaneous fatty tissues in pernicious anemia, giving a lemon-yellow color to the skin. Of the origin and nature of this pigment nothing definite is known. AUTOCHTHONOUS PIGMENTS. 187 Haemofuscin (von Recklinghausen, Goebel) is the iron-free, yel- lowish granular pigment' found in smooth muscle of stomach and in- testine. According to von Recklinghausen, this pigment is derived from the blood, but it has not been established that it is a haemoglobin-deriva- tive. The sulphur-content (Rosenfeld) makes it not unlikely that the hsemofuscin granules belong to the melanin group. It is a striking fact that when treated with " fat-stains " the hsemofuscin-granules are found to be fat-containing just as lipochrome stains as fat (Lubarsch). According to von Kblliker, " the pigment of the hair and epidermis is derived from pigmented connective-tissue cells which lie just beneath the deepest layers of the epithelium of the hair-bulbs and of the rete, and send processes between the delicate cells of these layers. These processes divide into long fine ramifications which lie in the intercellular spaces and may even penetrate into the cells them- selves, and in this way transfer their pigment to the latter." The pigment of the ganglion cells and of the cells of the retina arises, on the other hand, in the ecto- dermal cells themselves. Riehl and Ehrmann agree with von Kolliker. Karg ob- served that, following the transplantation of white skin on the surface of a leg- ulcer in a negro, the grafted portions became black in from twelve to fourteen weeks ; and he concludes that, in the pigmentation of the epidermis, pigmented con- nective-tissue cells penetrate between the epithelial cells and convey pigment to the latter. Microscopic examination showed the presence of pigmented processes be- tween the epithelial cells at a time when the latter had not yet became pigmented. Von Wild has shown that in melanosarcomata of the skin, pigmented connective- tissue cells may penetrate between the epithelial cells. Similar connective-tissue cells are found in the pigmented portions of the skin or mucous membranes in Addison's disease, usually, however, in certain areas only and not everywhere. According to von Fiirth, neither sulphur nor iron is necessary to the formation of melanin. The melanin-molecule contains, however, active atom-groups which enable it to combine with certain complexes rich in sulphur and iron. The investi- gations of Bertrand, Biedermann, Schneider, von Fiirth, Gessard, and others make it probable {von Fiirth) that the formation of melanotic pigment depends on the action of an oxidative ferment (tyrosinase), upon tyrosin or other hydroxylized substances of an aromatic nature. Iti the abundant formation of melanin in tumors, melanin or melanogen may be excreted in the urine, so that this at the time of dis- charge is black or gradually becomes black when expesed to the air and light. According to Spiegler, the results of chemical investigation exclude the deri- vation of melanin from haematin. He also demonstrated the existence of a white chromogen which is the cause of white wool in sheep and of gray hairs. In domesticated animals there occurs a peculiar melanosis of the inter- nal organs, occasionally associated with melanosis of the subcutaneous tissue. The affected organs (heart, lungs, intestines, etc.) present in varying numbers grayish or black spots, looking like ink-spots, which are produced by the deposit of pigment in connective-tissue cells which otherwise appear normal. Under the title of ochronosis, Virchow described a, condition characterized by the deposition of brownish, blackish, or bluish black iron-free pigment, particu- larly in the cartilaginous structures of the body, but also in tendons, joint capsules, periosteum, and certain internal organs. The pigment stands in close relationship to melanin. Clinically, the pigmentation is most frequently noted in the cartilages of the external ear and of the nose, and in the sclerae and skin. Pathologically, the costal cartilages, the intervertebral discs, the articular surfaces of the large joints and the rings of the trachea are almost constantly pigmented. The epiglottis and laryngeal cartilages are usually less often and less deeply colored. The ligaments and tendons are involved in a considerable percentage of cases. Of the internal organs, the intima of the heart or the aorta is the most frequently pigmented. In cartilage, the deposition of the pigment takes place in the matrix, the capsule and crlls being spared or only slightly affected, unless the cells themselves have been injured, and then pigment is apt to be deposited in large quantities. In a consider- able proportion of cases, ochronosis is attended by destructive lesions in the larger joints,- sometimes giving rise to symptoms comparable to those of arthritis defor- mans. In many instances ochronosis has been shown to follow the long continued application of dilute solutions of carbolic acid to chronic leg ulcers and the like (Poulsen: Ziegler's Beitr., 1910). The urine is characterized by the presence of 188 THE RETROGRADE CHANGES. homogentisic acid (alkapton) which is a substance derived chemically from the destruction of proteins, particularly tyrosin and phenylalanine. Whether the long continued .use of carbolic acid so influences protein metabolism as to cause the formation of homogentisic acid in the tissues and its liberation through the urine, has not been determined. Gross and AUard (Arch. f. exp. Path. u. Pharm., 1908) were unable to extract homogentisic acid from cartilage, but by placing pieces of fresh cartilage in dilute solutions for a period of from three to six weeks, they found the characteristic color changes of ochronosis. Literature. (Autochthonous Pigments.) Abel: Bemerk. iiber thier. Melanine u. das Hamosiderin. Virch. Arch., 120 Bd., 1890. von Fiirth: Phys. u. chem. Unters. iib. melanot. Pigment. C. f. a. P., xv., 1904 (Lit.). Goebel: Pigmentablagerung in der Darmmuskulatur. Virch. Ardh., 136 Bd., 1894. Krukenberg: Grundziige der vergl. Physiol, der Farbstoffe u. d. Farben, Heidel- berg, 1887. V. Nencki u. Sieber: Weitere Beitr. z. Kenntniss d. thier. Melanins. lb., xxiv.. V. Recklinghausen: Hamochromatose. Tagebl. d. Naturforschervers., Heidel- berg, 1889. For a complete review of the subject see Sprunt, Arch, of Int. Med, 1911. Rosenfeld: Das Pigment der Hamochromatose des Darms. Arch. f. exp. Path., 48 Bd., 1900. Rosin: Bau der Ganglienzellen. Deutsc'h. med. Woch., 1896. Schmiedeberg: Ueber die Elementarformeln einiger Eiweisskorper und iiber die Zusammensetzung u. d. Natur d. Melanine. Arch. f. exp. Path., 39 Bd., 1897. St>iegler: Ueber das Haarpigment. Beitr. z. chem. Phys., iv., 1903. § 70. Haematogeno.us pigments are those whose origin from the coloring-mailer of the blood may he demonstrated beyond doubt. Such pigmentations are known aS haemochromatoses. Extravasates of blood soon undergo changes wliich are visible to the naked eye. Extrava- sates in the skin become brown, then blue, green, and finally yellow. SmaU ' t W i / haemorrhages into the tis ^ ' § W }/ sues, as in the peritoneum, ,-v, . ^«' >% /n / pleura, and lungs, may ^i n\ /y< ^ show for a long time as i-^'*t p/'''\ ' ^ y^*^^ reddish-brown spots ; in de- *■»* ' -WjI^ •'^ ^"^^^^^ composing cadavers their '^- '■' color may be slate or black. Large haemorrhages, as in Fig. 96. — /4, Cells containing amorphous blood-pipment; o, thf> brntn n.r Inno-c ^conmp those with few large fragments of red blood-cells; b c, ^ "ram Or lUUgS, aSSUmC those containing great numbers of small disintegration- after a time a TUSt-brOWn products of red blood-cells; Bj rhombic plates and needles i , . - - - of hsematoidin. X 500. color, which later changcs to ochre-yellow, yellow, yellowish-brown, or brown. All these variations of color correspond to changes in the haemoglobin and in the iron which it contains. Whenever haemorrhage occurs in the tissues or into a cavity, a portion of the plasma and of the red cells may be taken up unchanged through the lymph-vessels. Another portion of the corpuscles loses its HEMATOGENOUS PIGMENTS. 189 haemoglobin, the pale stroma of the cells remaining. The escaped hwmo- glohin diffuses through the tissues, and from it are formed the different products which give rise to the changes of color in the neighborhood of the extravasate. A part of the absorbed haemoglobin may be excreted as urobilin {urobilinuria) ; another part may be precipitated in the tissues in the form of granules or crystals. The latter are yellowish-red or ruby-red rhombic plates and needles of hcematoidin (Fig. 96, B) ; and represent a frequent residuum of haemorrhages. A portion of the diffused haemoglobin may also be taken up by cells, the latter acquiring a diffuse yellowish pigmentation, or showing the presence of yellow and brown granules. A third portion of the blood-corpuscles disintegrates at the site of the extravasation, and forms yellow and brozvn granules and lumps. The pigment which arises directly from the disintegration of red cor- • • • Fig. gy. — Cells containing haamosiderin and hsematoidin from an old hemorrhagic focus in the brain. (Alcohol, Berlin-blue reaction.) a Cells containing haemosiderin ; b, cells containing hzematoidin; c, fat-granule cells which have become clear; d, newly formed connective tissue. X 300. puscles, as well as the crystals and granules precipitated from dissolved haemoglobin, are often taken up by cells, partly leucocytes and partly cells derived from proliferating tissue (Figs 96, A, and 97, a, b). At the beginning of the disintegration of red corpuscles the coloring- matter present is haemoglobin, but the yellow and rusty masses and granules which are found both in the cells and lying free, and which eventually become changed, into darker pigment, are no longer haemo- globin itself, but derivatives of haemoglobin. According to their com- position these may be divided into two groups, one iron-free, the other containing iron. The former is known as hcematoidin, the latter as hcemosiderin. /- t,\ Haematoidin (identical with bilirubin) is a ruby-red (Fig. 96, B) or reddish-yellow (Fig. 97, b) pigment occurring in crystalline form, or as granules, which may be amorphous, but often show a somewhat angular shape (Fig. 97, b), suggesting imperfect crystals. Haematoidin is soluble in chloroform, carbon disulphide, and ether; insoluble in water and alcohol. It appears to be formed when haemoglobin is but slightly exposed to the action of living cells, as in the centre of large extrava- sates and in hemorrhages into the body-cavities, for example, into the pelvis of the kidneys or the subdural space. It may be produced artificially by the introduction beneath the skin or into the peritoneal 190 THE RETROGRADE CHANGES. cavity of capsules containing blood, so that the blood in the capsules is exposed to the action of tissue-fluids but not of cells. The granules and crystals of haematoidin are found in the tissues free (Fig. 96, B), or enclosed in cells (Fig. 97, h). In the latter case they are taken up after they have been precipitated; occasionally it may happen that hsematoidin in solution is taken up by fixed connective-tissue cells, for example, cartilage or fat-cells, and then precipitated m solid form. , ,, , . , Haemosiderin, the derivative of the red blood-cells which contains ■iron in demonstrable quantity microscopically, is found in the tissues as yellow, orange, and brown granules and lumps which become darker m the course of time. They are for the greater part contained in cells, and in part are formed within the cells. When treated with potassium ferrocyanide and dilute hydrochloric acid haemosiderin be- comes deep-blue through the formation of Berlin blue (ferric oxide salt of hydro- ferrocyanic acid) (Fig. 97, a). When treated with ammonium sul- phide there is formed a black sulphide of iron. Haemosiderin appears to be formed particu- larly when the blood in an extravasate or in a thrombus is subjected to the action of living cells ; consequently it is seen more frequently in small extravasates and at the periphery of large ones. The formation of haemosiderin may take place either in the cells or free in the tissue. The pigment enclosed in cells (sideroferous cells) may have been formed from disintegrated red cor- puscles, or from dissolved haemoglobin which has been absorbed by the cells. In favor of the latter mode of formation is the diffuse yellow color seen in both wandering and fixed cells, which becomes blue when the Berlin-blue reaction is applied. Further, when haemoglobin is excreted through the kidneys, iron-containing pigment-granules form in the renal epithelium; and moreover fixed cells, as cartilage-cells, which could hardly be supposed to act as phagocytes and take up fragments of red cells, often contain granules of haemosiderin, even when lying outside the immediate neighborhood of the extravasate. The free pigment and pigmented cells cause distinct pigmentation of the extravasate and its neighborhood. The pigmented cells pass into the lymph-vessels and metastasis of pigment takes place, as a result of which pigment is found in the lymph-vessels and in the lymph-nodes, (Fig. 98). Later it may be taken up by the fixed tissue-cells. In time the haemosiderin is destroyed and disappears. The view that haemosiderin is changed into melanin, is not supported by facts. The brownish-black granules in the lungs, which have been explained as due to such a change, Fig. 98. — Accumulation of pigment-containing cells in the lymph-nodes after resorption of an extravasate of blood. (Miiller's fluid, carmine.) a, Cortical node; b, lymph-sinus; r, cells containing pigment-granules. X loo. HyEMATOGENOUS PIGMENTS. 191 consist of one or several minute particles of carbon surrounded by a coat- ing of hsemosiderin. If hsemosiderin is brought into contact with hydrogen sulphide it be- comes black; and as the result of such reaction there may be produced in the cadaver black and green spots or a more diffuse discoloration, known as pseudomelanosis. It is observed most often in the in- testine, peritoneum, and in suppurating wounds, since in these regions hydrogen sulphide is more likely to be formed by putrefaction. Zlegler uses the term hsemochromatosis in its strict sense, namely, to indicate a condition in which the associated pigments are derived from hemoglobin. The term hsemochromatosis, however, is widely, if somewhat loosely, employed to designate a condition which many regard as a distinct morbid entity and which is characterized by the deposition not only of an iron-containing pigment, but of one which is free from iron. Neither pigment is traceable to h;emoglobin. More- over, the condition is attended by increase in the pigmentation of those tissues which normally contain pigment. Hsemochromatosis is probably best interpreted as a metabolic process implicating different tissues, and characterized by the deposition in them of pigments formed as a result of disturbances in the chrorao- genic structures of the proteid molecule. According to this view, the iron-con- taining pigment in hsemochromatosis, hemosiderin, is derived from iron-containing proteids native to the pigmented tissues ; certainly there is no dissemination of pigment by metastasis. The non-iron-containing pigment in hjemochromatosis is hasmofucsin. In the majority of all cases of hsemochromatosis, the skin presents a diffuse bronze discoloration and diabetes is present (diabete bronze of the French). The cause of the diabetes is unknown. While in most cases the pan- creas is pigmented, the islands of Langerhans are unchanged, so that the diabetes cannot be ascribed to anatomical changes in these structures. In most cases of hsemochromatosis the liver is cirrhotic. Hsemochromatosis is not common. It occurs oftenest in males. Of sixty-three cases collected by Sprunt (Arch. Int. Med., 1911) only one was in a female. In Bellevue Hospital, eight cases were observed among 6,000 autopsies. Two of these were associated with cirrhosis and primary carci- noma of the liver, and still another with rnyelomatosis. Hsemochromatosis as an attendant phenomenon in cirrhosis of the liver with primary carcinoma is exceed- ingly rare, but has also been observed by Runte (Inaug. 'Disser. Wurzburg, 1901) and by Loehlein (Ziegler's Beitr., 1907) and Wintcrnitz (Virch. Archiv., 1913). In hsemochromatosis the organs iijiost frequently involved are the liver, pancreas, spleen, lymph nodes and heart muscle. In this connection it is interesting to recall that Kretz, in twenty-six cases of atrophic cirrhosis of the liver, was able to demonstrate iron-containing pigment in fourteen, the remaining organs being free from pigment. At Bellevue Hospital we have been able to confirm this observation in a number of instances. § 71. When large numbers of red blood-cells break down in the circulating blood, dissolved haemoglobin or methsemoglobin may pass into the plasma, and fragments of red cells may be carried in the circu- lation. Such destruction of red cells occurs to a marked degree in poison- ing with arsenic, toluylendiamin, potassium chlorate, and morels; to a lesser degree in other conditions, such as infections, malaria, in pernicious anasmia, and in overheating of the body. The passage of hsemoglobin or methaemoglobin into the blood-plasma leads to the condition of hamo- globinccmia ; the plasma is colored red. When the amount of dissolved hsemoglobin in the blood is large, a portion may be excreted through the kidneys, giving rise to hamoglohinnria or methamoglohlnuria , in which conditions the urine may present a bloody appearance, or vary from clear brownish-red to dark reddish-black. This occurs particularly in the first-named poisons, but occasionally after the action of other injurious influences, for example, exposure to cold (periodical hsemoglobinuria). When formed products arise from the disintegration of red cells, such as corpuscular fragments after extensive burns, they collect in the 192 THE RETROGRADE CHANGES. 'v 4 ^ capillaries of the liver, spleen, lymph-nodes, and bone-marrow, anjl to a less extent in other organs ; and are sooner or later taken up by phago- cytic cells. As the result of increased supply of hserhoglobin to the liver the functional activity of this organ ifeh^ ^.«=. is increased, so that the amount f*^ / of pigment in the bile may be greater than normal; under cer- tain conditions oxyhsemoglobin may appear in the bile (Stern). When the blood-destruction is great, the liver may not be able to dispose of all the pigment brought to it; and in conse- quence derivatives of haemo- globin are deposited in the liver and other organs, or ex- creted by the kidneys. In the former event there may arise more or less extensive hasmo- chromatosis of different organs, the cells of which The derivatives of haemoglobin deposited in this way are partly iron free pigments and partly hcemosiderin. Fig. 99. — Infiltration of the cells of the liver-rods "with yellow hemosiderin granules, from a case of pernicious anEcmia. (Ocmic acid.) a, Hasmosiderin; bf cells in a state of fatty degeneration, x 250. show an ochre-yellow or brown color. Fig. 100. — ^Hsemochromatosis of the liver CAlrnhnl na-rminp "^ « a«;«:. i. The deposits of iron-containing pigment in the liver appear in the form of yellow granules and lumps, which are enclosed in leucocytes HEMATOGENOUS PIGMENTS. 193 lying in the capillaries. The deposits are found also in the form of granules in the endothelial cells of the capillaries (to which the stellate cells of Kupffer belong), and in the liver-cells (Fig. 99, a). In many diseases, for example, pernicious anaemia, the cells contain so much iron pigment that the liver takes on a characteristic yellowish-brown color. The iron-pigment which is carried to the spleen is deposited chiefly in the free cells of the pulp; but granules are also found in the fixed cells. In the lymph-nodes the iron granules are found in the free cells ■W Fig. ioi, — Haemosiderin deposit in the bone-marrow (mixed fatty and lymphoid marrow) in icterus. (Alcohol, carmine, Berlin-blue reaction.) x 300. ' of the lymph-channels. In the bone-marrow retained hsemosiderih (Fig. 101) is found in cells lying in the capillaries, and partly in the endo- thelium and marrow-cells; the number of iron-containing cells may be marked. In the kidneys the haemosiderin granules are most abundant in the epithelium of the convoluted tubules (Fig. 102, a), but are also found in the lumina of the tubules (b), in the epithelium of Bowman's capsule (e), and in the endothelium of the capillaries. In marked deposits the kiclney may show signs of pigmentation to the naked eye. The haemosiderin found in different tissues is brought to them in the form of small lumps or granules contained in leucoc3'^tes. On the other hand, another part is precipitated in the cells from substances brought to them in solution. Since the cells (liver-cells, kidney epi- thelium, endothelium of the blood-vessels, and the cells of the lymph- nodes, bone-marrow, and spleen) not infrequently show a diffuse blue color after the iron-test has been applied, the iron must be diffused through the cell-protoplasm, and converted later into granular form. It is also possible that the diffuse coloration may arise from solution of iron in the cells. According to the observations of different investigators, it appears that besides the colored deposits of pigment, colorless granules or an iron-albuminate may be present in the cells. This theory is sup- ported by the fact that more pigment granules are visible after the iron reaction has been applied, than could.be seen before. 13 194 THE RETROGRADE CHANGES The deposit of iron-free pigments, hcsmatoidin or bilirubin is not of frequent occurrence in hasmochromatosis, but occasionally yellow gran- ules which do not give the iron reaction are found in the organs named above; and it may, therefore, be assumed that the pigment in part may be constantly free from iron. By certain writers the mottled pigmentation of the skin which develops in chronic arsenic poisoning, and which is due to the deposit of small yellOwish-brown granules in the corium and epidermis is classed with the hasmochromatoses and is referred to the degenerative influence of arsenic on the bone-marrow and blood. a .V>i>..*-V. % -^ V- .0 •■ ■ ...n't fe ** » :'■ -pis- ios.-^Hffimatogenous deposits of iron in the kidney in pernicious malaria (contracted in Hagamayo;. (Alcohol, carmine, Berlin-blue reaction.) a. Convoluted tubules whose epithelial cells contain iron granules and are stained diffusely blue; b, iron-granules in the lumen of the tubules; c, straight tubules; d, glomerulus; e, epithelium of the capsule, containins iron- granules. X 150. ' s "" It should be noted, however, that the pigment does not give the iron reaction and moreover, that pigment in epithelium that is derived from h^m^oglobin is not per- manent; and that no increased destruction of red blood-cells occurs in habitues of arsenic (Muir). In malaria two pigments are formed as a result of the destruction of red cells by the parasite. One of these is formed by the malarial Plasmodium itself is contamed m the parasite, is black, and gives no iron reaction. Its nature is not known. The second pigment is hasmosiderin, which passes into the blood-plasma as the result of the destruction of red blood-cells, and is deposited in the liver spleen and bone-marrow. In marked destruction of blood there may occur side'rosis of the kidneys (Fig. 102), and excretion of iron in the urine. Froin, Nonne and others have described a condition attended by yellowish dis- coloration of the spmal fluid (xanthochromia) in which the protein content is increased to such an extent that, when the fluid is removed, it coagulates sponta- neously. The condition may be encountered in compression of the spinal cord and Its memngjes from any cause which leads to the formation of a cul-de-sac distal to the site of compression. In these circumstances, Hanes (Amer. Jour. Med. Sc.,^ 1916) is of the opinion that the yellowish color of the fluid is due to transudation of blood serum owing to interference with the circulation at the site of compression Pleocytosis may or may not be present, depending on whether the meninges are mflamed Xanthochromia of the spinal fluid is to be sharclv dis- tinguished from staining by haemoglobin derivatives (erythrochromia) which mav occur m a number of conditions attended by hemorrhage into the cerebro-spinal ICTERUS. 195 Literature. (Hcemochromatosis; Iron Absorption; Deposit and Excretion.) Biondi: Ablagerung von Hamosiderin bei Hamatolyse. Beitr. v. Zieeler, xviii.. 1893 (Lit.). Button: Iron in the Liver and Spleen in Malaria. Jour, of Path., v., 1898. Futcher: Haemochromatosis with Diabetes Mellitus. Am. J. of the Med. Sc, 1907. Hunter: Action of Toluylendiamin. Journ. of Path., iii., 189S. Muir: Arsenical Poisoning. J. of Path., vii., 1901. Opie: Hsemochromatosis. Journ. of Exp. Med., iv., 1899. For an admirable review of this subject see Sprunt, Arch, of Int. Med., 1911. § 72. Icterus or jaundice is a pathological discoloration of tissues due to bile-pigment. It is a symptom wfhich occurs in numerous dis- eases of the liver, and is often encountered as a fugitive process in the first few days of life (icterus neonatorum) . The pigment which characterizes icterus is apparent during life in the skin, conjunctiva, and urine; in the cadaver the internal organs — serous membranes, lungs, kidneys, liver, subcutaneous and intermuscular tissues, blood-plasma, clots in vessels, etc. — may show icteric coloration. In recent cases the icteric color is yellow ; in long-standing cases the skin takes on an olive-green or dirty grayish-green color, while similar color- ations occur in the internal organs, particularly in the liver, and often in the kidneys. Icterus results from the entrance of bile-pigment (bilirubin) into the blood and fluids of the body. The urine excreted contains elements of bile, particularly the pigments. As the result of disease in the biliary passages or liver the outflow of bile is hindered, and the bile is then taken into the lymphatics and blood-vessels of the liver. Such damming back of bile may be caused by narrowing or closure of the large bile-ducts through scar-tissue, through gall-stones wedged in the lumen, or tumors developing in the bile ducts or compressing them ; or through inflam- matory processes or tumors of the liver which compress or obliterate the smaller ducts, and in this way hinder the outflow of bile. In the case of stasis of bile in the liver-lobules the intercellular bile- capillaries become dilated and filled with bile-thrombi (Fig. 103, a, b). The dilatation also affects the blind side branches extending toward thq capillaries, and these may be broken through, so that the bile eventually gains entrance into the lymph-channels and blood. Further, the bile- pignient is heaped up in the liver-cells themselves (c), and the endo- thelium of the blood-capillaries (d, rfj, e) is stained. When bile-pigment obtains entrance to the blood, the tissues of the body become gradually permeated and acquire an icteric color. If phago- cytes containing granules of bilirubin are present in the circulating blood, they may accumulate here and there, particularly in the spleen and bone- marrow. After a time the bile-pignient held in solution in the tissue- lymph may become precipitated as solid particles, chiefly in granular form, but sometimes as crystals in the fixed and wandering cells of the connective tissue, in the liver-cells, and in the renal epithelium. The crystals are in the form of rhombic plates and needles, similar to those of hasmatoidin (Fig. 96). In severe cases of icterus many of the tissue- cells contain pigment, and, as a result of metastasis of cells containing pigment, accumulations of the latter in the lymph-nodes may occur. 196 THE RETROGRADE CHANGES. In kidneys in which bile-pigment is being excreted deposits of bilirubin occur, particularly in the epithelium of the urinary tubules (Fig. 104, a, d), which in consequence may become desquamated. If, as the result of damage to the secreting cells through the excretion of bile-pigment, there are formed, as usually is the case, hyaline casts — that is, hyaline coagula in the albumin-containing urine in the tubules — these likewise become colored (Fig. \OA,b, c). Associated with the bilirubin in icterus there is sometimes a deposit I '^^;«i5-v Fig. 103. — Obstructive icterus of the liver, due to compression of the ductus choledochus by a cancer of the gall-bladder. (Sublimate, alum-carmine.) o. Intra-acinous bile-capiUaries, moderately dilated and filled with bile; &, widely dilated intra-acinous bile-capillary, containing large mass of pigment; c, bile-pigment in the liver-cells d, di, endothelium stained with bile- pigment; Cj desquamated endothelium stained with bile-pigment; /, pigment mass surrounded by cells; g, rupture of the pigment contained in a bile-capillary into a blood-capillary, with bile- stained cells in the neighborhood, x 365. 0/ hcemosiaerin which may become so abundant in the bone-marrow (Fig. 101), spleen, and lymph-nodes, and occasionally in the liver, that discoloration of the organs named is dependent in part on iron-pigment. When increased destruction of red blood-cells takes place in the blood-vessels, hsematoidin or bilirubin, in addition to hsemosiderin, is formed in different parts of the body (see § 71) ; but the formation of bilirubin outside of the liver is slight and is not sufficient to cause ex- tensive icteric coloration of the tissue, so that, according to one view, pure hcematogenous jaundice does not occur. The liver is the great elaborator of bilirubin, and in cases of increased destruction of blood- cells the liver-function is increased and there is increased production and excretion of bile-pigment. Icterus due to increased destruction of blood- cells can occur only when there are present in the liver such changes as cause passage of bile into the blood. The questioti as to whether there is a hsematogenous as well as a hepatogenous variety of jaundice has long- been an object of discussion, and remains unsettled at the present time, in s.pite of numerous experimental investigations directed toward ICTERUS. 197 its solution. Since, as a matter of fact, bilirubin may be formed in different kinds of tissue from extravasated blood, the occurrence of hematogenous icterus would a priori appear probable. Experimental investigations as to the results of the destruction of red cells in the circulating blood, particularly through the action of arsenic, toluylendiamin, and potassium chlorate, have shown that the derivatives of blood-pigment which are formed in the tissues and there retained for a long time are essentially iron-containing pigments (hsmosiderin), while the production of bilirubin is practically confined to the liver, which for the time being secretes an increased amount of richly pigmented bile. According to the investigations of Minkowski and Naunyn, the urine of geese and ducks after removal of the liver contains no bile-pigment — a fact which would :*H9i I a,- ^1 Fig. 104- — Icterus of the kidney in obstructive Jaundice. (Sublimate, carmine.) a, Tubular epithelium containing yellowish-brown granules; b, large casts stained yellowish-green; c, cast containing pigmented cells; d, desquamented epithelium containing bile-pigment granules, x 200. indicate that the transforrnation of blood-pigment into bile-pigment is ordinarily confined to the liver. The inhalation of arseniuretted hydrogen for a few minutes is sufficient to produce in geese an intense polycholia and haematuria, the urine containing haemoglobin in solution, disintegrating red cells and biliverdin. If the liver from such a goose be removed, the biliverdin quickly disappears from the urine, and no trace of bile-pigment can be demonstrated in the blood. It is there- fore evident that in arsenic poisoning the formation of bile-pigment is confined to the liver, in which organ leucocytes enclosing iron-containing fragments of broken- down red cells are found to be. present. In so far as it is possible to judge from experimental investigations which have been made up to the present time, pure haematogenous jaundice does not appear to be improbable. The mere fact of the occurrence of jaundice after intoxications, inhalation of ether and chloroform, transfusion of blood, snake-bite, septicemia, typhoid fever, yellow fever, paroxysmal haemoglobinuria, etc., cannot be taken as proof of the existence of haematogenous jaundice. There is, indeed, in these con- ditions increased destruction of red blood-cells; but jaundice, if it occurs, may be due to the fact that a portion of bile-pigment, which is ^produced in excess, has found its way into the blood. According, however, to Whipple and Hooper, the in- travenous injection of haemoglobin into dogs with the liver excluded is followed by the excretion of bile pigment in the urine and jaundice of the fat tissues. (Jour, of Exp. Med., 1913.) Moreover, there are well-defined varieties of hemolytic icterus in which the destruction of red cells takes place in the spleen and in which removal of the spleen is almost invariably followed by disappearance of the jaundice. According to von Kupffer and Pfeiffer, the bile-capillaries terminate in intra- cellular secretory vacuoles ; from these, according to Nauwerch, Stroehe, and Browicz, delicate intracellular secretory canaliculi are given o.ff, forming a network around the nucleus. Schafer describes small canaliculi within the liver-cell com- 198 THE RETROGRADE CHANGES. municating with the blood-capillaries. Arnold opposes the view that any preformed system of canals exists in the liver cells. In the icetrus occurring so frequently in the new-bom {Schmorl) there occurs both a diffuse and a scattered yellowish coloration of the brain limited to the neighborhood of the nuclei, while in later life the brain, even after long-continued icterus, remains free from pigment. With the nuclear icterus there are also found ganghon-cells stained with bile. Literature. {Icterus.) Abramow u. Samoilowicz: Pathogenese d. Ikterus. Virch. Arch., 176 Bd., 1904. Auld: Haematogenous Jaundice. Brit. Med. Journ., i., 1896. Harley: Pathology of Obstructive Jaundice. Brit. Med. Journ., 1892; Leber u. Galle wahrend dauernden Verschlusses von Gallen- und Brustgang. Du Bois-Reymond's Arch., 1893. Minkowski u. Naunyn: Pathologic d. Lefcer u. d. Ikterus. Arch. f. exp. Path., xxi., 1886. § 73. Pigmentation of the tissues through materials introduced from without occurs when substances possessing a color of their own gain entrance and are able to remain for some time without suffering changes. The number of such substances is large, and the manner of Fig. 105. — Deposit of cinnabar in tattooed skin. (Alcoliol, alum-carmine.) n. Epithelium; h, cerium; c^ cinnabar, x 80. entrance varied. The most common avenues of entrance are the lungs, wounds, and intestinal tract. The most familiar pigmentation through wounds is tattooing of the skin, which is frequently practiced by indi- viduals civilized as well as uncivilized. The method of tattooing colored figures, etc., consists in the intro- duction of insoluble granular pigments, such as carbon, india-ink, cin- nabar, sepia, burnt sienna, ultramarine, chromate of lead, etc., into slight wounds of the skin. The pigments are rubbed into the wounds, whence they penetrate and infiltrate the tissue in their immediate neighbor- hood. A portion of the pigment remains in the corium (Fig. 105, c) ; another portion is carried to the lymph nodes, which become pigmented. The lungs and their lymph nodes may become intensely pigmented through the inhalation of colored dust, such as coal-dust, soot, iron-dust, etc. Through the inhalation of coal-dust the lungs may become black! EXTRINSIC PIGMENTS. 199 « « When coal-dust is taken into the lungs in the respired air a portion of the pigment is carried to the peribronchial lymph nodes, which may become black. When the deposit is abundant the lymph nodes may undergo softening and give off pigment into the lymph-stream. If the nodes are situated in the neighborhood of a vein, the pigment-deposit and the softening may involve the vein-wall, so that particles of coal- dust may pass into the blood-stream, and be carried to other organs, the spleen, liver, and bone-marrow (see § 21). From the intestine only soluble substances are absorbed, and perma- nent pigmentation can therefore occur only when these are precipitated in the tissue as solid particles which retain a distinguishing color. The most frequent of such pigmenta- tions is that known as argyria, which is due to the long-continued use of silver preparations, whether taken by mouth or applied to mucous membranes, e.g., the nose, or to chronic ulcerative lesions of the skin. In argyria the skin may show only a slight bluish tinge, but in more pronounced cases the sil- very discoloration lends a ghastly appearance. The internal organs may present more or less pigmenta- tion. The silver is deposited in the ground-substance of the tissue in the form of fine granules, more especially in the glomeruli, and the connective tissue of the medullary pyramids (Fig. 106, b), the intima of the great vessels, adventitia of the smaller ones, in the neighbor- hood of mucous glands, the papillje of the skin, connective tissue of the intestinal villi, and in the choroid plexus of the lateral ventricles. Deposits may also occur in the ser- ous membranes, but the epithelial tissues, the brain, and the cerebral vessels escape. Extensive deposits of silver in the medullary portion of the kidneys may lead to the formation of hyaline connective tissue and to calcification. Iron taken into the body in excessive amounts, may be deposited in the botie-marrow, spleen, and lymph-nodes; but the pigmentation thus produced is rarely visible to the naked eye. In lead- poisoning there may be seen a grayish-black discoloration of the gums, due to the deposit of sulphide of lead in the connective tissue produced through the action of hydrogen sulphide on lead which is present in solution in the mucous membrane. » Fig. io6. — Deposits of silver in the pyra- midal portion of a _ rabbit's kidney, after seven months' administration of silver salts (experiment by von Kahlden.) (Alcohol, liEEmatoxylin.) a, Epithelium of the collect- ing tubes; b, connective tissue with brown silver granules. X 500. A variety of exogenous pigmentation has recently been d'escribed under the title of carotinaemia, and is characterized by the presence in the blood and urine 200 THE RETROGRADE CHANGES. of pigments derived from diet rich in carotin — carrots, spinach, the yolk of eggs, oranges, etc. The condition is evidenced by a peculiar orange-yellow tint of the skin which simulates jaundice, but is easily differentiated from the latter by lack of discoloration of the conjunctivaE. (Palmer and Eckles, Journ. Biol. Chem., 1914; Palmer, Ibd., 1916; Hess and Myers, Carotinasmia, Journ. Amer. Med. Assn., 1919.) XV. The Pathological Absence of Pigment. § 74. Absence of pigment occurs as a congenital condition, and is termed albinism or leucopathia congenita. In such cases the absence of pigment may extend over the entire body (albinismus universalis, albi- nos) ; in other cases it is restricted to certain portions of the skin (albi- nismus partialis). In those parts of the skin which are destitvrte of pig- ment the hairs likewise contain no pigment, and appear white or yellowish- white (poliosis or leucotrichia congenita universalis, et circumscripta). In universal albinism the pigment of the retina, choroid, and iris may be wanting, so that the choroid, from the blood which it contains, appears red, and the iris, according to the angle of obser- vation and the degree of illumination, appears bluish-white or red. On micro- scopic examination no pigmented cells are to be found. A second form of albinism is known as vitiligo or leucopathia acquisita. This occurs later in life, either as a sequel to certain diseases (scarlet fever, typhus, recurrent fever), or as a symp- tom of an epidemic disease of unknov\rn etiology (vitiligo endemica), or finally without any recognizable cause. The formation of white spots, in which the hairs are also white (leucotrichia ac- quisita circumscripta) , takes place usu- ally symmetrically, and may extend over the greater part of the body (Fig. 107). The white areas are surrounded by a border of deeply pigmented skin; this suggests that with disappearance of pig- ment at one point the pigment is trans- ferred to adjacent parts. The loss of color in the hairs (as in old age) begins in the root, no more pigment being trans- ferred from the hair-papilla to the bulb. Finally the pigment-cells of the papilla disappear altogether. A third form of loss of pigment is associated with traumatic or infectious inflammations of the skin, particularly in syphilis and leprosy; this condition is known as leucoderma. In scars of the skin which remain white, the newly formed tissue replacing the defect- does not possess the power of producing pigment. Not infrequently such a scar may be surrounded by a pigmented border. Fig, 107. — Vitiligo endemica (after a photograph received from Professor Miinch.) FORMATION OF CYSTS. 201 In mild forms of inflammation, in which the tissue of the skin suffers no loss (syphilis), the disappearance of color may immediately follow the inflammation, or not until later, in which case there may occasionally occur a preceding stage of increased pigmentation. According to Ehr- mann the lack of pigment in such cases is to be explained either by the fact that no chromatophores are present in the corium to furnish pigment to the epithelium, or the changed epithelium is not able to take up the pigment from the latter when present. The pigment which still remains in the cutis may then be absorbed. According to Munch, vitiligo is of common occurrence in Turkestan, and is considered by the natives (Sarts) to be contagious, so that they isolate the affected individuals and confine them with lepers in enclosed courts. It is probable that in the literature vitiligo endemica has been mtany times confused with lepra maculosa, and has been described under the designation " white leprosy of the Jews." XVI. The Formation of Cysts. §75. A cyst is a circumscribed cavity which is shut off from the sur- rounding tissues by a connective-tissue membrane or by tissue of a more complex structure, and possessing contents differing in nature from the capsule. Cysts may occur in any tissue. When composed of but a sin- gle chamber, the cyst is called a simple cyst; wlien divided into a number of compartments, it is known as a mul- tilocular cyst. The most common form is the so- called retention-cyst, which arises from the accumulation of secretions in pre- existing spaces which are lined with epithelium or endothelium. In glands provided with ducts, re- tention-cysts are formed as the result of obstruction of the duct, provided secret- ing epithelium exists behind the point of obstruction. Such cysts are of frequent occurrence in the sebaceous glands, hair follicles, uterine glands, mucous glands of the intestinal tract, tubules of the epididymis (Fig. 108, c), urinary tubules; less frequent in the biliary passages, in the breast, pancreas, in the glands of the mouth, etc. Larger open canals, such as the ureters, vermiform appendix, and Fallopian tubes, may also undergo cystic dilatation as the result of the collection of secretions. Obstruction of a duct may be due to accumulation of secretion, to the formation of adhesions, cicatricial obliteration, compression, or constriction of its lumen. Closed glandular cavities and tubes, such as the follicles of the thyroid and the glandular tubes of the parovarium, may become cystic when their walls produce an abnormal amount of secretion. Likewise, the remains of fcEtal passages and clefts, for example, remains of the branchial clefts, urachus, Miiller's ducts, etc., may become cystic. Fig. io8. — Section of the testicle and epididymis, with multiple cysts in the head of the epididymis. a, Testis; b, epididymis; c, multilocular cysts. Slightly reduced. 202 THE RETROGRADE CHAXGES. Small cysts such as those developing in mucous glands, vary in size from a millet seed to that of a pea. Larger cysts, such as occur in the liver and ovaries, may attain the size of a fist and even larger. The contents of cysts depend on the nature of the tissue in which they are formed. Thus cysts of sebaceous glands and hair-follicles con- tain a pultaceous, white, or grayish- white, more rarely brown, mass, which consists of squamous cells in various stages of disintegration, fat- globules and cholesterin. The cysts occurring in mucous glands contain a fluid which is either clear, or white and cloudy, as the result of the presence of cellular elements. Haemorrhage into a cyst gives a red or brown color to the contents. When great numbers of cells are present in cyst-contents, the whole may become converted into a semi-solid fatty mass, and eventually undergo calcification. Cysts of the thyroid and kidneys contain colloid masses, or a clear though occasionally cloudy fluid. Retention-cysts lined with endothelium may develop from lymph- vessels, lymph-spaces, bursse, and tendon-sheaths. Here also the content of the cyst is dependent on its place and mode of origin. As retention-cysts tend to increase in size the stretching of the cyst- wall would ultimately lead to a defect in the continuity of the wall if no new formation of tissue took place. Cyst formation is not purely a de- generative process ; new formation of tissue takes place in the epithelial or endothelial lining of the cyst, and the connective-tissue elements of the wall also increase, so that in spite of the stretching, the wall becomes no thinner, and may even increase in thickness. Moreover, cyst forma- tion is often associated with pathological overgrowth of glandular tissue, and in this way constitutes a secondary change in hyperplastic or tumor growths. It is, therefore, sometimes impossible to draw a sharp line between the simple cystic dilatations of preexisting gland- canals and gland-spaces, and those tumors, the cystomata, which are characterized by cyst formation (see Cystoma). A second form of cyst is the degeneration-cyst, which arises through partial disintegration and liquefaction of tissue. Cysts formed in this manner occur in the brain, hypertrophic thyroids, and in tumors. They may contain a clear or cloudy, or at times hasmorrhagic exudate. A third form of cyst results from the formation of a connective- tissue capsule around foreign bodies, which have found entrance to the tissues, for example, about a bullet; or about necrotic areas, or haemorrhagic extravasates. A fourth variety of cyst is formed by parasites which pass through a cystic stage in the course of their development in the body, and are likewise surrounded by a connective-tissue capsule. CHAPTER VI. Hypertrophy and Regeneration. Results of Tissue-Trans- plantation. Metaplasia. I. General Considerations. § 7(i. In a broad sense, hypertrophy is increase in the size of a tissue or organ, due either to increase in the size or in the number of the in- dividual elements, in such a way that the structure of the hypertrophic tissue is Hke that of the normal, or at least does not differ essentially from it. In a limited sense hypertrophy is increase in size due to enlargement of the individual elements alone; enlargement due to i" crease in the number of t. individual elements being d« ignated hy perplasi a. If the enlargement affects the entire body, for example, if a newly born child weighs 5-8 kgm., or if an individual should reach the height of 180-200 cm., the condition Is called giant growth. When the enlargement affects in- dividual parts of the body, for example, the entire head or one-half of it, or one ex- tremity, or the vulva, it is called partial giant growth. Hypertrophic growths of the skin and subcutaneous tissues, leading to disfigurement sug- gesting the appearance of the pachydermata, are known as elephantiasis (Figs. 109, 110). In giant growth all the elements are uniformly en- larged. In elephantiasis the connective tissue of the skin and subcutaneous structures is especially likely to become increased; nevertheless the structure of these growths may vary greatly. In one case all the connective-tissue elements may be uniformly increased, in another case only individual elements ; for example, the connective tissue of the nerves, blood- or lymph-vessels. It is therefore possible to dis- tinguish different forms of elephantiasis according to the structure of the hypertrophic part; elephantiasis neuromatosa, angiomatosa, lymphan- giectatica, lipomatosa, fibrosa, etc. 203 Fig. 109. — Elephantiasis feraorum neuromatosa. 204 THE PROGRESSIVE CHANGES. Hypertrophy of the horny layer of the epidermis attended by the formation of plates, scales, or even spines, is designated ichthyosis be- cause of a fancied resemblance to the external covering of the fish. 'The condition is usually inherited and its cause is unknown (ichthyosis con- genita) Fig. Ill, c. In other cases during the first years of life, localized thickenings of the horny layer develop, consisting of small scales or plates, or larger ones, giving the skin a rough and checkered appearance. The corium and the papillae are usually not involved in the ichthyosis ; but occasionally the papillary bodies may be hyper- trophic, thus increasing the rough and nodular appearance of the sur- face {ichthyosis hystrix). When the excessive cornification is sharply limited to areas of small size, there are formed circum- scribed warts with roug'h epithelial covering, known as ichthyotic warts. In rare cases there may be developed a more extensive horny layer over the hypertrophic papillae, whose scales are arranged at right angles to the surface of the skin; these occasionally attain such size that they are called cutaneous horns (Figs. 112, 113). The excessive and coarse de- velopment of hair over those parts of the body where only downy hair, or no hair at all, should be found 1- known as hypertrichosis. Ab- ncirmal hairiness may cover a large or small area, and depends either on persistence and abnormal de- M.lopment of the lanugo (hyper- trichosis lanuginosa foetalis) (Fig. 114), or on pathological develop- ment of the secondary hairs. Ex- cessive growth of the nails leads to the condition known as hvper- onychia, which is often followed by the claw-like deformity desig- nated onychogryphosis. It is to be noted, however, that pathological over- growths of the nails are usually acquired. Next to the enlargements associated with general or partial giantism the bones most frequently undergo hypertrophy corresponding to ele- phantiasis of the skin. The head is usually affected, the bones of which may undergo enlargement (Fig. 115), leading to a deformity in which the head comes to resemble that of a lion, hence the name leontiasis ossea. Further, there often develop on the skull or other bones circum- scribed bony growths known as exostoses. It cannot always be stated to what extent hypertrophy of the tissue is to be attributed to congenital predisposiion, inasmuch as many extrinsic Fig. -Elephantiasis cruris lymphan- giectatica. CONGENITAL HYPERTROPHIES. 205 influences are able to produce proliferations of tissue similar to those due to intrinsic causes. For example, cutaneous horns and elephantiasis- like thickenings of the skin may develop as the result of inflammation. Fig. III. — Ichthyosis congenita. Section through the skin of the trunk of the body (alcohol, picrocarmine.) Oj Corium, with glands; b, papillary bodjr, with rete Malpighii; c, hypertrophic norny layer of the epidermis; d, dilated hair-follicles, lined with horny epithelium; e, hairs. X 40. In general, the early appearance of a hypertrophic growth and the absence of any obvious etiological factor, speak for the congenital nature of the condition. The fact that later influences may apparently cause .the growth does not preclude the existence of a congenital predisposition. Thus the excessive bony growths of the head above mentioned may fol- low trauma or acute in- flammations. External in- fluences may therefore be the exciting but not the primary cause of the change. Not infrequently the tendency to excessive growth may show itself in premature development of certain organs, the structure remaining normal. The sexual organs are most frequently affected. Girls, even in the first years of life, may show development of breasts and external genitals and growth of hair corresponding to that of the sexually ripe woman ; and menstruation may be established at this early period. The size of the body as well as of its separate parts and organs shows con- sideraible variation within physiological litoits, according to the race, family, and individual. The variation in the relation of the size of single- parts and organs to that of the entire body is less marked. Fig. neum, (Natural size.) 112, — Cornu cuta- from back of hand. Fig. 113. — Cornu cuta- neum,_ from arm. (Nat- ural size.) 206 THE PROGRESSIVE CHANGES. The average height of the body in well-built individuals is, according to Vierordt ("Daten u. Tabellen fur Med.," Jena, 1893), as follows: Men 172 cm., women 160 cm.; of the new-born, males 47.4 cm., females 46.75 cm. The average body-weight in Europe is for men about 65 kgm,, that of women about 55 kgm., that of the new-^born about 3,250 gm. The average weight of the internal organs is as follows, the figures in paren- theses being for the new-born: Brain 1,397 (385) gra., heart 304 (24) gm., lungs 1,172 (58) gm., liver 1,612 (118) .^^^'^ '^^^ gm., spleen 201 (11.1) gm., right kidney 131, left kidney 150 gm., both kidneys 299 (23.6) gm., testicles 48 (0.8) gm., muscles 29,880 (625) gra., skeleton Fig, 114. — Head of a hairy individual, a woman. (After Hebra.) Fig. 115. — Leontiasis ossea, occurring in a boy affected witli general giant-growth. (Ob- served by Buhl.) 11,560 (445) gm. Expressed in percentages of body-weight the figures for adults and new-born are (the latter in parentheses) : Heart 0.52 (0.89), kidneys 0.48 (0.88), lungs 2.01 (2.16), stomach and intestines 2,34 (2.53), spleen 0.346 (0.41), liver 2.77 (4.30), brain 2.37 (14.34), adrenals 0.014 (0.31), thymus 0.0086 (0.54), skeleton 15.35 (16.17), muscles 43.09 (23.4). Literature. (Tissue-Hypertrophy of Congenital Origin.) Amheim: Congen. halbseitige Hypertrophie. Virch. Arch., 154 Bd., 1898 (Lit.). Behrend: Hypertrichosis. Eulenburg's Realencyklop., 1896 (Lit). Esoff: Ichthyosis. Virch. Arch., 69 Bd., 1877. Nonne: Elephantiasis congenita hereditaria. Virch. Arch., 125 Bd., 1891. § 77. Hypertrophies due to external causes arise in response to increase in the activity of the tissue, to diminished use, defective retro- grade change, or to prolonged or frequently repeated mechanical, chem- ical, and infectious irritations. Removal of pressure may sometimes be followed by localized hypertrophy. Hypertrophy from overwork is most frequently observed in muscles and glands, but may also occur in other tissues. If the heart is called on to do an extra amount of work as the result of diseased conditions of the valves, aorta or kidneys, and if such conditions exist for some ACQUIRED HYPERTROPHY. 207 time, that part of the heart-muscle on which the extra work falls suffers more or less pronounced hypertrophy, so that as a result the mass of the heart may reach several times that of the normal. In similar manner the unstriped muscle of the bladder, ureters, uterus, intestine, and blood-vessels may become hypertrophic from persistent increase in activity. As the result of increase of strain from whatever cause bones may become thickened, and the trabeculse of the medullary por- tion increase in size. Of the glands the kidneys, and liver in particular are able to change their size according to functional demands, and may present marked hyper- trophy. Should one kidney be destroyed, the other may be- come so enlarged that it reaches approximately the same weight that the two together originally possessed. . Likewise the liver after destruction of a part of its parenchyma may make good its loss by hypertrophy of the remainder. Since in this way compensation for the defect and restoration of function are brought about, such increase is designated compensatory hypertrophy. The same term may be applied to muscle- hypertrophy, if through it functional disturbances are compensated. Compensatory hypertrophy is said to occur in similar circumstances in adre- nal tissue. In other glands, such as the salivary glands, ovaries, testicles, and mammae, compensatory hypertrophy either does not occur at all, or takes place only dur- ing the period of development. The loss of an ovary or testis in adult life can hardly result in increased activity and hyper- trophy of the remaining organ. Extirpation of the larger part of the thyroid gland is not followed by pronounced hypertrophy of the remain- ing portion; on the other hand, the hypophysis undergoes enlargement which must be regarded as compensatory. In the lungs, increase in the activity of one portion after the loss of another results usually in over- distention which eventually may lead to atrophy. On the other hand, if during embryonic life defective development of one lung takes place, the other lung may undergo compensatory growth, which in case of total agenesia of one lung may reach a pronounced degree. For the other Fig. 1 1 6. — (Bellevue Hospital.) Showing the peculiar hypertrophy and malformation of the lower extremities in Paget's disease, so-called osteitis deformans. 208 THE PROGRESSIVE CHANGES. organs the general principle may be applied that compensatory hyper- trophy more nearly approaches perfection the younger the individual. In the brain compensatory growth of one part after the loss of another is possible only during the early stages of development. Hypertrophy from lessened use occurs in tissues which are nor- mally subject to attrition from constant use. For example, diminished desquamation of the horny layer of the epidermis leads to pathological thickening. If, as the result of the destruction of an opposing tooth or an oblique position, the incisor teeth in rodents are not worn down by use, they may grow into long, curved tusks. Hypertrophy due to de- fective retrograde change occurs in organs which after a definite period of physiological growth undergo diminution in size. For ex- ample, the uterus after pregnancy may remain ajsnormally large as the result of failure of involution. The thymus gland, which should begin to atrophy after the tenth year of life, may persist for a much longer period. In bones lessening of pressure may be followed by hypertrophy. In idiots whose brains are deficient in size there is often hyperostosis of the inner surface of the base of the skull (Chiari), and unilateral hyperostosis of the skull is sometimes associated with corresponding hypoplasia of the brain. Frequently repeated or protracted mechanical, thermal, chemical, or infectious irritations give rise to proliferative processes leading to hypertrophies, which because of their etiology and course must be re- garded as chronic inflammations; such formations are placed under the head of inflammatory hypertrophy. They are characterized often by the fact that in the enlargement of the organ, not all of its parts are equally involved; certain elements, usually the connective tissue, occa- sionally the epithelium, undergd' hypertrophy to such a degree that the structure of the organ (skin, gland, etc.) is no longer typical. If the skin is frequently subjected to irritation and pressure, for example, the toes through an ill-fitting boot, there may arise thickening of the horny layer of the epidermis, known as callus or corn (clavus): Prolonged irritation of the skin in the neighborhood of the genital open- ings, caused by gonorrhoeal discharges, may be followed by elongation and branching of the papillae with thickening of the epithelium, leading to the formation of warty, cauliflower-like growths known as venereal warts or condylomata acuminata. Chronic inflammations of the corium and subcutaneous tissue, due to infection or to animal parasites (Filaria Bancroft!) , not infrequently give rise to fibrous hypertrophies known as elephantiasis. Such hypertrophies may attain extraordinary proportions. In similar manner there may occur in the bones, as the result of chronic infectious processes (syphilis, for example), extensive hypertrophies characterized by increased formation of bone-substance. In the majority of cases those tissue-hypertrophies which appear during life as acquired formations, the causa efficiens may be recognized with more or less certainty but there are also cases in which, at the pres- ent time, this is either impossible or possible to a limited extent. For example, there are enlargements of the spleen, and of hmphadenoid tis- sues in various localities which are of the nature of hypertrophies, whose causes we are unable to recognize. Imperfect, also, is our knowledge of (the etiology of the enlargements of the extremities, resembling partial giant-growth, which have been described as osteoarthropathie hypertro- phiante (Marie). REGENERATION. 209 In Germany the designation acromegaly is applied to all forms of enlargement of the ends of, the extremities that lead to paw-shaped deformity of the hands and gigantesque appearance of the feet, while Marie attempts to draw a line between acromegaly and osteoarthropathie hypertrophiante. He holds that in acromegaly the hands and feet are not deformed, but are symmetrically enlarged, the thicken- ing and broadening diminishing toward the tips of the extremities, so that the terminal phalanges of the fingers and toes are but slightly thickened, while, on the other hand, in osteoarthropathie hypertrophiante the terminal phalanges are enlarged to resemble drumsticks, and the articular ends of the bones are irregularly thick- ened. In the first affection the lower jaw is lengthened, in the latter it is thickened. Marie believes that osteoarthropathie hypertrophiante is a sequel of inflammatory affections of the lungs and pleurse, and designates the condition osteoarthropathie "^ mp:^ I. ^£ijL^^fc:^^i,^i£i..::ij:r^^ Fig. 117. — ^The skin-portion of a laparotomy wound sixteen days old (MuHer's fluid. Van Gieson's). a^ Epithelium; b, corium; r, subcutaneous adipose tissue; d^ scar in corium; e^ new epithelium; f, scar in adipose tissue, x 38. hypertrophiante pneumique, and holds that the connection between these processes is to be found in the taking up into the body-fluids of poisonous products from the inflammatory foci in the lungs, so that the affection of the bones is to he regarded as an infectious toxic hypertrophic inflammation. The association of acromegaly with tumors of the hypophysis of different kinds has been definitely determined, but the character of the tumors in some cases would indicate increase of function, in other cases diminution or loss. The cause of the nodular hypertrophy of the thyroid gland, occurring so fre- quently in many regions, is unknown. § 78. Regeneration is that process through which tissues which have been destroyed are restored. It is the result of new-formation of cells, which arise' through the division of preexisting 'cells. Regeneration presupposes that the injured tissue is capable of pro- liferation, and is a phenomenon which in all cases is dependent on extrinsic causes. In the fully developed organism, each tissue can pro- 14 210 THE PROGRESSIVE CHANGES. duce only new tissue of its own or a closely related kind. The specifi- city of tissues is so decided that epithehal cells can never give rise to connective tissue, and connective tissue can never produce epithelium. Ectodermal cells cannot produce intestinal epithelium ; kidney epithelium can produce only cells having the character of kidney epithelium, but never liver-cells or those of mucous glands, or connective tissue. Muscle- tissue can arise only from muscle-cells. Nerves and neuroglia can never arise from connective tissue. Only cells which are closely related can arise from the same parent-tissue. Thus the periosteum can produce SiPp^f- feJ*'!S<^SS^S_2:g3 Fig. 1 1 8. — Healing ulcer of the small intestine, with formation o£ new gland-tubes in the proliferating submucosa (Miiller*s fluid, hasmatoxylin) . a. Mucosa; &, siJbmucosa; c, d, muscu- laris; e, serosa; f, remains of the floor of the ulcer not yet covered over with epithelium; g. over- hanging edge of the ulcer; h, portion of floor of ulcer covered with epithelium; i, newly formed glands in the submucosa; k, deep crypt lined with epithelium, x i8. ordinary connective tissue, cartilage, or bone — that is, tissues which are modifications of the same connective-tissue. In tissue defects in which only single cells are lost (for example, in the loss of single connective-tissue cells), or in more extensive de- struction of cells without interruption in the continuity of the connective tissue of the blood-vessels (as the loss of localized areas of surface epi- thelium, or a group of gland cells or of pulmonary epithelium), com- plete regeneration, restitutio ad integrum, may take place, and the tissue be restored to a condition corresponding to that existing before the in- jury. After injuries in which the continuity of the mesodermal support- ing tissue is broken, with or without associated injury to tissues of ento- and ectodermal origin, regeneration is incomplete ; at the point of in- jury tissue is formed which departs more or less from the normal in both structure and function. In general this is newly formed connective tissue, designated scar (Fig. 117, d) or cicatricial tissue. Defects of the skele- ton are replaced by scar-tissue which arises from the periosteum and endosteum, and by virtue of the peculiar properties of these tissues new bone develops in the scar, the structure coming eventually to resemble that of normal bone. In many instances cicatricial tissue consists purely of vascularized con- nective tissue (Fig. 117, d). Scars bordering on ectodermal or entoder- mal tissue may become covered by epithelium (Fig. 117, e). Occasionally REGENERATION. 211 the structure of cicatricial tissue may be modified, in tliat specific tissue- formations grozv into it secondarily or are preserved in it as remains of preexisting structures. The first process occurs most frequently in scars of the mucous membrane of the in- testine (Fig. 118), and of glands in the neighborhood of their ex- cretory ducts. In defects of mucous membranes which are re- placed by scars formed through proliferation of connective tissue (Fig. 118, b, /), the surface is first covered with epithelium {g, h, k), later epithelial ingrowths develop which bear the character of tubular glands (i). Gland-ducts (bile- ducts, ducts of the salivary glands) may grow into developing scar- tissue, and form new tubes or solid cords of cells. Such new-forma- tion of ducts may occur not only in the neighborhood of traumatic injuries, but also in the course of inflammations of the glands in question. On the other hand, regeneration of gland-tissue proper in the neigh- borhood of scars is wanting in the majority of instances, (liver, kid- neys, testicles, ovaries, thyroid, mammary glands). Only in the salivary glands does the develop- ment of new ducts lead to the formation of gland-lobules. In muscle-scars (Fig. 119) it is said that new muscle-fibres (d) grow from the ends of the old ones (o), so that the scar becomes gradually replaced by muscle. The remains of specific tissue- elements in the area of cicatrization may be observed in both muscles and glands, especially at the per- iphery of traumatic injuries and ansemic necroses (Fig. 120), and in inflammatory foci. The gland- ular remnants in the scar usually present an atrophic appearance, (Fig. 120, b), but islands of normal tissue (d) may also be enclosed, _ „ , , J ,. „j „ tTiirtv and it is possible that these may Fig. :i9. — Scar of muscle and tendon, ttiirty- ""^ i, ... ^ j two days old (Fiemming's solution. Van evcu Undergo compcnsatory growth. Gieson's). a, Old muscle; b, tendon; c, scar; j I'nflntnTnat-nrv nrnrpiscps in d, newly formed muscle-fibres, x loo. -in mnammatory proccsses m 212 THE PROGRESSIVE CHANGES. glandular organs characterized by destruction of perenchyma, and by the regeneration and overgrowth of connective tissue, there are often seen atrophic remains of gland-tissue, and between these, islands of un- injured gland-tissue that have undergone hypertrophy. The mass of the scar is rarely equal to the mass of the tissue lost; there persists after the loss of considerable tissue a more or less marked defect. In circumscribed areas of skin, mucous mernbranes, glands, brain, etc., such a defect gives rise to cicatricial depression. Numerous Fig. 120. — Peripheral zone of an embolic scar (Mijller's fluid, hematoxylin and eosin). a. Scar showing obliterated glomeruli, but no tubules; b, indurated tissue with atrophic tubules, the glomeruli being preserved; c, normal cortical tissue; d, island of normal tubules in the scar. X 30. cicatricial depressions in an organ may occasion atrophy characterized by irregular configuration of the surface. The loss of tissue en masse, for example, a toe, is in man never replaced. Such defects are closed by scar-tissue which on superficial parts of the body becomes covered with epithelium. In man and other mammals, the regenerative capacity of tissues is rela- tively slight. This depends on the fact that human and other mammalian cells are so highly differentiated that they are unable to revert to such a low embryonal state as to produce different forms of tissue. In spite of this limitation the regen- erative powers are sufficient to restore continuity and to preserve the external covering of the body. If as the result of local loss of tissue, the life of the organ- ism be endangered through inability of the tissues to restore the lost part, there exists in certain organs (liver, kidneys) the power of compensating for such loss through hypertrophy of remaining normal tissue. In the lower animals the power of regeneration is greater than in mammals; and further is greater in the earher stages of ontogenesis, so that, in many animals (tritons, ascidians, echinoderms, teleosts), the first two or even the first four segmentation cells still possess the power of forming an entire embryo.. Insects possess during the larval state marked power of regeneration, which later is lost. In protozoa each animal may quickly supplement itself through division. In the fresh-water polypi fragments of the body may develop into the entire animal. The angle-worm is able to replace either tail or head end when these are cut off. The wood-louse can replace its feet and antennae, the snail its tentacles and anterior extremity, crabs and crayfish their claws and legs. Salamanders are able to restore legs, eyes, and tails, and lizards and slow-worms their tails, when these are broken REGENERATION. 213 off. In frogs, snakes, and fishes, on the other hand, the power of regeneration diminishes as the scale of animal life is ascended, yet this does not happen equally in the case of all animals, and animals closely related to' each other may show dif- ferent capacities for regeneration. Further, in the same animal the regenerative power is not the same in all organs ; for example, in tritons the regenerative capacity of the internal organs is slight. Moreover, the power to form a new portion of the body, as a tail or extremity, for example, does not prove that all the tissues of the portion of the body in question possess an especial capacity for proliferation. In crayfish and crabs regeneration of the claws and legs takes place only from certain places; in injuries occurring at other points, the new extremity is thrown off only at that place where a new-formation is possible. In tritons, fractures of the bones heal slowly, although they are able to reproduce their extremities. § 79. The cause of cell-proliferation underlying hyperplastic and re- generative changes in tissue varies according to the conditions under which proliferation occurs. The "stimulus" may consist in the removal of hindrances to growth, since experience teaches that the majority of the cells of the body possess the power to divide, even those cells in which the process of division has apparently been in abeyance for long periods of time. There may also be present a formative stimulus, which increases both the reproductive capacity and the tendency to reproduction. Such a stimulus may act independently — that is, without the removal of influ- ences inhibiting growth — this is assumed in cases in which after the loss of a portion of an organ the remaining portion (Hver, kidney) undergoes compensaitory hypertrophy, although, even in these circum- stances, it is difficult to exclude changes in the equihbrium of cells brought about mechanically or otherwise, and affecting the relationship of cells to one another or the elements of individual cells. The stimuli which are able to excite growth and cell division are known in part only. They appear to be identical with the stimuli which excite' or increase functional and nutritive activity. In muscles, hyper- trophy is brought about by increased contraction following nervous excita- tion. Liver and kidney tissue undergo hypertrophy when, as a result of loss of a large area, the remaining portions are obliged to do an increased amount of work. Whether other formative stimuli exist cannot be stated with certainty. Increased supply of blood and nutrition, believed by many to act as a formative stimulus, is not in itself sufficient to excite regeneration of cells; it gives rise merely to increased deposit of fat. Increase of the temperature of tissues may hasten the process of cell division and thus promote tissue proliferation; but it is doubtful if it can directly excite proliferation in resting tissues. The action of heat followed by prolifera- tion (for example, in the skin) produces local changes of a degenerative nature, so that the occurrence of proliferation may be explained as due to the removal of influences that otherwise inhibit growth. There are chemically active substances that are capable of exciting proliferation. Thus, slight irritation of the skin produced by iodine is capable of causing proliferation without preceding detectable degenerative changes, although it is probable that degenerative changes in these circum- stances do occur, but are of such nature as readily to be overlooked. In addition, such substances as Sudan III, scarlet-red, ether, indol, etc., when injected in the tissues, provoke a remarkable growth of epithelium and other tissues that, in certain instances, may resemble a neoplasm. It has been suggested that the effect of such substances is due to solution 214 THE PROGRESSIVE CHANGES. of the lipoid membrane which is supposed to envelop each cell, thus exposing the nucleus to influences from which it otherwise is protected. Finally, it must be noted that even the hypertrophied muscles and glands, following increased activity, cannot be regarded as the direct result of nervous or chemical stimuH, but we must assume that, with the increased labor, there is excessive consumption of cell elements which excites regenerative processes, the latter leading not only to restora- tion of the elements that are lost, but also to enlargement of the cell mass, together with the formation of new cells. § 80. The division of the nucleus and cell-body, on which the formation of new tissue depends, may occur through direct segmenta- FlG. 121. Fig. i2i Fig. 123. Fig. 121. — Enlarged nucleus. Increase in the chromatin framework. Fig. 122. — Thick, open skein, with segmentation of the threads into chromosomes; the nucleolus and nuclear membrane have disappeared. Fig. 123.— Grouping of the completed chromosomes into a star-or wreath-form. tion, that is, through transverse constriction of the elongated nucleus and protoplasm without increase or characteristic grouping or move- ment of the chromatin elements of the nucleus. It appears, however, that direct division of the nucleus leads to the production of cells which are able to form new tissue only when it is connected with that form of cell-division known as karyokinesis or karyomitosis or indirect segmentation, which is characterized by increase of the nuclein or chromatin, and a definite cycle of changes of form and movements on the part of the latter. Karyomitosis follows a typical course in the normal growth of tissue, but deviations are frequently seen in pathological formations. A resting nucleus consists of the nuclear membrane, and the nuclear contents. The latter are composed of a colorless nuclear fluid and the nuclear substance. To the nuclear substance belong the nucleolus and scattered granules and threads which form a framework staining with nuclear stains. When the nucleus undergoes division, there occurs, first, increase of the chromatin, and the chromatin framework becomes more distinct (Fig. 121). The nuclear substance then forms a close skein, which, with disappearance of the nuclear membrane and the nucleolus, becomes changed into an open skein with thick threads (Fig. 122), whose indi- vidual components divide themselves into nuclear segments or chro- mosomes (in man these number eighteen) (Figs. 122, 123). These segments then group themselves in the equatorial plane of the nucleus with their angles directed toward the centre, forming, when KARYOKINESIS. 215 viewed from the polar aspect, a wreath-like (Fig. 123), and later a star- like figure, lying in the equatorial plane, that has been designated the mother-star (Figs. 124, 125), or equatorial plate. Sooner or later two poles become visible in the so-called polar field — that is, two extremely small spherules, which are known as the polar or central corpuscles or centrosomes. At first these lie close together, but later separate and act as centres about which the nuclear elements group Fig, 124. Fig. 125. Fig. 126. Fig. 127. Fig. 128. Fig. 129. Fig. 124. — Completely developed mother-star; polar view. Fig. 123. — Mother-star; equatorial view. Fig. 126, — Stage of metakinesis. Single loops visible, their angles pointed toward the pole; delicate spindle-figure within the nucleus. Fig. 127. — Daughter-star; side view (nucleus barrel-shaped); spindle-figure in the nucleus and the radial arrangement of protoplasm are visible. Fig. 12S. — Daughter-stars separated; the upper one presenting polar aspect, the lower one a side view. Fig. 129. — Daughter-skein with fine threads (above), and with lattice-work (below). Com- pleted division of the protoplasm. themselves. Between these there is formed the nuclear spindle (Figs. 126, 127) which consists of fine threads which do not stain with nuclear stains, and converge in the polar corpuscles, In the neighborhood of the polar corpuscles themselves the granules of the protoplasm present a radial arrangement, giving rise to figures (Fig. 127) which are known as ray-figures, stars, or attraction-spheres. In the succeeding stage of division of the nucleus, a movement takes place among the chromosomes leading to the formation of loops, whose angles are directed toward the pole. Later the loops divide in halves which, following the direction of the spindle-fibres, move toward the poles and form two stars (Figs. 126- 216 THE PROGRESSIVE CHANGES. 128) which are known as daughter stars. From the star-figures the daughter-star passes successively through the thick-skein and then the fine-skein stage (Fig. 129, upper part) which finally changes into the nuclear framework (Fig. 129, lower part). During the later stages of the process a new nuclear membrane is formed. In the stages of the segmented skein, or later as may be seen in the large nucleated cells of cold-blooded animals, there occurs longitudinal Fig. 130. Fig. 131. Fig. 130. — Mother-star, with chromosomes split longitudinally. (After Rabl.) Fig. 131. — Metakinesis. The halves of the chromosomes are separating from each other and turning toward the poles. (After Rabl.) Splitting of the chromosomes (Fig. 130). In the change of position of the chromosomes known as metakinesis the halves of the split threads separate from each other (Fig. 131) so that each daughter-star receives half of the substance of each chromosome. Division of the cell-protoplasm usually takes place at the time the daughter-star changes into the ordinary nuclear condition, and con- sists in constriction and separation of the protoplasm (Fig. 129). It is probable that a complicated interrelation- ship exists between the nucleus and cell- protoplasm; but the nucleus is to be re- garded as the more highly organized sub- stance, as the centre of cellular potentiality. The nuclei are also the bearers of heredity, while the protoplasm governs the relations of the cell with the outer world. Variations from the typical karyokin- esis may consist in the occurrence of pluripolar division in place of the bipolar, so that two to six or more nuclear spindles and a correspondingly increased number of equatorial plates (Fig. 132, a) may be formed. Further, in place of the simple mother-star there may be formed a complicated figure out of the chromatin loops, from which several daughter-stars may be evolved. Not infrequently there occur asymmetrical divisions of the nucleus (Fig. 132, b, c), particularly in tumors, but also in regenerative or inflammatory new-formations of tissue. There are also divisions of the nucleus which are characterized by abnormal size, abnormal richness in chromatin, and manifold variations Fig. 132.- figure ; b, c figures. a, Pluripolar division- asymmetrical division- ATYPICAL CELL DIVISION. 217 of form. As types of such division are the large oval or bean-shaped (Fig. 133), knobbed or convoluted, lobulated and branched (Fig. 134), wreath-shaped, linked, basket-shaiped (Fig. 135) nuclei, and other forms. Finally, there are occasionally found in the cells more or less extensive, indistinctly-outlined heaps of granular and lumpy chromatin (Fig. 136). Fig. 133. Fig. 134. Fig. 135. Fig. 136 Fig. 133. — Cell with oval, slightly knobbed giant-nucleus, rich in chromatin. Fig. 134. — Cell with lobulated £iant-nucleus. Fig. 135. — Cell with basket-shaped giant-nucleus. Fig. 136. — Cell with large masses of chromatin. All these cells from a sarcoma of bone, iStroebe^ Beitrdge von Ziegler, VII.) Such nuclear forms are found in the cells of the bone-marrow, and in tumors which arise from the bone-marrow or periosteum, but have been observed elsewhere, particularly in certain sarcomata. Certain of these forms are due to contraction, and have nothing to do with cell-division. In other cases these changes of size and form pre- cede division of the nucleus through con- striction, sometimes with, sometimes with- out increase of the chromatin. Arnold has designated divi- sion by constriction with increase of the chromatin as indirect fragmentation, that without such increase as direct fragmenta- tion. Indirect frag- m e n t a tion differs from mitosis or in- direct segmentation in the lack of orderly arrangement of the chromatin in threads, and in the irregularity with which the separation of portions of chromatin results in new nuclei. Variations in the cell-protoplasm occur, either as total failure of the protoplasm, to divide after division of the nucleus has taken place, or as delayed division. These phenomena are observed in both mitotic and amitotic division of the nucleus, and lead to the formation of multinuclear giant-cells (Fig. 137). ^!5«Bss**JS.7^\ . Fig. 137. — ^Proliferating adipose tissue from the subcutaneous panniculus, twenty-six days after cauterization with trichloracetic acid (formalin, haematoxylin) . o, Multinuclear fat-cells; b, pro- iferating connective tissue. X 300. 218 THE PROGRESSIVE CHANGES. Cells of the bone-marrow and of tumors arising from the bones show this phenomenon with special frequency. Proliferating fat-cells like- wise form multinuclear giant-cells (Fig. 137, a). Besides this form of multinuclear giant-cell there also occur those formed by the confluence of cells, which are known as syncytial giant-cells. (Compare the sections on Inflammation and Tuberculosis). Literature. {Cells and Cell-division.) For a complete exposition, see Wilson : Inheritance," New York, 1897. ' The Cell in Development and II. The Processes of Hyperplasia and Regeneration in Various Tissues. § 81. The morphological changes in the regeneration and hyptx- plasia of epithelium are relatively simple. The karyomitoses (Fig. 138, a~d) show for the greater part a typical course. The division of the protoplasm takes place either in the later stages of nuclear division or follows shortly thereafter. Giant-cells may arise through failure of the protoplasm to divide. Epithelium arises only from epithelium. It is to be noted, however, that under certain conditions regenerating epithelium may change its character. This may occur, for example, in cicatriza- tion of ulcers in the trachea. Defects in the ciliated col- umnar epithelium are re- paired by low columnar or flat cells which later be- come changed into high columnar cells. Small losses of super- ficial epithelium are re- placed through regenera- tive growth of neighboring cells (Fig. 139, d, d^, d^), The epithelium bordering on the defect pushes over the denuded surface and begins to proliferate. The division of the nucleus and cell-protoplasm takes place not only on the edge of the defect, but at some distance from it. In the intestine the loss of superficial epithelium is made good by proliferation of the epithelial cells in the crypts of Lieberkiihn. Likewise glandular epithe- lium may_ be restored after loss, provided the basement membrane on which it rests is not changed. After destruction of liver-tissue the epithelium of the bile-ducts (Fig. 138) proliferate, and the cell-division may extend to a relatively great distance from the site of injury. Ex- perimental wounds of the liver heal through the formation of connective tissue, into which offshoots of the bile-ducts penetrate, while local re- production of liver-tissue does not take place. Likewise, in the kidneys, Fig. 138. — Regenerative proliferation of the epithelium of bile-ducts, in the neighborhood of a wound of the liver five days old (Flemming's solution, safranin). a, Enlarged nucleus of epithelial cell, with increase of chromatin; 6, epithelial cell with mother-skein; c epithelial cell with mother-star; d, epithelial cell with daughter-skein; f, con- nective-tissue cell with daughter-star, x 400. REGENERATION OF EPITHELIUM. 219 testicles, thyroid, and ovary the production of glandular tissue in the connective-tissue scar is slight or wanting, and does not lead to the formation of functionating tissue. In the salivary and mucous glands. Fig. 139. — ^Healing of blister caused by a burn (alcohol, alum-carmine). Section through the skin of a cat's paw, forty-eight hours after the production of a blister, a. Horny layer; b, rete Malpighii; c, corium; d, newly formed epithelium; d\, dz, newly formed epithelium already differentiated into different layers; e^ old, degenerated epithelium; /, pus-cells; g, exudate; /r, sweat-glands. X 25. on the other hand, branching of the gland-ducts is followed by the forma- tion of new alveoli. When portions of the mucosa and submucosa of the intestine are lost as a result of ulcerative processes, there occurs during healing glandular proliferation, which, according to the nature of the defect, forms partly typical, partly atypical (Fig. 118, i) glands that grow into the submucosa. Fig. 140. — Development of blood-vessels by formation of offshoots; from preparations taken from inflammatory granulations, a, b, c, d, Different forms of offshoots, some solid (6, c), others becoming hollow (a, b, d) , some simple (a, d) , some branching (b, c), some without nuclei (a, d) ; some with nuclei (fc, c) ; d, offshoot to which fibroblasts have applied themselves. 220 THE PROGRESSIVE CHANGES. The new formation takes its start from the old glands, whose epithelium pushes over the edge and base of the ulcer (Fig. 118, g, h) and lines any depressions which may be present (/e). In similar manner ulcerative defects of the gastric mucosa are made good; and even extensive ulcers may become covered with gland-containing mucosa, although the glands seldom attain mature development. The epithelial portions of the uterine mucosa which are lost, as a physiological process, during menstruation and parturition, are restored in a manner similar to the healing of patho^gical defects of the endo- metrium. The new-formation of epithelium takes its origin from the glandular remains. Compensatory hypertrophy of a kidney or liver is brought about through the enlargement of existing renal tubules, or liver-columns respectively. After wounds or other injuries of the liver and kidney it is highly doubtful if regeneration of functionating par- enchyma ever occurs. § 82. If tissue is to be reproduced in considera- ble amount, the presence of blood-vessels is essen- tial, since it is only through these that sufficient nutrition can be brought to the growing tissue. The development of new blood-vessels takes place through the formation of offshoots from pre- existing vessels (Fig. 140). In the vessel-wall there occurs proliferation of the endothelium (Fig. 141), in which division of the nucleus occurs by karyomitosis. As the first step in the formation of a new vessel, there is seen on the outer side of some capillary loop a tent-like elevation which terminates of papillary whose endothelial cells are in process of proliferation (six days after painting in a fine protoplasmic thread standing out from the tinctur^of iodfne^rcFrem''- ming's solution, safranin, and picric acid). a. Nu- cleus with chromatin framework; b, hi., skein- forms; c, mother-star; d^ connective-tissue cell with nuclear division-fip-ure; ff, lymphocytes. X" 350. vessel (Fig. 140, a), and gradually becoming longer and longer. There is thus , formed at the beginning an arch of granular protoplasm, which ends in a protoplasmic thread (a), and after a time comes to contain nuclei. This thread may penetrate into another vessel, or unite with some other arch which it meets, or may finally return to the same vessel from which it started. Further, from the solid arch itself new secondary arches may spring (Fig. 140, h, c), or at its end there may be formed a club-shaped swell- ing (^)- The originally solid arch becomes hollow after a certain time {h, a) through liquefaction of its central part, and the space thus formed im- mediately or soon comes to communicate with the lumen of the blood- vessel (a), or else there is developed an extension of the vessel-lumen into the arch. The blood of the mother-vessel finds its way at once into the daughter-vessel and widens it. As the hollowing-out process ad- vances and extends to the point of entrance of the protoplasmic arch into another vessel, there is finally formed a new capillary loop permeable for blood. REGENERATION OF BLOOD-VESSELS. 221 Immediately after the opening of a way for the blood the capillary tube possesses a homogenous wall. After a certain length of time the protoplasm groups itself about the nuclei, which have in the mean time divided and multiplied in the wall, so that ultimately the capillary conies to be made up of flattened endothelial cells. As Arnold has shown, the boundaries of the individual endothelial cells may be made visible through the injection of a solution of silver into the vessel. At this time the wall for the greater part appears thickened, partly from proliferation of the cells of the vessel-wall, but also from the fact that formative cells from the neighborhood heap themselves on the surface of the young vessel (Fig. 140, d), adapt themselves to the wall, and so strengthen it. At the time of the formation of the offshoots, the endothelial cells of the capillaries are swollen, and often reach such a size that the cross- section of a capillary looks not unlike a gland-tube lined with epithelium (Fig. 142, d). At the same time mitotic figures appear in the endothelium (Fig. 141, a-c), and later division of the nucleus and cell-protoplasm takes place. In what relation this pro- liferation stands to the forma- tion of the offshoots is not clearly understood; but doubt- less the latter spring from pro- liferating cells and represent cell-processes. The proliferation of endothelium, on the other hand, does not always lead to new vessels, but may result only in thickening of the vessel-wall and finally in obliteration of the lum.en. In the transformation of newly formed capillaries into arteries and veins the increase of tissue is> the result of continued proliferation of the cells of the vessel-wall. The muscle-fibres first appearing in the outer wall of the capillary tube are finely-branched cells whose nuclei lie parallel to the long axis of the capillary and whose processes surround the endothelial tube. After about fourteen days elastic fibres may appear in new-formed vessels (arteries). It is difficult to decide whether the new-formation of blood-vessels is intra- ■cellular through the hollowing out of the solid buds of a single cell or whether it is intercellular through the formation of a space between two cells. The off- shoots from the sides of the vessel-wall or from the end of the vessel give the im.pression of solid cell processes, but the possible participation of the protoplasm of two cells in the formation of such processes cannot be excluded. The new-formation of lymph-vessels in new connective tissue is intercellular. Fig. 142. — Proliferating periosteum, four days after 'fracture of a bone (Flemming's solution, hxmatoxylin) . a. Osteoblasts with large nuclei; b, osteoblast with division-figure; c, two cells siiortly after division, showing thread-skein in nucleus; dj blood-vessel vi^ith proliferating en- dothelium; e, endothelial cell with nuclear division- figure; /, large lymphocytes; g, small lymphocytes. X 350. 222 THE PROGRESSIVE CHANGES. Literature. (New-formation of Blood-vessels.) Arnold: Die Entwicklung d. Blutcapillaren. Virch. Arch., 53 Bd., 1871; 54 Bd., Flemming: Theilung von Pigmentzellen u. Capillarwandzellen. Arch. f. mikr. Anat., 35 Bd., 1890. . Mayer: Muskularisierung der KapiUaren. Anat. Anz,, xxi„ 1902. Maximow: Entziindl, Neubild. v. Bindegewebe. B. v. Ziegler, Supp. v., 1902. § 83. The connective-tissue structures are almost all capable of both hyperplastic and regenerative proliferation. This is especially true of formed connective tissue, and periosteum and endosteum; while cartilage possesses but slight regenerative capacity, and fully developed Fig. 143. — Isolated cells from a granulating wound (picrocarmine). a, Lymphocyte; fli polynuclear leucocytes; b, different forms of mononuclear fibroblasts: c, formative cell with two nuclei; ci, multinuclear formative cells; d, fibroblasts in stage of connective-tissue formation; e, fully developed connective tissue. X 500. bone none at all. Usually proliferating fibrous connective tissue gives rise to fibrous tissue, both in independent formations of connective tissue and in the supporting tissue of the glands, lungs, lymph-nodes, etc. The periosteum, bone-marrow, perichondrium and cartilage produce in addi- tion to fibrous connective tissue and marrow-tissue also cartilage and bone. Hyperplastic and regenerative proliferations of connective tissues are ushered in by cell-division in the course of which karyomitoses occur. After injuries of the tissue these proliferations begin soon, for ex- ample, in wounds of the skin, or in fractures of bones; in the latter case even as early as the second day single cells of the periosteum become en- larged and show division-figures. Besides mitoses, direct division of nuclei takes place. REGENERATION OF CONNECTIVE TISSUE. 223 When only a few cells are destroyed newly formed cells replace them •without the occurrence of marked structural changes in the tissues. If, on the other hand, a considerable amount of new tissue is produced in a short time, the proliferating cells form embryonic tissue consisting of cells, blood-vessels, and fibrillated ground-substance (Fig. 142). The extent of such formation naturally varies and is dependent partly on the capacity of the tissue for proliferation, and partly on the lesion leading to the prolifera- tion. Proliferating cells are always larger than the cells of fully developed, resting connec- tive tissue. They contain one, sometimes two large, bladder-like nuclei with nucleoli, (Figs. 142, 143), though multinuclear cells (Fig. 143, Ci), so-called giant-cells, also occur. In association with proliferating cells there are often cells that have escaped from the blood vessels, but which take no part in the formation of the new tissue. All those cells which are the antecedents of future tissue are designated formative cells; those giving rise to fibrous connective tissue are called fibroblasts (Figs. 143, b, c, d, e; 144, a), those forming cartilage and bone are known as chondroblasts (Fig. 146, a, c) and osteoblasts (Fig. 142, a, b, c) respectively. The shape of formative cells varies greatly (Fig. 143, b, c, d, e), and is dependent, partly on spontaneous changes of form and partly on the Fig. 144. — Development of con- nective tissue from fibroblasts (Miiller's fluid, picrocarmine). a. Fibroblasts; b, hyaline ground- substance with scattered fibrillas; c, fibroblast with adjacent fibres. X 400. Fig. 14s. — Scar of the skin, two years old, showing newly, formed elastic fibres (alcohol, orcein), a, Corium with normal elastic fibres; b, scar with newly formed elastic fibres. X 500. influence of environment, which under certain conditions compels the cells to take definite forms. The cells producing connective tissue usually present the greatest variety of form. When connective tissue is developed from cellular embryonic tissue, fine fibrillce (Fig. 143, d, e) appear in certain parts of the cell- protoplasm, or there is formed a homogeneous intercellular substance (Fig. 144, '&) in which fibrillje later appear. The formative cells at the same time diminish in size, and lie, for the most part, in small clefts (Fig. 143, e) in the ground-substance. 224 THE PROGRESSIVE CHANGES. Elastic fibres appear in newly formed connective tissue at a late stage, about three weeks at the earliest, and at the beginning form fine Fig. 146.— Periosteal formation of cartilape in a fracture five days old (Flemmmg s solution, hematoxylin, glycerin). a. Cellular embryonic tissue; b. cartilace; c, proliferating periosteal chondroblasts; d, cartilage-cells; di, 62, nuclear division- figures in cartilage-cells; e, ground- substance of embryonic tissue; /, ground-substance of the cartilage; g, capsule ot cartuage-ceus, h, proliferating endothelium of a blood-vessel. X 320. fibrillffi, which (Fig. 145, b) represent processes of older fibrils (a) and in part arise independently. , They are a differentiation product of the ground-substance and have no relation to the cells. nm^B^z^^ ^^ ^-^^ Fig, 147. — Endosteal formation of bone from masses of osteoblasts (Muller*s fluid, picric acid, hasmatoxylin, carmine). Preparation from the inner callus of a fourteen-day old fracture of the fibula of a man twenty-five years of age. a. Fat-cells of the endosteum; b, endosteum con- taining no fat; c, scattered osteoblasts; d, groups of osteoblasts; e, first step in the formation of ■the ground-substance of bone; f, developing trabeculse of bone; g, layer of osteoblasts lying upon the newly formed trabecule of bone; /t. Wood-vessel, x 150. They develop most abundantly in newly formed connective tissue in the blood-vessels and in the skin, but also in other regions, for example, in connective-tissue proliferations of glands, serous membranes, etc. REGENERATION OF BONE AND CARTILAGE. 225 In the development of hyaline cartilage there appears between the cells a hyaline basement-substance (Fig. 146, /), Avhile the chondroblasts (c) assume a more rounded form (rf). In time the ground-substance in- creases, the chondroblasts grow smaller and lie in rounded cavities whose walls are denser than the rest of the ground-substance and later form the part of the basement-substance called the cartilage-capsule {g). In the development of bone from cellular embryonic tissue there appears between the formative cells a dense homogeneous or fibrillated Fig. 148. — Formation of osteoid trabeculse from the proliferating periosteum. Preparation from a fourteen-day old fracture (Muller's fluid, picric acid, hematoxylin, carmirie). a. Fibres belonging to the outer periosteum; &, embryonic tissue; c, osteoid tissue; rf, cartilage; e, bone- marrow. X 75. basement-substance (Figs. 147, e, f; 148, c), osteoid tissue, which becomes impregnated with lime-salts and transformed into bone. When the ground-substance between the osteoblasts is of a loose fibrillar nature (Fig. 147, d) the transition into osteoid tissue is brought about through thickening of the ground-substance {e, /). The osteoblasts He in spaces of irregular outline (Figs. 148, c; 149, b), and are known as bone-cor- puscles. In extensive development of cellular embryonic tissue the change into bone is limited to certain parts of the tissue, and trabeculse (Fig. 148, c) are formed, which do not undergo full development into bone and are not calcified, so-called osteoid trabeculae. The embryonic tissue (&) lying between becomes changed into marrow-tissue, the cells being united to each other through processes, while be- tween them there appears a fluid base- ment-substance, in which round-cells later are embedded. If bone-tissue is to be deposited around old bony trabeculae, the osteoblasts (Fig. 149, c) arrange them- selves on the surface of the latter, and later produce bone (b) which appears as a lamella. Fibrillated connective tissue, bone, and cartilage are closely related and one may be transformed into the other (see § 88). Mucous tissue arises from embryonic tissue through the forma- tion of a mucin-containing, homogeneous, gelatinous basement-substance between the cells, which become united through processes to form a net- work. IS Fig. 149. — Formation of bone, through deposits made by osteoblasts upon tlie surface of old bone (Miil- ler's fluid, picric acid, hsematoxylin, carmine). a. Old bone; b, newly formed bone; c, osteoblasts, x 260. 226 THE PROGRESSIVE CHANGES. Lymphadenoid tissue can develop from embryonic tissue through the formation of a supporting reticulum in which lymphocytes gather. In injured lymph-nodes, the cells of the reticulum proliferate and form fibrous tissue; development of this connective tissue into lymphadenoid tissue either does not take place at all or but to a very slight degree. Spleen-tissue is not formed anew after injury; the wound heals through cicatrisation, nor does compensatory hypertrophy take place after the removal of large portions of the organ. Fat-tissue arises through the taking up of fat into fibroblasts, the cells becoming changed through the confluence of the infiltrated fat- droplets. The basement-substance of the tissues described above is a pro- duct of the protoplasm of the formative cells. Whether portions of the cell-protoplasm are changed directly into intercellular substance, or whether they secrete the latter, or separate it from the intercellular fluid, is a difficult question to answer; it is probable that only the firS't two methods of formation occur. Fibrillar connective tissue can develop from any connective tissue possessing the power of proliferation, but there must first be formed an intermediate stage of embryonic tissue. Bone arises from the periosteum, perichondrium, and endosteum, but may also develop from other connective-tissue substances, for example, from the inter-, muscular connective tissue and the connective tissue of blood-vessels. Cartilage arises from proliferating perichondrium, periosteum, endosteum, and from cartilage itself ; but may also be developed from other connective tissues, for example, the connective tissue of the testicle and parotid. New lymphadenoid tissue may, under pathological conditions, arise either from lymphadenoid tissue or fat-tissue {Bayer) or from fibrillated connective tissue. It is formed from the latter most frequently in the connective tissue of the mucosa and submucosa of the intestinal tract, as well as in the glandular organs ; rarely in the intermuscular connective tissue. New haemolymph-nodes are formed in adipose tissue after splenectomy (IVarthin). Mucous tissue may develop from any proliferating connective-tissue substance, but rarely appears in large masses, and is usually a transitory form passing over either into fat or connective tissue. Fat-tissue develops particularly in those regions normally containing fat, but occurs also at times in other places, for example, in the reticular connective tissue of atrophic lymph-nodes, in tlie perimysium internum of atrophic muscles, etc. The close relationship of the connective-tissue substances to each other enables the different forms to pass from one to another without the need of an intermediate stage of embryonic tissue produced by proliferation. Further details in regard to this point are contained in § 88. § 84. The regeneration of red blood-cells or erythrocytes occurs through mitotic division of nucleated young forms known as er5rthro- blasts (Bizzozero, Neumann, Flemming). In the adult this new- formation is restricted to the bone-marrow, and this is true also of other mammals, birds, reptiles, and tailless amphibians, while in the tailed amphibians and in fishes the spleen also shares in the process. In em- bryonic life the formation of the red blood-cell takes place throughout the vascular system, but later becomes restricted to the spleen, liver, and bone-marrow, and finally tO' the bone-marrow alone. The entrance of the red blood-cell into the circulation takes place after loss of its nucleus. In increased new-formation of red cells following loss of blood, as well as in chronic anaemias, nucleated red cells may appear in the circu- lating blood. The fatty marrow may again take on the character of REGENERATION OF BLOOD AND MUSCLE. 227 splenoid marrow, this change being accomplished by congestion of the blood-vessels with increase in the red cells of the marrow, while the fat in the recticulum disappears. The new-formation of colorless cells of blood and lymph, the leucocytes, occurs in the lymph-nodes and in the lymphoid deposits in the mucous membranes and spleen; and in the bone-marrow. The mononuclear cells, known as lymphocytes, develop almost exclusively in lymphoid foci, in the germinal centres of which mitoses may not in- frequently be found. (Fig. 150). The poly- nuclear leucocytes and eosinophile cells, on the other hand, are formed in the bone- marrow. Whether the large cells with clear nuclei known as mononuclear leucocytes, and the transition- forms with horseshoe-shaped nuclei, are formed in the bone-marrow is doubtful. They are often regarded as lymphocytes. A pathological increase of the colorless cells (leucocytosis) may take place through increased emigration of cells from the forma- tive tissues without actual increase in cell- production. Long-continued persistence of such an efflux, however, presupposes in- creased production. Transitory increase in the white cells is designated leucocytosis, while a permanent one is called leukcemia. The former is characterized by increase in the neutrophile polynuclear leucocytes, rarely by increase in the lymphocytes. Two forms of leujcsemia are distinguished: lymphatic leukamia, in which the lymphocytes are increased, and myeloid leukcemia, characterized by the appearance in the blood of myelocytes, mononuclear cells arising in the bone-marrow and provided with neutrophilic or eosinophilic granules. § 85. The regeneration of transversely striated muscle takes its start from portions of old muscle-fibres; and although, after injury to a muscle, the intermuscular connective tissue may be excited to prolifera- tion, there is formed only connective tissue, or probably the sarcolemma of new fibres, but never new contractile substance. The first signs of formative activity in muscle-fibres after injury ap- pear in the nuclei, which become elongated and 'divide into a varying number of fragmehts. Mitotic division occurs early and seems to be the only way in which multiplication takes place. The behavior of the contractile substance of the muscle differs ac- cording to the nature and extent of the injury. In traumatic, toxic, arid anaemic injuries it suffers fragmentation, so that the muscle-cells lie between the detritus of the muscle-fibres. Crushing and tearing bring about separation of the contractile substance. The ends of the muscle- fibres, in such case, may be conical, oblique, transverse, or irregular, but not infrequently become split into pointed filaments (Fig. 151, a). Mitotic division takes place, not only in nuclei that rest on living fibres (a), but also in the muscle-cells between the separated fibres (&) ; and in both places leads to the production of large cells, which form multinuclear masses at the ends of the muscle-fibres {e, f) as well as in Fig. 150. — Section from the germinal centre of mesenteric gland (after Flamming), a. Large; &, small lymphocytes; c, karyomi- toses; d, direct nuclear division or nuclear fragmentation; e, cells containing near the nucleus " tin- gible bodies " and small yellow pigment granules, whose signifi- cance is unknown, x 400, 228 THE PROGRESSIVE CHANGES. the body of the fibres (c). Into these the transversely striated muscle- substance passes without a sharp line of demarcation. There occurs, there- fore, with the multiplication of nuclei an increase of the sarcoplasm of the muscle-fibres. The muscle-cells not connected with living contractile substance be- come changed into cells with large nuclei (b). Through continued divi- sion of the nucleus these cells become transformed into_ multinuclear protoplasmic masses (d) ; a scar in muscle tissue from eight to thirty Fig. 151. — Portions of muscle-fibres showing regenerative proliferation, from muscle-wounds of diSEerent ages (Flemming's, safranin). a_. Pointed ends of the split stump of a muscle-fibre, with nuclear division-figures, three days after laceration of the muscle; b, proliferated muscle- nuclei transformed into cells rich in protoplasm, one of which is in process of mitotic division; c, piece of a muscle-fibre eight days after tying the muscle; d, giant-cells, enclosing necrotic pieces of muscle, from a muscle scar twenty-six days old; e, f, muscle-fibres ending in proto- plasmic masses (muscle-buds), e, from a muscle scar ten days old; J, from one twenty-one days old; g, dividing muscle-fibres from a muscle-scar forty-three days old. X 315. days old, contains giant-cells which often enclose the remains of old mus- cle-fibres (d) in large numbers. New muscle develops for the greater part from the richly nucleated sarcoplasm, which appears in and at the ends of the fibres, and through increase of size causes increase in the thickness and length of the mus- cles. With the transformation of the sarcoplasm into fibrillse there gradually appears longitudinal and later transverse striation, a sign that the structure has completed its development in the way characteristic of muscle. The greater number of proliferating muscle-cells which have no con- nection with living fibres die ; but it is to be noted that they persist for a long time, so that not infrequently there may be seen in muscle-scars from eight to forty days old protoplasmic masses rich in nuclei. These may form long, connected bands, or rows of separate pieces of proto- plasm. There can be no doubt that certain of these cells become trans- formed into transversely striated muscle-substance; this takes place by the formation of new and independent muscle-fibres or by union with old muscle-fibres or muscle-buds. The formation of disconnected muscle occurs particularly when the contractile substancfe is destroyed while the sarcolemma remains intact (as in Zenker's degeneration in typhoid fever). On the other hand, the formation of buds is observed especially at the ends of fibres which have been divided. REGENERATION. 229 The buds springing from the ends or sides of muscle-fibres may cause simple elongation of the fibre, frequently ■ deviating from its original direction (/). Often there are fibres which have split into two or three parts (g), and thus pass into the muscle-scar. As far as we know, this splitting of the fibre occurs early (a), before the proliferating muscle- nuclei have formed much sarcoplasm, so that proliferation appears first in the split portions. As a result of such splitting a muscle-scar may contain a greater number of muscle-fibres than were originally present in the affected area. Hypertrophy of transversely striated muscle takes place through en- largement of the individual fibres; the thin muscle-fibres in particular becoming increased in thickness. The nuclei do not increase in number. On the other hand, nuclear increase does take place in growth in the length of the muscle; and is the result, most probably, of amitotic division (Morpurgo). Regeneration of heart-muscle has not been positively demon- strated. After injuries of the heart, division figures appear in the mus- cle-cells, but after a few days these can no longer be demonstrated, and the wound heals through the formation of ordinary scar-tissue. Focal degenerations of the myocardium likewise heal by connective-tissue cica- trization. New-formation of smooth muscle-fibres occurs after traumatic or toxic and ischsemic degeneration. It occurs also in muscle tumors and is initiated by mitotic division of 'the nuclei, followed by division of the cells. According to the results of experimental work and of observa- tions on the muscle tissues of man, the reproduction of fibres after in- juries and focal degenerations is slight, ceasing after a short period. Thus, defects in the muscularis of the stomach and intestines or of the bladder are, for the most part, closed by connective tissue. Hypertrophy of smooth muscle-fibre is a phenomenon of frequent occurrence. In the pregnant uterus the muscle-cells may reach five to ten times the ordinary size. Of other organs the bladder most fre- quently shows marked hypertrophy of smooth muscle. § 86. Regeneration of the nerve-elements of the central nervous system through the reproduction of ganglion-cells most probably does not occur in man and mammals in post-embryonal life. According to the investigations of Stroebe, on the other hand, divided nerve-fibrils (in mammals) may grow lengthwise to a certain extent through sprouting of the axis-cylinder ; this is particularly true of the fibres of the pyramidal tracts and the posterior roots, both of which after being divided grow into the scar-tissue at the site of the wound, the former in a downward direction, the latter upward. Complete restoration of nervous tissue does not take place, and a defect in the spinal cord due to trauma is replaced partly by connective-tissue, in part by neuroglia. According to Borst, new axis-cylinders may be formed within the new neuroglia in the neigh- borhood of cerebral lesions, and medullary nerve-fibrils may be produced by the outgrowth of old fibres. Regenerative and hypertrophic proliferations of neuroglia are phe- nomena which occur frequently in diseased conditions of the central nervous system, and follow degenerative changes of the nervous ele- ments, or destruction of the neuroglia, or they may appear without such antecedents, in the latter case arising during the period of development. 230 THE PROGRESSIVE CHANGES. Fig. 152. — Sclerotic tissue from the posterior columns of a case of multiple sclerosis (Miillcr's fluid, Mallory's method), a, Glia-cells with numerous processes, seen in longitudinal sec- tion; b^ sclerotic tissue with transversely cut glia fibres, x 500, The new-formation is brought about by mitotic division of the nuclei and bodies of the gHa- or of the ependyma-cells.' The newly formed gha-cells produce a profusion of dehcate fibrillar processes (Fig. 152, a), and, as in the normal tissues of the central nerv- ous system, there may be distinguished among these two varieties of cells which are known as astrocytes (Deiter's cells), the so-called "mossy cells" (Kursstrahler) and "spider-cells" (Lang- strahler) with long, stiff, less-freely branching processes (a). The processes of these cells form sometimes a loose, sometimes a dense felt-work of fine fibrillje (a, b) in which the cells, which have but little protoplasm, are embedded. After full development of the tissue separation of the processes from the cell-bodies may take place. The thickening of the tissue caused by the proliferation be- longs to the process known as sclerosis. Regenerative new-formation of the nerve-fibres of the peripheral nervous system is of frequent occurrence and takes place in all those cases in which the con- tinuity of a nerve-fil?re is entirely or partially interrupted. For its accomplishment, how- ever, it is necessary that the ganglion-cells whose processes form the -nerve-fibres in question be preserved. When a nerve has been severed, the axis- cylinders and medullary sheaths, in the distal portion, undergo degeneration, the latter breaking up into drop-like detritus, which later is dissolved. During the disintegration of nerve-fibres the nuclei beneath the sheath of Schwann undergo mitotic division and form cells rich in protoplasm, which may take up the products of destruction of the nerve-fibres. Of the proximal portion of the nerve the peripheral extremity alone degenerates, as far as the next Ranvier's node, or the one beyond. Fig. 153. — Old and newly formed nerve-fibres from an ampu- tation-stump, in longitudinal sec- tion (Miiller's fluid, Weigert's stain). a, b. Old nerve-fibres, from which several young nerve- fibres have grown; c, neurilemma with young nerve-fibres, x 180. REGENERATION. 231 _ The regeneration of nerves begins a few days after the operation, in the proximal portion, about 0.4-2 cm. above the cut end. The first change consists in swelhng ^'-C''**''^~'* of individual axis-cyhnders in the peri- ^' ■■ pheral parts of the nerve-bundle of the 'rt^l4? proximal end, which is followed by ^-'f^r splitting-off of two to five or more new axis-cylinders. The axis-cylinders aris- ing in this way from the old ones ^rcw in a longitudinal direction (Fig. 153, a, b) and form, within the sheath of Schwann, whole bundles (Figs. 153, c; 154, e) of newly formed nerve-fibres, which fill the old nerve-tubes, and indeed stretch them; sometimes remains of old fibres are visible in the same sheath (Fig. 154, /)■ Single fibres may even break through the old sheath of Schwann, and then extend further in the e n d o neurium, or penetrate the perineurium in to the epineur ium. In this way there are formed on the lower end of the proximal portion of the nerve a large number of new nerve-fibres, which in the beginning consist only of the newly formed axis-cylinders, but immedi- ately surround themselves with a medullary sheath, which by reason of its irregular de- velopment gives to the nerve-fibres a vari- cose appearance (Fig. 153, c). Later the fibres acquire a neurilemma-sheath — that is, a connective-tissue covering which is probably formed from the nerve-corpuscles concerned in the proliferation. When a nerve is entirely severed and there is no possibility of union with the distal portion — as, for example, occurs in all amputations — there is formed in the region of the cut end an embryonic tissue, springing from the connective tissue of the nerves, which later becomes changed into connective tissue. In the beginning free from nerves this connective tissue be- ^'°- 1 5 s-— Amputation -neuroma of llt,c lium licivcs, LUIS 1,U11UCL,UVC LlbbUC uc (.ji^ sciatic nerve, in longitudinal sec- COmeS penetrated by young nerves grow- tlon (amputation of nerve nine years ing out from the fibres of the nerve-stump, Tnlro'^l^^x";."''"'"'^^- "' """"'= Fig, 154. — Cross-section of a nerve- bundle of the median nerve just above a wound dividing the nerve, made four months previously (Miil- ler's fluid, carmine), a. Perineurium; h, endoneurium; c cross-section of a vessel ; d, old unchanged nerve-fibre ; e, bundle of newly formed nerve- fibres; f, newly formed nerves, with remains of old fibres inside the same sheath, x 200. 232 THE PROGRESSIVE CHANGES. which, arranged in small bundles, or scattered, grow into the connective tissue in every direction (Fig. 155). Not infrequently the growth of nerves is so extensive thait nodular or clubbed swellings (Fig. 155, b) arise on the ends of the nerves. Such a swelling is known as an amputa- tion-neuroma. When a nerve after division is again united, or if the division is only partial, the nerve-fibres growing out from the proximal end, after pene- trating the connective tissue formed in the wound, may in part, or all, find their way into the peripheral portion of the nerve where, in the mean time, the nerve-fibres have been destroyed. In this way the distal end may again become neurotized — that is, supplied by new nerves. According to investigations of Forssmann, the direction of the newly growing fibres is governed by chemotactic influences arising from the disintegration-products of the old nerve-fibres. According to the investigations of Vanlair the growth of a regenerat- ing nerve is about 0.2—1 mm. daily, according to the character of the tissue. A portion of the new nerve-fibres may penetrate into the old, empty sheath of Schwann ; others extend into the epineurium and peri- neurium, and in this situation grow toward the periphery to the end-organ. Single fibres may pass by the end of the nerves, and grow toward the periphery, either along the old nerves or by an independent route. Many fibres, which leave the old route, are finally lost in the tissues. In the lower portion of the intermediate substance (Vanlair) the nerve-strands begin to collect into bundles again, and with the formation of a peri- neurium about the latter, the regenerated nerve takes on more and more the structure of a normal nerve. The above-described process of regeneration requires for its accom- plishment weeks or even months, and sometimes is not complete after several months. The question of the regeneration of the central nervous system is still under discussion. It is generally accepted that in the cold-blooded animals, reptiles, and tailed amphibia, regenerative new-formation of portions of the central nervous system can take place. In warm-blooded animals, particularly in the mammals, the majority of experimental investigations have failed to demonstrate regenerative new-formation of ganglion-cells. Tedeschi, Vitzou and others, claim to have observed, after injuries of various kinds, both new-formation of neuroglia and of ganglion-cells and nerve-fibres; but the investigations carried out in my laboratory by Tschistowitsch seem to me to contradict these assertions. The results obtained by Grunert in experimental work with pigeons agree with the con- clusions arrived at by Tschistowitsch. Monti and Fieschi could demonstrate no evidences of regeneration in the ganglion-cells of the sympathetic after injuries. Torelli found only degenerative changes in the ganglion-cells of the intervertebral ganglion after injury. The new-formation of peripheral nerve-fibres has been made the subject of experimental research, and different observers have come to different con- clusions (see Stroehe, I. c). The above-described mode of new-formation I regard as firmly established, in so far as its essentials are concerned, on the ground of personal investigations. I have been unable to confirm the views of Neumann, Dobbert, Daszkiewicz, Cattani, Wier Mitchell, Gluck, Beneke, von BUngner, Wieting, and others, who hold that the new fibres in the distal portion of the severed nerve rise autochthonously from the nuclei of the sheath of Schwann, or from the old axis-cylinder, or from a protoplasmic mass formed by chemical transformation of the medullary sheath and axis-cylinders (Neumann-Dobbert). The view held by Bethe, that the nerve-fibres arise without participation of the ganglion-cells in the fused ectodermic cells whose remains later represent the cells of Schwann, appears to me to have been shown by von Kolliker to be incorrect. Likewise the attempt made by Neumann and Wieting (Marchand) to bring into accord the established REGENERATION. 233 fact of the outgrowth of the axis-cylinders of the proximal portion into the scar uniting the severed ends, with the theory of the origin of new nerve-fibres from the nuclei of the sheath of Schwann, or from the remains of old fibres, or from both, by the assumption that the axds-cylinders growing from the proximal end convey a stimulus from the nerve-centres to the distal portion and thereby make possible the development of new fibres, I regard as unsuccessful, and hold to the above-given view. I am further of the opinion that the medullary sheath is not formed by the cells of the sheath of Schwann, but represents a product of the axis-cylinders. According to Nissl, Marinesco, and others (see Barbacci, I. c.) there occurs, after severing of a nerve, degeneration in the corresponding ganglion- cells with disintegration of the Nissl's bodies, and this may lead to the destruction of individual cells. Later, progressive changes with new-formation of chromatin take place, and may lead to hypertrophy of the cells (Marinesco) ; these changes reach their maximum in about ninety days, after which time there is a return to the normal condition. The fegenerative new-formation of the tissues of the eye has repeatedly been an object of research. According to Wolff, Miiller, and Kochs the lens of tritons may regenerate, after removal, by proliferation of the epithelium of the inner layer of the iris. According to Rothig, the same thing occurs in the trout. Gonin observed in rabbits, after the lens had been removed in such a manner that the capsule and some of the equatorial lenticular fibres and epithelium of the antej-ior wall were left behind, that there occurred proliferation of this epithelium, leading to the union of the anterior and posterior walls through cells resembling connective- tissue cells. A new-formation of lenticular fibres from these cells does not take place. Remains of the lenticular fibres may form a rudimentary, useless lens, which in young animals may become somewhat enlarged through the growth of the fibres. Randolph obtained somewhat better results in guinea-pigs. In the human eye sim- ilar form,ations are seen after removal of the lens, and are known under the name of " Krystallwulst " (Baas). According to Pranke, Kruckmann, and Stoewer, the sclera possesses but slight power of proliferation. Wounds of the same are healed chiefly through proliferation of the choroid and_ episcleral tissue. According to Baquis, there occurs, in the injured retina of the rabbit, division of both ganglion and neuroepithelial cells. According to Kriickmann, the pigment- epithelium is capable of extensive regeneration, but neuroepithelium, on the other hand, is not again formed. Literature. (Regeneration of the Elements of the Central Nervous System.) Bardeen: The Histogenesis of the Cerebrospinal Nerves. Am. J. of Anat., iv., 1903. Borst: Regenerationsfahigkeit des Gehirns. B. v. Ziegler, xxxvi., 1904. Grunert: Regenerationsfahigkeit d. Gehirns. Arb. a. d. path. Inst. Tiibingen, ii., 1899. Monti et Fieschi: Guerison des bless, des ganglions sympathiques. Arch ital. de Biol., xxiii., 189S. Stroebe: Heilung v. Riickenmarkswunden. Beitr. v. Ziegler, xv., 1894; Histol. d degen. u. regen. Processe im centralen Nervensystem. Cbl. f. allg. Path., 1895 (Lit.). „ . ^. , Tedeschi: Regen. d. Gewebe d. Centralnervensystems. Beitr. v. Ziegler, xxi., 1897. , , ^ Tirelli: Proc. repar. dans le ganglion intervertebral. Arch. ital. de Biol., xxiii., Tschisto'witsch: Heilung von Hirnverletzungen. B. v. Ziegler, xxiii., 1898. Vitzou: La neoform. des cell, nerveuses dans le cerv. du singe. Arch, de phys., ix., 1897. {Regeneration of the Peripheral Nerves.) Barbacci: Die Nervenzellen (Verand. nach Nervendurchschneid.). Cbl. f. a. Path., x., 1899 (Lit). . . Bethe: Allg. Anat. u. Phys. des Nervensystems, Leipzig, 1903. Forssmann: Ursache der Wachsthumsrichtung d. periph. Nervenfasern. Beitr. V Ziegler, xxiv., 1898; Neurotropismus. lb., xxvii., 1900. Galeotti u. Levi: Neubildungen nerv. Elem. im regen. Muskelgewebe. Beitr. V. Ziegler, xvii., 189S (Lit.) 234 THE PROGRESSIVE CHANGES. Huber: A Study of the Operative Treatment for Loss of Nerve Substance in Peripheral Nerves. Jour, of Morph., vol. xi., 1895. V. KoUiker: Die Entwickelung der Nervenfasern. Anat. Anz., xxv., 1904. Neumann: Degeneration u. Regeneration nach Nervendurchschneidung. Arch. d. Heilk., ix., 1868; Nervenquetschung u. Nervenregeneration. Arch. f. mikr. Anat., xviii., 1880; Axencylindertropfen. Virch. Arch., 158 Bd., 1898. Nissl: Verand. d. Ganglienz. d. Fac. n. Ausreiss. d. Nerven. A. Zeit. f. Psych., 48 Bd. Peterson: Peripheral Nerve Transplantation Amer. Jour, of Med. Sc, 1899. Stroebe: Degeneration u. Regeneration periph. Nerven. Beitr. v. Ziegler, xiii., 1893; Cbl f. allg. Path., vi., 1895 (Zusfass. Ref. iib. Regen. d. Nerven u. d. Endapparate). Vanlair: Arch, de biol. de van Beneden et van Bambeke, 1882-85; Arch, de phys., x., 1882; vi., 1885; viii., 1886; Compt. rend, de I'Acad. des sciences, 1885 ; Sur I'innervat. indirecte de la peau. lb., 1886 ; De I'organisat, des drains de caoutchouc, etc. Revue de Chir., 1886; La suture des nerfs, Bruxelles, 1889; La persistance de I'aptitude regeneratrice des nerfs. Bull, de I'Acad. Roy. de Belgique, 1888; Rech. chronometriques sur la regen. des nerfs. Arch, de phys., vi., 1894. Wieting: Regen. periph. Nerven. Beitr. v. Ziegler, xxiii., 1898. {Regeneration of the Tissues of the Eye.) Baquis: fitude exper. sur les retinites. Beitr. v. Ziegler, vi., 1888. Gonin: Regen. du cristallin. Beitr. v. Ziegler, xix., 1896 (Lit.). Kochs: Regen. d. Organe bei Amphibien. Arch. f. mikr. Anat, 49 Bd., 1897. Kriickmann:' Pigmentzellen der Retina. Arch. f. Ophthalm., 48 Bd., 1899. Miiller: Regen. der Linse bei Tritonen. Arch. f. mikr. Anat., 48 Bd., 1896. Randolph: The Regeneration of the Crystalline Lens. Johns Hopkins Hosp. Rep., ix., 1900. Schimkowitsch: Linsenregen. bei Amphibien. Anat. Anz., xxi., 1902. Stoevyer: Heilungsvorg. bei Wunden d. Auges. Arch. f. Ophthalm., 46 Bd., 1899. Wolff: Linsenregeneration bei Tritonen. Biol. Cbl., xiv., 1896; An. Anz., xviii., 1900; Regen. d. Urodelenlinse. A. f. Entwickelungmech., xii., 1901. III. The Results of Transplantation and Implantation of Tissues and Organs. § 87. The local regeneration of tissue is, as mentioned in the last part, often but slight, so that losses of tissue may be followed by permanent defects, and in place of the original structures there may appear only cicatrical tissue of lesser value. Consequently, many attempts have been made, through transplantation and implantation of tissue, to improve the healing-process ; such attempts have in part been successful. At the same time they have thrown light on the individual life of the tissues and on the behavior of the organism toward implanted living tissue. The most successful results have been obtained in the transplantation of tissues zt'hich remain connected with their nutrient vessels, since, at the point of union the transplanted portion and the fixed tissues grow- together in essentially the same manner as do the edges of an incised wound. This method is utilized most frequently in plastic operations on^ the surface of the body, but it also finds application in internal surgery. Transplantations of tissues completely freed from their basement- structvu-es have been successfully performed. The cells of the epi- dermis are able to live for the longest time. Ciliated epithelium may be preserved for days and still show movements of the cilia. Next to the surface-epithelium stand the connective tissues, other tissues quickly die, the cells of the brain and kidney within a few hours after TRANSPLANTATION OF TISSUES. 235 obstruction to the blood supply. According to the investigations which have been made up to the present time the tissues of the skin, periosteum, inter-articular cartilages, muscle and cartilage most easily preserve their vitality. Morpurgo found cells of the periosteum to be capable of repro- duction after seven to eight days. The vessels, tendons, and neurilemma appear to be even more resistant. Transplantations of skin give the best results, and were first recom- mended by Reverdin and Thiersch for the healing over of open wounds 0JM - Fig. 156. — Skin-graft four and one-half days old (formalin, hsematoxylin, picrofuchsin). c. Deep layer of the cerium; b, proliferating granulation-tissue; c, boundary of proliferating zone; d, e, transplanted portion of skin; f, desquamation of the horny layer; g, vascular offshoots and granulation-tissue extending into the transplanted connective tissue. X 107. and have since been extensively used for this purpose. The material used consists of pieces of skin taken from the same individual or from another person. Ordinarily, strips of skin removed by means of a sharp knife are used, and include the tips of the papillae and the upper layers of the corium. Epithelium in connection with a thicker layer of the corium may also be successfully transplanted, and in injuries large portions of skin which have been completely torn off may be again joined to the deeper tissues on the same spot from which they were removed. The transplantation may be made either on a fresh wound or on one showing proliferation. The strips of skin are held in place by mechanical means. The pieces of skin become fastened to the surface of the wound by coagulated blood or lymph. In successful cases union with the under- lying tissue takes place in about eight days. The nourishment of the transplanted pieces (Fig. 156, rf) is obtained 236 THE PROGRESSIVE CHANGES. from the fluids which exude from the underlying tissues. Later, there begins in the latter vascular connective-tissue proliferation (b, c), and the transplanted portion becomes penetrated from below by «ew blood- vessels (g) and by fibroblasts, so that it finally becomes interspersed with granulation tissue. Under favorable conditions the old vessels may again become opened through the ingrowth of new vessels. The behavior of the transplanted portion varies in individual cases. A part of the transplanted tissue is always lost (/). Other cells, both epithelial and connective-tissue, proliferate and produce new tissue. The outcome of a successful transplantation is the covering over of the area with epithelium and corium. Through the latter it is possible for the cicatricial area to possess papillae. To what extent the superficial layers of the cutis arise from the graft or to what extent from the tissue upon which it is planted, cannot be determined. If the papillary bodies are preserved, a portion of the tissue may be formed from immigrating fibroblasts. After a time the transplanted area comes to contain nerves. The tactile sense is first restored (Stransky), later the sensibility to pain and temperature. New elastic tissue also develops, as in ordinary scars, from the ends of old fibres. Besides skin-transplantations, there have been attempted transplanta- tions of almost all the tissues : periosteum, bone-marrow, bone, muscle, nerves, thyroid, pancreas, adrenals, mammary gland, mucous glands, ovary, testis, etc. ; also of tissue-combinations, for example, a rat's tail from which the skin has been stripped. Embryonal tissue has also been transplanted in a variety of ways. Finally the attempt has been made to transplant tissues from one animal to another of different species. Such transplantations have been made on open wounds, in the sub- cutaneous tissues, peritoneal cavity, glandular organs and lungs, either by direct operative procedures or by the introduction of the tissue into the blood-stream. The results of these experiments may be summed up as follows : In all transplanted tissues there first occurs degeneration, and a part of the tissue dies. After a time there usually results proliferation of the remaining portion, which may lead to new-formation of tissue. Con- nective-tissue cells form new connective tissue; periosteum and end- osteum form bone or connective tissue ; muscle-cells, new muscle ; carti- lage, new cartilage; surface epithelium, new epithelium (epithelial cysts). Of the glands the thyroid, mucous glands, and mammary glands may form new glandular tissue; such new- formation does not take place in the case of the kidney, liver, testis, and ovary. Of the liver only the epithelium of the bile-ducts proliferates. Only in the transplantation of the ovary into the peritoneal cavity of the same animal can the ova ripen and pregnancy occur (Knauer, Ribbert, Gregorieff). The tissues of young individuals in general show a greater capacity for proliferation than those of old ones. In the transplantation of complicated tissues, for example, the skinned tail of a rat, all the tissues may produce new tissue and the whole may grow. Embryonal tissue can likewise grow after transplantation and become differentiated ;_ cartilage, which in later life shows but little power of proliferation, _is longer preserved and shows further growth, while the delicate soft tissue-formations easily die. After a time there occurs in almost all transplanted tissues, as well as in t'-e revly formed tissue, a retrograde change, and they are finally ' METAPLASIA. 237 destroyed through the ingrowth of tissue from the neighborhood. The time at which this occurs varies with different tissues, and is dependent partly on the character of the tissue, and partly on surrounding con- ditions. Implanted surface-epithelium can remain permanently, and give rise to epithelial cysts. Portions of thyroid, mammary gland, and pan- creas are preserved for a long time. Cristiani found pieces of thyroid iritact two years after implantation. The majority of tissues, however, disappear_ in a few months. In glands which are not capable of proliferation the gland-cells die first. If all of the implanted piece is not destroyed it may become encapsulated. Tissue of different species, when transplanted, does not grow, but is destroyed or encapsulated, sometimes quickly, sometimes slowly. According to published observations, the implantation of tissue does not lead to the formation of permanent tissue except in transplantation of skin. Nevertheless, such implantation may have a transitory or perma- nent value. The implantation of thyroid or pancreas may for a time check the harmful consequences of the loss of these glands. Through implantation of tissue into a defect temporary filling of the latter may be produced, and the neighboring tissues are thus permitted to proliferate for a longer time, and to form a greater amount of new tissue along the framework afforded by the implanted portion, and so to close the defect completely. Bone (not connected with nutrient vessels) when implanted into a part of the skeleton is absorbed (equally so whether living or dead bone is implanted), and is replaced by new bone arising from the neigh- boring periosteum and endosteum. In this way there may be better heal- ing of the defect; implantations of bone or cartilage may also be made use of in other tissues, for the stimulation of more abundant production of tissue for the purpose of filling tissue-defects. The transplantation of nerves has never resulted in the new-formation of nerve from the transplanted piece. The attraction which the prod- ucts of disintegration of a nerve (Forssmann) exerts on the axis-cylin-, ders growing into a wound may be utilized to direct the course of grow- ing nerves into certain channels. IV. Metaplasia. § 88. Metaplasia is that process by which a tissue is changed into an- other closely related without the intermediation of embryonic or granula- tion-tissue. Metaplasias play an important role in the development of indi- vidual connective-tissue formations, particularly in bone, cartilage, and marrow-tissue. Through proliferation of the periosteum or -endosteum there is produced ordinary fibrillated connective tissue which later under- goes metaplasia into osteoid tissue, bone, or cartilage. In the metaplasia of connective tissue into osteoid tissue there occurs without further cell- proliferation condensation of the ground-substance (Fig. 157, a, b) which leads by gradual transformation to an osseous ground-substance (c) staining red with carmine or eosin or fuchsin. Deposit of lime-salts (Fig. 158, r) completes the process of metaplasia into true bony trabeculce. In the metaplasia of connective tissue into cartilage the ground-sub- stance becomes thicker but more clear and stains less intensely (Fig. 159, c) than the connective tissue (&). The cells increase in size and lie in round spaces. Such changes may be observed in the periosteum and endosteum as the result of traumatic or infectious processes or in 238 THE PROGRESSIVE CHANGES. the new-formation of fibrous tissue associated with tumor formations (Figs. 157 and 159). In wounds of the trachea which are first closed by scar-tissue, cartilage may be later developed by proliferation of intact perichondrium and metaplasia into cartilage (Fig. 160, b). If normal or pathological new-formed cartilage becomes penetrated by Fig. 157. — Periosteal formation of bone in a case of metastatic carcinoma of a rib. (Heema- toxylin, picric acid, fuchsin.) a, Fibrillated connective tissue; h, connective tissue undergoing condensation; Cj fully developed bone, x 300. blood-vessels the ground-substance may undergo solution and the carti- lage cells form reticular connective tissue with branched processes in the interstices of which certain cells gather, so that the whole takes on the character of bone-marrow; by taking up fat it may be transformed into adipose tissue (Figs. 161, b, c, and 162, /). If, in the vascularization of cartilage, trabecule of cartilage re- main, these may be transformed into osteoid tissue (Fig. 162, /) which when stained with hjEmatoxyl'.n and eosin takes an intense red stain, while the unchanged cartilage stains blue. Through the deposit of lime-salts it may later be changed into bone. In chronic inflammation of the joints, cartilage may be transformed into ordinary fibrillated connective tissue, particularly when its free surface is covered with connective tissue. The metaplastic processes thus de- ■'ii?;°'d? scribed are connected with preceding proliferations and may be associated with further appearances of pro- liferation. But there are metaplasias which have no connection with any proliferative change, or are only associated with it at a later period ; thus rnyxomatous becomes changed into adipose tissue when the star-shaped tissue-cells become round through the taking up of fat, while the mucoid Fig. 158.- — Formation of bone from con- nective tissue (alcohol, hasmatoxylin). Cross- section through a bone trabecula in process of formation; from an. ossifying fibroma of the periosteum of the upper jaw. a. Con- nective tissue; 6, thickened tissue, forming the groundwork of the new bone; c, of lime-salts; d, connective-tissue cell bone-cells, x i8o. METAPLASIA. 239 ' ground-substance disappears. Lymphadenoid tissue may, after disap- pearance of the lymphoid elements, be changed into adipose tissue through the absorption of fat droplets by the cells of the stroma. Through Fig. 159, — Periosteal formation of cartilage in metastatic carcinoma of a rib. (Hsema- toxylin, picric acid, fuchsin.) a, Fibrillated connective tissue; b, connective tissue undergoing condensation; c, fully developed cartilage, x 300. Fig. 160. — Healed tracheotomy wound in the cricoid cartilage, fifty-two days old. (Formalin, hajmatoxylin, and eosin.) o. Old cartilage; b, b, connective tissue arising from the perichondrium undergoing metaplasia into cartilage, x 60. 240 THE PROGRESSIVE CHANGES. the disappearance of fat, adipose tissue may take on the appearance of mucoid tissue, and occasionally comes to contain mucin. In the change of connective tissue into myxomatous tissue the fibrillas 4t> l-i. . I j^ Fig. i6i. — Metaplasia of cartilage into reticular tissue, in arthritis fungosa (alcohol, hasma- toxylin). a. Hyaline cartilage; h, tissue consisting of branched cells; c, cartilage-cells, set free by the liquefaction of the basement-substance of the cartilage, and becoming transformed into cells of mucous tissue. X 400. 9 . j^"?' 162.— Metaplasia of cartilage into osteoid tissue, in a callus fourteen days old (Mailer's fluid, picric acid, hematoxylin, carmine), a, Hyaline cartilage; b, marrow-spaces; c, blood-vessel; a, cellular, e, fibrocellular marrow; f, osteoid tissue; g, osteoblasts; h, cartilage-cells freed through the disappearance of the ground-substance; i, proliferating cartilage-cells in opened capsule; ft, proliferating cartilage-cells in closed capsule, x 200. vanish and there appears in their place a jelly-like mucus. If sufficient numbers of lymphoid cells collect in connective tissue and there occurs at the same time disappearance of the connective-tissue fibres, while METAPLASIA. 241 the connective-tissue cells unite through their processes to form a reticu- lum, lymphadenoid tissue is developed. Epithelial metaplasia occurs most frequently in chronically inflamed mucous membranes, for example, uterus, urethra (gonorrhoea), nose (ozsena), and trachea, cylindrical being transformed into pavement epithelium. This change occurs in the following manner: after repeated loss of epithelium the regenerating epithelium changes its character. In mucous membranes possessing stratified pavement-epithelium the upper layers may show^ cornification, not only in places which nor- mally possess pavement-epithelium, as the tongue and cheeks, but also in those possessing transitional epithelium (the urinary tract), or cylindrical epithelium (nose, ureters, and gall-bladder). In con- nection with this phenomenon should be mentioned the fact that epithelial tumors arising in mucous membranes possessing transi- tional or cylindrical epithelium may bear the character of squamous- cell tumors. Literature. (Metaplasia.) Dietz: Plattenepithelkrebs d. Gallenblase. V. A., 164 Bd., 1901. Hansemann: Studien iib. Specificitat, Altruismus u. Anaplasie d. Zellen, Berlin, 1893. Kischensky: Plattenepithelkrebs der Nierenkelche. B. v. Ziegler, xxxi., 1901. Lubarsch: Die Metaplasiefrage. Arb. a. d. p. I. v. Lubarsch, Wiesb., 1901. ZeUer: Plattenepithel im Uterus. Zeitschr. f. Geburtsh., xi., 1885. CHAPTER VII. Inflammation. I. The Early Stages of Acute Inflammation. § 89. Under the designation inflammation are grouped phe- nomena which represent a combination of pathological J»rocesses, consisting of tissue-degenerations and tissue-proliferations, and of exudations from the blood-vessels. Degenerations of tissue and patho- logical exudations initiate the process; with these tissue-proliferation is sooner or later associated, the latter leading in the further course of the process to compensation for the disturbance — that is, to healing. The proliferation of tissue may, therefore, be regarded as regenerative, but such new-formation of tissue may be in excess of that which is useful to the body. The tissue-degenerations and proliferative processes de- scribed in the previous chapters appear for the greater part as participat- ing factors in inflammation ; the inflammatory process acquiring its char- acter through the combination of tissue-degenerations and tissue-pro- liferations zvith pathological exudations. ' Injury of tissues containing blood-vessels produces changes which con- stantly bear at some time during their course the character of an inflam- mation. The formation of scar tissue, the healing of transplanted tissues, as briefly described in the last chapter, always take place through proc- esses that are essentially inflammatory in nature. Exudation in acute inflammation is constantly associated with hypercumia, which appears even before the beginning of exudation, and hence ushers in the latter. As a result of the combination of hypersemia and exudation the inflamed tissue becomes reddened and swollen. When situated on the surface of the body the increased flow of warm blood from the deeper tissues causes local increase of temperature. If the in- flamed tissue contains sensory nerves, pain will be produced as the result of the mechanical effects of the exudate. Redness, swelling, increased warmth, and pain are phenomena which even in ancient times were regarded as the signs of inflamma- tion ; rubor, tumor, calor, and dolor were designated by Celsus the cardinal symptoms of inflammation. To these four was then added a further symptom, functio laesa, altered function of the inflamed tissue. The causes of inflammation lie in mechanical, thermal, bacterial, electrical, or chemical influences. The common characteristic of all these injurious agencies is the production, in the first place, of local tissue- degeneration, which, when of a certain extent and intensity, is associated with disturbances of the circulation and exudation from the vessels. The causes of inflammation are not specific; any injurious agent may excite inflammation if its action is sufficiently intense to cause certain disturb- ances of circulation in assooiation with tissue-degenerations, but not so intense as to destroy the tissue and stop the circulation. The majority of the causes of inflammation reach the body from the outside, but excitants of inflammation may be formed within the body. 242 CAUSES OF INFLAMMATION. 243 Bacteria which have penetrated into the tissues often form in their proto- plasm or from substances present in the body products which are capable of exciting inflammation. Moreover, substances that excite inflammation may arise in the organism without the aid of parasites ; particularly as the result of the death of large masses of tissue from any cause, or when in metabolic processes abnormal products are deposited in the tis- sues. The causes of inflammation may act on the tissues from portions of the body accessible from without, or from the lymph and the blood ; and we may, therefore, distinguish ectogenous, lymphogenous, and haematogenous inflammations. Through the spread of inflammation to neighboring tissues there arises inflammation by continuity; as the re- sult of transportation through the lymph or blood stream of an agent causing inflammation, there are produced metastatic inflammations. If injurious substances are discharged through the excretory organs, excretory inflammations may arise. When local injury to tissues has reached such a degree as to produce the exudation characterisitic of inflammation, there is an associated hyperaemia, as a result of which the blood flows through the dilated vessels with increased velocity. After a short time, lessening of the speed of the circulation leads to abnormal slowing of the current. The disturbances of circulation, which find expression in hyper- emia, may be due to stimulation or paralysis of the vasomotor system or to direct action on the vessel-walls, particularly the arterial walls, leading to dilatation of the lumen. Although these disturbances fre- quently precede the inflammatory exudation, they do not belong ex- clusively to the process of inflammation, but often occur without being followed by inflammatory exudation. Further, they may be absent dur- ing the course of an inflammation. The circulatory disturbances charac- teristic of inflammation are shown only when slowing of the blood-cur- rent and exudation from the blood-vessels set in. Slowing of the blood- stream and exudation are dependent on a change in structure, an alter- ation of the vascular walls, through which there results lasting dilata- tion of the vessel and adhesion of the blood to the vessel-wall, causing increase of frictional resistance and increased permeability of the vessel- wall. In the capillaries the persistent dilatation is in part the result of relaxation of the connective tissue surrounding the capillaries, inasmuch as the thinness of the capillary walls makes this tissue bear the greater part of the blood-pressure resting upon them. The tissue-lesion which leads to disturbances of circulation and exu- dation usually affects all parts, but under certain conditions may_ be limited to the vessel-wall, particularly in haematogenous inflammation, in which the injurious agent acts from the blood. However, the tissue adjoining the capillary walls must soon become involved. The tissue- changes brought about by the excitants of inflammation are sometimes slight, and even on microscopic examination are not recognizable at all or with difficulty; at other times they are so severe that they may be easily recognized on macroscopic examination. The latter is particularly true when some time has elapsed afier the action of the injurious agent. During the further course of the inflammatory process there are often added to the lesions produced directly, by the causes of inflammation other tissuc'changes, which are brought about by disturbances of circu- lation and the collection of exudate in the tissues. 244 INFLAMMATION. If in any tissue the cause of inflammation has led to that alteration of the vessels which is the requisite antecedent for the formation of an exudate, and if as a result of this alteration there is slowing of the blood-stream, the capillary circulation becomes irregular, due either to complete or transitory stasis in different areas. In this event the white blood-corpuscles often remain .clmging to the vessel-walls while the red blood-cells are carried on, and there arises in the capillaries a more or less marked increase of white blood-corpuscles as compared to the red. Fig. 163. — Inflamed human mesentery (osmic-acid preparation). a, Normal trabecula; fc, normal epithelium (endothelium); c, small artery; d, vein with leucocytes arranged peri- pherally; e, white blood-cells which have emigrated or are emigrating; /. desquamating endO' thelium; ji, multinuclear cells; g, extravasated red blood-cells. X 180. In the veins, in which there can be distinguished in the normal circu- lation an axial red stream and a peripheral plasma-zone free from cells, greater or less numbers of leucocytes pass over into the plasma-zone, when the slowing of the circulation has reached a certain degree. Still greater slowing of the current leads to the passing over of blood-plates and red cells, and finally the distinction between axial-stream and peri- pheral zone may be entirely lost. When leucocytes pass over into the peripheral zone they either roll along or cling to the wall of the vein, either to roll on again or to remain attached. If this leads to marked accumulation of leucocytes along the vein-walls, the condition is known as marginal disposition of white cor- puscles (Fig. 163, (i). Following the accumulation of the leucocytes in the capillaries and the marginal disposition in the veins there occurs emigration of leucocytes (Fig. 163, d, e) from the vessels involved, and at the same time fluid escapes from the vessels into the tissues. The emigration of white corpuscles is an active process, and is ac- complished through the amoeboid movement of the cells; to a certain extent it occurs under normal conditions. The cause of the marked emi- EXUDATION. 245 gration seen in inflammations is doubtless a change in the vessel-walls, which favors the clinging of the cells to the walls and their passage through the latter. According to investigations by Arnold, Thoma, and others, the leucocytes pass out through the lines of cement-substance between the endothelial cells ; and in the alteration of the vessel-wall due to inflammation localized defects occur as the result of widening of these lines. The emigration is accomplished by the leucocytes sending a process through the vessel-wall, the remainder of the cell-body flowing after the process, until finally the entire cell is outside the vessel. Ar- rived here the leucocytes remain for a while in the immediate neigh- borhood of the point of diapedesis, but then wander farther, the direc- tion being determined partly by mechanical stimuli, partly by chemotaxis — that is, the repulsion or attraction exerted by chemical substances in the tissue-juices. Possibly chemotactic influences exert an action even on the leucocytes in the capillaries or in the peripheral zone of the veins. The cells emigrating from the vessels are almost exclusively polynuclear leucocytes, but lymphocytes may accompany them. Polynuclear leucocytes, passing out in great numbers and accumulating in the adjacent tissues, are known as pus cells.. The pouring-out of fluid exudate, whose composition differs more or less from that of normal tissue-lymph, and is characterized by a relatively high albumin-content, is a process also to be referred to alteration of the vessel-wall. It takes place at the same time as the emigration of leuco- cytes, but may begin before this event, and may also occur in cases in which the emigration of leucocytes does not take place at all, or remains within narrow limits. The composition of the exudate varies, but it may be assumed that the albumin-content is higher the greater the damage to the vessel- walls. If the extravasated fluid contains fibrinogenic sub- stances separation of fibrin and coagulation occur. If the alteration of the vessels is of high degree, or if at the same time there is marked stasis, red blood-cells may pass out of the vessels (Fig. 163, gr) with the fluid, either by rhexis or diapedesis. According to Thoma and Engelmann rhexis of red cells occurs particularly in those places where leucocytes have previously passed through the vessel-wall. Since red cells are not motile, their escape must be regarded as a passive process performed under the influence of pressure. The escape of blood-plates may take place both in exudates rich in cells and those containing few, but occurs particularly in exudates with an abundance of fibrin and red blood-cells. Tissue-proliferation — that is, division of cells and nuclei- — is first recognizable about eight hours after the action of the injurious agent; and in many cases appears later. In other words, tissue degeneration and exudation from the vessels precede proliferation, assuming, of course, that the inflammation does not arise in a tissue which is already in a state of proliferation. The clinical significance of the term inflammation (inflammatio, phlogosis) has changed biit little in the course of time, since the cardinal symptoms of inflammation set forth by Celsus, and accepted by Galen, are recognized as such at the present day. Nevertheless, the views regarding the differentiation of the essential from the unessential in the symptom-complex of inflammation and the accurate determination of the true nature of the process have differed greatly. A comparison of the expressions concerning these points made by the more modern writers (Virchmv, von Recklinghausen, Cohnheim, Ponfick, Samuel, Thoma, Neumann, Strieker, 246 INFLAMMATION. Heitzmann, Grawitz, Leber, Metschnikoff, and others) shows that no single writer defines inflammation in the same way as any other, or interprets in exactly the same way any one of the individual phenomena of inflammation. Ponfick designates as the cause of inflammation the disturbance of equilibrium in the tissues, " but hesi- tates to designate retrogressive changes as an indispensable attribute of the inflam- matory process, and doubts wholly that they should be regarded as the point of departure and the chief feature of the process." I am of the opinion that " a dis- turbance of the tissue-equilibrium " is nothing more than a degenerative change of tissue, and regard Ponfick's statement, though directed against my definition, as harmonizing with my views. Moreover, I once again emphasize the fact that the alteration of the vessels is a necessary requisite for exudation, and that this altera- tion is nothing else than a tissue-degeneration. It was formerly believed that hyperemia was the essential symptom of inflam- mation. Rokitansky held that every inflammation was characterized by dilatation of the capillaries, slowing of the blood-stream, and by stasis caused by thickening of the blood through the effusion of serum and adhesion of the red blood-cells to one another. Henle, Stilling, and Rokitansky attributed dilatation of the vessels and slowing of the circulation to paralysis of the nerves of the vessels, the cause of which, according to Henle and Rokitansky, is increased stimulation of the sen- sory nerves; while according to Stilling, the cause lies in paralysis due to the in- flammatory irritant. Eisemann, Heine, and Brilcke sought to attribute the circu- latory disturbances to primary spasm of the vessels brought about by irritation of sensory nerves, which produces behind the contracted portions of the vessels slow- ing of the current, irregular circulation, and finally stasis. Vogel, Emmert, Paget, and others, on the other hand, attributed dilatation of the vessels and stasisi to ab- normal attraction of the blood by the tissues. Against these views it must be maintained that the disturbances of circulation produced by contraction or dilatation of the vessels introduce or accompany those leading to exudation, and may exert a modifying influence on the course of inflammation, but do not form an essential part of the process, and may be entirely wanting, or may appear without the accompaniment of an inflammatory exudate. The recognition that the formation of the exudate is to be referred to injury of the vessel-walls we owe chiefly to Cohnheim, whose investigations were com- pleted by Samuel, Arnold, Thoma, Binz, and others. Cohnheim also showed that in inflammation the colorless corpuscles emigrate, and form an essential constituent of the exudate. Dutrochet (" Rech. anatomiques et physiologiques sur la structure interne des animaux et des vegetaux et sur leur motilite," Paris, 1842, p. 214) and Waller {Philosoph. Magaz., xxix., 1846, pp. 271, 398) as early as 1842 and 1846, respectively, described the escape of colorless corpuscles from the blood-vessels. These observa- tions had, however, fallen into oblivion until Cohnheim, in 1867, rediscovered the phenomenon. According to researches of Schklarewsky^ {P finger's Arch., Bd. i.), the peri- pheral disposition of the leucocytes in the veins is purely a physical phenomenon. If fluids, in which are suspended finely powdered substances of different specific gravity, are made to flow through tubes, it will be found that at a certain degree of retardation of the current, the bodies of lighter specific gravity pass over into the peripheral zone and at a more marked retardation the heavier bodies also enter this zone. For~ the emigration of the white corpuscles, it is necessary, according to Binz, Thoma, and Lavdowsky, that they be capable of motion and of adhering to the vessel-wall. According to these observers, the emigration of the white blood-cells is not a passive, but an active process. If the amoeboid power of the white cells be lessened by means of irrigation of the mesentery with a 1.5-per-cent. solution of salt {Thoma), or if the energy of these cells be lowered by means of quinine or iodoform {Bim, Appert, Kerner), there results inhibition of emigration. On the other hand, Pekelharing believes that quinine, oil of. eucalyptus, and salicylic acid cause contraction of the veins, lessen the permeability of their walls, and thereby hinder the passing-out of white cells. This view is rejected, however by Dissel- horst, who observed dilatation of the veins after irrigation of the tissues with quinine, carbolic acid, salicylic acid, and mercuric chloride. As there occurs in this case retardation of the current after transitory acceleration, without emigra- tion of the^leucocytes collected in the peripheral zone; and as, on the other hind, leucocytes from blood-vessels that have been irrigated for an hour with quinine still retain complete vitahty (Eberth), Disselhorst is of the opinion that the drugs EMIGRATION. 247 mentioned so change the inflamed vessel-wall that adhesion of the leucocytes roll- ing along the wall either cannot occur at all or only with difficulty. It is probable that a lesion of the vessel-wall is not necessary for the emigra- tion of leucocytes (r/jojMo). Since vasomotor disturbances of circulation can pro- duce migration (von Recklinghausen, Thoma), it is probable that all conditions necessary for 'this process are furnished by slowing of the blood-stream with peripheral disposition of the colorless corpuscles and the ability of the leucocytes to perform amceboid movements and to adhere to the vessel-walls. It is possible that differences in the water-content of the tissues (Thoma) exert some influence, since an increased amount of water causes increased amoeboid movement. It is also possible that the presence in the tissue-fluids, of substances having active chemo- FlG. 164. — Recent purulent meningitis (Miiller's fluid, hematoxylin). a, Arachnoid; b, sub- arachnoideal tissue; c, d, desquamated endothelium; e, pus-corpuscles, x 300. tactic properties causes emigration of those leucocytes in the peripheral zone that are adherent to the vessel-wall. According to the investigations of Arnold, Thoma, and Engelmann, there is present between the edges of the endothelial cells a soft cement-substance which suffers a change in the circulatory disturbance associated with cell-migration. This change may sometimes, but not always (Lomit), be recognized, on histological examination, in the form of numerous circumscribed widenings of these inter- cellular areas (Engelmann). If leucocytes pass through these places in great numbers the cement-substance becomes still more permeable, and lymphocytes and red cells escape in rapid succession (Thoma). The inflammatory disturbances of circulation and the formation of exudates may be most easily followed in the transparent membranes of cold-blooded animals, particularly in the mesentery, or the extended tongue or web of the frog. In the frog's mesentery, which has been spread out on a suitable glass plate, circulatory disturbances and inflammation develop simply through exposure to the air and the resulting' evaporation; in the case of the tongue and web, it is necessary to cauterize- in order to produce inflammation. By the employment of suitable apparatus the circulation of the blood and the formation of the inflammatory exudate may also be observed under the microscope in the thin membranes of mammals (mesentery of rabbit, wing-membrane of bat), an-d observations thus made harmonize wholly ■with those made on the frog. The modern conception of inflammation is that it is a pathological complex essentially adaptive, protective, and reparative, called into action by a primary tis- sue-lesion. For a presentation of this view see Warthin, Chapter on Inflammation, "American Practice of Surgery," Vol. I. § 90. The cellular and fluid exudate from the vessels collects first in the immediate neig-hborhood (Fig-. 164, e), but soon spreads in the lymph-spaces and thus forms a tissue-infiltrate (Figs. 1,65, h; 168, p). 248 INFLAMMATION.. When the exudate is abundant it may infiltrate tissue that has not been injured by the inflammatory irritant. This infiltration may be so marked Fig. 165. — Hematogenous staphylococcus myositis (alcohol, hsematoxylin-eosin). a. Transversely cut muscle-bundles; b, purulent; c, seropurulent, partly coagulated exudate, x 45. Fig. 166. — Section through the border of a blister caused by a burn (alcohol, carmine), a. Horny layer; b, rete Malpighii; c, normal papilla; d, swollen cells, some of whose nuclei are still visible though pale, while others have been destroyed; e, interpapillary epithelial cells, the deeper ones intact, those of the upper layers are drawn out longitudinally and in part are swollen and have lost their nuclei; f, total liquefaction of the cells; g, interpapillary cells, with- out nuclei, swollen and raised from the cutis; h, total degeneration of interpapillary cells which have been rai?ed from the cutis; k, coagulated exudate (fibrin) lying beneath the uplifted epithelium; i, flattened papillae infiltrated with cells. x 150. that new disturbances of circulation and nutrition are produced, and the area of tissue-degeneration and inflammatory exudation becomes in- creased in extent. EXUDATION. 249 The fluid exudate may be partly absorbed by the tissue-elements, so that they become swollen, separated from their surroundings (Fig. 164, c, d), and contain drops of fluid (d) which are commonly designated vacuoles. Fig. 167. — Parenchymatous hepatitis (Flemming's solution, safranin), a, Liver-capsule; b, livCT- rods showing fatty degeneration; c, liver-cells showing total degeneration, x 300. Pig. 168. — Mucous catarrh of a bronchus (Miiller's fluid, aniline-brown), a. Ciliated epi- thelium; ai, deeper cell-layers; b, goblet-cells; c, cells showing marked mucous degeneration; Ci, mucoid cells with mucoid nuclei; d, desquamated mucoid cells; e, desquamated ciliated cells; f, layers of drops of mucus; ft, layer consisting of thready mucus and pus-corpuscles; g, duct of mucous gland filled with mucus and cells; h, desquamated epithelium of the excretory (iuct; i, intact epithelium of the duct; k, swollen hyaline basement-membrane; /, connective tissue of the mucosa, infiltrated with cells in part; m, dilated blood-vessels; n. mucous pland filled with mucus; «i, lobule of mucous gland without mucus; o, wandering cells in epithelium; p, cellular infiltration of the connective tissue of the mucous glands, x no. 250 INFLAMMATION. There also occurs solution of tissue-elements in the exudate (Fig. 166, d, /) and of connective tissue cells, and intercellular substances. In this way brain and muscle tissue, as well as ordinary connective tissue, which have been killed as the result of injury, may become completely liquefied in the course of inflammation. If dead cells become satu- _ rated with lymph containing fibrinogen, and if fibrin-fer- ment is formed, the liquefac- tion of the infiltrated tissue may be preceded by coagula- tion, and the cells become changed into homogeneous masses without nuclei, or partly into granular and fibrillar masses. If the exudate — for ex- ample, in a muscle — lies in the supporting tissue, while the parenchyma suffers but little change, the inflammation is designated interstitial in- flammation (Fig. 165, b). If, on the other hand, degenera- tion of the parenchyma — e.g., the epithelium of the kid- ney tubules, the liver-cells (Fig. 167, b, c), or the con- tractile substance of muscles — is the most prominent feature of the process, the condition is called parenchy- matous inflammation. When the seat of inflam- mation is the surface of an organ it is termed superficial inflammation (Fig. 168). If the exudate gains access to the surface and escapes mixed with desquamated portions of tissue (Fig. 168, d, e, f, fi, g, h), the inflammation is called catarrh. If the pour- ing out of fluid exudate on the surface of skin or mucous membrane is hindered by Fig. 169. — Purulent desquamative catarrh of the trachea in measles (alcohol, hxmatoxylin, eosin). a Layer of pus-corpuscles and deso.uamated epi- thelium; 6, intact deepest layer of epithelium; c, basement-membrane; d, hyper.-emic and infiltrated connective tissue of the mucosa; e, infiltrated sub- mucosa with mucous glands, x loo. a horny epithelial layer (Fig. 166, a), and if beneath this there are circumscribed collections of fluid, in which the deeper and softer layers of the epithelium dissolve (Fig. I66,d,f,g,h), the lesions produced are called vesicles and blisters. The exudate from serous surfaces collecting in the body cavities are termed inflammatory effusions, and may reach such size as to distend the aflfected cavity and com- press the organs contained in it. EXUDATION. 251 It is customary to express the occurrence of inflammation by adding the termination "itis" to the Greek name of the organ. Thus are formed the terms endocarditis, myocarditis, pericarditis, pleuritis, peritonitis, en- cephalitis, pharyngitis, keratitis, orchitis, oophoritis, colpitis, m'etritis, hepatitis, nephritis, amygdalitis, glossitis, and gastritis. The ending " itis" is sometimes affixed to the Latin names, for example, conjuctivitis, tonsillitis, vaginitis, etc. To denote inflammation of the serous covering of an organ or of the tissues immediately about it the prefixes " peri " Fig. 170. — Caharrhat secretion of different mucous membranes. A, Secretion from mucous membranes with columnar cells; B, from the mouth; C, from the bladder. i, Round cells (f'US-cells) ; 2, large^ round cells with bright nuclei, from the nose; 3, mucoid columnar cells from the nose; 4, spirillum from the nose; s, mucoid cells with cilia, from the nose; 6, goblet-cells from the trachea; 7, round-cells with spherules of mucus from the nose; 8, epithelial cells con- taining pus-corpuscles, from the nose; 9, fatty cells from a chronic catarrh of the pharynx and larynx; 10, cells containing carbon pigment, from the sputum; 11 and 12, squamous epithelium from the mouth; 13, mucoid pus-corpuscles; 14, micrococci; 15 bacteria; 16, leptothrix buccalis; 17, spirochaete denticola; 18, superficial, 19, middle layer of bladder epithelium; 20, pus-cor- puscles; zi, schizomycetes. X 400. and "para" are placed before the Greek names with the termination " itis." Thus are formed the words perimetritis, parametritis, periproct- itis, paranephritis, perihepatitis, etc. For certain forms of inflammation special names are used, for ex- ample, inflammation of the lungs is called pneumonia, and inflammation of the palate and tonsillar regions, angina. § 91. Local tissue-degeneration and exudation vary in different cases, and there may accordingly be distinguished different forms of inflam- mation. If the exudate consists essentially of fluid, while the cellular con- stituents are insignificant, it is called a serous exudate ; circumscribed collections of clear fluid beneath the horny layer of the epidermis with liquefaction of the soft layers of the epithelium lead to the formation of vesicles and blisters (Fig. 166, d, /). 252 INFLAMMATION. When the exudation of fluid on a mucous membrane is associated with mucoid degeneration of the surface epithelium (Fig. 168, b, c, cj, and of the mucous glands («), the con- dition is termed mucous catarrh {d, f, /i, ^f). If marked desquamation of the epithelium, with or without mucoid change, occurs (Fig. 169, a), the condition is termed desquamative catarrh; such a process may occur not only on mucous membranes, but also in the air vesicles of the lungs, in the kidney-tubules, etc. If pus- corpuscles are present in the exudate it may be spoken of as purulent catarrh; in which condition the exudate becomes white or yellowish- white, milky or creamy. The form and character of the cells of a catarrhal secretion vary with the location and the variety of catarrh (Fig. 170). Bacteria are often present in the cells of the exudate (Fig. 170, 4, 14, 15, 16, 17, 21). If in a fluid exudate there is depo- sition of fibrin, serofibrinous exu- dates are formed, and are often desig- nated croupous. These occur chiefly on the surface of serous and mucous membranes, and in the lungs; but masses of fibrin may be formed in tissues infiltrated with exudate, as well as in lymph-vessels. On mucous membranes fibrinous exudates form whitish patches, which sonietimes lie loosely, at other times are attached. In the serous cavities fibrinous coagula float in the fluid portion of the exudate, or are de- posited on the surface. Such deposits consist of thin films or gran- ules which give to the surface a cloudy, lustreless, rough, or granular appearance ; or of larger yellowish or yellowish-red, firm membranes, which im- part a felted or villous appearance (cor vil- losum). In the lung, croupous inflammation leads to filling of the alveoli with a coagulated mass, in consequence of which the lung acquires a firm consistence. Fig. 171. — Acute liEEmorrhagic fibrinous inflammation of the trachea, caused by vapor of ammonia (Miiller's fluid, hasma- toxylin, eosin). a. Superficial layer of the connective tissue of the mucosa, with greatly dilated blood-vessels and extrava- sated red blood-cells; b, deep layer of epi- thelium raised up in toto; c, desquamated epithelial cells; d, hsemorrhagic fibrinous exudate with radiating, crystal-like masses of fibrin, in part proceeding from small, colorless spherules. X 300. !- S,i Fig. 172. — Croupous membrane from the trachea, o. Section through membrane; h, uppermost layer of the mucosa in- filtrated with pus-corpuscles (d) ; c, fibrin threads and granules; d, pus-corpuscles. x 250. EXUDATION. 253 On mucous surfaces the formation of croupous membranes takes place when the epithelium is desquamated and the connective tissue, at least in part, is exposed; but tissues covered with epithelium may become the seat of fibrinous deposits extending from denuded areas. The desquama- tion- of epithelium may follow gradually, at other times rapidly through ^ ^:^5s"- Fig. 173. — Section from an inflamed uvula covered with a stratified fibrinous membrane, from a case of diphtheritic croup of the pharyngeal organs (Miiller's fluid, hematoxylin, eosin). a. Surface layer of coagulum, consisting of epithelial plates and fibrin and containing numerous colonies of cocci; b, second layer of coagulum, consisting of fine-meshed fibrin network enclos- ing leucocytes ; c, third layer of coagulum, lying upon the connective tissue, consisting of a wide-meshed reticulum of fibrin enclosing, leucocytes; d, connective tissue infiltrated with cells; e, infiltrated boundary layer of the connective tissue of the mucous membrane; f, heaps of red blood-cells; g, widely dilated blood-vessels; h, dilated lymph-vessels filled with fluid, fibrin and leucocytes; i, duct of a mucous gland distended with secretion; k, transverse section of a gland; I, fibrin reticulum in the superficial layer of connective tissue, x 45. the lifting up of wihole layers of epithelium (Fig. 171, &), which are either well preserved or degenerate or necrotic, and infiltrated with exudate (Fig. 173, a). The deposition of fibrin may begin under the raised epithelium with the formation of fine needle-like forms (Fig. 171, d) ranged radially about a centre, in which at times there lies a small body, or blood-plate. Soon there form threads (Figs. 172, c; 173, b, c) which enclose variable numbers 254 INFLAMMATION. of leucocytes and red cells. The arrangement of the threads is usually reticular, but the thickness of the network and the size of the meshes vary. When there is unequal development of the fibrin threads, the prin- cipal strands sometimes lie parallel with the surface of the mucous mem- brane (Fig. 172, c), sometimes perpendicular to it (Fig. 173, c). Thick fibrinous membranes frequently show distinct stratification (Fig. 173, a, b, c), indicating that their formation has occurred in successive layers. When a mucous membrance becomes the seat of fibrin deposit, the un- FlG. 174.— Croupous tracheitis. Section through the connective tissue of the mucosa (carmine and fibrm-stain. a, b, c, d, Blood-vessels with fibrin precipitates; e oedematously swollen connective tissue with leucocytes; /, connective tissue with fibrin-threads, x 500. derlying connective tissue is more or less hypersemic (Fig. 173, g), cede- matous and swollen, infiltrated with leucocytes (Figs. 173, d, e ; 174, e), and usually contains thready fibrin precipitates (Figs. 173,' /; 174,' /)'. Often the tendency to precipitation of fibrin is manifested in the blood- vessels (Fig. 174), at times these contain tangled threads and rods (Fig. 174, h), at other times fibrin-needles grouped in stellate forms or clusters (a, c, d), which proceed from blood-plates, or radiate from portions of the vessel-wall where the endothelium is lost. Likewise, fibrin-threads may be found in dilated lympli-vessels, in association with fluid and cellular exudate (Fig. 173, /i). On serous membranes deposits of fibrin appear in granular and thready, or in thick, homogeneous masses, or even in the form of ribbon-like bands. Here also the epithelium is exfoliated at the point of deposition or preserved in patches and covered with fibrin. The con- nective tissue of serous membranes in croupous inflammation is more or less infiltrated, and may contain leucocytes and fibrin, both in the congested vessels and in the connective-tissue spaces (Fig 175 c) More marked exudations on serous membranes produce thick felted deposits, the elements of which consist of thready fibrin and EXUDATES. 255 pus corpuscles (Fig. 175, d, e), as well as micro-organisms (b). An abundance of pus corpuscles gives to the exudate a fibrino purulent char- acter, the deposits becoming whitish in color. Fibrinous exudates in the lungs are characterized by a more or less close network of fibrin (Fig. 176, &), in whose meshes and in the immediate neighbor- hood of which lie leucocytes mingled with red blood-cells {e), and desquamated epi- thelium. In the early stages there are occasionally found globular, wreath-shaped pre- cipitates of fibrin joined to- gether in rows. In the kidneys fibrin may occur in the form of fine threads or hyaline masses in the tubules and glomerular capsules. In lymph nodes fibrin-threads are formed in the lymph-channels. Haemcrrhagic exudate — that is, an exudate con- taining large numbers of red cells — occurs in connection with the exudation of fibrin. The exudate of croupous pneumonia contains a larger or smaller number of red blood-cells (Fig. 176, c), and in fibrinous pericarditis and pleuritis great numbers of red cells may escape from <£, the vessels. Hasmorrhagic inflammations occur not in- frequently in the central nervous system, in lymph nodes, in the skin and kid- neys. Jn the last case the blood escapes from the glomerular vessels. Serous, fibrinous, and serofibrinous inflammations are caused by thermal and chemical influences, as well as by bacteria ; but are most frequently the result of in- fection, particularly with the Diplococcus pneumonice Fig. i75.-Fibri„opurulent diplococcus pleuritis in a f ^^S';. 7^' ^) and the 5ao7- three-year-old child (formalin, fibrin-stain), a. Inflamed lus diphtheria . The former f^XL \ f P^°=°="= '' ^^""' ^' '• fibri^°P"™i^''t causes croupous inflamma- 256 INFLAMMATION. tions of the lungs and pleura, the latter fibrinous inflammations of the throat, palate, and respiratory passages. Fig 176— Croupous pneumonia. Red hepatization of the lung (alcohol, carmine, fibrin-stain). a, Infiltrated alveolar septa; b, fibrinous exudate; c, red blood-cells. X 200. ■53S"3'^2->Of^ Fig, 177. — ^1 ulent bronchitis, peribronchitis, and peribronchial bronchopneumonia in a child one year and three months old (Miiller's fluid, heematoxylin, eosin). a, Purulent, b, mucoid bronchial contents; c, ci, bronchial epithelium infiltrated with round cells and partly desquamated dj infiltrated bronchial wall with greatly dilated blood-vessels; e, infiltrated peribronchial and periarterial connective tissue; f, alveolar septa, in part infiltrated with cells; g, fibrinous exudate in the alveoli; h, alveoli filled with exudate rich in cells; i, alveoli filled with exudate containing few cells; kt- cross-section of a pulmonary artery; I, bronchial, peribronchial, and interacinous vessels showing marked congestion, x 43. PURULENT INFLAMMATION. 257 § 92. When the inflammatory exudate is made up chiefly of leuco- cytes, infiltration (Figs. 165, b; 177, d, e, f) may be so marked that the structure of the tissue is obscured. If polynuclear leucocytes or pus-cells are present in large numbers in the exudate on a mucous membrane or Fig. 178. — Section of a smallpox pustule (injected hematoxylin preparation), a, Horny layer; b^ stratum mucosum of the epidermis; d, cutis; e, smallpox pustule; /. cavity of the pock, containing at /, pus-corpuscles; g, interpapillary remains of epithelium infiltrated with pus- corpuscles; h, papillary bodies infiltrated with cells; t, umbilication with thin pock cover; ti, edge of the pock, the roof at this point consisting of the horny and transitional layers, x 25. wound, so that the exudate is white or yellowish-white in color and of a milky or creamy consistence, it is called pus; such an inflammation is designated purulent (Fig. 177, a). Persistent marked secretion is termed blennorrhcea. Collections of pus in the body-cavities — for example, '-^^ Fig. 179. — Embolic abscess of the intestinal wall with embolic purulent arteritis, and embolic aneurism in cross-section (alcohol, fuchsin). a, b, c, d, e, Layers of intestinal wall; f, remains of arterial wall, cross-section; g, embolus, surrounded by pus-corpuscles lying within the dilated and partly suppurating artery; h, parietal thrombus; i, periarterial purulent infiltration of the submucosa; fe, vein showing marked congestion. X 28. 17 258 INFLAMMATION. the pericardial, pleural, or joint cavities — give rise to purulent effusions or empyemata. If in a blister arising through liquefaction of epithelium below the horny layer of the epidermis there takes place marked col- lection of leucocytes, the fluid becomes turbid, and the vesicle is changed into a pustule (Fig. 178, /J. When leucocytes collect in a tissue in such numbers as to give it a white, gray-white, or yellowish-white color the process is known as Fig. i8o. — Suppuration and necrosis of the mucosa of the large intestine in dysentery (MuUer's fluid, ha^matoxylin, eosin). Section through the mucosa (a") and submucosa (&) of the large intestine: c, muscularis; d, interglandular, di, subglandular infiltration of the mucosa; e, focus of infiltration in the submucosa; f, infiltrated upper glandular layer undergoing desquama- tion; g, ulcer with infiltrated base. X25. purulent infiltration. This may be followed by liquefaction and abscess- formation (Fig. 179, i) — that is, the formation of a circumscribed cavity filled with pus. When purulent infiltration involves the superficial parts of an organ — for example, a mucous membrane (Fig. 180, d, f, g) — the process leads to localized loss of substance — an ulcer. The formation, through suppuration, of duct-like excavations gives rise to fistulous tracts. If an accumulation of pus-corpuscles is associated with abundant collection of fluid, the exudate is spoken of as seropurulent. The rapid spread of purulent or seropurulent inflammation over wide areas — for example, through extensive areas of subcutaneous or submucosal tissues — is known as phlegmon (Fig. 181, c, d). This often leads to the forma- tion of pus-cavities, in which lie shreds of disintegrating tissue infiltrated with pus. The association of serous exudation and fibrin precipitation with suppuration leads to the formation of fibrinopurulent exudates (Fig. 175, d, e) ; effusions into the body-cavities, meningeal exudates, croupous exudates on mucous surfaces and in the iungs, and phlegmons may bear this character. It is to be noted, however, that with increase of suppuration the formation of fibrin becomes decreased, and coagula already present dissolve. Fibrin-masses infiltrated with pus are white and easily torn. Suppurations and the associated formation of abscesses and ulcers are in the majority of cases caused by bacteria, most frequently by the CAUSES OF SUPPURATION. 259 Staphylococcus pyogenes aureus, Streptococcus pyogenes, and the Gono- coccus; but suppurations due to Actinomyces, Bacillus anthracis. Bacillus mallei, or the Bacterium coli commune, are not rare. Staphyloccoci gen- erally produce localized inflammations; streptococci, on the other hand, phlegmonous. The presence of certain bacteria {Bacillus phlegmones emphysematosa, Frankel; Bacillus aerogenes capsulatus, Welch) may cause the formation of gas {gas- phlegmon). Suppuration is sometimes ectogenous, sometimes lymphogenous or haematogenous ; in the last case it bears the character of an embolic process (Fig. 179). Of the chemical substances which, when introduced into the tissues, pro- duce liquefaction resembling suppura- tion may be mentioned mercury, oil of turpentine, petroleum, five- to ten-per- cent, solutions of silver nitrate, creolin, digitoxin, dilute croton-oil, and steril- ized cultures of various bacteria, in which the bacterial proteins are the active agents. The liquefactions thus produced differ from those of infection, in that they heal more easily, do not spread in the tissues, or give rise to metastases, and their products when inoculated possess no virulence. § 93. Suppurative inflammation al- ways leads to tissue-necrosis; but this necrosis is submerged in and obscured by the liquefaction and dissolution which form the characteristic feature of suppuration. In other circumstances necrosis may occur, recognizable even to the unaided eye, and is not followed by suppuration, but is characterized by the fact that the necrotic portions re- main unchanged for a long time, and ultimately are removed through seques- tisS^-;ftn^™S^f a^\™^^1h3g"^ tration, sloughing, or absorption. Since oedema (Muller's fluid, hsmatoxyhneosm) jjecrOsis in SUch a CaSC forms the a, Corium: b, epidermis; c, infiltrated fat tissue; d, focus of pus; e, cellular foci in chief feature, the condition mav be adeZ' X ^"''^P'*^''^' ""'"''' ''"^ '° appropriately designated necrotic in- flammation. Necrosis associated with inflammation may be caused by caustic chemicals, high or low temperatures, ischaemia, and infection (typhoid fever, diphtheria, dysentery, and tuberculosis). Necrosis of tissue may appear as the immediate efl'ect of injury, exu- dation following, being confined to the region adjoining the necrosis; this is especially the case after the action of corrosive substances, high temperature, and ischaemia. In other cases, inflammation is first es- tablished, the infiltrated tissue later becoming necrosed. In tuberculous 260 INFLAMMATION. \ infection necrosis occurs, as a rule, after proliferation has existed for some time. Necrotic inflammations are most frequently seen in mucous mem- FiG. 182. — Necrosis of the epithelium of the epiglottis (Miiller's fluid, hsematoxylin). a. Living epithelium with well-stained nuclei; b, necrotic epithelium with nuclei not staining; Cj leucocytes lying in the epithelium; d, hyperaemic, inflamed, and infiltrated connective tissue, X 300. branes, and are sometimes by infection. The necrosis its nuclei (Fig. 182, b) and acquires a granular appearance. If white opaque patches are formed on the mucous membrane, as in the pharynx in dipli- theria, the condition may be spoken of as epithelial or superficial diphtheritis. Usually, however, the des- ignation diphtheritis is ap- plied only to necroses in which the inflamed and in- filtrated connective tissue (Fig. 183, a), becomes converted into a granular mass without nuclei, or into a homogeneous mass containing fibrin, in which the structure of the tissue can no longer be recog- nized. Diphtheritic sloughing of a mucous membrane is observed particularly often in the intestine (Fig. 183), but occurs also in the called diphtheritis, particularly those caused may first affect the epithelium, which loses Fig. 183. — Bacillary diphtheritis of the large intestine in dysentery (alcohol, gentian violet). a, Necrotic portion of the glandular layer of the mucosa, infiltrated with bacilli; b, intact inflamed mucosa; c, muscularis mucosae; d, submucosa; e, colonies of bacilli; f, glands with living epithelium; g, glands with necrotic epithe- lium and bacilli; h, connective tissue infiltrated with cells; t, blood-vessels, x 80. NECROTIC INFLAMMATION. 261 vagina, the descending urinary passages, and the region of the throat, where the tonsils are especially affected, etc. The necrotic tissue forms white, or grayish white sloughs, which are surrounded by reddened and inflamed tissue. If some time has elapsed since its formation, and ,if liquefaction at the ^ J^ boundary between - the living and dead tissues has oc- curred, with sepa- ration of the latter, the necrosed parts form loosely at- tached or free de- posits lying on the surface, consisting at times of small flakes, at other times of larger sloughs. Diphtheritis of mucous membranes may be associated with croupous de- posits (Fig. 184, c, d), so that the area of necrosis (d) may be covered with fibrin (c). Wound-granulations may necrose in the same way as inflamed mucous membranes ; such may therefore be called wound-diphtheritis. Acute tissue-necroses caused by infection occur in internal organs, notably in typhoid fever, in the lymph nodes (Fig. 185), spleen and bone-marrow, and are characterized by the formation of opaque grayish-white, yellowish, or dirty-gray sloughs. Not infrequently fibrinous collections are seen in the necrotic tissue (Figs. 184, d; 185). In the necrosis caused by tuber- culosis, destruction of tissue occurs gradually, and bears the character of caseation. When an inflammatory focus con- tains bacteria which excite putrid de- pj^ jSs.— niphtheritic necrosis within a composition of albuminoid bodies, the swollen mesenteric lymph-gland in typhoid . n ' 1 ii 1 i lever (alcohol, nbrin-stain). Fibrin net- mflammation may take on the character work between the necrotic cells, x 300. of putrid gangrene ; the tissue may dis- integrate into a dirty gray or black, tinder-like mass which gradually dissolves and gives off an extremely disagreeable odor. Gas-bubbles are sometimes developed in the focus. (See § 92.) Fig, 184. — Section of the tivula in pharyngeal diphtheria with croupous deposits (alcohol, aniline brown) . a, Normal epithelium ; b, connective tissue of the mucous membrane; c, reticulated fibrin; d, connective tissue of mucosa infiltrated with coagulated fibrin and round cells, and partly necrotic; e, blood-vessels; f, haemorrhage; gj clumps of micrococci. X 73. 262 INFLAMMATION. II. The Termination of Acute Inflammation in Healing. § 94. Should acute inflammation occur in any tissue, sooner or later processes arise whose object is restoration of the damaged tissue, and may therefore be regarded as processes of repair. These consist in the cessation of pathological exudation and its replacerrient by normal secre- tions, the removal or absorption of exudate and of necrotic tissue, and restoration of destroyed tissue. If the exciting cause of the inflammation is still present in the tissue and active, it must be removed or rendered inert. The repair of the vessel-walls is brought about through restoration of the blood-supply, so that the nutrition of the vessels becomes normal. If the alteration is slight, restoration may take place in a time that may be measured in minutes and hours. When the exciting cause of the inflammation acts at some length — as in the case of bacteria which live and multiply in the tissues, and if there Fig. i86. — Phagocytes from granulation tissue with included leucocytes and fragments of same (sublimate, Biondi's stain), a, Round, h, spindle, fibroblast with leucocytes; c, d, e, fibro- blasts containing remains of leucocytes, x 500. has been, for example, necrosis of the vessel-walls, complete restoration is hindered or prevented entirely. The absorption of exudate occurs in many cases easily and quickly, in that it is taken up by the lymph-stream, eventually by the blood. This takes place most rapidly in serous exudates, in many places fibrinous exudates may also be removed, but only when the coagula liquefy. Foi; example, coagulated exudate in the lung may be liquefied and made cap- able of absorption through the action of a proteolytic enzyme (Miiller) that arises most probably from the leucocytes. The absorption of exu- dates is often aided by phagocytes, that is, through amoeboid cells taking up corpuscular substances and destroying them. Thus, large mononu- clear cells (macrophages) may take up polynuclear leucocytes (Fig. 186, a, b) and digest them (c, d, e). In the same manner red blood-cells and their disintegration-products may be disposed of (Fig. 96). Firmer fibrinous exudates such as are formed on serous membranes, and large collections of pus, offer considerable resistance to absorption. In many cases absorption is accomplished by the substitution for the exudate of embryonic tissue which later becomes changed into connective tissue. The sequestration and absorption of necrosed tissue, with the ex- ception of dead epithelium, which may be quickly accomplished, require a length of time which varies according to the nature, situation, and extent of the lesion. In general, inflammation persists as long as necrotic tissue is present. Superficial necrosed tissues may be cast off after sequestration from the living. In deep-seated necroses in which HEALING OF ACUTE INFLAMMATION. 263 the tissue does not undergo total liquefaction, absorption is slow, and is brough about through gradual substitution of living tissue for the dead. Phagocytosis often takes place in the absorption of necrotic tissue. The regeneration of tissue in inflammatory lesions is dependent on the degree and extent of degeneration, on the nature of the tissue, and on the mode of action of the agent exciting the iniiammation. If the tissue-cells of the inflamed area are but slightly degenerated, they are quickly restored when the nutrition becomes normal. If single cells are lost but the organization of the whole is not disturbed, there can take place in certain tissues renewal of cells through regenerative growth of remaining cells. This is particularly true of dififerent forms of con- nective tissue, surface epithelium, the cells of lymph nodes, etc., while ganglion-cells and heart-muscle possess little or no power of regeneration (see Chapter VI.). Extensive destruction of tissue with solution of continuity, wounds, fractures, suppuration, necrotic inflammations, etc., produce proliferations which are sufficient to close the defect, but do not lead to restoraition of the normal tissue, rather to the formation of tissue of lower grade, which in its earliest stages is known as granulation tissue, in its mature form as cicatricial tissue, the whole process being included under the title of productive inflammation. The phenomena of proliferation begin in inflamed tissues, at the earliest after eight hours, but are firsit clearly recognizable after from tvcenty-four to forty-eight hours. In general, they appear more rapidly the milder the inflamma- tion and the more quickly as exudation is overcome or diminished. Suppuration, necrosis, and gangrene hinder proliferation and retard repair, or at least confine the reparative processes to neighboring tissues. Every tissue capable of proliferation furnishes formative cells for tissue of its own kind or for one closely related to it. On the other hand, newly developed tissue-cells may become mixed unth the exudate, degenerate, and die. Thus not all cells developed through proliferation fulfil their function of producing new tissue. .The removal of the exciting cause of inflammation takes place differently in different cases, and depends on the nature of the cause. Many traumatisms and thermal influences act for a short time, land have no further influence on the course of the inflammation. Sub- stances acting chemically may be taken up by the tissue-juices and made inert, or excreted, while others remain locally active for a long time. Insoluble bodies in the form of dust which have penetrated into the tissue, for example, into the lungs, are for the greater part taken up by phagocytes and carried away (see § 21) and either deposited or re- moved from the body. Of the bacteria exciting inflammation, many die as the result of bactericidal substances formed in the diseased area (see § 31). The destruction of bacteria takes place partly in the tissue-fluids and partly by phagocytosis, the bacteria being taken up by the cells alive, or, having first been killed, are then digested. Of the bacteria causing inflammation, many live and produce new generations which in turn cause new inflammation, often in such a way that in the first focus the inflammation may subside and healing take place, while in the neighbor- hood, or eVen in distant regions, metastatic inflammations develop. On account of the diff"erences in the nature and behavior of the exciting cause of inflammation, as well as in the course of tissue-degen- 264 INFLAMMATION. eration, exudaition, and healing, it is easy to understand that the whole course may vary greatly in different cases, and that all the possibilities cannot be reviewed. At the same time it is not difficult to comprehend the decline of the different forms of inflammation, since the whole proc- ess is always made up of the same factors — that is, tissue-degeneration, exudation, and proliferative processes, the last of which are intended to counterbalance the disturbances caused by the first two. The phenomenon of chemotaxis, that is, the attraction or repulsion of motile cells by chemical substances soluble in water, was first observed by Strahl and Pfeffer, who carried out observations on the myxomycetes, infusoria, bacteria, spermatozoa, and zoospores. Investigations by Leber, Massart, Bordet, Borissow, Cahritschewsky, and others have shown that the leucocytes likewise are attracted by chemical substances {positive c! emota.ris) or are repelled by them (negative chemotaxis). In particular do products of fission-fungi (Leber, hiassart, Bordet, Cahritschewsky), or bacterial proteins, even in great dilution (according to Buchner, pyocyaneus protein acts even in a three-hundred-fold dilution), possess positive chemotactic action. According to Buchner, this property is also shown by gluten- casein from wheat-gluten and legumin, aleuronate, glue from bones, and alkali albuminates from peas, while ammonium butyrate, trimethylamin, ammonia, leucin, tyrosin, urea, and skatol show negative chemotaxis. III. Inflammatory New-formation of Tissue ; Healing of Wounds and Substitution of Exudates and Tissue-necroses by Connective Tissue. § 95. The inflammatory proliferation of tissue is essentially a re- generative process. Not rarely hyperplastic proliferations of con- FiG. 187.— Isolated cells from a wound-granulation (Miiller's fluid, picrocarmine). a Mono- nuclear, a,, polynuclear leucocytes; b different forms of mononuclear fibroblasts; c, fibroblast with two nuclei; c,, multinuclear fibroblast; d, fibroblasts in the stage of connective-tissue forma- tion; e, fully developed connective tissue, x 500. nective tissue fail to accomplish this purpose and cause new injury; this is especially the case when persistent infection or the residues of acute inflamiTiation (exudates, abscesses, necroses) keep up a chronic condition of inflammation. GRAXULATION TISSUE. 26S The inflammatory new-formations of tissue may be distinguished from simple regeneration by the fact that they are accompanied by circulatory disturbances and pathological exudations, especially by im- migration of lymphocytes and leucocytes, and that these have a modifying action on the course of the process. The granulation tissue formed during inflammation is an em- bryonic tissue arising through cell proliferation and infiltrated with y- ^.. - .j^w.< -^'^^ ::::*.. T a -- ^ ..b -^'S '? Fic, i88. — Scar fifteen days old (Maximow, 1. c). c. Fibroblasts; b, polymorphous lympho- cytes ( polyblasts) ; f, unchanged lymphocyte (polyblast). X 500. leucocytes and lymphocytes. In the beginning it consists essentially of cells and of new-formed blood-vessels which at first find support in the ground substance of the tissue from which they pass out, but soon form a ground substance for themselves. The cells of granulation tissue are proliferated tissue-cells (Fig. 187, b, c, d), polynuclear leucocytes (Oi) and mononuclear lymphocytes (a). In most cases the proliferated cells are derivatives of fibrous con- nective tissue, and are known as fibroblasts. Granulation tissue, how- ever, may contain derivatives of other tissues, for example, of perios- teum, marrow-'tissue, and muscle, in the form of osteoblasts, chondro- hlasts, and sarcoblas-ts, which are able to form bone, cartilage, and muscle, respectively. Further, newly formed epithelium may occur in glands, while in mucous membranes and in the skin new-formed surface epi- thelium may be found in or on the granulation tissue. The fibroblasts of granulation tissue are large polymorphous cells, with clear nuclei (Fig. 187, b), and may possess long processes. Young forms without p'rocesses resemble epithelial cells and are therefore called epithelioid cells. With the help of their processes they can push into the tissue spaces, but usually show no lively amoeboid movements. In the development of granulation tissue the fibroblasts form con- nective-tissue fibrillae, a portion of the protoplasm taking on a fibrillar appearance, or first becoming homogeneous and then producing fibrillae (Figs. 1^7, d,e; 188, a; 189, a). 266 INFLAMMATION. The polynuclear leucocytes of granulation tissue (Fig. 187, a) are not capable of further development and either wander farther or die, particularly those which collect on the surface or in abscesses. If bacteria are present (streptococci, staphylococci, gonococci, anthrax- bacilli, etc.) the leucocytes may act as phagocytes {micro phages) and aid in the destruction of the bacteria. The lymphocytes and mononuclear leucocytes of granulation tissue arise from the blood, or are attracted from the lymphoid depots Fig. 189. — Tissue from a scar sixty-five days old (Maximow, 1. c), a, Fibroblasts; b, ox, spindle-formed lymphocytes (polyblasts), with elonjated nuclei embedded in the tissue; c, plasma cell. X 500. and mingle with the cells of the exudate. Many of them die, as do the polj'nuclear leucocytes; or, on the other hand, may change into various cell-forms; from this they may be designated polyblasts. Enlargement of the protoplasm and enlargement and clearing of the nucleus give them the character of epithelioid cells; usually they are smaller than fibroblasts and their nuclei stain darker (iron-hsematoxylin or methylene blue). By sending out pseudopodia they may assume various forms (Fig. 188, h). On the surface of smooth foreign bodies they may form an epithelial-like deposit or covering. In the development of cicatricial tissue polyblasts, it is held, may be embedded as permanent elements in the form of spindle cells which are to be distinguished with difficulty or not at all from ordinary connective- tissue cells (Fig. 189, b, b^). Occasionally they assume a character cor- responding to that of the so-called klasmatocytes of Ranvier (Fig. 190, h), that is, they form spindle or branched cells, coarsely granular, show- ing many vacuoles and often containing granules staining metachro- matically (polychrome methylene blue). Further, among the polyblasts of granulation tissue may be included the so-called plasma-cells (Figs. GIANT CELLS. 267 189, c; 190, c), that is, round or irregularly formed cells having an eccentric nucleus and a bright central and dark granular periphery. _ The polyblasts are those cells which show the greatest activity in granu- lation tissue as phagocytes, and not only take up bacteria but disintegrat- FiG. 190.- -Plasma cells and klasmatocytes within scar tissue, forty days old (Maximow, 1. c). a. Fibroblasts; 6, klasmatocytes; c, plasma cells; d, blood-vessel. X 500. ing or dead red cells and leucocytes (Fig. 186), and destroy or carry them away. They also have an inclination to form multinucleated giant-cells by continuous division of the nuclei in the same cell, usually by amitosis, rarely by karyokinesis, and syncytial forms, the latter, through confluence of cells lying in close contact. This is frequently observed Fig. 191. — Dog*s hair encapsulated in the subcutaneous tissue (alcohol, Bismarck brown), a, Hair; &, fibrous tissue; c, proliferating granulation tissue; J, giant-cells, x 66. when foreign bodies or necrotic portions of tissue lie in the granulation tissue (Fig. 191, d) ; such multinucleated cells are there- fore designated foreign-body giant-cells. Soluble substances, for ex- ample, catgut sutures or necrotic muscle-substance, can be gradually dissolved by them. The presence of foreign substances in the form of the bodies of bacteria (tubercle-bacilli and lepra-bacilli) can also lead to their formatioa 268 INFLAMMATION. The blood-vessels of granulation tissue arise through offshoots from old vessels (see Fig, 140), which show prohferative processes early in the inflammatory state, (a), and in the formation of granu- lation tissue take on very lively proliferation. The young granula- tion tissue, as a result, becomes permeated by blood-vessels, so that it acquires a red appearance. During the transformation of granu- lation into connective or scar-tissue, obliteration of vessels occurs and,, the scar becomes pale. The structure of granulation tissue, the origin and the fate of the cells contained in it, have been for decades the object of investigation and dis- cussion, and even to-day not all of the questions can be regarded as solved. It has been demonstrated beyond doubt, however, that the builders of cicatricial tissue, the fibroblasts, are derivatives of fixed connective-tissue cells; further, it is certain that the polynuclear leucocytes emigrate from the blood and undergo no further develop- ment. The origin of the small mononuclear cells which resemble lymphocytes and the mononuclear leucocytes of the blood is still a matter of dispute, as is also the role which they play in the granulation-tissue. Even in the year 1876, on the ground of ex- perimental investigations, I expressed the opinion that they were capable of development into epithelioid cells and that at the time of their formation and transformation they exert phagocytosis and take up other cells and digest them and that they can become changed into permanent elements of cicatricial tissue. I have demonstrated that under special condi- tions they form syncytial giant-cells. Maximow, through investigations carried on in my laboratory in 1901-1902, has confirmed the view that the mononuclear leucocytes and lymphocytes, after passing out from the blood- vessels, may undergo further development, and has demonstrated that in cicatricial tissue they take on the appearance of klasmatocytes, plasma-cells, and mast-cells, also appearances similar to those of ordinary fixed connective-tissue cells, so that finially differentia- tion of the two original cell-forms is no longer possible. They also change to fixed connective-tissue cells, but do not produce, as I formerly assumed, the fibrillary ground-substance. With reference 'to the varied forms which these cells show, Maxtmow has designated them polyblasts. The differentiation of the different cell-forms as given above, rests essentially on differences- in the structure of the protoplasm. Plasma cells (Unna) or the " kriimelzellen " {von Marschalko) are mononuclear, round or oval, at times elongated cells that stain intensely with methylene blue and possess an eccentrically placed nucleus showing a chromatin network and five to eight chromatin granules. At the periphery of the cell the protophasm is more densely clumped, so that there is formed a lighter area surrounding the nucleus. The klasmatocytes (Ranvier) are spindle shaped, branched or stellate cells with blunt or swollen ends and a granular protoplasm that often contains little vacuoles. The mast-cells (Ehrlich) are round or flat or spindle-shaped cells, with numerous distinct coarse granules that, with the basic aniline stains, show an intense metachromatic reaction. Cells of the character of lymphocytes, plasma-cells, and mast-cells occur in normal tissue and are regarded by some as tissue cells and by others as ceflls arising from the blood. The correct view is probably that which regards them as different stages of development of a mesenchymal group of cells to be separated from the tissue-building fixed cells, and to this group there should be added the polynuclear leucocytes and eosinophile ceHs. Certain stages of development are present in the blood, others are found in the tissue, partly in special tissue- formations (lymphadenoid tissue, bone-marrow) , and partly in ordinary connective tissue. Under certain conditions it is possible that individual forms may pass into one another, for example, that lymphocytes may become transformed into plasma cells and klasmatocytes into mast cells. Fig. 192. — Cross-section of blood- vessel from the deep layers of the skin, forty hours after painting the skin of a rabbit with tincture of iodine (Flem- ming's solution, safranin). a. Endo- thelial cells with mitoses; b, bi, \e\ica cytes. X 350. HEALING OF WOUNDS. 269 § 96. If on any part of the body there occurs an open wound, which does not become infected or otherwise seriously injured, the edges and base of the wound after twenty-four hours become deep red and somewhat swollen, and here and there small shreds of necrotic tissue may be seen. On the second day the gelatinous condition of the tissues is more apparent, the outlines of individual tissue-elements are effaced, and the color of the wound becomes grayish-red. From the second day on there appear over the wound small red papules, which increase in number and size, become con- fluent, and after two to three days form a granular surface. This is covered with more or less abundant secretion, which forms a gray, gelatinous layer, later becoming yellow and creamy. This layer consists of coagulahle exudate and polynuclear leucocytes. The changes which the surface of the wound show in the first two days are de- pendent on local hypersemia, and the infiltration of cellular and fluid exudate, and on swelling and liquefaction of the tissue ; as early as the sec- ond day there is proliferation leading to the development of wound-granulations, or granulation tissue (Fig. 193, a), consisting of flhrohlasts and leucocytes, and wide ves- sels (c), among all of which there soon appears a fibrillar ground-substance. The leuco- cytes, which are mostly of the polynuclear form, are found in all the layers in fresh granulations, but heap them- selves particularly in the superficial strata, and, embedded in fibrin, cover the surface (b). The fibroblasts are found most abundantly in the deeper layers (Fig. 193, a), and it is here that the new-formation of connective tissue proceeds most actively. When a certain degree of fibrillse-formation has been reached, the process comes to a standstill, the fibroblasts with their nuclei remain as fixed connective-tissue cells (Fig. 187, e), and attach themselves to the surface of the fibrillse. The process has now reached its termination — granulation tissue has become scar-tissue. In open wounds of the skin, when infection does not disturb the course of healing, the formation of granulation tissue lasts until the wound is covered with epithelium. The regeneration of the latter pro- ceeds from the edges, the epithelium gradually pushing itself over the Fig. 193. — Wound-granulations from an open wound with fibrinopurulent covering (Miiller's fluid, haematoxylin) . a, Granulation tissue; b, fibrinopuru- lent layer; c, blood-vessels, x 135. 270 INFLAMMATION. granulations. With the formation of connective tissue the reproductive processes terminate, but transformation processes continue in the cica- tricial tissue for some length of time. Shortly after its formation the cicatrix is rich in blood and appears red; later it loses a portion of its vessels through obliteration, becomes pale, and contracts to much less than the original volume. Large scars of the skin show permanently a smooth surface, since the papillary bodies are not again formed or only imperfectly (Fig. 195, e). The scar remains for several months abnor- c c Fig. 194. — Healing of incised wound of slcin united by suture (Flemming's solution, safranin). Preparation made on the sixth day. a. Epidermis; b, corium; c, fibrinous exudate, in part hjemorrliagic; d, newly formed epidermis, containing numerous division-figures, and with plugs of epithelium extending into the underlying exudate; e, division-figures in epithelium at a dis- tance from the cut; f^ .proliferating embryonic tissue, developing from the connective-tissue spaces, and containing cells with nuclear division-figures, and in part also vessels with pro- liferating walls; g, proliferating embryonic tissue with leucocytes; h, focus of leucocytes in deepest angle of wound; i, fibroblasts lying within the exudate, one showing a nuclear division- figure; k, sebaceous-gland; /, sweat-gland, x 70. mally rich in cells, but in time becomes poor in cells and firm in consistence. When the healing of a wound occurs in such manner that the defect is closed by granulation tissue visible to the naked eye, the process is designated repair by second intention (per secundam intentionem) . Incised vsrounds of the skin, whose edges are united by sutures, grow together by first intention, and healing takes place in essentially the same manner as that of an open wound by second intention ; but inflammation, proliferation, and new-formation of tissue are less prominent, partly because they take place below the skin, and partly because they are of less extent and intensity. The result of such a cut is hsemorrhage together with more or less abundant exudation (Fig. 194, c), which glues the opposing wound-sur- HEALING BY FIRST INTENTION. 271 faces. Soon there arises inflammatory infiltration of the edges of the wound, which varies greatly in different cases, and when repair is aseptic never reaches a significant degree {g, h), attaining its maximum in from two to four days, diminishing from the fifth to the seventh day, and completely disappearing at or soon after the end of the second week. The inflammatory infiltration is usually greater in the neighborhood of the sutures than at the edges of the wound. As early as the second day regenerative processes begin in the con- fit - , i^v*** bT-^- '-^""v-v'^-'J- ¥ ■'•-A .Xh^..^ - c Fig, igs. — Cutaneous portion of a laparotomy cicatrix, sixteen days after the operation (Muller's fluid, hematoxylin, Van Gieson's). o^ Epithelium; fc, corium; c, subcutaneous fair tissue; d, scar in corium; e, new epithelial covering; /, scar in fat tissue, x 38. nective tissue and in the vessels, and lead, in the course of several days, to the formation of embryonic tissue at the edges of the wound (Fig. 194, /), partly extending into the wound itself (i) ; and gradually replacing the coagulum. This tissue is present in varying quantity in different parts of the wound (Fig. 194). After a time, varying according to the size of the wound, the thickness of the exudate, and the intensity of proliferation, the masses of embryonic tissue growing from the edges of the wound blend and young connective tissue joins the edges together, and at the same time extends into the old tissue, so that the boundary between old and new becomes indistinct. While connective tissue is being formed in the deeper parts of the wound, the epithelium on the surface is also being regenerated (Fig. 194), and through continuous cell-divisions (d, e) forms a covering of many layers. The young connective tissue uniting the edges of the wound is distin- guishable for a long time from the neighboring older tissue through its 272 INFLAMMATION. richness in cells (Fig. 195, d, f), and the finer fibrillation of its ground- substance; in large incised wounds of the skin there may be found in the scar, after the lapse of weeks or even months, slight evidence of proliferation and in- flammation. In general, however, transforma- tion processes gradually occur in the scar, so that its tissues approach more closely to the nor- mal, and finally the place of incision can no longer be easily recog- nized. If the wound heals by the interposi- tion of abundant em- bryonic tissue, there may occur a defect of the papillary bodies Fig. 196. — Fibrin deposit and beginning formation of granula- /-rp- 1Q^ p\ en thai" ^°" tissue in a fibrinous pericarditis five days old (Mialler's fluid, V-'^^^g- i-^J, ^jt SO ^^^'^^a^rnAioyiyM'n) . a, Epicardium; b, fibrin-membrane; c, dilated, the scar remains smooth. congested vessels; i round cells infiltrating the .tissue ;?, lymph- r^ «^ TXT, .1 vessel filled with cells and clots; f, fibroblasts within the deposit. § 97. When on thcx 150. surface of an inflamed serous membrane (Fig. 196, a) there is an adherent layer of fibrin (&), beneath it granulation tissue is apt to form rapidly. The beginnings can be seen as soon as the fourth day and consist in the appearance of fihro- blasts (/) in the deepest layers of fibrinous mem- brane. These arise through proliferation of the con- nective-tissue cells of the affected part, and penetrate the fibrin. There follows soon new-formation of blood-vessels, and in the course of days or of weeks there is developed on the surface vascular embryonic or granulation tissue, which, when the overlying fibrin is compact, lifts this up tn toto (Fig. 197, h, c) ; Fig. 197- — Development of granulation tissue in the or penetrates the intcrsticCS pleura, in bronchopneumonia and pleuritis of fourteen days' r a i ^i • i duration (alcohol. Van Gieson) . a, Hyperamic, infiltrated 1 the tlbrin-membrane pleura; b, very vascular granulation tissue; c, fibrin; d, (P\a<: IQfi -f • IQR h f}^ pus-corpuscles, and granules of precipitated albumin. '^ = ." .' ■' ' ' "' "/' X 100. and in time replaces the fibrin. Remains of fibrin (Fig. 198, c) may, however, persist for weeks or months in the granula- tion tissue. In the formation of granulation tissue and the development of scar-tissue the epithelium (endothelium) of the serous membranes takes ORGANIZATION OF EXUDATES. 273 no part, since it produces no fibroblasts. On the other hand, the products of the in- flammatory proliferation be- come covered later with epithelium. The result is the forma- tion of connective tissue, which leads either to thicken- ing of the serosa or to ad- hesion of opposing surfaces, so that the inflammation may be designated adhesive. The result in individual cases de- pends on the amount of fibrin and the situation of the affected organ, and its condi- tion during the process of healing. Small deposits of fibrin, limited to one surface of the serous membrane, lead to thickenings of the serosa, which, becoming pale with the obliteration of vessels, are finally represented by so- called milk-spots or tendinous spots. The glueing together of two serous layers by abundant fibrin leads to an adhesion through the Fig. 198. — Formation of granulation tissue in tlie fibrinous deposits of a pericarditis several weeks old (Miiller's fluid, hsematoxylin, eosin"), a, Epicardium; h, deposit on the epicardium, consisting of granulation tissue (d), and fibrin (c). X 40. formation of connective tissue, and repeated rubbing of the membranes upon each other, there develop loose membran- ous or stringy adhesions, which still permit the serous sur- faces to move upon one an- other. Very large amounts of fibrin may permanently re- sist absorption and usually become calcified. Coagulated e:{udates in the lungs may become lique- fied and absorbed, but it sometimes happens that their removal is associated with connective-tissue proliferation and induration of the lung. The proliferation proceeding from the lung tissue leads to thickening of the septa (Fig. 199, a, b) or extends into the exudate in the alveoli in 18 In the case of a smaller amount of fibrin, Fig. 199. — Intraseptal and intra-alveolar formation of connective tissue in the lung Calcohol, haematoxylin), a. Thickened fibrocellular alveolar septum, in part in- filtrated with round cells (6) ; c, fibrinocellular exudate in the alveoli; d, intra-alveolar formative cells; e, strand of spindle-cell fibroblasts; g, intra-alveolar newly formed blood-vessel, x 200. 274 INFLAMMATION. the form of embry- onic tissue {dj e) which later may con- tain newly formed blood-vessels (g). Masses of coagula within blood-vessels, called thrombi, give rise, in case no in- fection occurs, to in- flammatory prolifera- tion of the vessel- wall, a proliferating vasculitis. This pro- cess corresponds ex- actly to the inflam- matory proliferation of serous membranes. It is immaterial whether thrombosis has been caused by a preceding inflamma- tory process or by other conditions, inas- much as the mere presence of the coagulum is sufficient to cause inflam- mation and tissue-proliferation. Fig. 200. — Development of embryonic tissue in a thrombosed femoral artery of an old man, three weeks after ligation (alcohol, hematoxylin), a, Media; b, elastic limiting membrane; c, intima, thickened through older inflammatory processes; d, coagulated blood; e, cellular infiltration of the media, /, of the intima; g, round cells, partly in the thrombus, partly between it and the intima; h, different forms of fibroblasts. X 300. ?J. v*?-.ir»^^ '! ■yi 1^ — * ..jL*r.^ T"?*.. Q Fig, 201. — Periphery of a healing pulmonary infarct (MuUer's fluid, haematoxylin, eosin). a, Blood-extravasate changed into a yellowish granular mass; b, necrotic alveolar septa without nuclei; c, newly formed connective tissue; d, vascular granulation tissue within the alveoli; e, fibroblasts within alveoli containing the residue of the htTsmorrhage; /, artery; g^ vascular con- nective tissue formed within the artery at the place of the embolus, x 40. ORGANIZATION OF NECROTIC TISSUE. 275 The first change introduced in the substitution of the thrombus by connective tissue is the appearance of fibroblasts (Fig. 200, h), which arise from the vessel-wall, and later, with the aid of vessels growing in from the vessel-wall and its neighborhood, form embryonic tissue, which ulti- mately changes into connective tissue. The complete substitution of an obturating thrombus leads to obliteration of the vessel-lumen by vascular- ized connective tissue (Fig. 201, g) ; the substitution of a parietal throm- bus, on the other hand, results in the formation of fibrous thickening of the vessel-wall. As the result of imperfect substitution or liquefaction of the part not substituted, strands and threads of connective tissue cross the lumen of the ves- sel. Calcification of portions of thrombi not replaced bj'' con- nective tissue leads to the formation of ves- sel-stones (arterio- or phleboliths). Necrotic tissue which cannot be se- questrated and dis- charged externally, is also replaced by vascular connective tissue, which be- comes converted into scar-tissue ; this sub- stitution takes place in the same manner as in fibrinous exudates and thrombi. The requisite condition is that the necrotic tis- sue shall contain no substances (bacteria) which hinder tissue- proliferation. In gen- eral it" is immaterial how the necrosis has occurred, or whether the necrotic tissue is free from or infiltrated with exudate or blood. The change leading to healing consists in the production of granu- lation tissue, which grows toward the necrotic tissue (Fig. 201, c, d), and finally replaces it. If this process is not disturbed large tissue-necroses (for example, a hsemorrhagic infarct of the lung) may in the course of weeks or months disappear and be replaced by con- nective tissue. It may also happen, however, that certain tissues resist absorption, or that the development of granulation tissue stops so early that remains of the necrosed tissues persist and become calcified. When, as the result of inflammation or ischaemia, only the more sensi- tive elements die — for example, epithelial or muscle cells — while the connective tissue remains intact, the absorption of necrotic portions takes Fig. 202. — Fibroid area in heart-muscle. Section through a muscle-trabecula which has undergone fibroid change (Miiller's fluid, hasmatoxylin) . a, Endocardium; h, cross-section of normal muscle-cells; c, hyperplastic connective tissue rich in cells; d, atrophic muscle-cells in hyperplastic connective tissue ; e, dense connective tissue, poor in nuclei and containing no muscle-cells; /, vein, in whose neighborhood muscle-cells are still preserved; g, small" biood-vessels; hj small-cell infiltration. X 40. 276 INFLAMMATION. place quickly, and there is formed in a short time a scar of connective tissue (Fig. 202, ^), in which specific tissue-elements are lackmg. Pus is quickly absorbed from small abscesses, and the defect ts closed by granulation and scar tissue. Large amounts of pus may be absorbed from the body-cavities and from the lungs. Abscesses cause in their immediate neighborhood granulation tissue which leads to the formation of a limiting, so-called pyogenic or abscess- membrane. The abscess-cavity may become obliterated through absorp- tion of the pus and union of the walls of the cavity; the abscess finally heals and leaves a scar. Incomplete absorption may lead to thickening of the pus and cal- cification of the residue. If the pus does not become inspissated, the abscess may persist and in- crease in size by exudation from its walls. Empyemata may heal in similar manner to abscesses through the absorption of pus. The tissues enclosing the pus produce granulation- and scar- tissue, which may reach a con- siderable size when absorption is delayed (Fig. 204). When in- completely absorbed, calcification may occur. Foreign bodies, so far as they are absorbable and exert no specific influence on their sur- roundings, are dissolved, and re- placed by connective tissue in the same way as are tissue-necroses or fibrin masses. If they pos- sess accessible interstices, these may be penetrated by granulation j/- i-'-r^/rotthf ^^^s^^Tkti^^Z tissue. If not absorbed, they be- o Sequestrum; 6 c edges of the opening m the 1 , J thickened bone (alcoholic preparation). Reducea come encapsulated. one-third. IV. Chronic Inflammations. § 98. Inflammation is essentially an acute process, but various con- ditions may cause the phenomena of tissue-degeneration and exudation to persist, and inflammation then becomes chronic. The causes of chronic inflammations are to be sought in the fact that in an acute inflammation changes occur which prevent healing. When masses of necrotic tissue are not completely absorbable, such as large pieces of bone, they may become sequestrated, but persist as sequestra for years (Fig. 203, a), and keep up inflammation. Following a large, super- ficial defect of the skin, such as results from a burn, granulation tissue CHRONIC INFLAMMATION. 277 develops, but months may pass before the Fig. 204. — Changes in the pleura and lung after a purulent pleuritis lasting six months (alcohol, orcein). a, Thickened lung tissue with gland-like alveolij and elastic fibres in the newly formed connective tissue; h, thickened pleura; c, newly formed connective tissue without elastic fibres; A, granulation tissue covered with pus; e, elastic limiting membrane of the pleura; f, elastic fibres, x 46. wound is covered with epithe- lium from the edges and the process brought to a close. A further cause of chronic inflammation is constantly repeated injury. For example, frequently- repeated inhalation of dust may cause chronic inflam- mation of the lungs; re- peated rubbing of the skin may cause chronic inflam- mation of the part affected ; pathological alterations of the stomach contents may cause chronic inflammation of the stomach. In canals or reservoirs, such as the gall-bladder, the ducts of the pancreas, etc., concre- tions may give rise to last- ing tissue-lesions. Unfavorable nutritive conditions — e. g., marked congestion — may enable external influences that, under normal conditions, produce no inflammation at all or one soon subsiding, to set up ulcerative pro- cesses showing no tendency to heal. In this manner, for example, chronic ulcers of the leg may arise. A frequent cause of chronic inflammation is furnished by infections, particularly . bacteria and moulds, which multiply in the body and constantly give rise' to irritation. The inflammations which they cause are distinguished by the fact that they lead to connective- tissue prolifera- tions and that they usually show a progressive char- acter, and form secondary deposits through the lymph- and blood-vessels. Finally, chronic intoxi- cations form a cause. These 278 INFLAMMATION. r^r *•*■***. ^v H 4 - w J y? V' V '%, ^ affect chiefly the kidneys and liver, and may be attributed either to the continued introduction through the gastro-intestinal tract, lungs, or skin of substances harmful to the organs directly concerned or to others; or injurious substances may be produced in the body itself, through dis- turbances of metabolism. The forms of chronic in- flammation are determined partly by their causes, partly by the character of the tissue affected. Chronic inflammations characterized by hyper- plastic formations of con- nective tissue are found in serous membranes, lungs, and skin, but may occur in other tissues. Chronic pleuritis, caused by exudates which are with difficulty absorbable, or by chronic infections, lead to ^^^ ,o5.-Sectio„ of a stonecutter's lung with fibroid extensive scar-like thickenings nodules (alcohol, picrocarmine) . a, Group of fibroid fX^' Of\A 7, ^ 4-1^ 1 nodules: b, normal lung tissue; c, thickened lung tissue V-TIg. ZU4, (7, C), on tne pieura stlll containing bronchi, vessels, and a few alveoli, x g. (c) and in it (&). Moreover, induration of the lung (&)may follow infectious inflammations, or may be caused by the continued inhalation of stone dust, the latter character- ized by the formation of fibroid nodules (Fig. 205; a), or by diffuse induration (c) Continued irritation of the orifices of the urogenital apparatus, through the discharge of secretions (chronic gonorrhoea), frequently leads to the forma- tion of pointed condylomata {condylomata acuminata'), in which inflamed and infiltrated papillae grow out with their vessels (Fig. 206, a, h) and divide into branches. Frequently repeated or continued slight inflammations of the skin and subcutaneous tissue, due to mechanical lesions, parasites, or other irritation, may, if they reach a considerable extent, give rise to diffuse ^hyperplasia of con- nective tissue, known as elephantiasis. Inflammatory prolifera- tions of the periosteum and bone-marrow, which give rise to pathological new- formations of hone or hyperostoses (Fig. 207), may be caused both by non-specific irritations -^ for example, by inflammations Which run their course in the neighborhood of chronic ulcers — as well as by specific infections — for example, syphilis or tuberculosis. Fig. 2o6.- tion). a, X 20. -Condyloma acuminatum (injected prepara- Enlarged branching papillae; b, epidermis. CHRONIC INFLAMMATION. 279 Chronic catarrhs of mucous membranes are caused by specific infec- tion (gonorrhcea, tuberculosis), by non-specific injuries (concretions, pathological changes in the gastric or intestinal contents), and by con- tinued disturbances of circulation (congestion). Chronic abscesses usually arise from acute abscesses, and have the same etiology; but may develop gradually and are then caused by such infections as tuberculosis and actinomycosis. They are usually limited by a connective-tissue membrane lined on the inside by granulation tissue, and may increase in size through secretion of pus from the abscess-wall, and through destruction of the wall and neigh- boring tissue. Progressive extension toward the deep parts leads to the formation of bur- rowing abscesses. Their increase in size is always to be ascribed to persistence of infection. Perforation into neighboring tissues leads to secondary infective inflammations. The tuberculous and actinomycotic forms of chronic abscesses are distinguished by the specific character of the pus and by the peculiar structure of the abscess-membrane (see Tuber- culosis and Actinomycosis, Chapter X.). Chronic ulcers are caused chiefly by spe- cific infections (tuberculosis, syphilis, glanders), but non-specific agents may lead to chronic ulcerative processes in tissues which are especially susceptible. Thus chronic congestion in the vessels of the leg may have such an effect that ulcers arising through any influence may be prevented from healing under the mechanical conditions in which the leg finds itself. Like- wise peculiar qualities of the stomach contents may hinder the healing of an ulcer of the stomach. If healing begins at one edge of an ulcer while ulceration advances at other parts, the ulcer is known as serpiginous. The exces- sive development of granulation tissue in an ulcer leads to the production of the condition • known as exuberant granulation, or " proud flesh ; " dense thickening of the edsre and base gives rise to the form known as indolent ulcer. Chronic proliferations of granulatibn tissue — i. e., granulations which persist with- out becoming changed into connective tissue — occur in various specific infections, notably in tuberculosis, syphilis, leprosy, glanders, rhino- scleroma, and actinomycosis. Since the granu- lations in these infections form fungoid proliferations and tumor-like formations, they are often called fungous granulations or infectious granulomata. All these show certain structural and other peculiarities which enable us to reco-gnize their specific nature (see Chapter X.). It should be noted, however, thart the etiology of some of the granulomata is still unknown. Fig. 207. — Periosteal hyper- ostosis of the tibia, at the base of a chronic ulcer of the leg. Reduced two-fifths. 280 INFLAMMATION. Chronic inflammations in which atrophy of specific tissue is asso- ciated with hyperplasia of connective tissue, occur particularly often in the mucous membrane of the gastro-intestinal tract, and in the kidneys and liver. In the intestinal canal the cause may lie in specific infections (dysen- tery) as well as in non-specific irritations; the latter dependent on some abnormal property of the contents of the canal. The epithelial elements may undergo necrosis with persistent desquamation, the connective tissue being unaffected ; or they may necrose and disintegrate at the same time as the connective tissue on which they rest. The result is a mucous mem- Fig. 208. — Section through the mucosa of an atrophic large intestine, (alcohol, alum-carmine), a, Glandular layer decreased to one half its normal height; b, muscularis mucosa; c, submucosa; d, muscularis; ■ ■ ,_^>, ^1 % » ' .,.*• "\. ■v """-> "N .j« • • • ^ -J^, ^^^^BBbK^^t^ ^'' 1 • ». Fig, 212 — (Bellevue Hospital.) Primary carcinoma of the gall-bladder with secondary- infiltration of the substance of the liver, showing the presence of a larre gall-stone in the lumen of the gall-bladder, present at birth, or in extra-uterine life, during the period of growth dr* later, in which case trauma not infrequently gives the immediate occasion for the beginning of the tumor. To this group belong many osteomata, chondromata, angiomata, gliomata, fibromata (of the nerves and skin), and adenomata. Further, many teratoid tumors and cysts are to be included, inasmuch as they repre- sent either remains of foetal structures, transpositions or mpnogerminal inclusions of embryonic tissue, implantations of rudimentary portions of a twin embryo (bigerminal implantations), or the results of disturbances of the earliest stages of the development of the ovum. A second group develops after traumatic injuries of tissues; it has been reckoned that in about seven to fourteen per cent of cases a trau- matic origin can be assigned; particularly in sarcoma, carcinoma, and osteoma. It may be a single injury, a stab, a blow, crushing fracture, etc., or repeated mechanical irritation, such as rubbing, etc. In a third group the development of the tumor follows inflammation, particularly granulation tissue with subsequent cicatrisation. The inflam- 286 TUMORS. mation and ulceration may be caiased by non-specific as well as by specific agents. For example, cancer of the gall-bladder (Fig. 212), develops almost invariably only in gall-bladders which contain stones, and are consequently the seat of chronic inflammation. In the stomach, cancer may develop in the edge of an ulcer or in the resulting scar and also in a mucous membrane which has sufjfered severe changes as the result of previous inflammation. In the skin and in the mucous membranes of the pharynx and larynx cancers occasionally arise in the base of a tubercu- lous or syphilitic ulcer or in the scar of such a process. In a fourth group the development of tumors appears to owe its origin to unequal atrophy of the elements which make up a tissue, so that certain hindrances to growth are removed or lessened. Not mechanical resistance alone, but influences dependent on chemical conditions, should be con- sidered in this connection. Certain epithelial proliferations {cancers) develop in old age, or in organs which after a period of increased activity become atrophic. For example, the development of cancer of the skin may be explained on the ground that the connective tissue undergoes retrogression leading to relaxation, while the epithelium is still possessed of full power of proliferation. At the same time the chemical composition of the connective tissue may be altered. It cannot be doubted that the etiology of tumors is not always the same, as shown by the variety of conditions under which they arise. It is difficult to say what is the nature of the influence which excites the cells to the prodiiction of an atypical tissue. We are at first inclined to think of the same causes which underlie hypertrophy and regeneration of tissue, also of stimuli which increase the formative activity of cells, or of lessening or removal of hindrances to growth. But it still remains a problem why there should not be formed typical tissues which would so fit into the organization of the body that they would be of service. In the attempt to explain this phenomenon, many writers have sought and would recognize as the cause the presence of parasites (see Etiology of Car- cinoma) ; but our present knowledge does not in any way justify us in attributing the development of true tumors to the influence of parasites. On the contrary, the development and life-history of tumors, and the formation of metastases, which arise through the multiplication of living tumor-cells transported in the lymph- or blood-stream, speak against the hypothesis of the parasitic nature of tumors. Cohnheim advanced the theory that all true tumors arose from the persistence of foci of etnlbryonal tissue. Neither the results of clinical observation nor of anatomical investigation speak in favor of such a theory. Rihhert is of the opinion that the cause of the proliferation which leads to tumor-formation is to be found in separation of cells or cell-groups from their organic relations, such separation occurring as the result of intra-uterine disturb- ances of development or later under the influence of external agencies. Neverthe- less, such transplantations or separations of cell-groups take place frequently in intra-uterine life, or after traitma, after ulceration, in scars and in infectious granulomata, without subsequent development of a tumor. These transplantations of tissue constitute only one of the predisposing causes of tumor-formation; some other factor is necessary to excite the atypical progressive tissue-proliferation — i. e., the development of the tumor. The development of a tumor is, therefore, in no wise dependent upon transplantation of tissue; rather the tmnor-proliferation takes its origin in cells which are normally situated; this may be actually demon- strated particularly in epithelial tumors. Our knowledge of the causes of tumor-development at the present time may be summed up as follows : Inherited and acquired conditions of certain cells and cell- groups, which assert themselves in a tendency to increased formative activity with the production of atypical tissue, lead to the formation of tumors. In many cases this proliferation is prepare?! for, favored, and excited by the transplantation of cells and cell-groups, but often also through changes in the neighborhood of the cells concerned. No general scheme applicable to the development of all tumors can be given. On the contrary, the conditions vary not only with the different forms of tumors, but with individual cases of the same tumor-type. Moreover, GROWTH OF TUMORS. 287 it should not be forgotten that the formations which we class as tumors do not all possess the same significance, and that many more properly might be classed with other phenornena of growth (malformations). § 101. When once a tumor has arisen and has reached a certain stage of development it may become quiescent, and remain for a hfe-time without undergoing further change. This is true particularly of those which are regarded as local tissue-malformations; but tumors which Fig, 213. — Section throujrh primary cancer of the liver (a), with multiple metastases (b) within the liver itcelf. Three-sevenths natural size. first develop in later Hfe may come to a standstill after attaining a certain size. The growth of a tumor takes place independently, and in many cases continues until death. Frorp the surrounding tissues the tumor acquires its blood-vessels and hence its food material, but may besides glow independently — i. e., through increase of the cells which form the elements of the tumor. In many cases the tumor increases in size through interstitial expansive growth, and the neighboring tissue is crowded or pushed aside. In other cases the tumor grows by infiltration and forces its way into the inter- cellular spaces of the neighboring tissue, so that new areas are brought under the influence of the tumor. In this way the cells of the invaded tissue are often excited to proliferation, and enlargement takes place through oppositional growth. The characteristic feature of growth by infiltration consists in involvement of the tissues of the organ that lie in the neighborhood of the primary tumor. Further, the tissue of neighboring organs may become involved by the tumor through contiguity. If tumor-cells gain entrance into the great body-cavities they m,ay spread over the serous surfaces and lead to the development of secondary tumors. 288 TUMORS. If, in the process of infiltration, a tumor gains entrance to a lymph- or blood-vessel — an event which is likely to occur in carcinoma and sarcoma — and if tumor-cells capable of proliferation are transported through the lymph or blood, tumor-metastases arise — that is, secondary or daugh- FiG. 214. — ^Periglandular lymph-vessel (in the axillary region) filled with cancer-cells arising from a primary carcinoma of the mammary gland (Miiller's fluid, hjematoxylin), a, Cancer- cells; bj wall of lymph-vessel. X 300. ter tumors which are not directly connected with the original focus of growth. The daughter-tumors may develop first in the organ primarily affected (Fig. 213, b), but usually involve other organs as well ; in the case of rupture into lymph-vessels the lymph nodes are first affected ; in rupture •n ■' ^'A"r",¥^^J^^^'''^, development of cancer in the branches of the portal vein and liver- capillaries (Muller s fluid, hematoxylin, and eosin). a, Liver tissue; b, plugs of cancer-cells m the portal vem; c, cancer-cells in the capillaries, x loo. into blood-vessels, those organs to which the blood carries the living cells. The direction of transportation is usually that of the lymph- or "blood- stream, but retrograde transportation not infrequently occurs, particularly m the lymph-vessels, the lumina of which are easily obstructed by tumors. METASTASIS OF TUMORS. 289 The development of daughter-tumors takes place from transported cells. In lymphatic metastasis the lymph-vessels (Fig. 214, a) are in- vaded by tumor-cells which are deposited at a distant point, this is followed by proliferation and metastatic nodules develop. It not infrequently hap- pens that the lymph-vessels are uniformly distended by the growth (Fig. 214, a), without the formation of nodules, or at least only small swellings develop along the course of the lymph-vessels. In metastasis into lymph nodes the latter become swollen, forming nodules of smaller or larger size, ;*^,., /** ♦rf-. Fig. 2i6. — Metastatic sarcoma of the liver from a primary sarcoma of the parotid (Flem- ming's solution, safranin, picric acid), o. Liver-rods; b, sarcoma tissue developing within the vessels; c, isolated tumor-cells in the liver-capillaries; d, liver-cells which have undergone atrophy "and fatty degeneration. x 150. and the structures of the node are gradually replaced by tumor tissue. In metastasis through blood-vessels the development of the secondary tumor begins with the deposit of tumor-cell emboli in artery, capillary, or vein, and the vessels (Figs. 215, b, c; 216, h, c) may eventually be filled and dilated by proliferating tumor-cells. The tissue in which the tumor- embolus develops may reinain passive, and the specific tissue-elements — gland-cells (Fig. 216, d) and muscle-cells — may vanish as the result of pressure atrophy. Later, the blood-vessels and connective tissue may take part in the development of the secondary tumor. In the further course of development the secondary nodule is usually sharply circumscribed from its surroundings and grows by expansion. It not infrequently happens, however, that the infiltrative growth persists, and under these conditions widespread diffuse tumors develop, particu- larly in the bone-marrow and the liver (Fig. 216). The number of lymphogenous and hsematogenous metastases varies greatly in different cases. At one time the metastases may be confined to one organ, at other times they may be scattered through several. In rare cases cells of the original tumor may be spread through the entire body, so that in diverse organs — glands, muscles, skin, etc. — larger and smaller nodules appear in quick succession. This phenomenon is possible when tumor-nodules break into blood or lymph vessels and the tumor cells are thus enabled to spread throughout the body and to lodge and grow in different parts (carcinomatosis, sarcomatosis>,melanomatosis, etc.). 19 290 TUMORS. If a living bit of tumor (carcinoma, sarcoma) capable of forxning metastases is transplanted from one animal into the. tissues of another animal of the same species, it sometimes happens that it will develop in the second animal. In man, tumor particles may be. transplanted during operations from one part of the body to another and there grow (im- plantation metastasis), or rupture of an encapsulated tumor may be fol- lowed by secondary implantations in neighboring surfaces, e. g., in cer- tain ovarian tumors rupture may be succeeded by extensive implantation metastases in the peritoneum. Side by side with progressive proliferation of tissue there frequently occur in tumors retrogressive changes, particularly in rapidly growing and infiltrating cellular tumors, in which fatty and mucous degeneration, necrobi- otic processes, and haemorrhages may take place to such marked degree as to bring about extensive destruction of the tumor tissues. This disintegration is due to the fact that the tumor grows into or compresses the blood-vessels and obstructs them. If the cells are badl}* nourished they undergo necrosis and be- come dissolved through the action of proteolytic ferments. In nodular tumors the destruction of tumor-'cells, followed by softening or partial resorp- tion of the products of degeneration, kads to local areas of umbilication. Often ulcers may thus be formed ; in carcinomatous tumors of mucous mem- branes the parts growing above the sur- face often undergo disintegration. In slowly growing tumors of hard con- sistence extensive retrograde changes do' not usually occur. The necrosis and disintegration of a tumor rarely terminate in cure. This event is most likely to happen when a polypoid new-growth becomes totally necrotic (for example, as a result of Fig- .217-— Recurrent sarcoma in the , • ,. ^ , • ^%'. ,. , " "• , amputation-stump of the femur, a. Fungoid tWlStmg or tearmg of its pedicle) and tumor arising from the bone-marrow- b, is thrown off. In the majority of Sa?u°ai'dze.°'^"'"' "' "'t^^'^^^^- One-haif tumors showing a tendency to retro- gressive changes and disintegration, while the older portions are dying the growth advances at the periphery, and new tissues are pro^ressivelv attacked. If the tumor is completely extirpated, cure may be brought about. This IS most easily accomplished in slowly growing and sharply circum- scribed tumors which increase by expansion. In infiltrating tumors it is difiicult to determine the boundary of the growth, since this may extend far beyond the point where macroscopic change is apparent. Conse- quently, in such cases, recurrence sooner or later takes place in the scar, and (Fig. 217, a) arises from portions of the tumor remaining in the tis- sues. Such recurrences behave exactly like the primary tumor, and may FIBROMA. 291 form metastases (Fig. 217, c). In those cases in which recurrence in the scar following operation is long delayed, it is possible that this circum- stance depends on the fact that in the aifected area the conditions favor- ing tumor development again occur. According to their clinical and anatomical characteristics tumors may be classed as benign and malignant. Benign tumors are generally re- garded as those which grow slowly and by expansion and do not form metastases; malignant, those which show complete emancipation from the. normal laws of proliferation, grow quickly and by infiltration, easily undergo degenerative changes and form, metastases. The malignant tumors, on the whole, coincide with those forms which are known as carcinoma and sarcoma. It must, however, be borne in mind that the malignancy of a tumor depends not only on its character, but also on its location {local malignancy) . A benign tumor takes on malignant character as soon as its presence interferes with the functions of vital organs. Hence every tumor of the brain or meninges becomes a dangerous affection at the moment when it gives rise to disturbances of the cerebral functions. Under certain conditions such benign tumors as fibromata of the uterus become destructive, or locally malignant, as soon as they reach such size as to displace and compress neighboring organs. After a tumor has existed for a certain period there frequently results marked lowering of the general nutrition, marasmus, which is designated tumor-cachexia. This occurs oftenest in association with the malignant growths known as cancer and sarcoma ; and may depend, in part at least, on the great demands made on the food supply by the rapid growth of the tumor, particularly if there are metastases. A still more important cause may be that the tumor interferes with the ingestion of food. In cancer of the oesophagus, stomach, and intestine the function of the affected organ is interfered with, and the entrance and assimilation of food may be entirely prevented or nearly so. Further, it should be borne in mind that through degeneration of the tumor and from resulting ulcers large amounts of albuminous material are lost; and that through putrid decomposition there may arise substances which, when absorbed, act injuriously on the organism.. Finally, the pain which is often felt in a tumor may rob the patient of sleep. Whether the tumor itself produces substances harmful to the organism is unknown, but is, however, not improbable. Metastases occasionally occur with benign tumors, chondromata, myo- mata, and adenomata. Of these, the metastases in the bones of thryoid tumors are of special importance; they occur when no carcinomatous proliferation can be demonstrated in the thyroid, so that it would seem probable that under certain conditions even the cells of a normal or hypertrophic tissue may be transported into the bone-marrow and there proliferate. II. The Different Forms of Tumors. I. Tumors Derived from Connective Tissue or the Supporting Framework. (a) Fibroma. § 102. A fibroma is a tumor composed of fibrous connective tissue. It occurs most frequently in the form of nodules, which are sharply cir- cumscribed from the surrounding tissues, and usually involve but a por- tion of the aifected organ. Rarely an entire organ (ovary) may become 292 TUMORS. at. im^^ Fig. 2i8. — Hard fibroma from lobe of the ear (alcohol, hEematoxylin), a, Longitudinal section; h, transverse section of bundles of fibres. X 400. changed into a single tumor-mass. On a free epithelial surface and on mucous membranes a fibroma may appear in the form of a papilloma or polyp. According to the character of the connective tissue of which it is com- posed, the consistence of a fibroma may vary greatly. Often it is hard and tough, creaking under the knife, and showing on its surface a white, tendon-like, shining tissue {desmoid) ; but in other cases the growth may be soft, flaccid, the cut surface more uniformly grayish-white and somewhat translucent. In still other cases the individual strands of connective tissue are white and shining, but the tumor as a whole has a looser sti-ucture and is cor- respondingly flaccid. Between the hard and soft growths there are all possible tran- sition-forms, and even in one tumor different parts may possess differ- ent characteristics. Under the mi- croscope the hard fibromata appear to be composed chiefly of thick bundles of coarse fibres (Fig 218, a, b), in which lie scattered a larger or smaller number of cells. In the softer forms the bundles of fibres are more delicate (Fig. 219, a). If as a result of congestion or other cause clear fluid collects between the fibrillse, there is formed an edematous fibroma, whose bundles of fibres (Fig. 219, b) are pressed apart by the fluid, the tumor becoming softer and more translucent, finally resembhng the tissue of the umbilical cord. The soft fibroma, which presents a trans- lucent, grayish-white cut surface, is usually rich in cells ; so that it is possible by teasing to isolate nu- merous slender spindle- shaped forms with term- inal fibrils. The inter- cellular substance is cor- respondingly less in amount, the fibrillse more delicate and arranged in finer bundles. Sections of such fibromata, when stained, appear rich in nuclei (Fig. 220, b). Fibromata develop from proliferating connective-tissue cells, and it is usually possible to find in the tumor areas which are richer in cells than others, and in which the cells appear not only as small spindle cells, but as round cells, or as short, thick spindles, or even as stellate cells. The transformation of the newly formed cellular tissue into connective tissue takes place in the same way as that described under Hyperplasia of Con- nective Tissue. New-formation of elastic fibres is usually wanting, but Fig. 219. — Section of an cedematous fibroma of the uterus (osmic acid, glycerin). a. Closely lying fibres; bj fibres pressed apart by fluid; c, spindle-shaped cells; d, swollen round cells; e, blood-vessel. X 200. FIBROMA. 293 at times does occur, particularly in the neighborhood of the blood-vessels. Fibromata may appear in any part of the body which contains any form of connective tissue. They occur most frequently in the nerves, skin, periosteum, fascia, mammae, and mucous membrane of the nose; more rarely in the ovary, intestinal tract, etc. In the mammary gland the development of the fibroma takes place particularly around the cana- liculi (Fig. 220, b), which become surrounded by connective tissue rich in cells. Fibromata do not form metastases, but often occur as multiple tumors, especially in the nerves and skin (see Neurofibroma, § HI). Moreover, Fig. 220. — Fibroma pericanaliculare mammse (Muller's fluid, alum carmine, eosm). a, Gland- tubules; t, newly formed pericanalicular connective tissue ricli in cells; c, connective tissue poor in cells. X 35. it is not uncommon to see in a tumor several centers of growth — that is, the mass of the tumor is made up of several nodules or bands held to- gether by ordinary connective tissue (Fig. 220, b). Fibromata are malig- nant only through size and position. Fibromata may undergo mucous or fatty degeneration or may soften and disintegrate, so that cavities are formed in them. They may also break down and give rise to ulcers. Their blood-supply varies greatly, at times being, scanty, at other times abundant. Occasionally the blood-ves- sels are ectatic, so that the tissue is interspersed with wide channels and clefts, from which blood escapes when the tumor is incised and examined in the fresh state. In other cases dilated lymph-channels are seen. Keloid is the designation applied to a hard, nodular, or flat and banded, or stellate growth of the skin, which in its fully developed state consists of dense fibrous tissue without elastic fibres. The direction of the fibres is often at right angles to the surface of the skin, or at least does not accord with that of the normal fibres. It usually develops after injuries or inflammations (cicatrix-keloid) , but may appear without such association (spontaneous keloid). The cause of keloid growth is not known ; the tendency to recurrence after removal, the multiple occurrence. 294 TUMORS. and the fact that cases frequently occur in the same family (Hutchinson) speak in favor of some special predisposition on the part of the skin. (b) Myxoma. § 103. A myxoma is a tumor which consists essentially of mucous tissue, and is made up of cells and a fluid or gelatinous intercellular sub- stance containing mucin. The cells are for the greater part polymorphous, with processes of varying length (Fig. 221) which anastomose with one another (Fig. 222, a). The tissue is markedly translucent, soft and the blood-vessels are easily seen through it. From the cut surface gelatinous or stringy masses which swell in water, may be obtained. No tumor is ever made up wholly of myxomatous tissue; the latter is usually combined with other forms of tissue, particularly with fibrous connective tissue, fat tissue, cartilage, and sarcomatous tissue. For this reason such tumors are designated fibromyxoma, lipomyxoma (Fig. 224), chondromyxoma (Fig. 227, c), and myxosarcoma (Fig. 222). Mucous tissue may develop from fibrous connective tissue through the collection of a mucin-containing fluid between the fibrillae and the gradual dis- appearance of the latter. Adi- pose tissue may pass over into myxomatous tissue through the disappearance of fat from the fat-cells and the a/ppearance of a mucin-containing gelatinous sub- stance between the cells, during which process the fat becomes broken into droplets (Fig. 224, b, c), while the cells themselves become smaller and star-shaped (d). Cartilage may also be- come transformed into mucous tissue through mucoid degenera- tion of the basement-substance and change of form of the cells (Fig. 227, c, d). Myxosarco- „ ^„ , , f-T^' ooo\ • 'j-i Fig, 221.— Cells from a myxoma of the periosteum mata (i^lg. ZZZ) arise either of the femur (gold preparation). X 400. through local increased activity of cell-proliferation in myxomata or through a collection of mucoid sub- stance between the sarcoma cells. Myxomata, myxofibromata, and myxolipomata develop most fre- quently in the connective tissue of the periosteum and endosteum, skin, heart, fascia, and sheaths of the muscles, as well as in the fat tissue of the subcutaneous and subserous tissues. Myxochondromata occur par- ticularly in the parotid, and constitute the most common form of tumor found there. These forms are all benign tumors, which rarely produce metastases. Myxosarcomata, on the other hand, have characteristics of malignancy, and may form metastases. LIPOMA. 295 (c) Lipoma. § 104. A lipoma is a tumor consisting of adipose tissue (Fig. 223) These tumors are sometimes soft, almost fluctuating, sometimes firm usually nodular and lobulated, and often attain great size. ' Fig. 222. — Section of a myxosarcoma (Miiller's fluid, carmine, glycerin), u, Myxomatous tissue; b, strands of cells; c, fibrous tissue, x 22$. Histologically, the tissue of a lipoma resembles the fat-lobules of the subcutaneous panniculus (Fig. 223), although the tendency to form typical grape-like clusters of fat-cells is wanting. If, as not infrequently happens, mucous tissue is formed in connection with the fat tissue, or if the latter, following disappear- ance of its fat, becomes changed into myxomatous tissue, the tumor is designated lipomyxoma (Fig. 224) ; if there is an abun- dance of fibrous tissue present, it is called lipofibroma or fibro- lipoma. Calcification, necrosis, gangrene, and sloughing are not infrequent in lipamata of large size. These tumors do not produce metastases, but are often multiple. Complete disappearance of a lipoma does not take place even in extreme emacia- tion of the host. Lipomata are sometimes ob- served in new-born children — for example, as tumors developing in or over the cleft-formations of spina bifida — but occur much more frequently in later years. The most common seats of these growths are the subcutaneous tissues of the back, buttocks, neck, axilla, abdomen, and thigh; they are also found in the intermuscular Fig. 223. — Lipoma of shoulder region, with relatively small fat-cells (Miiller's fluid, hasma- toxylin). X 300. 296 TUMORS. connective tissue, subserous fat tissue, in the kidneys, intestine, manimary gland, under the aponeurosis of the forehead, in the skin, fingers, joints, etc. They may occur as multiple growths symmetrically distributed. In man the formation of fat tissue about the neck and throat, leading to Fig. 224. — Lipomyxoma of the back (Muller's fluid. Van Gieson's). a. Large fat-cells; h, c, fat-cells in which the fat is broken up into little droplets; d, mucous tissue; e, blood vessel. X 300. nodular and lobulated disfigurations of this region, occasions the designation fatty collar. The development of fat in these cases takes place in the subcutaneous tissue, in and under the fascia and between the muscles. Abnormal development of fat in an extremity may give rise to the condition known as lipomatous elephantiasis. There are at least two other varieties of lipomatosis that deserve mention, namely, Dercum's syndrome and that of Frolich. The former, known as adiposis dolorosa, is characterized by symmetrical deposits of fat in various parts of the body, preceded or attended by pain and sometimes associated with asthenia and mental disturbances. The lipomatous masses involve the abdomen, chest, arms or legs, or may be localized on the limbs or trunk. The affection is more common in females. The few cases which have been investigated post-mortem have shown, among other things, in addition to the lipomatosis, interstitial neuritis, changes in the thyroid gland and sometimes in the pituitary. The syndrome of Frolich or dystrophia adiposo-genitalis is a condition of obesity which occurs in connection with tumors of the pituitary and is associated with h3rpoplasia of the genital organs and infantilism. Lyon (Archives of Internal Medicine, 1910) has con- tributed an admirable paper on the subject of lipomatosis. He includes (1) Der- cum's syndrome, (2) simple adiposity, (3) solitary multiple or symmetrical nod- ular circumscribed lipomatosis, (4) diffuse symmetrical lipomatosis, including the so-called " fat neck," (S) neuropathic oedema, pseudo-oedema and pseudo-Upoma, and (6) the syndrome of Frolich. He believes that all of these conditions are merely different expressions of the same morbid process. In addition to the forma already described, there are lipomata com.posed of proliferating embryonal fat cells which display a disposition to invade surrounding tissues and thus to become diverted in the direction of malignancy. Still another but rare variety of lipoma consists in a combination o^f adult and embryonal fat cells supported in a reticulum of connective tissue and as'iociated with the presence of rr'i='-tions of newly formed or dilated capillary or other small vessels (lipoma CHONDROMA. 297 cavernosum). A patient at Bellevue Ho'spital presented these growths in the sub- cutaneous tissue literally by dozens. There is a large group of chronic productive inflammatory lesions characterized by the infiltration of greater or less numbers of embryonal fat ceils. Sometimes these are so numerous and so closely packed or so vfidely distributed through the tissues as to suggest neoplasmic transformation. Suoh changes are not uncommonly encountered in productive inflammatory lesions in the breast, the walls of the gall-bladder and intestine, the interstitial tissues of the bone marrow, occasionally in the kidney in chronic interstitial nephritis and particularly in tissues which are normally rich in fat, such as the omentum and mesentery (Symmers and Fraser, Arch. Internal Medicine, 1917). Extensive hyperplasia of embryonal fat cells is sometimes to be seen in maran- tic infants. In such a case investigated by myself at the New York Hospital, em- bryonal fat cells occurred in such enormous numbers as to suggest the presence of a new growth. They were distributed, however, through those regions where fat is normally encountered and consisted of bright cherry-red nodules composed of embryonal fat cells lying in a network of capillary vessels. (d) Chondroma. § 105. A chondroma or enchondroma is a tumor consisting essen- tially of cartilage. The amount of connective tissue covering its surface or accompanying the blood-vessels into its interior, is so slight as to fall completely into the background when compared with the cartilage. Chondromata develop chiefly in those places where cartilage is normally found — that is, in the osseous system or in the cartilages of the respiratory tract; but also occur in tissues which nor- ^ . • , % • mally possess no cartilage — ••••^, •_ * I » * ' * • ' *.*•'•• • , t ' * » ' - > • • 1 \ , - ^ » # '* -..'»' : * 1 # * , - ^ * ^ * ^ • ' • I * Fig. 225. Fi<5- "^6. Fig. 225. Periosteal chondroma of a digital phalanx, seen in longitudinal section. a. Chondroma; b, phalanx. Natural size. Fio. 226. Section from a chondroma of the ribs (hematoxylin, carmine), a, Cartilage rich in small cells; b, cartilage rich in large cells, x 80. for example, in the salivary glands, particularly the parotid, and in the testicles, rarely in other organs. In bones which develop from cartilage, chondromata arise from cartilaginous remains that persist after ossification ; but more often take their origin from the periosteum and endosteum (Fig. 225). They form tumors which vary greatly in size. The small ones are usually spherical (Fig. 225) ; the larger ones nodular or lobulated. The individual nodules are often separated from one another by connective tissue. Not infrequently they are multiple, particularly in the skeleton, where they sometimes may be found literally by dozens. 298 TUMORS. « 3 , -S5)j' The tissue of an enchondroma most often presents the characteristics of hyahne cartilage (Fig. 226), more rarely that of reticular or fibrous cartilage. At the peri- phery of the tumor the cartilage passes over into connective tissue^ which forms a kind of perichon- drium. The number, size, form, and grouping of the cartilage cells vary greatly in different cases and in different parts of the same tumor. Many enchondromata are cellu- lar (Fig. 226), others poor in cells,, many con- tain large cells, others small cells, or both large and small cells. The cells are some- times surrounded by a so- ,i^''%- ,((t (?■■• «r fi Fig. 227. — Chondromyxosarcoma parqtidis (alcohol, carmine), a. Cartilage; h, sarcomatous tissue; c, myxo- Called capsule, at other matous tissue; d, cartilage in process of liquefaction and times not ; sometimes they ^^'Z. ~°""^'='' '"'° sarcomatous and myxomatous tissue. lie in groups inside the mot'her-capsule, at other times they are more regularly distributed. All varieties of cartilage normally occurring in the body are found in Fig. 228.— Periosteal chondroma of the calcaneus, with areas of calcification (Mailer's fluid. hematoxylin), o. Hyaline cartilage; h, c, calcified cartilage, x 225. " " "• CHONDROMA. 299 enchondromata. Accordingly the cells vary in form; the majority showing the familiar spherical form, but spindle and stellate cells are not rare, particularly in the neighborhood of the connective-tissue bands FiG,^ 229. — Osteochondroma of the humerus (alcohol, picric acid, hasmatoxylin, carmine. o. Hyaline cartilage; fc, bone; c, cartilage which is becoming converted into bone; d, blood- vessel. X 250. which divide the tumor 'vs±*erves, theouter laj'ers of whose endoneurium have under- gone marked proliferation; the nerve-fibres lie in the axial portion; c, nerve with markedly proliferated endoneurium and separated nerve-fihres; d, thickened nerve with a small strand of nerve-fibres at the left end; e, loose connective tissue, rich in nuclei and containing fat, lying between thb nerves. X 7, in nodular thickening. In ad- dition, it may be found that the nerves of the affected area 3.re lengthened and tortuous, and at the same time increased in number. In these circum- stances the condition must be regarded as one of true neu- roma, or neuroma associated with fibromatosis. The nerves for the greater part are medul- lated {neuroma myelinicum). It is difficult to determine to what extent non-medullated nerves are present in such formations, but cases have been reported in which the nerve- fibres were largely of the non- medullated variety (neuroma amyelinicum) . Cirsoid neuro- mata occur on the head, trunk, „ „ ,, ^. . , , ^. , . and extremities, and give rise Fig. 256. — Cirsoid neuroma of the sacral region. ... f. /- (After a drawing by P. Bruns.) The nodular, twisted, tO elephantiaSlS-hke disfioura- and interwoven nerves are in part free (a), and ill ,* part (b) covered by connective tissue. Natural size. tlOns. SARCOMA, 32,1 True neuromata consisting of nerve-fibres and ganglion-cells (neu.- roma gangliocellulare verum) are rare; but the occurrence of such growths cannot be doubted. They form tumors varying in size from a millet-seed to that of an apple, and consist of connective tissue, non- medullated and medullated nerve-fibres, and ganglion-cells which resemble those of the sympathetic ganglia. Neither the neurofibroma nor the true neuroma forms metastases, but cases occur in which neurofibromata take on a sarcomatous character and thus become malignant. {k) Sarcoma. § 112. A sarcoma is a connective-tissue tumor whose cellular elements, either because of their number or size, predominate over the intercellular substance. Sarcomata are closely related to undeveloped connective tissue, and may be compared with embryonal tissue. Sarcomata develop either in previously normal tissue belonging to the connective-tissue group — in the skin, subcutaneous or intermuscular con- nective tissue, periosteum, spinal cord, meninges, connective tissue of glands, etc. — or in some preexisting connective-tissue tumor, as a fibroma, myoma, chondroma, hypertrophic lymphangioma, etc. The transforma- tion of the parent tissue into tumor tissue takes place through the multi- plication of existing cells. The division of cells takes place chiefly by mitosis, and mitoses are the more abundant the more rapid the growth of the tumor. In addition to typical mitoses there are frequently observed atypical forms, nuclear fragmentation, and, more rarely, segmentation. Fully developed sarcomata form more or less sharply circumscribed growths. They may appear in any portion of the body where connective tissue is present ; but are found in certain tissues more frequently than in others. Thus, they are found much oftener in the skin, fascia, intermus- cular conriective tissue, bone-marrow, periosteum, brain, and ovaries, than in the liver, intestines, and lungs. The development and form of the cells vary greatly in dififerent sarcomata. The intercellular substance is sometimes scanty, soft, and delicate ; at other times abundant and resembling the ground-substance of mature connective-tissue. The amount of intercellular substance has a marked influence on the consistence and color of the tumor. The medullary forms are soft and cellular, and poor in intercellular substance; on section they present a marrow-like white or grayish-white surface. The hard, dense forms, on the other hand, are poor in cells and rich in fibrous intercellular substance ; they pass by insensible gradations into transition-forms known as fibro- sarcomata. The cut surface of a sarcoma presents a nearly uniform appearance, provided retrograde changes or. differences in the blood- content do not interfere ; sometimes the vessels are numerous, large, and ectatic (teleangiectatic sarcoma). Usually the vessels have walls easily distinguishable from the tumor tissue ; but the tumor-cells may form the vessel-wall. Retrograde changes — fatty degeneration, mucous degenera- tion, necrosis, haemorrhage, gangrene, ulceration — are of frequent occur- rence in sarcomata. The sarcomata may be divided into three classes. The first includes simple sarcomata — tumors of the type of embryonal connective tissue, showing more or less uniform distribution of cells without the formation of distinct groups of cells. The second class includes sarcomata which 21 322 TUMORS. show special arrangement and grouping of the individual elements, so that growths arise which are similar to the epithelial tumors. The third class is characterized by secondary changes in the cells, intercellular substance, and blood-vessels. The etiology of sarcoma is not simple. It occurs more frequently in youth than in old age. Some sarcomata develop even in embryonal life. Occasionally trauma appears to be an exciting cause. A parasitic origin has not been demonstrated (see Etiology of Carcinoma). Usually only one primary tumor is formed, but multiple primary sarcomata sometimes occur, particularly in the skin, bone-marrow and lymphoid depots. The softer tumors give rise to metastases. § 113. The simple sarcomata include medullary forms and those of c Ah Fig. 25q. Fig. 260. Fig. 259. — Section from a fungoid large round-cell sarcoma of the skin of the leg (carmine preparation), x 400. Fig, 260. — Section from a sarcoma of the mamma with cells of different shapes (alcohol, Bismarck-brown), a, Connective tissue; b, sarcoma tissue; c, small cells; d, cells with hyper- trophic nuclei ; e, multinuclear cells. X 300. reticulum (Fig. 258, a) composed of branching and anastomosing cells (b). According to the amount of reticulum, the lymphosarcowiata may be divided into soft and hard forms. In the denser varieties the reticular framework may take on the appearance of ordinary fibrous connective Fig. 261. — (Bellevue Hospital.) Massive spindle cell sarcoma of breast (weight 25 lbs.). 324 TUMORS. tissue. Special forms of round-cell sarcoma arising in the bone-marrow are known as myelomata. Lymphosarcomata arise most frequently in the lymph-nodes and the adenoid tissue of the mucous membranes and of the spleen, but are found in other places. Large round-cell sarcomata, the cells of which are larger than those of the forms just described, appear in the same places as do the small round-cell variety, and closely resemble the latter. The cells possess abundant protoplasm and large, bladder-like, oval nuclei (Fig. 259). Many of the cells have two nuclei, some more than two. Between tl;e round cells there lies a reticulated sub- stance (Fig. 259), as well as spindle- shaped and branched cells, which form a supporting alveolar network. Fig. 262. Fig. 263. Fig. 262. — Spindle-cells from a large spindle-cell sarcoma of the cheek (teased preparation). X 400. Fig. 263. — Cells from a myelogenous giant-cell sarcoma of the tibia. (Hsematoxylin.) X 400, In Other forms of large round-cell sarcomata the tumor-cells are unequal in size (Fig. 260), and at the same time there are mingled with them elongated or irregularly shaped cells, so that the tumor may be regarded as a sarcoma with polymorphous cells. The nuclei; likewise vary in size (Fig. 260), and (e) may be present in large numbers (multi- nuclear giant-cells) . The large round-cell sarcomata and the polymorphous-cell variety are on the whole less malignant than the small-cell, but they also give rise to metastases. Spindle-cell sarcomata belong to the most commonly occurring tumors. As a rule, they are firmer than the round-cell varieties, but medullary forms also occur. On section they present a grayish-white or yellowish- ■white, translucent surface, which may be more or less reddened according to the degree of vascularity. Medullary tumors whose cells have under- gone fatty degeneration may possess a pure white color. In general, these sarcomata are more benign than the round-cell varieties, but their character in this respect varies according to location and their richness in cells. SARCOMA. 325 According to the size of the cells there are distinguished large spindle-cell and small spindle-cell sarcomata. The cells lie with their ilat sides approximated, and are grouped in bundles, which, in section, are cut longitudinally, transversely, and obliquely — evidence that they are interwoven in different directions. The arrangement in bundles is often striking; in other cases it is wanting; and the spindles for considerable distances run in the same direction. Sometimes the direction of the spindles is determined by that of the blood-vessels — that is, individual bundles form sheaths about the blood-vessels. Between the spindles there is often but scanty intercellular substance, or it may not be possible to demonstrate it at all. In other cases it may Fig. 264. — Giant-cell sarcoma of the upper jaw (Mullet's fluid, hEeraatoxylin) . x 100, be more abundant, and show a fibrillar character. Such varieties are dense and hard. They represent the connecting-link between sarcomata and fibromata, and are designated fibrosarcomata. Sarcomata with polymorphous cells are also found among the spindle-cell forms; and contain spindle-shaped, pyramidal, prismatic, stellate, and various irregular forms (Fig. 263). Both in polymorphous- and spindle-cell sarcomata there may be numerous giant cells (Figs. 260, 263, and 264), and the designation giant- cell sarcoma is applied to these tumors. They arise particularly from the bones, but may also occur in other places. If a sarcoma develops in preexisting new growths there may be formed mixed tumors, known as myxosarcoma (Fig. 222), chondrosar- coma (Fig. 227), myosarcoma, etc. Lymphosarcoma is essentially a growth of regional distribution and anatomi- cally may be divided into five groups, (a) involving regional collections of super- ficial lymph nodes, as in the neck, axilla and groin, (b) implicating the lymphoid structures of the thorax, notably the remains of the thymus gland and the lymph nodes at the root of the lung, (c) involving the lymphoid tissues of the abdomen, including the stomach,' intestines, spleen and lymph nodes, (d) diffuse infiltration of tissues, especially the paired organs, and (e) leukosarcoma, which is characterized 326 TUMORS. by the formation of lymphoid tumors in peculiar situations, such as the uterus, breast, skin, etc., the growths pouring lymphocytes into the blood in such quan- tities as to constitute a form of leukemia. In the same category certain pathologists are inclined to place chronic lymphatic leukemia and its companion lesion, pseudo- leukemia. The implication of paired organs in lymphosarcoma is well shown by the lesion first fully described by Mikulicz, which is characterized by infiltrative over- growth of the lymphoid) cells in the stroma of the lachrymal glands, and is mani- fested by symmetrical enlargement of the outer two-thirds of the upper lids, fol- lowed by symmetrical invasion of the parotid and submaxillary glands. There is also a form of symmetrical conjunctival lymphosarcoma. In still another variety, lymphosarcoma brings about symmetrical neoplasmic infiltration of other paired viscera, such as the mammary gland, ovaries, testicles, suprarenal capsules and kidneys. In three cases of the latter description encountered at Bellevue Hospital, the kidneys were enormously increased in size, due to the infiltration of hordes of lymphocytes associated with lymphosarcomata in other parts of the body. Fig. 265. — ^^(Bellevue Hospital.) Changes in tl«e spleen in Hodgkin's disease, the whitish areas representing nodular formations, the histology of which corresponds to that found in the lymph nodes and elsewhere. At this point may be mentioned another pecuhar process involving lymphoid tissues, namely, the so-called Hodgkin's disease, Clinically it often resembles lymphosarcoma, pseudo-leukemia and even true chronic lymphatic leukemia, but histologically it is distinctive. It is characterized by multiple, discrete enlargement of regional lymph nodes, notably those of the neck, axilla and groin, followed by similar changes in the lymph nodes of the thorax and abdomen. The lymphoid structures in the spleen are likewise changed and the organ becomes markedly en- larged and nodulated ; the liver may be similarly riddled. Histologically the changes in the lymph nodes and elsewhere are characterized by diffuse overgrowth of con- nective tissue with varying degrees of hyperplasia of the lymphoid cells, together with numbers of mononuclear and multinuclear giant cells, eosinophiles and eosino- philic myelocytes, the composite histological picture being not unlike that of a polymorphous sarcoma. The cause of the disease is totally unknoum. In certain quarters it is regarded as a variety of tuberculosis, but this origin has never been demonstrated, in spite of much investigation. It is possible that Hodgkin's disease, like the lymphosarcomata and multiple myelomata, represents a peculiar reaction to stimuli acting on functionally related tissues at the same or approximately the same time, the first effect of which, in Hodgkin's disease, is to promote hyper- plasia of the lymphoid cells, and that the peculiar giant cells and the eosinophiles and eosinophilic myelocytes are derived from the bone marrow and are filtered out PSEUDO-LEUKEMIA; MYELOMATA. 327 by the hyperplastic lymph nodes. Clinically the disease first shows itself, as a rule, by enlargement of the cervical or other superficial groups of lymph nodes. There are, in addition, well defined varieties of Hodgkin's disease in which the changes are first manifested in other parts, as the thymic remains, the peribronchial lymph nodes, spleen, intestinal lymph follicles, etc. Cohnheim (Virchow's Arch., 1865) described a disease under the title of pseudo-leukemia, characterized by marked hyperplasia of lymph nodes in various parts of the body but without increase in the number of circulating lymphocytes. This latter fact distinguishes it at once from chronic lymphatic leukemia, which presents virtually identical changes in the lymphoid tissues, but, in addition, is at- tended by enormous numbers of lymphocytes in the blood. CHnically, pseudo-leukemia cannot be distinguished from Hodgkin's disease except by microscopic examination of excised lymph nodes. From true leukemia it is at once differentiated, of course, by examination of the blood. In many quarters the term pseudo-leukemia still is erro- neously employed as a synonym for Hodgkin's dis- ease. The neoplasmic disease described under the caption of multiple myelomata is characterized by foci of growth arising in different parts of the marrow system at approximately the same time, the individual tumors springing from certain primi- tive cells of the blood-form- ing series, variously de- scribed as lymphoblasts, neu- trophilic myelocytes, erythro- blasts, plasma cells and myeloblasts. It is highly doubtful, however, if there are myelomata composed of each of these varieties, but that all myelomata are made up of myeloblasts — in other words, the tumor is a myelo- blastoma. The disease is rare. It occurs apparently exclusively in individuals over thirty-five years of age, oftenest in men, and pursues a rapidly fatal course. The bones involved are those with red marrow, notably the vertebrae, sternum, ribs, skull, scapulae and ileum, and are exquisitely tender. Spontaneous fractures are common. The Bence-Jones albumose frequently is found in the urine in these cases. A notable feature of the myeloma consists in a tendency on the part of the growth to confine itself to the marrow system, albhough it may bring about continuate infiltration of adjacent structures by direct erosion of the bony casement. Genuine "letas- tasizing myelomata are extremely rare, but do occur, cases having been recorded by Christian and Symmers, the metastases occurring in tissues having no relation either to bone marrow' or to the extrameduUary hemopoietic system. In still another group of cases, myelomata of the marrow are associated with identical growths in such tissues as the tonsil, spleen, lymph nodes and liver, but in these localities" the tumor cells spring from or are implanted in tissue which is tunction- FiG. 266. — (Bellevue Hospital.) Mixed spindle and giant cell sarcoma of the upper end of the tibia. 328 TUMORS. ally related to bone marrow (autochthonous myeloma). Surgical intervention is sometimes necessary for the relief of mechanical symptoms, such as those produced by pressure on the spinal cord, but is otherwise hopeless. There is another variety of medullary bone disease that has been variously designated medullary giant cell sarcoma, giant cell myeloma, chronic. hemorrhagic osteomyelitis (Barrie), benign bone cysts, etc. It is of great surgical importance. Two forms of growth are recognized — solitary and multiple, the latter having been described by Martland. In both forms the histology is the same; the lesion consists of medullary formations, in or near the ends of long bones, that are com- posed of innumerable giant cells of the osteoclastic type, imbedded in richly vascu- larized fibroblastic tissue, poor in mitoses, and associated with hsemorrhage and necrosis, the naked eye appearance of the growth being comparatile to that of red- FiG. 267. — Section through an endothelioma of the pia mater and cerebral cortex, difFusely spread over the surface of the brain and spinal cord (Miiller's fluid, hjematoxylin). a. Superficial pia; b, pia in a sulcus; c, cortex; d, e, endothelial^ proliferations in the pia sheaths of the cortical vessels; /, g. h, endothelial proliferations in the pia sheaths of the cortical vessels; i, longitudinal section through a vein. X 28. currant jelly. Growth is expansive and slow, often stretching over a period of years, and the individual nodules are localized and circumscribed by relatively intact bone and periosteum. Infiltration of surrounding tissues and metastasis have not been observed, there is no Bence-Jones proteinuria, and the growths are painless. Spontaneous fractures are common. Simple curettement usually suffices, although local recurrence may take place. The multiple variety described by Martland con- stitutes a pathological entity with a close clinical resemblance to the multiple myelo- blastomata already considered. It is obvious that differentiation of the two is important since, in Martland's disease, surgical intervention offers a hope of cure, and, in the solitary form, is distinctly promising. In this connection it is to be recalled, however, that mixed spindle and giant-cell sarcomata occur in the medul- lary ends of certain bones, notably the femur and tibia, that they grow expansively and rapidly and not uncommonly metastasize, and that the histology of these growths may simulate that of the formations described by Barrie and by Martland. SARCOMA. 329 In such tumors, however, giant cells are less numerous and the stroma is more richly nucleated and poor in both intercellular substance and vascular channels, while mitotic figures are often discernible. When malignancy is fully established and flourishing, giant cells may be rare or wanting, the growth partaking of the nature of a pure spindle cell sarcoma. ^ Three examples of this type of tumor have been encountered in the pathological laboratories of Bellevue Hospital in the past two years. In such cases, of course, amputation is imperative, all things else being equal. (Barrie, Annals of Surgery, 1913; Surgery, Gynecology and ObstetVics, 1914; Martland, Proceedings New York Pathological Society, 1915 ; Haussling and Mart- land, Annals of Surgery, 1916.) § 114. Sarcomata which present an organoid structure appear as alveolar and tubular growths in which it is possible to distinguish a vas- cular connective-tissue stroma and strands or nests of cells. According to their genesis, these growths may he divided into two types : lymphangio- sarcoma and hcFmangiosarcoma. There are, however, alveolar sarcomata which cannqt be included with the above-named types. The lymphangiosarcomata arise from proliferation of the endothelium of lymph-vessels and lymph-spaces. They may accordingly be designated 'jL-^'f.i...^--.^ Fig. 268. — Endothelioma durse matris (MuUer's fluid, hacmatoxylin) . a. Connective-tissue stroma; b, -small-cell focus; c, groups and strands of cells arising from the proliferation _ of lymph-vessel endothelium; d, endothelial cell-strand with a lumen; e, area of fatty degeneration in nest of endothelial cells; f, strand of cells, passing gradually, on the right, into the surround- ing connective tissue. X 25. lymphangioendotheliomata or as endotheliomata in the narrower sense. They may develop in previously normal tissue, or in preexisting tumor-like formations, such as the hypertrophic lymphangioma (pigmented moles and warts, see § 108) , and from myxochondromata. The first occur par- ticularly in the meninges of the brain, and in tlie serous membranes of the great body-cavities, but may develop in other organs; the second are found chiefly in the skin; those arising from myxochondromata develop in the salivary glands, palate, and orbit. The endotheliomata of the meninges of the brain and spinal cord occur as nodular growths and as plaque-like prohf erations ; they develop through transformation of the flattened endothelium, which covers the connective- tissue of the subarachnoid tissue and pia, into cubical or cylindrical cells (Fig. 267, d, e). In consequence, the new-growth at first presents the appearance of gland-like formoHons ; in the event of more active 330 TUMORS. proliferation solid nests of cells are formed. Inasmuch as the pia is continued as a lymph-sheath about the cerebral vessels, there are formed around the latter strands of large epithelial-like cells (Fig. 267, f, g,h). Endothelioma of the dura mater arises through proliferation of the endothelium of the lymph-vessels, and leads, through filling of the latter with large cells, to the formation of anastomosing cords of cells (Fig. 268, c, d, e), which in places may contain a lumen. Endotheliomata of the pleura or of the peritoneum appear as flattened thickenings of the affected membrane, but scattered nodular elevations may occur. These growths are characterized by cords of large cells Fig. 269. — Endothelioma of the pleura (alcohol, hematoxylin), pleural connective tissue; b, cell-strands. , Proliferated and thickened 100. (Fig. 269, b), which correspond to the course of the lymph-vessels in the serosa. _ Endothelioma of the mammary gland is a rare tumor and takes its origin from proliferation of the endothelium of the lymph-vessels and lymph-spaces (Fig. 270, h, c), and gives rise to the formation of large cords of cells (c) or of smaller cell-nests. The proliferating cells are marked by great variation in the size, character, and form of the nucleus and cell-body. Endothelioma of the skin, which arises from hypertrophic lymphan- gioma (warts and pigmented moles), resembles these in its general struc- ture, and also possesses cell-nests of varying size (Fig. 246). Further, there occur endotheliomata of the skin, which do not arise from warts, and may develop in great numbers (Spiegler, Mulert). The endothelial proliferations which arise in myxomata and myxo- chondromata form cords of cells of different shapes (Fig. 222, h) ; but it should be noted that in these cases similar proliferations may arise from the blood-vessels (Fig. 274, c, d), so that it is often impossible to decide as to the nature of the cell-strands. ENDOTHELIOMA. 331 The alveolar, tubular, or plexiform structure of the endothelioma is well marked only in the first stages of the tumor, and usually disappears with advancing growth. This is due to the fact that the endothelial pro- liferation extends, without sharp limits, into the neighboring connective '^ ■^.^%,'>.^\\ Fig. 270. — Endothelioma of the mammary gland (alcohol, hematoxylin, eosin)._ a. Con- nective tissue ; b^ enlarged cells in the connective-tissue spaces; c, strands of cells; rf, diffuse cell- proliferation. X 300. tissue (Fig. 268, /) ; and to the circumstance that the connective-tissue cells take on proHferative activity similar to that of the endothelium, so that there is formed a diffuse, cellular new growth of the character of an ordinary sarcoma (Fig. 270, d). Accordingly, endotheliomata cannot be sharply distinguished from sarcomata. Fig. 271,— Blood-vessel endothelioma of the VMney fformRlin, hematoxylin, eosin). Vessels filled with blood; b, vessels filled with proliferated endothelial cells, x 300. 332 TUMORS. The similarity in structure between endotheliomata and carcinomata raises the question whether it would not be expedient to class the iormer as endothelial cancers. The structure of these tumors would certainly justify such a classification, but I Fig. 272. — Section through a nodular angiosarcoma of the thyroid (Flemming*s solution, safranin). a. Transversely cut vessels; b, perivascular cylinders of cells cut transversely and showing numerous mitoses; c^ granular masses, with scattered cells, between the cell-cylinders. X 73- consider it better to avoid the use of this term. In the first place, the term endothelioma is in general use and is entirely appropriate, and the introduction of the term' endothelial cancer would easily give rise to confusion; by the term cancer Fig 273 — \nir osarcoma of the test s (Muller s fl ud hasmatoxyl n eosin) a Perivascular masses of closely packed cells; b, areas poor in cells; c, hyaline lumps; d, hyaline masses con- taining blood; e, seminiferous tubules; /, large vein. X 80. H^MANGIOSARCOMA. 333 in general is understood an epithelial tumor, and it does not seem desirable to introduce two types of cancer — an epithelial and an endothelial. I have classed as endotheliomata those tumors of the serous membranes which are characterized by the formation of cell-cords in the lymph channels, on the assumption that these arise from the endothelium of the lymph-vessels and lymph- spaces. I must admit, however, that I do not consider this assumption entirely justified, in spite of the concurring statements of a number of authors. The pos- sibility of their development from the epithelium of the serosa is not excluded ^ Fig. 274. — Chondrofibroma o£ the parotid with angiosarcoma (Muller's fluid, hematoxylin, «osin). a. Areas of cartilage; b, dense sarcoma tissue; c, blood-vessel; d, cell-strands arising from blood-vessels, and in part containing a hyaline substance, x So. (Benda), and if such an origin could be proved, the question would arise whether it would not be better to class these tumors with the carcinomata, since the corre- sponding tumors of the kidneys and ovaries, whose gland-cells arise from peritoneal epithelium, are classed with the epithelial tumors. § 115. The haemangiosarcomata represent a group of organoid sar- comata in which blood-vessels constitute a characteristic feature. One form of hsemangiosarcoma is the hsemangioendothelioma, a turrior which arises, either from preexisting blood-vessels or from those newly formed in hsemangiomata, active proHferation giving rise to blood spaces •lined with cubical or cylindrical endothelium (Fig. 271, a), or to canals completely filled with such cells (b). According to the number of blood- containing vessels the tumor is dark-red, pale, grayish-white or yellowish- white. A second form of haemangiosarcoma (occasionally called peritheli- oma), arises through proliferation of the outer layers of the blood- vessel walls and their immediate surroundings, so that the vessel-lumina are surrounded by a more or less thick mantle of cells (Fig. 272, b). In typical cases the tumor-tissue consists almost wholly of a tangle of blood- 334 TUMORS. vessels (Fig. 272, a), whose walls are banked by a thick layer of cells, which often reach to the endothelium. The cellular tubes sometimes run an isolated course, at other times anastomose, so that twistings and inter- FiG. 275. — (Bellevue Hospital.) Melanoma of instep. weavings result (plexiform angiosarcoma). Between the cell-strands the remains of the original tissue (Fig. 273, b) may retain characteristic formations, for example, glands {e). Should more active prolifera- tion of the perivascular mantle of cells occur, and if these become confluent (Fig. 273) the tumor passes into an ordinary sarcoma. This change almost invariably oc- curs in larger tumors of this kind. Hsmangiosarcomata occur in various organs : testicles, kidneys, salivary glands, bones, brain, mamma, thyroid, skin, carotid gland, coccygeal gland, ovaries, and liver. Lymphangiosarcomata and hsemangiosarcomata cannot always be sharply differentiated from each other, and tumors occur to which both designations may be applied with propriety. The perivascular endothelial proliferation in the sub- stance of the brain associated with endothelioma of the pia (Fig. 267, /, g, h) also justify the application of the term hsemangiosarcoma. Fig. 276. — Alveolar melanotic sarcoma of the skin (alcohol, haematoxylin) . a. Mononuclear, ai, multi-nuclear sarcoma cells; b, pigment-con- taining cells; e^ stroma with blood-vessels and pigment. X 300. Borst, in his work on tumors, has separated the endotheliomata (lymphangio- and hsemangio-endothelioma) from the sarcomata, and has attempted to class them as a special form of neoplasm. In so far as typical microscopic pictures are concerned, such a separation is possible, but the endotheliomata in general do not show so typical a structure that they can be distinguished from ordinary sarcomata. MELANOSARCOMA. 335 Further, it is by no means determined that endothelial cells of lymph spaces and vessels do not take part in the formation of sarcomata. It seems to me, therefore, better to consider the endotheliomata as a form of sarcoma. § 116. Sarcomata which acquire a peculiar character through special products of the cells or through changes in their ground-sub- stance are to be found both among the simple and organoid forms. The chief types in this class are the melanosarcoma, osteosarcoma, osteoid sarcoma, the petrifying sarcoma, psammoma, and sarcomata containing hyaline formatioiis. Melanosarcomata occur in tissues which contain pigmented connec- tive-tissue cells — chromatophores. They develop most frequently in the Fig. 277. — Melanotic sarcoma of the skin (alcohol, carmine, eosin). ^ a. Sarcoma tissue rich in cells; b, cell-nests; c, pigment-cells; d, blood-vessels with hyaline walls, x 300. choroid of the eye and in the skin. In the latter situation they arise chiefly from pigmented moles. They belong to the mahgnant sarcomata, grow into neighboring tissues, and give rise to extensive metastases. The fully developed tumor is in whole or part smoky-gray, black or brownish- black, the color being due to the presence of round, angular, fusiform, and branched cells, which are filled with yellowish-brown pigment granules (Figs. 277, b, e; 278, c). In the alveolar forms both the large cell-nests, as well as the cells of the supporting framework, may contain pigment. It is often abundant in the neighborhood of the blood-vessels (Figs. 276, e; 277, d), although the pigment is not hsemosiderin. The metastases are likewise more or less pigmented (Fig. 278) ; the smallest ones may consist largely of pigmented cells (c, d). Cases occur in which numerous organs, the skin, muscles, pia, serous mem- branes and adipose tissue (Fig. 278) are spotted black through the formation of metastases. 336 TUMORS. There is scarcely an individual who does not possess one or more skin moles, and every skin mole is a potential source of a milignant melanoma. The mole is ■'^,rn.ecuiues ndrueneQ, aiinOUgn with three concreitions. x i8o. no typical bone is formcd. PSAMMOMA. 339 Psammomata or sand tumors are sarcomata or fibro-sarcomata of the dura, inner meninges, or pineal gland, which contain concretions of lime-salts in greater or less abundance. Some of these concretions are Fig. 284. — Myxo-angiosarcoma of the parotid, with hyaline formations (Miiller's fluid, has- matoxylin, eosin), a. Myxomatous tissue; h, cell-strands inclosing hyaline spherules; c, hyaline spherules in myxomatous tissue; rf, blood-vessels with proliferating endothelium and hyaline spherules. X 90. similar in structure to the normal brain-sand, the basis of their formation being concentric layers of cells which have previously undergone hyaline degeneration (Fig. 283, a, b, c). Occasionally the chalky spherules lie inside individual cells and represent hyaline products of the cells that Fig. 285. — -Papillary epithelioma or ichthyotic wart of the skin (Muller's fluid, hjematoxylin, eosin). a, Corium; b, enlarged papillary body; c, laminated horny layer. X 25. have become calcified. Others are of the nature of spicules (d), and arise through the deposit of lime-salts in connective tissue or blood- vessels which have undergone hyaline degeneration. Psammomata usually form round nodules, and are often multiple. 340 TUMORS. Sarcomata with hyaline formations (the myxosarcomata excepted) arise as follows : Either the cells form hyaline products, or they them- selves become converted into such, or the fully developed connective tissue and the blood-vessels undergo hyaline degeneration. These changes may ■ take place in simple sarcomata as well as in endotheliomata and hserriangiosarcomata ; but occur more frequently in the latter (Figs. 280, b; 274, d; 284). The hyaline masses form spherules, or club-like forms, or cords, of net-like 'or factus-hke figures. They push the cells apart, and often reducfe them to harrow strands.,' "Billroth has designated such Fig. 286. — (Bellevue Hospital.) Papillary epithelioma of back. tumors cylindromata. In endotheliomata hyaline degeneration may be associated with the formatin of laminated masses of flattened cells around a nucleus, like the layers of an onion. Hyaline degeneration of the vessel-walls and connective-tissue bundles results in thickening, (Fig. 277, d), sometimes uniformly and some- times irregularly distributed. Hyaline products of cells have a tendency to assume spherical form (Figs. 269, b; 27 A, d; 284, c, d). The disintegra- tion of larger cell-masses with hyalinisation leads to the formation of spherules, strands, or branching structures. If, in endotheliomata and angiosarcomata, the cord-like masses of cells in the lymph- or blood-vessels become converted into hyalin, struc- tures arise which resemble glands containing colloid (Fig. 284, d) and have often been mistaken for such. THE EPITHELIAL TUMORS. 341 2. The Epithelial Tumors. (a) General Remarks. § 117. The epithelial tumors are new growths in the formation of which vascular connective tissue and cells derived from surface or glandular epithelium take part. The distribution of epithelium and con- nective tissue follows, in a general way, the normal arrangement of these tissues, the connective tissue formmg a basement structure covered with epithelium (skin and mucous membranes), or a stroma, in the meshes of which the epithelial cells are distributed in gland-like array. The imitation of skin structure leads to the formation of papillary new-growths; that of mucous membrane, to more of less sharply cir- cumscribed nodules or to extensive superficial thickenings of tissue. -ii^aV Fig. 287. — Senile horny wart of forehead, from a woman eighty-four years of age (alcohol, haematoxylin, eosin). a, Corium; b, epithelium; c^ atrophic sebaceous glands with development of horny epithelium in their ducts; d, hypertrophic horny layers; Cj enlarged papilla, x 15. According to the physical characteristics and arrangement of the epi- thelial cells, as well as the clinical behavior of these tumors, epithelial new-growths may be divided into two groups ; one including papillary epi- theliomata, adenomata, and cystadenomata ; the other carcinomata and cystocarcinomata. The first group is characterized clinically by the benign character of the growths, which are sharply circumscribed and form no metastases. The second group includes new-growths which in- filtrate and give rise to metastases. The two groups, however, are not sharply separated, as papillary epitheliomata and adenomata may, through changes in the mode of reproduction and spread of the epithelial cells, ■ become changed into carcinomata. 342 TUMORS. (&) Papillary Epithelioma, Adenoma, and Cystadenoma. § 118. A papillary epithelioma is a new-growth composed of a framework of connective-tissue papillae covered with epithelial cells. _ In structure, therefore, it is similar to the papillae of the skin ; but the papillae are, as a rule, higher and often branched, and the epithelial covering thicker. The papillary epithelioma of the skin occurs in the form of warty protuberances, which consist of slender papillae (Fig. 285), covered with epithelium, the superficial layers of which show marked cornifica- tion {ichthyotic warts and horny warts). These warts may ap- pear during childhood (ichthy- otic warts) or in old age {ver- FlG. 2 Fio. 289. Fig. 28 Fig. 28^ -Papillary epithelioma of the larynx, a. Epiglottis; b, ossified cricoid cartilage; tf, thyroid cartilage; d, trachea; e^ f, papillary proliferations. Natural size. -Papillary epithelioma of the urinary bladder, a, Epithelioma; 6, c, enlarged prostate; d, thickened bladder-wall. Five-sixths natural size. ruca senilis). The first-narned represents a local malformation of the skin (Fig. 285) ; while the latter is due to pathological proliferation and cornification of the epithelium (Fig. 287, c, d) followed by outgrowth of the papillae at the periphery. Excessive cornification of epithelium over hypertrophic papillae, giving rise to cylindrical or conical masses of cells in which the hojny kyers lie at right angles to the surface, leads to the formation of a cutaneous horn or cornu cutaneum (Figs. 112, 113). EPITHELIOMA. 343 Papillary epitheliomata of mucous membranes occur as warty, nodu- lar formations (Fig. 288, e, f), or as long, slender papillary excrescences (Fig. 289, a), which, springing from a narrow base, are often repeatedly branched. The former variety is found especially in the larynx, more rarely in the nose and urinary bladder ; the latter in the urinary bladder and pelvis of the kidney, vaginal portion of the uterus, and rarely in the ureters, gall-bladder, and biliary passages. In brth varieties the excrescences are formed of slender, connective- tissue papillae (Fig. 290) which contain blood-vessels, and are covered by a thick layer of epithelium the character of which corresponds in Fig. 2go. — Papillary epithelioma of the urinary bladder (alcohol, hematoxylin, eosin). X 35. general to that of the part in which the growth occurs, although papillo- mata covered with stratified squamous cells are sometimes seen in regions that normally possess cylindrical epithelium (nose, trachea). Papillary epitheliomata in cysts, or so-called papillary cystomata, occur most frequently in cysts of the ovary and of the mammary gland, more rarely in the skin. Within the cyst are formed small, warty ele- vations or cauliflower-like outgrowths, which may fill the entire cyst- cavity. Papillary epitheliomata of the surface of the ovary appear in forms similar to those of the urinary bladder, but are rare. Papillary epithelio- mata of the cerebral ventricles rise in part from the telse choroidese. It is difficult to draw a line between papillary epitheliomata and other formations. Inflammatory proliferations of the skin and mucous membranes — pointed condylomata — which develop on the external genitals under the influ- ence of chronic irritation (compare Fig. 246), so closely resemble epitheliomata that their inflammatory origin forms the only point of difference. If the con- nective-tissue framework of the papillary outgrowth is developed to a greater extent than the epithelium, the tumor may be classed with the papillary fibro- mata, and it becomes a question of individual standpoint as to which designa- tion shall be employed. Intermediate forms can be designated as papillary fibroepitheliomata. Finally, the benign papillary epitheliomata may pass into carc'nomata, either through the growth of epithelium at the base of the papillse 344 TUMORS. into the underlying connective tissue, or through extension of the proliferating surface epithelium into neighboring organs (as in the papillary epitheliomata of the ovary). Among the epitheliomata may be classed those formations known as cholesteatomata or pearl tumors, which in part are caused by inflammation, and in part represent misplaced embryonal tissue. The most striking characteristic of the cholesteatoma is the formation of glistening white pearls, which consist of thin, scale-like epithelial cells pressed closely together, and which often inclose cholesterin. These tumors are found most frequently in the descending urinary passages, the cavities of the middle ear, and the pia of the brain; rarely in the spinal cord. Pathological cornifications, with the formation of glistening white scales and pearls, occur in the urinary passages, particularly in the course of chronic inflammations. In the tympanic cavity, mastoid antrum, and external auditory canal, the cholesteatomata appear as yellowish-white or bluish-white nodules, vary- ing in size from a cherry-stone to that of an tgg, and presenting an onion-like laminated structure. Through pressure on neighboring bone they may cause its disappearance. In chronic inflammatory conditions they arise as a product of squamous epithelium which has penetrated from the external ear through openings in the ear-drum into the cavities of the middle ear and has replaced the cylindrical epithelium. It is probable that in rare cases they arise from epidermoidal cells which during the period of embryonic development have found their way into the cavities in question. The intracranial cholesteatomata are found at the base of the brain (rarely in the spinal canal), in the region of the olfactory lobe, tuber cinereum, corpus cal- losum, in the choroid plexus, in the pons, medulla oblongata, and cerebellum. In these regions the cholesteatomata appear on the surface as silk-like, shining nodules of varying size which extend more or less deeply into the brain-substance. The nodules are single, but cholesteatoma-masses may become separated and be displaced into neighboring tissue. According to Bostrom, it is always possible to demonstrate, at some point, a connection between the pia and the cholesteatoma, where the scales composing the cholesteatoma take their origin from a cell-layer lying on vascular connective tissue, the cells throughout bearing the character of epidermoidal cells. The cholesteatomata of the pia may therefore be designated as epitheliomata or as epidermoids {Bostrom^ ; and their origin may be explained by the assumption that in the early period of development epidermal germs are misplaced into the priraordium of the pia. § 119. The adenomata are usually nodular tumors with sharply de- fined borders ; and are situated in glands, or in the skin or mucous mem- branes. In the latter situations they frequently appear as polypi elevated above the surface. They may also occur in the form of papillary pro- liferations (Fig. 211). The absence of any tendency to grovi? by infiltra- tion or to produce metastases stamps these tuinors as benign. The chief characteristic of the adenoma is the formation of new glands, which depart more or less from the typical glands of the affected organ. According to their structure adenomata may be classed as tubular or acinous; but the two forms cannot be sharply separated. Through the formation of papillary excrescences on the inner walls of the gland- spaces there is formed an adenoma papilliferum. Adenomata develop in apparently normal tissue, malformed tissue,^ in tissues altered by disease (chronically inflamed mucous membrane, cirrhotic liver, contracted kid- ney), or from remains of fatal structures. The new- formation of glands is dependent on proliferation of glandular epithelium similar to that occur- ring in regeneration of normal gland-tissue. The beginning of the adenomatous process may be recognized by changes in the form and staining of the cells. This is particularly true of the stomach and in- testme, m which adenomatous proliferations often develop in connection with chronic inflammatory and ulcerative processes. The change of normal gland-cells into high cylindrical cells may occur contemporane- ADENOMA. 345 ously or successively in a number of glands and is followed by cell-pro- liferation and new-formation of glands. The cause of the new-formation of gland-tissue in normal organs is Fig. 291. — Adenoma tubulare (plandular polyp) of the intestine f alcohol, alum-carmine), a. Transverse section, b, longitudinal section of gland-tubules; c, stroma rich in cells, x 90. unknown. Glandular new-formations developing in tissues which have been altered by inflammation, and which lead to tumor-like growths, may, in the beginning, bear the character of a regenerative or hyperplastic new- FiG. 292. — Adenoma tubulare of the stomach in an atrophic mucosa (formalin, alcohol, hsema- tcxylin, eosin). a. Mucosa; h, muspularis mucosae; c, submucosa; d, muscularis; e, serosa; /, adenoma, x 14. formation, and for this reason the adenomata cannot he sharply differ- entiated from regenerative and hyperplastic proliferations. Tubular adenomata represent the most common form. They occur 346 TUMORS. particularly in mucous membranes (Fig. 291,292,/) provided with tubular glands (intestine, uterus) ; but are also found in the breast (Fig. 293), liver, ovary, and not infrequently in the kidneys. They are characterized Fig. 293. — Adenoma mammae tubulare (alcohol, alum-carmine), a, Branched and dilated glandular spaces cut longitudinally; b^ same, cut transversely; c^ stroma. X 27. by the formation of simple and branched tubules (Figs. 291, a, h; 292, f; 293, a, b) lined by columnar or cubical epithelium and form nodular tumors varying in size from a pea to that of an apple or a man's fist, or even larger. Fig. 294. — Adenoma mammae alveolare (alcohol, alum-carmine), a, Terminal alveoli; 6, gland- ducts; c, connective-tissue stroma. x 27. The alveolar adenomata arise from glands (mamma, ovary, thyroid, sebaceous glands) ; and are characterized by the formation of numerous terminal berry-like alveoli (Fig. 294, a), as well as ducts (&). ADENOMA. 347 Papillary adenomata (Fig. 295, a) arise through the formation in the tubules of an adenoma of elevations of epitheUum into each of which a connective-tissue papilla grows. Fig. 295. — Developing papillary ad?noma of the kidney. (Alcohol, hematoxylin, picrofuchsin.) a, b, Fully developed tumor-tissue; c, d, early stages of development of the tumor. X 150. Fig. 296. — Fibroma intracanaliculare mammae (fibro-adenoma papilliferum) (alcohol, alum- carmine), a. Dense, intercanalicular growth of fibrosis tissue; b, pericanalicular tissue rich in cells; c, d, e, nodular intracanalicular connective-tissue proliferations cut longitudinally; f, intra- canalicular proliferations cut transversely. X 23. 348 TUMORS. The stroma of an adenoma is at times well developed, at other times but slightly. Consequently adenomata may be divided into hard (mam- mary gland) and soft varieties (kidney, liver, ovary, testicle). Marked development of the connective tis- sue leads to the formation of fibro- adenomata or fibrous adenomata. Such forms occur most frequently in the mammary gland. If, as happens not infrequently in the mammary gland, the con- nective-tissue proliferation in an adenoma is not of diffuse character, but takes place more particularly around the canaliculi (see Fig. 220), the tumor is designated fibroma pericanalicular e . If, as the result of more marked local pro- liferative activity on the part of the connective tissue (Fig. 296, c, d, e), an ingrowth of papillaa {e) into the gland-spaces takes place, Fig. .g7.-Sectian of a cystadenoma ovarii pa- the resulting tUmOr is kucwn aS a piiiiferum (Miiiier's fluid, hasmatoxyiin) . X 40. fibroma intracanaliculare. Adenomata cannot be sharply differentiated from tumor-like glandular hyper- trophies on the one hand, and carcinomata on the other. For example, in the heal- ing of intestinal ulcers regenerative processes in the glands may be so active as to give rise to polypoid formations, which may be called glandular hypertrophies or adenomata, according to the individual standpoint. Likewise,^ different names may be applied to the glandular polypi which occur so frequently in the uterus. Fig. 298.—Adenocystoma of the bile-passages in the first stages of development (alcohol, hema- toxylin), a, Liver tissue: b. adenoma tissue in the periportal connective tissue, x 90. CYSTADENOMA. 349 The carcinomatous nature of a new-growth resembling an adenoma (see § 121) is generally made evident by more marked epithelial proliferation and by infiltrative gi-owth. There are, however, adenomata having a single layer of columnar cells, that grow by infiltration (particularly in the intestine), and assume the character of malignant tumors. They should accordingly be classed with the carcinomata, and must be designated adenocarcinoma. On the other hand, there are also adenomata with marked atypical epithelial proliferation (mamma, endometrium), which — for a long time at least — do not show any malignant characteristics. § 120. A cystadenoma or adenocystoma is an adenoma whose gland- spaces have undergone cystic dilatation through the accumulation of secre- tions. Such tumors are usually composed of numerous cysts, and are, therefore, designated multjlocular cystomata. According to the char- acter of the wall there may be distinguished a simple and a papuliferous cystoma. Small amounts of secretion are often seen in the ordinary adenomata Fig. 299. Fig. 300. Fig. 299.— Section of a portion of a multilocular adenocystoma of the ovary. Reduced about one-sixth. Fig. 300. — Section through an adenocystoma of the testis of a four-year-old boy. Natural size. (Fig. 291), and the spaces of both simple and papillary adenomata are often so wide (Figs. 293, a; 296) that they attract the eye on cross-section of the growth. In cystadenomata cyst-formation is the predominating feature. The early stages of the cysts are represented by gland-tubules of vary- ing shape (Figs. 297 and 298, b), that lie in a more or less richly de- veloped connective-tissue stroma. Through the accumulation of secre- tion these tubules become gradually dilated so that numerous small cysts (Fig. 297), or both large and small cysts (Figs. 300-303) are formed. Often the relationship is such that the tumor may consist of a few large cysts in which smaller cysts occur ; or there may be found, by the side of large cysts, (Fig. 301, c) portions of tissue which contain only small cysts (e) or even appear solid — that is, consisting of tissue the glands of which are not dilated. 350 TUMORS. All the different varieties of cystomata may develop in the ovaries (Fig. 299), testicles (Fig. 300), liver (Figs. 298 and 301), kidneys (Fig. 302), and the mammary glands. In the ovaries cystomata not infrequently develop coincidently on both sides, and may be associated with dermoid formations. Adenocys- tomata of the testicles not infrequently inclose in their stroma foci of cartilage or other tissue, so that such growths should be classed with the teratomata (§ 128). j j- • i The epithelial lining of cystomata is usually composed of simple colum- nar cells, but may be ciliated, cubical, or flattened. The cyst-contents usually consist of clear, often ropy fluid, lyhich con- tains a mucin-like substance (pseudomucin, see § 59). This is a product Fig. 301. — Multilocular adenocystoma of the liver, seen in section, a. Liver parenchyma; b, membranous margin of the left lobe; c, d, large cysts; e, group of smaller cysts, separated from each other only by connective tissue; /, portal vein; g, hepatic artery. Two-thirds natural size. of the epithelial lining in which goblet-cells are found (Fig. 304, c). Not infrequently the fluid contains whitish flakes, the products of cells which have undergone fatty degeneration ; or it may be more or less reddish or brownish from previous hemorrhage. Abundant secretion in multiple cysts may lead to tumors of enormous size; in the ovary, for example, they may reach a weight of from ten to twelve kilograms or more. The papillary adenocystomata constitute a common variety. They are characterized by the fact that sooner or later papillary excrescences develop in glands which have undergone cystic dilatation. In the adenocystomata of the ovary such excrescences are usually slender and delicate, forming villous-like (Fig. 303) or cauliflower elevations, which fill a larger or smaller part of the cysts. Minute papil- lary elevations, extending over an extensive area of the inner surface of the cyst-wall, may give to the latter a velvety appearance similar to that CYSTADENOMA. 351 of a mucous membrane. If the excrescences develop in cysts of small size, they may fill these, and the tissue may take on the appearance of a medullary tumor. Larger papillae are always more or less branched (Fig. 304), and consist of a cellular stroma (a), whose surface is covered with tall cells (c) of the character of goblet-cells. The contents of the cysts consist of ropy mucus (d) mingled with desquamated cells which have undergone mucous degeneration. In rare cases the connective tissue of the papilla Fig. 302. — Cystoma of the kidney, cut transversely. Eleven-fourteenths natural size. may undergo mucous degeneration (Fig. 305, a, b), and swell to a marked degree, and finally become changed into myxomatous spheres covered with epithelium. Adenocystomata of the liver, testicles, and kidneys usually form no papillae, or at most small ones. In the papillary adenocystomata of the mammary gland the excrescences are broad and plump (Fig. 306), as are those of the papillary adenomata (hig. 296). Accordingly, on cross- section the cyst-spaces are found to be filled with polypoid proliferations of various forms (Fig. 306), which are flattened through mutual pres- sure, and give to the cut surface a laminated appearance. Since in these tumors the connective-tissue elements predominate over the epithelial, these growths are often classed with the connective-tissue tumors, and designated, according to the character of the connective tissue, cystofibroma, cystomyxoma, or cystosarcoma. When showing a structure of leaf-like layers they receive the name of sarcoma phyllodes. 352 TUMORS. The papillary adenocystomata show a certain degree of malignancy. The papillary proliferations may break through the cyst-wall in such tumors of the ovary and mammary gland ; in the latter situation they may break through the skin. Papillary ovarian cystomata in this way give rise to metastases in the peritoneal cavity. Polycystic degeneration of the kidneys is an affection which leads, during embryonal development, to the formation of innumerable cysts throughout both organs, and frequently is associated with the presence of cysts in the liver and other anomalies of growth. The occurrence of renal cysts in these circumstances is apparently due to the fact that the kidney is developed from two primordia, one giving rise to the glomeruli and convoluted tubules and the other to the straight and collecting tubules. Failure of the two primordia properly to unite permits cystic distention of the glomerular capsule and of the convoluted tubules. -Fig. 303. — Portion of a papillary adenocystoma of the ovary, seen in ^'ection. (Drawn from a specimen hardened in chromic acid.) Four-fifths natural size. In one group of cases polycystic degeneration of the kidneys is encountered during intrauterine life and there are instances in which distention of the cysts had reached such a stage as to interfere with birth. In another group of cases the child is born with well developed polycystic kidneys and dies shortly after birth. In still another group, however, the individual attains adult life. The condition is not common. For example, in 6,500 autopsies at Bellevue Hospital, polycystic degen- eration of the kidneys was encountered in four cases only. All of them were in adults. It seems that in certain cases the individual is born with cystic kidneys in which the amount of secreting substance, however, is compatible with life, but that, as time goes on, the gradual distention of the cysts so reacts on the inter- vening kidney tissue as to cause pressure atrophy. In the Bellevue Hospital cases, the patients, toward the end, passed remarkably small quantities of urine and died with symptoms of uraemia. Histologically, polycystic degeneration of the kidneys may, I think, be classified among the cyst-adenomata. (c) Carcinoma and Cystocarcinoma. § 121. The carcinomata are malignant epithelial tumors characterized by infiltrative growth and the formation of metastases. They develop : (1) In skin, mucous membranes and glands, all of which appear pre- viously to be normal. CARCINOMA. 353 (2) In skin, mucous membranes, and glands, which have already suf- fered changes. (3) In papillary epitheliomata, adenomata and adenocystomata. (4) From the remains of foetal epithelial structures, and from epi- thelial tissues which have been misplaced through disturbances of de- velopment, and have already developed into pathological formations. (5) From the epithelial tissues of the chorionic villi"and placenta. The outstanding characteristic of a carcinoma is represented by atypical proliferations of epithelium which sooner or later penetrate the bor- dering tissue. This phenomenon is usually accompanied by proliferation ^n ,;;#^il'v^ W^iM ' dW, Fig. 304. — Cystoma papilliferum ovarii (Muller's fluid, haematoxylin, eosin). a. Stroma with papillae; 6, gland-tubule with small papillae; c, higk cylindrical epithelium; d, mucus-containing cells, within the cyst-spaces, x 150. of connective tissue. The invaded tissue is sooner or later destroyed by the growth. In the stroma of the carcinoma there may occt^r new-forma- tion of other tissue, for example, bone. The cause of the atypical growth of epithelium is not known; it can only be said that certain conditions favor such growth. For example, old age predisposes to the development of carcinomata of the skin, inas- much as in this period of hfe the connective tissue of the skin undergoes atrophy and becomes looser in structure, while the epithelium, at least in part, continues to increase (formation of coarser hairs on the nasal septum, lobes of the ears, and in the eyebrows). Likewise carcinomata of mucous membranes and glands usually appear in later years, although they may occur earlier in life, even in childhood. A further predisposition to the development of carcinoma is found in regenerative processes following the destruction of surface epithelium and 23 354 TUMORS. glandular tissue. These occur most frequently in old inflammatory proc- esses, particularly in the mucous membrane of the intestinal tract, gall- bladder, and uterus, and in glands and in the skin. In the stoniach the round ulcer may form the starting-point of a cancer. In the first place the regenerative proliferations following injury may form the basis for malignant proliferation. In addition an important role is played by snaring-off and misplacement of epithelial cells into the neighboring altered connective tissue, as in the healing of ulcers, the growth of epi- thelium over granulation-tissue, and in tuberculosis, and other chronic infective granulomata, both in the mucous membranes and skin and in glands. These predisposing factors may exist for a long time without giving rise to cancer. Something else must be added to cause unlimited atypical Fig. 305. — Papillary adenocystoma of the ovary with myxomatous degeneration of the con- nective tissue of the papilla (Muller's fluid, ha;matoxylin), a. Fibrous stroma; h, papillae which have undergone myxomatous change; c, epithelium, x 80. proliferation of epithelium, and what this something is is unknown. Whether to be found in a bioplastic stimulus comparable to that of fertili- zation, or in chemical influences, or in the removal of influences that inhibit and regulate proliferation, cannot be stated. In recent years the opinion has been advanced that parasites cause carcinomatous and sarcomatous proliferations. But the majority of forms described as parasites (protozoa, especially sporozoa, and yeast- fungi) are not parasites at all, but degenerated nuclei and nuclear division-figures, or leucocytes inclosed in tumor-cells, or degeneration- products of such, or of cell-protoplasm, particularly keratohyalin and colloid, or epithelial hyalin and mucin. In the few cases in which true parasites are present in the tissues, this occurrence could well be a sec- ondary infection, in no way to be regarded as a cause of the tumor. In not a single case has it been proved that parasites are the cause of either carcinoma or sarcoma. Certain portions of the intestinal tract — the rectum, the flexures of the colon, the pylorus and cardia of the stomach, the oesophagus, pharynx, CARCINOMA. 355 tongue, and gums — are favorite seats for the development of cancer. Cancer may develop in any portion ot the skin, but occurs more frequently on the lips and nose than on the remaining portions of the face; on the extremities, more frequently than on the trunk. Of the sexual apparatus the parts most commonly affected are the mammary gland and cervical portion of the uterus; less frequently, though relatively often, the ovary, testicles, body of the uterus, vulva, vagina, and penis. The liver, kidneys, bladder, trachea, bronchi, lungs and pancreas occupy a middle ground; while the larynx and gall-bladder are frequently affected. Cancer usually develops in the form of nodules, which are not sharply Fig. 306. — Papillary systoma or intracanalicular papillary fibroma of the breast, laid open by a longitudinal incision. One-half natural size. differentiated from the neighboring tissues; on the mucous membranes they are not infrequently elevated in the form of sponge-like, polypoid, or papillary growths. From the point of origin they spread by infiltrative growth of epithelial prolongations, and the nodules increase in size or there are formed diffuse superficial thickenings, as in the intestinal wall. The ovaries, testicles, uterus, kidneys, etc., may be partly or wholly transformed into carcinomatous tissue. Often the boundaries of the organ originally affected are overstepped, and the epithelial infiltration ex- tends into neighboring tissues and organs. Thus, carcinoma of the mamma may infiltrate neighboring fat, skin, and muscle ; carcinoma of the gums, the maxillary bone; carcinoma of the uterus, the vagina, para- metrium, bladder, and rectum ; cancer of the gall bladder may involve the liver; one of the thyroid, the trachea; and one arising in the bronchi, the lungs, etc. 356 TUMORS. The formation of metastases may take place through the lymph- or blood-vessels, and is of frequent occurrence by both routes. It leads to the development of secondary nodules in different organs; but it may happen that large lymphatic areas • — ■ for example, the lymphatics of the lung — -may be dilated by the new-growth, without the formation of cir- cumscribed nodules. The transportation of cancer-cells to the bone- marrow may lead to carcinomatous transformation of the marrow of an entire bone or of several bones. However, it should be noted that probably not every transportation of cancer-cells is followed by the de- velopment of a cancer, but that many transplanted cells die. The tissue of a carcinoma is sometimes white and soft, sometimes Fig. 307. — (Bellevue Hospital.) Rodent ulcer of forehead. firm and dense; but it is almost always possible to obtain from the cut surface whitish, cloudy fluid called cancer juice. Often the cut surface presents a tough, fibrous framework in the meshes of which the softer masses lie ; and from which the latter may be squeezed out in the form of plugs or crumb-like masses which consist of atypically proliferating epi- thelial cells, so-called cancer-cells, which are found in a great variety of forms, and usually show degenerative changes, particularly fatty de- generation. A true secretion of cancer cells is usually not found; but cancers occur — particularly in the mucous membranes, ovaries, mammary glands, and thyroid — which produce mucin, pseudo-mucin, or colloid. The amount of secretion may be so abundant as to lead to the formation of cystocarcinonm: Retrograde changes often occur in cancers at an early stage. They are caused by the feeble vitality of the new growth, by circulatory dis- turbances, which may be due to filling of capillaries and veins by cancer- cells, and by external causes. These changes lead to destruction of certain portions of the tumor and the formation of cavities due to lique- CARCINOMA. 357 faction of the dead portions, so that, after resorption, the tissues sink in. Such depressed areas are seen particularly in cancer-nodules in the mammary gland, and in secondary nodules in the liver, lungs, and other organs, and are spoken of as umbilications. Retrograde changes often lead to destruction of tumor-tissue, and to the formation of ulcers. This occurs particularly in cancers of mucous membranes, but may also take place in carcinomata of the mammary glands and skin. In the latter situation the cancer may take on the appear- ance of a rodent ulcer. The edge of such ulcers is sometimes elevated and studded with nodules; at other times it is sharply defined and only slightly infiltrated. The base of the ulcer is sometimes fissured and ragged, and covered with necrotic tissue; at other times it is smooth. (Fig. 307.) Fig. 308.— Transverse section through a carcinoma of the lip (alcohol, hematoxylin, eosin). a, Corium,_ in a state of proliferation; b, epithelium; c, thickened horny layer; d, epithelial plugs extending into the corium; e, epithelial plugs with horny pearls, cut obliquely; /, enlarged papilla. The view that the cause of carcinoma and sarcoma is to be found in para- sites still finds adherents, although the investigations of recent years do not support it. Publications concerning cancer and sarcoma parasites have not been wanting, but in the majority of cases proof has been wanting that the supposed parasites were really living organisms ; or, when living organisms (yeasts, rhizopods) have been cultivated from tumors, there has been no positive pi oof that they stood in causal relation to the neoplasm. The experiments, in particular, of Sanfelice, Wlaeff, Leopold, and Sjohring are far from convincing. It is worthy of note that nearly every author has found a different parasite and has not recognized the parasitic forms described by the others. This speaks against the interpretation of the findings. Moreover, in the majority of the forma- tions described as parasites another interpretation is possible. Some of them are degenerating leucocytes or the remains of such enclosed in cancer-cells ; others are vacuoles, hyaline or mucoid products of the cancer-cells, or degenerating nuclei or cell-division figures, or fragments of these. Only rarely is it impossible to give a satisfactory interpretation of the findings, but this fact is not sufficient for ascribing a parasitic nature to the formations. The attempt to compare the " bird's eyes " of von Leyden, or the Plimmer's bodies, to which they correspond, with the parasite found in the root-tumors of cabbage, the Plasmodiophora brassica, and to regard these root-tumors as analogous to cancer, is, likewise, without justification, since the two diseases have scarcely anything in common. The plasmodiophora multiplies within the plant-cells and distends the latter. Only after the destruction of the affected cells does regenerative proliferation occur in neighboring cells. In cancer there is from the beginning an unlimited and infiltrative growth of tissue- cells. The natural history and clinical behavior of cancer are not such as to make it probable that it is of parasitic nature. The formation of cancerous tumors as a 358 TUMORS. result of disturbances of development speaks against this view. The metastases develop from transported tumor-cells, and cell-inclusions are not necessary to their formation. The transplantation of cancer and sarcoma into animals of the same species, and the implantation-cancers occasionally observed after operation, are the result wholly of the transplantation of living tumor-cells, and cannot be used as arguments in favor of the parasitic theory. If protozoa are the cause of cancer we must assume, according to our present knowledge of these parasites, that a given species can find a suitable soil only in a certain variety of epithelium. Cases of transmission of cancer from man to man, occasionally cited as evidence, can be utilized hypothetically in support of the parasitic theory only when the cancer in the affected individual develops in the same mother-tissue. Fig. 309. — Beginning development of carcinoma in the vaginal portion of the uterus (alcohol, Bismarck-brown), a, Epithelium; b, connective tissue; c, surface epithelium growing into the deeper tissues; d, dilated glands; e, glandular epithelium growing out in form of plugs; /, cross- section of a gland, the cylindrical epithelium of which has become converted into stratified epithelium. X 45. § 122. The development of carcinoma of the skin takes place most often from surface epithelium, and is characterized by growth of the inter- papillary portions into the deeper structures in the form of epithelial plugs (Fig. 308, d) which fill the connective-tissue spaces. The stratum corneum (c) may undergo hypertrophy along with the cells of the rete Malpighii, and penetrate into the deeper tissues with the epithelial plugs (d). The horny cells which get into the deeper tissues may form epi- thelial pearls (e). CARCINOMA. 359 Besides the surface-epithelium, the epithelium of the hair-follicles and sebaceous glands may take part in the development of cancer; there Fl«. 310. — Developing adenocarcinoma of the large intestine (Miiller's fluid, hasmatoxylin, eosin) . a, Mucosa with unchanged glands ; b, glands showing carcinomatous change ; c, carcino- matous areas in the submucosa. X 100. are carcinomata of the skin which develop entirely from sebaceous glands, and should be classed with the adenocarcinomata. The connective tissue may remain passive during the ingrowth of epithelium, but sooner or later (Fig. 308, a), the papillae develop into long, Fig. 311. — Adenocarcinoma of stomach in process of development (formalin, alcohol, haema- toxylin, eosin). a. Mucosa; b, muscularis mucosas; c, submucosa; d, muscularis; e, serosa; /, g^ adenocarcinoma. X 15. 360 TUMORS. branched formations (/). In the proliferating connective tissue there are often found, in association with fibroblasts, leucocytes and lymphocytes. They become especially numerous in the event of tissue-destruction, and in such circumstances the proliferation of connective tissue acquires the character of granulation tissue. The origin of carcinomata from mucous membranes covered with squamous epithelium may be the same as that of cancer of the skin — that is, it i.s introduced by proliferation of surface epithelium (Fig. 309, a, c). If glands are present they may take part in the development of the cancer. It is a remarkable fact that in the formation of such a tumor, glands with cylindrical epithelium may furnish epithelial products which Fig. 312. — Developing cystocarcinoma of mamma (alcohol, hematoxylin). Tumor of the size of a bean, a. Normal gland-tissue; b, proliferating gland- tissue, x loo. correspond with those of the surface-epithelium. The epithelial pro- liferation may at first be intracanalicular and lead to diffuse thickening and stratification of the epithelium (Fig. ), or to the formation of ex- crescences {e). Later, the proliferating epithelium beaks into the con- nective tissue. The connective tissue behaves in the same manner as in cancer of the skin. The cylindrical-cell carcinomata of mucous membranes arise in the intestine from the tubular glands or from the crypts, the epithelium of which undergoes proliferation, and becomes stratified, while the glands dilate (Fig. 310, b). Later, the glands become changed into branching, atypical structures {c), which possess epithelium arranged in layers, and which grow into neighboring tissues. In the stomach the glands change their character (Fig. 311, /), and through continued growth infiltrate the submucosa {g), the muscularis ((f), and the serosa {e). CARCINOMA. 361 The epithelium of the newly- formed glands stains more deeply with nuclear stains than normal epithelium. The connective tissue, as in cancer of the skin, sooner or later pro- liferates, and in connection with this there may occur emigration of leuco- cytes and lymphocytes. The development of cancer in glands — for example, in the mammary gland — likewise begins with epithelial proliferation, as the result of which the glands (Fig. 312, o) become widened and altered in form (&), while their lining epithelium becomes stratified {b). With breaking through of epithelium into neighboring tissue spaces, infiltration is begun. Fig. 313. — Tubular adenoma of mamma showing a beginning transition to carcinoma (for- malin, hsematoxylin). a, Branching gland-tubules with simple epithelium; the pericanalicular connective tissue is proliferating and very cellular; b, c, gland-tubules, the epithelium of which is partly simple, partly stratified, x loo. According to the structure of the gland in which the cancer arises, and to the variety of the cancer itself, varying microscopic pictures are produced. The connective tissue of the gland through proliferation takes part in building up the tumor; in the early stages of development such prolifera- tion may be slight or wanting. The development of carcinoma in an adenoma or fibro-adenoma (Fig. 313, a) is likewise initiated by change in the character of the cells and by more active proliferation of the epithelium, in that simple epi- thelium becomes stratified {b, c). The ingrowth of •epithelium into the connective tissue, which often occurs at a late stage, is a further sign of malignancy — that is, of carcinomatous transformation. The development of carcinoma from papillary epitheliomata takes place in the same manner as from the skin and mucous membranes; and is characterized by the infiltration of epithelium into the basement- tissue on which the epithelioma rests. 362 TUMORS. The development of carcinoma from transplanted or misplaced epithelium or from remains of foetal structures proceeds in the same manner as that of carcinomata arising in surface or glandular epithelium. Carcinomatous proliferations of the cell-layer and the syncytium of the chorion, both of which arise- from the foetal ectoderm, may occur in the chorion of young ova or in the placenta of older embryos, and in atypical cases are characterized by a mixture of the two forms of cells (Fig. 314). They grow into the neighboring uterine tissue, particu- larly the blood-vessels (c) and through the formation of thrombi may lead to extensive destruction of the tissues of the uterus, and give rise to metastases. Myxomatous degeneration of the chorion or placental villi (hydatid mole) appears to favor the development of such growths. Fig. 314. — Intravascular epithelial plugs of a placental carcinoma. The development and growth of carcinoma have been the object of search- ing investigation. All writers agree that the developing neoplasm, in so far as its , epithelial elements are concerned, grows through its own resources and does not excite neighboring epithelium to proliferation. The neighboring tissue is com- pressed and infiltrated. On the other hand, differences of opinion exist concerning the beginning of cancer. According to Hauser, Krompecher, Petersen and Colmers, the development may be unicentric or multicentric, in the latter case starting in several places in the epithelium. Borrmann assumes a unicentric origin; in those cases in which the development apparently proceeds from several places he assumes that there is coincident development of several primary cancers. According to Hauser, Krompecher, and Petersen, with whom I agree, the de- velopment of carcinoma takes place from cells of the superficial epitheliiim, hair- follicles, glands, and gland-ducts. According to Borrmann, a developing carcinoma is a growing cell-complex, which existed as such before it began to grow; it is an isolated embryonal cell-complex. Squamous-cell cancers, although not all 'of them. CARCINOMA. 363 arise from extremely small cell-complexes that lie in the superficial epithelium, and probably become isolated during foetal life through closure of a furrow or other anomaly of development. According to the first-named authors, the pathological new-formation has its origin from epithelium or at least takes its point of departure from it. According to Borrmann and Ribhert, the process begins with inflammatory changes in the connective tissue; in the skin these may be caused by retention and infection of the secretion of the sebaceous glands causing elevation and stretching of the epithelium. As the result of this stretching and accompanying hyperxmia, the included foetal cell-complex proliferates and grows into the deeper tissues. The independent proliferations of the fcetal ectoderm are usually designated chorioepithelioma {Marchand) in accordance with the view that they represent epithelial proliferation. There is no reason for not classing them with the carcino- FiG. 315. — (Bellevue Hospital.) Carcinoma of tlie kidney. mata, since they are characterized by epithelial proliferation which infiltrates neigh- boring tissues. The metastasis through the blood-vessels which characterizes the chorionic carcinomata occurs frequently in other carcinomata, for example, carcino- toata of the stomach. To a certain extent the character of the parent tissue is preserved in cancer- cells, but careful examination shows in all cases that there is a certain amount of change both in their morphological and in their physiological character (anaplasia). This is shown in changes in the form and structure of the cells, their behavior toward stains, in altered position and arrangement of cells, and in their relations to surrounding tissues. The traumatic displacement of surface-epithelium in wounds may lead to the formation of so-called traumatic epithelial cysts — that is, cysts varying in size from a hemp-seed to that of a nut, which are lined with epithelium, and, in case they arise from the epidermis, contain a pultaceous mass of desquamated epithelium. They occur most frequently after puncture-wounds of the volar surface of the fingers and in the hollow of the hand. § 123. The structure of a carcinoma is determined by its origin. The manner in which the epithelium proliferates and the associated pro- 364 TUMORS. liferation of connective tissue make it possible to distinguish a connective- tissue stroma which contains the blood-vessels, and nests and strands of cells— the so-called cancer-plugs — which aire imbedded in the stroma. If the cancer grows into tissue having a special structure, the stroma may thus be provided with muscle-fibres, bone trabeculae, unchanged glandular tissue, etc. ; but these tissues usually die after a time. In general, carci- noma possesses an alveolar structure, at times suggesting an imperfectly developed acinous gland, at other times a tubular gland, so that it is possible to distinguish acinous and tubular types. When the cell-plugs are solid the growth may be called carcinoma solidum or merely carci- Fig. 316.- - Horny cancer of the tongue (Miiller's fluid, hematoxylin, eosin). a. Epithelial plugs with epithelial pearls; b, stroma, x 100. noma. The presence of a lumen in the cell-plugs gives to the growth an appearance resembling the adenomata, and warrants the designation carci- noma adenomatosum or adenocarcinoma. The type of carcinoma is to a degree dependent on the parent-tissue, and the cells may still show the characteristics of the parent epithelium. Squamous-cell carcinoma may occur wherever there is squamous epi- thelium, and cylindrical-cell carcinomata in mucous membranes having cylindrical cells. Cornification takes place in carcinomata of the skin, mucoid degeneration in those of mucous membranes, while the formation, of colloid occurs in those arising from the thyroid. Departures from this rule are common, in that the epithelial cells may remain at a less highly differentiated stage, so that the type of cell concerned may not be de- veloped to its fullest; or it may happen that the cells lose their original character and take on others. For example, colloid-like substances may be formed in cancers of the skin, mucous may be produced in mammary cancers, or squamous-cell carcinomata may develop in mucous mem- branes possessing cylindrical epithelium (gall-bladder) or in those having transitional epithelium (pelvis of kidney). (1) Squamous-cell cancers develop in the skin and in mucous mem- branes covered with squamous cells. They occur, therefore, in the CARCINOMA. 365 external skin, mouth cavity, pharynx, oesophagus, larynx, vaginal portion of the cervix, vagina, and external genitals. In rare cases they may develop in mucous membranes possessing cylindrical epithelium — for ex- ample, in the trachea ^^^^^'^3^^^i^^^''^°''^'^'^'^'J'-'f^^'^i'f^ ^^^ gall-bladder, or in the remains of foetal structures, such as the branchial clefts, and dermoids. The flat-cell cancer is characterized by the formation of relatively large cell-nests (Fig. 316, a) of irregular shape; but often forms small strands of cells. The epithelial cells show the character of strati- fied squamous epitihel- ium with the formation of prickle-cells, but on account of their multi- plication in the tissue- spaces are usually poly- (Afcohoi, morphous, and no lon- ger- manifest typical characteristics. Often the formation of keratohyalin and cornification takes place in the large epithelial plugs which have penetrated the deeper tissues. The cells which have undergone horny change become arranged in concentric Fig. 317. — Carcinoma of the skin, with delicate cellular network and areas of hyaline connective tissue, haematoxylin.) x 80. Fig. 318. — Adenocarcinoma recti tubulare (alcohol, alum-carmine), a, b, Epithelial gland-tubules; Cj ci, stroma; d, collections of leucocytes in the gland-tubules, x 65. laminae resembling those of an onion (Fig. 316, a). Such cell-nests are known as epithelial pearls or horny bodies, and occasion the designation of horny cancer. If, instead of cornificartion, the central portions of the 366 TUMORS. cell-nests undergo necrosis and liquefaction, the carcinoma may take on an adenoma-like structure. , _ Besides typical flat-cell cancers there often occur in the skin and in mucous membranes possessing squamous cells, carcinomata having epi- thelium persisting at a lower stage of development, so that the cell- strands remain slender and delicate, and consist of small epithelial cells of different forms (Fig. 317) that do not change into_ prickle and horny cells. Such cancers are called basal-cell carcinomata, since they develop from the layer of basal cells. The cell-cords are usually solid, but through the Fig, 319, — Adenocarcinoma fundi uteri. cancer-plugs ; isolated cancer-cellSo production of hyaline products in the centre of the cell-masses they may take on an adenomatous appearance, (2) Cylindrical-cell carcinomata develop chiefly in mucous mem- branes possessing cylindrical epithelium — • intestines, stomach, respiratory tract, body of the uterus, and gall-bladder, but occur in glands — ovary, mammary gland, liver, etc, — as well as in the cerebral ventricles. Such tumors exhibit, at least in the early stages of development, the character of carcinoma adenomatosum or adenocarcinoma (Figs, 310, 311, 318), in that they form epithelial structures which consist of tubules lined by simple or stratified epithelium. More acti\ e proliferation of the epithelial cells finally leads to the formation of compact cell-nests possessing no lumen (Fig, 319), The stroma of cylindrical-cell carcinomata is usually poorly developed ; and the tumor consequently bears the character of a soft cancer, carci- noma medullare. Nevertheless the cancer tissue may in some cases possess a firm consistence. CARCINOMA. 367 (3) The carcinoma simplex occurs most frequently in glands, but may develop in mucous membranes and skin. The cell-nests are irregu- larly shaped (Fig. 320),- round (Fig. 321), or elongated or fusiform (Fig. 322). These variations occasion the terms carcinoma acinosum (Fig. Fig. 320. — Carcinoma simplex mamrn^ (alcohol, hematoxylin), a. Stroma; b, cancer-plugs; c, isolated cancer-cells; dj blood-vessels; e^ small-cell infiltration of the stroma. X zoo. 321) and carcinoma tubulare (Fig. 322) as distinguishing types of corre- sponding character. It should be noted, however, that different types may be present in the same tumor (Fig. 323, e, f, g), since the character of the cell-nests depends partly on their manner of growth and partly on Fig. 321. — Acinous carcinoma of the mammary gland with large nests of cells (Miiller's fluid, haematoxylin). x loo. that of the connective-tissue stroma in which they develop. At the seat of origin the cell-nests may have a variety of shapes {e) ; in adipose tissue they are rounded (/) ; in the unyielding connective tissue of the skin they are small and fusiform (g^. 368 TUMORS. Abundant development of cell-nests in a delicate connective-tissue stroma leads to the formation of carcinoma meduUare. Marked devel- FiG. 322. — Tubular scirrhous cancer of the mammary gland (Muller's fluid, hematoxylin). a. Area with well-developed elongated nests of cells; b, portion of tumor in which the cell-nests have for the greater part disappeared. X 100. opment of stroma with the formation of relatively few cancer-cells gives rise to a hard tumor, called carcinoma durum or scirrhus (Fig. 322). Fig. 323.. — -Section through a segment of a carcinoma of the breast (alcohol, hEematoxylin). c. Nipple; b, tissue of gland; c, skin; d, gland-ducts; e, carcinomatous masses occupying the place of the gland tissue; fj carcinomatous infiltration of fat tissue; g, portion of skin infiltrated with carcinoma; h, nests of cancer-cells in the nipple; i, normal gland-lobule; k^ small-cell infiltration of the connective tissue. Magnified by hand-lens. The hard variety of cancer owes its origin to the fact that cell-nests are few and small, while the stroma is abundant and hard. Such tumors CARCINOMA. 369 are formed especially when epithelial proliferation infiltrates into hard connective tissue, for example, in the mammary gland and skin, but the Fig. 324. — Mucoid carcinoma of the mammary gland (Miiller's fluid, hEematoxylin, eosin). a. Normal gland tissue; b, c, early stages of carcinomatous proliferation with beginning formation of mucus; d, larger cell-nests with masses of mucus; e, f, carcinoma tissue showing marked mucous degeneration, x 30. same characteristics may be exhibited in newly-formed connective tissue. In the course of time a cancer becomes harder by reason of the destruc- tion of its epithelial cells ( Fig. 322, h ) , while the connective tissue increases Fig. 32S. — Early stages of development of a mucoid carcinoma of stomach, arising in an atrophic mucosa (formalin, alcohol, hasmatoxylin, eosin). a, mucosa; b, muscularis mucosae; c, submucosa; d, muscularis; e, serosa; /, g, mucoid cancer, x 9. 24 370 TUMORS. Fig. 326. — Carcinoma mucosum mammffi (alcohol, haema- toxylin). a, Stroma; b, cancer-plugs; c, alveoli without cancer- cells; d, cells containing spherules of mucus. X zoo. The in amount. An originally soft cancer may become hard through shrink- age of the cancer tissue with corresponding induration of the connective tissue. Carcinomata of the mammary gland, stomach, and intestine often show secondary hardening, and in such tumors cancer-cells may be almost entirely re- placed by fibrous over- growth. (4) The chorion- carcinoma or malignant chorio-epithelioma is distinguished from other carcinomata by a mix- ture of cell-forms (Fig. 314) belonging to t h e foetal ectoderm. Suoh a combination is not everywhere present, and does not occur where single cells or - . , cell-groups penetrate the blood-stream or are transported passively, conditions favoring development within the blood-vessels are found when fluid and coagulated masses of blood lie between the tumor-cells. (5) Cancers characterized by peculiar secondary changes arise through the formation of special products by the cancer cells, or through metamorphoses of the same, or through changes in the stroma. Mucoid or gelatinous cancer — carcinoma mucosum (C gelatino- sum, C. colloides) — is that form of carcinoma in which the epithelial cells produce mucus (mucin or pseudomucin) or a colloid-like gelatinous substance. Such pro- duction of mucus occurs particu- larly in cancers of the intestine, stomach (Fig. 325), and mam- mary gland (Fig. 324) ; and may be manifest in the earliest stages of the development of the tumor (Figs. 324, b, c; 325, /, g), so that the mucoid products of the cells collect in the centre of the cell- nests after the manner of a gland- secretion. Later the border of cells surrounding the mucoid material is broken through, the cells pushed aside, separated from the underlying structures, and crowded toward the centre of the mucus-containing alveolus (Fig. 324, d, e, f). Ultimately, the epithelial cells are wholly destroyed. Fig. 327. — -Carcinoma with hyaline drops within the cell-nests (Carcinoma cylindroma- tosum). 0, Cell-nest without; b, cell-nest with a few hyaline spherules; c, cells which have been reduced to strands arranged in a network, as the result of the formation of numerous hyaline spherules. X 150. CARCINOMA. 371 In intestinal cancers the formation of mucin takes place in goblet-cells, which are similar to the goblet-cells occurring in normal conditions. In cancer of the breast the mucus appears in the form of droplets within the cancer-cells (Fig. 326, d), and becomes free by escaping from the cell, or through destruction of the cell rg _^fr«r;spir»5;____^ itself. "^ ' "' '" Through the development of mucoid or colloid-like masses in the cancer-cell nests, the latter may become studded with hyaline drops, and acquire a mesh-like appearance (Fig. 327). Such formations were formerly designated cylindro- mata. Should it be thought desirable to retain this nomen- clature, such a tumor might be designated carcinoma cylindro- matosum; but it seems un- necessary to separate these growths from the mucoid and colloid carcinomata. When the cancer-cells attain an extraordinarily large size, for example, in flat-cell cancers or in cancers of the breast, the tumor may be termed carcinoma gigantocellulare. If the enlargement of the cells is not due to increase in the protoplasm, but to swelling of the cells or to collection Fig. 328. — Enlarged hydropic cancer-cells, from a carcinoma of the mammje (Muller's fluid, IJismarck- brown). a, Ordinary cancer-cells; b, hydropic cells containing drops of fluid; c, swollen nucleus; d, swol- len nucleolus; e, wandering cells, x 300. Fig. 329. — Carcinoma myxomatodes ventriculi (Miiller's fluid, hematoxylin). a. Cancer- plugs; b, connective-tissue stroma; c, stroma of myxomatous tissue; d, cancer-cells which have undergone mucous degeneration. X 200. of fluid in the cells and their nuclei (Fig. 328), the cells are designated physalides (carcinoma physaliferum). Myxomatous degeneration may occur in portions of a cancer, so that the cancer-cells become separated by myxomatous stroma (Fig. 329, c). Such growths may be called carcinoma myxomatosum. 372 TUMORS. Hyaline degeneration of the connective tissue occurs in different forms of cancer, but is usually confined to small areas. Deposits of lime-salts in carcinomata occur as masses similar to those in psammomata. The concretions may form either from the cells or in the connective tissue. They are observed particularly in papillary adeno- mata and carcinomata of the ovary, and in cancers of the mammary gland. There also occur more extensive calcifications, which may lead to com- plete petrifaction; tumors showing such changes occur in the skin and Fig. 330. — Adenosarcoma malignum of the kidney, from a child seven years of age (formalin, haematoxylin, eosin). a, Tissue with gland-tubules; b, sarcoma-like tissue. X 300. subcutaneous tissues, in the form of sharply defined, hard, rounded nodules. Some of these tumors are to be classed with the carcinomata, others represent calcified adenomata of the sebaceous glands. If, at the same time with development of the epithelial new-growth, there occurs marked proliferation of the connective tissue, leading to the formation of cellular tissue, there arise tumors which may be designated adenosarcoma or sarcocarcinoma. Typical examples occur in the kid- neys (Fig. 330, a, b), forming medullary tumors, the origin of which is probably to be referred to disturbance of development of the kidney. Such tumors show a varying structure in different parts, at one time of adenomatous or carcinomatous character, at another time sarcomatous. The metastases of such tumors exhibit a similar character. The tumor of the kidney referred to by Ziegler as adeno-sarcoma was care- fully studied by Wilms and frequently goes by his name or under the designation of erabryoma. It is a composite tumor which occurs most frequently in the kidneys of infants and children, the growths reaching enormous size and frequently metastasiz- ing to distant parts. Most of them are unilateral, but bilateral growths are by no means unknown. The majority occur in children under twelve years of age, but examples have been recorded in adults. In fact, it is safe to say that an over- whelming majority of all tumors of the kidney encountered in individuals under twelve years of age belong in the category of the so-called Wilms' embryoma. They are made up of a mixture of tissues in which cartilage, smooth muscle, osteoid and myxomatous connective tissue are associated with complex arrangements of epithe- lial cells, the la'.tcr rresenting a striking histological resemblance to the tubules CARCINOMA. 373 of the developing kidney. (Fig. 330.) Unlike the so-called hypernephromata, the composite tumors of the kidney seldom cause hematuria and are recognized, as a rule, by their rapid growth and massive size. Hedren, of Stockholm (Ziegler's Beitr., 1907), was able to collect only 90 cases from the literature and to add five from his own experience. In the past IS years I have seen five cases in New York City; three from the service of Bellevue Hospital, one from the New York Hospital and one from an independent source. Of these five tumors, attention was directed to one as a result of the microscopic examination of a small nodule removed from the subcutaneous tissues between the scapulae, subsequent examina- FiG. 331, — (Bellevue Hospital.) Massive recurrent Wilms' erabryoma of left kidney. The tumor, when removed, weighed 2y pounds. tion of the abdomen revealing a large embryoma of the left kidney. Surgical removal of these growths is sometimes followed by recovery. Spontaneous healing of carcinomata does not take place, but many of them grow slowly, and many processes within cancers may be interpretated as local attempts at healing. In this category belong degenerative processes in the cancer- cells that lead to their death and dissolution, so that in large areas (for example, in cancer of the stomach) there may be found hyperplastic masses of connective tissue, but no cancer-cells. It is probable that in the destruction of the cells pro- teolytic ferments play a role. The occurrence of calcification in a cancer depends on previous death of cells. Further, the fact that transported cancer-cells (com- pare § 125) do not always give rise to daughter-tumors, but frequently die at the place where they lodge, may be interpretated as a healing process. Various authors (Becker, Petersen, Schwarz, Orth) also look on the occurrence of giant-cells in tumors as a process of healing; it would be more correct, how- 374 TUMORS. ever, to say that in the course of certain retrograde processes giant-cells appear. The cause of the retrogression lies not in the giant-cells ; they appear only under certain conditions, and especially when in cancers elements of certain kinds, corni- FlG, 332. — Cystocarcinoma papilliferum mammiE. a, Stroma; Z?, smooth-walled _ cysts ; (?, cysts containing papillary proliferations; d, cysts entirely filled with papillary proliferations; e, small, encysted papillary growths; /, adenomatous proliferations; g, papilla of the mamma. Reduced about one-third. fied cells in particular, come in contact with connective tissue. They are foreign- body giant-cells, and' their occurrence is to be regarded as secondary to retrograde processes. I'lG. 333. — Cystocarcinoma papilliferum ovarii (Mtiller's fluid, hematoxylin). h, epithelium; c, d, papillae, x 72. ti. Stroma; § 124. The cystocarcinomata represent a form of tumor which stands in the same relation to cancer as the cystadenomata to the adeno- mata. The majority of cancers form no demonstrable secretion, but there are certain varieties, particularly in the group of adenocarcinomata, in which the epithelial cells produce mucus or colloid (thyroid) ; and in ■ CARCINOMA. 375 adenocarcinomata of the liver secretion of bile has been observed. In cystocarcinomata the mucous secretion of the epithelium may lead to the formation of large spaces filled with fluid. Cystocarcinomata occur chiefly in the ovary and mammary gland, usually bearing the character of cystocarcinoma papilliferum (Fig. 332), in that the cyst-spaces, in certain parts or throughout, are partially (b, c) or wholly {d, e) filled with papillary proliferations. These excrescences possess a soft, medul- lary appearance, and when developed in great numbers give to the tumor a marrow-like character. Both the cyst-wall and the papillary proliferations, which branch in the same manner as those of the papillary cystadenomata, are covered with a thick, stratified layer of epithelium (Fig. m, b, c, d; 334, c). The Fig. 334. — Papillary cystocarcinoma of the mamma with papillae which have tindergone myxomatous degeneration (Miiller's fluid, hematoxylin, eosin). a. Dense connective tissue; b, myxomatous papillae; c, proliferating epithelium, arranged in several layers, x 73. papillae are usually slender (Fig. 333, c, d), but through myxomatous degeneration of their connective tissue may attain large size (Fig. 334, b). Through total myxomatous degeneration of the connective tissue of the papillae the latter may become converted into mucous cysts surrounded by epithelium. If at the same time the epithelial layers of neighboring papillae become confluent, the epithelium finally comes to represent a stroma which incloses balls of mucus. The metastases of cystocarcinomata may have the character of cauli- flower-like, papillary growths. This is particularly the case when ovarian tumors of this nature spread throughout the peritoneal cavity. Other metastases show the characteristics of ordinary carcinomata. § 125. Growth by infiltration and involvement of surrounding tis- sues takes place during the early stages of development (§ 122), through penetration of the epithelial elements into the neighboring tissue in the form of connected plugs or cords of cells. Not infrequently there appear in the tissue-spaces single epithelial cells that multiply and form strands or masses of cells. In the growth of a tumor into neighboring 376 TUMORS. organs, the connective-tissue stroma (Fig. 335, d) surrounding the cell- nests breaks into the neighboring tissue (a) and replaces it. Such infil- tration occurs to the most marked degree in carcinomatous invasion of cartilage (fl) and bones. The formation of metastases, which takes place more frequently in carcinoma than in any other form of tumor, is the natural result of its in- filtrative mode of growth. In the process of infiltration the cancer-cells break into the lymph-vessels (Fig. 214), and are carried to the lymph- nodes. In both places there results multiplication of the transported Fig. 335- — CoUoid-containmg cancer of thyroid infiltrating the thyroid cartilage (alcohol, haimatoxylin, eosin). a. Cartilage; bj cancer-tissue; c, colloid; d^ cancer-tissue growing into the cartilage, x 8$. cancer-cells (Figs. 214, a; 336, d). In lymph-nodes the lymphadenoid tissue becomes replaced by cancer tissue; the lymphocytes vanish, and the connective tissue of the lymph-nodes serves as a framework for the cancer. The development of cancer in lymph-channels is limited to filling and distention of the lymph-vessels by cancer-cells (Fig. 214) or it may lead to the formation in this situation of daughter-nodules. The epithelial obstruction of lymph-vessels is often extensive; and through blocking of individual lymph-channels or of the thoracic duct itself, retrograde metastasis of cancer-cells may he caused. For example, in cancer of the stomach the lymph-vessels of the mesentery and the thoracic duct, and those of the lungs, or even of the upper extremities, may become the seat of metastatic growths. Through the thoracic duct cancer-cells may be carried into the blood-stream. The epithelial proliferation involves blood-vessels not less frequently than lymphatics; the invasion of veins by cancer-cells is to be re- garded as a common phenomenon. In consequence the vessel becomes CARCINOMA. 377 filled with cancer-cells, and at a later stage is converted into cancer-tissue, the framework of which is formed through proliferation of constituents of the vessel-wall. If cancer-cells pass from the thoracic duct or from a vein into the Fig. 336. — Section from an enlarged axillary gland, with beginning development of cancer (alcohol, hrematoxvlin). a. Germ-centre of a lymph-node; b, lymph-sinuses; c, artery; rf, nests of cancer cells, x 60. circulation hcsmatogenotis metastases are formed. In carcinoma of the stomach and intestine cancer-cells are often carried through the portal vein into the liver (Fig. 215, b, c). The thoracic duct and the systemic veins permit transportation of cancer-cells to the lungs. In fact, the Fig. 337. Fig. 338. Fig. 337. — Metastatic collection of young cancer-cells within a liver-capillary, arising from a primary adenocarcinoma of the stomach (alcohol, hematoxylin) . x 300. Fig. 338. — Metastatic development of cancer within the liver-capillaries, arising from a primary carcinoma of the pancreas (alcohol, carmine). Both connective tissue and nests of carcinoma cells have developed within the capillaries. X 250. 378 TUMORS. lungs are frequently the seat of metastases which do not develop into nodules visible macroscopically. Frequently microscopic groups of can- cer-cells embedded in thrombi are found. A part of these metastases, through proliferation of the tumor-cells, develops into daughter-nodules, and the lungs may contain numbers of these. The transported cells may die, and there occurs proliferation of connective tissue in the vessel-wall, leading to organization of the thrombus. In other cases the cancer-cells increase within the vessel-lumen without forming large nodules. When cancer-cells enter the systemic circulation distribution to various Fig. 339. — Carcinomatous metastases in the tipper layer of the uterine inucosa, m universal carcinomatosis following carcinoma of the mamma (formalin, hematoxylin and eosm). o, Muscularis of the uterus; b, normal mucosa; c, nests of cancer-cel!s_ in the vessels between the uterine glands; d, upper layer of the mucosa densely inliltrated with nests of cancer-cells; e, uterine epithelium; /, ulcerated area. (Blood-clots containing cancer-cells were found in the uterus.) X loo. organs occurs, although many of the cells die. The favorite seats of secondary development of cancer are the liver, lungs, lymph-nodes and bones. Occasionally development of carcinoma may take place in all the organs of the body; the resulting condition is called carcinomatosis. The secondary cancer-foci develop first intravascularly (Figs. 337, 338, and 339, c). In the beginning the neighboring tissues are but little changed. Later there occur tissue-degenerations (Fig. 339, /) and con- nective-tissue proliferations (Figs. 338, 340, c, d), the newly formed connective tissue serving as the stroma for the developing cancer-nodule. The amount of connective tissue varies greatly, and is dependent on the parent-tissue in which the tumor develops and on the variety of cancer. The most marked connective-tissue proliferation occurs in metastases in CARCINOMA. 179 bones (Fig. 340), particularly when there is diffuse growth of carcinoma through the bone. With destruction of old bone the carcinoma may form an abundant fibrous stroma in which osteoid tissue or new bone may be produced in large amount. It would appear that certain carcinomata produce substances that excite marked proliferation of the periosteum and endosteum. As has already been mentioned in § 101, carcinomata may sometimes be transplanted to individuals of the same species, and after operations implantation-carcinomata may develop. Recurrences after removal of the tumor by operation are common in cancers, and in advanced cases can scarcely be avoided. They arise Fig. 340. — Metastatic development of cancer in the diploe of the sVr.ll-cap in primary car- cinoma of the stomach (formalin^ hematoxylin, eosin). a. Marrow-tissue; b, nest of cancer- cells; c, proliferated endosteum with nests of cancer-cells; d, fully developed area of carcinoma. X 40. usually from remains of the primary tumor or from metastases already present in the body in the immediate neighborhood or in distant organs. In rare cases the conditions favoring growth of cancer may again arise in the neighborhood of the scar, so that after several years a new cancer develops. Recurrences and metastases of chorionic carcinomata occasionally grow extremely rapidly so that in a few days tumors of considerable size may be formed. The dark-red color shows even to the naked eye that blood is largely concerned in their make-up, and the microscopic examination demonstrates that the rapid in- crease in size is in large measure due to the hcEmorrhages caused by the development of the tumor. The epithelial masses may form a relatively small part of the bulk of the growth. Chorion carcinomata, that is, the epithelial cell-masses characteristic of these tumors, have been repeatedly observed outside the litems, in various organs and in cardiac thrombi without any tumor of the uterus having heen demonstrable. This phenomenon may be explained by the fact that the epithelial cells of the chorion or of the hydatid mole, that is, of mvxomatous chorionic villi, may be transported through the blood-stream and proliferate without the development of a tumor at *he placental site. 380 TUMORS. 3. The Teratoid Tumors and Cysts. § 126. Under the head of teratoid tumors and cysts may be grouped those tumor-like growths which are characterized by the fact that the tissue-formations of which they are composed do not occur normally at the site in question {heterotopous growth), or at least do not normally appear there at the time at which they are found (heterochronous growth). Part of the teratoid tumors and cysts classed as teratomata, are composed of a variety of tissues. The teratoid tumors and cysts may be divided, according to their structure and origin, into three groups: (1) The simple teratoid tumors; Fig. 341. — (Bellevue Hospital.) Recurrent carcinoma of the breast, (2) the simple teratoid cysts; (3) the complex teratomata, which contain tissues derived from all the germ-layers. The heterotopous tissue-growths, which are classed with the teratoid tumors, may occur in various organs, but are more frequently found in certain regions than in others. Among the common tumors of this class are the chondromata and chondromyxomata of the salivary glands and testicle, osteomata of the muscles, lipomata of the pia mater, adenosarco- mata of the kidney containing muscle, and the adrenal tumors found in the kidney. Among those occurring more rarely are the chon- dromata and osteomata of the skin or of the mammary gland, rhabdomyo- mata of the testicle, etc. The occurrence of tissue-formations in regions in which such tissues are not normally present can be explained in part by the assumption that TERATOMA. 381 cells or groups of cells have not undergone normal differentiation into definite tissue-forms, but retain the capacity of forming different kinds of tissues. Nevertheless, in many cases the explanation is to be sought rather in germinal aberration or misplacement of tissue, in that in early embryonic life cells of one organ find their way into the primordium of another organ, or that, later, tissues in process of development or already formed are displaced from their normal position. The first process can be inferred only from the subsequent appearance of pathological tissue- formations; the latter, on the other hand, may at times be recognized, later on, in the anatomical relations. Thus, in the retrograde changes occurring in hernias of the sacral portion of the spinal cord, adipose and muscle-tissue may find their way into the spinal canal and the arachnoidal sac and grow around the nerves. Arnold observed transposition of fat- tissue, gland-tissue, cartilage, and neuroglia at the lower end of the trunk, in a myelocyst with complete absence of the lumbar, sacral, and coccygeal portions of the spinal column. He also found in a Hpomatous teratoma of the frontal region that the intracranial portion of the tumor communi- cated with the extracranial through a defect in the cranium. The teratoid cysts may be divided into two great groups: the ecto- dermal, and the entodermal and mesodermal epithelial cysts. The ectodermal cysts vary in size from a pea to that of a man's fist. Their walls present ectodermal characteristics, in that they consist of a smooth connective-tissue membrane, covered with stratified squamous cells — the so-called epidermoids ; or the cyst walls present all the char- acteristics of skin — that is, papillae, sebaceous glands, hair follicles, hairs and sweat-glands, and often subcutaneous fat — the so-called dermoids or dermoid cysts or dermatocysts. The cyst-contents consist of desquamated horny cells, or of a com- bination of such cells, fat, and hair. Epidermoids and dermoids are found chiefly in the skin and subcuta- neous tissues, in the form of growths containing a pultaceous material, and resemble tumors caused by the retention of secretion in sebaceous glands. They are also found at the sides of the neck and in the median line above or below the hyoid bone ; in the thoracic cavity, particularly in the mediastinum, in the peritoneal cavity (rarely), pelvic cellular tissue, coccygeal region, and in the raphe of the perineum. Finally, they appear within the cranium, in the dura or hypophysis. Of frequent occurrence are the intracranial formations known as cholesteatoma or pearl tumors. These growths vary in size from a pea to that of an apple; they form spherical or nodular tumors, having a white satiny surface, and consist of thin, non-nucleated, scale-like cells, arranged in closely crowded laminae. They are invariably situated at some point on the pia, and at such places the vascular pia is covered with stratified squamous cells, which in the course of years produce the delicate epithelial scales of which the tumor is composed. The neighboring brain tissue and the arachnoid, which may extend over the growth, are not concerned in the formation of the horny scales. In rare cases cholesteatomata contain sebaceous material and fine hairs in addition to horny scales and cholesterin. In these cases there may be found here and there on the pia dermal structures, i. e., skin containing sebaceous glands and hair-follicles, from which sebaceous material and hairs arise. The simple cholesteatomata may be designated epidermoids, those containing hair as dermoids. Cholesteatomata occur at the base of the brain, in the neighborhood of the olfactory lobe, tuber 382 TUMORS. cinereum, corpus callosum, choroid plexus, pons, medulla oblongata (rarel}- in the spinal cord), and in the cerebellum. The dermoids and epidermoids probably owe their origin to transplan- tation of epithelial germs to the sites in question. In the epidermoids probably only embryonal epithelial cells are transplanted; in dermoids embryonal dermal tissue is also transplanted. The intracranial cholestea- tomata originate probably in early implantation of epidermal cell groups in the pia. Mediastinal' dermoids probably depend on disturbances of development of the thymus, which arises from the ectoderm. The der- moids on the sides of the neck arise from remains of the branchial clefts. Fig. 342. — Adenoma-like isolation in the submucosa of a portion of the mucous membrane of the small intestine, giving rise to a ridge-like prominence of the mucosa 2 cm. in length (alcohol, hematoxylin). From a child six weeks of age. a, fc, c, Normal intestinal wall; rf, e^ portions of mucosa, included within the submucosa; /, mucous tissue rich in cells. X 35. particularly the second ; those hanging from the hyoid bone or lying beneath it are probably to be regarded as remains of the ductus thyreo- glossus. Dermoids of the pelvic cellular tissue may be explained as arising from epithelial inshoots from the perineum. Simple entodermal and mesodermal epithelial cysts are character- ized by a lining of cylindrical cells, which are often ciliated. They occur most frequently in the broad ligament and tubes. They are also found in other portions of the peritoneal cavity, in the intestine, in the neigh- borhood of the trachea and bronchi, in the lungs, pleura, neck, tongue, vagina, glandular organs, etc. They form cysts varying in size from a pin-head to that of a man's head. The occurrence of these cysts may be explained in most cases by the persistence of foetal glands or canals or by separation through con- striction of portions of entodermal or mesodermal epithelial tubes. In the neck remains of the internal branchial clefts, in the posterior portions of the tongue the remains of the ductus thyreoglossus or of TERATOID CYSTS. 383 epithelial buds and glands developing from the same, m the oesophagus and respiratory tract snared-off portions of the intestinal canal or of the air-passages, or remains of the communication between alimentary tract and air-passages, may form the foundation for the development of such cysts. In the broad ligament, uterine wall, and tubes, the cysts arise from remains of the Wolffian duct and the duct of Gartner; in the tubes, cervix, portio vaginalis, vagina, and hymen they arise from the remains of the latter; in the peritoneal cavity from snared-ofiE portions of the intestine (enterocysts) , or from portions of the urachus (urachus-cysts) . Within glands — for example, the liver or kidneys — portions of tubules Fig. 343. — Adenoma-like remains of the Wolffian body, within the uterine musculature (formalm, alcohol, haematoxylin, eosin). a, Muscle tissue; b, glandular tissue; c, sections of vessels, x 100. may become constricted during the period of development, and develop into cysts (adenocysts) . Cysts located in the central nervous system or its immediate neighbor- hood — for example, at the lower end of the trunk — • may arise from the medullary canal (myelocysts) , in the latter place also from remains of the hind-gut (enterocysts) . The origin of cysts lined with cylindrical epithelium can, as a rule, be determined only from their position and the character of their walls, but in the majority of cases the origin can usually be ascertained beyond doubt. The diagnosis can be made with relative assurance when the misplacement of the separated portion is slight (Fig. 342, d, e), and when the formation still shows the character of the mother-tissue. The significance of ectodermal, entodermal, and mesodermal cysts is dependent on their position, size, and the secondary changes which occur in them. Their size varies from a pin-head to that of a man's head. Among secondary changes — aside from inflammation — may be men- tioned the development of adenomata and carcinomata. For example, remains of the Wolffian body in the dorsal wall of the uterus near the 384 TUMORS. angles of the tubes, or in the broad ligament in the inguinal region, may give rise to adenomata, cystadenomata (Fig. 343, &), or adenomyomata. Dermoids may be the seat of development of a squamous-cell cancer (branchiogenic and subcutaneous carcinoma) ; while from separated por- tions of the intestinal mucous membrane (Fig. 342) cylmdrical-cell carci- nomata may take origin. Cysts, cystadenomata, and carcmomata may Fig. 344. — Section through a prominence in a mutilocular dermoid (alcohol, nitnc a^id, hsematoxylin, eosin), a, ai, az, Epidermis; h, cerium with sebaceous glands; c, sinus lined_ with squamous epithelium; d, sinus lined with cylindrical epithelium; e, tubular glands; f, fat-tissue; 5.' bone; h, teeth; i, brain-tissue with corpora amylacea; h, ovarian tissue, x s. develop in the jaw from misplaced portions of the epithelial primordia of the teeth. § 127. Complex teratomata occur most frequently in the sexual glands, in the form of dermoid cysts and as solid tumors associated with multiple cyst-formation. The first occur particularly in the ovary, the latter in the testicles. The so-called dermoid cysts of the ovary form rather thick-walled cysts, varying in size from a pea to that of a man's head, and are filled with fatty material and hair. At some point in the wall there will be found extending into the cyst-cavity a villus-like , nodular, flat- TERATOID CYSTS. 385 tened, or septum-like prominence, covered with hairs and often studded with teeth. The uppen. layers of this prominence contain the char- acteristic structures of the skin (Fig. 344, a, a-^, a^, b), namely, hair- follicles with hairs, sebaceous and sweat-glands; subcutaneous fat is usually present (/). In the deeper layers are found tissue- formations, such as cysts and tubes lined with ciliated columnar epithelium (d), bone (g), cartilage, teeth (h), muscle-tissue (heart-muscle [Katsurado]), brain-tissue (J), nerves, groups of ganglion-cells, mucous glands, intestinal mucosa, and thyroid tissue, as well as pigmented formations resembling the rudimentary tissues of the eye. The remaining portion of the wall of the dermoid is either covered with cylindrical epithelium or is bare; if hairs are present in this portion, they are the result of secondary implantation, and may be surrounded by granulation-tissue, often by giant-cells. If in association with the cysts containing fat and hairs there are also found cysts filled with serous or mucoid fluid, the latter may be explained as arising through dilatation of spaces which are lined with cylindrical cells. More frequently, however, they represent formations resulting from cystic degeneration of neighboring ovarian follicles Or of adenomatous new-growths. The ovary may be entirely destroyed by the dermoid; but remains of its tissue are often present (k). In rare cases several dermoids may develop coincidently in one ovary; a double- sided occurrence is seen in about fifteen per cent, of all cases. Ovarian dermoids are observed most frequently in individuals of middle age, but occur in children. The most characteristic feature of ovarian dermoids is that they contain elements of all three germ-layers, and that a certain order in the arrangement of the different elements is observed. The derivatives of the ectoderm and mesoderm, in particular the skin and its appendages, also bone and teeth, and often brain substance, are developed to the great- est extent; while entodermal formations, cylindrical-cell tubules, and mucous glands are developed to a less degree, and lie concealed in the deeper parts of the growth. The structure of the growth as a whole gives the impression of a rudimentary embryo with unequal development of ecto- and entodermal tissue; such tumors have been appropriately designated embryomata (Wilms). The solid teratomata of the ovary are more rare than dermoid cysts. They form tumors composed of a confused mixture of tissue-formations, e. g., epidermis, epithelial pearls, hairs, sebaceous glands, sweat-glands, tubules, and cysts lined with ciliated epithelium, acinous glands, connec- tive tissue rich in cells, adipose tissue, muscle, cartilage, and bone. In rare cases teeth, intestine, thyroid and brain tissue of rudimentary char- acter may be present. Since these formations contain elements of all three germ-layers, and are distinguishable from the dermoids only through lack of orderly ar- rangement of the different tissues, and through the more rudimentary development of the individual tissues, they may likewise be classed with the embryomata. Because of lack of structural organization approach- ing that of the human embryo, Wilms has designated these formations embryoid tumors. Since the embryoma contains elements of all three germ-layers, in more or less orderly arrangement, the genesis of such a tumor may be explained by the assumption of development from an ovum. Bonnet regards it as probable that in the development of a fertilized ovum, in 2S 386 TUMORS. the early stages of division, a blastomere (or several) may be delayed in division and later give rise to an independent formation containing ele- ments of all germ-layers, or that (Marchand) a fertilized polar body finds its way between the blastomeres of a developing ovum, and later develops within the embryo. The first assumption seems more probable, _ and the embryomata of the ovary may consequently be regarded as rudimentary unioval twin malformations (§ 128), which are to be placed in the same category with the foetal inclusions of other organs. That the ovaries Fig. 345. — Congenital adenocystoma (teratoma) of the testicle with pigmentation and forma- tion of cartilage (Miiller's fluid, hajmatoxylin). a. Connective-tissue stroma; b, simple cubical epithelium; c, stratified cylindrical epithelium; d, stratified ciliated cylindrical epithelium; e^ pigmented epithelium lining gland-tubule; /, pigmented connective-tissue cells; g, cartilage in con- nective tissue; h, cartilage lying in a gland-tubule. (Section taken from tumor pictured in fig. 300.) X 100. (and testicles) form the favorite seats of such growths is probably dependent on the fact that the urogenital primordium in its earliest stage forms relatively such a large part of the embryonal primordium (Bonnet), or that the blastomeres, from which the sexual glands later arise, more easily than others take on special development, that may lead to the formation of a rudimentary twin. The teratomata of the testicle occur most frequently as adenocystoma, chondroadenoma, chondrosarcoma, adenomyosarcoma, cystosarcoma, cys- tocarcinoma, etc. In some cases the formation of cysts with fluid con- tents is the most striking feature of the tumor (Fig. 300) ; in other cases cysts are found only in certain parts of the growth; and in still other TERATOID CYSTS. 387 cases the tumor may be solid throughout. These growths may reach the size of a child's head. They may be present at birth, but develop more frequently in adult life, and grow rapidly. The hning of the cysts is, as a rule, of entodermal character, but may vary in one and the same cyst (Fig. 344). Simple cubical (Fig. 344, b) and cylindrical epithelium either with or without cilia, as well as stratified ciliated (d) and pigmented epithelium (e), may be found. Ectodermal tissue is present in scanty amount, and is limited to pig- mented epithelium or to scattered groups of cells showing cornification ; or it may be absent, or, at all events, cannot be demonstrated in tumors of large size. Besides the cysts, mucous glands may be found. Of the connective-tissue substances, fibrous tissue, myxomatous tissue. cartilage (Fig. 345, g, h) and occasionally muscle (Fig. 346, a), fat tissue, and more rarely bone, are present. The teratomata of the testicle may contain tissue-formations corre- sponding in structure to the malignant chorio-epitheliomata, characterized in particular by syncytial formations. Teratomata of the character of dermoids, containing, as in the ovarian dermoids, such structures as skin, brain tissue, cranial and tracheal tissues, and more rarely teeth and structures resembling the eyes, are of rare occurrence in the testicles, but are found both in children and adults. To what extent the different teratomata of the testicles are to be classed with the embryomata, or to what extent they can be explained by the assumption of tissue-implanations at later stages of embryonal development, cannot be stated. When elements of all the germ-layers are present in the tumor, the assumption is justified that the growth belongs to the embryomata or embryoid tumors, and that it has arisen in the same manner as the ovarian dermoids. The occurrence of syncytial formations is in favor of this assumption. The presence of single tissue- 388 TUMORS. formations — for example, cartilage or muscle — in tumor-formations of a more simple character, may be explained on the ground that such tissues find their way into the testicle during embryonal development. The proliferations of chorio -epithelial character found in teratomata of the testicles are believed to depend on the development of fcetal membranes, and that the myxomatous tissues present in such tumors represent the chorionic stroma. According to Marchand and Risel, they are to be regarded only as products of the foetal ectoderm having the same histogenetic significance as the other ectoderrnal structures of the teratoma. It is yet to be determined to what extent corresponding ectodermal formations occur in teratomata or other organs. Pick found them in a teratoma of the ovary in a nine-year-old girl. Further, it is to be noted that syncytial formations occur in tumors (angiosarcoma, endothelioma) having nothing to do with foetal ectoderm. It cannot, therefore, be regarded as positive.y determined that the syncytial formations in teratomata of the testis actually corre- spond to chorio-epithelioma. Wlassow believes that the chorio-epitheliomatous proliferations observed by him in tumors of the testis, and designated epithelioma syncytiomatodes, are to be regarded as derivatives of incompletely developed epithe- lium of embryonal gland tubules. § 128. Complex teratoid cysts and solid teratomata are found, out- side the sexual glands, in the same regions as the simple teratoid cysts, but show a predilection for the region of the coccyx. The complex char- acter of the cysts is shown by the presence in the wall of cartilage, bone, fat tissue, mucous glands, smooth and striped muscle fibres, nerve-tissue, and tissue of sarcomatous or carcinomatous nature. Dermoid cysts may contain teeth, and ciliated epithelial cysts. The solid teratomata occur as hairy polypi (nose, throat, and mouth) ■ — ^ tumors covered with hairy skin, and consisting of adipose tissue, muscle fibres, cartilage, bones, teeth, and cysts. Another group consists of kidney-tumors which, in addition to tubular glands, inclose sarcomatous tissue, cartilage, fibrous, adipose, and muscle tissue, in rare cases ectodermal tissues. In the vagina and cervix uteri of children there occur tumors, for the greater part of a race- mose character, which, in addition to connective tissue, myxomatous tissue, round and spindle-cell tissue, contain smooth and striped muscle-fibres, and in rare cases cartilage. Finally, there occur tumor-like growths of complicated structure in the cranium, thorax, abdomen, urinary bladder, neck, lower jaw, and especially in the region of the coccyx. They contain connective tissue, adipose tissue, cartilage, bone, gland tissue, muscle, nerve and brain substance, as well as ectodermal and entodermal cysts. They may inclose rudimentary, or completely formed, or at least easily recognizable, portions of the body. Both the complex teratoid cysts and- the solid teratomata are in many instances to be regarded as local disturbances of development character- ized by misplacement or separation of tissues by constriction in a single individual {monogerminal tissue-implantation , autochthonous tera- toma^. The hairy polypi of the throat, the cystic or solid teratomata at the base of the skull or in the hypophysis may be explained by the assump- tion of misplacement of ectodermal tissue. The presence of cartilage and mucous glands in teratoid cysts of the mediastinum may be explained by the proximity of the trachea. The teratoid mixed tumors of the kidney may be explained by the assumption that, in addition to kidney-tubules and remains of the Wolffian body, products of the mesenchyma arising from the myotome undergo proliferation. The occurrence of squamous- cell formations in such tumors must depend on the fact that ectodermal tissue has found its way into the developing kidney. The presence of TERATOID CYSTS. 389 striped muscle-fibres and cartilage in tumOrs of the vagina and uterus is explainable by implantation of myotome or of sclerotome ; although many hold that striped muscle may be formed from unstriped. Wilms believes that the Wolffian duct and its development occasion implantations into the cervix and vagina. In teratomata of the coccygeal region the mani- fold character of these growths may be explained by the fact that portions of the terminal vertebrae, of the pelvis, and of muscular tissue, as well as remains of the neuroenteric canal, the hind-gut, and the medullary canal, take part in the formation of the tumor. In intracranial teratomata, as well as in simple dermoids, tissue-implantations probably form the basis for the growth. Moreover, there exists the possibility of another mode of origin for these growths — namely, the presence of a rudimentary twin, a bigerminal implantation. Such an assumption is well founded in those cases in which the teratoma contains fully developed or rudimentary parts of the body, or tissue-formations which cannot be explained by misplacement of the tissue elements of a single foetus at the spot in question. CHAPTER IX. Disturbances of Development and the Resulting Malformations. I. General Considerations Regarding Disturbances of Development and the Origin of Malformations. § 129. After the copulation of sexual nuclei has taken place, the development of the embryo proceeds by progressive division of_ nuclei and cells, associated with which there arise in orderly manner special cell- complexes and differentiation of the same into tissues and organs. The multiplication of cells, as well as the development of individual cell- groups into organs and parts of the body, depends on intrinsic causes, and is determined by the characteristics which the embryo has received through inheritable paternal or maternal characteristics at the moment of union of the sexual nuclei, which are to be regarded as the carriers. It follows that the characteristics of the species as well as the peculiarities of the individual are predetermined in the germ, and the development of the embryo proceeds under the control of innate moulding forces. Never- theless, this development is not accomplished without the influence of environment, since the embryo receives its nourishment from the maternal organism, and is exposed to the mechanical influences of its membranes and of the uterus. These influences may operate to modify the develop- ment of the foetus. In every species of animal, man included, bodily shape and the con- figuration of organs conform to a type, which experience has shown con- stantly to recur, and which is therefore looked on as normal. If more or less marked departures from this type occur, the condition is designated congenital malformation. When departure from the normal is marked, so that the individual is grossly malformed, it is spoken of as a monster. According to usage, the term malformation is applied to anomalies in the form of the body as a whole, or to parts of it which present departures from the normal. A malformation afifecting a single individual is known as a single malformation or single monster; one made up from two individuals is termed a double malformation or double monster. Malformations may owe their origin to intrinsic or extrinsic causes. As intrinsic causes may be considered such as exist in the germ. When such a malformation occurs in a family for the first time, it must be regarded as a primary germ-variation. This may be explained in one of two ways: either one or both of the sexual nuclei entering into union have been abnormal, or both have been normal, but from their union a variety has arisen which is to be regarded as pathological (cf. § 17). It is also possible that disturbances in the processes of fertilization can give rise to pathological variations. If a similar malformation has already occurred in the parent, the case may be regarded as one of inheritance. If the malformation appearing 390 CAUSES OF MALFORMATIONS. 391 is a peculiarity which was not present in the parents, but did show itself in remote ancestors, while wanting in the intermediate links, the phenome- non is designated atavism. Only those malformations are inheritable which originally appeared as primary germ-variations. To such inheritable malformations belong increase in the number of the fingers and toes (polydactylism), malforma- tions of hands and feet, abnormal hairiness, harelip, and certain patho- logical conditions of the nervous system, for example, multiple fibromata of the peripheral nerves. Under extrinsic causes are to be considered concussion, pressure, disturbances in the supply of oxygen and nourishment, and infections. Concussions of the uterus in all probability directly damage the embryo at an early stage. At a later stage the efifects of trauma are more often to be sought in tearing loose of the egg and in decidual hamor- FiG. 347. — (Bellevue Hospital.) Polydactylism. rhages, whereby the nourishment of the embryo is disturbed. It is evident that haemorrhages from other causes, and changes in the maternal blood, as in infections, and pathological conditions of the uterus itself, have a harmful influence on the developing egg; yet these conditions probably lead more often to death of the foetus and expulsion of the egg than to the development of a malformation. Infectious diseases in the mother may be transmitted to the foetus and give rise to characteristic changes in the latter. Abnormal pressure from the uterus or its membranes may be exerted on the embryo, especially when there is deficient amniotic fluid ; malformations of the extremities not infrequently show evidences of pressure having been exerted. In many malformations it appears that pathological conditions of the amnion exert a damaging influence on the embryo. This may be brought about through adhesions between embryo and amnion, and by pressure of the amnion on the embryo. At the birth of the child adhesions may not infrequently be demonstrated, and their connection with the malformed parts is such as to leave no doubt that they stand in causal relation to the malformation. Such adhesions may give rise to malformations of the cerebral or facial (Fig. 348) por- tions of the head. Not infrequently extremities are snared oflf by amniotic bands (Fig. 349), amputated and absorbed. 392 DISTURBANCES OF DEVELOPMENT. Some malformations are typical — that is, they always appear in the same form ; others are atypical, so that astonishing ^anomalies may arise. Geoffrey St.-Hilaire ("Hist. gen. et partic. des anomalies de I'organization Chez I'homme et les animaux," Paris, 1832-37) discards entirely the teaching of a primary abnormality of the germ {Holler and mnslow), and attributes arrests of development purely to mechanical influences. Panum ("Untersuch. uber de Entste- hung der Missbildungen," Berlin, 1860) agrees with him on the whole, although he admits the possibility of a primary abnormality, lie produced malformations m hens' eggs by temperature variations and by varnishing the shtus. Daresie (' Re- cherches sur la production artificielle des monstruosites," Paris, 1877) made similar Fig. 348. — Malformation of the face, caused by amniotic adhesion and pressure. Asymmetry of the face, a. Malformed nose; b, bi, rudimentary lid-clefts; c, ci, clefts in the upper lip and alveolar process of_ the upper jaw; d, intermaxillary bone with prominent lip; ?, oblique facial fissure closed by scar tissue so as to form a groove. Fig. 349. — Hand stunted by amniotic adhesions; ring- finger snared oif ; middle and index fingers grown together and distorted. Reduced one- sixth. experiments and produced malformations due to arrested development by keeping the eggs in a vertical position, by varnishing the shells, by raising the temperature above 45° C, and also by irregular warming of the eggs. L. Gerlach, Fol, Warynsky, Richier, Roux, and Schultze have carried on ex' periments in this line, and have attempted, with partial success, to produce mal- formations in chicken-embryos through the localized influence of radiant heat, variations of temperature, varnishing of eggs, changes of position, injuries, removal of a portion of the white of the egg, and by agitation. Rou.v, experimenting on frogs' eggs, found that, after destruction of one of the first segmentation-spheres, the other continued to develop and formed the half of an embryo, thus demon- strating that each of the first two segmentation-cells, corresponding in their posi- tion to the right and left body-halves, contains within itself material for the corre- sponding half of the body. But since the body-half which is wanting may later be replaced by subsequent development from the undestroyed half, and a whole structure be produced, each half must also possess the power of producing the other half. According to investigations by Herlifzka, Driesch. Morgan. Wilson, and others, the first two or even the first four segmentation-cells in tritons, teleosts, ascidians, and echinoderms possess the power of forming an entire embryo. CLASSIFICATION OF MONSTERS. 393 Schultze experimented on the eggs of amphibia; these normally always assume such a position that the darkly pigmented protoplasmic substance of lighter specific gravity lies above, the heavier clear protoplasm rich in yolk granules lies below. By placing the eggs in an abnormal position and preventing their return to the' normal position malformations may be produced, the degree of malformation standing in direct relation to the size of the angle formed by the line of gravity and the abnormally-placed axis of the egg. By turning the egg through an angle of 180° in the two-cell stage a double monster is regularly produced. The same turn- ing in the eight-cell stage causes complete cessation of develo.pment. These dis- turbances arise from displacements consequent upon sinking of the heavier and rising of the lighter constituents of the egg. According to the investigations of O. Hertwig, the eggs of axolotl, when kept in a 0.7-.per-cent. solution of sodium chloride, undergo pathological development, which is confined to the central nervous system in the region of the head and trunk. If frogs' eggs are left before fertilization for one to four days in the uterus of the dead female and are then fertilized, there are formed, besides normal embryos, various malformations due to defective development, for example, spina bifida. Recent studies have shown that monsters and malformations may be produced by Roentgen irradiation of fertilized ova or of either ova or spermatozoa before fertilization. Cilman and Baeijer found that the eggs of amblystoma developed aibnormally under Roentgen irradiation, the embryos showing no mouths. Chicks developed in exposed eggs presented malformations of the occipital region and extremities and in the distribution of the feathers. Bardeen found that in frogs injury to the spermatozoa by Roentgen rays caused the development of monsters from eggs fertilized by such damaged spermatozoa. § 130. Single malformations may be conveniently divided into five groups. Among monsters due to defective development may be classed those malformations in which the whole or a part of the body is small and imperfectly developed {hypoplasia), and those malformations character- ized by absence or stunting {agenesia or aplasia) of individual organs or parts of the body. _ If, in parts or organs which are normally formed by the union of primordia which are originally separated, such union should fail to take place, arrest of development may show itself in the form of clefts and reduplications. Thus imperfect development of the plates forming the anterior body-wall gives rise to clefts in the median line of the thorax and abdomen; failure of union of the maxillary processes of the first branchial arch with each other or with the nasal process of the frontal bone gives rise to clefts in the face. Defective union of the bilateral portions of the female genital tract results in more or less extensive reduplication of the uterus or vagina. When the primordia of two organs lie near to each other, these may become united to produce coalescence between organs or parts which nor- mally should be separated. For example, the kidneys may be united and the eyes merged into a single organ. Malformations due to excessive growth are characterized by abnormal size or increase in number of individual parts. For example, an extrem- ity or a portion of one, as a finger, may reach abnormal size {partial giant growth), or the whole body may be involved in abnormal growth {general giant growth). Increase in number occurs particularly in the mammary gland, spleen, adrenals, and fingers, accessory or supernumerary organs. Among malformations due to abnormal disposition of organs are certain anomalies of the organs of the thorax and abdomen. In this class belongs the condition known as situs tran.<;versus — that is, transposition of the thoracic or abdominal organs, or of both. Various defects in the 394 DISTURBANCES OF DEVELOPMENT. heart and great vessels may also be classed here, though it should be noted that these are more properly regarded as arrests of development. A fourth group of malformations includes those characterized by displacement of tissues and by persistence of foetal formations, as already mentioned in §§ 126 and 128. In the fifth group may be classed those malformations exhibiting a mixture of sexual characteristics, known as true and false hermaphro- ditism. True hermaphrodites possess both male and female sexual glands; false hermaphrodites are unisexual, but the remainder of the sexual apparatus does not correspond to the sexual gland, or there is simultaneous formation of organs belonging to both the male and female. Some of these malformations are arrests of development; others are to be regarded as cases in which from the original bisexual primordia the organs of both sexes have developed, whereas normally those of one sex undergo retrograde change, and persist only in rudimentary form. § 131. Double monsters are malformations consisting of two indi- viduals; if both twins are developed {symmetrical twins) they are always of the same sex and are united to each other in the same portions of the body ; the duplicated portions are usually equally developed, but unequal forms occur in which one twin is stunted in its development. Asymmetri- cal forms also occur in which one twin remains rudimentary and is dependent on the other for its nutrition {parasitic double monster). Often it is implanted in the other (see § 127). All double monsters arise from, one egg and have a common chorion. In the formation of symmetrical double monsters two separate embryonal primordia are probably formed from one germinal vesicle, and in their growth blend with each other to a greater or less extent, but duplication or splitting may occur within a single primordium ; this process occurs particularly in anterior reduplications and can be produced experimentally in animals. The genesis of rudimentary asymmetrical twins occurs in the manner described in § 127 (Teratomata). II. The Different Forms of Malformations in Man. I. Arrests of Development in a Single Individual. {a) Arrest of the Development of the Entire Embryonal Primordium. § 132. Arrest in the development of the entire embryo manifests itself in two ways. If the disturbance is marked, further development of the embryo is impossible, and it either dies at once or becomes stunted, and after a certain time perishes. If the disturbance is less severe there develops a normally formed foetus, but it remains small and stunted — that is, a dwarf is formed. A dead foetus in the majority of cases is expelled together with its membranes (abortion). In other cases the embryo for some cause re- mains stationary in development, the tgg may stay for weeks or even months in the uterus and increase in size, and there arises disproportion between the size of the embryo and the .egg. The first changes after death are shown in swelling of the central nervous organs, leading to changes in the configuration of the head. Later there occurs infiltration of the tissues with wandering cells, the boundaries of the organs are indistinct, the entire embryo becomes cloudy and soft, and finally is completely dissolved. LITHOP^DION. 395 When a fcetus well advanced in development dies and remains in the maternal organism a lithopaedion may result. This occurs most fre- quently in extrauterine pregnancy, in which the embryo lies in the peri- toneal cavity, in a tube, or in an ovary. If the fcetus dies at such an advanced stage of development that it cannot be absorbed, it may be carried in the maternal body for years. Not infrequently 'its form is Fig. 350. — Lithopsdion, entirely inclosed in connective-tissue membranes (removed from abdominal cavity by operation two years after beginning of pregnancy). Extrauterine pregnancy caused by embryo breaking through the uterine portion of a tube into the abdominal cavity. Reduced to one-third. perfectly preserved (Fig. 350), and the foetus becomes inclosed in a con- nective-tissue membrane. In other cases the fcetus, in time, becomes par- tially converted into a fluid mass, which contains osseous remains, fat, cholesterin, and pigment, and is surrounded by a fibrous capsule. Lime-salts are usually deposited in the newly formed membranes as well as in the portions of the foetus remaining, and for this reason the foetus is known as a " stone-child " or " petrified child." According to the condition of the fcetus there may be distinguished three forms of lithopaedion. In the first the mummified foetus may be shelled out from the calcified membranes. In the second form the fcetus becomes adherent to the membranes at various points which become calci- fied, while the other portions become mummified. In the third form the foetus is discharged into the peritoneal cavity, and becomes encrusted with Hme-salts. Z96 DISTURBANCES OF DEVELOPMENT. {h) Defective Closure of the Cerebrospinal Canal and the Accompanying Malformations of the Nervous System. § 133. Defective closure of the vertebral canal leads to malforma- tions. If the defect in the vertebral column is open so that at the bottom of the cleft the bodies of the vertebrae covered by membrane are seen, the malformation is termed rachischisis: When, at the site of the defect, there is a protruding sac, the malformation is designated spina bifida, or spina bifida cystica. Fig. 351. — Craniorachischisis -with total absence of the brain and spinal cord. The base of the skull is covered with ragged membranous masses, the open spinal furrow with a delicate membrane (pia mater). Kypholordotic curvature and shortening of the spinal column. Reduced one-sixth. In rachischisis totalis (Fig. 351) the bodies of the vertebrae form a shallow groove opening posteriorly, usually covered by a thin, transparent membrane ; in rare cases rudiments of the spinal cord are present in the form of whitish bands and lines. In this manner there occurs total or partial amyelia. The defect involves principally the motor tracts and centres, as well as the columns of Clarke and the lateral cerebellar tract, while the spinal ganglia are developed and may send sensory fibres into the membranous masses of the spinal groove. The delicate membrane which lines the furrow and covers the dura mater lying beneath it on the bones is the ventral portion of the spinal pia mater. A part of the nerve-roots may have undergone development, arising either from rudiments of the spinal cord or from spinal ganglia. Partial rachischisis usually involves the sacrolumbar or the upper cervical region, while the intervening portions of the vertebral column are only rarely the seat of malformations. The dorsal surfaces, with the overlying dura and pia mater, of the bodies of the vertebrae whose arches remain rudimentary are covered for the greater part by a mass of velvety, SPINA BIFIDA. 397 vascular tissue, which contains rudiments of the spinal cord (the area medullo-vasculosa, von Recklinghausen), though the amount of this tissue may be small or even wanting. To the outside of this layer, which is not everywhere equally abundant and which diminishes at the sides, there Fig. 352. — Spina bifida sacralis. (After Froriep and Forster.) A girl of nineteen years, born with a tumor the size of a pigeon's egg over the upper sacral and lower lumbar regions, which enlarged from the sixth year on, while at the same time club-feet developed. comes a delicate, transparent, vascular membrane which represents the continuation of the pia mater covered with epithelium ; and outside of this, a zone of epidermoidal tissue somewhat thinner than normal skin, and often Covered with many hairs {zona dermatica), separating the reddened central area from the normal skin. Spina bifida cystica or rachicele occurs in three forms : myelomen- ingocele, meningocele, and myelocystocele. According to site there may be distinguished cervical, dorsal, lumbar, lumbosacral, and sacral spina bifida. In general, spina bifida is characterized by the development of a fluctuating tumor, which in most cases is visible (Fig. 352) on the posterior aspect of the spinal column {spina bifida pos- terior) ; but instances occur in which the sac projects anteriorly {spina bifida an- terior), and others in which it is so small that it is covered with normal skin and is "•£ not visible externally {spina bifida occulta). Myelomeningocele appears most fre- quently as spina bifida lumbosacralis, and forms a tumor varying in size from a nut to that of an apple and increasing in size after birth, in the region of the lower lumbar and upper sacral vertebrje. It is covered by smooth or scar-like skin, or may be devoid of skin on its summit and there covered by a reddish, mucosa-like tissue (area medullovasculosa). The portion un- covered by skin may be drawn in, like a scar. In rare cases there may be no ex- ternal tumor {spina bifida occulta), the site of the cleft being indicated by more marked growth of hair or by a depression. On opening the sac, whidh is composed of arachnoid (Fig. 353, e) , and pia (f, fi), while the dura {g) does not extend over the dorsal portion of the sac, it may be seen that the lower end of the spinal cord (&i) is drawn outward, and that the cavity of the sac is crossed by nerve-roots {i, i-i). Fig. 353. — Myelomeningocele sa- cralis in sagittal section, a little to the left of the median line. (After von Recklinghausen.) a, Skin; b, bi, spinal cord; c, area medullovasculosa; d, cranial; ds., caudal polar groove; e, arachnoid: f, pia, somewhat sepa- rated from the arachnoid; fi, portion of pia mater turned over; g, dura mater; h, recurrent roots of the fourth lumbar nerve; i, radix anterior; ii, radix posterior of the fifth lumbar nerve, running free through the arachnoid sac; k, sacral nerve-roots between the arachnoid and pia; /, filum terminale. 398 DISTURBANCES OF DEVELOPMENT. Occasional nerve-roots {h) may g-lso spring from the columns of the cord (&i) in its course through the sac. There is, therefore, accumulation of fluid in the meninges, hydro- meningocele, combined with prolapse of the spinal cord, myelocele. At the site of the protrusion the vertebral arches are defective ; this defect may reach as far as the hiatus sacralis. Smaller defects may involve only one or two vertebrae. Dorsal and cervical meningoceles are more rare than the lumbosacral. The defect in the vertebral arch is usually confined to one or two verte- brae. The spinal cord is involved in the meningocele, in that portions of it are drawn outward in the form of a band or cone. Hydromeningocele spinalis arises from hernial protrusion of spinal arachnoid due to localized collection of fluid in the subarachnoid space. It may occur at the upper end of the spinal column in a cleft of the cervical vertebrae, at the same time with hernia of the brain in the oc- cipital region. More frequently, however, it occurs in the sacral region, where protrusion takes place either through a defect in the vertebral arches and bodies or through the hiatus sacralis, or between vertebral arches, or through intervertebral foramina. In the majority of cases the dura takes no part in the formation of the sac, although views differ on this point, and by many writers a dural sac is described. Through pro- gressive accumulation of fluid the sac may attain large size. Small men- ingoceles may be concealed in the deep tissues. According to the direction of the hernial protrusion there may be distinguished a meningocele posterior and a meningocele anterior, the latter taking place through defect in the bodies of the vertebrae. Myelocystocele or hydromyelocele {syringomyelocele) takes origin in dilatation of the central canal of the spinal cord, as a result of which a portion of the cord with its connective-tissue envelopes becomes converted into a cystic tumor. The dura is usually wanting over that portion of the sac protruding from the vertebrae. The wall of these sacs is formed of the inner spinal meninges, but is lined on the interior by cylindrical epithelium, and has at some part of its inner surface an area medullovasculosa — usually on the ventral side, rarely on the dorsal. The roots, if they are still preserved, spring from the ventral, rarely from the dorsal outer wall of the sac. The cavity itself is crossed neither by bands nor by nerves. Myelocystoceles occur, in the majority of cases, in lateral clefts of the vertebral column. They show a tendency to combine with defects and asymmetries of the bodies of the vertehrce, and therefore with shortening of the trunk, which at times affects only the dorsal region, at other times also the lumbar region. Frequently there co-exists exstrophy of the blad- der and intestine. Myelocystoceles usually are covered only by skin, but are sometimes concealed deep in the soft parts. They may be combined with meningocele — ■ myelocystomeningocele. In cases of rachischisis there sometimes occurs division of the spinal cord into two parts (diastematomyelia) , most often in total rachischisis, in which indeed only rudiments of the spinal cord are indicated. In partial rachischisis such division is rare, the separated strands of spinal cord are better developed, and the fibrous and bony coverings may, at the beginning or end of the cleft, send septa between them. Cases have occurred in which each cord-half possessed an H-shaped area of gray matter. RACHISCHISIS. 399 In the earliest embryonic period the medullary groove is formed by the de- velopment on both sides of the median line of wall-like elevations of the ectoderm •which are designated medullary folds. Through the converging growth and union of the latter the medullary groove is closed and formed into the medullary canal. Thereupon the cell-masses (primitive vertebral plates) lying at the sides of the newly formed canal form an envelope about it, which gives rise to a membranous, non-articulated vertebral column. In this, at the beginning of the second month, there arise discrete cartilaginous areas from which, in the course of further de- velopment, the vertebral bodies and arches are formed, while between them the intervertebral discs and vertebral ligaments appear. The development of the car- tilaginous vertebras is not completed until the fourth month, and up to this time the dorsal covering of the medullary tube consists of the united portions of the membranous vertebral column. The cartilaginous constituents of the vertebrse are in the course of development replaced by bone. The origin of rachischisis is to be referred to agenesia and hypoplasia of the medullary folds, which should form the medullary groove of the vertebral arches. The agenesia of the spinal cord is also to be dated from the very earliest period. •'''■?^^^^^ -= ^^. ^^ f§p^^m, ^H| t^kS^^^M- ^^^sH ^^^i^^M^^S'ij m^ ^^^>^^^^ i (i '^r 9 1 / ^ n 1 i ' ^^^^^^^ Fig. 354. — Anencephalia et acrania. one-half. Reduced Fig. 355. — Cranioschisis with Exenceplialia. Whether it is a primary agenesia predetermined in the germ, or whether extrinsic influences, perhaps toxic substances (Hertwig), pressure from without, or the in- closure of foetal membranes, may have secondarily checked development or have destroyed parts already formed, it is difficult to determine; the symmetrical dis- tribution of the arrested development speaks in favor of the former view. In cases of spina bifida with hernial protrusion, local defects in the bony verte- bral column and defective development of the dura mater, which is usually wanting at the site of the protrusion, are to be regarded as the primary condition. The growth of the sac may be explained as due to congestive and inflammatory transudation, and the residue of inflammatory changes, such as thickenings and membranous ad- hesions, may often be demonstrated in the pia. Von Recklinghausen refers the origin of myelocystocele and myelocystomen- ingocde to deficient growth in the long axis of the vertebral column, character- ized anatomically by shortness of the column, absence of vertebrae or parts of vertebrae, separation of wedge-shaped bony pieces from the bodies of the verte- brse, and by unilateral defects in the arches. The neural canal, then, in the course of normal development, becomes too long for the vertebral canal, and in conse- quence becomes curled or kinked, and there is a tendency to partial protrusion of the medullary tube at the point of sharpest bending. Marcland believes that this hypothesis is not applicable to all cases, and Arnold is also of the opinion that the cai-sal relations between arrests of development in the muscle-plates and verte- bral primordium on the one hand, and those of the medullary canal on the other, are not constant, but that a variety of harmiful influences may give rise to one or more 400 DISTURBANCES OF DEVELOPMENT. of these anomalies. Lucksch emphasizes the effects of pressure as the cause of myeloschisis, but without excluding other causes. According to O. Hertwig, the ordinary spina bifida is an arrest of development depending on partially prevented closure of the blastopore (" Urmundspalte"). § 134. Faulty de- velopment of the cranium and asso- ciated disturbances of cerebral development lead to those malfor- mations known as cranioschisis, acranla, hemicrania, microcep- halus, anencephalus, exencephalus, micren- cephalus, and cephalo- cele. Acrania and hemi- crania or cranioschisis are the results of agen- esia or hypoplasia of bone; c, parietal bone; d, frontal bone. Reduced one-fifth, the bony and mem- branous portions of the cranial vault, which arise as primary disturbances of development or as the result of harmful extrinsic influences on the cerebral primordium. In acrania both the bony portion and the skin of the cranial vault (Figs. 354, 356) are wanting, the base of the skull being covered with mem- branous vascular tissue. If the defect in the cranial vault is associated with a similar defect in the vertebral arches, there is produced the condition known as craniora- FiG, 3s6. — Partial agenesia of the bones of the cranium in anencephalia._ a, Defect; b, squamous portion of the occipital Fig. 357. — Hydrencephalocele occipitalis. Fig. 358. — Encephalomeningocele nasofrontalis. chischisis (Fig. 351), in which the spinal column is usually shortened and bent, the head in consequence being drawn sharply backward and the face turned upward. Through bulging of the eyes with deficient de- velopment of the forehead, these malformations may resemble frogs {frog foetus). In hemicrania the flat bones of the cranial vault have undergone more or less extensive development (Fig. 356, b, c, d) and form a cranial cavity, which IS small, in that the flat bones of the vault are elevated but a short distance above the base of the skull. If the bones of the cranium DEFECTS OF CRANIUM. 401 have undergone imperfect development but unite with one another as under normal conditions, there is produced simple microcephalus, which may be present at birth or develop later, as the result of im- perfect development of the skull. Acrania and hemicrania are often associated with total anenceph- alus, the base of the skull being covered by vascular connective tissue with no trace of brain tissue or only rudiments (area cerebrovasculosa). In other cases the meninges contain, besides cystic cavities and gland- like remnants of the medullary plate, brain-substance, which usually pro- trudes through the defect in the cranial vault, giving rise to exenceph- alus (Fig. 355). The hernial masses are inclosed by a soft membrane corresponding to the inner meninges, or are covered by skin. If the cranium presents partial defects, portions of the contents may protrude in the form of a sac. Such a condition is known as hernia cerebri or cephalocele (Figs. 357, 358). The dura mater is wanting over the extracranial portion of the sac. The size of the protruding sac varies; it may be so small as to be found only after careful examination, or it may be so large as to approach the brain in volume. If the arachnoid and pia protrude as the result of collection of fluid in the subarachnoid space, the hernia is desig- nated meningocele. If at the same time there is a protrusion of brain-substance, it is known as meningoencephalocele. A hernia of brain-sub- stance and pia without collection of fluid is an encephalocele ; if the protruding brain-sub- stance contains a portion of a ventricle filled with fluid, it is designated hydrencephalocele. Cerebral hernias occur chiefly in the occipital region (hernia occipitalis) , close above the fora- men magnum (Fig. 357), and at the root of 359.— Synophthaimos or the_ nose (hernia syncipitalis) . In the latter cyclopia. region it may involve the frontal bone (hernia nasofrontalis) , (Fig. 358), the ethmoid (hernia naso-ethmoidalis) or the lachrymal bone (hernia naso-orbitalis). More rarely hernias occur on the sides (hernia lateralis) or at the base of the skull (hernia basalis). The latter may bulge toward the nasopharynx (hernia sphenopharyngea) , into the orbit (hernia spheno-orhitalis) , or into the fossa sphenomaxillaris (hernia sphenomaxillaris) . In central hernia the brain may be normal or malformed. As a result of marked stunting of development, particularly in the region of the fore- most of the three cerebral vesicles, the cerebrum may remain single, while at the same time deficient separation of the ocular vesicles takes place (cyclencephalia or cyclocephalia of St.-Hilaire) . In severe grades of this form of maldevelopment only one eye may be formed, lying in the middle of the forehead, or two united eyes may be found in one orbital cavity — (Fig. 359), cyclopia, (or synophthalmus,) and arrhinencephalus. The nose is also stunted (Fig. 359) and forms a cutaneous tag attached above the eye, and devoid of bony foundation (ethmocephalia). When the eyes are separate, yet abnormally close together, the nose may be normal, though small at the root (cebocephalia). In more severe grades of these malformations the ethmoid bone and nasal septum may be wanting, and the upper lip and palate cleft in the 26 402 DISTURBANCES OF DEVELOPMENT. median line, on one or both sides. In lighter grades the forehead is reduced in size and pointed. In the severe forms the cerebrupi consists of a sac, occupying more or less of the cranial cavity and filled with clear fluid; at those points where the sac does not touch the cranial wall the intervening space is filled by fluid distending the subarachnoid space (h). In the less marked forms only individual portions of the brain are unde- veloped, those parts chiefly affected being the olfactory lobes and nerves, the corpus callosum, a part of the convolutions, etc. The optic thalami are often blended. The chiasm and the optic tract may be absent or present. The corpora quadrigemina (k), pons, medulla oblongata, and cerebellum (/) are usually unaffected. The spinal cord and brain arise from the medullary canal. In that portionthat is to become the brain, the neural canal changes very early into three vesicles. The most anterior of these, the forebrain, throws out from its lateral portions the primary optic vesicles, while the middle portion grows _ forward and upward and divides into the telencephalon or forebrain, and the diencephalon or tweenbrain. From the former are developed the cerebral hemispheres, corpora striata, corpus callosum, and the fornix. From the tweenbrain are formed the optic thalami and the floor of the third ventricle. The second vesicle or midbrain forms the corpora quadrigemina, while the third vesicle divides into the isthmus, metencephalon, and myelencephalon, from which there are developed the pons, cerebellum, and medulla oblongata. The cerebral portion of the medullary canal becomes inclosed by the primitive vertebral plates of the head, which form the membranous primitive skull, the basal portions of which become cartilaginous in the second month of foetal life. In the third month the basal cartilage and the membranous vault_ begin to ossify. According to G. St.-Hilaire, Forster, and Panum, acrania and ^nencephalus are to be referred to abnormal accumulation of fluid in the cerebral vesicles, hydro' cephalus, occurring before the fourth month. Dareste and Perls oppose this view, and point out that in acrania the base of the skull is usually bulged inward and not pressed outward. They therefore seek the cause of acrania in pressure exerted on the cranium from -without (Perls), due to abnormal tightness of the cephalic cap of the amnion, which retards the development of the cranium. Lebedeff seeks the cause of acrania is abnormally sharp bending of the body of the embryo, which, he thinks, occurs when the cephalic end of the embryo grows abnormally in the longitudinal axis, or in case the cephalic covering lags behind in its development. By sharp bending the change of the medullary groove into the medullary canal is thought to be hindered, or the canal after its formation is destroyed. From this could be explained the later absence of the brain, as well as of the mem- branous and osseous cranial covering. The cystic formations in the membranes lying on the base of the skull are, according to Lebedeff, formed from the folds of the medullary plate, which sink into the mesoderm and are snared, off. Hertwig thinks it possible that chemical substances circulating in the blood or secreted from the wall of the uterus may destroy the primordium of the brain. According to K. and A. Petren, the spinal ganglia in anencephalus are always normally developed; on the other hand, the columns of Clarke, the lateral cere- bellar tracts, and the bundles of Cowers are either wanting or imperfectly de- veloped. Likewise the pyramidal tracts are wanting, while the anterior-horn gang- lion-cells and the anterior roots are developed. K. and A. Petren, therefore, regard the malformation as a system-defect in which neurones of the second order are not formed. (c) The Malformations of the Face and Neck. § 135. The development of the face not infrequently suffers disturb- ances leading to more or less marked malformations, which may appear alone or in association with malformations of the cranium. If the frontal process and the maxillary processes of the first branchial arch remain in a rudimentary state or are destroyed, there persists at the site of the face an DEFECTS OF FACE AND NECK. 403 open sinus giving rise to the conditions known as aprosopia (absence of the face) and schistoprosopia (cleft face), which may be associated with defective development of the nose and eyes. More frequently than these large defects are smaller clefts involving the hps, alveolar process of the upper jaw, the upper jaw itself, and the hard and soft palates (Fig. 360), which are designated cheilo-gnatho- palatoschisis or " wolf's jaw." This nialformation gives rise to a com- munication between the mouth and the nasal cavity (Fig. 360) . The hard palate is cleft in the part bordering on the vomer; the soft palate in the median line. In the alveolar process of the upper jaw the cleft runs be- tween the canine tooth and the outer incisor or between the outer and inner incisors. The malformation may be bilateral or unilateral. Not infrequently the cleft involves portions of the regions mentioned, Fig. 360. — Double clieilo-gnathopalatoschisis, (Wolf's jaw.) Fig. 361. — Agnathia and synotia. (After Guardan.) as the upper lip (harelip, labium leporinum), or the hard or soft palate. The lightest grades of this form of cleft-malformation are represented by a notch in the lips or by bifurcation of the uvula. Prosoposchisis or oblique facial cleft (Fig. 348) is the designation applied to a cleft running obliquely from the mouth to an orbit. It is usually associated with malformations of the brain. Three forms may be distinguished. The first is a cleft beginning in the upper lip as a harelip, passing into the nasal cavity, thence around the ala nasi toward the orbit, and even beyond the latter. The second form likewise begins in the region of a harelip, but extends outward from the nose toward the orbit. The third form extends from the corner of the mouth, outward through the cheek toward the canthus of the eye, and divides the superior maxillary process externally to the canine tooth. A transverse cleft of the cheek also occurs, passing from the corner of the mouth toward the temporal region. Median facial clefts (nasal cleft) run in the median line involving the nose, upper jaw, and also the lower jaw, and may extend as far as the sternum. The tongue may be cleft. The defect may extend even to the frontal bone and brain. 404 DISTURBANCES OF DEVELOPMENT. All of the above-mentioned clefts may be confined to small portions of the regions mentioned, and may attain varying depths. If the development of the inferior maxillary process of the first branchial arch is retarded, the inferior maxilla is imperfectly developed or granting, and there arise those malformations known as brachygnathia or agnathia (Fig. 361). The lower portion of the face appears as if cut away; the ears are sometimes brought so close as to touch (synotia). Uusually the superior maxillary processes are imperfectly developed ; not infrequently the ear is malformed. Abnormal largeness of the mouth (macrostomia) , abnormal smallness (microstomia) closure (atresia oris), and duplication of the mouth (dis- tomia) are all rare. When the embryonic external branchial clefts or internal branchial pockets fail to close, there persist fistulse opening externally or internally, or closed cysts. The former condition is known as fistula colli congenita. The mouths of the external fistulse are usually found at the side of the neck, more rarely nearer to or in the median line; those of the internal fistulas open into the pharynx, trachea or larynx. Often the remains of the branchial pockets form diverticula of the last-named organs. The fistulse are covered with mucous epithelium, sometimes ciliated, arising from the visceral branchial pockets, usually from the second. In rare cases there is a complete branchial fistula with both external and internal openings. Branchial cysts are sometimes lined with ciliated epithelium and con- tain fluid ; they are called hydrocele colli congenita. At other times they possess an epidermoidal covering and inclose epidermoidal cell-masses. Cysts of the neck lying in the median line and reaching to the hyoid bone may develop from remains of the ductus thyreoglossus. The face and neck are developed in part from a single and in part from paired primordia. The latter are represented in the branchiaj or visceral arches growing from the lateral portions of the base of the skull ventrally in the primitive throat-wall. The single primordium, designated the frontal process, is a prolongation downward of the base and vault of the cranium, and is, in fact, nothing more than the anterior end of the skull. Between the individual branchial arches there are at a certain period cleft-like depressions known as the branchial pockets. The frontal process and the first branchial arch form the boundaries of the great primitive mouth-opening, which has a diamond shape. In the course of development the first branchial arch sends out two processes, the shorter of which applies itself to the under surface of the anterior portion of the head and forms the upper jaw, while from the longer one the lower jaw is developed. The frontal process, which forms the anterior boundary, gives rise to a broad prolongation of the forehead, and then pushes on two processes which are known as the lateral nasal processes. By further differentiation of the central portion of the frontal process proper, the septum narium is formed, which by means of two spurs, the inner nasal processes, produces the borders of the external nasal opening and the nasal furrow. The lateral nasal processes are the lateral portions of the skull, and later develop within themselves the ethmoid labyrinth, the cartilaginous roof, and the sides of the anterior portion of the nares. At a certain stage they form with the superior maxillary process a furrow running from the nasal furrow to the eye, the lachrymal fissure. In the beginning the mouth is a large sinus, but is soon separated inlto a lower and larger digestive and an upper and smaller respiratory portion. This separation is brought about by the development, from the superior maxillary pro- cesses of the first branchial arch, of the palatal plates, which from the eighth week on blend into each other and at the same time unite with the lower border of the nasal septum. The union of the anterior portions of the palatal plates takes place earlier than that of the posterior portions. DEFECTS OF THORAX AND ABDOMEN. 405 Through union of the contiguous portions of the frontal and nasal processes with the superior maxillary processes the cheek is formed and a continuous superior maxillary border, from which are developed later the lip and the alveolar process of the upper jaw and intermaxillary bones, while the external portion of the nose develops from the frontal process. The intermaxillary bones are de- veloped as independent bones, but unite very early with each other and with the upper jaw. (d) Faulty Closure of the Abdominal and Thor^ic Cavities, and the Accompanying Malformations. § 136. Arrests of development of the ventral body- wall may take place at different points and exhibit different grades of severity. They occur most frequently in the region of the umfciHcus, where the closure of the abdominal cavity takes place latest. In the event of imperfect development of the ab- dominal wall at this point, so that this area is closed only by peritoneum and the sheath of the umbilical cord, and if these are pushed for- ward by the abdominal organs (Fig. 362), there is produced the condition known as om- phalocele, or umbilical hernia. The umbilical cord is attached to the sum- mit or at one side of the hernial sac, and is more or less shortened. If the anterior abdominal walls wholly or in part fail to unite, there arise those conditions which are desig- nated fissura abdominalis, or gastroschisis completa and thoracogastroschisis. These are characterized by the undeveloped abdominal coverings not having been separated from the amnion, but passing into it. The greater part of the ab- dominal organs lies in a sac formed by the amnion and peritoneum (eventration). The peritoneum, however, may be wanting, likewise the umbilical cord, and the umhilical vessels may pursue their course to the placenta independently. A cleft confined to the thorax is called thoracoschisis. Should the heart, covered only with pericardium or free, protrude, the condition is designated ectopia cordis. When the failure to close is confined to the region of the sternum, the condition is designated fissura sterni. This defect may involve the whole or a part of the sternum, at times affecting the bones, at other times only the skin. , The protrusion of the urinary bladder through a cleft in the abdominal wall is known as ectopia vesicae urinariae. Fig. 362. — Hernia funiculi umbilicalis. Reduced to one-third. 406 DISTURBANCES OF DEVELOPMENT. Clefts of the abdominal wall are not infrequently associated with I clefts of the parts lying behind the wall, not only large clefts (total), but smaller ones (partial). When a cleft of the lower portion of the ab- j dominal wall is associated with a cleft of the urinary bladder, so that the 1 posterior wall of the latter protrudes through the abdominal fissure, the condition is known as fissura, or exstrophia, or inversio vesicae urinarice. j Occasionally the pelvic girdle and the urethra are cleft, the latter being ' represented by a groove open anteriorly. The exstrophy is then said to be complicated by fissura genitalis and epispadias. When an abdominal fissure or an abdominal and vesical fissure is combined with a fissure of the intestines, there is produced fissura ab- dominalis intestinalis or vesicointestinalis. The intestinal fissure is sit- uated in the caecum or beginning of the colon, and the mucous membrane of the cleft intestine protrudes through the opening in the same manner as the posterior wall of the bladder; the condition is called exstrophia or inversio intestini. If the omphalomesenteric duct does not undergo normal involution, there remains at the lower end of the small intestine an appendix of intes- tine called Meckel's diverticulum, which arises perpendicularly from the outer margin of the intestine. It has the appearance of a glove-finger, and either swings free or is attached to the umbilical ring, sometimes being di- lated at its end. In case of adhesion to the umbilical ring the intestinal mucosa may appear at the navel in the form of a tumor (ectopia intestini, adenoma umhilicale) . In rare cases a cyst lined with mucous membrane may be formed in the abdominal wall (omphalomesenteric cyst). Congenital fistulse of the urachus, that is, fistulas lying in the umbilicus and connecting with the bladder by a tract, depend on incomplete oblitera- tion of the urachus or of the stalk of the allantois. They may be associated with an open or a closed urethra. The development of the body-form from the flat embryonic primordium begins by snaring-off of the individual germ-layers from the outer embryonal area, and their folding to form two tubes, the body-wall and the alimentary canal. The infolding of these layers takes place at the cephalic and caudal ends, as well as at the lateral portions of the embryonal primordium, and as the summits of the folds gradually grow together from all directions, those which form the body-wall produce a tube whose cavity finally communicates only at the parietal umbilicus, by means of a peduncle-like prolongation, with the cavity of the extra- embryonic portion of the blastoderm known at this time as the vitelline membrane. While the lateral and ventral walls of the embryo are being formed, in the body the intestinal furrow also closes to form a tube, which is in communication at only one point lying within the parietal umbilicus, known as the visceral umbilicus, with the cavity of the umbilical vesicle, by means of a channel known as the omphalo- mesenteric duct. Umbilical hernia and clefts of the upper portion of the abdominal wall are frequently combined with craniorachischisis, while exstrophy of the bladder and intestine is often associated with myelocystocele. According to von Recklinghausen, the two malformations are to be regarded as coordinated with each other. Further, large abdominal clefts are often associated with lordotic and scoliotic curvatures of the spinal column. {e) Malformations of the External Genitalia and Anus, due to Arrested Development. § 137. Malformations of the external genitals may be associated with malformations of the abdominal wall, bladder, and the internal genital organs, or may occur independently of these. Complete absence of the external genitalia occurs most frequently in connection with other mal- DEFECTS OF GENITALS. 407 formations of this region, particularly in the case of sirenomelia, (Fig. 363). The internal genitals usually are also malformed. A stunted condition of the penis is not rare, the organ in consequence coming to resemble more, or less the clitoris. This condition is usually associated with hypospadias — that is, the urethra opens on the under side, either beneath the glans, the body or the root of the penis, or even behind the scrotum (hypospadias perineoscrotalis). These malformations may exist in penises otlierwise normally developed, and depend on partial failure of the sexual furrovi? to close. Epispadias is that condition in which the urethral opening is found on the dorsum of the penis. It is more rare than hypospadias, and is de- pendent on defective or delayed closure of the pelvis, so that the cloaca, before the closure, becomes divided into an in- testinal (anal) and a genital opening. Under certain conditions the penis re- mains cleft throughout its length; at the saime time a fissure of the bladder and ab- domen may be present. Hypertrophy of the prepuce is not rare. If the preputial opening is nar- rowed so that the prepuce cannot be drawn back over the glans, the condition is designated hypertrophic phimosis. Total absence of the prepuce is rare; abnormal shortness is more frequent. Defective development of the scro- tum is usually associated with retention of the testicles in the abdominal cavity or in the inguinal canal, and leads to appear- ances whereby the external genital organs of the male resemble those of the female, especially when the penis is stunted. In the female the clitoris as well as the labia majora and minora may show stunted development. Epispadias and hypospadias also occur in the female sex, the former coincidently with a fissure of the abdominal and bladder walls. In hypospadias a portion of the posterior wall of the urethra is lacking, and the urethral opening may be found within the vagina. Absence of the urethra occurs in both sexes (Fig. 363). In girls the bladder may open directly into the vagina. Closure (atresia) of the urethra likewise occurs in both sexes, and results either from a partial defect of the same or from obliteration of the orifice. Accumulation of urine in the bladder may lead to marked dilata- tion of the viscus (Fig. 363). Abnormal narrowness of the urethra may exist in a portion of its course or throughout its length. Further, its lumen may be narrowed as the result of hypertrophic development of the colliculus seminalis. Fig. 363. — Complete absence of the urethra and external genitals, with ex- treme distention of the body due to an enormous dilatation of the bladder. Compression and stunting of the lower extremities. (In the posterior wall of the ^ bladder rudiments of a female genital apparatus in the form of por- tions of the tubes and ovaries were found.) 408 DISTURBANCES OF DEVELOPMENT. In rare cases multiple orifices of the urethra have been observed. Further, in men there may be found in the glans penis a blind tube lying beside the urethra. Atresia ani simplex is closure of the anus, the intestine being at the same time well developed. It may arise from failure of the ectoderm to fold in at the anal site, or a cloaca already existing and opening outward may again become closed through adhesions. If the rectum does not end immediately above the anal membrane but higher up, there exists in addi- tion to the atresia ani atresia recti, a malformation which may occur even when the anus is well developed. When, with absence of the anus, there is also arrested development of the vaginal wall, which grows downward, between the sinus urogenitalis Fig. 364. — Amelus. Fig. 365. — Micromelus with cretin-like fades. and intestine, to unite with the perineum, there remains a cloaca in which the sinus urogenitalis and the end of the bowel unite. In other cases there are found fistulous communications between the rectum and the blad- der or urethra (in boys), or between the rectum and the vagina or uterus (atresia ani vesicalis, urethralis, vaginalis, uterina). In rare cases the intestine, in anal atresia, may open by external fistulae in the perineum, scrotum, or sacrum. External fistulae below the anus may occur as remains of the post-anal gut. (/) Malformations of the Extremities due to Arrested Development. § 13.8. DefectivjE development of the extremities is not rare, and is to be referred to primary defect of the primordium of an extremity, to disturbance in the later development of the limbs or the bones, and to con- strictions caused by strands of foetal membranes or by loops of the um- bilical cord. Defective development of the extremities may also follow malformations of the central nervous system. The following forms mav be distinguished: ^ MALFORMATIONS OF EXTREMITIES. 40^ (1) Amelits. The extremities are completely absent; in their place are found warty or stump-like rudiments. The trunk is usually well formed (Fig. 364). (2) Peromelus. Stunting of all the extremities. (3) Phocomelus. The hands and feet are alone developed and are attached directly to the shoulder and pelvis respectively. (4) Micromelus. The extremities are developed, but are abnormally small (Fig. 365). (5) Abrachius and Apus. Absence of upper extremities with well- developed lower ones, or vice versa. Fig. 366. — Sympus apus. Fig. 367. — Sympus dipus. (6) Perobrachius and Peropus. Stunting of the upper or lower ex- tremities. (7) Monobrachius or Mono pus. Absence of one of the upper or lower extremities. (8) Sympus, Sirenomelia, Symmelia. The lower extremities are fused (Figs. 366, Z67), and rotated on theit- axes so that their external aspects are in contact. The pelvis is usually defective, as are also the external genitalia, the bladder, urethra, and anus. At the end of the blended ex- tremities feet may be entirely wanting {sympus apus) and only a few toes may be present; in other cases one {sympus monopus) or both feet may be present (sympus dipus). (9) Absence of individual bones may occur in any part of the ex- tremities. 410 DISTURBANCES OF DEVELOPMENT. (10) Perodactylism — stunting of the fingers of toes — appears in a great variety of forms, but in general is seen as defective development (brachyphalangism) or absence of individual phalanges, or as mem- branous or bony connections between the fingers (^syndactylism). If only the outer fingers or toes are developed while the middle ones are lacking, there arise those formations designated cleft-hand and cleft- foot. In more extensive malformations of the fingers there occur defects in the region of the tarsal and metatarsal bones or carpal and metacarpal bones respectively. These malformations are designated respectively peropus and perochirus. Absence of the hand or foot is known as achirus or apus. § 139. Among the abnormal positions of the extremities congenital luxations (slipping of the articular heads from their sockets) are of special interest. They are most common at the hip-joint, rare at the elbow-, shoulder- and knee-joints. Congenital luxations are due to local arrests of development, but may be the result of mechanical influences. In the hip-joint the disturbance of development results in a small and imperfect acetabular socket, and the head of the femur is more or less imperfectly developed. The small acetabulum lies in the normal position, but the head of the femur is displaced, most often backward (luxatio iliaca). At birth the ligamentum teres is intact, and the capsule of the joint covers both the head of the femur and the acetabulum. After much use of the leg the ligamentum teres becomes stretched and may tear, the capsule becomes dilated and bag.-like, and, at the point where it is pressed against the bone, may become perforated. A new joint may then be formed through proliferation of the surrounding tissues. Abnormal positions of the feet and hands are to be referred partly to disturbances of development and partly to mechanical influences exerted on the extremities during their growth. The most important is congenital club-foot (pes equinovarus). The foot is left in the fcetal position, with accoriipanying abnormal development of the bones and their articular sur- faces. The inner border of the foot is sharply elevated, and the foot at the same time is brought into plantar flexion. The collum tali is elongated in an anterior and inferior direction. If children thus afflicted learn to walk, they tread on the outer side of the foot, which becomes flattened, while the foot becomes still more sharply turned inward. Congenital club-foot, though usually to be regarded as a primary dis- turbance of development, may also be caused by pressure due to a rela- tively small uterus. Under these conditions those pathological positions of tlae foot known as pes calcaneus and pes valgus also develop, and are characterized by strong dorsal flexion and by outward twisting of the foot. Frequently the evidences of pressure to which the feet have been subjected are seen in atrophy of the skin and portions of the bones. The position of the hand known as club-hand or talipomanus is caused by rudimentary development of the radius, and is usually asso- ciated with other malformations. 2. Abnormal Position of the Internal Organs and of the Extremities. § 140. Of the abnormal positions of the internal organs, the most im- portant is known as situs inversus viscerum — i.e., lateral transposition of_ the internal organs, so that the thoracic and abdominal organs form a, mirror-image of the normal position. This condition has been observed EXCESSIVE GROWTH; SUPERNUMERARY PARTS. 411 both in double monsters and in single individuals. It is entirely compatible with life, and may be restricted to the heart alone, or to the abdominal organs, or to a part of the latter (situs irregularis). Abnormal positions occur especially often in the abdominal organs. For example, the kidney is not infrequently found in an abnormal position (dystopia renis), usually low, so that it approaches the sacral promontory or lies in front of it. The testis is not rarely retained in the abdominal cavity (ectopia in- terna, or abdominalis testis, or cryptorchismus) , or in the inguinal canal (ectopia inguinalis), or at the external ring (ectopia pubica), or in the fold between the thigh and scrotum (ectopia cruroscrotalis) , or in the perineal region (ectopia perinealis) , .or in the fold of the groin (ectopia cruralis). Abnormal positions of the intestines, particularly of the colon, are not rare. 3. Malformations due to Excessive Growth or Multiplications OF Organs or Body-parts. § 141. The malformation known as giantism occurs, as the result of excessive growth of the entire body, during intra-uterine life or later. During extra-uterine life such growth may occur that the size of the individual far exceeds the maximum normal limits. Partial giant growth may take place during intra-uterine life or after birth. The head and portions of the extremi- ties are usually affected. Unilateral giant growth is restricted to half O'f the face or to one extremity, although in rare cases the hypertrophy may involve all the parts of one side : face, trunk, and extremities. Should other tissues become in- creased, as in the extremities, trunk, or face, so that malformations resembling the skin of the pachyderms are pro- ing^o" tie'l^Ind^'firJirLa^ce'eauxO duced, the growth is designated elephan- tiasis (see § 76, Figs. 109, 110). Circumscribed hypertrophies of bones occur in various portions of the skeleton, and are sometimes multiple. The bones of the skull as well as those of the face may be affected. There are cases in which hypertrophy may be so extensive that one or both of these regions show marked dis- figuration, the condition being known as leontiasis ossium (Fig. 115. On the trunk and extremities local growths of bone may lead to enlargement of single bones or to atypical excrescences known as exostoses. § 142. The occurrence of supernumerary organs, or of multiplica- tion of parts of the skeleton, and of the muscular system, is relatively frequent. 1. Duplication of the extremities. Duplication of an entire ex- tremity without duplication of the pelvic or shoulder bones has not been observed in man. Duplication of the hands and feet is rare (Fig. 368). The number of fingers may reach nine or ten. Much more frequent is multiplication of the fingers or toes (polydactylism) on a single hand (or foot respectively), in which condition the super- 412 DISTURBANCES OF DEVELOPMENT. numerary fingers (or toes) are attached at the ulnar or radial side (or tibial and fibular sides, respectively), or intercalated between the others. Often the fingers are duplicated only in part — that is, by cleavage of the first or the first and second terminal joints. Those at- tached at the margin of the hand may be well developed or rudimentary. Occasionally they appear as pedunculated fibrous growths. In the fully developed supernumerary fingers or toes the phalanges may articulate with the metacarpal or metatarsal bones of a neighboring finger or toe, or with their own (supernumerary) carpal or tarsal bones. Polydactyl- ism in certain cases is inherited and is therefore dependent on intrinsic causes. 2. Supernumerary nipples and breasts (hyperthelia, hypermastia) are not uncommon in both sexes, and are probably to be regarded as a reversion to polymastic racial ancestors. The supernumerary organs are usually situated on the thorax, along two lines converging from the axil- lary to the inguinal regions, but in rare cases may be found elsewhere — in the axilla, on the shoulder, on the abdomen, back or thigh. They are usually small, but in the event of pregnancy may take on functional activity. The number of nipples may reach as high as ten. 3. The formation in men of breasts resembling those of ywomen {gyncBcomastia) is rarely seen in well-developed men with normal sexual apparatus (see Hermaphrodism, § 143), but it not infrequently happens that the male breast undergoes moderate enlargement at the time of puberty. 4. Duplication of the penis is of rare occurrence, and may be asso- ciated with the formation of two urethrse having independent openings into the bladder, and with two scrota, the two penises being typically de- veloped. 5. Supernumerary bones and muscles are of frequent occurrence. Supernumerary vertehrcz may be found in any part of the spinal column ; and at its lower end may cause lengthening, resulting in the formation of a tail. Three forms of tails may be distinguished : true tails containing bones; false or imperfect tails which represent an elongation of the verte- bral column, but contain neither cartilage nor bones (so-called pig's tail) ; and tail-like appendages of skin which consist of different forms of tissue, and are to be classed with the teratomata. True tails are rare ; they are more often the result of separation or elongation of the vertebrae than of an increase in their number. Reduplication of the phalanges of one finger is rare. Supernumerary ribs in the neck or lumbar region, as well as forking of the ribs, are not rare. Supernumerary teeth occur. 6. Duplication or cleavage of the primordium of the thoracic and abdominal organs occurs most frequently in the case of the spleen, pan- creas, adrenals, ureters, pelvis of the kidneys, and lungs, more rarely in that of the ovary, liver, kidney, testicle, and bladder. 4. True and False Hermaphrodism. § 143. The fact that the sexual organs of both sexes develop from originally similar primordia makes it a priori probable that malforma- tions might result through unequal development of the right and left sides. HERMAPHRODISMUS. 413 or through simultaneous development of organs peculiar to both sexes, or through lack of harmonious development of the external and internal genitals. Those malformations which are characterized by the fact that, the sexual apparatus of a single individual contains parts belonging to both the male and female, are grouped under the designation hermaphrodis- mus. When both sexual glands (testis and ovary) are present the con- dition is called hermaphrodismus varus (hermaphrodismus glandularis). If the mixing of sexual characteristics consists of a combination of male and female genital passages with the external genitalia of the opposite sex, the condition is known as pseudohermaphrodismus. The true sex is determined by the nature of the sexual glands. The build of hermaphrodites frequently shows a curious mixture of male and female characteristics. For example, the breasts, neck, and shoulders may correspond to the female type, while the beard, face, larynx, and voice correspond to the male type. In false hermaphrodites the body characteristics do not always correspond to the true nature of the sexual glands ; a male may resemble a female and vice versa. The following types of hermaphrodism may be distinguished : 1. Hermaphrodismus verus or androgynes. — 1. Hermaphrodismus verus bi- lateralis, or double-sided hermaphrodism, is characterized by the presence on both sides of both ovary and testis, or the presence on both sides of an organ containing both ovarian and testicular tissue. Heppner asserts that in a nine-months-old child, having hermaphroditic external genitals, with vagina, uterus, and tubes, both ovary and testis were found in the broad ligament; epididymis and vas deferens were wanting. 2. Hermaphrodismus v&us unilateralis, or one-sided hermaphrodism, is that condition in which on one side there exists' but one sexual gland, while on the other both testis and ovary are present. Salen has reported a case of a woman qf forty- three years of age, who had menstruated since her seventeenth year, in whom there was found on the right side (castration on account of uterine myoma) a herma- phroditic gland, the nature of which was confirmed by microscopic examination. The ovarian portion of the gland was typically developed; the epithelium of the seminiferous tubules of the testicular portion consisted of follicular cells and cells of Sertoli, but lacked spermatogonia and seminal cells. Blacker and Lawrence have also described a case of hermaphroditic gland occurring in a child still-born at eight and a half months. In the hernial sac of an individual twenty years old Garre demonstrated the presence of a tube and both sexual glands with parovarium and epididymis (the microscopic examination was made by Sirnon). 3. Hermaphrodismus verus lateralis is that condition in which there is an ovary on one side and a testis on the other. It has been many times observed in man, though in the majority of cases no careful microscopic examination was made, and when carried out, ovarian tissue could not with certainty be demonstrated. Obolonsky reported a case (a twelve-year-old girl) in which histological examina- tion showed on the right side a -testicle, and on the left side an ovary, but it is to be noted that ova were not seen in the latter. The right broad ligament contained a testis, an epididymis, a vas deferens, a rudimentary tube, a round ligament; the left broad ligament contained an ovary, with an ovarian ligament, and a well-devel- oped tube. Moveover, a uterus, vagina, and also a prostate were present. Accord- ing to reported observations, the corresponding sexual passages may be present or in part wanting. The external genitals are malformed, and combine structures belonging to both sexes. II. Hermaphrodismus spurius, or pseudohermaphrodismus, is characterized by bisexual development of the sexual passages and external sexual organs in association with the unisexual development of the essential sexual gland. The most pronounced cases occur in males, who, in addition to their proper sexual organs, possess a more or less well-developed vagina, uterus, and t'^bes. It is much more rare to find in females development of a portion of the Wolffian duct. 414 DISTURBANCES OF DEVELOPMENT. In male false hermaphrodites the external genitals are frequently malformed and approach the female type, while in female false hermaphrodites the external genitals resemble those of the male. The resemblance of the male external genitals to those of the female is brought abo.ut by stunting of the p'enis and total or partial failure of the sexual furrow in the penis to close (hypospadias), so that the two halves of the scrotum are separated, leaving a depression beneath the root of the penis, which represents the remains of the sinus urogenitalis. The scrotal halves come, therefore, to resemble the labia majora, particularly in non-descent of the testicles. The external genitals of the female approach in appearance those of the male through development of the clitoris into a sort of penis, while the vaginal opening is narrowed or closed through union of the labia. The vagina and urethra have a common opening, or open separately beneath the penis-like clitoris. The atypical development of the external genitals may or may not be associated with malformations of the sexual passages, and is, therefore, not dependent on malformations in other portions of the sexual apparatus. 1. Psetidohermaphrodismus mascutinus occurs in three varieties: , First, pseudohermaphrodismus masculinus internus, in v/hich the external genitals are of the male type, and the prostate is developed, but is usually pierced at the coUiculus seminalis by a 'canal opening into the urethra, the former being continued above into a rudimentary or more or less well-developed vagina, often into a more or less well-formed uterus, and even tubes. The male organs may be well developed or malformed. Second, pseudohermaphrodismus masculinus computus, or externus et internus, in which the vagina, uterus, and tubes are present in rudimentary or more or less complete development, while the external genitals resemble the female type. The penis presents the condition of hypospadias and resembles the clitoris ; beneath it lies a furrow at whose posterior end there is usually an orifice leading into a short vestibule which divides at once into a urethra and a vagina. Sometimes the vagina and vestibule are separate. In rare cases the external genitals appear normal, but the penis contains a double canal, the upper one representing the urethra, the other the sexual passage. In the case of more marked development of the ducts of Miiller the vasa deferentia are frequently defective, and the seminal vesicles are sometimes wanting. Third, pseudohermaphrodismus masculinus externus, in which only the external genitals depart from the male type, and resemble the female. Since in these cases the bodjly habitus often simulates that of the female, the sex of the individual may easily be mistaken. 2. Pseudohermaphrodismus femininus also occurs in three similar varieties, but is much more rare. In pseudohermaphrodismus femininus interims rudiments of the Wolffian ducts, lying in the broad ligament or in the uterovaginal wall, and sometimes extending to the clitoris, are found in association with well-developed external genitals. Pseudohermaphrodismus femininus externus is characterized by exiternal gen- italia resembling those of the male. Pseudohermaphrodismus femininus externus et internus, in which the external genitals resemble those of the male and there is persistence of parts of the Wolffian ducts, is rare. Of the internal male genitalia, there was found in one case a pros- tate, and in another case a prostate pierced by the vagina, an ejaculatory duct, and a sac resembling a seminal vesicle, which opened into the vagina. The internal sexual organs develop from the same undifferentiated primor- dium in both males and females. These consist of a sexual gland lying on the medial anterior side of the Wolffian body, and a sexual passage known as the duct of Miiller. The latter develops beside the Wolffian duct, and, like it, empties into the lower end of the bladder or into the sinus urogenitalis. In the male the duct of Miiller disappears, only traces in the form of the uterus masculinus or vesicula prostatica remaining; the primitive sexual gland unites with a small part of the Wolffian body, which becomes the head of the epididymis, another small portion forming the vasa aberrantia testis (organ of Giraldes), the remainder disappears, while the Wolffian duct becomes the vas deferens and vesicula seminalis. In the female the Wolffian body and its duct disappear, leaving only a trace in the form of gland-tubules known as the parovarium, but remains of the duct are not infrequently found in the uterine wall. From the ducts of Miiller, which in part coalesce at their lower ends, develop the vagina, uterus, and tubes. The extreme upper end of the duct of Miiller not infrequently persists in the form of MONSTERS. 415 a little pedicled sac attached to the abdominal end of the tube, the hydatid of Morgagni. The primordia of the sexual glands appear in the fifth week. In mammalia (probably also in man) they develop through localized thickening of the peritoneal epithelium, which becomes the germinal epithelium, while at the same time the meso- derm proliferates. Whether the seminal tubules arise from peritoneal epithelium {Bornhaupt Egli), or whether they are derived from an ingrowth of the Wolffian •body into the testis (IValdeyer), is an undecided question {Kolliker). The ova arise from germinal epithelium. The environing cells of the Graafian follicle are regarded by IValdeyer as derived from the germinal epithelium; while Kolliker believes that they arise from the Wolffian body. The significance of the pedunculated and non-pedunctilated hydatids, found in varying numbers near the globus major of the epididymis, is not yet determined (Kolliker). The non-pedunculated cyst known as the hydatid of Morgagni is regarded by Waldeyer as a remnant of the duct of MUller. According to Roth, it may stand in close relation to the Wolffian body, inasmuch as there is occasionally found a vas aberrans of the epididymis communicating with it. In the development of the vagina and uterus the ducts of Midler and the Wolffian ducts unite at their lower portion to form the genital cord. At the end of the second month the ducts of MUller blend to form a single canal, which then develops into the vagina and uterus. This union takes place near the middle of the genital cord. The Wolffian ducts play no role, though remains of these are found at birth in the broad ligament and in the wall of the uterus. According to observations of Riedel, remains of the Wolffin duct are found in about a third of adult females, in the form of a tube lined by cylindrical epithelium surrounded by muscle, or as a muscle-bundle without epithelium, lying anteriorly and to the side of the uterus and vagina. The external genitals begin to develop, even before the cloaca has separated into the intestinal and genito-urinary orifices, by the formation, in the sixth week, of a median genital tubercle in front of the cloaca, and further, of two lateral folds, the genital folds. Toward the end of the second month the tubercle becomes more prominent, and shows on its lower surface a furrow, the genital furrow. In the third month the cloaca becomes divided to form the anal and genito-urinary open- ings. In the male embryo the genital tubercle becomes the penis, the glans being recognizable as early as the third month. In the fourth month the furrow closes to form a tube; at the same time the two genital folds unite to form the scrotum. The prepuce is formed in the fourth month. The prostate arises in the third month as a thickening of the tissues at the junction of the urethra and the genital cord. The glands of the prostate develop in the fourth month from the epithelium of the canal and grow into the surrounding connective tissue. In the female embryo the closure of the genital furrow and the genital folds does not take place, so that the sinus urogenitalis remains short. The genital eminence becomes the clitoris, the folds become the labia majora, and the edges of the genital furrow the labia minora. 5. Double Monsters. (o) Classification of Double Monsters. § 144. Twin-formations lying in a single chorion may be divided into two large groups : twins completely separated from, one another, and twins united by some portion of their bodies. Of the twins completely separated fron;i one another there may be distinguished two types ; one in which both twins are fully developed, and one in which one twin is stunted. Twins joined by portions of their bodies may likewise be divided into two groups : twins showing uniform development and twins showing unequal development. To the latter belongs a group of stunted parasitic forms that may be classed as teratomata. 416 DISTURBANCES OF DEVELOPMENT. According to the situation of the duplicated portions of the body, there may be distinguished: 1. Monstra duplicia katadidyma or duplicitas anterior. 2. Monstra duplicia anadidyma or duplicitas posterior. ' 3. Monstra duplicia anakatadidyma or duplicitas parallela. These may be divided into three classes : 1. Twins united chiefly by the epigastrium and thorax. 2. Twins united chiefly by the heads. 3. Twins united chiefly by the pelves. Ahlfeld divides the double monsters into two groups, those with com- plete and those with partial doubling of the axial structures. In rare instances triple monsters occur. (b) The Chief Forms of Double Monsters. § 145. Twins separated from each other and lying in a single chorion are designated homologous twins. They are always of the same sex, have usually a common placenta, and resemble each other closely. If one of the twins should die after its body has been developed, it may be pressed flat by the growth of its fellow, giving rise to the condition known at foetus papyraceus. Fig. 370. Fig. 369. — Pygopagus. (After Marchand.) A, B, The two twins; a, b, separated umbilical cords; c, blended umbilical cords; d, common placenta. There is a single coccyx and sacrum (from the second vertebra downward), and the lower end of the medullary canal is single. The two intestinal canals terminate in one anal opening. Vestibule of vagina single, the remain- ing portions of the sexual organs double. Fig. 370. — Ischiopagus. (After Levy.) MONSTERS. 417 When twins possess a common placenta in which the blood vessels have abundant anastomoses, the heart of the stronger foetus may control the circulation and thereby cause changes in the direction of the blood- stream in the weaker twin. As a result of this the latter suffers disturb- ances of development, and becomes changed into an acardius, a monster without a heart, developing no heart at all or a rudimentary one. In the majority of such cases the head also fails to develop (acardius acephalus) or remains rudimentary {acardius par acephalus), and likewise there is usually no development, or only a rudimentary one, of the upper extremi- ties, thorax walls, lungs, and liver, while the abdomen, pelvis, and lower Fig. 371. — Dicephalus dibrachius dipus. Fig. 372. — Diprosopus distomiis tetrophthalmus dio- ttis dibrachius. extremities are more or less perfectly formed. According to the develop- ment of the extremities the following varieties may be distinguished: acardius paracephalus {or acephalus) sympus, monopus, dipus, mono- brachius, dibrachius. In rarer cases there is no recognizable development of any part of the body, and there is formed an acardius amorphus, consisting of a shapeless mass covered with skin, usually without any indication of extremities and possessing only rudiments of organs. Of rare occurrence is the formation known as acardius pseudoacor- yyius — that is, a monster in which the head only is developed, while the other parts of the body are represented by rudiments. § 146. Twins equally developed and united occur in the following types : 27 418 DISTURBANCES OF DEVELOPMENT. 1. Duplicitas anterior {monstra duplicia katadidyma). Anterior du- plication with union of posterior portions of the body. Pygopagus (Fig. 369). Union of twins in the region of the_ coccyx or of the sacrum. According as the union is more or less extensive, the sacrum, coccyx, lower end of the medullary canal, anus, lower end of the bowel, and the sexual apparatus are doubled or single. Ischiopagus (Fig. 370). Union of twins in the pelvis, which forms a wide ring, the two sacra being placed opposite each other. The anus, lower end of the bowel, and the sexual organs may be single or double, and the number of the lower extremities two to four. Dicephalus (Fig. 371) and diprosopus (Fig. 372). The duplication is limited to the upper part of the trunk and head, or to the neck and head, or the head alone, or, finally, to por- tions of the head. As the external blend- FlG. 373. FiG. 373. — Craniopagus parietalis. Fig. 374. Fig. 374. — Cephalothoracopagus or syncephalus,_ with janus head. Both anterior and posterior faces are rfialformed, and possess but one eye, while the nose is represented by a proboscis-like organ situated above the eye. ing increases in extent, there occurs blending of the internal organs, the intestine, liver, lungs, heart, spinal cord, brain, etc. According to the number of the lower and upper extremities there may be distin- MONSTERS. 419 guished dicephalus tetrapus, dipus, tetrabrachius, tribrachius, dibrachius (Fig. 371). When the heads have blended there may be distinguished diprosopus tetrophthalmus, triophthalmus, diophthalmus, tetrotus, triotus, diotus, distomus, monostomus, tribrachius and dibrachius (Fig. 372). The mildest grades of dupHcitas anterior are represented by duplica- tion of the jaw, mouth, or nose. 2. Duplicitas posterior (monstra duplicia anadidyma). Union of the twins at the head and thence downward with duplication of the posterior parts of the body. Craniopagus (Fig. 373). Union of twins in the cranial region. Ac- cording to the site of union there may be distinguished craniopagus pari- FlG. 375. — ^Thoracopagus tribrachius tripus. The hand of the third arm, common to both halves, possesses two dorsal surfaces, and the laterally distorted fingers possess nails on both sides. The common third foot has eight toes. etalis, frontalis, occipitalis. When the union is more extensive portions of the brain are single. Cephalothoracopagus or syncephalus (Fig. 374). Blending of twins in the region of the forehead and face, and of the abdomen. In the region of the united heads there is an anterior and a posterior face (janus, janiceps). The two faces may be equally (janus symmetros) or unequally developed {janus asymmetros) , one face being well developed, the other imperfectly. The internal organs present different degrees of blending into single organs. Dipygus. The duplication is limited to the lower half of the body and the lower extremities, while the upper parts are single or partly cleft. The duplication of the spinal cord may begin at different heights. Accord- ing to the number of extremities different forms may be distinguished. 420 DISTURBANCES OF DEVELOPMENT. The mildest grades of duplication are confined to the lower end of the spinal column, the anus, and the external genitals. 3. Duplicitas parallela {monstra duplicia anakatadidyma) . Duplica- tion of the anterior and posterior ends of the body with parallel positions of the trunk. Thoracopagus (Fig. 375). Union of twins by the thorax. Accord- ing to the site and extent of the union, as well as the number of extrem- ities present, there may be distinguished different forms, particularly the following: xiphopagus (union at the xiphoid process), sternopagus Fig. 376. — Polymelos. (After Lancereaux.) Fig. 377. — ^Polymelos. (After Liesching.) (union at the sternum), thoracopagus tetrabrachius, tribrachius, dibra- chius, tetrapus, tripus, and dipus. When portions of the faces have blended there results prosopothoracopagus. Blending of the internal organs into single organs varies with the degree of external blending. The heart may be double or single, in the latter case malformed. Thora- copagus is relatively frequent. Rachipagus. Blending of twins in the region of the spinal column is rare. § 147. Twins joined but unequally developed may occur in any of the double forms described in § 146. If the development of one of the twins remains rudimentary and if its heart does not develop, its nourish- ment can come only through its well-developed fellow. The better devel- oped of the two is then known as the autosite, the other as the parasite. If the parasite is of markedly rudimentary development, it may be classed with the bigerminal teratomata (cf. §§ 127 and 128). At the posterior ends of the body there may occur a rudimentary double monstrosity in the form of increase in the number of the extrem- ities, polymelos (Figs. 376, 377). In so far as the lower extremities are concerned such a malformation may be classed as an ischiopagus or a MONSTERS. 421 dipygus. The supernumerary extremities may be one or two in number, and more or less well developed. Further, there not infrequently occur coccygeal teratomata in which the presence of rudimentary extremities Fig. 378. Fig. 379. Fig. 378. — ^Bigerminal teratoma of the coccygeal region (pygopagus parasiticus.) a, b, c. Extremities lying in a sac formed by the skin of the autosite. Fig. 379. — ^Thoracopagusparasiticus (thoracomelus). Three legs spring from the pelvis; one of them has a double foot. Two upper extremities project from the anterior chest-wall. Fig. 380. Fig. 381. Fig. 380.— Thoracopagus parasiticus. (After Schenk von Grafenberg.) Parasite attached to ohest of autosite. Fig. 381. — Epignathus. (After Lancereaux.) 422 DISTURBANCES OF DEVELOPMENT. (Fig. 378, a, b, c) or of various body elements leaves no doubt that the tumor-like formation covered by the skin of the autosite is to be regarded as a double monster, a rudimentary pygopagus, or as dipygus parasiticus. Such a parasite is designated epipygus. Supernumerary extremities (Fig. Z79) may also be found on the trunk or there may occur a headless trunk with extremities (Fig. 380), or a rudimentary thorax without extremities, or, finally, teratomata which may be interpreted as thoracopagus parasiticus ( omphalopagus) and as dipygus parasiticus. The malformation is also called epigastrius. The inclusion of such teratomata beneath the skin of the abdomen or thorax, or in the abdominal or thoracic cavities of the autosite, gives rise to the condition known as inclusio fcetalis suhcutanea, or abdominalis, or mediastinalis. In the region of the head rudimentary twin-formations appear most often in the mouth cavity, forming an amorphous mass, firmly attached to the base of the skull, consisting of skin, connective tissue, cartilage, bone, brain-tissue, teeth, intestinal elements and muscle, and, rarely, developed extremities. Such malformations are included under the desig- nation epignathus (Fig. 381). On other parts of the head {prosopopagus parasiticus) rudimentary twin formations or bigerminal teratomata are rare (cf. §§ 127, 128) ; they also occur in the cranial cavity (encranius) and in the neck (hygroma colli) . CHAPTER X. The Pathogenic Fission-Fungi and the Diseases Caused by Them. I. General Considerations Regarding the Schizomycetes or Fission- fungi. 1. General Morphology and Biology of the Fission-fungi. § 148. The Schizomycetes or fission-fungi, designated collectively as bacteria, belong to the protophytes — that is, to the smallest and simplest forms of plant-life. Many of them are so small that they stand on the border-line of invisibility even with the use of the highest-power objectives and eye-pieces. In animal tissues, it is frequently difficult to distinguish them from the products of cell-disintegration; often this can be accom- plished only through the employment of specific reagents or staining- methods, and occasionally only through culture experiments. The Schizomycetes are non-chlorophyllaceons, unicellular organisms, but as a result of growth and multiplication they form colonies of cells. The form and character of single cells, as well as their manner of growth, division, and multiplication, vary greatly, and these differences are used as a basis for the classification of bacteria. In the first class are placed the Cocci, often designated Micrococci, or that form of bacteria which occurs in the form of spherical or oval cells. There may be distin- guished six forms of cocci : double-cocci or Diplococci, chain-cocci or Streptococci, clustered cocci or Staphylococci, tablet-cocci or Merismo- pedia, packet-shaped cocci or Sarcince, and tube-cocci or Ascococci. The second class constitutes the Bacilli (rod-shaped bacteria). Long thread-like bacteria are called Leptothrix. To the third class belong the Spirilla (screw-shaped bacteria) . Screw- shaped forms with short, wide turns are known as Spirilla, those with drawn-out turns as Vibrios, those with a long, closely wound screw as Spirochetes. The Schizomycetes are composed of cell-contents and cell-membrane, both of which consist of an albuminoid body, which varies with the species. Many bacilli contain fat in their cell-bodies, at times so abundantly that it may be demonstrated by staining with Sudan III. Some of these bacteria (tubercle-bacillus, lepra-bacillus, and actinomyces) show the presence of fat both when growing in living tissues and when cultivated on artificial media; others (staphylococcus aureus, anthrax-bacillus, bacillus of glanders) show the presence of fat only when grown on special media. In many forms of bacteria the membrane may appear as a hyaline capsule surrounding the cell. In all forms of ba,cteria, with the exception of the cocci, there have been observed swarming movements which are brought about by fine thread-like flagella attached at the ends or scattered over the entire cell. In addition there occur slow oscillatory or gliding and creeping 423 424 THE PATHOGENIC FISSION-FUNGI. movements which are dependent on the contractile and flexible qualities of the plasma. Both forms of motion occur only under certain conditions of nutrition and growth, and only in certain species. Multiplication of bacteria takes place through transverse division of cells which have previously become elongated. In some forms divi- sion can take place in two or even three dimensions. After division the cells separate immediately or remain for a time attached to each other. When the cells remain attached after dividing transversely, threads are formed (Streptococcus, Leptothrix) ; after dividing both transversely and longitudinally, flat, tablet-like colonies; after dividing in all three dimensions, colonies resembling a solid body (Sarcina) are produced. Long threads may become segmented into shorter pieces. If resting bacterial cells, as the result of constantly progressing repro- duction or through the accumulation of neighboring cells, heap themselves in masses, there are formed colonies, which are called zoogloea. Many of the bacteria form spores. These cells are distinguished by the fact that they remain alive under conditions in which ordinary forms die ; and, when brought into fresh nutrient solutions, are able to produce a new generation. Spore-formation is most frequently endogenous — that is, the spore arises "inside the cells (particularly in bacilli), and is developed out of the cell-protoplasm, in which there appears a small granule which grows into an oblong or round, highly refractive, sharply- contoured body always remaining smaller than the mother-cell. After the death of the latter the spore is set free. In old cultures bacteria show degeneration-forms, which are distorted, and stain poorly and irregularly. As non-chlorophyllaceous plants, the schizomycetes are restricted in their nutrition to ready-formed organic substances which are soluble in water, and which are supplied to them in an abundance of water. In addition they need various mineral substances, especially sulphur, phos- phorus, potassium or rubidium, or caesium and calcium (or magnesium, barium, or strontium). Changes in the conditions of nutrition may modify the form and dimension of bacteria and also their vital properties. Some of the fission-fungi are restricted for their food-supply to dead organisms or to solutions of organic matter, and are, therefore, classed as saprophytes; others are able to take their nutrition from living animals or plants, and live as parasites. Free oxygen is necessary for the development of many bacteria; others can dispense with it as long as they are under favorable conditions of nutrition in other respects; others develop only in the absence of oxygen. The first are designated obligate aerobes, the second facultative anaerobes, the third obligate anaerobes. The pathogenic bacteria are facultative or obligate anaerobes. Carbon dioxide has no influence on the development of many bacteria, for example, on the typhoid-bacillus and Friedlander's pneumobacillus. On others, it has an inhibitory action, for example, on Bacillus indicus, Proteus vulgaris, Bacillus phosphorescens, the bacilli of anthrax and cholera, the pus-cocci, and others. The bacilli of anthrax, Asiatic cholera, and of rabbit septicaemia die in a few hours in artificial Seltzer water, but anthrax-spores remain alive in it indefinitely. Light has an injurious or destructive influence on many forms of bacteria, and it is therefore possible to disinfect, by means of strong light, water which is infected. The virulence of the bacillus of anthrax may DEVELOPMENT OF BACTERIA. 425 be lessened by exposure to sunlight. When exposed to the direct rays of the sun anthrax bacilli die in twenty-four to thirty hours, the spores sur- vive as long as six to eight weeks. According to Geisler the green, violet, and ultra-violet rays are particularly active. According to Rieder bacteria may be destroyed by the Roentgen-rays. The temperature of the surrounding medium acts on bacteria in such a way that when it falls the life-processes of the organisms become weaker and slower, and finally cease entirely, whereas with elevation of tempera- ture they rise to a certain maximum, and at a slight increase above this suddenly cease; higher temperatures kill the fungi. The maximum of permissible temperature lies at a different height for different fungi, and is dependent also on the character of the nutrient substance. There are forms of bacteria which grow well at a temperature of 55° C. or higher. A low temperature checks development in all varieties ; they fall into a state of immobility, but do not die even at great degrees of cold. The immobility due to cold occurs at different temperatures with different varieties. The most favorable temperature for development lies between 30° and 40° C. for the anthrax bacillus ; at temperatures above 44° and below 15° C. its development ceases. Many bacilli form spores only at high temperatures. Boiling water and steam at 100° C. kill all bacteria and bacterial spores, if allowed to act for some time. In dry air bacteria and their spores withstand higher temperatures, so that a temperature of 140° C. for three hours is necessary to kill the latter. Many bacteria are killed at a temperature of 60° to 70° C, provided it is kept up for a long time. Anthrax-spores die in boiling water in two hours, in confined steam in ten minutes. The action of steam at 105° C. for ten minutes kills all spores. Live steam kills all spores in ten to fifteen minutes, and pene- trates well into objects to be disinfected. If fission-fungi find themselves in a suitable medium, their multiplica- tion can be brought to a standstill, since the fluid may contain substances which hinder the growth of bacteria or even kill them. This effect is produced by many substances (sublimate, lysol, carbolic acid, iodine, formaldehyde, etc. ) — even in comparatively great dilution. Other sub- stances act injuriously on bacteria only when in stronger concentration. The point at which multiplication is hindered is reached at a greater dilution than that at which the bacteria are killed. Spores are much more resistant than the vegetative forms. The growth and multiplication of bacteria also cease with insufficient amount of water. The fact that fruits preserved in sugar do not fer- ment and that salted and dried meats do not putrefy depends on this fact. Food-stuffs can be preserved through the removal of water and by the addition of substances which. are dissolved in the tissue-fluids and inthis way increase the proportion of the same in solid contents. The limit at which the fission-fungi and yeast-fungi cease to develop is reached at a much higher degree of humidity than for the moulds. If a nutrient fluid contains other lower fungi besides bacteria there often takes place competition between the different micro-organisms; anfi fission-fungi, yeasts, and moulds may crowd one another out. Like- wise reciprocal crowding between the bacteria themselves tnay occur. For example, cocci may be crowded out and destroyed by bacilli, or one form of bacillus by another. This would appear to happen when the composition or the temperature of the nutrient medium is more favorable 426 THE PATHOGENIC FISSION-FUNGI. to one form than to the other; or when one form of bacteria produces substances which act injuriously on the other, or when one form grows more rapidly than the other, and thereby deprives its competitor of necessary food-supply. According to investigations by Pasteur, Emmerich, Bouchard, Wood- head, Blagovestchensky, and others, the antagonism between many forms of bacteria is shown in inoculation experiments on animals. By simulta- neous inoculation with different bacteria the development of a pathogenic bacterium in the body of a susceptible animal may be hindered. For example, the development of anthrax bacilli may be hindered by simulta- neous inoculation with erysipelas-cocci (Emmerich) or with the Bacillus pyocyaneus (Bouchard). The question, as to whether the bacterial cell contains a nucleus has been a subject of much discussion. A. Fischer denies it, while Biitschli, Schottelius, Zie- mann, Zettnow, Nakanishi, and Feinberg are inclined to favor the affirmative view. According to Zettnow, the bacterial cell contains chromatin or nuclear sub- stance mixed with the entoplasm ; while the covering of the cell, or ectoplasm, does not contain chromatin. According to the investigations of Ziemann, Zettnow, and Feinberg, it is possible through staining with a mixture of methylene-blue and eosin. (Romanowski-stain) to demonstrate within the majority of bacteria a "nuclear substance" or "chromatin" (Ziemann, Zettnow) or a "nucleus" (Fein- berg) — that is, there may be demonstrated within the bacteria structures of varying size which stain red like the nuclei of malarial Plasmodia (Romanowshi) or of other protozoa or of tissue-cells, while the cell-plasma takes a blue stain. According to Nakanishi, circumscribed nuclei are found in young forms. The Romanowski-siam is a mixture of methylene-blue and eosin, whereby a red dye contained in methylene-blue (Rosin, Berl. klin. Wochen., 1899; Nocht, Cbl. f. Bakt., 1899) is precipitated. Zettnow's formula is as follows : 50 c.c. of a one- per-cent. solution of a Hochst methylene-blue is treated with 3-4 c.c. of a five-per- cent, solution of soda. To 2 c.c. of this there is added drop by drop while shaking 1 c.c. of one-per-centT solution of Hochst eosin BA. Stain five minutes on cover- glass and examine in water. According to N'dgeli, Zopf, and others, many fission-fungi possess a membrane of cellulose or of a carbohydrate closely related to cellulose. Certain bacteria (red sulphur bacteria) combine within their cell-substance coloring-matter; others (Bacil- lus amylobacter, Spirillum amyloferum) give at certain stages of their development the starch reaction with iodin. Babes and Ernst, by means of special staining methods with Loffler's methylene-blue, haematoxylin, and Plainer's nuclear black, have demonstrated the presence of granules within different forms of bacteria, which according to their behavior probably stand in some relation to the processes of division and spore- formation. Ernst designated the appearances seen by him as sporogenous granules, since he was able in certain bacteria to demonstrate their transition into spores; he is inclined to regard them as of the nature of cell-nuclei, a view which Biitschli also favors. Bunge regards the granules described by Ernst as cell-granules which have nothing to do with spore-formation, and describes other granules, which stain with Loffle-Ps methylene-blue, as the forerunners of sipores. Marx and Woithe regard the Babes-Ernst granules as not being nuclei in the ordinary sense of the word, but as products of the maximal condensation of the euchromatic substance of the cells, which are a sign of the highest intensity of vitality on the part of the cell. Wagner, on the contrary, holds that certain bodies, which he has observed in typhoid- and colon-bacilli, are nuclei. According to Nakanishi, the spores form (in anthrax- and hay-bacilli) by concentration of the chromophile substance about the nucleus, while the remaining portion of the protoplasm becomes clear ; a membrane is then formed about the chromatin body, it takes on a fat-like shine, and loses its power to take stains (methylene-blue BB). The bacteria are able to take the carbon necessary for their growth from most of the carbon compounds^ which are soluble in water. They can also derive their carbon from dilute solutions of substances which, in greater concentration, are injurious to them — for example, from benzoic acid, alcohol, salicylic acid, phenoL etc. ACTIVITIES OF BACTERIA. 427 Their nitrogen is derived from albuminous matter; further, from those com- pounds designated as amins (methyl-, ethyl-, propylamin), amido-acids (asparagin, leucin) and amides (oxamide, urea), as well as from the ammonia salts and also from nitrates. The albuminates, previous to their assimilation, are changed into peptone by means of a ferment given off from the bacteria. Free nitrogen cannot be assimilated as such. Nitrogenous and non-nitrogenous compounds are not only assimilable as such, but also in combination. The fission-fungi are able to take nitrogen from ammonia and nitric acid only in the presence of organic carbon compounds. Sulphur, according to Ndgeli, is essential to the schizomycetes, and they take it from sulphates, sulphites, and hyposulphites. The other mineral substances men- tioned above are derived from various salts. If in the case of an abundance of nutrient material there is too little water present, all further growth ceases ; yet many of the fission-fungi are able to dispense with water temporarily. Spores suffer little from drying. Many bacteria are sensitive to acids, so that even a slight dgree of acidity hinders their growth (for example, anthrax bacilli and (he Frankel-Weichselbaum pneumococcus). Others are able to grow with a moderate amount of acid in the nutrient fluid. As a general rule they are especially sensitive to mineral acids, but the presence of a large amount of citric, butyric, acetic and lactic acids also hinders their multiplication. In this connection belongs the fact that the products of decomposition caused by the fermentative action of the fungi are at a certain degree of concentration harmful to the development of the fungus, and fin'ally stop its growth entirely. Thus, in butyric-acid and lactic-acid fermentation the amount of butyric or lactic acid gradually formed finally checks the multiplication of the fungus. A similar result occurs in the bacterial putrefaction of albumin, since the products of the same, such as phenol, indol, skatol, phenylacetic acid, phenylpro- prionic acid, etc., hinder the further development of the bacteria. To alkalies the fission-fungi are less sensitive, and many can bear a rather high degree of alkalinity in the nutrient fluid, but there also exist forms which do not thrive in alkaline fluids (acetic-acid fungus). According to the investigations of Pfeffer and Ali-Cohen, many motile bacteria show chemotactic properties — that is, they are attracted or repelled by certain chemical substances dissolved in water. Bacteria swimming about in fluids collect, therefore, at places where there are chemical substances which, attract ; for example, typhoid-bacilli and cholera-spirilla are attracted by potato-juice {Ali-Cohen). Potas- sium salts, peptone, and dextrin likewise attract, but the individual forms of bac- teria behave differently toward these substances {Pfeffer). Free acids, alkalies, and alcohol have a repelling action. § 149. The growth and multiplication of fission-fungi give rise to chemical transformations of the nutrient material, brought about through ferments produced by the bacteria, and through metabolic processes occurring in the cells themselves. Among ferments or enzymes are to be mentioned the proteolytic or albumin-dissolving enzymes (bacteriotrypsins) which bring about solu- tion of the albuminous bodies and cause disintegration of the peptone- molecule. Further, bacteria give rise to diastatic ferments which convert starch into sugar, also to inverting ferments which transform cane-sugar (disaccharid) into grape-sugar (monosaccharid). The chemical results of bacterial metabolism, brought about by the vital activities of fission-fungi aided by the enzymes produced by them, consist of decomposition of complex organic compounds. By many authors all these processes are designated fermentations, while others (Lehmann) speak of fermentation only when a fission-fungus breaks down a given food-material with especial ease, thereby giving rise to one or more products in marked quantity, in association with or in place of its other metabolic products. Other authors narrow the term fermenta- tion to the decomposition of carbohydrates. In the decompositions caused by fission-fungi different products are formed, according to the composition of the nutrient material and the 428 THE PATHOGENIC FISSION-FUNGI. character of the fission- fungus. For the production' of fermentation fer- mentable material is necessary. Many fungi are able to cause fermenta- tion in the presence as well as in the absence of oxygen, while to some of them lack of oxygen is necessary. Among the products of bacteria of importance to the physician are those which have a poisonous action and cause tissue-changes, particu- larly those described as ptomdins, toxins, and endotoxins. The ptomains are basic, crystallizable, nitrogenous products of the bacterial decomposition of albumin; they are also known as putrefactive alkaloids or cadaveric alkaloids. They show poisonous properties. The best known are sepsin, putrescin (dimethylethylendiamin), cadaverin (pentamethylendiamin), collidin (pyridine derivative), peptotoxin, neu- ridin, neurin, cholin, gadinin, and substances resembling muscarin. The true toxins are specific bacterial poisons produced by pathogenic bacteria and are secreted by the latter, giving rise to the severe symptoms in diphtheria, tetanus, and sausage poisoning. The endotoxins are sub- stances clinging to the bacterial cells that also have a poisonous action. In the bacterial cell there also occur bacterial proteins which give rise to local tissue-necrosis and inflammation. The significance of these sub- stances in the infectious diseases has already been mentioned in § 11. Among other decompositions produced by bacteria the following are worthy of note : the formation of lactic, formic, acetic, propionic and butyric acid, alcohol and carbonic acid from sugar; the formation of acids (acetic, butyric, propionic, valerianic, succinic, formic, and carbonic) from alcohol and organic acids; the formation of indol, skatol, phenol, cresol, pyrocatechin, !iydrochinon, hydroparacu- maric acid, and paroxyphenylactic acid {von Nencki, Salkowski, Brieger), and finally hydrogen sulphide, ammonia, carbonic acid, and water from albumin; the formation of ammonium carbonate from urea; the transformation of nitrous and nitric acids into free nitrogen ; the reduction of nitrates to nitrites and to ammonia, etc. Finally, there are bacteria living in the soil — ^the nitro-bacteria — which are able to form nitrous and nitric acids from ammonia (Winogradsky) . Along with the nitrification of nitrogen there occurs decomposition of earthy alkali carbonates, as shown by the fact that the nitrobacteria arc able in the presence of organic carbon compounds to derive from the carbonates the carbon necessary to the building-up of cells. There takes place, therefore, through the vital activity of these organisms, synthesis of organic out of inorganic substances. Under the influence of the fission-fungi there are formed bitter, sharp, nauseat- ing substances (bitter milk)_. Further, bacteria occasionally produce pigments of red, yellow, green, blue, or vTolet color. For example, Bacillus prodigiosus produces a blood-red coating on bread (bleeding bread) ; bandages and pus take on a bluish- green color as the result of the presence of Bacillus pyocyaneus. In many cultures there is formed fluorescent coloring-matter. The phosphorescence not infrequently seen on decomposing sea-fish depends on bacterial products of decomposition, as has been shown by PflUger, and appears when there is active multiplication of the bacteria. 2. General Considerations Concerning the Pathogenic Schizo- MYCETES and ThEIR BeHAVIOR IN THE HuMAN ORGANISM. § 150. Among the schizomycetes there are numerous species which are capable of causing disease-processes in the human organism, and are therefore called pathogenic schizomycetes. The bacteria concerned must possess properties enabling them to multiply in the tissues of the living human body. They must therefore find in the 'tissues suitable nutrient material, and in the body-temperature the warmth necessary to their growth. The tissues, moreover, must not contain substances which are a' hindrance to growth (cf. § 31). ACTIVITIES OF BACTERIA. 429 If pathogenic fission-fungi succeed in growing in the tissues of the body, if infection takes place (cf. § 11), their action is characterized at the point of multiplication, by tissue-degenerations, necrosis, inflammation, and new-growths of tissue, while at the same time the toxins produced by them cause manifestations of poisoning. In individufel cases the pathological processes vary greatly, in that the distribution of the bacteria, their local action, and the production of poisons, differ with different forms of bacteria. With many the local action on tissue is the most prominent character- istic, with others the general intoxication. Many bacteria confine them- selves to the region in which they have gained entrance; others advance uninterruptedly on the surrounding tissues; still others are carried by the blood and lymph streams and lead to the formation of metastatic foci, and, finally, others increase in the blood. If spread of bacteria takes place through the blood, the bacteria may pass from, the mother to the foztus during pregnancy, since the placenta forms no certain filter against pathogenic bacteria. This has been demon- strated, for example, in the case of anthrax-bacilli, bacilli of symptomatic anthrax, glanders-bacilli, spirilla of relapsing fever, typhoid-bacilli, the pneumococcus, and the spirochete of syphilis. Changes in the placenta, such as haemorrhage, loss of epithelium, and alterations of vessel-walls, favor the passage of bacteria. Bacteria which multiply in the human body die out in many cases in a short time; and the disease produced by them proceeds to recovery (cf. § 31). Nevertheless, it not infrequently happfens that they are preserved for a long time in the body, and excite continuous disease, or remain in a condition of inactivity, so that no pathological processes are recognizable until, after a period of latency, active reproduction again takes place and manifestations of disease show themselves anew. Not infrequently secondary infection associates itself with infection already existing. The relation between the two is either that the second follows the fiirst accidentally, or that through the first infection the soil is prepared for the second (cf. § 11). Finally, there not infrequently occur double infections, in that two or more forms of bacteria develop coincidently in the tissues, and produce their characteristic injurious influence on the latter. Each pathogenic fission-fungus has a specific action on the tissues of the human organism ; but different species may exert a similar action. For example, there are various bacteria capable of producing suppuration. Only in a certain proportion of cases do the tissue-changes show such characteristics that from these the species of the pathogenic fission-fungus can be recognized with certainty. Further, it has been demonstrated that pathogenic properties of bacteria are by no means constant; on the contrary, their virulence varies, so that bacteria, which cause severe infections may become changed (weakened) through external influences, so that they lose their power of causing disease, or cause only mild forms. This peculiarity is of great practical importance. It explains to a certain extent why a given infection does not always run the same course, and, moreover, why with severe attacks light ones also occur. On the other hand, it affords the possibility of obtaining material for inoculation from attenuated cultures of bacteria, by means of which mild grades of infection or intoxication 430 THE PATHOGENIC FISSION-FUNGI. can be produced, which are able to protect the organism from severe infections or to bring about the cure of an infection already acquired (cf. § 32). Weakening of the pathogenic properties of a fission-fungus can be brought about through the action on cultures of high temperatures, oxy- gen, light, or antiseptic substances, as well as by cultivation of the fungus in the body of a less susceptible animal. In some forms it is only neces- sary to cultivate the bacteria for some time on artificial media (diplococcus of pneumonia), or to expose the culture to the air (bacillus of chicken- cholera), in order to bring about attenuation. If it is desired to pre- serve the virulence of the pneumococcus, it is necessary, from time to time, to pass the bacteria cultivated on artificial media through rabbits, which are very susceptible. The glanders-bacilli, tubercle-bacilli, and the cholera-spirilla lose virulence when cultivated uninterruptedly on artificial media. The streptococcus of erysipelas becomes so attenuated through continued cultivation in bouillon that it is no longer capable of killing even mice. If the presence of bacteria be suspected in tissue-fluid or in the tissue-paren- chyma, their demonstration may first be attempted by means of microscopic investigation. Occasionally this is successful by the mere examination of a drop of the suspected fluid or of a smear-preparation of the tissue-juice diluted with salt- solution or distilled water. In other cases it is necessary to employ staining- methods, in which case cover-glass smears of the fluid are made and allowed to dry. The smear is then fixed by passing through the flame, and after cooling is stained. For this purpose methylene-blue is preferably employed, a preparation of one-per-cent. methylene-blue solution in l-to-10,000 solution of caustic potash. Water solutions of fuchsin and methyl-violet are also used. For many bacteria there are emploj'ed special staining methods, in which ordinarily the preparations are heavily overstained with a solution of gentian-violet or fuchsin in aniline water, or with a water solution of methyl-violet, the excess of stain then being removed by means of weak acids or by iodine and alcohol (Gram's method). In this way it is often brought about 1:hat the bacteria alone remaiti stained, often certain forms of bacteria only. When it is desired to demonstrate the presence of bacteria in tissues, small portions of tissue are hardened in formalin or in absolute alcohol, and are then cut into the thinnest possible sections, which are stained by appropriate methods. Here again the methods most frequently employed are those mentioned above : gentian- violet, methyl-violet, and fuchsin. Good objectives are necessary for the microscopic examination ; if possible, oil-immersion lenses and illumination with substage con- denser shouM be employed. If through any method the presence of bacteria in tissue has been demon- strated, the attempt is next made to cultivate them. For this purpose the methods developed by Koch are usually employed. These, in principle, consist in obtaining first a fluid containing the bacteria, by means of scraping or by rubbing up pieces of tissue in sterilized salt-solution. This fluid is then evenly distributed in a solu- tion of gelatin or agar which has been liquefied by warming; and the mixture is then poured upon horizontal glass plates, solidifying as it cools. The individual bacteria or spores, thus separated from each other, develop in the nutrient medium. By proper application of this method there are obtained in the layer of gelatin various colonies, which differ in appearance so that they may often be differentiated from each other by the naked eye alone. When sufficiently separated from one another, the individual coloniesmay be taken up by means of a fine plati- num needle, and transferred either to boiled potato, or to a sterile gelatin plate, or streaked on the surface of the solidified nutrient fluid in a test-tube. Very often the infected needle is stuck into the solidified transparent medium contained in a test-tube. If the culture on the gelatin plate is pure, and if the entire procedure is cartied out with the necessary care and the avoidance of contamination, pure cultures may be obtained by this method. In stab-cultures, as well as in smear-cultures on pota- CULTIVATION OF BACTERIA. 431 toes or any other nutrient medium, special peculiarities often show themselves which tnake it possible for the experienced observer to recognize the form of bacteria. At times, however, it is necessary to make a thorough microscopic examination of the colonies. An infusion of meat containing peptone and gelatin is commonly employed for making plates. It consists of a watery infusion of chopped meat, to which a definite amount of peptone and salt is added. This is neutralized with carbonate of soda, and enough gelatin is added to give a solid consistence at ordinary tem- peratures. For streak- and stab-cultures this same gelatin is sometimes used; at other times a jelly made of a mixture of a watery extract of meat, peptone, and agar-agar ; or again blood-serum which has been coagulated by warming. For stab-cultures the jelly is allowed to solidify within the test-tube in a per- pendicular ^position ; for streak-cultures the test-tube is kept in an oblique position until the jelly is set. ' Sterilized bouillon is often used for cultures. The inoculated nutrient media are kept either at room-temperature or at higher temperatures in an incubating oven (30°-40° C). The proper nutrient medium to be used in individual cases must be determined by experiment. Experience has shown that individual bacteria behave differently in this respect, some growing best on one, others on another medium. To the nutrient medium there are often added with advantage such sub- stances_as sugar, glycerin, urine, brain-substance, etc. It is evident that the processes briefly described above may be modified accord- ing to the necessities of the case. For example, in those cases in which it is neces- sary to grow bacteria at high temperatures, the use of gelatin should be avoided and agar-agar plates should be made instead. Occasionally membranes or exu- dates from mucous surfaces (diphtheria) or small bits of excised tissue are placed directly into the culture-medium. In the case of many bacteria, as cholera-spirilla, the use of hanging-drop cultures is advised. In this method a drop of sterilized bouillon hangs down from the under surface of a cover-glass, and is inoculated from a previously cultivated pure culture of the fungus. The cover-glass is then placed over the excavation in a hollow ground-glass slide. Evaporation is prevented by the exclusion of the outer air from the cavity in the slide, by a rim of oil or vaseline placed beneath the edge of the cover-glass. By this method the multiplica- tion of bacteria can be observed for a long time. When bacteria are sought in water, a definite amount of suspected water is dis- tributed in gelatin, and plate cultures are made. Earth is rubbed up with sterilized salt-solution ; air is made to pass in definite amount through sterilized salt-solution ; the salt-solutions thus infected are then mixed with gelatin, and from this gelatin, plates are made. The culture of bacteria on and in different media, accompanied by the micro- scopic examination of the different stages of development, serves for more exact identification, and for the differentiation of species: After its properties have been studied in this way, the influence of the bacterium on the animal organism is tested. As experimental animals, rabbits, dogs, guinea-pigs, rats, mice, and small birds are employed. The bacteria to be tested are introduced, sometimes under the skin, sometimes directly into the blood-current, sometimes by inoculation into the internal organs, sometimes by inhalation into the lungs, or by administration with the food into the intestinal canal. Bacteria can be regarded as pathogenic for a given animal when they multiply within the tissues and excite disease. If relatively large amounts are inoculated, the animal experimented on may die, even if the bacteria do not increase in its body, since the poisonous substances formed in the culture and introduced by inoculation often suffice to kill the animal. Experience has taught that only some of the bacterial infections which occur in man, when inoculated into animals, run the same course as in man, and, indeed, only those which also- occur in animals. In other cases the pathogenic fission- fungi occurring in man or in certain animals are, it is true, pathogenic for the experi- mental animal, but the pathological process shows another localization and another course. In a third case the experimental animals are in part or wholly immune. Inversely, fission-fungi that are often extremely pathogenic for experimental animals are harmless for other animals or for man. 432 THE PATHOGENIC FISSION-FUNGI. II. The Different Forms of Bacteria and the Diseases Caused by Them. I. The Cocci, or Sph^robacteria, and the Morbid Processes Caused BY Them. (a) General Considerations Regarding the Cocci. § 151. The cocci are bacteria that occur exclusively in the form of round or oval or lanceolate cells. In their multiplication by division they often form peculiar aggregations of cells, which are designated by special names according to the character of the different forms. Since certain forms of cocci are likely to develop in definitely shaped aggregations, advantage is taken of this fact, to classify them in different species. It should be noted, however, that a given species does not always appear in the same form, but may vary according to nutrient conditions. Many of the cocci multiply by division in one plane only — at right angles to the length of the cell. If the spheres resulting from division remain together for some time in the form of double spheres, and if this form ap- pears with frequency Fig. 384. Fig. 382. Fig. 383. Fig. 385. Fig. 382.^Streptococcus from a purulent peritoneal exudate of a case of puerperal peritonitis. cl. Single cocci; b, diplococci; c, streptococci or torula-chains. X 500. Fig. 383.— Colonies of micrococci in blood-capillaries of the liver, causing metastatic abscess- formation. From a case of pyaemia. Necrosis of liver-cells, x 400. Fig. 384.— Cocci grouped in tetrads (merismopedia), from a softening infarct of the lung X 500. Fig. 385. — Sarcina ventriculi. v 400. in any one species, it is designated diplococcus (Fig. 382, h). If, from further division of the cells in one plane, rows of cocci result, these are known as streptococci (Fig. 382, c) ; this term is used also as the name for a group. If the division of the cells takes place irregularly, and the cells remain in small collections or heaps, the bacteria are designated micrococci (Fig. 383). The name staphylococcus or grape-coccus is commonly used to indicate some of these forms. Larger collections of cells, held together hy a gelatinous substance derived from the cell- membranes, are designated sooglooa masses. If the masses of cocci are united into larger collections by means of a gelatinous envelope, they are spoken of as ascococci or tube-cocci. To those cocci which remain united for a long time in a four-cell tablet (Fig. 384), the name of tetracoccus or tablet-coccus is applied. Others class such bacteria with the micrococci. The cocci that go by the name sarcinae are characterized by division in three directions of space, so that compound cubical packets of spherical cells are formed from tetrads (Fig. 385). THE COCCI. 433 The cocci not infrequently show a tremulous molecular motion in fluids. The saprophytic cocci grow on different nutrient substrata and cause in suitable media various processes of decomposition. Many form pig- rnents. Micrococcus ureae causes fermentation in urine by which ammo- nium carbonate is formed from urea. Micrococcus viscosus is the cause of the slimy fermentation of wine. The cause of the phosphorescence of decomposing meat was found by Pfliiger to be a micrococcus that forms slimy coatings on the surface of the meat. Of the pigment-producers the best known are Micrococcus luteus, Mi- crococcus aurantiacus, Sarcina liitea. Micrococcus cyaneus and Micro- coc-cus violaceus, which, when grown 6n boiled eggs or potatoes, produce yellow, blue, and violet pigment, respectively. Saprophytic cocci are found in the mouth cavity and intestine, as well as on the surface of the skin, and in the lungs. Sarcina ventriculi (Fig. 385) occurs not infrequently in the stomach of man and animals, especially when abnormal fermentations are going •^It*? ''. '■''5 « It'. iJ - a»^ .' -■■:■■ ,-'\ Fig. 386. — Streptococcus tracheitis in scarlet fever (alcohol, carmine, methyl-violet, iodine). «, Connective tissue; b, desquamated epithelium; c, membrane composed of cells and streptococci; a, fibrin-threads. X 300. on. According to Falkenheim the stomach sarcines can be cultivated on gelatin, and form round, yellow colonies, which contain colorless mono- cocci, diplococci, and tetrads, but never cubical packets. They form these, however, in neutralized hay-infusion, and their growth causes souring of the infusion. The membrane of the sarcinas is said to consist of cellulose. Micrococcus tetragenus is not infrequently found in human sputum, and in the mouth and throat ; it may be present in tuberculous cavities, or in hsemorrhagic or gangrenous foci of the lungs. It forms tetrads (Fig. 384) whose cells are held together by a gelatinous membrane. On gelatin- plates it forms round or oval,' lemon-yellow colonies. It is pathogenic for white mice and guinea-pigs, to a less extent for rabbits, and, when injected subcutaneously, excites purulent inflammations in the mouse, often sep- ticaemia. Intratracheal injections may give rise to inflammations of the respiratory passages and lungs. The pathogenic cocci cause acute inflammations which usually heal after death of the bacteria ; but it not infrequently happens that cocci may remain in the body for a long time and give rise to chronic processes. 434 THE PATHOGENIC FISSION-FUNGI. "-7 .;•• Fig. 387. — Streptococcus pyogenes from a phleg- monous focus of the stomach (alcohol, carmine, methyl-violet, iodine), a, Leucocytes; h, leucocytes containing streptococci; c, free streptococci. X 50D. (&) The Pathogenic Cocci. § 152. The Streptococcus pyogenes is a coccus which, in multiplying, forms double spheres and chains of spheres (Fig. 382) of different lengths, containing from four to twelve or more cells. This chain-forma- tion comes to especially full development when the streptococcus is grow- ing in fluids — in nutrient bouil- lon or fluid exudates — but is r ^ also seen when growing in '.,;' ,- " \ ^J^ tissues. ' ^ ' ' I'-i,. '' ...;-. ( •.!, ' -i?. The cocci stain well by i'" ''■■.■' -i.^" V. Gram's method, are facultative anaerobes, grow best at ?)7° C, and form small whitish colonies on gelatin and agar. Streptococcus pyogenes causes in man inflammaitions, which usually, though not al- ways, assume a purulent char- acter. Occasionally it is found on normal mucous membranes, for example, in the upper air-passages, or in the vagina and cervix uteri ; it may be assumed in such cases that its virulence is slight, or that the mucous membranes offer successful resistance to its entrance into the tissues. Infection with streptococci may occur either in healthy individuals, or in those who have received some injury, or as an accompaniment or sequel of other infections, particularly scarlet fever, smallpox, diphtheria, and pulmonary tuberculosis. If the streptococcus mul- tiplies on the surface of mucous membranes — for ex- ample, of the respiratory tract (Fig. 386) — it excites inflammation, which may bear the character of desquamative or purulent catarrh (c), or of a croupous exudation (d). If it penetrates the connective tissues of the submucosa, it causes inflammations which are phlegmonous in character — i.e., a more or less quickly sipreading, seropurulent, or purulent, or fibrinopurulent, or serofibrinous inflammation, which may lead to suppuration and abscess-formation. In the exudate the cocci may be found free (Fig. 387, c), or inclosed in cells (b). The multiplication of streptococci in the stratum germinativum of the skin leads to necrosis of epithelium and the formation of purulent vesi- cles or blebs. If the streptococcus spreads in the corium, into which it penetrates through small wounds of the skin, it utilizes the lymph-spaces and lymph- FiG. 388. — Streptococcus erysipelatis (a) inside a lymph-vessel (b) , in part composed of thickly crowded spheres, in part of toruTa-chains (alcohol, gentian- violet) ; c, neighborhood of lymph-vessel, with pale, non- staining nuclei; d, vein; e, perivenous cellular infiltra- tion of tissue; /, accumulation of cells in the lymph- vessel. Section of rabbit's ear two days after inocula- tion with erysipelas-cocci, X 225. STREPTOCOCCI. 435 vessels (Figs. 388, a; 389, h, i; 390, c) as pathways and as places for the development of colonies, causing more or less severe inflammation, char- acterized macroscopically by advancing redness and swelling of the skin known as erysipelas. To tlie external appearance there corresponds more or less severe serous and cellular infiltration (Figs. 388, d, e, j ; 389, m; 392,c), and often fibrinocellular exudation (Fig. 389, m.^). The infection of the lymph-vessels in erysipelas involves at times the superficial layers of the cutis (Fig. 389), at other times the deeper layers (Fig. 390, c). In the latter case the erysipelatous process becomes phlegmonous. With infection of the deeper layers streptococci may spread on the surface of the epithelium — that is, beneath the homy layer (Fig. 390, g), and cause loosening of the epithelial cells and desquamation of the horny layer (/). In severe infection with virulent streptococci the process may go on to / « Fig. 389. — Section of theskin in erysipelas bullosum (alcohol, alum-carmine), a. Epidermis; &,_corium; c, vesicle; d, covering of vesicle; e, epithelial cells containing vacuoles; /, swollen cells with swollen nuclei; g, gi, cavity caused by the liquefaction of epithelial cells, and containing frag- ments of epithelium and pus-corpuscles; h, lymph-vessel, partly filled with streptococci; i, lymph- vessel filled full of streptococci; k, colony of streptococci in the tissue; /, h, necrotic tissue; tw, cellular, Wi, fibrinocellular infiltration; n, fibrinocellular exudate in the vesicle, x 60. liquefaction of epithelium (Fig. 389, e, f, g, g-^), and to the formation of vesicles {c, erysipelas bullosum), or to necrosis and gangrene of the corium (/, l^, erysipelas gangrenosum), or to suppuration. In the subcutaneous tissue the spread and multiplication of the cocci (Fig. 391, c) lead to progressive seropurulent (d) and fibrinopurulent inflammation, often with subsequent suppuration. Such forms of infec- tion are known as phlegmons. If the muscles become involved in a phlegmonous process, the strepto- cocci increase and spread (Fig. 392, a) in the connective tissue of the peri- mysium internum, and may penetrate the sarcolemma-tubes. Here also the consequences of infection are more or less severe inflammations lead- ing to suppuration. Bronchogenous infection of the lungs causes purulent, or croupous, or haemorrhagic exudations into the alveoli. Should bone become involved from the skin or mucous membrane — for example, from the middle ear • — • the cocci may increase in the marrow 436 THE PATHOGENIC FISSION-FUNGI. (Fig. 393, a, b) and give rise to necrosis, and later to purulent inflam- mation of neighboring tissues. Streptococcus infection may terminate, sooner or later, in that opposing forces restrict the further spread of the bacteria, and destroy them. Not infrequently, however, infection progresses up to the time of death. If streptococci break into the lymph- and blood-vessels, metastases are formed, and distant organs are involved. Infection of the lungs leads easily to infection of the pleura. Infection of the female genital tract, during delivery or the puerperium, leads often to infection of the peritoneum by the lymphatics. Infection of the serous membranes is Fig. 390. — Erysipelas of the head in a. child of one month of age (bacterial staining, carmine). a, Cutis with hair-follicles; b, subcutis; c, lymph-vessel with streptococci and inflamed surrounding area; d, rete Malpighii; e, f, horny layer; g, streptococci lying upon the rete Malpighii. x 45. usually associated v^^ith seropurulent, or fibrinopurulent exudation, the streptococci developing luxuriantly in the exudate, and forming long chains. In infection of the blood, the streptococci do not increase in the circulating blood, but at points where they come to rest ; in the small capil- laries of the lungs, heart, liver, kidneys, spleen, bone-marrow, joints, etc., or on the valves of the heart. At the point of increase there is likewise produced inflammation, which bears the same general character as the primary inflammation, but is less severe and more circumscribed. HcEmatogenous streptococcus-infection of the lung leads to the forma- tion of inflammatory foci (Fig. 394, a), vi^hich for the greater part show central suppuration. Collections of streptococci on the surface of the endocardium, of the valves or of the heart wall (Fig. 395, a) lead to superficial necrosis and to the formation of coagula (h), collections of leucocvtes C?',) and proliferations of granulation tissue {c, d). Deeper infection with streptococci causes extensive necrosis accompanied by in- STREPTOCOCCI. 437 flammation of the surrounding tissues. If streptococci are carried by the blood-stream into the coronary arteries, there are produced in the heart- muscle inflammatory foci, usually purulent in character. If the cocci pass to a blood-vessel of the skin or subcutaneous tissue, they may increase to such an extent that they form casts of the capillaries (Fig. 396, c). As the result of surrounding hypersemia there are produced in the skin red spots and swellings, and eventually purulent foci. In the kidneys, in whose vessels there often occurs an extraordinary multiplica- tion of streptococci (Fig. 397, a, b), there arise grayish-yellow circum- FiG. 391. Beginning streptococcus phlegmon on the trunk, after phlegmon of the arm (formalin, carmine, methyl-violet), a, b. Skin; c, streptococci in the subcutaneous connective tissue; d, beginning collection of leucocytes, x 15. scribed areas of discoloration, which are dependent on collection of bac- teria, local anaemia, necrosis, and often serofibrinous exudation (d). Later, yellow discolorations and softening of tissue appear, corresponding to foci of suppuration. Similar changes may be demonstrated in other organs. The danger of streptococcus infection depends on progressive local changes and the formation of metastases, and on the accompanying in- toxication, which finds expression in fever and severe general syniptoms. If the symptoms of intoxication are prominent the condition \s designated septicaemia. Metastatic suppuration leads to the form of disease desig- nated pyaemia. A combination of both conditions is known as septico- pyaemia. 438 THE PATHOGENIC EISSION-FUNGI. The course of streptococcus infection, as well as the mode of entrance of the cocci into the bpdy, can usually be recognized, since the infection ordinarily starts in injured skin or from penetrating wounds, from the mucosa of the digestive and respiratory tracts, or from the genital appa- ratus as the result of childbirth. Cryptogenic infection is, however, not rare; in such cases the first symptoms recognizable clinically are those dependent on disease of an internal organ, so that it appears as if the infection were primary in this organ. The individual foci in streptococcus infection may present different degrees of inflammation; this is dependent on the virulence of the bac- teria, on individual differences of the infected persons, on the seat of the infection, and on the influence of preceding or accompanying condi- FiG. 392. — Streptococcus phlegmon in muscle. (Alcohol, Weigert's stain.) a, Masses of streptococci; &, leucocyte infiltration; c, transverse section of muscle-fibres. X 100. tions. In respect of this last factor it may be noted that many infectious diseases (diphtheria, scarlatina, smallpox, tuberculosis, typhoid fever, in- fluenza) which lower resistance increase the predisposition to strepto- coccus infection. In the growth of streptococci on the surface of the endocardium, the inflammation often bears a pronounced proliferative character (Fig. 395, d, c). In hasmatogenous streptococcus-dermatitis (Fig. 396) the process may cease with the formation of red spots. Phlegmons, although they usually pursue a rapid course and lead in a short time to necrosis and suppuration, niay also have a chronic course, particularly in the neck, and are characterized by progressive swelling and induration of the affected area, so that the affection is famiharly designated "wooden phlegmon." Fever may be absent. The process consists of progressive proliferation of granulation tissue and new-formation of con- nective tissue due to streptococci (or staphylococci), while suppuration is absent or confined to circumscribed areas. STREPTOCOCCI. 439 The biological characteristics of Streptococcus pyogenes are variable; this is well shown both in its behavior as a disease-producing agent and in cultures- of streptococci taken from different cases. Consequently an efforf has been made to divide streptococci into different species, in particular has the streptococcus which causes erysipelas been regarded as a distinct form — the Streptococcus erysipelatis:. Further, according "to the place in which the streptococcus was found, it was for- merly customary to speak of Streptococcus puerperalis, Str. articulorum, Str. scarla- tinosus; or, according to the manner of growth, of Str. longus and Str. brevis, etc. These characteristics are, however, not sufficient to form a basis for the separa-. tion of streptococci into different species ; and it appears more correct, or at least m,ore expedient, to consider all the chain-forming streptococci as one species, which appears in many varieties. According to Howard and Perkins (Jour, of Med. Re- search, 1901) there is a small group of pathogenic capsulated streptococci char- acterized by the viscidity of their growth and by the formation of gelatinous exuda- tions in animals. For this group they propose the name of Streptococcus mucosus. Fig. 393. — Streptococcus infection of the petrous portion of ^ the teraporal bone, from a child of eight months of age (formalin, nitric-acid decalcification, carmine, methyl-violet), a. Medullary spaces completely filled with streptococci; b, beginning . invasion by streptococci; c, bone marrow; o, trabecule of bone, x 300. In diphtheria and scarlet fever, streptococcus infections of the throat and air- passages' are extremely common, " particularly in the first-named, so that many authors are inclined to assign to the streptococcus a co-ordinate position with the diphtheria-bacillus in the causation of diphtheria — the diphtheria-bacilli predomin- ating in the lighter forms of infection, the streptococci in the more severe. Pure streptococcus infections rnay present the same picture as that produced by Loeffler's bacillus. If both forms of bacteria are present, their effects may be combined ; per- haps the presence of streptococci increases the virulence of diphtheria-bacilli. The Streptococcus pyogenes is especially pathogenic for mice and rabbits (less so for dogs and rats) ; but its virulence varies greatly, and rapidly decreases in cultures grown on ordinary media. Its virulence is retained for a relatively long time (Marmorek) in cultures of the cocci in human- or in horse-serum (serum two parts, bouillon one part) , or in a mixture of bouillon and ascitic fluid. The nature of the poisons produced by streptococci is not known. It has been definitely determined that filtered cultures sterilized at 65-70° C. contain poisons ; but it is not yet known whether this poison, like the toxin of the diphtheria- bacillus, produces an antitoxin. 440 THE PATHOGENIC FISSION-FUNGI. According to Simon there can be distinguished an intracellular weakly virulent poison and a toxin excreted by the streptococcus. The latter, however, is produced only under certain conditions, for example, under the influence of the bactericidal juices of the animal body. Under certain conditions the streptococcus can also produce haemolysin. Numerous investigators (Neufeld, Rimpau, Tavel, Memer, Aronson, Marmorek, Moser, and others) have atteniipted to immunize animals against streptococci and to produce an antistreptococcus serum, and the sera thus obtained have been used in the treatment of streptococcus affections in man. At present it is not possible to judge as to the therapeutic value of these procedures. ■^3':i-i. m^' m^-nj^t Fig. 394. — Metastatic hajmatogenous streptococcus pneumonia, after angina (alcohol, alum- carmine, methyl-violet, iodine), a, Pneumonic focus with (blue) streptococci; b, slightly inflamed lung tissue about the focus, x 80. § 153. The Diplococcus pneumoniae. Streptococcus lanceolatus, or Diplococcus lanceolatus, familiarly known as the Pnenmococciis, is of frequent occurrence. It forms spherical, oval, and lanceolate cocci (Fig. 398, a), which in the human body are usually surrounded by a capsule, and are grouped in pairs (b, d), or more rarely in chains of such pairs (c), or in large colonies ((/). The pneumococcus stains well with fuchsin and with gentian violet, and by these stains the capsule may be demonstrated in smear-prepara- tions. The cocci are also stained by Gram's method. The cocci are facultative anaerobes. They will not grow on gelatin at ordinary room-temperature, but do so on slightly alkaline blood-serum- gelatin, on agar and in bouillon, at a temperature above 22° C, and best at the temperature of the body. They form on the surface of the mediiim a delicate, translucent, glistening culture, which suggests the dew-hke deposit of moisture on glass (Frankel) ; and consists of diplococci and chain-cocci without capsules. The growth is, however, scanty; and easily dies out. Upon potatoes cultures do not thrive. PNEUMOCOCCUS. 441 The Diplococcus pneumoniae is in a great number of cases (according to Weichselbaum in seventy-one per cent.) the cause of croupous pneu- monia, in which the lung is the seat of an acute inflammation ushered in by congestive hyperaemia (Fig. 399, a). In the course of the disease the alveoli over large areas become filled with coagulated exudate consisting of desquamated epithelium, leucocytes, red blood-cells, serous fluid and fibrin (Fig. 176). In favorable cases the exudate becomes liquefied and absorbed. As has been shown by numerous observations, the Diplococcus Fig. 395. — Endocarditis of the wall of the left auricle, due to streptococci (alcohol, methyl- violet, carmine), a, Masses of cocci; b, fcij leucocytes and coagula; c, area of proliferation; d, inilamed endocardium, x loo. pneumoniae may also cause other inflammatory processes bearing the character of a catarrhal or bronchopneumonia. During the course of the disease the cocci are found in the inflamed areas, in greatest numbers at the beginning of the inflammation; they lie free in the alveoli (b) and clinging to cells (d). They are also found in parts of the lung bordering on the inflamed area, in the pleura, and under certain conditions in the pericardium, peritoneum, meninges, accessory nasal cavities, cellular tis- sue of the neck, in the mediastinum, submucosa of the soft palate and pharynx, in the conjunctiva, and skin. In all these places they may give rise to inflammatory changes. At times they may be demonstrated in the spleen, and in the blood, and in pregnant women may pass into the foetus (Viti). Under certain circumstances they may be widely distributed through the body; and may cause, in the meninges, pleurae, pericardium, and peritoneum, fibrinous, serofibrinous, and at times seropurulent and fibrinopurulent inflammations, without giving rise to pneumonia. Fur- ther, they may cause inflammations of the conjunctiva, middle ear, endo- cardium, joints; these inflammations may lead to suppuration. In many cases the mouth and nasopharynx appear to be the avenue of entrance — in these regions the cocci are not infrequently found in healthy in- 442 THE PATHOGENIC FISSION-FUNGI. dividuals Correspondingly, in cerebral and cerebrospinal meningitis the maxillary cavities, tympanic cavity, and the ethmoid labyrinth often con- tain exudates with diplococci. They are found in the exudates in all the forms above mentioned; the gelatinous capsule may present a variable thickness. When inoculated into , rabbits, guinea:pigs, and mice, the Diplococcus pneu- moniae increases in the form of encapsulated cocci, particularly in the blood and serous cavities, and may cause pneumonia with bloody serous exudate. When in- jected beneath the skin of the rabbit's ear (Neufeld) they produce erysipelatous inflammations. Rabbits are especially susceptible; they die with syntptoms of septicemia in from thirty-six to forty-eight hours after subcutaneous inoculation. y tv tf ;',>-!. W: ■■■A-s;'".^ ■':..,' --■ .. rv--. -..■'.- "' • ■■ " -:■ -.-■-.-;:. Pig 306 — Erythema multiforme, due to streptococcus infection, arising in the middle ear (Fig 303) from a child eight montha old. Section through a red spot in the skm of the back of the foot (alcohol, methyl-violet, carmine), a, Corium; b, subcutaneous tissue; c, capillaries filled with streptococci, x 46. The injection of pure cultures into the pleural cavity of rabbits gives rise to pleur- itis as well as splenization of the lung, in which the parenchyma of the organ is filled with a haemorrhagic serous exudate. According to A. Frankel the cocci easily lose their virulence, particularly when cultivated on milk; and if it is desired to retain their viriilence they must, from time to time, be passed through susceptible animals. Cultivation of the cocci at 42° C. for one or two days destroys their virulence. It may be regarded as demonstrated that VaeDiplococcns pneumonia can cause meningitis; there also exists a coccus, the Diplococcus intracellularis meningitidis {Weichselhaum) , which is dififerent from the pneumococcus and is to be regarded as the cause of epideniic cerebrospinal meningitis. Albrecht, Ghon, and Weichsel- haum point out its great similarity to the gonococcus. It is found in the nasal secretions of epidemic meningitis and also in that of individuals coming in contact with such cases. In the cerebrospinal exudate it is found particularly in the poly- nuclear leucocytes. The essential pathological lesions are inflammatory chanees in the membranes of the cord and brain, and in the tissue of the brain, cord, and nerves. Flexner and Jobling (lour. Anier. Med. Assoc., July, 1908) report en- couraging results in the treatment of epidemic meningitis with a serum prepared in the horse by inoculation of Diplococcus intracellularis. PNEUMOCOCCUS. 443 Pneumotoxin is formed by , pneumocooci most abundantly in the human and animal organism^ but only sparsely in nutritive media {Isaeff). It is doubtful whether bactericidal antibodies or antitoxins arise during the course of the disease. It is therefore probable that the pneumotoxin does not belong to the true toxins. Animals may be immunized in various ways against pneumococci, and the serum of an immunized animal may be used as a healing serum. The results of treat- ment in man are still doubtful. Difficulties arise through the fact that pneumonia can be caused by other bacteria (pneumo-bacilli, pus cocci, influenza-bacilli, etc.). Literature. {Pneumococcus and Meningococcus.) Albrecht u. Ghon: Meningococcus intracellularis. Cbl. f. Bakt., Orig., xxxiii., 1903. Councilman, Mallory, and Wright: Epidemic Cerebrospinal Meningitis, Boston, 1.898. Flexner: Antimeningitis serum. Jour, of Exper. Med., 1908. Herrick: Pneumococcic Arthritis. Amer. Jour, of Med. Sc, 1902. Weichselbaum: Aetiologie der acuten Lungen- und Rippenfellerttziindungen. Med. Jahrb., Wien, 188^; Histor. Bericht iib. die Aetiologie der acuten Lungen- und Rippenfellentziiiiiungen. Cbl. f. Bakt., i., 1887; Aetiologie d. acuten Fia 307 Extreme streptococcus infection of the kidney (grayish areas), arising after ;ptococcus angina (alcohol, Weigert's stain) . a. Cocci in the intertubular; b, in the glomerular streptococcus angina ^ , •,—=-.--.-, - .- ^ u i o capillaries; c, urinary tubules; d, fibrin m the urinary tubules, x 280. Meningitis cerebrospinalis. Fortschr. d. Med., v.; 1887; Aetiologie u. path. Ana- tomic der Endocarditis. Beitr. v. Ziegler, iv., 1888: Seltenere Localisation des pneumonischen Virus. Wien. klin. Woch., 1888; Der Diplocoocus pneu- moniae als Ursache der primaren acuten Peritonitis. (Tbl. f. Bakt., v. 1889; Diplococcus pneum. u. Meningokokken. Handb. d. path. Mikroorg., iii., 1903. 444 THE PATHOGENIC FISSION-FUNGI. § 154. The Staphylococcus pyogenes aureus or Micrococcus pyo- genes consists of spherical cells occurring singly or in pairs, by multipli- cation forming grape-like clusters. The cocci are easily stained by various aniline dyes, and by Gram's method. They are facultative anaerobes, but grow better when sup- plied with oxygen. The staphylococcus thrives on all culture-media, even at room-temperatures, though better at i7° C. It forms colonies which produce pigment in those parts exposed to the air and become orange-yel- low. The pigment-formation is most marked on agar and potatoes. Gelatin is slowly liquefied. In the presence of grape-sugar it forms lactic, acetic, and valerianic acid. In bouillon-cultures there are produced poisons of violent action. The Staphylococcus pyogenes is one of the most fre- quently occurring pathogenic bacteria, and is, with Streptococcus pyo- genes, the most common cause of suppuration. Both forms are therefore designated pus-cocci. It is widely distributed through the external world, and has been demonstrated in milk, wash-water, and waste-water. Fic. 398. — Diplococcus pneumonia;. (Weichsel- baum.) a. Cocci without capsule; b, single and double cocci with a gela- tinous capsule; c, chain of encapsulated cocci; d, col- ony of cocci. X 500. 4 f^^y^"^^>-'^^^-'''-^^ 1^ © ^■c - - T, < M: _.r'i«'k I'M Om "b® ,jr Fig. 399, — Diplococcus pneumonia in early stage (formalin, fuchsin). a. Hypersmic vessels; b, diplococci; c, cellular exudate; d, swollen epithelial cells covered with cocci, x 500. as well as in the air of operating-rooms and sick-chambers. Increasing in the tissues of the human body (Figs. 400-402) it causes tissue-degenera- tions and necroses followed by inflammation (Figs. 400, d, e; 401, h, c; 402, r, d) which is usually purulent in character, but not infrequently it does not lead to suppuration. STAPHYLOCOCCI. 445 The suppurations produced by .staphylococci are usually circumscribed (Figs. 400, 401), and show less tendency to involve surrounding tissue than the suppurations caused by streptococci. In the skin they give rise to furuncle, and cutaneous and subcutaneous abscesses. In the osseous system they are the most frequent cause of suppurative osteomyelitis Fig. 402) and periostitis. They not infrequently cause purulent inflam- mations of the liver, lungs, pleura, peritoneum, brain, meninges, muscle, myocardium, spleen, kidneys, joints, etc.; and are often the cause of inflammations of the endocardium. Since the virulence of staphylococci varies, they may produce, in the regions named, transitory inflammations which heal with or without scar-formation. The portal of entrance of staphylococci is often easily recognizable (especially wounds), and the same is true of the path of metastasis to internal organs, whereby inflammations of the lymph-vessels (lymphango- FiG. 400. — Multiple abscesses of the skin due to staphylococci (alcohol, carmine, Gran.'s method). Child of three weeks, a. Epithelium; b, corium; r, hair-follicle; rf, e, purulent foci with cocci. X 40. itis) and of the blood-vessels (phlebitis, arteritis) make their appearance. Cryptogenic infections are, however, not infrequent, so that the first recognizable localization of the infection appears in the endocardium, myocardium, or bone-marrow. The spread of staphylococci through the blood leads to multiple localizations with abscess formation ; this condition is designated pyaemia. The complication of staphylococcus infection with severe symptoms of intoxication is known as septicaemia; and the com- bination of staphylococcus-pysemia with septicaemia is known as septi- copyaemia (cf. § 11). Staphylococcus pyogenes aureus is also pathogenic for animals: horse, dog, cattle, goat, sheep, rabbit, guinea-pig, and mouse, particularly for the hrst-named, less so for the last. In these animals, it causes suppu- ration. The staphylococcus loses its virulence easily in cultures. The inoculation of cultures of high virulence into susceptible animals causes gelatinous oedema. 446 THE PATHOGENIC FISSION-FUNGI. Related to the Staphylococcus pyogenes aureus are the Staphy- lococcus pyogenes albus and the Staphylococcus pyogenes citreus. The albus forms whitish, the citreus lemon-yellow colonies. The former is the cause of the so-called " stitch-abscesses " in surgical wounds, but is otherwise of negligible significance. Staphylococcus pyogenes aureus usually occurs alone in pus-foci, but may be associated with other pus-cocci or even bacilli, for example, the Bacterium coli commune, or the typhoid-bacillus. The staphylococcus forms a hsemolysin and a leukocidin (Van der Velde, Neisser, and Wechsberg) which destroys the leucocytes of rabbits, and also poisons which have a degenerative action on the tissues. The bodies of dead staphylococci cause inflammation when injected into tissues. Staphylolysin arid hemolysin and leukocidin form in the organism antistaphylolysin and antileukocidin and therefore belong to the toxins. A serum produced by pathogenic staphylococci will agglutinate both the homol- ogous strain as well as the majority of other pathogenic strains {Kloppstock and Bockenheimer). Fig. 401. — Miliary purulent nephritis, caused by staphylococci, primary focus in slcin (furunculosis) (alcohol, methyl-violet, carmine), a, Normal kidney tissue; h, collections of cocci; Cj purulent focus, x 43. § 155. The Micrococcus Gonorrhoeae or Gonococcus (Fig. 403) was described by Neisser in 1879. It is constantly present in the discharges of the purulent catarrh, known as gonorrhoea, of the male and female urethra, and the female genital canal (especially of the cervix), as well as in the secretions of gonorrhoeal ophthalmia. It is universally regarded as the cause of gonorrhoea. Besides the specific cocci, other cocci may be present in gonorrhoeal secretions, some of them closely resembling the gonococcus ; pus-cocci «iay also be present. The gonococcus may be cultivated on coagulated human blood-serum, blood-serum gelatin, on human blood-serum-agar, on urine-agar; and forms on the surface of the nutrient medium a thin grayish-yellow layer having a smooth surface. It dies easily, and grows only at higher tem- peratures. GONOCOCCUS. 447 The gonococcus contains a poison (Wassermann) which, when injected into the tissues, excites inflammation. Animals are immune against inoculations with the gonococcus with the exception of the higher apes. Efforts to inoculate human beings with artificially cultivated gonococci have been successful in producing purulent catarrh of the inoculated mucous membrane. In the purulent secretion of the mucous membrane infected with gon- orrhoea the coccus usually forms clumps, and appears in the form of diplococci, the opposing surfaces of which are flattened (Fig. 403) ; but occurs also free (a), and inclosed within cells (b). It stains easily with aniline dyes, but is decolorized by Gram's method. The gonococcus penetrates into the epithelial layer of the affected Fig. 402. — Staphylococcus osteomyelitis of calcaneus. (Alcoliol, metliyl violet, carmine.) iij Trabeculae of bone; b, fatty marrow; c, purulent area; d, cocci. X loo. mucous membrane, and lies between and in the epithelial cells, and in leucocytes. Only the uppermost layers of the connective tissue are infiltrated. The infiltration is most marked in the case of cylindrical epithelium, while in regions covered by squamous epithelium (fossa navicularis, vagina) the cocci lie more superficially. They cause inflam- mations which bear the character of purulent catarrhs, and are associated with cellular infiltration of the tissue of the mucosa (Fig. 404, b, c, d) and with epithelial desquamation. The male and female urethra and the adjoining parts of the genital glands and ducts and the urinary passages form the chief seats of localization. According to Scholz there occurs, after three-weeks' duration of the disease in the male urethra, meta- plasia of cylindrical into stratified squamous cells, and the secretion decreases after this time. To what extent the deeper inflammations so 448 THE PATHOGENIC FISSION-FUNGI. P,-~. frequently accompanying or following gonorrhoea (peri-urethral abscesses, prostatitis, epididymitis, vesiculitis, cystitis, inflammation of the ducts of Bartholin's glands, salpingitis, ovaritis, pelvic peritonitis, arthritis, etc.) are to be referred to the spread of the gonococcus or to what extent to secondary infections by pus-cocci is a question. There can be no doubt that the gonococcus may become widely spread over the surface of mucous membranes. It has been demon- ---_--' ^ ,^^ . £. strated in the blood, in the inflamed epidi- dymis, tubes, ovaries, joints, cardiac valves, tendon-sheaths, bursas, in peri- and para- metritic foci of inflammation, and in peri- urethral abscesses. In these cases it is usually regarded as the cause of the inflam- mation, yet the processes which lead to sup- puration, and even the metastases in dis- tant organs, appear to be more frequently Fig. 403.— Gonococc! in the urethral dependent OH the presence of pus-cocci. secretion from a fresh case of gonor- /^ ^ „i^, 1 ■_£ ,* „ • , .i 1 _■ • rhcea (methyiene-biue, eosin). a. Cjonorrhoeal mfectioH IS at the bcgmnmg Mucus with single cocci and dipio- an acute proccss, but may become chronic, cocci; b, pus-cells with, c, pus-cells , . , . , -^ ,.-„ , . without dipiococci. X 700. and IS cured With great difficulty, since gonococci maintain themselves in the urethra, tubes, etc., for years, and continue to cause inflammation. ^z:^ Irons (Jour. Infect. Dis., 1908) found that the injection of dead gonococci into individuals suffering from chronic gonococcus infections gave a " gonococcus-re- action " which may be of assistance in diagnosis. Fig. 404.— Urethritis gonorrhoica. Cross-section through the mucous membrane which had been thrown into folds (Miiller's fluid, hematoxylin, eosin). a, Normal connective tissue; b, c, inflammatory, infiltrated, proliferating connective tissue of the mucosa; d, infiltrated and desquamating epithelium; e, desquamated epithelial cells and pus-corpuscles, x 100. BACILLI. 449 2. The Bacilli and the Polymorphous Bacteria, and the Patho- logical Processes Produced by Them. (a) General Considerations Regarding Bacilli and the Polymorphous Bacteria. § 157. Under the designation bacilli may be classed all those bacteria which occur in the form of straight rods or rods which are slightly bent in one plane. The bacilli multiply by division. The rods grow in length, and divide into approximately equal parts through the formation of a transverse partition-wall. If the division of one of the elongating bacilli is delayed, or if the separation of the individual rods from one another is not dis- tinctly recognizable, there arise long, unbranched rods or threads (Fig. 406, b). If the divided rods remain attached to each other, there Fig. 405. Fig. 406. Fig. 405. — Bacillus subtilis in various stages of development (Prazmowski) , a. Single rods; b, rods with flagella; c, chain of rods; d, single cells with spores; e, chain of rods with spores; / ^ — ■*, germination of a spore. X 800. Fig. 406. — Clostridium butyricum (Prazmowski). a. Short rods; 6, long rods; c, chain of rods; rf, cells with spores; e ^ — ^, germination of a spore, x 800. are formed chains of rods (Figs. 405, c; 406, c). In many forms of bacilli the ends of the individual rods are blunt, in others rounded or pointed. In many bacilli, resting as well as swarming stages are observed. Flagella serve as the organs of motion (Fig. 405, b) ; they are situated sometimes at the ends, sometimes on the sides, of the rods, and may occur in large numbers. In many bacilli endogenous spore-formation is observed (Figs. 405, d, e; 406, d), the spores lying sometimes in the middle, sometimes at one end, of the cell. Not infrequently the spores appear within jointed threads. The germination of spores results in the form'ation of new rods (Figs. 405, /, 1-5 ; 406, e, 1-7). During spore-formation the rods usually do not change their shape to any marked extent. In other cases they assume a spindle-, club-, or pear-shape (Fig. 406, d). The polymorphous bacteria are distinguished from bacilli by the fact that they form, besides rods, long threads, with false or true branch- ing; in individual cases a basal non-proliferating end and an apical pro- liferating end may be distinguished. In this category may be placed the fungi designated Streptothrix, Cladothrix, Beggiatoa, and Crenothrix. They are placed with the bacilli, because their botanical position is not 29 450 THE PATHOGENIC FISSION-FUNGJ. definitely determined, while, in so far as they are pathogenic, they con- form closely to the bacilli in their biological properties (c/. diphtheria- bacilli, tubercle-bacilli and actinomyces). The saprophytic bacilli produce various forms of fermentation by their growth in nutrient fluids ; many form pigments. A sharp line cannot be drawn between saprophytic bacilli and pathogenic forms, since some saphrophytes {proteus vulgaris, Bacillus pyocyaneus, B. tetani, B. cedematis maligni) occasionally develop in the human organism. Some also form toxins (B. botulinus, B. pyocyaneus) which when taken into the organism produce intoxication. Bacillus botulinus (Van Ermengem) is an obligate anaerobic bacillus which develops occasionally in sausage, particulai'ly in blood and liver sausages, in smoked meat, canned meats, game pies, salted fish, and in preserved fruits and vegetables. The bacillus is 4—6 n long, 0.9—1.2 fi broad and possesses 4—8 peripherally arranged flagella. It stains accord- ing to Gram. In ordinary nutritive media it grows best under anaerobic conditions at a temperature of 18°— 25° C, and forms endogenous spores. Acids inhibit its growth. When growing in the foods mentioned, it produces a toxin which is poisonous for experimental animals, and causes the formation of an antitoxin. The poison is rendered inactive by heating to 80° C, but is not changed by the digestive juices. The consumption of food in which the bacillus has already formed its toxins leads, therefore, to intoxication. On the other hand, the bacillus ddes not develop in the human organism, its growth being hindered by the high body temperature. The bacillus should be classed as a toxicogenic saprophyte. The intoxication known as botulismus comes on about twenty-four to thirty^six hours after the taking of poisoned food, and is characterized by nervous disturbances of central origin (paralysis of accommodation, mydriasis, ptosis, and double vision), dryness and redness of the mucous membrane of mouth and pharynx, aphonia, dysphagia, etc. Constipation and retention of urine frequently take place, or there may be diarrhoea and ' vomiting. Death often results after a short time through bulbar paralysis. It has been shown that the designation botulism, or sausage poisoning, is inappropriate to this form of bacterial intoxication, at least as it occurs in the United States. Canned string beans, asparagus, corn, apricots, ripe olives and cheese have at various times and places been implicated. The majority of outbreaks recorded in this country have been due to house- hold canned foods, but the bacillus may also find its way into canning factories. In either event, the spores of the causative micro-organism may survive relatively high temperatures and subsequently germinate to produce a potent toxin, the ingestion of which gives rise to symptoms of poisoning. There seems to be no doubt that the early statements of Van Ermengem relative to the low heat resistance of this organism are incorrect as applied to all strains. For example, most of the American strains have been found to withstand much higher temperatures, some even resisting the temperature of boiling water for a considerable period. Outbreaks of botulism have been recorded in Belgium, France and Ger- many. Thus far. Great Britain appears to have been exempt. In the United States, the majority of cases have been reported from California, Idaho, Colorado, Indiana, Massachusetts, Michigan, New York, Kentucky and Illinois, so that the disease occurs in widely separated parts of the BACILLI. 451 country. Several recent outbreaks have been traced to canned ripe olives. (Journal of the American Medical Association, December 13 and 20, 1919.) As Proteus vulgaris, Hauser has described a bacillus which is fre- quently present in decomposing animal substances and in human cadavers, and in gangrenous ulcers. It forms rods of varying length, and produces substances poisorious for animals. It is not infrequently found in human tissues, in association with streptococci, pneumococci, and diphtheria- bacilli ; and by its presence aggravates infection and causes putrid decom- position of pus and necrotic tissue. In rare cases it may alone cause inflammation, particularly of the urinary bladder (cystitis). Cases of hcemorrhagic enteritis have been described, in which a form of proteus was regarded as the causal agent. The pathogenic bacilli and polymorphous bacteria cause both acute and chronic affections, the former terminating in death or in healing after destruction of the bacteria. In acute diseases the bacteria may remain in the body for a long time after the disappearance of symptoms. The chronic affections are characterized by persistence and multiplication of the bacteria in the body, so that the disease assumes a progressive character, and sometimes slowly, sometimes rapidly, new regions are invaded and suffer changes. Bacillus subtilis is a fission-fungus whose spores are widely distributed in the ground, in hay (hay-bacillus), and in the air. When cultivated on potato or on the dung of herbivorous animals, it forms whitish-yellow colonies ; on liquids it forms pellicles. It requires oxygen for development. The fully developed rods (Fig. 405, o) are 6 l^- long. The snake-like motions occurring at times are produced by lateral and terminal flagella. Through the growth of the rods undivided threads are formed which after division form chains of rods. The separate cells may develop in their interior glistening, sharply con- toured spores {d, e), which lie either in the middle or nearer to one end of the cell. Later the cells in which the spores have been formed die. During germination the spores become pale (Fig. 405, /, ^-^), lose their glistening appearance and sharp contour. A shadow then appears at each pole, while the spore begins a tremulous motion. After a time the contents of the spore project from the membrane of the spore in the form of a germinal utricle, which later becomes elongated, divides and produces swarming rods. Bacillus prodigiosus grows on potatoes and bread, as well as on agar-agar, and on gelatin, liquefying the latter. It forms a red coloring matter which is soluble in alcohol. The pigment is formed only in the presence of oxygen; in the' growth in milk the coloring-matter is contained in the fat-droplets. The bacilli themselves are colorless. Bacillus pyocyaneus occurs occasionally in bandages on suppurating wounds and causes a greenish-blue discoloration of the same. The coloring-matter called pyocyanin is soluble in chloroform and crystallizes from the solution in long blue needles. In addition, it forms a coloring matter soluble in water that produces a greenish fluorescence of gelatin. (&) The Pathogenic Bacilli and Polymorphous Bacteria. § 158. The Bacillus anthracis (Bacteridie du charbon) is the cause of anthrax, a disease occurring chiefly in cattle and sheep, occasionally transmitted to man. It is a fission-fungus which, when inoculated into a susceptible animal, increases locally in the tissues and later enters the blood. Anthrax-bacilli (Fig. 407) are 3 to 10 /* long and 1 to 1.5 /^ broad. In the blood of animals affected with anthrax they occur either singly or in thread-like jointed bands of two to ten rods, whose ends are sharply 452 THE PATHOGENIC FISSION-FUNGI. cut across (Figs. 407, 408), more rarely concave or slightly convex. They possess a gelatinous capsule which is best brought out by staining dried preparations by the method of His or Welch. They can be culti- vated on blood-serum-gelaltin, in bouillon, on slices of potatoes or turnips, and on plain agar, in the presence of oxygen, and grow most rapidly at a temperature of from 30° to 40° C. At temperatures below 15° and above 43° C. development is impossible. Under suitable conditions of growth the rods increase in length, and within a few hours form non-encapsulated threads of considerable length. These consist of short segments whose outlines may be made visible by treatment with iodine or by stains (Fig. 408). Ten hours later the clear contents of the threads become / ^24. granular, and at regular inter- // ^t;--^ vals there become apparent ^"^ 'y^j^ bodies which, after a few hours, A^- 4: •v-;. N-^-^^ ^x-: .^N Fig. 407. — Section from a Hver whose capil- laries contain numerous anthrax-bacilli _ and scattered leucocytes (alcohol, gentian-violet, vesuvin). x 300, * ^ ^ "C^GO i^sT: Fin. 408. — Spore-containing anthrax-bacilli and free spores. Cover-glass prepara- tion from a culture of the bacilli grown in the incubator upon a potato, and stained with fuchsin and methylene- blue. X 800. enlarge into strongly refractive spores (Fig. 408). Later the threads disintegrate and the spores become free. If the bacilli or spores gain entrance to the blood, they increase and form rods as described, that stain with aniline dyes, and by Gram's method. Sections of hardened tissue show that they are present in large numbers in the capillaries (Fig. 407), particularly in the spleen, liver, lungs, and kidneys. The neighboring parenchyma appears unchanged; still local proliferation of the bacilli can cause tissue-degeneration, necrosis, and hsemorrhagic inflammation. If infection of the blood takes place during pregnancy the infection may pass to the foetus. Anthrax-bacilli or their spores may gain entrance into the skin of man through small wounds, an event which is particularly likely to happen in individuals who butcher, or shear, or prepare the skins of animals infected with anthrax; occasionally infection may be transmitted by means of the sting of a fly which has taken up blood from an animal infected with anthrax. Infection not uncommonly is due to the use of shaving brushes made of infested hairs or to the wearing of contami- nated furs. There develops at the place of infection a pustule (Fig. 409) from 6 mm. to several centimetres in diameter, having an arched or flat- tened surface, and a red or yellowish color. This is after a time covered with vesicles, or after the loss of epithelium becomes moist, so that through drying of the exudate, a scab is formed (Fig. 409, g'). ANTHRAX. 453 The centre may become depressed through the formation of an area of softening, so that the edges form a wall about the latter. The neigh-, borhood of the pustule is sometimes but slightly changed, at other times reddened and swollen, and may be set with minute yellow or bluish-red vesicles. If the process remains local, the gangrenous pustule may be thrown off. Infection of the blood is fatal. In rare cases the infection from the beginning may show itself as an extensive, intense, oedematous swelling of the tissue without the formation of a circumscribed elevation (malignant anthrax osdema). In the region of a fully developed anthrax-pustule (Fig. 409), the corium {d, d-^) and the papillary body (c) are infiltrated with serocel- lular exudate as well as by bacilli. The bacilli lie particularly in the outer portions of the corium (d^) and in the papillary body (c), but may pene- \ \ / 1; - - ,_-^ Fig. 409. — Section from an anthrax-pustule ten days old, taken from the arm of a man (alcohol. Gram's method, vesuvin). a, Epidermis; b, corium; c, papillary body ffidematously swollen and infiltrated with exudate and bacilli; d, outer layer of corium, infiltrated with cells; di, the same containing also bacilli; e, deep layers of the corium infiltrated by cords of cells; f, dermal tissue infiltrated with bacilli and cells; g, bloody exudate containing bacilli, lying upon the surface; h, hair-follicle; i, sweat-gland, x 33. trate the deeper layers of the corium (/). In the neighborhood of the papillary body (c) the exudate is sanguineous. Vesicles filled with bloody fluid result, if the exudate extends to the epithelial covering, and if the deeper portions of the latter become liquefied, permitting lifting of the superficial layers by the exuded fluid. If the upper layers of the skin are lost, the bloody fluid containing bacilli (g) appears on the surface. The cellular infiltration has its seat chiefly in the corium (d, d^, e), and the impression is gained that massing of cells forms a protection against the spread of the bacilli. The cells which collect belong for_ the greater part to the polynuclear leucocytes (Fig. 410). The bacilli lie sometimes in, sometimes between the cells. 454 ANTHRAX. If infection with anthrax-spores takes place in the intestinal canal, an event which occurs most frequently in the small intestine, less often in the stoma:ch and large intestine, there develop dark-red or brownish- red hsemorrhagic foci, the size of a lentil or bean or larger, with a grayish- yellow or greenish-yellow slough in the centre. In other cases the crests of the folds of the mucosa are swollen and hjemorrhagic, and show evi- dences of sloughing. The mucosa and submucosa are infiltrated with blood in the region of the foci ; the surrounding tissues are oedematous and hypersemic. Bacilli are found in the tissues in and about the foci, particularly in the blood- and lymph-vessels, and may be demonstrated in neighboring lymph-nodes. Primary lung infection may occur in man as the result of inhalation of anthrax-spores, proving fatal in from two to seven days. Individuals who handle the hair of animals that have died of anthrax are especially exposed to infection ; the rag-sorter's disease, "^r'l^t'i which occurs in men and women employed in '"' '""' the sorting of rags in paper-factories, is an anthrax infection. The spores taken into the lungs in respired air develop in the bronchi and alveoli, in the lymph-spaces of the lungs and pleura and in the bronchial nodes, and penetrate into vessels. Their growth causes inflammatory haemorrhagic processes in the lungs, as well as hsemorrhagic exudations into Fig. 410. — Portion of an- the pleural cavity and mediastinal tissue, and thrax pustule trom the arm /, . . , -^ . , , - , (Fig. 409), containing bacilli. swcIlings of the lympli-uodes. it may also ^ •'^°' lead to necrotic foci in the lungs and in the bronchial and tracheal mucosa. Mice, rabbits, sheep, horses, and sparrows are susceptible to anthrax; white rats, dogs, and Algerian sheep are less susceptible or immune. Cattle are easily infected through taking in of spores from the alimentary canal, but are less susceptible to inoculation. Formation of spores does not take place in the tissues and blood. Among certain animals, geographically as well as zoologically, anthrax is the most widespread of all acute infective diseases. In occasional instances it is trans- mitted to man, usually through abrasions of the skin that have been in contact with infested hides, furs, shaving brushes made of containinated hairs, and the like, but sometimes by swallowing or breathing. In recent years the occurrence of anthrax in human beings has undergone increase and is now regarded by students of industrial conditions as an occupational disease of moment. Moreover, in view of the fact that hides, furs and other products of anthrax-infested districts are seldom, if ever, subjected to disinfection before shipping, it is to be expected that anthrax will undergo still further increase as our trade with the cattle countries enlarges. In this climate anthrax is most often encountered among handlers of hides imported from the Argentine and Far East. Sometimes the disease appears in epidemic form among longshoremen engaged in unloading the same cargo. Malignant anthrax oedema of the face and neck is practically always fatal. In the same way the so-called wool-sorters' disease, which is an anthrax septicemia with intense pulmonary and cerebral symptoms, and anthrax of the intestinal tract, are likewise deadly. The malignant pustule, on the other hand, not infrequently heals and the patient recovers. In malignant pustule of the face, however, the mortality is five times greater than that of an extremity, in which only a small percentage of cases terminates fatally. In the past four j^ears 20 cases of malig- nant pustule have been treated at Bellevue Hospital. Of these, 13 recovered. This variety of anthrax is, at the beginning, a purely local lesion. The malignant pustule is a characteristic and easily recognized lesion. At the site of inoculation a small papule appears and within a few hours is surrounded by extensive oedema. The ANTHRAX. 455 papule rapidly undergoes enlargement and central necrosis attended by the forma- tion of a series of silvery vesicles scattered over the scab or immediately circum- ferential to the necrotic zone. The patient's mentality is usually preserved through- out. The swelling of the tissues in the immediate vicinity of the pustule may be extreme and depends on infiltration by so-called anthraco-mucin, which is a pro- tective substance. In it anthrax bacilli do not thrive. Incision of the oedematous area, therefore, is contraindicated. In recent years the serum treatment of anthrax has received a great deal of attention. The serum is injected intravenously in large doses at frequent inter- vals. Local injection of serum at multiple points in the immediate vicinity of the anthrax pustule is an exceedingly important part of the specific treatment and should Fig, 411. — (Bellevue Hospital.) Anthrax pustule of left side of neck showing the wide- spread swelling of the surrounding tissues due to infiltration by anthraco-mucin. never be neglected. There are those who advocate at the same time excision or cauterization of the pustule, while others depend entirely on the local injection of serum to control the infection. After the bacillus invades the blood stream, of course, the outlook is hopeless, serum or no serum. The bacilli of anthrax are killed by high temperatures, drying, and through ' decomposition of the nutrient fluid. The spores, on the other hand, are resistant, and are usually the medium of spread of the disease. The colonies on gelatin show a wavy, irregularly shaped margin, and consist of interlacing strands or threads, which grow out of the culture in all directions. Tha gelatin is liquefied immediately about the culture. On potato the bacillus forms grayish-white, slightly granular colonies having a sharply outlined border. On blood-serum it forms a white coating. Stab-cultures in gelatin are white and during the process of growth radiate at right angles from the line of inoculation into the gelatin, particularly near the sur- face. After liquefaction of the gelatin they sink to the bottom. Marked attenuation of anthrax-bacilli may be produced by keeping the bacilli for ten minutes at a temperature of S5° C. (Toussaint) or for fifteen minutes at 456 THE PATHOGENIC FISSION-FUNGI. 52° C., or for twenty minutes at 50° C. {Chauveau), or through the influence of oxygen under high pressure {Chauveau). The bacilli attenuated by exposure to high temperatures quickly regain their virulence; those attenuated at lower tem- peratures remain weakened for many generations. The addition of carbolic acid to the nutrient fluid in a proportion of 1 :600 permits the development of anthrax-bacilli, but destroys their virulence within twenty-nine days {Chamberland, Roux). Likewise, attenuation may be produced by the addition of potassium bichromate '(1:2,000-1:5,000). The addition of car- bolic acid up to 1 :800 hinders the formation of spores. Through cultivation of the bacilli at 42-43° C. {Xoussaint, Pasteur, Koch) their virulence may be so weakened that they no longer kill first sheep, then rabbits and guinea-pigs, and finally mice. If the temperature is kept in the neighborhood of 43° C. this result may be obtained in six days; at 42° C. it may require about thirty days to decrease the virulence to this extent {Koch). By fi;rst inoculating with bacilli which kill mice but are harmless for guinea-pigs, and afterward with bacilli which kill guinea-pigs but not strong rabbits, immunity against anthrax may be obtained in sheep and cattle but not in mice, guinea-pigs, and rabbits. Such pro- tective inoculations are, however, not of practical value, since, in order to protect against natural infection with spores from the intestinal canal, such virulent inocu- FiG. 412. Fig. 413. Fig. 412. — Typhoid-bacilli from a pure culture. Streak-preparation (methylene-blue). X 1,000. Fig. 413. — Typhoid-bacilli with flagella. (After Bunge.) X 1,200. lation-material must be used that a large per cent, of sheep (ten to fifteen per cent.) die from the inoculations. Further, the protection afforded by the inoculation is of short duration, and the inoculation must be repeated within a year's time. According to observations by Roux and Chamberland anthrax bacilli which are cultivated in bouillon to which a small amount of potassium bichromate (1 :2,000) or carbolic acid (1 to 2:1,000) has been added, permanently lose their power of spore-formation while retaining their virulence. True toxins or endotoxins have not yet been demonstrated in anthrax bacilli. § 159. The Bacillus typhi abdominalis (Fig. 412) is a fission fugus which occurs in the form of rods 2 to 3 /x long, having rounded ends, in cultures grovi^ifig in 'pseudo-threads. It is regarded as the cause of typhoid fever, a disease which was once widely prevalent, but is now rarely encountered. In cultures the typhoid bacillus shows lively move- ments which are accomplished by flagella (Fig. 413) attached to the sides of the bacilli and to their ends. The flagella may be demonstrated by staining-methods. The bacilli gain entrance to the body through drinking-water and food. They develop in the solitary and agminated follicles of the small and large intestines, as well as in the m-esenteric lymph-nodes, and in the spleen. In the intestine they cause hyperplasia of the lymphoid tissues, which project above the surface as flattened or rounded elevations, and later undergo necrosis and sloughing with the formation of ulcers. In the TYPHOID BACILLUS. 457 process of ulceration blood vessels may be opened with the production of haemorrhages of greater or less degree, or perforation 'of the gut may- occur with the escape of intestinal contents into the cavity of the peri- toneum and secondary peritonitis. The swelling of the lymph-nodes, in the mesentery and vicinity, ends either in healing through absorption of the hyperplastic lymphoid cells, or may lead to necrosis. Rupture of necrotic lymph- nodes into the peri- toneum sometimes occurs, and results in the escape of typhoid bacilli and peritonitis. The bacilli are usually distributed through other parts of the body, and it is probable that inflammatory exudations in the lungs occurring during the course of typhoid fever are due to increase of the bacilli in the lungs. It should always be borne in mind that aspiration-pneumonias are of frequent occurrence in typhoid patients, and that secondary infec- tions may take place from the intestinal ulcers and give rise to metastatic inflammations. The swellings of the mucosa and submucosa and of the perichondrial tissue, which occur in the palate, throat, and larynx, are in part the result of the specific infection, and in part of secondary disease. Typhoid-bacilli have been demonstrated in the blood, liver, gall-bladder, in the rose-spots of the skin, in the kidneys, central nervous system, testicles, in pleuritic and peritoneal fluids, in the periosteum, bone-mar- row, etc. The bacilli circulate in the blood for about two or three weeks and cultivation from this source is often employed as a diagnostic method. When typhoid fever occurs during pregnancy the bacilli may pass to the foetus. In the course o'f typhoid fever there appear in the blood certain sub- stances which cause degeneration of typhoid-bacilli (cf. § 31). This may be demonstrated by the fact that (Widal-Gruber reaction), through the addition of serum from an individual ill or convalescent from typhoid fever, to a bouillon-culture of freely motile typhoid-bacilli, the latter become motionless, clump (agglutination), and die. This reaction may be used as a means, of diagnosis, but is not infallible, since agglutination may be produced by the serum of individuals who have not had typhoid fever, and may be absent in typhoid. The agglutinating power can last for years, or may vanish after a month. Individuals who have had typhoid fever may harbor the bacilli in their bodies for years after the attack, without showing any symptoms of infection (" typhoid carriers"). By giving off bacilli through urine or faeces typhoid carriers become an element of danger to the community in which they live. ("Typhoid BacilU Carriers." Park, J. Amer. Med. Assoc, 1908.) The typhoid-bacillus stains well in cover-glass preparations, with gentian- violet alkaline methylene-blue, and Bismarck brown. It is decolorized by Gram's method. It is difficult to demonstrate it in sections of hardened tissues. The bacillus may be cultivated on gelatin, agar-agar, and blood-serum, m milk, and on potato On the last named it forms a coating which can be scarcely recog- nized by the naked eye ; but when touched with a platmum wire it becomes apparent that it is covered with a pellicle. , , , . On gelatin and agar-agar the bacilli form grayish-white, irregularly shaped, flat growths: Gelaiin 'is not liquefied. Milk in which the bacilli are grown is not changed externally. .. , , , -n ^ i. The cultures thrive at room as well as body temperature. Potato -cultures made in the usual manner, when kept between 30° and 42° C, produce rods which have glistening bodies in their poles. Gaffky regarded these as spores, and the maiority of authors formerly accepted this view. According to Buchner and Pfuhl, however these granules are degeneration phenomena, which occur particularly when acid is present in the culture medium. The polar granules represent condensed 458 THE PATHOGENIC FISSION-FUNGI. protoplasm, and therefore stain in fresh preparations more quickly with aniline dyes than the other parts of the cell. The clear, colorless spots which are seen at the ends of the rods in dried and stained bacilli have been held to be identical with the polar granules and therefore regarded as spores, but are due, according to Buchner, to hollow spaces formed at the ends of the rods as the result of retraction of the protoplasmic tube following death and drying of the bacilli. Spore-formation has, therefore, not been demonstrated. Cultures of typhoid-bacillus show few characteristic appearances and are with difficulty distinguished from those of other bacteria widely scattered in the outer world. Their properties are similar to those of Bacillus coli communis (§ 160). Certain points of difference are as follows : The typhoid-bacilli produce no indol, while similar bacteria, such as Bacillus coli, produce it, so that bouillon cultures become red through the addition ol potassium nitrite and sulphuric acid. The typhoid-bacillus produces no gas in a two-per-cent. grape-sugar bouillon, while Bacillus coli produces gas. Finally typhoid-bacilli in milk cause weak acidity but no coagulation, while the Bacillus coli will cause at 37° C, even in twenty-four to forty- eight hours, strong acidity and coagulation of the milk. When typhoid bacilli are grown on agar colored blue with litmus, the color remains unchanged, while Bacillus coli decolorizes the blue. In moist earth, in pure and impure water, typhoid-bacilli may remain alive for weeks. In artificial Seltzer water they do not die out for a longer period. In privy vaults and fascal masses, or in earth saturated with fascal matter they may live for weeks and months. Inoculations of the bacilli in animals ordinarily used for experiment do not produce a disease corresponding to typhoid fever in man. Experimental investiga- tions show, however, that the typhoid-bacilli produce active toxins (endotoxins?) which in large doses kill the animals, causing hyperemia and swelling of the intestinal follicles, mesenteric nodes, and spleen. Cultures injected into the tissues cause local inflammation of greater or less intensity. The value of the agglutination, test is limited, since it is hard to decide whether the agglutinating effect of the serum is brought out by the same kind of bacillus or by a related variety. In general the serum of a patient agglutinates the species causing the disease in a greater dilution than in the case of a related organ- ism, but there occur exceptions to this rule. According to Lubowski and Steinberg the agglutinatibility of typhoid-bacilli can be increased in guinea-pigs and rabbits through proteus or staphylococcus infection. Much more positive as a diagnostic method is the demonstration of typhoid-bacilli in the blood by means of cultures. Paratyphoid fever is a disease similar to typhoid fever, but is caused by a form of bacillus of which a type A and a type B have been described. Clini- cally the disease runs a lighter course than typhoid fever and is rarely fatal. The anatomical findings are similar to those of typhoid fever, but the intestinal changes are less marked and ordinarily are confined to the colon. It is possible to make a differential diagnosis by means of the Widal reaction; yet it should be noted that paratyphoid serum may agglutinate typhoid-bacilli. The paratyphoid bacteria stand, as far as their cultural characteristics are con- cerned, between the typhoid-bacillus and the Bacillus coli communis. The round, smooth-edged gelatin colonies of freshly cultivated strains do not show the super- ficial vein-like furrowing. In type A they are almost colorless, while in type B they are whitish. Both consist of short rods and are motile; they ferment sugar without coagulating milk; cause fluorescence in neutral-red media; grow as blue colonies on Drigalski-Conradi plates and do not produce indol in bouillon cultures. Type A forms more delicate pellicles than B, and grows on potatoes in a manner similar to the bacillus of typhoid fever. Milk is not changed by type A, while it is cleared (alkaline) after several weeks by type B. § 160. The Bacillus coli communis or Bacterium coli commune is a fission-fungus which is constantly present in the intestinal tract of man as well as of other mammalia. The bacilli are 2-3 /x long and 0.3-0.4 /i thick. They are motile and may possess as many as twenty flagella on one rod. The bacilli grow at room-temperature as well as at the tem- perature of the body. They form in gelatin small, round, white colonies ; on Its surface pellicle-like coatings. Upon potatoes they form moist coatings of the yellow color of maize or pease. They do not form spores ; and are not stained by Gram's method. DYSENTERY BACILLUS. 459 Bacillus coli is similar to the typhoid bacillus, but may be differen- tiated by cultivation and by the employment of suitable reactions (cf. § 159). It was formerly regarded as a harmless saprophyte; but it cannot be doubted that it possesses pathogenic properties. Under suit- able conditions (perforation or incarceration of the intestine, or impac- tion of faeces) it may pass into the peritoneal cavity and excite purulent inflammation, or at least take part with other bacteria in the production of inflammation. It not infrequently gains access to the bile-passages and gall-bladder, as well as to the descending urinary passages and the kid- neys, giving rise to inflammations of varying intensity. § 161. Under the designation Bacillus enteritidis (Gartner) there is a group of bacilli found in animals sufliering from inflammations of the intestine, luilgs, uterus, or udder, and with septicaemia. Gaining entrance into the human alimentary tract these bacilli excite more or less severe inflammations of the intestine characterized by swellings of the follicles. Man is infected by eating meat from animals slaughtered while in a diseased condition ; such infection takes place most often through the meat of calves. Other sources of infection (drinking-water, milk, fish that have eaten diseased meat, oysters, etc.) are not excluded. The affection belongs to the group of meaf-poisonings (see Bac. botulinus, § 157) occurring in the form of local epidemics. The bacilli are short, often ovoid, at times motile, and possess four to twelve flagella. They are not stained by Gram's method. They form poisons that are resistant to high temperatures ; and are pathogenic for mice, guinea-pigs, rabbits, calves, and apes. Injected into the tissue they cause local inflammation and give rise to haematogenous and lymph- ogenous metastases in different organs. Their entrance into the alimentary tract causes gastro-enteritis. The Bacillus enteritidis was first studied by Gartner in 1888 and recognized as the cause of the gastro-intestinal form of meat-poisoning. His findings were confirmed by the investigations of Van Ermengewii, Fischer, Durham, Thomassen, Petri, and others. The bacillus is distinguished from other bacilli such as the Bac. typhi', Bac. coli, etc., by its cultural characteristics and by the agglutinating action of the serum of infected individuals or of previously immunized experimental ani- ■ mals. Surface colonies on gelatin are similar to those of the colon-bacillus. They form no indol, do not coagulate milk, but cause it to take on a yellow color ; they ferment sugar with the production of gas. The infection is caused most often through the consumption of the flesh or organs of calves and cattle that have suf- fered from the various diseases designated as septicaemia of calves, dysentery, enteritis, pneumo-enteritis ; and infectious inflammation of the intestine. Intoxications caused by the consumption of meat undergoing ordinary putrid decomposition {Proteus, Bac. coli) are rare and are not severe. Game and cheese are often eaten in a condition of decomposition without exciting gastro- intestinal disturbances or other symptoms of intoxication. § 162. The Bacillus dysenteriae is probably the cause of catarrhal, diphtheritic, haemorrhagic, and purulent inflammations of the colon_ that are classed with epidemic dysentery. Besides this form of_ hacillary dysentery there occur affections classed as dysentery that clinically and anatomically are similar to it, but are due to other parasites, amcehce in particular, or to chemically active substances (sublimate, septic poisons), or are induced by faecal retention. The dysentery bacillus is a plump, short rod, with rounded ends, often tapering. They have no flagella and are non-motile. They are easily stained by aniline dyes (methylene-blue, carbol fuchsin) and often show 460 TETANUS BACILLUS. polar staining. They are decolorized by Gram's method. On ordinary nutrient media the bacillus grows best at a temperature of 2>7° C, either under aerobic or anaerobic conditions. According to American investigators, bacillary, dysentery is due to a number O'f types of bacilli, differing in their fermentative action, bacteriolytic and agglutina- tion tests. In the treatment of the disease Shiga recommends a polyvalent serum active against all types. § 163. The Bacillus pyocyaneus was first demonstrated in the pus of wounds in which it had produced a bluish-green discoloration. It is widely distributed throughout the outer world, being found particularly in liquid manure- and dung-heaps, in water, and in the intestinal contents of animals (swine) and of man. Bacillus pyocyaneus forms rods of varying size (0.6-1—6 ft.). They possess a terminal flagellum. It is decolorized by Gram's method. Spores are not formed. It is easily cultivated on ordinary media and pro- duces ferments that liquefy gelatin, coagulate milk, and break up albumin. It produces in the presence of oxygen, bluish-green pyocyanin, which is soluble in chloroform, and a greenish fluorescent pigment soluble in water but not in chloroform and which in gelatin cultures causes greenish fluorescence of the gelatin. For the majority of experimental animals it is pathogenic, particularly for guinea-pigs and goats, and causes inflammation at the seat of inoculation, but later may spread through the blood. In bouillon cultures it -^^^ 414— t eta- forms both a true toxin and an endotoxin. nus-badm with § 164. The Bacillus tetani is (Fig. 414) widely dis- xT,o"oo. '''°"'- tributed through the superficial layers of the earth, and is the cause of tetanus. According to observations made by Nicolaier in 1885, it is possible to produce in mice, guinea-pigs, and rabbits, by sub- cutaneous inoculation of surface-earth, typical tetanus with fatal termination. It was demonstrated by Rosenbach in 1886 that this bacillus is present at the seat of injury in tetanus in man following trauma or freezing; and that when inoculated into guinea-pigs and mice it again produces tetanus. This discovery has been corroborated. The tetanus-bacillus is anaerobic and thrives in an atmosphere of hydrogen, but not in carbonic-acid gas. It grows on peptone-agar that is slightly alkaline, on blood-serum, and in nutrient gelatin. The latter is liquefied with evolution of gas. The addition of from 1.5 to 2 per cent, grape-sugar to agar accelerates the growth; a temperature of 36°-38° C. is most favorable for its development. The bacillus forms long, thin, bristle-shaped rods which develop spores (Fig. 414) giving rise to a spherical swelling at the end of the rod (knobbed bacilli). In cultures it may form long pseudothreads. Cultures give off an oflfensive odor ; gelatin is slowly liquefied. The bacilli stain .by Gram's method. They are motile except during the time_ of spore-formation, and possess peritrichous flagella. Pure cultures inoculated , into horses, asses, guinea-pigs, mice, rats, and rabbits cause tetanus, but in rabbits larger amounts must be injected. The tetanic contractures begin in the neighborhood of the point of inoculation. Suppuration does not occur at the point of inocu- lation. The bacilli cannot be demonstrated after the death of the animal except at the seat of inoculation. BACILLUS OF MALIGNANT CEDEMA. 461 The specific action of the tetanus-bacillus is to be referred to a toxin (tetanus toxin) which, through its haptophore group, is bound to the cells of the nervous system, and after a certain period excites tetanic convulsions. An antitoxin is produced in the body of man and experi- mental animals and by it animals may be made immune against tetanus (see § 32). The infection — intoxication — of man usually takes place through small wounds ; idiopathic tetanus, which does not start from demonstrable wounds, may arise through infection from the mouth-cavity and respira- tory tract. When taken into the alimentary tract the poison becomes inactive as the result of changes produced by the digestive juices (see §29). The tetanus-bacillus is not isolated either in the earth or in infected wounds, and inoculations, therefore, consist of a mixture of bacteria. Attempts to isolate the bacillus by means of cultures were unsuccessful until the year 1889, when Kitasato succeeded by heating for a half-hour to one hour, on the water-bath, at 80° C. mixed cultures that had been kept for several days in the incubator, and then plating the cultures in an atmosphere of hydrogen. Through heat bacteria growing with the tetanus-bacilli were killed, while the latter survived. Tetanus toxin (Kitasato) is destroyed by heating (65° C. and over) for a few minutes and by direct sunlight (fifteen to eighteen hours), and also loses its virulence in a few weeks under the influence of diffuse daylight. Literature. (Bacillus Tetani.) Moschcowitz: Tetanus, a Study, etc. (Lit.). Studies from Dept. of Path, of Columbia University, 1899-1901. § 165. The Bacillus of malignant oedema (Vibrion septique of Pasteur) is an anaerobic bacillus present in various putrefying substances, and its spores are almost never absent from earth fertilized by decom- posing fluids or liquid manure. The bacilli are 3-3.5 fi. long, and 1—1.1 fi broad; they often form long pseudothreads. They resemble anthrax- bacilli, though somewhat more slender, and are rounded at the ends, not sharply cut across. In spore-formation a swelling of the rod takes place, as in the case of Bacillus butyricus, so that spindle- and tadpole-shaped forms arise. The bacillus is motile, and possesses flagella on the ends as well as on the sides. It is not stained by Gram's method. It grows in nutrient gelatin as well as in agar and coagulated blood- serum, but must be introduced deeply into the medium and protected from the air. Nutrient gelatin to which one to two per cent, of grape- sugar has been added is an especially favorable medium. Nutrient gelatin and blood-serum are liquefied, the latter \with evolution of gas. The bacillus can be obtained by sewing garden-earth under the skin of a guinea-pig, care being taken to prevent the access of air at the point of inoculation. The ensuing multiplication of the bacillus excites cedematous swelling of the subcutaneous tissue. At a later stage the bacilli spread over the serous membranes, and involve the spleen and other organs. Mice, guinea-pigs, horses, donkeys, sheep, swine, cattle, and pigeons are susceptible to the bacilli ; rabbits and fowls are less susceptible, while rats, dogs, and cats are still less so. ^>, 462 THE PATHOGENIC FISSION-FUNGI. The bacilli of malignant oedema occasionally develop in the human body, particularly when the tissues are poorly nourished and the bacilli through accident — puncture of a hypodermic syringe — get into the deeper tissues. They excite gangrenous processes associated with hsemor- rhagic cedema and gas-production. As the Bacillus phlegmones emphysematosas R. Fraenkel in 1892 described an anaerobic bacillus staining with Gram's method, that, in many cases, is to be regarded as the cause of phlegmonous inflammation associated with gas- formation. According to Fraenkel the bacillus is non- motile and only exceptionally forms spores. In cultures it forms gas. It occurs in the external world (by Fraenkel it was demonstrated on a splinter of wood with which a man dying of gas- phlegmon had been wounded) ; and when injected subcutaneously into guinea-pigs or sparrows pro- "'g) duces a progressive gangrenous process with disin- /jj »>"' ® tegration of the subcutaneous tissues and muscle, as ^ >» ^ I'v well as free collections of fluid and gas. Intra- <^^^^ yV venous injection into rabbits and guinea-pigs is fol- ^^ V. lowed by the formation of gas in the internal organs, fig. 415.— Bacillus pneu- Gas-phlegmon in man occurs most frequently ova/'^cins"lnd"'^ows o'f after severe injuries, for example, compound frac- ceiis with gelatinous cap- tures, but may also proceed from small wounds. The finous capsule, ^x 80^0!*' bacillus is found at times in company with other bac- teria, pus-cocci, colon-ibacilli ; at other times alone and may be present in great numbers. In pure infections there occurs production of gas asso- ciated with liquefaction of tissue, particularly of muscles and of reticular connective tissue. It is probable that this bacillus is identical with one described by Welch and Nuttall as Bacillus aerogenes capsulatus. Besides Fraenkel's gas-bacillus other bacteria cause changes cor- responding to those of gas-phlegmon and foamy organs, especially as the result of localization in an already infected tissue (lactic-acid-bacilli, proteus vulgaris, and colon-bacilH). Literature. {Bacillus CEdematis Maligni. Bacillus Phlegmones Emphysematosce.) Davids: Malignes Oedem. Ergebn. d. a. P. vi., 1901 (Lit.). Frankel: Ueber die Gaaphlegmone, Hamburg, 1893. Gasplegmone und Schaum- organe. Z. f. Hyg., 40 Bd., 1902; Gasphlegmone, Gascysten, Schaumorgane. Ergebn. d. allg. Path., viii., 1, 1904 (Lit.). Harris, Welch: Morbid Conditions caused by Bacillus Aerogenes Capsulatus. Bull, of Johns Hopkins Hosp., 1900. Howard: A Contribution to the Knowledge of Bacillus Aerogenes Capsulatus. Welch Festschrift, 1900 ; The Origin of Gas and Gas Cysts in the Central Ner- vous System. Jour, of Med. Res., 1901. Norris: Infection with Bacillus Aerogenes Capsulatus. Amer. Jour, of Med. Sciences, 1899. Pasteur: Vibrion septique. Bull, de I'Acad. de med., 1877, 1881. Simonds: Monographs of the Rockefeller Institute, 1915. Welch and Nuttall: Johns Hopkins Hospital Bull., 1892. § 166. The Bacillus pneumoniae (Friedlander) or Bacillus Mucosus Capsulatus, is plump, non-motile, without flagella, about 0.5-1.25 /* broad and 0.6-6.0 /x long. It forms no spores (Fig. 415). It belongs to the INFLUENZA BACILLUS. 463 group of capsulated bacilli. It is easily stained with aniline dyes, but is decolorized by Gram's method. It grows easily on the usual nutrient media, under both aerobic and anaerobic conditions, and does not liquefy gelatin. Stab cultures in gelatin show the so-called nail-culture, in that the bacteria growing over the stab-canal form a white mass of bacilli similar to a nail-head. White mice and guinea-pigs are especially susceptible to the bacillus. The first named die within sixteen to forty-eight hours after subcutaneous inoculation. The point of inoculation and the regional lymph-nodes are inflamed and contain encapsulated bacilli, the latter are also found in the blood. _ Rabbits are almost immune to inoculation. Friedlander and Frobenius, who first described the bacillus (1882), believed that it was the most frequent cause of , ,s ■^- "♦^^ croupous pneumonia, a view that may be ex- ^^T •■''vi- ^H* plained by its confusion with the, at that time un- »«^R.*''*'* ^Pt-i known, Diplococcus pneumonice. It is now recog- ' *■ t'l * w' nized that it is rarely the cause of this disease N"^ *^ '" t^U f'x ^^' (according to Weichselbaum, in about six per , '*, IflBfx^ "''' cent, of cases, according to Honl, in eight to ten »•'» ' WiP/^'^? per cent.); but it may cause focal pneumonia. /-•', pleuritis, pericarditis, pharyngitis, rhinitis, otitis Fig. 4ifi.— Influenza-bacilli media, and meningitis. In severe infections it s^p"umm^(fucS)?'"i ifoo" can pass into the blood and set up metastases. In inflammatory exudates the bacilli are found in the form of rods and short oval cells surrounded by capsules, often forming chains (Fig. 415). Capsule-bacilli similar to the pneumonia-bacillus are often found in the chronic inflammation of the nasal mucosa known as ozcena, which is characterized by a foul-smelling secretion and the formation of scabs ; they have been demonstrated in rhinoscleroma (see below), and it has been assumed that they stand in causal relation to these diseases. According to Fricke the bacterium of Friedlander is representative of a group of bacteria which are classed under the name Bacillus mucosus capsulatus, and rep- resent varieties of a single species. The fission-fungus described as the ozena-bacil- lus is identical with the pneumonia-bacillus,_ probably also the bacillus from the milk-faeces of nurslings described as Bacterium lactis aerogenes (Escherich). It is possible that a greater etiological significance may be attached to it so far as the origin of many diarrhoeas is concerned. § 167. The influenza-bacillus (Fig. 416) was described by R. Pfeiffer, in 1892; it is regarded as the cause of influenza. In influenza it is found in the catarrhal respiratory passages, occasionally in the lungs ; the small bronchi may contain enormous numbers in pure culture. It is assumed that their multiplication in the respiratory tract gives rise to inflammation, and that the bacilli produce poisons, which, when absorbed, cause the symptoms of influenza. Influenza-bacilli are small, thin rods with rounded ends (Fig. 416), separate or joined in twos. They stain with ordinary aniline dyes, but not by Gram's method. They may be cultivated at body-temperature on blood-agar on which they form small, dew-like colonies. The nutrient medium must contain hsemoglobin. Spore-formation has not been observed. In apes catarrhal inflammation of the respiratory tract may be produced by intratracheal injections of pure cultures. 464 THE PATHOGENIC FISSION-FUNGI. In 1918 a disease popularly known as influenza swept around the world, killing hundreds of thousands. It was characterized by a variety of pneumonia of abrupt onset and amazingly rapid course. Death not infrequently occurred in 24 or 36 hours, or within a week at the latest. The pneumonic lesions were bilateral in distribution, involved the bases of the lungs most frequently, and were lobular in type, confluence of the solidified lobules, giving rise to extensive areas of consolidation. The exudate was composed largely of red cells and exuded blood serum, together with polynuclear leucocytes. Interstitial, parenchymatous and pleural haemorrhages were almost constant. The pleura, in the majority of cases, was not involved by the inflammatory process. Areas of acute vesicular emphysema were common and rupture was sometimes followed by extensive subcutaneous infiltration of air. The naked eye and histological appearances of the lungs bore a striking resemblance to those of bubonic plague. Bacteriologically, the findings varied greatly, and the cause of the disease is still in doubt. Influenza bacilli, hssmolytic streptococci, pneumococci and other micro-organisms were to be found in the lungs in pure culture or in various combinations. The kidneys, in most cases, presented marked evidences of acute parenchymatous degeneration. In some instances, the rectus muscles were ^. the seat of Zenker's degeneration associated with haemor- m \^^ rhagic extravasation, occasionally ending in secondary in- Jj? fection and abscess formation. «»*'^X^^»» About a year later the same variety of disease recurred /\ ^"^l— X in various parts of the world, but in milder form. Pneu- *** ^ monia was relatively rare and its course was more pro- m v longed. The anatomical changes in the lungs were ex- V V tremely variable, but conformed in a general way to the f, ^ confluent lobular haemorrhagic and exudative pneumonia of ** £ ^1%. «iU' the pandemic year. Pulmonary and subpleural abscesses ^ \ "V*^ were frequent. The pleura was involved in the majority of cases and empyeraata were common. The interlobar Fio. 417. — Diphtheria- and interlobular pleural extensions were often richly in- °^"^'' st°'"k^ """^^ t™'" filtrated by inflammatory exudate. Recovery from the (m'ethylenl-blue)!''^'^* '°x pneumonia was commonly followed by sequelae in the form i.ooo. of persistence of pulmonary abscesses, empyemata, and organization of the pleura and its intrapulmonary prolongations. (Blanton and Irons, Jour. Amer. Med. Assn., 1918; Symmers, New York Med. Tour., 1918: Jour Amer. Med. Assn., 1918.) According to Czaplewski and Hensel and Koplik (Centralbl. f. Bakt., 1897), there is found in the respiratory tract in whooping-cough a small, non-motile bacillus similar to the influenza-bacillus, that is thought to be the cause of whoopJhg-cough. _ Later investigations have shown that bacilli of the same type are to be found in the respiratory mucous membraioes in a variety of conditions. Their significance is highly doubtful. § 168. The Bacillus diphtheriae (Fig. 417) is found in the croupous membrane in diphtheria, and is the cause of this disease. The bacilli are 1.5-3 /* long, and are often somewhat swollen at the ends. In cultures they form rods of varying length (Fig. — ), the ends of which are often clubbed. When stained the bacilli appear spotted or granular. They stain best in a solution of 30 c.c. of concentrated alcoholic methylene-blue in 100 c.c. of 0.0001 per cent, potassium hydroxide, after which the sections are treated for a few seconds in 0.5 per cent, acetic acid and then with alcohol. In stained preparations the bacilli often appear segmented. They also stain by Gram's method, provided treat- ment with Lugol's solution and alcohol is brief. Diphtheria-bacilH grow best in the presence of oxygen on a mixture of three parts of calf's or sheep's serum, and one part of neutrahzed veal-bouillon, to which one per cent, of peptone, one per cent, of grape- sugar, and 0.5 per cent, of common salt are added; or on blood-serum and agar with an addition of ten per cent, glycerin or of ' sugar-containing bouillon. They form grayish-white colonies. For developrnent they need DIPHTHERIA. 465 a temperature above 20° C. ; they grow best at 33°-37° C. They are resistant to drying; but may be quickly killed by moist heat. Spore- formation has not been observed. Guinea-pigs inoculated subcutaneously with cultures of diphtheria- bacilli die in two to three days. Haemorrhagic oedema is found at the point of inoculation. The inoculation-area contains bacilli, the internal organs, on the contrary, are free, although the adrenals are intensely injected or even hasmorrhagic. The introduction of cultures into the trachea of rabbits, chickens, and pigeons, as well as inoculation of the conjunctiva of rabbits and the vagina of guinea-pigs is followed by inflammation with the formation of a pseudomembrane. Sheep, horses, cats, dogs, cows, rabbits, and pigeons are susceptible to subcutaneous inoculation. Rats and white mice are nearly immune. Roux, Yersin, Loffler, Spronck, and others observed paralysis in pigeons and guinea-pigs surviving inoculation. Roux and Yersin assert that the intravenous injection of filtered bouillon-cultures free from bacteria will cause in guinea-pigs and rabbits after two to three days paralysis and death. The virulence of cultures varies greatly. Diphtheria bacilli produce in the human body and in cultures toxins, which may be precipitated by alcohol as a whitish powder. Water-solutions of the poison injected subcutaneously into animals cause local necrosis, hsemorrhagic oedema, and inflammation ; when taken into the body-juices they give rise to pleural effusions, nephritis, fatty degeneration of the liver, and paralysis. Diphtheria in man is characterized by inflammation involving the mucous membrane of the pharynx, palate, arch of the palate, and upper respiratory passages, sometimes localized areas of skin. It appears as a febrile disease associated with symptoms of intoxication and gives rise to localized croupous exudations, and to sloughing (cf. § 91, Figs. — , — ). The croupous membranes constitute the most striking feature of the disease ; they are found in the throat and nose in the form of patches ; or they may form a continuous layer lining the larynx and trachea, or even the bronchi. Beneath the croupous membrane the epithelium is lost ; and the connective tissue is hyperaemic, infiltrated, and swollen (Fig. — ). In severe cases the superficial layers of the connective tissue are necrotic. Of the deeper tissues the regional lymph-nodes often reveal, microscop- ically, foci of necrosis. Of the internal organs the kidneys may show changes, in the form of fatty degeneration of the epithelium and of the cells of the capillary walls ; not infrequently they also present focal areas of small-cell infiltration. In the spleen there are frequently found necroses of the lymphoid follicles. Degenerative changes and areas of inflammation not infrequently occur in the heart-muscle. Paralyses are caused by degeneration and necrosis (Katz) of the ganglion-cells of the medulla oblongata and of the spinal cord and of the corresponding nerves. The lungs are not demonstrably changed by the diphtheria poison itself, but pneumonia, due to aspiration of irritating bronchial contents or to extension of inflammation to the pulmonary parenchyma, is of fre- quent occurrence. Local inflammations of mucous membranes as well as symptoms of intoxication may be caused by diphtheria bacilli and their toxins; hut it must be noted that streptococci are almost regularly present in the diseased area, and that a pure streptococcus infection may present the 30 466 THE PATHOGENIC FISSIO'N-FUNGI. clinical and anatomical picture of "diphtheria." When both micro- organisms are present the injurious effect of one may be supplemented by that of the other; the presence of streptococci appears to increase the virulence of diphtheria bacilli. In severe forms of diphtheria streptococci are usually present in numbers ; nevertheless streptococcus infection does not warrant a bad prognosis, since the virulence of the cocci vanes greatly. In the course of infection with diphtheria bacilli there arise anti- toxins, which nullify the action of the toxins, and aid recovery. The formation of antitoxins follows inoculation of animals with attenuated bacilli, and on this rests the possibility of obtaining from animals (sheep, horses), that have been repeatedly inoculated with bacilli of increasing virulence, a serum which contains antitoxin of therapeutic value (cf. § 32). There are frequently present in the mouth and throat bacilli, which are designated pseudo-diphtheria bacilli. Since diphtheria-'bacilli may lose their virulence, it is not impossible that both forms represent varieties of the same species. § 169. The bacillus of bubonic plague (Bacillus pestis) was dis- covered in 1894 by Kitasato and Yersin, of the Japanese and French commission, while investigating an epi- demic in Hong-Kong. The pest-bacillus V •. ^ j.» jj. h, \t^ ,. v.» is a small rod with rounded ends (re- ,^^ "» t °^* ' " 'h" sembling the bacillus of chicken-cholera). '^ 'Wt- *' ^-^j' It stains with aniline dyes, especially well "w _^_ ^| }f\f'2 *? -^ U with methylene-blue, and shows exquisite ' " - -— - polar staining (Fig. 418). It is decolor- ized by Gram's method. It is found in ^ ^ ^ .. ^ all cases of plague, in abundance in the * ** ^ - '^^ ' * jV swollen lymph-nodes, but also in the spleen ^ ^ <• ">> ^""'z' '"''j and blood. It may \>& cultivated on vari- '-• **_ <• JT \ %.w~ ''g-. ^ ous media, and forms bluish-gray colonies. It multiplies abundantly in bouillon con- ^'=- 4i8.-Piague ^ Wiiu (fuchsin). taining sugar, and forms toxins. Inde- pendent movements have not been observed. Spores are not formed. The bacilli are easily killed by warming, but are able to withstand drying. Bubonic plague, which destroyed great numbers of the inhabitants of Europe, at the close of the seventeenth and beginning of the eighteenth centuries ("Black Death"), has disappeared from Europe. In Asia (Yunnan in China, Arabia, Mesopotamia), and in the interior of Africa the disease seems to be endemic, and spreads from time to time in the same manner as cholera. Man is infected usually through the skin, more rarely from the mucous membrane of the mouth, nose, throat, and conjunctiva, still more rarely from the deeper parts of the respiratory tract, although cases of primary pest-bronchitis and pest-pneumonia occur. Small wounds usually form the avenue of entrance in the skin, but it appears (Albrecht and Ghon) that rubbing of the skin with infected fingers or clothing may be sufficient to bring about infection. The bacilli are taken up by the lymph-vessels and deposited in the regional lymph-nodes, where they cause marked swelling of the infected node or group — the primary bubo. Through infection of lymph-nodes BUBONIC PLAGUE. 467 situated farther along the lymph-system there arise primary buboes of the second class, and by metastasis through the blood-stream secondary buboes are formed. The plague is thus characterized by an acute polyadenitis. Since the poisons which are in association with the bodies of the pest-bacilli exert a degenerative and necrotic effect on the vessel- walls, numerous hcemorrhages are caused ; these are absent only in rare cases. To these changes there are also added circumscribed foci in the spleen, liver, kidneys, lungs, skin, etc. With the exception, therefore, of thoserare cases in which pest-infection is confined to the primary bubo, the disease is to be regarded as a general infection which arises from the taking-up_ of bacteria from a primary focus of infection, and runs its course with the clinical picture of polyadenitis and hcemorrhagic septi- ccemia. The individual foci are characterized by areas of coagulation-necrosis, inflammation, and hcemorrhage, and are caused by the presence of extraor- dinarily large numbers of bacilli. The lymph-nodes of the primary bubo are hsemorrhagic, swollen and of medullary consistence. After a few days they also show yellow necrotic areas which later undergo liquefac- tion. When the disease has lasted longer than six days, the liquefaction of lymph-nodes may take on the character of suppuration. The tissues in the neighborhood of the lymph-nodes are oedematous and infiltrated with blood; haemorrhages are also found in the walls of the neighboring large veins. The secondary inflammations of the lymph-nodes and of the lymph- adenoid tissue of the mouth and throat do not usually cause \ such a marked degree of swelling as do the primary ; they resemble the medullary swelling in typhoid fever. The surrounding tissues are also less changed, but if the process be prolonged the picture comes to resemble that of the primary buboes. The spleen of plague-patients is somewhat swollen, dark red, finely granular, shagreened, and often contains small necrotic foci, which are caused by the development of bacilli in great numbers. In the glandular organs and skin, there occur, besides haemorrhages, necrotic areas and exudative inflammations, all due to the presence of bacilli. In the lungs there may occur, in addition to the primary pest- pneumonia, secondary metastatic focal inflammations and aspiration- bronchopneumonias. The majority of individuals infected with pest die within the first eight days, but others may live several weeks and then die of marasmus. Not infrequently secondary infections, particularly by streptococci and diplococci, are associated with the pest-infection. They arise chiefly in the tonsils and follicular glands of the tongue following changes caused by the pest-bacilli. Among animals, rats, mice, apes, and cats are especially susceptible to pest; in rats, spontaneous infections occur, so that these rodents aid in the spread of epidemics. Swine and dogs are less susceptible, birds still less so. The changes in infected animals agree in general with those observed in man. The infection may remain local or become general. After lymphadenitis and multiple haemorrhages there arise miliary, tubercle-like foci in the spleen, liver, and lungs. The course is usually acute, rarely chronic. In the latter case the larger necrotic foci may be encapsulated by connective tissue. The animals are easily infected from the skin, as 468 THE PATHOGENIC FISSION-FUNGI. well as from the mucous membranes of the intestinal and respiratory tracts; infection may take place from an uninjured mucous membrane. The inoculation of one mouse confined in a cage with other mice may give rise to a cage-epidemic (Schottelius). Attempts to immunize animals and man against pest by means of dead and attenuated pest-bacilli have been many times carried out, especially by Yersin, Haffkin, and Lustig ; and have been successful in so far that rodents, horses, and apes have been rendered immune against inoculations otherwise fatal. According to the reports of such attempts in man, a smaller per cent, of inoculated individuals acquire the disease than of those not inoculated; but doubt is thrown upon the results of these inoculations by other authors {Bitter). Further, attempts at immunization and healing have been made in man, with the serum of animals which have been rendered immune, particularly of horses {Yersin, Lustig) ; and different authors ascribe to such serum a favorable influence. Sticker differentiates the following forms of pest according to the first localiza- tion of the bacilli: (1) Bubonic plague (the most common form) ; (2) the cutaneous form (formation of vesicles and ulcers or furuncle-like inflammations) ; (3) the pulmonary form; (4) the intestinal form. Through the investigations of Ducrey, Krefting, and Petersen (cf. Petersen, "Ulcus Molle." Arch. f. Derm., xxix., 1894; xxx., 1895, and Babes, " Handbuch d. pathog. Mikroorg., iii., 1903) it is probable that tdcus molle or soft chancre is caused by a bacillus. Tomasczewski (" Der Erreger des Ulcus," Z. f. Hyg., 42 Bd., 1903) has demonstrated through self-inoculation that typical ulcus molle can be produced with cultures grown on blood-agar or blood. The bacillus is non-motile, does not stain with Gram's method, and often forms chains. (See also "Observations on the Distribution and Culture of the Chancroid Bacillus," by Davis, Jour, of Med. Res., 1902). Literature. (Plague.) Albrecht u. Ghon: Ueber die Beulenpest in Bombay im J. 1897, Wien, 1898, 1900. Crowell: The Pathology of Plague. Philippine Jour, of Science, 1912. Dieudonne: Pest. Handb. d. path. Mikroorg., ii., Jena, 1903 (Lit.). Flexner: The Pathology of Bubonic Plague. Univ. of Penn. Med. Bull., 1901. Herzog: The Plague. Rep. of Gov. Laboratories, Manila, 1904, 1905. Kitasato: Preliminary Note on the Bacillus of Bubonic Plague, Hong-Kong, 1894. Metschnikoff: La peste bubonique. Ann. de ITnst. Pasteur, 1897. Netter: Le microbe de la peste. Arch, de med. exp., 1900 (Lit.). § 170. The Bacillus tuberculosis is the cause of the infectious disease occurring so frequently in man and the domestic animals which is known as tuberculosis, sometimes called pearl disease in animals. The tubercle-bacillus was discovered and thoroughly studied by Koch in 1882. It is a slender rod (Fig. 419), of 1.5-4 fj. in length, and is usually slightly curved. It may be stained by aniline-dyes (fuchsin, gentian- violet) to an aqueous solution of which an alkali, or carbolic acid, or aniHne oil is added. The bacilli when once stained retain the stain, even when the preparation is decolorized in dilute sulphuric acid, or nitric acid, or hydrochloric acid and alcohol. The stained bacilli not infrequently show in their interior clear, shin- ing, unstained al?eas, or are composed of little stained spherules. Koch regarded these clear spots as spores, and this view was accepted for a long time. Nevertheless, germination of these structures could not be demonstrated, and they are no longer regarded as spores. Consequently, TUBERCULOSIS. ■ 469 tubercle-bacilli are not specially resistant forms, although they are more resistant to external influences, for example, drying, than are many other bacteria. Tubercle-bacilli may be cultivated at the body temperature and in the presence of oxygen on coagulated blood-serum, blood-serum-gelatin, agar to which rabbits' blood has been added, and in glycerin bouillon. The special medium devised by Petroff is excellent. They increase, however, very slowly, so that only on the seventh to tenth day or even later, do the cultures become visible in the form of dull-white flakes resembling little scales. Larger cultures form, on the surface of coagulated blood-serum, whitish, irregularly shaped, lustreless deposits. According to Nocard, Roux, and Bischoff growth of the bacilli is aided by the addition of glycerin (four to eight per cent.). In cultures tubercle-bacilli form threads, which in part show branching. At temperatures below 28° C. and above 42° C. the growth of the bacilli ceases. Sunlight kills the bacilli in a short time. If bacilli from pure cultures are inoculated into certain experimental animals, tuberculosis is produced ; in- ,■:.,,,, fection may be produced by inocula- . - .^ ) , C'V <,*■ \ tion under the skin, into the peri- ^ (^ . f«»^i " 'X, I toneal cavity, or the anterior chamber ^ *"^ ^^ of the eye, by inhalation of an atom- •^ ^ -^ ~^\f ized suspension, by feeding, and by "^ -^"C'-i^ '" """^-5' injection into veins. In experimental , ^ '^ "y "^ ' '^' feeding success is often attained only ''■'■'^ '.\, ^'i' ^ after long administration of the j'lM. ''\ ^ "^ \ ^ bacilli, since not every bacillus gain- '■'— -^ \; - > .^ ^■^-!l:. ing' entrance into the intestinal tract leads to infection. It is also true that Fig. 419.— Tuhercie-baciii!. Sputum bacilli lodging On the mucous mem- from a man sufTenng with pulmonary , ,. 9 ° . , tuberculosis. Smear-preparation on DraUe Ot the reSpiratOl'V traCt dO not meXfen"biu\'.""x\o;'." '"='"" '"' always succeed _in growing in the tissue. Guinea-pigs, rabbits, cats, and gray field mice are especially susceptible ; dogs, rats, and white mice less so. Infection of man and of animals occurs from the taking up of tubercle- bacilli from the lungs, respiratory passages, and the intestinal tract, or from wounds and tissue-ulcerations. In the alimentary tract, the lymph- adenoid apparatus, tonsils, and the intestinal lymph-follicles form the most frequent avenue of entrance. Nurslings are particularlj' susceptible to intestinal infection. The opinion seems to be held by certain surgeons that primary or so-called surgical tuberculosis of the intestine is a not uncommon occurrence, and, based on this opinion, extensive resections have actually been carried out. Anatomically, there are two well recognized varieties of intestinal tuberculosis. One of them invites surgical interference. This lesion is a chronic productive tuberculous inflammation, usually located in the region of the caecum and often involving a large portion of the ileum. It produces massive thickening of the intestinal wall and obstruction or even occlusion of the lumen. Three such cases were encountered among approximately 30,000 surgical specimens examined at Bellevue Hospital. The second variety of surgical intestinal tuberculosis consists in solitary or multiple, discrete or confluent, tuberculous ulcers corresponding, as a rule, to the distribu- tion of the lympoid tissues of the gut. Among 6,000 consecutive autopsies at Bellevue Hospital, Palinsky (Proceedings New York Path. Soc, 1919) found 285 cases of tuberculous enteritis (46 per cent.). Of this number, however, only 3 (1 per cent.) were unaccompanied by tuberculous lesions in other portions of the 470 THE PATHOGENIC FISSIO'N-FUNGI. body In Zl per cent, of all cases of intestinal tuberculosis, more than one part of the gut was found to be involved. Not infrequently the ulcerative lesions occu- pied both the colon and the small intestine. It is apparent, therefore, that primary intestinal tuberculosis is an extremely rare condition and that operative^ removal of any portion of the gut for tuberculosis should be approached with caution. Direct transmission of the bacilli from mother to fa:tus in utero may occur, but is rare. The production of tuberculosis occurs usually at the points of entrance of the bacilli, but may occur at distant points after transportation of bacilli through the blood or lymph, so that hasmato- genous or lymphogenous disease of the internal organs, for example, of the lymph-nodes, bones, brain, and tubes, may oc- cur as the primary local- ization. The bacilli are spread through the external world chiefly by sputa, under certain conditions by the faeces and urine, from tuberculous ulcers, or from tuberculous or- gans taken from living or dead persons. Since the bacilli are rather resis- tant, they may be pre- served outside the animal body for a long time un- der certain conditions, aiid may become mixed with the respired air, as well as with food and drink. The milk of tuberculous cows con- tains the bacilli, espec- ially when the udder is diseased; but bacilli may also pass into the milk when no disease of the udder can be demonstrated (Hirschberg, Ernst, Leuch). If tubercle bacilli succeed in developing in any tissue of the human body, they lead by a series of changes to the formation of nodular masses of fibroblastic tissue or tubercles, which are devoid of blood-vessels, and after reaching a certain stage of development undergo retrogressive changes. The formation of the nodule may be accompanied by more or less extensive inflammatory exudation. The first effect of the development of the bacilli in tissue is degenera- tion, in which the tissue-cells as well as the connective-tissue ground-sub- stance over a larger or smaller area are destroyed. To the degenerative processes there is added inflammatory exudation — emigration of leuco- cytes and lymphocytes — and proliferation of the tissue-cells that remain preserved in the affected area (Fig. 420, a). The degree of the exudative processes in the region of the nodule varies and is dependent on the number and virulence of the bacilli present and on the mode of infection. When a large number of bacilli are introduced into the lung through the Fig. 420. — Tubercle from a fungous granulation of bone (Miiller's fluid, Bismarck brown), a, Giant-cell; h, epitheli- oid cells; c, lymphoid cells. X 400. TUBERCULOSIS. 471 respiratory tract the exudative inflammation is pronounced. It is fess marked in the introduction of bacilli into the liver through the portal vein. The cells of the exudate are chiefly polynuclear leucocytes, but later mononuclear lymphocytes and leucocytes predominate. The appearances of proliferation may be shown by the second day. The cellular nodule which, after a few days represents the tubercle at Fig. 421. — Giant-cell containing bacilli, and showing necrotic centre, from a tubercle. Stained with gentian-violet and vesuvin, mounted in Canada balsam, x 350. the height of its development, usually shows three types of cells — large epithelioid cells, with clear nuclei (Fig. 420, b), multinuclear giant-cells (a), and lymphocytes (c). The first two are found particularly in the central part of the tubercle, the latter at the periphery. The number of the individual cell-forms varies, and under certain conditions the lympho- FiG. 422.— Tuberculosis of the pleura (alcohol, Van Gieson's). a, Thickened and proliferating pleura; b, tubercle with giant-cells; i, deposit of fibrin. X 200. cytes may be so numerous as to overshadow the larger cell-forms.^ At other times epithelioid cells with lightly staining nuclei predominate. These cells are in part changed lymphocytes arising from the blood ; in part fibroblasts arising through proliferation of connective-tissue cells in loco. 472 THE PATHOGENIC FISSION-FUNGI. The giant-cells belong usually to the syncytial type and arise through confluence of cells, it is also possible that they arise through the multi- plication of the nucleus in a single cell. The nuclei lie usually in the peri- Fig. 423. — Large-cell tubercle containing fibrin, from a tuberculous lung (alcohol, fibrin-stain), a, Fibrin; b, giant-cell; c, Isrge-cell tissue. X 300. pheral portion of the protoplasmic mass (Figs. 420, a and 421) ; some- times collected at one pole, sometimes at both poles ; sometimes arranged in a wreath or crescent. They often contain bacilli (Figs.'421 and 424, c). The non-nucleated portion of the protoplasm may often be recognized as degenerate or necrotic because of its re- action toward stains (Fig. 421). Through proliferation of cells the con- nective-tissue stroma of the original tissue is pushed farther and farther apart, so that the individual cells are finally sepa- rated from one another only by scanty fibres, whose general arrangement in the form of a network is consequently called the reticulum of the tubercle. New vessels are not formed in the tubercle; and old vessels are closed through proliferation of the vessel-rvalls. Usually the new-formation of connective tissue stops with the production of fibro- blasts. e^ '-.:-? Fig. 424. — Caseous necrosis of tuber- culous granulation tissue (alcohol, fuchsin, aniline blue), a. Granular, oi, lumpy caseous masses ; b, fibrocellular tissue; c, giant-cell with bacilli; d, bacilli in cellular tissue; e, bacilli in The neighborhood of the tubercle may ceils"" x *loo"'= ^' ''^""' ^""'"'"^ '" show no essential change, but usually presents small-cell infiltration or proliferation (Fig. 422, a). Serous exudation is usually associated with the cellular emigration, and fibrin may be formed both in the tubercle itself (Fig. 423, a) and in its neighborhood (Fig. 422, c). CASEATION OF TUBERCLES. 473 At the height of development the tubercle forms a small, gray, trans- lucent cellular nodule, which may reach the size of a millet-seed, and encloses in its tissue tubercle-bacilli in larger or smaller numbers. When it has reached a certain size retrogressive changes usually appear in its centre, the tubercle becoming cloudy, opaque, and of a white or grayish- zvhite or yellowish-white color — ; these changes are designated caseation. Caseation of the tubercle is dependent on necrobiosis of cells, and on the deposit of coagulated substances between the cells. The cell> necrosis is characterized by loss of nuclei and transformation of the cells into lumpy masses which disintegrate and become granular (Fig. 424, flj, a). Thd deposit between the cells consists of a network of fibrin (Fig. 423, a) or of a granular or hyaline reticulated fibrinoid substance Fig. 425. — Section of miliary tubercle of the omentum (alcohol, ha:matoxylin, eosin). a. Caseous centre containing remains of fat-cells; b, fibrocellular periphery; c, giant-cells; d, fat tissue, x loo. but which does not take Weigert's fibrin stain and is stained yellow by Van Gieson's method. In the further course of the process of caseation the fibrin and fibrinoid substance disintegrate into a granular mass which fuses with the cell-detritus (Figs. 424, a; 426, a). Caseation affects first the central portion of the tubercle, and is usually confined to this, while connective tissue is formed at the periphery, so that the tubercle comes to consist of a caseous centre (Fig. 425, a) and a fibrocellular periphery (b) which usually contains giant-cells. Under certain conditions caseation may involve the entire tubercle. If caseation does not afifect the periphery, the fibrocellular tissue of the peripheral zone, sooner or later, becomes transformed into pure fibrous tissue, a fibrocaseous tubercle (Fig. 426, a, b) is formed, the connective tissue of which is coarsely fibrillar or hyaline and poor in cells (&), and in the course of time usually becomes sharply defined from the caseous centre (a), so that the latter appears to be encapsulated. If the disease runs a favorable course the centre instead of caseating may undergo connective- tissue replacement, and (Fig. 427, b, c, d), the tubercle becomes changed into a fibrous nodule. 474 THE PATHOGENIC FISSION-FUNGI. The infectious nature of tuberculosis was determined by experimental trans- mission of tuberculosis to animals ( Villemin, Lehert, Wyss, Cohnheim, Klebs, Lang- hans, and others), before the discovery of the tubercle-bacillus. Nevertheless, it was a long time before the view that tuberculosis is an infectious disease received general acceptance, and opposition to this view has even to-day not wholly dis- appeared. The peculiar behavior of the tubercle-bacillus toward stains — that is, its prop- erty of retaining the stain after treatment of the preparation with acids and alcohol, the so-called acid- and alcohol-resistance — makes it possible to demonstrate tubercle-bacilli in the sputum or in tissues, and to differentiate it from other bacteria. It should be noted, however, that other bacteria show these properties; the bacillus of leprosy, the smegma-bacillus (a bacillus frequently found on the corona glandis, between the scrotum and thigh and in the folds between the labia majora and minora), two bacilli found in butter (one described by L. Rabinowitsch and Petri, the other by Korn), and finally different bacilli cultivated_ by Moeller from grasses (timothy-grass) and from cow-dung. All these acid-resisting bacilli Fig. 426, — Fibrocaseous tubercle of the lung (alcohol, Van Gieson*s). _ a, Caseous centre; h, thick, homogeneous connective tissue poor in nuclei; c, connective tissue rich in cells; d, lung tissue. X 80. may under certain conditions lead to errors of diagnosis ; for example, the smegma- bacillus in the examination of urine, the butter-bacilli in the examination of butter, the latter particularly, since tihe bacillus described by Rabinowitsch, when injected into the peritoneal cavity of guinea-pigs, causes a disease of the abdomen similar to true inoculation-tuberculosis, while the bacillus described by Korn causes pseudo- tuberculosis in white mice (these animals showing but slight suceptibility to true tuberculosis). Acid-fast bacilli, which probably represent a variety of the Rabi- nowitsch butter bacillus, have been found in gangrenous foci in the lung {Rabinowitsch) as well as in the sputum of pulmonary gangrene (Folli, Mayer, Ophiils, Birt and Leishman) . Moeller has found acid-fast bacilli in nasal and pharyngeal mucus. Since the tubercle-bacillus in cultures forms simple and branching threads (Klein, Fischel, Coppen-Jones, Nocard, Maffucci, and others) and bud- and club- like swellings, many authors are inclined to group it with the thread-fungi. Leh- mann and Newmann designate it as Mycobacterium tuberculosis, Coppen-Jones as Tuberculomyces. Since the tubercle-bacillus in caseous pulmonary foci {Coppen-Jones'), and after direct injection into the parenchyma of the brain, kidneys, mammary glands, and testicles, as well as after the intra-arterial injection of large numbers of bacilli {Babes, Levaditi, Schulse, Lubarsch, Friedrich, and Nosske) forms, 'in addition to the ordinary colonies of bacilli, fungus-masses resembling those of actinomyces, on TUBERCULOSIS. 475 the outer surface of which ray-like clubs radiate into the surrounding tissue, Luharsch and others, on the assumption that the fungus-masses consist of branch- ing threads, have classed the tubercle bacillus with the actinomyces or ray-fungi. Lubarsch regards the ray-fungi as a sub-class of the Streptothrices, an intermediate group between the Schizomycetes and the Hyphomycetes, and characterized by the formation of clubs ; and to this class he assigns the butter- and dung-fungi men- tioned above. According to Friedrich and Nosske the fungus-masses regarded as resembling those of actinomyces consist only of rods. According to the investigations of Hammerschlag, Ruppel, Sata, and others, tubercle-bacilH contain an abundance of fat, which under proper conditions may be demonstrated by staining with sudan (Sata). According to Hammerschlag tubercle-bacilli contain twenty-seven per cent, of substances soluble in alcohol and ether (fats, lecithin, poisonous substances), while other bacteria contain only 1.7-10 per cent, of the same. The remaining substance insoluble in alcohol contains albumin and cellulose. Apparently the acid resistance of the bacilli is dependent on the rich fat content; young bacilli which lack the fat covering are not acid-fast {,Marmorek}. Fig, 427. — Fibrous tubercle in the thickened synovial membrane of the knee-joint (alcohol, haema- toxylin, picric acid, fuchsin). a. Connective tissue; b, c, d, fibrous tubercle, x 75. According to the investigations of Prudden, Hodenpyl, Kostenitsch, Vissmann, Masur, Kickel, and others, dead tubercle-bacilli, when introduced into the tissues of an animal by inoculation, or into the blood-stream, or through introduction into the respiratory passages, excite, at the point of deposit, inflammation and tissue- proliferation similar to that caused by living bacilli, and in the case of a large inocu- lation may lead to suppuration. These changes differ, however, from those pro- duced by living bacilli, in that the bacilli are destroyed after a few weeks and the nodules heal through transformation into fibrous tissue; and by the fact that the severity of the local tissue-proliferation is dependent wholly on the amount of dead bacilli introduced, and that there is no spread of the process throughout the body. The dead bacilli must therefore contain substances (proteins) which cause inflam- mation and later tissue-proliferation. The active substance of the bodies of the bacilli — tuberculin — -was first pro- duced by Koch (1890) from six- to eight-weeks-old cultures in a weak alkaline veal-infu?ion, to which one per cent, of peptone and four to five per cent, of glycerin were added, by evaporation on a water-bath to one-tenth of the original volume and filtering through a fijter of earthenware and silicious marl. Later (1897) he dried highly virulent cultures of tubercle-bacilli in a vacuum-exsiccator, then triturated the dry substance, mixed it with distilled water and centrifugated it. The active principle is in the muddy precipitate thus obtained, which is again dried and triturated and dissolved in water to which twenty per cent, of glycerin 476 THE PATHOGENIC FISSION-FUNGI. is added for the purpose of preservation. This tuberculin (designated by Koch as T. R.) is said to contain 10 mgm. of solid substance in 1 c.c. Whether tubercle-bacilli produce a true toxin is a question that has not yet been decided, but this is probably not the case; in favor of this is the fact that localized tuberculosis clinically shows no symptoms of intoxication. The tuberculins obtained by various methods contain a mixture of different^ substances which, like the substances derived from other bacteria, excite inflammation. Perhaps they con- tain also specific albumin bodies which, in the organism, cause the production of specific bactericidal protective forces, either through the formation of bacteriolysins or of agglutinins and precipitins that act on bacteria. (See § 33.) Through the investigations of Arloing and Courmont we know that an emul- sion of tubercle-bacilli grown on potatoes is agglutinated by the serum of tuber- culous men and animals. Through a special method Koch has prepared ia fluid containing bacilli in which clouding and a flocculent precipitate is produced by an Fig. 428. — Lupus of the skin with atypical growth of epithelium, from the region of the knee (alcohol, hematoxylin, fuchsin, picric acid).^ a, Corium converted into granulation tissue in which there are scattered tuhercles; b, epidermis; c, epithelial plugs growing into the deeper tissues; d, tubercle, x 50. agglutinating serum. The serum of healthy animals (rabbits, dogs, cow, and donkey) shows no agglutinating action when the test fluid is added to the serum in the proportion of 1:25; yet there are exceptions to this, and horse serum usually shows an agglutinative power. According to Koch and Romberg the serum of children possesses no agglutinative power. After the fourteenth year it is frequently present, probably as the result of latent tuberculosis. Through treat- ment of an animal with dead or living cultures of tubercle-bacilli it is possible to produce a serum capable of agglutination {Koch) or to increase that already pres- ent, particularly easily in goats and donkeys. Animals possessing the power of agglutination show a more or less high degree of immunity against artificial infection with tubercle-bacilli, and the agglutinative power may therefore be regarded as an indication of the existence of protective substances. In men suffering from tuberculosis the power to agglutinate is not usually shown in dilutions of 1 :2S. In advanced tuberculosis the agglutination power is usually wanting, since in the course of malignant tuberculosis the protective sub- stances are either not formed at all or at least only in small amounts. A mixture of pulverized tubercle-bacilli in lOO parts of water plus 100 parts of glycerin when •TUBERCULOSIS. 477 injected in increasing doses (0.8 per cent, salt solution, the first dose contains 0.0025 mg. of the cell substance of the bacilli) has, in the hands of Koch, increased the agglutination power of numerous consumptives (from 1 :25 to 1 :100 and 1 :300), so that it may be assumed that it is also possible to produce in consumptives a certain amount of protective substance. As to the value _ of the old and new tuberculin of Koch writers differ. Its worth as a diagnostic aid is not questioned, particularly the old tuberculin, since small doses excite fever in tuberculous animals but not in healthy ones, yet there are exceptions to this.^ The old tuberculin finds use in the recognition and removal of tuberculous domestic animals. As a curative method (it is used in small doses in tuberculosis) it is praised by some, but at present its use is not extensive. Much clinical interest has been excited over the diagnostic use of tuberculin in the cutaneous reaction {" Pirquet's reaction") and the conjunctival reaction (" Calmette's reaction ") . Von Behring has succeeded in rendering cattle immune against virulent bovine tubercle-bacilli. He uses fitst cultures of human tubercle-bacilli which are less virulent for cattle, and begins with an intravenous injection of 1 mgm. of a serum- culture of a definite strength of infection. In younger animals the immunization is more easily produced than in older ones. Von Behring regards it as possible to feed nurslings with milk of cows made immune against tuberculosis and thus to convey to them antibodies which may serve to protect them from infection. Literature. (^Tubercle-bacilli and Formation of Tubercles.) Arloing et Courmont: De I'agglutination du bacille de Koch. Z. f. Tub., i., 1900, u. D. med. Woch., 1900. Baumgarten: Tuberkelbakterien. Cbl. f. d. med. Wiss., 1882; 1883; Tuberkel u. Tuberkulose. Zeitschr. f. klin. Med., xi., 188S ; Verhjiltniss von Perlsucht und Tuberkulose. Berl. klin. Woch., 1901; Wirksamkeit d. Tuberkelbacillen. lb., 1901. V. Behring: Phthisiogenese u. Tuberkulosebekampfung. D. med. Woch., 1904, u. S.-A., Berlin, 1904. V. Behring, Rbmer, Ruppel: Tuberkulose, Marburg, 1902. Koch: Die Aetiologie der Tuberkulose. Berl. klin. Woch., 1882, No. 16; 1883, No. 10. Verb. d. Congresses f. inn. Med., Wiesbaden, 1882; Mittheil. a. d. Kais. Gesundheitsamte, ii., Berlin, 1884; Mittheil. iib. ein Heilmittel geg. d. Tuberkulose. Deut. med. Woch., 1890; Mittheil. iiber das Tuberculin. lb., 1891; Neue Tuberkulinpraparate. lb., 1897; Ueber die Agglutination der Tuberkelbacillen. D. med. Woch., 1901. Petroff: Johns. H. Hosp. Bull., Aug., 191S. Prudden: A Study of Experimental Pneumonitis in the Rabbit Injiuced by the Infection of Dead Tubercle Bacilli. New York Med. Journ., 1891. Prudden and Hodenpyl: Action of Dead Bacteria in Living Body. New York Med. Jour., 1891. Ziegler: Ueber die Herkunft der Tuberkelelemente, Wurzburg, 1875; Ueber patholog Bindegewebs- u. Gefassneubildung, Wiirzburg, 1876; Tuberkulose. Eulenburg's Realencyklop., xxiv., 1900 (Lit.), u. Eulenb. Jahrb., ii., 1904. See also § 171. § 171. Tuberculosis is at the beginning a local disease, which occurs most frequently in the lungs, intestinal tract, and skin ; that is, in places accessible from without. Cases of cryptogenic infection are by no means rare ; in these the first demonstrable changes appear in tissues concealed in the deeper portions of the body-parenchyma — for example, in the lymph- nodes, adrenals, bones, joints, brain, tubes — and it is to be assumed that under certain conditions the bacilli enter the body without causing de- tectable changes at the point of entrance, and develop in some distant organ to which they are carried by the blood or lymph, and through multi- pHcation give rise to tissue-degeneration, emigration of white blood-cells, and proliferation of tissue. 478 THE PATHOGENIC FISSION-FUNGI. The local disease usually begins with the formation of miliary tu- bercles — that is, cellular nodules of the kind described above — which arise in the tissue singly or (in case of multiple infection) in great num- bers simultaneously, or one after another (secondary dissemination of the multiplying bacteria). The tissue in the neighborhood of the individual tubercles, as well as that between the tubercles, shows more or less pro- nounced inflammatory exudation and proliferation of a cellular type; through these processes there are frequently formed large granula- tion-areas in the infected connective tissue. In surface colonization of the bacilli, such as is possible in the alveoli of the lung and in the smallest bronchioles, exudative catarrhal in- flammation may be the first sign of the infection, while proliferative processes in the j;onnective-tissue stroma and in the pulmonary ves- sels appear at a later period. In mucous membranes and in the skin (Fig. 428) large areas of mucosa and submucosa, or corium respectively, may undergo, through the formation of such granulations, nodular or diffuse flattened thicken- ing. In serous membranes there may develop large, flattened nodules in whose neighborhood the serosa is thickened and covered with fibrinous exudate. In the synovial membrane of joints and bursse there often arise soft, spongy proliferations, the so-called fungous granulations (Fig. 429) ; in the periosteum and bone- marrow round, grayish-red, or gray granulation-areas of varying size ap- pear. All these areas have one feature in common — namely, in their neighborhood are found in- flammatory infiltrations and proli- ferations of tissue, which bear the character of granulation tissue (Figs. 428, a; 429, b) inclosing char- acteristic non-vascular, cellular nodules — tubercles (Figs. 428, d; 429, r)— which often contain giant-cells. In grayish-red tissues rich' in blood the tubercles may often be recognized by the naked eye as gray, or, when undergoing caseation, as white or yellowish-white nodules. _ The area of tuberculous granulation tissue becomes larger by apposi- tional growth, by means of which the same processes, as just described, consurnmate themselves at the periphery. There may arise in this way, either in an infected organ, or on its surface, nodules of large size, solitary tubercles TFig. 430, c) for example, in the pia, brain, and on 'the dura Fig. 429. — Tuberculous granulation tissue from the synovial membrane of the knee-joint (Muller's fluid, Bismarck brown). a. Con- nective tissue; &, granulation tissue; c, tubercle, X 80. TUBERCULOSIS. 479 mater, that not infrequently resemble tumors. Further, the tissue trans- formed by the tuberculous process or the newly formed tissue respectively, may suffer various fates; there may be distinguished three chief forms of termination, which may, however, be combined in various ways. In one group of cases the production of connective tissue results in induration (Fig. 431) with the de- velopment of dense, fibrous tissue (a). If the process does not come to a standstill, there rhay be found in asso- ciation with the fibrous tis- sue proliferations of granu- lation tissue (&), and often a larger or smaller number of typical tubercles {c). If the process comes to a standstill and to cure of the infection, the entire area may be converted into dense fibrous tissue (Fig. 432, a, b) which in part shows a nodular arrangement (a), and in part is hyaline and homogeneous in character. In the lungs such connective- tissue nodules contain more or less carbon-pigment (Fig. 432). Fig. 430. — ^Large solitary tubercle of the pia mater o£ the cerebellum in vertical section, a. Cerebellum; b, dura mater adherent to the tubercle; c, laminated tubercle; d, gray peripheral zone adherent to the dura mater and beset with yellowish-white, nodular deposits. Natural size. Fig. 431 — Tuberc lous indurat on of the lung (alcohol hymatoxvl n and eos n) fibrous tssue, h, cellular granulat on t ssue c g ant cells X 40 Dense, A second form of termination is a combination of caseation and fibrous induration comprising dense fibrous tissue (Fig. 433, b, d) and caseous foci (a) of varying size. 480 THE PATHOGENIC FISSION-FUNGI. The third termination consists essentially in caseation, the tuberculous granulation tissue dying and producing no connective tissue at 'all, or only in such slight amount that it is completely overshadowed by the caseous masses (Fig. 434, c). Both the fibrocaseous and the purely caseous areas may become healed, through encapsulation by the surrounding connective tissue (Figs. 433, b; 434, c, e). Such healing can be regarded as complete only when in the connective-tissue capsule (Fig. 434, c, e), and its neighborhood (a) neither fresh granulation-tissue nor tubercles are present. Occasionally calcifi- cation of the encapsulated caseous mass may occur as a further sign of termination of the process. The caseous masses of tuberculous foci are sometimes firm, some- times soft, and in the latter case often suffer disintegration and lique- Jiu. ^j^. — Tu.^c.^.L<.wi.i:. .nd».a..^^n of .h^ ."-.g ^a ho., hjematoxylin, eosin), a. Homogenous filjrous nodules poor in cells and in part pigmented; b, diffuse induration of the lung. X 24. faction leading to the formation of milk-white, crumbling, and pultaceous or thin fluid masses, so that the tuberculous area presents the picture of an abscess {cold abscess). Rupture and emptying of the abscess ex- ternally leads to the formation of cavities and fistulous passages and to ulcers. Disintegration and cavity- formation occur particularly in the lung, and may lead to cavities as large as a man's fist or larger. They also occur not infrequently in caseating lymph-nodes, and in caseous foci in the kidneys, brain, muscles, skin, and bones (Fig. 435). The cavities (h) contain in the beginning the liquefied tuberculous tissue, in which remains of the original tissue may not infrequently be recognized in the form of sequestra (/). After evacuation of the contents the wall may furnish sufficient material to fill the cavity again, through secretion of pus or the breaking-off of necrotic tissue. Hcemorrhages commonly arise through erosion of blood-vessels. TUBERCULOSIS. 481 The walls of the caverns and abscesses are lined by caseating granu- lation tissue containing tubercles (Fig. 435, e) ; the surrounding tissue be- comes indurated, and the seat of caseating foci. Ulcers occur most frequently in mucous membranes (Fig. 436, h) and in the skin, since the softening caseous masses in these regions most frequently break through to the surface. The edges and base of the ulcers are surrounded by a zone of infiltrated granulation tissue, often containing tubercles. If a tuberculous focus does not become healed through induration, sequestration or encapsulation of the dead tissue, or through the removal or death of the bacilli, there exists the danger of metastasis. This takes place oftenest by the lymph-channels; and a part of the FrG. 433. — Encapsulated area of caseation of the lung with induration and eruption of tubercles in the neirhborhood (formalin, alcohol, hosmatoxylin, eosin). a, Caseous area; &, fibrous capsule; c, tubercle; d, indurated lung tissue; e, area of granulation tissue, x 40. picture of progressive tuberculosis is the development of tubercles in the lymph-spaces and in the vsralls of the lymph-vessels (Figs. 436, i, i^; 437, ^> f> 9, h, i) in t)he neighborhood of the primary focus. Lymphogenous miliary tuberculosis is in some cases limited to the immediate neighborhood of the primary focus (Fig. 437), at other times it involves larger areas and may, for example, extend from a caseating tubercle in the lung over a large part of the pulmonary lymphatic system. These lymphangoitic tubercles present the appearance of gray nodules, often surrounded by a red zone, and consist essentially of the same structure as the primary focus. The lymph-nodes may be affected early and tubercles develop in them, leading through successive crops to more or less enlargement and finally to caseation of the nodes, or to induration, or to a combination of these 31 482 THE PATHOGENIC FISSIO'N-FUNGI. processes. The thoracic duct may become infected from caseating and disintegrating lymph-nodes, and through this channel infection of the blood may take place. Often the formation of metastases takes place through the blood- stream; in the first place, by the entrance of bacilli through the lymph from the thoracic duct as mentioned above, but also as the result of direct entrance into the circulating blood. In tuberculous tissue bacilli may pass directly into small veins, though obstruction to the circulation due to closure of the vessels usually prevents further dissemination. Often enough the bacilli gain entrance into larger veins — for example, through adhesion of caseating lymph-nodes at the hilum of the lungs with neighboring veins, the tuberculous process thus involving the vein- FlG. 434. — Encapsulated area of tuberculous caFeation in the lung, a, Normal lung tissue; b, pleura; c, area of caseation; d, remains of elastic fibres in the area of caseation; e^ small encapsulated caseous nodules; /, thickened pleura, x 15. walls by _ direct extension. Moreover, infection of veins may occur in the neighborhood of a tuberculous focus, so that the small veins of an entire vascular system may present well-marked tuberculous disease — that is, inflammatory proliferation of the vessel-walls with the forma- tion of tubercles and subsequent caseation (Fig. 440, b), and, if thrombosis does not occur, large numbers of bacilli may enter the blood-stream from the diseased walls. In rare cases the arteries, particularly the pulmonary arteries, become tuberculous through infection from surrounding tissues, and may give off bacilli to the blood-stream. The transportation of bacilli through the blood-stream gives rise to haematogenous miliary tuberculosis — that is, to an eruption of miliary tubercles (Fig. 441, a) at those places where the bacilli become lodged and multiply. Just where these places will be, and how numerous the tubercles, depend on the location of the point of rupture and on the number of bacilli entering the blood. The entrance of many bacilli may lead to n^^r'-^l f'P'arv t'"berculosis. TUBERCULOSIS. 483 If bacilli enter the blood- stream in small numbers and are deposited in only one organ, and if death does not ensue, there arises in this organ progressive local tuberculosis. The exudative inflammation accompanying lymphogenous and haematogenous eruption of tubercles is sometimes more, sometimes less pronounced, and is usually most severe in the meninges and in the lungs. Should a tuberculous focus in the lung break into a bronchus, as the result oi softening of a caseous area, or if a caseating focus in the kidney should invade the kidney-pelvis, there will result dissemination of tuber- cle-bacilli over the surface of the mucous membranes. From the bronchi the bacilli spread into the trachea, larynx, mouth-cavity, and Fig. 435. — ^Tuberculous cavern in the tibia (alcohol, picric acid, hematoxylin, carmine). Transverse section, a. Periosteum; h, rarefied cortex; c, periosteal deposit of bone; d, fibrous tissue on the inner surface of the cortex; e, granulation tissue containing tubercles; f, sequestrum with bony trabecule, infiltrated with granulation tissue; g, union of the granulation tissue with the sequestrum; h^ cavity that had been filled with pus and caseous masses. X aj-^. thence into the alimentary canal ; through aspiration they may be carried into other portions of the lungs. From the kidneys the bacilli may spread through the descending urinary passages. Secondary infection may result from this spreading of the bacilli, although only a small percentage thus distributed give rise to infection; experience has taught us that only certain portions of the mucous mem- branes are susceptible to infection — notably the tonsils and the lymphade- noid tissue of the intestines, while the oesophagus and stomach are almost immune ; in the descending urinary passages, the kidney-pelvis, the ureters, and bladder are usually infected, while the urethra almost always escapes. If bacilli enter the great body-cavities they may spread over the surfaces of the serous membranes, infect the latter, excite diffuse inflam- mation and the formation of nodules (Fig. 442). New-formations of connective tissue may follow later 484 THE PATHOGENIC FISSION-FUNGI. Should tubercle-bacilli be present in the circulating blood of a woman during pregnancy, infection of the placenta and foetus may follow, so that the child will be born infected. In so far as data concerning this point exist, this event is not of frequent occurrence ; it is more usual for children of tuberculous parents to become infected after birth. Concep- tional infection of the embryo through infected semen has not been demonstrated, and is unlikely. Secondary infections are not infrequently associated with that caused by tubercle-bacilli; this occurs particularly when tuberculous cavities or ulcers are accessible from without. Secondary infections of tuberculous lungs are of frequent occurrence, and are due particularly to streptococci and staphylococci, pneumococci, influenza-bacilli, micrococcus tetragenus, and baterium coli. Many authors are inclined to refer all severe inflam- FiG. 436. — Tuberculous ulcer of the intestine with eruption of tubercles in the neighborhood (alcohol, Bismarck brown). a, Mucosa; b, submucosa; c, muscularis interna; d, muscularis externa; e, serosa; /, solitary follicle; g, mucosa infiltrated with cells; h, ulcer; hi, area of softening; i, recent, ii, caseous tubercle. X 30. matory exudations accompanying pulmonary tuberculosis to secondary infections ; but this is not correct in that the formation of tubercles by tubercle-bacilli may be accompanied by inflammatory exudations of such severity that serous or serofibrinous, or pure fibrinous, or fibrinopurulent exudates may collect in large quantities in the tissues (in the pulmonary alveoli, on the pleura, and in the subarachnoid space, etc.). High (septic) fever, rapid destruction of tissues with a tendency to suppuration, and unusually severe inflammation, in part of hsemorrhagic character, point to secondary infection. Nevertheless, it is often impossible to de- termine, without special investigation directed to this point, whether pure tuberculosis or mixed infection is present. For the treatment of tuberculosis with bacterial extracts and curative serum see § 32. The question as to how often tuberculosis is transmitted by the passage of bacilli from the mother to the child is an open one. It has, however, been shown by Schmorl, Birch-Hirschfeld, and Landouzy that in cases of miliary tuber- TUBERCULOSIS. 485 culosis in pregnant women, tubercle-bacilli are present both in the intervillous spaces and m the blood of the chorionic vessels, and that the liver of the foetus may contain bacilli. Further, cases of tuberculosis of the placenta occur {Schmorl, Kockel, Lungwttz, Warthm and Cowie), which may be regarded as stages on the way of the tubercle-bacillus from the mother to the fcetus. Cases of tuberculosis occurring at an early period of life reported by Demme, Baumgarten, Rilhet, Charrin, and others, as well as the statements of Armanni, Landouzy, and Martin, that the inoculation of portions of the organs of human foetuses obtained from tuberculous mothers produced tuberculosis in guinea-pigs, speak in favor of passage of tubercle-bacilli from the mother to the fcEtus. Still more important are the experimental investigations of de Rensi and Gartner, who succeeded through the inoculation of pregnant guinea-pigs, white mice, and rabbits in producing tuberculosis in a part of the young born of these animals. Gartner FiG- 437- — Beginning tuberculosis of the lung without catarrh (alcohol, orcein), a. Caseous area with_ remains of elastic .tissue; b, normal lung tissue; c, pleura with tubercles; d, e, tubercles in the neighborhood of the caseous area; /, tubercle in the pleura; g, periarterial, h, peribronchial, i, perivenous tubercles of the lymph- vessels; k, new-formation of fibrous tissue beneath the limiting elastic layer of the pleura, X i6. is consequently of the opinion that under certain conditions tubercle-bacilli may pass from the mother to the fcetus in the case of both animals and man. Finally, Maffucci and Baumgarten succeeded in effecting transfer of tubercle-bacilli to im- pregnated hen's eggs, and discovered that the infection did not disturb the develop- ment of the chick, but, on the contrary, the bacilli that were taken up by the embryo remained in the tissue of the latter without multiplying to any extent, later to cause tuberculosis in the body of the hatched-out chick. According to the evi- dence of anatomical investigations placental transmission of tuberculosis to the child cannot be doubted. On the other hand, conceptional transmission of tuber- culosis from the father to the embryo has not been proved. Moreover, according to the investigations made up to the present time it may be emphasized that tuber- culosis is to be referred usually to extrauterine infection and that children of tuber- culous parents suffer from tuberculosis so frequently because they are more ex- posed to infection than are the children of healthy parents. Special predisposition to tuberculosis in the children of tuberculous parents has not been demonstrated In animals transmission of tuberculosis to the foetus seems occasionally to occur, according to the reports of Zippelius, lessen, PUtz, Grothans, Malvoz, Lydtin, Brouvier, Adams, and others. Johne was not only able to demonstrate in a foetal calf the presence of miliary nodes and larger nodules in the lungs, liver, and various lymph-nodes, but to show the presence of characteristic bacilli in the lesions. 486 THE PATHOGENIC FISSION-FUNGI. Fig. 438. — (Bellevue lymph-nodes of neck. HosDital.) Tuberculosis of By clinicians so-called scrofula is often regarded as a special pathological condition of the organism of the child, predisposing it to tuberculosis. As scro- fulous are regarded those chil- dren who frequently suffer from inflammations of the mucous membranes (nose and its accessory cavities, con- junctiva, middle ear), as well as of the skin, from swelling of the lymph-nodes, leading occasionally to necrosis and suppuration, finally from chronic inflammations of the bones and joints, and who present a flabby, pale, often bloated appearance. In many cases these symptoms are due to tuberculosis ; in other cases they are caused by infection with streptococci or staphylo- cocci, or are the results of syphilis. Scrofula is not a disease-entity, but a special symptom-complex belonging to different diseases. Whether the affected children possess special predisposition to all these infections which may be designated scrofula is difficult of proof. The organism of the child is in general easily in- fected by these agents, and the frequent illness of certain chil- dren due to these infections may be referred to lack of cleanliness, or to conditions of environment, or to in- juries, etc., as well as to predisposition of the child itself. According to the elder Gross, many so-called scroful- ous children are born with the stigmata of status lymphaticus and are hence more susceptible to infections, particularly those that enter through the lym- phoid tissues. Von Behring upheld the view that tuberculosis is al- most always the result of bacilli entering through the in- testine in infancy, and that later infections play a sub- ordinate role. This theory is correct in so far as the long- known fact is concerned, that the intestine of infants takes up bacilli more easily than the adult intestine, and that in- fection is not always manifest at the point through which the bacillus enters, but develops in those organs, the lymph-nodes, lungs, brain, bones, etc., to which it has been carried by Fig. 439.— Eruption of tubercles in a lymph-gland (aico- the blood or lymph._ Infection 3iol, haematoxylin). a, Tubercle; ai, caseous tubercle; b, with tubercle-bacilli may OC- tissue of the lymph-gland; c, giant-cell in the centre of a ^ur at any age. The primary tubercle; ci, giant-cell at the edge 01 a caseous focus; o, • . .• 1 • r i* • *. a.u large-cell tissue between the tubercles; e, blood-vessel, mtestmal mtectlOn IS not the X ISO. dominating one, but the infec- TUBERCULOSIS. 487 tion of the respiratory tract is. The latter usually results from direct entrance of the bacilli into the respiratory parenchyma. Primary infection of the nose, larynx, trachea, and bronchi also occurs, but is relatively less frequent than primary lung-infection. Calmette's view of the intestinal origin of anthracosis has also been turned as an argument favoring the ingestion-theory of tuberculosis. Much has been written on this subject during the last several years, and while the opinion of the majority of pathologists favors the aerogenous nature of tuberculous infection in late childhood and adult life, the etiological importance of infection through the intes- tme in infancy cannot be disregarded. Tuberculosis of mammals is observed most frequently in cattle, and pre- sents a course similar to that of the disease in man, though the granulation- areas develop more frequently into tumor-like nodules, particularly in cattle, and the tendency to generalization of the disease is less. The tuberculosis of serous membranes which is often designated pearl disease begins with the Fig 440 Tuberculosis of the veins in the neighborhood of a tuberculous retroperitoneal lymph-giand (formalin, hsmatoxylin, eosin). a, Tuberculous lymph-gland with giant-cells and caseous foci; large blood-vessels at the periphery; b, veins whose walls are thickened by tuber- culous granulation tissue, the inner layers of which show caseation; c, fat tissue, x 28. formation of small nodules, leading then to more marked proliferation of con- nective tissue, giving rise to the formation in the thickened serosa of nodules the size of a pea' or bean or even as large as a hen's egg or man's fist, which in the beginning are soft and sarcoma-like, but later become firm and dense and often enclose calcified areas. The form of the proliferation is sometimes villous-Iike and warty, at other times mulberry- or grape-like, cauliflower-like or polypoid. Next to cattle the hog is most frequently affected with tuberculosis, more rarely the horse, goat, sheep and cat, and still more rarely the dog. _ Of wild animals in captivity, the ape, lion, tiger bear, jackal, panther, jaguar, giraffe and dromedary easily acquire tuberculosis. Of the small animals used for experiment the guinea-pig is the most susceptible. After stabcutaneous moculations there results progressive tuberculosis which kills the animal m .f^m about four to eleven weeks. In rabbits inoculation tuberculosis may heal. Field mice and white mice are infected with difficulty. . . . j / i,- 1 • u Tuherculosis is of frequent occurrence m birds (chickens, pigeons, pheas- ants, and parrots), and is usually localized in the abdominal organs. 488 THE PATHOGENIC FISSION-FUNGI. The cultures of tubercle-bacilli from man are dry, warty, or scaly and lustre- less ; those of avian tuberculosis moist, wrinkled, and soft, and grow best at 43° C. Dggs are immune to avian tuber- culosis, but not to human tuberculosis. The intra-peritoneal inoculation of mammalian tuberculosis (Leray) causes in rabbits numerous caseous foci in the liver and spleen with few giant-cells and scanty bacilli, and _ in the lungs caseous nodules containing numerous bacilli. Inoculations into these animals of chicken-tuberculosis, on the other hand, cause scanty pro- duction of non-caseating cellular pro- liferations containing giant-cells and great numbers of bacilli. According to Maffucci, Martin, Gartner, and others, the inoculation of human tuberculosis into chickens does not produce tuberculosis, although the bacilli remain alive for weeks' in the body of the chicken. Pigeons _(^M- clair) die after intra-peritoneal inocu- lation, but no tubercles are found in the tissues; the liver and lungs may p^^^ 44i.-ifematogeno«s miliary tuberculosis contam llvmg bacilli tourteen days of the liver (alcohol, carmine). a, Developed after inoculation. In guinea-pigs tubercle in the connective tissue about the portal (Straus) the bacilli of human tuber- ^""^ ''' ■^oH^'^tio^ °i leucocytes, x 150. culosis cause more severe changes than do the bacilli of chicken-tuberculosis. In mice infected with avian tuber- culosis (Weber and Bofinger) there occurs moderate increase of the bacilli with- out intoxication and without marked reaction on the part of the tissue. When kept in the mammalian body (guinea- pigs and mice) for one or two years the virulence of avian bacilli for guinea-pigs is not changed. Whether man is sus- ceptible to avian tuberculosis is still an open question. The question whether tuberculosis of animals, par- ticularly of domestic an'.mals, is identical with that of man has been the subject of lively discussion. The majority of writers believe in their iden- tity. Koch and von Baum- garten deny it. In favor of the latter view may be taken the fact that the bacilli of different sources show differ- ences in cultures, cultures of avian tuberculosis in particular showing essential differences from those of human tuber- culosis. Further, inoculations of human tubercle-bacilli into domestic animals, for example, cattle, are either negative or cause a milder disease than that resulting from the in- oculation of bacilli obtained from sick cattle. In spite of these facts it cannot be doubted that we have to deal, not with dififerent forms of disease, but that the tuberculosis of man and that of the domestic animals are identical Fig. 442. — Tuberculosis omenti (Miiller's fluid, carmine). a, Centre of tubercle; b, cells of epitheloid character; c, lymphatic elements; d, proliferating epithelium (endo- thelium) in the neighborhood. X 200. TUBERCULOSIS. 489 diseases produced by varieties of the same species of bacillus. When the bacilli increase for a long time in the same species of animal they acquire properties that make them less virulent for other species and they are with difficulty made to grow in the latter. Human tuberculosis is nevertheless still directly transmissible into other mammals, and man may be infected with the bacilli of mammalian tuber- culosis. Uncooked cow's milk and meat containing tubercle-bacilli can convey bovine tuberculosis into man, and the attendants of cattle can be infected from sick animals through wounds or the respiratory tract. The avian strain of tubercle- bacilli is the farthest removed in its properties from the human strain. In parrots there occurs tuberculosis the bacilli of which are identical in their properties with those of human tuberculosis. Tuberculosis occurs also in cold-blooded animals, fish, blind worms, frogs, snakes, lizards, tortoises, etc., and is likewise caused by an acid-fast bacillus, that possesses an optimum of growth at 15° C, and grows at temperatures of 10°-31° C. It has been assumed {Bataillon, Ferre, and others) that this bacillus is a variety of the bacillus of mammalian tuberculosis. Friedman attempted to immunize guinea- pigs against tuberculosis by inoculating them with less virulent bacilli of the tuber- culosis of cold-blooded animals. As pseudotuberculosis may be classed those affections characterized by the formation of cellular and fibrous nodules, in part undergoing necrosis, and which are similar to tubercles, but which are not caused by Koch's bacillus. According to etiology the following forms may be distinguished : 1. Pseudotuberculosis due to dead foreign bodies. This may be caused by the experimental injection of lycopodium-spores, olive-oil, and mercury into the blood- vessels, the inhalation of irritating material into the lungs, the injection of large quantities of milk into the peritoneal cavity, etc. The presence in the tissue of caterpillar hairs, pieces of wadding, silk threads, cholesterin tablets from ruptured ovarian cysts, etc., may lead to the formation of fibrocellular nodules. 2. Pseudotuberculosis caused by monomorphous and polymorphous bacteria. Eppinger, Bucholz, and Flexner have described forms of Cladothrix and Strepto- thrix obtained from apparently tuberculous lungs and bronchial glands which they are inclined to regard as the cause of the disease. Courmont found in an appar- ently tuberculous elbow-joint a bacillus which was not identical with Koch's bacillus. An affection of the peritoneum resembling tuberculosis may be produced in guinea- pigs by injection of the butter-bacillus of Rabinoimtsch (which probably comes from cow-dung) as well as by the grass-bacillus of Moeller; and in white mice by inocula- tion of the butter-bacillus of Korn. In rodents a disease resembling tuberculosis is not infrequently produced by a plump, thick bacillus with rounded ends (Pfeiffer, Preiss, Zagari, Nocard, Bonome, Delbanco, and others). Other forms of bacillary pseudotuberculosis have been observed 'in rabbits (Eberth), in birds (Muir), in the cow (Courmont), etc. 3. Pseudotuberculosis due to hyphomycetes occurs in the lungs and may be pro- duced artificially by the injection of different forms of aspergillus and mucor; but the affections so produced show peculiarities which permit differentiation from true tuberculosis. 4. Pseudotuberculosis caused by animal parasites occurs m the sheep, hog, goat, cat, hare, roe, stag, and chamois, and is caused by different forms of Strongylus and by Pseudalius capillaris (Miiller) ; it is a vermian pseudotuberculosis. Literature. (Pathology of Tuberculosis.) d'Arrigo: Uebertragung der Tuberk. durch die Placenta. Cbl. f. Bakt., xxvii., Baumgarten: Samml. klin. Vortrage v. Volkmann, No. 218. Berliner klin. Woch., 1883; Experimentelle congen. Tuberkulose. Arb. a. d. path. Inst. zu Tiibingen, i., 1892. Benda: Acute Miliartuberkulose. Berl. klin. Woch., 1899. Ortner- Die Lungentuberkulose als Mischinfection, Leipzig, 1893. Pasquaie: Die Streptokokken bei der Tuberkehnfection. Cbl. f. Bakt., xiv., 1894. 490 THE PATHOGENIC FISSION-FUNGI. Pertik: Pathologic d. Tuberkulose. Ergebn. d. a. P., viii., 2 Wiesb., 1904 (Lit.). Ponfick: Skrofulose u. Tuberkulose. Jahrb. f. Kinderheilk., 1901. Ribbert: Ueber die Ausbreitung der Tuberkulose im Korper, Marburg, 1900. Romberg: Die Serumdiagnose beit Tuberkulose. D. med. Woch., 1901. § 172. Syphilis, like tuberculosis, is an infectious disease, which, from a local infection, spreads throughout the body by the blood- and lymph- channels, and leads to the formation of localized inflammations and pro- liferations of granulation tissue, which, however, do not present so char- acteristic a structure as the tubercle. In 1905 Schaudihn and Hoffman announced the discovery of the constant occur- rence in syphilitic lesions of a characteristic organism. Control examinations of non-syphilitic lesions failed to reveal it. To the newly discovered parasite the name of Spirochaete pallida was given. Corroboration of the finding of Schaudinn and Hoffman was soon forthcoming from investigators in all parts of the world. It was found to be constantly present in the primary lesions, in all forms of secondary and tertiary lesions, in the blood, lymph, and cerebrospinal fluid of syphilitics, in the lesions of congenital syphilis and in the blood, lymph, cerebro- spinal fluid and organs of cases of congenital syphilis, and in the placenta of such cases. It has also been demonstrated in the experimental syphilis of apes (Met- schnikoff and Roux, Ann. de I'inst. Pasteur, 1903, 1904, 1905). The spirochaete of syphilis has recently been cultivated on artificial media and its etiological signifi- cance is now established beyond all doubt {Schereschewsky, Miihlens, Nogouchi, Zinsser and Hopkins). The Spiroclicrte pallida is a delicate, non-refractile spiral organism, varying in length from 2-20 /t, the average length being about 4-14 A*. The spirals are tight and corkscrewlike, fading out at the pointed ends. They vary in number from three to twenty-five or more. The large number of spirals in proportion to the length of the entire organism is characteristic. The whole organism is usually somewhat curved. Delicate terminal flagella have been observed. The spiral form is retained when the organism is at rest. It has the power of rotation on its long axis, of moving forward and backward, and of making whip-like undulations. A nucleus has not been demonstrated. It does not bear spores and no evidence of transverse division has been observed. Schaudinn believed that it possesses an undulating membrane. At the present time it is not definitely decided whether to regard the organism as a protozoon or as a spirillum. Schaudinn favored the former view. In accordance with this belief the names Spironema and Treponema pallidum have been proposed for it. The Spirochcete pallida stains poorly, but can be demonstrated in smears from primary lesions by Wright's stain, the Romanowsky or Giemsa stain. It is import- ant that the smears be stained as soon as made ; it often cannot be found in smears that are not perfectly fresh. From the Spirochcete refringens it is distinguished by its delicacy, pale staining, and the number of its spirals and their tight, cork- screw arrangement. The refringens is larger, thicker, more refractile, stains easily, and has broad, wavy spirals, and its ends are usually blunt. Levaditi's method may be used for staining the pallida in sections. The micro-organism in the living state may be demonstrated by appropriate methods (hanging-drop preparation and dark- field illumination) and is an easy and extremely valuable means of early diagnosis. The infective agent through whose inoculation syphilis is produced occurs only in the human organism, where it is reproduced, and com- municated by direct or indirect transfer. Metschnikofif, Roux, Lassar, and Neisser succeeded in conveying syphilis to anthrapoid apes (the chimpanzee) through the inoculation of syphilitic tissue. When im- planted the infective agent excites inflammatory processes of varied in- tensity and extent — from local transitory hypersemia to the production of large tumor-like granulations, or extensive hyperplasias of connective tissue. The child of a mother infected with syphilis may receive infection through the placenta. SYPHILIS. 491 In acquired syphilis the first focus of inflammation develops at the point of infection, which is usually located in the skin or mucous mem- branes (mouth, throat, mucosa of genital apparatus). There is first formed a papule which spreads towards the surface, and within eight Fig. 443. — Initial sclerosis (alcohol, hasmatoxylin, eosin). a, Corium, slightly inflamed; b, initial sclerosis; connective tissue infiltrated with cells; c, rupture of the cells into the epithelium; d, e, lymph-vessels filled with round cells. X 35. to ten days forms scales, or ulcerates and secretes a small amount of serous fluid which dries to a scab ; at the same time its base becomes hardened and forms a thick disc-like or a thin parchment-like deposit. Occasionally a vesicle is formed, this becomes an erosion, and then an ulcer with scanty secretion and indurated base. In still other cases an ulcer is first formed, and the base becomes in- durated subsequently. The induration is called the initial sclerosis (Fig. 443, 6) ; the ulcer is known as a hard chancre. (Hunterian chancre). The former is caused by a collection of small round cells (Figs. 443, h; 444, o) in the spaces of the connective tissue. Occasionally epithelioid cells (Fig. 444, b) and isolated giant-cells are formed (c). With these changes the height of the process is reached ; the tissue disintegrates and ulcerates, or is absorbed after disintegration. A part of the cells is utilized in the formation of scar tissue. Within the area of initial sclerosis and in its immediate neighborhood the lymph-vessels (Fig. 443, d, e) are dilated and filled with round cells. After the lapse of a certain length of time the lymph-nodes, skin, and mucous membranes become involved in inflammatory processes (symp- FiG. 444. — Section from a syphilitic initial sclerosis (alcohol, alum carmine), a, Round- cell infiltration; b, large mononuclear formative cells; c, multinuclear giant cells. X zi°- 492 THE PATHOGENIC FISSION-FUNGI. toms of the secondary stage). Still later, there follow syphilitic inflam- mations of the internal organs and the bones (tertiary stage). These, in many respects, resemble non-syphihtic inflammations, but special forms of granulation tissue are sometimes produced. The syphilitic afifections of the skin, which are grouped under the term syphilides, sometimes form red spots, sometimes larger or smaller papillary elevations which may be associated with vesicles and pustules as well Fig. 445. — CBellevue Hospital.) Ulcerative annular syphilide of back. as with scales. Accordingly, the cutaneous syphilides are called by different names, as follow: Roseola syphilitica, and papular, macular, papulo-macular, vesicular, pustular, and ulcerative syphilides as well as psoriasis sypJiilitica. A common element in these affections is inflamma- tion, characterized by infiltration and in part by proliferation. Thus, in the large papular syphilide or condyloma latum there is a teat-like eleva- tion of the skin caused by infiltration of the papillary body (Fig. 446, i), the corium {k), and the epithelium (e,f,g,h) with cells and fluid exudate which coagulates, causing induration of the part. If the horny layer of the epidermis becomes macerated, quantities of exudate appear on the surface, and give rise to a moist condition of the condyloma. In pustular SYPHILIS. 493 syphilides inflammation leads to liquefaction of epithelium, and in the ulcerating forms to softening and disappearance of the papillary body and cerium. Inflammatory and degenerative changes appear m the secondary stage of syphilis, in the mucous membranes of the mouth, throat, and respira- tory passages, particularly in the form of localized, whitish plaques known as mucous patches. Syphilitic lesions of the tertiary stage in internal organs, glands, bones, muscles, subcutaneous and submucosal tissues, m the meninges of the' Fig. 446.— Condyloma latum ani (alcohol, Bismarck-brown), a. Horny layer; b, mucous layer of the epidermis; c, corium; d, loosened horny layer infiltrated with small cells; e^ swollen, f, swollen and infiltrated mucous layer; g, epithelial cells containing round cells; h, granular masses of coagula; i, swollen papillary body infiltrated with cells and fluid; k, corium, swollen, and infiltrated with cells, fluid and coagulated albumin; /^ dilated lymph-vessels filled with clots; »K, sweat-glands. X 150. brain, etc., consist of degenerative and inflammatory processes or hyper- plasias of connective tissue without characteristic features, and are desig- nated gummata or syphilomata. In its early stages the gumma represents a localized inflammatory process ; it is usually rich in cells and undergoes central caseous necrosis (Fig. 447, d.^), while at the periphery, granulation tissue (d) and later connective tissue (c/i) are developed. The gumma occurs in the periosteum (Fig. 448) and membranes of the brain (Fig. 447), as well as in the parenchymatous organs, especially in the liver (Fig. 449, a, b), lymph-nodes and lungs. In the meninges of the brain and spinal cord syphilitic inflammations lead to cicatricial thickenings and to the formation of gummata. Peri- 494 THE PATHOGENIC FISSION-FUNGI. osteal syphilis occurs most frequently in the flat bones of the skull-cap, (Fig. 448), in the facial bones and the great long bones (tibia), but may extend over the greater part of the skeleton, and exhibits the char- acter of a granulomatous inflammation which leads to scar-tissue and new bone, so that osteophytes or hyperostosis result. The severe forms, rep- resented by gummata, lead to caries and necrosis. The fresh inflamma- tory focus appears as a translucent, yellow or grayish-white area sur- rounded by hypersemic tissue that may extend to the marrow. The yellowish foci consisting of masses of small cells (Fig. 448, c) may die, the cells losing their nuclei {d) ; in such places necrosis of bone may Fig. 447. — Meningo-encephalitis syphilitica gummosa (Miiller's fluid, alcohol, hematoxylin). a. Brain cortex; b, inner meninges; c, vein surrounded by cellular exudate, rf, fresh cellular granulation tissue; rfi, fibrocellular granulation _ tissue; d2, paseated granulation tissue;_ e^ artery with markedly thickened intima and adventitia infiltrated with cells; /, cellular infiltration of the pia-sheaths of the cortical vessels; fi, perivascular cellular infiltration of the cortical substance; g, diffusely spreading cellular infiltration invading the brain-substance. X 14. result. In living periosteal and endosteal tissue there occurs new-forma- tion of connective tissue {e, /), which, with the formation of multi- nucleated osteoclasts {g) and of Howship's lacunae, leads to destruction of the bony trabeculas. In the process of healing this connective tissue may be changed into bone. In the liver syphilitic lesions lead to the formation of radiating scars (Fig. 449, h, c, d), which often enclose cheesy remnants of the original inflammatory focus (a), that is, a gumma. The process is similar in other organs, for example, in the testicles and spleen. The disintegration of syphilitic foci of the skin and subcutaneous tissue, and of the mucosa and submucosa, leads to the formation of ulcers, which, in mucous membranes, occur most frequently in the region of the mouth, throat, and upper respiratory tract. In the neighborhood of the ulcers in mucous membranes there are not infrequently papillary pro- liferations. HEREDITARY SYPHILIS. 495 The cause of the disintegration and necrosis occurring in syphihtic inflammations lies in the peculiar character of the infective agent. A second factor is the extensive participation of blood-vessels, particularly arteries, in the inflammation. When syphilitic inflammation leads to the formation of granulation tissue or to connective-tissue hyperplasia, the vessel-walls become thickened, particularly the intima (Fig. 447, e) and the lumen is narrowed and not infrequently closed. Occasionally the syphilitic process is localized in the vessels. Besides the foci of inflammation which point to localization of the spirochaete of syphilis, there not infrequently occurs in syphilitic indi- viduals specific degenerations of the central nervous system (tabes, pro- FiG. 448.— Syphilis of the skull-cap. a, Periosteum; b, bony trabecule; c, small-cell infiltra- tion of the marrow; d, necrotic infiltrated marrow-tissue; e, periosteum proliferatmg into the bone; /, fibrous endosteum; g, osteoclasts and Howship's lacunas, x 40. gressive paralysis), associated with proliferation of neuroglia. Although these afl'ections now regarded as sequelae of syphilis, present no histo- logical peculiarities characteristic of syphilis, they are universally accepted as due to infection by spirochaeta pallida. Spirochaetes have been demon- strated in the brains of subjects dead of general paralysis of the insane, or paresis. (Nogouchi and Moore.) _ Hereditary syphilis is characterized by tissue-changes which diifer from the manifestations of acquired syphilis, although changes occur which correspond to the latter. In the skin hereditary syphilis causes macular, papular, and pustular syphilides which may lead to ulceration. The liver, kidneys, adrenals, and bones may show circumscribed necrotic foci or cellular infiltrations. The spleen is usually more or less enlarged. 496 THE PATHOGENIC FISSION-FUNGI. and may attain many times its normal volume. In the liver there occur collections of round cells in closely packed foci associated with new- formation of connective tissue in the perilobular spaces and with hyper- plasia of connective tissue throughout the liver (Fig. 452, a, b), giving to the organ a firm consistence and a peculiar yellowish-brown color (pericellular cirrhosis). The lungs may present, throughout or in part, a dense gray or grayish-white structure resembling that of sarcoma. This appearance is due to the formation of cellular connective tissue (Fig. 453, a, b) which contains imperfectly developed alveoli {e, e^) and bronchi (d, d.^) or none at all. In cases of slight severity there is thicken- ing of the peribronchial and perivascular tissue and interalveolar septa. Fig. 449. — Gumma hepatis (alcoTiol, alum carmine), a. Caseous nodule; b, homogeneous connective tissue; c, connective tissue with remains of liver tissue; d, connective-tissue bands radiating into the liver tissue; e, cellular focus at the edge of the caseous nodule; f, cellular focus within the confiective-tissue rays; g, liver tissue, x 12. associated with accumulation of desquamated epithelium in the alveoli. Interstitial gummata may be present in the more advanced cases. The lesion is known as pneumonia alba (Virchow). In the kidneys and testi- cles the supporting connective tissue may be increased in places, and abnormally rich in cells. Congenital syphilis often causes in glandular organs development of connective-tissue elements and collections of round cells, while epithelial tissues are retarded. This is well shown in con- genital syphilitic pancreatitis, which is characterized by diffuse overgrowth of connective tissue and diminution in the glandular elements. Finally, there not infrequently occur in bones disturbances of endochondral ossi- fication, characterized by irregularity in the formation of the medullary cavity and by the deposit of lime-salts in the cartilage, leading to disturb- ances in the structure of the subchondral spongy bone-substance. Through the formation of granulation-tissue which undergoes caseous necrosis, larger defects may arise in the bone substance. LEPROSY. 497 ,§ 173. The Bacillus leprae (described by Armauer Hansen in 1879) is a slender bacillus, from 4 to 6 /* long. It is regarded as the cause of leprosy. It is found constantly in great numbers in the diseased tissues (Figs. 454, 455, 456) and in the excretions from leprous sores. Foci of leprosy are characterized by proliferation (Fig. 454) of cells of different sizes and a fibrous ground tissue. The bacilli lie between (e), and in the cells (c, d), in the latter in such numbers that the cells become swollen (d) and changed into mono- and multinuclear giant-cells (Fig. 455). The latter occasionally enclose large vacuoles which con- tain great numbers of bacilli. The nuclei remain preserved for a long time, and are pressed to the periphery by the vacuoles containing the Fig. 450. — (Bellevue Hospital.) Gumma of cheek. bacilli. Later the nuclei are destroyed, and the cell becomes changed into a vacuole containing bacilli (Fig. 455). The bacilli react to stains in much the same manner as tubercle-bacilli. The same methods may be used for the former as for the latter, with certain slight modifications, since the bacillus of leprosy stains more easily and is decolorized more readily than the tubercle bacillus. In tissues, the leprosy bacillus is easily to be detected by proper methods of staining, while the tubercle bacillus is evasive. The leprosy bacillus is less apt to display a beaded appearance and is rather less slender than the tubercle bacillus. Attempts to cultivate lepra bacilli have led to no conclusive results. In the transplantation of leprous tissues into animals the bacilli do not multiply and leprosy is not reproduced. The infection of man takes place by direst transfer from individual to individual. The nasal secretion is especially infectious when leprous lesions are present in the nose. In leprous affections of the respiratory 32 498 THE PATHOGENIC FISSION-FUNGI. tract the sputum contains bacilli; the excretions from ulcers in the skin contain them in vast numbers. Contagion seems to result most frequently from the nose; in favor of this view is the fact that the anterior nasal region is usually involved early. The bacilli are spread through the body by the lymphatic system ; they may also invade the blood-stream. The peripheral nerves are often concerned in the disease; the bacilli may also multiply in the testicles, liver, ganglia, and spleen, giving rise to foci of disease in these organs. At the place of colonization the bacilli excite inflammation. Granu- lation tissue is formed; this for a long time is characterized by great richness in cells, and forms nodules and tumors in the skin and nose and spindle-shaped thickenings of the nerves. The tissue-proliferations often group themselves in the skin about the hair-follicles (Fig. 456, d), the ducts (/), and the coil (g) of the sweat-glands, although such a re- lationship is not always to be seen (h). Moreover, the bacilli may penetrate the hair-follicles, and sweat-glands, and thence the surface of the skin. Infection of the arterial walls causes arteritis, by which the walls become thickened and the lumina narrowed. In the nervous system the bacilli are found in the connective tissue and ganglion cells. The cells occupied by them undergo degeneration, with the formation of vacuoles. Leprosy of the skin occurs oftenest on the face, on the extensor surface of the knees and elbows, and on the back of the hands and feet. It begins with the formation of red spots which vanish, leaving pig- mented spots behind, or become elevated into nodules of a brownish- red color. In the region of the red spots the tissue contains large num- bers of bacilli and even at this stage proliferation of cells can be demon- strated. According to Miiller, the vesicular eruptions which occur in leprosy, and which were formerly regarded as sequelae of leprous disease of the nerves, are caused by the presence of bacilli. The nodules may remain unchanged for months, or increase in size and become confluent, so that large protuberances are formed, which, because of the distortion of the face that they occasion, have given rise to the designation fades leontina. Through external influences ulcers may be produced which show no tendency to heal. New nodules occasionally appear following erysipelas. Fig. 451. — (BellevTie Hospital.) ilitic sclerosis of testicle. Syph- LEPROSY. 499 Leprosy of the nerves {lepra nervorum sive ancesihetica) leads first to hypersesthesia and pain, later to anaesthesia, more rarely to motor paraly- ses. Further consequences of disease of the nerves are disturbances which Fig. 452. — Induration of the liver in congenital syphilis (Muller's fluid, hematoxylin, eosin). a. Hypertrophic periportal connective tissue; b, indurated gland tissue infiltrated with con- nective tissue; c, collection of cells, x 100. express themselves in the skin by the formation of white and brown spots (lepra maculosa, maculo-anwsthetica, morphcea nigra et alba), and, in the bones and muscles, by atrophy. Since those suffering from the disease are likely to injure themselves after the appearance of anaesthesia, ulcers d J c f Fig. 45,3.— Changes in the lung in congenital syphilis (Muller's fluid, hematoxylin, eosin) a, Proliferating stroma rich in cells; b, cellular granulation-foci; c, artery with thickened adventitia; d, di, gland-like bronchi, which in part (di) contain desquamated epithelium and round cells; e, ei, alveoli, which in part (d) contain desquamated epithelium and round cells. X 52. are often formed which cause deep erosions and may lead to the loss of entire phalanges (lepra mutilans). Leprosy of the skin and of the nerves are usually combined; more rarely do they occur alone. Besides the nose, skin, and nerves, the 500 THE PATHOGENIC FISSION-FUNGI. central nervous system, mucous membranes, cornea, the cartilages, liver, lungs, spleen, lymph-nodes, and testicles, become diseased. In Europe leprosy is confined mainly to Norway, Sweden, Finland, the Baltic Sea provinces of Russia, and the coasts of the Mediterranean; r 1 r^a mm^M Fig. 454. Fig. 455. Fig. 454. — Tissue from a leprous nodule (alcohol, fuchsin, methylenc-blue). _ a, Fibrocellular tissue; b, round-cells; c, medium-sized cells; d, very large cells filled with bacilli; e, free bacilli. X 200. Fig. 455. — Giant-cells with vacuoles containing bacilli, from leprous proliferations of the nasal mucosa (alcohol, Gabbet's stain), x 400. but occurs sporadically in other regions. It occurs frequently in Hindu- stan, China, Sumatra, Borneo, Java, and Mexico, on the northern and eastern coasts of South America, in Upper and Lower Guinea, in Cape Colony, and on the northern coast of Africa. .iMW&^- ^'>"^^lt^ife.:^£^S>^§S^*^^^pfe^^^^^*^^ Fig. 456. — Section through a leprous nodule of the skin Calcohol, Gabbet's method), a Epidermis; b, corium; c, hair-follicle; d, leprous focus in the neighborhood of the liair-foliicle; e, duct of sweat-gland; f, leprous nodule about duct of sweat-gland; r;, leprous foci in the neighborhood of sweat gland; h, leprous focus having no especial relation with any of the specific skin structures; t, foci of bacilli, x 32. LEPROSY. 501- Leprosy is prevalent in Mexico, the West Indies, and in the Philippines, and cases are found in New Brunswick and other parts of Canada and scattered throughout the United States, the most important centres being in Louisana, Cali- fornia, and Minnesota. According to a Senate report of 1902, there were at that time 278 known cases of leprosy within the borders of the United States. Fig. 457. — (Bellevue Hospital.) Leprosy in a Filipino, showing the lion-like facies, the macular eruption on the arms and legs, a nodule in the left groin and another on the left fore- arm. In this patient, leprosy bacilli occurred in the nasal secretions in great profusion. 502 THE PATHOGENIC FISSION-FUNGI. § 174. The Bacillus mallei was discovered by Loffler, Schiitz, and Israel in glanders foci, and later confirmed and studied by Weichselbaum, Kitt, and others. It is the cause of glanders (malleus, maliasmus) and of farcy {skin glanders, malleus farciminosus) , a contagious disease of horses, which occurs in man chiefly through transmission from horses. The glanders bacilli are small, slender rods, which occur in the diseased foci, sometimes scattered, sometimes lying in small clumps. Alkaline methylene-blue or gentian-violet is employed for their staining. The bacilli at times appear in the blood (Loffler, Kitt). The bacilli grow at a temperature of 30°-40° C, on coagulated blood- serum, potato, and agar. On blood-serum they form small yellowish transparent drops which later become milky white. On agar the colonies W^' Fig. 45S. — Glanders of a cat's testicle (Mullet's fluid, hEematoxylin), a, Seminiferous tubules; b, c, tubules filled with leucocytes; d, foci of leucocytes in the cennective tissue. X go. are grayish-white. In cultures club-shaped forms and threads are not infrequently seen. Spore-formation has not been demonstrated. Horses, asses, sheep, young dogs, goats, cats, guinea-pigs, and field- mice are suitable for inoculation. In cats, after inoculation, there develop in the testicles cellular foci consisting of leucocytes (Fig. 458), which lie in the canaliculi {h, c) and around them (d). The injection of the pus of glanders into the peritoneal cavity of male guinea-pigs causes the testicles to swell rapidly (Straus). This reaction is of great diagnostic value. After subcutaneous inoculation ulcers develop at the seat of inoculation, followed by swelling of the neighboring lymph-nodes. Later, nodules may develop in the internal organs, and ulcers may be formed in the nose. Typical glanders may be produced in horses and asses. Cattle, white mice, and house-mice are immune. The usual atrium of infection in horses is the mucous membrane of the nose ; following this is involvement of the submaxillary glands, and GLANDERS, RHINOSCLEROMA. 503 metastasis in various organs. In the nasal mucosa there arise diffuse cellular infiltration or subepithelial nodules the size of a millet-seed or pea. In chronic farcy larger nodules are developed which join in rows, forming worm-like cords. The nodules in the mucous membrane break down easily. The cells of which they are composed are for the greater part pus-corpuscles. Through disintegration, softening, and suppuration ulcers with yellowish, infiltrated bases are formed. These enlarge through progressive infiltra- tion and subsequent disintegration of the edges of the ulcer, as well as through confluence of neighboring ulcers. Horses dying of glanders often present in the mucosa of the nasal septum extensive, irregularly shaped, sinuate ulcers, with eroded edges and floors covered with gray and yellowish material. In addition to these there are numerous small, lenticu- lar ulcerations and gray or yellowish nodular foci which are on the point of breaking down. Healing is characterized by the formation of radiating scars. The cervical lymph-nodes are constantly swollen and inflamed. Of the internal organs the lungs especially are involved. They contain nodules having a caseated centre and a grayish periphery, or foci of lobular pneu- monia, which -present a gray or haemorrhagic appearance, or through fatty and cheesy metamorphosis become opaque and yellowish-white. Occasionally the mucosa of the alimentary tract contains nodules of varying size, in part clear gray and consisting of cellular tissue, or opaque yellowish-white, undergoing caseation or approaching suppuration. The spleen, liver, kidneys, and bone-marrow may also contain nodules. In farcy, which runs a more chronic course than glanders, there are formed in the skin and muscles nodules consisting of small-cell tissue which later undergoes retrogressive metamorphoses, caseates and disin- tegrates. In man infection with glanders usually takes place through small wounds of the skin, but may occur primarily in mucous membranes ad- jacent to the skin. In the skin and subcutaneous tissue it gives rise to roseolar spots, haemorrhages, and papular, nodular, and pustular exan- themata, carbuncular and phlegmonous inflammations which may result in suppuration, and to purulent inflammations of the lymph-vessels and lymph-nodes. In the mucosa of the respiratory tract catarrhs are pro- duced and suppurating nodules and nodes are formed, leaving ulcers behind. In the internal organs metastatic nodules are formed, showing a tendency to suppuration; also abscesses and purulent infiltrations, especially in the muscles. In chronic farcy, which may last for years, large nodules are occasionally formed in the skin and muscles that, through disintegration, give rise to ulcers which heal with difficulty. For diagnosis of the condition bacteriological examination and inoculation experiments are necessary. According to the investigations of Kalning, Preusse, and others, an active poison, mallein, may be extracted from cultures of glanders bacilli, that, when injected in small doses into horses sick of glanders, causes a febrile rise of tempera- ture, and may be used as a diagnostic aid. § 175. The Bacillus of rhinoscleroma is constantly present in the disease known as rhinoscleroma or scleroma respiratorium, and is re- garded as the cause. It stains best with methyl-violet, the sections being left in the stain for twenty-four to forty-eight hours. After staining, the 504 THE PATHOGENIC FISSION-FUNGI. sections are treated with iodine water, or left in absolute alcohol for one to three days. The bacilli possess a capsule and belong in the Friedlander group. Rhinoscleroma occurs chiefly in eastern Austria and southwestern Russia ; isolated cases have been observed in Silesia, Italy, Egypt, Belgium, Sweden, Switzerland, and Central America. It is a chronic disease beginning in the nose, more rarely in the pharynx, larynx, or palate, and extending thence to neighboring parts — the external nose, lips, lachrymal duct, trachea, etc. In the nose the disease is characterized by thickening of the nasal wall which is sometimes diffuse, sometimes elevated or nodular. The external skin takes on a red or brownish-red color, be- comes stiff and fissured and covered with scales. In the throat and respiratory tract dense, cartilage-like infiltrations are sometimes present, at other times contracting cicatricial tissue is formed. The infiltrations appear in the form of nodes and nodules or as elevations and flattened areas of thickening, or may spread out more diffusely. By transformation into scar tissue marked deformities are produced. Deep destruction of Fig. 459. Fig. 460. Fig. 459. — Section of rTiinoscleromatous tissue, with numerous degenerated and vacuolated cells containing bacilli Cosmic acid, lismatoxylinj . Preparation by Stepanow. x 340. Fig. 460. — Cells in condition of hyaline degeneration, and hyaline spherules, from rhino- scleromatous tissue of the vocal cord and of the nose. Preparation bv Stepanow. a, b, c, d. Hyaline-degenerated cells containing small bacilli; penheimer, it is probably an endotoxin which is labile and easily passes over to a secondary poisonous mixture rich in toxoids. Further, the spirilla contain a protein which is not specific and which excites in- flammation. The virulence of cholera-cultures differs greatly, according to the place of origin and the age. Virulence decreases with age. Guinea-pigs, which are susceptible to intraperitoneal inoculations of cholera, may be protected against infection by the intraperitoneal injection of attenuated cultures; but no absolute immunity can be produced in this way. The blood-serum of human individuals that have re- covered from an attack of cholera shows prcrtective properties for guinea-pigs for several weeks after the attack. The nitroso-indol reaction in cultures of the cholera-spirilla is due to the fact that the cholera-spirillum in pepton solutions not only forms indol but also nitrites. The addition of hydrochloric or sulphuric acid sets free nitrous acid which forms a red color with indol. With the Spirillum of Finkler, the Spirillum of Metsch- nikoff, and the Spirillum of Deneke, which also produce indol, the red color of the cultures occurs only when potassium nitrite is added with sulphuric acid, or when nitrous acid alone is added. Spirilla Resembling the Cholera-Spirillum. (1) The Spirillum of Finkler and Prior, was found by these observers in the dejecta of persons suffering from cholera-nostras, after the discharges had stood for some time in a vessel. The spirilla are similar to the cholera-spirilla, only some- what longer and thicker. In plate-cultures they are distinguished from the latter only in the fact that the small colonies are not distinctly granular and have a sharp contour. Gelatin is quickly liquefied ; and in stab-cultures after twenty-four hours a sac-like tube filled with cloudy fluid is formed, which soon reaches the walls of the tube. On potatoes (Fliigge), even at room temperatures, they form within forty-eight hours a grayish-yellow, slimy coating, sharply marked off from the substance of the potato by a whitish border; while cholera-spirilla do not grow at room-temper- ature, and at higher temperatures form brown coatings. Further, they cause foul-smelling decomposition; and are rather resistant to drying. When introduced into the intestine of guinea-pigs by the method given above, they produce effects similar to those caused by cholera-spirilla, but less intense. It is doubtful whether the Spirillum of Finkler and Prior possesses a patho- genic significance for cholera-nostras, since the dejecta from which these investigators obtained their cultures were not fresh; and other authors have failed to find the spirilla in corresponding cases {Kartulis, " Zur Aetiologie der Cholera nostras," Zeitschr.. f. Hyg., vi., 1889). Knisl (Miinchener arstliches IntelUgenzblatt, 188S), on the other hand, found them in the cacal contents of a suicide. (2) Spirillum tyrogenum, found in cheese by Deneke (Deut. med. Wochenschr., 188S), is also much like the cholera-spirillum, but somewhat smaller, and the long spiral threads are more closely wound. Cultures on gelatin-plates form sharply contoured discs that by low magnification appear dark, and liquefy the gelatin more rapidly than the spirillum of Koch. In stab-cultures they behave like the Finkler- Prior spirillum, but do not grow on potato. (3) Vibrio of Metschnikoff {Gamaleia, "Vibrio Metschnikovi et ses rapports avec le microbe du cholera asiatique," Annal. d. I'Inst. Past., ii., 1888; iii., 1889; Pfeiffer, " Ueber den Vibrio Metschnikovi und sein Verhaltniss zur Cholera asiat- ica," Zeitschr. f. Hyg., 1889) is a fission-fungus isolated by Gamaleia in an epidemic disease occurring in chickens in Odessa, characterized by diarrhea and enteritis. When cultivated it shows a great resemblance to the cholera-spirillum of Koch. The spirillum is most easily obtained pure by inoculating pigeons with the blood of diseased chickens. The pigeons die in from twelve to twenty hours and show the spirilla in the blood and in the intestinal tract. Ziegler has transferred Relapsing Fever to the protozoan diseases, following Schaudinn's view that the spirochetes are protozoa. If this opinion be correct, Syphilis should likewise be classed with the protozoan infections. As mentioned below, the correctness of such a view is doubted by other writers {Novy) who beheve that the spirochaetes are bacterial and are to be classed with the spirilla' CHAPTER XI. The Yeasts and Moulds, and the Diseases Caused by Them. § 180. The yeasts (Blastomycetes) and the moulds (Hyphomy- cetes) belong, as do the schizomycetes, to the non-chlorophyllaceous thallophytes. With the schizomycetes they have no phylogenetic relation- ship ; on the other hand, they are closely related to one another, and both belong to the branching fungi or the eumycetes. The moulds and yeasts, like the schizomycetes, derive their nourish- ment from_ organic substances containing carbon. The majority find their food in dead organic substances, and belong therefore to the sapro- phytes; some are able to obtain nourishment from living tissues, and are to be classed, at least at times, with the parasites. In human beings both forms occur. Outside the organism the moulds are generally known as producers of the different mouldy films which so frequently develop on organic substances. They belong to different groups of fungi. The yeast-fungi are the cause of alcohohc fermenta- tion, and form the scum on the top of alcohoHc beverages. '§ 181. Yeasts occur in man in the form of naked or encapsulated, oval or round cells of varying size. They are found chiefly as harmless saprophytes, most fre- quently in the upper part of the intestinal canal — in Fig. /i66—Saccha- the stomach — where they are almost constantly present ; deM™^'x^4oo"'*'''"' when beverages in the process of alcoholic fermentation are taken they occur in large numbers, and may multiply. In the bladder they may likewise multiply if the urine contains sugar; and may cause fermentation of the urine with evolution of carbonic- acid gas. As parasites no importance was attached to them until recently, but the investigations of Busse, Buschke, Sanfelice, Curtis, and others have established the fact that there are species of Saccharomycetes of patho- genic importance. According to these observations the pathogenic yeasts multiply in different tissues, in the skin, periosteum, lungs, and glandular organs, and excite purulent inflammations, or proliferations of granu- lation tissue, which run a course similar to that of infection with actino- mycosis or tuberculosis. In inflammatory foci the yeast cells are for the chief part provided with a capsule. In solutions containing sugar the blastomycetes form oval cells (Fig. 466). Reproduction takes place through budding and constriction; on any portion of the parent cell there may develop on excrescence, which is constricted off after it reaches the size of the mother cell. The cells may grow out into threads or hyphae, but in these threads nO' subsequent seg- mentation occurs; jointed threads arise through hudding. A dilute culture-medium favors the formation of threads. Mould-fungi are found in man in the form of simple or branched, unjointed or jointed threads of varying thickness; and as oblong or 515 516 THE PATHOGENIC YEASTS AND MOULDS. spherical cells. The threads are designated hyphae (Figs. 467, 468), and the mass which they form as mycelium ; the spherical or long oval or short cylindrical cells, which are frequently arranged in the form of a rosary, as spores, or better as conidia-spores (Figs. 467, 468). Only rarely has there been observed in the body fructification on spcQial organs. The moulds are partly saprophytes and partly parasites; and- are found almost exclusively in regions accessible from without, as the skm, intestinal canal, respiratory tract, external ear, vagina, etc. Only excep- tionally do they reach the internal organs, for example, the brain. On the whole, the living tissues of the human organism do not afford a suit- able nutrient medium for the mould-fungi, and the life-activities of the tissue-cells do not permit their development and multiplication. The need for oxygen prevents the growth of moulds in many tissues; and for many the temperature of the body is too high. Moulds growing as saprophytes occur in man most frequently m the alimentary canal, particularly in the mouth, pharynx, and oesophagus. They develop in these regions par- ticularly when the ingesta or desquamated cells lie undisturbed in one position for a long time, and when the function of the organ con- cerned is lowered. They are recog- nized through the formation of hyphae and conidia. Fig. 467. — Fresh favus-mass con- sisting of hypce, conidia, and epi- thelial cells. (After Neumann.) Fig. 468. — ^From a growth of thrush on the tongue of a man dying of typhoid fever. X 275. In the external auditory canal moulds may grow in masses which fill the passage and consist of cerumen, or of inflammatory exudates and desquamated cells, and of substances introduced from without. In the lungs moulds are occasionally found on the necrotic walls of cavities, particularly those due to tuberculosis, in necrotic and gangrenous infarcts, etc. In the air-passages they are observed most frequently in bronchiectases. In the alimentary tract, and in the ear and lungs, the moulds form a whitish deposit on or in the tissues. In the event of fructification on special fruit-bearers they take on a brown, gray, or even black appear- ance. In the intestinal canal the food and drink may give them various colors. At first the moulds grow in dead material, but may penetrate thence into living tissue ; cases have been observed in which they entered the circulation and were carried to distant organs. THRUSH. 517 The fungous growth called thrush, which appears chiefly on the mucous membrane of the mouth, pharynx, and oesophagus, more rarely on that of the stomach, intestine, and vagina, and on the nipples of nursing women, cannot be regarded as a pure saprophytic, but as a parasitic growth, which penetrates living epithelium (Fig. 469, c), and even the underlying connective tissue. It is true that thrush occurs chiefly in infants and in debilitated invalids who are no longer able to. cleanse the mouth, throat, and oesophagus, so that some local predisposition appears to be necessary for its development ; thus it is probable that primary coloni- zation of the fungus takes place in dead material. Nevertheless, penetra- tion into living tissue occurs — first, into the epithelium (c, d), but often into connective tissue {a, f), and blood-vessels, and from these portals of invasion metastases may develop in the internal organs. Thus, Zenker observed hyphae and conidia in an abscess of the brain; and Paltauf Fig. 469.^Section through a thrush-covered cesophagus of a small child (alcohol, carmine, Gram's), a. Connective tissue; b, normal epithelium; c, swollen and desquamated epithelium infiltrated with fungus-threads; d, epithelium infiltrated with cells; e. cocci and bacilli; /, cellular focus in the connective tissue, x 95. reported a case in which a mould-fungus was conveyed from an intestinal ulcer to the brain and lung. Schmorl and Heubner have described thrush- metastases in the kidneys. Moreover, growths of moulds in the lungs are not always confined to dead material or to the cavity of the bronchus, but it occasionally happens that they penetrate the living respiratory parenchyma, forming small white or yellowish, nodular masses, in which the lung tissue is necrotic, while in the neighborhood there is inflammatory infiltration. In the injured cornea they may likewise penetrate and cause necrosis and inflammation. Local colonizations of moulds cause more or less marked irritation of the surrounding tissues, and give rise to degeneration (Fig. 469, c) and inflammation. Such changes may be observed in mycosis of the lung, and of the intestine (i:, d, f) and ear. Invading the lungs they form hyphas which resemble the granules of actinomycosis, and are surrounded by collections of cells. Their action, however, is limited ; they produce no substances which are injurious to the organism as a whole, or which cause symptoms of poisoning. The finding of moulds in abscesses of the subcutaneous tissues and internal organs is probably due to the fact that. 518 THE PATHOGENIC YEASTS AND MOULDS. with the bacteria of suppuration, moulds get into the tissues, as well as into the circulation. Generahzation of mould-fungi does not occur in these cases; the development of the mould is confined to the place of metastasis. The moulds which are saprophytic, or, to a limited extent, parasitic in man, belong to the Mucor, Aspergillus, and Eurotium genera. From the ear various species have been obtained : Aspergillus fumigatus, As- pergillus flavus or flavescens, Aspergillus niger or nigri- cans, Aspergillus nidulans, Eurotium malignuwij Mucor corymbifer, and Trichothe- ciuni roseum; so far as known, these are the same species which occasionally occur in the respiratory tract. In the mucors there ap- pear special fruit-bearers (Fig. 470, C), which accord- Yio. 470. — Mucor corymbifer in fructification (culture in? to tlie species are single "1?°" glass-slide). a. Aerial hjphx- b, mycelia lying ^, 111 1 1 within the nutrient gelatin; c, branching fruit -bearers; or branched, and on the ends d, sporangia, x 100. of which are knob-like swell- ings from which the sporangia (d) — that is, spherical vesicles 'filled with conidia-spores — grow. Mucor corymbifer, for example, forms branched fruit-bearers (Fig. 470, c). The sporangia (d) on the ends possess a smooth membrane and enclose at the time of ripening yellowish conidia-spores. The aspergilli form conidia- bearers, which swell spherically above, and then produce numer- ous sterigmata — that is, cone- like outgrowths, radially arranged, thickly crowded, and sprouting from the uppar half of the sphere. From each sterigma a chain of conidia is later constricted off (Fig. 471, a, b). The botanical position of the fungus of thrush is still unsettled. Formerly it was called Oidium albicans, and classed with the Fig. 471.— HyphK with conidia-bearers of Asper- genUS Oldium, which OCCUrS in gillus fumigatus. a, Frnit-head in optical cross- j*iv . ■ •„ .i e ^r section; b, fruit-head seen from above, x 275. dlttercnt SpecieS in the torm Ot filmy coatings on organic sub- stances. When cultivated from conidia is produces hyphse which be- come joined and develop conidia through transverse division of the threads, but form no peculiar fruit-bearers. According to Rees, Grawitz, Kehrer, the thrush-fungus grows by budding and by the production of mycelia and conidia, which in turn EFFECTS OF PATHOGENIC YEASTS. 519 produce at their ends, by a process of constriction, new conidia, in a inanner similar to that which takes place in the forms of mycoderma belonging to the yeast-fungi. Consequently this fungus should be desig- nated Mycoderma albicans. Linossier and Roux are, however, of the opinion that the thrush-fungus does not belong to the saccharomycetes. Cao, who has investigated numerous varieties of didium, regards the oidia as a well-defined class of fungi standing between the blastomycetes and the hyphomycetes, which they approach through the production of mycelia. According_ to Plaut the thrush-fungus is identical with a mould, Moniha^ Candida, which occurs frequently in nature. Kehrer suspects that it is one of the higher moulds that has become degenerate through parasitism. According to Neunmyer all varieties of yeasts are resistant to the digestive juices, and may pass through the human intestinal tract without being killed. They exert an influence on the intestinal canal only when fermentable substances are introduced, whereby at the high temperature of the body abnormal products of fermentation are produced having an irritating action on the intestinal tract. Biisse found (1894) great numbers of yeast-cells developing in the diseased areas present in a woman, thirty-one years of age, who died from multiple inflam- maitions of the bones, skin, lungs, kidneys, and spleen, partly tumor-like and partly abscess-forming. According to his findings it may be regarded as certain that the yeast was the cause of the disease. The yeast could be easily cultivated on suit- able media. Mice were particularly susceptible to inoculation, dying in from four to eighty-three days after the injection. At death the yeast-cells were found to have increased both at the point of inoculation, and in the internal organs. Pro- liferation of tissue occurred only after long duration of the infection. Buschke found yeasts in multiple ulcers of head and neck, arising from acne- like lesions. Gilchrist and Stokes found yeasts in a lupus-like affection of the skin. Loivenhach and Oppenheim found a yeast in the skin of the nose showing nodules and scar-tissue. In 1896 Gilchrist described a progressive affection of the skin characterized by epithelial hyperplasia, miliary abscesses, and infiltration of the cutis. In the abscesses doubly-contoured, refractive, round and oval bodies were found. They varied in size from 10-20 M and presented buds of varying size. To this organism the name of Blastomyces dermatitidis was given, and the skin condition was called hlastomycetic dermatitis. Many cases of this kind have since been reported, the majority of them by Chicago observers. In some of the cases a fatal generalized infection has been seen. The organisms cultivated from the cases fall into three groups : 1, blastomycetoid ; 2, oidium-like ; and 3, a hyphomycetoid group. Accord- ing to Ricketts they m^ be included in a common genus, Oidiiim, and he has pro- posed the term oidiomycosis for the various lesions produced by these organisms. At the present time the exact botanical classification of the latter is not possible. Under the designation of coccidioidal granuloma there has been described a condition closely resembling oidiomycosis, but apparently differing from it in certain clinical characteristics and in the nature of the organisms found in the lesions. It runs a more severe and progressive course than the latter condition, and gener- aHzed infection is the rule. The organism multiplies by endogenous sporulation instead of by budding. Ophiils would class it with the oidia under the name of Oidium, coccidioides. The lesions produced by it resemble tubercles closely in the majority of cases, and clinically the disease has been mistaken for tuberculosis. Of 35 cases collated by Hektoen and by Brown up to 1907, 34 originated in Cali- fornia, many of them in the San Joaquin Valley, chiefly in men engaged in railway construction. The disease occurs (o) as a primary pulmonary affection with or without cutaneous lesions, (&) as a primary lesion of the skin, and (c) as a gener- alized process following either primary cutaneous or pulmonary infection. Clini- cally, the cutaneous lesions may resemble those of glanders. Moreover, injection of the pus into male guinea-pigs may be followed bv changes in the scrotum and testicles resembling those produced by glanders bacilli. 520 THE PATHOGENIC YEASTS AND MOULDS. Sanfelice experimented with yeasts from fruit-juices, and found among these one pathigenic for guinea-pigs {Saccharomyces neofonnans) and one pathogenic for chicki.ns and dogs {Saccharomyces lithogenes). Curtis found, in multiple pro- liferations of the skin resembling myxosarcoma, yeast-cells which were pathogenic for mice, rats, and dogs. Cohn, who experimented with the yeast described by Klein, found that its inoculation into the peritoneal cavity of mice caused death through the formation of great yeast-tumors. The intravenous injection of larger animals led to severe disturbances of brain and spinal cord, associated with in- flammation of the mucous membranes, particularly of the conjunctiva. Sanfelice, Corselli, Frisco, Rancali, Binaghi, Leopold, and others believe that blastomycetes may be the cause of true tumors, sarcoma and carcinoma; but true tumors have never yet been produced experimentally by inoculations of yeast-cells or by injections of the same into the blood. Only suppurations and inflammatory tissue-proliferations have been produced by such experiments; and the finding of yeast-like structures in true tumors, even if part of these were true yeast-cells, does not permit the conclusion that tumors arS caused by yeasts. According to investigations by Koch, Loffler, Lichtheim, Hiickel, and Lindt, the conidia of Aspergillus fumigatns, A. flavescens, A. nidulans, Eurotium malig- Hum, Mucor rhizopodiformis, M. corymbifer, M. pusillus, and M. ramosiis, grow at the body-temperature, and, when introduced into the blood-current of animals, grow into the tissues and form hyphae, although there is no new-formation of conidia, and consequently no progressive infection of the animal extending beyond the area within which the spores have been introduced. Conidia of Mucor rhizo- podiformis and M. corymbifer grow, when introduced into the blood-stream of rabbits, chiefly in the kidneys and the lympathic apparatus of the intestines, where they cause hemorrhagic inflammation. According to Cad, there are different species of oidia which, when injected into rabbits, cause inflammations, abscesses, or proliferations of granulation tissue; many produce also a toxic action on the organism. According to Ceni, Aspergillus fumigatus which grows at summer temperature produces poisons in its conidia. One of these can be extracted with alcohol and causes tetanic convulsions in experimental animals. It is possible that the asper- gillus growing on corn plays a role in the etiology of pellagra. Aspergillus mycoses of the respiratory tract are not rare in animals, espe- cially in birds, and the proliferating mycelia cause tissue-necrosis and inflammation. According to Chantemesse, Aspergillus fumigatus causes in pigeons diseased condi- tions of the mouth, lungs, liver, and kidney, that of the first two organs resembling diphtheria, that of the latter two closely resembling tuberculosis. It may, there- fore, be designated pseudotuberculosis aspergillina. According to Potain, the in- fection may be transmitted to man and give rise to ulcerative diseases of the lung. Eurotium and Aspergillus, according to Siebenm^nn, are two different families, having, however, a close resemblance to each other, in that the mycelia and conidia are similarly formed. The essential differences between the two lie in the fact that Eurotium, produces perithecia in the form of shining, light-yellow or sulphur-yellow,' translucent bodies the' size of a grain of sand, delicate and easily crushed, and which ultimately develop into spores capable of germination; while the true Asper- gillus forms hard, woody sclerotia usually embedded in a thick, white matted mass of mycelia. The development of these takes place in two periods. The second part of the development occurs only when the sclerotium finds lodgment upon a moist substratum. Aspergillus flavus of Brefeld {Eurotium Aspergillus flaviis of de Bary) forms golden yellow, green, and brown growths ; round, yellow, olive-green, or brown fruit-heads ; round, rarely oval, sulphur yellow to brown conidia with minute warts on the surface ; diameter S-7 M. Aspergillus fumigatus of Fresen {Aspergillus nigrescens of Robin) forms green, bluish, or gray growths ; the fruit-heads are long, in shape resembling an inverted cone ; conidia, round, rarely oval, smooth, mostly clear and colorless ; diameter 2.5-3 M. Aspergillus niger of Van Tieghen {Eurotium Aspergillus niger of de Bary) forms dark chocolate-brown growths; conidia are round, brownish-black, or grayish-brown when ripe ; surface smooth or warty ; diameter 3.6-S M. Aspergillus can develop upon the injured cornea and give rise to purulent in- flammation. Leber {Graefe's Arch., xxv.) cultivated it upon the cornea and in the anterior chamber of the eye of the rabbit. Finally, Aspergillus also appears in the pelves of the kidneys. Babes {Biol. Centralbl., ii.) fovmd the conidia and hyphae of a mould in ulcers of the skin which were covered by scabs, and gave to it the name of Oidium subtile cutis. FAVUS. 521 Literature. (Pathogenic Blast omycetes.) Brown: Coccidioidal Granuloma. Jour. Am. Med. Assoc, 1907. Evans: Blastomycosis of Skin from Accidental Inoculation. Tour, of Amer. Med. Assn., 1903. Foulerton: Pathogenic Action of Blastomycetes. Jour, of Path., vi., 1899. Frothingham: Tumor-like Lesion in the Lung of a Horse Caused by a Blas- tomyces (Torula). Jour, of Med. Res., 1902. Gilchrist and Stokes: Pseudolupus Caused by a Blastomyces. Jour, of Exp. Med., iii., 1898. Hyde: Blastomycetic Dermatitis. Jour, of Amer. Med. Assn., 1902. Nichols: The Relation of Blastomycetes to Cancer. Jour, of Med. Res., 1902. Ophiils: Coccidioidal Granuloma. Jour, of Amer. Med. Assn., 190S. Ormsby and Miller: Systemic Blastomycosis. Jour. Cut. Dis., March, 1903. Ricketts: Oidiomycosis (Blastomycosis) of the Skin and its Fungi. Jour, of Med Res., 1901. Weis: Four Pathogenic Torulae (Blastomycetes). Jour, of Med. Res., 1902. Wolbach: The Life Cycle of the Organism of "Dermatitis Coccidioides." Jour, of Med. Res., 1904. ( The Moulds and the Mould-Mycoses. ) Boyce: Remarks upon a Case of Aspergillus Pneumonomycosis. Jour, of Path., i., 1892. Hochheim: Pneumonomykosis aspergillina. V. A., 169 Bd., 1902. Pearson: Pneumonomycosis due to the Aspergillus fumigatus. Proc. of the Path. Soc. of Philadelphia, 1900. Rothwell: Experimental Aspergillus. Jour, of Path., vii., 1900. Schenck: Subcutaneous Abscess Caused by a Fungus. J. Hopkins Hosp. Bull., 1898. § 182. Thread-fungi are to be regarded as the exciting cause of certain affections of the skin, as favus, herpes tonsurans, pityriasis versi- color, erythrasma. In all of these diseases the epithelial parts of the skin contain colonies of hyphse and conidia. The fungus of favus (Fig. 467) is usually called Achorion Schonleini (discovered by Schonlein in 1839). Favus {tinea favosa, scald-head) affects the hairy portions of the head, more rarely other regions, for example, the substance of the nails. It is characterized by the formation of discs {favus scutula), varying in size from a lentil to that of a five-cent piece, of surphur-yellow color, and indented or pierced by a hair. In an abortive course it may merely form scales similar to those of herpes. According to Kaposi, the favus scutulum originates as a small, puncti- form, yellow focus lying under the epidermis and penetrated by a hair. This grows in a few weeks to the size of a lentil and then forms a sulphur-yellow, indented disc showing through the upper layers of the skin. The scutulum consists of hyphse and conidia spores, and lies in a cup-shaped depression of the skin, beneath the horny layer, which is drawn away above it. If the mass be removed during life, the cavity shows a red moist surface. The favus itself forms a white, crumbling mass which is easily disintegrated in water. If the scutula are not removed, they join to form larger masses. When the epidermis is desquamated the favus-mass becomes exposed and dries into a yellowish-white, mortar-like material. The hairs appear 522 THE PATHOGENIC YEASTS AND MOULDS. lustreless, as if covered with dust, and are easily pulled out, since the mycelia and conidia of the fungus penetrate into the hair-shaft and hair- bulb, as well as into the sheath of the hair-root. Through the growth of the fungus-masses the hairs may not only be shed, but the papillse become atrophic. At the same time there is pro- duced in the neighborhood of the hair-follicle more or less intense inflam- mation which may take on an eczematous cliaracter. The development of achorion in the nails (onychomycosis favosa) gives rise to sulphur-yellow deposits or uniform thickenings of the parenchyma of the nails with simultaneous loosening and cheesy disintegration. Trichophyton tonsurans, the fungus of herpes tonsurans ("barber's itch," " ringzvorm"), consists of long narrow threads, branching but little, and with few conidia. It forms no scutulous masses, but penetrates easily into the hair-shaft, and makes the hairs brittle. It shows certain differences of growth, ac- cording to whether the herpes de- velops on hairy surfaces or on areas devoid of hairs. Herpes or Trichophytosis ton- surans capiUitii forms bare discs varying in size from a five-cent piece to that of a dollar. Those spots in which the hairs are broken off short resemble places in which the hair has been badly shaven. The surface is smooth or covered with scales, and somewhat red- dened at the border of the disc. If the fungus-threads penetrate the hair-follicles, pustules and scabs are formed. Such discs may ap- pear in many places, and may in- crease in size until healing finally takes place. On places devoid of hairs the herpes forms vesicles (Herpes ton- surans vesiculosus) , and red scaly spots, discs, and circles (Herpes ton- surans squamosus) . At times red spots appear in numerous places ; these quickly spread, and as rapidly heal. The fungus is found between the uppermost layers of the epidermis, beneath the stratum corneum (Kaposi). If trichophyton develops in the nail, the nail becomes cloudy, scales off, and is easily broken — a condition designated onychomycosis tricho- phytina. Sycosis parasitaria arises through development of the fungus accom- panied by severe inflammation of the hairy parts of the skin, leading to infiltration and suppuration — that is, to the formation of pustules, abscesses, andpapillary proliferations. According to Kaposi and others eczema marginatum is also caused by trichophyton tonsurans. The condition occurs in those regions where two surfaces of skin come into Fig. 472. — Culture of Trichophyton tonsurans, a, Branching threads with long joints which have delicate walls; h, threads with thick-walled, short segments, some of them being spherical, x 270. THREAD-FUNGI. 523 contact with each other and are macerated by sweat ; and is characterized by the formation of vesicles, pustules, and scabs, which are situated at the periphery of a pigmented surface. Microsporon furfur, the fungus of pityriasis or mycosis versicolor or dermatomycosis furfuracea, likewise occurs in the form of hyphae and conidia, which are somewhat smaller than those of other skin-fungi. The pathological changes produced by this fungus are characterized by the formation of pale yellow or yellowish-brown to dark-brown and brownish-red spots, varying in size from a lentil to that of the hand, sometimes smooth and shining, at other times dull and exfoliating, and of irregular shape. They may be spread uniformly over large areas of skin ; and are found chiefly on the trunk, neck, and flexor surfaces of the extremities, but never on the hands, feet, or face. Microsporon minutissium is the name given to a thread-fungus, which is found in the skin affection known as erythrasma. The disease is characterized by the formation, on the inner side of the thigh, of brown or reddish-brown patches, which are only slightly scaly, and may be as large as the palm of the hand. The fungus is found in the epidermis, and is smaller than that of pityriasis. The thread-fungi occurring in the diseased areas of the skin may be cultivated on proper media (agar-agar, agar-glycerin, gelatin, potatoes, blood-serum, etc.), and on such the conidia develop into single and branching threads, which become jointed (Fig. 472, a), and form chains of short cells (&). Club-like formations which frequently appear on the ends of the threads in cultures, are. regarded by Quincke and Elsenberg as imperfect sporangia. The botanical position of these fungi is not yet determined ; and nothing is known with certainty concerning their distri- bution outside the human and animal body. According to Quincke, three forms of fun^i occur in favus-masses, two of these being varieties of one species of fungus. Elsenberg found only two, which he regards as varieties of the same species. Pick, Plaut, and Biro believe in the eitological unity of favus. ,Sahoiiraud advances the view that the fungi causing trichophytosis represent different species, all of which belong to the genus Botrytis. Krosing distinguishes three groups of trichophyton-fungi according to the different appearances of the cultures on potato, and emphasizes, moreover, the differences in their organs of generation and fructification. Rosenbach, who has studied the moulds occurring in deep suppurating inflammations of the skin, differentiates several trichophyton-fungi as the cause of these affections. According to Spietschka, the Microsporon furfur may be cultivated from the scales of the skin, and in cultures can be well differentiated from other pathogenic thread-fungi. Through inoculation of the fungus typical mycosis may be produced in man. From the great number of recent investigations by various writers it is im- possible to deduce anything definite concerning the number of kinds of favus- and trichophyton-fungi. It is, however, evident from these investigations that the nature of the nutrient medium influences the character of the growth {Sabouraud, Waelsch), and the difference in findings is to be referred in great measure to dif- ferences in the nutrient media on which the moulds were grown. Inoculations with fungi grown in cultures into the skin of human beings, rab- bits, mice, etc., which were made by Grawitz, Boer, Milnnich, and others, gave partly negative, partly positive results. According to Plaut, the inoculations never give positive results when spore-formation has taken place in the cultures. Von Hebra has described ( Wiener med. Blatter, 1881 : " Die krankh. Verand. d. Haut," Braunschweig, 1881) as dermatomycosis diffusa flexorum, a peculiar itching dermatosis, which occurs on the elbow and bend of the knee and is thought to be caused by fungi, which are like, those of pityriasis versicolor. 524 THE PATHOGENIC YEASTS AND MOULDS. According to the investigations by Wehmer, the cause of the skin eruption known as tokelau which occurs in various South Sea Islands (Fiji, Samoa, and Solomon) and which is characterized by the formation of scaly rings, is an Aspergillus. Favus and herpes tonsurans occur in domestic animals, as well as in mice and rats (cf. Friedeberger and Frbhner, "Lehr. d. spec. Pathologic der Hausthiere "). Waelsch inoculated human individuals with favus fungi, which he had cultivated from mice affected with favus, and obtained typical favus scutularis. Intravenous injections of favus-fungi into rabbits {Bukovsky) produced in the lungs of these animals a form of pseudotuberculosis; and cellular nodules are found in which fungus threads have developed in a manner suggesting the lesions of actinomycosis. After a time the fungi die. In Invertebrate animals there not infrequently occur diseases produced by mycelium-fungi. Thus Botrytis Bassiani causes the so-called muscardine in silk- worms; Cordyceps militaris destroys the injurious pine-spider Gastropachia pini; Tarichium megaspermum, a black-colored fungus, kills the destructive earth-cater- pillar Agrotis segetum. Fungi belonging to the genus Empusa attack the caterpil- lars of the cabbage-butterfly {Empusa radicans), and the house-fly {Empusa mus- ca), their mycelia growing through the caterpillar and finally killing it. Achyla prolifera, according to Harz {Jahresher. d. Miinchener Thierarzneischule, 1882-83), grows through the musculature of crayfish, and is the cause of the crayfish pest. CHAPTER XII. Fig. 473. — Amoeba coli mitis. (After !Roos.) a. Free motile amce- b^e; b, encysted amoebas. X 590. The Animal Parasites and the Diseases Produced by Them. I. Protozoa. § 183. Of the Protozoa occurring as parasites in man, only a small number was known up to a few years ago; and even the known forms possessed but slight significance, since there could be ascribed to them no marked influence on the tissues. Through the investigations of the last few years, however, different forms have been recognized as the cause of morbid proc- esses; and it is quite possible that there are still other protozoa capable of exciting patho- logical changes in the human body. The forms already recognized are representatives of all four classes of protozoa. Of the Rhizopoda there occur in the in- testine three amoebae, known as Amcrba coli vulgaris, Amceba coli mitis, and Amosba dysenteries. The Amoeba dysenterise is dis- tinguishable from the other two, while the Amoeba coli vulgaris and the Amoeba coli mitis resemble each other closely, and may be identical. The Amoeba coli vulgaris is a harmless parasite -which is not infre- quently present in the intestine (Roos, Kruse, Pasquale). The Amoeba coli mitis was observed by Roos and Quincke in cases of chronic enteritis in patients who had always lived in North Germany. The Amoeba coli mitis con- sists, according to Roos, of a protoplasmic cell-body, from 28-30 /J. in diameter, (in the spherical condition). It ex- hibits slow movements, and frequently encloses foreign bodies, for example, bacteria dysevteriae stye Amoeba , coli ^^^ f^^jj remains (Fig. 473, a). Besides the motile form, there occur, according to Roos, encysted spherical forms which are surrounded by a double-contoured membrane, and enclose clear, round vesicles in their interior {h). When fed to animals (cats) no pathogenic properties are disclosed. The Amoeba dysenteriae (identical with the Amoeba coli described by Loesch) has a diameter, according to Roos, of from 15—25 fi, but accord- ing to Kruse and Pasquale, from 10—50 /x. In the cell-body there may be recognized a homogeneous ectoplasm and a granular entoplasm, the arrangement of which varies according to the form of the animal (Fig. 523 Fig. 474, — Amoeba _^ -- felis. (After Roos.) a, Amcebae without inclusions; h, amoebae containing blood; c, amcebae with large vacuoles in their protoplasm; d, young forms; e, en- cysted forms. X 665. 526 THE ANIMAL PARASITES. 474, a) . By staining, a nucleus becomes visible in the cell. The cells are capable of active movement, and thereby assume varied shapes (d). They often contain foreign bodies, particularly red blood-cells or remains of such (b), or are studded with clear vacuoles (c). According to Roos, they may also become encysted (e). According to Koch, Kartulis, Kruse, and Pasquale, they are invariably present in the dysentery prevailing in Egypt, and are usually demonstrable in the dejecta. They have also been observed in dysentery in Russia, in America, in Germany, and in Austria. According to investigations by Kartulis, Councilman, Lafleur, Kovacs, Roos, Kruse, Pasquale, and others, it cannot be doubted that they are of significance in the origin of certain forms of dysentery. It is only questionable whether they alone, or with the aid of changes produced by bacteria, are able to bring about pathological alterations. In support of the latter theory is the fact that, when present in the tisues, they are always accompanied by bacteria. Amoebic dysentery is characterized by the occurrence of a hasmor- rhagic catarrh, and by the formation of circumscribed ulcers with under- mined edges. The amoebse increase not only in the intestinal mucosa, but penetrate into the mucosa and submucosa, and form large colonies, in the region of which the tissue undergoes necrosis without the formation of any large amount of exudate. By rupture of the submucosal foci through the mucosa there are formed ulcers with undermined edges, which, gradually increasing in size, may attain large dimensions. If abscesses of the liver arise during the course of amoebic dysentery, these may contain the amcebas in addition to bacteria ; it may be assumed that the former also take part in destruction of the liver tissue. The amcebcE of dysentery are pathogenic for cats, and, when fed to them or when introduced into the rectum of the animal, cause a rapidly progressive, often fatal dysentery, which is similar in all respects to amoebic dysentery in man. The amoebae also penetrate into the mucosa and submucosa of these animals. Von Leyden and Schaudinn ("Leydenia gemmipara,'' Sitzber. d. K. Akad. d. Wiss., Berlin, 1896), found, in the fluid of two cases of ascites occurring in malig- nant disease of the abdomen, an amoeba which consisted of colorless gelatinous cells, which put out pseudopodia, and showed a hyaline entoplasm and a granular ectoplasm. They were found chiefly in groups. Literature. (Am(rb(s.) V. Baumgarten: Jahresbericht, xvii., Leipzig, 1903. Behla: Die Amoben, Berlin, 1898 (Lit.). Celli u. Fiocca: Beitr. z. Amobenforschung. Obi. f. Bakt., xvi., 1894. Councilman and Lafleur: Amcebic Dysentery. Johns Hopkins Hosp. Rep., ii., Baltimore, 1891. Gilchrist: Protozoan Infection. Johns Hopkins Hosp. Rep., 1896. Harris: Amcebic Dysentery. Am. Journ. of the Med. Sc._, 1898. Kartulis: Zur Aetiologie der Leberalbscesse. Cbl. f. Bakt., ii., 1887; Pathogenese der Dysenterieamoten. lb., ix., 1891; Pathogene Protozoen. Zeitschr. f. Hyg., xiii., 1893. Kruse u. Pasquale: Unters. tib. Dysenteric u. Leberabscess. Zeitschr. f. Hyg., xvi., 1894. Losch: Massenhafte Entwickelung von Amoben im Dickdarm. Virch. Arch., 65 Bd., 1875. Walker: The Parasitic Amoebae of the Intestinal Tract of Man and Other Ani- mals. Jour, of Med. Res., 1908. FLAGELLATES. 527 § 184. A large number of species of the Flagellates (sub-class of the Mastigophora) occur in man, mammals, and birds, most frequently as parasites of the body-psissages accessible from without, but occurring also in the blood. Cercomonas, a small flagellate (Fig. 475) with a flagellum on the anterior end and a long-drawn-out posterior extremity, was observed by Kannenberg and Streng in gangrenous foci of the lung. ^ Fic. 475. — Cercomonas in- testmalis. (After Davaine.) Fig. 476. — Trichomonas hom- inis, after Grassi (from Doflein). Fig. 477. — Trichomonas vaginalis (from Dofiein). Trichomonas (Cercomonas intestinalis, Lambl; Trichomonas intes- tinalis, Leuckart; Monocercomonas hominis, Grassi) is a pear-shaped flagellate, 4-10 11 long, with three flagella on the anterior end (Fig. 476), Trichomonas hominis occurs in the small intestine of man. It appears to be a harmless inhabitant of alkaline intestinal contents. Trichomonas vaginalis is a flagellate similar to Trichomonas hominis (Fig. 477), and is often found in the human vagina. According to Miura, Marchand, and Dock, it may occur in the human urinary bladder. Lamblia intestinalis (Megastoma entericum, Grassi; Megastoma intestinalis, Blanchard; Cerco- monas intestinalis, Lambl; Hexamitus duodenalis, Davaine) is a turnip-shaped animal, having an in- dentation on the ventral surface (Fig. 478, A, B). It is about 10-16 fx long, and is found especially in the upper part of the small intestine, and has been observed in man, mice, dogs, cats, sheep, and rab- bits. The parasite clings tightly to the epithelium of the intestine, but no pathological changes can be demonstrated in the underlying tissue. § 185. Of the Flagellates that occur as blood- parasites of man the form known as Spirochaete obermeieri has been known for some time, but for- FiG. 478.— Lamblia in- rnerly was classed with the spiral varieties of bac- qnd'"''s*chewfakoff). "a] tcria (spirilla). The investigations of Schaudinn, View from ventral sur- howevcr, make it probablc that the spirochetes are face; B, view from the , , J i , left side. to be added to the protozoa. Schaudinn's conclusions are not universally accepted. According to Novy, Spirillum obermeieri telongs to the bacteria and not to the protozoa, and he believes that the majority, if not all, of the spirochsetes will be returned to their former place among the bacteria. Sp. duttoni and Sp. gallinarum have both been, shown to be non-pi^tozoal in nature. 528 THE ANIMAL PARASITES. The Spirochaete obermeieri (Fig. 479) is found constantly in the blood of patients suffering from relapsing fever during the attacks of fever, and the multiplication of these organisms in the body is the cause of the disease. The spirochaete is 16-40 /j, long, and possesses numerous spiral turns. In a fresh drop of blood it shows active motion. The subcutaneous inocu- lation into apes of blood containing the spirochaete is followed after several days by an attack of fever, and the spirochaete is found in the blood during the febrile stage. The life history of the Spirochaete obermeieri is not known, but it may be similar to that of the spirochastes occurring in the blood of birds as studied by Schaudinn (see below). Accord- ing to autopsy-findings in man, the spleen is swollen and contains numerous yellow foci of degeneration, and anaemic infarcts. According to investigations by Nikiforofif, with methyiene*'tiiue. the histological examination of the spleen shows extensive cell-necrosis and cell-degeneration (Fig. 480, c), as well as deposits of fibrin in the veins of the pulp, and proliferative proc- esses in the pulp-cells. Further, numerous large pulp-cells (/) enclose red and white blood-cells or the remains of such. Finally, numerous spirilla are found, especially in regions which are not wholly necrosed but contain degenerate and necrotic cells, free (a), and enclosed in Fig. 479. — Spirochaete Ober- meieri from the blood of an indi- vidual ill with relapsing fever. After a dried preparation stained X 475- Fig. 480. — Portion of tissue and isolated cells from a splenic follicle with partial necrosis, in relapsing fever. (After Nikiforoff.) (Potassium bichromate and sublimate, methylene-blue.) a. Free spirilla: b, lymphocytes with spirilla; c, non-nucleated lymphocytes; d, large, e, small mononuclear pulp-cells; /, phagocytes enclosing leucocytes and red blood cells and their remains; g^ free red blod-cells. x about 600. leucocytes (b), partly well-preserved, and partly beginning to show disintegration. According to Karlinski and Schaudinn, the infection is probably transmitted by bed-bugs. Spirochaetes have been observed also in birds, owls (Schaudinn), geese (Sacharoff, Gabritschewsky), and fowls (Marchaux, Salimbeni, Levaditi), and may cause epidemics in which great numbers of animals perish. SPIROCHETES. 529 The life-history of the Spirochaetes classed with the bacteria was not known until recently. Through the investigations of Laveran and Schaudinn it was first determined that in their life-cycle there occurs an alternation of generation and of host. Schaudinn carried out his studies on the spirochetes found in the small owl (Athene noctua), which he named Spirochata ziemanni (called by Laveran the Hamamceba ziemanni). As a result of his investigations he believed that he had demonstrated the transmission of this spirochete from the owl to the mosquito, Ciilex pipiens, in the intestine of which it passed certain stages of development, as described in the following paragraphs. Within the owl there develop male and female individuals, the microgameto- cytes and the macrogametes. Copulation takes place in the intestine of the mos- quito. From the fertilized macrogamete there develops an ookinete which pro- duces in the intestine of the mosquito an enormous number of trypanosome-like offspring. These become transformed into true spirochsetes, spread through the body of the mosquito, increase by logitudinal division, and wander into the oeso- phagus, whence, in the act of biting, they again pass inio the blood of the owl. After an asexual period of multiplication in the form of spirochjetes they again form gametes or sexual individuals in the blood of the owl. As a result of their distribution through the body of the mosquito the spirochaetes pass into the ovaries of the latter and are transmitted to the next generation. The fertilization in the intestine of ihe mosquito follows ripening of the macrogametes (female cells) and the formation of microgametes (spermatozoa) from the microgametocytes. The ookinete resulting from the fertilization of a macro- gamete is a worm-like body rolled up into a complicated skein. Through grouping of the protoplasmic masses around the individual nuclei there are formed small trypanosome-like individuals having a characteristic fiarjellum-apparatus. Further, there may be developed both male and female individuals. The female forms are larger than the indifferent forms, their plasma is dark, the nucleus and ble- pharoplast relatively small, and the margin of the undulating membrane is not continued to form a flagellum. The males are small and scarcely recognizable. Through continued division the indifferent spirochaetes in the intestine of the mosquito also become very small, so that single individuals can barely be made out. Within the blood of the owl the spirochaetes become parasites of the haemo- globin-containing erythroblasts, in that they attach themselves to these by their posterior extremities. This is seen particularly in the bone-marrow and also in the spleen. After a certain time they form in the blood macrogametes and micro- gametes, which, on gaining entrance into the mosquito, again form new generations in the manner described. The macrogametes can also produce new generations in the blood without fertilization (parthenogenesis) and thereby cause relapses. The above-given life-cycle of the spirochaetes according to Schaudinn falls to the ground in the light of Navy's studies. The latter has shown that the Spirochcete ziemanni is not a spirochete, but a trypanosome, and has no connection with the intracellular parasites of the owl's b!ood._ Further, Novy regards Sp. ohermeieri as belonging to the bacteria, basing his view on his_ inability to demon- strate in the organism a nucleus, blepharoplast, undulating membrane, or flagellum of the protozoan type. On the other hand the spirilla of relapsing fever possess whips having all the characteristics of those of bacteria, divide transversely, multiply rapidly, resist changes in osmotic tension, show a greater resistance to heat than do the trypanosomes, excite the production of immune and germicidal bodies, and do not exhibit the aerotropism shown by trypanosomes. In relapsing fever we have most probably to deal with a group of closely re- lated organisms (Novy), which, while they may in one sense be regarded as dis- tinct species, are derived from one stem. Five distinct strains of spirilla causing relapsing fever have been discovered : Spir. obermeicri, Spir. novyi, Spir. kochi, Spir. duttoni, and Spir. carteri. These differ from each other in the duration and severity of the initial attack, the frequency and intensity of relapses, and in the mortality following injection of a uniform dose of 0.2S c.c of spirillar blood. The relapse is probably due to the survival of a few individuals that are more or less immune, so that a serum-fast strain develops. This in turn calls out a new anti-body. If this is less active or more unstable, or more readily eliminated, the relapses con- tinue . If Schaudinn's views on the protozoan nature of the organism found in syphilis (Spir. pallida, Treponema pallidum) are correct, that organism should then be classed with the protozoa. At the present time this question cannot be regarded as settled, but it is most probable that the organism is of bacterial nature and should be classed, along with the spirochaetes of relapsing fever, with the spiral forms of bacteria (spirilla). (See Syphilis.) 34 530 THE ANIMAL PARASITES. Literature. {SpirochcEtes.) Cantacuzina: Spirilloses des oies. Ann. de ITnst. Pasteur, 1899. Gabritschewsky : Zur Pathol, d. Spirochaeteninfection. Cbl. f. Bakt., xxvi., 1899, u. xxvii., 1900. Honl: Febris recurrens. Ergebn. d. allg. Path., iii., 1897. Karlinski: Aetiol. des Gefliigeltyphus. Cbl. f. Bakt., Orig., xxxi., 1902. Levaditi: Spirillose des poules. Ann. de I'lnst. Pasteur, 1904. Marchoux et Salimbeni: Spirillose des poules. Ann. de I'lnst. Pasteur, 1903. Metschnikoff: Ueb. den Phagocytenkampf bei Riickfalltyphus. Virch. Arch., 109 Bd., 1887. Nikiforoff: Zur path. Anat. u. Histol. d. Milz bei Recurrens. Beitr. v. Ziegler, xii., 1892. Novy: Studies on Spirillum Obermeieri and Related Organisms. Jour, of In- fect. Dis., 1906. Obermeier: Cbl. f. d. med. Wiss., 1873; Berl. klin. Woch., 1873, No. 33. Puschkarell: Zur pathol. Anatomie der Febris recurrens. Virch. Arch., 118 Bd., 1888. Schaudinn: Generations- u. Wirtswechsel bei Try.panosomen u. Spirochaten, Berlin, 1904. Sudakewitsch : Rech. sur la fievre recurrente. Ann. de I'lnst. Pasteur, v. 1891. Wladiniiroff: Riickfallfieber. Handb. d. pathog. Mikr'oorg., iii., Jena, 1903 (Lit). § 186. The genus Trypanosoma forms a second class of blood-para- sites belonging to the Flagellata, found in man, mammals, and birds, and also in cold-blooded animals. Most authors place all the parasites of this class in the genus trypanosoma and distinguish different species. Doflein Fig. 481. — Trypanosoma (.herpetosoma) leviisi in the blood of the rat. Rabinowitsch and Kempner.) Er, Erythrocytes; (From Doflein after divides them according to the character of the flagella into three sub- genera: Trypanosoma, Trypanomonas, and Herpetosoma. Van Wasie- lewski classes only the blood-parasites of the frogs and fish with the trypanosomes, and would apply the name Herpetomonas, given by Kent, to. the trypanosomes found in mammals. TRYPANOSOMES. 531 Trypanosoma lewisi (Herpetomonas, Trypanomonas, Trichomonas, Hczmatomonas) h a common parasite of rats. It is 8-30 ju. long and 3-8 IX broad (Fig. 481), consists of a nucleated granular entoplasm and a delicate hyaline ectoplasm or periplastem, the latter forming an undulat- ing membrance (Fig. 482, c) and a flagellum (rf) which arises in the beak-like posterior end from a rod-like body and extends anteriorly along the edge of the undulating membrane. The rod-shaped body {b) is, designated micronucleus, or nucleolus, or centrosome, or blepharoplast. It has the significance of a nucleus and arises from the chief nucleus. The trypanosome infection occurs extensively among rats of many regions. In other animals these trypanosomes do not appear to develop. The infected rats are apparently healthy, yet epidemics occur in which great numbers of them die. Intraperitoneal inoculations of rats are followed by multiplication of the trypanosomes, in the abdominal cavity and in the blood. According to Rabinowitsch and Kempner reproduction Fig. 482. — Trypanosoma (.herpetomonas) lewisi, in different stages of development. (After A. von Wasielewski.) A, Fully developed parasite with nucleus (a), rod-shaped body (&), undulating membrane (c), and flagellum (cf) ; B, parasite with two nuclei and one -rod-shaped body: C, parasite with one nucleus and two rod-shaped bodies; D, division into two parasites; B, parasite with four nuclei and four ilagella; F, daughter-individuals still united into a colony. X 1,500. takes place by longitudinal and transverse division of flagellated indi- viduals, and through the segmentation of large non-flagellated forms in which cell-division is initiated by division of the nucleus, designated as the chromatin framework, while new nucleoli are snared off from the chromatin mass. According to von AA'asielewski the chief nucleus {B) sometimes first divides, at another time the rod-shaped root of the flagellum or the blepharoplast (C) ; the cells sometimes divide with two nuclei (-D), and sometimes after the formation of several nuclei and flagellum- roots {E, F), so that the resulting dividing flagellates remain for some time united in colonies. The infection of rats occurs probably through the medium of fleas and lice. Trypanosoma brucei, Plimmer and Bradford, is similar to Tr. lewisi, only the body is somewhat broader and the posterior end somewhat blunter. It is the cause of Nagana or the tsetse-fly disease of cattle, horses, antelopes, buffalo, donkeys, dogs, sheep, and goats, occurring in Southern and Southeastern Africa, which is transmitted through the tsetse- fly (Glossina morsitans). The number of parasites in the blood may be great; infected animals suffer from fever and become anjemic- 532 THE ANIMAL PARASITES. oedema develops in different parts of their bodies; there is conjunctivitis and the spleen is swollen. The period of incubation is not more than nine days. The infected animals die after one and one-half to eight months. It is probable that the disease known as Surra, occurring endemically in horses, mules, camels, buffalo, cattle, and elephants in Dutch India, Indochina, and the Philippines, and which is transmitted by gad-flies, is due to this trypanosome. It is likewise regarded as the cause of the trypanosome disease ofjiorses and donkeys known as the coitus-disease or dourine occurring in Algiers, Southern France, Sumatra, Novarra, and the Pyrenees, and which is spread by coitus, and is inoculable into rab- bits, rats, and dogs. Many authors regard the parasites found in these •diseases as representing different species, giving to the first the name of Trypanosoma evansi and to the latter that of Tr. equiperdum. A variety of trypanosome found in Central South America and which causes the disease of horses known as mal de caderas is designated Tr. equinum. It is assumed that Stomoxys calcitrans acts as the agent of transmission of the parasite. A variety of trypanosome known as Tr. theileri is found in cattle in South Africa and is inoculable only into cattle. The occurrence of trypanosomes in man was first observed by Nep- veu (1898). The investigations of Button, Todd, Boyce, Ross, Sherring- ton, Bruce, Castellani, Manson, Daniels, Laveran, etc., have shown that trypanosome diseases also occur in man. The sleeping-sickness of the negro is now known to be due to trypanosome infection. Castellani found the parasite in the cerebrospinal fluid of sleeping-sickness, and his findings have been confirmed by different observers. The disease occurs throughout tropical West Africa, and in recent years has spread through Central and Eastern Africa. Negroes are chiefly affected, but cases have also been observed in Europeans. The infection is transmitted by a biting-fly (Glossina palpalis). The parasites develop in the blood, and during this period symptoms may be wanting, or there may be attacks of fever. When the parasites gain access to the cerebrospinal fluid and increase, cerebral symptoms, particularly coma, are produced as the result of meningitis. The disease runs a chronic course and is invariably fatal. Trypanosomes are also found in the disease known as Gamba-fever which occurs in Senegambia and the Congo, both in the natives and Europeans. According to Laveran, it is due to the same species of try- panosomes observed by Castellani in Uganda. Further, trypanosomes are believed to be the cause of tropical splenomegaly, which occurs in India, China, Arabia, Egypt, and Tunis, and is characterized by intermit- tent or remittent attacks of fever associated with marked swelling of the spleen, leading after many months' duration to progressive anasmia and cachexia having a fatal termination. It is probable that the disease known as Kdla-azdr (hleLck fever), which is widely distributed through the valley of Assam watered by the Brahmaputra, is related to tropical splenomegaly. The life-history of the trypanosomes is similar to that of the spirochaetes. According to investigations by Schaudinn the Haltertda (Hamoproteus noctuoe of Celli and San Felice') of the little owl are the sexual stages of a trypanosome which multiplies in the comtnon m-osquito, Culex pipiens, so that after a compli- cated wandering through the body of the mosquito, through its bite again reaches the blood of the owl, in which after a period of asexual increase it changes into the familiar male and female Halteridia. The parasite must, therefore, be called the Trypanosoma noctuce. (Whether other members of the genus Halteridium or Hxmoproteus are to be classed with trypanosomes remains to be settled.) Accord- TRYPANOSOMES. 533 ing to Novy {Jour, of Infect. Dis., 1905) the observations of Schaudinn are open to an entirely different interpretation. He believes that the Trypanosoma noctuae and the Spirochata ziemanni of Schaudinn probably represent trypanosomes that have multiplied in the mosquito and are not to be considered as stages in the life- history of cytozoa. According to Novy's investigations trypanosome infection of birds is widespread. With the trypanosomes there may be associated intracellular parasites, but no constancy can be shown to exist between a given trypanosome and a given cytozoon. It has not been decided whether human trypanosomiasis is due to more than one variety of trypanosome. The different clinical course of the affections makes this probable. In the forms known as tropical splenomegaly or cachectic fever and k&la-azdr, there are found {Leishman, Marchand) in the spleen, liver, bone-marrow, lymph-nodes, and in intestinal ulcers, great numbers of small bodies, partly free and partly intracellular, consisting of an intensely staining ring-shaped chromatin body surrounded by a circular or oval, clear area staining lightly with eosin. Besides the chromatin-body there is often found (Marchand, Ledingham) a small, intensely staining round or elongated granule, which is often connected with the chromatin-ring by a delicate stalk. These bodies {," Leishman-Donovan bodies") were first found by Leishman and Donovan in smears from the spleen, and were later studied by Marchand, Ledingham, Manson and Low, Bentley, Rogers, and others, the general opinion being that they represented degeneration forms of trypanosomes. Rogers has succeeded in growing them outside the body and in demonstrating their transformation into elongated flagellated organisms resembling trypanosomes. On account of the absence of an undulating membrane Rogers believes the organism to be a herpetomonas. Ross regards it as a new genus and has called it Leishmani donovani. Nothing is absolutely determined concerning the transmission of this fatal infection. Rogers believes that it is transmitted by bed-bugs or mosquitoes. Nicolle {Arch, de I'Inst. Pasteur, Tunis, 1908) has suc- ceeded in cultivating the Leishman-Donovan bodies from cases of infantile splenomegaly in Tunis. He regards the protozoon obtained as a new species. Leishmania infantum. The protozoa found in a case of tropical sore by M'right (Jour, of Med. Res., 1903) and called by him Helcosoma tropicuin, are regarded as Leishman-Donovan bodies, and designated by Nicolle as Leishmania ivrighti. They are regarded as the infective agent of " Delhi boil." According to the majority of writers trypanosome or Gambian fever is but the early stage of sleeping-sickness, both conditions being due to infection with the same parasite, the Trypanosoma gambiense. The first stage is of variable duration, lasting from three months to three years or longer. During this stage there is polyadenitis and the trypanosomes may be demonstrated in the blood and lymph- nodes. As a diagnostic method the examination of a drop of fluid removed from an enlarged cervical node by means of a hypodermic needle is advised, since the parasites can be found in this way immediately if they are present in the body. Literature. ( Trypanosomes. ) Baker: Trypanosoma in Man. Brit. Med. Journ., i., 1903. Bradford and Plimnier: The Trypanosoma Brucei. Quart. Jour, of Micr. Sc, xlv., 1901. Bruce: Rep. on the Tsetse Fly Disease. Ubomlbo, 1895 and 1896; Trypanoso- miasis. Brit. Med. Journ., ii., 1904. Bruce, Nabano, and Greig: The Etiol. of Sleeping Sickness. Brit. Med. Journ., ii., 1903. Castellani: Aetiologie der Schlafkrankheit. Centralblatt fiir Bakteriol., Orig., XXXV., 1903. Donovan: The Etiology of One of the Heterogeneous Fevers of India. Brit. Med. Journ., ii., 1903. Button: Trypanosoma Occurr. in the Blood of Man. Thompson-Yates Lab. Rep., iv., 1902. Dutton and Todd: Rep. to the Trypanosomiasis Exped. to Senegambia. Thomp- son-Yates Lab. Rep., v., 1903. Giinther: Trypanosomen bei Menschen. Miinch. med. Woch., 1904. 534 THE ANIMAL PARASITES. Laveran: Des trypanosomes parasites du sang. A. de med. exp., iv., 1892; Trypanosomiase humaine. Compt. rend, de I'Ac. d. Sc, cxxxviii., 1904. Laveran et Mesnil: Maladie de la mouche tsetse. Ann. de I'lnst. Pasteur, 1902; Trypanosomes et Trypanosomiases. Paris, 1904. Leishman: On the Possibility of the Occurrence of Trypanosomiases in India. Brit. Med. Journ., i., 1903, p. 1252; Discussion on the Leishman-Donovan Body. lb., ii., 1904, p. 642. MacNeal: The Life-history of Tr. Lewisi and Tr. Brucei. Journ of Infectious Dis., 1904. Manson and Daniels: A Case of Trypanosomiasis. British Medical Journal, i., 1903. Marchand u. Ledingham: Uefcer Infektion mit Leishmanchen Korperchen. Z. f. Hyg., 47 Bd., 1904 (Lit.). Marchoux: La fievre jaune. Ann. de I'lnst. Pasteur, 1903. Novy: The Trypanosomes of Tsetse Flies. Journ. of Infect. Dis., 1906. Novy and MacNeal: Cultivat. of Trypanosoma Brucei. Journ. of Infect. Dis., i., Chicago, 1902, u. Biol. Obi., xxiv., 1904; On the Trypanosomes of Birds. Journ. of Infect. Dis., 1905. Novy, MacNeal, and Torrey: The Trypanosomes of Mosquitoes. Journ. of Infect. Dis., 1907. Salmon and Stiles: Rep. on Surra: XVIII. Ann. Rep. of the Bureau of Animal Industry, Washington, 1902. Schaudinn: Generations- u. Wirtswechsel bei Trypanosomen u. Spirochaten. Arb. a. d. K. Gesundheitsamte, xx., 1904. § 187. Of the Sporozoa occurring as parasites in man and other mammals, the coccidia are to be mentioned first. In their young state they exist as non-encapsulated inhabitants of epithelial cells, particularly in those of the intestinal canal and its adnexa, the liver especially, and more rarely in the organs of excretion. Some of the mature forms sur- ft-^^.£:S.? Fig. 483. — Section through the wall of a dilated bile-duct, filled with coccidia and lined with papillary proliferations. From a rabbit's liver that was studded with coccidia nodules (Miiller's fluid, hsematoxylin, eosin). a, Connective tissue; b, branching papillary proliferations covered with epithelium; c, coccidia. X 23. round themselves with a capsule and become changed into round or oval permanent cysts or oocysts (Schaudinn), which leave their resting-place and usually also their host, and under certain conditions form sickle- shaped sporosoites through repeated division of their cell body (sporogony). Through the taking-up of sporozoite-containing oocysts into a new host there is produced an infection of the latter, in that the sporozoites are set free and seek out epithelial cells for their further development. COCCIDIA. 535 Besides this form of multiplication there occurs in the infected organ reproduction by schizogony — that is, there are developed from mature but non-encysted individuals, by means of segmentation, a large number of new sickle-shaped individuals, the so-called merosoites, which seek out epithelial cells, and develop in them. Coccidium oviforme (Fig. 484) is a parasite of the intestine and biliary passages, occurring especially in rab- bits. Podwyssozki claims to have observed them in the human liv^r. In the liver of rabbits the invasion of coccidia leads to the formation of white nodules which may reach the size of a hazel- nut. These nodules contain a soft, white, or yellowish-white mass, and consist of dilated Fig. 484.— Coccidia from the bile-passagcs, the inner surface of which is \Wg.' 483), °*shSvving'''''diffe"rIm ^lorc or less richly furnished with papillary stages o£ development (Miiller'a growths (Fig'. 483), and whoSC lumCH COU- fluid, hematoxylin), o, b, Small, ? . i r -j- coarsely granular young forms; taiUS HUmbcrS Of COCCldia. c, d, large forms with darkly stain- -pj^g coccidia occur in the bilc-passages >ng peripheral granules; e, f. B, , . , ^ ,. 11 h, oval, encapsulated forms, the partly m the form of non-encapsulated proto- ?oars?iy^granuiar''and Tart!/ fine plasmic Structures, and partly in the form of — fills up only a portion of the encapsulated bodies. The smallest coccidia, capsule. X 400. , . , 111 r which are regarded as the younger forms, ex- hibit a coarsely granular protoplasmic structure (Fig. 484, a, b), within which a nucleus (a) may occasionally be demonstrated. The larger forms exhibit on their outer surfaces regularly arranged granules (c, d), which stain intensely with hsematoxylin. The encapsulated forms occur as oval, doubly contoured, clear bodies (e, f, g, h) within which lies a variously shaped mass exhibiting various forms of granulation, but never entirely filling the space within the capsule. To the coccidia belong those parasites which occur in the epidermis Fig. 48s. — Epithelioma contagiosum. Section through greatest diameter (Muller s^ fluid, hematoxylin), a. Epidermis; b, connective tissue; c, sebaceous gland; d, gland-like epithelial proliferations; e, parasites; f, horny cells mingled with parasites; g, duct filled with horny epithelium and parasites. X 13. of man and form peculiar growths known as epithelioma contagiosum (Fig. 485). In its fully developed condition the growth consists of a nodule, the size of a pea or larger, which is elevated above the surface of the skin, shows a small groove in its centre, and possesses a waxy lustre. On section there maybe seen a lobulated epithelial growth (Fig. 485, d), 536 THE ANIMAL PARASITES. with a central cavity opening externally (g), thus resembling a gland ; it has many times been mistaken for a hypertrophic sebaceous gland. It represents an independent new-formation of epithelium due to a parasite. The parasites develop inside the epithelial cells of the growth (e), but are pressed by the growth of adjacent epithelium toward the central cavity (/), and lie in a meshwork of desquamated and horny epithelial cells. The earliest stages of develop- ment of the parasites occur in the epithelial cells as small proto- plasmic bodies (Fig. 486, a, h), which can be distinguished from the cell-protoplasm only with diffi- culty; occasionally they contain in their interior small, distinct 486. — Parasites of Epithelioma contagiosum trrpnulps anrl arf> tViprpfnrp mnrp ious stages of development, lying inside epi- granuics, anQ are tnerciore more " ' •• - • evident. Later they increase in size, and finally fill the cell (c, d, e), pressing the nucleus to one side. At the same time the gran- ules in the cell (c) increase, and grow to larger bodies, so that the ^parasite finally becomes divided into a greater or less number of well- defined structures {d, e, f) lying in a finely granular network. The nucleus of the epithelial cell is destroyed during this time. Fig. in van — „__ ____--. , , „ thelial cells (Miiller's fluid, hiematoxylin). o, b, Epithelial cells, enclosing a protoplasmic body in- side of which lie single large granules; c, epithelial cell almost completely filled with parasites; d, e, i, parasites completely filling the epithelial cells, and divided into numerous separate bodies lying in a granular network; the cell-nucleus has been de- stroyed in /. X about 500. \ ..4-. aw 1 .■»*io!*« ■". ^" V Fig. 487. — Miescher's sacs, from swine-muscle, a, h, Muscle cut longitudinally and transversely, X 100. c. Longitudinal section, x 580. The epithelial cells which enclose parasites develop early a distinct membrane, which becomes more and more clearly defined, and surrounds the parasite. The parasites which are expelled from the cells form oval bodies enclosed in a capsule and present a homogeneous appearance. They stain deeply with hasmatoxylin. The contagious epitheliomata may appear in great numbers in one and MIESCHER'S SACS. 537 the same individual, and several persons living together may be simul- taneously or successively attacked. By many writers the molluscum bodies are not believed to be parasites, but are regarded as hyaline or horny products of cell-degeneration. Our knowledge of the significance of the so-called Miescher's sacs IS still mcomplete. They are tube-shaped structures which are not infre- quently found in the muscles of the hog (Fig. 487, a, b), cattle, sheep (especially in the oesophagus), and mice. They vary in size, and lie in the muscle-fibres. In mature parasites the contents of the tubes are dif- ferentiated into single segments defined by a membrane (Fig. 487), which enclose spherical (c), kidney-shaped, or sickle-shaped bodies. The Fig, 4_88. — Cycle of development of Coccidium Schubergi. (After Schaudinn and Liihe). I, Sporozoite (or merozoite) penetrating into an epithelial cell; 2, mononuclear schizont in an epithelial cell; 3, multinuclear schizont; 4, division of the schizont (schizogony) into numerous merozoites; 5, macrogamete (female cell) arising from a merozoite; 6, fully developed marco- gamete surrounded by extruded chromatin granules; 5a, microgametocyte (male cell) arising from a merozoite; 6a, microgametocyte surrounded by loosened microgametes (spermatozoa); 7, fer- tilization of the macrogametes by microgametes; 8, young oocysts; 9, oocysts with sporoblasts; 10, oocysts with sporocysts, each containing two sporozoites; 11, sporozoite. parasite is classed with the Sarcosporidia. The separate segments are designated sporocysts or sporoblasts, since within these the round or sickle-shaped spores (Rainey's bodies) arise. From the latter, new Miescher's sacs may develop under favorable conditions (Pfeiffer). Ingestion of meat containing sarcosporidia is not dangerous to man, although sarcocysts have been observed in man in the muscles, heart, intestine, and liver. As early as 1870 Eimer published observations on the development of coccidia, but their life-history has been accurately determined only in recent years through the investigations of R. Pfeiffer, Simond, Leger, Schaudinn, Schuberg, Siedlecki, Schneider, von Wasielewski, Labbe, and others. 538 THE ANIMAL PARASITES. The reproduction of coccidia occurs (Liihe) partly through sporogony, pa<-tly through schizogony. The first method serves for the spreading of infection and the preservation of the species, the second increases the extent of the infection in the infected host. Sporogony is closely connected with a previously occurring copula- tion which in its course suggests the fertilization of the egg of the metazoa. Alter- nation of generations also takes place. • The development and reproduction take place in the following manner: In schizogony the sickle-shaped germ (Fig. 488, 1) arising as a sporozoite or merozoite develops within an epithelial cell into a schizont (2) in which there soon takes place multiplication of the nucleus (3). There then results (on the second day after the over-feeding of sporocysts) formation of merozoites (4) corresponding in number to the nuclei, and a residual body which is left behind after the seg- mentation. The merozoites again seek epithelial cells, and the same development begins anew. If the affected organ, as the result of these processes, becomes overcrowded with parasites, there are then formed sexual individuals (Schaudinn). Some of the merozoites grow into large cells, the macrogametes (S, 6) or female cells, which, wihen mature throw off a portion of their chromatin-substance (6), and either remain naked or surround themselves with a capsule, which is provided with a micropyle. At the same time other merozoites develop into the male sexual cells' or microgametocytes (So, 6a), the nuclei of which divide into many daughter- nuclei. The latter approach the surface of the cell, and, surrounded by a certain amount of protoplasm, are constricted off, (6a) and then represent the micro- gametes (corresponding to the spermatozoa of the higher animals). The copulation of the microgametes with the macrogametes takes place in a manner similar to that of the fertilization of the metazoan egg, in that the microgamete penetrates the encapsulated form of macrogamete through the micropyle and the naked form through a certain point which pushes itself outward to form a prominence (7), the conceptional protuberance. Sporogony follows the fertilization — that is, the oocyst (8) is formed, in which, through division of the nucleus and proto- plasm, there arise four sporoblasts (9), each of which later produces two sickle- shaped sporozoites (10). Numerous authors hold the view that local pathological conditions of the tissues in man other than those described above may be referred to sporozoa, par- ticularly carcinoma. Darter's disease, Paget's disease, peculiar diseases of the urin- ary passages, etc. It may, however, be remarked that this assumption in part is based on error, and has not been proved by investigations made up to the present time. So far as carcinoma is concerned, in spite of the great number of works on the subject, so numerous indeed that they can scarcely be perused (cf. § 121), no proof has been given that protozoa, coccidia in particular, are present in the epithelial proliferation and are to be regarded as the cause of the same. All the appearances described as occurring as carcinoma cells, even the sickle-shaped forma- tions which have been thought to be convincing and those provided with a sort of capsule, may be otherwise interpreted, and may be explained as changed nuclei, as altered protoplasm of the cancer-cells, as cell excretions, and finally as a product of cell-fusion or of the taking up of leucocytes by the cancer cells. The disease described by Darier as psorospertnose folliculaire vcgetante, and re- ferred by him to the presence of sporozoa, is probably an inflammatory affection of the skin characterized by pathological cornification (keratosis follicularis of von Withe), in which horny plugs and pegs are developed successively in the epithe- lium of certain parts O'f the body, while the cutis shows slight inflammatory changes. According to Bussi, Miethke, Rieck, Krosing, Petersen, and others, the " corps ronds," described by Darier as parasites, contain kerotohyalin and eleidin, sub- stances which are present in comified cells but not in gregarinse. Paget's disease is an affection spreading from the nipple, beginning with an eczema-like inflammation, and leading to superficial ulceration, and ending in carci- nomatous infiltration of the skin. It has been referred by Darter, Wiechham, Malassez, and others to the presence of a parasitic sporozoon in the epithelial cells; but is, however, either eczema arising from other causes, and leading to cancer, or a primary cancer accompanied by inflammatory processes (Ehrhardt), in which peculiar changes take place in the epidermis, particularly swelling of the protoplasm and nuclei, with formation of vacuoles, and proliferative changes, the peculiar appearances of which might be mistaken for parasites. According to Jacobaeus these appearances are brought about through penetration oif the carcinoma into the superficial epithelium. THE MALARIAL PARASITE. 539 In variola and vaccinia there occur constantly in the epithelium that has ■undergone recent changes small lightly staining bodies surrounded by a clear zone, often in great numbers. Their constant occurrence in repeated inoculations and their characteristics make it very probable that they represent parasites belonging to the protozoa, and this view is favored by numerous authors {Guarnieri, E. Pfeiffer, L. Pfeiffer, Bosc, Funk, Councilman, von Wasielewski, and others). Huckel and Barrel have attempted to interpret these structures in another way. Afepri _ (" Etiologie der Tollwut," Z. f. Hyg., 43 und 44 Bd., 1903) describes small bodies found in the nervous system of dogs inoculated subdurally with the virus of rabies that he regards as protozoa and considers to be the cause of rabies. Investigations by Volpino ("Struttura dei corpi descr. da Negri nella Rabbia." A. per le Sc. Med., xxviii., 1904), and by Luzzani ("La dimonstraz. del Parass. specif, in un caso di rabbia nel I'uomo." Ibid.) support the view of Negri, but offer no further information as to the nature of the parasite. Accord- ing to A. W. Williams, the Negri bodies possess a definite chromidium and are, therefore, to be classed with the rhizopods {Jottrn. of Infect. Dis., 1906). Mallory ("Scarlet Fever." Jour, of Med. Res., x., 1904) found a protozoon- like body in four cases of scarlet fever. Field {Journ. of E.rper. Med., 1905) believes that these bodies are products of degenerating tissue-cells and leucocytes. Gotschlich (" Protozoenbefunde im Blute von Flecktyphuskranken." D. nied. Wochenschr., 1903) found pear-shaped bodies in six cases of typhus fever that resembled the parasites of Texas fever, and in four cases he also found flagellated bodies. According to Hess and Guillebeaii, coccidia may occasion in young cattle dis- eases of the intestme resembling dysentery. According to Olt and Voisin, the shotty eruption of swine characterized by the formation of little cysts in the skin is caused by coccidia (C. fuscum), but according to Liihe the description of the parasites does not correspond to coccidia. Literature. (Coccidia; Parasite of Epithelioma Contagiosum; Miescher's Sacs.) Barrat: The Nature of Psorospermosis. Journ. of Path., iv., 1896. Councilman: A Preliminary Communication on the Etiology of Variola. Journ, of Med. Res., 1903. Delepine and Cooper: A Few Facts Concerning Psorospermosis. British Med Journ., ii., 1893. Gilchrist: Protozoa, etc. Johns Hopkins Hosp. Rep., i., 1896. Johnson: A New Sporozoan Parasite of Anopheles. Journ. of Med. Res., 1902. Kartulis: Pathogene Protozoen. Zietschr. f. Hyg., xiii., 1893. Nocard: Coccidial Tumor from the Small Intestine of the Sheep. Journ. of Path., i., 1893. Rixford and Gilchrist: Protozoan Infection. Johns Hopkms Hosp. Rep., i., 1896. Thomas: Bone Tumor Surrounding Encysted Coccidia. Report ol the Boston City Hosp., 1899. Tyzzer: Coccidium Infection of the Rabbit's Liver. Journ. of Med. Res., 1902. White and Robey: Molluscum contagiosum. Journ. of Med. Res., 1902. § 188. Under the designation Plasmodium malariae (Marchiafava and Celli) or the haemosporidia of malaria are grouped those parasites which are regarded as the cause of human malaria. The parasites are found in the blood of malarial patients in different forms, usually enclosed in cells ; and, according to the observations of Golgi, Celli, Marchiafava, and others, a definite relation can be demonstrated between the number and the stage of the development of the parasite and the attacks of fever. The parasites pass through different stages of development in the interval between the attacks of fever, these stages, according to the authors mentioned, differing in fehris quartana, febris tertiana, and fehris quotidiana. At the same time the parasites of the different forms of fever exhibit certain differences in their physiological characteristics. 540 THE ANIMAL PARASITES. Supported by these facts, there may therefore be distinguished in man different species of the malarial plasmodium. In its narrower sense the designation Plasmodium malarice is used only with reference to the para- sites of quartan fever. The parasite of vernal tertian on account of its active movements is known as Plasmodium vivax (Grassi and Feletti) ; and the parasite of tropical malaria, which in Italy appears in the autumn, is designated Plasmodium prcscox. Schaudinn's classification of the malarial parasites is accepted by most writers. He recognizes three varieties: Plasmodium vivax (tertian), Plasmodium malaria (quartan), and Plasmodium immaculatum (aestivo-autumnal parasite). The development and increase of the plasmodia take place within the red blood-corpuscles, in which, first of all, small, colorless amoeboid Fig. 489. — Plasmodium malarias of quartan fever, in different stages of development. (After Golgi.) a. Red blood-cell with a small non-pigmented Plasmodium; b, c, d, e, pigmented Plasmodia of varying size inside the red blood-cells; /, Plasmodium in beginning segmentation; with centrally placed pigment; g, segmented Plasmodium; /i, Plasmodium divided into separate spherules; i, {rte gamete (sexual individual). bodies (Fig. 489, a) appear. In quartan fever the further development of the parasite proceeds by enlargement of the small amoeboid forms (Fig. 489, a, b, c, d, e), so that the red cell becomes more and more filled by the parasite. At the same time pigment-granules appear within the bodies of the plasmodia. When the plasmodia have attained a cer- tain size, the pigment-granules move toward the centre, while at the same time a radiating cleavage sets in, and daisy-like figures {"rosettes") (/, g) are formed, which consist of a pigmented centre and non-pig- mented, radiating club-shaped petals. Later the clubs become detached from the central mass of pigment and take on a circular form (/i). 'According to Golgi, the development and division of the plasmodia of quartan fever require three days for completion, and the attacks of fever coincide with the division of the plasmodia. The red cells occupied by the parasites are destroyed ; the young plasmodia formed by division penetrate into blood-corpuscles, and the cycle of development begins anew. The pigment-granules formed by the plasmodia are taken out of the circulating blood partly free and partly enclosed in cells, and are deposited in different organs, particularly in the spleen, liver, and bone- marrow. In febris tertiana (vernal tertian) the cycle of development is com- pleted in two days. The plasmodia developing within the red cells (Fig. 490, a-d), which are designated Plasmodium vivax, show much livelier motion and lead much more quickly to decolorization of the red blood- corpuscles than those of quartan fever; the red cells become decolorized on the first day after the fever, while the plasmodia are still small. The THE MALARIAL PARASITE. 541 protoplasm of the plasmodia of tertian fever is also more delicate and less sharply contoured and the pigment-granules are smaller. In its division each Plasmodium splits up into from fifteen to twenty new cells {e), while the parasite of quar- tan fever forms only from six to twelve. According to Celli and Marchiafava, sporulation not infrequently occurs prema- turely, from five to ten spores arising within a red corpuscle. The parasite of tropical or pernicious malaria, the Plas- modium prcBcox, differs from the haemosporidia of the vernal Fic. 49o.-p/«^.A-.™ ....„ of a vernal tertian, i^^f.^' Particularly in the fact showing different stages of development. (After that it IS Smaller (Fig. 491, 0, Golgi.)o, First stages of development; 6,,;, enlarged h r rl\ ariH pvprlll-pc liVplir Plasmodia with pseudopodia; d, plasmodia before •" ''•' "/ ""*-' CXeCUtes llVCly sporulation, the red blopd-cell decolorized; e spor- movements Within the red Cells. ulation; f. free parasite with flagellum (micro- -r, , . . ,. . ^^^-^"•'• gametocyte). It Completes its liie-cycle in twenty-four to forty-eight hours. Through the formation of a central vacuole it often appears in the form of a ring. During the stage of multiplication the parasite collects in the internal organs, so that division-figures (d) must be sought in the spleen, liver, bone-marrow, and brain (where they are present in great numbers). Some of the infected red cells become crenated and prickly, and of a brassy color (Marchiafava, Celli) ; they die prematurely, and blood-cells which contain no parasites are also destroyed. The attacks of fever can in the case of autum- nal tertian fever become so pro- longed that they pass into one another, and the condition thereby assumes the character of a sub-continuous or con- tinuous fever. According to Marchiafava and Celli, there also occurs a quotidian parasite similar to the ^^t.t. - t~, i J ■ _ „ • Fig. 401. — Plasmodium praccox of tropical malaria, latter, but producing no pig- showing different stages of development. (After ment at all Golgi and Sanfelice.) o. First stages of development; b, Plasmodia with pseudopodia; c, round Plasmodium Nuclear bodies may be with pioment, before segmentation; d, sporulation; demonstrated, during certain c'eiii"'"'"""'" "''"'' '"'''"'^"^'^ ^' '■ ^"^ =^""^' stages of development, in the protoplasm of all the endoglobular forms of malarial haematozoa. Ac- cording to Ziemann, in sporulation there first occurs division of the chromatin into small clumps, and later division of the cell-body, so that every clump of chromatin is surrounded by a zone of protoplasm. Besides the forms of development which lead to intracellular increase of the plasmodia through schizogony, there occur extraglobular, also endoglobular, round and oval, sickle- or crescent-shaped structures (Figs. 489, i,- 491, e,f), as well as round bodies with flagella (Figs. 490, /; 491,, 9) which also contain a nucleus and pigment. The crescent forms occur 542 THE ANIMAL PARASITES. particularly in the pernicious fever (Fig. 491, e, f). Celli regards them as diagnostic of this form of fever; Ziemann also holds that typical crescents are not formed in other varieties of malaria. The last-named forms Laveran described as structures belonging to Fig. 492. Fig. 493. Fig. 492. — Anopheles claviger. (After Meigen, loc. cit.) x 4. To the right a wing at higher magnification. Fig, 493. — Ookinete of human pernicious malaria (.Plasmodium praecox) in the intestinal wall of a mosquito. (After Grassi.) the cycle of development of the plasmodia, vi^hile Golgi, Canalis, Celli, Marchiafava, Bignami, Bastianelli, Ziemann, and others regarded them as sterile vegetation- forms that die without further development. First through the investigations of Manson, Bignami, Ross, and MacCallum, to which were later added those of Grassi, Bastianelli, Bignami, Celli, Laveran, Koch, Schaudinn, and others, it was shown that the crescents, the oval bodies, the spherical bodies, as well as the flagellated bodies known as polymitus, are intended for repro- duction by copulation. The flagella- producing hyaline spheres arising from the crescents are male sexual individ- uals or microgametocytes, and the flagella developing from them, in whose formation the chromatin of the cell takes an essential part (Sach- aroff), have the significance of seminal cells, spermatozoa, or microgametes; while the non-flagellated spheres arising from the granular crescents have the significance of female sexual cells or macrogametes. The crescents leading to the formation of the sexual cells ap- pear only after infection has lasted for several days. In the chronic cachexia following malaria the forms lead- ing to schizogony are absent, and the crescents alone are present. The copulation of the malarial parasites of man takes place normally in the stomach of the mosquito, in different species of Anopheles (Fig. 492), which take up parasites during the sucking of blood from malarial patients. Fig. 494. — Oocyst of Plasmodium prae- cox, filled with sporozoites. (After Grassi.) THE MALARIAL PARASITE. 543 The copula arising from the union of the macrogamete and micro- gamete is designated ookinete (Schaudinn), a long, motile structure which penetrates into the stomach-wall of the mosquito (Fig. 493), where through the formation of a capsule it becomes the oocyst. The latter then enlarges, and forms numerous daughter-nuclei, and then sporoblasts, which break up into the sporozoites (Fig. 494) and the residual body. According to Grassi, as many as 10,000 sporozoites may be formed in one oocyst. The sporozoites, which are formed in enormous numbers, pass into the body-cavity after the rupture of the oocyst, and collect principally in the salivary glands, and through the bite of the infected mosquito are again transmitted to man, in whose blood they multiply within the red blood-cells through schizogony. The pathogenic significance of the malarial Plasmodia rests on the destruction of red blood-cells. In the pernicious form this may be so extensive that hasmoglobinuria may take place. The melanotic pig- ment formed in the parasite is a product of the vital activity of the parasites. In addition, as the result of the destruction of haemoglobin, there occur deposits of hsemosiderin in the bone-marrow, spleen, liver, and occasionally in the kidneys. In marked destruction of the red bl'ood- cells there may occur excretion of dark red urine, hsemoglobinuria {black- water fever.) The massing of the parasites of pernicious malaria in the cerebral capillaries may cause circulatory disturbances with the occurrence of numerous hemorrhages, and severe cerebral syrhptoms. As the result of retention of pigment-containing malarial parasites and the deposit of the products of blood-destruction, there occurs marked swelling of the spleen associated with hypersemia, followed by tissue- degenerations and by tissue-proliferations. After a long duration of the process the spleen may become markedly enlarged, pigmented, and greatly changed in structure. Likewise, in the liver there may be found degenerations and pigmentations, and also indurative proliferations. Certain varieties of the Plasmodium correspond to the individual types of fever, as given above, but it must be noted that the fever- forms known as quotidian, subcontinuous, and continuous {" comitata") may also arise through the presence in the blood of different generations of the Plasmodia of tertian or quartan fevers, so that daily a portion of the parasites comes to sporulation. In this way there arise quotidian forms of fever, which must be regarded as a double tertian infection or as a triple quartan. According to Schaudinn, the relapses that occur sometimes weeks and months after the original attack may be explained by the .fact that the macrogametes, which are longer-lived, revert to schizonts by throw- ing off a portion of their nucleus and protoplasm. According to Plehn, basophile granules are found in the red blood-cells as long as the infection persists. They vanish when the infection comes to an end. The malaria occuring in northern countries corresponds in general to the vernal forms of Italy, while the asstivo-autumnal form is found in the tropics. Haemosporidia — that is, sporozoa whdch live at the cost of the red blood- cells, and thereby produce diseases which are to be classed with malaria — ^ occur frequently in animals. Those of birds are best known (Danilewsky, MacCallum. Ross Grassi, Dionisi, CelU, and Schaudinn) and the life-cycles of the haemosporidia of the pigeon, owl, and skylark have been determined. Lahhe distinguishes two 544 THE ANIMAL PARASITES. genera in birds, Halteridium and Proteosoma (Hwmoproteus of Kruse) ; as to the number of undifferentiated species, notiiing can be said at the present time. Celli obtained from the birds mentioned three well-defined species. Schaudinn assigns the parasites of birds designated as proteosoma to the genus Plasmodium. Of the Mammalia, cattle in particular suffer in different countries (Southern States of North America, Italy, South Africa, Roumania) from malaria character- ized by high fever and hemoglobinuria. In the malaria of cattle known as Texas- fever, Smith and Kilbourne foun'd in the red-blood cells a small, often pear-shaped, and paired parasite {Piroplasma bigeminnm), whose pathogenic significance they determined throug'h the inoculation of healthy cattle with blood containing the parasites. Babes found the same parasite in the epidemic haemoglobinuria of cattle prevalent in Roumania. The first-named observers showed that infection takes place through parasitic ticks (Boophilus bovis) living on the cattle, the infec- tion being transmitted, not by the same tick which takes up the infected blood, but through the generation descending from the same. This mode of infection was confirmed by Koch in the haemoglobinuria of cattle occurring in .German East Africa and by Grassi in that occurring in cattle in Italy. The mode of development of the piroplasma in the body of the tick is still unknown ; and it therefore cannot be decided whether the parasite should be classed with the known malaria parasites. Against a near relationship with the latter is the fact {Liihe) that it increases in the red blood-cells by repeated simple division. According to Kolle, there occurs in South Africa, besides Texas-fever, another malarial disease of cattle (Febris ma- lariaformis), which is caused by an endoglobular parasite. Theiler also distinguishes two forms of piroplasmosis of cattle in South Africa. The piroplasma occurring in dogs and in horses he regards as a form distinct from Piroplasma bigeminum. According to observations by Nocard and Almy and Moias piroplasmosis associated with hemoglobinuria is not uncommon in dogs in France. According to Galli, Valeria, and Fiona, it also occurs in Italy. According to Bonome and Celli, hemosporidia also cause malaria in sheep and lambs, according to Koch and Kassel in apes, and according to Dionisi in bats ; but the life-history of these parasites is unknown. Danilewsky and Celli have described hsemosporidia in the frog, and the latter observer determined the development of the parasite in the blood. Whether the malarial parasites of man can be transmitted to animals, or whether the malaria of animals can lead to infection of man through the medium of mos- quitoes, is not decided with certainty, but it appears improbable. The Plasmodia of the bat most closely resemble those of man, yet attempts at inoculation made by Dionisi gave no positive results. It may therefore be assumed that malaria would die out in a given region, either when all susceptible anopheles were killed, or all infected human individuals healed or protected from mosquito bites. The malarial Plasmodia are stained best by the Rotaanowski stain, which dif- ferentiates the nulceus. The view that mosquitoes were concerned in the distribution of malaria is old, and has obtained in Italy since Roman times. Koch found it a popular belief among negroes. Manson (1896) and Bignami (1896) were the first to turn their attention to the problem ai^d to give hypotheses concerning the role played by mos- quitoes in the spread of malaria. Bignami carried out experiments along this line, but came to no positive result. Ross was the first (1897-^8) to determine the cycle of development of the malarial Plasmodium of birds (usually known as proteo- soma). According to his investigations, the parasites taken up with the blood of the infected bird into the intestinal canal of mosquitoes penetrate into the intestinal wall, and there change into cysts in which innumerable rod-shaped germs develop. Becoming free, these germs gain entrance into the salivary glands of the mosquitoes, and thence into the organism of the bird during the act of blood-sucking. Ross found the parasites in the blood of the infected bird in .from five to nine days after infection. About the same time, Grassi found that the distribution of malaria in man cor- responded to the distribution of Anopheles claviger (Fabricius) (Fig. 492), and not to that of the common mosquito (Culex pipiens). Basing his experiments on this observation, Bignami succeeded in producing malaria in healthy men by means of the bite of anopheles. Later Grassi in cooperation with Bastianelli and Bignami, succeeded in determining the life cycle of the malarial parasite. It was then shown that several species of anopheles native in Italy (Anopheles claviger [Fabricius'] or Anopheles maculipennis [Meigen], Anopheles superpictus, pseudopictus, bifurcatus) spread the malaria occurring in man, while Culex pipiens is the host of the para- sites of bird-inalaria. THE MALARIAL PARASITE. 545 The cycle of development of the malarial Plasmodium is as follows: Within the blood (of man as well as of birds) multiplication takes place first by schizogony. The young form of the Plasmodia, represented by a small, unpigmented body, grows in the red cells (Fig. 495, 1) into a larger body (2), in whose central portion pig- ment-granules collect. This cell-body known as schizont shows in preparation for schizogony an increase of nuclei (3), and then divides into a number (varying with the species) of spores or merozoites (4) with the abandonment of a pigmented residual body. The merozoites then seek a red blood-cell (1), and the cycle is again begun. In sporogony the merozoites develop into sexual individuals, macrogamietes (5) and microgametocytes (Sa). When taken up into the stomach by blood-sucking mosquitoes, the sexual individuals become ripe for fertilization, the macrogamete by throwing off the karyosome (6), the microgametocyte through the formation of miicrogametes (6a). Copulation then follows (7). From the copula arises the mo- tile ookinete (8), which in the wall of the mosquito's in- testine becomes the oocyst, in which through the divi- sion of the nucleus the sporo- blasts (9) are formed, which in turn break up into a large number of sporozoites (10), which (11), becoming free, collect chiefly in the salivary glands, and are thence trans- ferred by the bite of the fcSS-**^ mosquito to a new host, in i«j^^S If whose blood they increase -C./W' through schizogony (1-4). According to the investi- gations of Schaudinn, the macrogametes and the micro- gametocytes of Plasmodium vivax may be distinguished from each other in the earliest stages of develop- ment in the red blood-cell, and also from the schizonts, at first through the peculiar structure of the nucleus and later through that of the protoplasm. In a new infec- tion of tertian malaria the differentiation of the gametes began after the third attack. The growth takes place es- sentially slower than in the case of the schizonts. The pigment production is more abundant, while the nucleus is larger and less dense. The larvae of anopheles live chiefly in slowly flowing water. The eggs of Anopheles claviger require about thirty days at 20°-2S° C. for the development of the insects, and these, in turn lay eggs when twenty days old. The pupje are re- sistant to drying, to cold, and to contamination of the water. The mosquitoes fly during the evening and night, but do not rise very high above the level of the earth, and do not go very far away from the place of development. According to Grassi, Bignami and Bastianelli, the aistivo-autumnal parasites will not develop in ano- pheles at a temperature of 14MS° C.,-and grow only slowly at 20°-29° C. ; at 30° C. they complete their entire development up to the formation of sporozoites m about seven days. , . , . . ^ i • i ti, i^ r The literature concerning malarial parasites is extremely ncli. the results ot the latest investigations are given in the publications of Grassi, Schaudinn, Manna- berg, Nuttall, Celli, Marchiafava, Bignami, and Liihe. 3S Fig. 495. — Cycle of development of Prateosoma. (After Schaudinn and Ltihe.) i, Sporozoite (or merozoite) within a red blood-corpuscle; 2, schizont; 3, schizont_ with numerous nuclei; 4, schizogony, formation of merozoites; 5, macro- gamete (female cell) arising from a merozoite; 6, fully de- veloped macrogamete after extrusion of the karyosome; sa, microgametocyte (male cell) arising from a merozoite; 60, microgametocyte surrounded by loosened microgametes (spermatoza) ; 7, fertilization of the macrogamete; 8, ookmete; 9, oocysts with sporoblasts; 10, oocysts with sporozoites; 11, free sporozoite. 546 THE ANIMAL PARASITES. Literature. (HcBmosporidia. ) Barker: Fatal Cases of Malaria. Johns Hopkins Hosp. Rep., 1895. Celli: Le Malaria, Rome, 1899; Die Malaria, Berlin, 1900 (Lit.). Celli u. Marchiafava: Die Veranderung der rothen Blutkorperchen bei Malaria- kranken. Fortschr. d. Med., i., 1883, iii., 188S, ix., 1891; Arch. p. le Sc. Med., ix., 1885, xi., 1886, xii., 1888, xiv., 1890; Ueber die Parasiten der rothen Blutkorperchen. Internat. Beitr., Festchr. f. Virchow, iii., Berlin, 1891. Celli u. Santori: Die Rindermalaria in d. Campagna. Obi. f. Bakt., xxi., 1897. Councilman: Unters, iiber Laveran's Organismus d. Malaria. Fortschr. d. Med., vi., 1888; Further Observations on the Blood in Cases of Malarial Fever. Med. News, i., 1889. Crookshank: Flagellated Protozoa in the Blood of Diseased and Apparently Healthy Animals. Journ. of the Roy. Microsc. Soc, Ser. ii., vol. iv., 1886. Ewing: Pathological Anatomy of Malarial Fever. Journ. of Exp. Med., vol. V]., 1902; Malarial Parasitology. Journ. of Exp. Med., vol. v. Laveran: Nature parasitaire des accidents de I'imipaludisme, Paris, 1881; Traite des fievres palustres, 1884; Les hematozoaires du paludisme. Ann. de I'lnst. Pasteur, i., 1887; Arch. de. med. exp., i., 1889; ii., 1890; Du paludisme et de son hematozoaire, Paris, 1891; Traite du paludisme, Paris, 1897. Laveran et Blanchard: Les hematozoaires de I'homme et des animaux, Paris, 1895. MacCallum: Haematozoan Infections of Birds. Journ. of Exper. Med., iii., 1898. Manson: The Mosquito and Malaria. Brit. Med. Journ., ii., 1898. Nuttal: Die Rolle d. Mosquitos bei Verbr. d. Mai. Cbl. f. Bakt., xxv., xxvi., 1899; xxvii., 1900 (Lit.). Opie: On the Haemocytozoa of Birds. Journ. of Exp. Med., iii., 1898. Ross: Mosquitos and Malaria. Brit. Med. J., i., 1899; Annr de ITnst. Pasteur, 1899. Sambon: Life History of Anopheles. Brit Med. Journ., i., 1901. Thayer and Hewetson: Malarial Fevers of Baltimore. Johns Hopkins Press. 1895. § 189. Of the ciliates or infusoria occurring within the human organism the best known and most important is the Balantidium or Paramaecium coli, a unicellular animal 60-70 /j. long, covered with short uniform cilia. At its anterior end it has a short peri- V — * stoma (Fig. 496, a) which opens into a short gullet. v' The body is marked with parallel stripes and encloses a ^\ bean-shaped chief nucleus (b) and an accessory nucleus V '■" and two vacuoles. Multiplication takes place by divi- C If I., » ,''i<" , g sion into two new individuals. It develops a permanent \A' f ' form in the shape of a spherical cyst with a firm mem- ^ J - brane. '^ Balantidium coli occurs often in the colon of swine % „i /•/ without causing apparent changes. In cases of chronic diarrhoea in man it has been found in the dejections and ium"- ff^ammaltium) i" the colou, and probably stands in causal relation to t "'active ^varaoTes' *e intestinal catarrh. According to investigations by (After ciaus.) o, Solowjcw, Askanazy, Klimenko, and others the balan- Mouth; b, nucleus; ... . , c, included starch tidia may penetrate into the mucosa and submucosa of body ^ in the act of the intestine and cause ulcers. Tbey may also wander mtnilStw!'- ^'^"^ into the blood-vessels. ,*., FLAT WORMS. 547 Other species of ciliates have been observed in the intestine of man, Balanti- dium minutum (Schaudinn, 1899) and Nyktotherus faba (Schaudinn). In the paunch and reticulum of ruminants, in which cellulose digestion is carried on, and in tihe blind intestine of horses, infusoria are universally present and occur in enormous numbers, for example Isotricha prostoma, Entodinium caudatum, Ophryos- colex caudatus, and others. II. Vermes (Worms). A, Platyhelminthes (Flat-Worms.) 1. Trematoda, Sucking Worms. § 190. The Trematodes or sucking-worms, are flat-worms of torigue or leaf shape. They possess a dinging apparatus in the form of ventral sucking-cups of varying number, and are sometimes furnished with hooks or clasp-like horny projections. The intestinal canal is without an anus, and is usually forked. The development takes place either by the direct growth to maturity of the embryos (miracidium) hatch- ing from the eggs, or by alternate generation through the formation of germs within the host. The miracidium, or ciliated embryo, penetrates into a snail or mussel, and there grows into a germ-sac (sporocyst), within which there develops, either directly or after the formation of an intermediate generation of germ-sacs (redice), a swarming generation of cercaricE, which are provided with rudder-like tails. These lose their tails and penetrate into a new host (mollusks, arthropods, fish, am- phibia), become encapsulated, and attain sex- ual maturity as soon as they reach the final host. The germ-sacs which produce cercarise are designated primary germ-sacs ; if they first form TtAis. and then cercariae, they are called secondary germ-sacs. Fig. 497. Fig. 498. Fig. 497. — Distoma hepaticum with male and female sexual apparatus. (After Leuckart.) Fig. 498. — Eggs of Distoma hepaticum. (After Leuckart.) x 200. Distoma hepaticum, or liver-fluke, is a leaf-shaped sucking-worm about 28 mm. long and 12 mm. broad (Fig. 497). The cephalic end projects like a beak, and bears a small sucking-cup, in which the mouth is placed. Close behind this, on the ventral surface, is a second sucking- cup, and between the two lies the sexual orifice. 548 THE ANIMAL PARASITES. The uterus consists of a convoluted, globular sac behind the posterior sucking-cup. On each side of the hinder part of the body lie the yolk- sacs, and between are found the testicular canals, which branch many times. The forked intestinal tract (not visible in Fig. 497) is repeatedly branched. The eggs (Fig. 498) are oval, 0.13 mm. long and 0.08 mm. broad. In water there developes an embryo, the miracidium (Fig. 499, A), with cellular germ-balls (a) ; with the aid of its ciliated covering the embryo swims about, and seeks out a new host from the family of the mollusks {Limnwus minutus). On penetration into the snail the cutaneous layer is thrown off, and the miracidium, which possesses an intestine, an excre- tion-organ and a brain-ganglion, becomes changed into a sporocyst {B), in which the intestine and nervous system atrophy, while the cellular germ-balls {B, a) form a second generation of germ-sacs, the redice (B, b). The redise (C), which possess an intestine (C, a), produce then Fig. 499. — Development of the liver-fluke. (After Leuckart.) A, Miracidium with germ-balls (a) ; B, sporocyst with germ-balls (a) and redise (b) ; C, redia, with intestine (a) and germ- balls (6); D, cercaria with mouth (o), abdominal sucking-cup (b), intestine (c), and glands (d). within the same host the cer caries (D) from cells which are loosened from their germ-matrix (C, b) ; these abandon the host and with the aid of a rudder-like tail swim about in the water. With the loss of their tails they become encysted on almost any foreign body, and reach their final host (usually through the food), in which they attain sexual ma- turity. The sexually mature animal inhabits the biliary passages; more rarely it is found in the intestine or inferior vena cava. The liver-fluke is rare in rnan but common in cattle and sheep. The results of its invasion, especially when it is present in great numbers, are obstruction and ulcera- tive strictures of the bile-passages, formation of biliary concretions, in- flammation of the tissues in the neighborhood of the bile-ducts, and hyperplasia of the periportal connective tissue with atrophy of the glandu- lar tissue. The same changes are found in cattle. In sheep, following marked invasion of the liver, there may develop a general cachexia. Distoma lanceolatum is only 8-9 mm. long and 2-2.5 mm. broad, is lancet-shaped, and the cephalic portion is not especially marked ofif from the body (Fig. 500). The skin of the body is smooth. Two irregularly lobed testicles (h) lie close behind the ventral sucking-cup," in front of the ovary (o) and FLAT WORMS. 549 the uterus (u), the coils of which shine through the transparent body. The anterior coils are black with the ripe eggs, the others are rusty red. The yellowish- white yolk-sacs {d) lie in the middle of the lateral margin. The oval eggs are 0.04 mm. long, and while still in the uterus con- tain an embryo which escapes only after several weeks following the casting-off of the eggs. Its metamorphoses are unknown. Distoma lanceolatum likewise inhabits the bile-passages, but is rare in man. It is of frequent occurrence in sheep and cattle. When present in small numbers, it causes no marked changes; but large numbers may excite inflammation and proliferation of the periportal connective tissue. Distoma spathulatum (Fig. 501) is a sucking- worm occurring in man in Japan and China. It is 10-14 mm. long and 2.5-4 mm. broad. The eggs are 0.027-0.03 mm. long and 0.015-0.018 mm. broad. The parasite inhabits usually the bile passages and gall- bladder, but may gain access to the pancreatic duct (Katsurada), and pass into the intestine. When occurring in great numbers (Katsurada counted 4,361 in one case) it causes obstruction to the out- flow of the bile, and often excites more or less severe inflammation and proliferation of connective tissue. The parasite is found also in cats and dogs (Katsurada). Distoma Westermanni (Kerbert), or Distoma pulmonale (Baelz) occurs in Japan, China, and Corea. The worm is 7.5-10 mm. long, 5-7.5 mm. broad, egg-shaped, with slightly flattened ventral surface. The oval eggs are 0.09 mm. long and 0.056 mm. broad. The internal organization (Fig. 502) resembles that of the other trematodes. It occurs in man as well as in cats and dogs (Katsu- rada). It is found most frequently in the lungs. Fig. soo. — Distoma lan- ceolatum. (After Hertwig.) i". Anterior sucking-cup, and entrance into the ^y)- occurs in Other Organs: the pleura, brain, liver, forked intestine; s , pos- - - - -- - ° .'^. .'.'.. .' terior sucking-cup; A. tes- ticles with vasa deferentia; c, cirrus; m, uterus; intestinal wall, peritoneum, orbital cavity, eyelid, scrotum, etc. In each case it occupies small cavities ovary; /.' duct of Laurer surrounded by newly formed connective tissue, and and shell-gland; d, yolk- .-' „ t" . tj.ii -i. t, stalks and duct leading to occurs Occasionally m pairs. In the lung it may be ve1se'i-'";^grnjiio™'. ^x^'. found in the bronchi, the walls of which show in- flammatory changes (Katsurada). Its presence in the lung may give rise to hsemoptoe and cause death. The number of lung-flukes may run from twenty to thirty or even higher. Healing is possible after death of the parasite. Distoma felineum or Distoma sibiricum is a flat, almost transparent sucking-worm, of from 8-10 mm. in length and 1.5-2.5 mm. broad, which is present in the bile-passages of the cat and dog, and in a few countries (Siberia) has been observed in man. According to Winogradow it is the most common parasite in Tomsk. Askanazy observed several cases in Konigsberg. The sources of the infection were fish eaten raw (roach, Lenciscus rutilus). The inflammatory proliferations which the different forms of distoma cause in the liver of man, as well as in animals, may be followed by the development of carcinoma. '550 THE ANIMAL PARASITES. In Distoma haematobium or Bilharzia hcematohia (Fig. 503) the two sexes are separate. The mouth and ventral cups lie close together on the tapering anterior extremity. In both sexes the sexual openings lie close behind the ventral sucking-cup. The male is 13-14 mm. long. The body is flat, but in its posterior portion is rolled together to form a tube (Fig. 503) which serves for the reception of the female. The female is 16-19 mm. long and nearly cylindrical. The eggs are an elongated oval (Fig. 504), 0.12 mm. long, and possess a terminal or a lateral spine. According to observations by Sonsino, no alternation of Fig. 501. Fig. 503. Fig. 501. — Distoma spatkulatum. (After Katsurada.) a, Mouth sucking-cup; &, intestine; €,', uterus; dj testicles; e^ yolk-stalks; f^ sperm-pouch; g, ovarium, x 6. Fig. 502. — Distoma Westermanni, flattened by pressure, in the ventral position. (After Katsurada.) a, ai, -Mouth and abdominal sucking-cup respectively; h, intestinal loops; c, testicles; d, ovarium; e, yolk-stalks; /, shell-gland; fir, uterus; /i, excretory vessel. X 7.2. generations occurs in the development of Distoma Hcematohium. The part of intermediate host is taken by small Crustacea, into which the ciliated embryo, swimming around in water, bores its way to become encapsulated in the tissues of its host. It is probable that infection may be transmitted through the drinking of water containing larvae. The worms are found in the trunk and branches of the portal vein, in the splenic vein, mesenteric veins, as well as in the vessels of the rectum and bladder ; and may pass through the inferior mesenteric vein into the hsemorrhoidal and vesical veins, the veins of the ureter and prostate, and by chance into the inferior vena cava, and thence into the lungs. Their eggs are distributed, therefore, especially throughout the mucosa and submucosa of the ureters, bladder, and rectum, and occasionally FLAT WORMS. 551 in the liver, lungs, kidneys, and prostate. While still in the urinary pas- sages the cylindrical embryos (miracidia) covered with fine cilia may develop. Kartulis found them also in the skin of the leg and foot, and is of the opinion that the infection may take place not only through the intestine, but through the skin. The deposit of eggs causes severe inflammations which lead to tissue- destruction and to proliferations of tissue, which appear in the mucous membranes as papillary and polypoid formations. In the bladder it may lead to incrustations and concretions, and to the development of fistulous tracts. In the liver the process leads to connective-tissue induration. Following the inflammatory process, development of carcinoma may take place in the bladder, seminal vesicles, prostate, and in the skin (Kartulis). Fig. 503. Fig. 504. Fig. S03. — Distoma haematobium. (After Leuckart.) Male and female, the latter lying in -the canalis gynaecophorus of the former, x 10. Fig. 504. — Eggs of Distoma haematobium. (After Leuckart.) a. Egg with terminal spine; b, egg with lateral spine, x ISO. ' , The parasite is found along the entire eastern coast of Africa, and also in Zanzibar, Tunis, Lake Nyassa, in 'Beyrout, and in Sicily. It is most common in Egypt, where about twenty-five per cent, of the native population suffers from the disease. 2. Cestoda (Tapeworms). § 191. The tapeworms are flat-worms devoid of mouth or intestine, which increase after the method of alternate generation through the germi- nation of a pear-shaped primary head or scolex, and remain united to the latter for a long time as a (usually) long, band-shaped colony. The single segments of this colony, the sexually active individuals, or proglottides, increase in size the more widely they become separated from their place of origin by the formation of new members, but outside of this are de- void of any distinguishing peculiarity. The pear-shaped head or scolex, on the other hand, is provided with from two to four suckers, and usually with curved claw-like hooks. With the aid of these clinging organs the tapeworms fasten themselves to the intestinal wall of their host, which appears to be invariably one of the vertebrate animals. The scolices de- velop from a round embryo having four to six hooks, and are found as the so-called " measles " in different organs, chiefly the parenchymatous ones, from which they pass by passive migration into the intestine of their future host. . . The tapeworms occurring as parasites tn man belong to different families : the Tceniadce and the BothriocepMidw. The first occur in man as " measles " or tapeworms, the latter only as tapeworms. 552 THE ANIMAL PARASITES. § 192. Tasnia solium in its fully developed condition possesses a length of 2-3 meters. The head (Fig. 505) is the size of a small pin-head, spherical in form, with rather prominent sucking-cups. The crown of L-_J wi'mm M m Fig. 505. Fig. 5o6. Fig. 507. Fig. 505. — Head of Taenia solium with protruding rostellum (carmine, balsam). X 50. Fig. 506. — Half-developed and fully matured segmSits. Natural size. (After Leuckart.) Fig. 507. — Two proglottides with uterus. (After Leuckart.) v z. the head is not infrequently pigmented and bears a fairly large rostellum with about twenty-six plump, close booklets having short root-processes. Following the head there is a thread-like neck about an inch in length. At a certain distance from the head segmentation begins, the first segments being short, but their length increases with their distance from the head (Fig. 506) ; they become quadratic and finally longer than broad. The mature seg- ments appear about 130 cm. behind the head, although the sexual organs are fully de- . 1„„„J ;„ „„_!;„_ „ ™.^„<-„ Fig. 508. — Segment of Taenia solium with fully de- veloped in earlier segments, veloped sexual apparatus. (After Sommer.) ^, Sur- The ripe segments (Fig. 507) face view of segment; B border of next anterior seg- f ° 1 J n iA ™<="t; ^' that °t ns^t posterior segment; a, longitudmal are, when stretched out, y-lU excretory trunk; ai, transverse anastomosis; b, longi- ■mm 1r>Tirr otirl ft 7 mm hrr,i,A tpdinal plasma-vessel; c, testicular vesicles; d, seminal mm. long, ana O-/ mm. Oroaa, ducts; e, vas deferens; f, cirrus-bag with cirrus; g, porus and have rounded comers, genitalis; li border papilla; », vagina; a, ovarium; ?, _,, , • ■ • -J J J albumin-gland; m, shell-gland, and oviduct in front of The sexual opening is situated same; n, uterus. laterally just behind the mid- dle of the segment. The uterus, which is filled with eggs, possesses seven to ten lateral branches separated from each other by a wide interval, and which break up into a varying number of boughs branching like a tree. TAPEWORMS. 553 The parenchyma of the body of mature as well as of immature proglot- tides, or tapeworm segments (Fig. 508), is divided into two chief layers, the central one being designated the middle layer, the peripheral one the cortical layer. The middle layer contains the sexual apparatus (Fig. 508), c, d, e, f, g, h, i, k, I, m, n), as well as the water vascular system (o), an excretory apparatus, which traverses the whole tapeworm from the head to the last segment in the form of two canals lying in the lateral border of the middle layer. The canals are connected with each other at the posterior end of each segment (a^) and also send out numerous fine, subdividing branches into the body-parenchyma. The sexual apparatus consists of male and female sexual organs, which lie close together. A number of small, clear vesicles serve as testicles (c), they lie chiefly in the anterior portion of the middle layer. The vas deferens (e), which is connected with the testicles by the seminal ducts (d), empties into a grooved papilla situated on the lateral border (h). The coiled end (/, g) lies in a muscular bag and may be protruded through the sexual opening (cirrus). The female sexual opening lies close be- hind the male orifice in the same sexual cloaca. The vagina (i) leads thence to the posterior border of the segment. Before this is reached it widens into the seminal vesicle, and behind this into the fructifying canal and the so-called F«=- 5°9- ^'°- S'"- "globular body." The germ-pre- FiG. 509.— Epgs of Taenia solium, fc. With parine Organs, which must be sought primitive vitelline membrane; a, without -T ^, * . ° , ' , _^ „• 4.° r primitive vitelline membrane. (After Leuck- m the immature Segments, COUSlSt 01 art.) X 300. ^ double ovary (k) and a single f:g. sic— Cysticercus ceiiiiioKe, with fully albumin ffland (I) ] thcse are sac- devdoped head in situ. (After Leuckart.^ ^.^^ ^^ ^^^^^^^ ^^^^^^ j^.^^ .^ ^^^ posterior portion of the segment and communicating with the globular body. The latter is joined to the anteriorly located uterus (n), which at the time of sexual maturity forms a straight canal. When the eggs enter the uterus from the globular body, in which they pass their first stage of development, the above-mentioned lateral branches sprout and become filled with eggs. During this process the remaining sexual organs disappear. The cortical layer of the proglottides is essentially muscular in nature, but in addition contains a number of so-called calcareous bodies, which are not entirely wanting in the middle layer^as well. The musculature con- sists of smooth fibres, which form special groups in the suckers of the head. The surface of the tapeworm is covered with a clear cuticle, which forms the hooks on the heads. The eggs in the ovary are thin-skinned, pale and yellow, nearly globu- lar cells. In the uterus they change into yellow balls having a thick, more or less opaque shell, covered with closely set spicules (Fig 509, a) and often surrounded by a second layer, an albuminous envelope (&) limited by a membrane; in it there are embedded granules (primitive vitelline membrane). The diameter of the eggs, not including the vitel- line membrane, is about 0.03 mm. The thick-shell spheres are not undeveloped eggs, but contain an embryo with six booklets. Intra-uterine development_ of the embryo therefore takes place, the ripe segments are pregnant animals. 554 THE ANIMAL PARASITES. The further development of the embryos enclosed in the brownish shells takes place ordinarily in a new host. Should they gain access to the stomach of a hog, the egg-shell is dissolved, and the embryos, thus set free, penetrate into the stomach or intestinal wall. Thence they pass either by the blood-stream or by active migration through the tissues into different organs. Having reached a resting-place, the embryos undergo various metamorphoses and become changed in two or three months into a cyst filled with serum (Fig. 510), the inner wall of which shoots forth into a bud from which there develops a new tapeworm head, scolex, as well as a sac enclosing the same, receptaculum scolicis. The cyst containing a tape- worm head is known as a "measle" or cysticercus cellulosae. The scolices, when fully developed, pos- sess a circle of booklets, suckers, a water-vascular system and numer- ous calcareous bodies in their body-parenchyma. If they gain access to the human stomach, the cyst is dissolved, and there develops through the formation of segments from the scolex (Amme), a new chain of proglot- tides, a new Tcenia solium.. The Tcenia solium inhabits the small intestine of man, and is ac- quired by eating uncooked pork,- since the " measles " belonging to this parasite occur almost exclu- sively in the hog and in man. By means of its sucking-cups and its circlet of hooks it clings firmly to the mucosa of the intestine ; the remaining portions float in the in- testine. Usually but a single para- site is present in the intestine, al- though several at the same time is not rare. Occasionally as many as thirty or forty have been observed in one individual. They excite irritation of the intestinal mucosa, colic, and reflex disturbances of the central nervous system. The " measles " occur in the tissues of the hog, sometimes singly, sometimes in great numbers (Fig. 511) ; individual organs, for example, a muscle or the heart, may be thickly studded with them. _ In man, cysticerci occur in varied tissues — the muscles, brain, eyes, skin, etc. In the meninges and in the brain the measle may appear in the form of mulberry or grape-like collection of cysts, known as cysticer- cus racemosus. The cysts are for the greater part sterile, though some of them may contain a scolex. The importance of the measle depends on its location, but is in gen- eral slight. Its presence in the brain often causes severe disturbances, but Fig. 511. — Cysticerci of the Taenia solium, iti the epicardium and myocardium of a hog. TAPEWORMS. 555 in other cases all signs of disease may be lacking. Locally it excites slight inflammation, which leads to thickening of the connective tissue in Its immediate neighborhood. The cyst may retain its vitality for years After the death of the scolex the cyst contracts and there is deposited within it a chalky mass. The booklets are preserved in this mass for a long time. In- fection with the "measles" follows the in- troduction of eggs or proglottides into the stomach of man. Tasnia mediocanellata or saginata sur- passes the Tania solium not only in length, as it measures 4-7 metres and more, but also in its breadth and thickness, as well as in size of the proglottides (Fig. 512). The head is devoid of rostellum and circle of booklets (Fig. 513), has a flat crown and four large, powerful suckers, which are usually surrounded by a black border of pigment. The eggs resemble those of Tania solium. The fully developed pregnant uterus (Fig. 514) has a large number of lateral branches which run close to each other, and instead of branching dendritically divide dichotomously. Fig. 512. Fig. 512. — Portions of a Taenia saginata. Fig. S13. Fig. 514. (After Leuckart.) Natural size. Fig. 513. — Head of Taenia saginata, retracted suckers. Unstained glycerin preparation. X 30. Black pigmentation in and between the Fig. 514. — Segment of Taenia saginata. (After Leuckart.) ^ i^. The sexual opening lies back of the middle of the lateral border. The segments discharged spontaneously are for the greater part empty of eggs. The " measles " are found usually in the muscles and the heart, more rarely in the other organs of cattle {Cysticercus bovis). They are some- what smaller than the measles found in pork. 556 THE ANIMAL PARASITES. The development follows a course similar to that of Tcenia solium. Malformations of this tapeworm are of frequent occurrence. The parasite is acquired by man through eating- raw beef. It has not been definitely settled whether the " measles " of this worm occur in man, but some authors (Arndt, Heller) believe that such an occurrence does take place. By means of its powerful suckers the parasite is able to cling firmly to the intestinal wall. Stieda has observed a case in which a taenia 15 cm. long had penetrated the wall of the duodenum into the pancreas, and had caused tissue-necrosis and haemorrhage in its neighborhood. Tasnia cucumerina or elliptica is 15-20 cm. long, and possesses a head with rostellum and circle of hooklets. It is of frequent occurrence in dogs and cats, but rare in man. Its cysticercoid inhabits the louse and flea of the dog, more rarely the flea of human beings (Grassi). Taenia nana, a small tapeworm of from 8 to IS mm. in length, has a head with four suckers and a circle of hooklets. It has been observed chiefly in Egypt and in Italy. B. Grassi was able to obtain several thousands of specimens from two Sicilians Who had suffered from severe nervous disturbances. According to his investigations, the tjenia passes its entire develop- ment, from the embryo on, in the same host. Visconti (Rendiconti R. Institute Lombardo, xviii., 1886) found, at the autopsy of a young man from northern Italy, great numbers of Tania naitain the lower portion of the ileum. In Germany it has been observed in only a few cases {Mertens, Leichtenstern, Roder). Taenia diminuta (Rud.) or flavopuncta (Weinland), minima (Grassi) is a tapeworm, 20-60 mm. long, and has_ a head without hooklets. It is of common occurrence in rats and mice, and has been observed in a few cases in man. According to Grassi and Rovelli, the measles live in a small butterfly, as well as in beetles. Von Linstow has described as Taenia africana a large tapeworm with scolex devoid of hooklets, which he observed among the negroes of German East Africa. Besides those which also occur in man, taeniae are of frequent occurrence in domestic animals, both in the carnivora and in birds, as well as in the herbivora. Tania marginata of the dog is a tapeworm, 1-S m. long, provided with a double circle of hooklets. Its cysticercus forms cysts (cysti- cercus tenuicollis) of varying size in and under the serous mem- branes of sheep, cattle, goats, and hogs. Fig. 515.^ TcBnia serrata is found in the dog. It is 50-100 cm. long, and Full - grown possesses a circle of hooklets. The cysticerci (cysticercus pisiformis) Tffinia '=<*'j'J°- are found in rabbits and hares. Leuckart.) X TcBnia cccnurus is a tapeworm of the dog, 40-100 cm. long, and 12. is provided with hooklets. It passes its cystic stage most frequently in sheep, where it seeks the central nervous system and forms cysts varying in size from a millet seed to that of a hen's egg, that contain great num- bers of scolices. Its presence in the brain (comunt^ cerebralis) gives rise to the so-called " staggers " of sheep. I § 193. The Taenia echinococcus lives in the intestinal canal of the dog. It is 4-5 mm. long and possesses only four segments, the most posterior of these surpassing in length all the rest put together (Fig. 515). The small hooklets have coarse root processes and are implanted on a rather bulging rostellum. Their number runs from about thirty to fifty. The cyst-worm (hydatid) alone is found in man. It results from the introduction of taenia eggs into the intestinal canal. If the embryo wanders from the intestinal canal into an organ, it changes into a cyst, which is not capable of active motion. It consists of ECHINOCOCCUS. 557 an outer lamellated, elastic cuticle (Fig. 516, a) and a parencliymatous layer {h) lying internal to this, consisting of granular masses and cells, and containing muscle-fibres and a vascular system. When the cyst has reached the size of a walnut (sometimes earlier), there are formed from the parenchymatous layer small brood-capsules (c) which produce a great number of scolices. The first stage of these tapeworm heads consists of coarsely granular protoplasmic masses (d) lying in the wall of the brood-capsule; these develop further and sl^ow cavities {e) com- municating with the cavity of the brood-capsule, and later become dif- ferentiated into a tapeworm head (/) furnished with a circle of booklets. The head (/?), which now protrudes into the lumen of the brood-capsule, {g, h) is about 0.3 mm. long, possesses a rostellum with small, plump booklets, four suckers, a water-vascular system, and numerous chalky Fig. 516. — ^Wall of an echinococcus-cyst containing brood-capsules and scolices (alcohol, carmine), a, Chitinous membrane; fc, parenchymatous layer with vesicular cells; c, brood-cap- sules; d, e, f, g, h, scolices in different stages of developfment. X loo, bodies 'in it^s parenchyma. Frequently the anterior part of the body is telescoped into the posterior (g). In many cases the echinococcus cyst remains single. Its only change consists in enlargement to the size of an orange or fist, through the formation of new brood-capsules and heads. The surrounding tissue forms a capsule, in which the cuticular cyst lies. The cavity of the cyst is filled with clear fluid, which does not coagulate on boiling or on the addition of acids, and contains none or but little albumen, but does contain sodium chloride, calcium oxalate, triple phosphates, uric acid, sugar (in the liver), and often cholesterin. The brood-capsules are al- ways situated on the inner surface, if not mechanically dislodged; and are visible through the transparent parenchyma as small white points. Occasionally the cyst remains sterile. In many cases daughter-cysts (Fig. 517, c) are formed. Their de- velopment proceeds in the depth of the cuticle independently of the real parenchymatous layer. Between two lamellae of the cuticle there arises a collection of granules, which surround themselves with a cuticle, and thereby become the centre of a new set of layers. As the number 558 THE ANIMAL PARASITES. of layers increases, the cavity grows larger and the contents become clear. If the daughter-cysts grow they bulge out the wall of the mother-cyst like a hernial sac, until it finally gives way and liberates its contents. If they now pass outward by the side of the parent-cyst, they obtain from the parenchyma in which they lie an external capsule of connective tissue, and then produce brood capsules in the same manner as the primary cysts arising from the six-hooked embryos. An echinococcus with exogenous proliferation is called echinococcus granulosus, or sometimes echinococcus veterinorum from the fact that it is of frequent occurrence among domestic animals. Fig. 517. — Echinococcus hydatidosus. a, Surface of liver; h, indurated connective tissue; c, daughter-cysts within a parent-cyst, which has been opened by an incision; d, adhesions. Three-fifths natural size. A second compound form of echinococcus is the echinococcus hydati- dosus. It is characterized by the presence of inner daughter-cysts (Fig. 517, c). According to statements by Naunyn, and confirmed by Leuckart, the scolices and brood-capsules undergo cystic metamorphosis, and so become changed into daughter-cysts which occasionally produce grand- daughter cysts. Through the formation of numerous daughter-cysts the chief cyst may attain large size. Infection of man follows the ingestion of the eggs of the taenia which occurs in dogs. The cysts are most often found in the liver, but the echinococcus occasionally occurs in the lungs, spleen, kidneys, intestine, in a bone or in the heart. With the exception of the disturbance from pressure and of the local inflammation which it causes (the latter leading to the formation of a connective-tissue capsule in many organs) the cyst produces no harmful effects. It often dies on attaining a certain size ECHINOCOCCUS. 559 (that of a walnut to an apple), the fluid is absorbed, the cyst contracts, and there remains in it fatty, cheesy detritus, which often calcifies. The booklets are preserved for a long time. In other cases the echinococcus becomes larger, particularly when endogenous or exogenous daughter-cysts develop. It may become dan- gerous through size alone. Severe inflammations are occasionally pro- duced, particularly after trauma, or after rupture of the cyst into one of the body cavities. Rupture into a blood vessel may occur and lead to the metastasis of cysts and embolic blocking of vessels. In more favorable cases rupture may take place externally or into the intestines. The spontaneous spread of brood-capsules and scolices in the same host, as well as the experimental transplantation of the same into another host, may lead to the formation of new cysts. The form known as echinococcus alveolaris or multilocularis pre- Fig. 518. — ^Transverse section of an Echinococcus multilocularis. a, Alveolar echinococcus tissue; b^ liver tissue; c, cavity produced by softening; d, fresh nodules. Natural size. sents itself as a hard tumor, situated usually in the liver, rarely in other organs (brain, spleen, adrenal), and possesses an alveolar structure (Fig. 518), in that a firm, dense connective-tissue mass encloses numer- ous cavities. Its contents are translucent and gelatinous, or consist of fluid and a gelatinous substance. The cavities are spherical or irregular in shape. Usiially, through softening and disintegration of the paren- chyma, ulcerative cavities (c) are formed. In other places the tissue is fibrocaseous, necrotic or calcified, or impregnated with bile. At times caseation of the proliferating tissue is the most prominent feature of the process ; at other times the alveolar structure. When the development of the colonies has progressed further, there appear in the tissue gray and yellowish nodules {d) in which cavities containing colloid plugs (chitin- cysts and coils) are developed. The exquisite alveolar structure gave rise to the now abandoned theory that this form of echinococcus is an alveolar, colloid-containing tumor of the liver. Virchow first recognized the true 560 THE ANIMAL PARASITES. nature of the condition, and demonstrated that the so-called colloid masses were echinococcus cysts. According to the investigations of Melnikow-Raswedenkow the alve- olar echinococcus is to be regarded as a different species, which increases in the tissue of the host in a peculiar manner, suggesting the mode of development of the Trematodes; and in many cases spreads by hsematogenous and lympho- genous metastases from the primary focus of development to other organs (lymph-nodes, lungs, brain). Should the alveolar echinococcus occurring in any organ, for example, in the liver, en- croach on neighboring tissues, there are found in the latter finely granular multinucleated protoplasmic structures surrounded by granu- lation tissue. Later, small chitinous cysts de- velop or a folded membrane studded with granular masses, while the granulation tissue becomes changed into fibrous connective tissue. The majority of the cysts remain sterile. Scolices develop only in a few. Ovoid granu- lar structures with a thin membrane may be formed, and are regarded by Melnikow as em- bryos. The chitinous membranes which lie in the granulation tissue are often surrounded by giant-cells. The life-history of the alveolar echino- coccus outside the parenchyma of the organ is unknown; feeding to dogs has given no positive results. It appears that the embryos and scolices are not capable of development in the intestine of the dog. The ordinary echinococcus is widely distributed, though not common. It is of most frequent occurrence in Iceland, where the inhabitants live in close associa- tion with dogs. The alveolar echinococcus has been observed chiefly in Switzerland, South Germany, Austria, and in Russia. § 194. Bothriocephalus latus or pithead is the most formidable tapeworm of man, measuring 5-8 metres in length, and consisting of three to four thousand short but broad segments (Fig. 519), which are broadest in the middle region and narrower at the end. The length of the largest segment is about 3.5 mm., the breadth about 10-12 mm. The head (Fig. 520) has a long oval or club shape, is about 2.5 mm. long and 1 mm. broad. It is somewhat flattened, possesses on each mar- gin a slit-like depression and is mounted on a filiform neck. Fig. 520. (After Leuck- Fig. 519. Fig. 519. — Bothriocephalus latus. art.) Natural size. Fig, 520. — Head of Bothriocephalus latus of Bremser, (After Heller.) Enlarged. TAPEWORMS. 561 The body is thin and flat like a ribbon, with the exception of the central parts of the segments, which project somewhat outward. At this spot the ^*?5'"^^^. found, in the shape of a single canal, which forms a number of cods (Fig. 521, m). When the eggs collect here in great numbers the lateral coils of the uterus arrange themselves in folds, so that a remarkable rosette-hke appearance is produced. The sexual openings lie in the middle line of the ventral surface, near the anterior border of the seg- ment, the female orifice (o) being close behind the male opening (/). The ovary (g) is a double organ which lies in the middle layer; the yolk-chambers (/?), on the other hand, are located in the cortical layer. Fig. 521. — Median portion of a proglottis of Bothriocephalus laius, seen from the dorsal surface. The cortical layer of the segment has been removed except a border on each side, and the middle layer thus exposed. (After Sommer.) a, Lateral vessels; b, testicular vesicles; c, testicular canalicuH; d, seminal ducts; e, posterior, /, anterior hollow-muscle apparatus (cirrus- sac of vas deferens); g, ovary; h, yolk-chambers lying in the cortical area; i, collecting-duct of yolk-stalk, branches of which lead ventrally to the yolk-chambers; k, shell-gland; /, beginning of the uterus; w,_ loop of uterus filled with eggs, the orifice of uterus opening on the anterior surface; n, vagina; o^ vaginal opening, x 35. The shell-gland (k) lies behind the collecting-tube (i) of the yolk- chambers. The testicles consist of clear vesicles (b) which lie in the lateral portions of the middle layer, and communicate by means of fine canals (c) with the vas deferens (d), which terminates in the cirrus- sac (e, /). The eggs (Fig. 522) are oval, and about 0.07 mm. long and 0.045 mm. broad. They are surrounded by a thin, brown shell, the anterior pole of which forms a sharply outlined cap-like cover. The Bothriocephalus latus occurs chiefly in Switzerland, in the north- eastern parts of Europe, in Holland and in Japan, and lives, as does the Taenia, in the small intestine of man. According to Bollinger it is rather fre- quent in Munich. The first stage of development of the eggs takes place in water. After the lapse of months there develops an embryo (Oncos- phara) armed with six booklets and covered with cilise (Fig. 523). This 36 562 THE ANIMAL PARASITES. develops, in some intermediate host as yet unknown, into a measle (Plero- cercoid), which, according to the investigations of Braun in the Russian Baltic provinces, seeks out as second intermediate host the pike or tad- pole, and develops in the muscle or internal organs of these animals into a sexless tapeworm. According to Grassi and Parona, the measle of Bothriocephalus latus in Italy occurs in the pike and in the river-perch. In Japan it is found most frequently in the Onchorhynchus Perry (Ijima, Leuckart). Zschokke found it in the Lake of Geneva in the following forms of fish : Lota vulgaris, Perca fluviatilis, Salmo umbla, Esox lucius, Trutta vulgaris and Trutta lacustris. It is found most often in the tad- pole (Lota vulgaris) and perch (Perca fluviatilis). Should th^ measle gain entrance, through ingestion of the fish mentioned, into the intestinal canal of man, it again attains sexual maturity. Ac- cording to Braun and Parona the measles may also be brought to development in both dogs and cats. The presence of Bothriocephalus in the intestine gives rise to a gradually in- creasing anaemia, which resembles per- nicious anaemia. The diminution of the red blood-cells and of the haemoglobin content of the blood is prob- ably due to the fact that, after the death of the tapeworm, poisonous products arise having an injurious action on the blood-corpuscles Fig. 522. Fig. 523. Fig. 522. — Eggs of Bothriocephalus latus, right having been emptied of its yolk-cohtents. art.) the one (After at the Leuck- FiG. 523, — Free embryo of Bothriocephalus latus with ciliated envelope. (After Leuckart.) Bothriocephalus cordatus (Leuckart) is a taipeworm, of 80-115 cm. long, and has a heart-shaped head, whose sucking-grooves are flattened. The breadth of the ripe segments is about 7-8 mm. ; the length, about 3-4 mm. In Greenland and Iceland it is a frequent parasite of the dog, seal, and walrus, and is found occa- sionally in man. The measles likewise occur in fishes. Bothriocephalus Mansoni {Cohhold) or liguloides (Leuckart) is the measle (plerocercoid) of a tapeworm which has been observed a few times (Manson, Ijima, Murata) in the body-tissues and in the descending urinary passages or in the urine. Its origin is not known. Bothriocephalus felis, which occurs in cats, is similar to Bothriocephalus latus. Bothriocephalus latus occurs also in dogs. In the United States this worm is found occasionally in individuals who have come from various infected regions of Europe. In the mining regions of Northern Michigan it has been found a number of times in Finns. B. Nemathelminthes (Round Worms). § 195. All the round worms which occur as parasites belong to the Nematoda. They possess a slender, cylindrical, elongated, at times fili- form body without segments or appendages. The cuticle is thick and elastic. The mouth opening is found at one extremity, and is provided sometimes with soft and sometimes with horn-like lips. The elongated intestine, together with the pharynx and chyle-stomach, extends through ROUND-WORMS. 563 Fig. S24- Fig. 525. Fig. 524. — Ascaris lumbncoides. (After Perls.) A, Female; B, male. Natural size. At a is the female sexual orifice; c, the two spicules of the male; h, the (enlarged) cephalic end with the three lips. Fig. 525. — Egg of Ascaris lumbricoideSt with shell and albuminous covering. (After Leuckart.) X 300. the entire body-cavity (Fig. 524) and opens on the ventral surface a short distance from the posterior extremity, which is usually awl-shaped. The sex- ual organs and their openings are also found on the ventral surface. The fe- male sexual orifice is located at about the middle of the body, less frequently near the anterior or posterior extrem- ity (Fig. 524, A, a). In the male the sexual opening and the anus are to- gether {B, c). The chitinous covering of the lower gut forms in the male the means of clinging during the act of copulation. The males are usually smaller than the females. The develop- ment is direct, and the metamorphoses are not striking. The nematodes occur- ring in man are in part harmless para- sites of the intestine, and in part danger- ous, sometimes even fatal. § 196. Ascaris lumbricoides, the common round-worm (Fig. 524) is a light-brown or reddish, cylindrical worm with tapering ends. The female (^) is 25-40 cm. long, the male (5) is much smaller, and the posterior extrem- ity of the latter is bent in the form of a hook and provided with two spicules (c) or chitin processes. The mouth (&) is surrounded by three muscular lips bearing fine teeth. The female sexual opening '{A, a) lies anterior to the middle of the body. The eggs which the mature female carries in enormous number possess in their fully developed condition a double shell (Fig. 525) and around this an albuminous envelope. They are about 50-70 IX. in length. The worm inhabits the intestinal tract, most frequently the small intestine. It is the most common parasite of man, and is frequently found in great numbers. When mature fe- males are present the fasces contain the eggs in abundance. These are resistant to external influences, for example to drying and freezing. The eggs require no intermediate host (Lutz, Leukart, Grassi, Epstein). Man is infected by the ingestion of eggs which have been expelled from the bowel and have matured in the faeces. 564 THE ANIMAL PARASITES. According to feeding-experiments which Epstein carried out on human be- ings with eggs which had been cultivated in damp faeces for a long time, the round-worm attains its maturity in from ten to twelve weeks after the ingestion of the eggs. At this time the male is 13-15 cm. long, and the female from 20-30 cm. Their presence in the intestine may not cause any noticeable disturbance. When present in large numbers they sometimes, especially in children, cause intestinal catarrh, vomiting, nervous disturbances and convulsions. Occasionally the worm crawls into normal and pathological openings in the wall of the intestinal canal, and in this way causes trouble. Thus, when it crawls into the ductus choledochus, it may produce bile-stasis. If it penetrates an ulcer into the peritoneal cavity or into a hernia sac, it may excite inflammation of the tissues concerned. According to Leuckart it may penetrate the un- injured intestinal wall. It is frequently passed with the stools, but at times per os in vomiting. From the pharynx it may wander into the larynx. According to Crowell, the dangers of ascariasis are apt to be under-estimated. The worms may cause symptoms and even death through toxic, reflex and mechani- cal effects either in the larval stage, or while adult in the intestine, or in the course of migration to other parts of the body. The number of worms in the intestine varies from one or two to hundreds, occasionally producing symptoms of intes- tinal obstruction. Collections of worms in the sigmoid may cause palpable masses simulating tumor growth and the abdomen has actually been opened under this misconception. The worm is often found in the peritoneal cavity as a result of escape through any available exit, or by direct passage through the intestinal wall by separation of its fibers which, coming together again, leave no trace of perfora- tion. Sometimes the worm escapes through the umbilicus or from fistulous tracts in the groin or urethra. In countries where the parasite abounds, the worm not infrequently opens repaired wounds of the intestine with the production of fatal peritonitis. Migration of the ascaris into the comimon bile duct; gall-bladder, intrahepatic and pancreatic ducts is common. In this way severe infections of these passages arise. It may also invade the accessory nasal sinuses, the antrum of High- more, the lachrymal duct. Eustachian tube, larynx and trachea. The reproduction of ascariasis in animals and in man is O'ften associated with the occurrence of broncho-pneumonia due to the presence of larva: in the respiratory passages. Crowell suggests that, in certain tropical countries, broncho-pneumonia in infants and children may not uncommonly be due to the same cause. Qinical observations and the therapeutic effects of vermifuges unite to incriminate the ascaris as the cause of all sorts of toxic and nervous phenomena — fevers, nausea, flatulence, abdominal pains, convulsions, tetany, symptoms of chorea, hysteria and epilepsy, psychic disturbances, symptoms simulating meningitis, and many other disorders of similar nature. The disturbances of the central nervous sys.tem are attributable to chronic poisoning by volatile aldehydes of fatty acids, Flury having found these and other pharmacologically active substances both in the body and in the excretions of pig-ascaris. In this climate, ascaris is not uncommon. At Bellevue Hospital we meet with the worm in the intestine in about S per cent, of all autopsies, particu- larly in Europeans. In the Philippine Islands, on the contrary, infestation with ascaris was demonstrated by Willets in 62.3 per cent, of nearly 20,000 persons. (Crowell, American Journal of Medical Sciences, 1920; Flury, Arch. f. exp. Path. U. Pharm., 1912; Willets, Philippine Journal of Science, Section B, 1911.) In domestic animals ascarides are of frequent occurrence. Ascaris lumbri- coides is found in swine {Ascaris suilla) and in cattle {Ascaris vituli). Ascaris megalocephala, a round worm whose female is 18-37 cm. long, is a common para- site of the horse and donkey. Ascaris mystax, whose female reaches a length of 12 cm., is found frequently in dogs and cats, and has also been observed in man. Various species, designated as Heterakis, occur in birds. Heterakis maculosa, the round ■worm of pigeons, may cause the death of the pigeon when occurring in large numbers in its intestine. PINWORM. 565 § 197. Oxyuris vermicularis, awl-tail, pinworm, or threadworm is a small round worms (Fig. 526), the female being about 10 mm. long {a, b) and pointed at the caudal extremity like an awl, while the male is about 4 mm. long (c) with a blunt posterior end, the anus being provided with a spiculum. The eggs (Fig. 527, a), which the body O'f the female often contains in great num- bers, are 50 /x long and 24 /a broad, have a flat' and a curved surface, and a shell which is covered by a thin albuminous layer. Oxyuris vermicularis inhabits the large in- testine and the lower portion of the small intestine. According to Zenker and Heller only the impregnated mature females are found in "the large intestine, the young indi- viduals and the males remain in the small intestine. They occur frequently in larger or smaller numbers. At night they often wander from the rectum over the anal region, and may enter the vagina ; they excite itching of the affected parts. In the pelvic peri- toneum encapsulated worms or eggs have been observed a number of times. It has not •been determined whether they can penetrate the intestinal wall (Vuillemin). Wagener found dead and calcified worms in the sub- mucosa of the intestine. For the development of the eggs (Fig. '527, a^e), it is necessary after their expul- FiG. sz6. — Oxyuris , Sexually mature :' vermicularis. : female; 6 female sion with the fseces that they again be taken Ml of eggs; c, male. (After Seller.) jj^^^ ^^^ stomach of man or beast. It is prob- able that the original host may again infect himself with oxyuris, for- example, the eggs becoming attached to his finger during the act of scratching may later get into his mouth. ■Fig. 527, — Eggs -of Oxyuris vermicularis in different stages of development. (After Zenker and Heller.) a, b, c, Segmentation of yolk; d, tadpole-shaped embryo; e, worm-shaped embryo. X 250. The eggs are resistant to drying, and in this condition may be widely scattered. 566 THE ANIMAL PARASITES. Oxyuris is a corarmon inhabitant of the appendix and sometimes gives rise to grave symptoms. Brumpt, in Paris, found pin worms in the appendix in 3.5 per cent, of normal cases and in 40 per cent, of all cases of appendicitis. Hoepfl, in Germany, demonstrated them in the appendix in 21 per cent, of all cases of appen- FiG. 529. Fig. 530. Fig. 528. Fig. 528. — Male of Anchylostoma duodenale. (After Schulthess.) a, Head witn mouth- capsule; b, oesophagus; c, intestine; d, anal-glands; e, cervical glands; /, skin; g muscle-layer- h, porus excretorius; i, three-Iobed bursa; k, ribs of the bursa; /, testicular canal- m seminal vesicle; n, ejaculatory duct; o, groove of latter; p, penis; q, penis sheath, x 18. ' ' Fig. 529. — Cephalic end of Anchylostoma duodenale. (After Schulthess.) a Mouth- capsule; b, teeth of ventral border; c, teeth of dorsal border; d, mouth cavity; e, skin pro- tuberance on ventral side of head; f, muscular layer; g, dorsal groove; h^ oesophagus.' x 100. Fig. 530. — Eggs of Anchylostoma duodenale. (After Perroncito and Schulthess ) a-d Different stages of segmentation ; e, f, eggs with embryos, x 200. " ' ANCHYLOSTOMA DUODENALE. 567 dicitis. In. London, Still found oxyuris in 19 per cent, of all normal childrens' appendices examined at autopsy. In this country, Cecil and Bulkley found oxyuris in 13 per cent, of 129 cases of appendicitis in children. The oxyuris burrows into the submucosal tissues and its invasion is usually accompanied by extravasation of blood and sometimes by the formation of hcemorrhagic ulcers of the mucosa. A characteristic feature of the lesions is absence of inflammatory reaction about them, except in those cases where there is secondary bacterial infection. In some instances the process may heal spontaneously. (Journal Experimental Medicine, § 198. Anchylostoma duodenale (Dochmius duodenalis, or Stron- gylus duodenalis, Uncinaria duodenalis, Uncinaria Americana [Stiles], Hook-worm, is a small worm belonging to the family of Strongylides, which inhabits the upper part of the small intestine (Fig. 528). The cylindrical body of the female is 5-18 mm. long, that of the male 6-10 mm. The cephalic end (Fig. 529) is curved toward the dorsal surface, and possesses a bellied mouth-capsule {d). It is almost completely divided dorsally, and the cleft is covered by two chitinous lamellje. On the ventral border there are four incurving teeth (&), on the dorsal border two teeth which are perpendicularly placed \c), all being held together by chitinous bands. The male is provided at its caudal extremity with a threefold bursa (Fig. 528, i) and two thin, fishbone-like spicules (/>). In the female the posterior end is pointed, and bears an awl-shaped spine; the vulva lies posterior to the body centre. The oval eggs (Fig. 530) are 44-67 fi. long, 23-40 jit broad. They undergo the first stages of cleavage in the human intestine (o-rf), develop further in muddy water {e, f), and may then, if brought into the human intestinal tract, develop into sexually mature animals. With its teeth the worm works its way into the mucous membrane as far as the submucosa, and sucks itself full of blood. Its point of attack is distinguishable later by a small ecchymosis in the middle of which there is a white spot with a central perforation. Occasionally there are found in the intestinal mucosa small cavities filled with blood, in each of which there lies a coiled-up worm. The parasites, when present in large numbers, cause continuous and serious loss of blood, which may lead to severe forms of anaemia (Egyptian chlorosis), but they are not infrequently found in individuals who present no symptoms of disease. The parasite is common in the tropics, also in Japan. Accord- ing to Griesinger and Bilharz about one-quarter of the native Egyptians suffer from this disease. The parasite was often observed in the work- men engaged in the Saint Gotthard tunnel. According to Menche and Leichtenstern the brickfields of the Rhine provinces are to a great extent infected with anchylostoma (brick-burner's anaemia). In 1903 the worm was distributed to an extraordinary degree through- out the mines of the district of Dortmund, so that in the autumn of that year over seventeen hundred individuals infected with the worm were found. The infection takes place chiefly through larvae ingested with the drinking-water and food. According to the investigations of Looss and Schaudinn, the larvae may penetrate through the skin into the veins, thence are carried into the lungs, whence they wander through the brdnchi, trachea, and larynx and into the intestinal tract. In experiments made on apes the larvas may be found in the intestine within twenty-four hours. 568 THE ANIMAL PARASITES. According to Stiles (1902), the hookworm disease of the American continent is due to a species distinct from that found in Europe. He distinguishes them as the Old-World hookworm and the New-World hookworm (Necator americanus or Uncinaria americana). The latter form is prevalent throughout the Southern United States as far north as the Potomac River, and in the West Indies, and has also been found in Italy, Africa, China, and the Philippines. It is a cylindrical worm 7-11 mm. long, with a dorsal and ventral pair of lips, a prominent dorse- median 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 have more sharply rounded poles than those of the Old-World worm. It is estimated that about ninety per cent of the rural population of Porto Rico is infected with this parasite, and in some parts of Florida a similar degree of infection is reported. According to Stiles, the piney- wood and sandy-soil portions of the South are especially regions of infection. In these regions " ground itch " is of common occurrence, and is believed to be due to the penetration into the skin of the larvae of the hookworm. Among the most strik- ing symptoms of the American infection are anaemia, perverted appetite ("clay- eaters "), pain and tenderness in the epigastrium, delayed puberty, mental lassitude, etc. The "cotton-mill anemia" of the South is due to a moderate degree of hook- worm infection. The economic importance of uncinariasis in America is great. It is estimated that thirty per cent of all deaths in Porto Rico are the result of hook- worm infection. According to Stiles, this infection is chiefly responsible for the inferior mental and physical condition of the poorer classes of whites in certain parts of the Southern States. Eustrongylus gigas, a palisade-worm of red color, whose female reaches a length of 1 metre, is a rare parasite, which has been observed a few times in the kidney-pelvis of man. It occurs frequently in dogs. It possesses a mouth-opening with six papillae ; the male has on its posterior- extremity a bursa with a single spiculum. The eggs are oval, 0.06 mm. long, and provided with a rough albumin- ous capsule. Strongylus longevaginatus, a thread-like, white worm, 26 mm. long, was once observed in the lung of a boy. In the domestic animals Strongylides occur in greater numbers than in man, and are in part inhabitants of the intestine, and in part of the lungs (Miiller, " Die Nematoden der Saugerthierlungen," Deut. Zeitschr. f. Thiermed., xv., 1886). Dochmius trigonocephalus and Dochmius stenocephalus occur in the intestine of dogs, and give rise to anaemia similar to that produced by the Anchylostoma in man. Strongylus armatus is a common parasite of the horse, which enters the intes- tinal tract as an embryo, bores into the intestinal wall (0/0, thence into the liver, by way of the portal vein, and into the lungs and organs of the major circulation. Following this migration, it may develop in diverse organs and cause the formation of fibrous nodules, which become calcified after the death of the parasite enclosed in them. In the intestinal wall it may develop after direct migration or after embolic lodgment in the part, and leads to the formation of cavities, from which it again breaks through into the intestinal lumen. In the mesenteric arteries it attains sexual maturity, and causes thrombosis and the formation of aneurisms. The male of the mature worm is 20-30 mm. long ; the female, 20-55 mm. Strongylus tetracanthus, which inhabits the large intestine of the horse, causes hsemorrhagic enteritis when present in large numbers. Strongylus paradoxus is an extremely common parasite of the lungs of hogs. Strongylus capillaris, Str. commutatus, and Str. fitaria are frequent parasites of the lungs of goats and sheep, and different species may be present in the same lung at one time (Schlegel, "Die durch Strong, capillaris verursachte Lungenwurmseuche der Ziege," Arch. f. wiss. Thierheil., 25 Bd., 1899). The latter causes in sheep bronchitis and nodular proliferating pulmonary inflammations ; through the swal- lowing of many embryos inflammations of the intestine may be produced. Strongylus rufescens and Str. paradoxus, Nematoidium ovis pulmonalis (Lyd- tin), or Pseudalius ovis pulmonalis (Koch) are also inhabitants of the lungs of sheep, the last-named causing pseudotuberculosis. Str. commutatus and Str. pusil- lus occur in the lungs of the hare and rabbit ; Str. syngamus and bronchialus in the trachea of birds ; and excite inflammations.^ Str. micrurtis (Strose, " Bau von Strongylus micrurus," Deut. Zeitschr. f. Thiermed., xviii., 1892) occurs in cows and calves, in arterial aneurisms as well as in the respiratory passages. Strongylus pusillus causes in cats a pulmonary disease resembling tuberculosis {Jeaniiiaire, "Ueber die hist. Verand. der Lunge bei der verminosen Pneumonic ANGUILLULA INTESTINALIS. 569 der Katze und des Hasen," Inaug.-Diss., Freiburg, 1900). Syngamus trachealis {Klee, " Der ge paarte Luftrohrenwurm des Gafliigels," Deut. Thierarzt. Wochen- schr., 1899) is a dangerous parasite of birds, particularly of pheasants, in the trachea of which it appears in great numbers, and attaches itself to the mucous membrane. It is easily recognized by its red color. Similar to the last-named is Syngamus hronchialis, which has been observed a few times in geese and ducks. Literature. (Anchylostoma and Strongylus.) Looss: Lebansgesdiichte d. Anchylostomum. Cbl. f. Bakt., xx., 1896, xxi., 1897, xxiv., 1898; Eniwanderung des Ankylostoma von der Haut aus. C. f. B., xxix., 1901, u. Orig. xxxiii., 1903. Stiles: Prevalence and Geographic Distribution of Hookworm Disease (Unci- nariasis or Anchylostomiasis) in the United States. Bull, of Hyg. Lalb., Pub. Health and Marine-Hospital Service of the United States, 1903; Osier's Modern Medicine, vol. i. Ward: Nematoda. Ref. Hdb. of Med. Sc, 2d ed., vol. vi. Fig. 531. — Anguillula intestinaUs, (After Braun.) Fig. 532. — Female of Anguillula stercoralis, with eggs and embryos. (After Perroncito.) X 85. § 199. Anguillula intestinalis (Fig. 531) is a worm of 2.25 mm. length, which is found in the intestine, particularly in the tropics, and in Italy, and has been occasionally observed in Switzerland, Germany, Bel- gium, and Holland (probably transported from Italy), under similar 570 THE ANIMAL PARASITES. conditions as the Anchylostbma duodenale. According to the observa- tions of Leuckart, Golgi, Grassi, Leichtenstern, Zinn and others, the Anguillula intestinalis. is a hermaphrodite, the eggs of which develop even in the intestine to efnbryos of 0.2 mm. in length; and, in the presence in the intestine of numerous parent-worms, are found in the faeces in great numbers. In the stools they become changed in about twelve hours into filaria-like larvae, which, when gaining entrance into the human intestine, again grow into parasitic anguillulse, which are in turn able to produce eggs capable of development. In addition there also occurs development with an intermediate sexual generation, a heterogony. In the event of sexual develop- ment the embryos grow outside the body in about three days into sex- ually mature animals (female 1.2 mm. long, male 0.88 mm.) which are known as Anguillula or Rhab- ditis st ere oralis (Fig. 532), and were formerly regarded as a sepa- rate species. The embryos of the separate sexual individuals Sevelop into filaria-like larvae, which, enter- ing the intestine of man, again grow into parasitic anguillulae. According 'to Leichtenstern and Zinn the filaria-like larvae- of direct development are more resistant than those of the sexual. The sexual mode of multiplication occurs par- ticularly in the anguillula, coming from the tropics, while in the in- digenous form (brick-laborers of Germany, Belgium, Holland) direct metamorphosis predominates. Leich- tenstern explained this by the as- -Tricocephahis dispar. (AiteT sumptlon that the tropical anguillula, Kuchenmeister and Ziirn ) ^. Male; B, caudal ^f^^j. transportation into 3. temperate end of female; a, cephalic end; b, anterior , '^ . , ^ , , { portion of body with oesophagus; c, stomach; ZOne, adapts itSClf tO the ICSS tavOr- ^'idtsha^k^'ptfs'ilL^atr^fh tnd^o'f ?lnil; able climatic conditions of the latter m, intestine of the female; n, anus; o, uterus; jjj gyj^Jj manner that the anguillula of the temperate zone favors the simpler mode of development which is the more independent of the climate — namely, the direct transformation of the embryo into the filaria-shaped larvae, which in turn grow directly into parasitic anguillulae. According to the statements of various authors Anguillula stercoralis, when present in large numbers, causes diarrhoea. According to Normand, Grassi, Golgi, Leichtenstern, and others, the worms are found chiefly in the upper parts of the small intestine. According to Leichtenstern and Askanazy the mature animals and the larvae penetrate not only into the crypts of Lieberkiihn, but also into their epithelium and into the con- nective tissue of the mucosa, and in cases may break through the muscularis mucosae. The mother animals lay their eggs in the intestinal crypts. The embryos when hatched wander out into the intestine. Fig. 533. Fig. 534. , Fig. 533.- p, vaginal opening. X 9. Fig. 534. — Egg of TricocepJialus dispar. ter Hellar.) x 315. (Af- TRICHINA. 571 Literature. (Anguillula Stercoralis and Intestinalis.) Thayer: On the Occurrence of Strongyloides Intestinalis in the United States. Journ. of Exp. Med., 1901. § 200. Tricocephalus dispar (Trichuris, trichuria), the whipworm, IS a common and relatively harmless parasite, though according to Askanazy it sucks blood from the intestinal mucosa. It inhabits the caecum and the neighboring portions of the intestine. It is found also in domestic animals. The male and female are about 4-5 cm. in length (Fig. 533). The anterior body-half (a, h) is thin, thread-like; the posterior, which bears the sexual organs (/, g, I, o, p), is much thicker, m the female (5) cylindrical, in the male {A) rolled up and provided with a spiculum {g). The eggs (Fig. 534) are an elongated oval, 50 ju, long, and possess •a thick brown shell, which shows at both poles a peg-shaped, glassy swelling. The first stage of development of the embryos takes place in water and moist earth. It advances slowly, even in summer lasting four to five months, and in the colder months of the year much longer. The eggs are resistant to cold and drying. (For the literature see Ruber, " Bibliogra- phic der klin. Helminthologie," Miinchen, 1893, p. 213; Askanazy, " Der Peitschenwurm," Deut. Arch. f. klin. Med., 57 Bd., 1896 ; Heine, "Anatomic d. Tricocephalus," Cbl. f. Bakt, xxviii, 1900). § 201. Trichina spiralis occurs in two forms — the trichina of the intestine and the trichina of the muscles. The intestinal trichina (Fig. 535) is the sexually mature form, and is a small, white, hair-like worm scarcely visible to the naked eye. The female {A) is 3 mm. long, the male (J5) is much smaller. The posterior part of the body is elongated in both sexes, and in the male (B) is pro- vided on the dorsal half with two conical terminal pegs, which are directed toward the belly and are separated from each other by four knob-like papillae. Instead of a spiculum the muscular cloaca is pro- truded outward during copulation. The intestinal canal begins with a muscular mouth, and this, becoming wider, passes into the oesophagus, which throughout its length is sur- rounded by the so-called cell-body — that is, by rows of large cells. The stomach, which follows the oesophagus, is a flask-shaped dilatation of the intestine, and is lined with finely granular cells. The stomach passes without essential change of structure into the intestine, which in the male unites with the seminal duct at the posterior end to form the cloaca. The testicles consist of a pouch, which begins near the caudal end as a blind sac, proceeds as far forward as the cell-bodies, and bending there, passes over into the seminal duct. The sexual organs of the female {A) consist of a single ovary, a uterus and a vagina, which opens externally at the junction of the first and second quarters. The ovary likewise forms a pouch lying close to the posterior end of the body, in which the round eggs develop. The pouch passes anteriorly into the sac-shaped uterus. The eggs develop iii the uterus into embryos which are set free at birth. 572 THE ANIMAL parasites. The muscle-trichina (Fig. 536) is a worm 0.7-1 mm. in length, wliich lives in the muscles of the body. It is usually rolled into a spiral and lies in a capsule, which occasionally contains ^ lime-salts. Between the coils of the worm there is a finely granular mass. A single capsule may contain three to five trichinae. If a piece of muscle containing living trichinae is taken into the stomach of a host — for example, man -I- the capsule is dissolved and the trichinae are set free. In the intestinal canal they attain sexual maturity within two and a half days, when copulation takes place. On the seventh day after the ingestion of muscle trichinae the birth of em- broyos begins, and continues some time, even for weeks. A single female trichina may laear from one thousand to thirteen hundred young. Ac- cording to Pagensitecher, Chatin, Cerfontaine, and Askanazy, the female trichinae penetrate into the intestinal villi and deposit the embryos in the chyle- vessels, whence their migration begins. To what extent they are swept along passively by the lymph, ox to what extent active migration is concerned in their spreading, is difficult to determine. When arriving in the muscles they penetrate the primitive fibres, cause the adjacent contents of the fibre to degenerate, and grow in about fourteen days to fully developed trichinae. In the neighborhood of the trichinae there occurs proliferation of muscle- nuclei. At first the muscle-trichinae are enclosed only by the sarcolemma, which appears thickened and hyaline about them. Later there occurs in the neighborhood inflammatory proliferation of granu- lation tissue which leads to the production of con- nective tissue on the outside of the sarcolemma and penetrates even within the sarcolemma tube, the muscle-nuclei being destroyed. Fat-cells may appear later in the connective tissue of the cap- sule, the development of the latter being especially marked at the poles. The intestinal trichinae have a limited life of '*^ from five to eight weeks. The muscle-trichinae, on the other hand, may live for long, possibly an un- limited time — that is, until death of the affected pPli individual ; at any rate for years, although, accord- ing to Ehrhardt, a few may die before encapsula- tion. After some time there frequently occurs de- position of lime-salts in the capsule, especially at the poles, causing it to appear glistening-white by reflected light, and cloudy and dark by transmitted light. In rare cases the trichinae after dving be- rnmp nc^nil^cA . .^'?- 535.— "Sexually mature come Caicmea. trichina. a. Female; B, Trichinae have been observed, besides in man, x^'fio. ^^^^" Leuckart.) W TRICHINA. 573 in the hog, cat, dog, rat, mouse, marmot, polecat, fox, marten, badger, hedgehog, and raccoon. Through feeding of trichinous meat muscle- trichin£E may be developed in rabbits, guinea-pigs, sheep, dogs, etc. Man becomes infected through eating uncooked pork. The invasion of trichinse produces various phenomena in man. The introduction of trichinous meat mto the intestine is followed by the symptoms of intestinal catarrh. With the invasion of the muscles there are produced pain, swelling, cedema, paralysis, and not infrequently fever. In the blood there occurs marked increase of eosin- ophile cells (Opie, Schleip). The symptoms are most severe in the fourth and fifth weeks. Death not infrequently results. The intensity and severity of the symp- toms depend on the num- ber of worms wandering into the muscles. The trichinae are found most abundantly in the diaphragm, tongue, inter- costal muscles, the mus- cles of the neck and Fig. 536-— Encapsulated muscle tricMna. (After Leuck- larynx, the lumbar mUS- art.) X 60. tant muscles of the extremities, the insertions of tendons. cles, and are scattered most sparsely in the dis- They are usually most numerous about According to Frothingham (Jour, of Med. Res., 1906), the trichina embryos are found in the sinuses. of the mesenteric lymph-nodes and in the hver sinusoids, showing that they enter the lymph-stream and are distributed by the circulating blood. Trichina embryos are found in the areas of haemorrhage occurring in the lungs. Local destruction of tissue may take place in the liver, pancreas, brain, and heart as a result of the parasite leaving the blood-vessel. The capsule of the ency- sted trichinae is formed of connective tissue which surrounds the whole of the invaded fibre. Staubli, in 1905, recovered embryos from the heart's blood of infected guinea- pigs by laking a small quantity of blood with 3 per cent acetic acid, certifugalizing, and examining the sediment. This method has since been successfully employed by Herrick and Janeway in human infection. In view of the fact that examination of the fasces is practically always fruitless and since consent for the removal of a portion of muscle for histological examination is not always to be obtained, this method of diagnosis is of particular value. Staubli, Verhandlung des Kongress f. klin Med., Wiesbaden, 1905; Herrick and Janeway, Archives Internal Medicine, 1909.) Literature. (^Trichina Spiralis; Trichinosis.) Chatin: La trichina et la trichinose, Paris, 1883. Ehrhardt: Muskelveranderungen bei Trichinose. Beitr. v. Ziegler, xx., 1896. Opie: Relation of Cells with Eosinophile Granulation to Infection with Trich. spir. Am. J. of the Med. Sc, 1904. Stiles: Trichinosis in Germany. Bull. 30, U. S. Bureau of Animal Indus., 1901. Williams: The Frequency of Trichinosis in the United States. Jour, of Med. Res., 1901. 574 THE ANIMAL PARASITES. § 202. Filaria or Dracunculus medinensis, the Guinea-worm (Fig. 537), is a thin, thread-hke fe- male worm from 60 to 100 cm. in length. The males (observed by Charles) which were attached to fe- male filariae, were only 4 cm. long. The anterior extremity is rounded off, while the posterior tapers into a pointed tail which is curved toward the belly. The external covering consists of a firm cuticle, which at the cephalic end is thickened in the form of a shield. The intestinal canal is narrow and has no anus. The uterus, filled with young, takes up nearly the whole of the body-cavity. The embryos, which are set free by bursting of the mother- worm, have a firm cuticle and an awl-shaped tail. As inter- mediate host, the embryos seek out small crustacese, in which they are probably taken into the stomach of man with drinking water. In Africa and Asia the worm is of frequent occurrence. It developes in the skin to sexual maturity and causes abscesses of the affected region. It is usually found on the lower extremities, especially in the region of the heels. Filaria sanguinis hominis is the name given to larva (Fig. 538) that occur in the blood and lymph of man, and are about 0.35 mm. in length. The sexually mat- ure worm is filiform, the male about 8 cm. long and the female 15 cm. It is called Filaria Ban- crofti after its discoverer. The worm inhabits the lymph-vessels, particularly those of the scrotum and lower extremities, and may be present in large numbers. It causes lymph-stasis and inflamma- tions which lead to swelling of the lymph-nodes and to elephantiasis- like thickening of the tissue, asso- ciated with oedema and lymphan- giectasis. Purulent inflammation, lymph-abscesses, buboes, chylous hydrocele, and chylous ascites may appear in consequence of its presence. From the lymphatics of the limbs and scrotum the eggs and embryos (0.35 mm. long ) (Fig. 538) pass into parts of the lymphatic system and into the Fig. 537- — Filaria sive Dracunculus medinensis. blood, PfivinSf rise to hsematUria (After Leuckart.) Natural size u i • » i i »• i ' chyluria, and chylous diarrhoea. Fig. 538. — Embryo of Filaria Bancrofti, known AcCOrdinP' tO Man<;on and ^rVipnbp ^s Filaria sanguinis hominis. (After Lewis.) X f^'->-"'^'"S ^u ivianson ana_;3CneUDe 400. the nlanas are present m blood Fig. 537. Fig. 538. PILARIS. 5;5 taken from the skin only during the night ; von Linstow explains this phe- nomenon as due to the fact that during sleep the peripheral vessels become dilated, and so permit the entrance of the filarise, while the capil- larieSj being narrower during the day, do not permit such entrance. The hematuria is the result of the collection of embryos in the blood-vessels of the urinary tract. The chyluria and the chylous dia:rrhcea, on the other hand, are due to obstruction by the parasites of the thoracic duct, thus causing lymph-stasis which extends to the lymphatics of the bladder and intestine and there occasions the escape of lymph. According to Scheube rupture of the lymphatics is attended by rupture of blood- vessels, so that blood becomes mixed with the lymph. The embryos may pass out through the urine. The distribution of the embryos is, according to Manson, accomplished by means of mosquitoes, which take up the parasite during the act of blood-sucking. In the mosquitoes they pass through a second stage of Fig. 539. — Female itch-mite, ventral surface. X 40. development and are then (James) after two or three weeks ready for the infection of a new host. Manson formerly held the opinion that they entered the water, and in a free condition were taken up in the water into the intestinal tract. The investigatioris of James, Low, Grassi, and Noe, who followed their development and migration in the body of mosquitoes, make it probable that they are transmitted to a new host through the bite of the mosquito. The Filaria sanguinis occurs most commonly in the tropics (Brazil, Egypt, Algiers, Madagascar, Zanzibar, Soudan, South China, Calcutta, Bahai, Guadeloupe), sometimes in the Southern States. Of the Acanthocephala, nematode-like worms having no intestine, and possessing at the anterior end a retractile proboscis set with booklets, the most important is the Echinorhyncus gigas. The male is 10-15 cm. long, and the female 30-50. It occurs chiefly in the intestine of the pig, and penetrates into the intestinal wall. According to Lindemann, it occurs occasionally in man. The rose chafer and the May beetle serve as inter- mediate hosts. 576 THE ANIMAL PARASITES. Mackenzie estimated the number of filaria-embryos present in the total bulk of the blood of a case of hsematochyluria studied by him at from thirty-six to forty millions. The patient died from empyema; during the disease the filariae died. In domestic animals numerous filaria-species occur and inhabit different parts of the body. Filaria papulosa is a common parasite of the horse, donkey, and cattle ; it lives in the serous cavities and reaches a length of from 5-18 cm. Filaria hxematica, a worm 3-13 cm. long, inhabits the right heart and the pulmonary artery Fig. 540. — Scabies (alcohol, carmine), a. Horny layer of the epidermis, perforated by numerous burrows of the itch-mite; h, mucous layer, and papillary body, the latter greatly en^ larged and infiltrated with cells; c, cutis infiltrated with cells; rf, section through a fully de- veloped itch-mite; e, eggs and embryos of different sizes; f, fasces, x 20. of the dog, and in this situation gives off its embryos to the blood-stream. It occurs particularly in America, China, and India. Filaria hemorrhagica or multipapillosa causes a nodular cutaneous affection in the horse and donkey. Literature. {Filaria. ) Blanchard: Filaria loa. Arch, de parasitol., ii., 1899. Charles: History of the Male of Filaria Medinensis. Scient. Mem. Med. Office Army of India, vii., Calcutta, 1892. James: On the Metamorphosis of Filaria sanguinis in Mosquitoes. Brit. Med. Journ., ii., 1900. Kaseworm u. Steinbriick: Nematoden bei Haustieren. Ergebn. d. a. P., viii., 1904 (Lit.). Lothrop and Pratt: Two Cases of Filariasis. Amer. Journ. of Med. Sc, cxx., 1900 (Lit.). Low: Filaria nocturna in culex. Brit. Med. Journ., i., 1900. Mackenzie, St.; Transactions of the Pathological Society of London, 1892.^ Manson: The Filaria Sanguinis, London, 1883; The Filaria Sanguinis Hominis Major and Minor, Two New Species of Haematozoa. Lancet, 1891; ref., Cbl. f. allg. Path., ii., 1891. Sonsino: The Life-history of Filaria Bancroft!. Brit. Med. Journ., i., 1900. MITES. 577 III. Arthropoda. I. Arachnida. § 203. The parasites included among the Arachnida are chiefly epizoa, which either temporarily or permanently inhabit the skin. Only one species — Pentastoma — occurs in the larval form in the tissues. The most common parasites of this group belong to the Mites [Acarina). The pentastoma belongs to the family of tongue-worms {PentastomidcB or Linguatulidce) . (1) Acarus scabei or Sarcoptes hominis, the itch-mite, is the size of a pinhead with a turtle-shaped body, provided on the ventral surface Fig. s«. ''TTTTT'n-j-j-i'r7-;-7-i rr / ?''• "^' Fig. 541. Fig. 542. FiG. 54*. Fig 541. — Leptus autumnalis. (After Kiichenmeister and Zurn.) Fig. 542. — Acarus folliculorum hominis. (After Perls.) x 300, Fig. 543. — Ixodes ricinvs, sucked half full of blood, x 2. Fig 544. Cephalic end of Pentastoma denticulafum. (After Perls.) X 40. both anteriorly and posteriorly with two pairs of legs, each of which is furnished with bristles (Fig. 539). The anterior pairs of legs extend out into pedicled clinging-discs. The same arrangement is found in the posterior two pairs in the male, while in the female both of the posterior , pairs end in long bristles. Several bristles are also found along the border of the posterior portion of the body, while the back is studded with tooth-like knobs. The head is round and likewise set with bristles. The female is nearly double the size of the male. . , • r The mite lives in the epidermis (Fig. 540, a, d), in which it forms burrows, some of which are 10 cm. long. In -the burrows the female (d) lays the eggs, which develop m situ into the young itch-mites {e), which penetrate still deeper into the epi- 37 578 THE ANIMAL PARASITES. dermis, and after repeated sheddings of their skins grow into sexually mature animals. The skin responds to the irritation produced by the presence of the mites by increased production of epithelial cells (a) and inflammation (c). The latter is further increased through the scratching of the spots which itch in consequence of the invasion. 2. Leptus autumnalis, the harvest-mite (Fig. 541) is the red- colored larva of a variety of Trombidida, which lives on grasses and bushes and on grain, and when occasion offers alights on the skin of man, where it penetrates the epithelium and causes itching and inflammation. 3. Demodex or Acarus folliculorum hominis (Fig. 542) occurs either singly or in numbers in the hair-follicles of the face, as well as in the ducts of the sebaceous and Meibomian glands. Hausche found the demodex on the eyelashes in seventy-nine per cent., and Joers in sixty- four per cent, of the cases examined. Children under one year of age were free. The female is 0.4 mm. long, the male 0.3 mm. The eggs are deposited on the shaft of the hair or on any other portion of tissue, and develop after two sheddings into sexually mature animals- which are found in the entrances to the hair-follicles and sebaceous glands, with their heads directed inward. The assumption that the demodex causes inflammation (acne, blepharitis acarica)^ is not supported (Joers, Hausche), since in spite of its presence ift the great majority of cases signs of inflammation are wanting. '! It has on its anterior ventral surface (Fig. 542) four pairs of short thick feet. The head possesses a snout and two feelers. 4. Ixodes ricinus, the wood-jack or wood-tick (Fig. 543), is. a fairly large yellowish-brown member of the Arachnida belonging to the ticks. It has a black head provided with a sucking apparatus, and a dis- tensible leathery body. It is of common occurrence on grass and bushes, and sometimes alights on man or beast. By means of its sucking appa- ratus it 'draws blood from the skin and swells to a remarkable extent. 5. Pentastoma denticulatum is the larva of Pentastoma taenoides, a lancet-shaped animal belonging to the tongue-worms or PentastomidcE. It inhabits the nasal, frontal, and maxillary cavities of various animals, especially of the dog, rarely of man (Laudon) and occasions inflam- mations. The female of the mature animal is 50—80 mm. long, and anteriorly from 8-10 mm. broad; the male is 16—22 mm. long, and anteriorly from 3—4 mm. broad. The body consists of eighty-seven to ninety segments, the most anterior of vv^hich bear lateral segment- appendages, the pairs of limbs. The eggs, which are produced in great numbers, are oval. The larva is 4—5 mm. long, 1.5 mm. broad, plump, flattened, and inhabits chiefly the liver, lung, or spleen, or more rarely the other organs of man and the herbivora. It occurs in the form of a small nodule encapsulated in connective tissue. The body consists of about fifty ring-shaped segments which are provided at the borders with spines (Fig. 544), and the cephalic end is provided with four hook-shaped feet. The eggs are taken in from the external world through the intestinal tract. The parasites set free in the intestine wander by means of a boring apparatus through the mesentery into the mesenteric lymph-nodes, or penetrate directly into blood-vessels, and are carried to the liver or even to the lumgs, where after shedding they develop into the encysted larvae. The larvae may in their wanderings gain access to the nasal cavity of their host, and develop into mature animals, although the further development usually takes place only after their reception into a new host. MITES. 579 „„ df'^°'^'^^'i?a *^^ pubUshed reports of Tanaka a small red mite occurs in great nmnDers in ditterent parts of Japan during midsummer, and clinging firmly to the slcm ot rnan causes the so-called Kedani-disease, which is characterized by inflamma- r.r°1 Ki ^f t.u ^""^ lymph-nodes, with high fever, and often ends fatally. It is r^.A •„ i'lf l-!'^ symptoms are due to secondary infections (proteus and strepto- W.l infl.l,^,/- ' °u *^^ "'''^- .■^''^"^ reflexus, a tick, causes by its bite not only local milamniation, but nausea, diarrhoea, cardiac palpitation, asthma, etc., through a poison derived from its salivary glands. It is found also in pigeons. in domestic animals living mites occur frequently as parasites of the skin, ana represent different species of various families (Sarcoptides, Dermatocoptes, Dermatophages, and Acarides). ^ f , f , Sarcoptes hominis, the burrow-mite or itch-mite of man, is also found in horses and Neapolitan sheep. In addition still other different species of sarcoptes may be distinguished as parasites of the domestic animals — for exalhiple, Sarcoptes squamiferus in dogs, hogs, sheep and goats, and Sarcoptes minor in cats and KV % I Fig. 545. Fig. 546. Fig. 545. — Male of Dermatophagus communis seen from the ventral side. (After Futz.) x 50. Fig. S46. — Male of Dermatocoptes communis^ seen from the ventral side. (After Putz.) x 50. Dermatophagus, the devouring-mite (Fig. S4S), with a broad head, occurs in different animals, and different species may be distinguished. It lives on the cells of the epidermis and causes desquamation of tnc skin. Dermatocoptes, the sucking-mite (Fig. S46), with long narrow head, takes blood and lymph from the skin and causes inflammation. Dermatocoptes communis occurs in horses, cattle, and sheep. Dermatocoptes cuniculi is a parasite of the rabbit's ear, and causes the ear-scab which usually occurs on the inner side of the auricle. Symbiotes equi of Gerlach is a mite which occurs chiefly on the feet of the heavy English and Scptch horses, and causes a moist dermatitis, often incorrectly called malanders.- Dermanyssus avium is a long, red, blood-sucking mite, about 1 mm. long, and is often found on birds. Dermatoryctes mutans causes the foot-itch of chickens whereby the skin ac- quires a mortar-like scabby covering. Acarus folliculorum or Demodex folliculorum, the mite of the hair-follicles, occurs most frequently in the dog or cat, more rarely in the hog, cattle, and the goat. In the dog it causes the formation of scales, falling out of the hair, and a pustular eruption. Demodex phylloides causes in swine nodular inflammations and ulcers particu- larly on the snout, neck, breasts and flanks, and the inner surface of the thighs. The purulent foci contain great numbers of the mites. The mite may develop also on cattle. 580 THE ANIMAL PARASITES. Various species of Ixodes of the tick family occur on dogs, cattle, and sheep; Argas reflexus occurs on pigeons; and other forms of ticks occur on the domestic animals. Leptus autumnalis occurs also on dogs and chickens. Pentastomata occur also in cattle, sheep, and goats, and in certain regions are very common in the first-named. 2. Insecta. § 204. The parasites belonging to the class of Insecta are for the greater part epizoa. In part they are but transient inhabitants of the skin, deriving from it their nourishment; in part they are permanent inhabi- tants and utihze the skin structures for the deposit of their eggs. Of the numerous species belonging to this class the following may be mentioned : (1) Pediculus capitis, the head-louse (Fig. 547), inhabits the hairy portions of the head, and derives its nourishment (i.e., blood) from the skin, by means of its feeding apparatus. Its eggs (nits) are barrel' Fig- 547- Fig. 548. Fig. 549. Fig. 547. — Female of Pediculus capitis, seen from the ventral surface. (Kuchenmeister and Zurn.) X 13. Fig. 548. — Male of Pediculus pubis, seen from the ventral surface. (Kuchenmeister and Ziirn.) X 13. Fig. 549. — Female of Pediculus vestimentorum, seen from the ventral surface. (Kiichen- meisten and Ziirn.) X 9. shaped and white, and are attached to the hairs by means of a chitinous shell. The embryo hatches in about eight days. In consequence of the scratching induced by the itching there often arise inflammations of the skin, in particular eczemas, which are often severe. (2) Pediculus pubis (Phthirius inguinalis), the felt or crab-louse (Fig. 548), inhabits the hairy parts of the trunk and extremities. Its habits of life are the same as those of Pediculus capitis. (3) Pediculus vestimentorum, the clothing or body-louse (Fig. 549), lives in the wearing apparel, and lays its eggs in the same. It gets on man to obtain its nourishment. (4) Cimex lectularius, the bedbug, dwells in beds, floors, closets, etc. During the night it gets on man to suck blood. It causes wheals in the skin. (5) Pulex irritans, the common flea, also draws blood from the skin. At the point where it has sucked there is found a little punctate hsemor- rhage. Occasionally it causes wheals and swellings. It lays its eggs in the cracks of floors, in sawdust, etc. MOSQUITOES; FLIES. 581 (6) Pulex penetrans {Scwcopsylla penetrans), the sand flea, occurs in South Africa in the sand. The female lays her eggs in the skin thereby causing intense inflammation. (7) Mosquitoes ptovided with stinging and sucking apparatus {CulicidcE and Tipulida), horse-flies {Tabanid^), and fiies {Stomox- yidw) draw blood frequently from the skin of man. Various flies {CEstridcB, biting bot-flies, Muscidce or blow-flies) occasionally lay their eggs in the skin, in ulcers or wounds, or in the accessible body-cavities, in consequence of which the maggots developing cause local destruction of tissue and inflammation {myiasis). Under certain conditions their larvae (for example, that of Anthomia canicularis. Fig. 550) may get into the Fig- 550. Fig. 551. Fig. 552. Fig. 553. Fig. 550. — Larva of Anthomia canicularis. (After Braun.) About x 6. Fig. 551. — Larva of Musca vomitoria. (After Braun.) About X 6. Fig. 552. — Larva of Lucilia macellaria. (After Braun.) About X 6. Fig. 553. — "LaTya of Dermatobia cyaniventris. (After Blanchard.) About X 6. intestinal tract with the food and there undergo further development {myiasis intestinalis) . This is especially likely to occur when abnormal conditions which interfere with digestion are present in the stomach and intestine. The eggs' of the Muscidce (in Europe usually of Sarcofhila wohlfarti and Musca vomitoria [Fig. 551], in America of Compsomyia or Lucilia macellaria [Fig. 552], and Musca anthropophaga) , when laid on the mucous membranes or in wounds, hatch after a few hours, and cause destruction of the neighboring soft parts through their efforts to obtain nourishment. In the auditory canal, nose, and antrum of High- more the bones may be laid bare {myiasis mucosa). In the course of about a week the larvse leave the ulcers and pass into the pupa stage in the earth. The CEstridcs (in Europe, Hypoderma bovis and Hypoderma diana; in America, Dermatobia cyaniventris [Fig. 553] or Cuterebra noxialis) lay their eggs on wounds or in the intact skin. The larvse, hatching soon, penetrate into the cutis by means of their booklets, and after several sheddings grow in from one to six months into larger larvae about 2 cm. long. They cause, particularly in their later stages, painful swellings of the neighboring tissue {myiasis cestrosa). 582 THE ANIMAL PARASITES. Parasites belonging to the Muscidm and Oestridce play a more important role in th« case of the domestic animals than in man; and the larvas ai the species of Oestrus in particular occur as parasites in animals. For example, the larvae of Gastrophilus equi (Fig. 554), Cast, pecorum and Cast, hcemorrhoidalis inhabit the stomach and adjacent portions of the intestinal tract of the horse, where they com- plete their development up to the pupa- stage, when they leave the animal. Oestrus ovis lays its larvae in the nasal cavities of sheep, whence they may wander, under certain conditions, into the frontal, nasal, and maxillary cavitie;;, or even into the cranial cavity, and ex- cite inflammation. Hypoderma or Oestrus bovis, the biting fly, or bot-fly, lays its eggs on the skin of cattle. The larva bores into the skin and enters the spinal canal of cattle, completing here its development up to the pupa-stage, at which time it leaves the animal. According to Schneidemuhl, the larvae do not always enter th'rough the skin, but are often taken in with the food, whereupon they penetrate through the wall of the oesophagus toward the ^'g. skin and spinal canal. The latter follows from the fact that they are found in the wall of the oesophagus from October to January, and under the skin, on the other hand, from January to April. In the skin they cause the so-called " fly-boils." Sarcophila wohlfarti (Sarcophaga magnifica) lays its larvae on the skin of horses, sheep, cattle, dogs, awi geese. Lucilia macellaria lays its eggs between the hind legs of lambs suffering with diarrhoea. The larvae seek the thick-wooled portions of the root of the tail and the lumbar region and bore into the skin. 554. — Gastrophilus a, Male; equi. (After b, larva. Brauer.) GENERAL INDEX. Abdomen, congenital fissure of, 40S Abrachius, 409 Abscess chronic, 279 definition of, 258, 276 Acanthocephala, S7S Acardius, 417 Acarus folliculorum hominis, 578 scabei, 577 Achorion Schonleini, 521 Achromatopsia, 38 Acid-fast bacilli, 474 Acrania, 400 Acromegaly, 63 status lymphaticus and, 68 Actinomyces, 505 Actinomycosis, 505 Addison's disease, 65 status lymphaticus and, 68 Adenocarcinoma, 366 Adenocystoma, 349 Adenoma, 344 Adenomyoma, 313 Adenosarcoma, 372 Adhesions, formation of, 272 Adipositas, 147 Adiposis dolorosa, 296 jEgagropilse, 180 Agglutination, diagnostic use of, 94 Agglutinative thrombi, 111 Agglutinins, 94 Aggressins, 29 Agnathia, 404 Albinism, 200 Albinos, 200 Alexins, 78, 79 Algor mortis, 130 Alkaloids, cadaveric, 23 Alveolar echinococcus cysts, 559 Amelus, 409 Amoebae, 525 Amphimixis, 43 Aimyelia, 396 Amyloid experimental production of, 168 incidence of, 166 occurrence of, 166 origin of, 169 stains for, 165 Amyloid degeneration, 164 Amyloid infiltrations, 170 Anabiosis, 7 Anaemia, 100 anchylostoma duodenale m, 657 and bothriocephalus latus, 562 Anaemia, blood-sucking worms in, 32 " cotton-mill," 568 local, 102, 105 Anaesthetic leprosy, 499 Anaphylaxis, 95 Anaplasia, 363 Anasarca, 120 Anchylostoma duodenale, 567 Androgynes, 413 Anencephalus, 401 Aneurism, cirsoid, 309 Angioma, 303 arteriale racemosum, 309 hepatic, 306 lymphaticum, 309 Angioneurotic oedema, 121 Anguillula intestinalis, 569 Anhydrasmia, 100 Anthrax, 4S2 Antibodies bactericidal, 80, 82 globulicidal, 80 Antitoxins, 80, 82, 83, 95 Anus, malformations of, 408 Apparent death, 131 Appendix, oxyuris in, 566 Aprosopia, 403 Arachnida, 577 Argyria, 18, 199 Arrhinencephalus, 401 Arsphenamine, untoward effects of, 17 Arterioliths, 115 Arthropodes, 32, 577 Ascariasis, dangers of, 564 Ascaris lumbricoides, 563 Asiatic cholera, 511 Aspergillus, 518 mycoses, 520 Asphyxia, 3 Atmospheric pressure, effects of sudden lowering, 10 Atrophy, 5, 141 active, 143 degenerative, 143 disuse, 144 neuropathic, 144 nutritional, 144 of fat tissue, 147 passive, 143 pressure, 144 senile, 143 simple, 143 Autointoxication, 46 application of ter,m, 58 eclampsia as a form of, 58 583 584 GENERAL INDEX. Autointoxication, mode of origin, 56 varieties of, 57 Autolytic degeneration, 146 Avian tuberculosis, 487 Bacillary dysentery, 459 Bacilli, 449 acid-fast, 474 encapsulated, 463 pathogenic, 451 saprophytic, 450 Bacillus aerogenes capsulatus, 462 arathracis, 451 botulinus, 450 coli communis, 458 comma, of cholera, 511 diphtheriae, 464 Ducrey's (chancroid), 468 dysenterije, 459 enteritidis, 459 Friedlander's, 462 influenzae, 463 leprae, 497 mallei, 502 mucosus capsulatus, 462 pestis, 466 phlegmones emphysematosae, 462 pneumoniae, 462 prodigiosus, 451 proteus vulgaris, 451 pseudo-diphtheriae, 466 pyocyaneus, 451, 460 subtilis, 451 tetani, 460 tuberculosis, 468 typhi abdominalis, 456 Bacillus of anthrax, 451 blue-pus, 451, 460 bubonic plague, 466 chancroid, 468 cholera, 511 diphtheria, 464 dysentery, 459 glanders, 502 influenza, 463 leprosy, 497 malignant oedema, 461 rhinoscleroma, 503 tetanus, 460 tuberculosis, 468 typhoid fever, 456 Bacteria action on tissues, 429 and chemical conditions, 425 and double infections, 429 and temperature conditions, 425 and transformations of nutrient ma- terial, 427 avenues of entrance in-to body, 25 cocci, forms of, 432 development of, 424 diplococcus intracellularis menin- gitidis, 442 fission-fungi, morphology and bi- ology of, 423 Bacteria, general considerations, 423 general effects, 26 gonococcus, 44^ identification and growth of, 430 infection by, 22 influence on animal organism, 431 intoxication by, 25 local effects; 25 method of increase, 24, 27 •method of spread, 24, 26 micrococcus of gonorrhoea, 446 micrococcus pyogenes, 444 pneumococcus, 440 polymorphous, 449 products of, 25, 428 relation to infection, 23 saprophytic, 450 schizomycetes, infection by, 428 secondary infection by, 429 staphylococcus pyogenes albus and citreus, 446 staphylococcus pyogenes aureus, 444 ■streptococcus pyogenes, 434 transmission to foetus, 27 variation in virulence of, 429 Bacteriaemia, 26 Bacterial proteins, 24, 29 Bacterial toxins, 23 Balantidium coli, 546 " Barber's itch," 522 Bedbug, 580 Bedsore, 138 Beggiatoa, 499 Beri-beri, 15 Bezoar stones, 180 Bilharzia haematobia, SSO Biliary calculi, 180 Blastomycetes, 515, 519 Blastomycosis, 30, 519 Blood coagulation of, 106 platelets, 109 ■regeneration of, 226 stagnation of, 118 Blood-poisons, 18 Blood-pressure, 97 Blood-vessels, regeneration of, 220 Boil, Delhi, 533 Bone, regeneration of, 225 Bone-marrow, Martland's tumor of, 328 Bothriocephalus cordatus, 562 felis, 562 latus, 560 Mansoni, 562 Botulismus, 15, 450 Bovine tuberculosis, 487 Brachygnathia, 404 Branchial cysts, 404 Bronchial calculi, 180 Bubonic plague, 466 Burns, 6 Cachectic oedema, 123 Cachexia, 4 suprarenal, 65 thyreopriva, 61 GENERAL INDEX. sa§ Cachexia, tumor, 291 Caisson disease, 10 Calcification, 174 ossification and, 177 Calculi, 179 urinary, 182 Calmette's reaction, 477 Carcinoma, cancer, 3S2 adenocarcinoma, 366 chorioncarcinoma. 370, 379 coccidia in, 535, 538 conditions favoring, 353 durum, 368 gelatinous, 370 gigantocellulare, 371 hyaline spherules in, 163 infiltrative growth of, 355 metastasis of, 356, 376 mucoid, 370 parasites, as possible cause of, 354 ■retrograde changes in, 356 sarcocarcinoma, 372 scirrhous, 368 secondary changes in, 370 simplex, 367 tubular, 2^1 Carcinomatosis, 378 Cardiopathy, idiopathic, 63 Carotinsemia, 199 Cartilage, regeneration of, 225 Caseous necrosis, 135 Castration, effects of, 66 Catarrhal inflammation, 252 Cell-division, atypical. 216 mechanism of, 214 Cephalocele, 401 Cephalothoracopagus, 419 Cercomonas, 527 _ Cerebral concussion, 13 Cestodes, 551 Chancre, 491 Chancroid, bacillus of, 468 Cheilo-gnatho-palatoschisis, 403 Chemotaxis, 77, 254 Chemotropismus, 77 " Chicken-fat " clots, 107 Chilblains, 6 Chills, 71 Chlorosis, Egyptian, 567 Choking, 3 Cholaemia, 57 Cholera, 511 Cholesteatoma, 344, 381 Cholesterin, 155 Chondroma, 297 Chondrosarcoma, 299 Chordoma, 300 Chorion-carcinoma, 363, 370, 379 Chorio-epithelioma. 363, 370, 379 and teratoma, 388 Chromaffine cells, 65 Chronic inflammation, 276 Chyluria, 128 Ciliates, 546 Cimex lectularius, 580 Circulation Circulation, disturbances of, 97 - collateral development of, 106 in inflammation, 243 Cirsoid aneurism, 309 Cladothrix, 449 Cladothrix asteroides, 510 Clinical signs of inflammation, 242 Cloudy swelling, 144 Club-foot, 410 Coal-dust, pigmentation by, 198 Coagulation necrosis, 134 Cocci, 432 diplococcus intracellularis menin- gitidis, 442 diplococcus pneumoniae, 440 gonococcus, 446 micrococcus of gonorrhoea, 446 ■micrococcus pyogenes, 444 pneumococcus, 440 staphylococcus albus and citreuS, 446 staphylococcus aureus, 444 streptococcus lanceolatus, 440 streptococcus pyogenes, 434 Coccidia, 534 reproduction of, 537 Coccidioidal granuloma, 30, 519 Coccidium oviforme, 535 Colds, 6 Collateral circulation, development of, 106 Colliquation necrosis, 136 Colloid, 160, 162 Comma bacillus, 511 Commotio cerebri, 13 Concretions, 179 amyloid, 164 calcification of, 174, 177" corpora amylacea, 170 hyaline, 162 Concussion effects of, 12 sequete of, 12 Congenital syphilis, 495 Congestion, hypostatic, lOS Conglutination, 112 Connective-tissue, regeneration of, 222 Contagion, direct, 22 Copraemia, 57 Cornification, 163 Corpora amylacea, 170 Corpulence, 36 - Craniopagus, 419 Craniorachischisis, 400 Crenothrix, 449 Cretinism, 62 Croupous inflammation, 252 Cruor, 107 Cutaneous horns, 204 Cyanosis, 98 Cyclopia, 401 Cystadenotfia, 349 multiple, of kidneys, 352 Cysticercus cellulosx, 554 Cystocarcinoma, 352, 374 Cystoma adenocystoma, 349, 352 papillary, 343 586 GENERAL INDEX. Cysts, 201 branchial, 404 echinococcus, 556 ectodermal. 381 ■teratoid, 380 Cytolysins, 93 Cytotoxins, 93 Darier's disease, 538 Deaf-mutism, 38 Death, 130 apparent, 131 Decubitus, 138 Degeneration, 144 amyloid, 164 autolytic, 146 fatty, 146, 151, 152, 154 hyaline, 171 hydropic, 146 lardaceous, 164 mucous, 158 Zenker's, 163 ' Degenerative atrophies, 143 " Delhi boil," 533 Demodex, 578 Dercum's syndrome, 296 Dermatitis, blastomycetic, 519 Dermoid cysts, 381, 384 Dermoids, 381, 384 Desmoid, 292 Diabetes mellitus, 59 and acromegaly, 64 changes in Islands of Langerhans in, 60 experimental production of, 60 Diapedesis, 125 Diathesis, 126 Dicephalus, 418 Diphtheria, 465 Diphtheritic inflammation, 260 Diplococcus intracellularis meningitidis, 442 pneumoniae, 440 Diprosopus, 418 Dipygus, 419 Disease Addison's. 65 caisson, 10 Darier's, 538 due to disturbances of internal secretions, 59 Graves', 63 hookworm, 567 hypersusceptibility to, 33, 34, 35 immunity to, 33 inheritance of pathological qualities, 39 Hodgkin's, 326 Nagana, 531 Paget's, 538 secondary, 54 trophoneurotic, 56 tsetse-fly, 531 Distoma felinum, 549 hsematobium, 550 hepaticum, 547 Distoma, lanceolatum, 548 pulmonale, 549 sibiricum, 549 spathulatum, 549 Westermanni, 549 Disuse atrophy, 144 Diverticulum, Meckel's, 406 Dochmius duodenalis, 567 Dourine, 532 Dracunculus medinensis, 574 Drill-bone, 302 Dropsy, 120 Ducrey's bacillus (chancroid), 468 Dwarfism, 36 Dyschromatopsia, 38 Dysentery amcebic, 525 bacillus of, 459 ECCHONDROSES, 299 Echinococcus cysts, 556 Eclampsia, 58 Ectodermal cysts, 381 Ectopia cordis, 405 of urinary bladder, 405 Eczema marginatum, 522 Egyptian chlorosis, 567 Ehrlich's side-chain theory,-91 Elastic fibres, regeneration of, 224 Electric discharges, 11 Elephantiasis, 203. 411 Emboli, secondary changes in, 116 Embolisotn, 47 air, 52 fat, 50 paradoxical, 48 Embolus, 47 fate of. 51 straddling. 51 Embryoma, Wilms', 372, 385 Emphysema, traumatic, 52 Emphysematous gangrene, 137 Empyema, 258 Encephalocele, 401 Enchondroma, 297 Endothelioma, 329, 334 Endotoxins, 24, 28 Enitozoa, 31 Enzymes, 28 Epidemic, 21 Epidermoids, 381 Epinephrin, 66 Epithelial pearls, 365 Epithelial tumors, 283, 341 Epithelioma, 364 chorion, 363, 370 contagiosum, 535 papillary, 342 Epithelium, regeneration of, 218 Epispadias, 407 Epizoa, 31 Ergot, effects of, 18 Erysipelas, 435 Erythrasma, 523 Eunuchoidism, €7 Eurotium, 518 GENERAL, INDEX. 58Z Eustrongylus gigas, 568 Exencephalus, 401 Exophthalmic goitre, 63 Exostoses, 300 multiple, 303 External genitals, development of, 415 Extremities, duplication of, 411 Extrophy, 406 Exudates, 244 absorption of, 262 catarrhal, 252 croupous, 253 distribution of, 247 fate of, 249 fibrinopurulent, 258 fibrinous, 254 fluid, 245 haemorrhagic, 255 purulent, 257 serofibrinous, 252 seropurulent, 258 Exudation, inflammatory, 244 mechanism of, 246 Eye, regeneration of, 233 False hermaphrodism, 413 Fat-cells, embryonal, 297 Fat deposit, 146 Fat stains, 147 Fats animal, ISO body, nature of, 155 food, 151 from albumin, 151 from carbohydrates, 151 glandular, 150 granule-cells, 151 synthesis of, 151 Fatty degeneration, 146, 151 transportation of fat in, 152, 154 Favus, 521 Fever, 69 significance of, 84 Fever, Gaimba, 532 Fever, malarial, 539 development of parasite, 545 in animals, 543 mosquitoes in, 544 Fever, relapsing, 514, 528 Fever, typhus parasites in, 539 Fibrin, in inflammatory exudates, 254 Fibrin thrombi, 111 Fibrinopurulent inflammation, 258 Fibroma, 291 intracanalicular, 348 multiple, of skin, 319 Fibromyoma, 312 Fibrosarcoma, 321 Filaria, 574 Fission-fungi, 423 Fissura abdominalis, 405 genitalis, 406 stemi, 405 vesicae urinariae, 406 Fistulous tracts, 258 Flagellates, 527 Flat-worms, 547 Fleas, 580 Fhes, 581 Foetus paipyraceus, 416 transmission of bacteria to, 27 transmission of tuberculosis to, 484 Food and water, effects of total d^Wiva- tion of, 4 Foreign-body giant-cells, 267 Formative cells, 223 Freckles, 310 Friedlander's bacillus, 462 Frolich's syndrome, 296 Fungus of favus, 521 Gall-stones, 180 Gamba-fever, 532 Gangrene, 137 Gas-phlegmon, 462 Gastroschisis, 405 Gelatinous carcinoma, 370 Genitalia development of, 414 malformation of, 406 Germinal acquisition, 44 Germinal transmission, 44 Giant-cell carcinoma, 371 Giant-cells, 217 foreign-body, 267 in tuberculosis, 471 syncitial, 218 Giant-growth, partial, 411 Giantism, 36, 203 acromegalic, 64 Glanders, 502 Glioma, 316 Globular thrombi, 114 Glycogen, 156 Glycosuria, 59 Goitre, exophthalmic, 63 histological changes in, 63 iodine content in, 62 Gonococcus, 446 Gonorrhoea, 447 Gout, 36, 178 Granular degeneration, 144 Granulation-tissue, 265 tuberculous, 478 Granuloma, infective, 279 actinomycosis, 505 blastomycosis, 30, 519 coccidiosis, 30, 519 glanders, 502 leprosy, 498 rhinoscleroma, 503 syphilis, 490 tuberculosis, 468 Gravel, 182 Graves' disease, 63 " Ground itch," 568 Gummata, 493 Gynecomastia, 412 HEMANGIOMA cavernosum, 305 588 GENERAI. INDEX. Haemangioma, hypertrophicum, 308 simplex, 303 Hsemangiosarcoma, 333 Haematogenous infection, 26 Haematogenous pigments, 188 haematoidin, 189 haemosiderin, 190 Haemochromatosis, 188, 191 Haemofuchsin, 187 Haemoglobinaemia, 191 Haemolysins, action of, 93 Haemophilia, 126 Haemorrhage, 123 diabrosin, 125 diapedesin, 125 rhexin, 125 Haemorrhagic inflammation, 255 Hasmosporidia of malaria, 539 Hair-fungi, 509 Haptins, 29, 93 Haptophorous group, 29 Harvest-mite, 578 Healing, 262 of carcinoma, 373 of wounds, 269 Heart action of, 97 effect of poisons on, 21 impaired action. 98 increased action. 100 Heart, diseases of, 97 hypertrophy, 99, 102 valvular lesions, 99 Heart-muscle, regeneration of, 229 Heat-stroke, 5 Height of body, average, 206 Hemicrania, 400 Hereditary syphilis. 495 Hermaphrodism, 412 types of, 413 Hernia cerebri, 401 umbilical, 405 Herpes tonsurans, 521 Herxheimer's reaction, 18 High-tension currents, effects of. 11 Histoid tumors, 282 Hodgkin's disease, 326 Hook-worm, 568 Horns, cutaneous, 204 Hunterian chancre, 491 Hyalin concretions. 162 epithelial, 161 nature of, 173 spherules in cancer, 163 Hyaline degeneration, 171 Hyaline products, 173 Hyaline thrombi, 111, 114 Hydrencephalocele, 401 Hydromeningocele, 398 Hydromyelocele, 398 Hydropic degeneration, 146 Hydrops, 120 Hyperjemia, 98 active, 103 local. 102 Hyperasmia, passive, 103 Hyperkeratosis, 163 Hypermastia, 412 Hyperplasia definition of, 203 of. adipose tissue, 147 Hjrpersusceptibility to disease, 33 age, and, 34, 35 variations in, 34 Hyperthelia, 412 Hyperthyreosis. 63 Hyperthyroidism, 63 Hypertrichosis, 204 Hypertrophy. 5 compensatory, 213, 220 definition of, 203 varieties of, 206 Hyphomycetes, 514 Hypochondria, 14 Hypospadias, 407 Hypostasis livores, 105 postmortem, 105 ' Hysteria, 14 Ichthyosis, 204 Ichthyotoxin, 16 Icterus, 195 haematogenous, 196 hsemolytic, 197 hepatogenous, 196 of new-born, 198 Idiosyncrasy, 33 Immunity, 33. 74 acquired, 85 artificial, 85 natural, 75 Immunization active, 86 passive, 86 Induced thrombi, 113 Infarcts, 123, 126 anaemic, 126 embolic, 127 haemorrhagic, 126 uric acid, 182 Infection bacterial, 22 climate and, 23 cryptogenic, 27, 438 definition of, 21 entrance of bacteria in, 25 epidemic, 21 general effects of. 25 haematogenous, 27 intrauterine, postconceptional, 44 local effects of, 25 lymphogenous, 27 metastasis in. 26 method of spread, 21 mixed, 27 parasitic. 22 production of poisons in, 23, 28 relation of bacteria to, 23 relation of moulds to, 29 secondary, 27 spread of bacteria in, 24 GENERAL INDEX. 589 Infection, status lymphaticus and, 68 streptococcus, 434 transmission by insects, 32 wound, 34 Infiltrations, 129 amyloid, 170 'hasmorrhagic, 123 hydropic, 144 cedematous, 119 ■of lyimph, 128 Inflammation, 242 arrangement of fibrin in, 252 by continuity, 243 catarrhal, 252 causes of, 242 chronic, 276 clinical signs of, 242 coagulation in, 250 croupous, 252 designations of, 251 diphtheritic, 260 disturbances of circulation in, 243 eotogenous, 243 effusions in, 250 emigration of white cells in, 244 escape of fluid in, 245 excretory, 243 fibrinopurulent, 258 haematogenous, 243 metastatic, 243 nature of changes in, 245 necrotic, 259 parenchymatous, 250 purulent, 257 removal of cause in, 263 serofibrinous, 252 seropurulent, 258 streptococcal, 434 , superficial, 250 tissue infiltrates in, 247 tissue lesions in. 243 tissue proliferation in, 245, 263, 264 tuberculous, 477 Inflammatory cedema, 123 Influenza, 464 Infusoria, 546 Inheritance of pathological qualities, 39 Insects, 580 conveying infection, 32 Insolation, 6 Internal genitals, development of, 414 _ Internal secretions, diseases due to dis- turbances of, 59 Interstitial inflammation, 250 Intestinal trichina, 571 Intestinal tuberculosis, 469 Intoxication, 46 effects of, 14 general, 26 intestinal, 25 tissue changes in, 280 lodothyrin, 62 Irradiation, experimental, 8 Ischasmia, 105 Ischiopagus, 418 Islands of Langerhans in diabetes, 60 Itch-mite, 577 Ixodes ricinus, 578 Jaundice, 195 haematogenous, 196 hsemolytic, 197 hepaitogenous, 196 of new-born, 198 Kakke, is Kala-azar, 532 Karyokinesis, atypical, 216 mechanism of, 214 Karyomitosis atypical, 216 mechanism of, 214 Keloid, 293 Keratin, 163 Keratohyalin, 163 Kidneys, polycystic, 352 Kinetoses, 14 Lamblia intestinalis, 527 Laminated thrombi, 110 Lardaceous clots, 107 Lardaceous degeneration, 164 Lardaceous spleen, 164 Lead, effects of, 18 Leiomyoma, 312 Leischman-'Donovan bodies, 533 Lentigines, 310 Leontiasis ossea, 204 Lepra mutilans, 499 Leprosy facies in, 498 forms of, 499 geography of, 500 of nerves, 499 of skin, 498 tissue changes in. 498 white, of Jews, 201 Leptus autumnalis, 578 Leucocytic thrombi, 111 Leucocytosis, definition of, 227 Leucoderma, 200 Leucopathia acquisita, 200 congenita, 200 Leukaemia, varieties of, 227 Lightning-stroke, 11 Lipochrome, 186 Lipoma, 295 Lipomatosis, 147 varieties of, 296 Liquefaction necrosis, 136 Liquefaction of tissues, iion-bacterial, 259 Lithopaedion, 395 Liver-flukes, 547 Luxations, congenital, 410 Lymphangioma, 303 Lymph angiosarcoma. 329 Lymphangoitis, 26, 27 Lymph nodes, as filters, 78 LymTihoErenous infpction, 26 Lymioborrhaeia, l'** Lymphosarcoma, 323., 325 590 GENERAL INDEX. Macrocheilia, 310 Macroglossia, 310 Madura foot, 510 Malaria, pigments in, 194 Malarial fever, 539 development of parasite, 545 in animals, 543 mosquitoes in, 544 Malformations, congenital, 390 different forms of, 394 due to excessive growth or multi- plication, 411 experimental production of, 392 of abdominal cavity, 405 of cranium, 400 of external genitalia and anus, 406 of extremities, 408 of face and neck, 402 ■of thoracic cavity, 405 of vertebral canal, 396 rachischisis, 396 spina bifida, 397 Malignant oedema, 461 Marasmus, 4 Martland's tumor of bone-marrow, 328 " Measles," 554 Meat-poisoning, 450, 459 Meckel's diverticulum, 406 Medullary sarcoma, 321 Meischer's sacs, 537 Melanin, 185 Melanoma, benifm, 310 Melanosarcoma, 335 Melanosis, of viscera, 187 Melasma suprarenale, 65 Meningocele, 401 Meningoencephalocele, 401 Metamorphosis, viscous, 112 Metaplasia, 237 Metastasis, 47 in actinomycosis, 509 in tuberculosis, 482 of benign tumors, 291 of bile pigment, 52 of carcinoma, 356, 376 of dust, 48 of fat droplets, SO of iron-containing derivatives, 52 of parasites, 51 of parenchyma-cells, 49 of pigment-granules, 53 of silver particles, 52 of tumor cells, 51, 288, 291, 356, 376 results of, 50 retrograde, 48, 376 Miasma, 22 Microcephalus, 401 Micrococcus of gonorrhoea, 446 pyogenes, 444 Micromelus, 409 Microsporon furfur, 523 minutissium, 523 Milk-spots, 273 Mites, 577, 579 Mixed thrombi, 110 Moist gangrene, 137 Moles non-pigmented, 311 pigmented, 310, 336 Monobrachius, 409 Monsters, 390 double, 415 single, 394 Mosquitoes, 581 in malaria, 544 Moulds, 515 pathogenic, 29 Mucins, 159 Mucoid carcinoma, 370 Mucor, 518 ■Mucous degeneration, 158 Mucous membrane, cancer of, 360 Multilocular echinococcus cysts, 559 Multiple myeloma, 327 Mummification, 137 Muscle, regeneration of, 227, 229 Muscle trichina, 572 Mycetoma, 510 Mycoses, aspergillus, 520 Myelin, 155 Myelocystocele, 398 Myelocystomeningocele, 398 Myeloma, multiple, 327 Myelomeningocele, 397 Myofibroma, 312 Myoma adenomyoma, 313 la;vicellulare, 312 malignant transformation of, 314 striocellulare, 315 Myosarcoma, 314 Myositis ossificans, 302 Myxoedema, 62 Myxoma, 294 Myxosarcoma, 294 N^vi, vascular, 304 Naval stones, 180 Necrosis, 131 caseous, 135 causes of, 132 coagulation, 134 colliquation, 136 course of, 134 histology of, 132 results of, 134 Necrotic inflammation, 259 Necrotic tissue, replacement of, 275 Nemathelminthes, 562 Nematodes, 562 Nervous system effect of poisons on, 21 regeneration of, 229 syphilis of, 495 Neurasthenia, 14 Neuroblastoma, 318 Neurofibroma, 319 Neuroglioma ganglionaire, 316 Neuroma amputation, 318 true, 321 Neuropathic atrophy, 144 GENERAL INDEX. 591 Neuroses, traumatic, 13 Nitroso-indol reaction, 514 Nutritional atrophy, 144 Obesity, 147 Obturating thrombus, 113 Ochronosis, 187 Odontoma, 300 CEdema ex vacuo, 123 malignant, 461 varieties of, 121 CEstrus, 582 Oidiomycosis, 30, 519 Oidium albicans, 518 Omphalocele, 405 Opsonic index, 80 Opsonins, 80 Organs, supernumerary, 411 Ossifying myositis, 302 Osteoarthropathy, pulmonary, 209 Osteoma, 300 Osteomyelitis, chronic haemorrhagic (Barrie),328 Osteophyte, 300 Osteosarcoma, 338 Over-work, results of, 5 Oxygen, effects of deprivation or dimi- nution in supply of, 3 Oxyuris vermicularis, 565 Facet's disease, 538 Pandemic influenza, 464 Papillary cystoma, 343 Papillary epithelioma, 342 Parakeratoses, 163 Paralysis, pseudohypertrophic muscular, 149 Paramaecium coli, 546 Parasites, 31, 32 animal, 525 as possible cause of cancer, 354, 357 ectogenous, 31 endogenous, 31 Parasitic arthropoda, 32 Parasitic diseases, 22, 31, 32 Parasitic protozoa, 31, 32 Parasitic worms, 31 Paratyphoid fever, 4S8 Parenchymatous degeneration, 144 Parenchymatous inflammation, 250 Parietal thrombi, 113 Passive atrophy, 143 Pearl disease, 487 Pediculi, 580 Pellagra, 15, 30 Pentastoma denticulatum, 578 Perithelioma, 333 Perniones, 6 Perobrachius, 409 Perodactylism, 410 Peromelus, 409 Petrifaction, 174 " Petrified diild," 395 Phagocytosis. 74, 11, 78 Phimosis, 407 Phleboi:ths, 115 Phlegmon, 258, 438 gas, 259, 462 Phloridzin diabetes, 60 Phocomelus, 409 Pigment, absence of, 200 Pigments, pathological, 185 autochthonous, 185 exogenous, 198 in chronic arsenic poisoning, 194 in malaria, 194 Pin-worms, 565 Pirquet's reaction, 477 Pithead, 560 Pityriasis versicolor, 521 Placental transmission, 44 Plague, bubonic, 466 Plasmodium malarias, 539 Platyhelminthes, 547 Plethora, 100 Pneumococcus, 440 Pneumotoxin, 443 Poisons, poisoning action on heart, 21 action on nervous system, 21 animal, IS arsenic, pigmentation by, 194 bacterial, 15 blood-poisons, 18 caustics, 17 classification of, 15 definition of. 14 enterogenous, 46 ergotism, 18 gaseous, 17 histogenous, 46 an infection, 23, 28 meat-poisoning, 450, 459 method of action, 16 mineral. 15 poisonous eels, 16 poisonous fish, 15 poisonous mussels, 16 ptomaines, 23 snake-venom, 16, 18 vegetable, 15 Polyblasts, 267 Polycystic kidneys, 352 Precipitin reaction, 94 Precipitins, 93 Predisposition to disease, 33 racial differences in, 36 relationship of sexes, 36 Pressure-atrophy, 144 Primary thrombi, 113 Proliferation of cells, causes of, 213 Prosoposchisis, 403 Proteins, bacterial, 24, 29 Protozoa parasitic, 31, 32 pathogenic, 525 Psammoma, 339 Pseudohermaphrodismus, 413 Pseudohypertrophic muscular paralysis, 149 Pseudoleukemia, ?i21 Pseudotuberci'Iosis, 489 cladothrichica, 510 592 GENERAL, INDEX. Psorospermosis, 538 Psychoneurosis, 13 Ptomaines, 23 Pulex irritans, 580 Pulse, disturbances of, 99 Puriform thrombi, 115 Purulent infiltration, 258 Purulent inflammation, 257 Putrid gangrene, 137 Pyaemia, 26, 27 Pygopagus, 418 Rachipagus, 420 Rachischisis, 396 Radioactivity, 9 Rag-sorters' disease, 454 Ray-fungus, 505 Rays Becquerel, effects of, 9 effect of ultra-violet on bacteria, 7 effect on viriola-lesions, 7 Roentgen, effects of, 8 therapeutic use of ultra-violet, 7 ultra-violet, 7 violet, 7 Recurrence of carcinoma, 379 Red thrombi, 110 Regeneration of tissues, 209 in inflammation, 263 of blood, 226 of blood-vessels, 220 of bone and cartilage, 225 of connective-tissue, 222 of elastic fibres, 224 of epithelium, 218 of eye, 233 of heart-muscle, 229 of muscle, 227, 229 of nerve elements, 229 Regenerative capacity of tissues, 212 Relapsing fever, 514, 528 Repair, 262 Rhabdomyoma, 315 Rhinoscleroma, 503 Rhizopoda, 525 Rider's bone, 302 " Ringworm," 522 Rodent ulcer, 356 Round worms, 562 Sago spleen, 164 Saprophytic bacilli, 450 Saprophytic moulds, 516 Sarcocarcinoma, 321 Sarcoma, 321 adenosarcoma, 372 chondrosarcoma, 299 definition of, 321 fibrosarcoma, 321 giant-cell, 325 hsemangiosarcoma, 333 hyaline formations in, 340 intercellular substance in, 321 large round-cell, 324 lymphangiosarcoma, 329 lymphosarcoma, 323, 325 medullary, 321 Sarcoma, melanosarcoma, 335 myosarcoma, 314 myxosarcoma, 294 osteosarcoma, 338 small round-cell, 322 spindle-cell, 324 Sarcoptes hominis, 577 Sarcosporidia, 537 Scarlet-fever bodies, 539 Scirrhous carcinoma, 368 Schistoprosopia, 403 Schizomycetes, 423 infection by, 428 Sclerosis, 172 Scrofula, 486 Segmentation, direct and indirect, 214 Senile atrophy, 143 Senile gangrene, 138 Sepsis, 26 Septicjemia, 26 Septicopyasmia, 26, 27 Sera bactericidal, 95 healing, 86 protective, 86 Serofibrinous inflammation, 252 Seropurulent inflammation, 258 Shock erethistic, 13 torpid, 13 Simple atrophy, 143 Situs inversus viscerum, 410 Skin, cancer of, 358 Sleeping-sickness, 532 Snake-venom, 16, 18 Solitary tubercles, 479 Sphacelus, 137 Spina bifida, 397 Spirillae, 511 Spirillum of Asiatic cholera, 511 of Finkler and Prior, 514 of Metschnikoff, 514 of relapsing fever, 514 tyrogenum, 514 Spirochaete life-history of, 529 obermeieri, 527 pallida, 490 Splanchnomegaly, 64 Splenomegaly, tropical, 532 Sporozoa, 534 Squamous-cell carcinoma, 364 Staphylococcus pyogenes albus and citreus, 446 pyogenes aureus, 444 Stasis, 118 Status lymphaticus, 67 Sternum, congenital fissure of, 405 " Stone child," 395 Streptococci, pathogenic, 434 poisons produced by, 439 varieties of, 439 Streptococcus infection, 434 Streptococcus lanceolatus. 440 pyogenes, 434 GENERAL INDEX. 593 Streptothrix, 449 Strongylides, 567 Sucking-worms, 547 Suffocation, 3 Sun&troke, 6 Superficial inflammation, 250 Supernumerary organs, 411 bones and muscles, 412 breasts, 412 fingers, 411 Suprarenal capsules, 65 Surra, 532 Sympus, 409 Syncephalus, 419 'Syncope, 13 Syndrome Dercum's, 296 Frolich's, 296 Synophthalmus, 401 Syphilides, 492 Syphilis, 490 chancre in, 491 gummata in, 493 hereditary, 495 initial sclerosis of, 491 of nervous system, 495 spirochaeta pallida in, 490 syphilides in, 492 ulcers in, 494 visceral, 493 Syphilomata, 493 Tactile irritability, 77 Tsenia, 552 Africana, 556 cucumerina, 556 diminuta, 556 eohinococcus, 556 in domestic animals, 556 mediocanellata, 555 nana, 556 saginata, SSS solium, 552 Tape-worms, 551 Tattooing, 48, 198 Temperatures, effects of, 5 Tendinous spots, 273 Teratoid cys.ts, 380, 388 Teratoid tumors, 283, 380 Teratoma, 380, 384, 388 bigerminal. 420 Testicle, teratoma of, 386 Tetanus, 460 Thoracogastroschisis, 405 Thoracopagus, 420 Thoracoschisis, 405 Thread-fungi, 521 Thread-worms, 565 Thrombi, 110 calcification of, 115 formation of. 111 organization of, 115 puriform, 115 softening ol, 115 varieties of, 110, 113 Thrombosis, 108 disturbances of circulation in, 112 Thrombosis, of heart, 113 Thrush, 517 Thyroid gland hypersecretion of, 63 in acromegaly, 64 in cretinism, 62 in Graves' disease, 63 in idiopathic cardiopathy, 63 in myxoedema, 62 secretion of, 62 Thyroiodine, 62 Toxalbumins. 23, 28 Toxinasmia, 26 Toxins, 23, 28 Toxons, 29 Toxophore group, 29 Transplantation of tissues, 234 Trematodes, 547 Trichina spiralis, 571 embryos in blood, 573 Trichomonas, 527 Trichomycetes, 509 Trichophyton tonsurans, 522 Trichuris, 571 Tricocophalus dispar, 571 " Tropical sore," 533 Tropical splenomegaly, 532 True hermaphrodism, 413 Trypanosoma, 530 life-history of, 532 Trypanosomiasis, 532 Tsetse-fly disease, 531 Tubercle bacillus, 468 Tubercles, development of, 470 Tuberculin, 88, 475 Tuberculosis, 468 as a local disease, 477 avian, 487 bacillus of, 468 bovine, 487 Calmette's reaction in, 477 caseation in, 473 catarrhal inflammations in, 487 cryptogenic infection in, 477 formation of tubercles in, 470 fungous granulations in, 478 giant-cells in, 471 granulation-tissue in, 478 hsematogenous, 482 in cold-blooded animals, 489 infection through intestine, 486 infectious nature of, 474 intestinal, 469 lymphogenous, 481 method of infection, 469 of animals. 487 Pirquet's reaction in, 477 pseudo, 489 secondary infections in, 484 solitary tubercles in, 278 termination of, 479 transmission of, 470, 483 transmission to foetus, 484 Tumors, 281 adenocarcinoma, 366 adenocystoma, 349, 352 adenoma, 344 594 GENERAL INDEX. Tumors, adenosarcoma, 372 angioma, 303 benign, 291 cachexia in, 291 carcinoma, 352 causes of, 285 cholesteatoma, 344, 381 chondroma, 297 chordoma, 300 ■chorioepithelioma, 363, 370, 379 chorion-carcinoma, 370, 379 cure of, 290 cystadenoraa, 349 cystocarcinom.a, 352, 374 cystoma, 343 desmoid, 292 enchondroma, 297 endothelioma, 329, 334 epithelial, 283, 341 epithelioma, 342, 364 fibroma, 291, 319, 348 glioma, 316 grouping of, 212 growth of, 287 hasmangioma, 303, 305, 308 hsemangiosarcoma, 333 histoid, 282 hyaline changes in, 340 keloid, 293 lipoma, 295 lymplhangioma, 303 lymphangiosarcoma, 329 lymphosarcoma, 323, 325 Martland's, of bone marrow, 328 melanoma, benign, 310 melanosarcoma, 335 metastasis of, 288 myeloma, multiple, 327 myomia, 312 myxoma, 294 neuroblastoma, 318 neurofibroma, 319 neuroglioma ganglionaire, 316 neuroma, amputation, 318 ■odontoma, 300 of connective-tissue origin, 291 osteoma, 300 osteosarcoma, 338 pearl, 344 perithelioma, 333 psammoma, 339 retrogressive changes in, 290 rhabdomyoma, 315 sarcoc'arcinoma, 372 sarcoma, 321 teratoid, 283, 380 teratoma, 380, 384, 388, 420 theories of, 286 usefulness of, 284 Wilms', 372, 385 Twin monsters, varieties of, 416, 418 Typhoid carriers, 457 Typhoid fever Typhoid fever, bacillus of, 456 Widal reaction in, 458 Typhus fever, parasites in, 539 Ulcers, 258 chronic, 279 rodent, 356 syphilitic, 494 tropical, 533 Umbilical hernia, 405 Uncinarja. 567 UrKmia, 57 Urethra, malformation of, 407 Uric acid infarct, 182 Urinary-bladder congenital fissure of, 406 ectopia, 405 Urinary calculi, 182 Uterus, muscle tumors of, 313 Vaccines, 89 Valvular polypi, 114 Valvular thrombi, 113 Variola and vaccinia, 539 Vascular resistance, increase in, 101 Venous pulsation, 99 Vermes, 547 Vibrio choleras, 511 of Metscbnikoff, 514 Vibrion septique, 461 Viscera, transnosition of, 410 Visceral syphilis, 493 Vitiligo, 200 Weight of internal organs, average, 206 Welch's bacilltis, 462 Whipworm, 571 Whooping-cough, bacillus in, 464 Widal's reaction, 83 Wilms' embryoma, 372, 385 "Wolf's jaw," 403 Wood-jack, wood-tick, 578 Worms, parasitic, 31, 547 awl-tail, 565 blood-sucking, 31, 547 flat, 547 hook, 568 pin, S65_ production of anseniia by, 32 round, 562 ta)pe, 551 thread, 565 whip, 571 Wounds, healing of, 269 Xanthochromia, 194 Yeasts, 515 Zenker's degeneration, 163 Zymase, 28