pos g o 5 ae : on ee eo Seo SS ae ras ee ee SS ee eee Ki hu Z be en CORNELL UNIVERSITY THE Flower Heterinary Library FOUNDED BY ~ ROSWELL P. FLOWER for the use of the N. Y. STATE VETERINARY COLLEGE 1897 This Volume is the Gift of Dr. S. H. Burnett. 356 CORNELL UNIVERSITY LIBRARY iii GENERAL PATHOLOGY OR THE SCIENCE OF THE CAUSES, NATURE AND COURSE OF THE PATHOLOGICAL DISTURBANCES WHICH OCCUR IN THE LIVING SUBJECT BY DR. ERNST ZIEGLER PROFESSOR OF PATHOLOGICAL ANATOMY AND OF GENERAL PATHOLOGY AT THE UNIVERSITY OF FREIBURG IN BREISGAU TRANSLATED FROM THE NINTH REVISED GERMAN EDITION BY DRS. THEODORE DUNHAM, EDWARD M. FOOTE, PHILIP H. HISS, JR., WALTER B. JAMES, WILLIAM G. LE BOUTILLIER, AND MATTHIAS NICOLL, JR., OF NEW YORK, DR. B. MEADE BOLTON, OF PHILADELPHIA, PA., AND DRS. LEONARD WOOLSEY BACON, JR., JOHN S. ELY, AND R. A. MCDONNELL, OF NEW HAVEN, CONN. Eprror, DR. ALBERT H. BUCK, New York NEW YORK WILLIAM WOOD AND COMPANY MDCCCXCIX Me, 1278 CopyRigHtT, 1899, By WILLIAM WOOD AND COMPANY. Ae ti 266 (e344 AUTHOR'S PREFACE TO THE EIGHTH EDITION. In making my preparations for the publication of an eighth edition of my “ Treatise on Pathological Anatomy,” I hesitated for a long time in regard to what method of revision I should adopt. During recent years a number of manuals of pathological anatomy have been pub- lished, and the authors of these seem to have laid stress ‘upon the point that a text-book intended for the use of medical men should deal with the subject-matter in the most concise manner possible; they believed, evidently, that compendious treatises of this nature would tend to pro- mote the study of pathological anatomy, and would at. the same time render the student’s task easier. I carefully examined a number of compends of pathological anatomy which had been written from this point of view, but they failed to convince me that this was the most use- ful manner of treating the subject. In the first place, it is not possible, within the limits of a small compend, to treat general pathology and - pathological anatomy in a scientific manner. Then, in the next place, it is extremely difficult, owing to the richness of the material at our dis- posal, to avoid treating the subject in such a manner that the book, when completed, shall not present the characteristics of a mere catalogue of facts, which would scarcely convey to the reader’s mind a clear concep- tion of the processes that take place in the living body when it or any of ite organs are diseased, and which, furthermore, would compel the be- ginner merely to commit to memory those things which, by the aid of his reasoning power, he should make a permanent and useful part of his medical knowledge. It is possible that if a compend were gotten up in the form of a cate- chism, it might prove helpful to a certain number of students in acquir- ing a knowledge of the principles of general pathology and pathological anatomy. Nevertheless I am disposed to believe that the number of those who would derive satisfaction from such a catechism must indeed besmall. General pathology and pathological anatomy should constitute the foundations of that knowledge which is to enable the practitioner of medicine to interpret correctly the symptoms of disease as they present themselves before him at the patient’s bedside. It must be conceded, I think, that simply a knowledge of the definitions given to the technical terms commonly employed in describing different pathological processes that take place in the living body, or merely a superficial insight into the pathological processes which affect individual organs and tissues, can scarcely suffice to furnish the practitioner with the fundamental knowledge which he requires for the satisfactory study of clinical medi- cine. He might be able, it is true, when called to treat a patient who presented certain well-defined symptoms of disease—as, for example, those belonging to an inflammation of an important organ—to form an approximate idea of the nature of this disease, and at the same time he A iv AUTHOR'S PREFACE TO THE EIGHTH EDITION. would also probably take satisfaction in the thought that he had already been instructed in regard to the occurrence of this very malady in this particular organ. But he certainly would not be able to form a clear conception of the essential nature of the entire process, or to analyze’ all the littlo pathological features which are dependent upon the peculiar construction of the organ affected; in a word, he would not be able to interpret, in its full breadth and depth, the significance of the disease under observation. In his endeavors to understand each new type of disease he would, by reason of his lack of a proper training in the fundamental principles of medicine, find his pathway constantly strewed with difficulties, and he would be forced in a slow and plodding fashion to commit to memory the sequence of symptoms as they occur in any given disease. Then, besides, he would fail to grasp the connection be- tween the latter and other correlated symptoms. On the other hand, if he had previously received proper instruction in the fundamental knowl- edge reyuired, he would at once be able to understand correctly the na- ture of the malady which he has been called to treat. Bearing all these things in mind, J felt as if it were perfectly clear what my aim ought to be in preparing this new edition of my “Treatise on Pathological Anatomy.” In the first place, it seemed to me that I should strive to perfect the knowledge of the mode of origin, nature, and significance of diseases as they occur in the living body, and conse- quently that I should make such improvements and alterations in the text as would carry out this idea. As a matter of course, in making this revision I did not forget for a moment that descriptions of histo- logical and pathologico-anatomical alterations must continue to form the: foundation-work of the book. Knowing, also, from experience how greatly good illustrations aid the reader in understanding the nature of these alterations, it seemed to me that I ought to provide a certain number of additional cuts, carefully prepared. At the same time I folt as if more space than was given to these matters in the preceding edi- tions should be allotted to the consideration of pathological processes— their causes, their mode of origin, the course which they pursue, and their sequele. In performing the task which I had thus set before me I found that extensive alterations were necessary, especially in that part of the work which treats of general pathology. On the one hand I found it neces- sary either greatly to alter or actually to rewrite certain chapters, while on the other I was obliged even to introduce entirely new chapters. In remodelling this general portion of the work special consideration has been given to the subjects of general etiology of diseases and pathologi- cal physiology, and in harmony with these alterations it has seemed to me advisable to change also the title of this general part. Accordingly I have abandoned the former title, “General Pathological Anatomy,” and have substituted for it that of “General Pathology.” The present work, it is true, does not cover the entire field of general pathology, but nevertheless it does treat of all those portions of the subject which are ordinarily taught, at least in the German universities, by the chairs of pathological anatomy and general pathology. The section which deals with the causes, modo of origin, and course of diseases has, with the exception of a few pages, been entirely rewritten and greatly amplified; and I have gone more thoroughly in the present edition than I did in the earlier ones into the subject of the origin of diseases from poisoning and from infection, hoping thereby to provide AUTHOR’S PREFACE TO THE EIGHTH EDITION. v the beginner with a thoroughly clear and simple description of the pathological changes which take place in these diseases. Furthermore, I have given full consideration to the subject of the dissemination of pathological foci throughout the body by means of the processes known as metastasis and embolism, by means of poisoning, or by means of the - extinction of certain glandular functions; and at the same time I have explained the relations of these foci to pathologically altered functions. Among the diseases which owe their origin to the extinction or modifi- cation of certain glandular functions I have given careful consideration to diabetes mellitus, to the cachexia which results from a withdrawal of the influence exerted by the thyroid gland upon the economy, to myxce- dema, to cretinism, and to Addison’s disease. I have introduced special chapters on the protective mechanisms and forces, and on the healing powers of the human body; on certain in- herited and acquired weaknesses or predispositions; on idiosyncrasy and immunity; and on the acquisition of immunity through the fact of one’s having already experienced an attack of the disease, or through inoculation; and it is my hope that these chapters will not only supply the practical needs of the medical practitioner, but will also serve to in- crease the existing stock of knowledge in regard to the origin, course, and essential nature of diseases, and particularly of those which are due to infection and poisoning. The chapter on the causes of internal diseases and on the inheritance of certain pathological conditions will, I think, be found to supply not only a clearer bird’s-eye view of the subject, but also at the same time more complete information than did the same chapter in the earlier _ editions. The section relating to disturbances of the circulation remains un- changed in its general features, but it has in many respects been made more complete than it formerly was; and, besides, it has been furnished with new illustrations. In the section relating to retrograde disturbances of nutrition and infiltrations of the tissues, the chapter devoted to hypoplasia, agenesia, , and atrophy and that relating to pigment-formation are the ones which have been remodelled to the greatest extent. In the section devoted to hypertrophy and regeneration I have introduced all the alterations and additions which the investigations of recent years in regard to these processes rendered necessary. The section on inflammation has been entirely rewritten, and the definition which I now give of this process is the same as that which I suggested two years ago and published in pamphlet form. I am well aware that my views in regard to the nature of inflammation will not be generally accepted, and yet I cannot help hoping that, in giving this new explanation of pathological changes which have received such varied interpretation at the hands of different authorities, I may have succeeded in furnishing satisfactory proof that, on the basis of the views here set forth, all the different processes which play a part in inflammation may be arranged in comprehensive groups; and, furthermore, that the sepa- ration of the reparative processes of proliferation from those which be- long more strictly to inflammation—which latter are characterized by a degeneration of the tissues, coupled with an exudation of pathological fluid products—is in harmony with the practical needs of the physician as well as with the unprejudiced requirements of science. In describing the healing processes which take place in the course of an inflammation, vi AUTHOR'S PREFACE TO THE EIGHTH EDITION. the formation of granulations, the resorption of necrosed tissues and exudations, and the substitution in their place first of granulation tis- sue and then of cicatricial tissue, I have striven by the aid of numerous pictorial illustrations to make it easier for the student to understand these important processes, and at the same time I have endeavored to manage my descriptive text in such away that it should throw light upon those diseases which are most commonly encountered in actual medical practice. The sections which relate to tumors and malformations remain funda- mentally the same as they were in the previous edition, and yet in both of these sections I have rewritten the portions which refer to the general aspects of these subjects, and at the same time I have altered, improved, and amplified many of the remaining paragraphs in these sections; this statement being particularly true of the paragraphs relating to cysto- mata, teratomata, and transposition of tissues. In the section devoted to parasites I have given due weight to the results of recent investigations, at least so far as they seemed to me to be thoroughly established. I have treated the infectious granulation tumors as heretofore in the section devoted to parasitic diseases, for it would scarcely be possible to acquire a complete understanding of their nature and significance unless full account were taken of the relationship which exists between their peculiarities and the special nature of the ex- citing cause. As a result of all these alterations and additions this general part of my text-book has increased in bulk; but, as I have already said, I be- lieve that, owing to the wealth of material which must be treated in a text-book of general pathology, it would scarcely be possible to handle. the subject more concisely unless important matters should be entirely omitted, and unless the idea of explaining fully the phenomena of dis- ease in the living subject should be abandoned. , But, after all, the extent of the text which the beginner must actually study is less than one might at first suppose it to be, for the illustrations, which have been increased in number by the addition of seventy-two, and the text printed in small type occupy a good deal of space in the volume. E. ZIEGLER. FREIBURG IM Breiseau, November, 1894. AUTHOR’S PREFACE TO THE NINTH EDITION. In the preparation of this new edition I have endeavored to take fully into account—so far, at least, as it is possible to do this within the com- pass of a text-book like the present one—the advances which have been made in general pathology and pathological anatomy during the last few years. At the same time I have been careful not materially to in- crease the bulk of the book. In order to accomplish these objects I have subjected all the chapters to a most careful revision, and wherever it seemed necessary, on account of some new light furnished by recent investigations, I have rewritten the text. The number of the illustrations has been increased from four hun- dred and fifty-eight to five hundred and forty-four, in the hope that thereby the text may be rendered easier to understand. The most radi- cal alterations will be found in Chapters IV. and VII., which have been entirely rewritten. I have arranged the different kinds of degenerations which lead to the formation of hyaline products in four groups (mucous degeneration not being included in this number): (1) The formation of colloid by epithelium and the epithelial hyaline concretions; (2) the pathological cornification of epithelium; (3) the amyloid degeneration of connective tissue and the amyloid concretions; (4) the hyaline degenera- tion of connective tissue and the hyaline products of connective-tissue cells. I believe that by means of this classification it will be possible to obtain a very good general idea of the different processes under con- sideration. In addition to the part which relates to the pathological formation of pigment I have written something in relation to the patho- logical absence of pigment. I have divided the tumors into three large groups: tumors of the connective substances, epithelial tumors, and teratoid tumors and cysts; and I have subdivided the epithelial tumors into two lesser groups, in one of which the papillary epitheliomata, the adenomata, and the cyst- adenomata are to be placed, while in the other belong the carcinomata and the cystocarcinomata. My views in regard to the nature and origin of tumors are essentially the same now as they were when I wrote the last edition of this work; and I can find nothing in the criticisms of Lubarsch, Hansemann, and others which would lead me to alter them in any respect. Many new illustrations have been introduced in the chapter on this subject, and at the same time the descriptive text has been made to cover the ground more thoroughly than before. In these two ways, therefore, I believe that I have succeeded in presenting my views on tumors in a sufficiently clear manner. Ribbert’s view, that the separation of individual cells, or groups of cells, from their physiological relationships constitutes the main cause of the development of a tumor, does not, as I have already often enough stated, commend itself to my judgment, I scarcely need to add that I am just as little able as are vill AUTHOR’S PREFACE TO THE NINTH EDITION. others to state what is the original cause of the atypical growth of the tumor cells. The term “tumor,” as is well known, comprises tissue- new growths which, so far as their origin is concerned, differ widely the one from the other; and equally numerous and various are the causes of this growth in the individual cases. In fact, more than one cause is competent to excite growth even in the malignant tumors which spread by a sort of infiltrative process. Then, again, the view that parasites cause the exuberant growth of the malignant tumors lacks as yet a solid foundation; and accordingly I have considered it wise to bring out this point in my definition of tumors. Finally, the disposition which still exists in certain quarters to classify the infectious granulation-growths among the tumors as infectious tumors, appears to me only to confuse the subject. This disposition, it must be remembered, first showed it- self at a time when nothing was known in regard to the causes of these infectious granulation-growths. The definition of inflammation which I gave in the last edition has been approved by some authorities and combated by others. The arguments brought forward by the latter do not appear to me to be valid, and accordingly I have not felt that I was called upon to modify my views. Indeed, a further study of the processes which take place in inflamma- tion has rather strengthened me in the determination to maintain my former position; and I trust that the present revised version of this chapter on inflammation will also furnish satisfactory proof that the definition which I have given serves as an excellent standpoint from which one may view the different processes that form an essential part of inflammation. It was a source of great pleasure and satisfaction to me that, after the publication of the last edition, some of my highly esteemed colleagues notified me of their approval of this definition. In my presentation of the doctrine of infection and of the efforts of the organism to antagonize the effects of such infection, I have been careful to consult the most recent publications on the subject, and I trust that no fact of importance has escaped my attention. In the chap- ter relating to bacteria I have retained the commonly accepted classifica- tion, and have introduced among them, as before—undeér the name of polymorphous bacilli, in the group of bacilli—those bacteria which, ac- cording to recent investigations, assume different forms as they advance in their development. To separate them from the group of bacilli would lead to a separation of pathological processes which stand closely related one to another, and consequently such a step would only render it more difficult to comprehend these processes. ' Ernst ZIEGLER. Freipure im Breiscau, November, 1897. 1 As already explained in an editorial note in the eighth edition, it has been de- cided to omit the bibliographical lists which are scattered throughout the original work. Their publication would require fully two hundred additional pages, and their value, to ae ee pe of English-speaking medical students, would be comparatively small. —Editor’s Note. LIST OF TRANSLATORS. CHAPTERS I. and II. * * * * * * * * CHAPTER III. Translated by Dr. Leonarp WoorsEy Bacon, JR. CHAPTER IV. Translated by Dr. Jonn S. Evy and Dr. Marrutias NIcout, JR. CHAPTER V. Trarislated by Dr. WaLrer B. James and Dr. Leonard WooLsey Bacon, JR. CHAPTER VI. Translated by Dr. WiLi1am G. Le BouriLurer. CHAPTER VII. Translated by Dr. E. M. Foore. CHAPTER VIII. Translated by Dr. THEODORE Dunnam. CHAPTERS IX. and X. Translated by Dr. B. Meave Botton and Dr. Puitipe H. Hiss, Jr. CHAPTER XI. Translated by Dr. R. A. McDonnett. CONTENTS. PREPACH iii oo Guaraitens ce oar sasha vale Satay meat eens pase W iets ieteho des arene bea oie iii CHAPTER I. IntropucTion.—HEALTH AND DIsEASE.—PROBLEMS OF GENERAL PATHOLOGY AND PATHOLOGICAL ANATOMY. ccn es pear pacedads oteeil Mebduenn ee bea yD acess 1 CHAPTER II. Cause, OrIGIN, AND CouRSE oF DISEASES. I. Origin of Diseases through External Pathological Influences................ 8 1. Origin of Diseases through Deficiency of Food and of Oxygen; by Fatigue; by Heat and Cold; by Changes of the Atmospheric Pressure ; ; by Electrical and by Mechanical Influences ...... . Sak GN dea aba 8 2. Origin of Diseases through Intoxication ......... 0 .. cee cece eee ee eee 18 3. Origin of Diseases through Infection or Parasitism. _“Miasms and Con- tagions.—Vegetable and Animal Parasites.................-.000000- 28 II. Metastasis and Embolism, and their Importance in the Etiology of Lymphog- enous and Heematogenous AVISCASESii nie SRG ye heehee ee RA Bao wee Nees he 40 III. Secondary Local and General Diseases.— Diseases Caused by the Cessation of the Functional Activity of Certain Glands..... Snare tea SNe reah aha tes ag 48 IVs Feversand: 1 ts: Stanificaneesiojssa.0 .acacca maaan oo. wa ditaaad eas aged 62 V. The Natural Protective Mechanisms, Protective Forces, and Healing Powers of the Human Organism, and their Action... 2.2.20... ce ec eee eee eee 67 VI. Congenital and Acquired Predisposition.—Idiosyncrasy and Immunity.—The Acquiring of Immunity.—Immunizing Inoculations. .................... 77 VII. The Internal Causes of Disease and the Inheritance of Pathological Condi- TIONS 2 eatin ace au) Gade Lily Se aL Lae WA Sidi! ha oG Gam naeRele Bee hecagan ... 89 CHAPTER III. DIsTURBANCES IN THE CIRCULATION OF THE BLOOD AND OF THE LYMPH. I. General Circulatory Disturbances Dependent upon Changes in the Function of the Heart, Changes in the General Vascular Resistance, and Changes in the Mass Of the Bloods... «..icccesasvyseete waceueesvcsesvovuacnse: II. Local Hyperzemia and Local AAW icGill a ance by new cmesaahnaent dexutehaneeendt III. Coagulation, Thrombosis, and Stasis ............ amas oe IV. Gidema and Dropsy. 2.0.0... ce cece ccc eee eee ee eeeee V. Hemorrhage and the Formation of Infarcts CHAPTER IV. RETROGRADE DISTURBANCES OF NUTRITION AND INFILTRATIONS OF THE TISSUES. I. On Retrograde Disturbances of Nutrition and Infiltrations of the Tissues in General en ss heck ceeee eyed stan aws Pek ns cas aden nes ta@ee BNE OSES 139 Ti, “Death... oss044 seainie sc asaandebeneae yee ak ae ee re Hacveneste se ARG 140 TEES INCGROSIS(g ie'24 4 ard ayy sceneas 4 Fp hy Se autvaudcene sala maser ok ayttade Godse’ De wae Sater etee ad 142 IV. Hypoplasia, Agenesia, and Atrophy............ autihtae Sik ocr erasers siawgiteins suis LOR xii CONTENTS. PAGE V. Cloudy Swelling and Hydropic Degeneration of Cells............. Wapnee .-- 161 VI. Lipomatosis, Atrophy of Adipose Tissue, and Fatty Degeneration of the Tissues 163 VII. The Formation and Deposit of Glycogen in the Tissues .............. seeee- 170 VAITT.. Mucous DE SET Era ti OM io. cisco od cect aii veede-e oie Susie ware gS oe iG is Uiteone oa ehearote asia asa 171 IX. The Formation of Colloid in Epithelium, and Epithelial Hyaline Concretions 174 X. The Pathological Cornification of Epithelium.................. cc eee eeeees 177 XI. Amyloid Degeneration and Amyloid Concretions.............-.0cceceecees 178 XII. Hyaline Degeneration of Connective Tissue and the Hyaline Products of Con- nective-Tissue Cell8,......... ccc cece ete eee eens Weal calalshetaiwhajansccis sesh 185 XIII. Calcification and the Formation of Concretions and Caleuli ................ 189 XIV. The Pathological Formation of Pigment. .......... ccc ceeceeaceeee weeeess 19% XV. The Pathological Absence of Pigment ...........cccecceeecces scaiedeanes, 212 XVI. The Formation of Cysts .......... cece cece cee cneccecceene danw-cceteeewe Ut CHAPTER V. HYPERTROPHY AND REGENERATION OF THE TISSUES AND ORGANS. I. General Considerations Concerning the Processes called Hypertrophy, Re- generation, and Heteroplasia, and the Cellular Changes that Accompany Them.—Transplantation of Tissues .......... 0... cece ees cece ee cceeenees 217 II. The Processes of Hyperplasia and Regeneration in the Various Tissues...... 236 III. Metaplasia of the Tissues 0.20.0... cc. ccc cee ec ee ccc eecccevccecsccevece 253 CHAPTER VI. INFLAMMATION AND THE AssocIATED Processes OF REPAIR, I, Acute Inflammation and its Various Forms................cccccececcccece 256 Granulation and Cicatricial Tissues.—Absorption of Exudates and Tissue- necroses, and Substitution of Connective Tissue for Them................ 277 I. Phagocytosis Occurring in the Course of Inflammations, and the Formation of Giant Cells.—Chemotaxis.............. cc ccuccuccceccencceeceeces .. 289 IV. Chronic Inflammations.........0... 0... cc ccc ec eee eeceee eslsieieie eeecccecees 293 CHAPTER VII. Tumors. I. General Considerations 0.0.00... 0c. c cece cece ce ccccuvececeses escesee 298 IL The Different Varieties of Tumors. 1, Connective-tissue Tumors. (2) ENDEOM A). cassie oiesries arois ae peargaueee en's Ualahnewd eres G4 Sradale eesaotere - 808 (BY MYXOMA, wcicscincetoy deurcad tees wins ¥o% arable meee b «.tiaibade seen a 310 (0) DAPOM A cine (hs aces siele vie be on & aew ea hee Vd anmaw He vis waleeuiien a x ove - 312 (2) Chonidroma) excuses 262 csyrctineeied cbias vases yivag gaaieres es edness 313 (e) OStCOME 5 a yuan Metta Scars. atch aaean oA SE RON awe ya NadroRAe oosean 316 (J) Hemangioma and Lymphangioma............................ . 320 (GY MY OU o e's Sisienoinls att apne & vctamired Ay oa lag Eee Syd Lapidot eer ie 329 (4) Glioma and Ganglionic Neuroglioma..................00.0..., - 332 (é) Neuroma and Neurofibroma..................0cc cece eee e ee 335 (ie) Sarcoma... sieves 8s44 Me te av ened waauew eer dei oem e cock 8387 2, The Epithelial Tomors. 2 tts (a) General Remarks. ........00 0.0... e cece ccc cececcceeeceucce 352 (0) Papillary Epitheliomata, Adenomata, and Cystadenomata... seaas BBS (c) Carcinomata and Cystocarcinomata .......2...........0.0....... 367 8. Teratoid Tumors and Cysts CHAPTER VIII. DisTURBANCES OF DEVELOPMENT AND THE RESULTING Ma .rormations. I. General Considerations in Regard to Disturbances of Development and the Origin of Malformations. ...................ccecesceeesecaeeees cece 897 CONTENTS. X1li AGE II. Special Malformations in Man. 1. Arrests of Development in a Single Individual. (a) Arrest in the Development of all the Embryonic Elements....... 404 (0) Deficient Closure of the Cerebrospinal Canal and the Accompany- ing Malformations of the Nervous System .................0.. 406 (c) Malformations of the Face and Neck ............ 0. 0c cece cece 414 (d) Faulty Closure of the Abdominal and Thoracic Cavities, and the Accompanying Malformations. ................0 cc cece neces 417 (e) Malformations of the External Genitalia and of Parts Belonging to the Anal Region, Caused by Arrested Development.......... 419 (f) Malformations of the Extremities due to Arrest of Development.. 421 2, Abnormal Positions of the Internal Organs and of the Extremities.... 424 8. Malpositions the Result of Excessive Growth or Multiplication of Or- gans or Parts of the Body........ cece eee cee ee eee eee eee tenes 425 4. True and False Hermaphrodism ...............000005 ieee dodanie Bate 428 5. Double Monsters. (a) Classification of Double Monsters............. 0.0 cece e eee eens 432 (0) The Chief Forms of Double Monsters.............-... Renesas oe 433 CHAPTER IX. FissIoN-FUNGI WHICH Exist aS PaRASITES AND THE DisEasEs CaUsED BY THEM. I. General Considerations in Regard to the Schizomycetes or Fission-fungi. 1. General Morphology and Biology of the Fission-fungi................. 439 2. General Considerations Concerning the Pathogenic Fission-fungi and their Behavior in the Human Organism. ........0. 0.0.0... e eee eee eee 447 8. General Considerations in Regard to the Examination of Fission-fungi. 450 Il. The Different Forms of Fission-fungi and the Infectious Diseases Caused by Them. 1. The Cocci, or the Spheerobacteria, and the Morbid Processes Caused by Them. (a) General Remarks upon the Cocci........ 6... cece eee eee eee 453 (0), PathOgeniG! C06) sciessicdcc cae Beane ae heed ae Wee agers ee au ews 455 2. The Bacilli and the Polymorphous Bacteria, and the Morbid Processes Caused by Them. (a) General Remarks upon Bacilli and upon Polymorphous Bacteria. . 467 (b) Pathogenic Bacilli and Polymorphous Bacteria.............0.... 470 8. The Spirilla and the Morbid Processes Caused by Them. (a) General Remarks upon the Spirilla..... ....... saeudielase bard Seaseals 524 (0) The Pathogenic Spirilla................ dite ce-Di ora ars hovemeucwees dusveetadaye 525 CHAPTER X. Movtp-Funer AND YEAST-FUNGI, AND THE Diseases CAUSED BY THEM,.........2... 531 CHAPTER XI. Tue ANIMAL PARASITES. I. Arthropoda, 1. ATACHNIGS: «2 spices tet aeeieee tee ered one (densi tear odtinmea sexy B42. 2. Insects...... sustaeigh Seti asthe ae SRS anwar dds sO4igd Siineeaes sees. 545 II. Vermes (Worms). 1. Nematodes (Roundworms) ...........++e008- suainracrotpandtedauaianciaptereaared ays 546 2. Trematodes (Sucking-worms)............... siiecaaeiacesevays suseamei nants seaee. 556 8. Cestodes (Tapeworms).............e eee eee gia iegs oie Si eadawe seeceeeeees 55D TIE. Prot0Z04 ics) 22.5 chee ee 88S RRR O EOS alg aiareichnwlieieeiese'ald s Sakgiarb oleies . 570 SOON OUR OOO LIST OF ILLUSTRATIONS. PAGE . Lightning-figures on the shoulder, breast, and arM.........cccccccccceccecess 15 . Multiple emboli in the branches of the pulmonary artery..........0..e..006- 41 . Fat-embolism of the lungs......... 00... c cece eee eeeen slasine esses cawaresmnn: ae Fat-embolism of the kidney. ........ cc. cece eee e eee tkeRieitesaiwceine AD Thyreoprival cachexia. .... 0... . cc cece ee eee eee Sel one disease asceeeeleegen “OL j« Case Of My xcedeMa oci.. occ senses Sos os Sern seers ss eae oes shwiistesestaarcee. (O08 . Same case, after three months’ treatment SisiirslewaGs te wees Heed clio. ivuatasieles 58 » Afemaleeretini jase ons «a2 4 sedne rh oe ae dd QuERUEEA ee aed TORRENS oe oe eeeInag 59 . Temperature-curve in a continued remittent fever with a slowly i increasing and a very gradually decreasing temperature ....... 0... eee cece ee eee cence 63 . Temperature-curve of a continued fever with rapid increase and rapid decline OE CEM PELAGIC cores chs a cies Sisntasesases tom seis agen antares arate's ares Si gracbligyaveneo Soh w areeay is 64 . Temperature-curve of an intermittent tertian fever............. wilt aie'e ected 64 . Recent hemorrhagic infarct of the lung.............. oe Siormaeln edie d ok 4.5 ..-. 113 . Section through a red thrombus in a muscular vein .......... siesoie'Seiere Garsrmaret 114 . Bundles and star-shaped clusters of fibrin threads or rods..... eaeGewesaeeae 14 . Section of a white thrombus containing but few cells. .........cceceeeeee Sait ALD 6. Section of a mixed thrombus rich in cells......... 0... cece eee aueigcaverarnua a 115 - Quickly flowing blood-stream............. rons a outew Gueanan Ao siden LIT . Somewhat retarded blood-stream......... supsbarelstaateech Phos a shaieliaistit's sielerstarios 117 . Greatly retarded blood-stream........... danse eumelee ee te ase tails de meneueen 117 . Thrombus-formation in the heart..... 2... cece eee ee ee eee saeaass canes L2L . Thrombosis of the femoral and of the saphenous VOiD 5 csasnecs Sse soe Ae yeres 122 . Remains of a thrombus of the right femoral vein ............. Didi iserexara SieSheis 123 . Closure of an artery of the lungs by a mass of conective tissue aie fanaa thea a/oy «se. 124 . Remains of an embolic plug of. a branch of the pulmonary artery............. 124 . Embolus of an intestinal artery with suppurative arteritis...............0005 125 . Stasis from venous hyperemia in the vessels of the corium and of the papille Of thE 10S: vinancn ge cea ee oediRava Gs tes de VaR Ea Nt dose PMR Ew eee Fane 126 Longitudinal section through cedematous muscle-fibres.............0.e0e0 ee 127 . Hemorrhage in the skin near the knee ................ J alevesagneiauinese foe ek Gye 132 . Anzmic infarct of the kidney ............... 2000000 sci Rkeslentiouere ooh aes 135 . Recent hemorrhagic infarct of the lung.......... 0.0... cece eee sctneseieettinn ceo 136 . Necrosis of the epithelium of the uriniferous tubes ......... signet oe Sasi Gree 143 . Croupous membrane from the trachea. .......... 0. cece eee ce cece ee eeeeeeeee 146 . Waxy degeneration of muscular fibres .... 2.0.0... eee cece eer ee ence eee 147 . Coagulation-necrosis in the interior of an enormously swollen mesenteric Lym pPDeP VAN acs Foi dlesais.c. 2%. ae leverages vee" Gane DUN oasa eae ese ep aiideucaraiouenles sare ens elec 147 . Tissue from a focus of tuberculous disease... 2.0.0... 2c eee eee wean S.geeeots 148 . Deposit of fibrin in a tubercle of the lung......... 00.0 eee 148 . Section through the epidermal and papillary portions of a cat’s paw, a short time after it had been burned with fluid sealing-wax...........0eeseeeeeee 149 . Dry gangrene of the toes from arteriosclerosis................008 ecvewesacan LOL . Skeleton of a female dwarf, thirty-one years of age.......... ce cece eee e neces 153 . Skeleton of a female dwarf, fifty-eight years of age ............. sacsiead «seein LOS . Head of Helene Becker (microcephalic)................0.000 08 ss gpewiete Sieg ie 154 . Brain of the same individual ........ 0... cece cece cece ences Mit ewaies seas iny 154 3. Hypoplasia and microgyria of the left cerebral hemisphere ............-..005 154 . Hypoplasia of the uterus ......... 0.0 cence eee eee e eens eeeeeees 155 . Hypoplasia of the small intestine of a new-born child............... eben 155 . Agenesia of the respiratory parenchyma of the left lung...............02-005 - 156 Juvenile muscular atrophy... ...... 0... e eee ee nee tect enees wees aa . 156 . Excentric atrophy of the lower ends of the tibia and fibula............. aieelsure LOE Senile atrophy of the calvarium................ 0c cece cee ee sence eeeees wee. 158 PAGE 50. Section of an atrophied muscle............ ccc cece cece eect cent ease ee eeeaee 158 51. Senile atrophy of the kidney... 0... eee cee eee eee rene eee eeeeee 159 52. Arteriosclerotic atrophy of the Kkidney............. cece eee eee eens a... 159 53. Pressure atrophy of the spinal column ...... 2.0... ccc e eee eee eee 160 54, Racial Remilatroph yn. sig ss ctasereis sesuw vis! aupinnny < Sieisis erapaieiele eis g SEAMEN 6 GO Hole & 160 55. Cloudy swelling of liver cells ........ 0... cece cece rece ent en ences teeneanees 161 56. Cloudy swelling of kidney epithelium .............. 0 cee cece eee tee eens 162 57. Hydropic degeneration of epithelial cells. ..... 0.0... cece cece eee e eee eee 162 58. Hydropically degenerated muscular fibres... 2.6... ck cee eee ee eee nee 163 59. Transverse section of a bundle of muscular fibres in a state of hydropic degen- CVatlON. 2. ca adadagined Boy 52044 { ge Were Fic. 3.—Fat-embolism of the lungs. (Flemming’s mixture; safranin.) a, Arteries plugged by blackened fat; }, fat-drops in capillaries; c, veins; d, cells in the alveoli. Magnified 100 diameters. than the capillaries remain impacted in the bifurcations of the artery (Fig. 2, 6), and generally effect occlusion of the vessel. This usually results from thrombi dislodged from other localities, or from fragments of them. The fat-droplets, on the other hand, generally pass into the capillaries, and some remain there, while others pass through their lumina and become arrested only in some other locality. It is because the fat-droplets occasionally pass into the veins and then into the heart that we find them collected especially in the capillaries of the lungs (Fig. 3, b). They may go, however, still further; passing through the lung, they may reach the capillaries of the major circulation, and thence enter the intertubular and glomerular capillaries of the kidney (Fig. 4, b), and occasionally they are also found to some extent in the capillaries of the brain. Fat-emboli in the capillaries produce noticeable altera- tions in the circulation only when they are present in great numbers; but when this is the case they can produce cedema at various places in the body (Virchow). Furthermore, fat is destroyed in the progress of metabolic changes. When transported by means of the arterial circulation, parenchyma METASTASIS AND EMBOLISM. 45 cells remain fixed in the arterioles or capillaries, the stoppage occurring in the former when the liver-cells enter the circulation en masse. At the point of impaction their presence can produce a collection of blood- plates associated with a hyaline coagulation, this occurrence taking place in the case of emboli formed of liver-cells. The cells themselves do not multiply, but may remain intact for a certain length of time (ac- cording to Lubarsch, three weeks) and then gradually die, when the protoplasm dissolves, and the nuclei swell or shrink and lose their chro- matin. In multinuclear cells the dissolving is followed by a cluster- ing together of the nuclei. The locality where fragments of thrombi, or thrombi which have become detached, are arrested is determined by the size of these masses and by that of the vessel in which they happen to be. Inasmuch as thrombi can be produced in the veins, in the right heart, and in the pulmonary arteries, as well as in the veins of the lung, in the left heart, and in the arteries of the body (see Chapter III.), it is possible for emboli to occur in any of the arteries of the major and minor circulation; and, further- more, emboli frequently remain fixed at the bifurcation of the arter- ies, forming straddling emboli (Fig. 2, c). Through transportation in the reverse direction of the current, emboli may be carried out of the greater veins into the lesser. De- fects in the septa of the heart may produce a paradoxical embolism. Small collections of débris from thrombi, dead red blood-corpuscles or fragments of them, fatty-degene- rated and broken-down endothelial Fic. 4.—Fat-embolism of the kidney. (Flem- cells, etc., in the same manner as ing’ wisture sifrning ) "A clewerlt with happens to particles of dust, either intertubwlar capillaries. Magnified 100 diameters, become incorporated into the sub- stance of cells or remain entirely free; in both of which conditions they are quickly removed from the circulation and deposited in the spleen, the liver, and the bone-marrow, where they undergo further changes and are destroyed. Nevertheless the products resulting from the de- struction of the blood form colored and colorless deposits in the organs mentioned, and remain there as such for a considerable period of time (see Part IX. of Chapter IV.). A third group of substances which produce metastases is composed of living cells which have originated in foci of growing tissues, and are carried to other organs through the lymphatics or through the blood-ves- sels, into which latter they find an entrance by a direct rupture of the walls of the vessel. This process is observed when a tumor, which has the characteristic of growing by a sort of infiltrative process, develops in some part of the body; and the transportation of living cells from this tumor to other spots in the body, partly by way of the lymphatics and partly by way of the blood-vessels, gives rise to the formation, by a process of proliferation, of metastatic daughter-tumors (see Chapter VIT.). Metastasis most frequently occurs in the natural direction of the blood- and lymph-streams; but it may also be effected by backward transportation, which explains how a tumor which has broken into one of the larger veins of the body produces daughter-tumors in the region 46 THE SPREADING OF DISEASE THROUGHOUT THE BODY. drained by another vein. A backward metastasis is frequently seen in the lymphatic system, when closure of one part of the lymph-channels occasions a change in the direction of the current. As a fourth group we may mention all those processes which are characterized by the entrance of vegetable and animal parasites into the circulation. If, under these circumstances, these organisms do not find conditions suitable for their further development, they are quickly eliminated from the blood-current and, under the influence of the meta- bolic changes, destroyed. But if they are able to reproduce themselves anywhere, they will lead to the production of metastatic infectious foci, which are located primarily in the vascular system, but may also force their way from there into the surrounding tissues. When the in- vading forces consist of bacteria, the secondary infection will have the same character as that of the primary focus (see also Chapters IX., X., and XI.). Should an embolus contain organisms which possess the power of inducing necrosis of the tissues, inflammation, and putrid de- composition, there will be produced, along with the embolism and the disturbances in the circulation which necessarily accompany it, suppu- ration and sloughing; or, in other words, there will be a transportation of the very same process which ran its course at the original seat of infection. As a fifth group of metastatic processes may be classed together the following pathoiogical occurrences: first, those cases in which constitu- ents of the human body, having undergone solution, pass into the circulation, are carried to some other part of the body, and are then deposited in the new location in a solid form; and second, those in which substances are taken up into the body from the outer world in a dissolved condition and are then deposited in the tissues in a solid form. Most frequently it happens that the coloring-matters of the bile are taken up in solution into the blood within the liver, are then dis- tributed to different tissues, and at the same time produce granular or crystalline deposits-of bile-piqment. Not infrequently, products Pi the destruction of red blood-corpuscles underyo solution in the blood-stream, and are deposited, in the form of drops, granules, and crystals, in the spleen, liver, and kidneys. Substances derived from the coloring-matter of the blood in hemorrhagic foci may also be taken up into the circulation and distributed to various organs. In rapid reabsorption of portions of the skeleton, lime-salts are brought into solution in great quantities, and may produce calcareous deposits in the mucous membrane of the lungs, the stomach, or the kidneys.’ Preparations of silver used medicinally for a long time may produce a deposit of fine granules of silver of a grayish-brown color in various organs. The tissues most frequently affected are the connective tissue of the skin, the glomeruli and connective tissue of the medullary sub- stance of the kidney, the intima of the larger blood-vessels, the adven- titia of the smaller arteries, the tissues in the neighborhood of the mu- cous glands, the connective tissues of the intestinal villi, the choroid plexuses of the cerebral ventricles, and the serous membranes. The fact that the epithelial tissues and the cerebrum are unaffected shows that there is a selective tendency exhibited by the tissues, and that this selective tendency differs materially from that which is seen in 1 The processes referred toin thisand in the next four uniumbered paragraphs prob- ably constitute the author's sixtngroup.—Transtaton’s Nore. ~ METASTASIS AND EMBOLISM. 47 the case of a metastatic deposit of the corpuscular elements. It is well to assume that, for this excretion and precipitation of substances in solution, the chemico-physical character and the functional activity of the tissues which come into contact with the blood containing these a exert a determining influence (compare Part XI. of Chap- er IV.). If a large amount of air gains entrance to the right heart, as may occur from the wounding of a large vein in the neighborhood of the thoracic cavity, or, which happens more rarely, from the opening of the veins (e.g., of the stomach) by an ulcerative process, the air mingling with the blood produces a foamy mass, which the contractions of the heart are scarcely able to drive onward. In consequence of this, the left heart contains little or no blood, the aortic pressure falls, and the individual speedily dies. Should the air enter the right heart only in shght or in interrupted amounts, air-bubbles are formed which may circulate through the entire body. Larger amounts sometimes remain for a time in the vessels of the major or minor circulation, cause their closure, and give rise to disturbances of the circulation which may in turn cause disorders of the nervous and respiratory functions. If this condition does not produce death, the air is reabsorbed after a time. If the lung-tissue is ruptured by some traumatism or by violent coughing, crying, or vomiting, the air may enter the connective-tissue spaces and lymphatics, and may extend along these into remoter parts of the lungs, into the pleura and the mediastinum, and even out as fai as the skin, thus giving rise to conditions which are termed emphysema of the skin, of the subcutaneous tissues, of the mediastinum, etc. Un- der certain circumstances the air may spread throughout a considerable portion of the subcutaneous lymph-channels and connective-tissue spaces, and when this happens the skin presents a blown-up appear- ance, and pressure upon it produces a crackling sound. Arnold believes that the lymphatic glands form a sure filter for dust, and that metastases can occur only after the rupture of a lymphatic gland into a blood-vessel. This opinion, which is supported by the results of numerous experiments, seems to me to be correct for all those cases in which the gland-structure is still not too much altered. I think, however, that when the lymph-glands soften, from being overloaded with dust, they may discharge dust-containing, broken-down material through their efferent lymphatics. As will be shown later (compare Part III. of Chapter VI.), it is an invariable fact that where foreign bodies or dead tissue-masses are present in the midst of living tissues, there wandering cells will be sure to appear, and these, so far as is possible, take up into their substance a smaller or larger quantity of whatever corpuscular ma- terials may happen to be present. This material is then carried further on, especially to the lymphatic vessels and lymphatic glands. Very probably this material is utilized —so far as it iscapable of being so utilized—for the nourishment of growing tissue-cells. * According to Siebel and Kunkel, cinnabar and indigo granules injected into the blood-stream of a frog are rapidly taken up by the leucocytes, and in one or two hours not a granule is to be found free in the blood. At the end of twenty-four hours the granule-containing leucocytes have all passed out of the circulation and lie for the most part rolled together in the capillaries, the largest number being found in the capillaries of the spleen, liver, bone-marrow, and the lungs, while they are found in smaller num- bers in the kidneys, and in still smaller numbers in the capillaries of the heart-muscle. Already at the end of two hours a few granule-containing cells and free granules are found in the tissues outside the vessels, and after a few days they have almost en- tirely disappeared from the vessels. The granules are then seen partly in the wander- ing cells, partly in the fixed cells, as well as in the free cells of the splenic pulp (Ponfick) * Ziegler, “Exper. Unters. tiber die Herkunft der Tuberkelelemente,” Wiirzburg, 1875; Nikiforoff, “Unters. tiber den Bau und die Entwickelung des Granulationsge- webes,” Beitriige von Ziegler, viii., 1890. 48 LOCAL AND GENERAL DISEASES. and of the bone-marrow. They may even still be found in these organisms weeks after- ward (Hoffmann, Langerhans). Both in frogs and in dogs some of the granule-holding cells find their way into the lumen of the alveoli and bronchioles of the lungs, and are then discharged from the system by these channels. Ina short time after the injection a large portion of the granules of coloring-matter are found adhering to the endothelial cells of the hepatic capillaries, while a second portion are found in the leucocytes, which later on escape from the vessels into the tissues. From this point many of them manage to enter the lympnatics of the liver and then ultimately reach the lymph-glands. Finally, a portion of the granules are cast out with the bile, but by what course they manage to enter this fluid is not known. In dogs the pigment granules also collect in the tonsils, and are carried by the leucocytes, into which they penetrate, through the epithelial covering to the outer surface. According to the observations of Jadassohn (“ Pigmentverschleppung aus der Haut,” Arch. f. Derm., 24 Bd., 1892) and Schmorl (“ Pigmentverschleppung aus der Haut,” Cen- tralbl. f. allg. Path., 4 Bd., 1893), skin pigment—both that which is normal and that which is the result of some pathological process—may be transported from this part of the body and lodged in the lymph-glands ; in other words, a pigment metastasis may take place. II. Secondary Local and General Diseases.—Auto-Infection.—Dis- eases Caused by the Cessation of the Functional Activity of Certain Glands. §19. If a local tissue-change is caused by any injurious influence, a primary local or organic disease will occur, which is accompanied by a disturbance of function of the affected part or organ. If the injurious agent finds its way into the juices of the body and into the blood, with- out causing any noticeable changes at its point of entrance, although inside the body it induces local alterations, we may speak of the condi- tion as a solitary or multiple lymphogenous or hematogenous local or organic disease. : The local malady may remain confined, during its entire course, to the organ originally affected, and yet it is a very common occurrence for some secondary organic disease, or even for a general disease, to develop. One way in which a pathological process may extend to other parts of the body is by the process of metastasis-—described already in § 18. Tt is in this way that not merely isolated, but also often a large number of foci of disease develop with such extraordinary frequency in the liv- ing body. In many cases the generalization of this process by aid of the blood- and lymph-channels is so widespread (as in tuberculosis, sup- purations, and carcinomatous growths) that the majority of the organs will be found to contain such foci of disease, and that at the same time they will give unmistakable evidences of being more or less disturbed in their functional activity, according to the extent to which each is involved. A second group of pathological phenomena owe their origin to the fact that poisonous products are generated in the primary foci of dis- ease, and that these products, when taken up into the juices of the body and into the blood, produce upon many of the organs effects which may be designated as due to poisoning by substances which have emanated from certain foci of disease. 'VYhis form of intoxication is, as I have already explained in $14, of extremely frequent occurrence in the infective dis- eases, and gives rise not only to secondary degenerations of different organs, but also to general disturbances of the metabolic processes— such, for example, as a feverish increase in the heat of the body, and some damaging of the central nervous system,—manifestations which indicate the existence of a more or less severe general disease. DISEASES OF THE BLOOD AND OF THE CIRCULATORY APPARATUS. 49 A third mode of distribution of pathological processes throughout the body becomes possible by reason of the fact that the integrity and the normal functional activity of many organs are dependent in large measure upon the function of certain other organs, and upon the further fact that the organism as a whole has need—if it is to maintain a normal condition for any considerable period of time—of the perfect functional — working of all its organs. Accordingly there is a large group of local and general diseases which owe their origin to the tmperfect functional work- ing of this or that organ. Finally, it is not a rare event for normal products of metabolism— which, under normal conditions, are cast out from the body or else are consumed again—to be retained in the body and to escape being con- sumed; in which event their influence upon the tissues of the body pro- duces conditions which may be described as an auto-intoxication. Auto-intoxications are in some measure the result of the defective functional activity of certain glands, and yet they may. also develop ander other circumstances; and furthermore the disturbance of the func- tions of certain glands may cause, not only auto-intoxications, but also other pathological changes. §$ 20. Secondary diseases, which develop in consequence of certain organic affections, occur with extraordinary frequency as a result of pathological alterations of the blood and of the circulatory apparatus. The vascular system and its contained blood’ have relations to all the tissues, and accordingly duninution in quantity and diseases of the blood, as well as pathological alterations of the blood-vessels, very often produce diseased conditions in this or that tissue, or even in the entire body. If the amount of hemoglobin in the blood is diminished by a decrease in the number of red blood-corpuscles (oligocythemia), or by some pathological change in the corpuscles themselves, or, finally, if the hemoglobin be made, by the action of carbon monoxide (§ 10), in a measure incapable of taking up the oxygen from the air, the normal amount of oxygen would no longer be carried to the tissues of the body. Consequently, if the amount of oxygen conveyed to the tissues, under the circumstances just stated, sinks below a certain point, deficient nutrition and its attendant fatty degeneration will result; in fact, in, exceptional cases, this deficiency of oxygen may produce death, by caus- ing a paralysis of the nerve-centres. Should the arteries be closed by thrombi or emboli (compare § 17 and Chapter III.), or narrowed or actually closed by thickening of their walls, as happens in the arterial disease known as arteriosclerosis, the regions supplied by the arteries thus affected become the seat of local deficiencies in nutrition and in oxygen-supply, of local asphyxia, and, later, of de- generative processes which very frequently end in the death of the tissues involved, and sometimes also of the connective-tissue framework of the organ. a the cerebrum and spinal cord the alterations in the blood-vessels tend to produce ischemic softening processes (see Chapter IV.), which frequently cause paralyses, and not infrequently end in death. In the heart, the changes in the vessels produce diffuse fatty degeneration, or local softening of the heart-muscle, as a result of which the function of this organ is disturbed, or it may even become entirely insufficient. In the kidney the secreting glandular parenchyma, together with a por- tion of the connective tissue, undergoes necrosis and atrophy, and the loss of these substances produces local or widespread shrinkings 50 EFFECTS OF AN ORGANIC DISEASE UPON OTHER ORGANS. which are called, according to their size, embolic and arteriosclerotic atrophies. In the stomach ischemia of the mucous membrane produces local ulcerations; in the liver and in the muscles it induces atrophy ; in short, no tissue can withstand the effects of a long-stariding bloodlessness or poverty of the blood. Consequently, narrowing or closing of the arte- ries by clots or by changes in their walls plays an exceedingly impor- tant part in pathology, and is not only the cause of ancemic necroses (see Chapter IV.) and hemorrhagic infarcts (see Chapter III.), but also of numberless progressive organic atrophies. In the production of organic atrophies arteriosclerosis possesses a prominent significance, since it is a very frequent disease with the aged, resulting in tissue-degenera- tion in various organs. As a result of these degenerative processes, most of the organs attacked contain at a later date cicatrized patches, in which the specific tissue has disappeared, while the connective tissue is increased. The active participation of the vascular apparatus in all inflammatory processes (see Chapter VI.), the disturbances of the circulation through alteration in the blood-vessel walls, the displacements and changing o the vascular channels which result in part from the closing of old vessels by proliferating endothelial cells or by thrombi and in part from the for- mation of new vessels, make it appear comprehensible how in all chronic inflammations the specific cells, deprived of regular nutrition, undergo degeneration, and frequently become replaced, but only to a limited extent, by connective tissue. This is especially true in the case of chronic inflammations of glandular organs. If there is a profuse watery discharge from the intestines the body will suffer for lack of water; and if stenosis of the oesophagus or of the pylorus prevents the intestinal tract from habitually receiving sufficient food, or if the stomach and the intestine are no longer able to digest the alimentary materials which are brought to them, and afterward to carry them along into the juices of the body, the organism as a whole will be made poorer in albumin and fat. If the heart is unable to drive out with normal vigor the contained blood, evidences of venous stasis will show themselves in the more re- motely situated organs. If the respiration is impeded, or in any way rendered imperfect, the composition of the blood will undergo altera- tions. A collection of fluid in the thoracic cavity results in compression of the lung; interference with expiration while inspiration remains per- fectly free gives rise to distention, and, later on, to atrophy of the lung. Tf a portion of the dung has been rendered useless by a chronic inflam- matory process, the inspiratory distention of the thorax acts only upon that portion of the lung which is functionally active. The effect of this is to produce first an overdistention of this part of the lung, and even- tually a condition of atrophy due to the abnormal stretching of the tissues. By increase in the size of the liver compression is exerted upon neighboring organs; diseases of the parenchyma of the liver are cften followed by disturbances in the circulation of blood through the organ, and at the same time by stasis in the area of distribution of the portal vein, together with abdominal dropsy. Prevention of the outflow of urine from the ureters retards the secre- tion of urine and leads to atrophy of the kidney. A large excretion of albumin in the urine produces a diminution of the albumin in the body. ‘RESULTS OF DISEASES OF THE NERVOUS SYSTEM. 51 The destruction of large portions of the parenchyma of the kidney is followed by increased arterial pressure in the aorta, increase in the heart’s action, and hypertrophy of that organ. : An increased resistance in the pulmonary circulation, on account of disease of the lungs, is often followed by dilatation and hypertrophy of the right side of the heart. Obstacles at the aortic opening which interfere with the emptying of blood from the left chamber lead to hypertrophy of the left ventricle. Stenosis and insufficiency of the mitral orifice cause backward pressure of the blood in the direction of the right heart. This influence may be counterbalanced by a hyper- trophy of the right ventricle, or, if this compensation fails, the back pressure exerts its influence upon the veins of the major circulation. An oblique position of the pelvis produces curvature of the spine. Stiffness of a joint and inability to use it produce atrophy of the sur- rounding muscles, this atrophy being due to inactivity. Diseases of the nervous system may give rise to functional derange- ents and anatomical changes in every organ of the body—in glands, muscles, skin, bones, lungs, heart, intestines, etc. These changes are due in part to an increase, in part to a diminution or even an arrest, of nervous impulses; they are also due to disturbances in the circulation, and perhaps also to the withdrawal of trophic nerve-influence upon which the tissues are dependent for their nutriment. Destruction of the large ganglionic cells in the anterior gray horns of the spinal cord produces atrophy of the corresponding peripheral nerves and the mus- cles supplied by them. Paralyzed extremities become atrophied. Dis- eased conditions in the region of the respiratory and vascular centres induce disturbances of the functions controlled by these centres. Inju- ries of certain portions of the medulla oblongata, concussions of the brain and spinal cord, the presence of tumors in the brain, psychical affections, and poisonings of the nervous system, cause, under certain circumstances, first a rapid absorption of the hepatic glycogen into the blood, and then a secretion of a saccharine urine. Ivritation of the peripheral nerves may produce abnormal reflex sensations and move- ments, as well as circulatory disturbances, in other parts of the body. Paralysis of both vagi, or of the branches which are given off by them, and which are called the recurrent laryngeal nerves, may be brought about by inflammatory processes or by pressure on the part of neigh- boring lymph-glands, etc.; and the condition is one which may be fol- lowed by inflammation of the lungs, by reason of the fact that the ac- companying paralysis of the laryngeal muscles permits the entrance of foreign substances into the lung during inspiration. The trophoneurotic diseases of the tissues are mentioned in the main text only cur- sorily, and their occurrence is set forth as only a possibility. This is done for the reason that the relations of the trophic nerve-system to the individual tissues are still imperfectly understood, and the opinions of different authors vary greatly in regard to the dependence of the tissues upon the nervous system. Many authors ascribe to the trophic action of the nervous system a far-reaching influence on the various diseased conditions to which the tissues are liable, and attribute to the motor, secretory, sentient, sensory, and reflex nerves the power of establishing the necessary connection with the nerve-centres. Others attribute the same power to special trophic nerves. Thus, for instance muscular atrophy, glandular atrophy, bone- and joint-atrophies (in tabes and syringomyelia), diverse diseased conditions of the skin characterized by thinning, ex- foliation of the epithelium, loss of hair, inflammation, etc., unilateral tissue-atrophies, and also hypertrophic growths of the muscles, the glands, the skin, the bones, etc., all are attributed to affections of the nerves. It is not to be questioned that, as the result of disturbances of innervation, there 52 EFFECTS OF AN ORGANIC DISEASE UPON OTHER ORGANS. are produced both degenerative and hypertrophic tissue-changes and inflammations ; but most probably these are dependent not upon a condition of the tissues caused by the re- moval of or change in nerve-influence, but much more upon the increased or decreased functional activity of the tissues, or upon injury or inflammation and disturbances in circulation which have developed coincidently with the disturbances of innervation. An example of this is seen in the tissue-disturbances which are observed when there is a loss of sensibility. Golz and Ewald, who in dogs thoroughly destroyed the thoracic and lumbar portions of the spinal marrow, were successful, by the exercise of great careful- ness, in preserving intact the skin of the animals thus operated upon ; and consequently they are also opposed to the idea that trophic centres and nerves exist. $21. Auto-intoxications or self-poisonings may take place in a vari- ety of ways. In the first place, poisonous products of metabolism, which are normal both in character and in quantity, may, through some hin- drance or other, fail to be excreted in adequate quantity, and in this way they may be carried over into the juices of the body and there be re- tained. In the next place, the physiological production of poisonous sub- stances may undergo an increase which is great enough to be considered pathological. Yn the third place, it may happen that poisonous products of metabolism, which under normal conditions are at once decomposed and thereby converted into something harmless, fai/]—as a result of some disturbance of metabolism of either a local or a general character—to undergo this decomposition. Finally, it also sometimes happens that, as a result of pathological changes in the functional activity of certain organs, or even of the entire cessation of such activity, poisonous substances make their appearance in the blood and at the same time also in the urine. Tf injurious substances resulting from the decouposition of albunin are retained in the intestinal cal, or if they are formed there in an abnor- mally plentiful manner, they may give rise, not only to local pathologi- cal disturbances, but also to general intoxications; and, furthermore, through the agency of the bacteria that are present in this canal, the sulphuretted hydrogen that originates from the sulphur which enters into the composition of the albuminous elements, may pass over into the blood in such large quantities that the odor of this gas can be recog- nized in the patients’ breath, while, at the same time, the sulphuretted hydrogen itself will also be found to be present in the urine. The ele- ments which, when taken up into the blood, are capable of producing manifestations of poisoning—such, for example, as vomiting, headache, vertigo, depression of spirits, urticaria, etc.—are, as a rule, those tox- ins which are derived from the decomposition of albumin through the agency of the intestinal bacteria. It is also probable that the tetany which occurs, as something exceptional, in dilatation of the stomach, owes its origin to an auto-intoxication. If the function of the kidneys is disordered to such a degree that the substances which are convertible into urea are excreted in only insuffi- cient quantities, symptoms of poisoning may manifest themselves in consequence of the retention of these substances; these symptoms con- sisting of a comatose condition, interrupted from time to time by con- vulsions, and of disturbances of the respiration— all of which taken together constitute what is designated as wrenia. According to von Limbeck the retained substances act like a narcotic, and the first effects. of this narcosis are a dulling of the powers of sensation and an inability to sleep. According to Fleischer, the poisoning, through an irritation of the vaso-motor centre, induces a spasm of the muscular elements of the blood-vessels, and this in turn causes a high degree of cerebral anz- mia. It is still an unsettled question whether the toxic effect is depend- AUTO-INTOXICATIONS RESULTING FROM ORGANIC DISEASES. 53 ent upon the action of a single element or upon that of a number of'sub- stances. According to the investigations of Bohne it is probable that the conditions described are dependent in the largest measure upon the retention of the chlorides within the organism. Inasmuch as many substances are also eliminated by way of the in- testinal tract, it is possible that some defective functional activity on the part of the intestines may thus, under certain circumstances, render it difficult for the organism to rid itself of retained poisonous substances, and in this way may lead to an auto-intoxication. Similarly, the over- charging of the blood with carbonic acid, through some interference with the exchange of gases in the lungs, may also give rise to symptoms of poisoning. When the excretion of bile from the liver is either arrested alto- gether or is merely hindered in its escape, through the existence of some pathological lesion in the gall-ducts or in some other part of the liver, the constituent elements of the bile will be taken up into the blood, and there will be produced that condition to which the term cholemia is commonly applied. When this happens, not only the col- oring matter of the bile but also the biliary salts enter the circulating blood, and their presence in this fluid produces general lassitude, irri- table temper, mental fatigue, a disposition to sleep, a slowing of the pulse rate, itching of the skin, and abnormal sensations of hearing and of taste. These effects upon the heart, the muscles, and the central ner- vous system are to be ascribed to the biliary salts, which in addition exert a solvent action upon the red blood-corpuscles. If the liver has already undergone marked pathological changes, there will be disturbances in the formation not only of bile, but also of sugar and of urea in this organ; and besides, it is likely that the sub- stances which are carried to the liver from the intestinal canal, and which under normal conditions undergo in this organ decomposition into other elements, in reality pass through it without undergoing any alteration. There are many who believe that at least the severe symp- toms—such as the various forms of mental excitement, delirium, drowsi- ness, coma, cerebral paralysis—which occur in degenerations of the liver (icterus gravis), ought to be ascribed to the presence of these sub- stances in the blood, and they mention, in support of their belief, the fact that under these circumstances abnormal substances (e.g., ammo- nium carbonate) make their appearance in the urine. If the pancreas has undergone degeneration, considerable quantities of dextrose, acetone, and acetic acid (compare § 22)—the last two of which substances are capable of producing poisunous effects—may ap- pear in the blood and in the urine; and consequently one is tempted to refer this pathological phenomenon to some defect in the functional activity of the pancreas. Finally, the observation has also been made that when the thyroid gland and the suprarenal capsules (§ 23 and § 24) undergo degeneration, pathological symptoms arise which may perhaps be explained (at least in part) by the assumption that, as a result of the degeneration of these organs, certain poisonous products of metabolism cease to undergo decomposition. The term auto-intoxication is not used with the same significance by all authors, many of them giving to it a wider scope than I have given in the preceding text, and even applying the term to the poisonings caused by pathogenic bacteria. In justification of this stand it may be said that these poisons have also in large part originated from 54 EFFECTS OF AN ORGANIC DISEASE UPON OTHER ORGANS. the component elements of the body. Nevertheless, it seems to me that such a widening of the significance of this term is not to be commended, inasmuch as the cause of this decomposition does not reside within the body but reaches it from the outside—in other words, a previous infection is indispensable for the establishment of the poisoning. I am therefore of the opinion that it is more correct to apply the term auto-intoxication only to those poisonings which owe their origin to products of metabolism which have come into existence either through the activity of cells belonging to the organism, or else through that of non-pathogenic bacteria which are always present in the organism (e.g., in the intestines). According to Bouchard’s view the auto-intoxications are caused chiefly by leuco- mains, i.e., by the earlier products of the retrograde metamorphosis of albuminous materials, which materials, under normal conditions, undergo decomposition, chiefly through a process of intra-organic oxidation, until they reach the form of urea, where- upon they are cast out from the body. Chronic diseases, which are characterized by a change in the whole tone of the bodily functions, are very commonly grouped together as constitutional diseases. Samuel places in this category the permanent anomalies of the blood, the lymph-glands, and the nervous tissues (neuropathic predisposition), rachitis, osteomalacia, mutiple ex- ostoses, feeble nuscular development, relaxed articular bands, etc. Hoffmann (“ Lehrbuch der Constitutionskrankheiten,” Stuttgart, 1894) applies the term to the different forms of anemia, the hemorrhagic diathesis, hemoglobinemia, rachitis, osteomalacia, chronic rheumatism, progressive ossifying myositis, the formation of multiple exostoses, obesity, gout, diabetes mellitus and diabetes insipidus, and Addison’s disease. Nothnagel, in his “‘ Handbook of Special Pathology,” omits diseases of the blood from the constitutional diseases, and includes among them only rachitis, osteomalacia, gout, obesity, chronic vheumatism, arthritis deformans, diabetes mellitus and diabetes insipidus. From these examples it becomes reasonably clear that the conception of a constitutional disease is made to apply to very different conditions. As a matter of fact, the diseases enumerated are not at all characterized by constitutional anomalies; they represent, rather, the sequelz of anomalies or diseases of certain tissues. Consequently the term “constitu- tional disease’? is commonly employed in an entirely erroneous manner. At most it may still be applied with some fitness to obesity and gout. § 22. If a gland produces an internal secretion—that is to say, if it contributes to the great mass of the juices of the body or to the blood certain materials which are important for the normal functional activity of other organs or for the organism as a whole—the alteration of this function ory its complete abolishment may cause more or less serious disturbances in the nutrition as well as in the functional activity of other organs and indeed of the entire organism. Weare in the habit of attrib- uting the power of producing such an internal secretion to the liver, the pancreas, the thyroid gland, the suprarenal capsules, the thymus and the sexual glands. Nevertheless, our actual knowledge in regard io the nature of these different secretions is still extremely scanty and hypothetical, and we are obliged to infer what influence each of these glands exerts upon the metabolic changes and the life of the organism almost entirely from the disturbances which arise when the glands in question become diseased. Among the most important of the diseases which belong in this category are diabetes mellitus, thyreoprival cachexia, myxedema, cretinismus, and Addison’s disease, as well as the functional and anatomical changes which occur in the body as a result of castration. In a certain sense it is proper to place in the same category asphyzia, which arises from the failure of the lungs to perform properly their func- tion; for it is through the functional activity of the lungs that the requi- site amount of oxygen is conveyed to the organism. Diabetes mellitus is a disease characterized by the presence of a large amount of grape-sugar in the urine (glycosuria), accompanied by a marked increase in the total amount of urine secreted (polyuria), often also by the pathological increase of acetone and by the excretion of aceto- acetic acid and /-oxybutyric acid in the urine. At the same time grape- DIABETES MELLITUS; GLYCOSURIA. 55 sugar and the acids just named are found in the blood, and frequently diminish its alkalinity. When the blood of these patients contains a large proportion of acids, headache, a feeling of anxiety, delirium, faint- ings, and finally arrest of consciousness (coma diabeticum) are apt to develop, and these conditions are probably attributable to intoxication by acids (Stadelmann, Minkowski). The presence of sugar in the urine may be due to the fact that too much sugar has been taken into the body, so that a portion has en- tered the urine unchanged (alimentary glycosuria). Glycosuria may also occur in consequence of injuries to particular parts of the medulla oblongata (puncture of Bernard), or as the result of disease in the cere- brum (softening, epilepsy, mental affections, severe psychical derange- ments, tumors, parasites), or of some form of poisoning (carbon monox- ide, curare, morphine, strychnine, amyl nitrite, nitrobenzol), in which the liver probably gives up its glycogen into the blood more rapidly than normal, so that a hyperglycemia is set up. Finally, glycosuria may occur when the kidneys are unable to hold back the slight amount of glucose which is normally present in the blood, a phenomenon which may be produced experimentally by the ad- ministration of phloridzin (von Mering) or of caffeine sulphate (Jacobi). These alimentary, neurotic, and toxic glycosurias are, however, to be distinguished from the ordinary diabetes in that the cause of glyco- suria is to be sought not in an increased conveyance of sugar into the blood or a pathological excretion of sugar contained in the blood, but rather in the fact that the diabetic patient is unable to decompose suffi- ciently the carbohydrates, and especially the dextrose, while the sugars which turn polarized light to the left (levulose and inulin) usually can be oxidized, if not entirely, certainly in greater amount than dextrose. In most cases, also, the power to form fats from the carbohydrates is lessened; yet there are cases in which this function is intact, and the sugars are stored up in the body as fats (diabetogenous obesity). According to the investigations of von Mering and Minkowski, which have been confirmed by different authors, this loss of power in the organ- ism to oxidize the sugar brought into the body, or to store it up as glyco- gen or fat, is to be explained by a weakened functional action of the pancreas. This conclusion is drawn from the fact that, after the total extirpation of the pancreas in dogs, a severe, and atter a few weeks fatal, diabetes is produced, which is characterized, as diabetes is in the human subject, by polyuria, polydipsia, hyperglycemia, glycosuria, a diminu- tion of the glycogen in the tissues, and occasionally also by the existence of active destruction of albumin, by emaciation, by excretion of large amounts of acetone, aceto-acetic acid, @-oxybutyric acid, and ammonia, and by the appearance of a comatose condition. In support of the sup- position that there is a definite relation between the disturbance of the pancreatic function and diabetes, we find in certain cases of this disease that the pancreas has undergone some alteration—that is, it is atrophied or degenerated; it should, however, be borne in mind that the anatomi- cal examination often fails to disclose a pathological condition of the pancreas, so that we must content ourselves with the belief that the anatomical alterations which may underlie the functional disturbance of this organ are not sufficiently well marked for us to be able to demon- strate them. A precise explanation of the causal relations existing between dis- eases of the pancreas and diabetes cannot be given at the present time; 56 EFFECTS OF AN ORGANIC DISEASE UPON OTHER ORGANS. yet from the foregoing experimental researches we may deduce the hypothesis that the pancreas yields a substance to the juices of the body which enables them to destroy the glucose, which power is lost after destruction of this gland. Likewise, an explanation cannot be given of the increase in the destruction of the albumins, and the attendant destruc- tion of 6-oxybutyric acid, aceto-acetic acid, and acetone. As these sub- stances are not always found in artificially produced pancreatic diabetes (Minkowski), it would appear that they have no direct connection with the excretion of sugar, but should be considered rather as constituting a complication of diabetes. They may also accompany other diseases (poisonings, carcinoma, derangements of digestion), and are not always to be found in eases of diabetes. The development of diabetes after the total extirpation of the pancreas furnishes evidence that the pancreas has an especial function which is of the greatest importance in the normal consumption of sugar in the organism. Lépine is of the opinion that there is in the blood a glycolytic ferment which is derived directly from the pancreas, and that, in diabetic patients and in dogs from whom the pancreas has been removed, the cause of the mellituria is to be sought in a decrease in the amount of this ferment. According to Minkowski, Lépine’s experiments are not sufficient for the support of this theory. A satisfactory explanation of the genesis of pancreatic diabetes cannot be given at the present time. If we remove only a part of the pancreas of a dog, no diabetes occurs, or at least the separation of sugar is much less than after total extirpation of the organ (Minkowski). In dogs under whose skin a portion of the pancreas has been ingrafted diabetes is not produced, even when the gland has been completely extirpated (Minkowski, Hédon) ; it recurs, however, as soon as the implanted portion is removed. According to Minkowski, there is no direct relation between the secretory functions of the pancreas and those which aid in the assimilation of sugar. According to von Mering and Minkowski, poisoning by phloridzin produces in man and in most animals a marked glycosuria, and symptoms similar to those seen in diabetes may be produced by a continuous administration of the poison. Since the cause of the pathological excretion of sugar lies in the kidney and thus represents a washing out of the sugars from the organism, the phloridzin diabetes cannot be identified with the ordi- nary diabetes—that is, the pancreatic diabetes as found in man. In dogs in which diabetes has been produced by extirpation of the pancreas, phloridzin produces an in- crease in the amount of sugar excreted (Minkowski). § 23. Cachexia thyreopriva is a peculiar disease which is produced by the decrease or suspension of the eon of the thyroid gland, these conditions resulting either from detective development or from patho- logical changes in the gland. To Kocher belongs the honor of having discovered the cause of this disease, he having observed that it fol- lowed the total extirpation of the thyroid gland. Numerous clinical observations and experimental researches which followed this dis- covery have confirmed the fact that the presence of thyroid tissue is necessary for the maintenance of the integrity of the organism, and that the body, especially during its growth, requires a thyroid gland capable of performing its functions in a normal manner. Probably this gland produces a substance (thyroiodine) that serves a useful purpose in the metabolism of the body; it is also possible that it changes or destroys deleterious substances circulating in the blood. According to experimental and clinical observations, the total extir- pation of the thyroid gland produces in man, as well as in animals, after a very short time, severe morbid symptoms, which are character- ized by the appearance of convulsions and cramps, and finally by palsies of the muscles, so that the condition has been called thyreoprival tet- any. Young animals and the carnivora are especially sensitive, and dogs die mostly in a short time after the total extirpation of the thyroid. THYREOPRIVAL CACHEXIA; MYXCIDEMA. 57 If the loss of the tissues of this gland is borne fairly well at first, as occurs in human subjects, then after the lapse of months, or perhaps even of years, peculiar disturbances of nutrition begin to show them- selves. At first these consist of a feeling of weakness and heaviness in the limbs, sensations of cold, often accompanied by pains and transient swellings of the limbs, and decreased mental activity; then, later, a cachexia, accompanied by anzemia, mani- pet! | | | | | Hh ii il iu | ey waxy swellings of the skin, especially of the face (Fig. 5) appear, and there is a i noticeable diminution of mental power, together with a decrease in muscular power; and, finally, the termination of these conditions is apt to be death. The removal of the thyroid gland in childhood produces disturbances in development, and may prevent either entirely or par- tially the growth of the bones in their longitudinal axes (Fig. 5). Animals (rab- bits, goats) that have had their thyroid gland removed early in life fail to attain ie full growth and acquire a stupid ook, In thyreoprival tetany the body-tem- perature is raised; in thyreoprival ca- chexia it is lowered. Pathological functional changes, as well as total extirpation of the thyroid, may produce pathological conditions of the body, and both experimental and clinical observations tend to show that myxcedema (Ord) is a disease (Fig. 6) which is especially dependent upon changes in the thyroid gland. Myxe-, dema is a condition in which the external appearance of the patient reminds one of the thyreoprival cachexia; there is the ,.2a,S.Teyreepiva ieberia with ¢ same peculiarly pale elastic swelling of growth such asis observed in cretins. Age the facial skin (Fig. 6), which does not jody 2am “this condition developed yield to the pressure of the finger, and ater gine rie Suen ote enn which may also be accompanied by simi- (Consult Grunater: "zur ‘Kachexia stru- lar pale and dry swellings in other parts tapingen,” 1 1884.) pea ce of the body. Later on, there is a de- crease in intellectual power, which shows itself in an increasing diffi- culty in thinking and acting, also in dulness of tactile sensation, in retardation of muscular reaction, and in the monotonous, nasal charac- ter of the voice. Finally, marked general weakness and often symptoms of actual mental derangement appear, and the fatal termination occurs under manifestations of increasing cachexia, anemia, and coma. So far as may be judged from the clinical and anatomical facts ob- served in patients affected with this disease, it is highly probable that cretinism (Fig. 8), or rather the alterations in the structure and func- tions of the body which characterize this disease, is also dependent upon disturbances of the functions of the thyroid gland. Thus we know fests itself, and at the same time pale | | ! a ‘ \ i di 58 DISEASES DUE TO THE CESSATION OF GLANDULAR FUNCTIONS. that in cretinism there is always degeneration of the thyroid gland, which may manifest itself in an enlargement of the organ, together with a certain amount of alteration of its structure (goitre), or in a contracted and atrophied condition of the gland. The fact should also be stated that cretins (Fig. 8) in their general aspect remind one of those indi- viduals whose growth has been stunted through a thyroidectomy (Fig. 5) having been performed upon them during childhood. The longitu- dinal growth of the hollow bones is more or less imperfect, while the soft parts are relatively well developed. The different portions of the body are unequally developed. The head, for example, is relatively large; the abdomen and neck are thick; the root of the nose is depressed, while the nose itself is broad and stumpy; the skin, especially of the Fic. 6.—Myxcedema (case observed by Meltzer). Fic. 7.—Myxoedema. The same individual (Fig. Age of patient, thirty-seven years. 6) three months after the pulverized thyroid gland of the sheep had been regularly administered. face, is pale, flabby, wrinkled, and puffy, as if cedematously swollen. The mental faculties are always feeble, sometimes markedly so. The power of speech and of understanding words may be entirely absent; and only those persons in whom cretinism is but slightly marked are capable of performing work of any kind. Since cretinism appears to be an endemic disease in certain regions, it is reasonable to suppose that an unknown local miasm, probably taken into the system in the drinking-water, acts in such a manner to cause de- generation of the thyroid gland during the time of bodily development, and injures the entire organism by disturbing the function of this gland. We have, then, a miasm the action of which produces the same effects as an operative removal of the gland; and since we call this action epi- demic cretinism, we might also term cachexia thyreopriva operative cret- trism. In addition, we might add myxcedema to the cretinisms, and term it a sporadic form, in contrast to the epidemic. The great importance of the thyroid gland for the nutrition of the body, the cerebral functions, and the growth of bones can no longer be doubted, after the numerous clinical e THYREOPRIVAL CACHEXIA; CRETINISM. 59 observations and experimental researches which have been made. Regarding the mode of action of the thyroid gland there are, however, many opinions. If an animal, after its thyroid gland has been extirpated, is fed with that belonging to some other animal, —say, for instance, the sheep,—the injurious effects which usually are observed after a thyreoidectomy will fail to appear, or, at all events, they will not appear until we stop feeding the animal with thyroid-gland substance. In the human being the systematic administration of thyroid-gland tissues, either in a fresh state or in that of an extract, exerts a curative influence upon thyreoprival cachexia and myxcedema (see Fig. 7); and, furthermore, reports have been published which show that favorable results may also be expected from a similar treatment of children who are suffering from cretinistic dis- orders of bodily and mental growth. Goitres (i.e., enlarged and hypertrophied thyroid glands) which have not yet undergone some form of secondary degeneration, often diminish greatly in size under the systematic administration of thyroid-gland tissues throughout a period of several weeks, In fact, the diminution in size begins to show itself already at the end of a few days. According to Lanz, the extirpation of the thyroid gland in hens causes the eges which they lay to diminish in size. On the other ; hand, the latter will be increased in size if the hens are fed with thyroid-gland substance. According to the investigations of Baumann the thyroid gland always contains a certain element in combination with iodine, viz., thyroiodine or iodo= thyrin. This substance is present in the largest quantity in individuals who are advanced in years, and in the smallest quantity in quite young children. Iodothyrin is generally combined, in the thyroid gland, with an albuminous substance and with one containing globulin, but it is also occasionally found in this gland in an uncombined form. A_ healthy thyroid gland is able to store up in its tissues the ex- tremely small quantities of iodine which are ingested with certain articles of vegetable food or with the drinking-water, and then to convert them into the combination mentioned above. When preparations of iodine are administered internally or when a wound is treated with some form of the remedy, a more con- siderable quantity of iodine is likely to accumulate in the thyroid gland. Baumann maintains that iodothyrin is the ele- _ ment of chief efficacy in the composition of this gland. Its employment in the treatment of goitres, myxc- dema, strumiprival cachexia, etc., produces precisely ' the same effects as those which are obtained from the administration of fresh thyroid-gland tissues. Fic. 8.—A female cretin, twenty-one According to the investigations of the same au- poets ot ae Ae ae er gla Tenet thority it may be assumed that the living organism circuit forenes OLCEnIL. 58 em. “s requires iodine for its proper maintenance, and that the thyroid gland provides the needed combination of iodine in whatever quantity may be required. In regions where goitres are not encoun- tered (North Germany, for instance) the thyroid glands are, on the average, much smaller (from 380 to 40 gm.) than they are in regions where the disease prevails (e.g., in Switzerland and in South Germany), but at the same time they contain more iodine (i.e., on theaverage, about 3} instead of 2mgm.). Whether the absence of a sufficient amount of iodine from the food and from the drinking-water is the cause of the hyper- trophied condition of the thyroid gland which is observed in cases of goitre, or whether this condition is the outcome of an injury, or whether, finally, some of the forms of the lower organisms are perhaps able to interfere with the specific function of the thyroid gland, are all questions which it is impossible at the present time to answer. Among the domestic animals, those which have a large quantity of iodine in their thyroid glands are the sheep, the cow, and the calf, whereas the quantity found in the thyroid gland of the hog is small. Anatomical investigations fail to throw any certain light upon the question of the internal secretion of the thyroid gland. It has been proved that the colloid material produced by the cells of the gland passes on into the lymph vessels. It is probable that iodothyrin is contained in this colloidsubstance. According to Bruns we may attribute the diminution in size which takes place in a goitre after thyroid-gland substance or thyroiodine has been regularly administered, to the fact that in the hypertrophied gland 60 DISEASES DUE TO THE CESSATION OF GLANDULAR FUNCTIONS. tissue of these goitres, which contains numerous follicles,—some of them having no col- loid material in them, others only a little of it, and still others being imperfectly de- veloped,—there are two different kinds of phenomena going on at the same time: on the one hand, an increase in the secretion of colloid takes place in the well-developed fol- licles, and the material thus formed is conveyed in abundance into the lymph-vessels ; whereas, on the other, processes of atrophy and decay are at work in the less perfectly developed follicles. After the secretion of effective thyroid-gland substance has been going on for some time, some of the secreting follicles begin to undergo atrophy. The investigations of Rogowitsch, Stieda, and Hofmeister show that the extirpation of the thyroid gland in rabbits causes an enlargement and a peculiar transformation of the hypophysis. It is possible that Basedow’s disease, which is characterized by a pulsating and highly vascular swelling of the thyroid gland, by projection of the eyeballs from their sockets, by accelerated heart action, and by a certain degree of excitability on the part of the patient, has some sort of relationship with a diseased condition of the thyroid gland—viz., with that of hypersecretion (hyperthyreosis); and in confirmation of this hypothesis it may be stated that the thyroid glands thus affected are noticeably rich in actively secreting gland tissue. However, it is not possible to furnish any convincing proofs in regard to the point in question. § 24, Addison’s disease is a peculiar affection which ends in death after a course, on an average, of two years, and which probably is pro- duced by some alteration of function in the suprarenal capsules. Its most noticeable characteristic is the appearance of a light-yellow-brown to dark-brown, diffuse, and spotted pigmentation of the skin, which first shows itself in exposed portions of the skin, as well as on the areas usually pigmented, then on the remaining superficial portions and on the mucous membranes of the mouth (melasma suprarenale). Already, before the recognizable beginning of the disease or before the pigmenta- tion of the skin, there occur loss of appetite, nausea, pain in the epigas- trium, diarrhea, and constipation—all of them symptoms of disturbance of the gastric and intestinal functions. Then, later, these are followed by muscular weakness, and finally also by manifestations on the part of the nervous system, such as asthenia, fatigue on slight exertion, head- ache, dizziness, faintings, epileptic seizures, and a comatose condition. At times a recognizable increase in the amount of pigment deposited in the skin is also lacking, the disease in these cases being characterized only by the symptoms which are due to gastro-intestinal irritation, and by progressive weakness and anzmia. According to the comprehensive statistics compiled by Lewin, altera- tions of the suprarenal capsules are found in about eighty per cent of all typical cases of Addison’s disease. Most frequently these organs are found to be changed into a caseous or a partly cheesy and partly fibrous mass. Other lesions which might be called characteristic of Addison’s disease are wanting. It can hardly be doubted that the disease of the suprarenal capsules holds a causal relation to this particular disease, so that one may describe it as a suprarenal cachexia. In what manner, however, the complete loss of the function of the suprarenal capsules, or simply some modification of their power, produces the injury to the organism, cannot be explained at present. It is not improbable that the suprarenal capsules produce, in a manner similar to that which has been observed in the case of the thyroid gland, a substance which is necessary to the organism. Possibly poisonous substances are also destroyed by the action of the suprarenal capsules. The literature of Addison's disease is unusually rich, but, nevertheless, the very numerous clinical and experimental observations have failed to make clear the genesis of the disease and the precise importance attaching to the suprarenal capsules in the human and animal organisms. At the same time it may be confidently assumed that a ADDISON’S DISEASE; CASTRATION. 61 normal functional activity of the suprarenal capsules is essential to the integrity of the organism—an hypothesis which is necessitated not only by the results of clinical observa- tion and by post-mortem examinations upon human beings, but also by the results of ex- perimentation. Thus, for example, the extirpation of the suprarenal capsules in dogs, rabbits, cats, and guinea-pigs causes a diminution in the tension of the vascular system, muscular weakness, nervous manifestations, paralyses, coma, and also—if life is pro- longed for a sufficient length of time—a falling-off in the vital powers. Tizzoni men- tions also, asan additional result, abnormal pigmentation of the mucous membrane of the mouth. When an extract of suparenal capsules is administered regularly to experi- mental animals, an increase in the blood-pressure takes place, the pulse-rate becomes slower, the muscular contractions which result from the irritation of a nerve grow stronger, and the movements of respiration become less marked. Some authorities (e.¢., Scymonowicz) attribute the increase in the blood-pressure to the effects of the extract upon the vaso-motor centre, while others (e.g., Schafer) refer it to the effects of the same extract upon the walls of the arteries. Inasmuch as the suprarenal capsules are not ana- tomically altered in all cases of Addison’s disease, many have been disposed to maintain that the disease is dependent upon some other local pathological alterations, as, for ex- ample, upon abnormal conditions of the sympathetic nerve and its ganglia. The con- ditions found thus far, however, scarcely furnish a satisfactory explanation of the disease. The fact that in a small minority of the cases the suprarenal capsules have appeared to be unaltered, cannot be accepted—even if it is conceded that a correct diagnosis was made in every one of these cases (a thing not likely to be true)—as valid evidence against the pathogenic significance of degeneration of these glands, inasmuch as an apparently nor- mal suprarenal capsule may not have performed its functions in a normal manner. Inflammatory and degenerative changes in the semilunar ganglia and in other parts of the sympathetic system, and also in the intervertebral ganglia, have been found fre- quently in Addison’s disease, and have been described by a number of writers. They can be explained upon the hypothesis of an extension of the inflammation and degenera- tion from the suprarenal capsules to these points. To conclude from this that Addison’s disease is dependent upon a lesion of the sympathetic nerves, and not of the suprarenal capsules, is not sufficiently well founded, since the suprarenal pathological alterations are constant, while those of the nerves have been found in only a few cases. Manasse found, in preparations that were removed and placed in a chromic-acid solution while they were still at the normal blood-temperature, that the cells of the suprarenal capsules are in most intimate relation with the veins, reaching out into their lumen, and that in the vessels, but especially in the veins, a peculiar hyaline substance is found, which by the chromic-acid solution is colored brown, in much the same manner as are the surrounding parenchyma-cells. It is therefore possible that from these cells a peculiar substance is furnished to the blood. Itshould be stated, furthermore, that this substance is also found in arteries. It cannot be demonstrated in alcoholic preparations. In the same category with the pathological conditions which result from the with- drawal of a glandular function are to be classed the abnormal symptoms in the growth and functions of the body which are produced by castration—i.e., the removal of the sexual glands. If the ovaries are removed from a woman after puberty menstruation usually ceases at once, although in rare cases it may continue for some time. Sexual desire and the erethism accompanying the culmination of the sexual act usually dimin- ish in intensity, but in some instances they persist without noticeable diminution. Retrograde changes take place in the rest of the genital apparatus, and more particularly in the uterus. Among the different nervous manifestations which are observed in some cases, the commonest are wave-like sensations, coupled with reddening and heat of the skin, especially of the face, and with outbreaks of perspiration; all of which manifesta- tions are particularly apt to occur during the period immediately following the castra- tion. So far as the patient’s spirits are concerned they often remain unchanged or may even grow more cheerful, especially if the castration puts an end to the severe suffering which previously existed. Now and then the patient shows some depression of spirits or even melancholia. If the ovaries are removed or destroyed in childhood the growth of the body approaches that of the male; the muscles are strongly developed, the changes in the pelvis do not take place, and the development of the breasts ceases. Castration in a man produces no marked change in the development of the body. If, on the contrary, boys are castrated the development of the body simulates in many respects that of woman. An increased amount of fat is stored up. especially on the abdomen, while the muscular structure is only feebly developed. The external genitalia remain small, the prostate gland is not of full size, and there is no development of either beard or pubic hair. The larynx remains small, and the voice is childlike. The mental powers are devoid of strength or energy. In castrated stags the antlers are not developed ; in cocks the growth of the comb is arrested. 62 EFFECTS OF ORGANIC DISEASES UPON THE ORGANISM AS A WHOLE. According to White, Kirby, Kiimmel, Bruns, and others, the operation of castration, when performed upon fully grown animals, producesa diminution of the prostate gland ; and also, in old men who suffer from hypertrophy of the prostate, a diminution in the size of the enlarged gland may be expected to result from the operation. Other authori- ties (e.g., Czerny and Socin) express a less favorable opinion in regard to the beneficial effects of the operation in cases of enlarged prostate. How the extirpation of the sexual glands affects the entire body has not been deter- mined with certainty. It is generally supposed that, by means of this operation, the trophic influence which is exerted upon the tissues by the sexual glands, through the nervous system, is withdrawn. The cessation of the menses may indeed be attributed to the fact that certain nervous stimuli have been withdrawn, and it is also likely that influences of the same character are responsible for the atrophy of the uterus. In the main, however, it is more likely that certain chemical substances which are formed in the sexual glands exert an appreciable influence upon the functions, increase in size, and development of the body. According to the opinion of Brown-Séquard, all glands produce a peculiar secretion within themselves, and they contribute substances to the blood which are useful to the organism. He ascribes to the juice of the generative glands a special, exciting, tonic influence upon the organism. According to Poehl, the active principle found in these glands is spermin, a base which is present in many glands (thyroid, pancreas, ovaries, spleen), and which, through its catalytic action, is able to restore the oxidizing power of the blood, whenever, through any cause, it becomes reduced below the normal, and to promote the so-called intra-organic oxidation. Zoth and Pregl, who have carried out experiments in regard to the effects of a glyc- erin extract of the testicles of animals, report that injections of this extract increase very materially the power of muscular contractions. IV. Fever and its Significance. § 25. When disease of an organ assumes a constitutional character, or when a disease manifests this character from the very beginning, there is seen very frequently a peculiar combination of symptoms which is called fever. It is particularly in the infectious diseases which run their course with toxic symptoms that fever plays an active part. The characteristic mark of fever is the increase of bodily temperature; yet other symptoms usually accompany it, as, for example, increased fre- quency of the pulse, disturbances in the distribution of the blood, and al- terations in the interchange of gases in the lungs and in the excretion of urine. There is usually also a subjective feeling of being ill; and yet it does not form a necessary part of the symptomatology of fever, but is rather the special effect of the infection when associated with symp- toms of poisoning; the infection occurring either at the same time with the feverish increase of temperature, or a little before it, or even after it. The study of the healthy individual teaches us that, in spite of changes in the surrounding temperature and in the external conditions, the bodily temperature maintains a mean height of 37.2-37.4° C. (98.8- 99.3° F.). The normal variation in thermal conditicn between morning and evening is 1.0-1.5° C, (1.8-2.7° F.), the evening temperature being the higher of the two. The raising of the temperature of the body above that of its sur- roundings is produced by chemical changes occurring in the organism, especially in the muscles and glands; so energetic, indeed, may be this process that a rise of 1° C. (1.8° F.) may be obtained within half an. hour. This phenomenon of heat-production stands in contrast to that of heat-dissipation, the latter taking place especially through the skin, the lungs, and the excreta. Both processes—heat-production and heat- dissipation—are governed by the nervous system, and it is such regula- FEVER AND ITS SIGNIFICANCE. 63 tion of both phenomena that makes possible the normal constancy of body temperature. : On _ exposure to low temperatures the bodily heat-production is in- creased (essentially by the action of the muscles), while heat-dispersion is hindered by contraction of the cutaneous blood-vessels and by the inhibition of sweat-production. On exposure to high temperatures the heat-dissipation is augmented by an increase in the frequency of respiration, by dilatation of the cutaneous arteries, and by an increase in the sweat-excretion. In those conditions which we call fever the proper balance between the production and the dissipation of heat is disturbed, the former being excessive; and as a result the temperature of the body becomes more or less elevated above the normal (Figs. 9,10, and 11). Elevations of tempera- ture (taken in the rectum) to 38° C. (100.4° F.) are called hypernormal ; from 38° to 38.5° C. (100.4° to 101.3° F.), slightly febrile ; from 38.5° to 39.5° C. (101.3° to 103.1° F.), moderately febrile ; from 39.5° to 40.5° C. (103.1° to 104.9° F.), markedly febrile; over 40.5° C. (104.9° F.) (even- Fic. 9.—Temperature-curve in a continued remittent fever, with a slowly increasing and a very gradually decreasing temperature (typhoid fever). ing), highly febrile; while any temperature over 41° C. (105.8° F.) is called hyperpyretic. Four periods may be distinguished in fevers. The first, called the pyrogenetic or initiai stage, or stadium incrementi, comprises the time during which the previously normal temperature reaches the character- istic height of the particular disease. This period is sometimes short— from half an hour to two hours in duration (Fig. 10)—and is then gene- rally accompanied by a chill ; sometimes it is longer (Fig. 9), extending over one or more days, and is then usually unaccompanied by a chill, but in some cases there may be repeated chills. The second period is called the fastigium, or the acme of the dis- ease; its duration is very variable, according to the disease, and may be from a few hours to many weeks. The temperature reaches one or more acme-like crisis-points, between which are found more or less marked remissions. In the period of decrease or defervescence, or stadium decrementi, the temperature sinks again to normal. If this occurs rapidly, by a sudden decrease in the temperature (Fig. 10), it is called crisis; if it occurs gradually (Fig. 9) it is termed lysis. The former is usually accompanied by profuse sweating, and in a few hours, or at most in one day or a day and a half, the temperature sinks two or three degrees, or even, under exceptional circumstances, five or six degrees (Centigrade).' 1 Nine or ten degrees Fahrenheit.—TRransLaTor. 64 EFFECTS OF ORGANIC DISEASES UPON THE ORGANISM AS A WHOLE. In lysis the temperature falls gradually in from three to four or more days, and may be either continuous or intermittent. The boundary-line between the acme of the disease and deferves- cence is not always sharply defined, and before the latter sets in defini- tively, increases in temperature may occur; this phenomenon is called the critical change, or perturbatio critica. If between the fastigium and defervescence there are days of uncertainty, with occasional changes in temperature downward and upward, we have what is called the am-= phibolous stage. Sometimes there is observed a short period during which, while the temperature is somewhat lowered, it yet remains con- stantly above the normal; but after a few days it sinks either rapidly, or by a gradual decrease, to the normal. In the convalescent period the temperature returns to the normal condition. The heat-regulating function during this time, however, is still imperfect, so that often slight increases and not infrequently sub- normal temperatures are observed. If in the course of a fever the daily variations are small, so that the difference between the maximum and minimum is no greater than under Fic. 10.—Temperature-curve of a continued Fic. 11.—Temperature-curve of an intermittent fever, with rapid increase and rapid decline of tem- tertain fever (malaria). perature (pneumonia). normal conditions, the fever is called a continuous fever (febris con- tinua) (Fig. 10). If the differences are greater the fever is termed a subcontinuous fever (febris subcontinua) or a remittent fever ( felyis remittens) (Fig. 9), or an intermittent fever (/ebris intermittens) (Fig. 11). In the latter condition afebrile periods (apyrexia) alternate with periods of high temperature (pyrewia), and each parorysm has its pe- riod of greatest intensity, or fastigium, and its defervesecence. In the infectious disease called relapsing fever (febris recurrens) there is first a continuous fever, which after a few days falls suddenly; after about one week a second rise in temperature may occur, to be followed, after - expiration of another period of apyrexia, by a third return of the ever. Many diseases—as, for example, typhoid, pneumonia, measles, re- lapsing fever, etc.—are characterized by typical temperature-curves, while others—like pleuritis, endocarditis, diphtheria, tuberculosis, phlegmon, etc.—show no typical febrile course. The elevation of the body-temperature in fever is dependent, pri- marily, upon an increase in the production of heat, and this in turn is due to an increased activity in the chemical changes which take place in the body. The respiratory interchange of gases—the giving up of carbonic acid (Liebermeister, Leyden), and the taking in of oxygen (Zunz, Fink- FEVER AND ITS SIGNIFICANCE. 65° ler)—is increased, a proof that the oxidation processes and the heat-pro- duction are increased. At the same time the excretion of nitrogenous substances in the urine (urea, uric acid, creatinin) is increased—on the average, from 70 to 100 per cent, but under certain conditions to as much as threefold. The destruction of the albuminoid substances in the body is also increased, and this occurs even as early as in the latent period of the fever (Naunyn). The second cause of the increase in body-heat is the defective manner in which heat is given off by the body. The incompleteness of the process of heat-dispersion may—even in cases in which the production of heat is ~ no greater than it is under certain physiological conditions (for example, increased muscular activity) —bring about a pathological increase of the body-temperature. : When the fever is at its height the patient, as a rule, gives up more heat than does a person who is in health. This dissipation of heat, how- ever, is not sufficiently rapid to offset the excess of heat produced within the bady. Furthermore, the excessive production goes on continuausly, whereas the dissipation of heat is an irregular process. In the initial period the skin is pale, and the cutaneous vessels, in . consequence of irritation of the vaso-motor nerves, are contracted; heat- dispersion is slight, and, under certain conditions, may even be less than normal. Rigors occur in fever when, through the contraction of the peripheral arteries, the amount of blood, and consequently the heat-supply, fur- nished to the cutaneous nerves is suddenly decreased, whereas in the interior of the body the temperature is rising. In the second stage of the fever the skin is frequently hot and red- dened, and in certain diseases sweating occurs; the increased heat- dispersion occasioned thereby is, however, not sufficient to reduce the temperature to normal. The increased irritability of the vaso-motor nerves, or the deficient irritability of the vaso-dilator nerves (Heiden- hain, Naunyn, Senator), is also present during this period, and, as -a result, the skin-temperature, as well as the heat-dispersion, varies con- siderably. The skin is at times pale and cold, at other times red and hot, and the hands may be cold while the trunk is hot. The centres governing heat-dispersion are therefore acting faultily. In the period of defervescence the relations of heat-dispersion to heat- production are altered, the former being more active than the latter. The cutaneous vessels become dilated, the skin gives out a great amount of heat from the rich supply of blood circulating through it, and, when the critical fall of the fever occurs, there is usually profuse sweating. We do not know certainly the cause of fever,, but we can say this much—that fever is generally the result of the absorption of a harmful agent into the fluids of the body. In many cases this harmful agent comes from a demonstrable local souree—for instance, from a mass of necrosed and broken-down tissue, or from some centre of erysipelatous and phleg- monous inflammation of the skin. Experimentally, fever may be pro- duced by various procedures—for instance, by the infusion, into the circulation of the animal experimented upon, of blood from another species, by the injection of vegetable or animal substances which have begun to undergo decomposition (Billroth, Weber), and by a great va- riety of infections. In man we may mention particularly the t/ectious diseases as instances of a fever which is produced by peculiar micro- parasites which multiply within the body. 5 66 EFFECTS OF ORGANIC DISEASES UPON THE ORGANISM AS A WHOLE. It is probable that the microparasites multiplying in the body cause —sometimes directly, and at other times by the production of unformed ferments—an increased retrograde metamorphosis of the tissues, and that at the same time substances are produced which act as poisons upon the nervous system. Their action may be supposed to be of such a nature that, on the one hand, through conditions of excitability, the activity of the muscles and glands and consequently the heat-producing metabolism is increased; while, on the other hand, by the lessened and disturbed functions of the nerves governing sweating, as also of the vaso- motor nerves, the increase of the heat-dispersion does not keep pace with that of heat-production; and, further, that the organism makes an effort to regulate the temperature, but is no longer able, in consequence of disturbances in the regulating apparatus, to maintain it at the normal height. To what extent the bacteria and the ferments produced by them contribute directly to the elevation of the body-temperature; how far this elevation is caused by the increased metabolism due to irritation of the nerves, and, further, how far it is caused by the disturbance of the heat-dispersion, are questions which cannot be determined; one thing, however, is certain—the causative factor is different in different cases. That, under certain conditions, changes in the nervous system, without infection of the tissue-juices, suffice to cause the production of a feverish increase in the temperature is shown by the appearance of fever in epi- leptic attacks, in the excitation periods that occur in the course of progres- sive paralysis, after severe frights, after the passage of a catheter into the bladder, ete. According to the researches made by Richet, Aronsohn, and Sachs, itis possible, in animals, by a prick which passes through the cerebral cortex and strikes the corpus striatum, to produce marked eleva- tion of temperature, with increase in the respiratory interchange of gases and in the excretion of nitrogenous material (Aronsohn and Sachs); and the same phenomena may also be produced by electrical irritation of the same portions of the brain. Nevertheless fevers which are the result of neurotic disturbance are seldom seen, and are overshadowed in impor- tance by those produced by different infections. The rise of temperature in fever is usually accompanied by an accel= eration of the pulse ; but still, in some cases, the effect of the elevation of temperature can be so greatly modified by stimulation of the vagus—as, for instance, in basilar meningitis—that the frequency of the pulse is di- minished. The pulse is at one time full and bounding; at another, through defective contraction of the heart, it is weak and without body. The weakening of the contractions of the heart-muscle is dependent partly on the steadily maintained high temperature and partly on the action of the harmful substances that are produced by the morbid proc- esses which are peculiar to the especial disease, and which exert an injurious effect upon the muscular or the nervous system. In feverish diseases the sensation of being ill is usually very pro- nounced, and the patient experiences a full sensation in the head. In a severe fever there are present disturbances of consciousness, symp- toms of excitation and depression, hallucinations, delirium, general apathy, involuntary evacuations, tremor of the hands, cramps (in chil- dren), etc. The muscles of the body become weak, and not infrequently they are painful. Digestion is decidedly impaired; the appetite for food is slight; the thirst, on the contrary, is increased; the mouth is dry. There is increased frequency of respiration, and upon the appear- ance of muscular weakness it becomes superficial. The excretion of FEVER AND ITS SIGNIFICANCE. 67 urine is usually diminished; the amount of urea in the urine is in- creased, and that of sodium chloride is decreased. In a long-continued fever marked wasting of the body is produced, a large part of the albuminous materials of the body and of the fatty tissue being destroyed. It is difficult to say to what extent these symptoms in individual cases depend upon the increased temperature, and to what extent upon the injury done to the organism by the particular morbid process itself, although most of the nervous disorders may be looked upon as resulting from the infection. Death is commonly due to insufficiency of the heart, and yet it may be produced by the severity of the infection—i.e., by the changes in the bodily juices, through their action upon the nervous system; by wasting of the strength; and also by an excessive elevation of the temperature— to 48°, 44°, and 45° C. (109°, 111°, and 118° F.). It should, however, be remembered that, under certain conditions, very high temperatures may be endured for a long time without producing death, and that death resulting after a very high temperature is not always due thereto, but is more frequently to be looked upon as 3 partly or entirely the result of the infection (compare § 5). The discussion concerning the nature of fevers, which Galen described as Calor preter naturam, has within the last few decades been greatly advanced by numerous ex- act clinical experimental studies, and we have learned from them of the disturbances of the inetabolic processes, of the increased consumption of oxygen, of the increased excre- tion of nitrogenous and carbon compounds, and of the changes in heat-dissipation. If, despite this, we have not as yet obtained a complete knowledge of all those morbid proc- esses which, in any given case, produce a feverish condition, we may attribute the difficulty to the fact that the efficient cause of fever is not something uniform, but may be any one of several things, and also to the fact that the feverish increase of the bodily temperature is not always produced in exactly the same way. The increased activity in tissue-metamorphosis and oxidation in the body is not always produced in the same manner. Then, furthermore, the disturbance in the heat-dissipation, through the radiation from the skin and through water-evaporation, is not always the same ; in fact it changes not only in the course of one febrile illness, but also in the diverse varieties of fever. The part which the nervous system takes in the production of the febrile in- crease in temperature is not the same in every case. According to Senator, there exists in fevers nc harmony between regulation of heat and metabolism. One must therefore suppose that in fever heat is produced by other processes besides those which lead to the formation of urea and carbonic acid. According to Herz, heat is set free by the disarrangement in the molecules of the cell protoplasm—a change which takes place in many cells in fever patients, and which leads to the destruction of the protoplasm. Heat may also be set free by the processes of swelling and coagulation which take place in the cell-protoplasm, while at the same time the diminished activity of the regenerative processes in fevers also necessitates a decrease in the power to retain heat. Krehl and Matthes, on the other hand, maintain the doctrine that oxidations are the sole source of the heat. V. The Natural Protective Mechanisms, Protective Forces, and Heal- ing Powers of the Human Organism, and their Action. § 26. The human organism is not entirely defenceless against the many harmful influences with which men come in contact during the natural course of their lives; it possesses various forms of protective contrivances and protective forces, which are capable in many in- stances of warding off noxious influences, or at least of rapidly counter- acting their harmful effects, so that a disease is either entirely prevented ‘or shows itself only as a slight lesion, of much less severity than the decided illness which, according to experience, can be produced by this 68 NATURAL PROTECTIVE MECHANISMS AND PROTECTIVE FORCES. | particular injurious agent. As the kinds of harmful influences are nu- merous, so are the kinds of protection, and they act at very varying periods—i.e., sometimes even before the tissues have begun to be dam- aged; sometimes not until such attack has advanced to a certain degree and has begun to spread itself, in part by attacking the surrounding tissues or by sending some of its products to distant spots (metastasis), in part by poisoning the body-fluids or by deranging the bodily func- tions. If the environment of the body is relatively cold or relatively warm, the regulating powers of the organism are at once brought into play, im- creasing the heat-production and heat-dissipation, or diminishing them, as the circumstances demand; so that the body is capable, within certain limits, of protecting itself against the influence of the surrounding tem- perature. If the functions of the regulating mechanism are defective— as happens, for instance, in consequence of a fit of drunkenness—a man is more liable to die from the effects of cold than heis when under normal conditions. One cannot speak of special protecting mechanisms against gross mechanical influences, yet it is to be noted that the tissues are able, through their peculiar qualities, to suffer numberless traumatisms with- out themselves receiving any harm. If small, hard bodies, such as dust- particles, reach the mucous membrane of the respiratory tract or that of the intestines, the epithelium forms a barrier to prevent their being taken into the tissue-spaces; and, further, if they are present in a locality where there are ciliated epithelia, these, through the movements of ther cilia, will keep them moving onward, or they will become surrounded by mucus produced by the epithelium and the mucous glands, and in this envelope they will be carried outside the body. Not infrequently cells come to the outer surface of the mucous mem- brane, encompass the dust-particles, and carry them away within them- selves, in a secretion derived from the mucous membrane. This phe- nomenon, which is called phagocytosis, is observed on the mucous membranes both of the pharynx and of the respiratory tract, as well as in the alveoli of the lung; and epithelial cells can also take part in the same work in company with the wandering cells which come out of the tissue-parenchyma to the surface, and which are derived mostly from the blood-vessels, and also from the groups of lymphadenoid tissue found in the mucous membrane. This peculiar phenomenon is made possible by the fact that the cells can, by the motion of their proto- plasm, take up small particles, which, like insoluble dust, exert no injurious influence upon their protoplasm. If these cells laden with dust escape outward, the act of taking up the dust into their substance appears as a useful activity—one which aids in the cleansing of the organs from dust. On the other hand, if these dust-laden cells—as hap- pens particularly in the lung-tissue—pass into the lymphatic channels and are laid up along the sides of the channels or are carried into the lymph-glands—in other words, if a metastasis of the dust-containing cells takes place into the internal organs (see § 18)—then the taking up of dust by these cells appears in a less favorable light, and one can speak of the act as a useful phenomenon only when one is prepared to consider the infiltration of the pulmonary connective tissue and lymph-glands with dust as less harmful than the collection of dust-particles on the inner surface of the alveoli. When the particles, either free or contained in cells, reach the lymph- PROTECTIVE FORCES AGAINST PARASITIC INFECTIONS. 69 glands, they are arrested at this point and stored away in the cells of these glands, so that the lymph-glands may be considered to be trust- worthy filters which guard the blood and the internal organs from the conveyance of dust to them. Against the action of poisons the human body possesses but feeble powers of defence. Against corrosive substances the epidermis of the outer skin and the mucus of the mucous membranes afford a certain amount of protection; and there may occur, under certain circumstances, a marked increase in the production of mucus—for instance, in the stomach—whereby the irritating action of a caustic fluid may be markedly reduced. Through the transudation of fluid from the blood-vessels upon the surface of the mucous membrane, a dilution of the corrosive solution may be produced, which modifies its action. On the other hand, the extension of the corrosive agent over a larger surface may thus be pro- duced, and may result in a more widespread injury to the tissues. If the poisonous substances are of such a character that, after being taken up into the juices of the body, they act injuriously upon the blood or the nervous system, a protective influence may be exerted by the organism in part through the action of the kidneys, liver, and intestine, which are sometimes able to excrete the poison rapidly, and in part through the occurrence of chemical changes in the poison itself; but this sort of protection is effective only when the processes referred to take place before any injury has been inflicted by the poison. § 27. The human organism possesses various kinds of protective mechanisms and protective forces against the parasitic infections and intoxications, and they play a very prominent part in all diseases caused by bacteria. According to their activity, these protective forces may be divided into four groups: the first prevents the entrance of the bacteria into the tissues; the second prevents the unlimited local spread of the bacteria which have already begun to multiply; the third prevents their passage into the blood and their transportation (metastasis) to other parts of the body; the fourth hinders the intoxication or weakens and reduces it to a low degree of power. For the prevention of the entrance of pathogenic bacteria into the tissues, the latter are provided with those peculiar powers which, as we have already mentioned, are also competent to hinder the entrance of dust; and in the accomplishment of this purpose the protective epithe- lial coverings and the mucus play a very important part. In the re- spiratory tract the movements of the ciliated epithelium furnish efficient protection, while in the stomach the gastric jitices are poisonous to many pathogenic bacteria. It is certain that many bacteria are not able to penetrate the unwounded external skin or the unwounded mucous mem- brane without some assistance favoring colonization and reproduction, and that the stomach secretions not infrequently destroy the activity of the bacteria (pneumococci, cholera-spirilla) or even kill them. It appears, also, not only that the mucus secreted by the mucous membranes can envelop the bacteria in its substance, and in this way hinder their entrance into the tissues, but that, what is more important, the mucus acts upon the bacteria with harmful effect, either through a substance which it contains that is injurious to them, or by producing a culture-medium unfavorable to their growth. It happens thus, for instance, according to Sanarelli and Dittrich, that pus-cocci, cholera- spirilla, and pneumococci gradually lose their virulence in the mucus of the mouth and die, while diphtheria-bacilli, as it appears, are not 70 NATURAL PROTECTIVE MECHANISMS AND PROTECTIVE FORCES. injured by the mucus. There are also many kinds of bacteria which soon die in the secretions of the vagina and uterus. Many pathogenic organisms, therefore, may obtain a foothold upon the skin or upon some accessible mucous membrane, or may enter the lungs; but comparatively few among them produce an infection. Inves- tigation has shown repeatedly that in healthy individuals there are found in the upper respiratory tract and in the mouth not only harmless bac- teria—i.e., those which cannot reproduce themselves in the human tissues—but also those which can undoubtedly cause disease, as, for instance, cocci which produce pus, or those which are capable of pro- ducing croupous inflammation of the lungs. From these facts we are warranted in drawing the conclusion that the bacteria which are found upon the mucous membranes, and have perhaps multiplied at these spots, often die and are carried away without having produced infection. This is probably what happens in the case of the above-named cocci and the tubercle-bacilli; and to this number should also be added the spirilla of cholera, which suffer when in contact with the acid secretions of the stom- ach. Finally, we may also assume that many of the pathogenic bacteria that are inhaled into the alveoli of the lungs do not reach the reproduc- tive stage, but die. If a wound exists at any point the granulations which form upon its surfaces afford a comparatively safe protection against infections, for the tissue-juices which escape from these granulations and pass through their substance, weaken the virulence of, or entirely destroy, many varie- ties of bacteria. If the bacteria have succeeded in effecting a lodgment at some spot, and have begun to multiply,—it matters not whether they effected a passage through the epithelial stratum without aid from some outside source (as in the case of ty phoid-bacilli and cholera-spirilla), or whether they succeeded in reaching the connective-tissue layer by way of some small wound (as in the case of tetanus-bacilli, pus-cocci, the cocci of erysipelas, and tubercle-bacilli),—and if their further progress is char- acterized partly by local tissue-destruction and partly by a poisoning of the juices of the body, there may be brought into action, on the part of the general organism, certain counter-influences which either restrain the further multiplication of the bacteria, or weaken or perhaps even neu- tralize completely the poisons produced by them. The fee in- hibitory influence must naturally be situated in the local surroundings, and depends either upon the vital action of the tissues or upon the action of certain chemical substances. As has already been mentioned, colonies of bacteria produce local tissue-degenerations, inflammation, and proliferation of tissue—all of which are processes in which the amount and the composition of the fluid which may happen to be at the time in the locality undergo a change; and similarly the cells of the locality also become altered. In- asmuch as, in some of these cases, it is noticed that in the course of the processes just enumerated the bacteria die, and that upon their death the infection often ceases, we may safely draw the inference that the cause of the death of the bacteria is confined to the locality involved.‘ The prevention of the spread of the bacteria and their destruction, in the spots where they are gathered together in colonies, have been ascribed by many authors to the activity of cells which have collected at the point of infection; and at the same time they have acknowledged that the process termed phagocytosis—i.e., the taking up of the bac- ANTAGONISTIC ACTION OF THE TISSUES IN THE INFECTIONS. 71 teria by the cells into their substance—plays a decisive part in this work. According to Metschnikoff and others, the amceboid cells of the body carry on a war against the foreign invaders, and endeavor to over- power and destroy them. Such a manner, however, of characterizing the phenomena of phagocxtosis amounts simply to a poetical way of expressing one s self, and does not do justice to the essential facts. Its faultiness consists in their attributing consciousness and will-power to the amceboid cells of the body—i.e., to the leucocytes and the multi- plying connective-tissue cells. These attributes, it is manifest, could not possibly belong to these cells. Scientifically considered, the gath- ering together of the cells at the point involved in the disease, and the subsequent phagocytosis, are simply an expression of certain forces which are natural to the amoeboid cells. The latter, therefore, in obe- dience to these laws of their nature, perform certain definite movements when they are subjected to the influence of mechanical, chemical, or even thermal irritants. We know, from numerous investigations made by Buchner, Gabritschewsky, Leber, Massar, and Bordet, that the mo- tile cells of the body can, by means of soluble chemical substances in certain concentrations of solution, be attracted or driven away, and some- times injured (see the chapter on Inflammation), and, further, that the contact with hard bodies can stimulate them into pushing out proto- plasmic prolongations. These phenomena are known as negative and positive chemotro- pismus or chemotaxis, and as tactile irritability. We must suppose that the bacteria multiplying within the tissues act upon the amceboid cells through a chemical substance which they produce, sometimes re- pelling and injuring, sometimes attracting, and in the latter case afford- ing conditions which are favorable to phagocytosis. This supposition is also in harmony with the actual behavior of the cells in the different local infections, since in one case the bacteria are quickly taken up by the cells, while in another they are left undisturbed. If one considers phagocytosis of the cells, in the infections, in the light of a process natural to the life of the cell, one can then classify it only as a specific process destined to facilitate the taking wp of nourishing material; and this interpretation would have to suffer only one excep- tion, and that is when certain microparasites, themselves possessing amoeboid motion, penetrate by their own movements into the cells. The result of the devouring of bacteria by cells depends sometimes on the activity of the devouring cells, sometimes on the peculiar proper- ties of the microparasite, and can either result in the death and disso- lution of the parasite or in the death of the cell; sometimes, also, the bacteria live quietly in the cells, thus furnishing an example of a sym- biosis of the cells with the parasites. In the first case the phagocytosis may prove to be a curative process, in that it hinders the multiplication and spread of the bacteria. In the second and third cases, on the con- trary, the phenomena are useless for inhibiting the further dissemina- tion of the parasites; in fact, there are cases (leprosy, and to a certain degree, also, tuberculosis) in which the parasites, finding therein a proper culture-medium, increase within the cells and finally destroy them. If these infected cells remain intact for a certain length of time they may wander into other regions and in this way effect a metastasis. Phagocytosis acts as a protective agent only in a limited number of cases, yet it is not to be doubted that the phagocytes in certain infections can take up not only dead or dying, but also living bacteria not yet in- 72. NATURAL PROTECTIVE MECHANISMS AND PROTECTIVE FORCES. jured by other agents, and can cause their death. If a large number of cells collect in the infected tissues, they may on this account, by fill- ing completely the lymphatics, produce a certain mechanical obstruc- tion to the spread of the bacteria; but the protection thus afforded is frequently insufficient. If the bacteria, either free or enclosed in cells, pass from the lym- phatics into the lymph-glands, these act as filters, as in the case of dust, and retain the bacteria; still this protection suffices only when the bacteria collected here are hindered in their reproduction and are killed by the influence of their surroundings. The destruction can-be fully ‘accomplished here, also, under the influence of phagocytosis; but this is in many instances possible only after the bacteria are weakened or have already been killed. The taking up of living bacteria by the cells does not always lead to their death; in fact, it is frequently followed by an intracellular multiplication of the bacteria. More powerful than phagocytosis for the inhibition of the spread of - bacteria and othex microparasites is the action of certain chemical sub- stances found in solution in the tissues. Furthermore, since sapro- phytic, non-pathogenic bacteria injected into living tissues can be killed in a very short time, we must suppose that there are in the tissues sub- stances which, by reason of their chemical powers, are poisonous to many varieties of bacteria and can cause their death rapidly. The same expla- nation may also be given of the fact (mentioned by Afanassieff) that pathogenic bacteria (bacilli of anthrax, vibrio of Metschnikoff) which are transferred to the granulating surface of a wound, very soon begin to degenerate and then die. Then, again, since many pathogenic bac- teria develop only locally —for example, the tetanus-bacilli, diphtheria- bacilli, and cholera-spirilla—and after a certain time die within the in- fected area without having spread more widely in the body, so is it very probable that the tissues of the body contain substances which are also poisonous for many pathogenic forms of. bacteria and prevent their wider diffusion. The phenomena observed in local infections show also that these substances are generated at times in increased amounts, or are augmented in their action by newly produced poisonous sub- stances. Itis, furthermore, probable that the crowding together of cells, which takes place either in the infected area or in the neighborhood, tends to increase the production of these poisonous substances, and may thus impede the spread of the bacteria; nevertheless attention should be directed to the fact that in some infections the spread of the bacteria comes to a standstill (e.g., in erysipelas) in certain places where there has been no crowding together of cells. It is a fact that in many infec- tions the spread of bacteria in the body by metastasis either is entirely wanting (as in tetanus and diphtheria) or at least is quite insignificant in comparison with the local infection, and is followed by relatively trifling changes (as happens, for example, in typhoid fever). Now the expla- nation of this fact is to be sought not so much in the circumstance that local changes in the tissues have hindered the spread of the bacteria into the lymph- and blood-vessels—for instance, by the production of peculiar chemical substances, or by the introduction of some mechani- cal impediment such as would result from the building of a wall of cells —as in the further fact that there are present in the lymph and blood itself forces whach are able to injure and weaken the bacteria that have been taken an, or even to destroy them. Some investigators have been led to believe that the hostile action of ANTIBACTERIAL CHEMICAL SUBSTANCES. 73 the blood upon bacteria depends upon the phagocytic action of the leu- cocytes, and they support this idea, first, by the fact that one very fre- quently can recognize, after acquired infection, or after one artificially produced by the introduction of bacteria into the blood, such a phago- cytosis; and also by the further fact that bacteria within the blood— very many of them contained in cells—are carried out of the blood-chan- nels and deposited in diverse organs—for instance, in the spleen, the liver, the bone-marrow, and the kidneys—in which they die, or from which they are excreted. These observations, however, do not warrant the conclusion that phagocytosis forms in any way a protection against the spread of bacteria in the lymph and blood, since in those very cases in which the bacteria are not carried off in the blood, the phagocytosis is absent; whereas, on the other hand, an entrance of bacteria into the blood, and their multiplication within the vessels, are very often accom- panied or followed by phagocytosis. Here, too, phagocytosis is a sec- ondary phenomenon, which occurs when bacteria or protozoa are pres- ent in the blood, and, like bland dust-particles, are not able to hinder their being taken up into the bodies of the leucocytes. When bacteria are taken up by cells they either die or continue to multiply inside the cells; and which of these two courses they will take depends upon their peculiarities and upon the condition in which they are at the time when they are taken up. According to the researches which have thus far been made, the power which is able to prevent the increase of bacteria in the blood re- sides principally in antibacterial chemical substances which probably belong to the albuminoid bodies (Buchner), and accordingly are termed protective albuminoid bodies or alexins (the mycosozins of Hankin). The mode of production and the action of these substances are not known, and can be spoken of only hypothetically. So far as conclu- sions can be drawn from the behavior of the human and animal organ- isms in infectious diseases, we may assume that in the human organism there are always present certain protective chemical substances, and that others, on the contrary, are produced only after infection has taken place ; so that not until a certain stage in the course of an infection has been reached is an inhibitory influence exerted upon the development of the bacteria by antibacterial poisons. Such an assumption is supported by the fact that many bacteria (typhoid-bacilli, the spirilla of cholera, and pus-cocci) possess their full power of virulence when they are first dis- tributed throughout the body in the blood, but afterward they lose their virulence and finally die. The protection which the alexins of the blood afford the organism is restricted to certain diseases —i.e., to those infections in which the mul- tiplication of the bacteria is confined to a limited area, or in which the transported bacteria have lost considerable virulence. On the contrary, in many infections the peculiar action of the blood in causing the bacteria to undergo degeneration seems to be entirely wanting, or, when itis pres- ent, is easily overcome—as, for instance, in those infections in which the bacteria multiply in the blood itself (anthrax), and also in those in which the bacteria, though not increasing in the blood (infections of tuberculosis and lepra) show no decrease in their virulence after metastasis. The protective power which the organism possesses against the poisons produced in the tissues by bacteria is to be found in the pos- sibility of a rapid excretion of the poisons, by the kidneys, and, under certain circumstances, through the stomach, the intestines, and the skin; T4 HEALING POWERS OF THE HUMAN BODY. and the action of these organs is sufficient, in certain cases, to prevent a fatal poisoning. Besides this, in certain infections there is evidently an antagonistic action on the part of the organism, in the sense that cer- tain poisons are rendered inactive or are actually destroyed by counter= poisons or so-called antitoxins, or that the toxins and antitoxins com- bine to produce non-poisonous substances, or, finally, that the products of metabolism of the tissues protect the latter from the action of the toxins. It is furthermore possible that by the spread of bacterial products through the body in certain concentration the tissues can be made immune against the same products, or also against the products of other bacteria (see § 30). The antibacterial properties of the blood and lymph in relation to certain bacteria have been established by the experimental researches of a number of authors. These experiments have shown that the destructive action of a definite kind of blood is ex- erted only upon certain species of bacteria, and never upon all; and that this action, at the same time, is subject to individual variations. According to the investigations of Fodor, Petruschky, Nuttall, Ogata, Buchner, Behring, Nissen, Pansini, and others, the blood and serum from dogs, rabbits, and white rats are capable of making the anthrax-bacillus powerless, and even of killing it; yet this action is a limited one, so that after the introduction of a large number of anthrax- bacilli into the blood taken from the blood-vessels, the bacilli after a little time begin to multiply. Defibrinated blood of dogs and rabbits can destroy the cholera-spirillum and typhoid-fever bacillus; it is, however, powerless against various forms of pus-cocci and against proteus; the same statement is also true with regard to the blood-serum. Human blood or blood-serum can cause the death of typhoid-bacilli, diphtheria-bacilli, and the bacilli of glanders, but it has no effect upon the bacilli of anthrax. If the bactericidal properties of the blood are exhausted, then these bacteria grow luxuriantly in either blood or serum. Hankin, Kanthack, Denys, Hahn, Léwit, and others, assume—on the strength of ex- perimental investigations—that the alexins are produced by the leucocytes. Kossel believes it to be possible that the nucleinic acid present in relatively large amounts in the leucocytes plays a part in the destruction of the bacteria. According to the opinion of Bitter, the bactericidal substance found in organs—that, for example, which one can derive from the lymphatic glands, the spleen, and the thymus gland—is to a certain extent different from that which is found in the blood and serum, and consequently does not originate entirely in the blood. It is certain that the bacteria- destroying power of the blood and blood-serum is not the only protective influence which can resist the spread of an infection or prevent it entirely, and can confer immunity. According to Emmerich and Tsuboi, the bactericidal albuminoids lose their power on being mixed with alcohol and dried in vacuo at 40° C., as also by being heated ; they recover it, however, when the dried material is dissolved in water containing from 0.05 to 0.08 per cent of potassium or sodium at 39° C., and their activity can thus be greatly increased (a thousandfold). According to the observations of Czaplewski, the anthrax-bacilli which have been taken up into the leucocytes degenerate more slowly within the infected organism than do those which are free in the blood or the tissue-fluids. It appears, therefore, that under certain conditions the cells protect the bacteria which are contained within them from the bactericidal substances in the fluids of the body. The antitoxins which render the bacterial poisons harmless, are generally first formed. during the course of the infection. Nevertheless, the investigations of Wassermann, Abel, Fischl, von Wunschheim, and others have shown that they are also contained in the serum of healthy human beings. Serum which contains an antitoxin that is effec- tive against a certain toxin—as, for example, against the toxin of diphtheria—may nevertheless serve as a medium in which the bacteria of this disease can be cultivated. The antitoxin, therefore, does not destroy the bacteria. § 28. The healing powers of the human body are furnished by those functions of life which are fitted to compensate for the derangements and changes produced by disease, and to render harmless or to remove altogether any harmful agent that may still be present in the body. When portions of tissue are destroyed, the healing consists essentially in the removal of the altered and dead parts, and in the replacement of these by new tissue. BACTERICIDA], SUBSTANCES; ANTITOXINS. 75 If from any cause the temperature of the body is abnormally low or abnormally high, compensation is effected by a suitable regulation of the heat-production and heat-dispersion, as a result of which the tem- perature of the body is once more restored to its normal height. If a portion of tissue is destroyed by a traumatism, the organism can repair the defect either by the production of new tissue on the spot (regenera- tion), or by providing a marked increase in other similar tissues (com- pensatory hypertrophy). If poisons have entered the body and have produced symptoms of poisoning, there are only two ways in which healing can result—namely, through the removal of the poison by the excretory organs, or through its being changed and made harmless within the body. At the same time the damaged tissues, under the influence of a normal nutrition, again receive a normal organization, and any defects that may remain are in due time compensated for. In infections the healing processes follow directly on the action of the protective forces ; indeed, the action of the latter constitutes the first stage of the healing process. Consequently the protective and the healing forces are in a measure identical. If the alexins succeed in hindering the growth of the bacteria, and then if the weakened bacteria are dis- solved and destroyed in the fluids of the tissues or within the cells, the first step in the healing process will have been taken, inasmuch as the causa eficiens has been removed. If by the massing together of cells in the infected tissues a protective wall is formed against the spread of the bacteria, or if the latter are retained in the lymph-glands and destroyed, then these phenomena may also be looked upon as processes which usher in the healing. In a similar manner the removal of the poisons or the bacteria which have entered the blood, by way of the excretory organs—the kidneys, the liver, and the intestines—not only acts as a protection against further localization of the bacteria and against in- creased intoxication, but also makes possible, through the removal of the noxious materials, the restoration of the injured tissues. In many infectious diseases the healing action of the protective agents already in the body(§ 27) is supplemented by the appearance on the scene of new substances, foreign to the normal organism, which as bactericidal substances, and as antitoxins, antagonize both the infection and the intoxication. These antagonistic poisons are produced either by the cells and the blood—both of which have been altered by the infection so as to perform other life-processes—or by the bacteria them- selves; they spread through the body by way of the tissue-juices, and thus form an impediment to the further spread and increase of the bacteria. These antagonistic bodies act. in one of two ways: they either hinder the reproduction of the bacteria and kill them, or they alter and render harmless the bacterial poisons, or they combine with them to produce an inactive, non-poisonous substance. It is also possible (cf. § 30) that in the case of a few infections they render the tissues to a certain extent unsusceptible to the effects of bacterial poisons. The cause of healing in infectivus diseases is most frequently referable to the fact that chemical substances produce an antagonistic action against the intoxication, and the bacteria are prevented from any further spread and thus die out. It has been proven, however, that in many cases the bacteria survive and probably continue to produce poi- sonous matters, which, however, remain harmless in consequence of the presence of the antitoxins. In individual cases the theory appears admissible that a lack of proper nutritive material produces the death of bacteria; this being true, perhaps, in the case ot localized. areas of infection (tuberculosis), in which bacteria remain for a long while 76 HEALING POWERS OF THE HUMAN BODY. enclosed in tissue which is dead and which, with the lapse of time, is undergoing altera- tion, and from which, consequently, they are unable to escape and find a new source of food. According to the investigations of R. Pfeiffer, which have been verified by Sobern- heim, Dunbar, Loeffler, and others, the blood-serum taken from animals which have been rendered immune as regards the bacilli of typhoid fever or the spirilla of cholera, and that taken from human beings who are either ill with or are convalescing from either typhoid fever or cholera, contains, besides certain antitoxins, a specific bactericidal substance (lysogenous substance of C. Fraenkel) which possesses this characteristic, viz., that when some of it is added to a virulent culture of the organisms belonging to either of the above-mentioned diseases, this culture becomes so modified in its composition that the bacteria, after being injected into the abdominal cavity of experimental ani- mals, rapidly break up into minute globules and become dissolved. According to the investigations of Gruber, Durham, Pfeiffer, Kolle, Sobernheim, Widal, and C. Fraenkel, the blood-serum obtained from persons who are actually ill with typhoid fever or with cholera, or who are convalescing from one or the other of these diseases, or who have even entirely recovered from such illness, exerts a damaging in- fluence upon the bacilli of the corresponding disease; this influence being of such a nature that in bouillon cultures the bacteria cease to make their ordinary movements, roll themselves together in clumps, sink to the bottom of the vessel, and then undergo disintegration. When the serum is added to a hanging drop of bouillon culture it causes the vibriones which were previously in active motion at once to become motionless and to collect together in little heaps. Gruber is of the opinion that this phenomenon is to be explained by the swelling up and bursting of the membranous coverings of the bacteria, and he assumes that this change at once renders it possible for the alexins to destroy whatever bacteria may be present in the body. In harmony with this view he applies the name agglutinins to the active substances or elements contained in the serum, and he believes that he is warranted in attributing to them the chief agency in bring- ing about a cure of the infectious diseases and in establishing the condition of immunity in respect to the same. Pfeiffer, on the other hand, denies that any such swelling of the cell-membrane takes place, and attributes the occurrence of the phenomenon referred to above to arrested development. To the active substances, the nature of which is wholly unknown, he gives the name paralysins. After Gruber had demonstrated the peculiar powers possessed by the blood-serum of typhoid-fever patients, Widal (Semaine médicale, Paris, 1896) made the proposition to utilize this action of blood-serum upon the bacilli of typhoid fever (or upon the spirilla of cholera) as an auxiliary method of establishing the correctness of the diagnosis during the actual progress of this disease (or of cholera). As a matter of fact, the investigations of C. Fraenkel, Du Mesnil, and others have since shown that it is possible, by means of this action of the blood-serum upon cultures of typhoid bacilli, to determine—both during the course of the attack and for a long time (even several months) afterward—whether the diagnosis of typhoid fever has been correctly made. Metschnikoff, Bordet, and others maintain that the recovery from any of the infec- tious diseases and the acquisition of the condition of immunity (compare § 30) are to be attributed chiefly to the activity of the leucocytes, which, as they contend, supply bac- tericidal substances to the juices of the body, and at the same time destroy the bacteria by taking them up into their cell-bodies. The latter performance, termed phagocytosis, plays nevertheless a subordinate réle, for the majority of the bacteria are destroyed by the cells only after they have been damaged or killed by bactericidal substances furnished py the blood and by the juices of the tissues. In many forms of infection the bacteria are, it is true, taken up into the cells, but they do not perish within the cell-bodies. Indeed, it is highly probable that they find, in the protoplasm of the cell, a soil favorable to their development. It has often been assumed that the fever present in infectious diseases is a process which favors the destruction of the bacteria, and it is not impossible that in individual cases it exerts such a beneficial influence. Thus, for example, it is easy to believe that a parasitic micro-organism that easily endures a temperature of from 37° to 38° C. (from 98.6° to 100.4° F.) may not endure one of from 40° to 41° C. (from 104° to 105.8° F.), and consequently that high fever-temperatures would be likely to hinder its powers of repro- duction. The conclusion must not be drawn from this fact, however, that the fever is a useful phenomenon or one that always favors the counter-balancing of one set of patho- logical disturbances by another set. And even in those cases in which the metabolism which goes on during the fever produces upon the bacteria a deleterious influence, it is not permissible to consider this as something useful which should be credited to the fever. One could only say that a portion of the morbid processes taking place in the course of an infectious fever induces the formation of certain products of chemical de- composition which act in an antibacterial or an antitoxic manner. CONGENITAL AND ACQUIRED PREDISPOSITION. 77 VI. Congenital and Acquired Predisposition.—Idiosyncrasy and Im- munity.—The Acquiring of Immunity.—Immunizing Inoculations. § 29. It is an old observation that different individuals are civersely disposed toward external harmful agents. In a certain number of cases this difference depends upon the general constitution—i.e., upon the gen- eral condition of the body; in other cases there are local conditions that produce these differences in behavior. Furthermore, the differences may be congenital and lasting, or they may be acquired, and are then often a transient peculiarity of the special individual. If an individual is markedly susceptible to the action of a certain disease, this condition is termed a predisposition to that particular dis- ease. If an individual shows an especial susceptibility to a particalar external influence, which is much more marked than the susceptibility thereto which is seen in the majority of mankind, and so constitutes an individual peculiarity, itis termed an idiosyncrasy. If, on the contrary, an individual is insusceptible to the action of an injurious force, so that the symptoms of the disease do not appear even when the individual exposes himself to this particular injurious influence, the condition is termed immunity, and, according to its grade, it may be distinguished as a relative or an absolute immunity. Predisposition has a great influence over the acquiring of infectious diseases, and also plays a prominent part in the causation of numerous other diseases. In one instance it is founded on general constitutional conditions, in another on those which are simply local; and besides it may be a lasting or a transient phenomenon. Mankind has a strong predisposition to measles, smallpox, scarlet fever, cholera, typhoid fever, malaria, tuberculosis, and syphilis;° and consequently, in those cases in which the protective forces against infection that belong natu- rally to every man prove to be insufficient, an infection would be sure to follow exposure, at least in the great majority of instances. It may also be assumed that the grade of susceptibility for these diseases is sot equally great in all individuals and that it varies in the same person at different times. Thus in epidemics of measles certain children who are exposed to infection escape, and later in life are taken ill during some subsequent epidemic,—a circumstance which in many cases can be ex- plained only by the supposition that the individual was for the time but slightly susceptible to measles. Excessive bodily exertion, as it appears, favors the entrance of an infectious disease into the system. Diabetes mellitus predisposes a person to tuberculous and suppura- tive infections. For the acquisition of many infections a peculiar local predisposition is often necessary, which is gained by local tisswe-changes, such as wounds, excoriations, and the formation of ulcers. In such cases, there- fore, the disease appears as a wound-infection. To this class belong many forms of suppurations, erysipelas, tetanus, hydrophobia, and, in part, tuberculosis, syphilis, glanders, anthrax, and other diseases; and although any of these diseases may occasion- ally be produced by infection through intact mucous membrane or skin or lung tissue, in the majority of cases a traumatic injury or an ulcera- tion furnishes the required locus minoris resistentice from which the infection can take its start. Thus, for instance, the suppurative infiam- mations produced by the so-called pus-cocci are mostly diseases which 78 PREDISPOSITION AND IMMUNITY. originate in wounds, excoriations, or ulcers; and in the last case they often represent secondary infections, which follow other infections that have resulted in the production of ulcers. Furthermore, they are fre- quently encountered in some part of the genital apparatus after parturi- tion—i.e., in tissues which, by reason of the childbirth, are torn or crushed, or, through the rubbing off of the epithelium and the-super- ficial layers of the connective tissue (as in the uterus), are laid open to the invasion of bacteria. Similarly, erysipelas and tetanus are diseases which ordinarily develop from small wounds, and the infection called hydrophobia is almost always caused by the bite of an animal having rabies. Finally, we may also assume that the virus of tuberculosis or of syphilis very often enters the tissues only where a local lesion has taken place. The predisposition to diseases which are not of an infectious origin is manifested particularly in those morbid affections which occur as the result of overexertion, as exhaustive conditions ; and also in those which are the result of temperature variations, such as the diseases due to chilling of the body or to the effects of heat-stroke. But this predisposi-. tion may also play a prominent part in still other diseases, as, for instance, in various forms of poisoning. Mental labor and psychical irritations, of which human life is full, can produce illness in predis- posed individuals—i.e., in those who have a certain weakness or imper- fect resisting power of the central nervous system when subjected to the demands made upon it; while in the majority of men the same amount of work will do no harm. It is well known that the functional capacity for work of the muscles is very different in different individuals, and that consequently many are easily tired; it is also known that many are very susceptible to heat and cold. Illness and death from heat-stroke occur only in a small percentage of individuals who find themselves situated in exactly the same circumstances—i.e., in those who, under the conditions named, are unable to endure the strain laid upon them. By chilling of the entire body, or of certain portions of it, which the majority of individuals can bear without receiving harm, many are made ill, and there are individuals who have an excessive susceptibility to influences of this nature. The weakened power of resistance to outward influences, and the easy exhaustion from work, constitute, in many cases, an tdividual peculi- arity of congenttal origin—a peculiarity which sometimes appears only in childhood and is then outgrown, and sometimes persists throughout life. In other cases it is an acquired state, which shows itself especially in convalescence from severe illness, and gradually disappears. Under certain conditions it may prove to be a permanent sequela of the illness out of which it developed. Idiosyncrasy in regard to certain injurious influences is generally congenital; at times, however, it is an acquired peculiarity of certain individuals, often showing itself in most peculiar ways. Thus, for ex- ample, the eating of fresh fruit, or of sugar, or of salad, produces, in certain individuals, nausea and vomiting. Others have an aversion to eating dishes prepared from liver or kidneys, and become ill if they compel themselves to eat these foods. Still others have a peculiar dis- ease, called urticaria, after eating crawfish, lobster, strawberries, rasp- berries, morels, or asparagus. The disease is characterized by itchy wheal-formations, characteristic skin-lesions, or abdominal cramps and vomiting. Nota few persons are unable to drink boiled milk without IDIOSYNCRASY AND IMMUNITY. 79 experiencing trouble therefrom. Alcohol, even in very small doses, may in certain individuals produce marked excitation, or even narcosis, or marked vaso-motor derangements. The drinking of cocoa can produce cardialgia and dyspeptic symptoms. Doses of morphine or chloroform that are borne by the majority of men without injury may produce, in certain individuals, severe symptoms or even death. A few individuals manifest a high degree of sensitiveness, on the part of the mucous mem- brane of the respiratory tract, to the effects of the pollen of certain grasses; and accordingly, upon the arrival of the hay-making time, through the inhalation of the pollen which are floating everywhere in the air, these individuals manifest symptoms of catarrhal inflammation of the nasal passages and the conjunctive, and often also of the larynx, the trachea, and the bronchial tubes. To these catarrhal symptoms, which in the severe cases may be accompanied by asthma and fever, the name of hay-fever or hay-asthma is given. Washing the skin with disinfecting fluids—as, for example, with sublimate or carbolic-acid solutions—in a strength usually borne without trouble, may cause not only local derangements of sensation and inflammation, but also, under certain circumstances, an eczema which spreads over the greater part of the body. On what, in particular cases, the idiosyncrasy depends is not clear. In many cases we may look upon a peculiar irritability of certain por- tions of the nervous system as the cause of the symptoms. In acquired idiosyncrasy —with regard, for instance, to the taking of certain foods— psychical factors may play a part. Immunity, like predisposition, is a peculiarity which plays an es- sential rdle in the pathogenesis of the infectious diseases, and the term “immunity ” is used to characterize the behavior of an individual with regard to infection. Ifa person is so constitued that the parasites under consideration cannot grow in his tissues, this condition is termed immu- nity, in the narrow sense of the term; if the peculiarity of the individ- ual is of such a nature that the poisons produced by the bacteria are, for him, harmless and produce no effect, one speaks of it as insuscepti- bility to poisons, and uses this term also in cases in which a person shows special powers of resistance when exposed to the influence of other poi- sons—as, for instance, those which come from the phanerogamous plants or from animals. Immunity and insusceptibility to the poisons of infections and intoxica- tions are partly congenital, partly acquired, and form, when they have existed from birth, a peculiarity which may belong to all men, or may be possessed by only a few individuals. Man is immune from various infectious diseases that are common to domestic animals—for instance, hog-cholera, symptomatic anthrax, and hen-cholera—while he is sus- ceptible to the infection of anthrax and glanders. So far as tubereu- Josis and actinomycosis are concerned, he is just about as susceptible to infection as are beeves, sheep, goats, and swine. There is an appar- ent immunity from scarlet fever in the case of a large number of persons ; and even as regards measles, small-pox, cholera, and influenza there exists in many persons a relative immunity. At all events, it happens that only a relatively small percentage of the population acquire scarlet fever, and also that, in regions where cholera and measles appear re- peatedly as epidemics, a portion of the population escape—a circum- stance which cannot be explained by the statement that these persons did not happen to come in contact with the infective poison which is . 80 NATURAL LACK OF SUSCEPTIBILITY TO PO.SONS. necessary for the production of the disease, but must be ascribed in part - to the fact that their bodies were, at the time the virus entered, not re- ceptive, or at least were only slightly so, so that the natural resistant power of the body was able to prevent the infection. It cannot, how- ever, be determined in these cases whether this immunity was absolute and general, or whether, at the point of infection, there were special local conditions which caused the infection to be suppressed. It is an interesting fact that the escape of an individual who has been often exposed to infection during an epidemic is no guaranty that he possesses a lasting immunity, since experience has shown that infection may take place during a later epidemic or later on during the same epidemic. The immunity may therefore be temporary and at the same time only relative; and it is probable that at certain times a stronger predisposi- tion may be present. Concerning natural immunity from the effects of poisons or natural lack of susceptibility to poisons, we know little at the present time; still, with- out doubt, many poisons are poisonous only to certain organisms, and it is probable that mankind is relatively insnsceptible to many poisons that are deadly to certain animals. This is true, for example, with regard to the toxic proteids and the organic bases which are derived from bacteria and also from higher animals (serpents) and plants. If one takes into consideration that many animals are slightly or not at all susceptible to poisons which act powerfully upon the human body— that, for instance, the hedgehog is not susceptible to the cantharidal poison and to the bite of poisonous snakes; that birds experience no bad effects from atropine and opium, nor goats from lead and nicotine; and, finally, that dogs, rats, and other animals used in experiments show a relatively greater resisting power to bacterial poisons and also to vege- table alkaloids than does the human being—it seems very probable that the converse may also be true. From this it would be proper to con- clude that the natural insusceptibility of man to many of the infectious diseases of animals rests upon his powers to resist the toxalbumins and toxins which the bacteria belonging to these diseases produce. The acquisition of relative or absolute immunity from poisoning by cer- tain infecting germs and poisonous substances is generally produced by either a single infection or intoxication, or by repeated infections or intoxications, which leave behind such an effect upon the body that it is no longer susceptible to the corresponding micro-organisms or poi- sons—in other words, that it can no longer be made ill by these micro- organisms or poisons. Besides, it often happens that the fact of an individual’s having passed through an attack of an infectious disease confers on him a relative or absolute insusceptibility to a disease which is closely related to it. The great importance which natural predisposition and immunity possess with reference to the origin of infectious diseases is contirmed not only by the consideration of the spread of plagues among men and animals, but much more by numerous experi- mental researches. Ifa mixture of diverse bacteria is injected into an animal, only a part of them develop and produce tissue-changes ; the others die. If the same mixture is injected into another animal of a different species, the bacteria which develop will be of different varieties from those which developed in the first instance. Further, a certain kind of Schizomycetes, inoculated into a certain species of mouse, produces cer- tain death, but when the same kind is injected into another species of mouse it proves harmless. Mice are very susceptible to anthrax ; rats are nearly immune. The poison of the so-called septicemia of rabbits kills with absolute certainty rabbits and mice; guinea-pigs and rats are, on the contrary, immune, while sparrows and pigeons are sus- ceptible to the poison. The spirilla of relapsing fever can be successfully inoculated PREDISPOSITION AT DIFFERENT AGES. Sl only in apes. Gonorrhea, syphilis, and leprosy cannot be successfully inoculated into any species of animals. Different animals of the same species, but of different ages, show dissimilar be- havior in this regard. Young dogs are easily infected by anthrax (Koch), while old ones are not. Diverse experiments have shown that, by suitable action upon the tissues, an exist- ing immunity from the effects of a certain infection can be rendered powerless. ! According to Roger,’ the natural immunity of rabbits and pigeons in respect to an- thrax can be overcome by injecting the non-pathogenic Bacillus prodigiosus at the same time that the anthrax is inoculated. The effective agent in this procedure, according to this author, is a decomposition product of the prodigiosus that is soluble in glycerin, and that produces a modifying action on the organism. According to Gottstein,? guinea-pigs may be made susceptible to the subcutaneous injection of hen-cholera bacilli, in respect to which they have a natural immunity, by previously injecting subcutaneously substances which dissolve blood-corpuscles, as hydracetin or pyrogallol; and he is of the opinion that toxic substances which make men or animals susceptible to infections act chiefly through their power of dissolving the blood-corpuscles. According to Leo,4 white mice, which are immune in respect to glanders, may be made susceptible by mixing with their food a slight amount of phlo- ridzin, which produces a toxic diabetes. According to Canalis and Morpurgo,’ pigeons may be made susceptible to anthrax by hunger. According to Lode, simple chilling of the body is capable of increasing the susceptibility to infections. The special diseases to which the new-born frequently succumb (aside from those which begin in intra-uterine life) are dependent partly upon a pathological weakness of the entire organism (especially in those born prematurely), partly upon the particular surroundings in which they are placed. Asphyxia, which is of such frequent occurrence, may originate either froma weakness of the body or from pathological intluences exerted during delivery. Infectious diseases may be acquired from infection through the cord, or through the accessible mucous membranes and the respiratory apparatus, during the passage through the parturient canal. Hemorrhages are dependent partly upon traumatic influences during birth and partly upon circulatory disturbances and infections. Icterus in the new-born is sometimes the result of a change in the mode of nutrition (reabsorption of the bile out of the meconium) ; sometimes, however, it is the result of infection. Children are, according to the observations of medical men, more susceptible than grown people to many infections; this is particularly true, for instance, with regard to whooping-cough, diphtheria, measles, and scarlet tever. In this connection it should be noted that the slight liability or the immunity of many grown-up people is due to the fact that they became immune through having had the disease during childhood. Further, it is to be remarked that children are more exposed to certain diseases—for instance, tuberculosis—than grown people. In advancing years hemorrhages, softening of the brain and heart, cancerous growths and the formation of gall-stones are especially frequent. Arterial diseases, designated by the term arteriosclerosis, and also gout, are seen already in the later years of middle life. This predisposition in old age to certain diseases depends in part upon degenerative processes, associated with early-developed senility of the tissues ; in part also upon the circumstance that certain effects which years bring with them gradually accumulate, so that finally the alterations which they produce become so prominent that they lead to disturbance of function, and ultimately to reeognizable morbid conditions. In general it is to be observed that many pathological symptoms of old age are secondary diseases, which show themselves only after other tissue-changes have reached a certain degree. We may mention, for example, hemorrhages of the aged, senile gangrene, and softening of the brain and heart, resulting from morbid processes in the arteries. The predisposition of the sexes to special diseases depends, in the first place, upon the 'Sirotinin, “Die Uebertragung von Typhusbacillen auf Versuchsthiere,’’ Zeitschr. f. Hyg., i., 1886. 2“ Contribution a ]’étude expérimentale du charbon symptomatique,”? Revue de méd., 1891. 3“ Beitrage zur Lehre von der Septikaimie,’” Deutsche med. Wochenschr., 1890. 4“ Beitrage zur Immunitatslehre,” Zeitschr. f. Hyg., vii., 1890. 5“ Ueber den Einfluss des Hungers aut die Empfanglichkeit fiir Infectionskrank- heiten,” Fortschr. d. Med., viii. 6 82 THE ACQUIRING OF IMMUNITY pectuiar construction and special functions of the genital organs ; the conditions present in pregnancy and during the puerperium furnishing a particularly favorable field for many diseases, as, for instance, infections from wounds. In general the diverse rela- tions of the sexes to certain diseases are explained by the differences which exist be- tween men and women as regards their respective modes of earning a livelihood, and, further, by the differences in the respective habits of the sexes. Differences in the predispositions of different races are shown in such diseases as malaria and dysentery, to which negroes are in general less liable than Europeans. The Japanese are said to be more susceptible to beriberi than Europeans. § 30. The acquiring of immunity with respect to a particular in- fectious disease is a thing of frequent occurrence, and has been known for a long time past by clinical observers to be a well-established fact. This fact is established principally by the observation that the greater number of men are ill only once with any of the infections such as measles, small-pox, whooping-cough, scarlet fever, and diphtheria, and that after such an attack they remain exempt from the influence of this particular disease even when they expose themselves in all sorts of ways to the danger of contracting it. The knowledge of this fact is old, and early in the eighteenth century it gave rise, in the Orient, to attempts to produce in men immunity against the natural contagion of small-pox by the inoculation of material from the pustules of the disease. In the latter part of the last century, Jenner discovered that the disease called cowpox—i.e., a milder form of pox, which is either a special variety of disease closely allied to human small-pox, or a weaker form of the latter— also afforded-protection against the true small-pox. Asa result of this observation, since the beginning of the year 1796, at first by Jenner himself, and after him by the practitioners of all the civilized world, artificial inoculations of cowpox have been carried out upon millions of men, and with the result that through these inoculations a high degree of immunity from the true small-pox has been secured, so that at the present time, in countries where vaccination is practised universally, we no longer have the extraordinarily widespread epidemics of small-pox which were constantly occurring in former years, nor does the disease any longer assume the form of a dangerous epidemic. The investigations with regard to the causes and origin of infectious diseases which have been undertaken during the last ten or fifteen years, and which have covered such a remarkably wide extent of pathological territory, have shown that the acquisition of immunity against a cer= tain infectious disease is secured by a person’s having once passed through an attack of that disease, and that this mode of acquiring immunity holds good for a number of infectious diseases, especially those which run an acute course; furthermore, that this immunity is sometimes a transitory, sometimes an enduring peculiarity of the indi- vidual who has had such an attack of the disease; and, finally, that when a pregnant woman acquires immunity she may transmit it to her child in utero. These observations have also shown that the inocula= tion, performed either once or repeatedly, of attenuated pathogenic bacteria—i.e., of bacteria which, on account of their decreased viru- lence, produce a disease that, in contrast to the natural infection with bacteria of full virulence, is merely a trifling affair, often confined to a circumscribed area—can also bestow, upon the individual so treated, immunity with regard to the corresponding disease. It has even been demonstrated that, for the production of insusceptibility to a certain disease, it suffices to inject certain chemical substances produced by the bacteria of that disease. PROTECTIVE INOCULATIONS. 83 In explaining how immunity from an infectious disease is acquired through the fact of once having had the disease, or by inoculation, we can as yet give only hypotheses; but it is a matter beyond dispute that the last few years have brought great increase to our knowledge concern- ing the forces which effect this immunity, and we have now reached a point where we at least know in what direction further researches should be made. After Pasteur had, in 1880, by experimentation proved that chickens could be made insusceptible to chicken-cholera by inoculation with attenuated chicken-cholera poison, and after it had been established by the repeated researches of various authors that similar results could be obtained with anthrax, symptomatic anthrax, and hog-cholera, they be- lieved they could explain acquired immunity by saying that, through either the inoculation or the first overcoming of the particular infec- tious disease, the food-material in the body had been destroyed (Pas- teur, Klebs), and consequently that the bacteria which entered the body later were unable to find food for themselves. This theory, termed the exhaustive theory, does not agree with the observed facts, and conse- quently at present it is generally no longer advocated. Metschnikoff’s view that, in consequence of the preventive inoculations, the mesoder- mic cells become accustomed to the inroads made upon their substance by the previously undisturbed virulent bacteria, and that when the lat- ter are again introduced they quickly take them up and destroy them, cannot in any wise be considered as an hypothesis possessing scientific foundations. According to the facts which have been ascertained by investigations concerning the natural protective powers of the body against infections, and concerning the natural mode of recovery from such infections, as also by the experiments made with regard to protective inoculation and with regard to the artificial healing of infective diseases, it is very prob- able that the acquired immunity is dependent upon the presence of certain chemical substances which are either poisonous to the particular variety of bacteria under consideration, or in some manner or other render harmless the poisonous products formed by these bacteria. (This is known as the poison theory.) It remains an unsettled question, however, whether these substances are the product of the bacteria or of the body-cells; further, whether the abolition of the poisonous action of the bacterial toxalbumins and toxins results from their destructive decomposition, or from the formation of some harmless combination of these substances, or from an immunizing of the cells with respect to these particular poisons. Some light is thrown upon this question by the past experiences in regard to the different ways in which it is possible to obtain, not only in experimental animals, but also to a certain extent in the human being, immunity as regards certain infectious diseases. Some further light is also obtained from experiments concerning the artificial healing of infec- tions which have already become manifest. As heretofore stated, it is possible in animals to produce, in agreement with the results obtained by Jenner’s cowpox inoculation, an immunity through the inoculation of attenuated specific disease-germs. This has been accomplished, for instance, in anthrax, in symptomatic anthrax, in chicken-cholera, in diphtheria, and in swine-plague. - The weakening of the virulence of bacteria is produced either by the action of high temperatures or by that of chemical agents, or by the air 84 DIFFERENT IMMUNIZING SUBSTANCES. only; further, it is also produced ‘by the inoculation of certain animals with the bacteria, and by long-continued cultivation of them on artificial media. Inoculation is generally carried out by injecting first markedly attenuated, then less attenuated, and finally fully virulent bacteria, along with their products, beneath the skin. According to the investigations of numerous authors, immunity may be produced by the injection of sterilized cultures in which the con- tained bacteria are dead. The diseases which may be warded off in this manner are the following: American hog-cholera, symptomatic an- thrax in cattle, diphtheria, the infectious disease produced in rabbits by the injection of the Bacillus pyocyaneus, and the infection produced in guinea-pigs experimentally by cholera-spirilla. Probably the immuniz- ing substances are contained in the cell-substance of the bacteria (Brieger, Kitasato, Wassermann). — A third form of artificial immunizing, which Raynaud tried as early as in 1877, but which was first.securely established by Behring in 1890, can be produced by the injection, into an experimental animal or even into man, of blood-serum taken from animals which were previously susceptible, but which have been artificially rendered immune by means of inoculations. The most extensive and at the same time the most successful experiments thus far made have related to tetanus and diphtheria—that is, to diseases in which the most striking feature is an intoxication by means of toxalbumins. Besides these, reports have been published of successful experiments with the blood-serum of immunized animals in cholera, swine-plague, anthrax, ty phoid fever, and the plague. The specific protection which the blood-serum affords can be secured not only by injections which are made before infection takes place, but also by injections which are made after infection has already occurred; thus justifying us in speaking of the serum not only as a protective, but also as a healing serum. Further experience has also shown that both for the prevention and for the cure of a particular infection « certain amount of serun is necessary, the precise amount depending, on the one hand, upon the severity of the infection, and, on the other, upon the activity of the serum itself, which increases with the completeness of the immunizing of the original susceptible individual who furnished the serum. If the injection is not made until after the infection has oc- curred, the amount of serum injected must be greater the longer the time which has elapsed since the infection took place. In the case of diphtheria the injection of curative diphtheria-serum has now been resorted to in thousands of cases of the disease—the se- vere forms as well as the mild ones—and there can no longer be any doubt in regard to its beneficial effects upon the course of the disease; these effects manifesting themselves in the establishment of a rapid im- provement of the patient’s general condition (increasing bodily comfort, diminution in the fever-temperature, and improvement in the state of the pulse) and also in the favorable course pursued by the local disease. In tetanus the curative effects of the serum treatment have been well es- tablished, so far as experimental animals (e.g., guinea-pigs and mice) are concerned; but it has not yet been surely established that the same effects can be produced in the human being. The blood-serum of immunized animals exerts its beneficial effects, without any doubt, through the presence in it of an antitoxin, which neutralizes the poisons produced by the bacteria. In the case of p#- tients, therefore, who have been treated with a certain aptitoxin—as, ORIGIN OF THE IMMUNIZING SUBSTANCE. 85 for instance, with the antitoxin of diphtheria—there is estaolished an immunity from the effects of the corresponding poison—that pro- duced by the diphtheria bacilli, in the case supposed; and this immu- nity is to be ascribed to the presence, in the circulating blood, of a fixed amount of this antitoxin. It has not yet been ascertained what is the chemical nature of the antitoxins, the presence of which in a great variety of infections and in- toxications (diphtheria, tetanus, pneumonia, snake poisons, ricin, abrin) has been demonstrated. It is ‘probable, however, that they should be classified as albuminous bodies. Their effective power is presumably that of destroying the specific bacterial poisons (Behring); it is also possible that they simply render the tissues insusceptible to the effects of these poisons (Buchner, Tizzoni, and others). Apart from the antitoxins the blood-serum of animals or of human beings who have been rendered immune may also contain bacterial substances which are capable of injuring or killing the bacteria them- selves; and it is claimed that this is true of cholera and typhoid fever infections (R. Pfeiffer, Gruber, Durham), and of the infections caused by the pneumococci (Emmerich). The origin of the immunizing substance in the blood is still an unsolved problem. One may suppose that it is the product of an espe- cial activity of the cells of the infected organism; yet it is very difficult to reconcile this theory with the fact that these substances which pro- duce immunity protect only against the particular form of disease in whose course they have originated; the tetanus antitoxin, for instance, being active only against tetanus, and the diphtheria antitoxin only against diphtheria. It is better to explain the phenomena by the sup- position that the antitoxins are substances which are produced by the bacteria themselves, or that the bacteria at least provide the material for the making of the antibody. Buchner is of the opinion that the antitoxins are specific bacterial cell-substances. On this theory the im- munization by means of healing serum would be effected in somewhat the same manner as it is by the injection of sterilized or attenuated bac- terial cultures. The distinguishing characteristics of the different modes of immunizing may then be stated as follows: in the injection of attenu- ated cultures (vaccine) the production of the immunizing substance occurs partly in the cultures, partly in the person inoculated; in the injection of sterilized cultures it takes place only in the cultures; and, finally, in injections of the so-called healing serum it takes place in the animal from which the serum is obtained. If the organism itself produces the immunizing substance, it is cus- tomary to speak of this as active immunization. On the other hand, if already prepared immunizing substances are introduced into the organ- ism from without, the term passive immunization is employed. For the foundation researches in regard to attenuated inoculation cultures grown in culture-media outside the body we must thank Pasteur, who, in the year 1880, dis- covered the fact that by the inoculation of cultures of chicken-cholera bacilli, which had become attenuated by remaining for a long time in the air, chickens could be made in- susceptible to this disease. Since that time numerous experiments have been carried on with other forms of bacteria—for example, with attenuated anthrax-bacilli and with symptomatic anthrax- bacilli. The best results have been obtained from inoculations of cattle against symp- tomatic anthrax. The results obtained by the inoculation of anthrax have been less successful, a portion of the animals dying from the inoculation, while in others no ab- solute immunity was obtained against a pew anthrax infection. 86 ATTENUATED INOCULATION CULTURES. Sheep and cattle may be made insusceptible to anthrax, and most easily in the fol- lowing manner (Koch): they are first inoculated with attenuated bacilli which will kill mice, but not guinea-pigs; then with bacilli which will kill guinea-pigs, but not strong rabbits, As vaccine against symptomatic anthrax, bacteria should be employed which have been attenuated by heat or by chemical agents, such as sublimate solutions, thymol, eucalyptol, and nitrate of silver; and by inoculations of this character cattle may be rendered immune. At the present time heat is most commonly used in preparing the vaccine (Hess, Kitt). A piece of infected muscle is taken from an animal that has died of symptomatic anthrax, and chopped into small bits; then it ismixed with one-half its weight of water, and squeezed through a linen cloth. Finally, the fluid is again filtered through a moistened piece of linen. This virulent mass is first spread upon glass plates or flat. dishes, and then transferred to a dry chamber where the temperature is kept at from 82° to 35° C. (from 89.6° to 95°F.). When thoroughly dried the virus may be scraped off and removed in the form of a powder. If one wishes to produce material for inocula- tion from this virulent virus, it should be triturated with double its weight of water, and this fluid is then to be steamed in a thermostat. By raising the temperature to 100° C, (212° F.) during six hours, one gets a weak immunizing material; by the action of a temperature of 85° C. (185° F.) for six hours, a more active preparation is produced. For immunizing an ox or a cow, about 0.5 gm. of a thin watery solution of the weak vaccine should be injected, preferably into the subcutaneous cellular tissue near the ani- mal’s tail; and, after the lapse of from eight to twelve days, the stronger solution should be injected in a similar manner. Hogs, according to Pasteur, may be made insusceptible to inoculation with virulent hog-cholera bacilli by the employment, as vaccine material, of bacilli which have become attenuated through a series of inoculations of rabbits. According to Emmerich, rab- bits may be made insusceptible to swine-erysipelas bacilli by the injection, into the veins of the ear, of small amounts of virulent bacilli-cultures diluted fiftyfold with water. For animals susceptible to diphtheria, immunity may be procured, according to Behring, by the injection, into their abdominal cavity, in small amounts ie c.c.), of cultures of diphtheria-bacilli which have been attenuated by exposing them for sixteen hours to the action of iodine trichloride (1: 500) ; and then, after the lapse of three weeks, by the employment of another injection containing a diphtheria-culture (0.2 c.c.) which has been permitted to grow for four days in bouillon to which iodine trichloride (1 : 5,500) has been added. Ata still later period, cultures of full strength are to be injected in increasing quantities. According to Emmerich, rabbits may be made completely insusceptible to pneumo- cocci by injections, first, of 0.3¢.c. of a strongly virulent bouillon-culture diluted in the proportion of 1:5,000, and afterward of bouillon-cultures of full virulence. Protective inoculations against rabies are resorted to only after the individual has actually been bitten by a rabid animal, and the practice is employed chiefly in France (at the Pasteur Institute), in Russia, and in Italy. For inoculation purposes it is customary to employ the spinal cord (desiccated in dry air at a temperature varying from 23° to 25° C.—from 73.4° to 77° F.) of rabbits in whom the disease has been created artificially. By means of this drying process, continued for a period of about fifteen days, the cord gradually loses its poisonous character. According to Protopopoff, it is not so much the drying as it is the heat which diminishes the virulence of the poison. From this piece of spinal cord, possessing diminished poisonous properties, small bits are taken and rubbed up in sterilized chicken-broth. Some of this mixture is then m- jected beneath the skin of the person who has been bitten; only a very weak mixture being employed at first, but afterward the strength being gradually increased. It is Pasteur’s opinion that the spinal cord, under the conditions we are now considering, contains partly microbes and partly a specific poison which they have produced ; and that this poison, if it becomes distributed throughout the body more rapidly than are the microbes, will confer on the organism immunity from the effects of a subsequent in- vasion of these microbes, and especially will protect the nervous system. It is there- fore necessary, if we wish to secure the desired degree of immunity, to introduce into the system as large quantities as possible of the chemical poison. The published reports of the institutes in which the Pasteur protective inoculations against rabies are made warrant the conclusion that these inoculations do actually prove effective in warding off an outbreak of rabies. According to the observations of Chauveau and others, it is possible, in making protective inoculations, to adopt the plan of injecting virulent bacteria in very small quantities, or in such a manner that they shall not be injuriousto life. In symptomatic anthrax, for example, this result may be obtained, in oxen or cows, by injecting very small quantities of the fluid into the extremity of the animal’s tail; these injections not causing a fatal illness, but merely some local disturbance. CULTURES OF TUBERCLE BACILLI. 87 According to Afanassieff it is possible to render animals immune by inoculating the granulating surface of a wound with virulent cultures. According to the researches of Schuetz, cattle may be rendered insusceptible to con- tagious pleuropneumonia by injections of the tissue-juices obtained from the lung of an animal suffering from the disease, provided the injections be made into the tail. There is produced by this means a localized inflammation, or one, at least, that is confined to the tail; and after it has quieted down, the animal will be found to be insusceptible both to the natural infection and to an infection of artificial origin. So far as cholera is concerned, both animals and men may be rendered immune (ac- cording to Hatfkine, Pfeiffer, Kolle, Voges, and others) by injecting into the body steri- lized and weakened cultures of cholera spirilla, and the immunity thus obtained (and which lasts for only a short time) is due to the formation, within the blood, of specific bactericidal antitoxic bodies (compare Voges: “ Die Choleraimmunitat,” C. f. Bakt., xx., 1896 [Lit.]). On the other hand, we do not possess any specific remedy by means of which we may save the life of an animal or a man that may happen to be infected with cholera. Immunity from the danger of being infected with typhoid fever may be secured (in the case of a human being) by the subcutaneous injection of sterilized cultures of typhoid bacilli (Pfeiffer, Kolle), and the establishment of this immunity may be recognized by the fact that the blood-serum of the person who has thus been inoculated will be found, at the end of a few days, to contain bactericidal substances. The immunization experi- ments which have been made in cases of persons who were already recognizably ill with typhoid fever have thus far, according to Brieger, Wassermann, and C. Fraenkel, given rather unsatisfactory results. According to the accounts published by Koch (British Medical Journal, 1897 ; Deut. med. Woch., 1897, No. 16; Centralbl. f. Bakt., xxi., p. 526), who, during the winter of 1896-97, carried on investigations into the cattle plague in Cape Colony, it is possible to immunize cows and oxen by the subcutaneous injection of 10 c.c. of the bile taken from cattle that have died of this disease; and, furthermore, the condition of immunity becomes established (according to the same authority) not later than on the tenth day. During the year 1890 Koch made the discovery that cultures of tubercle bacilli con- tain a toxin—tuberculin—which, when injected into the tissues of a person affected with tuberculosis, produces feverish elevations of temperature, and to some extent also local inflammations in the neighborhood of foci of tuberculous disease. For a certain length of time after this discovery had been made, the hope was entertained that in this tuberculin a remedy for the cure of tuberculosis had been found; but the trials made with it upon human beings and animals revealed the fact that it was indeed competent, after repeated injections had been made, to establish an immunity from the poisonous effects of the tuberculin, but that it was impotent to arrest the multiplication of the tubercle bacilli and also to prevent the disease from advancing; and, furthermore, that the local inflammations belonging to the disease were affected favorably by it only under certain special conditions, while in many instances the effect which it produced upon these inflammations was distinctly unfavorable (the tubercle bacilli being thereby more widely disseminated throughout the body). Notwithstanding these drawbacks, Koch’s discovery has proved to be one of great importance. In the first place, it possesses some practical value as a means of detecting the presence of tuberculosis in certain cases, for the injection of tuberculin, in the case of a healthy individual, gives rise to no fever; and besides, these inoculations are now used very widely for diagnostic purposes among the domestic animals. Then, in the next place, the reports published by Koch have stimulated others to make further investigations into the question of securing immunity by injecting the toxins of different bacteria; and in this way it has come to pass that we have discovered antitoxins for diphtheria, tetanus, cholera, and typhoid fever. Maragliano, during the last few years, has made attempts, by inoculating experi- mental animals (donkey, dog, horse) with the toxins derived from cultures of tubercle bacilli, to secure a serum that will cure tuberculosis. The observations thus far made, however, do not warrant the conclusion that this serum possesses the power to cure that disease in the human being. Koch, according to a communication which he published recently (‘‘ Ueber neue Tuberculinpraparate,” Deutsche med. Woch., 1897, No. 14), has suc- ceeded in obtaining, from highly virulent cultures of tubercle bacilli, asubstance which, as he claims, is able to confer immunity from the effects of all the constituent elements of these bacilli. In order to obtain this substance it is necessary that young cultures of tubercle bacilli should be dried in a vacuum-exsiccator and then reduced to a fine powder by trituration. The product of this triturating process is then thoroughly mixed with distilled water and placed in a centrifugal machine. The active substance is contained in the slimy deposit which forms as a result of the centrifugal action of the machine (Koch designates this slimy deposit by the letters T. R.), and the latter must again be dried and triturated, and then dissolved in water to which (for the proper preservation 88 DIPHTHERIA ANTITOXINS; SNAKE POISON. of the material) twenty per cent of glycerin should be added. (The preparation is inanufactured at the establishment of Meister, Lucius, and Briinning, in Hochst-on-the- Main, Germany.) In this fluid form the preparation contains 10 mgm. of solid sub- stance in each cubic centimetre ; and when it is to be used, it should be diluted by the addition of some physiological salt solution. When rather large quantities are in- jected, it is claimed that the animals become immunized in from two to three weeks. In treating human beings who are actually affected with tuberculosis it is well to begin with a dose of ;4, mgm. of the preparation, and then to increase the dose—the injec- tions being made every other day—up to 20 mgm. So far as one can judge from the published reports thus far available, the T. R. preparation does not appear to exert a curative action upon tuberculosis in the human being. The blood-serum treatment of diphtheria—i.e., the employment of the antitoxins con- tained: in the blood of animals that have been rendered immune as regards diphtheria, as a means of curing that disease when it is actually in progress or of warding off a diph- theria infection—is a discovery that we owe to Behring; and I may add that thousands of observers have confirmed the favorable effects which are produced by the procedure which he had first thoroughly tested by experimental methods. In the treatment of diphtheria patients it is customary to inject at a single sitting, beneath the skin of the thigh, quite large quantities (1,000 immunization units) of the serum. The term “normal serum ’’—i.e., a serum having the value of a single immunization unit—is applied by Behring to such serum as will, when mixed with a quantity of diph- theria poison equal to ten times the minimum fatal dose, and then injected, in the amount of jj, ¢.c., into a guinea-pig weighing between 200 and 300 gm., surely protect the animal from contracting the disease. Sheep and horses are the animals from which it is easiest to obtain the desired quality of serum. The preparation is put up and sold in quantities varying from 500 to 3,000 immunization units. If culture filtrates of the tetanus bacilli are rendered weaker by the addition of cer- tain chemical reagents (such as iodine trichloride or iodine in combination with potas- sium iodide) it is (according to Kitasato, Behring, Tizzoni, and Buchner) a possible thing, by repeatedly injecting such a filtrate, of increasing virulence, to establish in animals a condition of immunity as regards tetanus ; and, according to the same author- ities, the blood of these immunized animals contains an antitozin which can surely protect experimental animals from an infection with tetanus. The treatment of human beings who are actually suffering from this disease has thus far not produced very satisfactory results ; presumably because the curative inoculations can be instituted only at a com- paratively advanced stage of the disease. So far as the bubonic plague is concerned, animals and human beings that are sys- ceptible may be rendered immune by injections of-sterilized cultures of the plague bacilli ; and it appears, furthermore, that in the blood-serum of immunized animals (the horse, for example) there are present antitoxins which render it possible to utilize the serum both for immunization and for curative purposes. Calmette claims that by means of inoculations of very small doses of snake-poison, continued throughout a considerable period of time, animals may be rendered immune from the injurious effects of this poison, and that when this has been accomplished the blood-serum of these animals will also be found to possess antitoxic virtues (as regards the same poison) ; from which latter circumstance it may rightly be inferred that the serum may also be employed for curative purposes. In Brazil, Mexico, Africa, and some other places, various methods are employed for the purpose of protecting persons from the injurious effects of a snake-bite, or for that of curing them after they have been bitten ; and inall of these the snake-poison itself is used for the accomplishment of these purposes. Among these methods may be mentioned that of drinking some of the fluid secreted by the poison-glands, or that of rubbing some of the poison in a diluted state into small wounds made in the skin, etc. (Brenning). According to the researches of Ehrlich, mice may be made immune against ricin, to which they are most susceptible, by mixing very small doses of it with their food, and then afterward injecting additional small doses beneath the skin. The appearance of the immunity first shows itself six days after the first dose, so that upon this day the animal can withstand a dose thirteen times as great as at the beginning. By means of continued systematic inoculations the animal is rendered insusceptible to a dose eight- hundredfold stronger. The immunity is produced by an antitoxic substance, antiricin, which suspends the action of the poison. e CONSTITUTIONAL DISEASES FROM INTERNAL CAUSES. 89 VII. The Internal Causes of Disease and the Inheritance of Patho- logical Conditions. § 31. Among the internal causes of disease must be mentioned, first, all those peculiarities which have their foundation in the organiza- tion of the individual and owe their origin to some congenital local pre- disposition, and which, furthermore, superinduce diseases independ- ently of outside influences—i.e., without the aid of any other influences except such as our relations to the outside (more or less harmful) world necessarily bring with them. When morbid processes arise in this man- ner we speak of the special disease or of the special malformation thus arising as of spontaneous origin. Ina broader sense we may also reckon among the internal causes of disease the individual peculiarities which have been described in the last part (VI.), and to which the names predisposition and idiosyncrasy have been applied; but we are justified in doing this only in so far as the diseases in question clearly owe their immediate development not merely to the action of some outside injuri- ous influence, but also at the same time to the existence of a predisposi- tion or of an idiosyncrasy. Among the morbid conditions which arise from strictly internal causes—i.e., without the aid of specific external influences—and which either appear of themselves or are brought to development by some ex- ternal influence, it is possible to distinguish different groups, namely, one in which the body as a whole—the constitution—is involved; an- other, in which only a portion of the body, or a system, shows itself to be functionally deranged or perhaps even pathologically altered in its structure; and, finally, a third, in which either a single organ or even, perhaps, only a part of an organ, manifests these functional or structural alterations. At the same time it should be stated that no sharp divid- ing-line exists between these groups, for local pathological alterations may be associated with constitutional conditions. Then, again, it should be remembered that very frequently it is not only difficult, but at times impossible, to determine what part internal conditions and what part external exciting causes are playing in the production of a patho- logical condition, since we cannot measure the force of the external influ- ence which has called into activity the pathological processes. Among the constitutional diseases arising from internal causes are to be mentioned, in the first place, the development of dwarfs and the development of giants—i.e., disturbances of growth, of which the first is marked by an abnormal deficiency in the growth of all the parts of the body, of the skeleton as well as of the soft parts; while the second is characterized by a growth exceeding that of the ordinary individual. It cannot be doubted that both the dwarf and the giant growths are de- pendent on a congenital tendency ; but the same effects can be produced, at least so far as the inhibition of growth is concerned, by harmful influ- ences during the period of gestation and during later development, so that it cannot be always told with certainty whether an abnormal bodily growth is dependent upon a congenital tendency or upon pathological influences which have occurred during the period of growth (see § 22)— as, for instance, upon disturbances of growth due to disease or to the loss of the thyroid gland. The same difficulties are encountered when we attempt to explain the cases in which the body has perhaps attained a normal development of 90 INTERNAL CAUSES OF DISEASE. height, but manifests a general feebleness—a constitution which has no power to withstand a great variety of external influences; for this condi- tion may arise from an inherited weakly and defective body, or from harmful influences which have attacked it during intra- and extra-uterine development; and, again, a congenitally weak body and outside weaken- ing influences may both have acted upon the growth of the individual in a similar manner. Another constitutional peculiarity which may owe its origin to an inherited special predisposition is corpulence (obesitas, adipositas, lipo- matosis waversalis)—a condition in which fat is either deposited in excessive quantity only in tissues which normally should possess fat, or else is deposited also in regions which normally contain no fat, as, for instance, under the endocardium or between the muscles. In the ultimate analysis of this condition it must be recognized that this heap- ing up of fat in the body is always dependent upon a disproportion be- tween fat-production (that is, the supply of fat to the parts) and fat-con- sumption; this disproportion showing itself at one time in the form of greatly increased fat-production, at another in that of an abnormal de- crease in fat-consumption. As daily observation teaches, the energy with which metabolism goes on in the body is very different in different individuals, and changes also at different periods of life, so that the same amount of food tends at one time to fatten, while at another time it shows no such tendency. In the pathological constitution termed obesity, which sometimes depends on a congenital predisposition, the energy of the protoplasmic forces of destructive metamorphosis is weakened, so that an abnormal amount of fat collects even when a moderate or perhaps only a slight amount of nutritive material is supplied to the tissues. Gout, like obesity, is also a constitutional disease, which for the most part is dependent upon a constitutional inherited tendency, and consequently depends chiefly on internal causes. Exactly what is the essence of the disease we are unable as yet to state. One of its charac- teristic features is that a patient with this disease is subject to attacks in which deposits of uric acid are made in the tissues. According to Garrod and Ebstein, acute attacks of gout are dependent upon a stagna- tion of uric acid, which has its origin either in the kidney or in local conditions. Pfeiffer, on the other hand, is of the opinion that the essen- tial feature of a gouty predisposition consists in the fact that the uric acid is produced in a form which is soluble only with difficulty. Ac- cording to von Noorden, the production and deposit of uric acid are only secondary phenomena, which are induced by the presence of a particular ferment, which acts only locally and consequently is not dependent upon the amount and the behavior of the uric acid which is formed in another part of the body. Pathological changes which arise in single systems and organs from internal causes may manifest themselves in all the tissues of the body, and they involve at one time an entire system or organ, at another only a part of one. In the skeleton, in the first place, we may mention the following changes as illustrating what we have just stated: abnormal develop- ments, as regards size, of single parts—e.g., abnormal smallness of the extremities (micromelia), or of the head also (microcephalus), in con- trast with the trunk; or the abnormal size of one bone or of a group of bones (macrocephalus; the abnormal increase in the length of the fin- PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM. 91 gers; great growth of one finger, or of an entire foot, or of an extremity ; the formation of ribs in the neck, etc.). Occasionally supernumerary bones are developed—for instance, bones in the wrist or phalanges, thus leading to the formation of supernumerary fingers. There can also be developed atypical formations, such as bony growths (exostoses, hyper- ostoses), which may extend over a larger or a smaller portion of the skeleton, and may originate either spontaneously or as a result of some traumatism. . In the muscular system are to be noted the production of pathologi- cal bony formations, which occur either singly or in multiple form (my- ositis ossificans), and occasionally, in the period of childhood, give rise to a progressive stiffening of the muscular apparatus, by the transfor- mation of the muscles into osseous scales or plates. In the vascular system the lesions which are found consist in part of gross anatomical alterations—such as an abnormal division of the arteries, or some pathological development of the heart—and in part of ‘more delicate alterations, which reveal their existence only through some abnormal action on the part of the circulatory apparatus or through a tendency manifested by the patient to hemorrhages (hceemophilia) which take place spontaneously—i.e., without our being able to show that an injurious influence has been exerted upon the heart and blood-vessels. Some of the primary disturbances which the development of the central nervous system experiences manifest themselves only by some pathologi- cal disturbance of function or by a special predisposition to various forms of illness ; while others are distinguished by gross—i.e., by perceptible— anatomical changes, such as abnormal smallness of the cerebrum (micren- cephalon) or of the spinal cord (micromyelia), defective or absent development of particular parts (compare the chapter on Malformations), misplacement of the gray substance (heterotopia of the gray substance), the abnormal formation of cavities (syringomyelia), abnormal forma- tions of the neuroglia, etc. These disturbances may involve the func- tions of the organs of sensation and of the motor areas, as well as, and to an even greater extent, the psychical processes; and the pathological conditions termed idiocy, epilepsy, periodical and circular insanity, hysteria, and neurasthenia, as well as paralysis, mania, melancholia, and dementia, may have their origin in a congenital predisposition. Lately some persons have attempted to refer the tendency to crime to a congenital predisposition; and Lombroso in particular has sought to prove that the person who depends for his support upon crime and lives only for criminal purposes—the homo delinquens—is a congenital crimi- nal—i.e., he is a man who suffers from bodily and mental abnormali- ties; possesses other physical and psychical characteristics than those which belong to the normal man, or even to one who is simply mentally diseased; in a word, he must be looked upon as presenting the symp- toms of a special form of degeneration that tends in a well-defined direc- tion. According to Lombroso, a subnormal development of the anterior half of the cranium, together with a corresponding lack of development of the anterior portion of the cerebrum, when associated with an in- creased development of the posterior portion of the brain, necessarily produces a feebler development of the intelligence and of the moral sense, and favors a strongly developed instinct-life. Benedikt even goes so far as to maintain that we can distinguish in criminals a peculiar configuration of the cerebral convolutions, which are similar in type, as he claims, to those of animals of prey. 92 PATHOLOGICAL CEREBRAL FUNCTIONS. The views of Lombroso and Benedikt have met with opposition from various quarters, and have been attacked as incorrect; and there can be no doubt that there does not exist a species of human beings who are characterized by definite anatomical peculiarities by means of which one can say that they belong to the class termed homo delinquens in contra- distinction to that of the homo sapiens; for all the bodily peculiarities which have been mentioned as characteristic of the criminal type—as for instance, the beast-of-prey type of cerebral convolutions, the feebly developed frontal brain, the receding forehead, massiveness of the lower jaw, prognathia, asymmetry of the skull, marked prominence of the arcus superficialis and of the arcus frontalis, pathological conformations of the skull, etc.—are indeed frequent in criminals, but they are also far from infrequent in perfectly normal men. It is, however, not to be doubted that the tendency to criminality is very often dependent on a congenital predisposition, which is found in some special organization of the central nervous system; that, in this regard, the criminal has some resemblance to the insane person; and that also mental diseases —for instance, epilepsy and hysteria—are often observed in criminals. The pathological cerebral functions in persons who are pathologically predisposed to this class of diseases may develop primarily—1i.e., with- out external agencies having any influence on the disturbance; and under these circumstances the person concerned, even during the time of de- velopment and growth, or sometimes also later, manifests pathological changes in the functions of his cerebrum without having received any external injury that might explain such changes. In other cases, on the other hand, external influences—such as mental work, sorrow, care, psychical irritation, disease, etc.—are the causes which give rise to the particular illness—i.e., to the outbreak of pathological brain or spinal functions. In these cases the inherited prédisposition consists merely in an abnormal weakness, a tendency to disease of the central nervous system, which expresses itself in the circumstance that transitory influ- ences which would not act noticeably on a normal person are sufficient, in the case in question, to produce the morbid phenomena. Inasmuch as many influences—such as diseases, infections, psychical irritations— are adequate, under certain conditions, to produce mental disease in in- dividuals whom one must look upon as normal, so it is clear that, in many instances, it is difficult, if not impossible, to distinguish what part the internal causes—the inherited predisposition—and what part the external causes have had in producing disease of the central nervous system. As regards the peripheral nerves, it is especially their connective- tissue elements which often take on a pathological activity of growth under the influence of internal causes; and this activity manifests itself partly in the form of diffuse thickenings (fibromatosis of the nerves), partly in that of nodular thickenings (fbromata of the nerves), which either develop along the course of those nerves which are large enough to be dissected with the scalpel, or are scattered over the filaments of the finer nerves, often being present in large numbers throughout the areas of distribution of entire nerves, or even involving the entire terri- tory supplied by the peripheral nerves, the skin being the part most often affected (multiple fibromata of the skin). In certain cases the fibromatosis of the nerves is associated with an increase in the number of nerve-fibres; and as a result of this change there will be found in a given territory of nerve-supply abnormally numerous bands of nerve- INHERITANCE OF PATHOLOGICAL PECULIARITIES. 93 fibres, thickened by a pathological increase of the endoneurium, mostly thrown into serpentine or twisted shapes, or interwoven (cirsoid neu- roma, plexiform neuroma). Among the pathological conditions of the visual apparatus which arise from internal causes we should mention particularly dyschroma- topsia and achromatopsia, the congenital partial or total color-blind- ness, both of which conditions are frequently spoken of as daltonism, and are characterized by a want of perception for a portion of the colors (most frequently red and green), or even for all the colors. And, fur- ther, in this same category belongs the typical pigment-degeneration of the retina, in which a peculiar spotted-black pigmentation of the retina is seen, while simultaneously the acuteness of central vision and the perception of light are diminished and the visual field is narrowed. Finally, there should be added to this list certain forms of myopia, as well as albinism (the absence of pigment in the choroid), the latter of which conditions also involves some of the appendages of the skin. The only affection of the organ of hearing which, at least in part, can be considered as a primary developmental disturbance is deaf- mutism. Then, in the next place, we may also place in this category the various malformations of the external ear. In the skin and subcutaneous connective tissue new growths de- velop, which are the result of congenital predisposition. These growths are formed sometimes almost entirely of connective tissue, sometimes of epithelial tissues; they also often involve particular portions of the skin, as the cutaneous nerves, the blood-vessels, the lymphatics, or the adipose tissue. When they take on the form of extensive thickenings of the skin and the subcutaneous cellular tissues, they constitute the foundation of the conditions termed fibromatous, neuromatous, hemangioinatous, lymphangiomatous, and lipomatous elephantiasis. When they occur as circumscribed formations, they are known as birth-marks, soft moles, lentigo, freckles, and also as tumors of the lymph- and blood-vessels. Epithelial hypertrophy produces those changes which are called fish- scale disease or ichthyosis, ichthyotic warts, and cutaneous horns. In addition to the pathological conditions which have been enumer- ated there are many malformations of the body (compare the chapter on Malformations) or also of the internal organs, which must be con- sidered as of primary origin—i.e., which are not produced by the action of external influences on the already developing foetus. Finally, many forms of tumors (see the chapter relating to Tumors) belong in this . Class, especially those which are found to be already well developed at the time of birth, or which undergo development during childhood. § 32. Two explanations may be given of the mode of origin of those diseases which we attribute to internal agencies—diseases, therefore, in which external influences are either entirely absent during both intra- and extra-uterine life, or simply possess the significance of being a source of irritation sufficiently active to cause the development of a disease germ already present in the body. These two explanations are the following: either the pathological peculiarities of the particular individual are inherited from the ancestors, ov they are developed from the seed—i.e., from the sexual nuclet that have copnlated or from the segmenta- tion nucleus derived from such a combination. The inheritance of pathological peculiarities ig a fact which we learn, in the first place, from clinical observations; for many of the instances cited in § 31 of diseases which result from internal causes are 94 INHERITANCE OF PATHOLUGICAL PECULIARITIES. also illustrations of inherited tendencies within the family. In a certain number these peculiarities are transmitted from parent to child, while in other instances the hereditary factor is shown by the fact that tho grandchild manifests the peculiarities of the grandparents, the parents themselves remaining exempt; sometimes, again, it is shown by the fact that scattered members of the family (the collateral branches being in- cluded) manifest the pathological peculiarities which are under discus- sion. Dwarfishness and abnormal largeness of the body are peculiarities which frequently enough characterize certain families. Six fingers, harelip, right-sided position of the heart, birth-marks, multiple bony excrescences on the skeleton, fibromatous nerves, and multiple nerve- fibromata may appear in many generations of one family. Congenital hemophilia is also an inheritable pathological peculiar- ity, which in the descent is transmitted generally by the offspring to the male grandchild, whereby the daughters aid in the transmission, without themselves suffering from hemophilia. There may be, however, a direct transmission of the hemophilia to the children. Partial and total color-blindness is also sometimes an inherited family disease which attacks particularly the male members, and, like hemophilia, is trans- mitted through the female line, which does not suffer, to the male de- scendants. Typical pigmentation of the retina is inheritable, as are also near-sightedness, deaf-mutism, and certain forms of progressive muscular atrophy and polyuria (Weyl). Gairdner and Garrod state that in about ninety per cent of all per- sons suffering from gout the disease also existed in their forefathers. Of the pathological conditions of the nervous system, many are trans- missible; to these belong especially periodical and circular insanity, epilepsy, hysteria, and congenital madness (origindre Verritcktheit), and, to a somewhat less extent, melancholia, mania, frenzy, and alco- holism; while the progressive paralyses, the deliriums, and the condi- tions of mental exhaustion are but slightly influenced by heredity (Krae- pelin). Hagen estimated the number of hereditary insane at 28.9 per cent, Leidesdorf at 25 per cent, Tigges at over 40 per cent of all cases, and Forel holds that from 69 to 85 per cent may be accounted for by heredity. In the most severe forms of hereditary degeneration the pathological conditions themselves are inherited; but more frequently the hereditary influence only produces a predisposition to disease, and the actual mor- bid condition first shows itself only after the central nervous system has been acted upon by some external injurious influence. The form of the disease may remain the same in the descendants as in the ancestors (identical heredity). More frequently a change takes place in the form of the disease (transformational herecity), not infrequently in the sense that the severity of the disease increases from generation to generation, a condition which is termed degenerative heredity. According to Morel, there may appear, for instance, in the first gen- eration, nervous temperament, moral depravity, excesses; in the second, a tendency to apoplexy, severe neuroses, and alcoholism; in the third generation, psychical changes, suicide, intellectual incapacity ; finally, in the fourth generation, congenital imbecility, malformations, arrests of development. As already stated in § 29, the special predispositions to this or that disease which individual families or sometimes entire races show are hereditary peculiarities. Thus, for example, it cannot be doubted that DIRECT AND COLLATERAL HEREDITARY TRANSMISSION, 95 certain families have a stronger predisposition to certain infections (tu- berculosis) than others. But, on the other hand, it often happens that imsusceptibility to certain injurious influences is a valuable attribute of a family. There is nothing at all strange in the fact that there are inheritable diseases, since it is a well-known fact that in a family not only the pecu- liarities of race, but also those of that particular family, may be inher- ited, and that the qualities characteristic of one or the other or of both parents often enough recur in the children. In order that hereditary transmission may take place, it is simply necessary that the peculiar quality under consideration should represent not merely a somatic change accidentally acquired in the course of the life of an ancestor, but rather an individual peculiarity of this ancestor which he in turn had inherited from his forefathers. Diseases which, in a normal individual, originate only when he is subjected to external harmful influences are never in the true sense inherited (see § 34); this expression can be em- ployed only in regard to those pathological conditions which already existed m the germ. Tf, for example, a disease—such as a mental disease or nearsightedness—is the product of a special inherited predisposition plus the effect of harmful influences which have acted upon the body during life, only that part can be transmitted which was received by inheri- tance, but not that which was derived from external influences—i.e., the part which was acquired. In direct inheritance—i.e., in that form of inheritance in which pa- rental peculiarities are transmitted to the child—the transmission of both normal and pathological qualities can take place only when both sexual elements, in the condition in which they are at the moment of their union, contain, in a potential form, the characteristics of both pa- rents, in so far as these characteristics are of a transmissible nature; and consequently the product of their union—the segmentation-cell— must then contain within itself both the paternal and the maternal quali- ties. Since the sexual cells do not represent a product of the body which is formed only after a certain stage in the course of life is reached, but should rather be looked upon as independent formations which, located in special organs, separate themselves at an early period from the rest of the body (that is, from the somatic cells) and then— continuing to derive their protection and nourishment from the body to which they belong—lead an independent life, there remains but one way in which we can explain the phenomenon of inheritance: we must as- sume that the separate sexual cells contain, from the time of their ori- gin onward, essentially the same characteristics (in a potential form, of course) as belong to the body in which they dwell; in other words, that the sexual cells, as well as the body itself, have inherited in general the same qualities from the ancestors. Since in the act of fructification only the nuclei of the sexual cells—i.e., only parts of them—come to copulation, we are compelled further to assume that the bearers of these qualities are only the nuclei, and that the peculiarities belonging to the individual who grows out of this combination of the sexual nuclei reside in and are bound up with the organization of the nuclei. If there appear in the descendants normal or pathological character- istics which are found collaterally (in an uncle, a great-aunt, or a cousin) but not in the parents, this is spoken of as collateral hereditary transmis- sion; in this case the only supposition that will explain it is that the sexual nuclei, in their origin, received characteristics which the bodies 96 ATAVISTIC HEREDITARY TRANSMISSION. of the parents’ did not contain; or, at all events, we may assume that these characteristics did not undergo development and become manifest in these bodies, whereas in some of the relatives they did thus become manifest. If there appear in an individual normal or pathological characteris- tics which were wanting in his parents, but were present in the grand- parents or great-grandparents, this is spoken of as an «tavistic heredi- tary transmission ; and the appropriate explanation of this is to be found in the fact that the peculiarity of the grandparents or great-grandpa- rents was transmitted to the sexual nuclei of the son—i.e., of the son and grandson—but did not develop in the body of the first, while this latent quality manifested itself again in the grandson and in the great- grandson. The attempt has been made to give to the atavistic mode of trans- mission—which is of frequent occurrence and is confined to the nearest generations of the ancestors—a wider significance in pathology. Thus it has been proposed to explain many newly arising pathological mani- festations, which seemed to resemble certain somatic peculiarities pos- sessed by remote animal species in the ancestry of man, as a reversion to the type of those ancestors. Thus, for instance, microcephalia and micrencephalia have been explained as a reversion to the ape type, and Lombroso is also inclined to look on his homo delinguens as an ata- vistic appearance. Nevertheless there is no doubt but that they have gone too far in this respect, and have characterized, as atavistic forma- tions, various acquired pathological formations and fresh variations of germs (compare § 33). Aside from the question of a reversion to the type of the nearest generations of ancestors, atavism plays only a minor part in pathology, and it can really be employed only in the explana- tion of pathological formations when their tissues show a certain fluctu- ating behavior, characterized by the fact that frequently formations arise which in phylogeny or ontogeny represent the primary stages of the then normal conditions. In this category belong, for instance, the oc- currence of certain forms of the ear or of supernumerary ribs, the increase in number of the mammary glands and nipple, the develop- ment of certain muscles belonging to the Mammifera which come nearest to man in the scale of relationship. It is accepted by many authors that in isolated cases acquired diseases nay, under certain circumstances, be transmitted to the descendants, and some even go so far as to say that the possibility of hereditary transmission may be conceded to a deformity sustained through injury; indeed, they consider that this has actually been proved for some in- stances. In support of their opinion, they believe that they are warranted in pointing to the hereditary transmissibility of birthmarks, malformations of the fingers, myopia, mental diseases, predisposition to tuberculosis, and other conditions, in regard to which they assume that these conditions in the first instance showed themselves only as acquired inaladies, and that they were then transmitted to the descendants. Further, they believe that they can point to observations on animals—full accounts of many such observations are on record—as evidence that injuries give rise to deformities which later on are be- queathed to their offspring. An unprejudiced examination, however, of the collected material which is brought forward in support of this opinion shows that observations which establish the existence of such a thing as the hereditary transmission of acquired pathological characteristics in an individual do not exist; that in the observations in question the defectiveness of the proof consists at one time in an error of observation, at another ina false inference from a correctly made observation. Take, for instance, the fact that in a child a birth-mark appears in a region of the skin exactly corresponding to that in which the mother has a scar. The advocates of the doctrine under discussion would quote this as an example of the inheritance of a deformity ; and yet they would be entirely wrong, for scars and MODE OF ORIGIN OF TRANSMISSIBLE PATHOLOGICAL PECULIARITIES. 97 birth-marks represent two entirely different forms of tissue-change. When among the de- scendants of a man who suffered from any form whatever of mental disease, but revealed the existence of that disease by the perversity of his actions only after he had at- tained a certain age, there appears an inheritable affection of the central nervous system ; or if we make a similar observation in regard to the appearance of myopia, we must not conclude from such observations that the disease first observed (in the ancestor) was strictly an acquired condition. The term acquired, in the sense in which it is employed in physical science, can be applied only to that which, in the course of the life of an in- dividual, arises only through outward influences, but not to a peculiarity the first begin- nings of which already existed in the germ, although the peculiarity itself may not have become recognizable until outside exciting causes had exerted their intluence upon its development. Should there appear in a family hereditary mental disease or hereditary myopia, the first case may have already been due to a pathological condition of the germ, although no manifestations of the disease occurred until some of the outside influences of life called them into activity and so rendered the recognition of the pathological con- dition possible. Here, too, the particular pathological condition represents no true acquired disease. There is still another thing that militates against the idea that an acquired patho- logical condition may be transmitted from parent to child; I refer to the simple consid- eration that the human race is exposed to so many injurious influences, and its indi- vidual members are so frequently sufferers from diseased conditions and mutilations, that, if this doctrine of the transmission of acquired pathological conditions was true, mankind would soon be in a condition of extreme suffering and misery, and would then perish. And this statement would still be true if only a portion of the acquired ailments was transmitted to the descendants; for, despite all their diseases and mutilations, human beings continue to bring descendants into the world. The act of fructification—that is, the first step which leads to the production of a new individual—is accomplished by the copulation of the sexual nuclei—that is, of the ovum nucleus and that of the spermatozoén ; and, according to the researches of the last decade, there is no longer any doubt that these two nuclei are the bearers of the hereditary characteristics of the parents, and that the individuality of the two copulating nuclei re- sides in their organization. It is impossible to imagine in what manner processes that take place in the body-cells can bring about in the sexual nuclei, which are lying inside of certain special cells in the sexual glands, such an alteration in their organization tnat from that moment onward they shall contain in potential form the acquired characteris- tics of the body, and shall transmit them, after copulation has taken place, to the descendants. Darwin in his time defended the opinion that acquired characteristics could be transmitted to the succeeding generations, and sought to make these phenomena intel- ligible by assuming that molecules from all the cells of the body contribute to the forma- tion of the embryonal cells, and that, as a result of this, any alterations which take place in the organism can be transmitted to the embryonal cells. Notwithstanding this expression of his opinion, Darwin makes statements in his writings which do not agree with this opinion; indeed, some of them directly contradict this view. § 33. As is shown in the explanations given in § 32, inherited dis- eases are always such as arise in the first place from some internal predis- position—i.e., such as have developed from actual beginnings located in the germ or embryo—or at least they are diseases in which the element of pre- disposition is a congenital characteristic. Conversely, the statement may be made that all the normal or pathological qualities present in the embryo are transmissible. Consequently the question of the primary origin of inherited dis- eases coincides with the question concerning the nature of the causes of internal diseases—i.e., concerning the acquisition of those pathologi- cal characteristics which we regard, after they have made their appear- ance at some later date, as arising spontaneously, and as having their first traces in the germ or embryo. The first appearance of new pathological characteristics which are hereditary may be connected with the fact that, as a result of sexual procreation—i.e., of the union of two sexual nuclei, of which the one is the bearer of the transmitted qualities of the paternal ancestor, the other of those of the maternal—new variations are constantly appear- 7 g 98 MODE OF ORIGIN OF TRANSMISSIBLE PATHOLOGICAL PECULIARITIES. ing, so that the fruit—that is, the child—never entirely resembles one parent; more frequently, in addition to the qualities which the parents offer, it also possesses new qualities. Even if we assume that the sex- ual nuclei sometimes contain in potential form exactly the same charac- teristics as those belonging to the parent out of whom they originated, the product resulting from the copulation of these nuclei would never- theless present a certain degree of variation from the type of either parent. It may be said, however, that in a case like this the differ- ences between the children of such a couple would be only slight. As a matter of fact, the different products of the same parents may vary to an immeasurable extent by reason of the fact that the sexual nuclei themselves contain a mixture of the characteristics inherited from the paternal and maternal ancestors, and that this mixture is never the same in the separate sexual nuclei of the individual. This statement is in harmony with the fact that the children in one family always present important differences in their bodily and mental characteristics, and with the further fact that a strong degree of resem- blance is observed only in the case of twins that have been produced from one egg, or, in other words, only when the process of development has in both children started from the same act of copulation. The embryonal variations resulting from the mixture of two indi- vidually different hereditary tendencies can find their expression in most varied qualities of the body and mind of the developing child. If these do not deviate in a marked degree from the characteristics which the different members of the same family are wont to show, the condi- tions are looked upon as normal, and generally receive no particular attention; but if, on the contrary, important differences in character are produced, the occurrence attracts greater attention, and, according to the value which it has for the individual, it is considered at one time as something favorable, at another as something unfavorable, something pathological. When small, weak parents beget children who grow to be big, strong men, or whose mental ability surpasses considerably that of the parents, it is regarded as a favorable occurrence. If a genius in any branch of human knowledge and skill should, as sometimes actually happens, develop suddenly in a family—i.e., without any hint of a par- ticularly high mental development having been shown among the ances- tors—the occurrence would attract universal attention and would be con- sidered a fortunate event. But if, on the other hand, strong parents beget children that are weak or physically defective, or if their mental development remains considerably backward as compared with that of the parents, or if a complete arrest of development shows itself in some department of their mental faculties, we call this newly appearing varia- tion unnatural, pathological. If we take into account the experiences which the pathology of man and of animals furnishes, the assumption seems fully warranted that among the transmissible pathological conditions and tendencies very many, perhaps the majority, are referable to a variation of the germ based upon the amphimixis. This explanation is available, therefore, for the group of the hereditary diseased conditions and predispositions of the central nervous system, for hereditary myopia, for hemophilia, for pigment-degeneration of the retina, and for polydactylism. If such abnormal characteristics repeatedly show themselves in the offspring of parents who are healthy and have healthy ancestors, one can conclude that the sexual nuclei of the parents, although individually normal, have MODE OF ORIGIN OF TRANSMISSIBLE PATHOLOGICAL PECULIARITIES. 99 through their union produced a patholcgical variation. This conclu- sion is substantiated when one or both parents produce normal offspring through copulation with other individuals. Besides the variations which are the result of normal sexual repro- duction, it is highly probable that pathological variations of the germ, which lead to the production of transmissible pathological characteris- tics, also owe their origin to the circumstance that harmful influences. may have been exerted upon sexual nuclei or upon the segmentation nucleus, or else that the process of copulation—i.e., the union of the sexual nuclei—may have been disturbed in some manner. The sub- stance which acts prejudicially may be a product of the body, or it can come from without and at the same time also produce its harmful effect upon the body. Consequently in these cases one can speak of the acqui- sition of a transmissible pathological peculiarity through some harmful influ- ence emanating from the outer world. But this expression is not intended to convey the idea, as many seem to believe, that the tissues of the body, under the influence of outside harmful agencies, first undergo cer- tain alterations and then in some manner convey these alterations to the germ-cells. The proper explanation is, rather, that the injurious influ- ence exeris its force directly upon the sexual nuclei or upon the segmen- tation nucleus, and here produces some sort of a change, which at a later date leads to a pathological transformation of the individual who is undergoing development from the impregnated egg. So far as the na- ture of the resulting pathological variation is concerned, it is a matter of no importance whether the somatic tissues are also subjected to alter- ations, and of what nature these are. If a transmissible pathological characteristic has been produced, it may —provided it does not abridge life or prevent reproduction—actu- ally be transmitted from parent to offspring, although this need not necessarily happen. The chances that this particular characteristic will be transmitted are greatest when the parents both possess it; when, for instance, both parents are affected with hereditary deaf-mutism or with near-sightedness. If the characteristic is wanting in one parent, there is a good prospect that a new germ-variation may be produced, in which the pathological characteristic fails entirely to manifest itself, and in later generations completely disappears. If there are several descend- ants, and if the tendency to, this pathological defect has not entirely dis- appeared, it may show itself in only a few of the descendants, and then either in a modified or in an aggravated form. Finally, it sometimes happens that the characteristic remains latent in one generation—i.e., it does not extend beyond the sexual cells—and then reappears in the second. There seems to me to be no doubt that, through the copulation of two sexual germs possessing different hereditary tendencies, variations may be produced, and that among these theze may be certain ones which we should consider as pathological. It is amore difficult thing to answer the question whether, besides these, there are not trans- missible variations of a pathological character which owe their origin to influences that affect the sexual nuclei or the segmentation nucleus; and with what frequency, if the question is answered in the affirmative, these influences are exerted effectively. Weis- mann, according to the statements made by him in his most recent publication, is of the opinion that the first beginnings of the hereditary variations are not to be located in the amphimixis, but rather in the direct action of external influences upon the sexual nuclei. Starting out with the assumption that the variable cells or groups of cells derived from the germ (by him called hereditary pieces or determinates) are represented in the germ- plasma by special particles, which are formed by the grouping together of a number of life-trophoblasts, or biophores (molecular groups which represent the smallest units of 100 TRANSMISSIBILITY OF INFECTIOUS DISEASES. living matter), and which he calls determinants or determining pieces, he believes that he is warranted in ascribing the transmissible variation primarily to the circumstance that external agencies alter these groups of determinants and determinates contained within the nuclear chromatin, in such’ a manner that afterward the hereditary pieces or deter- minates which are dependent upon them also undergo a change. He believes that such an influence might be exerted by excessive nourishment of a determinant, causing it to assume a more rapid growth. Thus, for example, he believes that many congenital mal- formations—as, for instance, an increase in the number of fingers and toes—can be at- tributed to the overfeeding and consequent reduplication of the groups of determinants. The amphimixis has, according to Weismann, only a secondary influence on the produc- tion of a lasting variation, and this influence he defines to be the following: that it con- stantly, in some new manner, mixes the variations which are necessitated by the altera- tions of the determinants, and yet does not itself produce any new variations. “The alterations in character which the determinants undergo, through unequal influences of nutrition, constitute the material out of which, by means of amphinweds in connection with selection, the visible individual variations are developed ; and then, by an increase of these variations and by their combining one with another, entirely new varieties are created.” ; I agree with Weismann to this extent: I consider that the Appearance of new varia- tions of a pathological nature is partly to be considered as resulting from changes which have been effected in the determinants contained in the sexual nuclei through the direct action of outside influences. I do not, however, believe that there is sufficient ground for attributing, as does Weismann, the development of new separate parts to the greater nourishment of individual groups of determinants. Such a dependence of the germ- plasma upon the surrounding nutritive material appears to me to be scarcely conceivable, and is in opposition to all notions which we have hitherto held regarding the nutrition of cells. Accordingly, qualitative rather than quantitative alterations in the nutrient material would seem to be what is required in order to effect changes in the organiza- tion of the determinants ; and, further, I believe that aimphimixis holds not a secondary, but a primary position in the production of pathological variations, in the sense that it is itself competent to produce new variations. Finally, it seems to me that we cannot wholly set aside the hypothesis of Nageli, according to which the idioplasma is capable of altering its own condition, from within outward, in certain fixed directions and ac- cording to certain fixed laws, and thus may produce new characteristics. § 34. In addition to the pathological conditions already enumerated, there are a few infectious diseases in which an hereditary transmission seems to occur. These are syphilis, small-pox, varicella, intermittent and recurrent fevers. At all events, in these diseases cases are some- times observed in which a child, at the time of its birth or soon after- ward, develops symptoms of the same disease from which the father or the mother had been suffering either at the time of procreation or dur- ing the period of gestation. This, however, is a phenomenon entirely different from that already spoken of as hereditary transmission. Infectious diseases are caused by organisms which multiply in the body. The transmission of the disease to the child becomes possible only when the infecting organisms belonging to this particular disease either find their way into the sexual germ-cells and then also into the impregnated egg, or else pass from the maternal organism into the tis- sues of the child while developing in the uterus. The latter can occur so long as the child remains in the uterus, and it obliges us to assume that the infecting organisms pass through the decidual membranes and the outer coverings of the ovum—or, in the later periods of gestation, through the placenta—and thus are transported from the maternal to the child’s organism. It is also possible that, when the parents keep up cohabitation for a certain length of time after impregnation has taken place, the micro-organisms which enter the vagina with the sperm may pass on into the uterus, and in this manner infect the already impreg- nated egg which is within that organ. - The transmission of bacterial infectious diseases to the embryo is beyond all doubt a possible thing. In the case of syphilis this may A PSEUDO-FORM OF HEREDITARY TRANSMISSION. 101 take place at the instant of impregnation as well as later during intra- uterine development, and the syphilis may be communicated to the child as well by the father as by the mother. In the case of small-pox, endo- carditis, and scarlet fever, many instances of infection of the foetus in utero have been reported; and, from recent observations and experi- mental investigations, there can no longer be any doubt that anthrax- bacilli, pus-cocci and pneumococci, and, under certain conditions, also typhoid-bacilli, can pass through the placenta to the foetus. This can oceur only when the bacteria gain an entrance into the maternal blood- channels of the placenta, and are capable of multiplying there, and then of penetrating into the foetal vessels—a procedure which is rendered possible chiefly by the damage done by the multiplying bacteria to the placental tissue, thereby enabling them to penetrate into the latter and to multiply within it. There are therefore both conceptional and intra-uterine placental infections, which constitute a pseudo-form of hereditary transmission, in which the peculiar characteristics of the individual are not transmit- ted to the embryo, but instead an organized poison finds its way into the germ or into the already partially developed foetus, where it undergoes further development and then calls into activity the same disease as that with which the parent is infected. Our knowledge concerning the frequency of these occurrences is, un- fortunately, still deficient. In the case of the most frequent of all chronic infectious diseases, tuberculosis, the rdle played by the disease proper is still imperfectly understood. Such a form of hereditary transmis- ion is believed to exist by many persons in lepra, but it is denied by others; and in syphilis, in which the frequency of its occurrence is not denied, our knowledge of the nature of the specific poison is still very meagre. In acute bacterial infections we know only of a transmission of the infection to the already developed embryo. How far the egg can be infected in the early stages of impregnation or at the actual moment of conception, without its further development being hindered thereby, is unknown. If, during bacterial infections, infection occurs at the moment of con- ception, one must believe that the organisms belonging to the particular disease under consideration must have existed in the sexual glands at the time when the sexual cells were thrown off, then must have reached the egg at the moment when it became impregnated, or immediately afterward, and finally must have continued to live in it without hinder- ing the further development of the egg. Then, besides, the assumption must be made that the schizomycetes push their way into certain regions of tissues during foetal development, and yet do not give rise to patho- logical processes until a later date is reached. In a manner similar to that by which infections are carried to the fcetus can an acquired insusceptibility to some particular disease be transmitted from the mother to the child—that is, the antibodies (Ehrlich) present in the maternal organism can be trans- mitted tothe foetus. On the other hand, a transmission of immunity through the sperm, at the moment of conception, does not take place, and likewise there is no such thing as a genuine hereditary transmission of an acquired immunity. The experiments of Charrin and Gley, which are quoted in support of this idea, admit of a different inter- pretation. aaprmee é CHAPTER IIL. Disturbances in the Circulation of the Blood and of the Lymph. I. General Circulatory Disturbances Dependent upon Changes in the Function of the Heart, Changes in the General Vascular. Resistance, and Changes in the [lass of the Blood. § 35. Ir is by the work of the heart, in the rhythmical contractions of its auricles and ventricles, that the mass of the blood is kept con- stantly in motion. The blood within the elastic walls of the aorta, as it is driven toward the periphery of the body, meets, in the friction which exists within the innumerable divisions and subdivisions of the arterial system, a considerable degree of resistance; and this occasions a rela- tively high pressure throughout the whole arterial system, a pressure which in the human arteria femoralis equals that of about 120 mm. of mercury. After passing through the capillaries the blood arrives in the veins with very little velocity, and stands in the veins under a very low pressure, which varies, however, according to the location of the vein, and is greatest where the vessel sustains a blood-column of considerable height. In the great venous trunks in the neighborhood of the thorax the pressure is generally negative, particularly during inspiration, as the thorax during this stage of respiration aspirates the blood from the veins lying without the chest. Only during forced expiration does the positive pressure within the veins rise somewhat higher. Ata given moment, the degree of pressure in the aorta, the mass of the blood remaining constant, is dependent upon the work of the heart and upon the resistance in the arterial system, and this in turn is de- pendent upon the combined cross-sections of the blood-vessels, an area, which varies on account of the elasticity and contractility of the arte- ries. In the corporeal circulation the tension of the arteries is very considerable; in the pulmonary circulation it is but slight, the blood- pressure in the pulmonary artery being only from one-third to two-fifths that in the aorta. Both the heart and the arteries are under the influ- ence of the nervous system which regulates their action. The function of the heart consists in rhythmical contractions of the heart-muscle, and its normal efficiency presupposes that the heart-mus- cle as well as the heart-ganglia be sound. Every lesion of the heart, therefore, in just so much as it diminishes the contractility of the heart- muscle and disturbs the action of the cardiac ganglia, and in just so far as the diminution in the efficiency of certain parts of the heart-mechan- ism is not compensated by increased activity of other parts, will impede the effective working of the heart. In many cases in which the efficiency of the heart-muscle has become impaired, certain anatomical changes, such as fatty degeneration and the disintegration of its cells, can be demonstrated; in others micro- Z CHANGES IN THE HEART’S ACTION. 103 scopic examination fails to reveal any anatomical differences, particu- larly in cases in which the diminution of efficiency has resulted from the exhaustion consequent upon overexertion. This may occur either when —as, for instance, in cases of febrile temperature,—for a considerable length of time, the heart performs its fun¢tion under unfavorable condi- tions, though at no time forced to work more than slightly beyond. its normal rate; or when, for a brief period, the demands upon the heart -become excessively severe. Moreover, either trophic disturbances, or the toxic condition accompanying the febrile infectious diseases, or sud- den diminution of the blood-supply from obstruction of a coronary artery, may, under certain circumstances, bring about heart-failure within too short a time to allow anatomical lesions of the muscular tis- sue to become recognizable. A further obstacle to the working of the heart is occasionally caused by adhesions of the surface of the heart to the pericardium and to contiguous portions of the lung, inasmuch as the heart is thereby hindered in the amplitude of its contractions. Through the serous collections in the pericardium which occur dur- ing the course of certain diseases, through pronounced degrees of tho- racic deformity, through high convexity of the diaphragm, the ready enlargement of the heart during diastole may be impeded, and thereby the free afflux of blood from the venous system be interfered with to such an extent that ultimately the blood is but scantily furnished to the ventricles. Should rents or distortions of the flaps of the valves occur, or adhesions between them arise in consequence of pathological proc- esses, or should the valve-flaps, on account of dilatation of the heart and spreading of its orifices, become relatively too short, then there will be developed at the orifices of the ventricles and of the auricles the condi- tions which are known as insufficiency and stenosis. The former of these is a condition in which a valve, during the dilatation of the auricle or ven- tricle next ahead of it, fails to completely close its proper orifice, the latter a condition in which, during the contraction of the auricle or ven- tricle behind it, the ostium fails to become sufficiently widely open. The effect of a stenosis is that of opposing additional obstacles to the passage of the blood during systole; in the case of insufficiency, aortic or pulmonary, the blood escapes during the ventricular diastole from the great vessels back into the ventricles; in the case of mitral or of tri- cuspid insufficiency the ventricular systole forces the blood back into the respective auricles. Finally, clots are not infrequently formed in the heart, and these, un- der certain circumstances—particularly when they lie in proximity to the ostia—on the one hand interfere with the closure of the valves, and on the other hand cause a narrowing of the orifice. The universal operation of all the above-mentioned pathological con- ditions of the heart is to produce the following results: the efficiency of the heart’s function becomes impaired, too small a volume of blood is in a given time delivered to the arterial system, and consequently the blood-pressure in the aorta falls, the velocity of the blood-current is lessened, and the blood collects more and more in the venous system, while the pressure in the veins rises. There is consequently an inade- quate filling of the arteries throughout the whole body, varying, indeed, according to the degree of contraction maintained in individual groups of arteries, while both veins and capillaries are, on the other hand, over- filled with blood. The condition becomes one of general venous hyper= zmia, which may in some parts become so great that, on account of the 104 DISTURBANCES OF THE CIRCULATION. engorgement of the capillaries with venous blood, the tissues acquire a livid, cyanotic appearance. When the difference between the pressure in the arterial and that in the venous system reaches a certain mini- mum, the circulation is arrested, while the right auricle and ventricle become greatly distended with blood. Should the contractions of the heart have become, from any cause, feeble and incomplete, then the pulse-wave also is small. Should the rate of the heart-beats become slower, the arterial system during the interval between two systoles tends to empty itself more than normally. If the impairment of cardiac efficiency is essentially dependent upon imperfect function of the left side of the heart, as is the case, for in- stance, in valvular lesions of the left heart, then the disturbance of the circulation first becomes manifest in the arterial portion of the corporeal and in the pulmonary circulation. With stenosis at the aortic orifice, the arteries, if the heart’s action remains unchanged, fill but slowly and incompletely (pulsus tardus). With insufficiency of the aortic valves, a normal or even an increased volume of blood is indeed thrown into the arteries (pulsus celer), but a portion of this flows back into the ventricle during diastole. In both cases an overdistention of the left ventricle becomes more and more established, and eventually it leads to an interference with the emptying of the left auricle, and thereby to over-accumulation of blood in that chamber and subsequently in the pulmonary veins. Owing, however, to the low pressure in the pulmonary circulation, the blood is readily dammed back upon the right ventricle, and the tendency to blood-stasis, extending beyond this, reaches to the right auricle and finally to the venous system throughout the body. A similar effect upon those portions of the circulatory apparatus which lie back of the left auricle is caused by valvular lesions at the mitral orifice, as in these cases also there are blood-stasis in the pulmo- nary circulation and a rise of pressure in the pulmonary veins and in the pulmonary arteries; while the left ventricle either receives too small a supply of blood (stenosis) or during its contraction drives back a por- tion of its contents (insufficiency) into the auricle. , In valvular lesions at the orifices of the right heart, the damming back of the blood is limited to the veins of the corporeal circulation, while in the pulmonary circulation both velocity and pressure are di- minished. Ultimately the pressure falls in the aortic system also, as the left side of the heart receives a diminished supply of blood. Damming back of the blood in the great veins of the body often gives rise to venous pulsation in the neighborhood of the thorax, as in these velns waves moving toward the capillaries arise, which overcome and pass the venous valves, and in particular the valve in the bulb at the junction of the internal jugular and subclavian veins. The cause of the venous pulsation is the failure of the valves in the veins to close. In case of imperfect function of the valve at the bulb this pulsation may be observed in a slight degree even during normal action of the heart; but when there is distention of the veins, and particularly when there is tri- cuspid insufficiency, the pulsation is far stronger and is traceable much farther toward the periphery. If the tricuspid still closes completely, the venous pulsation is then only the expression of the rhythmical re- currence of a hindrance to the outflow of the blood from the veins: if the tricuspid is incompetent, blood is driven back upou the veins during the contraction of the right ventricle. INCREASED HEART ACTION; ANZEMIA. 105 When certain of the chambers of a heart affected with valvular le- sions become distended with blood, the muscular walls of these chambers may, by an increased activity, compensate, to a certain degree, for such valvular defects. In course of time an increase in volume—a hyper= trophy of the heart-muscle—follows, and enables the heart for an in- definite period to meet the increased demands upon it. Such compen- sation, however, frequently becomes inadequate, with the result that the pressure permanently remains abnormally low in the aorta and abnor- mally high in the veins. There is, at the same time, the danger that the heart-muscle may tire in time, or that avery slight illness may render the heart insufficient. Thus, for example, a prolonged quickening of the heart’s action, in that it abbreviates the diastolic rest of the heart-mus- cle, may suffice to bring about fatigue and insufficiency of the heart. Cardiac arrest finally follows, with great accumulation of blood in the heart from sheer inability of the organ to drive onward the mass of blood flowing into it. Increased heart action—that is, greater frequency of the contrac- tions, each being strong and full—causes a rise in arterial blood-press- ure and an increased velocity of the blood-current. When increased demands are repeatedly made upon the left side of the heart—as fre- quently happens in consequence of severe bodily labor, of high living, or of abnormal irritability of the cardiac nerves—the left ventricle may become hypertrophied and may act permanently with increased force. Inasmuch as from quickening of the blood-current the right cavities of the heart receive a larger amount of blood during diastole, the hyper- trophy of the left side of the heart ordinarily becomes accompanied by a similar condition of the right ventricle. Lessening of the mass of blood, or general anzmia, from hemor- rhage, leads to a temporary lowering of pressure in the aorta; but if the loss of blood was not excessive, this pressure presently rises again as the blood-vessels adapt themselves to their new conditions, and, as a consequence of the stimulation of the vaso-motor centre through local anemia, display a higher degree of contraction. Under normal condi- tions a speedy increase in the mass of the blood takes place through absorption of fluids, and later on through regeneration of the blood proper. Similarly, the arterial pressure is lowered and the blood-cur- rent slowed in anhydremia, —i.e., in diminution of the fluid portion of the blood. After severe hemorrhage the arterial pressure remains low for a considerable period of time, the circulation being slowed, and the pulse, because of lessened stimulation of the vagus-centre (Cohnheim), being frequent and small. In case of long-continued diminution of the mass of the blood—that condition which is known as chronic anemia, and appears under many different circumstances—the vascular system is but imperfectly filled, the blood-pressure is lowered, and the blood-current is slowed. Both the heart and the blood-vessels adapt themselves to the new conditions and become diminished in volume. With great deficiency in hemo- globin, degeneration of the heart-muscle—particularly fatty .degenera- tion—frequently takes place. In the lower avimals increase in the volume of the blood through injection of blood or of salt-solution into the vessels is followed by only a temporary increase in the blood-pressure and in the velocity of the blood-current. A return to the normal follows, partly through the dila- tation of a portion of the vascular system, particularly in the abdomen, 106 DISTURBANCES OF THE CIRCULATION. partly through the elimination of the surplus from the vessels. If the mass of the blood, as a result of some special diathesis or of high living, comes to stand in abnormally high proportion to the weight of the body, if there exists a permanent condition of plethora, the pressure in the aorta will then be permanently raised in consequence, the task of the heart will be permanently increased, and a corresponding degree of car- diac hypertrophy will ensue. § 36. Increase of general vascular resistance occurs as well in the corporeal as in the pulmonary circulation, and results in increased press- ure behind the point of increased resistance, and diminished pressure ahead of it. In the corporeal circulation the hindrance may lie either in the main vessel, the aorta, or else in the arterial branches, whose degree of con- traction maintains and governs the pressure in the aorta. Vascular contraction involving areas supplied by a large number of arteries, and sufficiently well marked to increase the blood-pressure, is generally but. a temporary phenomenon, passing off with the relaxation of the arterial excitement; nevertheless permanent increase in blood-pressure does. occur, accompanied by hypertrophy of the left ventricle, and it cannot well be accounted for otherwise than as the result of a contraction of the lumen of the smaller arteries. Ternporary arterial contraction and in- crease of pressure occur particularly through overcharging of the blood with carbonic acid; permanent increase of pressure in the aorta, on the contrary, is a result of chronic kidney-disease in which the secreting parenchyma of the kidney is cut off from the circulation. Inasmuch, however, as that portion of the vascular system which is in this case cut off is far too inconsiderable to cause, by itself, an increase of pressure. throughout the whole aortic system,—since the blood-vessels leading in other directions might well become correspondingly relaxed,—we are compelled to assume that in the case of “contracted kidney ” other ob- stacles to the circulation are developed throughout more considerable vas- cular areas, and these we most naturally seek in that apparatus which nor- mally serves to maintain the aortic pressure at its proper level—namely, in the smaller arteries distributed throughout the body. Whether we have to do with reflex stimulation from the kidneys through the nerves, or whether with retained urinary ingredients working upon the vaso- motor centres or directly upon the walls of the vessels, or whether with the heart driven to more forcible action through stimulation of its nerves, we are not at present able to determine. Increase of resistance in the aorta may result from stenosis of this. vessel, as occurs in rare cases at the isthmus,’ or from congenital nar- rowness of the whole aorta, or from large aortic thrombi, or from an advanced stage of disease of the vessel-wall, with the intima consequently rough and lumpy and the whole vessel rigid, inelastic, and unyielding, or, finally, from a general dilatation of the vessel, whereby counter-cur- rents are formed in the passing blood-stream. Diminution of the total resistance in the corporeal circulation jg possible through relaxation of the tone of a large part of the arteries, an event which follows when the vaso-motor centre is paralyzed or when 1 The “isthmus” is that part of the descending aorta which lies between the origin of the ieft subclavian artery and the attachment of the ligamentum arteriosum (the ob- literated ductus arteriosus Botalli). Its calibre during foetal life is commensurate with the relatively small amount of blood it carries from the left ventricle to the lower ex- tremities (Luschka, “Die Anatomie des Menschen”’).—TransLator’s Nore. INCREASED RESISTANCE IN THE PULMONARY CIRCULATION. 107 the cervical cord is divided or partly destroyed by any other process. As the blood, in this case, flows too quickly from the arteries over into the veins, an equalization of the pressure between arteries and veins fol- lows, the blood-current is slackened, the heart receives during diastole an insufficiency of blood, and the circulation may finally come to a standstill. Increase of the resistance in the pulmonary circulation arises most frequently in consequence of disease of the lungs and of the pleura. Simple adhesions of the pleura may be a cause of such increased resist- ance; and so also curvatures of the spine, in that they cause displace- ments of the lungs and hinder the respiratory movements of the chest- wall and thereby cause the withdrawal of an efticient aid to the. circulation. Of great influence, moreover, are such pulmonary affec- tions as hypertrophic emphysema, retractions and induratious of the lungs and the breaking down of portions of the lung-tissue,—all of which lead to impermeability of a portion of the pulmonary capillaries; and the same, furthermore, is true of compression of the lungs by pleural exudations, and of compression of the pulmonary arteries by aortic aneurism or by tumors. If the obstacle is but inconsiderable, the blood can still make for itself a free passage to the left side of the heart without increase in the blood-pressure, provided the velocity of the flow is increased through the channels that still are open. Greater obstacles cause increase of pressure in the pulmonary artery and in the right side of the heart, and, if they continue for a long time, may cause hypertrophy of the right ventricle through increased exertion of the heart. This can come to pass, however, only when the nutrition of the heart-muscle is mean- tame maintained, and when the mass of the blood is not diminished to correspond with the diminution in the area of the pulmonary tract. If the right side of the heart does not succeed in overcoming the obstacles in the pulmonary circulation, the blood is then dammed back upon the right side of the heart and eventually upon the venous system. Rise of the pressure in the right half of the thorax hinders the influx of the venous blood into the right auricle, and causes an accumulation of blood in the veins of the whole body. A sudden increase in the pressure may cause the blood to flow back into the neighboring veins. The observation that cardiac hypertrophy results from various renal diseases has been differently explained by different authors. Some seek the cause of the phenomenon in an increase in the mass of the blood (Traube, Bamberger) ; others (Senator, Ewald) think it dependent upon a change in the composition of the blood; others, again (Gull and Sutton), ascribe it to a widespread alteration in the walls of the smaller arteries. Buhl attributes it to over-nourishment of the heart. The result of recent investigations places beyond doubt the dependence of the cardiac hypertrophy accompanying renal dis- ease upon an increase of arterial pressure. This increase is very probably due to an in- crease in the degree of resistance offered by the small arteries generally throughout the’ body,—a resistance which owes its existence to the contraction of these small vessels. For an explanation of what causes the latter phenomenon we shall have to assume that it is due either to the direct stimulus supplied by the urinary elements that circulate in the blood, or to some reflex influence emanating from the kidney, or finally to some in- fluence exerted upon the vaso-motor centre. It is possible also that in this matter some importance should attach to increased heart activity. According to the observations of Loéwit, compression of the trunk of the aorta sometimes does and sometimes does not cause an increase of blood-pressure in the pul- monary artery. Léwit considers this rise in pressure to be independent of the stasis in the left auricle. In his opinion, the rise does not result from a damming back of the blood from the left on to the right side of the heart, but much rather is caused by an in- creased afflux of blood to the right side of the heart, which is in its turn brought about 108 DISTURBANCES OF THE CIRCULATION. by a relaxation of the contracted arterioles due to cerebral anemia. The correctness of Lowit’s observations cannot be called in question, and his interpretation also is to be accepted, but it is by no means to be considered as showing that in cases of permanent obstructions in the corporeal circulation, or in the left side of the heart, which cause a setting back of the blood, such a damming back of the blood does not reach the pulmo- nary artery and by way of the lungs extend beyond it into the right side of the heart. II. Local Hyperzemia and Local Anzmia. § 87. To the blood is assigned the function of carrying nourishment to all the organs and tissues of the body. The cells and cellular struc- tures of which the various tissues are composed are able to maintain their existence but a short time without the advent of fresh supplies of nutritive material, and for this reason most of the tissues are provided with blood-vessels, and such tissues as lack them are placed in the most intimate connection with vascular structures. The demands of the various tissues for blood are not always uniform, and there is consequently in the various tissues an alternating increase - and decrease in the afflux of blood, and at the same time in the amount of blood contained within the organ or tissue at a given moment. An organ richly filled with blood is designated as hyperemic; if contain- ing but little blood it is said to be anemic. ~ The regulation of the volume of blood which an organ receives under physiological conditions is brought about by a change of the resistance in the afferent arteries, and this change is effected exclusively by varia- tions in the calibre of these vessels. Inasmuch as the mass of the blood in the body does not sufiice to fill all the vessels at once, an extra supply for one organ becomes possible ouly by diverting the blood from other directions. The change in the calibre of an artery is determined, aside from the blood-pressure, by the elasticity of its walls and by the degree of contraction of its organic muscular fibres. These fibres are the regu- lating agents, and their action is dependent partly upon influences act- ing on them directly, partly upon nervous impulses from the intravas- cular plexuses and from the vaso-motor centres in the spinal cord and in the medulla oblongata; some stimulating and others inhibiting the muscular action. When the variations from a mean in the blood-supply of a part over- step the physiological limits, or when these variations arise without their physiological causes, or when the condition is unduly protracted, we then call the state one of pathological hyperzmia or of pathologi= cal anemia. These conditions are only in part caused by the same gov- erning mechanism which determines the normal blood-supply of an organ. § 38. Hyperzemia of an organ is caused, under pathological condi- tions, either by an increase of the arterial supply or by an obstruction and hindrance to the venous outflow, aud we distinguish, accordingly, an active or congestive (arterial) hyperemia and a passive or stagnation (venous) hyperemia. Active hyperemia arises from an increase of the afiux of blood (congestion), and is either idiopathic or collateral. “The first of these plays the more important role, and depends upon a relaxa- tion of the muscular tunics, which is caused either by paralysis of the vaso-constrictor nerves (neuroparalytic congestion), or by stimulation of the vaso-dilators (neurotic congestion), or by direct weakening or paralysis of the muscles (as, for instance, through heat, bruising, the action of atro- LOCAL HYPERZMIA AND LOCAL ANAEMIA. 109 pine, brief interruptions of the blood-current), or, finally, by diminution of the external pressure exerted upon the vessels. Collateral hyperemia is merely the result of a diminished flow of blood to other parts. It arises first in the immediate neighborhood of the parts whose blood-supply is lessened; afterward the blood may be driven also to such other more remote organs as may require it. Active hyperemia is accompanied by more or less marked redness and swelling of the part—changes which are quite striking in tissues that are rich in blood-vessels. The blood flows through its widened chan- nels with increased velocity and lends to the tissue the color of arterial blood. Tissues situated superficially, and thus exposed to cooling, grow warmer in consequence of the more active passage of blood through them than through the surrounding parts less generously supplied. Passive hyperzemia is a consequence of retardation or obstruction of the flow of blood in the veins. A general tendency to blood-stasis throughout the corporeal circulation follows directly whenever feebleness of the heart’s action, insufficiency or stenosis of the cardiac valves, or obstructions in the pulmonary circulation impede the emptying of the large veins into the right side of the heart. In the pulmonary circulation it is more particu- larly aortic or mitral lesions, or weakness of the left side of the heart, less frequently obstacles in the arterial portion of the corporeal circulation, which, by obstructing the outflow of blood from the lungs, lead to a pul- monary stasis; and this may not infrequently reach a degree that will cause the damming back of the blood to become appreciable in the right side of the heart as well as in the veins of the corporeal circulation (cf. § 85 and § 36). Local stasis may follow directly from the fact that the progress of the blood through the veins lacks the continued support of the action of the muscles and of the aspiration of the blood through the inspiratory enlargement of the thoracic cavity. The defection of the first of these auxiliary forces becomes most obvious in the area of distribution of the inferior vena cava; as, for instance, in subjects who live continuously sedentary lives, or who stand a great part of the time without active bodily movements, so that the task of emptying the deep-seated veins into the trunk of the vena cava falls almost exclusively upon the forces inherent in the walls of the veins—namely, their elasticity and contrac- tility, —these forces being insufficient to drive onward the column of blood which distends the walls of the vessel. An inadequate aspiration through the respiratory movements makes itself felt when respiration is inter- et with by inflammation or other disease processes in the lungs or the pleura. A further cause of local passive hypereemia consists in the narrowing or closing of particular veins, as occurs in compression, ligation, the formation of thrombi (§ 40), and the invasion of the veins by neoplasms. The pregnant uterus, for example, or a pelvic tumor may compress the veins of the pelvis, a thrombus may choke the cerebral sinuses or the femoral or the portal veins, or a sarcoma of the pelvis may grow into the great pelvic veins. Should any single vein become occluded by any of the above proc- esses, or be ligated during operation, the effect of such occlusion is often very inconsiderable, inasmuch as the vein in question may have free and manifold connection with other veins, so that no considerable ob- stacle is created to the progress of the blood. If, on the other hand, the occluded vein has no auxiliaries, or if these are insufficient for the 110 LOCAL HYPERZMIA AND LOCAL ANEMIA. passage of the blood—as, for instance, is the case with the main divi- sions of the portal vein, with the sinuses of the dura mater, with the femoral or with the renal veins—then a greater or less degree of stasis occurs in the area of distribution of the vein affected. The effect of the obstacle to the circulation shows itself first in the portion of the vein which lies between the obstruction and the periph- ery, the blood-current in this part becoming slowed or entirely checked, while at the same time, through continued afflux of blood from the capillaries, a progressive filling and stretching of the vein follows. If through the compensatory action of the elastic and contractile vessel- wall, in yielding more and more to the pressure, the obstruction can be overcome, circulation will persist, and, through such channels as it still finds open to it, the blood will flow on to the heart; oftentimes under these circumstances the small veins which have to perform this increased labor become gradually much dilated, and are eventually converted into veins of large size. If the obstruction cannot be overcome, and if no communicating vessels capable of dilatation are at hand, the circulation will be arrested, and a condition of complete stasis (§ 48) or of throm- bosis (§ 40) will be brought about in the area of distribution of the obstructed vessel. If the arrest of the blood-current in the area of distribution of a vein extends to the capillaries, so that these become distended with blood, this will impart a reddish-blue, cyanotic hue to the surrounding tissues, and a certain amount of swelling will take place in them. Both active hyperemia and passive hyperemia, observed during life, may take on quite a different appearance after death, and may even, in not a few instances, entirely disappear. This is especially the case with active hyperemia of the skin and sometimes with that of the mucous membranes, and it is dependent upon the fact that the tissues, put upon the stretch by the dilatation of the capillaries, contract down upon the latter after the ceasing of the circulation, and by their counter-pressure drive the contents of the capillaries on into the veins. Tissues which may have been reddened during life may accordingly appear pale after death. As converse to this, other tissues which during life were pale, ’ or at least showed no particular redness, may take on, after death, a reddish-blue color. This occurs especially upon the sides and back of the trunk (unless these parts happen to be uppermost) and upon the back of the neck and the posterior aspect of the extremities of a cadaver lying face upward, and is to be explained by the fact that after death the blood sinks to the most dependent parts, and fills not only the veins, but finally also the capillaries. The phenomenon is known as post-mortem hypostasis, and the spots are known as cadaveric petechiz or lividity (/ivores). They begin to appear at about the third hour after death, and their number and size are proportionate to the amount of blood contained in the skin and in the subcutaneous tissues at the moment of death. In the internal organs post-mortem hypostasis is particularly appar- ent in the pia mater, whose dependent veins are generally more com- pletely filled with blood than those lying above them. In the lungs we get, through the settling of the blood, engorgement not only of the veins, but also of the capillaries. Whenever during life, on account of cardiac insufficiency, the general circulation is imperfect and partial stagnation of the blood follows, the blood often collects in a similar way in the dependent portions of the HYPOSTASIS; LOCAL ANAEMIA. 111 body, partly because it is not driven out of them, and partly because it sinks into these parts from those situated on a higher level. This phenomenon, likewise designated as hypostasis, is particularly observed in the lungs (hy postatic congestion). For observing the circulation during life, and its behavior under changes of velocity and pressure, we make use of either the tongue or the web of the foot of a curarized frog! properly spread on an object-holder. A very simple expedient, for instance, is to draw out the tongue and spread it over a cork cemented upon the object-holder, and fasten it there with pins. With a normal, as well as with a quickened circulation both the pulsating arterial current and the steady-flowing venous current exhibit a marginal zone of blood-plasma. If by ligation of the efferent veins we induce a partial stagnation the flow becomes slowed, the clear marginal zone of blood-plasma disappears from the veins, and both veins and capillaries become greatly distended with accumulated red blood-corpuscles. After a certain time the tongue begins to swell through infiltration with transuded fluid. According to the investigations of Landerer,? the wall of a capillary vessel em- bedded in the tissues supports only from one-third to one-half the blood-pressure. The remainder is borne by the surrounding tissues, which afford an elastic resistance and so maintain the tension which is necessary to keep the blood in circulation. Hence in ac- tive hyperemia as well as in passive hyperemia, the tension of the tissues and the pressure upon them are increased ; in anemia both are diminished. § 39. Localized anemia or ischemia is a condition wherein certain tissues contain but a small amount of blood; it is always the result of a diminution in the afflux of blood. If the total bulk of the blood is normal, then the cause of the ischemia is purely local; if there is an insufficient quantity of blood in the whole yascular system, the local insufficiency may partly depend upon that. The pathological diminution in the afflux of blood to an organ is sometimes merely the result of an unusual increase tn the normal vesist- ance of the arteries—that is, of a contraction of the muscular tunics. In other cases abnormal obstructions—such as compression of the arteries, narrowing of the arterial lamen through pathological changes in the vessel-wall, deposits on the internal surface of the vessels, occlusion of the vessels by emboli (cf. § 17), ete.—act as hindrances to the blood-current. The immediate consequence of the narrowing of an artery is always slowing and diminution of the stream beyond the point of constriction. Complete occlusion of an artery brings the circulation beyond the ob- struction to an immediate standstill. If, back of the point of constric- tion or occlusion, the artery is provided with connecting branches of relatively considerable size—so-called collateral arteries—the disturbance of the circulation is abatétl by an increased flow through the collateral vessels; and the larger and the more distensible these are, the more complete the restoration of the circulation. If the constricted or oc- cluded artery possesses no communicating branch in its area of distribu- tion—if it is a so-called terminal artery—the slowing or the arrest of the circulation beyond the point of obstruction or of occlusion cannot be immediately done away with, and the area supplied by this vessel be- comes presently partly or completely emptied of blood, as, through the contraction of the arteries, and through the pressure of the tissues upon the capillaries and veins, the blood is more or less completely forced out of the area of distribution of the artery in question. Frequently, how- ever, after a time, an afflus of blood comes from neighboring capillaries. When the current and the pressure beyond a constricted point have 1Cohnheim, Virch. Arch., 40. Bd. 2“Die Gewebsspannung,” Leipzig, 1884. 112 COAGULATION, THROMBOSIS, AND STASIS. sunk below a certain minimum, little by little the driving force becomes less and less able to push along the mass of the blood. The red cor- puscles, particularly, cease to move, and collect in the veins and capil- _laries, and as a consequence the area supplied by the artery in question becomes filled with blood once more; only not with circulating, but with stagnant blood. The same thing occurs when, a terminal artery being completely occluded, the blood oozes into the affected area, under minimal pressure, through arteries incapable of adequate enlargement, or merely through communicating capillaries. An accumulation of blood within the anemic area may also occur by reflux from the veins. This occurs when the intravascular pressure within this area has sunk to nothing, whereas in the veins themselves a positive pressure exists. Arrest of the circulation in the veins will accordingly favor the reflux of the blood. A further cause of anemia in an organ may be the abnormal conges- tion of other organs, as in that case the total mass of the blood may not suffice to supply the remaining organs adequately. Anemia from this cause is called collateral ancemia. All ancemic tissues are characterized by pallor. They are at the same time flabby, not turgescent, and the color proper to each becomes dis- tinctly appreciable. The significance of a condition of ischaemia lies especially in the fact that, on account of the need of the tissues for a continuous supply of oxygen and other nutritive elements, the continuance, for a certain length of time, of the condition of imperfect blood-supply brings about tissue-degeneration (cf. § 8). Complete arrest of the blood-supply leads in a short time to death of the tissue involved. If blood comes to flow anew among the degenerated and dying tissues in the area of distribution of an obstructed vessel, and stagnates there, extravasation of blood into the tissues may follow, and a hemorrhagic infarct (cf. § 48) be formed. The rapidity and completeness with which a collateral circulation may be developed after the occlusion of an artery depend upon the size and distensibility of those vessels which are in communication with the area which has become ischemic. If these are numerous and distensible, the ischemic area becomes very soon irrigated with an ap- proximately normal volume of blood. If this is not the case the disturbance of the cir- culation corrects itself more slowly, and stasis and increased pressure are found to extend farther back from the point of obstruction toward the heart, so that a collateral hyperemia occurs likewise in vessels situated farther back on the course of the blood, i.e., nearer the heart. In the further course of the process of reéstablishing the circula- tion, the increase in the volume and velocity of the blood-current remains confined to such vessels as communicate with the area deprived of its natural blood-supply—that is, confined to the capillary and arterial anastomoses; and here this increase of volume and velocity becomes permanent. This leads in turn to a permanent distention of the vessels of the part, and at the same time to a substantial increase in the vascular walls, not only in thickness, but, as becomes evident from the crooking and twisting of the vessels, in length also. According to Nothnagel, in rabbits the phenomenon of the increase in thickness of the walls of the anastomotic vessels may be demonstrated about six days after the ligation of an artery; and after the ligation in continuity of vessels of some size, the small arteries which carry on the collateral circulation become transformed, in the course of a few weeks, into quite capacious, thick-walled arteries. II. Coagulation, Thrombosis, and Stasis. § 40. Upon the death of the individual, the blood lying in the heart and in the great vessels generally coagulates in part, sooner or later, and thence arise those formations known .as post-mortem clots. If the clotting occurs at a time when the red blood-corpuscles are still evenly COAGULATION OF THE BLOOD. 113 distributed in the blood, and the whole mass of the blood becomes coag- ulated, the clots form dark-red masses—a condition in which the blood is termed cruor. If before coagulation, through the settling of the red corpuscles, the mass divides itself into a substratum rich in red blood- corpuscles and an upper fluid layer containing none and consisting ex- clusively of the plasma,—then, if the latter coagulate, there will be formed soft gelatinous lumps and stringy masses light yellow in color, elastic, with a smooth surface, and not adherent to the vessel-wall, which are designated as lardaceous clots or as fibrinous deposits. Through the inclusion of red blood-corpuscles in these formations, they may ex- hibit in parts a red or reddish-black color; when a large proportion of leucocytes are present, the color at such spots will border on white. Tf blood is drawn from an artery or a vein and received into a vessel, within a short time coagulation will occur, as a result of the adhesion of ESSER TeN Ste Qo an Mins ree en Fic. 12.—Coagulated blood in a recent hemorrhagic infarct of the lung. (Miiller’s fluia; hematoxylin; eosin.) a, Interalveolar septa without nuclei, containing capillaries filled with deep-violet thrombi of homogeneous appearance; b, septa showing nuclei; c, vein containing a red thrombus; d, alveoli dis- tended by a firm blood-clot; ¢, alveoli filled with serous fluid, fibrin, and leucocytes. Magnified 100 diameters. this fluid to the sides of the receptacle. When this change takes place the appearance presented by the coagulated blood will be that of a soft coherent mass. If treshly drawn blood be beaten with a solid body, in a short time stringy fibrin will be separated from the surface of the blood. Jf within the body blood be extravasated in considerable quantity into the tissues—for instaice, into the pericardium or into the lungs— coagulation may occur here likewise, and among the red blood-corpus- cles stringy masses are formed (Fig. 12, d, ¢), whose fibres run in the most varying directions, interlacing with one anothér continually, and frequently also proceeding radially from a central point. The coagulation of the blood is a process difficult of chemical inter- pretation, and in spite of numerous investigations we have not succeeded in explaining this enigmatical phenomenon. We know, however, that for its occurrence the presence of a fibrinogenic substance, of a ferment, and of certain salts, especially calcium salts, is indispensable, and that the fibrinogenic substance is an albuminoid body, belonging to the class of the globulins, which is present in the blood, while the ferment is probably derived from the white (possibly also from the red) corpus- 114 THROMBOSIS. cles of the blood, which either are dissolved in the blood-plasma (Schmidt), or yield to it certain constituents of their mass (Lowit). According to A. Schmidt, by means of the fibrin-ferment a very bulky albuminoid body is formed, in a way still obscure, out of the globulins preéxisting in the al- kaline solution, which body is precipitated by the calcium salts present in the plasma; and in the process of coagulation we must recognize two stages—to wit, the stage of the production of the ferment and the stage of the fermentative action or coagu- lation proper. According to Pekelharing, on the other hand, the fibrin-ferment is itself a cal- cium compound (calcium-nu- cleo-albumin) which has the power of carrying lime over to the fibrinogen, whereby from Fig. 13.—Section through a red thrombus formed in she soluble BpHtDEee oe we S oe e the ey veins of the thigh after occlusion of uble albuminous compound 1S ie tenor eae, alas ood oman) jormed, containing caleinm, Magnified 250 diameters. \ which body is fibrin. Accord- ing to Freund, the substance which emanates from the cells and which excites coagulation, is phos- phorie acid. If coagulation of the blood within the heart and the vessels takes place during life, or if a solidifying mass separates from the circulat- ing blood, this process is called thrombosis and its product a thrombus. If coagulation or thrombo- sis occurs in a mass of blood deprived of motion, there is formed a dark-red thrombus (Fig. 12, c, and Fig. 13), which, like the reddish-black post-mortem clots, or like the coagula of extravasated blood (Fig. 12, d), contains all of the red blood-corpuscles; the precipitated fibrin forming granules (Fig. 138, b) and fibres (Fig. 18, @). When we find a clot which has recently formed in some small blood- vessel, itis quite often possible ; to demonstrate after death, by , Tc. 14—Bundles and star-shaped clusters of fibrin the employment of suitable Preparation taton “trom oe atone Waceat Gane methods, the presence of bun- membrane. Magnifled 500 diameters. dles and star-shaped clusters of slender fibrin rods (Fig. 14) which radiate from centres of coagulation. In such cases, however, it is often impossible to determine with cer- tainty to what extent the coagulation took place during the individual’s THROMBOSIS. 115 lifetime, and to what extent after death had occurred. In the majority of instances these coagulations are encountered in the midst of inflamed tissues, and we are therefore warranted in drawing the conclusion that it is the alterations in the blood which take place in such inflammatory foci which are the cause of the phenomena of coagulation. Immediately after its formation the red thrombus is soft and rich in the fluids of the blood; later, it becomes tougher, denser, and drier as the fibrin contracts and presses out a portion of the fluid. At the same time it becomes paler, brownish-red or rust-colored, inasmuch as the blood-pigment undergoes changes similar to those which take place in extravasated blood. The cause of the coagulation of blood inside a blood-vessel is to be found either in an increased production of fibrin-ferment and fibrino- genous substances (through the breaking down of cells), or in the with- Fic. 15.—Section of a white thrombus containing Fic. 16.—Section of a mixed thrombus rich in cells. but few cells. (Miiller’s fluid; hzematoxylin.) a, (Miiller’s fluid; haematoxylin.) a. Red blood-cor- Granular mass; b, granular and stringy fibrin in reti- puscles; b, granular mass; c, retiform disposition form arrangement; c, threads of fibrin in parallel of fibrin with numerous leucocytes; d, threads of arrangement. Magnifled 200 diameters. ae in parallel arrangement. Magnified 200 iameters. drawal of the power—which the living walls of a blood-vessel possess— to prevent coagulation (Bricke). It is probable that the mere fact of the firmer adhesion of the blood to the wall of the vessel at a spot where it is somewhat degenerated is sufficient to induce coagulation. This occurs, consequently, in vessels which have been ligated, when the endo- thelium is destroyed at the point of ligation. It takes place, further- more, when, through the breaking up of large numbers of white blood- corpuscles, fibrin-ferment is set free in large quantity in the blood-vessels —a condition which may be experimentally fulfilled by the injection of blood whose serum is stained lake-vred through the partial breaking up of the blood-cells (lackfarbenes Blut). The fibrinous deposits from blood in circulation, which not infre- quently are formed on the internal surface of the heart or vessel-walls, are composed of masses either white, or of various shades of red, or with alternating red and white layers, and we may distinguish, accord- ingly, between white, mixed, and laminated thrombi. With the mi- croscope we may discern that these thrombi are composed (Figs. 15 and 16) of granular and fibrous masses and of colorless and red corpus- 116 MODE OF DEVELOPMENT OF A THROMBUS. cles, which in varying proportions and arrangement make up their structure. The colorless thrombi may consist almost exclusively of granular masses (Fig. 15, «) and of fibro-granular fibrin, the latter dis- playing at one point (l) a retiform arrangement of its fibres, while at another point (c) they run more nearly in a parallel direction, both granular masses and fibrin-fibres enclosing only « scanty sprinkling of leucocytes. Other white thrombi contain more cells. In the mixed thrombi (Fig. 16), granular masses (J), more rarely hyaline masses, stringy fibrin (c), and red blood-corpuscles («), in varying proportions and in diverse situations, compose the coagulated mass, and all of these component parts include more or less numerous—frequently very nu- merous —leucocytes (Fig. 16). The fibro-granular masses which enter into the structure of the thrombi consist of fibrin which has been formed, just as takes place outside the vessels, by the action of a ferment. The granular and the hyaline masses, on the other hand, are at the present time regarded as structures formed from blood=-plates which have become agglutinated together, although granular and hyaline masses may also be formed from leucocytes entangled in the meshes of the fibrin. The granular masses in the thrombi exhibit occasionally an arrangement similar to that of coral. The formation of thrombi in circulating blood may be observed dis- tinctly under the microscope, in suitable subjects, both in warm-blooded and in cold-blooded animals; and in this line it is more particularly the observations of Bizzozero, Eberth, Schimmelbusch, and Lowit which have led to very weighty conclusions. When the blood flows through a vessel with its normal velocity, you may see under the microscope a broad, homogeneous, red stream in the axis of the blood-vessel (Fig. 17, a), while at the sides lies a clear zone of blood-plasma free from red blood-corpuscles. This may be observed as well in the arteries as in the veins and in the larger capillaries, but is: best seen in the veins; in the smaller capillaries, just large enough to permit the passage of the blood-corpuscles, this differentiation into an axial and a peripheral stream does not hold. In the axial stream the different constituents of the blood are not rec- ognizable; in the peripheral stream, however, isolated white blood-cor- puscles appear from time to time (Fig. 17, d), and these may be seen to roll slowly on along the vessel-wall. If the blood-current becomes retarded to about the degree which al- lows the observer to make out indistinctly the blood-corpuscles of the axial stream (Fig. 18, a), the number of white blood-corpuscles floating slowly along in the peripheral zone, and adhering also at times to the vessel-wall, becomes increased (Fig. 18, d), and they finally come to occupy this zone in considerable numbers. If the current is still further retarded so that the red blood-corpus- cles become clearly recognizable (Fig. 19, a), then, in the peripheral zone, alongside of the white blood-corpuscles appear blood-plates (d), which increase more and more in number with the progressive retarda- tion of the flow, while the number of the leucocytes becomes again diminished. When total arrest of the blood-current finally occurs, a distinct separation of the corpuscular elements in the lumen of the ves- sel follows. _ _ When, in a vessel in which the circulation is retarded, the intima is injured at a certain point by compression or by crushing, or by chemi- MODE OF DEVELOPMENT OF A THROMBUS. 117 cal agents such as corrosive sublimate, nitrate of silver, or strong salt- solutions, and yet the lesion of the vessel-wall does not cause a com- plete arrest of the blood-current, we may observe blood-plates adhering to the vessel-wall at the injured point, and before long they cover the site of the injury in several layers (Fig. 19, d,). Frequently more or less numerous leucocytes, or colorless blood-corpuscles, become lodged in this mass, and their number is proportionate to their abundance in the per- ipheral zone. Under some circumstances, indeed, the number of the leucocytes may be very considerable, and they may largely cover over the accumulation of blood-plates. In case of great irregularity of the circulation, or of extensive ’ lesion of the vascular wall, red blood-corpuscles also may separate from the circula- tion, and become adherent - to the intima, or to the color- less layers previously de- posited upon it. Not infrequently portions of the pas segregated mass are swept ie eS away, in which case a new PE deposit of blood-plates is A formed. Through a long- continued deposition of the elements of the blood the vessel may finally become completely closed. When at any point blood-plates have become adherent in considerable numbers, they become, after Fic. 17. a time, coarsely granular at the centre, and finely granu- lar or homogeneous at the periphery, and become fused together into one com- Fig. 17.—Quickly flowing blood-stream. a, Axial stream ; b, peripheral stream with isolated leucocytes, d. (After Eberth and Schimmelbusch.) Fig. 18.—Somewhat retarded blood-stream. a, Axial stream ; b, peripheral zone with numerous leucocytes, d. (Af- ter Eberth and Schimmelbusch.) pact mass. The final result of the process is the forma- tion of a colorless blood- plate thrombus, within which more or less numerous white blood-corpuscles may beimprisoned. Eberth designates the sticking together of the blood-plates by the term congluti- nation; their final fusion into a coherent thrombus he calls viscous metamorphosis. If we compare the observations of Bizzozero, Eberth, and Schimmel- busch, as well as the recent observations of Lowit, on warm-blooded ani- mals, with the histological findings in thrombi from the human subject, we are warranted in drawing the conclusion that the formation of thrombi in the circulating blood of man proceeds in a way similar to that observed in the lower animals, and we judge that their formation is directly dependent upon two causes: to wit, upon a retardation of the blood-current or other disturbance of the circulation—such as the formation of eddies, which direct the blood-plates against the vascular wall —and upon local changes in the wall of the vessel. Probably, too, 8 Fic. 19.—Greatly retarded blood-stream. a, Axial stream ; b, peripheral zone with blood-plates ; c, a considerable collec- tion of blood-plates; d, d,, white blood-corpuscles. (After Eberth and Schimmelbuseh.) 118 MODE OF DEVELOPMENT OF A THROMBUS. thrombosis is favored by pathological changes in the blood. From the variety of conditions under which thrombosis occurs in man we must assume, either that now one and again another of these causes plays the principal part in the formation of the thrombi, or that all three may concur in the process; and, on the other hand, that one of the factors, acting alone, is not under ordinary circumstances competent to cause thrombosis. If a blood-plate thrombus or a conglutinate thrombus has formed at any point, coagulation may subsequently take place there, yielding threads of fibrin which imprison, in greater or less number—frequently in very great number—the cellular elements of the blood. Conglutination and coagulation may accordingly occur together ; and the frequency with which this comes to pass, to judge from the composition of thrombi in man (Figs. 15 and 16), seems to denote that fibrin-ferment is set free in the formation of the blood-plate thrombus, and that hence, in the neighbor- hood of the conglutinated blood-plates, a process of coagulation occurs in the circumjacent peripheral zone of the blood-stream. If white blood-corpuscles alone are floating in the latter, the coagulating mass remains colorless (Fig. 15) and includes a greater or less number of leucocytes; while if red blood-corpuscles are circulating in the periph- eral zone, or if the influence of the ferment extends as far as the axial stream, mixed thrombi will be formed (Fig. 16). According to Eberth and Schimmelbusch, fibrin enters into the struc- ture of artificially produced thrombi in those cases in which thrombosis has been provoked by the action of strong silver-solutions or by the in- troduction of foreign bodies. Kohler and von Diiring are of the opinion that if, as somewhat often happens, extensive thromboses form in individuals who are in a condi- tion of marasmus, or in such as have been subjected to some trauma- tism, this pathological event must probably be dependent in some man- ner upon the toxic action of a ferment, and that local disturbances of the circulation merely determine the point of the coagulation. Vaquez is of the opinion that infection plays an important part in the formation of thrombi in cachectic subjects. According to Naunyn, Franken, Kéhler, Plosz, Gyorgyai, Hanau, and others, by the introduction of lake-red blood (lackfarbenes Blut), of solutions of hemoglobin, of the salts of gallic acid, of ether, and of other substances into the circulation, more or less extensive coagulation may be produced ; nevertheless the results of the experiments are not constant (Schiffer, Hégyes, Landois, Eberth), and coagulation may not occur. The probability of effecting coagulation is proportionate to the degree of disturbance produced in the blood by the substance injected. According to Arthus and Pagés, blood, as it flows from a blood-vessel, becomes in- capable of spontaneous coagulation when sodium oxalate, or sodium fluoride, or soaps are added to it in such quantities that the mixture comes to contain from 0.07 to 0.1 per cent of the oxalate, or about 0.2 per cent of the fluoride, or 0.5 per cent of soap. These salts all operate by precipitating the calcium salts. If to blood, kept fluid by treatment with sodium oxalate, one-tenth of its volume of a one-per-cent solution of cal- cium chloride is added, coagulation takes place in from six to eight minutes, and the calcium salts enter into the constitution of the tibrin-molecule. The fibrin-ferment can act upon the fibrinogen only in the presence of calcium salts. Under the influence of the fibrin-ferment, and in the presence of caicium salts, the fibrinogen undergoes a chemical metamorphosis which results in the formation of a caleium-albumin compound —tibrin. For the occurrence of coagulation it is not necessary to invoke the aid of any peculiar fibrinoplastic, globulinoid substance, but there is need merely of the presence of calcium salts. The ferment which induces the coagulation is formed by the disin- tegration of cellular elements. According to Freund, if blood is allowed to flow, beneath a layer of oil, intoa vessel whose walls are coated with a film of vaseline, it, will not coagulate; and from ORIGIN OF THE BLOOD-PLATES. 119 this it is fair to conclude that the cause of the coagulation is to be sought for in the ad- hesion of the blood to a foreign body. Bizzozero, in the year 1882, described as a new component of the blood certain minute, flat, homogeneous structures which he designated as blood-plates and regarded as identical with the hematoblasts described by Hayem. Relying upon profound ex- perimental research, he concluded that it was these which, in breaking up, induced coagulation, while he declined to attribute this property to the white blood-corpuscles. Rauschenbach, Heyl, Weigert, Lowit, Eberth, Schimmelbusch, Hlava, Groth, and others have taken a stand against this doctrine of Bizzozero, as part of them deny any connec- tion between the blood-plates and the coagulation of the blood, and part of them (Weigert, Hava, Halla, and Léwit) do not regard the blood-plates as constant morphological elements of the blood, but rather as the débris of disintegrated white blood-corpuscles, or as the product of a precipitation of globulin (Lowit). From their contributions we may also gather that the destruction of white blood-corpuscles in a fluid containing fibrinogen may be followed by coagulation, thus showing that the blood-plates are not the only producers of fibrin. According to Groth, for example, the injection of large numbers of leucocytes into the circulation produces thrombosis. According to Rauschen- bach, the dissolution of leucocytes is constantly occurring in the blood; but by an in- hibitory action of the organism the supervention of coagulation is prevented, and the tibrin-ferment rendered inefficient. Zahn, who in the year 1875 first undertook a strict differentiation of the red from the white and the mixed thrombi, held the view that the colorless substance of the white and of the mixed thrombi is a formation which is derived from the colorless blood- corpuscles which become separated from the blood-stream, then become adherent to rough points on the vessel-wall, and finally become fused together into a homogeneous or a granular mass. Up to afew years ago most authors coincided with this view, although since the investigations of Bizzozero, Lubnitzky, Eberth, Schimmelbusch, and Liéwit there can be no doubt of the existence of the blood-plate thrombus also, into whose com- position the white blood-corpuscles enter as but unimportant factors. It is equally well established that the thready fibrin observed in a thrombosis often contains very few leucocytes (Fig. 14). According to Léwit, the blood-plates are not a constituent of normal blood, but rather make their appearance under definite conditions, and are nothing more than globulin precipitated in the form of plates. For their appearance very slight alterations in the circulation or in the composition of the blood suffice, and it is therefore difficult to make observations upon blood in circulation without causing them to appear; it is nevertheless possible, with proper precautions in investigating, to prove that the blood circulating through the mesentery of the mouse contains no morphological elements be- yond the red and the white blood-corpuscles. Alterations of the vessel-wall and retarda- tion of the blood-current lead to the separation of blood-plates and their adhesion to the walls of the vessel; and the blood-plates so separated then quickly undergo metamor- phosis into a substance closely resembling ordinary fibrin, become comparatively in- soluble, swell up, and take on a partly granular appearance. The fibrin derived from the blood-plates is very like ordinary fibrin in its capacity for taking dyes, and the formation of a blood-plate thrombus is also, indeed, a kind of coagulation. In cold- blooded animals no blood-plates appear under the conditions which would cause them to be formed in warm-blooded animals, but globulin is precipitated in a granular condi- tion. Certain minute fusiform elements contained in the blood of birds and of cold- blooded animals, which Bizzozero, Eberth, and Schimmelbusch hold to be the equivalents of the blood-plates. are none other than young, colorless cells which develop, part into leucocytes and part into red blood-corpuscles. They accordingly are provided with a nucleus and may assume a spherical form, whereas the blood-plates are without a nucleus and are subject only to passive changes of form. Alterations of the vascular walls and retardation of the blood-current in cold-blooded animals lead to the formation of thrombi consisting essentially of leucocytes and capable of transformation into granular masses. At the beginning of cell-deposition we find the spindle-shaped leucocytes de- posited with especial frequency. I am unable to assent to the opinion expressed by Lowit in regard to the mode of origin of the blood-plates ; I am much more disposed to believe that the blood-plates area product of the red blood=corpuscles, and either are thrown off from the bodies of degenerating red blood-corpuscles, or are formed on the disintegration of the same. I base my opinion upon the investigations which Wlassow, at my suggestion, carried out in 1893 in my laboratory. He studied both the early stages of thrombus-formation and also the behavior of the blood-corpuscles when treated with various fluids, and his observations indicate, on the one hand, that at the beginning of a thrombosis, in cir- culating blood, red blood-corpuscles do become adherent to the vessel-wall and may sub- sequently become changed and transformed into a granular mass; and, on the other 120 . VARIETIES OF THROMBI. hand, that a portion of the red blood-corpuscles—presumably those which are the oldest and are approaching their decadence—are extremely unstable cells, out of which are readily formed structures with properties corresponding to those of the blood-plates. As to whether such structures are developed under normal conditions, or whether, in the normal breaking down of the red blood-corpuscles, the colorless components of their structure enter immediately into solution, cannot be decided; this much only can be demonstrated: that the most diverse influences caused a plasmoschisis (a splitting up of the blood-plasma), accompanied by a formation of the so-called blood-plates. Arnold has quite recently published reports upon the products that result from the transforma- tion of red blood-corpuscles (partly by a process of constriction, and partly by what might be termed excretion), and these confirm the observations made by Wlassow and myself. Z A. Schmidt, in his work on the blood, published in 1892, wherein he collects the re- sults of many years of study on coagulation, regards the fibrin-ferment or thrombin as a derivative of the life of the cells, which is developed from an inactive earlier state, pro- thrombin, under the influence of certain zymoplastic substances. In the same way he re- gards the jibrinogenous substance, or metaglobulin, as a product of the disintegration of cellular protoplasm. According to this view the generators of coagulation, as well as those of thrombosis, must all be regarded as cellular derivatives, and it would then be particularly the red blood-corpuscles which would be the source of the materials of coagulation. According to Corin, coagulation occurs in the blood after death, only when the blood already contained ferment during life; and the extent of the coagulation is directly proportional to the amount of ferment present at the time of death. A further production of ferment does not occur after death ; on the contrary, the vessel-walls probably constitute a body inhibiting coagulation. Between the blood of those who have died suddenly (cases of strangulation) and that of those who have died more slowly, the difference is only rela- tive, depending upon the amount of ferment present. No valuecan therefore be ascribed to the fluidity of the blood in the diagnosis of the mode of death. § 41. Thrombosis occurs most frequently in cases of degeneration and inflammation of the intima of the heart and of the vessels, as well as under certain circumstances which, like compression, stricture, or dilatation of the vessels, fatty infiltration and fatty degeneration of the heart, stenosis and insufficiency of the valvular orifices, etc., cause a retardation or an arrest of the circulation. If thrombi occur in cachectic individuals, they are called marasmic thrombi (thrombi marantici). When perforating wounds of vessels are not too large, they become closed by blood-plates and white blood-corpuscles which adhere to the edges of the opening and are also deposited all about it, so that in the wound there is formed a white thrombus projecting into the lumen of the vessel. Different varieties of thrombi are distinguished according to their . relations to the vessel containing them. Thus a parietal thrombus is one attached to the wall of the heart (Fig. 20, c) or of a vessel; a val- vular thrombus, one which is situated upon a valve of the heart or of a vein (Fig. 21, d). Hither kind may consist only of delicate, trans- parent, almost membranous, hyaline deposits; and then, again, they are often thicker and tougher, and project into the lumen of the heart or blood-vessel respectively. Their surface, in the latter case, often shows rib-like ridges of paler appearance than the other parts. If the lumen of a vessel becomes closed by a thrombus, the latter is spoken of as an obturating thrombus (Fig. 29, «, 6). The coagula first formed are designated as primary or autochthonous; those subsequently de- posited upon these, as induced thrombi. Through growth by accre- tion a parietal thrombus may become obturating. In such a case it not. infrequently happens that a red thrombus is superadded to one origi- nally white or mixed in color (Fig. 21, c), inasmuch as the thrombosis began in circulating blood, while later, after the closing off of the ves-: sel, the blood became stagnant and the whole mass then coagulated. VARIETIES OF THROMBI. 121 The converse occurs when a red thrombus, obturating a vessel, contracts down to a smaller volume, and thus leaves a channel once more for the passage of the blood. Thrombi may occur in all parts of the vascular system. In the heart it is particularly in the auricular appendages and in the recesses be- tween the trabecule carne, as well as on any diseased spot of the heart- wall (Fig. 20, b), that they establish themselves. Their formation starts in the deep intertrabecular recesses; but through continual accretions more considerable coagulation-masses are formed, which project in the Fic. 20.—Thrombus-formation in the heart as a result of inflammatory degeneration and aneurismal dilatation of the heart-wall. a. Inflammatory thickening of the endocardium ; ?), inflammatory degeneration of the myocardium, c, thrombus. (Two-thirds natural size.) form of polypi above the general surface (Fig. 20), and therefore are known as heart-polypi. They are sometimes more or less spherical in shape, with a broad base, and again they are more pear-shaped; their surface is often ribbed. As a rare occurrence, large globular or pear- shaped thrombi may become loosened, and then, in case they cannot pass the ostium, they lie free in the corresponding chamber of the heart. Free globular thrombi are sometimes seen in the auricles in cases of stenosis of the auriculo-ventricular orifices, although they are very rare. Very probably they become increased in size by the deposi- tion of fresh layers of fibrin after they have been set loose. If coagu- lated masses attach themselves to an inflamed valve, they are designated as valvular polypi. Parietal and valvular polypi may become very bulky and may fill up a large part of one of the heart-chambers. 122 VARIETIES OF THROMBI. In the arterial trunks thrombi are found in a great variety of places, and are particularly apt to occur behind constrictions and in dilatations. Occasionally, in cachectic individuals with a much-degen- erated intima, parietal thrombi, white or of a mixed color, and super- ficially adherent, are formed in the aorta. In the veins thrombi occasionally are formed in the pockets of the valves (Fig. 21, d), from which they gradually protrude and develop into obturating thrombi. Frequently a thrombus grows out from a lesser vein in which it was formed into the lumen of a larger vein. So, for in- stance, a thrombus having its origin in one of the lesser veins of the lower extremity may grow up through the vena cava inferior until it reaches the heart. Specially important, by rea- son of the local disturbances to which they give rise, are the obturating thrombi of the femoral veins, the renal veins, the sinuses of the dura mater, the large venze cave, and the portal veins. Thrombi of tine smallest vessels arise most frequently in consequence of disease of the surrounding tissues, and especially after infections and toxic inflammations and _ necrotic processes, and they have, for the most part, a hyaline composition. They are composed in large measure of the colorless elements of the red blood- corpuscles, which elements become fused into a homogeneous mass; and yet by a proper technique (Weigert’s fibrin stain) it may sometimes be demonstrated that they also contain stringy fibrin. They are found, furthermore, after superficial burns FIG. 21.—Thrombosis of the femoral and of - (Klebs, Welti, Silbermann) and after the saphenous vein. a,b, An obturating throm- ss 2 a Z 2 bus, of mixed coloring and laminated: c, red poisoning—for : lnstance, poisoning bus protruding frome eee sited with corrosive sublimate (Kaufmann) fourth.) —especially in the lungs. They fre- quently exist in hemorrhagic infarcts (Fig. 12, c). Thrombi, too, originating in the capillaries, may develop into the efferent veins, partly for the reason that through the obturation of a great number of capillaries the blood flows more slowly in the veins, and partly also’for the reason that disintegrating blood-corpus- cles and blood-plates find their way to the veins in great numbers. The first deposits in the formation of a parietal thrombus are deli- cate, transparent, or whitish layers. The fully formed thrombus is a compact, dry mass, firmly attached to the inner surface of a vessel or of the heart, with the different qualities of color and structure described above. Thrombi, originally soft and succulent, undergo in time a proc- ess of contraction, and thereby become firmer and more dry. In this SOFTENING OF THROMBI. 123 way, in case of obturating thrombi, an obliterated channel may become open once more for the passage of the blood. With long-continued contraction, the fibrin, the blood-plates, and the blood-corpuscles may become converted into a tough mass, which long remains in this condition, grows fast to the vessel-wall, and even- tually becomes calcified. This occurs both in valvular thrombi of the heart and in thrombi located in the vessels. The chalky concretions in the veins, known as phleboliths, are formed in this way. Similar forma- tions in the arteries, which occur, however, less frequently, may be called arterioliths. eee Shrinking and calcification constitute a com- K c £ paratively favorable issue of thrombosis. Far i ce less favorable are the various kinds of disin- ef tegration which frequently follow and are known as simple and as puriform or septic yellow soft- ening. In the simple softening the central portion of the thrombus becomes converted into a grayish-red, gray, or grayish-white grumous mass, consisting of broken-down and shrunken red blood-corpuscles, pigment granules, and colorless granular débris. If the softening ex- tends to the superficial layers, and if there is, at the same time, a certain strength of blood- current in the region of the thrombus, the soft- ening débris are swept along into the circulation. And if, under these conditions, somewhat large pieces become detached from their surroundings and are swept along with the blood-current, arterial emboli will be established (see Fig. 2, on page 41). In the yellow puriform or septic softening the thrombus breaks down into a yellow or grayish-yellow or reddish-yellow mass similar to pus, grumous, creamy, and foul-smelling, / which along with pus-corpuscles contains a — yy4q.22—Remains of a throm- great deal of a finely granular substance made bus of the right femoral vein, up of fatty and albuminous detritus and mi- @, Obliterated portion of the crococci. This mass acts as adestructive irritant, Yen (the Tent come ni causing inflammation by its contact. Asaresult — >, 6,4, bridles of connective tis: the intima becomes cloudy, and a suppurative and of its branches; ¢, recent inflammation arises in the media and adventitia, ™ombus: (Natural size.) as well asin the parts about the vessel. After a short time all the vascular tunics become infiltrated and present a dirty-yellow or grayish-yellow appearance. Ulcerative destruction of the tissues eventually supervenes. If the puriform masses are carried along by the blood-current to other places, there too they lead to necro- sis and septic disintegration of the tissues, and to suppurative inflam- mation, which affects not only the wall of the vessels, but also the circumjacent tissues. . The process of puriform softening of a venous or an arterial plug, coupled with the infiltration of the vascular wall, is denominated * thrombo-phlebitis purulenta or thrombo-arteritis purulenta. The inflammation of the vessel-wall may start either in the softening throm- bus or else in the parts adjacent to the vessel. In the latter case the 124 ORGANIZATION OF A THROMBUS. softening of the thrombus either goes on simultaneously with the inflam- mation of the vessel-wall or else succeeds it. These occurrences take place most frequently in the neighborhood of purulent foci. The most favorable issue of thrombosis is in the organization of the Fic. 23.—Closure of an artery of the lungs by a mass of connective tissue, which developed after the vessel had become plugged by an embolus. (Specimen preserved in Miiller’s fluid, and stained with hama- toxylin and eosin.) a, Wall of the artery; b, connective tissue in the interior of the vessel; c, d, newly formed blood-vessels. Magnified 45 diameters. thrombus—that is, in its being replaced by vascularized connective tissue. The new connective tissue is developed from proliferating endothe- lial cells; but if these have been destroyed in the formation of the throm- bus, then plastic migratory cells from the outer layers of the vessel-wall must take their place. The thrombus itself takes no part in the process of organization; it is a lifeless mass which excites inflammation in sur- rounding parts. In course of time the place of the lifeless thrombotic mass is taken by vascularized connec- tive tissue (Fig. 28, 0, c, d). The cicatricial tissue occupying the place of the thrombus shrinks more or less in course of time. Ci- catrices after ligation become in this way very small. Such a cicatrix in the continuity of a vessel may later have the appearance of merely a thick- ening of the vessel-wall, or there may remain only threads and_ trabecule (Fig. 22, b, c, d), which cross the lumen of the thrombosed vessel, so that the blood-current can once more pass the affected spot. It not infre- quently happens, nevertheless, that the ¥iG, 24.—Remains of an embolic plug ina COnnective-tissue bridles crossing the branch of the pulmonary artery. a, Sbrunken |ymen of the vessel cause a marked embolus traversed by threads of connective tissue: b, bridles of connective tissue crossing lessening of its calibre; and this may ssels. nub % . . Seah ee eee (Natural proceed to a complete obliteration of EMBOLI. _ 125 the vessel, so that the blood-vessels for a greater or less distance become converted entirely into solid fibrous cords. Pieces broken off from a thrombus and carried into an artery and there wedged—so-called emboli—generally induce fresh deposits of fibrin upon their surface. Afterward they undergo the same changes as thrombi, and may either soften and break down or become shrunken (Fig. 24, a) and calcified. If the emboli are non-infectious they gener- ally become replaced by vascular connective tissue (Fig. 23, 0, c). In many cases this new formation of connective tissue leads to the obliteration of the artery (Fig. 23). In other cases in the place of the embolus there becomes developed only a ridge of connective tissue or perhaps a knobbed or a flattened thickening of the intima. In still Fig. 25.—Embolus of an intestinal artery with suppurative arteritis, embolic aneurism, and periarteritic metastatic abscess. (Alcohol; fuchsin.) a, b,c, d,e, Layers of the intestinal wall: f, wall of the artery ; y, the embolus, surrounded with pus-corpuscles, lying within the dilated and partially suppurating artery ; h, parietal thrombus; i, periarterial purulent infiltration of the submucosa; k, veins gorged with blood, Magnified 30 diameters. . other cases the lumen of the vessel is traversed by bridles of connective tissue (Fig. 24, b), which either run separately, or, through mutual inter- lacings, form a wide- or a close-meshed network. If the emboli contain pyogenic organisms, which is especially apt to be the case if the emboli come from a thrombus lying in a suppurating focus, suppuration then arises at the site of the embolus (Fig. 25, g), and occasionally ulceration also. § 42. In those conditions which have been described above as active and passive hyperemia respectively, the blood during life is in circula- tion. In the active, congestive form the velocity of the blood-current is increased; in the passive form—venous hyperemia—it is diminished. If venous hypercemia becomes very marked, so that the blood entering a part cannot find exit, the circulation in the small veins and capillaries, and even in the smaller afferent arteries, may come to a complete stand- still; and that condition then obtains which is known as stasis or stag- 126 STAGNATION OF THE BLOOD. nation of the blood (Fig. 26). Inasmuch as fresh masses of blood from the arteries strive with each pulse-beat to force their way into the area of stagnation, and thus distend the capillaries and the veins more and more, the pressure within these rises to be the same as that at the point of divergence of the nearest permeable artery, and by this means a great portion of the fluids of the blood is pressed out of the capillaries and the veins. The red blood-corpuscles consequently become so closely jammed together that their contours are no longer discernible, and the total contents of the vessels form a homogeneous, scarlet-red column S SSS LESS LagBN SS SS ES S\ SE = Fic. 26.—Stasis from venous hypersemia in the vessels of the corium and of the papilla of the planta 1 2 r surface of the toes in a man succumbing to valvular disease, heart-failure, and arteriosclerosis. mlitler's fluid ; alum-carmine.) Deep-violet coloring and commencing gangrene of the toes. Magnified 20 diameters. (Fig. 26). At the same time, however, the blood-corpuscles are not fused together. As soon as the obstacle to the outflow is done away with and circulation is once more resumed, the individual blood-cor- puscles become once more separated from one another. Stasis is produced not only by damming back of the blood, but also by numerous influences affecting the vessel-walls and the blood itself. Thus heat and cold, irritation with acids or with alkalies, the action of con- centrated sugar- or common-salt solutions, of chloroform, alcohol, etc., may cause not only contraction or relaxation of the vessels and disturbances of the circulation, but may, under certain circumstances, produce stasis. The immediate harm effected by these injurious agents lies in their action in abstracting water from the blood and from the vessel-walls; (EDEMA AND DROPSY. ~ 127 in their further action, however, they induce essential changes in the . composition of the blood-corpuscles, of the blood-plasma and of the vessel-walls, whereby the blood-corpuscles become less mobile, and the vessel-walls come to offer increased frictional resistance to the blood-current, while they, at the same time, permit the fluid portions - to pass through them more readily. Stasis, accordingly, may also de- velop through the loss of water and the corresponding drying of the tis- sues, —an event which is likely to follow any injury which lays bare some structure (the intestine, for example) situated in the interior of the body. IV. Gedema and Dropsy. § 43. The unconfined fluid which permeates the tissues is essen- tially a transudation from the blood, though, under some circumstances, a portion of the juice contained in the cells and fibres may also pass over into the unconfined fluid of the tissues (Heidenhain). The exudation of fluid from the vessels is not a process of simple filtration, but is rather to be regarded as a process of secretion, effected by means of the spe- cific function of the capillary walls. The fluid secreted from the capil- laries, which becomes mingled with the products of tissue-metabolism, is absorbed by the lymphatics from the interstices of the tissues, and is returned to the veins through the ductus thoracicus. Every increase in the transudation of the blood-fiuids occasions pri- marily an increase in the permeation of the tissues, which, for the most part, is again reduced by an increased absorption through the lym- phatics. This equilibration, how- ever, has its limits; with in- creased transudation from the blood-vessels we get a more or less permanent oversaturation of the tissues with the transuded fluid. That condition which is pro- duced by this collection of fluid Fig. 27.—Longitudinal section through cedema- in the tissues is known as dropsy, {is imusele-Bores of the astrocnemiis of a sub cedema, or hydrops, and we distin- ‘mixture: saffranin.) Magnified 45 diameters. guish between a general and a localized dropsy according to the extent of the affection. idema ex- tending over superficial portions of the body is known as anasarca or as hyposarca. That transudate from the blood which constitutes the dropsical or cede- matous fluid is always considerably less rich in albumin than the blood- plasma: The fluid collects first in the interstices of the tissues as free tissue-fluid, and may then soak into the tissues themselves and thus cause swelling of the cells and of the fibres, and, under some circum- stances, the formation of vacuoles (Fig. 27), due to the accumulation of drops of fluid within the cells or their derivatives. This may be most freyuently demonstrated in tegumentary and in glandular epithelium, but becomes at times distinctly evident also in other tissue-elements, particularly in muscle-fibres (Fig. 27), whose fibrilles become separated by drops of fluid. It may happen, moreover, that cells in cedematous tissues, particularly in the lungs and the serous membranes, become loosened from their attachment, and the fluid then comes to contain an admixture of epithelial cells in considerable numbers. 128 VARIETIES OF CDEMA. Tissues which are the seat of cedema appear swollen, though the degree of swelling is essentially dependent upon the structure of the tissue. The skin and the subcutaneous cellular tissue are able to take up into the interstices of their structure large quantities of liquid, and an extremity may accordingly become enormously swollen with cedema. Its appearance is then pale, it has a doughy feeling, and upon pressure with the finger an indentation remains behind. An incision sets free an abundance of clear liquid and reveals the tissues thoroughly satu- rated with fluid. . The lung behaves in a similar way. Owing to its limited room it is not especially distensible, but it contains multitudes of cavities filled with air, and these, upon the advent of cedema, become filled with liquid, which on pressure escapes from a cut surface, generally min- gled with air-bubbles. Far less capable of retaining fluids is the kidney; consequently but little fluid flows off on section of an cedematous kidney, though the cut surface is moist and glistening. The amount of blood contained in cedematous tissues is variable, and their color is consequently so also. Such cavities of the body as are the seat of dropsical effusion con- tain at one time a considerable, and at another a very small amount of clear, generally light-yellow, rarely quite colorless, alkaline fluid, which occasionally contains a few flakes of fibrin (cf. the chapter on Inflam- mation). Compressible organs are compressed by the exudation, and cavities are dilated. A collection of fluid in the abdominal cavity goes by the name of ascites. The proportion of albumin in pure transudates is not the same in all the tissues and cavities of the body, but differs within wide limits. Ac- cording to Reuss, the proportion of albumin in transudations of the pleura is 22.5 pro mille; of the pericardium, 18.3; of the peritoneum, 11.1; of the subcutaneous cellular tissue, 5.8; of the cerebral and spinal cavities, 1.4. Therein lies a proof of the differing constitution of the vessel-wall in the several tissues of the body. The water of the various organs and tissues, according to Heidenhain,' is made up of three parts—of the water present in the blood, of the lymph of the organ under con- sideration, and of the water contained in the cells and in the fibres—the tissue-fluid proper. This tissue-fluid may, under certain circumstances, undergo considerable varia- tions, increasing at the expense of the watery part of the blood or of the lymph, or diminishing as the latter increases. If the proportion of crystalloids in the blood (urea, sugar, salts) becomes greater, both blood and Jymph come to contain a greater proportion of water, which is possible only in this way: that these substances, when thrown into the blood, pass over into the lymph-spaces, and, by their affinity for the tissue-fluids, excite a discharge of water from the tissue-elements. The prompt passage of the crystalloids from the blood and the lymph is accomplished with the aid of a force inherent in the capillary cells; that is, it is not a phenomenon of mere diffusion. The evidence of this lies in the fact that the proportion of salts or of sugar in the lymph is oftentimes greater than that 1n the blood. § 44. According to the etiology we distinguish four varieties of cedema—namely, oedema from stagnation of the blood in the blood- vessels, cedema caused by interference with the escape of the lymph, cedema due to some disturbance of the capillary secretion (the result of 1“Versuche und Fragen zur Lehre von der Lymphbildung” [Experiments and Queries Regarding the Theory of Lymph-formation], Arch. f. d. ges. Physiologie, 49. Bd., 1891, and Verh. des Y. internat. ined. Cong., ii., Berlin, 1891. VARIETIES OF C2DEMA. 129 alterations in the walls of the capillaries), and oedema ex vacuo. The third one of these varieties is designated by the practising physician by one or the other of the following terms: inflammatory cedema, hydremic or cachectic cedema, and neuropathic cedema. The cedema of stagnation owes its origin to the fact that when the escape of blood from the capillaries is seriously interfered with, the pressure in these small vessels increases, and the fluid portions of the blood then seek an outlet through their walls,—a state of affairs which gives rise to the escape of an abnormal amount of fluid from the vessels. The amount of the escaping fluids increases in proportion to the degree of discrepancy between the inflow and the outflow of the blood, and is therefore increased by an increase in the afflux of blood. The escaping fluid never contains much albumin, though with in- creased pressure in the veins the proportion of albumin rises (Senator) ; the fluid, furthermore, may contain more or less numerous red _ blood- corpuscles, and their number increases with the degree of obstruction. The immediate result of an increased transudation is an increased flow of lymph, and this may suffice to carry off all the fluid. If it does not so suffice, the fluid collects in the tissues and we have a condition of oedema or dropsy. According to Landerer, the occurrence of this condition is favored by the fact that the elasticity of the tissues becomes diminished in consequence of the long-continued increase of the press- ure to which they are subjected. Obstruction to the flow of the lymph, as experiments in this line have shown, is not ordinarily succeeded by oedema. In the first place, the lymph-vessels in the various parts of the body have elaborate anasto- moses, so that an obstruction to the flow of lymph does not readily occur; and even when all the efferent lymphatics of an extremity are closed off, provided the lymph-formation remains normal, no dropsy generally ensues, inasmuch as the blood-vessels themselves are able to take up the lymph again. Only the occlusion of the ductus thoracicus is ordinarily followed by stasis of the lymph and by cedema, particularly by ascites; but we must still observe that even in this case collateral channels may open up, and may suffice to carry off the lymph. Although lymphatic obstruction is not ordinarily sufficient to cause cedema of itself, yet it does increase an cedema already produced by excessive transudation from the blood-vessels. Pathological alterations in the walls of the capillaries and veins of sucha nature as to cause an increase in the vascular secretion’ (Heidenhain), and thus induce cedema, may occur as the outcome merely of long-continued passive congestion and the resulting imperfect renewal of the blood. Such alterations occur, however, in the majority of cases, as the result of protracted ischemia, of timperfect oxygenation, or of chemical changes in the blood; or they may be due to the effect of high or low temperatures, or to active traumatism. It ig also probable that either zrritation or paralysis of the vaso-motor nerves may lead to an increased vascular secretion.’ Just what changes the vessels suffer under these circumstances we are not able to state precisely, but it is proper enough to suppose that some alteration of the endothelial cells and of the cementing substance between them is the most important part ofthe lesion. If through these influences cedema arises, then we may dis- tinguish, according to the cause, toxic, infectious, thermal, trau- matic, ischemic, neuropathic cedema, etc., and such a division has , 1 Vide supra, § 43. 130 VARIETIES OF CEDEMA. much to commend it. Hitherto the kinds of cedema here under consid- eration have generally been relegated to two groups, inflammatory cedema and cachectic cedema. Inflammatory cedema is most undoubtedly to be referred to an alter- ation in the wall of the vessel, and is seen both as an independent affec- tion, in the shape of circumscribed or more extensive swellings and dropsical effusions, and also as an epiphenomenon in the neighborhood of severe inflammatory processes. In the latter case it is frequently called collateral edema. Inflammatory oedema is differentiated from the cedema of stagnation in that the transuded fluid holds far more albumin in solution and is much richer in white blood-corpuscles, and, further- more, in that considerable coagula occur in it (cf. the chapter on Inflam- mation). Its origin is to be sought sometimes in infectious and toxic, sometimes in thermal or traumatic influences, and again in a temporary ischemia. As to hydramic or cachectic oedema, it was long thought that hy- dremia proper—i.e., diminution of the solids of the blood—as well as hydreemic plethora—i.e., retention of water in the blood—could be an immediate cause of increased transudation from the blood-vessels. It was supposed that the vessel-walls behaved as animal membranes and allowed a fluid poor in albumin to pass through more readily than one containing a larger amount of albumin. The vessel-walls are not, how- _ ever, lifeless animal membranes, but are to be regarded as a living organ. Hydremia, experimentally produced, is not, according to Cohnheim, followed by cedema;.and even when we succeed, through the production of hydreemic plethora—i.e., through overfilling the vascular system with watered blood—in obtaining an increased transudation from the vessels, and eventually cedema, this oedema supervenes only after the proportion of water in the blood has become very large, and, moreover, it does not develop in the same localities where the so-called hydreemic cedema in man develops. We are driven, then, to assume that the cedema of ca- chectic individuals, as well as that of “nephritics ”’—i.e., of individuals whose renal function is imperfect—is due essentially to an alteration of the vessel-walls, an alteration caused either by the hydrated condition of the blood or by a poison circulating in that fluid. Probably other le- sions of the tissues should be considered in this connection (Landerer) —lesions which diminish the elasticity of the tissues. Under these conditions the hydrwmia indeed favors the appearance of cedema, but is not the sole cause thereof, nor does it determine the site of the same. Hydremic cedema is distinguished from inflammatory cedema by the facts that the transudate is less rich in albumin, and that it contains corpuscular elements in smaller proportion. (Edema ex vacuo occurs principally in the cranial cavity and in the spinal canal, and arises in all cases in which a portion of the brain or of the spinal cord is lost and its place is not taken by some other tissue. In atrophy of the brain and of the cord the subarachnoidal spaces in par- ticular become enlarged; occasionally the ventricles also. Local defects - either become filled by dilatation of the nearest subarachnoidal spaces or of the adjacent portions of the ventricles, or fluid collects directly at the site of the defect. According to Cohnheim and Lichtheim, injections of aqueous solutions of salt into the vascular system of dogs! show that hydration of the blood does not produce oedema. 1Virch. Arch., 69. Bd. HEMORRHAGE AND THE FORMATION OF INFARCTS. 131 If the mass of the blood is increased, an increase is observed in almost all the secretions (saliva, intestinal juices, bile, urine, etc.) and also in the flow of lymph; the last, how- ever, not universally—for instance, not in the extremities. In an advanced state of hydremic plethora the abdominal organs become edematous, but never the extremities. Control-experiments recently made by Francotte confirm the observation that hydremic plethora artificially induced in the lower animals results directly in dropsy of the ab- dominal organs ; but Francotte obtained cedema also of the skin and of the subcutaneous cellular tissue. : : The view that the so-called hydremic oedema is merely the result of an increase of the absolute amount of water in the blood is championed especially by von Reckling- hausen and by Pisenti. The distribution of the dropsy is, according to von Reckling- hausen, essentially dependent upon bodily position, external pressure, impeded circula- tion, difference 1n innervation of the several vascular areas, and upon the consequent difference in the fulness of their vessels. Ican subscribe to these opinions only in so far as they apply to the modifying factors named, not, however, as regards their general drift. Opposed to this are not only the experiments of Cohnheim and Lichtheim above referred to, but also the fact that in nephritic as well as in cachectic subjects cedema not infrequently appears at a time when no hydremic plethora is present, and that, conversely, with hydremic plethora present, edema may be wanting. I therefore look upon the increase in the amount of water as only one factor which is favorable to the occurrence of cedema. According to Lowit, for the development of an cedema of stagnation in the lungs, an obstruction to the outflow of the blood from the lungs is not alone sufficient ; there must at the same time be an increased afflux of blood to the lungs, which, moreover, must persist for a certain length of time. According to Heidenhain, the specific function of the capillary walls plays a con- trolling part in the formation of lymph, and consequently the formation of this material can be influenced by various substances present in the blood. The fact that crystalloid substances are quickly eliminated from the capillaries and cause a discharge of tissue- fluids into the lymph has already been mentioned in § 43. Heidenhain has, however, found substances which, when injected, increase the transudation of water from the blood-vessels into the lymph. This may be accomplished, for instance, with decoctions of the muscles of crabs and of fresh-water mussels, or of the heads and bodies of leeches or with injections of peptone and of egg-albumen ; and by these means the quantity of lymph flowing from the ductus thoracicus may be increased from five to six or even fifteen fold. There is also a concomitant increase in the proportion of organic matter inthe lymph. The exciting substance must then stimulate the specific function of those cells in the capillary walls which secrete the lymph. If we reason from these observa- tions, it seems very probable that many skin-affections described as neuropathic, and characterized by cutaneous hyperemia accompanied by edematous swelling—as, for ex- ample, urticaria, erythema nodosum, and herpes zoster—are to be regarded as intoxica- tions coupled with nervous affections and with disturbances of the secretory activity of the capillaries. Possibly the secretion of the capillaries may be affected also by direct innervation. V. Hemorrhage and the Formation of Infarcts. § 45. By hemorrhage we understand the escape of all the ingredi- ents of the blood from the vessels (extravasation) into the tissues or upon a free surface. It is either arterial or venous or capillary, or else occurs from all the vessels at ones. The blood which has escaped from the capillaries is termed an extravasate ; at the same time, for the differ- ent forms of hemorrhage there are a great variety of names in use. If the hemorrhagic foci are small and form more or less sharply defined, punctate, red or reddish-black spots, we designate them as petechic or ecchymoses ; if they are larger and less clearly defined, as suqqillations and as bloody suffusions. If the affected tissue is solidly infiltrated with the escaped blood, but yet not rent nor broken up, we call it a hemor- rhagic infarct. If the blood forms a tumor we speak of it as. a hema- toma, or a blood-tumor. The blood which escapes from the vessels into the neighboring tis- sues collects at first in the interstices (Fig. 28). If a large quantity of blood is poured out, the structure of the tissue may be completely con- 132 DIFFERENT FORMS OF HEMORRHAGE. cealed. The more delicate structures, like those of the brain and spinal cord, may be destroyed by a somewhat copious hemorrhage. If the hemorrhage occurs at the free surface of an organ the blood either escapes externally or is poured out into the cavity surrounding the organ. ; Hemorrhage from the mucous membrane of the nose is called epr- staxis ; vomiting of blood, hematemesis ; bleeding from the lungs, heemop- toé or hemoptysis ; from the uterus, metrorrhagia or menorrhagia (dur- ing menstruation); from the urinary organs, hematuria; and from the sweat-glands, hemathidrosis. A collection of blood in the uterus is designated as Acemetometra, in the pleural cavity as heemothoraz, in the tunica vaginalis testis as hcema- tocele, in the pericardium as hemopericardium. Those hemorrhages in the skin which are not the result of violence are generally designated as purpura (Fig. 28). What are called hemor- Fic. 28.—Hemorrhage in the skin near the knee ; from a man eighty-one years of age. (Formalin; hema- toxylin ; eosin.) Magnified 80 diameters. rhagic blebs—accumulations of blood and serum beneath the epidermis— form at spots where disintegration has taken place in the deeper layers of the epithelium. Recent extravasations of blood have the color characteristic of arterial or of venous blood. Later, the extravasate undergoes various altera- tions, which are particularly characterized by color-changes. Subcu- taneous suggillations become first brown, then blue and green, and finally yellow. In course of time extravasates become absorbed again (compare Chapter IV.), and while this is in progress a certain amount of proliferation of the tissues often takes place. Connective tissue may push out bourgeons into large collections of blood, growing through them in every direction, or may encapsulate them entirely (compare Chapter VI.). Hemorrhages may occur, on the one hand, from interruption in the continuity of the vessel-wall, and are then called hemorrhages per rhexin or per diabrosin. This is the only form of arterial hemorrhage. From the capillaries and the veins hemorrhage may occur, on the other HEMORRHAGE BY DIAPEDESIS. 133 hand, in still another manner—to wit, per diapedesin; that is, by a process in which red blood-corpuscles pass through the vessel-wall with- out any previous rent in the same. Such hemorrhages are often quite small and of inconsiderable extent; in other cases the process continues for a longer time, and the infiltration of the tissues with red blood-cor- puscles becomes very extensive. Hemorrhages by diapedesis are ac- cordingly not always small, and hemorrhages by rhexis not always great. Rupture of a capillary or of a small vein does not cause profuse bleeding; on the other hand, the escape of blood by diapedesis may attain to very great proportions. In a given case it is by no means always easy—indeed, it is often impossible—to make out whether hem- orrhage has taken place by rhexis or by diapedesis. ; The phenomenon of diapedesis may be observed under the microscope inthe frog’s mesentery or in the web of the frog’s foot. If before the examination we ligate the efferent veins, we see that the capillaries and the veins become gorged with blood. After a certain time the red blood-corpuscles begin to escape from the capillaries and the veins.'!' Hering? regards the process as one of filtration. As a result of obstruction to the outflow, the blood seeks to escape laterally and is forced through the vessel-wall by pressure. Exhaustive investigations in regard to diapedesis of the red blood-corpuscles, as well as in regard to the escape of other anatomical elements within the blood-vessels, have been carried on by Arnold.? He thought first that we must admit the presence of gaps in the endothelial tube at the points of exit of the corpuscular elements, and he designated these gaps as stigmata and stomata. He subsequently recognized the supposed openings to be but accumulations of the intercellular cement-substance between the en- dothelial cells. Under pathological conditions this cement-substance becomes softened and permits the passage of the red blood-corpuscles. § 46. The causes of interruptions of continuity in the vessel-walls are partly mechanical injury, partly increase in the intravascular pressure, partly disease of the blood-vessels. Increase in the blood-pressure in the capillaries and smallest veins is sufficient of itself to cause rupture with- out the aid of vascular changes, especially in cases of marked obstruc- tion. Sound arteries and sound veins of larger size, on the other hand, cannot be dilated to the point of rupture by the mere rise of blood-press- ure; diseased or abnormally thin-walled arteries, however, may burst. New-formed vessels are very fragile. Diapedesis follows upon rise of pressure in the capillaries and veins, as well as upon increased permeability of the vessel-walls. If the outflow of venous blood in a given vascular area is totally interrupted, diapede- sis of the red blood-corpuscles from the involved capillaries and veins starts up then and there; this is to be regarded as the result of the local increase in intravascular pressure. The exodus of blood-corpuscles through vascular degeneration occurs particularly after mechanical, chemical, and thermal lesions of the vessel-walls, and we may suppose that certain poisons affect the vessel-walls with especial virulence. An abnormal permeability of the vessel-walls may, furthermore, be observed when, for a long period, the vessels have not been traversed by the blood-stream, and have suffered in their nutrition in consequence. When an individual manifests a tendency to hemorrhage, the condi- tion is called one of hemorrhagic diathesis, of which we recognize a congenital and an acquired form. The congenital hemorrhagic diathesis or congenital hemophilia, 1Cf. Cohnheim, “ Allgemeine Pathologie,” I. Th., and Virchow’s Arch., 41. Bd. ® Sitzungsber. d. Wiener Akademie, 1868, 57. Bd. 3 Virchow's Arch., 58., 62., and 64. Bd. 134 HEMORRHAGIC DIATHESIS. which, as stated in §§ 81 and 82, belongs to the hereditary diseases, probably has its cause in an abnormal constitution of the vascular walls, though the constitution of the blood, withal, may not be normal, and, in consequence of this condition, it may not be possible to arrest, through a process of coagulation, a bleeding after it has once begun. An acquired hemorrhagic diathesis attends those diseases known as scurvy, morbus maculosus Werlholfii, purpura simplex, purpura (peli- osis) rheumatica, purpura hemorrhagica, hemophilia, and melena neo- natorum, and Moeller’s or Barlow’s disease (infantile scurvy), and fur- thermore plays a part in many infectious diseases and intoxications— e.g., septicemia, endocarditis, malignant pustule, spotted typhus, chol- era, small-pox, the plague, acute yellow atrophy of the liver, yellow fever, nephritis, phosphorus-poisoning, snake-bite, etc.—and also, finally, in pernicious anemia, leucocythemia, and pseudo-leucocythemia. The cause of the diseases named in the first group—in all of which the occur- rence of hemorrhages in the skin, as well as in the mucous membranes, and in the parenchyma of other organs and tissues,’ constitutes a promi- nent symptom—is ordinarily supposed to lie in a general disturbance of nutrition and circulation, although observations of the last few years make it probable that at least a great proportion of them belong to the class of infectious diseases. W. Koch is of the opinion that scurvy is an infectious disease, and that purpura in its many forms, and erythema nodosum, and the hemorrhages occurring in the new-born, are varieties of the same infection. In the last few years bacteria have frequently been found in these latter affections also—that is, in purpura heemor- rhagica and also in hemophilia neonatorum. In this connection we must refer particularly to the investigations of Kolb, Babes, Gartner, Tizzoni, and Giovannini, who have found in those suffering from these diseases bacilli which were also pathogenic for the lower animals, and when injected produced an affection characterized by hemorrhages. With these diseases those other infections which are characterized by hemorrhages are probably connected, and it is to be supposed that the bleeding is produced partly by local chanyes in the walls of the vessels, caused by localized growths of bacteria, partly by the injurious influence of toxic substances produced by the bacteria themselves. In this case they should in part be reckoned among the hemorrhages of intoxication. The hemorrhages occurring in conditions of anemia are to be re- garded as a consequence of anzmic degeneration of the vessels, though partly also as a result of disturbances of the circulation. A whole list, finally, of apparently spontaneous hemorrhages is con- nected with irritation or paralysis of the vaso-motor nerves, arising either from the central nervous system, or by reflex action, or through lesion of the conducting nerve-fibres. Here belong the hemorrhage of men- struation, many forms of nasal, intestinal, and bladder hemorrhage; furthermore, bleeding from the conjunctiva, from the skin (stigmatiza- tion), from healthy kidneys, from the breasts, from hemorrhoids, from wounds, etc. Here also are to be reckoned a portion of those pulmo- nary hemorrhages which follow upon severe cerebral lesions, though in a particular case a trustworthy judgment often cannot be given, because disturbances of respiration, as also the aspiration of irritating substances into the lungs, may likewise lead to hyperemia and to the escape of 1In Barlow’s disease, which in children of from one and a half to two years of age often develops in connection with rachitis, the hemorrhages are found to have taken place between the periosteum and the bone. HEMORRHAGE BY RUPTURE OF THE VESSEL WALL. 135 blood in the lungs. Lastly, there occur in brain disease—particularly in disease of the crura cerebri—gastric and intestinal hemorrhages which are dependent upon the cerebral lesion. According to von Preuschen, the gastric and intestinal hemorrhages occurring during the first days of life, and known as melena neonatorum, belong to this category, inas- much as during labor hemorrhages and ecchymoses are not infrequently produced in the brain, in consequence of which the intestinal hemor- rhages follow. By others, on the contrary (Gartner), melena neonato- rum is classed among the infectious diseases. Hemorrhages per rhexin cease as soon as the pressure upon the out- side of the bleeding vessel becomes as great as the intravascular press- ure, or as soon as the narrowing of the vessel and the processes of coag- Fic. 29.—Part of the edge of an anzemic infarct of the kidney. (Miiller’s fluid; heematoxylin ; eosin.) a, Normal uriniferous tubules in a normal stroma; a, normal uriniferous tubules in a stroma infiltrated with cells; b, normal glomerulus; c¢, necrotic tissue without nuclei, with granular coagula in the tubules: d, necrotic glomerulus, swollen and with few nuclei; ¢, uriniferous tubules without nuclei, in a stroma with sen ‘ persisting; f, necrotic tissue with cellular, and, g, with hemorrhagic infiltration. Magnified 50 ameters. ulation and of thrombus-formation effect a closure of the rupture. In the case of hemorrhage by diapedesis the bleeding will cease when blood is no longer supplied to the vessel which bleeds, when the abnormal in- travascular blood-pressure is withdrawn, and when the vessel-wall is restored to a normal state. : § 47. When an artery is suddenly closed by thrombosis, or by em- bolism, or by ligation, or by any other means, there occurs beyond the obstructed point, as has already been stated in § 39, an arrest of the circulation, after the vessel has more or less emptied itself by the con- traction of its walls; while from the point of obstruction back to the point of divergence of the nearest arterial branch the blood-pressure in- creases. If the branches of the artery beyond the point of obstruction have free arterial communication with some other unobstructed artery, this sabier by becoming dilated is able to carry a supply of blood sufi- 136 HEMORRHAGIC INFARCTS. cient for the area of distribution of the obstructed vessel, and the ar- rested circulation is thus restored. chet If the obstructed area has no vascular connections through which it can draw its blood-supply, that portion of tissue which is thus deprived of its nutrition remains empty of blood and dies; thus there is formed an anemic infarct. Parenchymatous organs, such as the spleen and the kidneys, in those portions which are deprived of blood, appear cloudy, opaque, yellowish-white, often clay-colored, and the microscope shows that the tissues are dead, and that therefore the nuclei of the cells (Fig. 29, c, d, e, f, g) no longer take the stain. If the area of distribution of the obstructed vessel has no arterial anastomosis, if the obstructed vessel is a terminal artery, but if there remains, on the other hand, the possibility of a scanty afflux of blood from adjacent capillaries or from the veins, a hemorrhagic infarct may Fig. 30.—Part of the edge of a recent hemorrhagic infarct of the lung. (Miiller’s fluid; heematoxylin ; eosin.) a, Interalveolar septa without nuclei, containing capillaries gorged with thrombotic masses, homo- geneous in appearance and deep-bluish violet in color; b, septa containing uuclei; c,a vein with a red thrombus; d, a‘veoli completely filled with clotted blood; e, alveoli Alled with serous fluid, fibrin, and leuco- cytes. Magnified 100 diameters. be formed. The capillaries of the region rendered anzmic by the ob- struction become slowly filled once more with blood, which comes in part from capillaries belonging to the domain of adjacent vessels, in part from the veins, from whence the blood flows in a retrograde direction. The blood flowing in from the adjacent capillaries is under very low pressure, which does not suffice to drive the blood promptly through the obstructed area into the veins. When the relative pressures be- come such that a retrograde current sets in from the veins into the capil- laries, a restoration ef the normal circulation becomes, at once, entirely out of the question. Unless, by a speedy adjustment of the conditions of pressure throughout the vascular system, a normal flow of blood is promptly reéstablished through the obstructed area, the imperfect circulation (which by the progress of coagulation in the veins (Fig. 30, c] and capillaries [a] will eventuate in complete arrest of the blood-current) leads sooner or later to degeneration, and even to necrosis of the vessel walls, and thus to their exaggerated permeability. As a result of this, if HEMORRHAGIC INFARCTS. 137 the afflux of blood is continued, diapedesis of the red blood-corpuscles be- gins in the obstructed area, and goes on to infiltration of the tissue with extravasated blood-corpuscles, whereby the affected area takes on a dark-red color and acquires a firmer consistency,—in short, there is formed a hemorrhagic infarct. Embolic hemorrhagic infarcts are to be found in the lungs (Fig. 30), but they are formed, after the embolic obstruction of an artery, only when there is a tendency to stagnation of the pulmonary circulation ; while with a normal pulmonary circulation such circulatory disturbances as follow upon embolism are generally promptly allayed. In the corpo- real circulation extensive hemorrhages from embolism are confined, almost exclusively, to the territory of the superior mesenteric artery, -whose branches, although they are not terminal vessels, yet possess but few anastomoses. Ancemic infarcts occur particularly in the spleen, in the heart, in the kidneys, and in the retina, though hemorrhage is found in these also, along the borders of the obstructed region, so that the bloodless foci have a hemorrhagic border surrounding them, or at least present hemorrhagic spots (Fig. 29, g). The necrotic tissue, further- more, becomes saturated with fluid, and may then swell (Fig. 29, d) and present granular or fibrous coagula in its interstices (Fig. 29, ¢). In case of the obstruction of arteries of the brain, or of those of the extrem- ities, or of the central artery of the retina, hemorrhages may also occur in spots. In the interior of the infarct the tissues are generally wholly or in greater part dead, and it is especially the specific elements of the affected organ (Fig. 29, c, d) which are the first to die. After a time exudative inflammation arises in the neighborhood of ischemic and of hemorrhagic infarcts, with the formation of a cellular (Fig. 29, 7) or fibro-cellular exudate (Fig. 30, e); and this is followed by tissue-prolif- eration, by means of which the dead tissue, with its hemorrhagic infil- tration, becomes absorbed, and its place is taken by connective tissue. (Compare Part IT. of Chapter VI.) In his published works Virchow, who was the first to institute any profound experi- mental researches into the matter of thrombosis and embolism, left the question of the origin of the hemorrhagic infarct still open, but he expresses the opinion that in the area of distribution of the obstructed artery the vascular walls suffer certain alterations which render them more fragile and permeable. If a collateral circulation afterward becomes established, this secondary hyperemia causes exudation and extravasation. Cohnheim, who observed directly under the microscope the results of embolism in the frog’s tongue, demonstrated the retrograde flow of the blood in the veins, the refilling of the capillaries, and the escape of the blood by diapedesis. The cause of the diapedesis he thought was essentially the disorganization of the vascular wall due to the anemia. Litten considers the reflux of the blood from the veins to be but an unessential part of the phenomenon, and ascribes the refilling of the exsanguinated area to the pouring in of blood from the neighboring vascular tields. The disorganization of the vessel-walls he thinks also unnecessary for the production of infarction, inasmuch as the stagnation suffices of itself, just as in venous obstruction, to explain thediapedesis. The diapedesis is therefore increased whenever in such foci the blood coagulates in the efferent veins. Von Recklinghausen considers the principal cause of the formation of a hemor- rhagic infarct to be the hyaline thrombosis of the capillary vessels of the region involved by the embolism. If subsequently blood from neighboring vessels enters the still per- vious portions of the implicated territory, it encounters resistance, becomes stagnant, and then escapes from the vessels. According to Klebs,! emboli thrown into the cir- culation of the lower animals cause infarction only when blood rich in ferment is thrown in after the embolus, or else when substances provoking coagulation become dissemi- nated through the obstructing plug. Grawitz is of the opinion that hemorrhagic infarcts of the lungs are never to be ascribed to vascular obstruction by embolism, but rather that stagnation and pulmonary 1 Schweizer Arch. f. Thierheilk., Bd. 28, 1886. 138 LYMPHORRHAGIA; CHYLURIA. inflammation are to be regarded as the cause of the hemorrhages. There is no room, however, to doubt the existence of embolic pulmonary infarcts. They can occur, it is true, only when there is a tendency to stagnation in the lungs, and therefore, in animals with unimpaired pulmonary circulation, they are not to be provoked by the introduction of obstructing particles into the pulmonary arteries. The essential causes of the escape of the blood are to be found in the stagnation of the blood within the obstructed area, and in the necrosis of the tissues as well as of the vessels themselves. This last may be positively recognized in the disappearance of the nuclei (Fig. 30, a). Secondary throm- boses in the vessels within the area of obstruction (Fig. 30, c) are frequent, and increase the extent of stagnation and of extravasation ; they are not, however, invariably present at the time of the extravasation, and are therefore not essential to the occurrence of the hemorrhage. When conditions of stagnation and inflammation exist in the lungs copious hemorrhages often occur, and these—if limited to distinctly circumscribed areas —would present a very close resemblance to embolic infarcts. They are generally, how- ever, less sharply defined and less firm, so that they are for the most part easily distin- guishable from embolic infarcts. VI. Lymphorrhagia. § 48. Lymphorrhagia occurs when the continuity of a lymphatic vessel becomes interrupted at a certain point and the lymph is poured out into the surrounding parts. As the pressure in the lymphatics is very low—that.is, is not greater than in the surrounding tissues—it fol- lows that lymph can be poured out from a lymphatic only when the affected vessel lies on the external surface, or when a natural cavity is at hand into which the lymph can flow, or when, by the same cause which effected the breach in the lymph-vessel, an open space was formed in the tissues. So, for example, in wounds we may see lymph escaping along with the blood, but the outflow is checked upon the least counterpressure. If after the wounding of a lymphatic vessel the aper- ture persists, so that there is a permanent flow of lymph escaping exter- nally (as in ulcers) or into one of the cavities of the body, we have a so- called lymphefistula, through which considerable quantities of lymph may become lost. Most important and also most dangerous is a division of the ductus thoracicus, observed sometimes after traumatism, and occa- sionally also as the result of obstruction tp the lymph-flow at some point through compression of the duct (after inflammation, or in the course of the development of tumors). The lymph is poured out into the thoracic or the abdominal cavity, and a chylous hydrothorax, or a chylous ascites, or, in very rare cases, a chylopericardium ensues. In very rare cases it happens that the urine, as it comes from the bladder, has the appearance of a milk-white, or a yellowish, or, through the admixture of blood, a red- dish emulsion, and contains, along with albumin, large quantities of fat subdivided into very minute globules. The phenomenon is consequently known as chyluria. It occurs endemically in certain tropical regions (Brazil, India, the Antilles, Zanzibar, Egypt), where it is caused by a parasite, the Filaria Bancroftii, which inhabits the ab- dominal lymph-vessels and there produces its embryos (Filaria sanguinis) ; these, during the repose of the patient in the horizontal posture, swarm in great numbers in the blood and are also contained in the chylous urine. The connection between the chyluria and the invasion of the lymph-vessels by the filaria has not yet been satisfactorily demon- strated by anatomical investigations ; it is nevertheless probable that, on account of the obstruction which occurs in the lymph-circulation, chyle escapes from the ruptured lymphatics of the bladder and mingles with the urine, so that the chyle-like fluid does not come from the blood and through the kidneys (Scheube, Grimm) ; and in corrobora- tion of this view we may mention the facts, first, that upon autopsy the abdominal lymphatics exhibit marked dilatation (Havelburg), while the kidneys are but slightly altered, and second, that, according to an observation of Havelburg’s, the urine coming directly from the ureter showed no admixture of chyle, although chyluria was present at the time. CHAPTER IV. Retrograde Disturbances of Nutrition and Infiltra- tions of the Tissues. I. On Retrograde Disturbances of Nutrition and Infiltrations of the Tissues in General. ; § 49. Retrograde disturbances are characterized in general by degen- eration of the affected tissue, often with diminution in its size as a whole and disappearance of its elements. Accompanying this there is disturb- ance of the function of the tissue. Infiltrations of the tissues are characterized, on the other hand, by a deposit in them of pathological substances which are either formed in the body itself.or have been introduced into it from without. In this case, also, the function of the tissue is usually interfered with. The infiltration is often only a result of preceding degenerative changes, or, on the other hand, t¢ may itself represent the principal manifestation of this degeneration. Retrograde disturbances of nutrition may affect the body in its com- pletely developed form or during its period of development and growth, and in either case they lead to an abnormal smallness of the affected organ or portion of the body. In the former case this diminution in size depends upon disappearance of the fundamental elements of the affected tissue, and is designated atrophy. In the latter case, on the other hand, it depends upon an imperfect development of the affected organ, shown by a more or less rudimentary condition of its elements. If in this way an organ or portion of an organ entirely fails of develop- ment, so that it is either completely absent or at most only a mere rudi- ment of it is present, the condition is spoken of as agenesia or aplasia. But if the affected portion of the body is only moderately below the norm in its development, the condition is spoken of as hypoplasia. The causes of agenesia and of hypoplasia may be either intrinsic or extrinsic—that is to say, the diminished size and imperfect formation of the organ may depend on pathological conditions within itself, or they may be the result of the action of injurious external influences. The maldevelopment may further affect either the entire body, in which case a dwarf results, or it may affect a portion of it only, giving rise then to imperfect formation of single parts or organs. The causes of degeneration of tissue and of the resulting atrophy are for the most part injurious extrinsic influences to which the tissue is exposed during life, and yet at times they may also be traced to intrinsic conditions. This latter is notably the case with the tissues during old age, when they are reaching their physiological limit and are gradually becoming incapable of properly nourishing and preserving themselves. In many tissues a similar retrograde change, dependent upon intrinsic causes, occurs earlier in life, as, for example, physiologically in the ovary and in the thymus gland. 4 140 RETROGRADE DISTURBANCES OF NUTRITION. Among the extrinsic harmful influences which may lead to degenera- tions, nearly all those should be mentioned which have been discussed in Chapter II. Thus an important part is played by disturbances of the circulation, with imperfect transport of oxygen and nutriment to the tis- sues, and by poisons. Usually degenerations are of limited extent, so that one speaks of degenerations of special tissues or of particular organs; but, on the other hand, disturbances of nutrition may be more general and the entire organism may suffer. Thus the picture of a general disease may be produced by a degenerative or atrophic condi- tion of the blood, which may show itself by a diminution either of the red blood-corpuscles or of their hemoglobin content, whereby a permanent condition of general anzemia or insufficient blood-supply is induced, the nutrition of the tissue being correspondingly impaired. Again, as the result of an insufficient ingestion of food or of disor- dered assimilation on the one hand, and of excessive waste of proteids and fats of the body on the other, there may result a condition of weak- ness and maluutrition, often associated with anemia, leading to atrophy of the body asa whole. This is spoken of as cachexia or marasmus. If, under these circumstances, it appears likely that certain substances are undergoing formation in the body which, when taken into the blood and various fluids, act as impurities and alter the constitution of those fluids, the condition is spoken of as one of dyscrasia. II. Death. § 50. All life comes sooner or later to an end—to death. When this occurs at an advanced age, without preceding well-defined symptoms of disease, it may be regarded as the normal termination of life, and is to be attributed, at least in part, to the cessation of function of certain of the organs necessary to the continuance of life. This occurs usually as the result of intrinsic causes, although in most cases it is impossible to exclude the influence of extrinsic conditions in bringing about the cessa- tion of function of the organs in question. When death occurs early in life—that is to say, at an age earlier than the average age of death in man—and when itis preceded by symp- toms of disease, it must be considered abnormal. Its occurrence under these circumstances is for the most part referable to extrinsic influences, though it may occasionally be due to intrinsic inherited conditions. It is obviously impossible to draw any sharp line of separation between what may be called physiological and pathological death. The causes of pathological death are those which have been discussed in Chapter IT. as the causes of disease. A body is said to be dead when all of its functions have forever ceased. Death is, however, inevitable at that instant when one or more of the functions imperatively necessary to life have ceased, although it is not necessary that at that moment c// functions shall have ceased. Indeed, after life is irrevocably lost, many organs are still capable of performing their function, and it is only after a little time that all the organs die. Thus the life of the organism passes gradually, by the progressive ces- sation of the functions of its various organs, into the state which we term death. Thé discontinuance of the functions of the heart, of the lungs, and of the nervous system results in an immediate death of the entire CHANGES IN THE BODY AFTER DEATH. 141 organism. Discontinuance of the functions of the intestine, of the liver, and. of the kidneys renders life impossible after a certain length of time, often measured by days. Destruction of the organs of reproduction in no wise endangers either the health or the life of the affected individual, and, similarly, one or more of the organs of special sense may be spared. Death is usually inevitable after cessation of respiration, and certain after cessation of the heart-beat. With discontinuance of breathing it is impossible for any organ to continue alive longer than a very short time. The stoppage of the heart similarly makes impossible any fur- ther nourishment of the tissues, and the central nervous system quickly becomes unable to continue the performance of its functions. After death the body may present considerable diversity of appear- ance. The distribution of the blood at the time of death has much to do with the aspect of its visible portions. Thus an abundant supply of blood in the skin causes it to have a bluish-red color, while if anzemic itis pale. Furthermore, disease may materially alter the appearance of the exterior of the body. Sooner or later after death certain changes occur in the tissues of the body which may be regarded as unquestionable signs of death, In the first place, the temperature of the body falls, so that after a variable inter- val it reaches the temperature of the surrounding air. It should, how- ever, be borne in mind that the temperature at times does not begin to sink immediately after death, but first rises somewhat. The rapidity of the cooling of the body depends partly upon the character of the body itself and partly upon the nature of its surroundings. The time required may vary from one to twenty-four hours. The coldness of the dead is spoken of as algor mortis. At the time of death the skin is usually pale, but after a variable period—from six to twelve hours, or even less—bluish-red blotches appear on the dependent portions of the body. These are designated livores mortis or blotches of cadaveric lividity, and depend upon the accu- mulation of the blood in the capillaries and veins of the more dependent portions of the skin. They are not observed in those parts of the body which are subjected to pressure. Their number and size depend upon the amount of blood in the skin at the time of death. Parts which have been cyanotic in life may retain this appearance after death; this is par- ticularly the case with the head, the fingers, and the toes. The color of these blotches of cadaveric lividity is for the most part bluish-red, and there may be considerable difference in the intensity of their coloring. In cases of poisoning by carbon monoxide it is bright red. The weight of the body causes flattening of those muscular parts of the body upon which it rests. Sooner or later there occurs a cadaveric stiffening of the muscles, to which the term rigor mortis is applied. This is characterized by contrac- tion of the muscles, which, according to Bruecke and Kuehne, is depen- dent upon the coagulation of their contractile substance. It makes its appearance usually in from four to twelve hours after death, though it may occur almost immediately thereafter, or may not appear until twenty-four hours have elapsed. It usually is first noticed in the mus- cles of the jaw, throat, and neck, and extends from them to the trunk and extremities. After from twenty-four to forty-eight hours it usually disappears, but may occasionally persist for several days. This rigor mortis affects the smooth muscle-fibres as well as the 142 NECROSIS OR LOCAL DEATH. striated. The contraction of these elements in the skin is the cause of the so-called goose-flesh of the cadaver. Putrefaction begins somewhat before the disappearance of rigor mor- tis. It is evinced by its peculiar odor, by change in color of the skin and of the mucous membranes, and by change in the consistence of the tissues. Much influence upon the commencement and progress of putre- faction is exerted by the condition of nutrition of the body, by the nature of the disease which has preceded death, and by the nature of the surrounding medium, especially the temperature. Occasionally putrefactive changes occur in portions of the body which are dead even before the death of the entire body; and in cases in which putrefactive bacteria are present in the body at the time of death putrefaction may begin immediately thereafter. As an early sign of putrefaction there is usually greenish discolora- tion of the skin, commonly appearing first over the abdomen. With the progress of putrefaction the unpleasant odor and discoloration increase, and gases are formed in the intestine, in the blood, and in the tissues, which at the same time become soft and friable. Shortly after death the cornea becomes lustreless and clouded, the eye- ball loses its prominence, and dark spots after a time develop i the sclera. These changes in the eye are due to evaporation and putrefaction. When the eyelids are not closed the results of drying are very evident in the uncovered portions of the eyeball. Wherever the skin has lost its epi- dermis the exposed tissues become dried. Under certain circumstances the evidence of life may be reduced to a minimum, and a condition of apparept death may result which may be mistaken for death. Post- mortem lividity, rigor mortis, and evidences of putrefaction are unmistakable signs of death ; but, since these changes do not appear until some time after death, an interval is left during which it may occasionally be doubtful whether death has actually taken place or not. To ascertain the truth with certainty under these circumstances it must be determined by an appropriate examination whether the heart still beats, whether respiration is going on, whether the blood still circulates, and whether the nerves and muscles still remain irritable. This condition of apparent death may occur under a variety of circumstances, as, for example, in the course of cholera, in catalepsy, in hysteria, after great bodily exer- tion, after violent concussion of the nervous system, after profuse hemorrhage, when respiration is suspended as the result of strangulation, hanging or drowning,.in certain cases of poisoning, in lightning-stroke, after prolonged exposure to cold, etc. The duration of this condition is usually short, but it may occasionally persist for hours or even days. III. Necrosis. § 51. By necrosis ig understood a condition of local death, or death of single cells and groups of cells. As the result of necrosis there is always a permanent cessation of the functions peculiar to the affected tissue. It is only occasionally that the necrosis of a cell-group or of an entire organ makes itself at once evident in recognizable changes of structure; that is to say, the slight histological changes which the cells undergo as the result of their death do not permit us always to determine with cer- tainty the moment of the cessation of their life, nor does the macro- scopic appearance of the visible portions of the body inform us when a portion thereof becomes necrotic. : Necrosis of a tissue is therefore evident upon anatomical examina- tion only when certain changes in its structure have occurred either NECROSIS OR LOCAL DEATH. 143 coincidently with its death or subsequently thereto. The immediate occurrence of such changes is met with occasionally in the case of trau- matism, while the changes which develop later always make their appear- ance after the lapse of a certain length of time. It is customary to dis- tinguish several forms of necrosis, according to the nature of the changes which take place. Histologically necrosis of a cell is very often indicated by the disin- tegration and disappearance of its nucleus (karyorrhexis and karyolysis). In this process the chromatin of the latter—the substance which is stained by the nuclear dyes—forms small masses and granules which occasion- ally leave the nucleus and get into the cell-body, where they dissolve and disappear. In some cases the nucleus, before disappearing, shows evidences of shrinking; and when this is the case it will receive from nuclear stains a deeper shade of color than it would under normal con- ditions. In other’cases the nu- CORA EER! “SEN Aten: cleus, while still retaining its form, ® Jirst loses its power of staining, “e and then gradually dissolves and disappears (Fig. 31, ¢, d), so that even in well hardened and stained preparations there may be no trace whatever of the nucleus. Thus, for example, in those portions of the spleen or kidney which have been ren- dered ischemic by the cutting «. off of the blood-supply in em- bolism of the arteries of these two organs, the nuclei of the ca ; Pe ie Fra. 31.—Necrosis of the epithelium of the uriniferous cells of the spleen and of the tubes po ese of ree gravis. a, Normal eae : is 2 = uw ubule ; b, ascending looped tubule; c, convolu a epithelium (Fig. a 4 tubule with necrotic epithelium ; d, convoluted tubule : with only a part o: epithelium necrotic ; ¢, stroma and 2 J 2g ) are YOLy 800n, 1081, an blood-vessels, as yet unaltered. (Preparation hardened at the same time the affected in Miter’s fluid, and stained with gentian violet.) Mag- tissues assume a distinctly Med 30 diameters. pale, cloudy, yellowish-white appearance, which makes it possible to recognize the onset of necrosis even with the naked eye. Sooner or later changes take place also in the protoplasm of the dying ' cells, and these, according to the mode of death, begin before the cells are actually dead, or they may occur only in the dead cells. The kind of change depends upon three factors: the nature of the cells themselves, the particular kind of destructive influence, and the number and condi- tion of the surrounding cells and fluid. Ameeboid cells usually take on a globular form after death. Delicate and only slightly modified cell- bodies, rich in protoplasm, often become, either before or after death has taken place, markedly granular—less frequently, homogeneous or flaky—through the access of fluid; the protoplasm and sometimes also the nucleus swell up and show in their interior drops of fluid—vacuoles ; and, as a result of this swelling, breaks occur in the continuity of the protoplasm (plasmoschisis). When this latter change occurs, portions of cell-bodies may be cut off entirely from the parent cell through a rocess of constriction, or they may simply be extruded. The ultimate issue of all these changes is the reduction of the protoplasm and nucleus toa granular mass, and fat is often formed at the same time. 144 NECROSIS OR LOCAL DEATH. Cells which, under natural conditions, have undergone a decided transformation—as is the case with cells which have become horny— show comparatively few striking changes; yet even they may swell up and finally disintegrate. The least pronounced morphological changes are those which occur in cells which, when dying, simply grow more dense and dry up (inspissation). Under these conditions the cells become smaller, and yet at times they also may lose their nuclei and may -be converted into a shapeless scaly mass. — The injuries which lead to death of limited portions of the body may be classed in five groups. The first two include those which de- stroy the tissue directly through mechanical violence or through the action of chemicals. Thus, for example, a finger may be crushed by violence, and sulphuric acid may destroy a portion of the skin. A third group of injurious influences are of a thermal character. Eleva- tion of the temperature of a tissue for any length of time to from 54° to 68° C. results in its death. Higher temperatures act more quickly. Similarly, excessive cold can be borne for only a short time (cf. § 5). A fourth group is composed of diseases which owe their origin to infections with vegetable or with animal parasites. A fifth form of necrosis, characterized as anazmic necrosis or as local asphyxia, is the result of discontinuance of the supply of nourishment and oxygen to the tissues. - In addition to these, many authors distinguish as a special group those forms of necrosis which result from lesions of the central nervous system or of the peripheral nerves, and which may be designated as neuropathic necroses. By some this form of necrosis is believed to be the direct result of lesion of the trophic nerves, while by others it is attributed to changes in the circulation and to the effects of pressure and mechanical injury of anesthetic and paralyzed portions of the body. The observations thus far made upon man, and experiments upon ani- mals, indicate that, at all events, an important part in the production of this form of necrosis is always played by external injuries and by dis- turbances of the circulation. Again, all those conditions seriously affecting the circulation and leading to stoppage of the blood-supply—such as thrombosis, embo- lism, closure of a vessel as the result of lasting abnormal contraction, disease of its wall, or ligation, pressure on the tissue, inflammation, hemorrhage, etc.—may result in necrosis of the affected part; nor is it necessary that the disturbance of the circulation should be permanent, since a comparatively transient interference with the blood-supply may be followed by death of tissue. Whether or not hemorrhage occurs in such cases, as was stated in § 47, would appear to be immaterial to the result, influencing only the appearance of the diseased tissue. Hemorrhagic infarction has therefore precisely the same significance as an anemic necrosis combined with hemorrhage. When death of a tissue supervenes quickly upon the infliction of an injury, it is called direct necrosis; when it occurs slowly, and is pre- ceded by degenerative changes in the tissue, it is termed indirect necro- sis or necrobiosis. Mechanical, chemical, thermal, and infectious sources of injury, as well as anemia, may exert their effect coincidently in the production of necrosis, or they may act separately, one after the other. When the tissue is damaged by either of the three injuries first named, the blood itself also frequently undergoes a change, which terminates in stasis and NECROSIS OR LOCAL DEATH. 145 coagulation of this fluid in the capillaries, as well as in the veins and arteries; and as a result of this the circulation is arrested. Whether or not any given injury will cause necrosis does not depend wholly upon its nature and severity, but is influenced to a considerable degree by the condition of the affected tissue at the time of the occur- rence. Thus, if a tissue has been subjected for a long time to the depressing influence of an impaired circulation, or if its vitality has been lowered by marasmus or hydrzmia or a diseased condition of the blood, it dies much more easily than if it had been previously healthy. As an example of this may be cited the frequency of necrosis after com- paratively slight injuries, more particularly of the extremities, in the aged and in those who suffer from uncompensated valvular lesions of the heart. Furthermore, disturbances of the nerves of the vessels, in so far as they lead to impairment of the circulation, may afford a predis- position to necrosis. In the prostration incident to typhoid fever, com- paratively slight pressure on the hip, elbow, sacrum, or heel may be sufficient to bring about gangrenous destruction of the skin and of the subcutaneous tissue. These forms are known ag senile and marasmic necrosis, or as Marasmic gangrene and as decubitus. The structure of the tissue, its position, the manner of its death, and the causes of the necrosis, all exert a determining influence upon the course of the necrosis, that is to say, upon the changes in the tissue which will result therefrom. An important influence is also exerted by the amount of blood and lymph in the tissue, and by the opportunity for access of the air and of the ferments of putrefaction. Not without influence, also, are alterations in the tissue which may have antedated the onset of necrosis—as, for example, fatty degeneration, inflamma- tion, hemorrhage, etc. As the result of necrosis there is always inflammation of more or less intensity in the surrounding tissue (ef. Figs. 29, f, and 30, e), and it is most intense when processes of decomposition set up in the necrotic tis- sues. Through the formation of a zone of inflammation the necrotic area is shut off from the surrounding tissue—is isolated and seques- tered; and the inflammation is accordingly spoken of as limiting or seques- tering, and the dead tissue thus shut off is termed a sequestrum. A detailed description of these inflammatory processes will be found in Chapter VI. If we exclude from consideration for the present the more special - complications of necrosis—-as, for example, the development of specific irritating materials—five sequelz are to be distinguished: 1. The dead tissue may be completely absorbed, or may be cast off from a surface, and its place taken by newly formed normal tissue. This is spoken of as regeneration, 2. The dead tissue is similarly removed, but, instead of the normal tissue of the part being reproduced, simple connective tissue, the so-called cicatricial tissue, more or less completely supplies the defect. 3. The necrotic tissue is either cast off entirely or becomes dissolved (as in the formation of gastric ulcers through the digestion of portions of tissue which have died), but the lost tissues are not again replaced; an ulcer remains. 4. The dead tissue is only partially ab- sorbed or cast off, and a sequestrum of necrotic tissue remains, which may later become calcified, and which is in time surrounded by a dense con- nective-tissue capsule. 5. There is cyst-formation at the site of the necrosis, resulting from encapsulation of the dead tissue by connective tissue, absorption of the necrotic mass, and substitution for it of a 146 COAGULATION NECROSIS. liquid, which fills the space within the capsule and thus forms a cyst. This result of necrosis is most often met with in the brain. The time required for the induction of necrosis after stoppage of the circulation varies with the different tissues. Ganglion-cells, renal epithelium, and the epithelium of the intestine die in so short a time as two hours, while skin, bone, and connective tissue may remain alive for twelve hours or more. In general it may be stated that all tissues performing special functions die much sooner than those, such as connective tissue, which have only themselves to sustain. The cause of the above-described changes in, and final disappearance of, the nuclei in necrotic areas is found in the infiltration of the necrotic tissue with lymph from the surrounding tissue; and these changes are consequently absent when, for any reason, the circulation of the lymph in the diseased organ is stopped. Putrefaction is alsoa potent influence in inducingarapid disintegration and disappearance of the nuclei ; but. Fr. Kraus has shown that portions of tissue preserved aseptically and out of all contact with bacteria, in moist chambers at the body-temperature, lose their nuclei after a time. The tissue of the liver most quickly shows this change (Goldmann), while it may not appear in the spleen and kidney until much later, and all nuclei may not have disap- peared even after the lapse of from eight to fourteen days. It has been found by Gold- mann that the disappearance of the nuclei occurs only in the presence of a considerable degree of moisture, and may be prevented by desiccation of the tissue. § 52. According to the various conditions in which the tissues are found after they have died, it is customary to distinguish four principal forms of necrosis, viz., coagulation necrosis, cheesy degeneration, liquefac- tive necrosis, and gangrene. Coagulation necrosis (Weigert, Cohnheim) is characterized by the previous occurrence of coagulation, which may take place outside the cells, in the surrounding fluid, or within the cells; and when the latter event happens, the alterations which occur in the cells are of a peculiar character. When the process of coagulation takes place outside the cells and leads to necrosis, there should be reckoned, as one of its phenomena, the coagulation of blood both within the blood-vessels (Figs. 13-16) and on their outside (Fig. 12, d); for in this phenomenon there are seen an actual death of the blood and a destruction of the cells. Among the other phenomena may be mentioned the coagulations which take place, in the progress of an inflammation, in the fluids (more or less rich in cells) which exude from the blood-vessels (compare Chapter VI.). These exudations, which occur partly on the surface and partly in the interior of the tissues, present, when coagu- lated, either a fibril- lated (Fig. 32, a), or a somewhat granular, or a hyaline appearance. Intracellular coagu- lation takes place when the dead cells or cell- preducts are thor- ; oughly permeated by Gone 2 ne ae ree trachea. a, Traniyere sec- fibrin-containing tis- With pus-cells, (y, scattered throughout its substance: ¢-fbrin threads = SUe-lymph. When and granules ; dl, pus-cells. (Magnified 250 diameters.) this occurs the cells lose their nuclei, and present either a granular (Fig. 29, c, d, and Fig. 31, c), or a hyaline (Fig. 33, 6) or ascaly appearance. They remain in this condition for a certain length of time, and then break down into granules and finally disappear. COAGULAUION NECROSIS; CHEESY DEGENERATION. 147 Coagulation necrosis is most often observed in anemic, toxic, and thermal tissue-necroses; as, for instance, in ischemic infarcts of the kidney (Fig. 29) and spleen, in necroses of muscular tissue, which occur in the course of certain infectious diseases, such as typhoid fever (Fig. 33), and in many inflammatory proc- esses in which there is marked infiltra- tion of the tissues, the result of exuda- tion from the blood-vessels. In the case of anemic infarcts, the necrotic tissue looks pale, yellowish- white, often clay-colored. Muscles in which there are many dead muscular fibres in a condition of hyaline coagu- lation are pale red, faintly glistening, and not unlike the flesh of fish. Tissues which have first been inflamed and then have undergone coagulation necrosis are opaque and grayish-white; but de- cided changes in color may result from the admixture of blood or bile (for ex- ; ample, in the intestine). dives Tea ceeeal nen irene Noe A. tissue which is the seat of coagu- mal muscular fibre; b, b, degenerated fibres, “ . . which have broken down into separate lation necrosis may—if only the more _ masses; ¢, ¢, cells lying inside of the sarco- delicate parts have been destroyed— ae AS aeimed 350 auc still be clearly recognized in its struc- ; ture. If, however, all the parts have been altered, the whole tissue may be changed into a structureless, hyaline, or granular mass, containing few or no nuclei; and this result occurs very often in the necrosis of tis- sues which have been inflamed and which are filled with fluid exudation. If the specimen has been properly treated, there may frequently be seen, in these necrotic areas, a fibrillated condition of the intercellular coagulation. The same thing may be seen even in ischemic infarcts, although it will be found more often in the necrosis of inflammatory tissue (Fig. 34). Cheesy degeneration is regarded as a form of coagulation necrosis in which the necrotic tissue presents the appearance either of hard or of cream cheese. In the first instance the ne- crotic tissue is firm, yellowish-white in color, and like hard cheese or raw potato; in the second, it is soft, white, sometimes dry, at other times Bl 4 she ; Ff Me \ Fic. 34.—Coagulation-necrosis in the interior : : : of ani enormously swollen mesenteric, Iymph- moist, and frequently it looks like a gland, from a patient who died of typhoid fever. ; (Alcobol; fibrin stain.) Network of fibrin sepa- mass of thick cream. : 7 rating the necrotic cells. Magnified 300 diam- Cheesy degeneration occurs in a os typical form most often in tubercu- lous new-formations, and represents, under these circumstances, the characteristic ending of the retrogressive changes. It also occurs in syphilitic granulations and in tumors rich in cells; and inflammatory exudations may also undergo cheesy degeneration. The process of cheesy degeneration of cellular tissues, which is a 148 CHEESY DEGENERATION. striking characteristic of tuberculous granulations, takes place gradu- ally, and is accordingly regarded as one of the phenomena of necrobiosis. The cells are changed, one after another, into non-nucleated, homoge- FiG. 35.—Tissue from a focus of tubercu- lous disease, showing bacilli and a limited area of cheesy degeneration. (Alcohol; fuchsin; aniline blue.) a, Granular cheesy material ; a,, cheesy material in the form of small separate aggregations; ), flbrocellular tissue; ¢c, partly necrotic giant cell, with bacilli; ¢, cellular tissue invaded by bacilli; €, a similar invasion in tissue that is necro- tic; f, bacilli enclosed in cells. Magnified 200 diameters. neous, scaly masses, which later split and break up into a granular mass (Fig. 35, a,, @). While these changes are taking place there often appears be- tween the cells a material which pre- sents different appearances at different times. Thus, at one time, it forms a hyaline framework around the cells; at another, it constitutes a somewhat gran- ular “fibrinoid mass”; and at still another, it has all the characteristics of typical fibrillated fibrin (Fig. 36, a), and assumes a deep biue color when treated with Weigert’s fibrin-staining material. It is therefore fair to assume that these substances are the result of the coagula- tion of fluid which has exuded from the blood-vessels. Through the progressive breaking up and disintegration of the necrotic cells, the fibrinoid substance, and the fibrin, the dead tissue is ultimately changed into a finely granular mass, in which it is no longer possible to recognize the original structure. The cheesy metamorphosis of the cellular and fibrinous exudations which are found, for instance, in the alveoli of the lungs, in the neigh- borhood of tubercles, is accomplished by the loss of the nuclei and by the breaking up of the cells and fibrin, until nothing remains but a granular mass in which there are no nuclei. Fic. 36.—Deposit of fibrin in a tubercle of the lung. (Alcohol; haematoxylin: fibrin-staining mixture.) a, Fibrin; b, giant cells; c, cellular portion of the tubercle. Magnified 300 diameters. LIQUEFACTION NECROSIS. 149 The granules of the soft cheesy masses in tuberculous and non- tuberculous foci are in part albumin granules, in part fat drops. The further fate of this mass may be either a liquefaction and conversion into a pap-like material, or a removal through absorption, or finally a solidifica- tion and conversion into calcareous material. Liquefaction necrosis is chiefly characterized by the fact that the necrotic parts are dissolved in the fluid present in the tissue. This dis- solution may be accomplished by swelling and liquefaction as well as by breaking up of the tissue, or through a combination of both proc- esses. Thus, for instance, in burns of moderate severity, those cells of the skin (exclusive of the horny layers) which have been killed by the heat, are dissolved in the fluid which exudes from the papillary bodies Fic. 87.—Section through the epidermal and papillary portions of a cat’s paw, a short time after it had been burned with fluid sealing-wax. (Alcohol; carmine.) a, Horny layer of the epidermis; b, rete Malpighii: ¢, normal papilla of the skin; d, swollen epithelial cells, the nuclei of which are still visible at a few points, while at others they have entirely disappeared ; ¢, epithelial cells lying between the papille, the upper ones. being swollen and elongated, while the lower still remain in a normal condition ; f, fibrinouS network com- posed of epithelial cells (broken down so as to be no longer recognizable as such) 1nd exudate; g,an inter- papillary mass of cells which have become swollen and have lost their nuclei; h, apart of a similar mass in which the cells have been entirely destroyed ; i, a papilla that has been flattened by pressure and that is in— filtrated with cells; k, solidified subepithelial exudate. Magnified 150 diameters. (Fig. 87, d, f). In ischemic brain necrosis the brain substance under- goes softening, and, in the course of this process, drops and granules are formed. As the process advances the brain tissue will be reduced to a milky, pap-like mass, in which the products of the destruction of the brain tissue are represented by smaller and smaller particles, which are sometimes free, sometimes are contained in the cells. Eventually these particles are dissolved, or they are entirely removed by absorp- tion. In the process known as tissue-suppuration, which occurs very often in purulent inflammations, the so-called pus corpuscles are destroyed, some of them first swelling up and bursting, while the others become disintegrated without any preliminary imbibition of fluid. The ground-substances—as, for example, the fibres of the con- nective tissue—gradually dissolve and disappear, in the course of tissue-_ suppuration. Necrotic tissue of the stomach-wall is dissolved by the action of the stomach secretion. 150 DIFFERENT FORMS OF GANGRENE. Coagulation necrosis may give rise to liquefaction, and, vice versa, lique- faction may induce coagulation. Thus, for example, in an inflammatory exudation the dissolution of the leucocytes may produce coagulation ; and later, the coagulation products may in their turn be dissolved. In gangrenous blebs produced by the dissolution of epithelial cells, there may occur a coagulation, the products of which are later dissolved. As already stated, fibrinous deposits which were originally produced in the course of some inflammation ‘or in connection with the development of granulation tissue, and which have become necrotic or have under- gone cheesy degeneration, very often at a later stage become liquefied. The changes described above as occurring in necrotic or dying tissues are not the only ones which may occur during the course of their destruction ; attention has been paid only to the principal types which occur in the course of a comparatively rapid death. Many of the forms of tissue-degeneration which are described in the following paragraphs also lead, not infrequently, to ultimate death of the tissue ; and consequently they must be reckoned as belonging under the heading tisswe-necrobiosis. Granular de- generation, fatty degeneration, mucous degeneration, and dropsical degeneration often end in the destruction of cells; and the same result may be produced in connective tissue by hyaline degeneration and by amyloid degeneration, for these processes are not only capable of producing a permanent change in the basis substance of the tissue, but they may also cause it to undergo disintegration, and they may even produce the death of the cellular elements of the tissue. § 53. Under the name of gangrene may be classed those forms of necrosis in which the tissue—partly through the influence of exposure to air and partly through the agency of bacteria—undergoes changes that give to it the appearance and also the physical characteristics of burned tissue. If the portion of tissue which has died becomes dry through exposure to the air, and through the resulting evaporation of the water which it contains, it is customary to apply to this condition the terms dry gangrene (gangrcena sicca) and mummification. But if the dead part continues to remain moist, the terms moist gangrene (gangreena humida) and sphacelus are the proper ones to employ. If, through the agency of bacteria, decomposition sets in, there will be established a foul-smelling gangrene—a putrid gangrene (gangrena feti- da). The formation of gas bubbles as a result of the putrefactive changes warrants the employment of the term emphysematous gan- grene (gangriena emphysematosa) . Moist gangrene and putrid gangrene are in general identical, since bacteria develop only in very moist tissues. Nevertheless, a dry gan- grene may also be a putrid gangrene—a fact which may be explained by the assumption that bacteria multiplied in the tissues before the process of drying took place. Dry gangrene may therefore develop from the moist form, and, on the other hand, it may also, through the absorption of water, develop into moist gangrene. If the necrotic, putrid, or mummified tissue contains a great deal of blood, it looks black, dark-brown, or dark-green in color, and is then called black gangrene. Gangrenous parts which are poor in blood are sometimes spoken of as being affected with white gangrene. This expression, however, is often inappropriate, for the dead parts are gen- erally more or less discolored. Tn the case of parts which are situated at the surface of the body, it is not unusual to distinguish, according to the temperature of the tis- sues which have died, a cold gangrene and a warm or hot gangrene ; the last of these terms being used when the dead parts are kept warm by the flow of blood through the tissues of the neighborhood. DIFFERENT FORMS OF GANGRENE. 151 Gangrene may be caused by external injuries, by heat, by cold, by eauterization, by crushing, by pressure, by infections, etc.; it may also be caused by disturbances of the circulation. Gangrene from disturbance of the circulation or from its entire arrest occurs most frequently in old people (senile gangrene), in the extremities, and particularly in the toes, the foot, and the leg. It is of the dry variety, and is caused by general disturbance of the circulation as well as by narrowing of the arteries of the extremities through thick- ening of their walls (Fig. 38). The dying parts look bluish-black from venous congestion. General circulatory disturbances, such as accom- pany heart disease and embolism of the arteries, may cause similar changes. Gangrene from cold affects especially the terminal parts of the ex- tremities, the nose, and the external ear, and it is characterized by the same pathological alterations as those which have already been de- scribed. Gangrene from heat is confined to the area directly influenced by the hot material. Gangrene from pressure, or bedsore (decubitus), is most frequently observed in marasmic individuals. The parts most often affected are Fic. 38.—Dry gangrene of the toes, caused by narrowing and closure of the arteries which supply these parts—arteriosclerosis, the region over the sacrum and the heels, both of which regions are exposed to pressure when the patient lies on the back. At first bluish- red spots appear, and within this area the tissues die, then undergo decomposition through the aid of bacteria, and finally break down into detritus. The putrid decomposition may involve an area of large extent when the part affected is the region of the sacrum. It is in this locality that the bony structures may be extensively laid bare through the dis- integration of the overlying soft parts. Toxic gangrene is observed at the very ends of the extremities, espe- cially in ergot poisoning, which causes closure of the smallest blood- vessels through contraction of their walls and the formation of thrombi. Infectious gangrene occurs particularly in various infections of the skin and subcutaneous tissue, and the process may be accompanied by gas-formation. Infections which are associated with foul-smelling disintegration of the tissues may occur in various internal organs, but more especially in the lungs and intestines. Neuropathic gangrene takes place when a part which is affected with either a sensory or a motor paralysis is wounded or is subjected to continued pressure. The cause is therefore to be sought for partly in an infection and partly in some disturbance of the circulation. As 152 HYPOPLASIA. already stated in § 51, it has not yet been demonstrated that the with- drawal of the trophic influence of nerves is competent to produce gan- grene. Symmetrical gangrene, which affects corresponding parts of the extremities, and is looked upon by many as a neuropathic affection, should rather be considered as the outcome of some circulatory disease. In moist gangrene the tissues break down and become dissolved with a varying degree of rapidity, the fascie resisting for the longest time. Among the crystalline products of the chemical changes which occur in the course of this disintegration, the following may be mentioned: needles both of fat and of tyrosin, globules of leucin, coffin-lid crystals of triple phosphate, and hematoidin crystals. When the gangrenous process comes to a standstill, a demarcation-line of inflammation will surround the necrotic tissue—that is to say, the dead will be separated from the living tissue, and will ultimately be removed from the organ- ism. In the case of necrotic osseous tissue a very long time will be re- quired before this separation can be effected. A continued extension of the gangrenous process—through infection, or through the continuance of a defective circulation—leads sooner or later to death, especially if toxic material from the gangrenous area or even bacteria are taken up into the blood and the lymph. IV. Hypoplasia, Agenesia, and Atrophy. § 54. Hypoplasia or defective development, may affect the entire body or only organs or parts of organs, and may occur either during the period of intra-uterine development or after birth, during the period of growth. When the entire skeleton or a very considerable part of it undergoes maldevelopment, so that the bones are much shorter than normal, abnormally small individuals result, called dwarfs (Figs. 39 and 40), whose parts may be either fairly well proportioned (Fig. 39) or else unsymmetrically developed (Fig. 40). In the latter figure may be seen an example of a dwarf whose trunk was of nearly the normal size, while the extremities were abnormally small. Again, the body and extremi- ties may be abnormally small, while the head develops to about the normal size, being then out of all proportion to the body. When the maldevelopment is confined to a single part of the skeleton, or is here much more marked than elsewhere, a rudimentary condition of that part results. Thus, as the result of maldevelopment of the cranium, condi- tions of microcephalus (Fig. 41) and micrencephalus (Fig. 42) are in- duced; as the result of maldevelopment of the humerus or of the bones of the hand we may have shortening of the upper arm or of the hand respectively ; and, similarly, imperfect development of the lateral masses of the sacrum may lead to transverse narrowing of the pelvis. Among the separate organs the central nervous system (Figs. 42 and 43) and the genito-urinary system suffer perhaps most frequently from maldevelopment, although the intestine, heart, lungs, and liver by no means escape. In Fig. 42 is presented an example of abnormal small- ness and retarded development of the whole brain; but there are also cases in which one hemisphere alone suffers (Fig. 43, c, d), either wholly or in part. A part of the intestine may be so imperfectly devel- oped as to form only a thin and quite useless canal (Fig. 45, d) or to be merely a small solid cord (Fig. 45, e). The uterus not infrequently HYPOPLASIA AND AGENESIA. 153 remains in an undeveloped state (Fig. 44), and occasionally the entire group of female generative organs, both internal and external, may remain at the time of puberty: in the undeveloped condition of a young child. Among the organs of the urinary system a more or less complete maldevelopment of the kidney is not uncommon. In the development Fic. 39.—Skeleton of a female dwarf, thirty-one years of age, 118 cm. in height, an idiot, and possessing a klinocephalic skull. All the discs of cartilage at the diaphyses of the long bones and pelvic bones are still present; so also is the frontal suture. The individual parts of the skeleton are, in the main, correctly re- lated to one another, the upper extremities alone being relatively somewhat short. Fic. 40.—Skeleton of a female dwarf, fifty-eight years of age, 117 cm. in height, and with a long trunk ce short arm- and leg-bones. The discs of cartilage are still present; the articular ends of the bones are thick. of the respiratory tract the alveoli of one portion of the lungs may fail to develop, as the result of which a whole lobe or a part of a lobe may be made up entirely of connective tissue and dilated bronchi (Fig. 46). The above-mentioned examples of hypoplasia, to which many others might be added, are all due either to causes operating within the devel- oping foetal organism itself, in which case they may be said to be in- herited, oe to external deleterious influences working upon normal. Li4 HYPOPLASILA AND AGENESIA. tissues during their developmental period. Thus, as causes of malde- velopment of the bones we may mention disease of the thyroid gland (cf. § 23), insufficient nutrition (rachitis), disuse (Fig. 43), and inflammation. When portions of the body or single organs fail of all development, the condition’ is spoken of as agenesia. This depends upon an entire failure of development of the part in question from the very start, or Fic. 42.—Brain of Helene Becker (microcepha- Fic. 41.—Head of Helene Becker (microcephalic), at the age of five years. (From a photograph taken by A. lic), who died at the age of eight years. (From von Ecker in 1868.) Bischoff.) This brain weighed 219 gm. (instead of 1,377 gm., as Vierordt claims that it should). upon a total destruction of the part after it has begun to develop (cf. the chapter on Malformations). . The tissue composing hypoplastic organs or parts of organs is at Fic. 43.—Hypoplasia and microgyria of the left cerebral hemisphere; case of a deaf-mute. a, Right hemisphere ; b, left hemisphere; c, occipital lobe, diminished in size and in a state of microgyria; d, mem- branous cyst in the region of the parietal lobe. (Seen from above, after removal of the cerebellum. Two- thirds natural size.) HYPOPLASIA AND AGENESIA. 155 times normal in structure; but there is often associated with the abnormal smallness of the organ an imperfect organization of its in- tegral parts, with failure of development of some of its more highly Fig. 44.—Hypoplasia of the uterus, with well-developed ovaries. (From an idiotic girl, eighteen years of ao specialized elements, so that associated with a hypoplasia of the entire organ there may be agenesia of some of its elements. Thus in hypo- plasia of the ovary the formation of ova may fail in part; in hypoplasia of the brain there may at the same time be a faulty development of the ganglion-cells and nerve-fibres, and at times portions of the brain may be represented by merely membranous masses (Fig. 48, d), in which ganglion-cells are entirely absent; and in hypoplasia of the lung (Fig. 46) there may occasionally be complete failure of development of the alveoli, the lung-tissue then con- sisting chiefly of rather vascular connective tissue in which bron- chi, usually dilated, lie. $55. Atrophy is diminution in size of an organ as the result of diminution in size and disap- pearance of its elements. It may occur at any period of life, and is, in fact, a very frequent result of many different pathological proc- esses. Within certain limits it may be regarded as a physiologi- cal process, since in advanced age * retrograde change an all the Fic. 45.—Hypoplasia of the small intestine of a new- organs is of constant occurrence bom child, a, 4 much-dilated portion: b, ¢, d. ¢ 7 zn 5 7 ortions that are much narrowed and wast ; J, nor- and 1s always associated with Tally developed small intestine. (Five-sevenths nat- more or less diminution in their wl size.) size. A few of the organs suffer a similar change even before old age—as, for example, the thymus, which becomes completely atrophied even before the completion of the period of adolescence, and the ovary, a part only of whose ova are discharged during the period of sexual activity, the remainder undergoing atrophy. 156 ATROPHY. In tho atrophy of old age the lymphadenoid tissues, the muscles, and the bones suffer most as a rule, though there is much difference in this regard in different individuals, the brain or the glands of some of them undergoing the ear- liest and most rapid change. The most striking evidence of atrophy’ of an organ is its diminution in size. When the muscles atrophy (Fig. 47) the affected portions of the body become ; Fig. 46. Agenesia of the respiratory parenchyma of the left lung, The smaller ; and in a ung consists of dense connective tissue in the midst of which dila c iv bronchi are found. (Horizontal section through the apex of the upper of extensiv eS atrop y lobe. Natural size.) of the muscles of the extremities the im- pression is given as if nothing intervened between the skin and the bones. When the atrophy of an organ goes on symmetrically in all its parts its normal shape may be preserved. But it often pragresses more rapidly in one part than in another, in which case great asym- metry of the organ may result, there being often deep pits upon its surface (Fig. 49) and cicatricial contractions (Fig. 52), so that the affect- ed organ—for example, liver or kid- ney—may present a knobbed or gran- ular surface. In cases in which the tissues undergoing atrophy are in any way prevented from contracting, as is the case in bones and in the lung, the outward form of the organ is preserved. In the case of bone, however, the Haversian canals and the medullary cavity become enlarged, and a condi- tion results which is designated excen- tric atrophy or osteoporosis (Fig. 48). In the lungs the alveoli become united into large air-spaces as the result of disappearance of the intervening al- veolar walls. When atrophy affects glands and muscles there is often a change in their color, though this is of but secondary importance, depending either upon an unusual distinctness of the pigment of the affected organ be- cause of the disappearance of parts or- dinarily overshadowing it, or upon the deposit of pigment in the atrophied tissue, or, finally, upon a changed blood-content of the atrophied tissue. The diminution in size of atrophic yy, organs is the result of diminution in size and disappearance of the structural ¥6- *-—Iuyenile muscular atrophy. (Case WM ATROPHY. 157 elements of the tissues composing them. Inthe majority of the organs— more particularly glandular organs, muscle, and bone—the more highly specialized portions suffer, in undergoing atrophy, to a much greater extent than the connective-tissue framework which supports them. In- deed, it is not uncoramon to find this latter tissue quite intact, or even increased in amount, in an organ from which all the more highly differ- entiated parenchyma has disappeared. Thus in atrophic muscle-tissue (Fig. 50) the contractile substance within the sarcolemma frequently disappears entirely without the occurrence of any noticeable atrophy in the connective tissue be- tween the muscle-bundles, the nuclei of which may be actually increased in num- ber (Fig. 50, ¢,). — In atrophy ofthe kidney the epithelial cells of the urinary tubules (Fig. 51, /) become smaller and smaller, and ultimately disappear, the tubules then undergoing ° complete collapse. A simi- lar change occurs in the epithelium of the glomeruli, the capillaries of which dis- appear. The same thing occurs in simple atrophy of the liver, in which the entire parenchyma of a lobe may disappear without any con- siderable diminution in the amount of its connective- tissue stroma. Similarly the ganglion-cells of the brain and of the spinal cord may atrophy without any diminution in the neuroglia, which is often actually in- ia ar in aati n atrophy of bone it is xs the true bone-tissue which T% #—Hgeie sph oie owe nt of isan becomes diminished in amount, and in excentric ee and osteoporosis the marrow is materially increased. In some cases, however, the fat of the marrow may also disappear, leaving spaces which then become filled with liquid. In atrophy of lymphatic tissue and of the spleen it is more particu- larly the free cells which undergo diminution and in parts completely disappear. ; The change in an organ resulting in its atrophy may occur without any appreciable change in the structure of its component parts (Fig. 50), the atrophy being the result of a simple diminution in size of the various tissue-elements. This form of atrophy, called simple atrophy, is to be carefully distinguished from the degenerative atrophies, in which changes in the structure of the various tissue-elements occur from 158 ATROPHY. the beginning and are frequently associated with deposits of patho- logical substances in them. Thus a cell may become granular and un- dergo fragmentation, or may swell up and liquefy, or droplets of fat or mucus may form in it, all of these changes being indicative of degenerative processes in the protoplasm of the cell. The special varieties of degenerative changes which occur in tissues will be treated of in the succeeding paragraphs of this chapter. Coincidently with changes in the protoplasm of the cell- body there may be similar degenerative changes in the nucleus, such as fragmentation, change of shape, irreg- Fic. 49.—Senile atrophy of the calvarium, with defect of theexternal y]lar distribution of the table and of the spongy portion throughout the central parts of the Z 7 parietal bones. chromatin, discharge of the chromatin into the cell-body, and swelling and disappearance of the nucleus, all of which ultimately lead to destruction of the nucleus, and secondarily of the cell itself. : Degenerations thus ultimately leading to atrophy of the affected organ are of very frequent occurrence, particularly in glandular organs. Frequently inflammation is also a complicating factor in the production of these conditions. § 56. The various atrophies may be separated according to their origin into active and passive. The cause of the first lies in the inabil- Fic. 50.—Section of an atrophied muscle, from a case of progressive muscular atrophy. (Miiller’s fluid; Bismarck brown.) «a, a, Normal muscular fibres; }), atrophic muscular fibres: c, perimysium internum, the nuclei of which, at c,, seem to be increased in number. Magnifled 200 diameters. ity of the cell to assimilate as it should the food which is brought to it. In the passive form insufficient food is brought to the cell, or such as is brought is of an improper kind, or harmful substances are contained in it which impair fhe nutritive function of the cell. Active atrophy is more particularly observed as a part of senile degeneration, but it occurs VARIOUS FORMS OF ATROPHY. 159 also under pathological conditions, especially in nerves, glands, and muscles (Fig. 47) whose function is interfered with. é Clinicians are apt to prefer to the above another classification of the atrophies, distinguishing senile atrophy, atrophy dependent upon im- paired uutrition, pressure atrophy, atrophy of disuse, and neuropathic atrophy. Senile atrophy (Fig. 49) is partly active, partly pass- ive, since it is not simply the result of gradually dimin- ishing energy on the part of the cell, but depends also in part upon narrowing and obliteration of the vessels conveying nourishment to it. It may occur in all the or- gans, and is often more pro- nounced in one organ than in another. The bones, the kidneys, the liver, the brain, and the heart may all thus _Fig. 51.—Senile atrophy of the kidney. (Alcohol; alum- * sos * earmine.) «, @, Normal uriniferous tubules; b, normal glo- suffer a decided diminution merulus; ¢, stroma. with blood-vessels ; a, erie goa 1 7 ulus; e, small artery, with somewhat thickened intima; f, in their volume. atrophied and collapsed uriniferous tubules. Magnified 200 The atrophy dependent diameters. upon impaired nutrition may result from an insufficient supply of food to the body as a whole or from extensive loss of the fluids of the body, and then affects the whole body, although even then the fat, the blood, the muscles, and the abdom- inal glands suffer most. Local atrophies may result from interference with the blood-supply of limited regions (Fig. 52), and are a frequent result of diseases of the blood-vessels. Furthermore, they are of frequent occurrence as a result of or as a part of inflammatory processes, though in this connection it should be stated that the disappearance of the tissue- elements is not, as a rule, the result of simple atrophy, but of a variety Fic. 52.—Arteriosclerotic atrophy of the kidney. (Natural size.) of degenerative changes which lead to the destruction of the cells and of the tissues. Occasionally atrophy of a tissue may result from the presence of dele- terious substances in the blood. Thus iodine causes in time a diminu- tion in size of the thyroid gland, and in chronic lead-poisoning the extensor muscles of the forearm are apt to undergo atrophy. 160 VARIOUS FORMS OF ATROPHY. Pressure atrophy results from continued and moderate pressure upon a tissue (Fig. 53). It would appear to depend both upon direct : injury to the tissue and upon interfer- ence with its circulation. Typical ex- amples are: the atrophy of the liver which results from tight lacing and consequent pressure of the ribs upon the liver; and the disappearance of bone as the result of pressure of an aneurism (Fig. 53) or of an accumulation of liquid in the ventricles of the brain. Disuse atrophy occurs in muscles and glands, as well as in bones, skin, and other tissues, and is due to non- use of the tissues in question. In the case of muscles and glands the atrophy ig essentially active, but as the result of their functional inactivity there is at the same time a considerable diminution in their nutritive activity and in the activity of the circulation in them. In the other tissues the atrophy is chiefly due to a lowering of the nutrition of the unused parts, though it is impossible to quite eliminate from consideration a change in the power of assimilation of the cells. When the disuse is operative during the developmental period, and origi rsa, rons of wewimat the tissue is on that account poorly aneurisin of the aorta, nourished and undergoes but an imper- fect development, the resulting condi- tion is properly regarded as one of hypoplasia; and yet it is impossible sharply to separate this condition from one of atrophy, since in hypo- plasia there may be also a disappearance of structures which had un- dergone a certain degree of development. Neuropathic atrophy is a result of diseased conditions of the ner- vous system, and is apparent most often in a rapid atrophy of the nerves and muscles, though it may also affect any of the other tissues. Thus disease of the anterior horns of the spinal cord or of the motor roots is followed by atrophy of the corresponding nerves and muscles. Injury of the peripheral nerves is commonly followed by atrophy of the skin. Numerous authors maintain that after the nerve-trunks of one side of the face have become diseased, a newropathic atrophy of the corresponding side of the face (Fig. 54) may take place, and yet there are many other au- thorities (e.g., Mobius) wh 0 deny Fic. 54.—Facial ergata (After Lichtheim CLOUDY SWELLING OF CELLS. 161 that this atrophy is of a neuropathic nature. Unilateral affections of the brain during foetal life or during childhood may lead to atrophy of the opposite half of the body (congenital and infantile hemiatrophy). In all these pathological alterations of neuropathic origin we very often have to deal not with true atrophies, but with various degenerative processes; and the term atrophy as applied to them is justifiable only to this extent, namely, that the ultimate result of the process is an atro- phic condition of the affected parts. The causes of the degenerative processes are found in part in vaso-motor disturbances, in part in loss of function, and in part in severance of the affected tissues, the nerves, from their centres in the spinal cord or brain. V. Cloudy Swelling and Hydropic Degeneration of Cells. § 57. The term cloudy swelling, or parenchymatous degeneration, or granular degeneration, was proposed by Virchow to indicate a condition of swelling and enlargement of cells resulting from absorption of vari- ous extraneous substances. He characterized it as a kind of hypertro- phy with tendency to degeneration. At all events, the greatest weight is to be laid upon the degenerative character of the change. Histolog- ically the process is characterized by the formation of fine granules within the bodies of the swollen cells—for example, in kidney epithe- lium, liver-cells (Fig. 55), or heart-muscle. Their microchemical reac- tions (solubility in acetic acid, insolubility in alkalies and ether) would indicate the albuminous nature of these granules. Their presence gives to the cell a cloudy, granular appearance, and at the same time, as the result of swelling, the normal struc- ture and form of the cell are lost. Thus in cloudy swelling of the tubular epithelium of the kidney the rod-like markings of its protoplasm (Fig. 56, a) and the cell-processes extending into tha lumen of the tubule disappear, the cell becomes larger (b, ¢, d), ee a and dark granules make their appearance throughout (Scraped from the cut its substance. This change is to be regarded ag a SUzface of the liver of @ disorganization of the cell-protoplasm following the septicemia: | examined absorption of liquid into its substance, and leading _ nined 350 diameters. to a partial separation of its solid and liquid constit- uents. The nucleus not infrequently participates in these changes, under- going a similar disorganization. Recovery from a moderate degree of this degeneration is quite pos- sible, in which case the cell is restored to its normal condition; but often there is a complete destruction of the cell, which then ultimately breaks up into finely granular fragments. Fatty degeneration is fre- quently associated with the degeneration under discussion. Cloudy swelling occurs in the cells of nearly all the parenchymatous organs in the course of the majority of the infectious diseases, particu- larly in scarlatina, typhoid fever, variola, erysipelas, diphtheria, septi- cemia, etc. Organs thus affected present a cloudy, less shining appear- ance than normal, and often appear gray. When the lesion is very marked the tissue has the appearance of having been boiled, its blood- content is generally very small, its consistence is doughy, and the finer details of its structure are lost. § 58. The term hydropic degeneration is very properly applied to a 162 CLOUDY SWELLING OF CELLS. change frequently observed, in cells of different kinds, whereby they become swollen as the result of imbibition of liquid. When epithelial 56.—Cloudy swelling of kidney epithelium. (Ammonium chromate; glycerin.) a, Normal epithelium; b, epithelium beginning to be cloudy; c, advanced’ degeneration; d, cast-off degenerated epithelial cells. Magnified 600 diameters. cells undergo this degeneration the cell-contents appear clear, the proto- plasm granules being pressed apart by the imbibed liquid, and often being present only as a granular ring at the periphery of the cell; the cells thus coming in a measure to resemble plant-cells (Fig. 57, b). Oc- casionally distinct vacuoles ()) are formed—i.e., globular drops of clear liquid in the cell-protoplasm. The nucleus (c) also becomes swollen, and may be indi- cated merely by a large glo- bule with liquid contents. When muscle is the affected tissue, clear droplets of liq- uid appear between the fibrils, pressing them apart (Fig. 58; Fig. 59, a, b; and Fig. 66, c), so that, when the disease is extensive, the for- FiG. 57-—Hyaropte degeneration of epithelial cells, from a mation of the clear round carcinoma of the breast. (Miiller’s fluid; aniline brown.) a, : ‘ Ordinary epithelial cell; b, hydropic cells, with bladder-like Spaces may give to the mus- Cate ak enlarged tude; ¢ wandering cells Naguinea Cl© @ distinctly bubbly ap- 300 diameters. pearance (Fig. 58). For a time the muscle-fibrils be- tween these drops may remain unchanged, but with a continuance of the process they degenerate and undergo liquefaction. Hydropic degeneration may be the result of edema (Figs. 58 and OBESITY OR LIPOMATOSIS. 163 59), or it may occur in inflammatory conditions or in tumors (Fig. 57). When it results from inflammation its degenerative character is usually much more pronounced than when it occurs merely as an ac- companiment of oedema, and it may then lead to complete disin- tegration of both the cells and the nuclei. In oedematous conditions Fig. 58. — Hydropically degenerated muscular Fig. 59.—Transverse section of a bundle of mus- fibres, from the gastrocnemius of a patient suffering cular fibres in a state of hydropic degeneration. from chronic cedema of the legs. (Flemming’s mix- (Miiller’s fluid; hematoxylin.) a, Muscular fibres ture; safranin.) Magnified 45 diameters. with small drops of fluid; b, fibres with large drops. Magnified 66 diameters. the cells often remain alive for a very considerable time, notwithstand- ing their hydropic condition. VI. Lipomatosis, Atrophy of Adipose Tissue, and Fatty Degenera- tion of the Tissues. § 59. Certain of the tissues contain, under normal conditions, a con- siderable amount of fat, which is present in their cells in such amount as to be readily recognizable by the naked eye. This fat has its origin in the fat ingested with the food, or has been formed in the body from albumin and carbohydrates, and has then been deposited in the tissues in which it is found. When the ingestion of fat or of fat-forming substances is abnormally great, or the body is unable to make proper use of the fat consumed or elaborated in it, a disturbance of the balance between fat-production and fat-consumption results, leading to an increase of the storing of fat in the body, and in time interfering with the performance of its functions, and thereby assuming pathological importance. This inordinate accumula- tion of fat leads to the condition termed obesity, or adiposity, or lipoma- tosis. The tissues in which fat is normally present are the first to be affected in this process, and consequently the subcutaneous fat-tissue, the fat underlying the serous membranes, the marrow of the bones, and the liver suffer first (Fig. 60, b). Subsequently fat appears in tissues of which it is not a normal constituent, as, for example, in the connective tissue between the muscle-fibres of the heart, in the endocardium of the ventricles and auricles, in the intermuscular connective tissue of the skeletal muscles (Fig. 61), etc. In connective-tissue cells and in the hepatic cells the fat is deposited in the form of small drops (Fig. 62, a, b), which soon coalesce to form larger drops, ultimately replacing the entire cell-body and converting it into a spheroidal mass of fat. The causes of the pathological deposition of fat (lipomatosis) are to be found in a congenital predisposition on the part of the tissues, and 164 OBESITY OR LIPOMATOSIS. in certain disorders of the vital processes. That variety of lipomatosis which is due to the existence of a congenital predisposition manifests itself in two forms, viz., as a general obesity and as one that is confined to certain limited areas. In general obesity the adipose tissue everywhere throughout the body is increased in volume. In the limited form of obesity, —the tumor-like accumulations of fat are here left out of the con- sideration,—the excessive development of fat is most often confined to the muscles of the lower extremities (Fig. 61). These muscles increase in volume, but at the same time they lose a part of their fibres (atrophia musculorum lipomatosa pseudohypertrophica). Among the disordered vital processes which lead to a pathological accu- mulation of fat must be mentioned: first, a luxurious mode of living ; second, overtaxing of one’s physical strength; and third, marasmus, such as is observed especially in connection with chronic tuberculosis. In the first of the conditions named the fat will be distributed generally throughout the body ; whereas in the last the accumulation of fat is gen- erally restricted to the liver (Fig. 60), where it lends to the tissues—at least those in which the fat is deposited—a light yellowish-brown or a straw-yellow color. The cause of the fat-accumulation in the first- named condition is the excess of nutritive material taken into the sys- tem, whereas in the last-named it is the inability of the organism to decompose, in sufticient quantity, the fat received into the body or already stored there. Tf, through a diminution in the amount of nourishment taken into the body, or through a deficient formation of fat in the body, or, finally, through an increased activity in the metabolic processes, the quantity of fat which belongs normally to the body is lost, then an atrophy of the fat tissue will be established. In this condition, while the processes of absorption and decomposition of the fat are going on, that Fig. 60.—Fatty liver from a man who died of pulmonary tuberculosis. (Flemming’s preparation : safra- nin.) «, Central portion of a lobule; }, peripheral zone, characterized by the presence 6 a ee rir connective tissue. Magnified 30 diameters. - 7 ae which remains in the cells again breaks up into small globules, and the connective-tissue cells are again converted into small connective-tissue cells. If, after the fat has largely disappeared from the spaces between ATROPHY OF FAT-TISSUE. 165 the shrinking fat-cells, a serous fluid finds its way into the tissues, the fa{-tissue—as can be seen with special frequency in the panniculus adi- posus of the heart—assumes a translucent appearance, not unlike that. Fic. 61.—Lipomatosis of the muscles of the calf of the leg, together witb atrophy. (Miiller’s fluid; car- mine.) Transverse sections of a normal (a) and an atrophied (a) muscular fibre; cg, transverse section of a tubular sarcolemma containing contractile substance in a condition of disintegration ; b, bands of connective tissue; c, fat-tissue. Magnified 60 diameters. of mucous tissue. Hence the name, which is often applied to this con- dition, of serous atrophy of fat-tissue. If, while these fat-cells are under- going atrophy, pigment is deposited in them, the tissue in which they lie will assume a yellowish or yellowish-brown color,—a condition to which the term pigment-atrophy of fat-tissue has been applied. ; According to Voit, the body may store up fat directly from the fat contained in the ingested food, or it may elaborate it from absorbed fatty acids by a process of synthesis. with glycerin, or from albumin and carbohydrates. The important factor in the metab- olism of nutrition is not the oxygen of the blood, but the cell itself, whose protoplasm possesses the power to convert complex chemical compounds into simpler ones. The substances most readily lending themselves to this change are the albumin brought to the cell insoluble form and the carbohydrates. Fat is, on the other hand, resistant, both that directly absorbed from the food and that formed in the body. Now, when fat is supplied to the cell in excess, or when the metabolic potential of the cell is lowered so that it is unable to further decompose the fat which it elaborates from the albumin brought to it, fat of necessity remains in its protoplasm. When these two influences act in combination, the effect is of course greater. Improved nutritive conditions, ex- ercise, and elevation of the body-temperature increase the metabolic activity of the cells, while it is diminished by alcohol, morphine, and quinine. Obesity depends on assimilation of food in excess of the ability of the body to make use of it. In its pro- duction the metabolic power of the cells of the body as a whole may be normal, or it may be diminished as the result of weakness or diminution in number of the cells. The ac- cumulation of fat which is often noticed in anemia is explained on the ground of diminution in the cell-mass of the body, resulting indiminished metabolic power. The deposit of fat in the intermuscular connective tissue of atrophied muscles would appear to be a direct result of the diminished metabolic changes in the paralyzed muscle-tissue. According to Gautier the metabolism of proteids in the cell occurs in two stages. In the first, the stage of ferment-action without oxidation, or of hydrolytic separation, uric acid or analogous substances (urates and creatin derivates) are formed from the protoplasm, the carbohydrates at the same time being converted into fats. In the second stage, that of oxidation, the sugars and fats disappear, both those originally derived from the food and those resulting from the metabolism of proteids. The carbohydrates are in part oxidized, but the greater part of them, particularly during muscular inac- 166 FATTY DEGENERATION. tivity, are converted into fat by a simple fermentative process in the course of which a large amount of carbonic acid is liberated. Ultimately the fats also undergo oxidation and disappear. § 60. The term fatty degeneration is applied to a form of cell-degen- eration in which fat is formed from the albumin of the cell-body—that is, from organic albumin; the fat thus formed manifesting itself in the shape of granules and drops of different sizes within the cell-body. Cells which are in the condition of fatty degenera- tion always contain easily recognizable drops of irregular size, colorless, highly refract- ing (Fig. 62, c, d, e, f, and Fig. 62,—Fat-containing liver-cells. a, b, Fat-infiltra- ; i i i tion; c, d,e,f, fatty degeneration. Magnified 400 diam- Fig. 63), insoluble in acetic Fic. 62. Fic. 63. eters. acid, soluble in alcohol and in FIG. 63,—Fatty degeneration of the muscular tissue of ether. Perosmic acid Stains the heart. Magnifled 350 diameters. these droplets black (Fig. 64, b, and Fig. 65, A, B, C); this coloration being due to the fact that the fat reduces the osmium tetra- oxide to a black osmium hydrate. Their number and size vary greatly, - though the largest rarely attain great size. Thus heart-muscle in a con- dition of fatty degeneration (Fig. 63; Fig. 64, 6; and Fig. 66, b) shows _ minute fat-droplets scattered through its substance, varying in number with the intensity of the process, but which sel- dom become conglome- rated together to form large drops. A similar appearance is presented by liver-cells (Fig. 62, c, d) and by the tubular epithelium of the kidney (Fig. 65, A, B) when undergoing fatty degeneration, though it should be said that here the fat-droplets are fre- quently of greater irregu- larity in size, and when the process is far ad- vanced in these organs many of the cells may wate ‘become broken up into a : et i 4 ‘Na fatty detritus composed of a ie RBQESESES 1% Ba! iW iN fine granules and minute che ls eg se B88 ayn) ag fat-droplets (Fig. 62, i a Fic. 64.—Marked fatty degeneration (chronic) of the heart. Fatt y degeneration (Flemming’s mixture; safranin.) a, Heaithy muscular tissue; D, : i places where the muscle has undergone fatty degeneration. Mag- affects connective-tissue nified 80 diameters. cells (Fig. 65, B, C, d) and muscles, as well as epithelium. When many cells closely associ- ated are affected, the condition is usually readily recognizable with the FATTY DEGENERANION. 167 naked eye; the more readily, of course, the more intense the process, the less striking the color of the tissue involved, and the smaller its blood-content. Colorless, transpar- ent tissues, like the intima of the heart and of the vessels, assume an opaque, whitish appearance; the cortical substance of the kidney be- comes grayish, and when the process is intense, even vellowish-white and opaque; the heart-muscle presents a yellowish and sometimes also a spotted appearance (this latter condi- tion being due to the existence of localized areas of fatty degeneration [Fig. 64]), and even the skeletal mus- cles may come to have a pale yellow- ish-brown color. The cells contained in liquids—as, for example, those in pus—frequently undergo extensive fatty degeneration, ending usually in the disintegra- tion of the cell. The same is true Fic. 65.—Fatty degeneration of the renal epi- thelial cells, the capillary endothelia, and the leucocytes, in diphtheria. (Flemming’s mixture ; safranin.) A, Uriniferous tubule, lined with epithelium (a) in a state of fatty degeneration, and containing a hyaline cast (b), both shown in transverse section: B, intertubular capillaries ; C, border of a glomerulus containing fatty epi- thelial cells (c) and capillaries (d) in the interior of which are fatty cells; e, Bowman’s capsule. Magnified 300 diameters. of the cells of coagulated exudates. . Fatty degeneration would appear to depend in part upon a change both in the supply and in the composition of the blood, consequently in the nutritive substance brought to the cells,—and in part upon a low- ered vitality of the cells themselves. An important part in its production is undoubtedly played by persistent diminution in the supply of oxygen to : the cells, as a result of which an increase takes place in the breaking down of albumin; and this latter change in turn is accompanied by the pro- duction of fat and by the excretion, by way of the urine, of the nitrogenous pro- ducts of the breaking-down process. Accordingly, fatty degeneration may be observed in a variety of diseases, as, for example, in acute anemia following any considerable loss of blood (fatty degenera- tion of heart and optic nerve) ; in chronic anemia and leuke- mia (organs affected: heart, liver, intima of the blood- vessels); in narrowing and occlusion of .arteries (part affected: the area supplied by the narrowed vessel); in per- sistent venous congestions; in various poiscnings, as by camphor, arsenic, chloroform, and certain vegetable fungi (parts affected: heart, liver, kidneys, and blood-vessels—especially the capillaries) ; in several Fic. 66.—Fatty degeneration, the formation of vacuoles, and the disorganization of the muscular tissue of the beart, . in a patient who died frc¢m pneumonia and nephritis. (Flem- ming’s mixture; safranin.) a, Transverse section of a nor- mal muscle cell ; b, muscle cell in a state of fatty degeneration; c, muscle cell containing vacuoles; d, disorganized cell. Magnified 400 diameters. 168 FATTY DEGENERATION. of the infectious diseases, such as diphtheria (kidneys, leucocytes, and heart), pneumonia (kidneys, heart [Fig. 66, b}) ; and in chronic ulcerous pulmonary tuberculosis (kidneys). , : In the infectious diseases the fatty degeneration which takes place in glandular organs, in leucocytes, and in the heart, may be attributed pri- marily to the effect of the poisons of these diseases. It must be remem- bered, however, that an elevated body-temperature, if continued for a long time, may also produce fatty degeneration of the organs. Cells which become detached from their natural positions and are transferred to some new situation among the tissues, are also very apt to undergo fatty degeneration; and the same is true in regard to cast-off epithelial cells and connective-tissue cells, and in regard to leucocytes which, in the course of an inflammation, have left the blood-vessels. Furthermore, a large part of the cells which are produced in the course of the proliferative activity incident to inflammatory and regenerative processes, and of those which are developed in tumors, die after passing through the stage of fatty degeneration; and the chief reason why this happens is, that the nutrition which they receive is insufficient. This fatty degeneration of the cells is usually the only histological change which we are able to demonstrate. Nevertheless, fatty degen- eration may be combined with other degenerative alterations. Zhe most frequent combination is that of cloudy swelling and granular degeneration with fatty degeneration ; and we may also encounter fatty degeneration in combination with hydropic degeneration and the formation of vacuoles (Fig. 66, c). Both of these combinations are observed in cases of poisoning and in inflammations of the tissues. As a general rule, fatty degenera- tion of the cells is associated with a variety of degenerations of the ground substance or framework (e.g., with amyloid degeneration of the connective tissue [compare § 66, Fig. 81)). 2 The question whether the fat which is found in the cells of an organ is the product of a degenerative process or merely represents an accumulation, is one which is easily determined in most cases. It is only. in a few instances that the problem is a difficult one to solve. It is generally assumed that in degenerative atrophy the fat occurs in the form of small drops, which show no disposition to run together, whereas in a simple accumulation of fat the tendency is to form large drops. This assumption is true as re- gards the majority of tissues, but not as regards all of them. It applies, for example, to transversely striated muscles, to those of the heart, to non-striated muscles, to glia cells, etc. On the other hand, drops of fairly large size are found in fatty degeneration of the renal epithelium, and when the liver is the seat of this pathological change, both small and large drops will be found (e.g., in phosphorus poisoning and in acute yellow atrophy of the liver). In addition to these facts it must not be forgotten that, even in simple accumulation of fat, this material is deposited first in the form of very small drops, and that at a later period, when the accumulated fat begins to be absorbed, the large drops break up into small globules. If from a mere histological examination we are unable to make a correct diagnosis, the locality in which the fat is found ought, asa rule, to throw some light upon the question. Thus, for example, if fat drops are found in cells which normally contain no fat, and if the circumstances are such that we can exclude an increased supply of this material, it may safely be concluded that it comes from cell-albumin, or, in other words, that the cells of the part are undergoing disintegration. It is only when we are dealing with tissues which, on the one hand, normally serve as places of deposit for fat, and, on the other, are prone to undergo fatty degeneration (the tissues of the liver, for example), that any serious difficulty is experienced. It is often hard to determine, in the case of the organ mentioned, just how much of the fat observed has originated at the spot, and how much of it has been brought there as a mere deposit. The difficulties are still further enhanced by the fact that fat which has been produced by a process of degenera- tion may be transported and lodged in certain spots as distinct deposits or in the form of an infiltration. FATTY DEGENERATION. 169 It is not an exceptional thing to find, in a disintegrating tissue, and particularly in disintegrating brain or spinal-cord tissue, cells which are entirely filled with fat globules and at the same time are more or less enlarged. Owing to the appearance which these cells present, they have been designated as fat-granule ceils (Fig. 67, a) or fat-granule globules. Many authorities have considered these large fat-granule globules to be tissue cells which have undergone fatty degeneraiion—or, in the case of the brain, to be gan- glion cells and glia cells which have undergone fatty degeneration. This, however, is not the correct view. The genuine fat-granule globules or cells are not the permanent tissue-cells which have undergone fatty degeneration, but rather ameeboid leucocytes and the offspring of proliferating permanent tissue-cells, which have, in their phagocytic activity, taken up into themselves either the fatty products of the disintegration of a tissue (the spinal cord, more particularly) or else fat in a dissolved state (which after- ward, within the leucocyte or newly produced cell, reassumed the form of drops). A cell which presents appearances of fatty degeneration in its protoplasm should, as a rule, be considered in the light of a cell which has to a certain extent begun to de- generate; and, as a matter of fact, this degeneration very often terminates in the de- struction of the cells which are thus affected. And yet, on the other hand, one may often note the fact that cells which possess a protoplasm that is in a fatty state, display karyokinetic figures—an evidence, therefore, that in these cells formative vital processes are still at work. In other words, these cells, so long as their nuclei remain in- tact, may be restored again to an integral condition. According to the inves- tigations of Starke, osmium tetraoxide is reduced only by olein or by oleic acid, whereas palmitin and ste- arin are not capable of directly producing this re- duction; they simply bind or fix the osmic acid. How- ever, a reduction of the. osmium tetraoxide which is thus bound to the palmitin and stearin fats, will take place when the material is transferred to alcohol. Fic. 67.—Fat-granule cells from an ischeemic centre of softening in the brain. (Marchi’s fluid.) a, Fat-granule cells; b, blood-vessel. §61. The fats Magnied 280 diameters. which occur in the hu- man body are mixtures of olein, palmitin, and stearin. The first of these is liquid at the ordinary temperature, the second melts at 46° C., ste- arin at 53° C. Since the fatty portions of various regions of the body contain these fats in different proportions, there is considerable variety as regards their firmness and melting-point. As fat is insoluble in water and aqueous liquids, that contained in the cells of the body or lying free among the tissues is not dissolved by their juices. At most, only traces of it can be dissolved in the blood, lymph, chyle, and bile, which contain small quantities of soaps. When the body is cooled after death to a point below the melting-point of the contained fats, the pal- mitin and stearin separate in the form of fine star-shaped or feathery needles (Fig. 68, b, c, d), which are commonly called margarin crystals, and which are often found both in fat-cells and free in the tissue-: liquids. Cholesterin in the form of thin rhombic plates, often with irregular corners and edges (Fig. 68, «), is frequently deposited in areas of fat- containing detritus which may have originated from extravasated blood or from degenerated masses of cells. This may occur, for example, in the tunica vaginalis testis, in a dilated sebaceous duct or gland, or in a softened area of the intima of a diseased aorta. When the substance in 11 170 GLYCOGEN IN THE TISSUES. which these cholesterin plates form is liquid, they may often be visible to the naked eye as little glistening scales. Cholesterin is a constant ingredient of the bile, which is furnished by the mucous membrane of the gall-bladder and gall-ducts, and in which the cholesterin is held in solution by the bile salts and soaps. It occurs also in the medullary sheath of nerve-fibres, and in small amount in the blood, where it is similarly held in solution by the fats and soaps. Burchard believes it to be present in small amount in all the organs. Water, dilute acids, caustic alkalies, and cold alcohol fail to dissolve cholesterin, which is, however, soluble in boiling alcohol, ether, chloro- form, and benzol. When treated with a mixture of 5 parts concentrated sulphuric acid and 1 part water, cholesterin crystals assume a deep carmine-red color, beginning at their borders, and this color then slowly changes into vio- let. A weaker solution (8 parts sulphuric acid, 1 part water) causes a | ‘Fig. 68.—a, Cholesterin plates; b, a free cluster of margarin needles: c, needles inclosed in fat-cells; d, grass-like bundle of margarin needles. Magnifled 300 diameters. violet coloration of the edges of the crystals. Sulphuric acid containing a trace of iodine colors the crystals violet, blue, green, and red. The source of cholesterin is not clearly understood. It is, however, in all probability an intermediate product in the metabolism of proteids. Accordingly it is encountered, under pathological conditions, in tissues and exudates which are in process of fatty degeneration. VII. The Formation and Deposit of Glycogen in the Tissues. § 62. Glycogen is a carbohydrate, readily convertible into sugar, which is obtained chiefly from the carbohydrates of the food, but which may also be formed from albumin and from gelatin. Glycogen is found in the tissues as a hyaline substance, which is more often situated in the cell-bodies than elsewhere, but may also at times lie in the intercellular spaces of the tissue. It is generally found in the form of spherules of different sizes, and in the ceils these spherules usually lie rather near the nucleus. Although glycogen is soluble in water, there would appear to be, acccrding to Langhans, some difference in the degree of its solubility MUCOUS DEGENERATION. 171 when obtained from different tissues; that contained in the liver, kidney, muscles, pus-corpuscles, etc., being distinctly more easily soluble than that from cartilage-cells and pavement epithelium. Hardening of tis- sues in alcohol makes the contained glycogen distinctly less soluble. The glycogen contained in the liver at the time of death is quickly con- verted into sugar by the diastatic ferment of the liver. Todine causes glycogen to assume a brownish-red color, To avoid the solution in water of the glycogen contained in fresh preparations, it is advisable to immerse the portions of tissue for examination in a syrupy mixture of gum and iodine (Ehrlich), or in glycerin to which a little iodine has been added (Barfurth). Sections of tissues which have been hardened in alcohol may be best studied after treatment with a dilute iodine tincture (1 part tincture of iodine, 4 parts absolute alcohol) and clearing in oil of origanum. The reaction after such treatment is of considerable duration. ; Glycogen occurs normally in the liver, in the muscles (including the heart-muscle), in the leucocytes, in the blood-serum (Gabritschewski), in cartilage-cells, and in almost all embryonic tissues, as well as in the foetal membranes of young embryos. During starvation the glycogen of the liver undergoes diminution, and under pathological conditions it may disappear entirely. In diabetes there is a deposit of glycogen in the epithelium of the kidney, particularly in that lining Henle’s loops, in the isthmus of which the cells are commonly almost filled with it, leaving, after solu- tion in water, clear spaces in the cell-bodies. In the blood of diabetic patients both the intracellular and the extracellular glycogen is increased. In fresh inflammatory exudates glycogen may be present in the pus- cells. The leucocytes of the blood contain glycogen in excess, more particularly in conditions of cachexia. Glycogen has also been observed in tumors of various kinds, as, for example, in the epithelial cells of condylomata, in carcinomata and adenomata of the testicle, in endothe- liomata, in myxosarcomata, enchondromata, and sarcomata of bone, and more rarely, also, in these same varieties of tumors when they are lo- cated in other tissues. It is almost never found in tumors of the breast (Langhans), and it is very unusual to meet with it in carcinomata of the stomach or intestine, and in tumors of the ovary, of the kidney, and of lymph-nodes. It is also absent from fibromata, lipomata, myxomata, osteomata, angiomata, and leiomyomata, and from the tissue of the infec- tious granulomata. According to Langhans, glycogen is met with in the epithelium of the body and portio vaginalis of the uterus, but is absent from the tubes and is very scanty in the cervix. It is also present in the epithelium of the vagina and in those tumors of the portio vaginalis and of the vagina which contain stratified epithelium. Carcinomata of the uterus rarely contain more than minute traces of glycogen. VIII. Mucous Degeneration. § 63. Mucous degeneration has its physiological prototype in the production of mucus by the mucous membranes and mucous glands, and in the formation. of mucus in the connective tissue of the umbilical cord, of tendons, of bursz, and of synovial membranes. In the umbilical cord the mucus occurs as a jelly-like matrix; in the joints, burs, and tendon- sheaths it forms a stringy, clear liquid. 172 MUCOUS DEGENERATION. The formation of mucus in mucous membranes takes place in epithe- lial ‘cells, called beaker- or goblet-cells (Fig. 69, «), whose cell-bodies are in great part occupied by clear substance, which may be stained with hematoxylin. In mucus-formation in mucous glands the epithelial cells swell, their centres become transparent, and the protoplasm gran- ules become reduced to small groups or strings. The so-called mucus- corpuscles of the salivary secretion, characterized by glassy transparent contents in which vibrating protoplasm granules are often present, are spheroidal cells which have undergone mucous degeneration. Tho mucus thus formed from the protoplasm of the cells may be dis- charged, and the cell may either retain its integrity or it may be completely destroyed. The formation of mucus occurs under pathological conditions (Fig. 69, a) in the same manner as normally. In catarrh of the mucous membranes the stringy excretion which forms is chiefly the result of excessive mucus-production by the cells of the mucous membrane and of its glands. Pus-corpuscles may also undergo mucous degeneration, in the course of which mucin would ap- pear to be formed from the nuclein of their nuclei (Kossel). In mucous mem- branes containing cylindrical epithelium the number of beaker-cells is greatly in- creased as the result of catarrhal inflam- mation, and the exudate often contains cells which have undergone complete mucous degeneration, and which appear as glassy masses often containing a few epithelial cells of an adenomatous polypus of fine granules. Again, the cells may a dottieliear oilky dareogedored Gemine contain mucus in the shape of irregular Eel drone of mua witha eerie: 2, drops of various sizes. Magnified 300 diameters. Just as in normal tissues, so also in pathological, the epithelial cells may. undergo mucous degeneration. Thus the epithelial lining of cysts of the ovary and of tumors of the intestine may often contain many beaker-cells (Fig. 70, a) and cells in which the entire cell-bodies have changed into mucus (5). In the so-called gelatinous carcinomata a large part of the epithelial cells undergo a mucous metamorphosis. A number of the connective-tissue group of tissues may also undergo a form of mucous degeneration, and in consequence acquire a gelatinous, transparent appearance. Besides connective tissue itself, cartilage, bone, fat, bone-marrow, and the tissue of sarcomata may be mentioned as belonging to this class. It is here more particularly the intercellular matrix (Fig. 71, b) which undergoes the mucous change, becoming con- verted into a homogeneous, structureless mass. The cells themselves may remain unchanged, may become fatty, or may also undergo mucous degeneration, in which case the whole tissue becomes a clear translucent mass, with scarcely anything left to suggest the original tissue, except here and there connective-tissue bands and single cells or groups of cells less degenerated. . c, newly formed connective tissue; d, vascular granulation tissue within the alveoli; e, fibroblasts within. alveoli containing the residue of the hemorrhage: f, artery ; g, vascular connective tissue formed within the artery at the place of the embolus. Magnified 45 diameters. muscle-cells—while the connective tissue is preserved, the absorption of the necrosis is performed quickly, and in a short time there develops a scar or callus of connective tissue (Fig. 205, e), in which the specific tissue-elements are lacking. PHAGOCYTOSIS; CHEMOTAXIS. 289 Pus is quickly absorbed from small abscesses, and the defect is closed by granulation and scar tissue. Large amounts of pus may also be absorbed from the , cavities of the body and from the lungs. Abscesses cause a development of granulations in their neighborhood, and this leads to the formation of an abscess membrane. The cavity may be obliterated by the absorption of the pus and by the growing together of the granulating ab- scess membrane; and so the abscess may heal, leaving a scar behind. In- complete absorption may lead to thick- ening of the pus, FIG. 205.—Callosity of heart. Section through 16 trabooudn, tat « 5 .—Callosity of heart. ction through a muscle tral a thai and later to calcifi- has undergone fibroid degeneration. (Miiller’s fluid; haematoxylin.) cation of the residue. % Endocardium; 6, transverse section of normal muscle-cells; c, con- : ‘ nective-tissue hyperplasia rich in cells; d, atrophic muscle-cells in hy- If the thickening of Pe tissue i es dense connective tissue without nuelet or muscle-cells; f, veins, in whose neighborhood a few muscle-cells still re- the pus, however, inain;: g. smaail blood-vessels; h, small-celled infiltration. Magnified 40 does not occur, the “iameters. abscess remains, and may increase in size in the course of time by secretion from its wall. Like abscesses, empyemata may heal by the absorption of the pus. At the time of absorption the tissues inclosing the pus produce granu-= lation and cicatricial tissues, which may attain considerable size when the absorption takes a long time. When incompletely absorbed, inspis- sated pus may calcify. Foreign bodies, so far as they are capable of absorption and exert no specific influence on their environment, are dissolved and replaced by connective tissue in the same way as are tissue-necroses or masses of fibrin. II. Phagocytosis Occurring in the Course of Inflammations, and the Formation of Giant Cells.—Chemotaxis. § 103. When small foreign bodies, or portions or particles of de- vitalized tissue, are found in the human body, there is very often a marked assembling of cells at their place of deposition. These are, first, leucocytes which have migrated from the vessels, but later also ftissxe-cells that have become motile, or that are proliferating, wander into the neigh- borhood of the foreign body or of the remains of devitalized tissue. According to the researches of Leber, Buchner, Massart, Bordet, 290 PHAGOCYTOSIS; CHEMOTAXIS. Gabritschewsky, and others, it is certain that this assembling of cells is partly brought about by chemotaxis—i.e., by an attraction exerted by fluid materials derived from the foreign bodies or from the particles of devitalized tissue; but doubtless other conditions also exert an influ- ence in determining the spot where the cells are to assemble. If the materials, while still undissolved, reach the sphere of the motile cells, they are very often taken up by them, and there occurs that phenomenon which is termed phagocytosis. If one observes the proc- ess under the microscope—which is easy to do, if tissue-lymph that has been taken from the frog and that is rich in cells, is mixed with gran- ules of soot—one sees that the motile cells pour their protoplasm, if one may use the expression, around the foreign bodies, and absorb them completely into their protoplasm by the union of the pseudopodia ex- Fic. 206.—Granular cells in a focus of degeneration of the brain. (Teased preparation treated with osmic acid.) a, Blood-vessel with blood; 6, media; c, adventitia with lymphatic sheath; d, unchanged glia-cells; e, fatty glia-cells ; f, binuclear glia-cells; g. sclerosed tissue: h, round cells; h;, round cells with single droplets of fat; he, fatty-granule spheres; h3, pigmented-granule spheres. Magnified 300 diameters. tended over the bodies. Among the foreign bodies that have penetrated from the outside, which are particularly often taken up by the leuco- cytes or tissue-cells, are chiefly the various forms of dust (especially soot), which are taken into the lungs with the respired air, and bacteria. It is to be noted, however, that phagocytosis does not occur in all infec- tions caused by bacteria, but is rather confined to special infections, and even in these does not appear in all stages of the local disease. Among the débris of tissues one finds most often fat-droplets (Fig. 206, h,, h,) and products of the destruction of the red blood-corpuscles (Fig. 206, h,, Fig. 208, ¢, and Fig. 102). These products of destruction may be taken up by the cells until they are stuffed with them and con- verted into large granular forms that are termed fatty-granule spheres and pigmented-granule spheres. Besides fat and blood-pigment, other frag- ments of tissue also—as, for example, particles of the contractile sub- PHAGOCYTOSIS; CHEMOTAXIS. 291 stance of muscle-cells or of elastic tissue-fibres or even of fibrin—may be taken up by the cells. The cells which take up all these substances are principally tissue-cells in luxuriant proliferation—fibroblasts, osteo- blasts, sarcoblasts, etc. If an inflam- matory exudation runs its course at the same time as the proliferation, and if the proliferating tissue contains leucocytes, these may also be taken up by the phagocytes (Fig. 207, a, b, c). The substances taken up by the phagocytes may be partly dissolved and destroyed within the cells; and 31, 20 Phagocytes trom eranmating tis: this is true particularly for the leuco- ments. (Corrosive sublimate; Biondi’s stain- . : : ing mixture.) a, Round fibroblast with two cytes, which gradually disappear in- jeucocytes; 6, swollen spindle-shaped connec- side of the cell-protoplasm of the pha- _ livetissue cell with one leucocyte; ¢, d. ¢, gocytes (Fig. 807, G e), but it Te oo. oo holds equally for various fragments of tissue, except blood-pigment (Fig. 208, c), which may remain a long time within the cells. The insoluble substances (soot) behave in the same way, while the bacteria taken up by the cells, in each case ac- cording to their vital properties and the condition in which thev en- tered the cells, are sometimes dissolved and destroyed, but sometimes, on the other hand, remain and multiply even in the cells. The cells loaded with foreign bodies are situated at first at the place where the phagocytosis occurred, but they may also migrate farther and enter the lymphatic circulation (Fig. 206, c) and the lymph-glands (Fig. 298), and later also the blood, from which they are deposited principally in+he spleen, marrow of bone, and liver (cf. §§ 17 and 18). If the foreign bodies which have penetrated into the body from the exterior, or the dying or already necrotic fragments of tissue, are too numerous to be taken up by leucocytes or proliferated tissue-cells, there form very often, in the granulation tissue that develops in their neigh- borhood, polynuclear giant cells, which arrange themselves on the sur- face of the foreign body or the superfluous mass of tissue, exactly as this occurs on the part of os- teoclasts under physio- logical conditions (Fig. 209, d). If the bodies are not too large they may be still taken up by these polynuclear cells; in the other case the cells remain attached to the surface and produce the Fig. 208.—Mass of pigmented-granule spheres in a lymphatic gradual dissolution of gland. (Alcohol; carmine.) a, Lymph-node; 0, trabeculz of the lymphatic gland; ¢, lymph-passage with pigmented-granule spheres. soluble substances (e.g., Magnified 80 diameters. strands of catgut, frag- ments of dead muscle- fibres). It sometimes happens that mononuclear cells take up small foreign bodies into their interior, and after this, by division, their nuclei become polynuclear. This is observed most often after the inclusion of bacteria (lepra, tuberculosis), which still multiply within the cells. 292 PHAGOCYTOSIS; CHEMOTAXIS. When a foreign body in the tissues cannot be absorbed it is sur- rounded by granulation tissue that changes later into connective tissue (Fig. 209, 6, c), and in this way becomes encapsulated. The prolifera- Fic. 209.—Dog’s hair encapsulated in subcutaneous tissue. (Alcohol; Bismarck brown.) a, Hair; b, fibrous tissue; c, proliferating granulation tissue; d, giant cells. Magnified 66 diameters. tion may be very slight, however, in the immediate vicinity of smooth, completely insoluble substances (glass beads). The phenomena of chemotropism or chemotaxis—i.e., the attraction or repulsion of freely motile cells by substances soluble in water—were first observed by Strahl and Pfeffer, who made researches particularly on myxomycetes, infusoria, bacteria, seminal filaments, and swarming spores. Researches of Leber, Buchner, Massart, Bordet, Gabrit- schewsky, and others have shown that the leucocytes may also be attracted (positive chemotropism or chemotaxis) or repelled (negative chemotropism) by chemical substances. There are particular products of the vital activity of fission-fungi (Leber, Massart, Bordet, Gabritschewsky) or bacterial proteins—i.e., the albuminoid bodies of dead bac- terial cells (Buchner)—which even after great dilution (according to Buchner, the protein of pyocyaneus is still active in a dilution of 1:3,000) are positively chemotactic. Ac- cording to Buchner, this property belongs also to gluten-casein from wheat-paste and legumin, to glue from bones, and to alkali albuminate froin peas, while ammonium buty- rate, trimethylamin, ammonia, leucin, tyrosin, urea, and skato] exhibit negative chemo- taxis. Phagocytosis is a vital phenomenon that has been long known and has many times been made the subject of investigation. Von Recklinghausen, Ponfick, Hoffmann, Langerhans, Slavjansky, von Ins, Ruppert, Langhans, Rindfleisch, and others conducted such experiments in the sixties and seventies, and described particularly the relations of cells to granules of dust and the disintegration products of the blood. In the year 1874 I made the observation that the fibroblasts of the granulation tissue take up and destroy leucocytes. It is to be assumed that one has in this phenomenon an act of nutrition—that the phagocytes digest and assimilate the leucocytes taken up. This is indicated by the fact that phagocytosis isa vital function of cells, which in the first place is directed to the taking up of nutriment. But since a phagocytosis is also ob- served in cells which give off substances to the excreta (e.g., in the renal epithelia) ; since, also, wandering cells loaded with dust appear at the surface of mucous membranes and in glands, and may thus cleanse the tissues of the substances mentioned, one may regard phagocytosis as a process which is directed also partly to the excretion of certain substances. Since the year 1883 Metschnikoff has occupied himself in a particularly thorough fashion with phagocytosis (he has also introduced this name), and has demonstrated that it is one of the most widely spread phenomena in the whole animal world, and is most often observed in mesodermal cells. He is of the opinion that phagocytosis represents the essential and characteristic token of inflammation, and that the inflammatory process is a combat waged by the cells against intruders or disease producers. This view is, how- ever, completely erroneous and finds no support in the actual conditions. Metschnikoff, in putting forward his definition of inflammation as a battle of phagocytes against dis- ease producers, pays no attention to those phenomena which have been termed inflam- mation from antiquity onward, and names inflammation only a single chosen vital process to which he has given his interest. If one starts from processes that are recog- nized on all sides as inflammation, it is apparent that legitimate inflammations occur in which no phagocytosis is present ; so that phagocytosis does not even form an in- separable concomitant of inflammation. For the rest, it is to be remarked that phago- cytosis is a phenomenon that often occurs in the course of even non-inflammatory processes (e.g., within tumors). Finally, one cannot see in phagocytosis any appearance CHRONIC INFLAMMATIONS. 293 of a struggle, since in the taking up of cinnabar or soot or fragments of red blood- corpuscles or pus-corpuscles every possibility of resistance on the part of that which is devoured is excluded. And even when bacteria are taken up, no struggle can be observed, at least in those cases in which (as actually often happens) the bacteria are only taken up when they are dead or at least dying. _1V. Chronic Inflammations. § 104. Inflammation is naturally an acute process, but various con- ditions may cause the phenomena of tissue-degeneration and exudation to last longer, and the inflammation to become chronic. The cause of an inflammation becoming chronic may be found, in the first place, in the fact that im the course of an acute inflammation changes occur which prevent a rapid healing. As may be deduced from the foregoing, all large defects of tissue and tissue-necroses, as well as large masses of exudate that el are difficult to absorb, act in this way. When necrotic mass- es of tissue are not completely absorbable, as in the case of large pieces of bone, they may indeed be sequestrated, but they then persist as sequestra for years (Fig. 210, a), and main- tain a constant inflammation. When a large superficial defect of the integument is produced by a burn, granulations develop, but if may be months before the wounded surface is skinned over from the edges and the process thus completed. A further cause of chronic inflammations is always found in repeated injury by external in- Jluences. Thus, for example, repeated inhalation of dust may cause chronic inflammation of the lung; repeated friction of the skin may perpetuate a chronic inflammation of the part; and repeated pathological altera- tions of the stomach-contents may promote inflammation of the stomach. I a the canals of Fic. 210.—Necrosis of fifteen years’ duration in the the body in which concretions lower part of the diaphysis of the femur. a, Seques- form, these latter may also be a fone.’ (Alcohol “preparation,” Reduced to. two-thirds cause of lasting tissue-lesions. natural size.) When unfavorable nutritive conditions exist in a tissue—e.g., great congestion—these may also en- able even slight external influences, that under normal conditions pro- duce no inflammation or one that soon stops, to set up ulceration with- out any tendency to heal. In this way, for example, chronic ulcers of the leg may occur. 294 CHRONIC INFLAMMATIONS. Infections are also a frequent cause of chronic inflammations, espe- cially those by bacteria and moulds, which multiply in the body and so constantly produce new inflammatory irritation. The inflammations which they cause are dis- tinguished from others chiefly by the fact that they often have a progres- sive character, and by the further fact that they cause metastases by way of the lymphatic vessels and the blood. Finally, chronic intoai- cations form a last cause. They act particularly on the kidneys and liver, and may be attributed either to the introduction into the Fig. 211.—Section of a stone-cutter’s lung with broncho- OF8anism, through the in- pheumonic fibrous nodules. (Alcohol: picrocarmine.) a. testinal canal or the lungs Group of fibrous nodules; 6, normal lung-tissue; c, pulmonary h . f tissue, thickened, but still containing bronchi, vessels, and a few or even the integument, 0 alveoli. Magnified 9 diameters. substances that are inju- rious to the organs af- fected or to others; or to the production in the body itself, by dis- turbances of the processes of metabolism, of injurious substances, so that there is a chronic auto-intoxication. § 105. The forms of chronic inflammation are determined partly by their fundamental causes, partly by the nature of the tissue affected. The remains of acute processes, as they are seen in fibrinous exu- dates and tissue-necroses, lead, when not complicated by specific infec- tions, to an inflammatory tissue-proliferation. For the rest, inflam- matory hypertrophies of connective tissue result from various chronic irritations of the tissues. So, for example, chronic ir- ritation of the lung by the deposition of stone-dust may lead to a connective-tissue hypertrophy in the lung, which is essentially characterized by the formation of circum- scribed nodules (Fig. 211, a), but oceurs also partly in the form of a diffuse hyper- trophy (ce). Continued irri- tating conditions in the neigh- borhood of the orifices of the urogenital apparatus, : oP Dy the ‘discharge of iunitat, Misia puiage tensor isediarepton) ing secretions, often lead to the formation of acuminate condylomata—i.e., to hypertrophy of the pa- pillee, in which the inflamed and infiltrated papille, with their vessels, enlarge (Fig. 212, a, b) and often also divide into branches. CHRONIC INFLAMMATIONS. 295 Frequently repeated and rather persistent mild inflammations of the skin and subcutaneous tissue, which are caused by mechanical lesions, by parasites, or by any other continued irritation, may also often, when they acquire a considerable extent, lead to diffuse connective-tissue hypertrophy, which is known as elephantiasis. Inflammatory growths of the periosteum and medulla of bone, which lead to pathological new formation of bone, or a hyperostosis (Fig. 213), may be caused both by non-specific irritations—e.g., by inflammations which run their course in the neighborhood of chronic uleers—and by specific infections, as the syphilitic and tuberculous. Chronic catarrhs of mucous membranes are sometimes caused by specific infections (gonorrhea, tuberculosis), sometimes by a non-specific injury (concretions, pathological changes in the contents of stomach and in- testine), sometimes by continued disturban- ces of the circulation (congestions). Chronic abscesses generally result from acute abscesses, and have the same etiol- ogy, but may also develop more gradually, and are then caused by special infections, generally tuberculosis or actinomycosis. They are usually limited externally by a connective-tissue membrane covered with granulations, and may increase in size partly by the secretion of pus from the abscess-wall, partly by the destruction of the wall and its neighborhood. Progressive enlargement to- ward the deep-lying parts leads to the for- mation of burrowing or congestive abscesses. Their increase in size is really always to be ascribed to the persistence of the infection. Perforation into neighboring tissues leads accordingly, also, to new infectious inflam- mations. The tuberculous and actinomycotic forms of chronic abscess are distinguished from others partly by the peculiar quality of the pus, partly by a special construction of the - abscess membrane (see Tuberculosis and Actinomycosis in Chapter IX.). Chronic ulcers are generally caused by specific infections (tuberculosis, syphilis, FiG. 213.—Periosteal hyperostosis glanders), but non-specific harmful factors tic ot the ba (eelaced ae also lead to chronic ulceration in tissue which ths natural size.) is specially susceptible to such ulceration. Thus chronic congestions in the vascular system of the leg may in- terfere with the healing of ulcers caused by any mechanical influence that may have been exerted under the ordinary conditions of the leg. In the same way the peculiar qualities of the stomach-contents may prevent the healing of an ulcer of the stomach. When healing begins at the border of an ulcer, while the ulceration advances at other parts, the ulcer is termed serpiginous. Active growth of granulation tissue in 17 296 CHRONIC INFLAMMATIONS. an ulcer leads to the formation of an ulcus elevatum hypertrophicum ; dense, callous, gristly induration of the edge and base leads to the for- mation of an ulcus callosum, or indolens, or atonicum. ; Chronic granulation growths (granulations) which persist as such a longer or shorter time, without undergoing conversion into connective Fig. 214.—Transverse section through the mucosa and submucosa of an atrophic large intestine. (Alcohol; alum carmine.) a, Glandular layer reduced to one-half its height ; b, muscularis mucose ; ¢, sub- mucosa; d, muscularis ; ¢, mucous membrane entirely atrophied. Magnified 30 diameters. tissue, reach, under various specific infections, conditions in which they are best known as tuberculosis, syphilis, leprosy, glanders, rhinoscleroma, and actinomycosis. Since the granulations, in these infections, often produce spongy growths and tumor-like formations, they are also called fungous granulations or caro luxurians, and infectious granulation tumors or granulomata. They show all the special peculiarities that Fig. 215.—Induration and atrophy of the renal tissue in chronic nephritis. (Alcohol; alum carmine.) a, Thickened and fibrous Bowman's capsule; 6, normal glomerular vessels: c, glomerulus whose vascular loops are partly impermeable and homogeneous, and its epithelium mostly lost; d, completely ruined glomerulus; ¢, homogeneous mass of coagulation studded with nuclei, and consisting of exudate and epithelium ; f, desquamated glomerular epithelium ; g, epithelium from the capsule; h, collapsed urinary tubule with atrophic epithelium ; i, collapsed tubule without epithelium ; i, hyperplastic connective-tissue stroma; l, collection of small cells ; m, normal, somewhat dilated urinary tubule; 7, afferent vessel ; 0, vein. Magnified 250 diameters. CHRONIC INFLAMMATIONS. 297 enable one to recognize, from the structure, the development and life- history of the granulation formations, as well as their special etiology (cf. Chapter IX.). It should, however, be mentioned that the etiology of some granulomata that develop in the skin is still unknown. Chronic inflammations, in which atrophy of the specific tissue ig associated with hypertrophy of the connective tissue, are observed principally in the mucous membrane of the intestinal canal, and in the kidneys and liver. In the intestinal canal the cause may reside both in specific causes (dysentery) and in non-specific irritations, which are set up by any ab- normal property of the contents of the intestinal canal. The epithelial constituents either die, under manifestations of persistent desquamation, while the connective tissue remains, or they decay at the same time as the connective tissue on which they are situated undergoes necrosis and Fig. 216.—Connective-tissue hyperplasia and development of bile-ducts in chronic hepatitis. (Alcohol; hematoxylin.) a, a, Lobules of the liver; 6, hyperplastic periportal connective tissue; c, old bile-cucts ; d, newly formed bile-ducts ; e, collection of small cells. Magnified 60 diameters. destruction. The final result is a mucous membrane (Fig. 214) which contains either no glands (e) or only rudimentary ones (a). In the liver and kidneys the chronic inflammations that lead to atrophy and induration, and whose results are called cirrhosis of the liver and indurated contracted kidneys, are hamatogenous diseases, so far as they do not depend on disturbances in the domain of the excretory ducts (obstruction, formation of concretions), and are caused partly by infections, partly by tntoxications. They begin either acutely or more insidiously, and are characterized by atrophy and degeneration of the glandular tissue (Fig. 215, h, 7), by hypertrophy of the connective tissue (Fig. 215, a, k, and Fig. 216, b), by cellular infiltration, by the formation of granulations (Fig. 215, J, and Fig. 216, e), by obliteration of old vessels (Fig. 215, c, d,) and by the formation of new vessels. In the liver there is often also the formation of new bile-ducts (Fig. 216, d), which, however, for the greater part do not perform their function. CHAPTER VII. Tumors. I. General Considerations. § 106. A neoplasm, or spontaneous new growth, or tumor in the narrower sense, is a new formation of tissue, not produced by infection, which has an atypical structure, serves no useful purpose in the organ- ism, and to whose growth there is no definite characteristic termination. The outward appearance of a tumor is atypical no less than its internal structure, for a true tumor differs more or less in its make-up from that of a normal organ. If this difference is slight, the tumor closely re- sembles an hypertrophy of tissue. Incertain instances this resemblance may be so close that one cannot say with certainty whether the new growth of tissue should be called a tumor or an hypertrophy. Tumors may develop in every tissue of the body which is capable of growth. They arise from a proliferation of the fixed cells of the part, and with the process is associated the formation of new blood-vessels. Frequently also there is a migration of leucocytes into the tumor tissue, Fic. 217.—Tissue taken from a mammary carcinoma, with numerous figures which show nuclear sub- division in the different phases of the mitosis. (Staining with Fl ing’: in. : i- thelial plugs. Magnified 500 diameters. ‘ 7 eee ei Roan meer but this is not an essential part of the process. The steps of cell-divi- sion and formation of new blood-vessels are the same as those described in §83 and § 88—i.e., the cells divide by karyomitosis, and the new vessels are formed from sprouts which shoot out from the growing cells of the existing vessels. The mitotic forms are usually typical (Fig. 217, b), but there are also many atypical forms, asymmetrical divisions, CONNECTIVE-TISSUE TUMORS. 299 nuclear figures with abnormally large chromatin masses (the so-called —-. giant mitoses), pluripolar mitoses, and finally examples of nuclear frag- mentation (cf. § 84, Figs. 146 to 150) and of direct segmentation. When developed a tumor is for the most part sharply defined from the surrounding tissue, but the opposite may be true. Moreover, several organs in their entirety may be changed into a single tumor, or considerable portions of tissue which are not sharply marked off from their surrounding tissues may take on the character of a tumor. By the degeneration of masses of tumor tissue, ulcers frequently arise. The difference in structure between tumors and physiological tissue is usually evident to the naked eye; but there are also tumors which so resemble the part from which they spring that the difference is to be made out only by the most exact examination. Tumors that have well-defined boundaries are generally nodular (Fig. 218, d; Fig. 219, d, e; Fig. 220, a); and the size of the nodules varies, according to the character of the tumor and the stage of development at the time of examination, from the smallest visible spéck to a mass of from twenty to sixty pounds or more. If nodular tumors grow on the surface of an organ they often take on the form of a sponge (Fig. 218, d) or of a polyp, and are named accordingly fungous or polypoid tumors. If a new growth develops on the surface of the mucous membrane or the skin, and the papille there present divide or new papille are developed, we have warty, verrucose, or papillary tumors, or papillomata. A further development of the papillary structure gives a dendritic or cauliflower mass. Tumors usually develop from small beginnings. It is a compara- tively rare thing for one to develop from a number of centres scattered diffusely throughout an entire organ. At one time their growth may be quite rapid, while at another it advances slowly and with occasional periods of quiescence. In some instances a tumor may remain perfectly quiet and unchanged for a period of several years, and then suddenly it may take on an active growth. The structure of a tumor is determined by the tissue from which it grows ; and although true tumors always show an atypical character, yet they also possess certain of the features of their parent-tissues. Tumors may be divided into three groups according to their structure and their genesis. The three are, a connective-tissue group, an epithelial group, and finally a group containing teratoid twmors and cysts. It should be remembered, however, that many forms of tumor may be classified as belonging at the same time to two or even to three groups, according to the point of view which is adopted. The connective-tissue tumors, which are often called histoid tumors, are made up of tissues which sometimes resemble, in their structure, the connective tissue of an adult, and sometimes that of the mesoderm; and, as a matter of fact, they may take their origin from mesodermal con- nective tissue. Usually the tumors which spring from the component parts of the nervous system—from the cells of the glia, as well as from those of the ganglia—are classed in this group; since in their structure they come much closer to the connective-tissue than they do to the epi- thelial tumors. The differences in the types of connective-tissue tumors are due to differences in their framework, in part also to differences in the cells. If a tumor is rich in cells while its framework is poorly developed, it is soft and is reckoned among the sarcomata. Very soft forms are spoken 300 . EPITHELIAL TUMORS; CYSTS. of as medullary or fungous. Mixed tumors contain several different kinds of connective tissue. Epithelial tumors are composed of cells which are the progeny of epithelial cells or of gland-cells, and also of connective tissue which is provided with blood-vessels; and the two are arranged in such a manner that the connective-tissue forms a support or network, in the meshes of: which the cells result- ing from the prolifera- tion of the epithelial cells or the gland-cells are grouped in a spe- cial manner. Inas- much as this arrange- ment of the tissues gives to these tumors a structure which re- minds one of that of a gland, they are often spoken of as organoid tumors—a designation which places them in contrast with the his- toid connective - tissue tumors. Attention should be called, how- ever, to the fact that certain tumors which are reckoned among the connective - tissue tumors (viz., the sar- Fig. 218.—Spongy carcinoma of the mucous membrane of the pos- terior wall of the cavity of the uterus. a, Body of the uterus; ), comata), possess an cervix; ¢, vagina; d. tumor. (Two-thirds life size.) organoid structure. : The cells which give the epithelial tumors their especial character spring from either the ectoderm or the entoderm, or from the glands derived from them; or it may be from the mesodermal epithelial layer of the pericardial or pleuro-peritoneal cavities, or from the glands which are developed from this layer—namely, the kidneys, suprarenal capsules, and genital glands. Such tumors often show more or less distinctly the especial characteristics of the parent tissue from which they are derived. Soft epithelial tumors which are rich in cells are also called medut- lary cancers. Teratoid tumors and cysts form a group whose especial character- istic is the fact that they may contain the most varying kinds of tissue, derived from all three layers of the embryo; and also the fact that the tumors come in places where the tissue which they contain is not normally found. Tumors, therefore, which according to their structure might be counted in one of the other groups, may be considered as tera- tomata on account of their situation. The class is also made to include formations which, according to their structure, origin, and physiological relations, ought not to be considered as tumors at all. Tumors usually develop singly; but it also happens that in a cer- tain system of tissue, simultaneously or one after the other, there will appear a great number of tumors of the same sort, so that we must £ ETIOLOGY OF TUMORS. : 301 assume that the conditions requisite for the development of these tumors are present in the different parts of the system where they ap- pear. Sometimes it happens that, at the same time, there appear in different parts of the body two entirely different varieties of tumor, which stand in no relation to each other, and whose simultaneous appearance is purely accidental. The exact determination of what should be included under the term tumor is scarcely a possible thing, and consequently the word is used by different authors differ- ently. I hold it advisable, and warranted by the characteristics of the life of the new growths which we are about to consider, to exclude from tumors all hyperplastic swell- ings and all retention cysts which are purely retention cysts and show no independent tissue-development. And furthermore, according to my view, all increase of tissue de- pendent upon the presence of parasites or upon infection is to be excluded from the domain of tumors; and soalso should the infectious granulation growths which occur in connection with tuberculosis, syphilis, leprosy, etc., be excluded. If it should be proved—which so far has not yet been done—that some of the new growths now reckoned among epithelial tumors are caused by infection, then we’ must exclude these also from the category of true tumors. : All authors do not give the same prominence to the atypical structure of tumors as is here insisted upon. This is especially the case with those tumors which are similar to the tissue from which they spring, and which may therefore be called homodplastic tumors. But, even in these tumors (chondromata, osteomata, fibromata, etc.), there are variations from the normal in microscopical and in coarse structure, as well as in out- ward appearance; and, besides, the proliferations due to infective inflammation may greatly resemble tumors in their structure. It is therefore not always easy to determine whether a new growth is a tumor or not. Tumors are in no sense useful to the organism, as hypertrophies may be, and a tumor does not have the special function of the tissue from which it originates. Hence they can in no way be looked upon as serviceable new formations of tissue. In certain tumors the processes of secretion may go on. Thus epithelial tumors may manufac- ture mucus or horny or colloid material (thyroid tumors), or biliary pigments (hepatic tumors), and indeed these processes may take place in metastatic nodules ; but from these facts we merely conclude that cells in tumors which do not differ too decidedly from the parent tissue may-retain their functional activities in a certain degree from genera- tion to generation. The inference that the organism has been enriched by new service- able tissue, similar to the tissue produced by hypertrophy from work, is wholly without foundation ; for the products are generally of no use to the body, or if it is conceivable that they may be used, as in the case of colloid material or bile, yet their value is cer- tainly far below that of the normal material. The tumors which spring from the mesodermal epithelium of the serous membranes or of the glands which originate from this epithelium, are also reckoned as epithelial tumors. This is justified by the fact that the tumors which originate from this epithe- lium are in structure and in clinical characteristics very like those which spring from the ectoderm and entoderm. Ihave considered the question whether it would not be advisable (as Hansemann has proposed) to reckon among the epithelial tumors (i.e., among the adenomata and carcinomata) such tumors as have a network of connective tissue whose meshes are filled with proliferated endothelial cells from blood- or lymph- vessels. In favor of this plan may be mentioned the similarity of structure, and also the fact that the endothelium of the vessels is frequently referred to as mesodermal epi- thelium. The following facts, on the other hand, militate against the plan: first, that the term endothelioma has been generally accepted; second, that the behavior of the proliferated endothelium of the blood- and lymph-vessels is quite different from that of epithelium ; and, finally, that in many tumors it is impossible to tell the products of the growth of the cells of the blood- or lymph-vessels, from those of the connective- tissue cells. When the tumors of the central nervous system (gliomata and ganglionic neuroglio- mata) are reckoned as connective-tissue tumors, a mistake is committed, inasmuch as these ganglion and glia cells do not spring from the mesoderm but from the ectoderm, and they represent modified ectodermal epithelium. Nevertheless, the character of the central nervous system, and of the tumors which arise from it, is such that it is far bet- ter to classify them with the connective-tissue tumors than with the epithelial ones. § 107. The etiology of tumors is by no means uniform, and often can- not be determined with certainty. Butin most cases the conditions under 302 ETIOLOGY OF TUMORS. which the new growth appeared can be given, and we may therefore. according to their origin, establish several groups of tumors. One group of tumors arises from some localized predisposition of the tissues of a distinctly congenital nature, and we may therefore speak of them as local malformations of tissue. They either develop during intra- uterine life, and are therefore present at birth, or they develop during Fig. 219.—Primary cancer of the gall-bladder with an impacted stone in this cavity. Coronal section through the gall-bladder and liver. a, Liver; b, duodenum; c¢, gall-stone; d, wall of the gall-bladder in- filtrated with cancer; ¢, cancerous infiltration in the neighboring liver-tissue; f, portion of duodenum which is infiltrated with cancer and adherent to the rest of the new growth. (Life size.) extra-uterine life, in the period of childhood or later; in which case traumatism not infrequently furnishes the immediate occasion for the beginning of the development of the tumors. To this group belong the osteomata, chondromata, angiomata, glio- mata, fibromata (nerve- and skin-fibromata), sarcomata, and adenomata. Furthermore, many teratoid tumors and cysts must also be placed in this group, inasmuch as they will be found, on closer examination, to represent the following conditions: residua of foetal formations; a transposition or a monogerminal implantation of the germs of certain tissues; an implantation of rudimentary portions of a twin embryo; a bigerminal implantation; and probably also pathological proliferations of male or female sexual cells. A second group is developed after traumatic injuries of the tissues, and it is reckoned that such a traumatic origin can be definitely determined in from seven to fourteen per cent. of the cases. The cause may be a ETIOLOGY OF TUMORS. 303 single injury, as a stab or a blow or a crushing or a fracture; or it may be a repeated mechanical irritation, like that due to rubbing, scratching, etc. In a third group of cases the development of the new growth follows an inflammation, especially if accompanied by ulceration and the formation of ascar. This inflammation and ulceration may or may not owe their origin to some specific injurious influence. Cancer of the gall-bladder, for example (Fig. 219, d, e), occurs almost invariably in gall-bladders which contained gall-stones, and which therefore have been the seat of chronic inflammation. Cancer of the stomach may form in the edge of an ulcer or in its scar-tissue after it has healed. Sometimes cancer de- velops inthe skin, or in the mucous membrane of the pharynx or larynx, in the base of a tuberculous or syphilitic granuloma, or in the scar which follows one of these processes. The tumors of a fourth group seem to owe their development to the un- equal atrophy of the elements which make up a tissue, as a result of which certain opposing forces are removed or lessened. This is especially true of epithelial growths (cancers), developed either in advanced age or in organs which, having just passed through a period of increased functional activity, are undergoing atrophy. In this way we can ex- plain the development of cancer of the skin, for example, by saying that the connective tissue of the skin is undergoing a certain atrophy, which is connected with relaxation of its strata, while the epithelium is still possessed of its full power of reproduction. Cohnheim formerly advanced the theory that all true tumors grew from distinct tumor-tissues, which were only persisting centres of embryonic tissue. This view re- ‘ceives no support, either from the results of clinical observation or from those of ana- tomical investigation of the tissues. : That the etiology of tumors is not always the same is shown by the variety of the conditions under which they arise. It is hard to say what is the nature of the influence which causes the cells to produce an atypical form of tissue. In this connection one is likely to think, at first, of the ‘causes which underlie hypertrophy and regeneration of tissue. There are, on the one hand, special congenital predisposing influences, or the various irritations which stimu- late the formative activity of the cells; and, on the other, those influences which tend to lessen or even to remove the hindrances to growth. But it still remains a puzzle why tissues which are not typical should be produced, and should so participate in the devel- opment of the organism that they can be considered as playing a useful part. In their effort to explain this phenomenon, which is associated with an increase in the capacity for living and for multiplying, even under pathological conditions (including that in which cells gain an entrance into and are transported through the lymph- and blood- channels), many authors have been disposed to find the cause in the presence of para- sites. But, according to our present knowledge, we are by no means justified in attrib- uting the development of true tumors, of autonomous new growths, to the influence of parasites. The development and life-history of tumors speak against this hypothesis, and so does especially the formation of metastases ; for there can be no doubt that these metastatic nodules are due to the proliferation of living tumor cells which have been carried in the lymph or blood stream. Ribbert is of the opinion that the cause of the pathological proliferation of tissue which leads to the formation of a tumor is the separation of cells or groups of cells from their normal connection with the rest of the body; this separation taking place either before birth (during some disturbance of intra-uterine growth) or afterward as the result of external influences. Nevertheless, such transplantations or separations of cell- masses take place very often both in uterine life and afterward (e.g., after the infliction of a wound or as the result of the formation of an ulcer; in cicatrices; in infectious granulation-growths) without any subsequent development of a tumor. At best, such transplantations of tissue constitute only one of the predisposing causes, and consequently some additional factor will still be necessary if the atypical progressive growth of tissue —that is, the development of a tumor—is to be started. Besides, the development of a tumor is in no wise dependent on a transplantation of tissue. It can just as well start in 304 MODE OF GROWTH OF TUMORS. normally placed cells—a statement which can be directly proved in the case of epithelial tumors, Our knowledge of the cause of tumors up to the present time may be thus summed up: Hereditary and acquired conditions of certain cells and cell-groups, which express themselves in a tendency to increased formative activity and to the production of atypi- cal tissue, lead to the formation of tumors. This growth may be prepared for, favored, or started by the transplantation of cells or groups of cells; but it is often facilitated by changes that take place in the neighborhood of the cells concerned. No general reliable scheme can be given for the development of tumors. The relations differ, not merely according to the particular type of tumor, but also among individual cases belonging to the same type. It must not be forgotten that the formations which we class together as tumors have a very different significance, and many of them ought rather to be classed under other headings (malformations). § 108. Whena tumor has arisen in any tissue it continues to grow independently. The tumor draws upon the vessels of the neighboring tissue for its nutrition, or it may grow independently by division of its Fic. 220.—Section through a primary carcinoma of the liver, a, with multiple metastases, b, in the liver- substance. (Three-sevenths life size.) own cells. In many cases the tumor increases only by interstitial ex- pansive growth, and the neighboring tissues are simply displaced and pressed together. In other cases the tumor grows by infiltration, and forces tts way into the intercellular spaces of the surrounding tissues, so that new territories are thus brought under the influence of the tumor. By this process a part of the cells of the invaded tissue are often stimu- lated to proliferation, so that an increase of the tumor takes place by an appositional grgwth, in which the cells both of the tumor and of the sur- rounding tissue take part. The characteristic feature of growth by infiltration consists in the tmvolvement, in the disease, of the tissues or organs which bound the original site of thetumor, Moreover, the tissue of organs which are simply adjacent to the organ originally affected may become involved by contiguity (Fig. 219, e, f)._ If tumor-cells find an entrance into any of the larger cavities of the body, they may spread on its surfaces and lead to the develop- ment of tumors. If, in the process of infiltrative growth, a tumor breaks into a MODE OF GROWTH OF TUMORS. 305 lymph-vessel or a blood-vessel—something which always happens in tumors called carcinomata and sarcomatu—and if cells of the tumors pos- sessed of the power of development escape into the vessel, tumor metas- Fig. 22'.—Filling of a periglandular lympb-vessel (in the region of the axiila) with cancer cells from a earcinoma «f the mammary gland. (Miiller’s fluid; hematoxylin.) a, Cancer cells; }), wall of the lymph- vessel.- Manified 300 diameters. tases are likely to follow; that is, there is likely to be a development of disconnected daughter-tumors. These secondary tumors may develop in the organ in which the primary tumor has its seat (Fig. 220, l), but F1G. 222.—Metastatic development of a carcinoma in the branches of the vena portz and in the hepatic capillary vessels. (Miiller’s fluid; Leematoxylin; eosin.) a, Tissue of the liver; 6, plugs of cancer cells in the vena porte ; ¢c, cancer cells in the capillaries. Magnified 100 diameters. they usually develop rapidly in other organs as well: in the case of the lymph-vessels in the lymph-glands, and in the case of the blood-vessels in those organs to which the living cells are carried by the blood (ef. S : Wee secondary tumors are developed directly from the transported cells. Jn metastasis by the lymph-channels the lymph-vessels are first filled with tumor-cells which have developed from the transported cells 306 TUMOR METASTASES. (Fig. 221, a). The surrounding tissue joins in this growth, new blood- vessels are formed, and in this way a tumor develops, usually in the form of smaller and larger nodules; but it may also happen that the lymph-chainels are more evenly distended by the growth (Fig. 221, a), 6p tL — F e) > ¢ a7 Sts a) iy RO : Fic. 223.—Me’astatic sarcoma of the liver following primary sarcoma of the parotid. (Flemming’s mix- ture; safranin; picric acid.) «a, Broad framework of liver-cells; b, sarcomatous tissue developed in the ves- sels; c, single tumor-cells in the liver-capillaries ; d, framework of liver-cells which have undergone atrophy and fatty degeneration. Magnified 150 diameters. without any real formation of nodules; or at most little swellings occur in the course of the lymph-vessels. If the metastasis takes place in lymph-glands, these swell up into nodules of smaller or larger size, and the tumor-tissue gradually takes the place of the gland-tissue. When the metastasis takes place through the blood-vessels the first de- velopment begins with the tumor-cells which form the embolus in artery, capillary, or vein; and under certain conditions the vessels (Fig. 222, b, ec, and Fig. 223, b, c) may be filled throughout a considerable extent by the growing tumor-cells. The tissue in which the tumor embolus develops remains passive at first, and its specific components—e.g., gland-cells (Fig. 223, d) and muscle-cells—undergo atrophy and finally disappear. Later, the blood-vessels and connective tissue take part in building up the secondary tumor. In its further development the secondary nodule becomes sharply differentiated from its surroundings and increases in bulk. But often enough, at least in places, growth by infiltration persists, and under proper conditions widespread diffuse tumors develop—as, for instance, in the liver (Fig. 223) and in bone-marrow. The number of metastases taking place by lymph- or blood-channels varies greatly in different cases, and may be limited to one organ or may affect many. In rare cases the seeds of the original tumor may spread through almost the whole body, so that larger and smaller nodules appear in quick succession in the most diverse parts—in gland, muscles, skin, ete. This is possible when a tumor situated in the lung or in a bronchial gland breaks into a pulmonary vein. If a bit of tumor capable of forming metastases is transplanted from one animal to another of the same species, it sometimes happens that it will develop in the second animal. We may therefore have such a RETROGRESSIVE CHANGES IN TUMORS. 307 thing as a metastasis from one animal to another. In a similar way we may have, in operations upon man, transplantation of bits of tumor from one part of the body to another, and these may continue their growth in the new situation. Side by side with the progressive development of tumors we find very often indeed retrogressive changes; and especially in rapidly growing cellular tumors, which increase by infiltrating the surrounding tissues, we may find, to a marked degree, fatty or myxomatous degeneration, pigmentation, necrobiotic changes, and hemorrhagic infarction, so that the tissue often sloughs completely. This rapid breaking down of the tissue is due in part to the fact that in carcinomata the proliferation of the epithelium advances into the blood-vessels, throughout a wide area, and thus causes them to become plugged. The destruction of the cells in nodular tumors, in case it is followed by a resorption of the products of degeneration, may lead to shrinking and the formation of cicatricial contractions. Very often, too, we find cysts containing the products of degeneration, and even ulcers; and in the case of carcinomata of the mucous membranes, the parts of the tumor which grow up above the surface are apt eventually to disinte- grate and disappear. MRetrogressive changes usually do not occur inslowly . growing dense tumors. { Necrosis and disintegration of the tumor-tissues seldom terminate in acure. This is most likely to hap- pen if a polypoid new-growth be- comes totally necrotic (for example, as a result of twisting of its peduncle) and sloughs away. Usually in tu- mors which have a tendency to un- dergo retrogressive changes and to disintegrate, while the older portions are falling to pieces, the tumor is con- stantly growing at the periphery and constantly involving new tissues. If a tumor is extirpated, recovery may take place; but to insure this all parts of the tumor must be removed or destroyed. This is most readily accomplished in the case of slow- growing tumors which grow by ex- pansion and have sharply defined borders. In tumors which grow by infiltration it is very difficult to define eZ the limit of the tumor, which often Fic. 224.—Sarcoma recurrent in the stump extends far beyond the point where Spaiee fae Eo ee any change in the tissue is apparent. al nodules. (One-half life size.) Consequently, in such cases, sooner or later a recurrence is apt to take place in the operation scar, the re- currence growing from portions of the original tumor which were not removed (Fig. 224, a). Such recurrences behave exactly like the original tumor, and can also form metastases (Fig. 224, c). : Tumors are usually classed as benign and malignant, according to their clinical and anatomical characteristics. The benign tumors, as a 308 THE DIFFERENT VARIETIES OF TUMORS. rule, grow slowly by expansion, and do not form metastases. The malig- nent tumors, on the other hand, grow rapidly and by infiltration, undergo degenerative changes more readily, and give rise to metastases. The malignant tumors, generally speaking, are the carcinomata and sarco- mata. It must be remembered, though, that the malignancy of a tumor depends on its location as well as on its nature. Thus a benign growth can cause malignant symptoms if its presence interferes with the func- tions of vital organs. So, for example, every tumor of the brain or of its membranes becomes a dangerous affection at the moment when it interferes with the functions of the brain; and such benign tumors as fibromata of the uterus, for example, as soon as they grow large enough to press upon and displace other organs, must be looked upon as de- structive growths: When a tumor has existed for a certain period there citen is produced an appreciable falling-off of nutrition in the body—a marasmus, com- monly called the cachexia of tumors. This occurs for the most part in connection with the malignant growths called cancer and sarcoma, and may be caused, at least in part, by the great demands which the rapid growth of these tumors and their metastases make upon the nutri- tive supply. A still more important cause may lie in the fact that the tumor may interfere with the taking in of nutritive material. For ex- ample, in carcinoma of the cesophagus, stomach, or intestine, the func- tion of the affected organ is profoundly interfered with, and the assimila- tion of food may be almost completely prevented. It must be further observed that, by the degeneration of the tumor and the continuous secretion from the resulting ulcers, often a great deal of albuminous material escapes from the body; while from the putrefactive processes substances are often formed which, when absorbed, act injuriously upon the system. Finally, the pain which is often experienced in a tumor may rob the unfortunate patient of his sleep. Whether the tumor itself, in certain cases, manufactures substances which are poisonous to the body in peu is unknown, but the possibility of such a thing cannot e denied. II. The Different Varieties of Tumors. 1. Connective- Tissue Tumors. (a) Fibroma. § 109. A fibroma is a tumor composed of connective tissue. It is usually in the form of a node, sharply differentiated from the surround- ing tissue; usually it affects only one part of an organ, but in exceptional cases it may convert an entire organ into a single great mass of tumor. If it occurs on the free surface of a mucous membrane or the skin, it often forms a papilloma. The consistence of the fibroma depends on the character of the con- nective tissue. It is often hard and tough, creaks under the knife (des- moid tumor), and presents, when cut, a white tissue much like tendon; and in other cases it is soft and flaccid, presents a grayish-white cut surface, and is somewhat translucent. In still other cases the bands of connective tissue are white and glistening, yet the tumor as a whole is more open in its structure and is correspondingly flaccid. There are all gradations between these hard and soft extremes, and even in one tumor different parts may possess different characteristics. FIBROMATA. 309 The hard kinds, as seen through the microscope, appear to be chiefly composed of thick bundles of coarse fibres (Fig. 225, a, b), among which are sprinkled a larger or smaller number of cells. In those kinds which are less hard the bundles of fibres are correspondingly more delicate (Fig. 226). If obstruction of the circulation and cedema supervene, the bundles of fibres (Fig. 226, b) may be pressed apart, and the cells (c) which lie upon them may become swollen (d). By reason of these changes the tis- sue is rendered softer. The softer kinds of fibroma, which present a translucent, gray- white surface on incision, are usually richer in cells; so that it : : ; Fic. 225.—Dense fibroma of the lobule of the ear. is possible, b y tearing a bit of the (Alcohol; hematoxylin.) a, Longitudinal section ; b, tissue to pieces, to isolate spin- transverse section, of bundles of fibres. Magnified 400 dle-shaped cells (nuclei with ‘ameter. tails). The intervening tissue is relatively less; the fibrillze are more tender and are arranged in narrower bundles. Sections through such tumors, when stained, appear full of nuclei (Fig. 227, b). The fibromata develop from actively growing cells of the connective tissue, and usually it is possible to find places which are richer in cells than the mass of the tissue, and in which the cells appear not only as small spindles, but also as round cells, or as short, thick spindles, or even as star-shaped cells. The change from this new-formed tissue rich in cells to mature connective tissue is brought about in the same way as was described in the chapter relating to Hyperplasia of Connective Tissue. Fibromata may occur in any tissue which contains connective tissue in any form. They are very common, for example, in the nerves, skin, periosteum, fasciz, uterus, and nasal mucous membrane; they are less common in the ovary, mamma, intestinal tract, etc. In the mamma the fibromata develop espe- cially around the canaliculi, so that the latter are found to be surrounded by connective tissue rich in cells (Fig. 227, b). 0S Fibromata do not form Fic. 226.—Section through an oedematous fibroma of the metastases, but a number of Grolinis Oise, wa Gwe meter are cogent nee, CHO Oru WenH ibe: apart at b by the fluid: ¢, spindle-shaped cells: d.ewoien Specially along the course round cells; €, blood-vessel. Magnified about 200diameters. of nerves and in the skin (see under Neurofibroma, in § 118). Moreover, it is not uncommon to see several centres of growth in a single tumor; that is, the mass of the tumor is made up of several nodules or bands which are separated from one another by ordinary connective tissue (Fig. 227, b). Fibromata are dangerous only by reason of their size or their position. 810 MYXOMATA. Fibromata may undergo fatty degeneration, or may soften and dis- integrate, so that cavities are formed inside of them. These may also break through, and so give rise to ulcers. The blood-supply varies greatly, and is sometimes abundant, sometimes scanty. Sometimes the blood-vessels are dilated, so that throughout the tissue there seem to be large canals or clefts, from which blood escapes when the tumor is ex- amined in a fresh state. Dilated lymph-channels are also sometimes observed. If the basic substance of a fibroma is strongly saturated with fluid, and the fibrillee are pressed apart, we have an edematous fibroma, closely resembling the umbilical cord in appearance. The term keloid is applied to a tumor of the skin which, in its fully developed state, is composed of tough fibrous tissue; and which, further- more, presents sometimes a knobbed and hard appearance, at other times ae: tx j M BLE Ue aN S WM Fig. 227.—Pericanalicular fibroma of breast. (Miiller’s fluid; alum carmine; eosin.) a, Tubules of gland ; b, pericanalicular connective tissue, newly formed and full of cells; c, connective tissue with few cells. Magnified 40 diameters. that of a star-shaped growth or a growth made up of bands and ridges. It commonly develops as a sequel to some injury or inflammation, but it may also develop independently of these processes. (6) Myxoma. _ § 110. A myxoma is a tumor consisting chiefly of mucous tissue, and is made up of cells and a liquid or gelatinous intercellular substance. The cells are for the most part of irregular shape, and are provided with processes of varying length (Fig. 228) which anastomose with one an- other (Fig. 229, a). The tissue is markedly translucent, soft, and shows plainly its blood-vessels when they are filled with blood. Gelatinous masses or a tenacious fluid, both of which swell up in water, may be obtained from the cut surface. No tumor is ever completely made up of myxomatous tissue; it is MYXOMATA. 311 found usually in combination with other kinds of tumor-tissue, especially with connective tissue, fat, cartilage, and sarcomatous tissue. For this reason the tumors are called fibromyxomata, lipomyxomata (Fig. 231), chondromyxomata (Fig. 234, c), and myxosarcomata (Fig. 229). Myxomatous tissue may be developed from fibrous tissue, this transformation being due to the fact that a fluid containing mucin collects in the meshes of the fibrille and then gradually causes the latter to disappear. When adipose tissue becomes myxomatous the fat in the fat- cells first breaks up into smaller drops (Fig. 231, 6, c), and then disappears from the cells alto- gether; after which the latter contract and_ become star- shaped (d), while a jelly-like material containing mucin ap- pears between the cells. When cartilage is transformed into myxomatous tissue a mucoid 1. wx. caus ¢ apenas ale degeneration takes place in the of the femur. (Gold preparation) ‘Magnified 400 diamn- basic substance, while the cells °™ change their shape (cf. Fig. 234, c,d). Myxosarcomata (Fig. 229) may develop out of myxomata through an increase in the proliferative activity of certain groups of cells, or they may develop from sarcomata through the accumulation of mucus between the cells of the tumor. Myxomata, myxofibromata, and myxolipomata are developed most frequently in the connective tissue of periosteum, skin, fascia, and sheaths of muscles, or in subcutaneous and subserous fatty tissue, or in oe rete ye EF Fic. 229.—Section of a myxosarcoma. (Miiller’s fluid; carmine; glycerin.) a, Mucous tissue; D, strings of cells; ¢, fibrous tissue. Magnified 250 diameters. 312 LIPOMATA. bone-marrow. Myxochondromata occur in the parotid, and are even quite common there. They are always benign tumors, which very rarely form metastases. Myxosarcomata, on the other hand, have the characteristics of sarcomata, and consequently may form metastases. (c) Lipoma. $111. A lipoma is a tumor composed of adipose tissue (Fig. 230). These tumors are sometimes soft, sometimes solid, usually nodular and lobulated, and they often reach great size. Their structure is very like normal subcutaneous fat-tissue; that is, they are com- posed of lobules of fat, which are held together by thicker or thinner connective-tissue septa. Microscopically, too, a lipoma greatly resembles the lobules of subcutaneous fat (Fig. 230), although the arrangement in clus- ters, like clusters of grapes, is usually lacking. If fat-tissue and mucous tissue grow together, as often happens, the tumor is Fig. 230.—Lipoma from the region of the shoulder, then called a lipomyxoma (Fig. with relatively small fat-cells. (Miiller’s fluid; hae- 231); or if there is a great deal SOLS TN REED Pe nee of fibrous tissue, it is called a lipofibroma or a fibrolipoma. Usually lipomata develop from fat-tissue, but they may also grow from connective tissue that has normally no fat. Calcification, necrosis, gangrene, and sloughing may all occur in large lipomata. These tumors LA 4H — SWE VK Reed Nya S ek) Lu Ni B 9 ANON, hs 5 NN =“ oe a Sk 4 a Fic. 231.—Lipomyxoma of the back. (Miiller’s fluid; Van Gieson’s staining mixture.) Li fat-cells; b, c, fat-cells in which the fat has broken up into small d: . See oa state Magnified 300 diameters. P Tops; d, mucous tissue; e, blood-vessel. CHONDROMATA. 313 do not form metastases, but sometimes many of them appear at one time. A complete disappearance of a lipoma does not occur, even when the individual undergoes a marked general loss of flesh. : Lipomata are sometimes observed even in new-born children, as, for instance, in those cases in which they are found in or over the clefts be- longing to spina bifida; but they much more often develop for the first time in later years. The favorite seats of these growths are the subcuta- neous tissues of the back, buttocks, neck, axilla, abdomen, and thigh; but they may also be found in the connective tissue separating individual muscles, in the subserous adipose tissue, in the kidneys, in the intestine, in the mamma, under the aponeurosis upon the forehead, in the me- ninges, in the hand, in the fingers, in the joints, etc. They sometimes also occur as multiple growths, and may then show a tendency to occu- py symmetrically placed parts of the body. A rare condition, which occurs in men, is that which is characterized by a new growth of fat on the neck and throat. ‘This condition, which has been described partic- ularly by English authors, manifests itself in the form of knobbed and lobulated alterations of the skin in this region. Madelung gives to the condition the name of fatty neck. The development of fat in these cases takes place partly in the subcutaneous tissue and partly in and under the fasciz and between the muscles. When this process of fat- production extends to the trunk, to the upper extremities, etc., conditions will be established which resemble very closely general obesity. (ad) Chondroma. § 112. A chondroma or enchondroma is a tumor consisting essen- tially of cartilage. The amount of connective tissue found in its struc- ture, covering its surface or ie penetrating its interior as a @ ° ee «@ framework for the blood-vessels, o%ee . - ° 8 ne ee Hee ae 43.503 . io. fe 0 ¢ é eae = 13% wi +e - . 4 "lee? fg tee 40% s Caw e ove ae 4 ig &* = » ‘ ° - ve pee ee - ‘8 ~~ * * eee ss Po att, sie NE St ee eee ° Cw wm em wes one 2"? 3s ¢ eo &» a @ie - ¢ . oe = = re ec our eg ae es » - * og a Na o Ne * o 2 = @ ys Yer. Fic. 282. Fic. 233. Fic. 232.—Periosteal chondroma of a digital phalanx, seen in longitudinal section. a, Chondroma; /), phalanx. Natural size. Fic. 283.—Section through a chondroma of the ribs. Cartilage containing many cells. a, Small, b, large cells. (Preparation stained with hematoxylin and carmine, and mounted in Canada balsam.) Mag- nified 80 diameters. is so slight as to be quite lost sight of when compared with the cartilagi- nous tissue. Cartilaginous tumors are usually developed in those places in which cartilage is found normally —that is to say, in some part of the osseous 314 CHONDROMATA. system or in the cartilaginous part of the Fic. 234.—Chondromyxosarcoma of the parotid gland. (Al- cohol; carmine.) a, Cartilage tissue; b, sarcoma tissue; Cc, mucous tissue; d, cartilage in process of breaking down and Reine connie jnto sarcoma and mucous tissue. Magnified 80 diameters. at the same time, particularly in the hands a also develop in other parts of the skeleton. The tissue of an enchondroma is usuall respiratory apparatus; but they do also occur in tis- sues which normally have no cartilage, as, for example, in the salivary glands, and particularly in the parotid, in the testicle, and more rarely in other organs. They may devel- op in bones, from remains of cartilage left intact at the time of ossification; but they are more apt to arise in the marrow or in the periosteum (Fig. 232). These tumors vary greatly insize. The small ones are usually spherical in shape; the larger ones knobbed or lobulated. The individual nodules are separated from one another by connective tissue. Several of them often occur nd feet, although they may y that of hyaline cartilage (Fig. 233) ; less often is it composed of reticular or fibro-cartilage. Still there are often fibrous patches in the hyaline cartilage. The periphery FG. 235.—Periosteal chondroma of the calcaneus, with areas of calcification. _(Miiller’s fluid; haematoxylin.’ a, Hyaline cartilage ; b, «, calcified cartilage. Magnified 250 diameters. CHONDROMATA. Bs) is often composed of fibrous tissue, which constitutes a sort of perichon- drium. The number, size, form, and arrangement of the cells vary greatly in different enchondromata, and also in the same tumor. Certain ones contain many cells (Fig. 233), others few; then, again, some have small cells and others large; and others still have both large and small cells. The cells themselves have sometimes capsules and sometimes none; sometimes they lie in groups in a mother-capsule, sometimes the indi- vidual cells are scattered about in a regular manner. All the varieties of cartilage which exist normally may befound in tumors. Accordingly we find cells of different forms, the majority of them, however, being of the round form. Nevertheless it is common enough to find spindle- and star-shaped cells, especially in the neighborhood of the connective- tissue bands, which separate the tumor into lobules or surround it as a Fic. 236.—Osteochondroma of the humerus. (Alcohol: picric acid; haematoxylin; carmine.) a, Hyaline cartilage; ), bone; c, cartilage which is being converted into bone; d, blood-vessel. Magnified 250 diameters. whole. What was said in § 89 holds good here with reference to the method of development. Sometimes cartilage forms the matrix, some- times bone-marrow, or periosteum, or bone, or one of the forms of con- nective tissue. Cartilaginous tumors growing from cartilage have been denominated ecchondroses. The tissue of enchondromata is often subject to retrograde metamor- phoses. Some of the cells often contain fat-drops. In large tumors the basic substance often undergoes a mucoid degeneration and becomes fluid. The result is either the formation of mucous tisswe (Fig. 234, c), thus giving rise to a chondromyxoma ; or the intercellular substance un- dergoes complete liquefaction and the cells are destroyed, in which case cysts with fluid contents are formed—the result of softening processes. In other cases cartilage calcifies (Fig. 235, b, c), or genuine bone may be formed (Fig. 236, c, b), so that the name osteochondroma must be em- ployed in designating such a growth. By excessive proliferation of the 18 316 OSTEOMATA. cells of the cartilage, sarcomatous tissue may result, and the neoplasm becomes a chordrosarcoma (Fig. 234, b). An enchondroma is usually a benign growth, although in certain cases of mixed tumors metastases may occur. In the vicinity of the place where the sphenoid and the occipital bones unite, in the median line of the clivus, there sometimes appears a very small tumor to which Virchow has given the name of an ecchondrosis physalifera spheno-occipitalis. This little tumor either occupies the space between the bone and the dura mater, or at its highest point it pierces the latter and penetrates into the arachnoid and the pia. In its typical form the tumor consists of bladder-like cells, not unlike the cells of plant life, and it takes its start from the medullary portion of the bone and also in some measure from its superficial portions. In addition to the tissue which is peculiar to the tumor there may enter into its composition a certain amount of cartilage and bone ; a circumstance which - has led Virchow to look upon the growth as a chondroma which has developed from re- mains of the spheno-occipital cartilage, and which is characterized by having cells that have undergone a peculiar bladder-like degeneration. However, the characteristic structure of the tissue rather favors the view, originally put forward by H. Miller and recently adopted by Ribbert, that this little tumor is the outcome of a proliferative activity on the part of some remains of the chorda (chordoma). (e€) Osteoma. § 113. An osteoma is a tumor consisting of bone. Tumors of this nature are generally found in connection with the osseous system (Figs. 237-239), but they may occur elsewhere. New growths of bone in connection with a normal bone have been variously designated according to their location and relations. If a new growth of bone is confined to a limited area it is called an osteophyte, or if of considerable size, an exostosis. Circumscribed bony growths inside of bones are called enostoses. New growths of bone which are not attached FIG. 237.—Ivory-like exostosis of the parietal bone. Natural size. to old bone are of four sorts: movable periosteal exostoses, which are sur- rounded by the tissues of the periosteum, but are separate from the bone; parosteal osteomata, which have their seat near a bone; discon- nected osteomata, which are removed to some distance from any bone and are situated in tendons and muscles; and finally, heteroplastic osteomata, which occur in other organs, as, for example, in the lungs, in the mucous membrane of the bronchial tubes, in the skin, in the mamma, etc. The teeth, too, may have excrescences. If they are formed from the OSTEOMATA. . BLT cement, they are called dental osteomata; if from the dentine, odonto- mata. We can divide osteomata into hard or eburneous (osteoma durum or eburneum) (Figs. 237 and 239) and softer spongy forms (osteoma ‘spongiosum or medullare) (Figs. 238 and 240). The former con- sist of a firm, compact tissue like the cortical portion of the shafts of long bones, and have very nar- row nutrient canals (Fig. 239, a); the latter are made up of thinner and more delicate masses of bone-tissue with wide medullary spaces (Fig. 240), imitating in their structure the cancellous tissue of bones. Sometimes the surface is regular and smooth, so that the whole tumor has the appearance of a cone with a rounded top (Fig. 237), or that of a ball, or that of a knob attached to a ‘stem; or it may be irregular in shape, rough and warty (Fig. 238). The former is the case with the ivory-like nodules which’ Fig. 238.—Cartilaginous exostosis of the upper dia- physis of the tibia. Reduced about one-half. most commonly appear as exostoses on the skull (Figs. 237 and 239), while the latter is true of the spongy exostoses and the disconnected and Fig. 239.—Eburneous osteoma of occipital bone, seen in frontal section. a, Osteoma; , wall of cranium, (Eight-ninths life size.) 318 OSTEOMATA. heteroplastic osteomata, such as are observed, for instance, in the falx of the dura mater (Fig. 240). Osteomata occur either singly or in multiple form, and the latter mode of occurrence is rather common. The ivory-like exostoses of the skull (Fig. 239) and the osteomata of the dura mater often develop in great numbers, and circumscribed bony growths may form in large numbers on the bones of the trunk and lower extremities. In such cases the epi- physes or points of insertion of tendons, or both together, are the favo- rite seats. Such growths are evidently to be referred to an inherited disposition, on the part of the points affected, to overgrowth, or else to a disturbance in the development of the skeleton. Sometimes a trans- mitted tendency can be proved. Thin discs and splinter-like pieces of bone, such as are found, in rare cases, in the lungs or in the mucous membrane of the air passages, may also at times be encountered in large numbers. The bony tissue is developed partly through the formation of osteo- blasts, as described in § 89, partly through the metaplasia of formed tis- sues (§ 93). The matrix is formed chiefly from the connective tissue of the periosteum, as well as from that of the site whence the osteoma springs; also from the cartilage and the marrow. If an exostosis devel- ops in such a manner that cartilage is first formed from the periosteum or the marrow, and then bone develops out of this, we apply to this the term cartilaginous exostosis (Fig. 238). But if this intermediate stage Fic. 240.—Osteoma of the dura mater. Clemo; pe acid; hematoxylin; carmine.) Magnified 40 iameters. of cartilage is wanting, and the exostosis develops directly from the pro- liferating periosteum, then we term the growth a connective-tissue exosto- sis (Figs. 237, 239, and 240). If a tumor is made up of connective tissue and bone in such a man- ner that the connective tissue makes up a considerable portion of the tumor, and does not simply represent the periosteum and marrow of the OSTEOMATA, 319 bone, the tumor is called an osteofibroma. Such tumors generally spring from the osseous system. If there is an abundant formation of bone in a chondroma, the name osteochondroma is used. Osteochon- dromata ‘(Figs. 236 and 241) are also usually connected with the long bones. The new growth may develop in the periosteum (Fig. 241, c), a a Fig. 241.—Osteochondroma of the humerus. (Alcohol: picric acid; hematoxylin; carmine.) a, Cortical part of the humerus; b, medullary cavity; c, layer of new bone deposited by the periosteum; d, normal Haversian canals; ¢, dilated Haversian canals filled with cartilage, which canals, at f, contain newly formed bone; g, cartilage which has been produced by the periosteum, and which, at h, contains bone-trabecule ; i, cartilage produced by the tissues of the bone-marrow and containing, at k, bone-trabeculz 3 1, old bone-trabeculz ; m, remnant of bone-marrow. Simply enlarged by means of a magnifying lens. or in the marrow (a, 6). An abundant growth of bone-trabecule (f, h, k) in the cartilage (e, g, 1) gives the tissue a firm, hard consistence. Many of the new growths of bone which come under observation are not tumors in the strict sense of the term, but hyperplasias resulting from excessive growth or inflammatory processes. This is true of many osteophytes and exostoses, and also, to a certain extent, of the parostoses and disconnected osteomata. Scales of bone which occasionally form in the falx of the dura mater, and which possess a normal medullary sub- stance (Fig. 240), are to be considered as dislocated or misplaced por- tions of the embryonic skeleton. The formations of bone which occur in the deltoid muscle and in the adductors of the thigh from constant carrying of a musket and horseback-riding must be looked upon as tu- mors which owe their origin to a local congenital predisposition; for the connective tissue belonging to muscles shows itself possessed of quali- ties which, as a rule, belong only to the periosteum and bone-marrow. The so-called myositis ossificuns—that peculiar disease of the muscles which is characterized by a progressive ossification, in childhood, of their connective tissue—is to be interpreted in the same way. 320 VASCULAR TUMORS. (f) Hemangiomata and Lymphangiomata. § 114. Under the name angioma are grouped those new growths in the structure of which blood-vessels or lymph-vessels constitute such an important part as to determine the character of the tumor. : Vascular tumors which arise from blood-vessels are called heemangi- omata, or angiomata in the restricted sense of this term; while those which arise from lymph-vessels are called lymphangiomata. They consist to a large degree of growths which may be looked upon as mal- formations of a more or less considerable vascular area. Four principal varieties may be distinguished: hemangioma simplex, hemangioma cav- ernosum, hemangioma hypertrophicum, and angioma arteriale racemosum. Hemangioma simplex, or telangiectasia, are terms used to describe a formation in which there are an abnormal number of normal blood-ves- Fic. 242.—Telangiectasia of the panniculus adiposus of the abdominal walls. (Formalin; hematoxylin; eosin.) a, Blood-vessels filled with blood; b, adipose tissue. Magnified 80 diameters. sels, or abnormally broad capillaries and veins, whose structure, in part at least, is abnormal. Such formations are most often found in the skin and in the subcu- taneous tissue. They are usually congenital, but grow after birth. They are called vascular nzvi (nevi vasculosi), and are often found in places where foetal clefts have closed (fisswral angiomata). It is often impossible to speak of such a formation as a true tumor, for the skin ‘may not be raised at all. But there are also telangiectases which de- serve the name of tumor. In these not only the skin, but also the sub- cutaneous tissue, may be the seat of the disease; and the tumor presents itself either as a sharply defined growth or merely as a thickening of the skin. The smooth nevus vasculosus, on the other hand, is a superficial substitution of another tissue for that of the skin. The color of the affected part is either bright red (nevus flammeus) or bluish red (nevus vinosus). Usually the line of demarcation between healthy and affected... . .. skin is not a sharp one. On the border of the chief discoloration or in VASCULAR TUMORS. 321 its neighborhood are often little circumscribed red spots, presenting sometimes the appearance of outrunners from the centre of the disease. 6 » Ah + f fe > Ds. YY VA Zi ty; Fig. 243.—Dilated capillaries from a telangiectatic tumor of the brain, all the attached portions of tumor- tissue having been shaken off in water. Magnified 200 diameters. The red color is produced by dilated vessels full of blood, which are situated either in the corium or in the subcutaneous adipose tissue (Fig. 242, a). There are also cases in which large areas of subcutaneous adi- pose tissue present a reddish appearance, by reason of the pathological development of new blood-vessels. More rarely than in skin do we find similar angiomata in glands (the breast), in bones, and in the brain (Fig. 243) and spinal cord and their membranes. On the other hand, we often find analogous alterations of the vessels in tumors—e.g., in glio- mata or sarcomata. If the vessels, which are usually abnormally abundant, are isolated, it becomes evident that the capillaries, or also the small veins (angioma Fic. 244.—Angioma cavernosum cutaneum congenitum. (Miiller’s fluid; hematoxylin.) a, Epidermis; b, : corium ; ¢, cavernous blood-spaces. Magnified 20 diameters. simplex venosum), are more or less dilated. These dilatations (Fig. 243) may be fusiform or cylindrical, sacculated, or spherical, and the 322 VASCULAR TUMORS. different forms of dilatations combine in the greatest variety of ways. The dilated blood-vessels are united with one another by capillaries of pola XA Bats UPR Pi eee ae Bm So Shiai Fig. 245.—Angioma cavernosum hepatis. (Miiller’s fluid; haematoxylin; eosin.) a. Liver tissue; b, angioma. Magnified 100 diameters. normal or slightly increased dimensions. The vessel walls are thin; that is to say, they are only slightly thicker than those of a normal capil- lary. A hemangioma cavernosum, or cavernous tumor, is a new growth of blood-vessels which consists of a cavernous spongy tissue, whose structure suggests that of the corpus cavernosum or spongiosum of the penis (Fig. 244 and Fig. 245). If the spaces are filled with blood the tumor has a bluish or dark reddish ap- pearance. A cavernous angioma, like a simple angioma, usually occurs in the skin (Fig. 244, c) or the sub- cutaneous tissue, where, at the time of its development, it ap- pears like a pathological sketch of the vascular system. Some- times itis a bluish-red spot (ne- vus vasculosus vinosus); sometimes it resembles a slightly elevated wart with a smooth surface (Fig. 244), or one with a bluish-red, Zif.2._ Seton tough he margin of 2 az somewhat irregular surface (aevis _ this margin was in process of active growth. (Car- vasculosus prominens, verruca vas- ™'ne Preparation.) Magnified 150 diameters. culosa) ; and finally, it may include more extensive areas of skin which are either discolored a bluish-red or are thickened, and if the development of cavernous tissue extends into the subcutaneous or even into the intermuscular connective tissue, there HEMORRHOIDS. 323 may result great tumors or disfiguring irregularities of the portions of the bees aint (elephantiasis hcemangiomatosa). emorrhoids are the bluish-red, knotty, vascular tumors which form ES uBR. feo OB Fic. 247.—Angioma simplex hypertrophicum. (Formalin; hematoxylin.) a, Blood-vessels containing blood; Ee cuLeNy and collapsed blood-vessels, with thick walls and richly supplied with nuclei. Magnified 100 diameters. in the thickened mucous membrane of the anus. They are generally considered to be varicose dilatations of the vessels, brought about by obstruction to the blood current, and by chronic inflammatory processes. According to the investigations of Reinbach, these tumors are true angi- omata, whose development, which may begin in early childhood, de- pends on a new formation and cavernous metamorphosis of the blocd- ace and may be quite independent of any obstruction to the blood ow. Within the body cavernous angiomata are most often found in the liver (Fig. 245, a, b), although they may also be found in the other or- gans—the kidneys, spleen, intes- tines, bladder, bones, muscles, uterus, brain, etc. In the liver they are found as dark-red areas, varying in size from that of a pin’s head to that of a body several centimetres in diameter. They displace the sub- stance of the liver and do not stand out above the surface of the organ. They are found in elderly persons, and owe their origin to a cavernous metamorphosis of the capillaries of Fig. 248.—Angioma simplex hypertrophicum the liver (Fig. 246); the liver cells gegen amen Agia aemme) perishing, while the walls of the sweat-gland cut transversely. Magnified 200 capillaries proliferate. In the case Mansions. of very small intra-acinous angio- mata, one can make out the com- munication between the capillaries of the liver and the cavernous spaces (Fig. 246). Larger angiomata are separated from the substance of the 324 CAVERNOUS ANGIOMATA. egos. x Li as ae Fic. 249.—Angioma cavernosum hypertro hicum of the skull-cap. (Mliller’s fluid; haematoxylin.) a, Blood-vessels with flattened endothelium; b, blood-vessels with cuboidal and cylindrical endothelium. Magnified 250 diameters. the capsule of Glisson, and in part of newly developed connective tissue. The blood spaces of a cavernous angioma are lined with a flattened Fic. 250.—Angioma arteriale plexiforme of the frontal and angular arteries of both sides. CAVERNOUS ANGIOMATA. 3825 endothelium. The walls are usually thin; but their thickness, as well as the amount of connective tissue between the individual vessels, varies greatly. Some of the blood spaces may undergo a fibrous degeneration, in connection with the formation of a thrombus. Hemangioma hypertrophicum, in its typical form (Hemangioma simplex hypertrophicum), occurs most frequently in the skin and subcu- taneous tissue, where it forms a circumscribed nodule, not unlike the soft, smooth warts. The pathologically altered vessels may lie in the papilla or in the corium or in the subcutaneous tissue. They present themselves either as narrow tubes filled with blood (Fig. 247, a, and Fig. 248), whose walls are more or less thick and abnormally rich in cells; or else as firm strings of cells (Fig. 247, b), which are either col- lapsed, thick-walled vessels, or possess no lumen whatever. In very rare instances it happens that an hypertrophy of the walls takes place in an angioma which, from the calibre of its vessels, is prop- erly classed as cavernous; and this hypertrophy is due to the fact that the pavement endothelial cells are altered to cubical or cylindrical cells (Fig. 249, 6). Such a tumor may therefore be called an angioma-ca- vernosum hypertrophicum (or, in some cases, angiosarcoma endotheliale). A cirsoid aneurism, or angioma arteriale racemosum, or angioma arteriale plexiforme (Fig. 250), is a condition in which the arteries of a whole group are dilated, tortwous, and thickened, so that they form a con- volution of enlarged arteries. They feel to the palpating finger like a bunch of earthworms. Many of these angiomata, which are found par- ticularly on the head, and which may cause erosion of bone, are con- genital in origin. Others appear to be acquired, and develop in conse- quence of a traumatism; and yet itis possible that, already before the injury was inflicted, certain special conditions existed at the affected point. —— SO) SO NSE . 251.—L hangioma cavernosum subcutaneum. (Alcohol; alum carmine.) a, Ectatic lymph-vessels ; = dD trons ee c, fat; d, larger blood-vessels ; ¢, cellular tissue. Magnified 20 diameters. Sy? Ee RSciveer steels Nis seer ES 8115. Angioma lymphaticum, or lymphangioma (Fig. 251), is composed of a tissue the greater part of which is made up of dilated lymph-vessels. The different forms are: lymphangioma simplex, or telan- 326 LYMPHANGIOMATA. giectasia lymphatica ; lynphanyioma cavernosumn ; lymprangioma cystoides ; and lymphangioma hypertrophicum. The fluid contained in the cavities is usually a clear and bright lymph, but sometimes it is milky. Tn the simple lymphangioma the lymph-vessels to a greater or less distance are dilated, and their walls are usually thickened. In the cavernous lymphangioma (Fig. 251) the vessels are still more increased both in number and in size, while the intervening tissue is diminished in quantity, so that even to the naked eye the tissue appears spongy. The cystic lymphangiomata contain cysts from the size of a pea to that of a walnut or greater. The tissue be- tween the dilated lymph-vessels is, according to the part from which the tumor springs, connective tissue, or fat (Fig. 251, c), or muscle, or some other tissue. Sometimes this tissue includes foci of lymphadenoid tissue (e). More- over, it may present the signs of active proliferation. Lymphangiomata are sometimes con- genital, and at other times they make their first appearance only later on in life. As a congenital phenomenon ec- tasia of the lymph-vessels is observed in different forms, particularly in the tongue (macroglossia), in the palate, in the lips (macrocheilia), in the skin (nevus lymphaticus), in subcutaneous tissue, in the neck (hygroma colli con- genitum), in the vulva, ete. Lymphan- guomata of the skin spread out over more or less extensive areas, and they may give rise to smooth or to slightly uneven elevations of the skin. When the blood- vessels are well developed they may lend a reddish appearance to the part. The bursting of dilated lymph-vessels which lie immediately beneath the epi- a | thelium, may keep up a constant moist Fic. 252.—Large, hard pigmented nevus condition of the surface and so establish eee ac r higiented spoteon teupeer @& lymphorrhcea. If the cavernous de- part of the body. (After Rohring.) velopment of the subcutaneous lymph- vessels spreads over large areas of the skin, conditions outwardly resembling those of elephantiasis may result. In such cases the intervening tissue usually takes part in the hyper- trophic growth, or there will be established a fibrous elephantiasis, with lymphangiectasia. In rare cases chylangiomata, containing chyle, appear in the course of the lymph-vessels of the intestine or mesentery. Cystic lymphan- giomata of the peritoneum are also extremely rare. The pathological formations, which may be grouped under the sin- gle heading of hypertrophic lymphangiomata, consist of peculiar alter- ations of the skin, which either are congenital or else first manifest themselves in early youth. They are commonly termed pigmented neevi, lentigines, ephelides, and fleshy warts. PIGMENTED NZEVI. 327 The pigmented nevi (nevi pigmentosi), or melanomata, form larger or smaller plaques situated on the same level with the surrounding skin Fic. 253.—Lymphangioma hypertrophicum. Section through a small, soft, smooth wart. (Formalin; hematoxylin; eosin.) Magnitied 40 diameters. (nevus spilus), or raised above it like warts (nevus prominens, nevus verrucosus), and often studded with hairs (nevus pilosus). They are pale brown or dark brown or black (Fig. 252), and are usually covered by normal, less often by hypertrophied epidermis. They are usually small, but they may be as large as an ordinary plate, and in rare in- stances they may cover a large part of the body. Lentigines appear at any time after birth, and on any part of the sur- face of the body; and when once formed they remain for life. They es te NOONE IN nase ae Fig. 254.—Lymphangioma hypertrophicum. Rounded summit of a rather large, soft, smooth wart. (Forma lin; fa nstogyle eosin.) Sharply limited nests of cells in the corium. Magnified 250 diameters. 328 FRECKLES; FLESHY WARTS. closely resemble the little pigmented nevi, and form well-defined spots of a yellow or brown or almost black color, and as large as a pin-head or larger. Freckles, or ephelides, are ill-defined, angular, pale-brown spots, not elevated above the surface, which appear in the early years of life espe- cially on the face, hands, and seldom elsewhere, and which either re- main permanently or in course of time disappear. The pigmentation is favored by the sunlight. Fleshy warts (verruce carnee) are non-pigmented, well-defined, smooth (Fig. 253), or slightly roughened, or very uneven papillary growths caused by a normal or hypertrophic epithelium (Fig. 253, a). Tn all of the pathological formations just described the connective: FIG. 255.—Section through two papille of a papillomatous fleshy wart. «a, Thickened horny layer of epi- dermis; b, epithelial pearls ; c, rete Malpighii; d, nests and strings of cells in the papilla; a), heck and calls in the reticular layer; e, connective tissue. (Preparation stained with carmine.) Magnified 50 diameters. tissue framework incloses masses of cells, either in round groups or drawn out into bands (Fig. 253, Fig. 254, Fig. 255, d, d,). They lie partly in the papille and partly in the corium, and are more abundant in those cases in which the growth is elevated above the surface of the skin. In the pigmented growths the cells of the cell-nests may also be bearers of the pigment, which either occurs in the form of separate brown and yellow granules, or else is diffused throughout the substance of the cells. In many instances, however, the pigment is to be found omer in the connective-tissue cells of the fibrous portions of tha growth. The cells of the cell-nests are comparatively large (Fig. 254), and they possess an abundant protoplasm and a bright, bladder-like nucleus. From the position which they occupy and from the appearance which they present, one is warranted in drawing the conclusion that they ara MYOMATA. 329 the product of the proliferation of the endothelial cells of the lymph-vessels. Accordingly, it would appear to be proper to place these growths in the category of the endotheliomata or in that of the lymphangiosarcomata, but the limited extent to which they grow makes it seem more correct to classify them among the lymphangiomata (compare § 123). The ag- gregations of cells which are found in the hypertrophic form of lym- phangioma may, to a certain extent, be spread out somewhat diffusely through the tissues, as also occurs in the case of an hypertrophic hem- angioma. When this happens, the peculiarities of structure which characterize this form of growth will be lost. Unna, Kromayer, and Delbanco hold the view that the cell-nests of the cellular nevi are of epithelial origin, representing portions of the surface epithelium which have dropped down to a lower level; and Kromayer goes so far as to assume a metaplasia of epithelium from the surface to the connective-tissue stratum. I have not at my disposal any preparations which show the first stages in the development of these nevi. More recent exhaustive studies relating to nevi and fleshy warts have failed to reveal any connection between the cell-nests and the epithelium, and consequently I favor the belief —notwithstanding the investigations of these last-named authors—that the pathology which is given in the main body of the text, in regard to these nevi and fleshy warts, is that which most perfectly harmonizes with their anatomy and clinical behavior, both when they are fully developed and when they undergo a change into malignant sarcomas (compare § 123). (g) Myoma. § 116. Myoma is the name applied to a tumor whose chief structural elements are newly developed muscular fibres. An obvious division is into leiomyomata if the muscular fibres are of the smooth variety, and rhab- domyomata if the fibres are striped. Leiomyomata, called also myomata Ilcevicellulares, occur most fre- quently in the uterus, less often in the Fallopian tubes, in the uterine ligaments, in the labia majora, and in the muscular layers of the alimen- tary tract and urinary channels. In these localities they form rounded and nodulated tumors of various sizes. In exceptional cases they are found in the skin and subcutaneous tissue, where they form small nodules which only rarely attain the size of a pigeon’s egg. They occur either singly or in larger number, and may appear in early childhood or even before birth (Marc). Tf the new growth takes place in muscular organs, it proceeds from the muscular layer, forming in its development bundles of muscle-fibres (Fig. 256), interwoven in various directions, and furnishing, therefore, in sections, a variety of pictures. Submucous myomata of the uterus may include in their substance uterine glands. Myomata which devel- op on the dorsal wall of the body of the uterus, and close to the angle formed by the Fallopian tube, may include in their substance a varying number of gland-tubules which come from the Wolffian body (von Reck- linghausen). When this happens, it is proper to call such tumors adeno- myomata. They differ from the ordinary spherical myomata, which have sharply defined limits, in these respects: their boundaries are ill- defined; and, furthermore, a few individual glands may, through the accumulation of secretion in them, become converted into cysts. Ac- cording to Ricker, the ordinary myomata of the uterus may contain epithelial tubes, which perhaps owe their origin to some portion of Miuller’s duct which has become displaced during intra-uterine life. In the skin and subcutaneous tissue, so far as there are any observations on the subject, the new growth of muscle-fibres has its origin in the mus- 330 MYOMATA. cularis of the vessels (Fig. 257), which layer not only becomes thickened (e), but also gives off separate offshoots of muscular fibres (6). This new formation of muscular tissue may easily be associated with the pathological formation of blood-vessels (a), and from this combination will result tumors that may properly be called angiomyomata (Fig. 257). According to the observations of Jadassohn, myomata of the skin may also spring from the erector muscles of the hairs—the arrectores pilo- rum. A certain amount of connective tissue takes part in the formation of a myoma, and often assumes such importance that the tumor deserves the name myofibroma or fibromyoma. For example, most of the my- omata of the uterus are myofibromata. The fibrous connective-tissue portions of the tumor appear glistening white, while the muscular parts are reddish-white or bright reddish-gray. The fusiform muscle-fibres may be isolated by teasing a fresh bit of tumor, or, better, a bit which has macerated for twenty-four hours in twenty-per-cent. sulphuric acid, or for twenty to thirty minutes in thirty-four-per-cent. potassic hydrate. In a longitudinal section the muscular fibres are best recognized by the staff-like nuclei (Fig. 256 and Fig. 257, b), as well as by the regular arrangement of the cells in bands or parallel lines. In cross-section the muscle-cells appear as little areas whose rounded boundary lines are somewhat flattened by pressure one against the other, while in the cen- tre of each of these areas is the nucleus cut transversely (Fig. 256). Leiomyomata are thoroughly benign tumors, although they often attain a very large size, and sometimes undergo a change into sarcoma- tous tissue. In fibromyomata of the uterus we often have processes of fatty degeneration and softening, which destroy the tumor or lead to the formation of cystic cavities. Calcification may also occur. A myofi- broma may become a pure fibroma through the degeneration and disap- pearance of the muscular fibres. A rhabdomyema (Zenker), or myoma striocellulare (Virchow), is a rare tumor whose essential part is made up of striated muscle-fibres either well or poorly developed. When well developed the muscular MYOMATA. 831 fibres form nucleated bands of various widths, which show a transverse (Fig. ae ee cea o) yr Lif pre (es EE Ee Fic. 257.—Subcutaneous angiomyoma of the back. (Alcohol; hematoxylin; eosin.) «a, Cavernous plood-vessels; muscular strings cut longitudinally at b, transversely at c ; d, connective tissue; e, artery with hypertrophied muscular layer; f, group of lympb-cells. Magnified 50 diameters. The ill-developed forms consist of narrow bands without transverse stri- ation (d); of spindle-cells with long-drawn-out thread-like processes without transverse striation (g) or with partial striation (7); and also of round cells of different sizes, which show either a radial or a con- centric striation (h, 7). Besides these there are also cells which possess FIG. 258.—Cells from a rhabdomyoma. (After Ribbert and Wolfensberger.) a, », ¢, Fibres of various sizes with transverse striation; d, small nucleated fibre without strive; e, spindle-cell with longitudinal strize ; f, spindle-cell with longitudinal and transverse stri#; g, spindle-cells, non-striated, with elongated processes ; h, i, round cells with concentric and radial striation. 19 332 GLIOMATA. ' no especial characteristic, so that it is impossible to decide whether they are young undeveloped muscle-cells or simple cells of the connec- tive tissue. The bands as well as the spindles are usually in bundles, and interwoven among themselves. It is usually not possible to demon- strate with certainty, on the surface of the fibres, a sarcolemma; but various delicate membranes have been described by different authors which apparently were fragments of a sarcolemma. Rhabdomyomata occur most frequently in the kidney or in its pel- vis, in the testicle, and in the uterus; seldom in other localities, as, for example, in the vagina, in the bladder, in the muscles, in the heart, in the nerves, in the subcutaneous tissue, in the mediastinum, in the cesoph- agus, ete. They form nodular tumors of varying size, and if situated on the surface of a mucous membrane the new growth is polypoid or papillomatous in shape. They may develop as well from transversely striated muscular tissue as from smooth muscular fibres. In the kidney and testicle they either form well-defined nodules or else they cause the destruction of the whole organ. The growth of these tumors is due ap- parently to misplaced portions of embryonic muscle-tissue, and conse- quently the condition is generally congenital. But these tumors may first develop at an advanced age. Sometimes another tissue—e.g., car- tilage—is included in the tumor. Moreover, fairly well-developed mus- cular fibres are found in complicated tumors of the testicle and kidney. (Compare the paragraphs relating to Teratomata. ) If a tumor contains only a few cells which can be definitely recog- nized as muscle-fibres, while most of the cells have no specific character, it is usually called a myosarcoma. (h) Glioma and Ganglionic Neuroglioma. § 117. Gliomata are tumors which grow from the cells of the stroma of the central nervous system, and which, when fully developed, consist essentially of these cells. In the brain they form growths which for the most part are not sharply defined from the normal brain-substance, but pass into the latter by insensible gradations. They often, therefore, convey the impression of a local swelling of the brain, and only the difference in color, and a comparison of the healthy with the pathologi- cal tissues, suffice to convince the eye that a real tumor is present. When they occur in the spinal cord these tumors are most apt to arise in the neighborhood of the central canal, and may spread over a consid- erable length of the cord. Their appearance varies considerably : sometimes they are light gray, translucent, of about the color of the cortex, and moderately firm in con- sistence; sometimes they are grayish-white and of firmer consistence; and at other times they may be reddish-gray or dark red in color. In the latter case they are traversed in every direction by numerous dilated vessels. Gliomata which contain much blood often exhibit hemorrhagic foci. Fatty degeneration, softening, and destruction of the tissue are also common occurrences. - A section of a fully developed glioma shows under the microscope a network of extremely delicate glistening fibres (Fig. 259, B), among which are embedded numerous short oval nuclei. A very scanty cell- protoplasm surrounds these nuclei, and can be distinguished only with difficulty. When the tissue is investigated in the fresh state or after maceration in Miiller’s fluid, it is easy to detect that these nuclei belong GLIOMATA. 383 to cells (astrocytes) that are characterized by the great number of fine branching processes which they possess, and which extend in every di- rection (Fig. 259, A). By the employment of suitable staining mixtures one may demonstrate, even in sections, the connection between some, at least, of the fibres (Fig. 260). The cells closely re- semble normal _ glia- cells, although at times they are much larger, and, in some instances, more spherical in shape. =a ‘ z 3 = is <= = a = @% Fy Ds A Fic. 280.—Melanosarcoma of the skin. (Alcohol; carmine; eosin.) a, Sarcoma tissue, rich in cells; b, nests of cells; c, pigment cells; d, blood-vessels with walls which have undergone hyaline degeneration. Magnified 300 diameters. 3850 OSTEOID SARCOMATA. ence in the cells of small shining spherules which give the microchemi- cal reaction of fat. The disappearance of the color in alcohol lends s on & a HR ® » Soe © ws, 2 9 9099, Fig. 281.—Osteoid sarcoma of the ethmoid bone. (Miiller’s fluid; haematoxylin; eosin.) a, Sarcoma-tis- sue; b, osteoid tissue; c, plate of old bone; d, vascular fibrous tissue. Magnified 45 diameters. support to this statement. On the other hand, von Recklinghausen claims that the color is parenchymatous. Osteoid sarcomata develop in the marrow of bones and in their peri- osteum, and are characterized by the fact that in certain portions of the framework of the growth a condensation of the tissue takes place, i.e., trabeculcee of osteoid tissue are formed (Fig. 281, b). A tumor of this na- Fig. 282.—Petrifying large-celled sarcoma of the tibia. (Muiller’s fluid; haematoxylin; eosin.) a, Poly- morphous tumor-cells; b, alveolar stroma; ¢c, trabeculz of the stroma with small calcareous concretions 5 d, petrified bands of the stroma. Magnified 265 diameters. ture, while closely resembling an osteosarcoma, still differs from it in one respect: it contains no deposit of lime salts. Petrifying sarcomata also develop most frequently in some part of the skeleton. They are characterized by the fact that trabecule of a tlelicate basis-substance develop among the cells of the tumor (Fig. PSAMMOMATA. 351 282, c) and afterward undergo calcification (d); thus giving a certain hardness to the tissue of the tumor. At the same time no actual bone- formation takes place. Psammomata or sand tumors (acervulomata) are sarcomata or fibro- sarcomata of the dura, or of the soft membranes of the brain, or of the pineal gland, which contain concretions of lime in greater or less abun- dance. Someof these concretions are similar in structure to the normal cerebral sand, the basis of their formation being concentric layers of cells which have undergone hyaline degeneration (Fig. 283, a, b, c). Others are shaped more like a lance (d), and probably owe their origin to the deposit of lime salts in connective tissue which has undergone hyaline degeneration, or in blood-vessels which have previously passed through the same pathological change. Psammomata usually occur in the form of round nodules. As a rule, several of them are found at the same time. If the myxosarcomata are left out of the account it may be said that the sarcomata which contain masses of hyaline substance acquire this feature in one of the following three ways: either the cells produce the Fic. 288.—Section of a psammoma of the dura. mater. (Alcohol; picric acid; haematoxylin; eosin.) a, Hyaline nucleated globule including a concretion: b, concretion with non-nucleated hyaline border, lying in fibrous tissue ; c, concretion with hyaline border; a, lanceolate concretion in connective tissue; ¢, lanceo- late formation containing three concretions. Magnified 200 diameters. hyaline substance ; or else they themselves become converted into this mate- rial; or, finally, both the fully developed connective tissue and the blood- vessels undergo a change into hyaline substance. The changes enumerated may take place not only in an ordinary sarcoma, but also in an endothe- lioma or an hemangiosarcoma, although they occur far more commonly in the last-named tumors (Fig. 274, b; Fig. 278, d; Fig. 284). The hy- aline masses are encountered in a variety of forms. They are some- times round, sometimes club-shaped, sometimes like cords, sometimes like a net, and sometimes branching like the leaves of a cactus plant. They crowd apart the masses of cells and sometimes compel them to assume the aspect of cords. Billroth has described such tumors as cyl- indromata. In endotheliomata the hyaline degeneration may be associ- ated with the formation of epithelial pearls—i.e., small bodies which are composed of cells that have been rendered flat and have been arranged, like the layers of an onion, around a central nucleus. Hyaline degeneration of the walls of the blood-vessels and of the bundles of connective tissue results in a thickening of these structures (Fig. 280, d); and this thickening is sometimes uniformly, sometimes irregularly, distributed. Hyaline products of the cells have a tendency to assume a 352 EPITHELIAL TUMORS. spherical shape (Fig. 274, b; Fig. 278, d; Fig. 284, c, d). The dis- integration of masses of cells of considerable size is followed by their conversion into large balls, or cords, or branching structures of hyaline material. If, in the case of endotheliomata and angiosarcomata, the cord-like a Cs ore ca 7 a z o CF et Fic. 284.—Myxoangiosarcoma of the parotid gland, with hyaline deposits. (Miiller’s fluid; hematoxy- lin; eosin.) a, Mucous tissue; , cord-like masses of cells, in the midst of which are spheres of hyaline ma- terial; c, hyaline spheres in mucous tissue; d, blood-vessels with proliferating endothelium and hyaline masses. Magnified 100 diameters. masses of cells which have developed in the lymph- or blood-vessels undergo a change into hyaline substance, there will be produced a vari- ety of structures that closely resemble glands which contain colloid (Fig. 284, d), and that have even, in not a few instances, been mistaken for the latter. Ribbert looks upon melanosarcomata as an independent variety of new growth. It is because they spring from the chromatophores that he believes they should be sepa- rated from the sarcomata and reckoned as a class by themselves. It is, however, to be noticed that, in addition to the chromatophores, other cells take on proliferative ac- tivity. Consequently the melanosarcomata can be considered only as sarcomata in the building up of which certain cells have taken part—cells which have the power of pro- ducing pigment. 2. The Epithelial Tumors. (a) General Remarks. § 124. Epithelial tumors are new growths in the formation of which both vascular connective tissue and epithelial cells—i.e., tissues which are derived either from epidermal or from glandular epithelial cells—take part. The arrangement of connective tissue and epithelial cells follows in general that of the normal physiological arrangement of these tissues; PAPILLARY EPITHELIOMATA. 853 that is to say, the connective tissue either forms a layer the surface of which is covered with epithelium, as in the normal skin and mucous membranes, or else it forms a network in the meshes of which the epi- thelial cells are disposed, after the pattern of a normal gland. The imi- tation of the first-named structure leads to the formation of papillary new growths; that of the second, to the formation of more or less sharply defined nodules or superficial patches of thickened tissue. The epithelial tumors may be divided into two groups, according to the physical characteristics and arrangement of the cells; one group in- cluding the papillary epitheliomata, the adenomata, and the cystade- nomata, and the other the carcinomata and the cystocarcinomata. ‘The chief clinical characteristic of the first group lies in the fact that it contains only benign tumors, which are sharply differentiated from the surrounding tissues and do not form metastases. The second group, on the other hand, includes the malignant new growths, which grow by in- filtration and form metastases. However, the two groups are not sharply separated the one from the other, for papillary epitheliomata and ade- nomata may, through the occurrence of certain changes in the mode of multiplication and distribution of their epithelial cells, become converted into carcinomata. (6) Papillary Epitheliomata, Adenomaia and Cystadenomata. § 125. A papillary epithelioma is a new growth which is composed of a framework of connective-tissue papille covered with epithelial cells. It is therefore constructed in very much the same manner as are the papille of the skin. Nevertheless, there are certain differences: the papille are higher and often branched, and the epithelial covering as a whole is thicker. Papillary epitheliomata of the skin appear in the form of knobbed warts, the slender papille of which (Fig. 285) are covered by epithelial cells that show a tendency, at least so far as the outermost layers are concerned, to become cornified (ichthyotic warts and horny warts). These warts may, like the fleshy warts (see § 115), appear in youth (ichthyotic warts) as well as in advanced age (verruca senilis). The first- Fic. 285.—Papillary epithelioma or ichthyotic wart of the skin. (Miiller’s fluid; baematoxylin: eosin.) a, Corium ; b, enlarged papillary body; c, laminated horny epithelium. Magnified 40 diameters. named sort is a local malformation of the skin (Fig. 285), while the last-named is due to a pathological growth and cornification of the epi- thelium (Fig. 286, c, d), followed by an outgrowth of the peripheral por- tions of ue same, in the form of papilla. The development of what is 3854 PAPILLARY EPITHELIOMATA. known as a cornu cutaneum or cutaneous horn (Fig. 121 and Fig. 122) is due to the excessive cornification of the epithelium covering hypertro- phied papilla; and in this process it will be found that the horny epi- thelial cells become piled up, with their long axes at right angles to the surrounding surfaces of the skin, in cylindrical or cone-shaped masses. Papillary epitheliomata of the mucous membranes are encountered either in the form of wart-like, nodulated growths (Fig. 287, e, f), or in that of long, slender, papillary growths (Fig. 288, a) which spring from a small stem that often breaks up into a number of branches. The former variety is found especially in the larynx, rarely in the nose or urinary bladder; while the latter variety is seen in the urinary bladder, in the pelvis of the kidney, and upon the vaginal portion of the uterus, more rarely in the ureters, the gall-bladder, or the biliary passages. In both varieties the individual excrescences are formed each one of a slender connective-tissue papilla (Fig. 289) which contains blood-ves- sels and is covered by a thick layer of epithelial cells. The character of the epithelium corresponds in general to that of the part in which the growth occurs, but there are papillomata which are covered with strati- fied, flat epithelial cells, although growing from a part (e.g., the nose) the normal epithelium of which is cylindrical in shape. Papillary epitheliomata in dilatation cysts, which are also called papillary cystomata, occur most frequently in cysts of the ovary and in cysts of the lactiferous ducts of the mammary gland; more rarely they F1G. 286.—Senile horny wart of the skin of the forehead. (From a woman eighty-four years old.) (Alco- hol; haematoxylin; eosin.) a, Corium; b, epithelium; ¢, atrophied sebaceous follicles, with horny epithe- lium at their outlets ; d, hypertrophied horny layers ; e, enlarged papillz of theskin. Magnified 15 diameters. are encountered in atheromata (dermoids) of the skin. They form little wart-like elevations, or cauliflower-like tumors which in some instances may fill up the whole cyst. Their structure is like that of the corre- sponding excrescences in papillary adenocystomata (cf. § 127), or the papillary epitheliomata of the skin or mucous membranes. CHOLESTEATOMATA. 3855 Papillary epitheliomata of the surface of the ovary develop in about the same manner as do those of the urinary bladder; but they are of rare occurrence. Papillary epitheliomata of the ventricles of the brain spring partly from the choroid plexus (tele choroi- dew), and partly from the ependyma. It is difficult to draw a sharp dividing line between papillary epi= Fig. 288. Fic. 287.—Papillary epithelioma of the larynx. a, Epiglottis; b, ossifled cricoid cartilage; c, thyroid cartilage; e, f, papillary growths, Natural size. 1G. 288.—Papillary epithelioma of the urinary bladder. a, Epithelioma; b, c, enlarged prostate; d, thickened wall of the bladder. Five-sixths natural size. A theliomata and other formations. Thus, inflammatory growths of the skin and mucous membranes—the pointed condylomata—which develop especially on the external geni- tals as the result of irritations of a chronic nature (cf. § 105), resemble the epitheliomata so closely that they can be told from them only by the history of an antecedent intlamma- tion. If the connective-tissue framework of the papilloma is well developed, in compari- son with the amount of epithelium that may be present, the tumor may be reckoned among the papillary fibromata. Whether sucha classification of the growth is to be adopted or not in any particular instance, is a matter which must be left to the judgment of each observer. Finally, the benign papillary epitheliomata may also change into carcino= mata, either by the growth of the epithelium, at the base of the papille, into the under- lying connective tissue, or by the growth of the superficial epithelium, while in a condition of proliferation, into neighboring organs, as takes place, for example, in papil- lary epitheliomata of the ovary. As a general remark it may be said that the term epithelioma is often applied to carcinomata which take their start from surface epithe- lium, but it seems far better to reserve this term for the benign tumors described above. Among the epitheliomata may be classed those formations which are called chole= steat. mata or pearl tumors. and which owe their existence partly to inflammations, partly to misplacement of embryonal tissue. The most striking feature of the chole- steatoma is due to the presence of glistening white pearls which are made up of thin, scaly 356 CHOLESTEATOMATA. epithelial cells pressed closely together, and which often inclose cholesterin. The prin- cipal localities in which these peculiar formations are found are the descending urinary passages, the cavities of the middle ear, the pia of the brain, and very rarely that of the spinal cord. a . . ; Pathological cornifications, accompanied by the formation of glistening white scales and the so-called pearls, occur in the urinary passages in the course of chronic inflam- (Alcohol; hematoxylin; eosin.) Magnified 35 ec = Fic. 289.—Papillary epithelioma of the urinary bladder. diameters. mations. Cholesteatomata are found in the tympanic cavity, in the mastoid antrum, and in the external auditory meatus in the form of yellowish-white or bluish-white spherical masses, with concentric layers like an onion, and varying in size from that of a cherry pit to that of an egg. In these situations they may, by pressure upon the neighboring bone, cause it to disappear. Such cholesteatomata owe their origin to the proliferation of flat epithelium which has penetrated from the outer ear, through defects in the mem- brana tympani, into the spaces of the middle ear ; in which localities they replace the cylin-. drical epithelium and, under special conditions (chronic inflammations), they form the spherical masses referred to above. They probably, in rare instances, also develop from epidermoidal cells which, during the period of embryonic life, have found their way into the cavities in question. The intracranial cholesteatomata are situated at the base of the brain (seldom in the vertebral canal), in the vicinity of the lobus olfactorius, tuber cinereum, corpus cal- losum, plexus choroides, pons, medulla oblongata, and cerebellum, in which localities they form on the surface shining silky nodules of varying sizes, that extend to a greater or Jess distance into the substance of the brain. The nodules are single, but masses of cholesteatomata may become separated from the chief nodule and push their way into the neighboring tissues. According to Bostroem it is always possible to demonstrate, at any point that may be selected, the connection between the pia and the cholesteatoma ; the nature of this connection being such that one can see how the scales of which the cholesteatoma is composed originate from a stratum of cells that rest upon vascular con- nective tissue, and how, furthermore, these latter cells present all the characteristics of epidermoidal cells. The cholesteatomata of the pia may therefore be called epitheliomata or epidermoids (Bostroem), and their development may be explained by the assumption that displaced epidermis germs have found their way into the pial layer at some time during early embryonal life. According to Bostroem this event occurs after the closure of the medullary canal and before the separation (by a process of constriction) of the secondary from the primary vesicle of the fore-brain or from the vesicle of the mid-brain ; or—to state the case in somewhat different terms—it occurs between the closure of the medullary canal and the separation of the hind-brain vesicle from that of the cerebellum. We may therefore place the time of the occurrence of this event in the fourth or the fifth week of intra-uterine life. These epidermoids may accordingly be classified as belong- ing to the teratoid tumors (gq. v.). ADENOMATA. 357 § 126. Adenomata are usually nodular tumors. They possess sharply defined boundaries and are commonly seated either in the midst of a gland, or in the skin, or in a mucous membrane. In the last- named situation they quite often protrude from the surface in the form of a polypus. The absence of any tendency to grow as it were by filtra- tion or to produce metastases justifies us in considering adenomata as benign tumors. One of the characteristics of an adenoma is its power to reproduce a tissue which resembles the glandular tissue of the parent organ more or less closely. The tissues thus reproduced imitate either the tubular or the acinous type of gland, and yet these two forms are not sharply separated, the one from the other. Papillary adenomata owe their ori- gin to the formation of papillary excrescences on the internal surface of the glandular tubes. The stroma which supports the gland is composed in part of pre- existing connective tissue, in part of that which has been newly formed. Adenomata develop in either normal tissues, in malformed tissues, in tissues which have been altered by disease (inflamed mucous membranes, cirrhotic livers, contracted kidneys), or in the remains of foetal structures (Wolffian bodies, canalis neurentericus, remains of fusion-germs). The material for the new gland structure is furnished by the proliferation of the epithelium of the old gland, the steps of the process being quite like those which occur in the regeneration of normal gland tissue. The rea- son why new gland formation takes place in normal organs is beyond human ken. Glandular new formations that develop in tissues which have heen altered by inflammation, and that ultimately assume many of the characteristics of tumors, may at first present the features of a regenerative or hyperplastic new growth; and on this account the adeno- ang os on few, be nN OIU iad Fig. 290.—Adenoma tubulare (glandular polyp) of the intestine. (Alcohol; alum carmine.) «a, Transverse sections, b, longitudinal sections, of gland-tubules; c, stroma, rich in cells. Magnified 100 diameters. mata Pie be sharply differentiated from regenerative and hyperplastic rowths, ‘ Tubular adenomata represent the commonest variety of adenomata. They occur especially in mucous membranes (Fig. 290) which are pro- vided with slender tube-like glands (intestine, uterus), but they are also often found in such glands as the breast (Fig. 291), the liver, the ovary, and the kidney. ‘These tumors, which vary in size from that of a pea 358 ADENOMATA. to that of a man’s fist (they rarely exceed this), are characterized by the fact that they develop simple or branching gland tubules (Fig. 290, a, 0, and Fig. 291, a, b) which are lined with a cylindrical or cubical epithe- lium. : Alveolar adenomata develop in glands (mamma, ovary, thyroid gland, sebaceous glands), and are characterized by the formation of nu- ao terminal berry-like alveoli (Fig. 292, a) as well as gland tubules (b). A papillary adenoma owes its origin to the circumstance that at Fig. 292,—Alveolar adenoma of the breast. a, Terminal alveoli of gland; h, ducts of gland; c, connective- tissue stroma. (Alcohol; alum carmine.) Magnified 30 diameters. different points in the tubules of an adenoma the epithelium multiplies and forms little elevations, into each of which a papilla of connective ADENOMATA. 359 tissue grows. Excrescences of this nature may multiply to such an ex- Fig. 293.—Adenoma tubulare papilliferum of the kidney. a, Connective-tissue stroma; b, glandular tubules with diverticula ; c, tubules with markedly developed papillary excrescences. (MlUler’s fluid; haema- toxylin.) Magnified 30 diameters. tent as to fill the gland tubules, sometimes even to the point of stretch- ing them (Fig. 293, 6, ¢). The stroma of an adenoma is sometimes slight, sometimes strongly developed, and consequently adenomata may be divided into a hard ra- vis a i} A e = 5 SIRE | PAE FER ice SSNS Fic. 294.—Intracanalicular fibroma of the breast (adenoma papilliferum). (Alcohol; alum carmine.) a, Dense fibrous tissue lying between the canals; h, pericanalicular tissue, rich in cells; c. d, €, nodular in- i hae growths, cut longitudinally; f, intracanalicular growths, cut transversely. Magnified 25 meters. 360 CYSTADENOMATA. riety (mammary gland) and a soft variety (kidney, liver, ovary, testicle). If the connective tissue is particularly well developed, the term fibro= adenoma, or fibrous adenoma, may appropriately be employed. The mammary gland is the favorite seat of such a fibro-adenoma. If—as happens rather often in the mammary gland—the growth of connective tissue in an adenoma does not take place in a diffuse man- ner, but remains confined to the immediate vicinity of the canaliculi (cf. Fig. 227), the tumor is commonly termed a fibroma pericanaliculare ; and when, under the impulse of a more active growth at certain points, the connective tissue advances into the interior of the glandular spaces in the form of rather broad and short papille (e), it is proper to name the tumor in which this phenomenon has occurred a fibroma intraca- naliculare (Fig. 294, c, d, e). It is also permissible, in accordance with its mode of origin, to apply to such a tumor the term fibro-adenoma papilliferum. Adenomata cannot be sharply differentiated from tumor-like hypertrophies of the glands on the one hand, nor from carcinomata on the other. For example, if, after the healing of an ulceration in the intestine, the regenerative processes in the glands are so active that polypoid masses are formed, they may be called either glandular hypertrophies of the mucous membrane or adenomata. according to the conception which one has of the word tumor. Inthe same way different names may be applied to the glandular polyps which occur so often in the uterus. The carcinomatous nature of a growth which resembles an adenoma (cf. § 129) is generally shown by the more marked epithelial proliferation and by its infiltrative mode ot growth. There are, however, adenomata which are covered with a single layer, of cylindrical epithelium and which show this same infiltrative manner of growing (espe- cially in the intestine). Such growths have assumed a malignant character, and they must therefore be counted among the carcinomata. They should be called either destructive adenomata, or adenocarcinomata. On the other hand, there are also adenomata which manifest a markedly atypical growth of their epithelial elements, and which—for at least a long time—do not show any malignant characteristics. Adenomata of this nature are encountered in the mammary gland and in the mucous membrane of the uterus. § 127. A cystadenoma or adenocystoma is an adenoma whose gland- ular canals ave dilated by the presence of accumulated secretion. As such tumors are almost always com- posed mainly of numerous cysts, they are also called multilocular cystomata. According to the character of the walls of the cysts, the tumor may be either a smooth-walled or simple cystoma (cystoma simplex), or a papillary cystoma (cystoma papilliferum). Smaller quantities of secre- tion can often be made out in ordinary adenomata (Fig. 290), and the interstices in both sim- ple and papillary adenomata (Fig. 291, a, Fig. 294) may be so wide that they at once attract attention in a cross section of Fic. 295.—Section of a papillary cystadenoma of the ovary. (Miiller’s fluid; hematoxylin.) Magnified 40 the growth. In cystadenomata diameters. this cyst formation is the strik- ing thing about the picture. The predecessors of the cysts are gland tubules of various shapes (Fig. 295 and Fig. 296, b), which lie in a more or less richly developed CYSTADENOMATA. 361 connective-tissue stroma. Through the accumulation of secretion these tubules are gradually dilated, and in consequence numerous small cysts Ae =, Sar ee Bays Ae ly. US eG IES SEY Ce see won 4 Bes BES REE Nas TN Fic. 296.—Adenocystoma of the gall-ducts, in the first stages of development. (Alcohol ; hematoxylin.) ft, Liver tissue; b, adenoma tissue in the midst of the periportal connective tissue. Magnified 100 diameters. (Fig. 297), or else cysts both large and small (Figs. 298-301), are formed. The relations of these are often such that the tumor may con- Fig. 298. Fig. 297.—Portion of a section of a multilocular adenocystoma of the ovary. Reduced about one- sixth in size. Fic. 298.—Section through an adenocystoma of the testicle of a four-year-old boy. (Life size.) 862 CYSTADENOMATA. sist of a few large cysts (Fig. 301) in whose walls little cysts are located; or there will be found, by the side of large cysts (Fig. 299, c), massés of tissue which contain only very small cysts (e) or even appear solid Fic. 299.—Multilocular adenocystoma of the liver, seen in section. a, Parenchyma of the liver; /), mem- branous margin of the left lobe; c, d, two of the larger cysts: e, group of smaller cysts, separated from one another only by connective tissue ; f, portal vein; g, hepatic artery. (Two-thirds life size.) —that is, they are composed of a tissue containing only undilated glands. All the different types of cystomata may be found in the ovaries (Fig. 297.and Fig. 301), the testicles (Fig. 298), the liver (Fig. 299), the kidneys (Fig. 300), and the mammary glands. Cystomata not infrequently develop in both ovaries at the same time, and may be associated with dermoid formations. Adenocystoma- ta of the testicle often have foci of cartilage or other kinds of tissue in their stroma; and when this is found to be the fact, these tumors must. be counted with the teratomata (§ 186). The epithelial lining is usually composed of simple cylindrical epi- thelium, but the latter may be ciliated or cubical or squamous. The contents of the cysts usually consist of a clear, often distinctly ropy fluid, which contains a substance like mucin (pseudomucin; cf. § 63). This substance is a product of the epithelial lining, and in it beaker-cells (Fig. 303, c) are often found. The fluid also often contains. whitish flakes, products of fatty-degenerated cells, or it may be cloudy or more or less reddish or brownish in color from previous hemorrhages. ‘When the cysts are numerous and they all contain an abundant secre- tion, the tumor may attain enormous proportions. In the ovary, for example, such tumors may reach a weight of from 10 to 20 kgm., cr even more. The papillary adenocystomata constitute a common variety of ade- nocystomata. They are characterized by the fact that sooner or later CYSTADENOMATA. 3863 papillary excrescences develop in the glands which have undergone cys- tic dilatation. In the adenocystomata of the ovary these excrescences are usually slender and delicate, presenting—when seen en masse—a villous appear- ance; or they may occur in the form of cauliflower-like elevations which fill, to a large or a small extent, the cysts. (Both forms are shown in Fig. 302.) Minute papillary elevations, which occupy an extensive sur- face, may give to the inner lining of the cyst a velvety character similar to that of a mucous membrane. If the excrescences develop in the smallest cysts, completely filling their cavities, the whole tissue may again present the appearance of a dense, non-cystic, medullary tumor, but it is almost always possible to obtain a greater or less quantity of mucus from the cut surface. The larger papillx are always more or less branched (Fig. 303), and are made up of a stroma rich in cells (a). They are generally covered with tall cylindrical cells (c), which possess a strong resemblance to beaker cells. The contents of the cysts consist of a ropy mucus (d) which contains a larger or smaller number of cast-off epithelial cells, that have usually undergone mucoid degeneration, or the remains of Ee : ~ Fig. 800.—Cystoma of the kidney, in section. (Eleven-fourteenths life size.) such cells. In rare cases the connective tissue of the papille undergoes mucoid degeneration (Fig. 304, a,b). When this takes place it is apt to swell up to a remarkable degree, and eventually to become converted into a ball of mucus, which is confined within an envelope of epithelium. 364 CYSTADENOMATA. Tn adenocystomata of the liver, the testicle, and the kidney, papillary excrescences are either wanting altogether or else they are very small. Fic. 301.—Adenocystoma of the ovary-—partly of the simple variety, partly of a papillary character. a, ‘Smooth-walled cysts; b, papillary growth which has broken through acyst-wall. (It is soft and covered with the ordinary cylindrical epithelium of mucous membranes.) There were, in this case, metastatic nodules in the peritoneum. (Reduced by about one-tbird.) In the papillary adenocystomata of the mammary gland the excrescences are usually thick and plump (Fig. 305), as is generally also the case with the papillary adenomata (Fig. 294). Accordingly in cross sections one Fic. 302.—Portion of a papillary adenocystoma of the ovary, seen in section. (Drawn from a specimen har- dened in chromic acid.) Four-fifths life-size. CYSTADENOMATA. 365 finds the cystic spaces filled with polypoid growths of the greatest variety LiL a ee om RT 7 ii AWW 5 Wie _.. FIG. 303.—Papillary cystoma of the ovary. (Miiller’s fluid ; hematoxylin ; eosin.) a, Stroma with pa- pille; h, gland-tube with small papill@; ¢, tall cylindrical epithelium which lines the cyst-cavities and covers the papillz ; «2, mucus filled with cells, in the interior of the cysts. Magnified 150 diameters. of shapes (Fig. 305), and often flattened through mutual pressure, so that the surface of such a cross section looks like the cut surface of a cabbage. Fig. 304.—Papillary adenocystoma of the ovary, with myxomatous degeneration of the connective tissue of the villi. (Miiller’s fluid; haematoxylin.) a, Fibrous stroma; b, papilla which have undergone myxo- matous degeneration ; ¢, epithelium. Magnifled 80 diameters. ‘ 366 CYSTADENOMATA. As the connective-tissue portions of these tumors preponderate over the epithelial portions, many authorities include them among the con- nective-tissue tumors; and, according to the characteristics of the con- nective tissue, they have received such specific names as cystofibromata, Fig. 305.—Papillary cystoma or intracanalicular papillary fibroma of the breast, laid,open by a longitudinal incision. (One-half life size.) : cystomyxomata, and cystosarcomata. When the tumor is made up of leaf-like layers, it has been designated as a sarcoma phyllodes. The papillary adenocystomata show a certain malignancy even when the papills are clothed with simple epithelium (cf. Cystocarcinomata). This tendency shows itself, for example, in the circumstance that the papillary growths break through the cyst wall, both when the tumor in- volves the ovary and when it has its seat in the mammary gland—in which location it may also break through the overlying skin. Papillary cystomata of the ovaries (Fig. 301, 0) may thus give rise to metastases in the peritoneal cavity, and these in their turn may display the charac- teristics of papillary epitheliomata. The adenocystomata must also be ranked as a variety of tumor which possesses no sharply defined limits. Thus, for example, papillary cystomata may also arise from the development of papillary excrescences in dilatation cysts-which are formed from pre- existing glands (cf. § 125). Malformations of the organs (e.g., of the kidneys) may lead to the development of multilocular cystomata, the cystic dilatation affecting not only the urinary tubules, but also Miiller’s capsules. It has already been mentioned that terato- mata may occur under the form of adenocystomata. Finally, there is also an inter- mediate form between cystadenoma and cystocarcinoma. CARCINOMATA. 367 (c) Carcinomata and Cystocarcinomata. § 128. Carcinomata are malignant epithelial tumors which possess: two special characteristics, viz., they grow by a sort of infiltrative process and they are apt to form metastases. They develop :— (1) In the skin, in mucous membranes, and in glands, all of which organs appeared to be normal before the carcinoma developed in them. (2) In the skin, in mucous membranes, and in glands, which had undergone pathological changes before the carcinoma developed in them. (3) In already existing papillary epitheliomata, adenomata, and ade- nocystomata. (4) From the remains of epithelial foetal structures and from epithe- ‘lial tissues which have been displaced by disturbances of development and are already predisposed to become the seat of some pathological new growth. (5) From the epithelial tissues of the villi of the chorion and placenta. The most characteristic feature in the development of a carcinoma is. the atypical manner in which the epithelium sooner or later forces its. way into the tissues which border upon the affected glands or the surface epithelium. Usually this growth of epithelium is accompanied by a growth of connective tissue, but this is not absolutely essential to. the development of a carcinoma. The tissue invaded by the epithelial growth—it matters not whether it be a gland, a muscle, a bone, or any: other tissue—will ultimately be destroyed by the carcinoma. The cause of the atypical growth of epithelium is not really known. It is merely possible to state that certain conditions predispose to such. growth. Thus, for example, an advanced age predisposes to the devel- opment of carcinomata of the skin. In this period of life the connective tissue of the skin undergoes a certain amount of atrophy and loss of firmness of texture, while the epithelium, at least in part, continues to increase, and here and there, under certain circumstances, shows evi- dences of an increased activity (development of heavier hairs upon the. nasal septum, upon the lobes of the ears, and in the eyebrows). Then again, carcinomata of the mucous membranes and of the glands usually appear in mature years, although they may develop in early aduli life, and even in childhood. Another predisposing factor in the formation of cancer is furnished by the displacement and separation of epithelium, as easily happens in the healing of ulcers (cf. Fig. 152), and also in infectious or non-infectious. granulation growths; in both of which the epithelium penetrates into the interior not only from the margin of the granulations, but also from any point upon their surface. Consequently, carcinomata often devel- op in ulcers, in scars, in infectious granulations (e.g., in tuberculous lupus of the skin and mucous membranes), or in tissues which have been changed by inflammation of any kind. All the predisposing factors which have been enumerated do not con- stitute the sole cause of the development of a carcinoma. They may exist for a long time without ever leading to the formation of a cancer. It appears, therefore, that something else must be added before the un- limited atypical growth of epithelium begins, and what this something is, is not known. In recent years, the opinion has often been expressed and stoutly 368 CARCINOMATA. maintained that parasites cause the growth of a carcinoma. Untortu- nately, most of those things which have been described as parasites (viz., protozoa, and especially the sporozoa and the yeast fungi) have not been parasites at. all, but degenerated nuclei and karyokinetic fig- ures, or leucocytes (or the products of their destruction) which have been included in tumor cells, or products of the cell-protoplasm, espe- cially keratohyalin and colloid. In the few cases in which genuine parasites have been found in the tissues, they may perfectly well have entered after the tumor had begun to develop. Under such circumstances they can in no sense be looked upon as the cause of the development of the carcinoma. There are certain portions of the alimentary canal which are more frequently involved in the development of carcinoma. Such are the rectum, the flexures of the colon, the pyloric and cardiac openings of the stomach, the cesophagus, the pharynx, the tongue, and the gums. A carcinoma may develop in any portion of the skin, but it is seen more frequently on the lips and the nose than it is on the remaining portions of the face, or on the extremities, and more frequently on these again than it is on the body. The parts of the sexual apparatus most often affected are the mammary gland and the cervical portion of the uterus. Less frequently, though still often enough, the ovaries, testicles, body of the uterus, vulva, vagina, and penis are affected. The liver, kidneys, urinary bladder, trachea, bronchi, lungs, and pancreas occupy a middle ground; while the larynx and the gall-bladder, on the other hand, are more frequently attacked. Cancer usually develops in the form of nodules, which are not sharply differentiated from their surroundings, and which often rise above the sur- face of the mucous membrane as sponge-like, or polypoid, or papillary masses. They spread from the point at which they begin to develop by . an infiltrative sort of growth of the epithelium, by which either the nodules are increased in size, or else an extensive thickening of the affected organ (the intestinal wall, for example) results. The ovaries, testicles, uterus, kidneys, etc., may be partly or wholly transformed into a carcinomatous mass. The epithelial infiltration, as it advances, may pass beyond the limits of the organ originally affected, and may involve the neighboring tissues and organs. Thus, for example, the infiltration may extend from the mammary gland to the contiguous fat and skin and muscle, from the gums to the maxillary bone, from the uterus to the vagina and the parametrium, as well as to the bladder and the rectum, from the gall-bladder to the liver, from the bronchi to the lungs, etc. The formation of metastases may take place as well through the lymph- as through the blood-channels, and is of frequent occurrence by both routes. It leads, for the most part, to the formation of secondary nodules in the various organs, but it may assume such a character that quite large portions of the system of lymph-vessels—as, for example, the pulmonary lymph-vessels—may be simply dilated by the new growth, without the formation of separate nodules. The transportation of cancerous germs to the marrow of bones may result in the cancerous degeneration of the marrow of an entire bone or of several related boues. It is also to be noted that probably not every transplantation of cancer cells leads to the formation of a cancerous growth. There are grounds for the belief that in the majority of instances the cells which are thus transplanted perish. CARCINOMATA. 369 The tissue of a carcinomatous tumor is sometimes soft like marrow, sometimes rather tough and solid; but it is almost always possible to scrape from its cut surface a certain amount of whitish, opaque fluid called cancer juice or cancer milk. It is often possible to make out, on the cut surface, a tough fibrous framework, in the meshes of which the softer masses lie, and from which they can often be squeezed by press- ure, either in the form of fluid, or as plugs, or as a crumbling material. The masses obtained by pressure and by scraping the cut surface are made up, for the most part, of the atypically developed epithelial cells, the so-called cancer calls, which are found in a great variety of forms and which often show degenerative changes, especially fatty degeneration. There is usually no true secretion emanating from the epithelial cells, and yet one sometimes encounters in the mucous membranes, in the ova- ries, and in the mammary glands, carcinomata which produce mucin or pseudo-mucin; and-the amount of the secretion thus produced may be great enough to form cysts, thus justifying the employment of the term cystocarcinoma. Retrograde changes occur very often in cancers at an early stage, and are due partly to the lack of vitality of the new growth and partly to disturbances of the circulation, which may be caused either by the growth of cancer cells into the capillaries and veins or by external influ- ences. These changes lead, in the first place, to a breaking down of the cancer cells in certain parts of the tumor, and then, after the broken- down material has been gotten rid of through absorption, a certain amount of shrinking of the tissues will take place at the corresponding spots. Depressions will thus be formed between the nodules. Such retracted areas are seen quite frequently in the primary nodules of the mammary gland and in the secondary nodules of the liver, lungs, and other internal organs. They have received the name of cancer-umbdlications. The retrograde changes often lead to a complete destruction of the cancerous tissue and the formation of an ulcer. This is observed more particularly in cases in which a mucous membrane is the part affected; a carcinoma in this locality usually revealing itself, at the time of the patient’s death, in the form of an ulcer of greater or less extent. Simi- lar ulcerative changes also occur in cancers of the mammary gland and of the external skin. Inthe latter situation, the cancer may present the appearance of a progressing, corrosive ulcer, an ulcus rodens. The border of such an ulcer is sometimes raised up like a wall or studded with nodules, while at other times it is sharply defined and only slightly infiltrated. The base is sometimes fissured and ragged, and covered with necrotic tissue, while at other times it is smooth. The deeper tissues which border upon the ulcer are often abnormally hard, this change being due either to a cancerous infiltration or to a growth of connective tissue which has taken place as a sequel to the retrograde changes and the ulceration. In recent years a large number of articles have been published by authors who have attempted to prove (successfully, as some of them have thought) that the formation of a cancer is due to parasites. Nevertheless, none of these treatises can be looked upon as furnishing satisfactory proof of the correctness of this hypothesis. Then, besides, it is extremely improbable that cancers owe their origin to infection. There are three facts which militate against the idea of a parasitic origin for these tumors: first, no parasites can be demonstrated in the beginning of the cancer’s development; second, the whole course of the disease is quite different from that of an epithelial growth produced by parasites ; and third, the formation of metastatic tumors is due, beyond all question, to the transportation of cancer cells. 370 CARCINOMATA. § 129. Cancer of the skin usually develops from the epidermis, and is characterized by the growth of the interpapillary portions of the same into the deeper parts of the chorion in the form of epithelial cones (Fig. 306, d) which fill up the interstices of the connective tissue. The Fic. 306.—Transverse section through a carcinoma of the lip. (Alcohol; hematoxylin; eosin.) a, Corium, in a proliferating condition ; b, epithelium ; c, thickened horny layer; d, epithelial plugs Se down into the corium; e, epithelial plug cut obliquely and showing a pearl of horny substance: f, enlarge papillee of the skin. Magnified 12 diameters. stratum corneum (c) may also undergo hypertrophy along with the cells of the rete Malpighii, and penetrate deeply into the subjacent tissues as a part of the epithelial cones (d). Furthermore, the cones of epithe- lium may produce horny epithelial plates (e) after they have reached these deeper regions. The epithelium of the hair follicles and the sebaceous glands may also take part in the formation of the cancer, and indeed there are cancers of the skin which develop entirely from the sebaceous glands, and which must therefore be reckoned among the glandular cancers. The connective tissue may remain entirely passive while the epithke- lium grows into it, but sooner or later it is excited to growth (Fig. 306, a) and the papille are often changed to long, branching structures (/). Besides the fibroblasts, leucocytes are often found in the connective tissue, and these latter may make their way into the epithelium. They are especially abundant after disintegration of the tissues begins, and at that time the proliferating connective tissue presents all the appearances of inflammatory granulation tissue. The mode of origin of a carcinoma that springs from a mucous membrane which is provided with flattened epithelium may be the same as that of a carcinoma of the skin—that is, it begins as a prolifera- tion of the epidermis (Fig. 307, a, c). If glands are present these may take part in the cancerous development. It is a noteworthy fact that, in the growth of such a cancer, even those glands which possess cylin- drical epithelium can furnish epithelial products which are exactly like those of the epidermis. The epithelial proliferation may at first ad- vance within the canaliculi and lead to a diffuse thickening and stratifi- cation of the epithelium (Fig. 307, /), or to the formation of distinct excrescences (e). Later on, however, the growing epithelium breaks into the connective tissue. The connective tissue acts as it does in cancer of the skin. CARCINOMATA. 871 The mode of origin of a mucous-membrane carcinoma which is made up of simple cylindrica! epithelium is the following: In cases in which the intestine is the seat of the disease the growth begins in the tubular glands or in the crypts, in both of which localities the epithe- lium first undergoes an active proliferation and then arranges itself in layers, while the glands, under the increasing pressure, undergo dilata- tion (Fig. 308, 6). At a later stage the glands become changed into branching, atypically formed structures (c), which are lined with a stratified epithelium and grow into the surrounding tissues. In comparatively rare cases newly formed atypical glands, in the in- testinal or the gastric mucous membrane, may take on an infiltrative mode of growth (Fig. 309, e) at a time when they still carry a single layer of tall cylindrical epithelial cells, and portions of the growth bear- ing this characteristic may be found not merely in the submucous tis- Fie. 307.—Commencing development o1 a carcinoma in the vaginal portion of the uterus. (Alcohol; Bismarck brown.) a, Epithelium ; b, connective tissue ; c, surface epithelium growing down into the deeper- lying tissues ; ‘d, dilated gland ; e, epithelium of agland growing out in the form of plugs; f, transverse sec- tion of a Eland, the cylindrical epithelium of which has become converted into laminated epithelial scales. Magnified 45 diameters. sues (Fig. 309, b), but also in the muscular layer (c) and even in the serosa (cd). The epithelial cells of the newly formed glands are usually more deeply Bo than normal epithelium by the dyes which stain nuclei. 3872 CARCINOMATA. As in the case of carcinoma of the skin, the connective tissue sooner tet z 9g ttt sx SS Sa ne fb i ee Bs SS Fic. 308.—Commencing development of an adenocarcinoma of the large intestine. (Miuller’s fluid ; hematoxylin; eosin.) a, Mucosa, with glandular tubules still unaffected ; b, a part of the mucosa where the glandular tubules have been involved in the carcinomatous disease; c, foci of carcinomatous disease in the submucosa, Magnified 100 diameters. PRA j "a0 eS ss or later takes on proliferative action, and with this proliferation there may be associated an emigration of leucocytes. The development of a cancer in a gland, o.g., in the mammary Fig. 309.—Section through the growing margin of a carcinoma adenomatosum of the stomach. (Alcohol ; hematoxylin.) a, Mucosa ; b, submucosa ; ¢, muscularis; d, serosa: e, new growth proceeding from the mucosa and infiltrating the other layers. A round-celled inflltration appears in parts in conjunction with the development of tubules. Magnified 15 diameters. DEVELOPMENT OF A CARCINOMA. 373 gland, also begins with a proliferation of the epithelium, and in conse- quence of this proliferation the affected gland increases in breadth (Fig. 310, a) and often changes its form ()), and at the same time its lining epithelium .nay become stratified (b). When the epithelium breaks through into the interstices of the neighboring connective tissue, an epi- thelial infiltration of that tissue begins. The microscopical pictures presented by the growth will vary according to the structure of the gland from which the cancer originally developed, and also according to the variety of the cancer itself. Through simple proliferation the connective tissue may contribute to the building up of the tumor, and yet in the early stages this participa- tion may amount to little or nothing. The development of a cancer from an adenoma or fibro-adenoma Fic. 310.—Cystocarcinoma of the mammary gland in an early stage of its development. (Tumor about as large asa bean.) a, Normal gland tissue; 6, proliferating gland tissue. (Alcohol; hematoxylin.) Mag- nifled 100 diameters. (Fig. 311, a) also begins as a somewhat active proliferation of the epithe- hum, as a result of which the single layer of epithelial cells becomes stratified (6, c). The growth of the epithelium into the connective tis- sue, which often first takes place only at a much later stage, furnishes additional evidence of the malignancy, i.e., of the carcinomatous trans- formation, of the new growth. The development of a cancer froma papillary epithelioma proceeds in the same manner as it does when the growth starts from previously normal skin or mucous membrane; thatis to say, itis characterized by the infiltration of epithelium into the base upon which the epithelioma rests. The development of cancer from transplanted or misplaced epithe- lium, or from remains of foetal structures, proceeds in the same manner as it does when the growth springs from the epidermis or from glandu- lar epithelium. 874 DEVELOPMENT OF A CARCINOMA. A carcinomatous transformation of chorionic or placental villi pro- ceeds either from the foetal ectodermal epithelium of the chorion and its villi, or from the cells which are known as the syicytiwm (which cells are situated upon the ectodermal epithelium, but are derived from the decidual uterine epithelium), or from both of these layers of cells. These carcinomatous growths spring from the points where the villi are attached to the main body of the uterus, and they penetrate from there into the adjacent tissues, especially into the blood-vessels (Fig. 312, d, d,, e¢, f, h). Ultimately they lead to the formation of thrombi, to exten- sive destruction of uterine tissue, and to the establishment of metastatic carcinomatous foci. Myxomatous degeneration of the villi both of the chorion and of the placenta (hydatid mole) appears to favor the devel- opment of such cancerous growths. The expressions placental carci- nomata and chorionic carcinomata seem to me on the whole to be com- mendable. ‘ A number of authorities apply to these growths the terms malignant placentomata, malignant deciduomata, and destructive placental polyps. Ribbert believes, as has already been stated in § 107, that he has found the cause of the formation of cancer in a separation of single epithelial cells from their normal rela- tions and a transplantation of them to points located between the cells of the connective tissue ; and he looks upon the proliferation of the connective tissue as the first step in the development of a cancer. From the pictures furnished on preceding pages it is evi- Fic. 3H.—Tubular adenoma of the mammary gland, with beginning transformation into a carcinoma. (Formalin; haematoxylin.) a, Branching gland tubes lined with simple epithelium; the connective tissue which surrounds the tubes being rich in cells and in a proliferating condition; , ¢, gland tubes, the epithe- lium of which is in some places still simple, while in others it has already reached a thickness of several layers. Magnified 100 diameters. dent that this view of the development of cancer is not supported by the facts, but that, on the contrary, the proliferation of the epithelium can begin in normally placed surface or glandular epithelium, and that the starting-point for the development of a cancer lies in such proliferation and not in that of the connective tissue. The transplantation of epithelium apparently favors the development of cancer, but does not of itself necessarily produce this result. The traumatic displacement of surface STRUCTURE OF A CARCINOMA. 375 epithelium in wounds may lead to the formation of the so-called traumatic epitheliai cysts, that is, cysts which vary in size from that of a hemp seed to that of a nut, which are lined with epithelium, and which are filled, in case they come from the external skin, with a grumous mass of cast-off epithelial cells. They are usually found, after punctured wounds, on the palmar surface of the fingers or in the hollow of the hand. Adenomata and carcinomata cannot always be sharply distinguished the one from the other, for the reason that tubular adenomata—especially those of the intestine, a, # Fic. 312.— Placental carcinoma of the uterus (destructive placental polypus). (Compare von Kahlden: ** Destruirende Placentarpolypen.””’ Centralbl. f. allg. Path., II., 1891.) a, Muscularis of the uterus; 6, large blood-space ; ¢, thrombus; d, d,, intravascular growths of the epithelium which covers the villi of the chorion. These growths project into a large blood-space which has been broken into from the cavity of the uterus, and which contains several thrombi; and at some spots (as at d) they lie free in the blood-space, while at others ~ (as at d,), they are attached to the wall of the vessel; ¢, proliferating mass of cells which have forced their way into a rather small blood-vessel: f, an aggregation of proliferating chorionic epithelial cells within the meine - the muscularis of the uterus; g, thrombus: h, proliferating cells in the wall of a vein. Magnified 70 iameters. more rarely those of the thyroid gland or the liver—although possessing a simple cylin- drical epithelium, may grow by infiltration, break into the surrounding tissues (Fig. 309), and develop metastases. Ifa special name is to be applied to such forms, in order to distinguish them from the ordinary carcinoma adenomatosum, or adenocarcinoma, the terms adenoma destruens, or malignum, or carcinomatosum, may be employed. It is further to be noticed that benign adenomata, which have existed as such for a long time, may change into carcinomata. To a certain extent the character of the parent tissue is preserved in the cells of the cancer, but a closer inspection shows a certain amount of change both in their morpho- logical and in their physiological characters. Hansemann has called this alteration in the character of the cells anaplasia. It manifests itself in an alteration both in the form and in the structure of the cells which usually also manifest a different affinity for dye-stuffs. Then, in addition, a difference may be noted in the arrangement and rela- tions of the cells, and in their relations to the surrounding tissues. § 130. The structure of a carcinoma is determined by its origin. The manner in which the epithelium proliferates, in the midst of connective tissue which may also take on proliferative action, makes it possible to distinguish a connective-tissue stroma, along which course the blood- vessels, from the nests and strings of cells—the cancer plugs, as they are called—which are embedded in that stroma. If the cancer pene- trates into a tissue which has a specialized structure, the stroma may contain muscle fibres, bone trabecule, unchanged glandular tissue, etc., but these tissues are apt, in the course of time, to perish and disappear. In general, it may be said that a cancer possesses an alveolar structure in which the nests of cells sometimes suggest an imperfectly developed 376 DIFFERENT FORMS OF CARCINOMA. acinous gland, at other times a tubular gland, thus justifying the estab- lishment of acinous and tubular types of carcinoma. _ If the plugs of cells are solid, without a lumen, the tumor is spoken of as carcinoma soli- dum, or merely as carcinoma. a, If there is a lumen in the cellular plugs, this circumstance will give to the growth a certain resemblance, in its anatomical structure, to the adenomata, and will therefore justify the employment of the term car- cinoma adenomatosum or adenocarcinoma (Fig. 308, Fig. 309, and Fig. 310). : Several forms of carcinoma may be distinguished, in part according to the character of the epithelial cells, in part according to that of the groups which they compose, and finally in part according to certain changes which take place at a later stage of the growth. As the charac- ter of the cells is dependent upon the nature of the matrix in which they develop, so are certain types of carcinoma characteristic for certain re- Fig. 313.—Horny carcinoma of the tongue. (Miiller’s Auid , haematoxylin; eosin.) a, Plugs of epithelium, with epithelial pearls; b, stroma. Magnified 100 diameters. gions of the body; as a matter of fact, they appear almost exclusively in these parts of the body. (1) Flat-celied cancer develops in those places where the skin or a mucous membrane is covered with flattened epithelium. It may de- velop, therefore, in the external skin, in the mouth, in the throat and the cesophagus, in the larynx, in the vaginal portion of the uterus, in the vagina, in the lower urinary passages, and especially in the bladder and external genitals. In rare cases flat-celled cancer may develop in a mucous membrane which is covered with cylindrical epithelial cells, e.g., in the trachea, or in remains of foetal structures (i.e., in the remains of maxillary clefts or dermoids), or finally, in the ependyma of the ven- tricles of the brain. The flat-celled epithelial cancer is characterized by the formation of relatively large strings of cells (Fig. 318, a, and Fig. 314) of irregular shape; but besides these there are often small strings of cells, especially in those cases in which the cancerous growth has begun to involve larger areas of the mucous membrane. The epithelial CYLINDRICAL EPITHELIAL CANCER. 377 cells which are massed together in separate collections still show plainly the character of laminated flattened epithelium, but in consequence of their growth and multiplication within the interstices of the tissue they generally assume a variety of shapes (Fig. 314) and no longer manifest their typical characteristics. Very often the formation of keratohyalin and the change into a horny condi- tion take place deep down in the cen- tre of the larger epithelial plugs; and along with the process of cornifi- cation the cells arrange themselves in concentric lamine like those of an onion (Fig. 313, a, Fig. 314, and Fig. 306, e). These rounded masses of laminated horny epithelium are = called epithelial pearls or horny me. 314.—xpitnelial plug froma cancer of the bodies ; and hence the name horny can- sin... Magn led cot) qiameters: cer has been applied to such a tumor. (2) Cylindrical epithelial cancer develops especially in mucous membranes which are provided with cylindrical epithelium, i.e., in the intestine, in the stomach, in the respiratory passages, in the body of the uterus, and in the gall-bladder; but it is also found in glands, such as the ovary, mamma, liver, etc., and in the ventricles of the brain. Such a tumor exhibits, at least in the beginning of its growth, the character of a carcinoma adenomatosum or of an adenocarcinoma (Fig. 308, Fig. 309, Fig. 315, Fig. 316); that is, it forms epithelial structures which suggest glands and are made up of gland tubules of various shapes which are lined with a simple or stratified epithelium. When Fic. 315.—Tubular adenocarcinoma of the rectum. «, b, Epithelial gland-tubules; c, c,, stroma; d, col- lection of leucocytes in the gland-tubules. (Alcohol; alum carmine.) Magnifled 80 diameters. the proliferative activity of the epithelial cells is unusually great, com- pact cell-nests without a lumen will be produced (Fig. 316). The stroma of a cylindrical-celled cancer is usually poorly developed, so that the tumor possesses the character of a soft cancer—a carcinoma medullare. In some instances, however, the cancerous tissue possesses a firmer consistence. 378 CARCINOMA SIMPLEX. (3) Carcinoma simplex, or carcinoma in the narrower sense, is a cancer whose especial characteristics are derived from the form and disposition Fig. 316.—Adenocarcinoma of the fundus of the uterus. a, Stroma; b, plugs of carcinoma cells; c, isolated carcinoma cells. Magnified 150 diameters. of the cells, which are arranged in irregularly shaped, compact groups (carcinoma solidum). It is most often found in glands, but may also develop in the mucous membranes or in the skin. The nests of cells are Fic. 317.—Carcinoma simplex of themammary gland. (Alcohol: hematoxylin.) a, Stroma; b, plugs of carcinoma cells; c, scattered carcinoma cells; d, blood-vessel ; ¢, infiltration of the stroma with small cells. Magnified 200 diameters. CARCINOMA TUBULARE. 379 in some cases shaped quite irregularly (Fig. 317), in others they are to a great extent round (Fig. 318), and finally in still others they are long drawn out or fusiform in shape (Fig. 319). These variations have led | BN alee ‘2: eAese.. AN ‘ rates!’ Fig. 318:—Acinous carcinoma of the mammary gland, with large nests of cells. (Miiller’s fluid; haematoxy- lin.) Magnified 100 diameters. to the subdivision of these growths into carcinoma acinosum (Fig. 318) and carcinoma tubulare (Fig. 319). It is, however, to be observed that. these different types may exist in the same tumor (Fig. 320, e, 7, 9), since the structure of the nests of cells is dependent partly upon the character of their own growth, partly upon that of the tissues in the midst of which they develop. Thus, for example, the cell-nests at the point of origin of the tumor may have a variety of shapes (e): some- Fig. 319.—Tubular scirrhous carcinoma of the mammary gland. (MUtiller’s fluid; hematoxylin.) a, Spot ‘at which there are well-developed, oblong nests of cells ; 5, spot at which the nests of cells have broken down cand have for the most, part disappeared. Magnified 100 diameters. what rounded in the adipose tissue (f), and small and fusiform when they develop in the unyielding connective tissue of the skin (q). An abundant development of cell-nests within a delicate connective- tissue network results in a carcinoma meduliare. A strong develop- 380 CARCINOMA DURUM. ment of the connective-tissue stroma with the formation of comparatively few cancer cells gives rise toa hard tumor which is called carcinoma durum, or scirrhus (Fig. 319). A hard cancer may owe its origin to the fact that from the beginning the nests of cells are small and relatively scarce, while the connective-tis- Fig. 320.—Section through a segment of a carcinoma of the breast. (Alcohol; hematoxylin.) a, Nipples b, tissue of the mammary gland ; ¢, skin; d, outlet-ducts of the gland; e, carcinomatous masses occupying the position of glandular tissue ; f, lobules of fat already infiltrated with cancer ; y, portion of skin also infil- trated with cancer ; h, carcinomatous cell-nests in the nipple; i, normal lobules of the gland ; k, infiltration. of small cells in the connective tissue. Drawn with the aid of a lens. sue stroma is abundant and firm. Such a condition of affairs is found when the epithelial proliferation takes place in firm connective tissue such as that of the breast or of the skin; and yet, on the other hand, newly formed connective tissue may possess the same characteristics. In the course of time, a cancer may grow harder by reason of the destruction of a part or of all of the nests of epithelial cells (Fig. 319, b), while the connective tissue increases. Accordingly, a cancer which was originally soft may become hard; that is, as the induration of the connective tissue advances, the cancerous portions undergo a corresponding shrinkage. Cancers of the breast or stomach or intes- tine often undergo such secondary induration, so that the nests of can- cer cells may be wholly wanting in the tissues which have undergone. this fibrous change. (4) Cancers which are characterized by peculiar secondary changes. are usually those in which the cancer cells form peculiar products or undergo peculiar metamorphoses. It happens less frequently that the stroma is the part which undergoes some alteration. Mucoid cancer or gelatinoid cancer—carcinoma muccsum ((Q. gela- tinosum, C. colloides) —owes its peculiar characteristics to the fact that. the epithelial cells produce mucus (mucin or pseudo-mucin) or a gelati- nous substance similar to colloid. This production of mucus occurs. CARCINOMA MUCOSUM. 381 in cancers of the intestine and breast and may be manifest in the very Fic. 321.—Mucous carcinoma of the mammary gland. (Miiller’s fluid; hematoxylin; eosin.) «, Nor- mal gland tissue; 6, c, first beginnings of the carcinomatous growth, in which the development of mucus may already be seen; d, rather large nests of cells, among whicb are masses of mucus; e, f, carcinomatous tissue in which the transformation into mucus is far advanced. Magnified 30 diameters. beginning of the development of the growth (Fig. 321, b, c), so that the mucoid products of the cells collect in the centre of the cell-nests like the secretion of a gland. As time goes on, the rows of cells which sur- FIG. 322.—Mucous carcinoma of the mammary gland. (Alcohol: hematoxylin.) a, Stroma; ), plugs of carcinoma cells; ¢, alveoli which do not contain any carcinoma cells; d, cells witb balls of mucus in their interior. Magnifled 200 diameters. round the mucoid material are usually broken through and the cells are loosened from their underlying support and crowded together in the 382 CARCINOMA GIGANTICO-CELLULARE. middle of the alveolus (Fig. 321, d, e, /). Ultimately, the epithelial cells are entirely destroyed. In intestinal cancers the formation of mucus takes place in the beaker cells, which are similar to the normal beaker cells. In cancer of the breast the mucus forms in drops in the cancer cells (Fig. 322) and becomes free either by escaping from the cell or through the complete destruction of the cell itself. ; If mucoid or colloid masses develop within the nests of cells, these nests may be studded by hyalin drops and so changed as to present the appearance of meshwork (Fig. 323). Such structures were formerly called cylindromata and classified with the corresponding sarcomata “i ($123). Ifany one wishes to re- FIG. 823.—Carcinoma, with hyaline drops in thein- tain this nomenclature he can terior of its nests of cells—carcinoma cylindromato- speak of such a tumor as a car- sum. ca, Cell-nests without; 0, cell-nests with a few b 2 ; byaline balls in their interior; c, cells which, through ¢inoma cylindromatosum, but it the formation of numerous hyaline balls, have been made to arrange themselves in the form ofa network, Seems unhecessary to separate Re ned uetameters these tumors from the mucoid and gelatinoid cancers. When the cancer cells grow to an extraordinarily large size, as occurs, for example, in flat-celled cancers or in cancers of the breast, the result- ing tumor is termed a carcinoma gigantico-cellulare. If the increased size of the cells is due, not to an increase in the amount of protoplasm, but to the collection of drops of fluid in the cells and in their nuclei (Fig. 324), the cells are designated physalides, and the tumor carcinoma physaliferum. If the stroma of a cancer undergoes a transformation into a mucoid tissue the name carcinoma myxomatodes may be applied to the tumor. This change, however, affects only certain parts of the tumor. In rare Fig. 324.—Enlarged dropsical cancer-cells from a carcinoma of the breast. a, Ordinary cancer-cells; 0, dropsical cells containing in their interior clear drops of fluid; ¢, swollen nucleus; d, swollen nucleolus ; ¢, wandering cells. (Miiller’s fluid; Bismarck brown.) Magnified 300 diameters. cases the connective tissue, in parts of the tumor, also undergoes a hyaline degeneration. CYSTOCARCINOMATA. 383 Chaiky deposits in carcinomata may take the form of concretions similar to those which occur in psammomata (vide §123). The deposits may be either in the cells or in the connective tissue. They are observed in papillary adenomata and carcinomata of the ovary and in cancer of the breast. There are also more extensive calcifications which lead to complete petrification. Such tumors are observed in the skin and sub- cutaneous tissue, in the form of sharply defined, hard, rounded nodules. Some of these tumors—so far as one can judge from the descriptions— are to be reckoned among the carcinomata, while others of them are either calcified atheromata or adenomata of the sebaceous glands. The cancers which develop from the surface epithelium were formerly called can= croids and epitheliomata, in contrast with other cancers which were supposed to grow from the connective tissue. The knowledge that the cancers which develop in glands are also epithelial formations makes such a distinction unnecessary. - Nevertheless, the Fig. 325.—Myxomatous carcinoma of the stomach. (Miiller’s fluid; haematoxylin.) a, Plugs of cancer- cells; b, connective-tissue stroma ; c, stroma of mucous tissue ; d, cancer-cells which have undergone mucous degeneration. Magnified 200 diameters. name cancroid is still much used. The term epithelioma ought to be reserved for be- nign epithelial tumors (§ 125). Formerly a carcinoma was defined as a tumor which possesses an alveolar structure and gives lodgment to nests of cells in aconnective-tissue stroma; and recently attempts have been made to restrict the use of the term carcinoma to growths which answer to this definition. The adoption of this definition, however, would be a step backward: it would bring together forms of tumors which, according to their origin, ought to be separated. Furthermore, in accordance with this idea one would have to distinguish an epithelial cancer. from a connective-tissue cancer (endotheliomata, alveolar sarcomata), inasmuch as the epithelial nature of the cell-nests would no longer be a requisite for the placing of a tumor among the carcinomata. Recently Lange las attempted to prove that the substance which gives to a mucoid cancer of the breast a gelatinoid appearance is a product of the connective tissue. I am entirely unable to indorse this opinion, but am convinced of the correctness of the view which is expressed in the main body of the text. § 131. The cystocarcinomata represent a form of new growth which stands in the same relation to simple cancer as the cystadenomata do to the adenomata. The majority of cancers furnish no demonstrable secre- tion, and yet in the group of the adenocarcinomata, for example, there are certain forms in which the epithelial cells produce mucus and also colloid (thyroid gland), and in adenocarcinomata of the liver a secretion 384 CYSTOCARCINOMATA. of bile has been observed (Schmidt). In cystocarcinomata the mucoid secretion of the epithelium may lead to the formation of quite large t Fic. 326.—Papillary cystocarcinoma of the breast. a, Stroma; }, smooth-walled cysts ; c, cysts studded on the inside with papillary growths; d, cysts completely filled with papillary growths; e, small encysted papillary growths ; f, adenomatous growths; g, nipple of the breast. (Reduced in size by about one-third.) e spaces filled with fluid. These growths are observed particularly in the ovary and in the mammary gland, and the form which they assume is that of a carcinoma papilliferum (Fig. 326); for the cyst-spaces are either partially (6, c) or completely (d, e) filled with papillary growths. These excrescences present a soft, marrow-like appearance, and when - FIG. 327.—Papillary cystocarcinoma of the ovary. (Mliller’s fluid; haematoxylin.) a, Stroma; b, epithelium; c, d, papilla. Magnified 80 diameters. their number is very large they lend a marrow-like consistence to the entire tumor. The cyst walls as well as the papillary growths, which branch in the same manner as do those of the papillary cystadenomata, are covered FORMATION OF METASTASES IN CARCINOMA. 385 with a thick, laminated stratum of epithelium (Fig. 327, 0, c, d, and Fig. 328, c). The papillx are generally slender structures (Fig. 327, c, d), but, through somewhat active proliferation of the connective tissue, or even through a mucoid degeneration of this tissue (Fig. 328, b}, these may attain larger dimensions. [If all of the connective tissue undergoes mucoid degeneration, the tumor will then consist of mucoid cysts in- closed in epithelium; and if at the same time the epithelium of adjoin- ing papille breaks down and disappears, there will ultimately be noth- ing left beyond an epithelial stroma inclosing globules of mucus. The metastases of cystocarcinomata may show cauliflower-like, pap- illary growths, and this is particularly the case when ovarian tumors. Ser Stecertr re a Se Fic. 328.—Papillary cystocarecmoma of the mammary gland, with papillae which have undergone a myxo- matous degeneration. (Miiller’s fluid; haematoxylin; eosin.) a, Firm connective tissue; b, papillae which have become myxomatous; c, epithelium which has proliferated to such an extent as to form several layers. Magnified 80 diameters. of this nature begin to spread throughout the peritoneal cavity. Other metastases show the characteristics of ordinary carcinomata. § 132. The formation of metastases, which occurs more frequently in. cancer than in any other form of tumor, is the natural result of its infil- trative mode of growth. The cancer cells at first break into the lymph- vessels (Fig. 221) and then along these they pass on into the lymph- glands. In both situations there occurs at once a multiplication of the invading cancer cells (Fig. 221, and Fig. 329, d). In the lymph-glands, at a later stage, the cancer tissue takes the place of the lymphoid tissue. When this occurs the lymphocytes disappear, and the connective tissue of the lymph-gland serves as the framework for the cancer. The development of cancer in the lymph-channels is limited either to the filling and distention of the same by the cancer cells (Fig. 221), or the latter may grow more vigorously at certain points and so lead to the formation of daughter nodules. The piling up of epithelial cells in the lymph-vessels often extends over a large territory, and then—either through the pushing of some of 386 FORMATION OF METASTASES IN CARCINOMA. the lymph-channels out of their proper places, or perhaps even by aid of the thoracic duct—it often happens that cancer cells are transported eaeteasec et aurea Sea Fre. 329.—Section of an enlarged lymph-gland taken from the axilla. It shows the beginnings of a can- cerous growth. (Alcohol; hematoxylin.) a, Aggregation of young cancer cells in a lymph-node; b, lymph- channels; c, artery; d, nests of fully developed cancer cells. Magnified 60 diameters. along what appears to be a retrograde course. Thus, for example, in the case of a carcinoma of the stomach both the lymphatic vessels of the lungs and those of the upper extremities may become infected. The epithelial cells, in their proliferative activity, are just as likely ile 5Ge Ee Nae 5 as JO) Fig. 330. © ae . ef Cl SS) Fig. 331. _ Fie. 330.—Metastatic collection of young cancer cells in the interior of a capillary blood-vessel of the ier apenas taken from an adenocarcinoma of the stomach. (Alcohol; hematoxylin.) Magnified 300 iameters. _ Fig. 331.—Metastatic ae of carcinoma within the capillaries of the liver; the primary growth being located in the pancreas. (Alcohol; carmine.) It will be observed that both cancer cells (in the form of nests) and connective tissue have developed in the interior of the capillaries. Magnified 250 diameters, TERATOID TUMORS AND CYSTS. 387 to break into the blood-vessels as into the lymphatics, and from the in- vestigations of Goldmann it appears that cancers force their way into veins with surprising regularity. When this latter event occurs the lu- men of the vein will be entirely occupied by cancer cells, while at a later stage the affected portions of the vessel become converted into cancer tissue, the framework for which is furnished by the proliferative activity of the vessel-wall. The transportation of cancer cells which have been set free in the blood-stream leads to the formation of metastases (Fig. 222, b, Fig. 330, and Fig. 331). Here also the cancer growth proceeds primarily from the invading epithelial cells, and a stroma for the new foci of disease is furnished by the vessel-walls and adjacent structures. The daughter nodules increase in size, partly by direct proliferative growth, partly by the fusing together of neighboring blood-vessels and lymph-spaces which have been invaded by the disease. In general the cancer metastases show a tendency to assume the nodular form. In the serous membranes and in the skin diffuse prolife- rations of tissue may occur, which present the character of dense infil- trations inclosing only the smaller-sized cancer nodules. Likewise the marrow of entire bones or of entire groups of bones may be involved in diffuse carcinomatous disease, and as this advances the bone substance gives place to cancer tissue, whose stroma often incloses newly formed osteoid tissue. Portions of cancer removed while still in a living condition from one animal and inoculated into another of the same species continue to de- velop in the new locality and form daughter nodules exactly as occurs - in the case of the metastases which form in the course of the original disease. 8. Teratoid Tumors and Cysts. § 133. Under the head of teratoid tumors and cysts may be grouped together all those tumor-like formations which are distinguished by the fact that the tissues from which they take their origin either do not nor- mally appear at the site in question (heterotopous growth) or at least do not normally appear there at the time at which they are found (hetero- chronous growth). Part of the teratoid tumors and cysts, which may be correctly classed together as teratomata, exhibit moreover the pecu- liarity that they are composed of a great variety of tissues. The teratoid tumors and cysts may be conveniently subdivided, ac- cording to their structure and their origin, into four groups, as follows: First, the simple teratoid tumors ; second, the simple teratoid cysts ; third, the teratomata which are of complex structure and which are found in different parts of the body ; fourth, the teratoid cysts and solid twnors of the germinal glands. - Heterotopous tissue-growths, which are included in the same class with the teratoid tumors, may occur in the most various organs, but are found at certain sites more often than at others. Among the more com- mon may be mentioned the following: Chondromata and chondromyxo- mata of the salivary glands and of the testicle, osteomata of the muscles, lipomata of the pia, rhabdomyomata of the kidneys, and tumors composed of the tissues of the suprarenal capsules within the kidney. The following are encountered somewhat rarely: chondromata and osteomata of the skin or of the mammary gland, rhabdomyomata of the testicle, etc. 388 TERATOID TUMORS AND CYSTS. The occurrence of tissue formations at points at which these tissues do not normally appear is to be explained only by the assumption of misplaced germinal matter or of a displacement of tissue. It is as- sumed, in other words, that during early embryonic life the embryonal cells of one organ must have found their way into the group cf cells which constitute the first beginnings of another organ. Thus, for ex- ample, cells possessing the character of periosteum cells might find their way into a group of embryonic muscle cells. As regards the assump- tion of a displacement of tissue, it is conceivable that this may occur through some change in the natural position of a tissue which is either in course of development or is already actually developed. The sub- sequent appearance of pathological tissue formations constitutes the only ground upon which we are able to base the first assumption; while, as regards the other hypothesis, we occasionally find corroborative evi- dence, later on, in the anatomical relations. Thus, for example, in the retrograde changes which take place in hernias of the sacral portion of the spinal cord adipose tissue (Fig. 332, 7) and muscular tissue (Fig. 332, k) may push their way into the spinal canal and the sac of the arachnoid and grow around the nerves. Arnold saw a case in which transposition of adipose tissue, gland tissue, cartilage, and glia tissue had taken place at the lower end of the trunk. In this case the patient had a myelocyst, with absence of the bony wall of the spinal column throughout the lumbar, sacral, and coccygeal regions. He also found, _ ina case of fatty teratoma of the frontal region, that there was a defect in the wall of the skull, and that through this opening the tumor on the outside was connected with an intracranial growth of a similar character. Teratoid cysts may be divided into two great groups: on the one hand, the ectodermal epithelial cysts, and on the other, the entodermal and mesodermal epithelial cysts. The ectodermal cysts vary in size from that of a pea to that of a man’s fist, and their walls show ectodermal characteristics. For ex- ample, the sac may consist of a smooth connective-tissue membrane, lined with several layers of flat epithelium. Such cysts are known as epidermoids. Or else the sac may present the characteristics of true skin; that is, it is furnished with papillw like those of the skin, with sebaceous glands, with hair follicles, with hair, with sweat glands, and also often with subcutaneous fat. These cysts have been named der- moids, or dermoid cysts, or dermatocysts. The contents of the cysts are composed either entirely of cast-off oe cells, or else of such cells intermingled with fat and pale-colored hairs. The localities in which such epidermoids and dermoids are found are the skin and the subcutaneous tissues, where they present themselves in the form of tumors which bear some resemblance to the collections of cheesy material, or atheromata, which owe their origin to the retention of secretion in the outlet channels of the sebaceous glands and in the hair- follicles. They are also encountered at the side of the neck and in the median line of the neck, either above or below the hyoid bone. They also occur in the thoracic cavity (more particularly in the mediastinum), in the peritoneal crvity (rarely), in the pelvic cellular tissue, in the coccy- geal region, and in the raphe of the perineum. Finally, they also appear within the cranium—on the dura and also in the hypophysis. More often, however, such intracranial growths are designated as cholesteato- mata or as pearl tumors. These vary in size from that of a pea to that TERATOID TUMORS AND CYSTS. 389 of an apple; they are globular or slightly nodulated tumors, with a white, satin-like surface, and they are composed in great part of non- nucleated, thin cellular scales, arranged in closely applied laminz. These are invariably situated at some point on the pia (Bostroem), and it is the vascular pia, covered with laminated squamous epithelium, which, in the course of years, produces the delicate epithelial scales of which the tumor is composed, while the adjacent brain or arachnoid, which the tumor may rest against in places, does not share in the pro- duction of the horny scales. In rare cases the cholesteatomata contain sebaceous material and small hairs in addition to the epithe- lial scales. In these cases one may find, seated here and ‘there upon the pia, dermal structures—i.e., true skin, provided with sebaceous glands and hair follicles, or, in other words, with the organs which produce the sebaceous ma- terial and the hairs. The simple cholesteatomata can therefore be designated as epidermoids (Bostroem), while those which contain hair may rightly be named dermoids. The cholesteatomata occur at the base of the brain, in the neighborhood of the olfactory lobe, the tuber cinereum, the corpus callosum, the - choroid plexus, the pons, the medulla oblongata, the cerebellum, and very rarely the spinal cord. Without doubt the der-- moids and epidermoids under consideration owe their origin to a transfer of the germinal epithelium from its original position to the sites in ques- tion. In the case of the epi- dermoids, probably only em- Fic. 332.—Spina bifida occulta, with myolipoma inside the vertebral canal. (Sagittal section about 1 cm. to the left of the median line. Reduced about one-half. Copied from von Recklinghausen.) a, Abnormally hairy skin ; b, fibrous covering which forms the posterior wall of the sa- cral canal, with a slit-like opening at c; d, spinal cord; ¢, conus medullaris, lying in the second sacral vertebra (2) instead of in the second lumbar vertebra, f, cauda equina ; g, dura mater; h, h,, recurrent left anterior nerve-roots of the third and fourth lumbar nerves; i, fat: k, muscular tissue: IV, fourth, and V, fifth lumbar vertebrae: 1-4 sa- cral vertebrae. bryonal epithelial cells are deposited, whereas in the case of the dermoids, embryonal dermal tissue is also deposited. The in- tracranial cholesteatomata originate probably in an early deposit of germinal epidermis in the pia. Mediastinal dermoids doubtless de- pend upon disturbances in the development of the thymus, which springs from ectoderm. Dermoids on the side of the neck originate in the re- mains of the branchial clefts, and particularly of the second. Those dermoids which hang down from the hyoid bone or lie behind it are probably to be regarded as the remains of the ductus thyreoglossus. Dermoids of the pelvic cellular tissue can be explained by attributing them to epithelial offshoots from the perineum, or they may be looked . upon as ooo from the Wolffian duct. 390 TERATOID TUMORS AND CYSTS. - Simple entodermal and mesodermal epithelial cysts are character- ized by the fact that they are lined with epithelium composed of cylin- dvical cells, which often possess cilia. They are found particularly often in the broad ligaments of the uterus, and in the Fallopian tubes. They are also found at other points in the abdominal cavity, on the intestine, in the neighborhood of the trachea and the bronchi, in the lungs, on the pleura, in the neck, in the tongue, in glandular organs, etc. They form cysts which vary in size from that of a pin’s head to that of a man’s fist The occurrence of these cysts may be explained in most cases by the assumption that foetal glands or canals, which normally should Fg. 333.—Adenoma-like isolation of a part of the mucous membrane of the small intestine. The isolated portion lies in the submucosa and gives rise to a ridge-like prominence of the mucous membrane, about 2 cm. in length. (Alcohol; hematoxylin.) Specimen taken from a child six weeks old. a, b, c, Normal intestinal wall; d, e, portions of mucous membrane lodged in the submucosa; f, mucous tissue rich in cells. Magnified 35 diameters. disappear early in life, have continued to exist, or else that por- tions of entodermal or mesodermal epithelial tubes, which have become separated from the original structure by a process of con- striction, have served as the starting-point for their formation. Thus, for example, the cysts on the side of the neck may owe their origin to remains of the internal branchial clefts; those at the back part of the tongue to the remains of the ductus thyreoglossus or to the epithelial buds and glands which develop from it; and those which are located in the cesophagus or in some part of the respiratory apparatus to separated portions of the intestinal canal or of the air passages, or to remains of the connecting link between the two. In the broad ligaments and the Fallopian tubes the cysts spring from remains of the canals of the Wolffian body; in the abdominal cavity they originate in part from separated portions of the intestine (entero-cysts) and in part from the urachus (urachus-cysts). Inside the glands—for example, in the liver or in the kidneys—portions of the gland tubules may become separated dur- TERATOID CYSTS. 391 ing the process of development (adeno-cysts), and from these, at a later period, cysts may develop. Cysts located in some part of the central nervous system, or in its immediate neighborhood, may take their origin from the medullary tube (myelo-cysts). The mode of origin of cysts lined with cylindrical epithelium can be inferred, in the majority of cases, only from their position and from the character of their walls, and yet in these cases there is no room for doubt concerning their origin. Our conclusions are of the most positive char- acter in those cases in which the portion of tissue separated (Fig. 333, d, e) ig small, and still retains plainly the character of the mother structure. The significance of ectodermal, entodermal, and mesodermal cysts depends upon their position, size, and the secondary changes which oc- cur in them. The size varies from that of the head of a pin to that of a man’s head. Among the secondary changes—aside from simple inflam- mations—the development of adenomata and carcinomata should be men- tioned. Itis in this manner that remains of the Wolffian body, which are present in the dorsal wall of the uterus and the angles of the tubes (von Recklinghausen) often develop into cystadenomata or adenomyo- mata. In dermoids squamous epithelial cancers (branchiogenic and subcutaneous carcinomata) and probably also cylindrical epithelial can- cers may originate from portions of intestinal mucous membrane (Fig. 333) which have become separated from the parent organ by a process of constriction.. Cysts, cystadenomata, and carcinomata may develop in the jaw from similarly separated portions of the embryonic dental epithelium. . Cholesteatomata of the pia are regarded by many authors (Virchow, Eppinger) as en- dothelial structures, although it seems to me that the structure of these formations speaks against such an assumption. Ifa cholesteatoma possesses hairs which can develop only in hair-follicles, any other than an ectodermal origin is excluded. And it is not clear why cholesteatomata free from hair should have a totally different genesis from those bearing hair. Bostroem, who has made exhaustive studies of this subject, also arrives at the same conclusion, and I believe that his researches demonstrate its correctness. § 134. Teratoid cysts of a more complicated structure and solid teratomata, originating outside the reproductive glands, appear in the same localities as the simple teratoid cysts, but show a particular predi- lection for the region of the coccyx. The complex character of these cysts is shown by the fact that cartilage, bone, fat, mucous glands, smooth and transversely striated muscle fibres, nerve tissue, and tissue similar to that of sarcomata and carcinomata may be found in the ¢yst- wall. Dermoid cysts may also contain teeth, and even ciliated epithe- lial cysts. Solid teratomata occur, in the first place, in the form of hairy polypt (in the cavities of the nose, throat, and mouth)—that is, in the form of polypoid growths which are covered with a hairy skin, and which are made up essentially of fat, but which may also contain muscle fibres and cartilage, bony structures, teeth, and cysts. Then, in the next place, tumor-like growths, of the most complicated structure, may appear in the cranium, the neck, the lower jaw, and by preference in the coccygeal region. They contain the most diverse tissues, such as connective tissue, fat, cartilage, bone, gland tissue, muscle, nerve tissue, and brain substance, as well as ectodermal and entodermal cysts. They may further inclose rudimentary or completely formed parts of the 392 TERATOID CYSTS. body, or at least masses which can be readily recognized as representing parts of the body. . The complex teratoid cysts and solid teratomata are, In many cases, to be regarded as local disturbances in development which are charac- terized by the fact that in the earlier stages of embryonic life a dis- placement of tissue or a separation of tissue by constriction has taken place in a single individual (monogerminal tissue-implantation ; autoch- thonous teratomata). Hairy polypi of the throat, as well as the cystic and solid teratomata found at the base of the skull or in the hypophysis, can be explained by assuming that a dislocation of ectodermal tissue has taken place. If teratoid cysts of the mediastinum contain cartilage and mucous glands, the presence of these tissues may be explained by the vicinity of the trachea. In the case of teratomata in the region of the coccyx the manifold character of the growth may be explained by the fact that not only portions of the terminal vertebre, of the pelvis, and of muscular tissue, but also remains of the neuroenteric canal, of the hind-gut, and of the medullary tube take part in the formation of the tumor. It is also possible that in intracranial teratomata, as in simple dermoids, the basis for the growth is furnished by embryonic tissues which have been displaced. Then besides, in these growths there is al- ways the possibility that we may be dealing with the presence of a rudimentary twin, or, in other words, that a bigerminal implantation has taken place; and such an assumption is warranted in all those cases in which the teratoma contains completed or rudimentary parts of the body, or tissue formations, which cannot be explained by assuming that at the spot in question the tissue elements of a single foetus have under- gone displacement (compare § 153). § 135. Teratomata of the ovary and of the testicle occur partly in the form of dermoid cysts, and partly in that of solid tumors in which multiple cystic formations are present. The dermoid cysts are encoun- tered chiefly in the ovary, while the solid tumors occur more frequently in the testicle. The so-called dermoid cysts of the ovary form rather thick-walled cysts which vary in size from that of a pea to that of a man’s fist, and which are filled with fatty material inclosing pale hairs. At some one point in the wall of the cyst there will be found a projecting mass of tis- sue, which is studded with hairs and often also with teeth (Fig. 334, b,c, d). This mass of tissue varies greatly in appearance in different cases, at one time being provided with villi, at another time presenting the aspect of a tuberosity or of a shallow elevation, and at still another time extending like a diaphragm across the cavity of the cyst. The uppermost layer of this prominence possesses all the characteristic parts of skin, viz., hair-folli- cles with hairs, sebaceous glands, and sweat glands (sometimes showing cystic degeneration). In the deeper layers are found other tissue forma- tions, such as cysts and tubules lined with ciliated cylindrical epithelium, bone, cartilage, muscle, brain substance, nerves, mucous glands, and intestinal mucosa, as well as pigmented structures resembling the rudi- mentary tissues of the eye. On the other hand, kidney tissue, or liver tissue, or heart muscle, has never been discovered in these growths. The ovary alongside the dermoid is destroyed or else only traces of it remain. According to Wilms, to whom we are indebted for the most laborious researches concerning these growths, ovarian dermoids cannot be ex- SOLID TERATOMATA. 393 plained either by the assumption of a displacement of germinal matter, or by the assumption of an inclusion of a rudimentary twin. The latter view is excluded by the mere fact that in about fifteen per cent. of the cases dermoids occur at the same time on both sides. Wilms holds strongly to the view that these ovarian dermoids are rudimentary em- bryos or rudimentary parasites, which develop from a single ovum, and in support of this view he points to the facts, first, that these structures contain the constituent parts of all the germinal layers, and second, that in the formation of individual constituent parts a certain uniformity prevails. Thus, for example, under the ectoderm, which projects in- Fic. 334.—Portion of the wall of an ovarian dermoid cyst. a, Smooth part of the wall: }, projecting por- tion, made up of fatty and cutaneous tissues; c, uneven part of the wall, containing hairs and teeth (d), and bending upon itself in the upper portion. Life size. ward and which is developed to a much higher degree than any of the other layers, bones are found which we are warranted in classifying as cranial and maxillary bones, and also at the same time brain substance is found along with the bones; whereas the entodermal tissues, which remain in a rudimentary condition, form the outer portion of the tumor. Ovarian dermoids may develop at any period of life, but they occur most frequently in the middle period. Solid teratomata of the ovary are much more rare than dermoid cysts, and they form ¢umors in which the greatest variety of tissue forma- tions is to be found. These, which are distributed throughout the growth in the most disorderly manner, comprise epidermis, epithelial pearls, hairs, sebaceous glands, sweat glands, tubules, and cysts lined with ciliated epithelium, acinous glands, connective tissue rich in cells, 394 SOLID TERATOMATA. adipose tissue, muscle, cartilage, and bone—in other words, constituent parts of all the three germinal layers. In rare cases, teeth, intestine, thyroid gland, and a rudimentary brain may be present. Wilms is of the opinion that growths of this character have developed from a single ovum, and he therefore calls these teratomata embryoid tumors. Teratomata of the testicle occur principally in forms which are described, according to their structure, as adenocystomata, chondro- adenomata, chondrosarcomata, adenomyosarcomata (Fig. 336), ete. In some cases the formation of cysts with fluid contents is a marked feature of the tumor (Fig. 298); in other cases cysts are found only in certain parts of the growth; and, finally, in still other cases the tumor is en- tirely solid. These growths sometimes attain the size of a child’s head. In some instances they are congenital, but more commonly they develop in adult life and then grow rapidly. The lining of the cyst presents as a rule the character of entodermal tissue, but in one and the same cyst these characteristics may differ Odvysm er, aaa) pe avloye, _ \ vung “4 ae EF of S609 0406 Fetal Se vo, TTT Mi ‘ a, ge @, +oge J oot, Lapy Be) ro, 4 Y : “8 S 5 Looe 265 2 Sef 2 2 eteg ° B 19800 oF 8 ‘So, o FG. 335.—Congenital adenocystoma of the testicle, with formation of pigment and iller’ fluid; hematoxylin.) a, Connective-tissue stroma: b, simple cubical epltisHon : C, Sone emer epenelay d, strafed fees oo jeitneluns e, pigmented epithelium lining a gland-tubule; f. pigmented connective-tissue cells ; g, focus of cartilage in connective ti sh i nd. tubule. Magnified 100 diameters. “8 issue; h, focus of cartilage in a gland- (Fig. 335), For example, at one point there may bea single layer of cubical epithelium (Fig. 335, b); at another, simple aulinaeiaal othe: lium, both with and without cilia; at still another, ciliated epithelium in layers; and finally, at a fourth, pigment epithelium (e). Ectodermal epithelium is present only in scanty amount in these tu- DERMOID CYSTS. 395 mors, and is then confined to a few groups of cells, some of which show the characters of cornified epithelium; then, again, it may be entirely absent, or, at all events, in the case of large tumors it cannot be demon- ewes 5» par ee Se ae A aad = ~~ gO eae PS tite ts ee, Sa 1 ew, { at ore rad gL aii = - 2 ye ee 8 gt . - 7 SSB e~.,* #; — oe ihe hes a { =m ast SsSarcs-= Wasa la eee OS Ae Fic. 336.—Adenorhabdomyoma (teratoma) of the testicle. (Formalin: hematoxylin; eosin.) a, Cellular tis- sue, with bands of muscles; b, gland tube. Magnified 100 diameters. strated. In addition to cysts, glands which produce mucus may also be found in these tumors. Among the framework substances connective tissue, mucous tissue, cartilage (Fig. 335, g, h), at times also muscle (Fig. 336, a), adipose tissue, and rarely bone, are present. Wilms holds that these growths also are embryoid tumors—i.e., struc- tures which are composed of all the germinal layers, and in the forma- tion of which the entoderm and the mesoderm play the principal part. Furthermore he believes that these tumors develop from a single sexual cell. Other authors refer their origin to a displacement of germinal matter. Dermoid cysts of the testicle are of rare occurrence. They develop, however, as often in children as in adults. In their structure they re- semble very closely the ovarian dermoids. They have their origin in germinal material that represents all three germinal layers, and accord- ing to Wilms they also should be looked upon as rudimentary parasites which have originated from a single sexual cell. The researches of Wilms were carried on in Bostroem’s laboratory in Giessen on a very large amount of material, and the results of the study of individual cases of tera- toid tumors of the reproductive glands agree so perfectly that the hypothesis advanced by him and Bostroem concerning the origin of these tumors appears to be well founded, and especially so in regard to the theory of the origin of the so-called dermoids. In respect to the other mixed tumors of the reproductive glands the assumption of a dis- placement of germinal matter cannot entirely be discarded. Repin, Duval, and Delbert have announced similar views concerning teratomata of the sexual glands. Waldeyer attributes the origin of dermoids of the ovary to germinal epithelium, and 396 DERMOIDS. he assumes that the cells of the latter, in their character of undeveloped eggs, can pro- duce further products in the direction of an imperfect embryonic development. Pilliet and Costes refer the origin of the teratoid tumors of the testicle to a further development of some ovarian tissue which remains at the hilus of the testicle, or to a development of the remains of the Wolffian body which, although forming a part of the testicle, play no useful part in its physiological work. CHAPTER VIII. Disturbances of Development and the Resulting Malformations. I. General Considerations in Regard to Disturbances of Develop- ment and the Origin of Malformations. § 136. After the union of the sexual elements has taken place, the development of the embryo progresses by a continual division of nuclei and cells. Along with this division there arise in an orderly manner special groupings and differentiations of the cells, leading to the forma- tion of special tissues and organs. The cell-proliferation, as well as the development of the individual cell-groups into special organs and parts of the body, depends upon internal causes, and is controlled by charac- teristics which the embryo has received by transfer of inheritable pater- nal or maternal characteristics which were in the ascendant at the mo- ment of the union of the sexual elements, which are to be regarded as the carriers of inherited characteristics. It follows that not only the characteristics proper to the species, but also the special peculiarities of the individual, are predetermined in the germ, and the development of the embryo proceeds essentially under the control of self-contained moulding forces. And yet this development is not accomplished with- out an influence from the environment, in that the embryo of necessity receives nourishment from the maternal organism, and is exposed to mechanical influences on the part of its envelopes and the uterus. These influences may operate to modify the development of the foetus. In every species of animal, man included, the bodily form and the shape of the organs present a particular type, which experience has shown recurs continually, and which is therefore looked upon as normal. If there are departures, more or less marked, from this type, which are to be referred to an abnormal course of the intra-uterine development, the condition is called a congenital malformation. If the departure from the normal build is very great, so that the affected individual is grossly misformed, it is spoken of as a monster. It ig customary to use the term malformation to designate only such anomalies in the form of the whole body or individual parts of it as pre- sent to a mere external inspection rather striking departures from the normal. It is nevertheless entirely correct to use this term for patho- logical conditions of intra-uterine origin, which consist not so much in an abnormal change in form, but rather in a partial or faulty organiza- tion of the affected part or organ. A single malformation is one which originates from a single indi- vidual, while a double malformation or a double monster is one which is made up from two individuals. Malformations may arise tn tivo ways: from internal causes and from external causes. 398 INTERNAL CAUSES OF MALFORMATIONS. As internal causes may be reckoned all such as already exist in the germ, so that in the development of the embryo abnormal forms arise spontaneously, without intervention from without. When such a mal- Fia. 337.—Malformation of the head, due to adhesions of the membranes to the frontal region (close ad- hesions of the placenta to the uterus). a, Cutaneous sac inclosing a vascular, spongy tissue containing abun- dant cysts; b, eye; ¢, distorted lip; d, funnel-shaped depression lined with mucous membrane; e, left, e;, right, ala nasi; f, florous bands. (Reduced to three-fourths natural size.) formation occurs for the first time in a family it must be regarded as a primary germ-variation. This is to be regarded in either of two ways: there may have .been an abnormality of one or the other of the sexual nuclei which entered into union, or they may both have been normal, but from their union a variety has arisen which from our point of view is to be looked upon as pathological (cf. § 33). It is also possible that disturbances in the process of fecundation can give rise to pathological variations. If a similar malformation has already occurred in a parent, the case may be one in which the defect has been inherited. If a malformation which has appeared is a peculiarity which was not present in one of the parents, but did occur in remoter ancestors, while it was wanting in the intermediate links, the occurrence is spoken of as atavism. As primary germ-variations we find the very same malformations that occur by inheritance; in other words, only those malformations are inherited that have originally presented themselves as primary germ- variations. To these malformations that may be transmitted by inheri- tance belong an increase in the number of fingers or toes (polydacty- lism), malformations of the hands and feet, abnormal hairiness, harelip, and certain pathological conditions of the nervous system, as, for example, fibromata of the peripheral nerves. EXTERNAL CAUSES OF MALFORMATIONS. 399 Under external causes of malformations the first to be considered are jarrings, pressure, disturbances in the supply of oxygen and nourish- ment, and infections. Jarrings of the uterus can very likely directly damage the egg at an early stage. At a later stage in the development of the embryo the damage worked by trauma is probably more often to be looked upon as the result of a tearing loose of the egg and bleeding from the decidua, leading to malnutrition of the egg. It is evident that bleeding from other causes, changes in and contaminations of the maternal blood, as they occur in infectious diseases, also disease of the uterus itself, will have a detrimental effect on the developing egg; yet all of these condi- tions probably lead more often to the death of the foetus and to extrusion of the egg than to the development of a malformation. Infectious dis- eases of the mother may be transmitted to the foetus and cause there characteristic disturbances. An abnormal pressure from the uterus or the membranes may be exerted upon the embryo, especially when the amniotic fluid is in small quantity. Deformities of the extremities—as, for example, club-foot, flat-foot, and club-hand (Fig. 340)—not rarely show signs of pressure having been exerted. From the anatomical appearances in some malformations it appears that pathological conditions of the amnion are particularly likely to exert a damaging influence on the embryo, and may give rise to a variety of malformations. This may be occasioned by abnormal adhesions of the embryo and am- nion, as well as by pressure of the amnion upon the embryonic rudiments. Even at the birth of the child bands and threads of union can, not infre- Fig. 338.—Malformation of the face, caused by amniotic adhesions and pressure (asymmetry of the face). a, Misshapen nose; b, b,, rudimentary openings between the eyelids ; c, ¢,, clefts in the upper lip and alveo- lar process of the upper jaw; d, intermaxillary bone with prominent lip; ¢, oblique facial fissure, closed so as to make a furrow by scar-tissues. quently, be made out (Fig. 337 f, and Fig. 338), and their connection with the misshapen portion of the child leaves no doubt that they stand in a causal relation to the malformation. Such adhesions may give rise to severe malformations of the cerebral (Fig. 337) or of the facial (Fig. 400 EXTERNAL CAUSES OF MALFORMATIONS. 338) portions of the head: Not rarely portions of extremities are snared off by threads of the amnion (Fig. 339) and may be completely ampu- tated and then absorbed. How far these connections between the amnion and the foetus are to be referred to a primary adherence and intergrowth, and how far to in- flammations of later occurrence, is as yet a moot question. At birth these connections are often no longer visible and the affected region presents only a scar-like appearance (Fig. 338). According to Dareste and Geoffroy St. Hilaire, an abnormal snug- ness of the amnion exerts also a damaging influence 6n the embryo. So it is also claimed that abnormal tightness of the cephalic cap of the Fic. 339. Fie. 340. Fic. 339.—A hand stunted by amniotic adhesions; ring-flnger snared off; middle and index fingers grown together and distorted. (Reduced one-sixth.) Fic. 340.—A hand stunted and misshapen by pressure ; thumb wanting ; hand flattened ; great bending and shortening of the forearm. (Reduced one-fifth.) amnion is capable of causing the malformations known as anencephalia and exencephalia (§ 141), cyclopia (§ 141), and cebocephalia or arrhin- encephalia (§ 141); while abnormal tightness of the caudal cap leads to stunted development of the lower extremities (§ 145). Marchand refers also phocomelia (§ 145) to pressure exerted at an early period. Finally, clefts which occur in the anterior abdominal and thoracic walls (§ 143) are associated with a deficient growth of the amnion; still the latter condition is often not so much the cause as it is a concomitant of the malformation, which may follow from a variety of causes, but. is doubt- less often to be classed with the spontaneous or primary malformations. The period at which the damaging influences exert themselves natur- ally varies much, and so also does the extent of the damage. The earlier the damage occurs the more extensive it generally is. Malfor- mations in the more restricted sense arise mostly in the first three SINGLE MALFORMATIONS. 401 months, a period when the body and its individual parts are assuming their proper forms. Damage to the foetus at a later period occasions departures which in appearance are more nearly allied to those acquired after birth. Some malformations are typical—that is to say, they always reap- pear in the same form; while others, again, are entirely atypical, so that often the most astonishing anomalies o: form arise. The latter are mostly the result of harmful influences operating secondarily from with- out, while the former may be regarded as chiefly lue to internal causes. External influences, however, may also cause typical deformities. Geoffroy St. Hilaire! discards entirely the teaching of primary abnormality of the germ (Haller and Winslow), and attributes arrests of development simply to mechanical influences. Panum ? agrees with him in general, although he admits the possibility of a primary abnormality. In hens’ eggs he produced malformations by temperature varia- tions of the incubator, and also by varnishing the shells. Dareste* made similar experi- ments, and produced deformities due to arrests of development by setting the eggs on end, by varnishing the shells, by raising the temperature above 45° C., and also by irregular warming of the eggs. Very recently L. Gerlach, Fol, Warynsky Richter, Roux, and Schultze have experi- mented in this direction, and have sought, with some success, to produce malformations in hen embryos by localized influence of radiant heat, variations of temperature, var- nishing the eggs, changes of position, injuries, removal of a portion of the white of the egg, and by agitation. Roux, experimenting on frogs’ eggs, found that, after destruc- tion of one of the divisions formed by the primitive streak, the other continued its de- velopment to the formation of half an embryo, demonstrating that the portion on either side of the primitive streak contains within itself the developmental power to form the corresponding half of the body. But the body-half which is wanting may be later re- placed by subsequent development from the undestroyed half, and a whole structure be produced, showing that a half contains powers to produce also the other half. Schultze experimented on the eggs of amphibia. They normally assume a position in which the darkly pigmented protoplasm of lighter specific gravity lies above, and the heavier clear protoplasm, rich in yolk granules, lies below. Malformations may be pro- duced by placing the eggs in an abnormal position and preventing their resuming the normal position ; and the degree of malformation stands in direct relation to the size of the angle which the attraction of gravity makes with 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. By the same turning in the eight-cell stage, development is com- pletely stopped. All this shows that gravity is another influence capable of causing dis- turbances of development, and that these disturbances arise from displacements con- sequent upon a sinking of the heavier and a rising of the lighter constituents of the egg. According to investigations by O. Hertwig the eggs of Axolotl when kept in a 0.7- per-cent. solution of sodium chloride undergo a pathological development, which is, however, restricted to the central nervous system in the region of the head and buttocks. It would thus appear that the sodium-chloride solution affects only those portions of the ectoderm which are in the process of changing into ganglion cells; and, as a result, with otherwise normal development, there may be a loss of portions of the central nervous system. For the production of a malformation, it is manifest that the damage to the embryo must not be too severe; otherwise the embryo will die. Above all, the activity of the circulatory apparatus must be preserved. If the embryo dies, it is either expelled from the uterus together with the membranes, or it is absorbed while the membranes continue for a time their development. A malformed foetus cannot sink below a certain mini- mum of development without perishing at an early period, unless maintained as a sort of parasite upon another fetus developing at the same time (cf. § 154). § 1387. Single malformations may conveniently be divided, accord- ing to the sort of departure which characterizes them, into five groups. As arrests of development, or monsters due to defective develop- 1“ Hist. gén. et partic. des anomalies de l’organisation chez l*‘homme et. les ani- maux,” Paris, 1832-87. 2 Untersuch. iiber die Entstehung der Missbildungen,” Berlin, 1860. 3 Recherches sur la production artificielle des monstruosités,” Paris, 1877. 402 SINGLE MALFORMATIONS, ment, are classed all those malformations in which the whole or a part of the body is abnormally small and poorly developed (hypoplasia), and also the malformations characterized by absence or very great dwarfing (agenesia, aplasia) of individual organs or parts of the body. In this class belong absence of the brain or parts of it, or abnormal smallness of the brain; defects in the septa of the heart; absence and dwarfing of the extremities, etc. Where parts of the body or organs are normally formed by the union of distinct centres of development, and by a primary or secondary arrest of development this union fails to take place, arrests of development may show themselves as clefts and reduplications. Thus imperfect develop- ment of the plates forming the anterior body-wall gives rise to clefts in the median line of the thorax and abdomen; failure of the maxillary processes of the first branchial arch to unite or to form a union with the intermaxillary process gives rise to clefts in the facial portion of the head. . Deficient union of the early lateral halves of the female genital tract results in more or less extensive duplication of the uterus or vagina. Where at an early stage the beginnings of two organs lie in proxim- ity, they may unite so as to produce a coalescence or adhesion between two organs or parts normally distinct. So it may happen that the kid- neys are more or less united, and the eyes may be more or less com- pletely merged into a single organ. Such mergings of organs arise in two ways: from secondary unicn of divided organs, or from deficient separation of two organs which develop from a single focus. [Malformations due to excessive growth, or monsters due to exces= sive development, are characterized sometimes by the abnormal size of individual parts, sometimes by multiplication of their number. An ex- tremity or a portion of a finger may attain an abnormal size (partial giant growth), or the whole body may be included in the abnormal growth (general giant growth). These are examples of increase in size of members. A multiplication of the number of parts occurs notably in the glands of the breast, the spleen, the suprarenal capsules, and the fingers. In the case of glandular organs, if additional ones occur, they are usually called supernumerary organs (Nebenorgane). Malformations occur, also, through an abnormal disposition of parts (monstra per fabricam alienam). Under this head are included certain anomalies of the thoracic and abdominal organs which are char- acterized by abnormal positions of the organs, and also in part by the changes in relations between individual parts. In this class belongs the transposition of the organs of the thorax or abdomen, or of both at the same time (situs transversus). Various cases of defective formation in the heart and great vascular trunks may also be classed here, though more properly these conditions should be looked upon as arrests of de- velopment. A fourth group of malformations is caused by the presence of tissues in unusual situations and the persistence of foetal structures, as already spoken of in §§ 133 and 134. Finally, a fifth group includes malformations exhibiting a mixture of the sexual characteritics, subdivided into true and false hermaphro- dites. ‘True hermaphrodites possess both a male and a female generative gland. False hermaphrodites are unisexual, but the remainder of the sexual apparatus does not correspond to the generative gland, or there is a simultaneous formation of organs belonging both to the male and DOUBLE MONSTERS. 4038 to the female, A part of these malformations are arrests of develop- ment; others are to be regarded as cases in which from the original bisex- ual embryonic formation the organs of both sexes have attained develop- ment, whereas normally the structures characteristic of one sex, instead es developing, dwindle away and persist only in a very rudimentary orm. § 188. Double monsters (monstra duplicia) are instances of a dupli- cation of the whole body or of parts of the body. The twins are always of the same sex, and are mostly united together at corresponding parts of the body. The duplicated parts exhibit sometimes equal, sometimes unequal development; in the latter case one of the parts is dwarfed and appears as a parasitic appendage to the well-developed individual. This permits’a subdivision into an equal and an unequal form of double monster. : All double monsters come from a single egg, and develop from a single germinal vesicle. Several views of the origin of double monsters may be entertained. First, it may be supposed that two embryonic areas arise in the wall of a single blastodermic vesicle, which grow, impinge one on the other, and blend to a greater or less extent. A second possibility is the formation within a single embryonic area of two primitive streaks and two medullary grooves, which either remain separate or partially merge one into another. A third case would be one in which the primitive streak was single, but the medullary groove was double either in a part or in the whole of its extent. Finally, it may be that a duplication takes place at a later period of development, and then affects only individual parts. In all of the above possible modes of duplication the duplication takes place by a double formation, at a certain stage in development, of a part that is normally single. In the first instance the duplication dates from the period of formation of the embryonic area; in the rest it begins within the embryonic area. In the first three instances it affects the structures in the body-axis, in the fourth it is confined to such as do not lie in the body-axis. To explain the formation of double monsters, it is essential to sup- pose a duplication of parts of the blastodermic vesicle or of the embry- onic area. The only question is how far it may be possible for a doub- ling that has already taken place to disappear by a subsequent blending. Thus, if there are two entirely distinct embryonic areas, it may be asked whether only separate homologous twins can arise, or whether a merging can take place at an early stage. From the observa- tions and experiments on this subject it may be accepted without ques- tion that embryonic areas which are already in the process of develop- ment can merge together. The causes of a duplication of the enbryonic beginnings in a single blastodermic vesicle are as yet little understood. Fol supposes that by an abnormal impregnation of the ovum by two, three, or more spermatozoa double and multiple monsters arise ; but other observations (Born) indicate that ova impregnated by two or more spermatozoa do not develop. According to Marchand, the duplication of the embryonic beginnings is to be referred back to conditions existing within the ovum previous to fertilization or to the character of the fertilization. Wiedemann inclines to the view that the origin of the double monster dates from the moment of impregnation and is due to the impregna- tion of ova containing two blastodermic vesicles by two spermatozoa. In recent years successful experiments have been made in the production of double monsters from the eggs of animals. They were conducted by Gerlach, O. Schultze, and A404 ARRESTS OF DEVELOPMENT. Born. Gerlach ptuinided double monsters (anterior duplication) from hens’ eggs by varnishing them before incubating, and leaving only a Y-shaped spot in the region of . ‘the primitive streak free. Schultze produced double monsters by turning frogs’ eggs ‘through an angle of 180° (cf. § 136). Born succeeded in uniting together portions of the larve of amphibia, not only of the same kind, but also of different species and families (rana esculenta with bombinato rigneus and with triton). From all these experiments the conclusion may with certainty be drawn that double formations may be produced from a normally constituted egg through secondary influences, and that neighboring embryonic elements may merge and grow one into the other. II. Special Malformations in [an. 1. Arrests of Development in a Single Individual. (a) Arrest in the Development of all the Embryonic Elements. § 139. Arrest in the development of all the embryonic elements "manifests itself intwo ways. If the disturbance is very marked, further development becomes impossible, and the embryo either dies at once or it becomes stunted and after a certain time perishes. If the disturbance is not so great a normally formed foetus develops, but it remains small and weakly—in other words, a dwarf is formed (nanosomia or micro- somia). When a footus dies it is, in the majority of cases, expelled from the uterus along with its membranes (abortion). In the earliest periods of development the embryo may disappear by absorption. The mem- branes are usually expelled; but they may also remain for atime and suf- Fie. 341.—Portion of a mole, presenting the form of a bunch of grapes. (Natural size.) fer further changes. Most frequently they form flesh-, thrombus-, or blood-moles—fleshy masses consisting of the membranes and blood- clots. The clots form the chief bulk, come from the placenta materna, and are often the cause of the death of the footus. In the case of the so-called grape-mole (Fig. 341) the villi of the chorion or of the pla- ARRESTS OF DEVELOPMENT. 405 centa undergo an enormous dropsical swelling, as a result of which portions of the villi expand to bladder-like structures held together by delicate connecting strands. In this process the solid portions of the connective tissue are thrust apart by fluid and eventually undergo lique- Joga SD Fic. 342.—Lithopzedion entirely inclosed in fibrous membranes. (Removed from abdominal cavity by operation two years after beginning of pregnancy.) Extra-uterine pregnancy caused by embryo breaking through uterine portion of a Fallopian tube into abdominal cavity. (Reduced one-third.) faction, especially in the central portions. The epithelium of the villi shows in some places proliferation, in others dropsical degeneration. The death of a foetus in an advanced stage of development results, provided it be not expelled, in the formation of a lithopedion. This occurs most freyuently in cases of extra-uterine pregnancy, in which the foetus occupies an abnormal site, as in the peritoneal cavity, in a Fallo- pian tube, or in anovary. If afcetus so placed dies at such an advanced state of development that it cannot be absorbed, it may be carried in the maternal organism for years. Not infrequently its form is perfectly re- tained (Fig. 342), and the whole foetus becomes enshrouded in an en- velope of connective tissue. In other cases the foetus, in the course of time, becomes converted into a partially fluid mass, which contains the osseous remains, as well as fat, cholesterin, and pigment, and is inclosed .in a fibrous capsule. Usually lime salts are deposited in the new-formed capsule, as well as in the foetal elements that remain. All of these forms are included in the term lithopedion, but they are subdivided under three heads (Kiichenmeister). The foetus may be 406 SPINA BIFIDA. mummified, but easily shelled out from calcified membranes (litho- celyphos). Or the foetus may become adherent at a number of points with the membranes, and later these points become calcified, while the remaining parts undergo mummification (lithocelyphopedion). Or, again, the membranes may rupture and the foetus be discharged free into the peritoneal cavity, and later become encrusted with lime-salts (lithopedion in the narrower sense). According to observations of His,! an embryo may for one reason or another come to a standstill in its development, and yet be retained for weeks or even months in its envelopes. ‘The first change that takes place at the approach of death is a great swelling of the central nervous system, which leads to deformities of the head. Later, the tissues become infiltrated with wandering cells, which make the boundaries between the organs vague. The whole embryo becomes soft and dark, and the superficial configuration of the body may become indistinct. (b) Deficient Closure of the Cerebrospinal Canal and the Accompanying Malformations of the Nervous System. § 140. Deficient closure of the vertebral canal leads to the malfor- mations known as rachischisis or spina bifida. Where the defect in the vertebral canal is broad so that at the bottom of the cleft the bodies of the vertebree are seen covered by membrane the condition is usually called rachischisis. Where, at the site of the defect, there is a sac which protrudes, the malformation is usually called spina bifida or, more cor- ___ Fig. 343.—Craniorachischisis, with total absence of the brain and spinal cord. The skull is covered with irregular skin-like masses, the spinal furrow. with a delicate envelope (pia mater). Kypholordotic bending and shortening of the spinal column. (Reduced one-sixth.) rectly, spina bifida cystica; though to this formation the names rachi- schisis cystica or hydrorachis cystica may also be applied. In rachischisis totalis (holorachischisis, Fig. 343) the bodies of the '“Fragen d. path. Embryologie”; Intern. Beitrage, Festschr. f. Virchow, i., 1891. PARTIAL RACHISCHISIS. 407 vertebre form a shallow groove open posteriorly, and usually covered only by a thin, transparent membrane; though, in rare cases, there are rudiments of spinal cord in the form of whitish bands and lines (total or partial amyelia) . The delicate membrane, which lines the furrow and rests upon the dura mater covering the bones, is the ventral portion of the pia mater spinalis. A part of the nerve-roots may have undergone development and be seen springing from rudiments of spinal cord or from spinal ganglia. Partial rachischisis (merorachischisis) involves usually the sacro- lumbar or the upper cervical region, while the intermediate portions of the vertebral column are sel- dom the seat of malformation. The dorsal surface of the vertebral bodies whose arches have remained rudimentary is mostly covered by a mass of velvety red tissue (Fig. 344, c) (von Recklinghausen) closed in by a delicate integument; though the amount of this tis- sue may be very small, or may even be wanting. External to this tissue-mass, which is not everywhere equally abundant, and which decreases at the sides, comes usually a deli- cate, transparent, vascular skin (Fig. 344, e); next, a zone of skin with an epider- mis, but somewhat thinner than the normal skin, and often bearing abundant hairs (Fig. 344, 7); then, finally, comes the normal skin. The soft red tissue-mass (c) Fic. 344.—Rachischisis partialis. (After von Reckling- lying in the median line is the hausen.) a, Outer skin with hairs; b, spinal cord, laid ° bare by dissection; ¢, area medullo-vasculosa : d, cranial. rudiment of the malformed d;, caudal polar furrow; ¢, zona epithelo-serosa; f, zona 2 . ne dermatica with hairs; g, space between dura mater and spinal cord, and is an 6x pia; h, anterior, /:,, posterior nerve-roots; i, ligamentum tremely vascular tissue, con- denticulatum. taining often more or less abundant parts of the spinal cord, as nerve-fibres, ganglion-cells, and glia-cells, and is therefore appropriately called area medullo-vasculosa (von Recklinghausen). The area medullo-vasculosa is sometimes a continuous tissue; some- times it is scattered in patches and bands, and forms only a delicate web. The cranial as well as the caudal extremity of this median area ‘may end in a distinct furrow, designated respectively as the cranial and the caudal polar furrow (Polgrube—von Recklinghausen) (d, d,). An- teriorly this is next to the spinal cord (b); in lumbrosacral rachischisis it is connected caudally with the filum terminale. The tegument on which the area lies is only the pia mater, which also continues into the red zone spoken of above (e), which, being covered also with epithelium, is designated as the zona epithelo-serosa (von Recklinghausen). The 408 RACHISCHISIS CYSTICA. prominent zone bordering this and covering the rudiments of the pos- terior vertebral arches (/'), is formed of cutis and is known as the zona dermatica. ; On the ventral side of the pia mater that forms the covering of the defect is a cavity (q), bounded on its deeper side by the dura mater and Fic. 345.—Spina biflda sacralis. (After Froriep and Forster.) 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. the external layer of the arachnoid; so that this space is in reality the ventral portion of the subarachnoid space, and, ag is normal with this space, is crossed by the ligamentum denticulatum (i) and the nerve- roots (h, h,), which, in the region of the area medullo-vasculosa, lose themselves in the pia-like tissue. Spina bifida cystica or rachicele (rachischisis cystica) occurs in three types: myelomeningocele, meningocele, and myelocystocele. According to its site we may further distinguish a cervical, a dorsal, a lumbar, a lumbo-sacral, and a sacral spina bifida. In general a spina bifida is characterized by the development of a fluctuating tumor, which is in most cases visible externally behind the spinal column (spina bifida pos- terior); but instances also occur in which the sac projects anteriorly from the spinal canal (spina bifida anterior), and others in which it is too small to be visible externally (spina bifida occulta). Myelomeningocele occurs most often as a spina bifida lumbosacralis and forms usually a tumor, at birth varying from the size of a nut to that of an apple and after birth increasing in size, in the region of the lower lumbar and upper sacral vertebrae. It is covered either by smooth or sear-like skin, or may be without any skin on its summit and there clothed by a reddish, mucosa-like tissue (area medullo-vasculosa). The portion devoid of skin may be drawn in like a scar. In rarer cases there may be no external tumor (spina bifida occulta), the site of the cleft being indicated only by a heavier growth of hair or by a depression. On opening the sac, which is composed of the arachnoid (Fig. 346, e) and pia (f, f,), while the dura (g) does not reach to the dorsal portion of the sac, one sees that the lower end of the cord (0,) is drawn outward and that the cavity of the sac is crossed by nerve-roots (i, 7,). Occa- sional nerve-roots (1) may also spring from the column of the cord as it courses through the sac. According to these findings there is an accumulation of fluid in the meninges, a hydromeningocele (hydrorrachis externa circumscripta), which is combined with a prolapse of the spinal cord, a myelocele. At the site of the protrusion the vertebral arches are defective, and this de- fect may reach as far as the hiatus sacralis. Smaller defects may involve only one or two vertebre. Dorsal and cervical myelomeningoceles are much rarer than those in the lumbo-sacral regions. The deficiency in the vertebral arch is usually confined to one or two vertebre. The cord here is involved in the me- RACHISCHISIS CYSTICA. 409 ningocele in so far that portions are drawn outward in the form of a band or a cone. Hydromeningocele spinalis arises from a hernial protrusion of spinal arachnoid, caused by a circumscribed collection of fluid in the subarach- noid space. It may occur at the upper end of the spinal column, when there exists a cleft of the superior cervical vertebra, together with her- nia of the brain in the occipital region. Most frequently, however, it occurs in the sacral region, and here the hernial protrusion takes place either through a defect in the vertebral arches and vertebral bodies, or through the hiatus sacralis, or between vertebral arches, or through in- tervertebral foramina. In most cases the dura has no share in the for- mation of the sac; but views differ on this point and some authors (Hil- debrand) describe a dural sac. By a progressive accumulation of fluid the sacs may attain a very considerable size. Small meningoceles may remain concealed in the deep tissues. In accordance with the direction the hernia takes we may distinguish a meningocele posterior and a meningocele anterior, the latter taking place through a defect in the bodies of the vertebra (rachischisis anterior). A myelocystocele or hydromyelocele (syringomyelocele) has its origin in an expansion of the central canal of the spinal cord, as a result of which a more or less considerable portion of the cord, together with its connective-tissue envelopes, becomes a cystic tumor. The dura is wanting in the portion of the sac which has pro- truded outside the vertebrez. According to von Recklinghausen, the wall of these sacs is formed, in the main, of the spinal membranes, but is lined on the inner surface by a cydindri- cal epithelium, and has at some part of its inner surface an area medullo-vascu- losa—usually on the ventral, seldom on the dorsal side. Corresponding with this condition, the nerve-roots, if they are present, spring mostly from the ventral, seldom from the dorsal wall of the sac. The cavity itself is crossed neither by bands nor by nerves. Myelocystoceles occur, in the major- ity of cases, in conjunction with lateral clefts of the vertebral canal, and have a tendency also to be combined with defects and asymmetries of the bodies of the vertebree, leading often to shortening of the trunk ; sometimes affecting only the dorsal region, and sometimes including also the lumbar region. There is Fic. 346.—Myelomeningocele sacralis in sagittal section, a little to the left of the median line. (After von Recklinghausen.) a, Skin: b, spinal cord; b,, column of the cord; c, area medullo-vasculosa; d, cra- nial, d,, caudal polar groove; e, pia mater ; f, arachnoid, somewhat separated from the pia mater; f;, portion of the pia mater turned over; g, dura mater; h, recurrent roots of the fourth lumbar nerves; i, radix anterior. i,, radix posterior of the fifth lum- bar nerve, running free in the arachnoid sac; k, sacral nerve-roots between the arachnoid and pia; l, fllum terminale. often, also, ecstrophy of the bladder, intestine, and abdominal cavity. Myelocystoceles are mostly covered only by the outer skin, but are sometimes concealed deep down in the soft parts. They may further- more be combined with meningoceles, producing myelocystomeningo- celes. In cases of rachischisis there is sometimes a division of the spinal cord inte eve parts (diastematomyelia), usually where the rachischisis 410 FAULTY DEVELOPMENT OF THE CRANIUM. is total—that is, where generally only rudiments of spinal cord are in- dicated. Where there is partial rachischisis such divisions are rarer ; but the separate cords are more fully developed, and the fibrous and bony envelopes may, at the beginning and end of the cleft, send dividing septa between them. Cases occur in which each cord-half shows an H-shaped area of gray matter. The production of vachischisis is to be referred back to agenesia and hypoplasia of the medullary folds, which should form the medullary groove of the vertebral arches; and the agenesia of the spinal cord is also to be referred back to the very earliest period. Whether it be a question of primary agenesia, already predetermined in the elemental germ, or whether damaging influences from without, perhaps toxic sub- stances (Hertwig), pressure from without or growing in of membranes, may have secondarily checked development or destroyed parts already formed, it is in most cases difficult to determine; yet the symmetrical distribution of the arrested development tends to support the former view. In cases of spina bifida with hernial protrusion, the local defects in the bony vertebral column and the deficient development of the dura mater, which is usually wanting at the site of the protrusion, are to be regarded as the primary defects. The growth of the sac may be explained by congestive and inflammatory transudation, and relics of inflammatory changes, as thickenings and membranous adhesions, may even some- times be demonstrated in ‘the pia. In the earliest embryonic period, the medullary groove is formed by the development on either side of the median line of wall-like elevations of the ectoderm. By converg- ing growth of these elevations the medullary groove is closed and formed into the neural canal. Thereupon the masses of cells (primitive vertebral plates) lying at the sides of the newly formed canal, form an envelope about it, which gives rise in the first place to a membranous, non-articulated, vertebral column. ‘This, at the beginning of the second month, becomes studded with discrete cartilaginous elements, from which in the course of the further development the vertebral bodies and arches are formed, while between them appear the intervertebral discs and the vertebral ligaments. The development of the cartilaginous vertebre is not completed until the fourth month, and until then the dorsal covering of the neural canal consists of the united portions of the membranous vertebral column. The cartilaginous vertebre are replaced in the course of development by bone. As to the origin of myelocystoceles and myelocystomeningoceles, one cannot, ac- cording to von Recklinghausen, ascribe as a cause either the persistence of a connection between the neural canal and the epiblast, or an excessive stretching of the medullary groove-wall through bending of the axis of the embryo. According to him, the myelo- cystocele is a deficient growth in the long axis of the vertebral column, characterized anatomically by shortness of the column, by failing of vertebre or portions of vertebra, by separation of bony wedges from the bodies of the vertebre, and by unilateral defects in the arches. The neural canal, then, pursuing its normal development, becomes too long for the vertebral canal, undergoes in consequence curling or kinking, and there is a tendency to a partial protrusion at the point where the bend is sharpest. Marchand, on the other hand, holds that this hypothesis does not fit all cases, and Arnold also believes that the causal relations between arrests of development in the muscle-plates and vertebral elements on the one hand, and those of the neural canal on the other hand, are not constant, but that a variety of disturbing influences may give rise to one or more of these anomalies. According to O. Hertwig, the ordinary spina bifida is an arrest of development dependent upon a partially prevented closure of the primitive mouth cleft. § 141. Faulty development of the cranial vault and the associated hindrance to the development of the brain lead to the malformations which are termed. cranioschisis, acrania, hemicrania, microcephalus, anen- cephalus, exencephalus, micrencephalus, and cephalocele. Acrania and hemicrania or cranioschisis are the results of an agene- CRANIORACHISCHISIS. 411 sia or hypoplasia of the bony and membranous portions of the cranial vault, which has either arisen as a primary disturbance of growth, or Fic. 347.—Anencephalia et ‘semi (Reduced Fic. 348.—Cranioschisis with exencephalia. one-half. has been caused by harmful external influences, damaging the primitive cerebral elements. In acrania both the -bony portion and the skin of the cranial vault are wanting (Fig. 347 and Fig. 349) almost entirely; the surface of the base of the skull is covered only by a skin-like, vascular tissue. If the defect in the cranial vault is extensive enough to include also the arches of the vertebra, there is produced the condition known as craniorachischisis (Fig. 343). In this case the spinal column is mostly shortened and bent, the head in consequence being drawn sharply back- ward and the face turned upward. When the eyes bulge out, owing to Fic. 349.—Partial agenesia of the bones of the cranium in anencephalia. a, Defect; b, occipital portion of skull; c, parietal bone; d. frontal bone. (Reduced one-fifth.) deficient development of the forehead, the malformations resemble frogs (frog fetus). In hemicrania the flat bones of the cranial vault have undergone 412 BRAIN HERNIAS. more or less extensive development (Fig. 349, b, c, d) and form a cranial cavity, which is, however, of small capacity, inasmuch as the flat bones of the vault are elevated but a short distance above the base of the skull. Tf the bones of the vault which have undergone but feeble development yet unite with one another after the nor- mal manner, there is produced a _ simple Fic. 350.—Hydrencephalocele oc- Fic. 351. — Encephalomeningo- Fic. 352,—Synophthalmus or cy- cipitalis. cele nasofrontalis. clopia. microcephalus. This may be already present at birth, or it may be produced later by insufficient development of the skull. Acrania and hemicrania are often associated with total anencephalus, and the base of the skull is covered only by a vascular, spongy, skin-like mass, composed of a connective tissue rich in blood-vessels, mostly spotted with hemorrhages and containing either no brain substance or only undeveloped rudiments (area cerebro-vasculosa). _ In other instances the meninges contain, beside cystic cavities and gland-like remnants of the medullary plate, also more or less developed brain substance, which usually protrudes through the defect in the cranial vault, causing exencephalus (Fig. 348 and Fig. 337). The hernial masses are either covered by only a soft membrane, representing the meninges, or they may have also a covering of skin. With microcephalus there is also micrencephalus, that is an abnor- mal smallness of the brain. Either there is a general lack of develop- ment, or special parts are wanting. Where the cranium is in general properly closed, but presents par= tial deficiencies, portions of the cranial contents. may protrude in the form of a hernial sac, and it is hence spoken of as a hernia cerebri or cephalocele (Fig. 350 and Fig. 351). Defects of ossification (Acker- mann), or deficient resistance of the membranous cranial envelope, are doubtless usually the primary cause; but adhesions of the meninges with the amnion (St. Hilaire) may also be a cause. On the extracranial portion of the sac the dura mater is lacking (Muscatello). The size of the protruding sac varies greatly. It may be so small as to be found only by careful examination, or it may be so large as to approach the brain in volume. When accumulation of fluid in the subarachnoid space has caused only the arachnoid and pia to protrude, the tumor is a meningocele; when brain-substance also protrudes, it is a meningo-encephalocele. A protrusion of brain-substance and pia without accumulation of fluid is called an encephalocele ; if the protrud- ing brain-substance contains part of a ventricle filled with fluid it is called a hydrencephalocele. These brain-hernias appear mostly in the occipital region (hernia CEREBRAL MALFORMATIONS. 413 occipitalis) close above the foramen magnum (Fig. 350) and at the root of the nose (hernia cyncipitalis). In the latter region it may involve more especially the frontal bone (hernia nasofrontalis, Fig. 351), or the ethmoid (hernia naso-ethmoidalis) or the lachrymal bone (hernia naso- orbitalis). More rarely hernias occur at the sides of the skull (hernire laterales) or at the base (hernice basales). The latter may bulge toward the nasopharynx (hernia sphenopharyngea) or the orbits (hernia spheno- orbitalis) or the sphenomaxillary fossa (hernia sphenomaxillaris). Marked stunting in the development of the anterior of the three cerebral vesicles may leave the cerebrum single (St. Hilaire’s cyclen- cephalia or cyclocephalia), while at the same time a deficient separation of the ocular vesicles takes place. When the stunting is very marked, only a single eye may be formed in the middle of the forehead, or there may be two united together and lying in a single orbit (Fig. 352); and this malformation is called cyclopia or synophthalmia, and arrhinen- cephalia (Kundrat). The nose is also stunted (Fig. 352), being present only as a cutaneous tag attached above the eye and devoid of bony foundation (ethmocephalia). When the eyes are separate, yet abrormally close together, the nose in general may be normal, but at the root it is very small (cebocephalia). In the severer forms of the malformation the ethmoid and the nasal septum may be wanting, and the upper lip and palate may be cleft in the median line, or laterally on one or on both sides (Kundrat). In the Fig. 353.-—Cranial cavity of a synophthalmus microstomus opened by a frontal section (viewed from be- hind). a, Skin and subcutaneous tissue: b, cranial vault; ec, dura mater; d, tentorium ; e, arachnoid; f, posterior surface of the cerebrum, consisting merely of a thin-walled sac covered with pia mater; g, tumefied border of the cerebral sac; h, subarachnoid space behind the cerebral sac; t, cavity of the cerebral sac, com- municating with the subarachnoid space by the enlarged transverse fissure ; k, section through the corpora quadrigemina ; 1, section through the cerebellum; m, the atlas. (Four-fifths natural size.) milder forms the forehead is merely reduced in size and pointed like a wedge. In the severest grades of these malformations the cerebrum consists of a sac (Fig. 353, /, 1) occupying more or less of the cranial cavity and filled with a clear fluid; where the sac does not lie against the cranial 414 MALFORMATIONS OF THE FACE. wall the intervening space is taken up by fluid distending the subarach- noid space (4). In milder instances only individual portions of the brain are wanting in development, those mostly affected being the olfac- tory nerve and olfactory bulb, the corpus callosum, a part of the convo- lutions, etc. The optic thalami are often blended together. The chiasma and optic tracts may be either wanting or present. The cor- pora quadrigemina (k), the pons, the medulla oblongata, and the cere- bellum (/) are usually unaffected. Spinal cord and brain develop from the neural canal. In the portion that is to be- come the brain, the neural canal changes at an early period into three vesicles. ‘The anterior of the three, the forebrain, throws out from its lateral portions the primary optic vesicle, while the middle portion grows forward and upward and divides into the pros- encephalon and the thalamencephalon. From the former are developed the cerebral hemispheres, the corpora striata, the corpus callosum, and the fornix. From the thalam- encephalon are formed the optic thalami and the floor of the third ventricle. The second cerebral vesicle or mesencephalon forms the corpora quadrigemina, while the third divides into epencephalon and metencephalon, from which are formed the pons, the cerebellum, and the medulla oblongata. The cerebral portion of the neural canal becomes inclosed in the primitive vertebral plates of the head, which form the membranous primordial skull. ‘The basal portions change to cartilage in the second foetal month. In the third month both the cartilages of the base and the membranous vault begin to ossify. According to G. St. Hilaire, Forster, and Panum, acrania and anencephalus are to be ascribed to an abnormal accumulation of fluid in the cerebral vesicles, a hydrocephalus, occurring before the fourth month. Dareste and Perls oppose this view and point out that in acrania the base of the skull is mostly bulged inward, hence is not pressed out- ward ; and they look for the cause of acrania in a pressure upon the skull exerted from without (Perls) and caused by the head cap of the amnion being very snug and retard- ing the development of the cranium. Lebedeff looks for the cause of acrania in an ab- normally sharp bending of the body of the embryo, which he conceives to occur in case the cephalic end of the embryo grows abnormally in the longitudinal axis or in case the cephalic covering lags behind in its development. By the sharp bending the change of the medullary groove into a neural canal is thought to be prevented, or the canal after its formation to be destroyed. From this could be explained also the absence later of the brain as well as of the teguments and bones of the cranium. The cystic formations in the teguments lying upon the base of the skull Lebedeff would have formed from the folds of the medullary groove, which sink into the mesoderm and then become snared off. Hertwig thinks it possible that chemical substances, circulating in the blood or secreted from the wall of the uterus, may destroy the earliest beginnings of the brain. It is very probable that acrania has not in every instance the same origin. While in one case the influences brought forward by Perls and Lebedeff, or adhesions with the membranes, may arrest the development of skull and brain, yet in other cases the mal- formation should probably be looked upon as a primary agenesia already predetermined in the germ. (c) Malformations of the Face and Neck. § 142. The development of the face is subject not infrequently to disturbances leading to more or less marked malformations, which may appear alone or be combined with malformations of the cranial portion of the head. When the frontal process and the maxillary processes of the first branchial arch remain in an entirely rudimentary state, or are more or less completely destroyed by pathological processes, there is present at the site where the face should be merely a surface or cleft (aprosopia and schistoprosopia), which may or may not be combined with malformations of the nose and eyes. _ But more frequent than these large defects are smaller clefts involv- ing the lip, the alveolar process of the upper jaw, the upper jaw itself, and the hard and soft palates (cheilo-gnatho-palatoschisis). This malformation establishes a communication between the mouth and the PROSOPOSCHISIS. 415 nasal cavity (Fig. 354). The hard palate, where it abuts against the vomer, is cleft in the median line where it meets the soft palate. In the alveolar process of the upper jaw the cleft runs between the eye-tooth and the lateral incisor, or between the lateral and central incisors. The malformation may be bilateral or unilateral, primary and hereditary or secondarily acquired, one of the causes of the latter condition being am- niotic adhesions (Fig. 337). ; ; Frequently the cleft involves only special portions of the region above mentioned, as the upper lip (harelip, labium leporinum), or, what is rarer, only the hard or only the soft palate. The mildest degree is indicated by a notch or a cicatricial line in the lip, or by a bifurcation of the uvula. : ‘ Prosoposchisis (Fig. 338, e) is the term applied to a cleft running obliquely from the mouth to an orbit. It is usually associated with malformations of the _ brain. Morian distinguishes three va- rieties. The first commences on the upper lip as a harelip, passes Fic. 354.—Double cheilognatho-palatoschisis. Fig. 355.—Agnatbia and synotia (Gcuardan). into the nostril, thence around the ala nasi toward the orbit, and may extend even beyond the orbit. The second variety begins likewise in the region of a harelip, but extends outward from the nose toward the orbit. The third variety extends from the corner of the mouth outward through the cheek, toward the canthus of the eye, and divides the su- perior maxillary process externally to the canine tooth. A transverse cleft of the cheek also occurs, coursing from the corner of the mouth toward the temporal region. Median facial clefts also occur, and may involve the nose and up- per jaw, and also the lower jaw, or even extend as far down as the ster- num. With this malformation the tongue may also be cleft (Wolfler). All of the above-described clefts may be confined to small portions of the regions mentioned, and may also attain various depths. When the inferior maxillary process of the first branchial arch is tardy in its development, the inferior maxilla becomes also imperfectly developed, and may be entirely wanting, producing the malformations known as brachygnathia and agnathia (Fig. 355), and the appearance presented is as if the lower half of the face had been cut away; the ears are sometimes so close to each other as to touch (synotia). Usually the 416 BRANCHIAL CYSTS. superior maxillary processes are also imperfectly developed, and fre- quently the ear is misshapen. ; ' Malformations of the mouth, as abnormally large size (macrostomia), abnormally small size (microstomia), closure (atresia oris), and duplica- tion (distomia), are all rare. : f When the embryonic external branchial clefts or internal branchial pockets fail in part to close, fistulae opening either externally or intern- ally, or closed cysts, remain. The former condition is called fistula colli congenita. The mouths of the external fistule are generally found at the side of the neck, more rarely approaching, or actually in, the median line; those of the internal fistule open into the pharynx, trachea, or larynx. Frequently slight remains of the branchial pockets form merely diverticula of the latter organs. The fistule are mostly clothed with a mucous epithelium, sometimes ciliated, originating, therefore, from the visceral branchial packets—according to von Kosta- necki and von Mielecki, mostly from the second. In rare cases a com- plete branchial fistula is found, having both an external and an internal opening. e The branchial cysts which arise from the branchial pockets are sometimes clothed with mucous membrane (ciliated epithelium), are filled with fluid, and receive the name of hydrocele colli congenita ; some- times they are lined with an epidermal covering, contain masses of epi- dermal cells, and are therefore reckoned among the atheromata and cer- moid cysts. Arrests in development of the anterior end of the branchial arch (mesobranchial field) and in the region of the third branchial pocket (the site of origin of the thymus) and branchial cleft may lead to the formation of dermoids in the submental region, at the root of the tongue, and in the mediastinum. (Compare § 133.) The face and neck are developed in part from a single embryonic rudiment, in part from paired rudiments. The latter are represented in the branchial or visceral arches growing from the lateral portions of the base of the skull ventrally in the primitive throat-wall. The single rudiment, called the frontal process, is a prolongation down- ward of the base and vault of the skull, and is, in fact, the anterior end of the skull. Between the individual branchial arches there are at a certain period cleft-like depres- sions or branchial pockets.” The frontal process and the first branchial arch form the borders of the great primi- tive mouth, which has a diamondshape. In thecourse of development the first branchial arch sends out two processes, of which the shorter applies itself to the under surface of the forehead and forms the upper jaw, while from the lower and longer one the lower jaw develops. The frontal process, which forms the anterior border of the mouth, pro- duces a wide and long forehead and then pushes on two lateral processes, called lateral nasal processes. By further differentiation of the central portion of the frontal process the septum narium is formed, which, by means of two spurs called the inner nasal proc- esses, produces the borders of the nostril and the nasal furrow. The lateral nasal proc- esses are the Jateral portions of the skull, and develop within themselves later the ethmoid labyrinth, the cartilaginous roof, and the sides of the anterior portion of the nares. Atacertain stage they form with the superior maxillary process a fissure run- ning from the nasal furrow to the eye, and called the lachrymal fissure. The mouth is at first simply a great cavern, but is soon subdivided into a lower and larger digestive and an upper and smaller respiratory portion. This is done by the de- velopment, from the superior maxillary processes of the first branchial arch, of the plates which are to form the palate, and which begin in the eighth week to unite with one another and also with the lower edge of the nasal septum. ‘The union of these lateral plates to form the palate begins anteriorly and progresses backward. The union of the contiguous surfaces of the frontal and nasal processes with the superior maxillary processes forms the cheek and a continuous superior maxillary border, from which are developed later the lip and the alveolar process of the upper jaw- bone and the intermaxillary bones, while the nose develops from the frontal process. The intermaxillary bones are formed as two entirely distinct symmetrical bones, but unite early one with the other, and both with the upper jaw-bones. ARRESTS OF DEVELOPMENT. 417 (ad) Faulty Closure of the Abdominal and Thoracic Cavities, and the Accompanying Malformations. § 148. The construction of the body-form from the flat embryonic layers begins by a turning over and drawing together of the layers at the periphery of the embryonic area, so that they become transformed into two tubes, one of which is the abdominal wall, the other the ali- mentary canal. The infolding of these layers takes place at the cephalic and caudal ends as well as at the sides; and as these folds approach one another from all directions, those which are to form the ab- dominal wall produce a tube whose interior finally communicates only at the parietal umbilicus, by means of a tubular pro- longation, with the cavity of the extra-embryonic portion of the blastodermic membrane. While these lateral and ventral walls of the embryo are being thus formed, within the body the intestinal furrow closes to form a tube which is in communication at only one point—namely, at the vis- ceral umbilicus (within the above-mentioned com- munication of the abdomi- nal cavity)—with the cavy- ity of the umbilical vesicle, the channel between the two being called the om- phalomesenteric duct. The omphalomesen- Fig. 356.—Hernia funiculi umbilicalis. (Two-thirds normal teric duct becomes oblit- ee erated in the sixth week. The complete closure of the abdominal cavity follows in the eighth week. Arrests of development in the formation of the abdominal wall may take place at various points and be more or less marked. They are most frequent in the region of the umbilicus, where the closure of the abdominal cavity occurs latest. When faulty development of the abdominal wall at’ this point—leaving the abdominal cavity closed over a greater or less area only by peritoneum and the covering of the um- bilical cord (the amnion)—gives rise to hernial protrusion over this area (Fig. 356), the condition is called omphalocele, hernia funiculi umbilicalis, or umbilical hernia. The remnant of the cord is situated either on the summit of the protrusion or at one side, and is more or less shortened. 418 UMBILICAL HERNIA. The anterior abdominal walls may entirely or almost fail to unite— conditions which are called fissura abdominalis, gastroschisis com- pleta, and thoracogastroschisis, and are characterized by the unde- Fic. 357.—Fissura abdominis et vesicze urinaria, in a girl eighteen days old. a, Border of the skin; bh, peritoneum ; c, bladder; d, small bladder-cavity composed of the trigone; ¢, trough-like urethra; f, the labia minora. veloped abdominal coverings not having been separated from the am- nion, but running into it. The greater bulk of the abdominal contents then lie in a sac composed of peritoneum and amnion; or the perito- neum may be wanting also. The umbilical cord is also often wanting, and the umbilical vessels run to the placenta without joining one an- other. Failure of the chest-wall to close is called thoracoschisis. The heart, covered with the pericardium or entirely free, may push out through an opening in the cardiac region. This condition is called ectopia cordis. When the failure to close is confined to the sternal region it is called fissura sterni. This may involve the whole sternum or only a part of it;.it may affect only the bones, or it may affect the skin also. ‘When the urinary bladder prolapses through a cleft in the abdomi- nal wall, the condition is known as ectopia vesice urinariz. Clefts of the abdominal wall, whether total or partial, are not infre- quently complicated by clefts of the parts lying behind the abdominal wall. When a cleft of the lower abdominal wall is combined with a cleft of the bladder also, so that the posterior wall of the bladder pro- trudes through the abdominal opening (Fig. 357, c), the condition is called fissura or ecstrophia or inversio vesicze urinariz. Sometimes the pelvic girdle and the urethra are also cleft, converting the latter into an exposed trough (Fig. 357, e). The ecstrophy is then said to be complicated with fissura genitalis and epispadias. When an abdominal fissure, or an abdominal fissure together with ecstrophy of the bladder, is complicated with fissure of the intestine, MALFORMATIONS OF THE EXTERNAL GENITALIA. 419 the condition is called fissura abdominalis intestinalis or vesico-in- testinalis. The intestinal fissure is situated in the cecum or in the beginning of the colon, and the mucous membrane of the intestine pro- trudes in the same manner as the posterior wall of the bladder; and hence it is called ecstrophia or inversio intestini. If the omphalomesenteric duct does not undergo its normal atrophy, an appendix of intestine, called Meckel’s diverticulum, remains. This diverticulum proceeds from the outer surface of the gut, having generally the appearance of a glove-finger, and either ends blindly or is attached . at the umbilicus, sometimes being dilated at the ends. It may be ad- herent in the umbilical ring, and its mucous surface may protrude (ectopia intestini, adenoma wumbilicale). In very rare cases a cyst lined with mucous membrane is found in the abdominal wall (cyst of the vitel- line duct). Umbilical hernia and clefts in the upper part of the abdominal wall are often combined with craniorachischisis, while ecstrophy of the blad- der and intestine is often combined with myelocystocele; and von Reck- linghausen regards the two malformations as bearing some relation to each other. Large abdominal clefts are furthermore often associated with lordotic or scoliotic curvatures of the spinal column. (e) Malformations of the External Genitalia and of Parts belonging to the Anal Region, caused by Arrested Development. § 144. Malformations of the external genital organs may be asso- ciated with malformations of the abdominal wall, the bladder, and the internal genital organs, or they may occur without these associations. Total absence of the external genitalia may be the only defect, but it usually forms only a part of a more extensive malformation of the parts of that region, and, as a rule, is associated with defects in the internal genital organs (Fig. 360). , A dwarfed condition of the penis is not rare, and when it exists Wyss. SSS Fic. 358.—Hypospadias, associated with a stunted penis. (Reduced one- Fic. 359. — Epispadias. fourth.) (After Ablfeld.) the organ presents externally a more or less close resemblance to a cli- toris. It is usually associated with hypospadias, the urethral opening being beneath the glans, the body, or the root of the penis (Fig. 358), 420 EPISPADIAS; ATRESIA ANI. or, in extreme cases, behind the scrotum (hypospadias perineoscrotalis). The same degrees of hypospadias may exist in penises otherwise nor- mal, being due simply to a more or less complete covering of the sexual furrow from which the urethra normally develops. iat oe ; Epispadias (Fig. 359) is the term applied to the condition in which the urethra opens upon the dorsal aspect of the penis. It is less com- mon than hypospadias, and results from an incomplete or retarded clos- ing of the pelvic cavity, of such a char- acter that the cloaca is divided into an anal and a genital portion (Thiersch). Sometimes the two penile halves may remain separate, with or without ec- strophy of the bladder or an incomplete closure of the abdominal cavity. Hypertrophy of the prepuce is not of rare occurrence. If a narrowing of the preputial opening is associated with it, and the prepuce cannot be pushed back over the glans, it is customary to speak of the condition as an hyper- trophic phimosis. Entire absence of the prepuce is rare, abnormal shortness more frequent. Deficient development of the scro- tum is usually associated with reten- tion of the testes in the abdominal cav- 2 ity or in the inguinal canal, and causes Fic. 360.—Complete absence of the urethra the external genitals to look like those fion of the abdomen byan accumulation of Of the female—a result which is height- pring ithe pladder: and compres and ened when the penis is small or ill de- posterior wall of the bladder there were rudi- veloped . ments of tubes and ovaries.) In the female the clitoris and the labia majora and minora may be de= ficiently developed ; epispadias and hypospadias may also occur, the former associated with ecstrophy and incomplete closure of the abdomen (Fig. 357). In hypospadias a part of the posterior wall of the urethra is wanting and the urethra opens more or less widely into the vagina. The urethra may be absent in either sex (Fig. 360). In young females the bladder may open directly into the vagina. Urethral atresia can also occur in either sex, and results from a local defective development or an obliteration of the orifice. An ac- cumulation of urine may in these cases cause extreme dilatation of the bladder (Fig. 360). An abnormal narrowness of the urethra may exist in a portion of its course or throughout its whole extent. Its lumen may be com- promised by an hypertrophy of the colliculus seminalis. Occasionally the urethra opens by multiple orifices, and sometimes there is a blind canal in the glans penis, lying beside the normal urethra. Atresia ani simplex is a term used to denote a condition in which the anus is closed and at the same time the bowel well developed. It may arise from a failure of the ectoderm to fold in at the anal site, or it may be (Frank) that a cloaca already existing and opening outwardly has closed by subsequent adhesion. MALFORMATIONS OF THE EXTREMITIES. 421 If the rectum does not end directly above the anal skin, but higher up, there is beside the atresia ani also an atresia recti, a malformation which may occur also when the anus is fully developed. When there is, together with absence of the anus, also an arrested development of the vaginal wall, which should grow downward between the sinus urogenitalis and the bowel and unite with the perineum, there remains a persistent cloaca in which the sinus urogenitalis and the termination of the bowel unite. In other cases are found fistulous communications between the rectum on the one hand, and the blad- der or urethra (in boys) or the vagina or uterus on the other hand (atresia ani vesicalis, urethralis, vaginalis, uterina). In rare cases of anal closure the bowel may communicate with the outer world by external fistula in the perineum, the scrotum, or the sacrum. (f) Malformations of the Extremities due to Arrest of Development. § 145. Defective development of the extremities ig not rare, and may owe its origin to a deficiency in the primary differentiation of the embryo, be secondary to some disturbance in the development of the limb or the bones, or result from constrictions caused by strands of the membranes or loops of the umbilical cord. The cause of such defective development of the extremities may sometimes be referred to precedent malformations of the central nervous system. They are grouped into the following classes, according to the degree of malformation: 1. Amelus.- The extremities are either all entirely wanting or are represented by mere stumps or wart-like rudiments (Fig. 361). Fig. 361.—Amelus. Fic. 362.—Micromelus with cretinitic facies. 2. Peromelus. All the extremities are dwarfed. 3. Phocomelus. The hands and feet are developed, but are attached directly to the shoulder and pelvis respectively. 422 MALFORMATIONS OF THE EXTREMITIES. 4, Micromelus (microbrachius, micropus). _The extremities are fully differentiated, but remain abnormally small (Fig. 362). 5. Abrachius and apus. Absence of the upper extremities with well- developed lower extremities, or vice versa. ; 6. Perobrachius and peropus. The arms and thighs well developed ; the forearms, hands, legs, and feet malformed. ; 7. Monobrachius and monopus. Absence of a single upper or lower extremity. i 8. Sympus, sirenomelia, symmyelia, The lower extremities are coal- escent in a position of semi-rotation around their axes, so that their ex- ternal aspects are in contact (Figs. 363 and 364). The pelvis is usually absent, as are also the external genitals, bladder, urethra, and anus. FIG. 363.—fympus apus. Fic. 364.—Sympus Cipus. The feet may be entirely wanting (sympus apus) and only a few toes be present (Fig. 363), or in other cases (Fig. 364) a single foot (sympus monopus) or both feet ae dipus) may be present. 9. Absence of individual bones may exist in any part of the extremi- ties (Fig. 365). 10. Perodactylism—dwarjing of the fingers or toes—is encountered in a great many forms. In general, the condition is due either to imper- fect development, or to the entire absence of some of the phalanges (Fig. 367, and Fig. 369, c) or frequently to the presence of membranous (Fig. 866 and Fig. 368) or even bony (Fig. 367 and Fig. 369, d, e) con- nections between the fingers (syndactylism). If only the lateral fingers or toes become developed, while the mid- dle are lacking, the forms arise to which the terms cleft hand and cleft MALFORMATIONS OF THE EXTREMITIES. 423 Fig. 365. Fig. 366. Fig. 365.—Absence of the femur and fibula. Diminution in the number of the phalanges. One-half natural size. Fic. 366.—Perodactylism with syndactylism. Left hand of anew-born child. Seven-eighths natural size. Fic. 367.—Picture of the hand shown in Fig. 366 when illuminated by the Réntgen rays. Seven-eighths natural size. foot (Kiimmel) are applied. When the fingers are badly malformed there are apt to be malformations and defects in the region of the tarsal Fic. 368, Fig. 369. Fic. 368.—Malformation of the right hand (perochirus) with coalescence of the fingers. (After Otto.) a, fee thumb; b, thumb proper; c, dwarfed index-flnger; d, middle finger ; e, ring-finger ; f, little nger. Fic. 369.—Bones of the perochirus depicted in Fig. 368, shown in their dorsal aspect. (After Otto.) a-f, Same as in Fig. 368: g, ulna; h, radius; 1, os nayiculare ; 2, os lunatum ; 3, os triangulare ; 4, os pisiforme ; 5a, 08 multangulum majus superfluum; 5b, 03 multangulum ordinarium; 6, 0s multangulum minus; 7, 0g capitatum ; 8, 0s hamatum. 424 ABNORMALLY PLACED ORGANS AND EXTREMITIES. and metatarsal bones (Fig. 371) (or of the carpal and metacarpal bones). Fic. 371. Fic. 870.—Peropus dexter. (After Otto.) a, Great toe; b, little toe. F1G. 371.—Bones of the foot depicted in Fig. 370, in the dorsal aspect. a, Big toe; b, little toe; ¢, rudi- ment of the third toe; d, tibia; e, fibula; 1, talus; 2, calcaneus; 3, os naviculare; 4, os cuneiforme majus; 5, os cuneiforme minus; 6, os cuneiforme tertium ; 7, os cubiforme. These conditions are designated respectively peropus and perochirus. The lack of a hand or a foot is designated as achirus or apus. 2. Abnormal Positions of the Internal Organs and of the Extremities. § 146. Of the abnormal positions of the internal organs, the most important is the situs inversus viscerum—i.e., a lateral transposition of the thoracic and abdominal viscera. It has been observed in double monsters as well as in single individuals, and may be restricted to a simple malposition of the heart alone, or, more rarely, of only the abdominal organs. Other malpositions affect most frequently the ab- dominal viscera. The kidney, for example, is not rarely malplaced (dystopia renis), in which cases it is usually found below its normal site, near or even in front of the sacral promontory. The testis is sometimes retained within the abdominal cavity (ectopia interna seu abdominalis testis ; cryptorchismus), or in the inguinal canal (ectopia inguinalis), or at the external ring (ectopia pubica), or, finally, at some point between the latter situation and its normal position (ectopia cruroscrotalis, peri- nealis, or cruralis). Abnormal positions of the intestine, especially of the large intestine, are not rare. Among the abnormal positions of the extremities congenital luxa- tions (slipping of the articular heads from their sockets) are of par- ticular interest. They are most common at the hip, more rare at the elbow, shoulder, and knee. Von Ammon, Grawitz, Krénlein, and Holtzmann, regard them as in part the result of a local arrested development, but mechanical influences may also lead to luxation. At the hip the acetabular socket remains small and imperfect, and the head of the femur is more or less incompletely developed. The small acetab- ulum is in the normal location, the head of the femur, on the contrary, is displaced, usually backward (luxatio iliaca). At birth the ligamentum PARTIAL AND GENERAL GIANT GROWTH. 425 teres is always intact, and the capsule of the joint embraces both the acetabulum and the head of the femur. After considerable use of the extremity, the ligamentum teres stretches and may tear apart; the cap- sule is stretched to a baglike form, and at the point where it is pressed _ against the bone it may become perforated A new joint-may then be formed by the proliferation of the surrounding tissues. Abnormal positions of the feet and hands are to be attributed sometimes to disturbances of development, sometimes to mechanical influences upon the extremities when they are growing. The most im- portant of these deformities is the congenital club-foot (pes equinova- rus), which, according to Eschricht, is due to an arrest of development, leaving the foot in its foetal position, with malformation of the bones and their articular surfaces. The inner border of the foot is sharply elevated and the foot at the same time is in plantar flexion. . The collum tali is elongated in an anterior and inferior direction (Hiiter, Adams). If the children learn to walk, they tread upon the outer side of the foot, which thereby becomes flattened, while the foot becomes still more sharply turned inward. The congenital club-foot, though, as stated, usually the result of arrest of development, may occasionally be caused by an abnormal pressure due to a relatively small uterus (Volkmann). Under these conditions the positions known as pes calcaneus and pes valgus may be produced. They are characterized in part by a strong dorsal flexion, in part by a twisting of the foot. Frequently the evidences of the press- ure to which the feet have been subjected are seen in an atrophic condi- tion of the skin and the relative positions of the bones. The position of the hand designated as clubbed-hand or talipomanus is caused by a rudimentary development of the radius, and is usually associated with other malpositions in the individual. 3. Malpositions the Result of Excessive Growth or Multiplication of Organs or Parts of the Body. § 147. A malformation known as general giant growth jis the re- sult of an excessive growth of the whole body, which may take place in utero or in after-life. During extra-uterine life growth far beyond the usual maximum may take place. Partial giant growth may also take place in utero or after birth, and usually affects portions of the extremities or the head. During extra-uterine life trauma sometimes gives an impulse to a pathological excess of growth. In these hypertrophies of an extremity—as, for example, a finger— the structure of the part may preserve its general normal relations, all its constituents participating in the abnormal development. In other cases certain tissues monopolize the growth, as, for example, the soft parts, especially the fat. Furthermore, the enlarged soft parts may show a pathological structure, as exemplified by cases in which the blood- or lymph-vessels are abnormally developed. When the extremi- ties are the seat of this growth the condition is usually designated as elephantiasis. When the thickened portions are sharply circumscribed they are usually regarded as tumors, and, according to their structures, are classed with the angiomata, lymphangiomata, or fibromata. On the trunk the hypertrophies usually resemble elephantiasis, but sometimes 426 SUPERNUMERARY ORGANS. they assume the form of a neoplasm. The same is true when the parts affected belong to the face; the lips, cheeks, and tongue being not in- frequently enlarged and distorted by a hyperplasia of the connective tissue richly endowed with lymphatic vessels. Circumscribed hypertrophies of the bones occur in various parts of the skeleton, and are sometimes multiple. The bones of the head— those of the skull as well as those of the face—may be the seat of hyper- trophy, which may be so extensive as to cause a deformity of one or both of these regions, a condition known as leovitiasis ossea (Fig. 124). Circumscribed hypertrophies also lead to the formation of osteomata or exostoses, often multiple. The bones of the hip and of the extremities may present hypertrophies which may involve single bones only, or a result in the formation of atypical, frequently multiple, masses of one. § 148. Supernumerary organs, or a multiplication of the parts of the skeleton and of the muscular system, are not uncommon, and are the result either of changes occurring early in the development of the parts, or of the persistence of parts that are normally suppressed as de- velopment advances, in which latter case they may perhaps be regarded as examples of atavism. 1. Duplications at the extremities. A duplication of a whole extremity, without involving either the shoulder or the pelvis, has never been observed in man. Duplication of the hands and feet is rare, but a number of cases are on record (Fig. 372). The number of fingers may reach nine or ten. Supernumerary fingers (poly- dactylism) on a simple hand, where the extra fingers are at- tached at the radial or ulnar side Fig. 372.—Polydactylism with duplication of Fie. 373.—Polydactylism in a new-born child. the hand. (After Lancereaux.) (Skeleton only.) Duplication of the phalanges of the fourth and fifth fingers. Natural size. of the hand, or intercalated between the normal fingers, are more com- mon than a duplication of the whole hand (Fig. 369, a, and Fig. 378). Similar anomalies occur on the lower extremities. Frequently the du- SUPERNUMERARY ORGANS. 427 plication involves only the first, or the first two, terminal joints of the fingers (Fig. 374 and Fig. 375). When attached to the edge of the hand the fingers may be well developed (Fig. 373), or they may be mere rudiments. Occasionally they appear as small pe- : dunculated fibrous tumors. In the fully 8 bk ACE Fig. 374.—Polydactylism and syndactylism of Fig. 375.—Polydactylism and syndactylism of the left hand. (Reduced one-fifth.) the right foot. (Reduced one-fifth.) developed supernumerary fingers the phalanges (Fig. 373) may artic- ulate with the metacarpal or metatarsal bones of neighboring fingers, or with supernumerary bones of the hand or foot, which in turn may articulate with supernumerary carpal or tarsal bones (Fig. 369, 5 a). Polydactylism is sometimes inherited, sometimes the result of intra- uterine influences and therefore independent of heredity. 2. Supernumerary nipples and breasts (hyperthelia, hypermastia) are not uncommon anomalies in both sexes, and are probably to be re- garded as examples of atavism. They are usually situated on the thorax, along two lines running from the axillw to the inguinal regions; but they may rarely be in other places—e.g., the axilla, shoulder, ab- domen, back, or thigh. They are usually small, but may acquire func- tional activity when pregnancy takes place. Supernumerary ripples may reach as high a number as ten. 3. The formation in men of breasts resembling those of women (gynz- comastia) is rare in well-developed men with perfect sexual organs (see Hermaphrodism, § 149); but it not infrequently happens that the male breast suffers moderate enlargement at puberty. 4, Duplication of the penis with the formation of two urethra, is of very rare occurrence. 5. Supernumerary bones and muscles are of frequent occurrence. Extra vertebree may be developed at any part of the spinal column, and, at the lower end, may result in the formation of a tail. Besides the true tails containing bones, there are, according to Virchow, two forms 428 TRUE AND FALSE HERMAPHRODISM. of false or imperfect tails, which contain neither bone nor cartilage. One of these forms he regards as a prolongation of the spinal column, while the other he looks upon as a cutaneous appendage of various make-up, which may sometimes be classed with the teratomata. The true tails are very rare, and, according to Bartels, aré usually the result of an elongation or separation of the vertebre rather than.of the pres- ence of supernumerary bones. ; Supernumerary ribs in the neck or loins, as well as a forking of the ribs, are not rare. Supernumnerary teeth also occur. ; 6. Within the thorax and abdomen duplications of the viscera are most frequent in the spleen, pancreas, suprarenal bodies, ureters, renal pelves, and lungs; they occur more rarely in the ovaries, liver, kidneys, testicles, and bladder. 4. True and False Hermaphrodism. § 149. The fact that the sexual organs of both sexes develop from structures that are originally common to both, and which contain the beginnings of all the organs of both sexes, makes it @ priort probable that malformations might result through an unequal development of the organs on the two sides of the body, or through a simultaneous develop- ment of organs peculiar to the two sexes, or, finally, through a lack of harmonious development of the external and internal genitalia. Those malformations in which a single individual acquires sexual organs belonging to both sexes are grouped under the title hermaph- rodism (Fig. 376). If both sexual glands (testis, ovary) are present the case is designated as hermaphrodismus verus. If the combination of the two sexes consists merely of a simultaneous development of male and female genital passages, or of internal organs belonging to one sex and sexual passages belonging to or simulating the other sex, the case is one of false hermaphrodism or pseudohermaphrodismus. The true sex is determined by the nature of the essential sexual glands present (ovary, testis). The bodily habit of hermaphrodites frequently shows a curious blending of male and female characteristics. For example, the breasts, neck, and shoulders may approach the female type, while a development of the beard, face, larynx, and voice may correspond to the male type. In false hermaphrodites the bodily habitus may by no means always correspond to the true nature of the sex of the individual; a male may resemble a female, and vice versa. The following chief forms of hermaphrodism are enumerated by Klebs : I. Hermaphrodismus verus, or androgynes. 1. Hermaphrodismus verus bilateralis, characterized by the presence of both testis and ovary on both sides, or the presence on both sides of a compound organ containing testicular and ovarian structures. Ac- cording to Klebs, no certainly authentic case of this kind is on record for the human species. Heppner asserts, however, that he found both ovary and testis in the broad ligaments of an individual with hermaph- roditic external genitals and possessed of a vagina, uterus, and Fallo- pian tubes. 2. Hermaphrodismus verus unilateralis. Cases in which both sexual TRUE AND FALSE HERMAPHRODISM. 429 glands are present on one side, while only one is present on the other side of the body. No authentic case of this malformation is on rec- ord. 3. Hermaphrodismus verus lateralis. These are cases in which there is an ovary on one side, a testis on the other. They have been fre- quently described in human beings (Rudolph, Stark, Berthold, Barkow, H. Meyer, Klebs, Messner, and others), but usually without exact mi- croscopical examination. Inthe cases in which that has been undertaken, ovarian structures had not been made out with certainty until Obolonsky made a histological study of a case in the collection of the German uni- versity in Prague, and established the fact of a testis on the right (Fig. 376, 0) and an ovary (k) on the left side. The broad ligament on the right side contained a testis (0), an epididymis (p), a vas deferens (q), Fic. 376.—Hermaphrodismus verus lateralis. (After Obolonsky.) a, Urethra; 0, prostate; c, colliculus seminalis; d, hymen; e, urogenital canal; f, bladder; g, vagina; h, uterus; h,, left uterine horn; i, left tube; i,, infundibuliform extremity of left tube; k, left ovary ; 1, ovarian ligament ; m, left round ligament; n, right tube; 0, right testis; p, epididymis; g, right vas deferens; 7, right round ligament (About one- half natural size. Specimen in the pathological collection of the German Pathological Institute in Prague.) a rudimentary tube (n), and a round ligament (r). The left broad liga- ment contained an ovary (k) with an ovarian ligament (/) and a well-de- veloped tube (7). There was also a uterus (i), vagina (g), and a prostate (b). According to published observations of cases falling in this class, the sexual passages corresponding to the glands may all be developed or some of them may be lacking. The external genitals are malformed, and combine structures belonging to both sexes. II. Hermaphrodismus spurius, or pseudohermaphrodismus, char- acterized by bisexual development of the external genitals and genital passages, associated with a unisexual development of the essential sex- ual glands. The most pronounced cases occur in males who, besides their proper sexual organs, possess more or less well-developed vagina, uterus, and tubes. It is much rarer to find that portions of the Wolffian duct have developed in females. In male false hermaphrodites the external genitals are frequently 430 TRUE AND FALSE HERMAPHRODISM. malformed and approach the female type, while in the female they re- semble the male (Fig. 377). This resemblance is brought about in the male when the penis is stunted, its ventral furrow fails to close (hypospadias), and the two halves of the scrotum remain separate, resembling the labia majora (especially when the testes do not descend), in which case there is usually a depression at the root of the penis between the scrotal halves. Tn the female the male genitalia are simulated by a development of the clitoris into a sort of penis (Fig. 377, a), a union of the labia, and nar- rowing or even closing of the ostium vagine. The vagina and urethra Fia. 377.—External genitalia of a female false hermaphrodite with vaginal stenosis. «, Clitoris resembling penis; b, labia majora. (Five-sixths natural size.) ne have a common opening or separate openings beneath the penile clitoris. Malformation of the external genitals does not necessarily imply malformations in other portions of the sexual apparatus. 1. Pseudohermaphrodismus masculinus occurs in three varieties : First, pseudohermaphrodismus masculinus internus. The external genitalia belong to the male type, and the prostate is also developed, but is usually pierced, generally at the colliculus seminalis, by a canal which communicates with the urethra and passes above into a rudimen- tary or more or less well-developed vagina, and occasionally uterus, and even tubes. The male organs may be well developed or more or less malformed. _ Second, pseudohermaphrodismus masculinus completus or externus et internus. Vagina, uterus, and tubes are present, either more or less completely developed or in a rudimentary state, and the external geni- talia more or less resemble the female type. The penis exhibits the condition of hypospadias resembling the clitoris, and at its root there is usually an orifice leading into a vestibule which divides into a urethra TRUE AND FALSE HERMAPHRODISM. 431 and a vagina. Sometimes the vestibule and vagina are separate. In rare cases the external genitals appear normal, but the penis contains two canals, one, the upper, being the urethra, the other the sexual pas- sage. When the ducts of Muller are highly developed the vasa defer- entia are frequently defective, and sometimes the vesicule seminales are wanting. Third, pseudohermaphrodismus masculinus externus. Only the exter- nal genitalia depart from the male type, resembling more or less _per- fectly those parts in the female. As in these cases the bodily habitus often simulates that of the female, they may readily cause a mistake in the sex. : 2. Pseudohermaphrodismus femininus also occurs in three varieties, but is rarer than masculine false hermaphrodism. In pseudohermaphrodismus femininus internus rudiments of the Wolf- fian ducts, lying in the broad ligaments or in the uterovaginal walls, and sometimes extending to the clitoris, are found in individuals with well-developed external genitals. Pseudohermaphrodismus femininus externus is characterized by exter- . nal genitalia resembling those of the male (Fig. 377). Pseudohermaphrodismus femininus externus et internus, in which the external genitals resemble the male and there is a persistence of parts of the Wolffian ducts, has been recorded in only two cases (Manec, Bouil- laud, and L. de Crecchio). In one of the cases there was a prostate, in the other 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 elements which in the beginning are the same and undifferentiated in the two sexes. These elements are a sexual gland lying antero-internally to the Wolffian body and a sexual canal known as Miiller’s duct. 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 nearly disappears, only a trace, the vesicula prostatica or uterus masculinus, remaining; the primitive sexual gland unites with a part of the Wolffian body, which becomes the epididymis, another small portion forming the vasa aberrantia testis (organ of Giraldés), while the chief bulk of the organ disappears, and the Wolfiian duct becomes the vas deferens and vesicula seminalis. In the female the Wolffian body and its duct disappear, leaving only a trace, the parovarium, behind. From the ducts of Miiller, which coalesce at their lower ends, de- velop the vagina, uterus, and Fallopian tubes, the extreme upper end often persisting as a little sac, the hydatid of Morgagni. The sexual gland first appears in the fifth week. It is produced in mammalia (and probably in man) by a thickening of the peritoneal epithelium, which becomes the ger- minal epithelium of the organ (Waldeyer), while the mesoderm also proliferates. Whether the seminal tubules are derived from the peritoneal epithelium (Bornhaupt, Egli), or whether they are derived from the Wolffian body (Waldeyer), is still a mooted question (K6lliker). The ova spring from the germinal epithelium. The environing cells of the Graafian follicle are regarded by Waldeyer as also derived from the germinal epithelium, while Koélliker thinks they are probably derived from the Wolffian body. The significance of the pedunculate and non-pedunculate hydatids, situated in vary- ing numbers near the globus major, is not as yet fully determined (K@élliker). Accord- ing to Waldeyer, the hydatid of Morgagni is to be regarded as a remnant of Miiller’s duct. Roth thinks it may also stand in close relation to the Wolffian body, inasmuch as occasionally a vas aberrans of the epididymis communicates with it. The ducts of Miiller and the Wolffian ducts join in the female to form a single strand. At the end of the second month the ducts of Miiller coalesce, at first near their centres and then farther down, to form the uterus and the vagina. The Wolffian ducts gradually disappear or are represented by mere remnants, situated at birth in the broad ligaments (K@élliker) or in the walls of the uterus (Beigel). Riedel holds that they per- sist throughout life in about one-third of the cases, consisting of a strand of cylindrical epithelium surrounded by muscular tissue, or of a mere muscular bundle lying in front and to the side of the uterus and vagina. 432 DOUBLE MONSTERS. The external genitals begin to develop even before the separation of the intestinal and genito-urinary orifices, by the formation, in the sixth week, of a median genital eminence just in front of the cloaca, and of two lateral sexual folds. Toward the end of the second month the eminence becomes more prominent and its lower surface is furrowed. In the third month the cloaca becomes divided to form the anal and genito- urinary orifices. In the male the genital eminence develops into the penis, the glans be- coming recognizable in the third month, and the furrow closing to form a tube (the urethra) in the fourth month. Meanwhile the two genital folds unite to form the scrotum, The prepuce is formed in the fourth month. The prostate starts in the third month as a thickening of the tissues at the junction of the urethra and sexual passages, its glandular portions springing from the epithelium of the canal and extending into the surrounding fibrous tissue. In the female embryo the genital furrows and genital-folds do not unite, so that the sinus urogenitalis remains short. The genital eminence becomes the clitoris, the folds become the labia majora, the borders of the genital furrows the labia minora. 5. Double Monsters. . (a) Classification of Double Monsters. § 150. Twin formations lying within a single chorion may be di- vided into two large groups: in one group they are entirely distinct one Jrom the other, in the second group por- tions of the bodies are united. In the group of twins entirely separate one from the other, there are again two types to be distinguished : that in which both twins are fully de- veloped, and that in which one twin ts stunted. Twins joined together by portions Fie. 378.—Acardiacus acephalus, showing a Fig. 379.—Acardiacus pseudoacormus. (After Bar- rudimentary development of the lower extremi- kow.) a, Head; b, rudiment of the left upper extrem- ties (acardiacus amorphus). « . ity; ¢, rudimentary intestine; d, artery; €, vein. of their bodies may in the same way be again divided into two groups, namely, into the equally and the unequally developed. In reference to the situation of duplicated parts of the body one may distinguish (Foerster, Marchand) : DOUBLE MONSTERS. 433 1. Monstra duplicia katadidyma or duplicitas anterior. 2. Monstra duplicia anadidyma or duplicitas posterior. 3. Monstra duplicia anakatadi- dyma or duplicitas parallela. They may further be conveniently grouped in three families (Taruffi) : Fie. 381. Fic. 380.—Pygopagus. (From Marchand.) A, B, The two twins; a, b, theseparate umbilical cords ; ¢, the two cords united into one; d, the common placenta. There is a single coccyx and sacrum (from the second vertebra downward), and the lower end of medullary is canal single. The two intestinal canals terminate in a single anus; while all the other sexual organs are double, there is a common vestibule for the two vagine. Fic. 381.—Ischiopagus. (From Levy.) 1. Twins united mainly by the epigastrium and thorax. 2. Twins united mainly by the heads. 3. Twins united mainly by the pelves. Ahlfeld divided double monsters into- two main groups, those with complete and those with partial duplication of the axial structures. In very rare instances triple monsters are found. (b) The Chief Forms of Double Monsters. § 151. Twins separated from each other and lying within the same chorion are designated homologous twins. They are always of the same sex, have usually a common placenta, and resemble one another very closely. If from any cause one of the twins dies after its body has been developed, it may be pressed flat by the farther growth of its fellow. A foetus papyraceus results. When twins possess a common placenta within which the blood- vessels have abundant anastomotic connections, the heart of the stronger 434 DOUBLE MONSTERS. twin may work the circulation alone, and thereby cause alterations in the direction of the blood stream in the weaker foetus. The result of this is that the latter suffers grave disturb- ances in its development and becomes an acardiacus, a monster without a heart, aud develops either no heart at all or only a ru- dimentary heart. In most of these cases the head also fails to develop (acardiacus acepha- lus) or remains rudimentary (acardiacus para- cephalus), and generally there is also no development, or only in a rudimentary form, of the upper extremities, the thoracic walls and lungs and the liver; while the abdomen, » | \ Hi Lay 4 ti } oY Wid Shad WL ne = SA 2B A MD LALA F1G. 382.—Diprosopus distomus tetrophthalmus diotus Fic. 383.—Craniopagus parietalis. dibrachius. pelvis, and lower extremities are more or less perfectly formed (Fig. 378). According to the development of the extremities one may distin- guish the following varieties: acardiacus paracephalus (or acephalus) sympus, monopus, dipus, monobrachius, dibrachius. In rarer cases there is no distinct formation of any part of the body and there results an acardiacus amorphus, a shapeless mass, mostly with- out indication of extremities, and having inside only rudiments of organs. _An acardiacus pseudoacormus is a very rare formation (Fig. 879). In this monster only the head (a) is developed, while merely small rudi- ments of the rest of the body are present. , a DOUBLE MONSTERS. 435 § 152. Twins equally developed and bound together occur in the following principal types: 1. Duplicitas anterior (monstra duplicia katadidyma), duplication of the anterior portions of the body with union of the posterior por- tions. Pygopagus (Fig. 380). Union of the twins in the region of the coccyx or of the sacrum. According as the union is more or less ex- tensive, the sacrum, coccyx, lower end of the medullary canal, anal opening, lower end of the bowel, and the sexual apparatus are duplicated or partly single. Ischiopagus (Fig. 381). Union of the twins in the pelvis, through which it comes to form a wide ring, while the two sacra are opposite one another. The anus, the end of the bowel, and the sexual organs may be single or duplicated, and the number of the lower extremities from two to four. Dicephalus and diprosopus (Fig. 382), This duplication is limited to the upper part of the trunk and the head, or to the neck and head alone, or, finally, only to portions of the head. As the external blend- ing increases, there comes also a unification of the internal organs, the spinal cord, brain, etc. According to the number of the lower and up- per extremities one may distinguish dicephalus tetrapus, dipus, tetrabra- Na FIG. 384.—Cephalothoracopagus or syniceph- FiG. 385.—Thoracopagus tribrachius tripus. The hand alus with janus head. Both anterior and of the third arm, common to both halves, has two dorsal posterior faces are malformed, having only surfaces, and the laterally distorted fingers possess nails one eye, and a nose resembling a proboscis on both sides. The third foot has eight toes. situated above the eye. chius, dibrachius. ‘When the heads have blended one may distinguish diprosopus tetrophthalmus, triophthalmus, diophthalmus, tetrotus, triotus, ciotus, distomus, monostomus, tribrachius, dibrachius. 436 DOUBLE MONSTERS. The mildest grades of duplicitas anterior are the rare cases of dupli- cation of the jaw or of the mouth and the nose. | chy ee 2. Duplicitas posterior (monstra duplicia anadidyma) . This is a union of the twins at the head and thence farther downward, with dupli- cation of the posterior parts of the body. Craniopagus (Fig. 383). This is a union of the twins in the cranial part ‘, f tea, JEZe ee Fig. 386.—Polymelos. (From Lancereaux.) F1G. 387.—Polymelos. (From Liesching.) of the head. According to the site of union one distinguishes cra- niopagus parietalis, frontalis, occipitalis. When union is extensive, portions of the brain are also single. Cephalothorocopagus s. Syncephalus (Fig. 384). A union of the twins in the region of the forehead, face, and partly also the belly. 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 (janus asymmetros) developed. The internal organs show varying degrees of blending and singleness. Dipygus. Duplication is confined to the lower half of the body and the lower extremities, while the upper parts are either wholly single or only partly cleft. The duplication of the spinal cord may begin at vari- ous elevations. One may distinguish various forms based on the num- ber of the extremities. The mildest grades of duplication are confined to the lower end of the spinal column, the anus, and the external sexual organs. 3. Duplicitas parallela (monstra duplicia anakadidyma). Duplica- tion at the anterior and posterior ends of the body with parallel posi- tions of the two trunks. Thoracopagus (Fig. 385). Union of the twins by the chests. Ac- cording to the seat and extent of the union, as well as according to the number of extremities present, one may distinguish various forms, as: Xiphopagus (union at the xiphoid process of the sternum), sternopagqus (union at the sternum), thoracopagus tetrabrachius, tribrachius, dibra- chius, tetrapus, tripus, dipus. If portions of the faces have melted to- DOUBLE MONSTERS. 437 gether as well, there results a prosopothoracopagus. Melting together and resulting singleness of the internal organs vary along with the de- gree of outward blending. The heart may be double or single, in the latter case being malformed. This monstrosity is comparatively fre- quent. Rachipagus. Blending of the twins in the region of the spinal col- umn is very rare. § 153. Twins joined together but unequally developed may occur in any of the double forms described in § 152. If the development of one of the twins remains only rudimentary and no heart develops, its nourishment can come only from its developed fellow. The well-de- veloped one is then known as the autosite and the rudimentary one as the parasite. If the parasite is only very rudimentary, it is classed with the bigerminal teratomata (cf. § 134). At the posterior end of the body a rudimentary parasitic double mon- strosity occurs in the form of increase in the number of the extremities, a polymelos (Fig. 886 and Fig. 387). The extra extremities may be one or two in number and may have undergone more or less perfect develop- ment. The malformation may be regarded as a dipygus parasiticus. In the coceygeal region it is not rare to find teratomata, in which the pres- ence of rudimentary extremities (Fig. 388 a, b, c) or various body portions leaves no doubt that what presents itself to external view as a tumor, covered as it is by the skin of the autosite, is in reality to be ieee Fic. 388.—Bigerminal teratoma of the coccygeal Fig. 389.—Thoracopagus parasiticus (polymelos). region. (Pyopagus parasiticus.) a, 6, c, Extremi- Three legs spring from the pelvis, and one of them ties, which are lying Ina sac formed by the skin of has a double foot. Two upper extremities project the autosite. from the anterior wall of the chest. regarded as a double monster, a rudimentary pygopagus (Fig. 388) or else a dipygus parasiticus. The parasite is called an epipygus. On the trunk, also, extra extremities occur (Fig. 389), or a headless 438 DOUBLE MONSTERS. trunk with extremities (Fig. 890), or a rudimentary one only, without ex- tremities ; or, finally, teratomata, formations which one may regard as thoracopagus parasiticus and as dipygus par- asiticus. The malformation is also often called an epigastrius. Where such teratomata lie beneath the Fig. 390. Fie. 391. Fic. 390.—Dipygus parasiticus. (From Schenk von Graefenberg.) Parasite springs from the thorax of the autosite. Fic. 891.—Epignathus. (After Lancereaux.) skin of the belly or chest of, or are within the abdominal or the thoracic cavity of, the autosite, the conditions are known as inclusio fetalis sub- cutanea or abdominalis or mediastinalis. The abdominal inclusion is also called engastrius. In the region of the head a rudimentary twin-formation is most fre- quent in the mouth, being usually a formless mass, firmly adherent to the base of the skull, called an epignathus (Fig. 391) and composed of skin, connective tissue, cartilage, bone, brain substance, teeth, intestinal elements and muscles, rarely containing well-formed extremities. On other parts of the head rudimentary twin-formations or biger- minal teratomata are very rare (cf. § 134). CHAPTER IX. Fission=-fungi which Exist as Parasites and the Dis-= eases Caused by Them. I. General Considerations in Regard to the Schizomycetes or Fis= sion-fungi. 1. General Morphology and Biology of the Fission-fungt. § 154. The schizomycetes or fission-fungi, also frequently called collectively bacteria, belong to the protophytes—i.e., to the very small- est, simplest plants. Many of them are so small that they stand upon the very border-line of invisibility even with the use of the strongest system of lenses. When they occur in animal tissues they are therefore often to be distinguished from disintegrated cell-products of the tissues only with the greatest trouble—i.e., only by the use of different re- agents or methods of staining. The jission-fungt throughout are devoid of chlorophyll and are unicellu- lar organisms, but they are often found aggregated in smaller and larger colonies. The form and character of the individual cells, as well as their growth, their division and reproduction, are different, and at present these differences are used to group the bacteria into different genera. The cocci, often also called micrococci, constitute the first genus of fis- sion-fungi, and constantly occur as spherical or oval cells, and were formerly often called spherobacteria (Cohn). Six forms of growth can be distinguished according to their grouping in the process of reproduc- tion: double cocci or diplococci, chain-cocci or streptococci, clustered cocct or staphylococci, tablet-formed cocci or merismopedia, packet-shaped cocci or sarcine, and tubular cocci or ascococci. - The bacilli (rod-shaped bacteria) form the second class, which was formerly divided by Cohn into microbacteria and desmobacteria, accord- ing to the length of the rods. Hence they may also be classified as short rods and long rods. Along with the designation bacillus many authors employ the name clostridium for bacilli which assume spindle and club shapes in the formation of spores. Long threads are also often called leptothrix. The spirilla (screw-like coiled rods) form the third genus. Screws with short, wide turns are called spirilla, those with drawn-out turns vibrios, those with a long, narrowly twisted screw, spirochaéte. They may also be subdivided, according to their length, into short screws and long screws. All of the bacteria as yet referred to occur either in one single form of growth or in a very limited cycle of forms of growth, and may there- fore be grouped together as monomorphic or oligomorphic bacteria. 440 MULTIPLICATION AND SPORE-FORMATION. Cohn, to whom we are indebted for the fundamental investigations of the bacteria, united under this term exclusively these oligomorphic organisms. : Ae fake By many authors, however, organisms which display in their indi- vidual development a long series of forms of growth—i.e., forming spherical cells as well as rods and simple and branched threads—have also been classified as bacteria. These can be brought together in a second group—the polymorphous bacteria—where belong especially such fungi as leptothrix, cladothrix, beggiatoa, and crenothrix. The fission-fungi are all made up of a plasma, or cell-contents, sur- rounded by a cell-membrane, both, according to Nencki, consisting for the most part of an albuminous substance, or mycoprotein. According to A. Fischer the contents are formed of a protoplasmic tube without a nucleus, but with acentral collection of fluid. Butschli, Schottelius, and others conceive the recognizable central bodies in the single bac- teria to be nuclei. According to Nageli, Zopf, and others, many fission- fungi possess a membrane consisting of cellulose, or at least of a carbo- hydrate very nearly resembling cellulose. This membrane becomes turgid under certain conditions of growth in many of the bacteria, and forms a capsule having a hyaline appearance. Tn all forms of the bacteria except the cocci wandering motion has been observed, which is brought about by means of fine flagellate threads in lively vibration. In addition there is a slow oscillatory or a gliding and creeping motion carried on by the contractile and flexile plasma. Both forms of motion appear only under certain conditions of nutrition and growth and only in certain species. Multiplication of the bacteria takes place by transverse division of the cell, which previously grows out longitudinally. In some forms division can take place in two or even in all three dimensions of space. After division the cells separate immediately or remain for a time hang- ing together. If they hang together after dividing according to the first method, they form threads (streptococci, leptothrix); according to the second method, colonies in a plane are formed (merismopedia); accord- ing to the third method, colonies are formed in a solid body (sarcine). Long threads can become segmented into shorter pieces. According to the investigations of Buchner, Longard, and Riedlin, the period of reproduction—i.e., the length of time from one cell-divi- sion to the next—in the cholera-spirillum under favorable conditions of nutrition varies from fifteen to forty minutes. If the bacteria in the period of rest aggregate into clumps in conse- quence of constantly progressing reproduction, or by the accumulation of neighboring cells anywhere in great masses, there are often formed glutinous colonies which are called zodgleea. The jelly is formed out of the cell-membranes of the fission-fungi, and, according to Nencki, it also consists of mycoprotein. The glutinous masses can assume the most various shapes, and reach at times a considerable size, forming clumps or patches or ropes of from one to three or more centimetres in diameter. Under certain circumstances many of the fission-fungi form spores. These are cells which are distinguished by the fact that they remain alive under conditions in which the ordinary vegetative forms die; and moreover, when they are put into fresh nutrient solutions, they can pro- duce a new generation. Most frequently the spore-formation is endogenic —i.e., the spore arises inside of a cell, especially in bacilli, and is de- NUTRITION OF FISSION-FUNGI. 441 veloped out of the protoplasm of the cell. In the latter a small granule appears, which grows out into an oblong or round, highly refractive, sharply contoured body, always remaining smaller than the mother-cell. The spore becomes free after the disintegration of the mother-cell. The formation of arthrospores, observed in micrococci, is said to take place by the assumption directly of the characteristics of spores by individual members of a colony or of one of the series of generations, while at the same time they either remain externally unaltered or take on other mor- phological peculiarities. In old cultures the bacteria nearly always show degeneration forms. ee are swollen and distorted, and take the stain poorly and irregu- arly. Babes and Ernst, by special methods of staining with Loffler’s methylene blue, hematoxylin, and Platner’s nuclear black, have found in the interior of different bac- teria granules which, according to their behavior, probably bear some relation to the cell-division and to the spore-formation. Ernst designates the bodies found by him as sporogenic granules, since he was able to trace in some bacteria the transition of these into spores. He is inclined to attribute to them the nature of a cell-nucleus, a view assented to by Biitschli. Bunge looks upon the bodies described by Ernst as cell-gran- ules, which have no connection with spore formation, and describes other bodies, stain- ing with Léffler’s solution, as the predecessors of the spores. § 155. The fission-fungi, owing to the absence of chlorophy] in them, are restricted in their nutrition entirely to ready-formed organic sub- stances which are soluble in water and which are supplied to them in an abundance of water. They need, moreover, various mineral sub- stances, especially sulphur, phosphorus, potassium or rubidium, or cesium and calcium, or magnesium or barium or strontium. They are capable of taking their necessary carbon from most of the carbohydrates that are soluble in water. They can derive their carbon from dilute solutions of compounds which in greater concentration are destructive, as, for example, benzoic acid, alcohol, salicylic acid, phenol, etc. The fission-fungi derive their nitrogen from albuminous matter ; they also obtain it from those compounds which are designated as amins (methylamin, ethylamin, propylamin), amido-acids (asparagin, leucin), and amides (oxamide, urea); and they may obtain it from the am- monia salts, and partly also from nitrates. The albuminates are changed into peptones, previous to their assimilation, by a ferment given off from the fission-fungi. Free nitrogen cannot be assimilated as such. Nitro- genous and non-nitrogenous compounds are not only assimilable as such, but alsoin combination. The fission-fungi can derive their nitrogen from ammonia and nitric acid only in the presence of organic carbon com- pounds. According to Nageli, sulphur is essential to the fission-fungi, and they take it from sulphates, sulphites, and hyposulphites. They take the other mineral substances enumerated above from various salts. If along with abundance of nutrient material there is too little water pres- ent, all further growth ceases; still many fission-fungi are able to dis- pense with water temporarily. Spores suffer very little from the effects of drying. Some of the fission-fungi are restricted, for their nourishment, main- ly or exclusively to dead organisms or to solutions of organic matter, and belong, therefore, to the saprophytes. Others are also able to 25 4492 NUTRITION OF FISSION-FUNGI. derive their nutrition from living animals or plants, and are therefore to be reckoned among the parasites. : 5 If the fission-fungi get into water containing no nutritive material, many of them dieintime. The spores resist the longest in this respect. Free oxygen is necessary for the growth of many bacteria; others can dispense with it so long as they are under favorable conditions in other respects; still others develop only where oxygen is cut off. The first of these are called obligatory aérobes, the second facultative anaé- robes, the third obligatory anaérobes. . ; Facultative anaerobes produce in part fermentation by their multi- plication in the absence of oxygen; but, according to the investigations of Fluigge and Liborius, fermentative phenomena seem also often to be absent. Pathogenic bacteria, according to Liborius, are facultative or obligatory anaérobes. Carbon dioxide has no influence upon the development of many bac- teria, as, for example, upon the typhoid-fever bacilli and upon the Friedlander pneumonia-bacilli. Upon others, on the contrary, it has an inhibitory action, as, for example, upon Bacillus indicus, Proteus vulgaris, and Bacillus phosphorescens, the bacilli of anthrax and of cholera, the pus-cocci, and others (C. Frankel). The bacilli of anthrax, of cholera Asiatica, and of rabbit septicemia die out in a few hours in artificial Seltzer water, but the spores of anthrax-bacilli keep alive indefinitely (Hochstetter). Intense light has an injurious or destructive effect upon the develop- ment of many bacteria, and consequently infected water can be disin- fected by light (Buchner). In Bacillus anthracis the virulence can be weakened by sunlight (Arnold, Gaillard). Anthrax-spores die out when exposed for a long time to light and air (Arloing, Roux). According to Geisler, the green, violet, and ultra-violet ara the rays which are par- ticularly injurious to them. According to Nageli, Hauser, Buchner, Zopf, and others, different conditions of nutrition act in modifying the form and dimensions of the Jission-fungi. For example, bacilli cultivated in different nutrient solu- tions have different lengths as well as different thicknesses. In many varieties, moreover, it is said that, in one nutrient solution, the change is generally into spherical cells and short rods, while in another, on the contrary, it is into long threads (Zopf). Finally, the physiological prop- erties can also change under different modifications of nutrition. The temperature of the medium surrounding the bacteria acts generally in such a way that when there is a fall the vital processes be- come weaker and slower, and finally cease, whereas with elevation of the temperature they rise to a certain maximum, and at a slight excess above this suddenly cease; still higher temperatures kill the fungi. The maximum of permissible temperature lies at a different height for different fungi, and is also partially dependent upon the character of the nutrient substance. A low temperature stops development in all. They fall into a state of numbness, but do not die even at very cold temperatures. The rigid- ity due to cold develops in the individual forms at different tempera- tures. The most favorable temperature for the Bacillus anthracis lies between 30° and 40° C.; at temperatures above 44° C. and below 15° C. there is cessation of development. Many bacilli form spores only at high temperatures. : Boiling water and steam at 100° ©. kill all bacteria and bacterial SUBSTANCES UNFAVORABLE TO THE FISSION-FUNGI. 443 spores if allowed to act for some time. Bacteria and their spores bear higher temperatures in dry air, so that a temperature of 140° C. for three hours is necessary to kill the latter. Many bacteria are killed at a tem- perature of from 60° to 70° C., provided it is kept up for a very long time. Anthrax-bacillt multiply within certain limits more and more slowly the lower the temperature is. Between 30° and 40° C. growth and spore-formation usually cease at the end of twenty-four hours. At 25° C. the time required rises to from thirty-five to forty hours. At 23° C. forty-eight to fifty hours are required for the spore-formation ; at 20° C., seventy-two hours. At 18° C. spores appear at the end of five days; at 16° C., after seven days. Below 15° C. all growth and spore formation cease (Koch). Spore- formation still takes place even at 42° C, In hot, dry air, bacilli free from spores do not withstand a temperature a little over 100° C. for an hour and a half. In hot, dry air, spores of the bacilli are destroyed ata temperature of 140° C. at the end of three hours. Anthrax-spores die in boiling water in two hours, in confined steam in ten minutes; but the spores of the garden-earth bacillus are not killed in this time. The action of steam at 105° C. for a period of ten minutes kills all spores. Watery vapor in motion kills all spores in from ten to fifteen minutes, and penetrates very well into the objects to be disinfected (Koch, Gaffky, Loffler). According to Arloing and Duclaux, anthrax-bacilli die in from twenty-four to thirty hours when expose to the direct rays of the sun; spores in from six to eight weeks. § 156. If fission-fungi find themselves in a medium which suits them, their multiplication can still be brought to a standstill provided the fluid contains substances which hinder their growth and even kill them. This effect is produced by many substances—sublimate, lysol, carbolic acid, iodine, etc.—even in comparatively great dilution. Other sub- stances operate injuriously upon the bacteria only when they are in stronger concentration. The point at which the multiplication is hin- dered is always reached at much greater dilution than that at which the ese are killed. Spores are much more resistant than the vegetative orms. Many bacteria are very sensitive to acids, so that even a small degree of acidity hinders the growth. This is true, for example, of the organ- ism of anthrax and of the Frankel-Weichselbaum pneumococcus. But still some are able to grow with a moderate amount of acid in the nutri- ent fluid. Asa general rule they are specially sensitive to the mineral acids, but the presence of a large amount of citric, butyric, acetic, and lactic acid also hinders the multiplication. In this connection belongs the fact that the products of decomposition caused by the fermentative action of the fungi at a certain degree of concentration are injurious to the development of the fungi, and finally stop their growth entirely. Thus in butyric-acid and lactic-acid fermentation the quantity of butyric acid and of lactic acid gradually formed may finally cause cessation of the growth of the fungus. A similar result occurs in the bacterial putrefaction of albumin, since the products, such as phenol, indol, skatol, phenyl acetic acid, phenyl propionic acid, etc., hinder the further development of the bacteria. The fission-fungi are less sensitive to alkalies, and many of them can bear a tolerably high degree of alka- linity in the nutrient fluid; but, on the other hand, there are certain forms which do not flourish in alkaline fluids—e.g., acetic-acid fungus. Multiplication also ceases in the presence of a superabundance of nutrient material—i.e., with an insufficent amount of water. Tie fact that fruit preserved in sugar, and salted and dried flesh, do not be- come foul depends upon this. Food-stuffs can also be preserved by de- priving them of water and by the addition of substances which are dis- solved in the tissue-fluids, and in this way increase the proportion of 444 FERMENTS PRODUCED BY GROWTH OF FISSION-FUNGI. solid matter. The limit at which development takes place is reached at a much higher degree of humidity for the fission-fungi and yeast-fungi than for mould-fungi. . According to investigations of Pfeffer and Ali-Cohen, many motile bacteria show chemotactic properties—i.e., they are attracted or re- pelled by chemical substances dissolved in water. The bacteria swim- ming around in the fluid consequently collect together at places where there are chemical substances which attract. Typhoid-fever bacilli and cholera-spirilla, for example, are attracted by the juice of a potato (Ali- Cohen). Potassium salts, peptone, and dextrin also act by attraction, but the individual bacteria behave differently toward these substances (Pfeffer). Free acids, alkalies, and alcohol have a repulsive action. If a nutrient fluid contains other lower fungi besides the bacteria there often takes place a competition between the different micro- organisms, and fission-fungi, budding fungi, and mould-fungi can crowd one another out. Ina similar manner a reciprocal crowding out occurs among the fission-fungi themselves. Thus, for example, cocci can be supplanted and destroyed by bacilli, or one form of bacillus by another. This would happen where either the composition or the tem- perature of the nutrient fluid is more favorable for-one or for the other, or also where one species of bacteria forms products which act inju- riously upon the other, or where one form grows more rapidly than the other and in this way takes away the necessary nutrient material from the competitor. According to the investigations made by Pasteur, Emmerich, Bou- chard, Woodhead, Blagovestchensky, and others, the antagonism be- tween many bacteria shows its influence even in inoculation experiments upon animals. By simultaneous inoculation with different bacteria it sometimes happens that the development of a pathogenic fission-fungus in the body of a susceptible animal is hindered. Thus, for example, the development of the anthrax-bacillus can be hindered by a simulta- neous inoculation with erysipelas-cocci (Emmerich) or with the Bacillus pyocyaneus (Bouchard). If, for example (Nageli), fission-fungi, yeast-fungi, and mould-fungi are introduced together into a solution of sugar, the fission-fungi alone increase and cause lactic-acid fermentation. If to the same solution five per cent of tartaric acid is added, the budding fungi alone multiply and cause alcoholic fermentation. If four or five per cent of tartaric acid is added, only the vegetation of mould is obtained. The addition of the tartaric acid does not make the life of the other fungi impossible, but only favors the develop- ment of one over the other. In the same way the budding fungi alone develop in grape- juice, although other germs find their way into it, and the fission-fungi can multiply and produce acetic acid only after all the sugar is used up. Mould-fungi, which destroy the acid, can develop on the vinegar. Subsequently fission-fungi again appear and produce putrefaction. § 157. The growth and multiplication of the fission-fungi always cause chemical transformations of the nutrient material, and these are brought about in part by the influence of the ferments secreted by the bacteria, in part directly through the metabolic processes occurring within the cells themselves. Among the ferments or enzymes are to be mentioned especially the proteolytic or albumin-dissolving enzymes (bacterio-trypsins), which bring about the solution of the albuminous bodies, and thereby cause the de- struction of the peptone molecule. The bacteria further give rise to diastatic ferments, which change starch into sugar, likewise to inverting PTOMAINS, TOXINS, AND TOXALBUMINS. 445 ferments which transform cane-sugar (disaccharid) into grape-sugar (monosaccharid). One of the first chemical results of the bacterial metabolism,— or, in other words, of the vital activity of the fission-fungi aided by their enzymes—is the breaking up of complex organic compounds. By many authors all these processes are designated as fermentations, while other authors (Lehmann) only speak of fermentations, when a fission-fungus breaks down a given food material with particular ease, and thereby gives rise to a special product, or, may be, several, in marked quanti- ties, along with or in place of its other metabolic products. Other authors, still, limit the term fermentation to the destruction of the car- bohydrates. In the decompositions caused by the fission-fungi many widely different products are formed, which vary according to the composition of the nutrient material and the character of the fission-fungus. For fermentation to take place proper fermentable material is necessary. Many fungi can cause fermentation as well in the presence as in the ab- sence of oxygen, while to some of them a paucity of oxygen is essential. Among the products of the bacteria, which are of especial importance to the physician, are those which act poisonously and cause tissue changes, and to which belong particularly those substances which are described as ptomains, toxins, and toxalbumins. The ptomains are basic, crystallizable, nitrogenous products of the destruction of albumin by bacteria; they are also known as the alkaloids of putrefaction or cadaveric alkaloids. When they display poisonous properties, they are classified among the toxins. The best known among them are sepsin, putrescin (dimethylethylendiamin), cadaverin (pentamethylendiamin), collidin (pyridin derivative), peptotoxin, neu- ridin, neurin, cholin, gadinin, and also substances resembling mus- carin. The toxalbumins are amorphous poisons, which occur in bouillon cultures of many of the bacteria. They are precipitated by the same methods that cause the precipitation of albumin, and hence are looked upon by most investigators as albuminous bodies. Nevertheless it is to be remarked that they are possibly, in part, bodies only carried down along with the precipitated albumin; and the proof (Brieger) that the specific poisons of tetanus and diphtheria, which have been classified among the toxalbumins, have been shown to be free from albumin argues for such a conception. It appears therefore more correct to classify these specific poisons also as toxins. They constitute those poisons which determine the special form of the intoxication in the various infectious diseases. Among other decompositions worthy of note which are caused by bacteria are: the formation of lactic acid, formic acid, acetic acid, pro- pionic acid, butyric acid, also often alcohol and carbonic acid from sugar; the formation of acids (acetic acid, butyric acid, propionic acid, valerianic acid, succinic acid, formic acid, carbonic acid) from alcohol and organic acids; the formation of indol, skatol, phenol, cresol, pyro- catechin, hydrochinon, hydroparacumaric acid, and paroxyphenylacetic 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 also in the soil living bacteria— 446 FERMENTATION. the nitrobacteria—which are able to form nitrous and nitric acids from ammonia (Winogradsky ). ; Along with the nitrification of nitrogen there takes place simulta- neously a destruction of the earthy alkali carbonates, as shown by the fact that the nitrobacteria are able, in the absence of organic carbon compounds, to derive the carbon necessary for the building up of their cells from the salts of carbonic acid. There takes place, therefore, as a result of the vital activity of these organisms, a synthesis of organic material out of inorganic substances. Under the influence of the fission-fungi there are formed bitter, sharp, disgusting substances that are but little known. Milk that has become bitter affords an example of this. Furthermore, fungi occasionally pro- duce pigments of red, yellow, green, blue, and violet color. Thus, for example, a blood-red coating of Bacillus prodigiosus forms on bread (bleeding bread); moreover, bandages and pus sometimes turn blue in consequence of the presence of the A/icrococcus cyaneus. In very many cultures a fluorescent coloring material is formed. The phosphorescent phenomena to be seen not infrequently on putre- fying sea-fish depend also upon bacterial products of decomposition, as proven by Pfliiger, and appear where there is a lively reproduction of the bacteria. The first investigations to establish the changes characteristic of putrefaction were made by Th. Schwann and Franz Schulze,! in the middle of the fifties, and upon the results of their experiments they expressed the opinion that fermentation and putrefac- tion depend upon tlse presence ot very small organisms. Almost at the same time (1857) Cagnard-Latour observed the multiplication of yeast-cells in alcoholic fermentation. The observation made by Schwann was subsequently corroborated by Helmholtz. H. Schroeder and von Dusch then showed that by filtering through cotton-wool the air ad- mitted to a fluid capable of fermentation, and also by the action of higher temperatures, the appearance of fermentation may be hindered. Since the investigations of Schwann there have been advanced many hypctheses upon the cause of fermentation, especially upon the alcoholic fermentation caused by the yeast-fungi. Certain authorities have sought to bring these processes into immediate relationship with the life of the cells that cause the fermentation ; others have sought to separate them from the latter. According to Liebig, the process is due to a molecular movement which an unformed ferment or a body in a state of chemical activity—i.e., decomposing—imparts to other bodies whose elements are not held strongly together. According to Hoppe-Seyler and Traube,? the cells excrete certain substances, so-called unformed ferments, which cause decomposition by contact action—i.e., merely by their presence, without taking part chemically or entering themselves into a compound. According to Pasteur,? fermentation is dependent directly upon the life of the fer- mentative cells. It occurs only when free oxygen is lacking to the cells, so tha* these have to take the oxygen from the chemical compounds in the nutrient fluid. In this way the molecular balance of the latter is destroyed. According to von Nencki, also, anaérobiosis is to be regarded as the cause of the different kinds of fermentation. According to Nageli’s molecular-physical theory,* fermentation is a transfer of molec- ular motion from the living protoplasm to the material undergoing fermentation. This motion is present in the molecules, groups of atoms, and atoms of all substances. The conipounds forming the living protoplasm remain themselves unchanged, but by the transfer of molecular motion they destroy the equipoise in the molecules of the ferment- ing substance, and these become disintegrated. According to E. and H. Buchner there can be obtained from yeast, by a pressure of 400-500 atmospheres, a cell-juice which causes fermentation in sugar solution directly. Fermentation is therefore not bound up with the life of the cells, but is caused by a cell 1 Poggend. Annal., 29 Bd., ref. in Schmidt's Jahrb., 1866. ?Cf. Hoppe-Seyler, Pfliiger’s Arch., 12 Bd., 1875, and “ Physiol. Chemie.” 8 Ann. de Chim. et de Phys., tome 58, 1860, et tome 64, 1862; Comptes rend. de V Acad. des Sciences, tomes 45, 46, 47, 52, 56, 80; and Duclaux, “ Ferments et Maladies,” Paris, 1882. 4 Abhandl. d. Bayr. Akad., Math.-phys:k. Kl., iii., 76, 1879. ee eee PATHOGENIC FISSION-FUNGI. 447 substance—“ zymase’’—which apparently is secreted by the cell, and on the surface of the latter splits the fermentable sugar into alcohol and carbonic acid. H. Buchner is of the opinion that the specific toxins (for example of tetanus and of diphtheria) also are ingredients of the plasma of the bacilli concerned. The power to produce fermentation—i.e, decomposition—in the nutrient fluid is very likely not only a property of fission-fungi and yeast-fungi, but also of the cells of more highly organized beings, therefore also of man. According to Voit,! the decom- position of the dissolved albumin circulating in the organism is attributable to a fer- mentative activity of the cells. Pasteur has shown that fruit and leaves possess fermen- tative properties under suitable conditions. Along with fermentation and putrefaction which result from fungi, there are other decompositions of organic substances in the production of which the fungi have no part. These consist mainly in a slow oxidation or burning, in which carbon dioxide and water are formed, and, in the case of nitrogenous substances, also ammonia. This form of decomposition takes place under conditions in which atmospheric air and moisture are in contact with organic matter. Moreover, it also takes place in the living organism. In dead organic matter this answers partially to the process usually called mouldering. 2. General Considerations concerning the Pathogenic Fission-fungi and their Behavior in the Human Organism. § 158. As has been already explained in §$ 12, 13, and 14, there are among the fission-fungi numerous species which are capable of produc- ing disease processes in the human organism, and they are therefore called pathogenic fission-fungi. The first condition of such action is evidently that the bacteria concerned must possess properties enabling them to multiply in the tissues of the living human body. They must Fig. 392.—Section through a vocal cord of a child with streptococcus colonies upon and in the epithelium. ‘a, Epithelium ; 6, connective tissue of the mucous membrane; c, swollen, degenerated epithelium, in part devoid of nuclei; cd, layer of cocci; e, reactive small-cell infiltration, partly inside the degenerated epithelium, partly in the connective tissue. Magnified 200 diameters. consequently find in the tissues the suitable nutrient material, and in the body-temperature the warmth necessary to their growth. The tis- sues, moreover, must not contain substances which are a hindrance to their growth (cf. §§ 29 and 30). If pathogenic fission-fungi succeed in growing in the tissues of the . body—i.e., if infection takes place (cf. § 14)—their action is in general characterized, at the point of multiplication, by degeneration (Fig. 392, 1 Physiologie des Sauerstoffwechsels,” Leipsic, 1881. 448. PATHOGENIC FISSION-FUNGI. d), necrosis, inflammation (e), and new growth of tissue, while the toxins produced by them cause manifestations of poisoning. ; - But in individual cases the disease process assumes different forms, in that the distribution of the bacteria in the organism and their local action, as well as the production of poisons, differ greatly with the differ- ent forms of bacteria. With many of them the local action upon the tissues comes to the front; with others the general intoxication. Many bacteria confine themselves to the region in which they have found entrance ; others advance uninter- ruptedly into the surrounding neighborhood ; still others are carried by the lymph- and blood-currents and lead to the formation of metastatic foct; and finally, still others increase in the blood. ; . If a spread of the bacteria takes place through the blood, the bacteria may go from the mother to the fetus during pregnancy, since the placenta forms no certain filter against pathogenic bacteria. This has been proved, for example, for anthrax-bacilli, for the bacilli of symptomatic anthrax, for the bacilli of glanders, for the spirilla of relapsing fever, for the bacilli of typhoid, and for the pneumococcus. According to certain observations of Malvoz, Birch-Hirschfeld, and Latis, changes in the placenta, such as hemorrhages, loss of epithelium, alterations of the vessel-walls, favor the transmigration of the bacteria. Bacteria—as, for example, anthrax-bacilli—can grow through the tissues. The passing over of bacteria from the mother to the foetus presupposes, as a rule, that after the entrance of these organisms into the circulating blood of the mother, the latter shall remain alive at least long enough to allow of the transmigration. The bacteria which succeed in multiplying in the human body die out again, in many cases, in a short time, and the diseases caused by them proceed to recovery (cf. § 28). Nevertheless it also not infrequent- ly happens that they are preserved for a long time in the body, and either continuously cause disease processes, or, on the other hand, remain in a state of inactivity, so that no disease processes of any kind are recog- nizable till, after a shorter or longer period of latency, a lively multiplica- tion takes place, and along with it new manifestations of disease show them- selves. Not infrequently a secondary infection associates itself with an infection already existing. The relation between the two infections is either that the second occurred accidentally after the first became estab- lished, or, on the other hand, that the way was prepared by the first infection for the subsequent one (cf. § 14). Finally, double infection, in which two or even more forms of bacteria come to development in the tissues simultaneously and exert their de- structive influence upon them, is not an infrequent occurrence. § 159. Each pathogenic fission-fungus has a specific action upon the tissues of the human body; but, nevertheless, different species of fission- fungi may exert similar action. Thus, for example, various bacteria can cause suppuration. Consequently it is only in a certain proportion of cases that the morbid changes in the tissues are so characteristic that the species of the pathogenic fission-fungus can be recognized with cer- tainty. It has been demonstrated, moreover, that the pathogenic properties of ‘the bacteria are not entirely constant; that, on the contrary, their virulence varies, so that bacteria that cause severe or fatal infection may PATHOGENIC FISSION-FUNGI. 449 become changed through external circumstances; that is to say, may become weakened so that they either lose entirely the power to produce processes of disease in the organism, or at least can cause only mild forms of disease. This peculiarity is not alone of theoretical interest, but is also of high practical interest. It explains, on the one hand, to a certain extent, why a certain infection does not always run the same course, and, moreover, why alongside of severe atiacks light ones also occur. On the other hand, it affords us the possibility of obtaining material for inoculation from attenuated cultures of bacteria, by means of which slight degrees of infection and also slight degrees of intoxica- tion can be produced, which protect the organism from severe infection, or cure an infection that has already taken place (cf. § 30). Attenuation of the pathogenic properties of a fission-fungus can be effected by allowing higher temperatures, oxygen or light, or chemi- cal antiseptic substances to act in a suitable manner upon the cultures as well as by cultivating the fungus in the body of animals possessing little susceptibility. In some forms, as in the diplococcus of pneumonia, it is only necessary to cultivate the bacteria in question upon artificial media to bring about attenuation; in others, such as the bacillus of chicken-cholera, prolonged exposure of the culture to the air suffices to bring about an attenuation. If it is desired to preserve the virulence of the pneumococci for a long time, it is necessary, from time to time, to inoculate the bacteria cultivated upon artificial media into rabbits, which are very susceptible animals. The glanders-bacilli and tubercle-bacilli and cholera-spirilla lose virulence if cultivated for a long time uninter- ruptedly upon artificial nutrient media. The streptococcus of erysipelas becomes so attenuated by continued cultivation in bouillon or nutrient jelly that it is no longer capable of killing even mice (Emmerich). It is possible to make only hypotheses in regard to the explanation of the nature of the attenuation of virulence of the bacteria by the methods above mentioned. If the bacteria cultivated for a long time upon artificial media change in virulence, perhaps this can be partially explained by assuming that in a series of generations the less virulent varieties, which certainly must often appear, gradually win the superi- ority. In the attenuation of virulence by heat, chemical reagents, etc., however, this explanation is not permissible. In this case it turns very likely upon a general weakening, a degeneration of the protoplasm. This assumption is in accord with the fact that such bacteria show a diminution.in energy of growth. According to the investigations of Pasteur and of Koch, the virulence of anthrax- bacilli may be so attenuated by cultivation at 43° C. for about six days, or at 42° C. for about thirty days, that guinea-pigs are no longer killed by the inoculation. A considerable attenuation of the anthrax-bacillus is obtained even by ten minutes’ heating at 55° C. (Toussaint), or by heating at 52° C. for fifteen minutes, or at 50° C. for twenty minutes (Chauveau) ; moreover, the same result is also obtained by the action of oxygen at high pressure (Chauveau). The bacilli weakened by the influence of high tem- perature for a short time regain their virulence very quickly by recultivation ; the bacilli, on the contrary, which have been weakened at lower temperatures remain attenuated through numerous generations. Spores of the bacillus of blackleg are rendered harmless by a temperature of 85° C. in six hours (Arloing, Thomas, Cornevin) without suffering any diminution in their power of reproduction. Moreover, the bacilli can be weakened without killing them by weak solutions of sublimate, thymol, eucalyptus-oil, nitrate of silver, etc. The addition of carbolic acid in the proportion of 1: 600 to the culture-fluid permits of the development of anthrax-bacilli, but destroys their virulence in twenty-nine days (Chamberland, Roux). In the same way attenuation is obtained by addition of bichro- 450 EXAMINATION OF FISSION-FUNGI. mate of potash (from 1: 2000 to 1: 5000). Carbolic acid added in the proportion of 1: 800 prevents at the same time the formation of spores. f : ; The poison of rabies, which kills rabbits in a short time on inoculation, may be attenuated by drying at temperatures of from 22° to 26° C. (Pasteur). According to Pro- topopoff, it is mainly the higher temperature which produces the attenuation. ’ If the bacilli of swine-erysipelas (Pasteur) are inoculated continuously into pigeons the virulence is so increased that not only pigeons die more quickly from the inoculation than at the beginning, but also hogs. But when, on the contrary, the swine-erysipelas bacilli are inoculated from rabbit to rabbit, they increase in virulence for rabbits, it is true, but lose in toxic power for swine. 3. General Considerations in Regard to the Examination of Fission-fungi. § 160. If bacteria are suspected in any tissue-fluid or in the paren- chyma it is first sought to discover them by microscopic examination. Occasionally this succeeds by merely looking at a drop of the fluid or of a smear-preparation of the tissue-juice diluted with salt-solution or distilled water. In other cases it is necessary to apply coloring. In ‘this case the fluid above mentioned is smeared on a cover-glass and allowed to dry. In order to fix the dried substance the cover-glass is then heated over a flame, allowed to cool, and stained. For this pur- pose methylene blue is used by preference, the solution consisting of a one-per-cent solution of the dye ina 1:10,000 solution of caustic potash. Aqueous solutions of fuchsin and methyl violet are also frequently used. For many bacteria special methods are also in use. In these methods the preparations are strongly overstained with a solution of gentian vio- let, or aniline-water fuchsin, or aqueous methyl violet, and the color is subsequently removed with weak acids or with iodine and alcohol (Gram’s method). In this way it is often brought about that only the bacteria remain stained, sometimes even certain bacteria only. If it is desired to show the presence of bacteria in tissues, the latter are cut in small pieces, hardened in absolute alcohol, then cut in thin- nest possible sections, and stained by appropriate methods. Here again the staining, as above mentioned, with gentian violet, methyl violet, and fuchsin is especially often employed. Good object-glasses are necessary for the microscopic examination; if possible, oil-immersion lenses and illumination with substage condenser are to be employed. If it has been possible to demonstrate the presence of bacteria in the tissues in any way, the attempt is next made to cultivate them. For this purpose the methods developed by Koch are generally employed. These, in principle, consist in distributing the fluid containing the bac- teria uniformly in a solution of gelatin or agar previously warmed, and pouring out some of the mixture upon horizontal glass plates. The fluid containing the bacteria is obtained either by scraping the tissue or by rabbing up pieces of tissue in sterilized salt-solution. The gelatin and agar solutions are liquid at higher temperatures and solid at lower. When the solutions become solidified the individual bacteria or spores become developed at points separated from one another. By a proper application of the method various colonies are subse- quently obtained in the layer of gelatin spread out on the plate (Fig. 393). The colonies often differ from one another in appearance, even when examined with the naked eye. If the colonies are sufficiently separated from one another a small amount is to be taken from the individual colonies by means of a fine platinum needle, and transferred to a boiled potato (Plate I., Figs. 5 and 6), or to a gelatin plate free from bacteria, Ziegler, General Pathology. Plate 1. 1, Stab-culture of 2. Stab-culture of 3. Stab-culture — +. Culture of Tubercle Staphylococcus Pyogenes Bacilli of Swine Erysipelas of Cholera Spirilla in Bacilli upon coagulated Aureus in Agar-Agar. in gelatine. gelatine. blood -serum (after Koch). wlll 5. Culture of Anthrax Bacilli 6. Culture of Staphylococcus Pyogenes Citreus upon a boiled potato. upon a boiled potato. CULTURE OF BACTERIA. 451 or upon the surface of the solidified nutrient fluid in a test-tube (Plate I., Fig. 4). Very often the infected needle is stuck into the solidified transparent medium contained in a test-tube (Plate I., Figs. 1-3). _ If the culture on the gelatin plate is pure, and the whole procedure is carried out with the necessary care and avoidance of contamination, pure cultures are obtained by the above method. In stab-cultures (Plate I., Figs. 1-3) as well as in smear-cultures on potatoes (Figs. 5 and 6) and on any other nutrient medium (Fig. 4), often special pecu- liarities show themselves which make it possible for the practised ob- server to recognize the form of bacteria. Still it will occasionally happen that a thorough microscopic examination of the colonies will also have to be made. It goes without saying that all the above manipulations must be carried out with care, and that care must be had for the absolute clean- liness of the instruments that come into use—of the glass plates and test-tubes, —and that the nutrient media must be free from bacteria. Suit- Fic. 393.—Gelatin plate containing colonies of small bacilli. These colonies are pellicle-like, with some- what sinuous margins. Also small, round white colonies of cocci are present. Obtained from the exudate of a purulent peritonitus. (Diminished by one-third.) able procedures are easiest learned in laboratories specially arranged for the purpose. The long-continued heating of the instruments used or their subjection to high temperatures plays an important réle. The necessary guidance is furnished in the various books on bacteriological methods of examination which have appeared recently. Infusion of meat containing peptone and gelatin is most usually em- ployed for making plates. This consists of a watery infusion of chopped meat, to which a definite amount of peptone and salt is added. This is, moreover, neutralized with carbonate of soda, and enough gelatin added to give a solid consistence at ordinary temperatures. For stroke- and stab-cultures sometimes this same gelatin is used (Plate I., Figs. 2 and 3), sometimes a jelly made of a mixture of watery extract of meat, pep- tone, and agar-agar (Plate I., Fig. 1), sometimes blood-serum that has been brought to coagulation by warming (Fig. 4). For stab-cultures the jelly is allowed to solidify with the test-tube in a perpendicular position (Fig. 3), for stroke-cultures in an oblique posi- tion (Fig. 4). 452 CULTURE OF BACTERIA. Sterilized bouillon is often used for cultures. The inoculated nutri- ent media are kept either at room-temperature or at higher temperatures of from 30° to 40° C. in an incubating-oven. The latter, however, is pos- sible only with agar-agar, blood-serum, and potatoes, as the gelatin that is used becomes fluid at the temperature of the incubating-oven. It goes without saying that the process just briefly described can be modified according to the exigencies of the case. Thus, for example, in cases in which the bacteria grow only at high temperatures it 1s neces- sary to use agar-agar plates and to do away with gelatin. Occasionally exudates formed on the mucous membranes (diphtheria) or small pieces of tissue which have been excised are introduced directly into the nu- trient solution. If it is desired to examine the cultures directly under the microscope, hanging-drop cultures are made. For many bacteria— for example, for cholera-spirilla—the use of cultures in hanging drops is to be recommended. In this method a drop of sterilized bouillon hangs down from the under surface of a cover-glass and is inoculated from a previously purified culture of a fission-fungus. After this the cover-glass is laid over the excavation in a hollow-ground slide. If evaporation of the drop is avoided by closing off the external air from the cavity in the slide—which may be effected by sticking on the cover-glass with oil or vaseline—the multiplication of the bacteria can be directly observed for a long time. If the bacteria are sought in water a small amount of the water is distributed in gelatin and plate-cultures are made. Earth may be rubbed up in sterilized salt-solution. Air is made to pass in definite amount through sterilized salt-solution, and the salt-solution infected in this way is then mixed with gelatin, and from this gelatin plates are made. The culture of the bacteria on different media, accompanied by the microscopic examination of the different stages of development, serves for a more precise characterization, and at the same time also for the determination of the species of fission-fungus in question. After its peculiarities have been sufficiently studied in this way its development in the animal body is tested. As experimental animals those most usually employed are rabbits, dogs, guinea-pigs, rats, mice, and small birds. Bacteria to be tested are introduced sometimes under the skin, sometimes directly into the blood-current, sometimes by inoculation into the inner organs, sometimes by inhalation into the lungs, some- times by administration with the food into the intestinal tract. The fungus can be regarded as pathogenic for the animal in question if it multiplies in the tissues of the latter and produces morbid conditions. If relatively large amounts are inoculated the experimental animal may, under certain conditions, die, even if the bacteria do not increase at all in its body; for the poisonous substances ready-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, if transmitted to animals by inoculation, run the same course as in man; that is to say, only those which also occur otherwise Inanimals. In other cases the pathogenic fission-fungi which occur in man or certain animals are, it is true, pathogenic for the ex- perimental animals, but the morbid process shows a different localiza- tion and a different course. In still a third case the experimental ani- mals are partially or completely immune. Inversely, fission-fungi that are extremely pathogenic for the experi- mental animals are often innocuous for other animals and for man. THE COCCI OR SPHAROBACTERIA. 453 ll. The Different Forms of Fission-fungi and the Infectious Diseases Caused by Them. 1. The Cocci, or the Spherobacteria, and the Morbid Processes Caused by Them. (a) General Remarks upon the Cocci. § 161. The cocci or coccacei (Zopf) are bacteria that always occur exclusively in the form of round or oval or lancet-shaped cells. In their multiplication by division they often form peculiar aggregations of cells hanging together, and it is customary to designate these by special names, according to the character of the different forms that appear. Since certain forms of cocci are specially apt to develop in definitely shaped aggregations, many authors have found in this circumstance a reason for making corresponding varieties. It is nevertheless to be noted that a given species does not always give rise to the same forms of growth, but may show variations a? Suse's called forth by the on? a JsO : : a surrounding nutrient eS) wg ee? conditions. Many of the cocci Fig. 396. ick re A “ea se wo co 6 o tae , £C *. . ee yy of Fie. 394. FIG. 395. FIG. 397. Fig. 394.—Streptococcus from a purulent peritoneal exudate of puerperal peritonitis. a, Separate cocci; b, diplococci:; ¢, streptococci. Magnified 500 diameters. Fig. 395.—Micrococcus colonies in a blood-capillary of the liver, as the cause of metastatic abscess-forma- tion in pyemic infection. Necrosis of the liver-cells. Magnified 400 diameters. Fig. 396.—Cocci grouped in tetrads (merismopedia), from a softening infarction of the lung. Magnified 500 diameters. Fic. 397.—Sarcina ventriculi. Magnified 400 diameters. multiply by division in one plane only, viz., at right angles to the length of the elongated spherical cell. If in this case the spheres resulting by division remain together for some time in the form of double spheres, and if this form appears with especial frequency, they are called diplococci (Fig. 394, b). If, froma further continued division of the cells in one plane, rows of cocci ( torula- chains) result, they are called streptococci (Fig. 394, c); and this term is used also as the name of a group. If the division of the cells takes place irregularly and the cells remain together thereafter, then the bac- teria are generally known as micrococci (Zopf) or heaped-cocci (Fig. 395). By Ogston and Rosenbach the name staphylococcus or grape-cocci has been brought into use to indicate some of these forms. Larger collec- tions of cells, which are held together by a gelatinous substance derived from the cell membranes, have been designated as zodqlwa masses. If the masses of cocci are united into larger collections by a gelatinous 454 _ THE COCCI OR SPHZZROBACTERIA. envelope, then they are spoken of also as ascococet or tubular collections of cocct (Schlauchkokken). ; j Zopf introduced the name merismopedia, or tablet-cocct, for cocel which remain for a long time united in a four-celled tablet (Fig. 396). Others regard such bacteria as micrococci. The cocci that go by the name Sarcine are characterized by dividing in three directions of space, go that compound cubical packets (Fig. 397) of round cells are formed from tetrads. er The cocci not infrequently show a tremulous molecular motion in fluids. Independent motion has not been observed with certainty. Spore-formation has not been observed in most of them. According to Cienkowski, van Tieghem, and Zopf, the Coccus mesenterioides (leucono- stoc), that makes a frog-spawn-like coating on sugar or parsnips, forms arthrogenic spores. When this is about to occur some particular cell in a torula-chain becomes somewhat larger and glistening. According to Prazmowsky, Micrococcus urece also forms spores. ; The saprophytic cocci grow upon very different nutrient substrata, and cause by their growth in suitable media various processes of de- composition. Many of them also produce pigment. IMicrococcus uree (Pasteur, van Tieghem, Leube) causes fermentative processes in urine, ' and in consequence of these carbonate of ammonia is formed out of urea. Micrococcus viscosus is the cause of the slimy fermentation of wine. The cause of the glow seen in foul meat was found by Pfliger to be due to a micrococcus that forms slimy coatings on the surface of the meat. Among the pigment-producers the best known are the Micrococcus luteus, the Micrococcus aurantiacus, the Sarcina lutea, the Micrococcus cyaneus, and the Micrococcus violaceus, which produce yellow, blue, and violet pigment respectively when grown on boiled eggs or potatoes. Saprophytic cocci are found as well in the cavity of the mouth and in the intestines as on the surface of the skin, and occur occasionally also in the lungs. Micrococcus hematodes (Babes) is said to be the cause of red sweat, and produces red-colored zodgloea masses. Sarcina ventriculi (Fig. 397) occurs not infrequently in the stomach of man and animals, especially when abnormal fermentations are going on. According to Falkenheim, the stomach sarcina can be cultivated upon gelatin, forming round yellow colonies which show colorless spherical monococci, diplococci, and tetrads, but never contain cubical packets. They form these, however, in neutralized hay-infusion, and their growth causes the souring of the infusion. The membrane of the sarcina is said to consist of cellulose. _ Micrococcus tetragenus (imerismopedia) is often found in human sputum and consequently also in the mouth and throat; it is also found in the walls of tuberculous cavities or in hemorrhagic softening foci in the lungs, and forms tetrads (Fig. 396) in multiplying, the cells of which are held together by a slimy membrane. On gelatin it forms round or oval lemon-yellow colonies. It is pathogenic for white mice, developing in their blood. Gray house-mice are almost immune. The pathogenic cocci cause acute inflammatory diseases, which for the most part go on to recovery after the destruction of the bacteria; but it not infrequently happens that the cocci maintain themselves for a long time in the body and give rise to chronic troubles. THE STREPTOCOCCUS PYOGENES. 455 (6) Puthogeniec Cocci. _ § 162. The streptococcus pyogenes (Rosenbach) is a coccus which, in multiplying, forms double spheres and chains of spheres of different lengths, containing from four to twelve or more cells. This chain for- mation comes to an especially full development when the streptococcus 1s growing in fluids—in nutrient bouillon or fluid exudates,—yet it is also generally to be observed when these organisms are developing within the tissues. The cocci stain very well by Gram’s method, are facultative anaé- robes, grow best at 37° C., and form small whitish colonies on gelatin and agar. The streptococcus pyogenes is especially pathogenic for mice and rabbits (much less so for dogs and rats), but its virulence varies very much, and disappears rapidly from cultures on the ordinary-nutrient Fig. 398.—Streptococcus tracheitis in scarlet fever. (Alcohol; carmine; methyl violet; iodine.) a, Con- nective tissue; 6, detached epithelium; c, membrane composed of cells and streptococci; d, fibrin threads. Magnified 300 diameters. media, Virulence is retained for a relatively long time by cultures of the cocci in human serum or horse serum (serum two parts, and bouil- lon one part), or in a mixture of bouillon and ascitic fluid (Marmorek). The streptococcus pyogenes causes in man inflammations which for the most part, but not always, assume a purulent character. Occasionally it is found also on the sound mucous membranes, for example, in the upper air-passages, or in the vagina and cervix uteri; and from this fact it is supposed that either its virulence is very slight, or that the mu- cous membranes offer a successful resistance to its entrance into their tissues. An infection with streptococci occurs either in sound individuals, or in those who have received some injury, or finally as an accompani- ment and consequence of other infections, such especially as scarlet fever, diphtheria, and pulmonary tuberculosis. If it multiplies on the surface of the mucous membranes—for ex- ample, of the air-passages (Fig. 398)—it causes inflammations which may assume the character of a desquamative or purulent catarrh (c), or that of a process accompanied by croupous exudations (d). If it pene- trates into the connective tissue of the submucosa, it causes most fre- 456 THE STREPTOCOCCUS PYOGENES. | quently inflammations, which assume the character of a phlegmon, LBsj a more or less quickly spreading, sero-purulent, or purulent, or fibrino- Fig. 399.—Streptococeus pyogenes from a phlegmonous inflammatory focus of the stomach. a, Leuco- colons b, leucocytes with streptococci inside; c, free streptococci. (Alcohol; Gram’s method.) Magnified diameters. purulent, or sero-fibrinous inflammation, which may at certain points lead to suppuration and to abscess-formation. In the exudate the cocci in part lie free (Fig. 399, c), in part they are inclosed within the cells (b). When the streptococcus spreads in the corium, into which it pene- trates when there is a small wound of the skin, it utilizes the lymph- spaces and lymph-vessels (Fig. 400, a, and 401 fh, 7) as pathways and breeding-places, and causes a more or less severe inflammation, which may be recognized macroscopically by an advancing reddening and swelling of the skin, which is known as erysipelas. These external symptoms correspond to more or less severe serous and cellular infiltra- tions (Fig. 400, d, e, 7, and Fig. 401, m), and often, also, to a cellulo- tibrinous exudation (m,). In cases of severe infection with more highly virulent streptococci, the process can go on to liquefaction of the epithe- lium (Fig. 401, e, 4, 9, g,), and to the formation of vesicles (Fig. 401, c; erysipelas bullosum), or even to necrosis and gangrene of the corium (Fig. 401, U1,; erysipelas gangreenosum) and to suppurations of the tissue. The spread and multiplication of the cocci in the subcutaneous tissue give rise to a spreading sero-purulent and fibrino-purulent inflamma- tion, often with subsequent suppuration of the tissue. These forms of infection are designated as phlegmons. - In the muscles the streptococci select principally the connective tis- sue of the perimysium internum (Fig. 402, a) as the place in which they Fic. 400.—Colonies of streptococcus erysipelatis : a, in a lymph-vessel ; b, In part composed of thickly packed spheres, in part of torula-chains; c, neighborhood of the lymph-vessel, with pale unstainable nuclei; d, vein; e, perivenous cellular infiltration of tissue; f, accumulation of cells in the lymph-vessel. Section of favs ear two days after inoculation with erysipelas-cocci. (Alcohol; gentian violet.) Magnified 250 iameters. multiply and spread, but they also penetrate into the sarcolemma tubes (d). Here also the consequences of infection are more or less severe in- flammations, often going on to suppuration. ‘ THE STREPTOCOCCUS PYOGENES. 457 Infection of the serous membranes is followed by a sero-purulent or Pee : 2 3 ___Fia. 401.—Section of the skin from a case of erysipelas bullosum. a, Epidermis: h, corium: c, bladder- like cavity; d, cover of this cavity; e, epithelial cell with vacuole: f, swollen cell with swollen nucleus; 9, 91, cavity caused by the melting down of epithelial cells, and containing fragments of the same and pus- corpuscles ; hk, lymph-vessel partially filled with streptococci ; i, lymph-vessels completely filled with strepto- cocci; k, colony of streptococci located in the midst of the tissues; 1, l,, necrotic tissue; m, cellular, mM, fibrinocellular infiltration of the tissues; n, fibrinocellular exudation in the bladder-like cavity. (Alcohol; alum carmine.) Magnified 60 diameters. fibrino-purulent exudation, during which the streptococci usually multi- ply abundantly in the free exudate. Infection of the lungs causes the formation of purulent or croupous exudations in the lung alveoli. The streptococcus infection may sooner or later cease, because the Fig. 402.—Pectoral muscle beset with large numbers of the streptococcus pyogenes, from a case of phlegmonous inflammation of the subcutaneous and intermuscular connective tissue, due to cadaveric poison= ing. (The phlegmon of the wall of the chest developed two days after the finger was injured, and the inter- mediate lymph-vessels of the arm showed no evidences of being involved.) a, Perimysium internum full of streptococci; b, transversely cut muscular flbres, still intact ; ¢, transversely cut muscular fibres which are beginning to degenerate ; , muscular fibres into which the cocci have penetrated. (Alcohol; gentian violet; vesuvin.) | Magnified 350 diameters. 458 THE STREPTOCOCCUS PYOGENES. opposing forces of the organism limit the further spreading of the bac- teria and destroy them. Often, however, the infection continues to spread until death occurs. If the streptococci break into the lymph- and blood-vessels, metas- tases are often formed, and distant organs also become involved. In infection of the blood, an increase of the bacteria does not take place in the circulating blood, but occurs at points where they are brought to rest—as, for example, in the small vessels of the lung, of the heart, of the liver, of the kidneys, of the spleen, of the brain membranes, of the bone-marrow, of the joints, etc., or even on the valves of the heart. At the spot where the multiplication of the cocci takes place, an inflamma- corse . eae Fy a ie Fic. 403.—Metastatic haematogenous streptococcus-pneumonia following angina. (Alcohol; alum car- mine; methyl violet; iodine.) a, Pneumonia area with streptococci (blue); 6, inflamed lung-tissue sur- rounding the area. Magnified 80 diameters. tion again develops, and it assumes the same characters in general as those manifested by the primary inflammation. The new inflammation, however, often appears less severe in character and may be more cir- cumscribed. A hematogenous streptococcus-infection of the lung leads to the forma- tion of areas of inflammation (Fig. 403, a) which for the most part sup- purate in the centre. In the kidneys, in the vessels of which a very extraordinary increase of the streptococci takes place, tissue-necrosis and suppuration likewise occur; and similar phenomena may also be recognized in other organs. ee The danger of a streptococcus infection depends partly upon the severe progressive local disease of the tissue, partly upon the intoxication, by means of toxins (toxalbumins), which accompanies the local disease, and finds expression in the fever and severe systemic symptoms. If the symptoms of intoxication come strongly to the fore in the disease pic- THE DIPLOCOCCUS PNEUMONLA. 459 ture, then the infection is known as septic intoxication, as toxcemia, or as septicemia. Preponderance of the metastatic suppuration leads to the form of disease designated as pyemia or as bacteriemia. If the symp- toms of both these forms of infection appear together, then one speaks of the condition as a septico-pyzmia or a pyo-septemia. The course of a streptococcus infection, as well as the mode of en- trance of the cocci into the body, can generally be recognized, because the infection usually starts from the injured outer skin or from deeply penetrating wounds, from the mucous membranes of the upper digestive and air passages, or—in the case of a woman who has recently given birth to a child—from the genital apparatus which has undergone some change during the act of parturition. Cases of cryptogenetic infection, however, are not so very rare. In these the first symptoms which are no- ticed at the bedside are those dependent upon disease of some internal or- gan, and it appears as if the infection had started primarily in this organ. The individual areas of disease in streptococcus-infection can show very different degrees of severity of inflammation, and this depends in part upon the virulence of the bacteria, in part upon individual differ- ences among those who are infected, in part upon the site of the infec- tion, and in part upon the influence of preceding or accompanying pathological conditions. As regards this last factor it may be said that many infectious diseases (diphtheria, scarlet fever, tuberculosis, ty phoid fever, influenza) increase the disposition to streptococcus-infection, and at the same time lower the patient’s powers of resistance. The biological characters of the streptococcus pyogenes are very variable, and this is shown as well in its behavior as a disease-producer as by the cultivations of strepto- cocci taken from different cases. As a consequence of this, an endeavor has been made to form different species, and especially has the streptococcus which causes erysipelas been differentiated as a special form—the streptococcus erysipelatis. Further, accord- ing to the place in which it was found, it was customary to speak of a streptococcus puerperalis (Arloing), a streptococcus articulorum (Fliigge), or a streptococcus scarlati- nosus (Klein); or, according to the manner of its growth (von Lingelsheim), to distin- guish a streptococcus longus and a streptococcus brevis, etc. These characters by them- selves are certainly not sufficient to permit of all these forms being separated from one another as distinct species, and it seems therefore more correct, or at least more ex- pedient, to consider the chain-forming pus-coccus as a single species, which, however, | appears in many varieties. In diphtheria and scarlet fever streptococcus infections of the throat and air-pass- ages are exceedingly frequent, especially in the first, and as a consequence many authors (Baumgarten, Dahmer) are inclined to assign to the streptococcus a coordinate place with the diphtheria bacillus in the causation of diphtheria—the diphtheria bacilli pre- dominating in the lighter cases, the streptococci in the severer. Pure streptococcus in- fections can also give rise to the picture of diphtheria. 1f both species of bacteria are present, their effects are combined ; perhaps also the presence of the streptococci exalts the virulence of the diphtheria bacilli. § 163. The diplococcus pneumoniz (Frankel, Weichselbaum), or the streptoceccus lanceolatus (Gamaleia), or the diplococcus lanceo- latus (Foa, Bordoni-Uffreduzzi)—also known as the pnewumococcus— is a pathogenic streptococcus of frequent occurrence. It forms spheri- cal, oval, and lance-shaped cocci (Fig. 404, a) that are generally, in the human body, surrounded by a transparent capsule and are grouped to- gether in pairs (b, d), less frequently in chains of such pairs (¢), or in large colonies (d). : The streptococcus pneumoniz stains very readily with fuchsin and with gentian-violet, and with these staining solutions the capsule also becomes visible. The cocci are also stained by Gram’s method. 460 THE DIPLOCOCCUS PNEUMONL&. These cocci are facultative anaérobes. They will not grow on gelatin at ordinary room-temperature, but on slightly alkaline blood-serum gelatin and agar-agar kept at a temperature above 22° C., best at the temperature of the human body. They form delicate, translucent, glistening cultures which suggest the deposit of dew on a cover-glass (Frankel) and consist of diplococci and chain-cocci without capsules. The growth is, however, scanty, and easily dies out. Cultures do not succeed on potatoes. The diplococeus pneumonia is the cause, in a large number of cases (according to Weichselbaum, in seventy-one per cent), of the lung af- fection called croupous pneumonia, in which the lung is the seat of an acute inflammation which is ushered in by a congestive hyperemia. In the course of the disease the alveoli over large areas become filled with a coagulated exudate which consists of desquamated epithelium, leuco- cytes, red blood-corpuscles, fluid, and fibrin, and which under favorable conditions becomes liquefied and absorbed. Numbers of observations have shown that it can cause inflammatory processes bearing the charac- teristics of catarrhal bronchopneumonia—processes, therefore, which are distinguished by the appearance of an exu- date partly serous, partly cellular. The cocci are found during the disease principally in the in- flamed area of the lung, but they may also be met with in neighboring areas—in the pleura, and, under certain circumstances, in the pericar- dium, in the peritoneum, in the meninges, in the cavities adjacent to the nose, in the cellular tis- Fie. 404.—Diplococeus sue of the neck, in the mediastinum, in the sub- De ee ot coed wii mucous tissue of the soft palate and throat, even out a, capsule; b, single cocci in the conjunctiva (Weichselbaum); and in all gelati- ays . nous envelope; ¢, chain-cocci Of these localities they cause inflammatory chan- With 9 gelatinous envPencd ~«©ges. Occasionally they may be found in the 500 diameters. juice of the spleen and in the blood, and are said to pass into the foetus in pregnant women ( Viti). They are therefore, under certain circumstances, widely distributed throughout the body. They may cause a serofibrinous inflammation in the meninges, the pleurz, the pericardium, and the peritoneum, and under certain conditions they may also cause seropurulent and fibri- nopurulent inflammation, without the appearance simultaneously of a pneumonia. They can, furthermore, cause inflammation of the en- docardium, of the kidneys, of the joints, of the Fallopian tubes, of the uterine mucous membrane, of the parotid, of the thyroid, of the bone marrow, and of the periosteum; and this inflammation may cause sup- puration. In many cases the mouth and the nose and throat—where they are occasionally also found in healthy individuals (Weichselbaum, Frankel)—seem to form the portal of entrance. Accordingly, in cere- bral and cerebrospinal meningitis (Weichselbaum) the maxillary cavity, the tympanic cavity, and the cribriform labyrinth often contain exudate with diplococci. The diplococci are found in the exudate in all the forms which we have enumerated. The gelatinous capsule may show a very variable thickness. Inoculated upon rabbits, guinea-pigs, and mice, they multiply in the form of capsule-cocci, especially in the blood and in the serous cavities, and may also cause pneumonia with bloody serous exudate (Weichsel- baum). Rabbits are specially sensitive, as they die in from thirty-six THE STAPHYLOCOCCUS PYOGENES AUREUS. 461 to forty-eight hours after subcutaneous inoculation, with symptoms of septicemia. If pure cultures are injected into the pleural cavity of rab- bits a pleurisy results, as well as a splenization of the lung in which the parenchyma is filled with a bloody serous exudate. The sputum of a pneumonia patient is pathogenic for rabbits, since it contains the cocci. According to A. Frankel, the cocci lose their poisonous properties very easily, especially if they are cultivated in milk; and if it is desired to retain the virulence they must be inoculated from time to time into susceptible animals. Cultivation of the cocci at 42° C. for one or. two days destroys their virulence. The diplococcus pneumonie belongs to those bacteria whose physiological character- istics are very variable. Foa distinguishes, according to the principal places in which they are encountered, a pneumococcus and a meningococcus. In cerebrospinal meningitis cocci have been found which in part resemble the streptococcus pyogenes (streptococcus meningitidis, Bonome), in part the diplococcus pneumoniz (diplococcus intracellularis meningitidis, Weichselbaum). Whether these forms represent distinct species or are only varieties of the species mentioned has not as yet been definitely determined. Jager is of the opinion that the diplococcus intracellularis meningitidis is the cause of epidemic cerebrospinal meningitis, and is entirely distinct from the pneumococcus. Sporadic meningitis may, on the other hand, be caused also by the pneumococcus. According to Emmerich, in bouillon cultures there is formed, at the bottom of the vessel, a sediment containing some resistant forms which remain capable of development for months. Rabbits may be rendered completely immune (Emmerich) by repeated in- jections of much-diluted cultures (five thousand times diluted) of increasing virulence, so that 30 c.c. of cultures of full virulence are borne without any striking disturbance. The injected bacteria are killed in the course of a few days. The serum of immunized rabbits can cure pneumococcus infection in rabbits and mice. § 164. The staphylococcus pyogenes aureus (Rosenbach) or micro- coccus pyogenes (Lehmann) is composed of spherical cells, which occur singly or in pairs, and by their multiplication generally form grape-like clusters and swarms. The cocci stain easily with the different aniline dyes, and also by Gram’s method. They are facultative anaérobes, but grow better in the presence of air. The staphylococcus thrives well on all the artificial media at the room-temperature, but grows better at 37° C. It forms whitish colo- nies, which produce pigment in the parts exposed to the air, and become colored orange-yellow (Fig. 1 of Plate I.). The color is most marked on agar and potato. Gelatin is slowly liquefied. When grape-sugar is present lactic-acid, acetic acid, and valerianic acid are formed. Active- ly poisonous products are formed in bouillon cultures. The staphy- lococcus pyogenes is one of the most frequently occurring of the patho- genic bacteria, and is, with the streptococcus pyogenes, the most common cause of suppuration, so that these two species have been frequently designated, in the narrower sense of the term, as pus-cocci. It is wide- ly distributed throughout the external world, and has been demonstrated in milk, in washing-water and waste water, as well as in the air of oper- ating-rooms and sick-rooms. Increasing in the tissues of the human organism (Fig. 405, ¢, c,, and Fig. 406, d, e) it causes tisswe-degenera- tions and tissue-necroses, on which supervenes an inflammation (Fig. 405, d, e, and Fig. 406, e, f, g) which generally assumes a purulent character. Not infrequently, however, the inflammation is less severe, i.e., does not go on to suppuration of the tissues. The suppurations caused by the action of the staphylococcus are generally circumscribed, and also have less tendency to spread rapidly to the neighboring tissues than have the suppurations which are caused by streptococci. In the skin they cause more particularly those inflam- 462 THE STAPHYLOCOCCUS PYOGENES AUREUS. mations which are termed acne, eczema, furuncle, and cutaneous and sub- cutaneous abscesses. In the bones they are the most frequent cause of the suppurative diseases of the bone-marrow and periosteum, which are designated as septic osteomyelitis and periostitis. They often give rise to purulent inflammations of the liver, lungs, pleura, peritoneum, brain, brain membranes, muscles, myocardium, spleen, kidneys, joints, etc., and are also often the cause of very severe, at times purulent, inflammations of the endocardium (Fig. 406). Inasmuch as the virulence of the straphy- locoeci fluctuates, they can cause, in all the above-mentioned places and also elsewhere, lighter transitory inflammations, which heal with or with- out scar-formation. The portal of entrance of the staphylococci is generally to be recog- nized without difficulty (especially in the case of wounds), and the same is true also of the route which they have followed when a metastasis occurs in some internal organ, in which event inflammations of the oat Luo Pie tere 2 Melts Simard “ ( Fig. 405.—Metastatic aggregation of micrococci in the liver. (Alcohol; Gram‘s method; vesuvin.) a, Normal lobule; 6, necrotic lobule; ¢, c,, capillaries and veins filled with micrococci; d, periportal small- cell infiltration ; €, a collection of small round cells partly inside, partly outside a vein into which a venula centralis filled with micrococci opens. Magnified 40 diameters. lymph-vessels (lymphangitis) and of the blood-vessels (phlebitis, arter- itis) make their appearance. Cryptogenetic infections, however, are not of rare occurrence, and they are of such a character that the myocar- dium or the endocardium or the bone-marrow or some other part of the body may be the first locality in which disease can be recognized. THE MICROCOCCUS GONORRH@. 463 Spreading of the staphylococci by means of the blood—an event which leads to multiple localization, with abscess-formation—is designated, as in the case of the spreading of the streptococci, as pyemia; when the disease is complicated by the development of severe symptoms of poison- @ f Fic. 406.—Endocarditis pustulosa caused by staphylococcus pyogenes aureus. (Alcohol; Gram’s method ; vesuvin.) a, Tissue of the posterior segment of the mitral valve ; b, threads of tendon; c, pustular protuberance of the upper surface of the mitral valve: d, staphylococcus pyogenes aureus; e, staphylococci intermixed with pus-corpuscles ; f, pus-corpuscles with cocci; g, small abscess. Magnifled 60 diameters. ing, the term septicemia is employed; and when there is a combination of both processes it is usual to designate the condition as septico- pyemia (comp. § 162). The staphylococcus pyogenes aureus is also pathogenic for animals— horses, dogs, cattle, goats, sheep, rabbits, guinea-pigs, and mice—and especially is this true for those named first. It gives rise to suppura- tions in these animals. In artificial cultures its virulence readily di- minishes. The inoculation of susceptible animals with cultures of very great virulence causes a gelatinous-cedema. The staphylococcus pyogenes albus (Rosenbach) and the staphy- lococcus pyogenes citreus (Passet) are very closely related to the staphylococcus pyogenes aureus, and apparently are only varieties of this organism. The first forms white colonies, the other citron-yellow colonies (Plate I., Fig. 6). These bacteria are found in the same local- ities as are the golden-yellow pus-cocci, and their mode of action is the same as that of the latter, but they are not encountered so frequently as is the aureus. The staphylococcus pyogenes aureus usually occurs alone in the pus- foci, yet, not infrequently, other pus-cocci or even bacilli are also found accompanying it—for example, the bacterium coli commune, or the ty phoid bacilli. § 165. Micrococcus gonorrhceze sive gonococcus (Fig. 407) is a coc- cus which was first described by Neisserin 1879. Itis constantly present in the purulent catarrh, called gonorrhea, of the male and female urethra and the female genital canal (especially that of the uterus), as well as in the secretion of blennorrhcea of the eye, and it is also regarded as the cause of the gonorrhea and of the blennorrhcea of tle eye. Besides the specific cocci, other cocci may also be present in the gonorrhwal secretion, some of them resembling the specific cocci very closely. The secretion may, moreover, also contain the pus-cocci. The gonococcus can be cultivated on coagulated human blood-serum, 464 THE MICROCOCCUS GONORRH@2. on blood-serum gelatin, on human blood-serum agar, and on urine agar; and it forms on the surface of the nutrient medium a yellowish-gray layer with a smooth surface. It dies out easily, and grows only at compara~- : tively high temperatures. ° : se Animals enjoy immunity from in- \ fection by inoculation. Efforts were made by Bockhart and Bumm to in- oe oculate human beings with gonococci . cultivated on artificial media, and they e . obtained in this way a purulent catarrh 6 = of the inoculated mucous membrane. Fic. 407. — Gonococei in the secretion from ‘The experiments of Bumm, particularly the urethra in fresh gonorrhoea. (Methylene : blue; eosin.) a, Mucus with separate cocci upon two women, seem to have given a and diplococei: b, pus-cells with diplococci ; ay = ¢. pus-cells without diplococei. Magnifed positive result. : 700 diameters. The coccus forms mostly clumps in the purulent secretion of the mucous membrane affected with gonorrhcea. It appears largely in the form of diplococei with the opposing surfaces flattened (Fig. 407), partly free (a) and partly inclosed in cells (b); it.stains readily with aniline dyes, but becomes decolorized by Gram’s method. The gonococcus penetrates into the epithelial layer of the mucous . membrane and lies sometimes between and sometimes within the epithe- lial cells and in leucocytes. Only the superficial layers of the connective tissue are penetrated. It causes inflammations which assume the char- acter of purulent catarrhs, and which are accompanied by cellular infil- . ss swe SSNs =p 32 Fra. 408.—-Gonorrhceal urethritis. Section through the wrinkled mucous membrane. (Miiller’s fluid; heematoxylin; eosin.) a, Normal connective tissue; }, c, inflamed, infiltrated, and proliferating connective tissue of the mucous membrane; cd, infiltrated and desquamating epithelium ; e, detached epithelial cells and pus corpuscles. Magnified 400 diameters. tration of the tissues of the mucous membrane (408, b, c, d) and by desquamation of the epithelium. The male and female urethra and the adjoining parts of the genital ducts and glands, and the urinary passages ANIMAL DISEASES CAUSED BY COCCI. 465 form the chief points of localization. The extent to which the inflam- mations following gonorrhoea (peri-urethral abscesses, inflammations of the prostate gland, of the epididymis, of the seminal vesicles, of the bladder, of Bartholin’s glands, of the tubes, of the ovary, of the pelvic peritoneum, and of the joints) are due to the spread of the gonococcus on the one hand, or to secondary infection with the pus-cocci on the other, is still a matter of dispute. From the investigations which have thus far been made it can no longer be doubted that the gonococcus may become widely spread over the mucous membranes. It has also been found repeatedly in inflamed Fallopian tubes, ovaries, and joints, in perimetritic and parametritic inflammatory foci and in peri-urethral abscesses, and is to be regarded as the cause of the inflammation. Still the processes leading to suppuration, and also the metastases in remote organs, seem to depend oftener upon the presence of pus-cocci. The gonorrhceal infection is at the outset an acute process, but can become chronic, and is cured only with great difficulty because the gonococci maintain themselves here and there in the urethra, in the Fallopian tubes, etc., for years, and cause inflammation. § 166. Cocci have been determined as the undoubted exciting causes of animal diseases in the case of a large number of those which are of an infectious nature, and that this statement is correct in regard to still others has been rendered at least probable. As has already been men- tioned before, the streptococcus pyogenes, the diplococcus pneumonia, and the micrococcus pyogenes aureus are pathogenic for various. animals, and the latter variety especially may often cause spontaneous. suppurative inflammations in animals—i.e., inflammations which have not been caused by the experimenter. On the other hand, diseases have also been produced experimentally in animals by various cocci which are not pathogenic for man. Furthermore, in several spontaneously occur- ring diseases of animals, cocci have also been demonstrated, and it is not unlikely that they are the exciting causes. 1. According to Schiitz,! Sand and Jensen,? and Poels,? the strangles of horses is an infectious disease in which the mucous membranes of the upper respiratory tract are the seat of a mucopurulent inflammation, in which, moreover, the lymph-glands pertain- ing to the part become swollen and some of them suppurate. It is caused by a coccus in chains, which may be cultivated and which produces strangles in horses on inocula- tion (Schiitz). 2. According to Schiitz,+ the epidemic lung-disease of horses, infectious pneumonia, is caused by an oval coccus, which is not identical with the diplococcus pneumonie of Frinkel or the bacillus pneumonie of Friedlander, and consequently not identical with the fission-fungus described by Perroncito® in the pneumonia of horses, and held to be identical with the diplococcus pneumonie. 3. According to Semmer and Archangelski,® the microparasite of cattle-pest is a mi- crococcus. According to Metschnikoff and Gamaleia,’ it is a bacillus. The disease is anatomically distinguished by inflammation of the intestinal tract, bearing partly a croupous and diphtheritic character, as well as by swelling and sometimes even by necrosis of Peyer’s plaques. ; 1“Der Streptococcus der Druse der Pferde,” Arch. f. wissensch. u. prakt. Thierheilk., xiv., 1888, and Zeitsch. f. Hygiene, iii. 2Die Aetiologie der Druse,” Deutsche Zeitsch. f. Thiermed., xiii. 3¢ Die Mikrokokken der Druse der Pferde,”’ Fortsch. d. Med., vi. 4“TDie Ursachen der Brustseuche des Pterdes,” Archiv f. wissensch. u. prakt. Thier- heilk., 1887, and Virch. Arch., 107 Bd., 1887. 5 Arch. Ital. de biol., vii., 1886. 6 Centralbl. f. d. med. Wiss., 1883, and D. Zeitschr. f. Thiermed., xi. 1 Centralbl. f. Bakt., i., 633. 26 466 ANIMAL DISEASES CAUSED BY COCCI. 4, According to Poels and Nolen,! monococci and diplococci, some of them with a gelatinous capsule, are found constantly in the lungs and pleural exudate, in contagious pleuropneumonia of cattle. On gelatin and agar-agar they make mostly white colonies that later become cream-colored. Pure cultures injected into the lungs of rabbits, guinea-pigs, dogs, and cows cause pneumonic changes. Cornil and Babes found various bacteria in the exudate. _ 5. In the udder-inflammations of domestic animals, which occur sometimes sporadi- cally, sometimes epidemically, different micrococci and streptococci have been described, and have also been designated by various names.” 6. According to Johne? the cerebrospinal meningitis, which occurs epidemically among horses, is caused by the diplococcus intracellularis (Weichselbaum, § 163). 7. Babes found in hemoglobinuria of cattle—a disease that occurs in epidemics in Roumania—a coccus resembling the gonococcus, which he regards as the cause of the dis- ease.4 8. According to Semmer, Friedberger, and Mathis,5 the distemper of dogs is also caused by a coccus. 9. The foot-and-mouth disease of cattle, according to Klein, is caused by a strepto- coccus.® In recent years, Schottelius? and Kurth® and others have also found cocci in the organs of animals sick of the foot-and-mouth disease ; but the bacteria described do’ not correspond with one another, and the pathological significance is doubtful.® 10. According to Rivolta and-Johne,!® and Rabe,!! there occurs in horses a peculiar tumor-like growth of the connective tissue, called by Johne mycofibroma or mycodesmoid, which is caused by a micrococcus that grows in the animal tissues in round or grape- cluster-like colonies. These quickly become surrounded by a hyaline capsule, and are therefore to be reckoned as ascococci (Micrococcus ascoformans). The tumefaction con- sists, similarly to that of actinomycosis, of connective tissue, inclosing small foci of pro- liferation, which break down into pus. The foci harbor the fungi. They seem to de- velop oftenest in the spermatic cord, after castration. They appear, however, in other parts of the body.!? 11. According to Eberth ' and M. Wolff! a large number of the gray parrots (Psit- tacus erithacus) imported into Europe die of a streptococcus mycosis. The micrococci are present in nearly all the organs, but especially in the capillaries of the liver and their neighborhood, where they cause necroses of the liver-cells, but no suppuration. 12. According to Eberth,'® some of the pseudotuberculous processes occurring in guinea-pigs represent a chronic suppuration that is produced by cocci, and that some- times leads to metastases in other organs. 1 Fortschr. der Med.,, 1886. °’ Hess and Bergeaud: “Contag. Euterentziindung, gelber Galt gennant,” Schweiz. Arch. f. Thierheilk., 30 Bd., 1888; Frank: “Euterentziindungen,” Deut. Zeitschr. f. Thiermed., ii., 1876; Kitt: “Euterentziindung,” “Lehrb. d. path. anat. Diagnostik,” Stuttgart, 1894. 3“Seuchenartige Cerebrospinalmeningitis d. Pferde,’? Deut. Zeitschr. f. Thiermed., xxii., 1887. 4Sur l’hémoglobinurie bactérienne du beeuf,” Compt. rend. del’ Acad. des Sciences de Paris, cvii., 1888; Virch. Arch., 115 Bd.; and Annal. de U'Instit. de Pathol. a Bu- carest, 1890. 5 Centralbl. f. Bakt., iii., 343. 6 Centralbl. f. d. med. Wiss., 1886. 7“ Ueber einen bakter. Befund bei Maul- u. Klauenseuche,” Centralbl. f. Bakt., xi., 1892. &§“Bakt. Untersuch. bei Maul- u. Klauenseuche,” “ Arb. aus dem Reichsgesund- heitsamt,” viii., 1893. 9 Johne: Deutsche Zeitsch. f. Thiermed., xix., 1893; Léffler und Frosch: Central- blatt f. Bakt., xxii., S. 257, 1897. ’ 10 Deutsche Zeitsch. f. Thiermed., xii., and “Bericht tiber das Veterinirwesen im K6nigr. Sachsen f. das Jahr 1885.” 1 Deutsche Zeitsch. f. Thiermed., xii. "2 Kitt, “Der Micrococcus ascoformans und das Mykofibrom des Pferdes,’? Centralbl. f. Bakt., iii., 1888. 13 Virch. Arch., 80 Bd. 14 Virch. Arch., 92 Bd. 15 Virch. Arch., 100 Bad. BACILLI AND POLYMORPHOUS BACTERIA. 467 2. The Bacilli and the Polymorphous Bacteria, and the Morbid Processes Caused by Them. (a) General Remarks upon Bacilli and upon Polymorphous Bacteria. § 167. Under the name Bacilli or Bacillacei (A. Fischer) or Bac- teriacei (Zopt) can be classified all those bacteria which appear in the form of straight rods, or rods that are only slightly bent in one plane. By many authors (Cohn, Htippe, Lehmann) the bacillacei are divided into two groups: bacterium and bacillus. Of these the latter is distin- guished by the formation of endogenous spores, while spore-formation is lacking in bacterium. The bacilli multiply by division. The rods grow in length and divide into approximately equal parts by the appearance of a transverse wall of division. If the division of the rod that is growing out in length does not take place forsome time, or if the division between the different fi, fi \ Y/, , 0 000 We Vi fF ee ord 7 Be | Fig. 409. Fia. 410. Fic. 409.—Bacillus subtilis in different stages of development. (After Prazmowski.) a, Separate rods : b, rods with flagella; c, chains of rods; d, separate cells with spores; e, chains of rods with spores, f\-f%, germination of spores. Magnified 800 diameters. Fie. 410.—Clostridium butyricum. (After Prazmowski.) a, Short rods; b, long rods; c, chains of rods; d, cells with spores ; ¢,-¢;, germination of spores. Maguifled 800 diameters. parts is not easily recognized, there result long jointless rods or threads (Fig. 410, 0). If the divided rods remain hanging together they form chains of rods (Fig. 409, c, and Fig. 410, c). In many forms of bac- teria the ends are blunt, in others rounded or even pointed. In many bacilli resting stages as well as swarming stages are ob- served, in which the flagella serve as organs of locomotion (Fig. 339, b). The flagella are situated sometimes at the ends, sometimes on the sides of the rods, and may occur in large numbers. In many bacilli endogenic spore-formation is observed (Fig. 409, d, e, and Fig. 410, d), in which the spore sometimes lies in the middle, sometimes in the end of the cell. Not. infrequently the spores appear in jointed threads. The germination of spores results in the formation of new rods (Fig. 409, f-f,, and Fig. 410, e,-e,). A noticeable change of shape does not usually take place in the rods in spore-formation. In other cases the rods assume a spindle shape or club shape or pear shape (Fig. 410, d), and this has been taken as ground for establishing a special group, clostridium. Numbers of au- thors, nevertheless, reckon these forms also with the bacilli. In the non-pathogenic bacilli spore-formation and germination have been more exactly studied, especially in bacillus subtilis and bacillus 468 BACILLI AND POLYMORPHOUS BACTERIA. amylobacter, and these offer good examples of the processes which come under consideration in this connection. Bacillus subtilis is a fission-fungus whose spores are very widely distributed in the ground, in hay (the hay bacillus), and in the air. Cultivated upon slices of potato or upon dung of herbivorous animals, it forms whitish-yellow clumps; on liquids, thin and thick pellicles. It requires oxygen for its: development. : ; The fully grown cells (Fig. 409, a) are 6 long. The snake-like motions sometimes seen are produced by one or two flagella (b). The growth of the rods is at first in the form of undivided threads; when these are segmented chains of bacilli are formed. The separate cells may develop in their interior glistening, sharply contoured spores (¢, e), which lie either in the middle or nearer to one end. Subsequently the cells out of which the spores have been formed perish. In germi- nation the spore (Fig. 409, /,-/,) becomes pale and loses its glistening appearance and its sharp contour. Then at each pole a shadow ap- pears, while the spore begins a tremulous motion. After a time the contents of the spore project from the side of the membrane in the form of a germinal diverticulum, which becomes elongated, divides, and pro- duces swarming staves. The empty spore membrane may remain pre- served for a time after the exit of the embryo. Bacillus butyricus (bacillus amylobacter of van Tieghem, vibrion butyrique of Pasteur, clostridium butyricwn of Prazmowski) possesses staves of from 3 to 10 » in length, and also produces threads and chains of rods. In spore-formation the cells become spindle-shaped or club- shaped and tadpole-shaped (Fig. 410, d), and then produce one or two glistening spores. In germination after absorption of the spore mem- brane a germinal tubule protrudes from one of the two poles (Fig. 410, e,-e,). This becomes prolonged and forms new staves by segmentation. Bacillus butyricus needs no oxygen for its development, and produces butyric-acid fermentation, with evolution of carbonic-acid gas, in solu- tions of starch, dextrin, sugar, or glycerin. In starch or glycerin or nutrient fluids containing cellulose the bacilli stain blue with iodine. The polymorphous bacteria are distinguished from the bacilli by the fact that they form, besides rods, also long, short-jointed threads, at times also true branchings of the threads; and also, in a few instances, a basal, non-growing, and an apical growing end can be differentiated. In this category belong the fungi known as the leptothrix, beggiatoa, crenothrix, and cladothrix. They are here placed with the bacilli, because, on the one hand, their botanical position is not determined, while, on the other, so far as they are pathogenic, they conform most closely to the bacilli in their biological characters. Saprophytic bacilli cause many kinds of fermentation by their growth in nutrient fluids; many of them also form pigments. Bacillus predigiosus grows on potatoes and bread, as well as on agar-agar and nutrient gelatin. It liquefies the latter, and produces a red coloring-matter which is soluble in alcohol. The coloring-matter develops only where oxygen is present. In the growth in milk the coloring-matter is contained in the fat-droplets. The bacilli themselves are always colorless. Bacillus fluorescens liquefaciens produces in gelatin whitish cul- tures, and in the neighborhood of these the gelatin becomes liquefied, while the gelatin in the more remote surrounding portions fluoresces with a yellowish-green color. BACILLI AND POLYMORPHOUS BACTERIA. 469 Bacillus cyanogenes (Neelsen, Hueppe), when cultivated in sterilized milk, produces a slate-gray color that changes to intense blue on the ad- dition of acid. In unsterilized milk, where lactic-acid bacteria develop simultaneously, the blue color appears without the addition of acid. On potatoes it forms yellowish slimy cultures, in the neighborhood of which the substance of the potato is colored grayish-blue (Fligge). Bacillus acidi lactici causes fermentation of sugar of milk in lactic acid, and produces coagulation of casein. The cultures obtained in gelatin are of a white color. . Bacillus caucasicus (dispora caucasica) forms one of the fungus con- glomerates that is called kefyr ferment, which the inhabitants of the Caucasian Mountains use in the preparation, from milk, of the alcoholic drink called kefyr. The kefyr ferment consists of small granules which contain yeast-cells along with rods. The bacilli occasionally show . motile forms and develop on the ends of each rod around spore. By their growth in the milk the milk-sugar is probably converted into glu- cose, while the yeast-cells produce alcoholic fermentation. According to Hueppe, the kefyr granules contain still other bacteria that peptonize casein. Hauser described, under the name of Proteus vulgaris (Bacterium vulgare, of Lehmann), a form of bacillus which very often occurs in putrefying animal substances and causes the foul putrefaction. It forms staves of very varied length, and produces when cultivated in meat (Car- bone) ethylendiamin, gadinin, and trimethylamin, of which the first two bases are poisonous for animals. According to observations of Bordoni-Uffreduzzi, Foa, Bonome, and Banti, certain bacilli closely resembling the proteus of Hauser seem to be pathogenic for human be- ings and capable of causing blood infection as well as intestinal affec- tions. — Bacillus aceticus (mycoderma acett) is a bacillus which converts the alcohol of fermented beverages into vinegar. Bacillus pyocyaneus occurs occasionally in bandages from suppurat- ing wounds, and causes a greenish-blue discoloration. The bacilli are small and slender. The cultures show different forms of growth. Gela- tin is liquefied and turned green. The coloring-matter called pyocya- nin is soluble in chloroform and crystallizes out of solution in long blue needles. The bacillus is pathogenic for rabbits, guinea-pigs, pigeons, and frogs, and causes on inoculation sometimes local ulceration, some- times general infection. According to Kossel, Kramhals, and others, it may also be pathogenic for man, and from suppurating wounds may cause septic intoxication with enlargement of the spleen and enteritis. The pathogenic bacilli and polymorphous bacteria cause diseases, sometimes acute, sometimes chronic, of which the first either end in death, or, by the destruction of the bacteria, go on to recovery. At the same time it occasionally happens that even in the acute diseases the bacteria maintain themselves for a long time in the body. The chronic diseases are especially characterized by the fact that the bacteria live and increase in the body, so that the disease assumes a progressive character, and sometimes quickly, sometimes more slowly, new regions _are taken possession of by the bacteria and become altered by them. 470 ANTHRAX-BACILLI. (b) Pathogenic Bacilli and Polymorphous Bacteria. § 168. Bacillus anthracis (Bactéridie du charbon) is the cause of an- thrax, an infectious disease which occurs mainly in cattle and sheep, but which is occasionally transferred to human beings. It is a fission- fungus that can multiply inside the tissues as well as in the blood .. when inoculated into a susceptible animal organism. Se The anthrax-bacilli (Fig. 411) are from 3 to 10 v long and from 1 to 1.5 » broad. In the Qo S msuemas Sean? af eq ~S eee ® eeIoe Fie. 411. : Fie. 412, Fig. 411.—Section of liver with capillaries containing numbers of anthrax-bacilli aad a few leucocytes. (Alcohol; gentian violet; vesuvin.) Magnified 300 diameters. Fic. 412.—Anthrax-bacilli containing spores, and free spores that have escaped from the bacilli. (Cover- glass preparation treated with fuchsin and methylene blue, from a culture of the bacilli on a potato, under the stimulation of heat in an incubator.) Magnified 800 diameters. blood of animals dead of anthrax they lie separate or in thread-like jointed bands of from two to ten staves. The ends are as a rule sharply cut across (Figs. 411 and 412), more seldom slightly concave or even convex (Johne). According to Serafini, Gunther, and Johne, they pos- sess a gelatinous capsule, which can be best made visible in dried pre- parations by staining with methylene blue (Giinther). They can be cultivated upon blood-serum, upon gelatin, in bouillon, on slices of po- tatoes and turnips, in infusions of pease and mashed seeds of different kinds, in the presence of oxygen. They grow most quickly at a temperature which varies from 30° to 40° ©. Development is impossible at a temperature below 15° C. and above 43° C.; it is also impossible in the absence of oxygen. If the conditions above mentioned are present, the staves grow in length, and may, in a few hours, form threads of considerable length, devoid of membranes. These are made up of short segments that are rendered visible by treatment with iodine or with some coloring-mate- rial (Fig. 412). Ten hours later, the clear contents of the threads become granular, and at regular intervals bright glistening bodies become ap- parent, which enlarge into strongly refractive spores (Fig. 412). Later on, the threads disintegrate and the spores become free. According to Brefeld, Prazmowski, Klein, and others, the spore con- sists of a protoplasmatic centre which is surrounded by a double mem- brane, the exosporium and the endosporium. In germination the former is ruptured and the latter becomes the membrane of the liberated embryo. The liberated embryo multiplies by division. ANTHRAX-BACILLI. 471 Swarming is not observable during the entire process of develop- ment; the bacilli are always motionless. The anthrax-bacilli easily die under the influence of high tempera- tures when subjected to drying, and in the presence of a nutrient me- dium whick has become putrefied. The spores, on the contrary, are very resistant, and consequently are the ordinary medium of the trans- fer of the disease. Colonies in gelatin show a wavy, irregularly shaped margin, and consist of wavy, curly bands of threads that subsequently grow out of the culture in various directions. The gelatin becomes liquefied in the immediate neighborhood of the culture. On slices of potato they form grayish-white cultures that appear slightly granular (Plate I., Fig. 5), with distinct outline. They form a whitish coating on blood-serum. Stab-cultures in gelatin are white, and in the process of growth they radiate at right angles from the track of inoculation, especially near the surface. After liquefaction of the gelatin they sink to the bottom. Tf the bacilli or spores get into the blood they multiply and produce the staves above described, which can be stained with various aniline Fic. 413.—Section through an anthrax-pustule ten days old, extirpated from the arm of a man. a, Epidermis; /), corium; ¢, papillary body, oedematous, swollen, filled with exudate and bacilli; d, external layer of the corium infiltrated with cells; d,, the same containing bacilli; e, deeper layers of the corium containing bands of cells; f, tissues of the skin interspersed with bacilli and cells; g, bloody exudate on the surface containing bacilli; h, hair-follicle; i, sweat-gland coil. (Alcohol; Gram’s method; vesuvin.) Mag- nifled 35 diameters. colors, and also by the employment of Gram’s method. Sections of hardened organs show that they are present in large numbers in the capillaries (Fig. 411), especially of the spleen, of the liver, of the lungs, and of the kidneys. The contiguous parenchyma of the tissue usually appears unchanged; still the local growth of the bacilli may produce degeneration of tissue and necrosis. If an infection of the blood takes place during pregnancy the infection may go over to the foetus. 4792 _ANTHRAX-BACILLI. Tf anthrax-bacilli or their spores get through little wounds of the skin in human beings they develop a somewhat elevated pustule with arched or flattened surface (Fig. 413), usually from six millimetres up to several centimetres in diameter. The pustule is red or possibly more of a yellowish color. It is often in time covered with vesicles, or. after the loss of epithelium it becomes moist; and by the drying of this ex- udate, which is often bloody, a scab is formed (Fig. 413, g). Infection takes place in persons that butcher or bury, or prepare the skins of animals affected with anthrax; occasionally also it is conveyed through the sting of a fly that has taken up the blood of an animal affected with anthrax. The centre may become depressed by the formation of the scab in the middle, the edges forming a wall around. The neighborhood ot the pustule is sometimes little changed and sometimes red and swollen, and may be occupied by small yellowish or bluish-red vesicles. If the proc- ess remains local the sloughing pustule may be thrown off. Infection of the blood is followed by fatal consequences. In rare cases infection shows itself in a widespread, intense edematous swelling of the tissues tay’ ra ao the formation of a circumscribed 3 LIA \ £08) ~oe Ge) ustule. weieseces 7 BR Re Sip Oy EO) In the region of a fully developed ® ue ene 1 Re) anthrax-pustule (Fig. 413) the corium (d, G0 aaah, uf d,) and papillary body (c) become _per- f ASEAN TAG pe meated by a cellular, serous, and bloody NES: e @: 2 lee geo) exudate as well as by bacilli. The bacilli aR Kop Bb lie in the external portions of the corium 0G) OD) NO N- S (d,) and in the papillary body (c); but they can penetrate into the deeper layers of ocfigiflt= section from, s portion of the corium (f'). In the region of the pa- Honea evatained “baet. seenined “pallary body (c) the exudate is sanguino- ? lent. Vesicles filled with bloody fluid result if the exudate extends up to the epi- thelial covering and if the deeper portions of the latter become liquefied, thereby permitting the superficial portions to be lifted up by the exuded fluid. If the upper layers of skin are lost the bloody fluid containing bacilli (7) appears on the surface. The cellular infiltration has its seat mainly in the corium (d, d,, e), and it makes the impression as if the great massing of cells would form, to a certain extent, a protection against the further encroachment of the bacteria. The cells that accumulate are for the most part polynuclear leucocytes (Fig. 414). The bacilli lie partly within the cells, and partly between them. If infection with anthrax-spores takes place in the intestinal canal— an event which occurs with special frequency in the small intestine, and only infrequently in the stomach and large intestine—-reddish-black or reddish-brown hemorrhagic foci, the size of a lentil or bean, with a gray- ish-yellow or greenish-yellow discolored slough in the middle, will de- velop. In other cases the crests of the folds of the mucous membrane are swollen and show hemorrhagic infiltration, and the most prominent parts show evidences of sloughing. The mucosa and submucosa are in- filtrated with blood in the region of the foci; the surrounding tissue is cedematous and hyperemic. In these foci, as well as in their surround- ings, the tissue contains bacilli, especially in the blood- and lymph-ves- sels, and they may be equally well seen in the swollen lymph-glands: THE BACILLUS OF TYPHOID FEVER. 473 . _ According to observations of Eppinger and Paltauf, primary lung infection occurs by inhalation of anthrax-spores, usually proving fatal in from two to seven days. Individuals who have to handle the hair of animals that have died of anthrax are specially exposed, and the infection of the men or women who are busied ia the sorting of rags in paper-facto- ries—an infection which is known as rag-sorters’ disease—is, in a part of the cases, nothing more than an anthrax infection. The bacilli are very probably taken into the lungs in the form of spores with the inspired air, and develop in the bronchi and alveoli, in the spaces that contain the tissue-juices of the lung and pleura, and in the bronchial glands, and they also penetrate into the vessels. Their multiplication causes inflammatory processes in the lung, as well as the pouring out of a bloody serous exudate in the pleural space and in the mediastinal tis- sues, and swelling of the lymph-glands. It may also lead to formation of necrotic foci in the lung and in the bronchial and tracheal mucous membrane. Mice, rabbits, sheep, horses, and sparrows are very susceptible to anthrax. White rats, dogs, and Algerian sheep are less susceptible or enjoy complete immunity. Cattle become easily infected through the intestines by taking in the spores into the alimentary canal, but are less susceptible to inoculation. Formation of spores does not take place in the tissues and in the blood. By cultivating the bacilli at from 42° to 43° C. (Toussaint, Pasteur, Koch) itis possible to weaken their activity, so that first sheep are not killed, then rabbits and guinea-pigs, and finally even mice are no-longer killed by inoculation. If the temperature is near 43° C., this condition can be reached in six days; at 42° C. it may take sixty days be- fore the virulence becomes weakened to this extent (Koch). By first inoculating with bacilli that kill mice, but are harmless for guinea-pigs, and by a second inoculation with bacilli that will kill guinea-pigs, but not strong rabbits, sheep and cattle can be rendered immune, but not mice, guinea-pigs, or rabbits. Practically, however, this protective inoculation cannot be employed, because it is necessary to inoculate with very virulent material in order to protect from natural infection with spores introduced into the intestines ; and consequently a large per cent—from ten to fifteen per cent—die from the protective inoculation itself. Moreover, the protection is only of short dura- tion, and the inoculation must be repeated in about a year. According to observations of Roux and Chamberland, the anthrax-bacilli can, while retaining their full virulence, be permanently deprived of the power of producing spores by cultivation in bouillon to which a small amount (1: 2000) of potassium per- manganate or carbolic acid (1-2: 1000) has been added. According to Koch, anthrax-bacilli can be cultivated on potatoes and alkaline or neutral infusions of hay, on cold infusions of pea-straw, on mashed barley and mashed wheat, in the juice of turnips, wheat, leguminous seeds, and numerous dead plants, in the presence of a sufficient quantity of water. Consequently the bacilli grow and de- velop outside the body—e.g., in marshes and on river-banks (R. Koch). The entrance into the animal body is to be regarded as an occasional excursion of the ectogenic bacil- lus. According to Soyka, the development of spores takes place very quickly in a moist medium containing the necessary nutrient material. According to Kitt, cattle- dung forms a nutrient substratum for the bacilli. $169. The bacillus typhi abdominalis (Fig. 415), or the bacterium typhi, is a fission-fungus which appears mostly in the form of plump staves 2 to 3 » long, with rounded ends growing out into long pseudo- threads in cultures. It is recognized as the cause of typhoid fever. When examined alive in cultures it shows lively, independent loco- motion, caused by flagella (Fig. 416) which are attached to the sides of the staves as well as to the ends. The flagella can be made visible by proper staining-methods. The bacillus was first observed and described by Eberth and Koch, and afterward cultivated pure by Gaffky. A. 474 THE BACILLUS OF TYPHOID FEVER. Pfeiffer showed its presence in the dejecta of typhoid patients, and his observations have been corroborated often since. According to Seitz, Hueppe, Neumann, and others, it may also be present in the urine of typhoid patients. It may be well stained in cover-glass preparations with gentian vio- let, alkaline methylene blue, and Bismarck brown; by treatment with Fig. 415.—Typhoid bacilli from a pure culture. Fic. 416.—Typhoid bacilli with flagella. (After Smear preparation. (Methylene blue.) Magni- Bunge). Magnified 1,200 diameters. fied 1,000 diameters. iodine according to Gram’s method it may be decolorized. The detec- tion of the baeilli in sections of hardened organs is somewhat difficult, because the cell-nuclei also become stained, and because the bacilli are not uniformly distributed, but usually lie in clumps in the tissue. The bacillus may be cultivated as well in nutrient gelatin, agar-agar, and blood-serum as in milk and on slices of potato. It forms a coating on the latter that can scarcely be distinguished by the naked eye. But if the surface is touched with a platinum wire it becomes apparent that it is covered with a pellicle, and the microscopic examination shows that this consists of bacilli. On gelatin and agar-agar the bacilli form whitish-gray, flat cultures. of irregular shape. (relatin is not liquefied. Milk in which the bacilli are grown is not changed externally. Cultures flourish at room-temperature as well as at body-temperature. Ordinary potato-cultures kept between 30° and 42° C. produce staves which have glistening granules in their poles. Gaffky interpreted these granules as spores, and formerly most authors accepted this interpreta- tion. According to Buchner and Pfuhl, however, these granules at the poles are degeneration forms occurring especially when the culture contains an acid. The polar granules represent condensed protoplasm, and consequently stain in fresh preparations more quickly with the ani- line dves than do the other parts. The clear, colorless flakes on the ends of the staves that are seen on dried and stained bacilli, and which were regarded as identical with the polar granules and declared to be spores, result, according to Buchner, from the formation of hollows in the ends of the staves, due to retraction of the tube of protoplasm on the death and drying of the bacilli. Consequently spore-formation has not been proved to exist. In moist earth (Grancher, Deschamps), in pure and impure water, typhoid-bacilli may remain alive for weeks. They do not die out for many weeks in artificial Seltzer water (Hochstetter). In privy-vaults and fecal masses, or in earth saturated with feecal matter, they may sur- vive, under certain circumstances, for weeks and months (Finkler, Uffel- mann, Karlinski). THE BACILLUS OF TYPHOID FEVER. 475 Inoculation of the bacilli in animals used ordinarily for experimental purposes does not produce a disease corresponding to typhoid fever in man. Still experiments of Sirotinin, Beumer, Peiper, and others have shown that the typhoid-bacilli produce active toxins and toxalbumins (Brieger) which kill animals in larger doses, causing hyperemia and swelling of the intestinal follicles, of the mesenteric glands, and of the spleen. Cultures injected into the tissues produce locally more or less severe inflammation. The bacilli or their spores get into the human organism probably with the drinking-water and food; still an infection through the lungs is not to be excluded. According to the results of the anatomical exami- nation, they develop in the wall of the intestines, in the region of the solitary and of the agminated follicles of the small and large intestines, as well as in the mesenteric lymph-glands and in the spleen. In the first of these localities they cause an inflammatory infiltration of the mucosa and submucosa (Fig. 417, a,, b,) that is extraordinarily rich in cells, and appears in the form of flat or somewhat elevated and rounded areas above the inner surface of the intestines. An exudation of fibrin in the form of threads may take place both on the free surface and in the deeper layers. Occasionally cellular inflammatory foci limited in area occur also in the muscularis (c,) and in the serosa (d,). A part of the infiltrated tissue usually sloughs and is then cast off, so that ulcers d 3 é Fieé. 417.—Typhoid fever. Section through the edge of a swollen Peyer’s plaque. (Alcohol; Bismarck brown.) a, Mucosa; b, submucosa; c, muscularis interna; d, muscularis externa; €, serosa; @y,)1, C1, dy, €15 the different layers of the intestine infiltrated; f, f, sections of a Lieberktihn’s gland; g, follicle. Magnified 15 diameters. : are formed. In another part the swelling may subside by the absorp- tion of the infiltration. The swelling of the lymph-glands, which is sometimes due to the accumulation of cells and fluid, may also be caused by an exudation of thready fibrin. It is a condition which either ends in recovery by the absorption of the infiltration, or leads to partial necrosis of tissue. In the spleen the pulp in particular swells, while its vessels are greatly dilated with blood, and later its parenchyma becomes crowded full of cells and fluid. 476 THE BACILLUS COLI COMMUNIS. According tc recent investigations, the bacilli are usually distributed to other parts of the body, and it is probable that the inflammatory exudates in the lung which occasionally appear in the course of typhoid fever depend in part upon the growth of the bacilli in the lung. Still it must be borne in wind that inflammations due to inhalation of irritating sub- stances very often occur in the lungs of typhoid patients, and also that secondary infections with cocci start from the ulcers and may cause metastatic inflammations in the different tissues. The swellings of the mucosa and submucosa and of the perichondrial tissue in the palate, throat, and larynx that often occur, and that depend upon inflammatory infiltration, are partly the consequences of specific infection and partly of secondary disease. Typhoid bacilli have been demonstrated in the liver, in the gall-bladder, in the roseola patches, in the kidneys, in the central nervous system, in the testicle, in the pleuritic and peritoneal effusions, in the periosteum, and in the bone marrow, etc., in part by means of the microscope, in part by the use of methods of cultivation. They can cause degeneration and inflammation in all of these places and give rise to suppuration in the tissues, so that inflammations arising in the course of a typhoid infection are due sometimes to the dissemination and localization of the typhoid bacilli, sometimes to secondary infec- tions, and sometimes to mixed infections. Neuhauss was able to find typhoid bacilli even in the spleen of a foetus four months old, whose mother aborted while suffering from typhoid fever. Reher, Eberth, Chantemesse, Widal, and Ernst report similar instances. Since the typhoid bacilli produce active toxins and toxalbumins, the morbid phenomena are to be referred largely to poisoning. In the course of typhoid fever bactericidal substances develop in the blood, and these cause a degeneration of the typhoid bacilli. (Comp. § 28. Note also the Widal-Gruber reaction which is there given.) The cultures of typhoid-bacilli show few characteristic properties, and are con- sequently difficult to distinguish from other widely distributed bacteria. Thus their properties are very similar to those of the bacillus coli communis (cf. § 170). As a dif- ferential mark, it is asserted that the typhoid-bacilli produce no indol, whereas other similar bacteria—for instance, the bacillus coli—produce indol, so that the cultures of the latter turn red on the addition of potassium nitrite and sulphuric acid. In two-per- cent grape-sugar bouillon the typhoid-bacillus produces no gas, whereas the bacillus coli develops gas. Finally the typhoid-bacillus produces faint acidity in milk, but no coagulation ; whereas the bacillus coli causes strong acidity and curdling of the milk in from twenty-four to forty-eight hours at 37° C. § 170. The bacillus coli communis, or the bacterium coli commune (Escherich), is a fission-fungus constantly present in the abdominal canal of man as well as of mammalian animals. The bacilli are staves 2 to 3 » long and 0.3 to 0.4 4 thick. They are capable of locomotion by means of flagella, which may number as many as twenty on one staff (Bunge, Luksch, Gunther). The bacilli grow at room-temperature as well as at the temperature of the incubator. In the depth of the gelatin they form small, round white colonies, on the surface pellicle-like colonies. On potatoes a yellow juicy coating is formed, of the same shade of color as maize or pease (Giinther). Spore-formation does not occur. The bacilli cannot be stained by Gram’s method. , The bacillus colt is very similar to the typhoid-bacillus; still-it may be distinguished from this by proper methods of cultivation and by the employment of suitable reactions (cf. § 169). Formerly it was regarded THE BACILLUS PNEUMONIL2. ATT as a harmless saprophyte of the large intestines, but it can no Jonger be doubted, according to recent investigations, that pathogenic properties are also attributable to it, and that it is capable of causing degenerations and inflammations in various tissues. Thus, under suitable conditions, such as perforation or incarceration of the intestines, or impacted feces, it may get into the peritoneal cavity and cause purulent inflammation, or at least take part with other bacteria in the production of in- flammation. It gets, moreover, not infrequently, into the gall-ducts and gall-bladder, and seems capable of causing inflammations of varying in- tensity. Moreover, the bacillus has also been found, in some cases of septic disease, in the exudate of the membranes of the brain; further- more, in pericarditis, pyelitis, pyelonephritis, cystitis, bronchopneu- monia, strumitis, scarlatinal angina, and acute yellow atrophy of the liver (Stroebe, von Kahlden); and one cannot doubt that it is the active morbific cause in these diseases. The similarity between the bacillus coli and the typhoid-bacillus has caused various authors to assume that the two bacilli represent only varieties of one kind, and that con- sequently the two forms may pass over into each other. Still, at present the opinion prevails that the two bacilli are to be entirely separated from each other (cf. § 169). As there are other bacilli that much resemble the bacillus coli, and often are not to be dis- tinguished with certainty from it, it may well be assumed that the publications on the bacillus coli have not always dealt with the same bacterium. § 171. The bacillus pneumoniz was discovered by Friedlander and Frobenius. This bacillus, it was assumed, was able to cause inflamma- tions, especially inflammations of the lungs, of the nose (ozena), of the middle-ear, and of the meninges, and less frequently of other organs. It is looked upon by Friedlander as the chief cause of croupous pneumonia, but this view is without 0 doubt incorrect (comp. § 163). According to © \o b Weichselbaum it has been demonstrated in only eo about five per cent of the cases of lobar pneumonia. @ § Baumgarten and others go so far as to maintain ©® @ that its pathogenic significance is not yet firmly established, because other bacteria are always Fig. 418,—Baeillus pneu- found present with it in the lungs. Oval cent and sows of eels The bacilli lie in the alveolar exudate, as well With gelatinous capsule; 1, as in the pleuritic exudates that form at the same Sule. Magnitied 300 diath- time as the inflammation of the lungs. They ap- “™* pear sometimes in the form of staves (Fig. 418, 0), sometimes in the form of oval cells (a), and not infrequently they are joined together so as to form short chains. Since the oval cells are more numerous than the staff forms, the bacillus was originally reck- oned with the cocci. The bacilli possess a hyaline, mucin-like capsule, soluble in alka- lies, insoluble in acetic acid, which forms a common sheath around the chains of the bacilli (Fig. 418). Independent motion has not been ob- served. The bacillus loses its color when stained with gentian violet and treated with iodine and alcohol, and may be easily distinguished in this way from the diplococcus. In order to stain it along with the capsule in sections, Friedlander recommends the employment of an acid solu- tion of gentian violet, consisting of 50 parts of concentrated alcoholic solution of gentian violet, 100 parts of distilled water, and 10 parts of 478 THE INFLUENZA BACILLUS. acetic acid. After staining for twenty-four hours the sections ara washed out in a 0.1-per-cent solution of acetic acid for a short time. The bacilli grow in nutrient gelatin at room-tem- perature, and form porcelain-white, knob-shaped cul- tures on the surface of the gelatin. The oval and staff-shaped cells possess no capsule. Stab-cultures in gelatin are nail-shaped (Fig. 419), this appearance being due to the fact that the bacilli*form a knob- shaped prominence at the entrance of the canal of inoculation. This is a peculiarity that the pneu- monia-bacilli share with many other bacteria. On blood-serum they form gray, transparent colonies, on agar-agar grayish-white, on potatoes grayish-white or yellowish-white, creamy colonies. Spore-forma- tion is not observed. Rabbits are almost entirely refractory to inocula- tion of the lung; mice, on the contrary, die with pleurisy and disseminated pneumonia in from eigh- teen to twenty hours after injection of the bacilli into the lung, and the exudate as well as the blood is found to contain bacilli with gelatinous capsule, some lying free, some inclosed in cells. A typical lobar pneu- monia cannot be produced in the ordinary experi- mental animals. The bacterium of Friedtainder, according to Fricke, is the principal representative of a group of bacteria which are gathered together under the name bacillus mucosus capsulatus, and represent varieties of a single species. The fission-fungus described as the ozena bacillus is identical with the pneumonia bacillus, and apparently so also is the bacillus from the milk feces of nursing children, known as the bacterium lactis aérogenes, to which is at- tached possibly a greater etiological significance as the cause of many diarrhceas. § 172. A bacillus was described in 1892 by R. Pfeiffer as the influenza-bacillus (Fig. 420), and the discovery has been frequently corroborated since ; it Fig. 419.Nail-shaped is regarded as the cause of the influenza. In indi- There “Mneumococeus Viduals who are sick of influenza it is found in the in gelatin. catarrhally affected air-passages, occasionally also in the lungs. The small bronchi may contain enor- mous numbers of the bacilli in pure culture. It is assumed that the multiplication of these organisms in the respiratory tracts causes inflam- mation, and that at the same time they produce poisons which on being absorbed cause the morbid phenomena peculiar to influenza. Canon states that the bacilli go over into the blood. The inflammatory changes which take place in different internal organs during the progress of in- ftuenza may be referred in part to the influenza bacilli, in part to the poisons which they produce, and finally in part to secondary infections. The influenza-bacilli are very small, thin staves with rounded ends (Fig. 420), which lie separate or joined in twos, and may be stained with the usual aniline dyes, but,not by Gram’s method. They may be cultivated at body-temperature upon blood-agar or on agar that is smeared with human or pigeon’s blood, and they form small, drop-like colonies as clear as water. They do not grow, on the contrary, upon THE BACILLUS DIPHTHERLA. ‘ 479 the other usual media. Spore-formation is not observed. In apes a catarrhal inflammation of the respiratory passages can be produced by intratracheal injection of pure cultures. Rabbits may be poisoned by inoculation of cultures, and they acquire, in consequence of the poisoning, a paralytic weak- ness of the muscles anddyspnoea. According to Cantani the poison produced by the influenza- bacilli exerts its effect chiefly upon the central nervous system. § 173. The bacillus diphtheriz (Fig. 421) is a bacillus, first accurately studied by Loffler, which is found in the croupous membrane that Fie, 420, — Influenza bacilli occurs in diphtheria, and is very probably the fog" ihe seutum, together with cause of diphtheria. In the internal organs, Magnified 1,000 diameters. such as the spleen and lymph-glands, the ba- cilli are either entirely absent or they are present in such small numbers that they can be detected only by methods of cultivation. The bacilli are from 1.5 to3.in length, and are often somewhat swollen at the ends. In cultures rods of various lengths are formed, tlie ends of which are thickened like clubs or pointed (Fig. 421), Stained bacilli appear spotted or granular. The best solution to use for staining is one composed of 30 ¢.c. of concentrated alcoholic solution of methylene blue and 100 ¢.c. of 0.0001-per-cent solution of potassium hydroxide, after which the preparation is treated for some seconds with 0.5 per cent acetic acid, and then with alcohol. In stained preparations the bacilli are often segmented. They also stain by Gram’s method, provided the treatment with iodine solution and alcohol is done quickly. The diphtheria bacilli grow best in the presence of air (Loffler) on a mixture of three parts of calf’s or sheep’s serum and one part of neutral- ized 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 on agar-agar with an addition of ten per cent of glycerin or of nutrient bouillon containing sugar (Kolisko, Paltauf, Kitasato). They form grayish-white colonies. For their development they require a temperature above 20° C., and grow best at from 33° to 87°C. The bacilli are resistant to drying, but they are soon destroyed a Ys ® by moist heat. Spore-formation has not been "1 paces observed. NN Guinea-pigs inoculated subcutaneously with cul- oer a tures of the bacilli (Loffler, Roux, Yersin) die in two or three days. At the point of inoculation ~ G there is found a whitish deposit and hemorrhagic In, ao cedema. The point of inoculation contains bacilli ; - € BN 2X the internal organs, on the contrary, are free. In / : rabbits, chickens, and pigeons, the introduction of au tin. ae ee cultures into the trachea through awoundt is followed Bee eae Te by the formation of a pseudo-membrane. Inocula- diameters. tions of the conjunctiva in rabbits and of the vagina in guinea-pigs are also followed by inflammation and by the formation of a false membrane. 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 subsequent 480 THE BACILLUS DIPHTHERLE. paralysis in pigeons and guinea-pigs that had survived inoculation. Roux and Yersin assert that intravenous injection of filtered cultures— i.e., bouillon-cultures containing no bacilli—causes in guinea-pigs and rabbits a severe illness characterized by paralysis, and fatal conse- quences in two or three days. The virulence of the cultures varies greatly. The diphtheria bacilli produce, both in the human body and in cultures, toxins which are precipitable with alcohol and are obtained as a whitish powder. This poison has been classed among the toxalbumins; however, according to Brieger and Boer, it is not an albuminous body, and is formed also when the bacilli are grown in alkaline urine (Guinochet). According to Kossel the poison is formed in the interior of the bacterial cells from the nutrient material, and is then secreted. The poison, injected subcutaneously in watery solution into animals, causes local tissue-necrosis, hemorrhagic oedema, and inflammation; taken up by the body fluids, it produces exudates in the pleura, nephritis, fatty degeneration of the liver, and paralyses. Diphtheria in man is characterized by an inflammation extending mostly over the mucous membrane of the throat, palate, palatal arches, and the upper respiratory passages. It appears as a febrile infectious disease combined with symptoms of intoxication, and gives rise locally to croupous exudates, partly also to diphtheritic desquamation (cf. § 96, Fig. 178 and Fig. 179). The croupous membranes constitute the most striking feature. They are spread over the throat and the nose usually in limited flat patches, more rarely uniformly over larger areas, or they may form a continuous lining upon the larynx and air-passages. Un- derneath the croupous membrane the epithelium is mostly lost, the con- nective tissue of the mucous membrane hyperemic, infiltrated, and swollen (Fig. 180). In severe cases the superficial layer of connective tissue is necrotic in places, most frequently on the tonsils, which are more or less swollen, often to a very marked degree. Deeper down in the tissues, the lymph-glands, especially those in the neck in near proximity, are swollen, and often show, on microscopic examination, small foci in which the cells are necrotic and disintegrated. Of the in- ternal organs the kidneys especially are usually changed, in that there is a more or less high degree of fatty degeneration in the epithelium and capillary walls, not infrequently also an oedematous swelling and foci of small-cell infiltration. In the spleen, in the interior of the white- looking follicles, areas of degeneration are often found, in which a larger or smaller number of the cells are necrotic, some of them being already in a disorganized state and having no nuclei. In the blood many leuco- cytes show fatty degeneration. Degenerative changes and areas of in- flammation are not infrequently found in the heart muscle, and in the intestine there is tumefaction of the follicular apparatus. The lungs are not notably changed by the diphtheria poison; still bronchopneumonias often occur which are due to inhalation of the irri- tating contents of the bronchi, or to an extension of the bronchial in- flammation upon the respiratory parenchyma. The local inflammations of the mucous membranes as well as the symp- toms of intoxication can be caused only by the diphtheria bacilli and their toxins, but it is to be remembered that streptococci also are with great regularity found in the diseased areas, and that a pure streptococcus in- fection may also call forth the clinical and anatomical picture of “diph- theria.” If both species of bacteria are present, then the harmful action THE BACILLUS TETANI. 481 of the one is supported by that of the other, and it appears that the pres- ence of the streptococci increases the virulence of the diphtheria bacilli. In severe forms of diphtheria, streptocvcci are usually present in great numbers; yet every streptococcus infection does not warrant a bad prog- nosis, for the virulence of the cocci also varies considerably. In the course of the infection due to the diphtheria bacilli, antitoxins arise in the body which nullify the poisonous action of the toxins; they aid and make possible recovery from the disease. This formation of antitoxins also follows the inoculation of animals with attenuated bacilli, and on this depends the possibility of obtaining from animals (sheep, horses), which are repeatedly inoculated with bacilli of increasing virulence, a2 serum which contains an antitoxin valuable for therapeutic purposes (comp. § 30). Lehmann and Neumann call the diphtheria bacillus coryne hacterium on account of the club-like shape of the rods. Inasmuch as the bacillus can also form branched threads in cultures, they count it among the hyphomycetes, among which the tubercle bacillus and the actinomyces-fungus (odspora) are also classified by them and by others. According to Léffler, von Hoffmann, Roux, Yersin, Babes, and others, bacilli des- ignated as pseudodiphtheria-bacilli occur very often in the mouth and throat, which look like the diphtheria-bacilli and even in cultures can only with difficulty be distinguished from these. Since the diphtheria-bacilli may lose their virulence, it is not improbable (Roux, Yersin) that the two bacilli are varieties of ove kind. § 174. The bacillus tetani (Kitasato) is a fine, slender bacillus (Fig. 422) which is widely distributed throughout the superficial layers of the earth, and is to be regarded as the cause of tetanus. According to ob- servations of Nicolaier made in 1885, it is often possible, in mice guinea-pigs, and rabbits, by a subcutaneous inocula- tion of earth taken from the superficial layers, to ob- ~ a tain typical tetanus with fatal termination. j gfe Z The demonstration was first made by Rosenbach —- &\ in the year 1886 that the bacilli found in traumatic ve tetanus and those found in tetanus due to frost-bite 08 \=- in human beings, in the region of the seat of injury, ose AY SN were one and the same, and that when inoculated Fic. 422.—Tetanus ba- into guinea-pigs and mice they cause genuine tetanus. _ ill, showing spore-tor- Since then this discovery has been often corroborated. _ located at one pole. The bacillus is present neither in the soil nor in the infected wound in an isolated condition, and consequently inocula- tions have been made with mixtures of bacteria. The effort to isolate in cultures the bacillus that was regarded as the cause of tetanus was unsuccessfully made by most investigators. Kitasato in 1889, in Koch’s laboratory, succeeded in isolating the tetanus-bacillus by allowing the mixed cultures to remain in the incubator a few days and heating for a half-hour or an hour at 80° C., and then subsequently making plate-cul- tures in an atmosphere of hydrogen. The bacteria growing along with the tetanus-bacillus are killed by the heating, while the tetanus-bacillus is preserved. The tetanus-bacillus is anaérobic and grows very well in an atmos- phere of hydrogen, but not in carbonic-acid gas. It grows in ordinary slightly alkaline agar-agar containing peptone, and in blood-serum and nutrient gelatin. It liquefies the latter with the production of gas. Addition of from 1.5 to 2 per cent grape-sugar accelerates the growth. The most favorable temperature is between 36° and 38° C. It forms long, thin, bristle-like staves that produce spores on one end (Fig. 422) which 482 THE BACILLUS GEDEMATIS MALIGNI. cause a swelling of the end of the staff, giving rise to the name knobbed bacilli. It may grow out in cultures into long pseudothreads. The cultures give out an offensive odor; gelatin is slowly liquefied. The bacilli stain by Gram’s method. They are motile except at the period of spore-formation, and they possess peritrichal flagella. Pure cultures inoculated into horses, asses, guinea-pigs, mice, rats, and rabbits cause tetanus; but rabbits must be inoculated with somewhat larger amounts. The tetanic contractures start first in the neighborhood of the point of inoculation. Suppuration does not occur at the point of inoculation. The bacilli are not to be found after the animal is dead, and are never found except at the seat of inoculation. : According to the experimental investigations of Kitasato, the filtrate which is obtained from bouillon-cultures of the bacilli, but which con- tains no bacilli, acts in the same way as the cultures containing the bacilli, and guinea-pigs especially are very sensitive to it. The blood or transudate from the thoracic cavity of an animal infected with teta- nus, although free from bacilli, causes tetanus when inoculated into mice. It is consequently to be assumed that in tetanus it is a matter of intoxication with a poison (tetanotoxin) that is distributed throughout the blood. The poison is destroyed by heat (Kitasato)—a temperature of 65° C. and over—in a few minutes, and by direct sunlight in from fifteen to eighteen hours, and loses its effects in diffuse daylight in a few weeks. According to investigations of Brieger and Cohn, the puri- fied poison gives no reaction for albumin, and consequently does not belong to the toxalbumins. The infection, i.e., the intoxication, of man results in most cases from small wounds. Rheumatic tetanus, which does not start from wounds, may apparently arise from a multiplication of the bacilli in the bronchi (Carbone and Perrero). It follows from this that there are also tetanus bacilli which grow in the presence of oxygen. The tetanus- toxin acts principally upon the nervous system. The bacillus cedematis maligni (vibrion septique of Pasteur) is an anaérobic bacillus which was first thoroughly investigated by R. Koch. It is found in various putrefying substances, and the spores almost never fail to be present in earth that is manured with foul liquids or liquid manure. The bacilli are from 3 to 3.5 » long and from 1 to 1.1 » broad, and often form long pseudothreads. They are similar to the an- thrax-bacilli, but are somewhat more slender and rounded on the ends, not sharply cut across, and are occasionally motile. In spore-formation a swelling develops from one part of the rod, as in bacillus butyricus, so that spindle-shaped and tadpole-shaped forms result. 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-agar and coagulated blood-serum, but it must be introduced deep down and cut off from the air. Nutrient gelatin with the addition of one or two per cent of grape- sugar is a specially favorable medium (Fligge). Nutrient gelatin and blood-serum are liquefied, the latter with the production of gas. The bacillus can be readily obtained by sewing up garden-earth un- der the skin of a guinea-pig and by taking care that the air does not find access to the point of inoculation. The subsequent multiplication of the bacilli causes a progressive edematous swelling of the subcutaneous tissue. At a more advanced stage the bacilli spread over the serous membranes, and into the spleen and other organs. THE BACILLUS OF THE BUBONIC PLAGUE. 483 Mice, guinea-pigs, horses, sheep, and swine are susceptible to the bacilli; cattle are not (Arloing, Chauveau). According to the observations of Brieger, Ehrlich, Chauveau, Arloing, and others, the cedema-bacilli also occasionally develop in the tissues of human beings, especially when the tissues are poorly nourished and the bacilli by any accident—e.g., by puncture of a hypodermic syringe— get into the depth of the tissues. They lead to a gangrenous process which is combined with bloody cedema and the development of gas. According to Vaillard and Vincent, tetanus does not follow inoculation of tetanus- bacilii deprived of poison. Consequently it must be assumed that the bacilli can only multiply in the tissues of man and animals and lead to poisoning when special condi- tions are present, when the tetanus poison itself is also present at the same time, or when other bacteria, such as bacillus prodigiosus, get into the tissues. Blumenthal believes that the bacilli excrete a ferment which produces, within the organism, the tetanus oison. . According to investigations of Kitasato, Tizzoni, Cattani, Baquis, Behring, and others, susceptible animals may be made immune from tetanus, or, more properly speak- ing, poison-proof against the poison of tetanus. The blood of animals that have been rendered poison-proof possesses the property of destroying the poison of tetanus, and consequently it is possible to immunize susceptible animals with the curative serum ob- tained from this blood, or to cure tetanus that has already broken out in man or ani- mals (cf. § 30). As regards the bacteria of hemorrhagic infection, compare § 46. § 175. The bacillus of the bubonic plague was discovered in 1894 by Kitasato and Yersin, of the Japanese and French commission of in- vestigation, while investigating an epidemic which had broken out in Hong-Kong. The plague bacillus is a small rod, rounded on the ends (like the bacillus of fowl-cholera), which stains easily with the basic aniline dyes, especially with methylene blue, and shows exquisite polar staining. It is decolorized by Gram’s method. According to Zettnow the bacilli possess capsules. It is found in all those affected with the plague, especially in the swollen lymph-glands, but also in the spleen and in the blood. It can be cultivated on the various artificial media, and forms bluish-gray colonies, which contain rods of various lengths. It multiplies abundantly in bouillon containing sugar. Spores are not formed. The bacilli are easily destroyed by heating, but can withstand drying well. Mice, rats, and pigs are especially susceptible to plague inoculation, and frogs also are said to be susceptible (Dewel). Inoculation of viru- lent cultures causes death in a few days, and the bacilli are then found in the blood as weli as in the edematous fluid at the point of inocula- tion. When less virulent cultures are inoculated, glandular swellings develop after a few days (Kolle), and the animals die only at the setting in of severe swelling of the glands in the second week. The bacilli are found ia the swollen lymph-glands and in the blood. The bubonic plague, which in Europe at the end of the seventeenth and the beginning of the eighteenth century still carried off the popu- lation in vast numbers (the “Black Death”), has since 1720 almost en- tirely disappeared from Europe, and has shown itself only here and there in Eastern Europe. In different districts of Asia (Yunnan in China, Arabia, Mesopotamia) the disease seems to be endemic, and to spread from time to time like the cholera. Man seems to be infected principally through small wounds (Kita- sato, Aoyama, Yersin), yet an infection by means of inhaled air cannot be ruled out. Rats and mice contribute essentially to the spreading of 484 THE BACILLUS TUBERCULOSIS. epidemics. Insects that have come in contact with sick animals or men can likewise spread the infection. Marked glandular swellings, which may go on to suppuration, are the chief symptom of the disease, which generally ends in death. Besides these appear enlargement of the spleen, degenerative changes in the glandular abdominal organs, and hemorrhages. In the later stages of the disease the enlarged and suv- purating lymph-glands may also contain streptococci beside the plague bacilli. Secondary infections also occur. Experiments carried on by Haffkine make it appear probable that successful protective inoculations may be undertaken with killed cul- tures of the plague bacilli. Yersin states that an active curative serum for the treatment of those infected may be obtained from immunized animals. From the investigations of Ducrey, Krefting and Petersen (comp. Petersen: ‘ Ulcus Molle,” Arch. f. Derm., XXIX., 1894, and XXX., 1895), it seems probable that the ulcus molle, or soft chancre, is caused by a bacillus. This view is, however, combated by competent authors (Finger: ‘Die Syphilis und die venerischen Krankheiten,” Leipsic, 1896), and the doctrine is advocated that the soft chancre does not possess a specific virus. It is to be noted also that attempts to cultivate the bacilli of chancre have not so far been successful. According to communications from Sanarelli (“Sur la Fiévre jaune,” Ann. de l’ Inst. Pasteur, 1897, and Centralbl. f. Bact., XXII.), which have but recently appeared, yellow fever seems to be caused by a bacillus which can be cultivated. Its isolation is often difficult, by reason of complicating secondary infections with bacterium coli, strepto- cocci, etc. § 176. The bacillus tuberculosis is the cause of the infectious dis- ease which is very frequent as well in man as in the domestic mammailia, and which is usually called tuberculosis, but is also sometimes called Pearl disease ( Perlsucht) in animals. The tubercle-bacilli, discovered and thoroughly investigated by Koch in the year 1882, form narrow staves (Fig. 423), from 1.5 to3.5 » in length, that are often slightly curved. Aniline dyes (fuchsin or gentian violet), in aqueous solution with the addition of an alkali or carbolic acid or aniline, are suitable for staining them. The bacilli once stained retain the dye even when the preparation is decolorized with dilute sulphuric or nitric acid, or with hydrochloric acid and alcohol. The stained bacilli show not infrequently in their interior clear, glistening, unstained places, or are composed of little stained globules. Koch interpreted these clear portions formerly as spores, and this view was generally accepted for a long time. But, nevertheless, a germina- tion of these structures cannot be proved, and at present the objects in question are no longer regarded as spores. Consequently the tubercle- bacilli produce no special resistant forms, but still the bacilli are more resistant against external influences—e.g., against drying—than are many other bacteria. The tubercle-bacilli may be cultivated at the body-temperature and in the presence of oxygen upon solidified blood-serum, upon blood-serum gelatin, upon nutrient agar, and in bouillon; they multiply, however, very slowly, so that only on the seventh to tenth day, or even later, cul- tures appear at the point of inoculation in the form of dull-white flakes resembling little scales. Larger cultures form, on the surface of solidi- fied blood-serum, white, irregularly shaped, dull coatings (Plate I., Fig. 4). According to Nocard, Roux, and Bischoff, the growth of the bacilli is greatly aided by the addition of from four to eight per cent of glyc- erin. Pawlowsky succeeded in cultivating them on potatoes in sealed. evn THE BACILLUS TUBERCULOSIS. “485 glass tubes. In cultures the tubercle bacilli also produce threads, which in some cases split into two branches. At temperatures below 28° C. and above 42° C. the growth of the bacilli ceases. Sunlight kills the ba- : cilli in a short time (Koch). If the bacilli from pure cultures are oy Se inoculated into experimental animals, &, ye tuberculosis is produced in these; and ero the infection succeeds as well by inocu- eae “ NS NG lation under the skin or in the abdominal cavity or in the anterior chamber of the eye as by inhalation of an atomized sus- pension of the culture and by injection of the bacilli into the veins. Guinea-pigs and cats are specially susceptible; dogs, Fig. 423.—Tubercle-bacilli. Sputum of rats, and white mice, on the contrary, a man suffering from tuberculosis of the lung, spread ina thin layer on a cover-glass are less so. and stained with fuchsin and methylene The infection of human beings ™% Magnifted 400 diameters. and of animals occurs from the taking up of the tubercle-bacilli from the lung or intestinal tract, or from wounds and ulcerations. In the alimentary canal the commonest ‘points of entrance for the bacilli are the lymphadenoid apparatuses, the tonsils, and the intestinal lymph-follicles. Moreover, a direct transfer of the bacilli from the mother to the foetus developing in the uterus also takes place. In the external world the bacilli are spread mainly by the sputa, under certain conditions also by the feces and by the urine; further- more, they emanate from tuberculous ulcers of the skin or tuberculous organs taken from living or dead persons. Since the bacilli are tolerably resistant, they may remain preserved here, under certain conditions, for a long time, and can become mixed with the respired air as well as with Fig. 424. Fig. 425. Fic. 424.—Tissue changes produced by a recent invasion of the tubercle-bacilli. (Diagrammatic, after Baumgarten.) a, Hyperplastic connective tissue; b, cross-section of a blood-vessel; c, karyomitoses in the connective tissue; d, mitoses of an endothelial cell of a vessel; e, emigrated leucocytes. Magnified 250 diameters. Fig. 425.—A giant cell containing bacilli with necrotic centre, from a tubercle. Preparation stained with gentian violet and vesuvin, and mounted in Canada balsam. Magnified 350 diameters. the food and drink. The milk of tuberculous cows contains the bacilli, especially when the udder is diseased; it seems, however, that the bacilli may also pass over to the milk when the udder is not demon- strably diseased (Hirschberg, Ernst, Leuch). 486 THE BACILLUS TUBERCULOSIS. If the bacilli succeed in developing and multiplying in any tissue of the human body, they lead by a series of changes to tho formation of nodular masses of granulation tissue or tubercles, which remain devoid of blood-vessels, and which, when they have arrived‘at a certain stage of evelopment, die out again. The first effect of the development of the bacilli in a tissue (Fig. 424) may be a hyperplasia of the fixed cells of the tissue, which begins with karyomitosis (c, d) and leads to the formation of epithelial-like proto- plasmic cells (fibroblasts), which are usually designated as epithelioid cells (a). By reason of the fact that the process of cell-division repeats itself many times, there are produced collections of epithelioid cells (a) which form knot-like foci at the point where the bacilli multiply, and in these foci the bacilli lie, some of them between the cells, others in the cells themselves (Fig. 424). By the hyperplastic development of cells the connective-tissue stroma of the original tissue is pushed more and more to one side, and even to Fic. 426.—Tubercle from a fungous granulation of bone. . a, Giant cells; b, epithelioid cells; c, lymphoid cells. (Miiller’s fluid; Bismarck brown.) Magnified 400 diameters. some extent obliterated, so that the individual cells come finally to be separated from one another only by scanty fibres whose general arrange- ment is in the form of a net, which is consequently spoken of as the reticulum of the tubercle. These exuberantly growing cells have for the most part one or two nuclei (Fig. 424, a, and Fig. 426, b); but usually cells containing several or many nuclei (giant cells) also appear (Fig. 425, Fig. 426, a) and these often inclose a very considerable number of large, oval, vesicular nuclei, as well as bacilli (Fig. 425). The nuclei of the giant-cells are nearly always distributed in the protoplasm in an irregular manner, sometimes grouped in the form of a wreath or horseshoe, sometimes massed _to- gether at one pole, sometimes at two or more points (Figs. 425 to 429). The nucleus-free part of the giant-cells, when they are properly stained, permits us to recognize conditions of degeneration and necrosis of the protoplasm which are brought about by the action of the bacilli present —__ in the giant-cells (Fig. 425 and Fig. 429, c). THE BACILLUS TUBERCULOSIS. 487 New vessels are not formed within the tubercles, and even the old vessels are obliterated by the hyperplasia. To the hyperplasia already described is added, sooner or later, an Fic. 427.—Tuberculosis of the pleura. (Alcohol; Van Gieson’s mixture.) a, Thickened and proliferating pleura; b, tubercle, with giant cells; c, deposit of fibrin. Magnified 200 diameters. inflammatory exudation, which is first recognized by the massing together of the leucocytes (Fig. 424, e, and Fig. 426, c). The time at which the emigration of the cells begins varies according to the mode of invasion of the bacilli, and probably also according to Fie. 428.—Large-cell tubercle from a tuberculous lung, with some exudation of fibrin. (Alcohol; fibrin stain.) a, Fibrin; b, giant cell; c, tissue composed of large cells. Magnified 300 diameters. the character of the infected tissue. It takes place earliest when the tissue is at the same time subjected to some other pernicious influence, 488 THE BACILLUS TUBERCULOSIS. e.g., to trauma. If a large-celled nodule has been formed by the exces- sive cell-reproduction, the emigration of cells leads first to an accumula- Fig. 429.—Tissue from a focus of tuber- culous disease, showing bacilli and a limited area of cheesy degeneration. (Alcohol; fuchsin ; aniline blue.) a, Granular cheesy material; @,, cheesy material in the form of small, separate aggregations; b, fibrocellu- lar tissue; ¢, partly necrotic giant cell with bacilli; d, cellular tissue invaded by ba- cilli; ¢,a similar invasion in tissue that is necrotic; f, bacilli inclosed in cells. Mag- nifled 200 diameters. focus ; tion of small round cells at its periphery (Fig. 426, c, and Fig. 427, b) and then to an infiltration with round cells, which infiltration may become so marked that the larve cells may be partly or entirely hidden. In this way a large-celled tu- bercle becomes a smail-celled tubercle. If the emigration of the cells takes place very early, the tubercle assumes from the start the character of a small-celled however, mononuclear fibro- blasts, or even giant-cells may generally be made out in the midst of the focus (Fig. 427, b). With the emigration of the cells there is usually combined a serous exudation, and fibrin may be deposited in the tubercle itself (Fig. 428, a) as well as in the surrounding tissue. The tubercle, when it has arrived at the height of its development, forms a small, gray, translucent, cellulur nodule which may attain the size of a millet-seed, and which incloses among its tissues more or less numerous bacilli. When it has reached a certain size retrograde changes usually appear in the centre, in consequence of which the tubercle be- comes cloudy and opaque, and presents a whitish, or grayish-white, or SERA ars En odin alert ty (222 2) ree ake teh di , Teh, Fic. 480.—Partly cheesy and partly fibrous tubercle of the lungs. (Alcohol: Van Gieson.) a, Cheesy centre; b, dense, homogeneous connective tissue, containing but few nuclei; c, connective tissue rich in nuclei; d, pulmonary tissue. Magnified 80 diameters. yellowish-white color—a change which is commonly termed cheesy de- generation of the tubercle. The caseation of the tubercle depends partly upon a necrobiosis of the cells, partly upon a deposition of coagulated substances in the spaces FIBRO-CASEOUS TUBERCLES. 489 between the cells. The cell-necrosis is characterized by the death of the nuclei and the transformation of the cells into flake-like bodies, which later disintegrate and become granular (Fig. 429, a, a,). The substance stratified between the cells is composed either of fibrin with a net-like arrangement (Fig. 428, a), or of a granular or hyaline fibri- noid substance, much resembling fibrin and arranged in nets. This substance does not take the Weigert fibrin-stain, but it stains yellow with Van Gieson’s stain. In the further course of the caseous degenera- tion the fibrin and the fibrinoid substance are reduced to a granular mass, which fuses with the cell-detritus, so that the central part of the tubercle is then composed of a flake-like granular mass, which is only feebly stained with nuclear stains. The caseous degeneration always attacks first the central parts of the tubercle, and generally also remains limited to these, but it may also affect the entire tubercle. If the caseous degeneration of the periphery does not occur, then the cellular character of the tubercle, after a shorter or longer time, undergoes at the periphery a fibrous metamor ‘phosis, 80 that a fibro-caseous tubercle is formed (Fig. 480), the connective tissue of which is rich in cells and finely fibrous, or more coarsely fibrous, or hyaline and poor in cells (b). Generally, in the course of time, it ‘be- comes sharply differentiated from the caseous centre (a), so that the latter appears to be encapsulated by the connective tissue. If the tuber- culosis runs a very favorable course, the centre instead of caseating may undergo a connective-tissue metamorphosis, so that the tubercle becomes a fibrous nodule. The infectious nature of the disease known as tuberculosis had already been deter- mined by the experimental transmission of tuberculosis to animals (Villemin, Lebert, Wyss, Cohnheim, Klebs, Langhans, and others) before the discovery of the tubercle bacillus. However, it was a long time before the view that tuberculosis is an infectious disease found general support, and the opposition (Middendorp) has even to-day not entirely disappeared. The manifestations of tuberculosis, the appearance of caseating granulations in connection with insignificant wounds, were formerly attributed to the existence of an especial anomaly of the constitution, upon which it depended that infected individuals responded to lesions of the tissues arising in one way or another, not with the produc- tion of sound tissue, but with the formation of frail, caseating granulations. Among animals used for experiment this peculiarity was ascribed to those animals which are especially susceptible to tuberculosis, viz., guinea-pigs and rabbits; in man, on the other hand, this supposed constitutional anomaly was designated as scrofulosis, and it was believed to manifest itself in a tendency to inflammations of the skin and mucous membranes, to swellings of the glands, and to joint- and bone-diseases. Such a scrofu- losis, however, does not exist. Pathological conditions which were, and still are, in- cluded under this name are for the most part manifestations of an already existing tuberculosis of the mucous membranes, likewise of the lymph glands and of the osseous system; and when inflammations of the mucous membranes and the skin, which are not of a tuberculous nature, recur frequently, and may, according to experience, in the course of time lead to tuberculosis (through secondary infection), then it is not a matter of an anomaly of the constitution, but of some other infection, for example, with pus cocci. According to investigations of Koch, an active poison, tuberculin, can be extracted in aqueous glycerin solutions from pure cultures of the tubercle bacilli. For obtaining large amounts of tuberculin, cultures of six or eight weeks old, in slightly alkaline veal- broth to which one per cent of peptone and four or five per cent of glycerin are added, are especially favorable. The cultures are evaporated to about one-tenth the original volume by warming, and then are filtered through porcelain or siliceous-marl filters. In this way tuberculin is obtained free of bacteria, in a mixture which contains from forty to fifty per cent of glycerin, and thus is protected against decomposition. Tuberculin may be purified by suitable manipulation—i.e., precipitation with sixty per cent of alcohol—and then forms a white mass which is very probably an albuminous body (Koch), but cari be ranked neither with the toxalbumins nor with the peptones, since it is very resistant to high temperatures and is precipitated with acetate of iron. 490 CRYPTOGENETIC INFECTION. According to later communications from Koch a poisonously acting substance may also be obtained by expressing the contents of ground-up bacilli (comp. § 30). Both substances have been tried for the immunization of man against tuberculosis, yet a satisfactory result cannot be recorded (comp. § 30). According to investigations of Prudden, Hodenpyl, Kostenitsch, Vissmann, Masur, and Kockel, dead tubercle-bacilli conveyed into the tissues of an animal by inoculation, or by injection into the blood-current, or by introduction into the respiratory passages, produce, at the point of introduction, inflammation and new growth of tissue very similar to that produced by the living bacilli. When introduced in large numbers, the dead bacilli may also produce suppuration. The process, however, caused by the dead bacilli differs from that caused by the living bacilli in the following respects: the dead bacilli become entirely destroyed in a few weeks, and the granulating nodules heal up by being changed into fibrous tissue ; furthermore, the extent of the local new formation of tissue depends entirely upon the number of bacilli introduced ; and, finally, no extension of the process takes place in the body. ‘The dead bacilli contain, therefore, substances (proteins) which cause inflammation and later new growth of tissue. Nocard, Roux, Mafucci, and C. Jones have observed that in cultures the tubercle bacilli form threads with branchings. Jones describes in these threads besides vacuoles also strongly refracting, bodies, which he is inclined to take for spores. He further found in caseous pulmonary areas formations resembling the actinomyces-clubs, and looks upon these as well as upon the actinomyces-wedges as collections of a vitreous substance on the thread-fungi or even on the elastic fibres. He considers the tubercle bacillus as well as the actinomyces-fungus as a single-celled, non septum-forming, branching thread-fungus. Lehmann, who agrees with Jones, places the tubercle bacillus among the hyphomycetes and designates it as mycobacterium. ; § 177. Tuberculosis at its commencement is a local disease that oftenest appears in the lungs, the intestinal tract, and the skin; that is to say, in places that are accessible from without. But cases of crypto- Fic. 431.—Lupus of the skin from the region of the knee, with atypical growth of epithelium. (Alcohol; Van Gieson.) a, Corium converted into granulation tissue in which there are scattered tubercles; D, epidermis; ¢, plugs of epithelium which have grown down into the deeper layers of the tissues; d, tubercles. Magnified 50 diameters. genetic infection are by no means of rare occurrence; they are character- ized by pathological changes which are concealed from view, deep down MILIARY TUBERCLES. 491 in the parenchyma of some internal organ; as, for example, in the lymph-glands, in the epididymides, in the bones and joints, in the brain, and in the Fallopian tubes. So there remains no other possi- bility except to assume that the bacilli under certain circumstances get into the body without leaving behind a permanent change at the portal of entrance; that they de- velop first in distant organs to which they have been conveyed by way of the blood- or lymph-cur- rents, and by their increase give rise to new formation of tissue and to emigration of white blood-cor- puscles. The local disease begins with the formation of miliary tuber- cles, that is, cellular nodules of the kind already described, which arise in the tissue either singly or in great numbers simultaneously (in multiple infection) or one after the other (in secondary dissemination of the multiplying bacilli). The tissue in the neighborhood of the individual tubercles, and therefore also that between the tubercles, show sometimes more, sometimes less, pronounced appearances of inflammatory exudation and pro- liferation, especially cellular, by which processes the formation of large granulating areas very fre- quently occurs. In the mucous membranes and in the skin (Fig. 431, a) large areas of the a Coee Fig. 432.— Growth of tuberculous granulations and submucosa, and of the cor1lum from the synovial membrane of the knee-joint. respectively, may, through the {itu },pranulation tissues c tabeteles, “Nagnie presence of such granulations, un- #¢4 60 diameters. dergo thickenings of a nodular or flatly spread-out character. In the serous membranes large, flat, nodules may develop, and in their neighborhood the serosa will be thickened and covered with fibrinous exudate. In the synovial membrane of the joints and in the burse mucose soft fungous growths, the so-called fungous granulations, often develop; and in the lungs or in the glandular organs, in the periosteum, and in the bone-marrow, roundish gray-red or gray granulation-areas of different sizes, etc., make their appearance. All these areas have one feature in common, viz., that in their neighborhood are found inflammatory infiltrations and proliferations of the tissue, which assume the character of granulation tissue (Fig. 431, a; Fig. 432, b); and this granulation tissue contains in its substance character- istic formations—tubercles (Fig. 481, d, and Fig. 432, c)—which are non-vascular cellular nodules that often contain giant-cells. In gray-red looking tissues, rich in blood, these tubercles. may often be recognized 3? Jo ba 5, os 6 i eT oe ig S008 am aroun 774 as neg G30. BEA), we. 883 eye, 499 TUBERCULOUS INDURATION. with the naked eye, as gray, or—in case they have already undergone caseous degeneration—as white or yellowish-white nodules. ; The area of tuberculous granulation when once formed continues to increase in its further development by appositional growth, whereby the : SEs Ei Fic. 433.—Tuberculous induration of the lungs. (Alcohol; bzmatoxylin; eosin.) a, Dense fibrous tissue ; b, granulation tissue rich in cells; c, giant cells. Magnified 40 diameters. ? same processes, which have just been described, are consummated in the periphery. The tissue altered by the tuberculous process may suffer various fates. The three principal terminations, which, however, are often combined in manifold wavs, are the following: In a first group of cases the production of connective tissue comes gradually to preponderate in the diseased area, and from this results a Fic. 434.—Large solitary tubercle of the pia mater cerebelli in vertical section. a, Cerebellum ; », dura mater grown to the tubercle; c, laminated tubercle; @, gray peripheral zone grown to the dura mater and beset with yellowish-white ncedular deposits. Natural size. connective-tissue induration of the part affected (Fig. 433). The tis- sue thus developed is a dense fibrous connective tissue (a), which for CASEATION. . 493 years, however, continues to manifest characteristics different from those of ordinary scar-tissue. Thus, for example, it incloses more or less numerous caseous foci, and in its substance new foci of inflammatory activity are constantly developing; in consequence of which the tissue remains rich in cells (b), and here and there also still produces giant-cells and characteristic tubercles. The second termination is that of firm caseation and of fibro-ca= seous transformation. When this termination occurs, rather firm ca- seous nodules are formed, as may be observed especially in the enlarged tuberculous lymph-glands, in the pia (Fig. 484, c), in the brain, in the spleen, etc. In the lungs this change is an almost constant accompani- Fic. 435.—Tuberculous cavern in the tibia. (Alcohol; picric acid; haematoxylin; carmine.) a, Perios- teum; ), rarefied cortex ; ¢, periosteal bone-deposit; d, fibrous tissue on the inner surface of the cortex; é, granulation tissue containing tubercles; f, sequestrum with scanty bone-scaffolding, permeated with granulations; g, union of the granulations with the sequestrum : h, cavity that had previously been filled with pus and caseous material. Magnified 4 diameters. ment of the tuberculous indurations, which have caseous nodules in their centres. In rare cases such nodules may attain very considerable dimensions in the pia and elsewhere, as in the brain, on the dura, and in different glandular organs (Fig. 434, c). Under these circumstances they consti- tute veritable tumors. The third termination is that of soft caseation, disintegration, and liquefaction, which lead to the formation of cold abscesses, and, after their evacuation, to the formation of caverns or cavities and fistulous passages, and, when there is a wide opening, to ulcers. Disintegration and cavity-formation occur especially often in the lungs, and may there lead to the formation of caverns as large and even larger than the fist. Then, too, they also occur not infrequently in caseating lymph glands, and in cheesy foci located in the kidneys, in the brain, in muscle tissue, and in bone (Fig. 485). The cavities contain at the 494 TUBERCULOUS ULCERATION. commencement the liquefied tuberculous tissue, in which the remains of the tissue originally present are often to be recognized in the form of sequestra (Fig. 435, f). After the contents of the cavity have been evacuated, its walls may furnish material enough to fill it once more, partly by secreting pus, partly by throwing off portions of necrotic tis- sue. Hemorrhages due to the erosion of blood-vessels are also not of infrequent occurrence. The walls of the caverns and abscesses are generally lined with caseat- ing granulations (e) containing tubercles, while the tissues lying outside these walls are in part indurated, and in part are also the seat of caseous foci. Ulcers are formed most often in the mucous membranes (Fig. 436, /) and in the skin, for here the softening cheesy masses break through to the exterior with the greatest frequency. The edge and floor of the Fic. 436.—Tuberculous ulceration of the intestine, with an eruption of tubercles in the neighborhood. (Alcohol; Bismarck brown.) a, Mucosa; b, submucosa; ¢, muscularis interna; d, muscularis externa; ¢, serosa; f, solitary follicle; g, mucosa infiltrated with cells; h, ulcer; h,, centre of softening; i, fresh, 7), cheesy tubercles. Magnified 30 diameters. ulcers are surrounded by infiltrated granulating inflammatory tissue, which often also contains tubercles. The local disease may, in various stages of the tuberculosis, go on to healing, or at least (and this is the more common event) come to a standstill for a long time. If the bacilli are destroyed at the very be- ginning of the tuberculosis, a healing is possible which leaves behind it no recognizable scars. If healing and a standstill of the disease occur at some later stage, firm cicatricial indurations (Fig. 433) are formed. These indurations, however, still contain for the most part caseous fo, less frequently small cavities. In the lungs of individuals who for years have shown no symptoms of tuberculosis, such foci are to be found com- paratively often; and in tuberculosis of the bones and joints the develop- ment of similar foci is not unusual, although here they are often com- bined with the pathological new formation of bone. At the same time the cicatrices, at least in the majority of cases, still possess marks characteristic of tuberculosis. Such are, for example, cheesy foci, TUBERCULOUS ULCERATION. ‘ 495 which may in part have become chalky, exuberant granulation-tissue, tubercles, and tubercle bacilli. In these cases, therefore, it is a question usually not of a complete healing but of a standstill of the disease. During the entire course of the local disease, which by its progres- WORT ay Rey Fic. 487.—Commencing tuberculosis of the lungs in a child two years old. Horizontal section through the right lung. (Miiller’s fluid; carmine.) a, Cheesy focus near the anterior border; b, inner posterior border free from tubercles: c, transverse section of a bronchus: d, d,, cheesy lymph-glands; ¢, pulmonary vein; f, point where the vein e has become adherent to the lymph-gland, d,; cheesy degeneration of the vein-wall has also begun at the same point; g, tubercles in the lymph-vessels of the pulmonary parenchyma ; h, periarterial, i, peribronchial, k, perivenous, 1, pleural, tubercles; m, tubercles of a lymph-vessel lying in the tissue of the hilus of the lung. Magnified 3 diameters. 496 » FORMATION OF METASTASES. sive extension to the neighboring tissues manifests a certain harmful- ness, there exists the further danger of the formation of metastases. The intoxication, which plays such an important role in many of the infec- tious diseases, and controls the picture of the disease, is not apparent Fig. 438.—Eruption of tubercles inalymph-gland. (Alcohol; hematoxylin.) a, Tubercles ; a, caseated tubercle; b, lymphatic-gland tissue; c, giant cell in the centre of a tubercle; ¢,, giant cell on the edge of an area of caseation ; «/, large-celled tissue between the tubercles; €, blood-vessel. Magnified 150 diameters. in local tuberculosis, and there may be individuals with local skin-, lymph-gland-, or bone-tuberculosis who in other respects are entirely well. The formation of metastases takes place primarily by way of the lymph-channels, and it belongs to the picture of advancing tuberculosis that, in the neighborhood of tuberculous areas, tubercles are developed in the lymph-spaces and lymph-vessels, i.e., in their walls (Fig. 436, 2, and Fig. 487, g, h, t, k, l,m). The lymphogenous miliary tuberculosis is limited in some cases to the immediate neighborhood of the original disease, while in other cases it involves large regions, and may even— in the lung, for example—spread from a caseous tuberculous focus (Fig. 487, a) over a great part of the pulmonary lymphatic system (Fig. 437, g, h, 1, k, m). These lymphangitic tubercles present the appearance of bright gray nodules, often surrounded by a red zone, and their struc- ture will be found to be the same as that of the primary nodules. The lymph-glands may also become, involved very early, whereupon tubercles are developed in them (Fig. 4388, a, a,), and these lead, by successive crops, to a more or less pronounced enlargement and ulti- mately to caseation (Fig. 487, d, d,), or to induration of the lymph- glands, or to a combination of both processes. The thoracic duct may also become infected from the caseating and disintegrating lymph- glands, and through this channel the blood may become infected. Quite frequently the formation of metastases takes place also by way of the blood-channels. Thus, for example, the bacilli may enter the blood current along with the lymph of the thoracic duct, in the manner described above; or they may, as very often happens, force a way for themselves FORMATION OF METASTASES. 497 directly into the circulating blood. In tuberculous tissues the bacilli may get directly into the small veins, but the arrest of the circulation and the occlusion of the vessels interfere generally with their further dissemina- tion. But often enough they enter the larger veins—as, for example, through a coalescence of the caseating lymph-glands, at the hilus of the lungs (Fig. 437, d,), with newghboring veins (e, 7,), whereby the tuberculous proc- ess spreads directly to the walls of the veins. But it may also happen that numerous veins in the neighborhood of tuberenlous areas become infected with tubercle bacilli, so that the small veins of an entire vascular region may display well-marked tuberculous disease, i.e., they show -inflam- matory granulating hyperplasia of the vessel-walls, with the formation of tubercles and subsequent caseation (Fig. 339, b), and consequently, if thrombosis does not occur, large numbers of bacilli are likely to be given off from the diseased walls to the blood-stream. In rare cases even arteries, especially those of the lung, may become tuberculous through infection derived from their surroundings, and so may give off bacilli to the blood-stream. The dispersal of the bacilli by means of the circulation has as a con- sequence a hematogenous miliary tuberculosis, i.e., an eruption of miliary tubercles (Fig. 440, a) at those places where the bacilli become lodged and where they multiply. Just where these places will be, and how bys Bees : Pe DS a 4 5 Fig. 439.—Tuberculous disease of the veins in the neighborhood of a retroperitoneal lymph-gland. (Formalin; hematoxylin; eosin.) a, Tuberculous lymph-gland, with giant cells and cheesy foci; at the periphery there are broad blood-vessels ; b, veins which show a thickening of their walls due to a growth of tuberculous granulation tissue, while in the parts that are farthest away from the periphery they show areas of cheesy degeneration ; c, adipose tissue. Magnified 30 diameters. numerous the tubercles will be, are matters which are determined by the location of the point of invasion and by the number of the bacilli which have gotten into the blood. The entrance of many bacilli into the blood may lead to general hematogenous miliary tuberculosis. If the bacilli have reached the blood in small numbers and have been ‘498 FORMATION OF METASTASES. deposited in one organ only, and if death does not supervene, then there arises in this organ a progressive local hematogenous tuberculosis, which : comports itself in the same man- ner as a primary infection coming from the exterior. The inflammation accompa- nying the hematogenous eruption of tubercles is sometimes more, sometimes less pronounced, and is wont to be most severe in the meninges and in the lungs. If an invasion of the bronchi takes place, say, from the soft- ening of a caseous focus of the lung, or if a centre of softening in the kidney breaks through into the pelvis of that organ, then the tubercle bacilli will be disseminated over the sur- face of the mucous membranes, Fic. 440.—Hematogenous miliary tuberculosis of the From the bronchi the bacilli liver. (Alcohol; carmine.) «ct, Fully developed tubercle fi in the connective tissue of the portal vein; b,accumu- spread into the trachea, the lation of round cells. Magnifled 150 diameters. larynx, and the buccal cavity, and from there again into the digestive tract; and by aspiration, through deep, quick inspiration, they gain access to other as yet sound parts of the lung; from the kidneys they spread into the discharging urinary passages. A secondary infection may also result from this spreading of the bacilli, yet only a small percentage of those which have thus escaped give rise to infection, and besides, there are, as experience teaches, only certain regions of the mucous membranes that are susceptible to infec- tion. Thus, for example, in the case of the digestive tract, it is espe- cially the tonsils and the lymphadenoid apparatus of the small and large intestines which are susceptible, while the cesophagus and stomach are nearly immune; and in the case of the discharging urinary passages, the susceptible parts are the pelvis of the kidney, the ureters, and the bladder, while the urethra nearly always remains free. If the bacilli reach the great body cavities, they can also here spread over the surfaces, and the serous membranes respond to the in- fection with diffuse inflammation and with the formation of nodules (Fig. 441). Later, the formation of new connective tissue may follow. If a woman is pregnant at a time when the tubercle bacilli are being disseminated throughout the body by the circulation, an infection of the placenta may take place, and from this an infection of the foetus may also result, so that the child will be born already infected. Never- theless, so far as experience covers this point, this occurrence is not common, and it is more usual for children of tuberculous parents to become infected after birth. A conceptional infection of the ovum by infected semen has not been demonstrated and is very unlikely. Secondary infections are often associated with that by tubercle bacilli, and this occurs principally when the cavities or ulcers caused by tuberculosis are accessible from the exterior. Secondary infections appear most frequently in tuberculous lungs, and are caused chiefly by streptococct and staphylococet. Many authors are inclined to refer all SECONDARY INFECTIONS. 499 severe inflammatory exudations which accompany pulmonary tubercu- losis to such secondary infections; but this is certainly not correct, for the formation of tubercles caused by tubercle bacilli can be accompanied by very pronounced inflammatory exudations, so that serous or sero- fibrinous, or pure fibrinous, or fibrino-purulent exudates may collect in considerable quantities in the tissues (in the lung-alveoli, on the pleura, in the subarachnoidal spaces, etc.). High (septic) fever, rapid destruc- tion of tissue with a tendency to suppuration, and unusually severe in- flammation point to secondary infections. However, it is very difficult to determine, unless a special investigation is directed to this point, whether a pure tuberculosis or a mixed infection exists. The question as to how often tuberculosis is transmitted by transfer of the bacilli from the mother to the child, is still open. Nevertheless, according to the investigations of Schmorl, Birch-Hirschfeld, and Landouzy, in regard to miliary tuberculosis in pregnant women, it is proved that tubercle-bacilli occur in the spaces between the villi as well as in the blood of chorionic vessels, and that the liver of the foetus may also contain bacilli. Furthermore, cases of tuberculosis of the placenta also occur which can be regarded as stages on the way of the tubercle-bacillus fromthe mother to the fruit (Schmorl, Kockel, Lungwitz). Cases of tuberculosis appearing at an early period of life, reported by Demme, Baumgarten, Rilliet, Charrin, and others, speak in favor of a passage of the tubercle- bacilli from the mother to the fruit; so do also the statements of Armanni, Landouzy, and Martin, that the inoculation of portions of the organs of human fcetuses obtained from tuberculous mothers produces tuberculosis in guinea-pigs. But still more impor- tant are the experimental investigations which de Renzi and Gartner made; for they succeeded, by inoculation of the pregnant female in guinea-pigs, white mice, and rab- bits, in producing tuberculosis in the offspring in a certain number of cases, and con- __ Fig. 441.—Tuberculosis omenti. (Miiller’s fluid; carmine.) a, Centre of a tubercle; ), cells of an spietiot character ; c, lymphatic elements; d, proliferating epithelium in ‘the neighborhood. Magnified iameters. sequently Gartner is of the opinion that under suitable conditions tubercle-bacilli may pass over from the mother to the foetus in animalsas well as in human beings. Finally, Maffucci and Baumgarten succeeded in effecting a transfer of tubercle-bacilli to impreg- nated hens’ eggs, and in accomplishing this they ascertained that the infection did not disturb the development of the chicken, but, on the contrary, the bacilli that were taken 500 TUBERCULOSIS OF ANIMALS. up by the embryo remained in the tissue of the latter without multiplying to any con- siderable extent, but subsequently caused tuberculosis in the body of the chick after it was hatched out. a The experiments cited above allow the assumption that the bacilli are transferred through the placenta from the mother to the fruit, and also that they may remain for a long time in the body of the embryo without causing any recognizable changes. Since, manifestly, congenital tuberculosis in human beings is extremely rare, while, on the other hand, tuberculosis in the first years of life is frequent, it is possible that in human beings also the infection may remain latent for along time and not be always recognized by anatomical examination, The question whether conceptional tuberculosis, through the transference of the virus by means of the semen, actually occurs, is one which is open to discussion. The probability is that it does not occur. However, it is worthy of note that the semen and the contents of the seminal vesicles may contain tubercle bacilli, and this, not only in the case of tuberculosis of the testicles and epididymis, but also when the tuberculous patients have no recognizable tuberculous affection of the genital apparatus. Nevertheless, it must be kept in view, according to the investigations which have thus far been made, that tuberculosis is to bereferred mostly to extra-uterine infection, and that children of tuberculous parents become so often affected with tuber- Fig. 442.—Growths from the pleura in a case of bovine tuberculosis (earl-disease). culosis because, on the one hand, they are predisposed to tuberculosis, and, on the other, they are more exposed to the infection with the bacilli than are the children of healthy arents. 5 In animals a transference of tuberculosis to the foetus seems occasionally to occur, according to the statement of Zippelius, Jessen, Piitz, Grothans, Malvoz, Lydtin, Brouvier, Adams, and others. Johne not only found nodules and larger consolidated areas in the lung and liver, and in various lymphatic glands of a calf foetus, but he also established beyond a doubt the presence of the characteristic bacilli. Tuberculosis of cattle and of the other domestic mammalia is a progressively spreading production of nodules, in which, along with small nodules, larger ones, the size of a potato and even larger, may form, and in which also there may be a certain amount of inflammatory action, resulting in exudations and in the production of con- nective tissue. The disease develops in cattle (Fig. 442), especially in the serous mem- branes, where the process is called the pearl disease ; then it is also found with the next greatest frequency in the lymph-glands, the lung, the liver, the kidneys, etc. In the serous membranes the nodules often have a stem—i.e., are pedunculated, and they pre- sent some resemblance to sarcomatous growths. Along with caseation, calcification occurs strikingly often. The nodules of tuberculosis of cattle and other domestic mammalia resemble pre- cisely in structure the tubercles of human beings, and inasmuch as they contain the same bacilli, and inasmuch, furthermore, as the inoculation of calves with human tuber- cles produces typical tuberculosis (Bollinger), the hypothesis that the two kinds of tubercles are identical is certainly justified. According to Maffucci, Rivolta, Straus, Gamaleia, and others, tuberculosis of birds BACILLUS OF SYPHILIS. . 601 is not caused by the same bacilli as those which produce the tuberculosis of man or other mammalia, Cultures of the tuberculosis of an are dry, warty or scaly, and lustreless ; those of bird-tuberculosis are moist, folded, and soft, and can grow even at a temperature of 43° C. Dogs are entirely immune from bird-tuberculosis, but not from tuberculosis of man. According to the researches of Leray, intraperitoneal inoculation of mammalian tuberculosis causes in the liver and spleen of rabbits numerous caseous foci with few giant-cells and few bacilli; in the lungs, numerous caseous nodules with many bacilli. Inceulation with fowl-tuberculosis causes, on the other hand, non-caseating cellular growths, with giant-cells and with an immense number of bacilli. According to Maffucci, Martin and Gartner, the inoculation of human tuberculosis into a fowl is not followed by tuberculosis, but the bacilli remain alive for weeks in the body of the fowl. Pigeons (Anclair) die after intraperitoneal inoculation, but no tubercles are found in the tissues; the liver and lungs may still contain living bacilli atter the lapse of fourteen days. In guinea-pigs the bacilli of human tuberculosis cause (Straus) much severer changes than the bacilli of fowd-tuberculosis. Whether man is susceptible to avian tuberculosis is as yet an open question. According to Malassez, Pfeiffer, Eberth, Roger, Grancher, Zagari, and others, a disease very like tuberculosis occurs in guinea-pigs, rabbits, lambs, and horses, and this disease is also characterized by the production of caseous nodules and is caused by a pleo- morphic bacillus that forms zodglea. The affection may be called pseudotuberculosis (Eberth, Pfeiffer). Malassez and Vignal call it tuberculose zodgléique. $178. At present a bacillus found by Lustgarten in syphilitic dis- eased foci is called the bacillus of syphilis, and it is possible that it has pathogenic significance and represents the contagiwin of syphilis. In favor of this, however, it can be said only that the bacilli have been found in various syphilitic foci in all stages; but it has not as vet been possible to cultivate these bacilli. The bacillus resembles the tubercle-bacillus, is from 3 to 7 » long, often bent, and somewhat swollen at the ends. According to Lustgarten, it may be made visible by a complicated staining-process, consisting in coloring the sections with aniline gentian-violet solution, then decolor- izing them in permanganate of potassium, and washing them out in sul- phurous acid. More recent authors have published other methods. The bacilli are found in syphilitic foci of disease always in limited numbers only. They lie mostly in the cells (from one to four ina single cell) (Lustgarten), but also to some extent between the cells, and may also at times appear in the blood (Doutrelepont). The Lustgarten — bacilli, at the present time, can hardly be used for differential diagno- sis, since other bacilli, described as smegma-bacilli, found in the secre- tion from the prepuce and in the smegma between the labia majora and - labia minora, stain by the method described by Lustgarten. According, however, to Doutrelepout, Klemperer, and Lewy, it is possible to dis- tinguish these from one another by proper staining-methods—i.e., by carbolic-acid fuchsin. The poison which on inoculation produces syphilis occurs only in the human organism, where it is alone reproduced. It igs communicated to other individuals only by direct or indirect transfer. When inoculated into an organism it causes inflammatory processes of the most varied in- tensity and extent—from a simple, local, transitory hyperemia to the production of large exudates or tumor-like granulations or extensive connective-tissue hyperplasias. If a child is begotten in the presence of syphilitic infection the disease may be transmitted to the child by the father as well as by the mother. If the primary focus of inflammation is formed at the point of infec- tion—which is usually some part of the skin, although it may be located in a mucous membrane (mouth, fauces, genital mucous membrane)— there is first a papule, which spreads over the surface and forms scales 502, HUNTER’S INDURATION. in eight or ten days after its appearance. But it may ulcerate and give rise to the secretion of a serous or purulent fluid which dries to a scab. Simultaneously the bottom becomes indurated and produces a thick dise-like deposit in the skin or a thin parchment-like thickening. Oc- casionally there is at first a vesicle that becomes eroded, and then an ulcer that throws off but little exudate, but which is indurated at the bottom. In still other cases there exists first an ulcer, and the bottom becomes indurated subsequently. 5 : The induration is called the initial sclerosis, or Hunter's induration (Fig. 443, b). The ulcer is called a hard chancre. The induration is caused mainly by an accumulation of small rownd cells (Fig. 443, b, and Fig. 444, a) in the interstices of the connective tissue. Occasionally epithelioid cells are formed (Fig. 444, b) and isolated giant cells (c). When this takes place the summit of development is reached; then the F1G. 443.—Initial sclerosis in syphilis. (Alcohol; hematoxylin; eosin.) a, Corium, slightly inflamed; b, initial sclerosis (connective tissue infiltrated with cells); c, a point where tbe cells have forced their way into tbe epithelium ; JS vi Srardien sive vibrio rugula (Fig. 465, b) forms > ~~ . staves from 6 to 16 » long and from 0.5 to 2.5 » Vv q thick, simply bent or having a shallow turn, which + ~~ SOCUumtvve’ themselves by means of a flagellum. The —s b spirillum occurs in water from swamps, in feces, Ce 7 7 *s and in slime from the teeth. Fig. 465.—Spirillum sive Spirillum sive vibrio serpens form thin threads vibrio rugula, b, and spiril- hum undwa, a, obtained from from 11 to 28 » long, with three or four wavy a onpel cathwenns, prawn bands. It occurs in stagnant fluids. ere ee ee Spirillum tenue has threads from 3 to 15 p Magnified 600 diameters. long, very thin, with from two to five spiral turns. Spirillum undula (Fig. 465, a) is a thread 1 or 1.5 » thick and from 8 to 12 » long, bearing on its end a flagellum and having from one and a half to three turns. It occurs in various putre- fying fluids and executes rapid twisting and darting motions. Spirillum volutans possesses threads 1.5 or 2 » thick and from 25 to 30 » long, with from two and a half to three and a half turns, bearing a flagellum at both ends. The species Spirochaéte (Fig. 468) is characterized by flexible, long, sharply turned spirals. Sptrochaéte plicatilis forms threads from 100 to 225 » long, very fine and closely turned. It is very abundant in water from marshes and gutters, and executes very rapid movements. Spirochaéte buccalis sive denticola is from 10 to 20 » long, pointed at both ends, and is not infrequently observed in the secretion from the cavities of the mouth and nose (cf. Fig. 176). It seems to have no pathogenic significance. The spirilla, so far as they are not pathogenic, are little known, and investigations particularly as to their life-history are wanting. They are present in large numbers in the contents of privy-vaults. Accord- ing to Prazmowski, spirillum rugula causes decomposition of cellulose and forms spores at the ends of the spirilla. According to Weibel, a vibrio which occurs in nasal slime has manifold forms of growth. Esmarch succeeded in cultivating a spirillum, called by him spirilhun rubrum, in the different ordinary media. In bouillon it forms spirals of from forty-three to fifty turns. Short spirilla execute lively motions, but long spirilla, on the contrary, sluggish motions, or they may be motionless. Colonies in solid media are at first pale, but assume after- ward in portions not in contact with air a wine-red color. In spirilla of old cultures three or four dull, glistening spots occur that do not stain and are probably to be interpreted as spores. Cultures containing THE SPIRILLUM OF ASIATIC CHOLERA. 525 spirilla of this kind are more resistant to drying than others; but they are, on the contrary, very easily killed by heat. The long spirals may break up into short segments possessing only about three-quarters of a turn, and these grow out in length and again divide. Kitasato and Kutscher have also succeeded in cultivating spirilla. {b) The Pathogenic Spirilla. § 185. Spirillum cholerz Asiaticz (or vibrio cholere), also called comma-bacillus (bacille virgule cholérigéne), was discovered by R. Koch in 1884 and recognized as the cause of Asiatic cholera (Fig. 382). It forms a small, comma-shaped, curved staff from 0.8 to 2 long (Fig. 466). Cultures of the cholera-spirilla are obtained upon a great variety of slightly alkaline media. The temperatures favorable for their growth are between 25° and 30°C. Between 16° and 8° C. they are still capable of puny development. On gelatin plates they form round, flat, yellowish discs which liquefy the gelatin only slowly. With low magnifying powers they appear ir- regular in outline, and the surface granular or grooved and rough; it conveys the impression as if the surface were strewn with small particles of glass (Koch). By the liquefaction of the gelatin in the immediate neighborhood a funnel-shaped cavity is formed, and the colony sinks down finally to the bottom of the cavity. Stab-cultures in gelatin form in two days a whitish cord correspond- ing to the line of inoculation (Plate I., Fig. 3). The gelatin becomes liquefied immediately around the line of inoculation. The canal widens out upward into a funnel filled with liquefied gelatin below and with air above. The widening of the funnel of the canal of inoculation takes place slowly, so that its edge reaches the wall of the tube only after five or six days. ee ‘ 2% On potatoes at from 30° to 35° C. the spirilla 2+ ( ox. form light-brown cultures, on agar-agar grayish- i yellow slimy cultures. They grow, moreover, also < _-+, Sie in bouillon, blood-serum, and milk. fe They do not increase in pure water (Bolton), but _ Fic. 468. —Cholera- do so in water that is contaminated with substances — {hre. ‘Cover-giass prep- which furnish nutrient material. fuchetd,. aeonged 100 The cholera-spirilla are aérobic, but they also are diameters. able to grow when oxygen is cut off. According to : the investigations of Hueppe, cultivation in the presence of a paucity of oxygen increases the toxic power of the cultures; but, on the contrary, the resisting power against injurious agents—e.g., against acids and similar substances—is diminished; with freé admission of oxygen the reverse takes place. Pfeiffer, however, found that young cultures cul- tivated in oxygen also contained poison. The spirilla present in fresh dejecta are easy to kill (Hueppe) and but little suited for infection, whereas the growth of the spirilla outside the body increases their re- sisting power against the stomach-juices, etc., and makes them more suitable for the infection of new individuals. They are readily de- stroyed by desiccation in free air (Guyon), by high temperatures, and by boiling for a short time. They are easily supplanted by saprophytic 526 THE SPIRILLUM OF ASIATIC CHOLERA. bacteria when the nutrient material and the temperature are not en- tirely suitable. In privy-soil they die out quickly, according to Koch. They are readily destroyed by acids, corrosive sublimate, and carbolic acid. According to the observations of Koch, they can be preserved in well-water thirty days, in sewage seven days, on moist linen three or four days. Nicati and Rietsch found them alive after eighty-one days in water taken from the harbor of Marseilles. In cultures they form sometimes short rods more or less curved (Fig. 466) and often hanging together in twos, sometimes long spirals. Along with these forms there also occur straight staves, and sometimes the majority of the rods that are present show the curve only imperfectly or not at all. In fluid media to which oxygen has access they show live- ly motility, which is easily seen ina hanging drop. According to the investigations of L6ffler, the motility is caused by a single flagellum on one end. When the nutrient material is exhausted to a certain extent, involu- tion-forms often appear, in which the rods are sometimes shrunken, sometimes swollen, thus causing them to present a variety of forms. Globular swelling, as well as uncolored places (in stained preparations) caused by degeneration, have often been erroneously regarded as phe- nomena of fructification. Formation of spores has not been proved. If hydrochloric or sulphuric acid is added to cultures of the cholera-bacilli in culture-media containing peptone, the cultures assume a rose or Bur- gundy-red color, due to the formation of a coloring-matter—cholera red. A suitable culture-medium for this reaction is a meat-infusion containing peptone, or a one-per-cent solution (rendered alkaline) of peptone con- taining one per cent of salt. According to Salkowski, this is a nitroso- indol reaction. When they get into the intestinal tract of human beings the spirilla develop in the small as well as in the large intestines, so far as they are not destroyed by the action of the gastric juice and are not hindered in their development by other influences. Their growth is followed by an extensive transudation from the intestinal mucous membrane, so that the intestine is filled with a fluid resembling meal-soup or rice-water, in which flakes of desquamated and slimy epithelial cells float about. The spirilla are always present in large numbers in. the contents of the intestine, and are also found in the lumina of the intestinal glands, and they may penetrate from there between and under the epithelial cells. In fresh eases the presence of the spirilla may be demonstrated usually by making a cover-glass preparation stained with methylene blue or with fuchsin. The fresh dejecta, as well as foul clothing, are suitable for the examination, since, according to Koch’s observations, the spirilla can multiply for a while vigorously on moist linen and moist earth. In old cases the detection of the spirilla is more difficult, but nevertheless succeeds in all cases, according to a number of authors, and is attainable most surely by making plate-cultures. In order to facilitate the separation of the cholera-spirilla from the other intestinal bacteria, Schottelius recommends the mixing of the dejecta with double the amount of meat-infusion rendered slightly alkaline, and allowing the mixture to remain uncovered at a temperature of from 30° to 40° C. for twelve hours. The spirilla, requiring oxygen as they do, develop es- pecially on the surface, and may be easily transferred thence to plate- eee Koch recommends for this purpose a solution of peptone with salt. THE SPIRILLUM OF ASIATIC CHOLERA. 527 The presence of cholera-spirilla in the intestines excites inflamma- tion, which finds expression at the start in reddening, swelling, transu- dation, mucoid degeneration of the epithelium, and desquamation; sub- sequently also in hemorrhages, formation of sloughs, and ulceration. It is characterized constantly by a more or less abundant cellular infiltra- tion of the tissues. The solitary follicles and Peyer’s plaques are swollen even in fresh cases. Death may take place in a few hours or in from one to three days. If the disease lasts longer the contents of the intestines become more consistent and the intestinal mucous membrane shows ulcerative changes. : According to present experience, the spirilla produce poisonous sub- stances which cause local damage to the mucous membrane of the intes- tinal canal, phenomena of intoxication, and paralysis of the vessels. In the liver and kidneys there often result small foci of degeneration, and within these the cells of the glands are cloudy or fatty and affected with hyaline degeneration or necrosis. Moreover, the kidneys very often show cloudiness caused by toxic degeneration of the epithelium; also there is occasionally swelling of the cortex. Frequently there are also ecchy moses in the epicardium; in the later stages also patches of necrosis in the mucous membrane of the vagina. The presence of the spirilla for a long time in the intestines may be followed by the formation of ulcers. Eventually they are crowded out by the putrefactive bacteria present in the intestines, and die out. A new intoxication, not dependent upon the original spirilla, may result from absorption of the products of putrid decomposition. According to Koch, Nicati, and Rietsch, the cholera-bacilli may be contained in the material vomited. Nicati, Rietsch, Tizzoni, and Cat- tani also found them in the ductus choledochus and in the gall-bladder. According to the statement of these authors, the spirilla do not usually get into the blood, and are also absent from the internal organs; never- theless, in cases of severe infection, they may gain access to all parts of the body. Koch detected the spirilla in a tank in India which furnished the inhabitants with their entire supply of water for drinking and other purposes at a time when a part of the inhabitants were sick and dying of cholera. Since then they have been often detected during cholera epidemics in water-supplies. According to the investigations of Nicati, Rietsch, van Ermengem, and Koch, symptoms resembling cholera can be produced in experi- mental animals by the introduction of cholera-spirilla into the intestinal canal. This succeeds when cultures are introduced directly into the duodenum or small intestines (Nicati and Rietsch); also (Koch) by rendering the gastric juice of the animals (guinea-pigs) alkaline with a five-per-cent solution of soda, then quieting the bowels by injecting into the abdominal cavity 1 c.c. of tincture of opium to every 200 gm. of weight of the animal, and finally introducing one or several drops of a pure culture into the stomach. Animals inoculated in this way die with severe symptoms of collapse. The small intestines are found to be filled with a watery, flocculent fluid containing numbers of spirilla; the intestinal mucous membrane is reddened and swollen. Asiatic cholera is endemic in Lower Bengal, and never entirely dis- appears there. Thence it spreads at times over India and over a larger or smaller territory of the earth by transportation. Since the spirilla 528 . SPIRILLUM OF FINKLER AND PRIOR. easily perish outside the body, the transportation must be effected mainly by persons suffering from cholera. Infection probably occurs exclusively from the intestinal canal by the introduction of infected beverages or food or some other substance into the mouth. But it is certain that the introduction of cholera-spirilla into the intestinal canal is not always followed by the disease. Moreover, it not infrequently happens that the spirilla increase in the intestines, but cause only slight changes, so that the infected per- son suffers no severe trouble, and the diagnosis can be made only by the detection of the spirilla in the stool. If the cholera-spirilla get into the drinking-water or water-supply in general, and succeed in multiplying, the cholera may develop with ex- traordinary rapidity in the locality. If, on the contrary, the infection follows by direct or indirect contagion from one person to another, the spread takes place more slowly, since it is limited to those who come in contact with the sick person or with the articles contaminated by the latter. . The period of incubation lasts one or two days. In the intestines of convalescents, according to investigations of ' Kolle, the spirilla may continue to live for a long time and to multiply, without giving rise to any symptoms that point to their presence. Kolle was able to detect them in a number of cases after from five to eighteen days, and in some cases even after from twenty to forty-eight days. Once recovered from the disease, the affected individual enjoys im- munity for a certain length of time. This immunity is to be ascribed to the presence in the body of bactericidal substances; and by means of these same substances it is possible to protect the body against an attack of cholera. In those, however, who have already contracted the disease, this protective effect is of no avail (compare § 30). The poison which the cholera-spirilla produce, and which mainly causes the symp- toms of cholera infection,.is unknown. Gamaleia believes that it is a nucleo-albumin, Scholl that it 1s a peptone (cholera toxopeptone). Pfeiffer is of the opinion that it is a component part of the cell-body. According to Metschnikoff and others it is excreted by the cells. Emmerich and Tsuboi seek to prove that the morbid phenomena in cholera are due to a nitrite-poisoning. They call attention to the fact that nitrites in small doses cause retching, vomiting, discharge of thin-gruel feces, fall of temperature, weak- ness of the heart, cyanosis, and cramps of the extremities and muscles of the neck—in other words, symptoms resembling an attack of cholera; and, moreover, that the cholera- spirilla are able to make nitrites out of the nitrates contained in nutrient substances. The virulence of cholera-cultures differs greatly, according to the source and the age. With increasing age the virulence decreases. Guinea-pigs, although very susceptible to intraperitoneal infection with cholera, may be protected from infection by intraperito- neal inoculation with attenuated cultures; but no absolute immunity can be brought about in this way. Blood-serum of human beings that have recovered from an attack of cholera shows protective properties for guinea-pigs some weeks after the attack. The production of the nitroso-indol reaction in cultures of the cholera-spirilla is due to the fact that the cholera-spirilla not only produce indol in peptone solution, but also nitrites. For this reason, nitrous acid is liberated by the addition of hydrochloric or of sulphuric acid, and makes a red color with the indol. With the Finkler spirillum, the spirillum of Metschnikoff, and the spirillum of Deneke, which also produce indol, the red color of the cultures occurs only when potassium nitrite is added along with sulphuric acid, or when nitrous acid is added. The following spirilla resemble the cholera-spirilla: 1. Spirillum of Finkler and Prior, found by the authors named in the dejecta of persons suffering from cholera nostras, when these have stood for some time in a vessel. The spirilla are very much like the cholera-spirilla, only somewhat longer and thicker. In plate cultures they are distinguished from the latter in that the small colonies are not distinctly granular and have a sharp contour. Gelatin is rapidly, not slowly, liquefied and consequently after twenty-four hours a sac-like tube (Fig. 467) filled with a cloudy fluid is formed in stab-cultures and rapidly spreads to the walls of the tube. THE SPIROCHAETE OBERMEIERI. 529 According to Fliigge, even in forty-eight hours at room-temperature they form a grayish-yellow slimy coating, sharply marked off from the substance of the potato by its whitish border ; whereas the cholera-spirilla do not grow at room- temperature at all, and at a higher temperature form a brown coating. They, moreover, cause a foul-smelling decomposition and are rather resistant to drying. When introduced into the intes- tines of guinea-pigs by the method above described, they operate similarly to the cholera-spirilla, but less intensely. It is very questionable whether the Finkler-Prior spirilla have pathological significance for cholera nostras, since the de- jecta from which the investigators made their culture were not fresh, and other authors in similar cases have not found the spirilla.1 Knisl? found them in the contents of the cecum of a suicide. 2. Spirillum tyrogenum, found in cheese by Deneke#® in Fliigge’s Institute, is also very much like the cholera-spirillum, but it issomewhat smaller and the long spiral threads are more narrowly wound. Cultures on gelatin plates form at first sharply contoured discs that appear dark with lower magnifying powers. They liquefy the gelatin much more quickly than do the Koch spirilla. In the line of puncture they behave similarly to the Finkler-Prior spirilla, but do not grow on potatoes. 8. Spirillum sputigenum is a spirillum whose shape is that of .a curved staff, somewhat longer and thinner than the cholera- spirillum. It occurs in saliva and cannot be cultivated on the media that are in use. 4. Vibrio of Metschnikoff‘ is a fission-fungus that Gamaleia was able to isolate in an epidemic of chickens in Odessa which was characterized by the appearance of diarrhcea and enteritis. On cultivation it shows very great resemblance to the Koch spirii- lum. 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. § 186. The spirochaéte Obermeieri (Fig. 468) is found constantly in the blood of patients suffering from relapsing fever during the attack of fever, and the multiplication of these organisms in the body is gure ine rimblonPaws the cause of the disease. bacillus in gelatin. The spirochaéte is from 16 to 40 » long and possesses numerous turns. In a fresh drop of blood it exhibits lively motion. Carter and Koch succeeded in producing the disease by inoculating apes with the spirochaéte; but nothing definite is known as to its mode of development and habitat outside the blood. It is also unknown where it or its eet “ spores are to be found in the afebrile stages Fig. 468.—Spirochacte Obermcicri of the disease. In apes an attack of fever from the blood of a person suffering | from relapsing fever. (From a dried occurs only after several days have elapsed preparation treated with methyl vio- .