CORNE LL UNIV ERSITY THE Sflompt Hctennarg ^library FOUNDED BY ROSWELL P. FLOWER for the use of the N. Y. STATE VETERINARY COLLEGE 1897 This Volume is the Gift of .Pr. Le.Qn...S.»..3..e.ar.d.sley Cornell University Library RB 111.Z661897 General pathology; or, The science of the 3 1924 000 217 749 Cornell University Library The original of tiiis book is in the Cornell University Library. There are no known copyright restrictions in the United States on the use of the text. http://www.archive.org/details/cu31924000217749 GENERAL PATHOLOGY OR THE SCIENCE OF THE CAUSES, NATURE AND COURSE OF THE PATHOLOGICAL DISTURBANCES WHICH OCCUR IN THE LIVING SUBJECT BY Dll. EENST ZIEGLEPv PROFESSOR OF PATHOIiOGICAL ANATOMY AND OF GENERAL PATHOLOGY AT THE LTNIVERSTTY OP FREIBURG IN BREISQAU TBANSLATED FEOM THE EIGHTH BEVISED GEEMAN EDITION BY DR. LEONARD WOOLSET BACON, JR., OP NlfiW HAVEN, CONN. DBS. B. MEADE BOLTON AND HENRY W. CATTELL, OF PHILADELPHIA, PA. DRS. THEODORE DUNHAM, JOHN S. ELY, E. M. FOOTS, "WALTER B. JAMES, AND WILLIAM G. LE BOUTILLIER, OP NEW-YORK, N. T. AND DR. R. A. McDONNELL, OP NEW HAVEN, CONN. EDITOE, DE. ALBERT H. BUCK, NEW-YOEK NEW-YORK WILLIAM WOOD AND COMPANY 1897 Copyright, 1895 By WILLIAM WOOD & COMPANY PRESS OF THE PUBLISHERS' PRINTING COMPANY 132-136 W. FOURTEENTH ST. NEW YORK AUTHOE'S PREFACE. 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 published, 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 promote 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 faUed to convince me that this was the most useful 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 dif&cult, owing to the richness of the material at our disposal, to avoid treating the subject in such a manner that the book, when completed, shaU not present the characteristics of a mere catalogue of facts, which would scarcely convey to the reader's mind a clear conception of the pro- cesses that take place in the living body when it or any of its organs are diseased, and which, furthermore, would compel the beginner to merely 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 certaia 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 be small. 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 know- edge which he requires for the satisfactory study of clinical medicine. 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 belong- ing to an inflammation of an important organ — to form an approximate idea of the nature of this disease, and at the same time he would also IV AUTHORS PREFACE. probably take satisfaction in the thought that he had already been in- structed 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 little 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 signiacance 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 comniit to memory the sequence of symptoms as they occur in any given disease. Then, besides, he would fail to grasp the connection between the latter and other correlated symptoms. On the other hand, if he had previously received proper instruction in the fundamental knowledge required, he would at once be able to understand correctly the nature of the malady which he has been called to treat. Bearing all these things in mind, I 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 consequently 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 histological 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 imderstanding the nature of these altera- tions, it seemed to me that I ought to provide a certain number of additional cuts, carefully prepared. At the same time I felt as if more space than was given to these matters in the preceding editions should be allotted to the consideration of pathological processes — their causes, their mode of origin, the course which they pursue, and their sequelae. 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 to greatly 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 thi^ 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 never- theless it does treat of all those portions of the subject which are ordi- narily taught, at least in the German universities, by the chairs of pathological anatomy and general pathology. The section which deals with the causes, mode 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 frbm poisoning and from infection, hoping thereby to provide AUTHOR'S PREFACE. 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 modifica- tion 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 myxcedema, 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 inher- ited 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 onlj- supply the practical needs of the medical practitioner, but wiU also serve to in- crease the existing stock of knowledge in regard to the origin, course, and essential natm-e 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 rewiitten, 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 in- terpretation 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 belong 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 vi author's preface. the healing processes which take place in the course of an inflammation, the formation of gi-anulations, the resorption of necrosed tissues and exudations, and the substitution, in their place, first of granulation tissue 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 a way 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 eystomata, 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 aU these alterations and additions this general part of my text-book has increased in bulk ; but, as I have ah-eady said, I believe 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 disease 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. ZlEGLER. Preibueg im Breisgau, November, 1894. EDITORIAL NOTE. It has been thought best to omit from this edition the bibliograph- ical lists which are scattered throughout the original work. They occupy a great deal of space, and consequently would add considerably to the bulk of the present volume ; they refer almost exclusively to books and articles published in the French, Italian, or German language, and would therefore prove of value to comparatively few students or practitioners in this country ; and, finally, the publication of these additional two hundred pages would necessarily add considerably to the cost of the work. For all these reasons it seemed advisable to leave them out altogether. LIST OF TRAITSLATOES. Sections I and II. Translated by Dr. Heney W, Cattell. Section III. Translated by Dr. Leonard Woolsey Bacon, Jr. Section IV. Translated by Dr. John S. Ely. Section V. Translated by De. Walter B. James. Section VI. Translated by De. William G. Le Boutilliee. Section VII. Translated by Dr. E. M. Footb. Section VIII. Translated by Dr. Theodore Dunham. Sections IX and X. Translated by Dr. B. Meade Bolton. Section XI. Translated by De. R. A. McDonnell. COI^TENTS. PAGE Preface iii Section I. — Introduction. — Health and Disease. — Problems of General Pathology and Pathological Anatomy 1 Section II. — Cause, Origin, and Course of Diseases; General Consider- ations. 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 Atmo- spheric Pressure ; by Electrical and by Mechanical Influences. 8 2. Origin of Diseases through Intoxication 17 3. Origin of Diseases through Infection or Parasitism. — Miasms and Contagions. — Vegetable and Animal Parasites 28 II. Metastasis and Embolism, and their Importance in the Etiology of Lymphogenous and Hsematogenous Diseases 40 III. Local and General Diseases, and their Eelations to One Another. — Intoxication after Infection, and Auto-intoxication. — Injurious Ef- fects of Diseases of One Organ on Other Organs, and on the Gen- eral Organism. — Diseases Caused by the Withdrawal of the Func- tions of Certain Glands 48 IV. Fever and its Significance 62 V. The Natural Protective Mechanisms, Protective Forces, and Healing Powers of the Human Organism, and their Action 68 VI. Congenital and Acquired Predisposition. — Idiosyncrasy and Immu- nity. — The Acquiring of Immunity. — Immunizing Inoculations . . 77 VII. The Intrinsic Causes of Disease and the Inheritance of Pathological Conditions 88 Section 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 Resis- tance, and Changes in the Mass of the Blood 103 11. Local Hypersemia and Local Anaemia 109 III. Coagulation, Thrombosis, and Stasis 114 IV. (Edema and Dropsy 129 V. HiEmorrhage and the Formation of Infarcts 134 VI. Lymphorrhagia 140 ix X CONTENTS. PAGE Section IV.— Retrograde Disturbances of Natrition and Infiltrations of the Tissues. I. On Retrograde Disturbances of Nutrition and Infiltrations of tlie Tissues in General 142 II. Death 143 III. Necrosis 145 IV. Hypoplasia, Agenesia, and Atrophy 156 V. Cloudy Swelling and Hydropic Degeneration of Cells 166 VI. Lipomatosis, Fatty Atrophy, and Fatty Degeneration 168 VII. Glycogen-deposit in the Tissues under Pathological Conditions 174. VIII. Mucous and Colloid Degenerations 176 IX. Amyloid Degeneration and Amyloid Concretions 180 X. Hyaline Degeneration of Connective Tissue 186 XI. Calcification and the Formation of Concretions and Calculi 188 XII. Pigment-formation in the Tissues 197 XIII. Cyst-formation 213 Section V. — Hypertrophy and Regeneration of the Tissues and Organs. I. General Considerations Concerning the Processes called Hyper- trophy and Regeneration, and the Cellular Changes that Accom- pany Them . . .' 217 II. The Processes of Hyperplasia and Regeneration in the Various Tissues 239 III. Metaplasia of the Tissues 257 Section VI. — Inflammation and the Associated Processes of Repair. I. Acute Inflammation and its Various Forms 260 II. The Processes of Repair Associated with Inflammation. — Formation of Granulation and Cicatricial Tissues. — Resorption of Exudates and Tissue-necroses, and Substitution of Connective Tissue for Them . 281 III. Phagocytosis Occurring in the Course of Inflammations, and the Formation of Giant Cells around Foreign Bodies. — Chemotaxis . . 294 rV. Chronic Inflammations 297 Section VII. — Tumors. I. General Considerations 303 II. The Different Varieties of Tumors 1. Tumors which Develop from the Middle Embryonic Layer. — Connective-tissue Tumors, (o) Fibroma 312 (b) Myxoma 314 (c) Lipoma 315 {d) Chondroma 316 (e) Osteoma 317 (/) Angioma 320 (^r) Myoma 327 (h) Glioma and GangUonic Neuroglioma 330 CONTENTS. Xi PAGE (i) Neuroma 332 (k) Lympliadenoina and Lymphosarcoma 334 (I) Sarcoma 336 ()») Mixed Forms of the Connective-tissue Tumors 348 2. Tumors whose Structure comprises Epithelium as well as Con- nective Tissue and Blood-vessels. — Epithehal Tumors. (a) Preliminary Eemarks 351 (6) The Adenomata and their Eolations to Glandular Hyper- trophies and Careinomata 352 (c) Carcinoma 357 (d) Epithelial Cystomata. — Cystadenoma and Cystocarcinoma 371 3. Teratomata and their Relations to Monogerminal and Bigerm- inal Implantations and to Remains of Foetal Structures 381 Section VIII. — Disturbances of Development and the Resulting Mal- formations. I. General Considerations in Regard to Disturbances of Development and the Origin of Malformations 386 II. Special Malformations in Man. 1. Arrests of Development in a Single Individual. (a) Arrest in the Development of all the Embryonic Elements 394 (6) Deficient Closure of the Cerebrospinal Canal and the Accom- panying Malformations of the Nervous System 396 (c) Malformations of the Face and Neck 405 (d) Faulty Closure of the Abdominal and Thoracic Cavities, and the Accompanying Malformations 408 (e) The Malformations in the External Genitalia and the Anal Region Caused by Arrested Development 410 (/) Malformations of the Extremities due to Arrest of Devel- opment 412 2. Abnormal Positions of the Internal Organs and of the Extremities 415 3. Malpositions the Result of Excessive Growth or Multiplication of Organs or Parts of the Body 416 4. True and False Hermaphrodism 418 5. Double Malformations. (a) Complete Duplication of the Axial Structures 423 (&) Partial Duplication of the Axial Structures 427 (c) Triple Monsters 430 Section 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 Biology of the Fission-fungi 431 2. General Considerations Concerning the Pathogenic Fission- fungi and their Behavior in the Human Organism 440 3. General Considerations in Regard to the Examination of Fis- sion-fungi 443 XU CONTENTS. PAGE II. The Different Forms of Fission-fungi and the Infectious Diseases Caused by Them. 1. The Cocci and the Morbid Processes Caused by Them. (a) Forms of Growth of the Cocci.— Saprophytic Cocci 446 (6) Pathogenic Cocci 448 2. The BacilU and the Morbid Processes Caused by Them. (a) Vegetative Forms and Method of Multiplication of the Ba- cilU. — Non-pathogenic Saprophytic Bacilh 459 (6) Pathogenic Bacilli 462 3. The Spirilla and the Morbid Processes Caused by Them. (a) Non-pathogenic Saprophytic Spirilla 516 (6) Pathogenic Spirilla 517 Section X. — Mould-fungi and Yeast-fungi, and the Pathological Tissue- changes Caused by Them 523 Section XI.— The Animal Parasites. I. Arthropoda. 1. Arachnida 534 2. Insects 537 II. Vermes (Worms). 1. Nematodes (Roundworms) 539 2. Trematodes (Sucking- worms) 549 3. Cestodes (Tapeworms) 552 III. Protozoa 563 LIST OF ILLUSTEATIOITS. PAGE 1. Lightning-figures on the shoulder, breast, and arm 14 2. Multiple emboli in the branches of the pulmonary artery 41 3. Temperature-curve in a continued remittent fever with a slowly in- creasing and a very gradually decreasing temperature 63 4. Temperature-curve of a continued fever with rapid increase and rapid decline of temperature 64 5. Temperature-curve of an intermittent tertian fever 64 6. Eecent hsemorrhagic infarct of the lung 114 7. Section through a red thrombus in a muscular vein 115 8. Section of a white thrombus in the vena cava inferior 116 9. Section of a mixed thrombus of the aorta 116 10. Quickly flowing blood-stream 118 11. Somewhat retarded blood-stream 118 12. Greatly retarded blood-stream 118 13. Thrombus-formation in the heart 122 14. Thrombosis of the femoral and of the saphenous vein 123 15. Eemains of a thrombus of the right femoral vein 125 16. Pulmonary infarct with obliteration of the artery in the process of heaUng 126 17. Eemains of an emboUc plug of a branch of the pulmonary artery 127 18. Embolus of an intestinal artery with suppurative arteritis 127 19. Stasis from venous hypereemia in the vessels of the corium and of the papillae of the toes 128 20. Longitudinal section through (Edematous muscle-fibres 130 21. Aneemie infarct of the kidney 137 22. Eecent hemorrhagic infarct of the lung 138 23. Necrosis of the epitheUum of the uriniEerous tubes 146 24. Croupous membrane from the trachea 149 25. Waxy degeneration of muscular fibres 149 26. Section of uvula after destruction of its epithehal covering by diphtheria 150 27. Tissue from a focus of tubercular disease, showing baciUi and a limited area of cheesy degeneration 151 28; Section through the epidermal and papillary portions of a cat's paw, a short time after it had been burned with fluid sealing-wax ] 52 29. Dry gangrene of the toes from arteriosclerosis 153 30. Skeleton of a female dwarf, thirty-one years of age 155 31. Skeleton of a female dwarf, fifty-eight years of age 155 xiv LIST OF ILLUSTRATIONS. PAGE 32. Head of Helene Beeker (microeeplialic) 156 33. Brain of Helene Becker 156 34. Hypoplasia of the os innominatum from coxitis 157 35. Hypoplasia and microgyria of the left cerebral hemisphere 158 36. Hypoplasia of the uterus with well-developed ovaries 158 37. Hypoplasia of the small intestine 159 38. Agenesia of the respiratory parenchyma of the lung 159 39. Juvenile muscular atrophy 160 40. Excentric atrophy of the lower ends of the tibia and fibula, with osteoporosis 161 41. Senile atrophy of the calvarium 161 42. Section of an atrophied muscle from a case of progressive muscular atrophy 162 43. Senile atrophy of the kidney 162 44. Arteriosclerotic atrophy of the kidney 164 45. Pressure atrophy of the spinal column 165 46. Facial hemiatrophy 166 47. Cloudy swelling of liver-cells 166 48. Cloudy swelling of kidney epithelium 167 49. Hydropic degeneration of epithehal cells 167 50. 51. HydropicaUy degenerated muscular fibres 168 52. Fat-containing liver-cells 170 53. Fatty degeneration of the muscular tissue of the heart 170 54. Fatty and amyloid degeneration of the kidney 171 55. Cholesteria plates and margarin needles 174 56. Mucous degeneration of epithelial cells 176 57. Mucous degeneration of connective tissue of aortic valves 176 58. Colloid in a specimen from an enlarged thyroid gland 178 59. Section of a contracted kidney, showing arteriosclerosis and masses of colloid ia the uriniferous tubules 179 60. Section of amyloid liver stained with iodine 181 61. Section of amyloid liver treated with methyl violet and acetic acid . . . 181 62. Section of an amyloid kidney 183 63. Amyloid swelling of the reticulum of a lymphatic gland 184 64. Corpora amylacea 185 65. Hyaliae degeneration of the blood-vessels of an atrophic lymph-gland . 186 66. Hyaline degeneration of the connective tissue of the myocardium .... 186 67. Calcification of the media of the aorta 189 68. Calcified ganglion-cells from the brain of a demented person 189 69. Calcareous concretions 190 70. Section of a psammoma of the dura mater, with calcareous formations . 190 71. Deposits of urates in the knee-joiat in gout 191 72. Needle-shaped crystals of urate of soda in the articular cartilage 191 73. Gouty urates of the hand 192 74. Faceted concretions from the gall-bladder 193 75. Transverse section of cholesterin calculus after the removal of all the cholesterin 194 76. Uric-acid infarction of the kidney 195 77. Coral-shaped calculus of oxalate and phosphate of lime 196 LIST OF ILLUSTRATIONS. XV PAGE 78. Transverse section of two stones from the bladder, closely fitted togeth- er, composed of urate of soda and ammonio-magnesium phosphate 196 79. Hairy pigmented mole over back and hips 197 80. Pigmented cells of the skin from a case of Addison's disease 198 81. Cells containing amorphous blood-pigment; rhombic plates and nee- dles of hsematoidin 201 82. Cells containing hsemosiderin and heematoidin 201 83. Cells containing pigment-granules in the lymph-glands 203 84. Infiltration of trabeculae of liver-cells with yellow hsemosiderin granules 204 85. Hsemochromatosis of the liver 205 86. Hsematogenous deposit of iron in the kidney 206 87. Icterus of the liver from compression of the ductus choledochus 209 88. Icterus of the lymph-glands in jaundice due to obstructed outflow of bile 210 89. Icterus of the kidney in jaundice due to obstructed outflow of bile . . . 210 90. Deposits of silver in the pyramidal portion of a rabbit's kidney 213 91. Multiple cysts in the head of the epididymis 214 92. Cyst of the pancreas from dilatation of a branch of Wirsung's duct . . . 214 93. Dropsy of the Fallopian tube, with adhesions 215 94. Elephantiasis neuromatosa 217 95. Elephantiasis lymphangiectatica 218 96. Leontiasis ossea 219 97. 98. Akromegaly of Erb and Arnold ' 220 99. Ichthyosis congenita 221 100, 101. Cornu cutaneum 222 102. Head of a hairy woman 222 103. Hypertrophy of the left ventricle in aortic-valve disease 223 104. Hypertrophy of incisor tooth of a white rat 224 105-120. Nuclear changes in cell-division 228 121-126. Nuclear changes in cell-division 230 127. Nuclear changes in cell-division 231 128, 129. Giant cells from sarcoma of the tibia 232 130. Regeneration of epithelium 240 131. HeaUng of an ulcer of the intestine 241 132. Development of blood-vessels by formation of offshoots 242 133. Vessels of the papillary layer whose endothelial cells are in process of growth 243 134. Proliferating periosteum 244 135. Isolated cells from a granulating wound 245 136. Development of connective tissue from fibroblasts 246 137. Periosteal cartUage-formation 246 138. Formation of osteoid trabecute from the proliferating periosteum .... 247 139. Bone-formation by heaping up of osteoblasts from old bone 247 140. Section from the centre of development of a mesenteric gland 249 141. Portions of muscle-fibre at various stages of regenerative growth .... 252 142. Old and newly formed nerve-fibres 255 143. Cross-section of a nerve-bundle just above a wound made four months previously 256 144. Amputation neuroma of the sciatic nerve 256 XVl LIST OF ILLUSTRATIONS. PAGE 145. Metaplasia of cartilage in reticular tissue 258 146. Bone-formation from connective tissue 259 147. Inflamed human mesentery 262 148. Section through the border of a blister 266 149. Recent interstitial hepatitis 267 150. Parenchymatous nephritis, with necrosis of epithelium of uriniferous tubules 267 151. Superficial catarrhal inflammation of a bronchus 268 152. Inflammatory oedema of the kidney, with catarrh of the uriniferous tubules 270 153. Catarrhal secretion of various mucous membranes 271 154. Acute hsemorrhagic fibrinous inflammation of the trachea 272 155. Croupous membrane from the trachea 272 156. Section of the uvula, showing stratified fibrin membrane, in a case of diphtheritic croup 273 157. Adhesive pericarditis 274 158. Croupous hepatization of lung 274 159. Purulent bronchitis, peribronchitis, and peribronchial broncho- pneumonia ■ 275 160. Section of a smallpox pustule 276 161. EmboHc abscess of the intestinal wall 276 162. Suppuration and necrosis of the mucous membrane of the large intes- tine in dysentery ^ 277 163. Necrosis of the epithelium of the epiglottis 279 164. Bacillary diphtheritis of the large intestine 280 165. Section of the uvula in pharyngeal diphtheria 280 166. Isolated cells from a wound-granulation 284 167. Blood-vessel from the deep layer of the skin after painting with iodine 285 168. Wound-granulations from an open wound, with flbrino-purulent surface deposit 285 169. Eepair of an incised wound of the skin united by suture 287 170. Cicatrix of skin six months after incision 288 171. Fibrin-deposit and beginning formation of granulations in pericarditis 289 172. Formation of granulations within a fibrinous deposit in pericarditis. . 290 173. Development of embryonal tissue in a thrombosed femoral artery. . . . 291 174. Recent hsemorrhagic infarct of the lung 291 175. Healing infarct of the lung 292 176. Callosity of heart— fibroid degeneration 293 177. Granular cells in a focus of degeneration of the brain 294 178. Phagocytes from granulating tissue 295 179. Pigmented granule-spheres in a lymphatic gland 295 180. Dog's hair encapsulated in subcutaneous tissue 296 181. Old necrosis of the femur 298 182. Stone-cutter's lung with bronchopneumonio fibrous nodules 299 183. Condyloma acuminatum 299 184. Periosteal hyperostosis of the tibia, at the base of a chronic ulcer of tlie leg 300 185. Transverse section through the mucosa and submucosa of an atrophic large intestine 301 LIST OF ILLUSTRATIONS. XVll PAGE 186. Induration and atrophy of the renal tissue in chronic nephritis 301 187. Connective-tissue hyperplasia and development of bUe-ducts in chronic hepatitis 302 188. Spongy carcinoma of the mucous membrane of the uterus 304 189. Section through a nodular angiosarcoma of the thyroid gland 305 190. Primary cancer of the gall-bladder, with an impacted stone iu this cavity 307 191. Section through a primary carcinoma of the liver 308 192. Metastatic carcinoma of the lung 309 193. Metastatic sarcoma of the liver 310 194. Sarcoma recurrent in an amputation stump 311 195. Section through an oedematous fibroma of the uterus 312 196. Paracanalicular fibroma of the breast 313 197. Cells from a myxoma of the periosteum 314 198. Section of a myxosarcoma 315 199. Section through a chondroma of the ribs 316 200. Multiple ebumeous exostoses of the frontal bone 318 201. Cartilaginous exostosis of the tibia 318 202. Eburneous osteoma of occipital bone 319 203. Dilated capillaries from a telangiectatic tumor of the braiu 321 204. Section through an angioma simplex hypertrophioum cutaneum et subcutaneum 322 205. Angioma cavemosum cutaneum congenitum 322 206. Section through cavernous angioma of the liver in process of active growth 323 207. Angioma arteriale plexif orme of the frontal and angular arteries 323 208. Lymphangioma cavemosum subcutaneum 324 209. Pigmented naevus of the back, buttocks, and thighs 325 210. Section through a fleshy wart 326 211. Section through two papillse of a papillomatous fleshy wart 326 212. Section through a leiomyoma, showing the nuclei cut both longitudi- nally and transversely 327 213. Subcutaneous angiomyoma of the back 328 214. Cells from a rhabdomyoma 329 215. Glioma of the cerebrum 330 216. Section from a nodular neuroglioma gangUonare of the cerebrum .... 331 217. Amputation neuroma of the ischiatic nerve 332 218. Nerves from a cirsoid neuroma which presented a close resemblance to elephantiasis 333 219. Cirsoid neuroma of the sacral region 334 220. Section through a sarcoma of the intermuscular connective tissue of the neck 338 221. Section through a lymphosarcoma of the mucous membrane of the nose 338 222. Section through a fungoid large round-celled sarcoma of the skin of the leg 339 223. Section of a sarcoma of the breast, with variously shaped cells 339 224. Spindle-cells from a sarcoma of the cheek 340 225. Cells from a medullary giant-celled sarcoma of the tibia 340 226. Section through an endothelioma of the pia mater and cerebral cortex 341 XVI LIST OF ILLUSTRATIONS. PAGE 145. Metaplasia of cartilage in reticular tissue 258 146. Bone-formation from connective tissue 259 147. Iniiamed human mesentery 262 148. Section through the border of a blister 266 149. Recent interstitial hepatitis 267 150. Parenchymatous nephritis, with necrosis of epithelium of uriniferous tubules 267 151. Superficial catarrhal inflammation of a bronchus 268 152. Inflammatory oedema of the kidney, with catarrh of the uriniferous tubules 270 153. Catarrhal secretion of various mucous membranes 271 154. Acute hsemorrhagic fibrinous inflammation of the trachea 272 155. Croupous membrane from the trachea 272 156. Section of the uvula, showing stratified fibrin membrane, in a case of diphtheritic croup 273 157. Adhesive pericarditis 274 158. Croupous hepatization of lung 274 159. Purulent bronchitis, peribronchitis, and peribronchial broncho- pneumonia ■ 275 160. Section of a smallpox pustule 276 161. Embolic abscess of the intestinal wall 276 162. Suppuration and necrosis of the mucous membrane of the large intes- tiae in dysentery 277 163. Necrosis of the epithelium of the epiglottis 279 164. Bacillary diphtheritis of the large intestine 280 165. Section of the uvula ia pharyngeal diphtheria 280 166. Isolated cells from a wound-granulation 284 167. Blood-vessel from the deep layer of the skin after painting with iodine 285 168. Wound-granulations from au open wound, with flbrino-purulent surface deposit 285 169. Repair of an incised wound of the skin united by suture 287 170. Cicatrix of skin six months after incision 288 171. Fibrin-deposit and beginning formation of granulations in pericarditis 289 172. Formation of granulations within a fibrinous deposit in pericarditis . . 290 173. Development of embryonal tissue in a thrombosed femoral artery .... 291 174. Recent hsemorrhagic infarct of the lung 291 175. Healing infarct of the lung 292 176. Callosity of heart— fibroid degeneration 293 177. Granular cells in a focus of degeneration of the brain 294 178. Phagocytes from granulating tissue 295 179. Pigmented granule-spheres in a lymphatic gland 295 180. Dog's hair encapsulated in subcutaneous tissue 296 181. Old necrosis of the femur 298 182. Stone-cutter's lung with bronchopneamonic fibrous nodules 299 183. Condyloma acuminatum 299 184. Periosteal hyperostosis of the tibia, at the base of a chronic ulcer of the leg 300 185. Transverse section through the mucosa and submucosa of an atrophic large mtestine 301 LIST OF ILLUSTRATIONS. XVH PAGE 186. Induration and atrophy of the renal tissue in chronic nephritis 301 187. Connective-tissue hyperplasia and development of bUe-duots in chronic hepatitis 302 188. Spongy carcinoma of the mucous membrane of the uterus 304 189. Section through a nodular angiosarcoma of the thyroid gland 305 190. Primary cancer of the gaU-bladder, with an impacted stone ia this cavity 307 191. Section through a primary carcinoma of the liver 308 192. Metastatic carcinoma of the lung 309 193. Metastatic sarcoma of the liver 310 194. Sarcoma recurrent in an amputation stump 311 195. Section through an cedematous fibroma of the uterus 312 196. ParacanaUcular fibroma of the breast 313 197. Cells from a myxoma of the periosteum 314 198. Section of a myxosarcoma 315 199. Section through a chondroma of the ribs 316 200. Multiple eburneous exostoses of the frontal bone 318 201. Cartilaginous exostosis of the tibia 318 202. Eburneous osteoma of occipital bone 319 203. DUated capillaries from a telangiectatic tumor of the brain 321 204. Section through an angioma simplex hypertrophicum cutaneum et subcutaneum 322 205. Angioma cavemosum cutaneum congenitum 322 206. Section through cavernous angioma of the liver in process of active growth 323 207. Angioma arteriale plexif orme of the frontal and angular arteries 323 208. Lymphangioma cavernosum subcutaneum 324 209. Pigmented nsevus of the back, buttocks, and thighs 325 210. Section through a fleshy wart 32G 211. Section through two papillee of a papillomatous fleshy wart 32G 212. Section through a leiomyoma, showing the nuclei cut both longitudi- nally and transversely 327 213. Subcutaneous angiomyoma of the back 328 214. Cells from a rhabdomyoma 329 215. GUoma of the cerebrum 330 216. Section from a nodular neuroglioma ganghonare of the cerebrum .... 331 217. Amputation neuroma of the ischiatio nerve 332 218. Nerves from a cirsoid neuroma which presented a close resemblance to elephantiasis 333 219. Cirsoid neuroma of the sacral region 334 220. Section through a sarcoma of the intermuscular connective tissue of the neck 338 221. Section through a lymphosarcoma of the mucous membrane of the nose 338 222. Section through a fungoid large round-celled sarcoma of the skin of the leg 339 223. Section of a sarcoma of the breast, with variously shaped cells 339 224. Spindle-cells from a sarcoma of the cheek 340 225. Cells from a medullary giant-celled sarcoma of the tibia 340 226. Section through an endothelioma of the pia mater and cerebral cortex 341 XVIU LIST OF ILLUSTRATIONS. PAGE 227. Endothelioma of the dura mater 342 228. Section through a nodular angiosarcoma of the thyroid gland 343 229. Section through an alveolar sarcoma of a lymphatic gland 343 230. Section through a melanotic alveolar sarcoma of the skin 344 231. Section of a psammoma of the dura mater 345 232. Petrifying large-celled sarcoma of the tibia 346 233. Sarcoma myxomatodes 346 234. Section through a myxosarcoma (cylindroma) 347 235. Cluster of blood-vessels having hyaline sheaths and hyaline processes ; from a cylindroma 347 236. Chondromyxosarcoma of the parotid 348 237. Osteoid sarcoma of the ethmoid bone 349 238. Section through an osteoid chondroma 350 239. Alveolar adenoma of the breast 353 240. Tubular adenoma of the breast 353 241. Adenoma tubulare papilliferum of the kidney 354 242. Section of a benign polyp of the large intestine 354 243. Hyperplasia of the mucous membrane of the uterus 355 244. Section of a glandular polyp of the stomach 355 245. Section through a tubular adenoma destruens of the stomach 356 246. Tubular adenocarcinoma of the rectum 358 247. Adenocarcinoma of the uterus 358 248. Section through a cancer of the skin in an early stage of development 359 249. Section through a carcinoma of the breast 360 250. Epithelial plug from a cancer of the skin 361 251. Section of a carcinoma simplex of the breast 363 252. Gelatinous carcinoma of the breast 364 253. Myxomatous carcinoma of the stomach 365 254. Carcinoma cylindromatosum, showing hyaline degeneration of the epithelium 365 255. Enlarged dropsical cancer-ceUs 366 256. Primary carcinoma of the hver 367 257. Section through an aggregation of very young cancer-ceUs, lodged hke an embolus within a capillary of the liver 368 258. Metastatic cancer development in the liver-capillaries 368 259. Cystoma of the ovary, partly simple, partly papillary in character . . . 371 260. Section of a multUocular cystoma of the ovary 372 261. Section of a papillary cystoma of the ovary 372 262. Section through an adenocystoma of the testicle 373 263. Section of multUocular cystoma of the Uver 373 264. Section of cystoma of the kidney 374 265. Longitudinal section of a congenital cystic kidney, with small cysts . . 374 266. Papillary cystoma of the breast 375 267. Section of a papillary cystadenoma of the ovary 376 268. PapiUary cystoma of the ovary 378 269. Section of a papillary adenocystoma of the ovary 379 270. Intracanalioular fibroma of the breast 379 271. PapiUary cystoma or intracanalicular papOlary fibroma of the breast 380 272. Congenital adenocystoma of the testicle 381 LIST OF ILLUSTRATIONS. XIX PAGE 273. "Wall of an ovarian dermoid cyst 382 274. Spina bifida occulta 385 275. Malformation of the head, due to adhesions of the membranes to the frontal region 388 276. Malformation of the face, caused by amniotic adhesions and pressure 388 277. A hand stunted by amniotic adhesions 389 278. A hand stunted and misshapen by pressure 389 279. Portion of a mole, presenting the form of a bunch of grapes 395 280. Foetus entirely iaelosed by fibrous membranes 396 281. Craniorachischisis, with total absence of the brain and spinal cord . . . 397 282. Rachischisis partialis 397 283. Spina bifida sacralis 399 284. Myelomeningocele sacralis 399 285. AnencephaUa et acrania 402 286. Cranioschisis 402 287. Partial agenesia of the cranial bones 403 288. Hydrencephalocele occipitalis 404 289. Synophthalmia or cyclopia 404 290. Cranial cavity of a synophthalmus microstomus 405 291. Double cheilo-gnatho-palatoschisis 406 292. Agnathia and synotia 406 293. Hernia funiculi umbUicalis 408 294. Fissura abdominis et vesicsB urinarise 410 295. Hypospadias 410 296. Epispadias 410 297. Complete absence of urethra and external genitals 411 298. Amelus 413 299. Mieromelus 413 300. Sympus apus 413 301. Sympus dipus 413 302. 303. Perochirus 414 304, 305. Peropus 414 306. Polydactylism with dupUcation of hand 417 307. Polydactylism and syndactylism of hand 417 308. Polydactylism and syndactylism of foot 417 309. Hermaphrodismus verus lateralis 420 310. External genitalia of a female false hermaphrodite 422 311. Thoracopagus tribrachius tripus 423 312. Craniopagus parietalis 423 313. Ischiopagus 424 314. Acardiacus acephalus 425 315. Acardiacus acormus 425 316. Epignathus 426 317. Diprosopus distomus tetrophthahnus diotus 428 318. Cephalothoracopagus or syncephalus with Janus-head 428 319-321. Dipygus parasiticus 429 322. Streptococcus colonies upon and in the epithehum of the vocal cord . 440 323. Gelatin plate containing colonies of small bacilli 444 324. Streptococcus from puerperal peritonitis 446 XX LIST OP ILLUSTRATIONS. PAGE 325. Micrococcus colonies 446 326. Cocci grouped ia tetrads (merismopedia) 446 327. Sarcina ventriculi 446 328. Metastatic aggregation of micrococci in the liver 449 329. Endocarditis pustulose caused by staphylococcus pyogenes aureus . . . 449 330. Streptococcus pyogenes 451 331. Pectoral muscle beset with large numbers of streptococcus pyogenes 452 332. Colonies of streptococcus erysipelatis 453 333. Section of the skin in erysipelas bullosum 454 334. Gonococci 455 335. Diplococous pneumoniae of Weichselbaum and Frankel 456 336. Bacillus subtilis 460 337. Clostridium butjT-icum 460 338. Capillaries of liver containing numbers of anthrax-bacUli and a few leucocytes 463 339. Anthrax -bacilli containing spores, and free spores that have escaped from the bacilli 463 340. Section through an anthrax-pustule 464 341. Section through a portion of anthrax-pustule containing bacilU 465 342. Bacillus of typhoid fever 467 343. Section through swollen Peyer's plaque in typhoid fever 469 344. BaeiUus pneumonise of Friedlander 471 345. Nail-shaped stab-culture of Friedlander's pneumo-bacillus 471 346. Tubercle-baciUi , 476 347. Tissue-changes produced by a recent invasion of the tubercle-bacilli. . 478 348. Giant cell containing baoiUi, from a tubercle 478 349. Tubercle from a fungous granulation of bone 479 350. Tissue from a focus of tubercular disease, showing bacUli and cheesy degeneration 480 351. Primary tubercular nodules in the lungs, with beginning tubercular lymphangitis 482 352. SubepitheUal tubercular granulations and scattered tubercles in the large intestine 483 353. Large soUtary tubercles of the pia mater 484 354. Section through skin affected with lupus 484 355. Tubercle of bone in advanced stage 485 356. Section through tubercular lung 486 357. Tubercular eruption in a lymph -gland 487 358. Tuberculosis omenti 488 359. Haematogenic miliary tuberculosis of the liver 489 360. Growths from the pleura in bovine tuberculosis 491 361 . Section of a syphilitic initial necrosis 493 362. Condyloma latum ani 494 363. Meningo-encephaUtis syphilitica gummosa 495 364. Gumma of the liver 496 365. SyphUitic ulceration of the larynx 497 366. Congenital syphilis of the lungs 497 367. Tissue from a leprosy-nodule 498 368. Two giant cells with vacuoles containing bacUli, from a leprous growth 498 LIST OF ILLUSTRATIONS. Xxi PAGE 369^ Section through a leprous skin-nodule 499 370. Leontiasis leprosa 500 371. Lepra anaesthetica ulcerosa 501 372. Lepra anaesthetica mutilans 502 373. Bacillus of rhinosoleroma 505 374. Section of rhinoscleromatous tissue 506 375. Cells with hyaline degeneration and hyaline globules from rhinoscle- romatous tissue of the vocal cord and nose 506 376. Section through an infected abdominal muscle of a guinea-pig 507 377. Plate-culture of the baciUus of swine-erysipelas 508 378. Actinomyces hominis 511 379. Section from a tongue affected with actinomycosis 511 380. Actinomycosis of the lung 512 381. Spirillum sive vibrio rugula and spirillum undula 516 382. Cholera-spiriUa 517 383. Stab-culture of Finkler-Prior bacillus 521 384. Spirochaete Obermeieri 522 385. Hyphse, conidia, and epitheUal ceUs from a fresh specimen of favus . 524 386. Conidia spores from aphthae of tongue 524 387. Saccharomyces eUipsoideus 525 388. Section through an aphthae-covered cesophagus of a small child 526 389. Mucor corymbif er in fructification 527 390. Hyphse of aspergillus fumigatus 527 391. Favus scutulum 529 392. Hair affected with favus 531 393. Culture of trichophyton tonsurans 532 394. Female itch-mite 534 395. Section of the skin in scabies 535 396. Leptus autumnaUs 535 397. Acarus foUiculorum hominis 536 398. Ixodes ricinus 536 399. Head end of pentastoma denticulatum 536 400. Male of dermatophagus communis 537 401. Male of dermatocoptes communis 537 402. Female pediculus capitis ■ 538 403. Male pediculus pubis 538 404. Female pediculus vestimentorum 538 405. Gastrophilus equi 539 406. Ascaris lumbricoides 540 407. Egg of ascaris limibricoides 540 408. Oxyuris vermicularis 541 409. Eggs of oxyuris vermicularis 541 410. Male of anchylostoma duodenale 543 411. Cephalic end of anchylostoma duodenale 543 412. Eggs of anchylostoma duodenale 543 413. Female of anguillula stercoralis 544 414. Trichocephalus dispar 545 415. Egg of trichocephalus dispar 545 416. Sexually mature trichinae 546 417. Encapsulated muscle -trichinae 546 XXU LIST OF ILLUSTRATIONS. PAGE 418. Filaria or dracuneulus medinensis 548 419. Embryo of filaria Bancrofti 548 420. Distoma hepaticum 549 421. Eggs of distoma hepaticum 550 422. Distoma lanceola turn 551 423. Eggs of distoma lanoeolatum 551 424. Distoma haematobium 552 425. Eggs of distoma haematobium 552 426. Head of ttenia solium 553 427. Segments of taenia solium 553 428. Proglottides of tffinia solium 553 429. Sexual apparatus of taenia solium 554 430. Eggs of taenia solium 555 431. Cysticercus cellulossB 555 432. Cysticerci in the heart of a pig 555 433. Taenia saginata 556 434. Head of taenia saginata 556 435. Segment of taenia saginata 556 436. Taenia echinococcus 558 437. Brood-oapsules of taenia echinococcus 558 438. Section of echinococcus multilocularis 559 439. Bothriooephalus latus 561 440. Head of bothriooephalus latus 561 441. Proglottis of bothriocephalus latus 562 442. Eggs of bothriocephalus latus 562 443. Free embryo of bothriocephalus latus 562 444. Amoeba coli mitis 563 445. Amoeba dysenterise or coli f elis 564 446. Balantidium (paramsecium) coli 565 447. Cercomonas intestinalis 565 448. Trichomonas vaginalis 565 449. Trichomonas intestinalis 565 450. Section through the wall of a bile-duct fiUed with coccidia 566 451. Coccidia from the bUe-ducts 566 452. Development of spores in encysted coccidia 567 453. EpitheUoma contagiosum 568 454. Parasites of epithelioma contagiosum 568 455. Miescher's sacs in various phases of development 569 456. Plasmodium malariae of a febris quartana 571 457. Plasmodium malariae of a febris tertiana 572 458. Plasmodium malarise of a febris quotidiana 572 SECTION I. Introduction. — Health and Disease. — Problems of General Pathology and Pathological Anatomy. § 1. When the act of fecundation is completed, by the union of the spermatozoon with the germinal vesicle, there occur in the ovum a series of changes leading to the formation of a large number of cells, and finally to the production of an embryo, which, in the course of nine months [in the human species], reaches a definite stage of development, and is thereupon expelled from the maternal organism. When it is de- tached from the latter, its growth continues until completed after a series of years, the attainment of its physical maturity being followed by a long period of time in which the bodily weight remains approximately the same. After a number of years — the extent of time not going beyond a certain limit either in man or in the lower animals — the organism perishes. In all Metazoa, in which the functions of the organism are allotted to certain cells and groups of cells, and in which, furthermore, the propa- gation of the species is dependent upon certain definite cells which are set loose from the maternal and paternal organisms, the parents invari- ably sink iato death. For the maintenance of the species the individual has only this importance : it produces the germinal cells, and in the first stage of development harbors and nourishes them. Thus, if the off- spring be freed from the maternal organs and be capable of existing without parental aid, the parents, if incapable of further production, have become superfluous for the maintenance of the species, and sooner or later cease to exist. So long as the human organism lives, and is in a condition which we consider as one of health, its manifestations of iife show a fixed charac- ter, and, within certain limits, are the same for all individuals. For example, the bodHy temperature is nearly the same for all persons, and, notwithstanding the changes in the surrounding media, varies only to a slight degree. The number of heart-contractions in a minute is confined within certain limits, and, while differing somewhat according to age and sex, their frequency does not overstep certain boundary-hnes for any length of time. The breathing is perform.ed in a distinct rhythm. The ingestion of food, and its changes in the alimentary canal, are made up of a series of mechanical and chemical phenomena which are always repeated by the individual in the same way. The kidneys secrete a fluid which contains certain definite substances which are always of the same (iomposition, and the chemical reactions going on in the body always re- 1 INTRODUCTION. produce themselves in the same way. Again, the nervous system, central and peripheral, with its end-apparatus, acts in a certain manner, which differs very little in different individuals. The condition of the organism which we designate as disease is principally characterized by the fact that some function or functions of the organism are no longer carried out in the way which, from the fact that it occurs in aU human beings, is considered as normal. One there- fore recognizes disease in the greater or less number of changes in the manifestations of life, and disease is nothing else than a life vv'liose manifestations partly deviate from the normal. Nearly every function through which life manifests its relations to the external woiid — in the human organism, for instance, all the different and partly very complicated processes through which the organism accomplishes its nourishment, removes the products of nitrogenous metabolism from the tissues, and cares for the maintenance of the spe- cies — brings with itself also the manifestations of disease. The symp- toms by which we determine that an individual i.s diseased are of a veiy manifold nature ; thus it may happen that the functions of the organism are increased or diminished or destroyed, or they may in a greater or less degree deviate from the normal. It is, furthermore, very common, in a condition of illness, that at the same time not only one function, but many, may vary more or less from the normal, or even be entirely suspended. It is therefore necessary to have an extended experience, and it requires a thorough study, to enable us to recognize all the phe- nomena of disease and to diagnose correctly their meaning. The symptoms of disease are partly subjective and partly objective. To the first group belong the feeling of uncomf ortableness, debility, and sense of painful feeling in some particular part of the body or in numer- ous parts of the organism : dyspnoea, tightness of the chest, palpitation of the heart, loss of appetite, chills, fever, etc. — in short, a great number of phenomena which are referred partly to changes in single organs and tissues and partly to an ailing condition of the whole organism. The objective sjmptoms, as well as the subjective, are partly local and partly general. The process of the digestion of food is often at fault; the contents of the bowel may be hurried along too rapidly, or may be retarded, or may not be discharged at all. The breathing is changed : at times slow, then hurried ; at times shallow, then deep ; over the lungs in these cases are not seldom heard abnormal sounds. The heart-contractions are often quickened or slowed, strengthened or weak- ened, and often of an irregular nature ; consequently the frequency and rhythm and quahty of the pulse are changed. The sounds which are heard in the neighborhood of the heart may also be changed, or replaced or accompanied by new sounds. The urine often exhibits an abnormal appearance, and contains substances which are not normally found in it. In many forms of disease the sensitiveness of particular nerves is low- ered ; in others it is increased. In the muscles there is sometimes more or less paralysis ; at other times involuntary contractions. In the cen- tral nervous system the greatest variety of distui'bances of function may appear, determining conditions of excitation as well as those of depres- sion or paralysis. Very often the bodily temperature, which normally only rises and falls within certain limits, is elevated, often very markedly, above the normal ; and that condition which we designate as fever is mainly characterized by the increase of the proper warmth of the body. HEALTH AND DISEASE. 3 The material substratum upon which the processes of a healthy life depend are the tissues of the body — that is, the cells and their deriva- tives, of which the tissues are composed. Diseased life is connected with the same material substratum, and what we consider as its symptoms are the life=manifestations of the tissues and of the organs of the human body. The function of a tissue is dependent upon the organization of its component parts. A kidney cannot perform any other function than the secretion of urine, and the constituents of the bile can only be sepa- rated by the liver-cells. If the functions of any tissue manifest a change from the normal, it necessarily follows that the organization of the tissue in question is changed. Concerning the character of such changes experience alone gives an explanation, and experience has shown that in most cases these changes of the organization result in a transformation of the physical mahe-up of the tissues — that organs which have functionated in a patho- logical manner are changed to a degree that often enables us to recog- nize by even macroscopical examination numerous deviations from the normal appearance. The number of observations which have been made in relation to tissue-changes in conditions of disease is already very considerable; and especially have the improved optical appliances which the last decade has brought to our aid greatly increased our knowledge in regard to the anatomical changes of diseased organs. Since most forms of disease in man show definite changes in the organs, when we speak of disease we now usually think not only of a group of symptoms, but rather of a group of anatomical changes ; our conceptions of disease have become materially anatomical, and we seek to know the character of a given disease by the investigation of the anatomical changes. StOl we are far from being able always to discern positively the cor- responding changes of organization and structure of the tissue. Even in very severe and fatal diseases (as epilepsy, diabetes) there are times when no anatomical changes in any way commensurate with the phe- nomena observed during life can be proved ; and numerous diseases are accompanied with functional disturbances the seat of which we are unable to locate with any certainty. Nevertheless we may fairly assiime in these cases also that the dis- turbed function is grounded on changes of organization. That we do not know what these changes are has its foundation in this : either that we do not look for them in the right place, or else that our optical aids are not sufficiently powerful to bring them to light. And even when histological changes are present we are often unable to recognize their pathological nature, from the fact that our knowledge concerning tlie nuclei and cells of the various tissues is not so far advanced as to enable us to distinguish in aU cases that which is normal from that which is pathological. It is difficult to say whether there exist any purehj functional (dy- namic) (listurhances, in which the tissues suffer neither physical nor chemical changes. Provisiona.llj'- we accept this in aU cases in which we cannot give any better information. An example of such disturb- ances is seen in the toxic action of nerve-poisons, concerning which we cannot say in what way they exert upon the nerve-cells and nerve-trunks a stimulant or a paralytic effect. 4 INTRODUCTION. The causes of sickness may be external or internal. The former are dependent on the numerous injurious influences exerted by the external surroundings, and can affect the organism as well in intra-uterine as in extra-uterine life. The internal causes are the innate, springing from the embryonic alterations of the organization, or of any particular organ, or of several organs, and appearing either as spontaneous variations or as some- thing inherited from progenitors. If an organism be easily affected by a certain disease, we speak of it as h&mg predisposed to that disease; if the reverse be true, we speak of it as being iymmtne. If a disease be entirely characterized by local symptoms, it is desig- nated as a local disease or disease of an organ ; when the organism appears diseased as a whole, one speaks of a general disease ; should the morbid processes deviate for a long time from the normal, so that the whole organism seems to have become subject to essential changes, the condition is called a constitutional disease. No definite separation, therefore, can be made between local and general diseases, for the reason that a disease may begin with local symptoms and, later on, lead to disturbances of the whole organism ; conversely, a disease may begin with general phenomena, and disease of the organ follow. This difference in the course of disease depends mainly on the differ- ent ways in which the deleterious influences of the external world act. If by such means only the tissues of an organ are damaged, local diseases occur. If, on the contrary, at the outset, changes of the blood and the fluids of the system appear, by means of which the function and the organization of numerous tissues are changed ; if fever appear, and the nervous system be also affected, then the picture of a general disease is produced. If, still further, one organ be more seriously damaged than another, so that consequent disturbances of function are markedly apparent, then it ^vill be proper to speak of the general disease as being accompanied by the symptoms of a local disease. If an organ be attacked with disease, a generalization of the disease may occur from the spreading of the noxious agent by continuity and contiguity ; also by its being conveyed in the blood and the other fluids of the body — either producing general disease or setting up in other organs the same condition of disease that was found in the organ first attacked. And furthermore, the changes in the functions of an organ may produce functional changes in another organ, or even, as a sequence, an ailing condition of the entire body. For instance, a chronic disturb- ance of the secretion of the kidney may produce a change in heart-func- tion, and, later, poisoning of the whole body, including the nervous sys- tem, by means of the harmful products of metabolism, now no longer capable of being discharged from the body in the ordinary manner. In many general diseases which begin with general symptoms we must assume that there was a primary lesion, this, however, being so mild as to produce only slight and circumscribed disturbances of func- tion, and consequently no symptoms capable of being recognized. For example, it is in the highest degree probable that, in an infectious dis- ease beginning with general phenomena, the poison causing the disease multiplies somewhere in the body, and at this point causes local tissue- changes and functional disturbances. Consequentlj'' even in this class of diseases it may be said that the morbid process has a local starting- point or several local seats. HEALTH AND DISEASE. 5 Strictly speaking, even the so-caJled general and constitutional dis- eases are not really such, inasmuch as the tissues of the organism are practically never all involved in a diseased condition. The disease has, even in such cases, its local seats, but these are very numerous and are distributed over the greater portion of the body. The duration of disease is very variable. A shock produced by a sudden fright, with the coexisting excitation of the vaso-motor nerves, is an instance of disease which may last but a few seconds. Tuberculosis, leprosy, and syphilis may give rise to sufferings lasting for years. Dis- eases characterized by a duration of a few weeks are called acute; those lasting for months or for a longer period are designated as chronic. Many diseases have a typical course — one which is repeated in every case without much variation ; in others the course is markedly irregular. Some begin abruptly, others slowly. The termination of an illness is either complete or incomplete recovery, or death. The first event is symptomatically marked by the return of the functions of the diseased organs little by little to their proper condition, u.ntil at last they do not deviate at all from the normal. In general diseases attended with fever the temperature sinks to the level of health, and the ailing condition of the body is transformed to one of weU-being. Ordinarily the return to health goes on without inteiTuption, or at least without much deviation. Not infrequently, however, it happens that while the patient is convalescing the disease breaks out anew; in other words, there is a relapse. The disappearance of the abnormal symptoms denotes a restitution of the tissues. The chemical processes of the body return to their normal state, the damage done to the cells is repaired, the dead cells being replaced by new ones of the same nature as the old, and the whole tissue is restored. In many cases, after the disease has run its course, a complete resto- ration of the former condition of the tissues is produced. In severe sick- ness — that is, in severe tissue-lesions — complete anatomical restoration of the tissue is impossible ; there will remain defects here and there, or tvhere a certain tissue is lost it may be replaced by another of a lower grade. If in such cases, nevertheless, restoration of health ensues, so far as regards the functions, it is for the reason that the individiial organs have a re- dundant amount of fiinctionaUy capable tissue, so that the disappearance of a small group of cells is not appreciable. It therefore happens that, upon the destruction of certain parts, others do compensatory work, increase in size, and show a greater activity of functional power. Thus there will be permanent disturbances of function only when the diseased organ has not enough healthy tissue to carry on the work and other organs are not capable of acting as a substitute for it, or as com- pensatory to it, or if the disease leaves such changes as to produce per- manent disturbances of function in the same organ or in another organ having similar functional capacity. "We must regard it as an incomplete convalescence when, although the symptoms of the disease have disappeared, the harmful influence which caused the trouble is not destroyed, but remains in the body, with the possibility that sooner or later the disease wiU break out anew. Strictly speaking, we have not a cure, but only the latency of the disease pro= cess. This condition occurs most frequently in the chronic infectious diseases. b INTRODUCTION. Upon the occurrence of death all functions of the organism cease. The order in which the various organs of the body suspend and annul their functions varies, in accordance with the nature of the disease. The death of the individual is absolutely determined when the functions of the heart and brain are definitively inoperative. Through the ridorjj of an organism over a disease the body not seldom becomes immnne against the particular poison which caused the disease from which it has recovered. Often, however, on the contraiy, the body, during the course of a disease, or during convalescence from it and after its disappearance, is predisposed to certain other diseases. § 2. The scientific investigation of diseased life may reach its conclusions from the symptoms of a disease, and practical medicine is markedly concerned in learning the meaning of morbid phenomena in each individual case observed by the physician. The exact investigation of pathological symptoms chiefly serves the purpose of determining the different forms of disease present in given cases, and of separating one disease from another; at the same time it should also furnish ns with the power of penetrating into the origin of the different phenomena, and of determining their connection with the changes in the organs and tissues. So far as an investigation of disease symptoms at the sick-bed serves useful diagnostic and therapeutic purposes, it belongs to the domain otjn'urtical medicine and of spiecial pathology, the object of which is to learn to know the phenomena, as well as the course and termina- tion, of the individual diseases, and to find means of controlling them. If the investigation is mainly concerned in determining the nature and the origin of disease phenomena, without regard to their assignment to special forms of disease, it falls within the scope of general pathology, which has for its object the acquisition of definite data concerning the nature and course of disease processes. Various authors, in seeking to define the field of general pathology, have sought its problems in different directions, and their ari'angement of its proper constituent elements is not always confined within the same boundaries. If one faces the task without regard to its practical bearing on the subdivision of science (specialism), it inevitably follows that general pathology must be held to deal not only with the theory of the nature and the course of disease processes, but also with their causes ; that it not only embraces that section of natural science which we call pathological physiology, but includes at the same time the theory of the causes and nature of disease. As the morbid symptoms are neither more nor less than biological manifestations of pathologically changed tissues, so the theory of dis= ease changes of the tissues, or general pathological anatomy, natu- rally falls into the domain of general pathology.- The great extent of the field embraced by general pathology, both in text-books and in the lecture courses, would make it appear reasonable that the limits of a course in general pathology should be narrowed, and that special portions of it should be relegated to the special departments to which they belong. Notwithstanding that the theory of the symptoms of disease forms the largest portion of general pathology, it seems to be expedient to leave to special works, to lectures, and to preparatory instruction those SCIENTIFIC IXA'ESTIGATION OF DISEASED LIFE. 7 facts which are perfected at the bedside and are readily capable of utili- zation for directly practical purposes. G-eneral pathology must also undergo a further contraction in the field of the study of the causes of disease, because the latter are pur- posely brought within the circle of consideration only so far as patho- logical changes are really caxised through them, while the further and more extended relations to the outer world in which we find om'selves — relations which eventually can produce harmful influences upon our or- ganism — are to be turned over to hygiene. The main point of interest in general pathology lies indisputably in the knowledge of the anatomical changes which are at the bottom of the disease processes. But the studies in this domain do not need to be confined to the effort to ascertain the morphological characteristics of disease processes ; they should rather penetrate into the questions of liow these processes are brought into existence and what is their nature. A scientific treatment of pathological anatomy, therefore, leads necessarily also to the study of the etiology and the genesis of the disease pro= cesses. -If hj the study of etiology we are able to prove the cause and development of the changes induced by disease, then shall we also be able to gain an understanding of the phenomena of disease as they come under observation during hie, and also at the same time to lay the foundations for an adequate knowledge of that part of general pathology which is designated by the term pathological physiology. SECTION II. Cause, Origin, and Course of Diseases ; General Considerations. I. Origin of Diseases through External Pathological Influences. 1. Origin of Diseases through Deficiency of Food and of Oxygen; by Fatigue; by Heat and Gold; by Changes of the Atmospheric Pressure; by Electrical and by Mechanical Influences. § 3. From birth until death man is continually subject to the influ- ences of the surrounding external world, some of which influences aid, while others hinder, the exercise of his functions. As long as the human body is able to utiUze its functions for the purpose of spontaneous changes of relation to the external world, and also to accommodate its functions to the external necessities of life, so long does it remain in health. If its contrivances of adjustment are no longer able to neutralize surrounding influences, and man can neither escape nor change the necessities of life, he falls into sickness or dies. For its preservation the body requires first of all a certain amount of nutrient material, as well as a definite quantity of water and of oxygen ; and while man is able to survive the loss of these agents for a short time, yet, beyond a certain degree and after a limited time, insufficiency of oxygen, food, and water must necessarily occasion sickness or death. The suppression or diminution of the supply of oxygen to the tissues is an occurrence that can happen at aU ages, and may be due either to a lack of oxygen in the surrounding medium, or to a hindrance in the transportation of the oxygen contained in the air to the lungs and the blood, or, finally, to an inability of the blood to take up the oxygen in sufficient quantity. Lack of oxygen can occur to the foetus within the uterus, through the mother herself suffering from want of oxygen, or through premature separation of the placenta, or by means of disease changes in the placenta, or through compression of the cord, the gaseous interchange between the blood of the mother and of the foetus being thereby hindered. After birth an insufficient supply of oxygen can hap- pen through hindrances occurring to the breathing-power of the lungs, or through the fact that the child itself is too weak to sufficiently expand the thorax, in order to introduce sufficient air, by means of the respira- tory movements of the lungs. If the supply of oxygen be stopped completely, either through any fluid — e.g., water — getting into the respiratory tract in place of air, or from the air-passages being closed, the individual thus affected dies in a DIMINISHED SUPPLY OF OXYGEN AND OF POOD. 9 sliort time from lack of oxygen, by " choking " or suffocation. If animals remain in a closed place for a certain length of time, death is found to occur as soon as the oxygen of the air reaches 2 or 3 per cent, by volume, it being normally 20.8 per cent, by volume (CI. Bernard, P. Bert). If the supply of oxygen be not entii-ely arrested, but only markedly diminished in amountr— as may occur in carbon-dioxide poisoning, where the firm combination of carbon-dioxide gas with the haemoglobin prevents the taking up of the oxygen by the blood-corpuscles — suffocation follows only after the lapse of several days. By the gradually increased shutting off of the supply of oxygen, and accumulation of carbon dioxide in the blood — as in cases of narrowing of the lumen of the larynx by inflamma- toi-y exudations and through compression of the windpipe from goitre — there occur breathlessness, cyanosis, cramps, and disturbances of con- sciousness, a condition which we call asphyxia. If the supply of oxygen be diminished even in a small degree, but for a long time — a condition which may occur, for example, in a diminu- tion of the blood-ceUs in ohgocythsemia — there wiU take place in the tissues of the organism degenerative processes which are characterized by an increase of the destruction of albumin, and by fatty changes in the organs (Fraiikel), and may cause not only disease, but ultimately death. If the body be deprived of all nourishment and water, then, as albumin and fat still continue to iindergo decomposition, a rapid diminu- tion in the body- weight occurs, and finally death ensues. According to Lehmann, Miiller, Munk, Senator, and Zuutz, the total amount of oxida- tion does not go below the amount which would be observed in the same individual under favorable circumstances and when in a normal condi- tion. There takes place a marked conversion of albumin into other products, as well as a decided loss of water. In animals death follows when about 40 per cent, of the body- weight has been lost, nearly half the deficiency being due to a diminution in the muscles. Pat disappears the most rapidlj^ and may be reduced even to 93 per cent, of the entij'e amount originally present. The diminution of sub- stance takes place in the various parts of the organism according to the following order : liver, spleen, testicles, miiscles, blood, alimentary tract, skin, kidneys, and lungs. The heart, the nervous system, and the bones show the least loss of weight, although the investigations of Lehmann, Miiller, Munk, Senator, and Zuntz have shown that an absorption of the bony tissue takes place during starvation, and if water be ingested an increased amount of phosphoric acid and calcium is found to occur in the urine. In the blood the white corpuscles diminish rapidly in num- ber (Luciani) ; the red blood-cells may, on the contrary, in a given quan- tity of blood, be increased. According to the investigations of Coen, the organs of starved animals plainly exhibit the evidences of vascular en- gorgement, with here and there hsemorrhages, and also inflammatory changes, as, for instance, in the intestines, the liver, and the kidneys. In the nervous system no special changes have been noted (Peri). The fatal issue in the case of absolute withdrawal of nourishment and water occurs in man in from seven to twelve days, under certain circumstances ; according to some authors, only after twenty to thirty days ; bodily exercise hastens the fatal termination. This period is con- siderably extended if water be taken into the system. In this case there is found an increase in the nitrogenous constituents of the urine. 10 EXTERNAL CAUSES OF DISEASE. Life can be maintained for a long time with insufficient nourish- ment; there occurs, however, a certain diminution of bodily weight, which may under certain circumstances lead to the most marked emacia- tion, and flnahy to death. The same thing happens when the com- position of the food is unsuitable, and only a portion of the nutrient material is offered in sufficient quantity, so that the body is starved in albumin, or in fats, or in salts, or in water. Dogs deprived of all nitro- genous nourishment die in from thirty-one to thirty-foui- days (Magen- die). If the nourishment be sufficient, but poor in albumin, there occur, after a certain length of time (in dogs after six weeks), loss of appetite and an unwillingness to take the proffered food, and digestion and assimilation in the animal are lessened (Munk). Especially is this the case if the nourishment be deprived of fat, while it holds to a lesser degree if the aliment l)e wanting in albumin and carbohydrates. Very likely this deficiency of absorption is chiefly dependent upon a diminu- tion of the secretions of the digestive juices, this being especially notice- able in the bile. The excrement at last is found to be nearly without bile. § 4. If the functional activity of an organ be exerted for a con= siderably longer time than that to which it is accustomed, there wUl occur, sooner or later, a state of exhaustion, due in part to the consump- tion of the parenchyma of the organ, and in part to the formation of toxic nitrogenous products of metabolism, these making such an organ unfit for further continued action. If this exhaustion affects a vital organ, such as the heart, death may ensue from this cause alone. This restdt can take place, however, as well when the heart is unable to per- form its ordinary function for a short time as when it acts a long time more nearly normally, indeed, but still under the conditions demanded of a maximum amount of work. If the wearied tissues are able to secure rest, and if a sufficient and proper amount of nourishment be suppHed to them, the extra material which was lost by the unusual activity will be again replaced, the effete products of metabohsm which are acting detrimentally to the functions of the tissue will be removed, and the part will again become ready for a renewal of its normal activity. If a tissue frequently becomes the seat of exhaustive functional activity, and the periods of rest are too short to admit of a complete restoration of the tissue, there will finally occur a condition of permanent insufficiency, a chronic exhaustion, which under certain circumstances may even lead to degeneration or atrophy of the affected organ. A gland or a muscle may thus become atrophied through excessive use, and a brain which, by too constant stimulation of any character without the required periods of rest, is exhausted by its continuous activity, may finally pass into such a condition of debility and exhaustion as to make even the performance of the normal function an impossibility. By means of rest and of regulated nourishment the brain may again' recover ; in a high degree of exhaustion, however, the functional insufficiency may become permanent, and may find its expression eventually in anatomical changes. If the excitation of the nervous system be very severe, there occurs under certain circumstances, by even a short continuation of the source of the irritation, a cessation of the nervous functions — a paralysis which, should it affect the functional capacity of the heart and the respiration, INCREASED FUNCTIONAL ACTIVITY. — HIGH TEMPERATURE. 11 may lead to death ; more often, however, it passes away after a short time. ' In organs from which much work is required, exhaustion and insuf- ficiency take place so much the more quickly in proportion as the nour- ishment is insufftcient. Fatigue and insufficiency of the heart are most often observed when the general nourishment is poorest, as from disease of a febrile character, or when the absorption of oxygen in the blood is more or less hindered by heart-defects poorly compensated for and by diseases of the lung. If the demands upon a muscle or a gland are only slightly increased, and if at the same time the nourishing material be good and sufficient for the carrjdng out of such increased work, the affected tissue becomes hypertrophied and is thereby rendered capable of accomphshing the in- creased work for a time. § 5. High temperatures act in part by a local destruction of the tissue (burning), in part by an overheating of the entire body. Naturally the latter condition is only possible when the high temperature acts for a length of time sufficient to render it impossible for the organism to pro- tect itself from the excess of temperature by giving up its heat. In dry air of 55-60° C. (131-140° F.) even the most profuse perspiration is no longer able to hinder the body from becoming overheated, and in moist air even a lower temperature suffices. If a rabbit is placed in an incubator at 36° C. (96.5° F.), its temper- ature rises up to 41-42° C. (105.8-107.6° F.). At the same time the res- piration and the j)ulse are accelerated, and the superficial vessels become dilated. At about 40° C. (104° F.) the body-temperature is elevated to 44-45° C. (111.2-113.° F.), and the acceleration of the breathing and of the contractions of the heart is enormous ; the pupils become dilated, and the muscles are relaxed. After a time death ensues through paralysis of the nervous and contractile systems, especially through failure of the heart. As the muscular substance of a mammiferous animal coagulates at 44-45° C. (Kiihne), it follows that, by such excessive heating, death may result from coagulation of the heart and respiratory muscles. Con- tinuous inclosure for several days in an incubator is fatal to animals even though the body-temperature does not exceed 42° C. (107.6° F.). The destruction of albumin is increased by the elevation of the body-temper- ature, while at the same time the elimination of carbonic-acid gas is diminished (Naunyn). In many of the tissues fatty changes occur. If a man is subjected to a high temperature, an overheating of the body may take place, and finally the condition may occur which is desig- nated by the name of heat-stroke. In this condition the pulse is in- creased, the respiration is rendered galloping and panting, the pupils are dilated, and death may take place in the same manner as in the case of an animal made the subject of experiment. The occurrence of the heat-stroke is hastened by severe bodily labor, by interference with heat-dissipation, by impermeable clothing, or by lack of water in the body. By direct action of the rays of the sun upon the head cerebral and meningeal symptoms may be produced. This condition is charac- terized by hypersemia a,nd inflammatory exudations, and is called sun= stroke or insolation. Local effects of heat upon the skin (burns), according to the time during which their action is exerted, and according to the intensity of 12 EXTERNAL CAUSES OP DISEASE. the heat, lead to hypersemia (first degree of a burn), or to the formation of bIebs(second degree), or to tissue-eschars (third degree), or to carbonization (fourth degree). The action on the tissues depends upon the heat — first locally and then more extensively, — and their destruction results from a certain degree of temperature acting for a certain length of time. If a large part of the surface of the body, about one third, is burned, the individual dies, even though the burning is only of a mild character and eschar-formation does not take place. An attempt has been made to explain this phenomenon in various ways. Billroth, Poa, Mendel, and others believed the cause of death to lie in the suppression of perspira- tion and the consequent collection of poisonous materials in the blood ; others, as Sonnenburg and Palk, believed the fatal result to be due to a reflex lowering of the vascular tone. In marked cases, according to Sonnenburg, the overheating of the blood causes paralysis of the heart. On the other hand, Ponfick, Klebs, von Lesser, and others consider the fatal outcome to be chiefly due to injury and destruction of the red blood-cells. Silbermann, Welti, and Salvioli also seek the cause of death in injury to the blood, laying especial stress, however, not so much upon the destruction of the red blood-cells as upon the occurrence of stasis and coagulation of blood within the vessels of the different organs, this condition being the consequence of the injury to the blo'der, which are especially noteworthy, are: the organic alkaloids, such as morphine, quin- ine, colchicine, atropin, hyoscyamine, veratrine, strychnine, curarine, solanine, nicotine, dlgitalin, santonin, aconitin, cocaine, coniine, mus- carine, and ergotine, all of which may cause severe poisoning, even in small doses. Lower forms of pdant life, especially the bacteria, produce non-poisonous and poisonous substances in the nutrient mafericd (albuminous bodies) in tvhich they develop. Some of these substances are similar to the vegetable alkaloids, some to the ferments, and are accordingly termed toxic cadav- eric alkcdoids, toxic ptomcunes, toxins, toxalbumins, and toxenzyms (com- pare § 12 ; also Section IX.). It follows that the blood, the flesh, or any organ of a healthy animal may acquire poisonous properties, in, conse- quence of changes which are set up in them by the influence of bacteria. Those diseases which are held to be due to sausage-, meat-, fish-, and cheese- poisonings are in part ascribable to the fact that bacteria have developed in these food-products, and out of albuminous material have produced the poisonous products of metaboHsm. In other cases the bacteria mSiy have developed in the slaughtered animal dro-ing its life, so that the ani- mal was diseased when killed ; and the person eating its flesh acquires the poison, or is infected by the identical disease with which the animal was affected. Under certain conditions food which is in no way spoiled, 18 EXTERNAL CAUSES OF DISEASE. but whicli contains bacteria, may be taken into the stomach and digested, and the bacteria thus liberated may develop in the alimentary tract of man and produce poisoning, by means of the toxins, toxalbumms, or enzyms which are formed by their multiplication. Among the animals ivUch normally ■produce poisons witJiin certain tissues of their ioclies the best known are : serpents, toads, salamanders, scoi-pions, Spanish flies, and many other insects which are supplied with stings. Latterly much attention has been given to the poisonous sub- stances which are to be found in the internal organs of fishes and mol- lusks. There are certain forms of sea-fish that are constantly poisonous, and others also that are only poisonous at certain times ; such observa- tions have been made especially on the fish in Japanese waters. Ac- cording to Saotschenko, the poison in many poisonous fishes is secreted by the glands of the skin at the roots of the dorsal and caudal fins, and may be found in their eggs. According to Remy, Miura, and Takesaki, the poisonous fish belonging to the family Gyninodontes (tetrodons) secrete poison only in the sexual organs. According to Mosso, there^ is found in the blood-serum of eels a poisonous substance, ichthyo toxin, which acts detrimentally if ingested into the intestines of the ordinary animals used for experimentation, and can produce death. Observations of poisoning from eating moUusks have been recently made at Wilhelms- hafen which have excited considerable interest. Se^-ere illness, with death in certain cases, followed the eating of moss-mussels {Mytilus edulis). According to M. WoLff, the poison is contained in the liver of the mussels. According to Scbmidtmann, Virchow, Salkowski, and Brieger, the action of the poison is similar to that of curari. According to Brie- ger, there can be obtained from the poisonous moss-mussels basic sub- stances which are similar in their composition to the ptomaines — that is, to the basic products of decomposition. How far the causes of the poi- soning are to be ascribed to normal and how far to diseased processes in the life of these fishes and moUusks has not been determined at the present time. From the fact that the moss-mussels were only poisonous in certain areas (Sohmidtmann, Wolff) where the water was impure, and that the starfish found in the same localities were similarly affected (Wolff), it would seem probable that in a certain number of cases the poisonous action observed in the mussels, as well as in the starfish, must be referred to the influence of uncleanliness, or to pathological alter- ations of the natural processes of life. It is probable that the bacteria which are found in mussels which live in stagnant canal-water may be the cause of the deadly action (Lustig). In other cases the cause seems to haA'e been connected directly mth special circumstances ; for instance, with the production of elements elaborated by the sexual organs. It is dLfiicult to give an exact definition of a poison and of poisoning, since the action of the substances considered above varies with the dose and the attenuation, as well as with the method of introduction into the tissues of the body. It is well known that even the most powerful poisons may be introduced into the tissues in small doses not only without doing damage, but even in such a manner as to produce a beneficial and curative effect upon them. On the other hand, substances which are not usuaUy classed among the poisons, as, for instance, non-corrosive sodium salts, when introduced into the organism in large quantities or in concentrated solutions, induce phenomena which must be as- cribed to the action of a poison. Furthermore, poisonous substances suflciently INTOXICATIONS. 19 diluted (phenol) may serve as foods. In the above definition I have come to the same conclusion as Kobert, and have utilized in the following paragraphs, concerning the workings of poisons, much material from his " Text-book on In- toxications," published in 1893. In this work a very large and rich amount of material is gathered together and well summarized. § 9. Poisons may be divided according to their action into three classes : first, those which produce local changes in the tissues ; second, those which produce an injurious action upon the blood; third, those which produce in the tissues anatomical alterations which are not recog- nizable. The poisons which produce pronounced local alterations in struc= ture injure primarily .the tissues with which they come dii-ectly in con- tact upon entering the body. If these siibstances are absorbed by the juices of the body, injury may result to the most diverse organs and tissues ; but they most frequently confine their action to the organ in which they are stored up, or to which they are brought for purposes of secretion, as, for instance, the liver, the intestines, or the kidneys. The most frequent situation for the primary injui-ious action is the mucous membrane of the upper alimentary canal and the respiratory tract ; but in many cases of poisoning the skin is the first point attacked. Very often poisons are employed as disinfectants — i.e., they are pur- posely used to prevent the growth of or to kill off bacteria which have come in contact with wounds. When thus used they can produce local changes in the tissues, or, through absorption by the circulatory streams, injure the internal organs or the entire body. The first group of poisons to be discussed here is made up of those substances which produce severe changes in the tissues at the point of contact. From the similarity of the results of this contact to burns, these poisons have been called caustics, or corrosive agents. If the action of the caustic reaches the highest characteristic grade, the tissue attacked wiR be entirely destroyed, in one case being converted into a dry, hard crust, in another case into a moist, soft one. If the action is less severe — ^because of the application of a less concentrated solution of the caustic, or because the chemical substance, though applied in concen- trated solution, acts incompletely, or because the tissue itscK is resistant, as in the case of the skin — we have less severe changes, which are char- acterized by redness, swelling, inflammation, and hsemorrhages. Very often one fijnds in the same organ diverse changes, as local sloughings or necroses, haemorrhages, inflammations, and swellings due to slight local extravasations of blood. If the condition has been present for some time, the local changes are more or less wide-spread, while in a single application of the caustic the tissues are inflamed only within a limited area. As substances which act in this manner should be mentioned the corrosive acids : sulphuric, nitric, hydrochloric, phosphoric, oxalic, acetic, arsenious, arsenic, osmio, lactic, carbolic, and salicylic. To this class also belong the corrosive compounds of the alkalis and alkaline earths, as potassium and sodium hydrate (wateiy solutions of KOH and NaOH), caustic ammonia (NH3 dissolved in water), ammonium carbonate, caustic lime, and barium sulphate. To this list should also be added a number of corrosive salts, as those of antimony (tartar emetic and antimony trichloride), salts of mercury (corrosive sublimate and red precipitate). 20 EXTERNAL CAUSES OF DISEASE. nitrate of silver, chloride of zinc, sulphate of zinc, sulphate of copper and acetate of copper, aluminium acetate, potassium chromate, potassium bichromate, and chloride of iron. Among the especially irritant poisons derived from animals are : can- tharidin, obtained from the beetle Lytta vesicatoria; phrynin, contained in the secretions from the cutaneous glands (parotid) of toads ; the secre- tions from the poisonous glands of snakes and scorpions ; the secretions from the sting-glands of bees, wasps, and hornets ; the secretions from the salivary glands of stinging gnats, flies, and horse-flies ; the secretions from the poisonous glands of the maxillary proboscis of spiders (Taran- tula), which produce local necrosis or give rise to inflammation. Finally, many of the higher plants produce substances which, when brought in contact with tlie tissues, cause local irritation and inflammation. Ex- amples are : daphne, various forms of Ranunculus, anemone, marsh-mari- gold, caUa, dragon-root, Croton tiglii (producing in its seed croton-oil), buckthorn {Rhamiius catharf lea), water-elder {Rhamnus frangula). These plants produce the poisonous substances either in their blossoms, or in their seeds, stems, or roots. The character of the local changes whicb the substances mentioned above produce is naturally very varied, and is dependent in part upon the activity of the poison, and in part upon the place a'nd manner of its application. Mineral salts, liquor potassse, and strongly concentrated corrosive-subHmate solutions produce marked eschar-formations, asso- ciated with severe hsemorrhagic inflammations, especially when taken into the stomach. Through the action of acids a strong demand is made upon the alkaline fluids of the body, and we find, in consequence, alter- ations in the respiration and the circulation. The poisons from the poisonous glands of snakes, which belong to the toxalbumins, cause usually very severe local inflammations and hemorrhages, which often become wide-spread and sometimes occasion marked gangrene of the tissues. There are other snake-poisons which produce only slight local changes, while the systemic poisonous symptoms are by far the most marked. There is a volatile or gaseous class of poisons which cause local irritation of the tissues, especially of the mucous membranes of the eye and of the respiratory tract {irrespirable gases). To this class belong the fumes of ammonia, chlorine, sulphuric acid, nitrogen monoxide, nitrogen dioxide, nitrogen trioxide, osmic acid, and mustard-oil. The intensity of action of these poisons varies also, often occasioning mere temporary redness, but being able also to produce severe inflammation and necroses of tissue. From the irritation of the respiratory tract coughing is pro- duced, and by spasm of the larynx the breathing may be interfered with. There are added, in many cases, to the local irritation and inflammation caused by the action of this class of poisons, further effects upon the internal organs. After the absorption of these poisons by the juices of the body, those organs suffer most, as a rule, in which the poison is retained or elaborated, although the action may extend also to those organs which, do not take part in the excretion of the poison. After the application of certain poisons the lesions at the point of entrance are transient and unrecognizable. The fli'st recognizable anatomical lesions occur in tis- sues to which the poison has been carried by the blood. Finally, a given poison may act as a nerve- and heart-poison, so that, clinically, this action appears more prominently than the local tissue-degeneration. After cor- rosive-subHmate poisoning, cell-necrosis takes place in the secreting por- ■ INTOXICATIONS. 21 tion of the kidneys, combined with marked inflammation of the colon. Salts of chromic acid, cantharidin, and many acids cause more or less marked tissue-necrosis and inflammation in the secreting portion of the kidneys and in other parts of the urinary tract. Phosphorus, arsenic, and antimony, which are but mildly corrosive, produce tissue-degenerations, principally of a hemorrhagic or fatty nature, in the kidneys, liver, heart, muscles, and capillaries of different organs. These changes are seen especially after phosphorus-poisoning. If an individual is exposed for months or years to the vapor of yel- low phosphorus, it may produce an inflammatory necrosis of the jaw- bones ; but this necrosis only takes place when the inhalation of the vapor is combined with such conditions as putrid decomposition in the mouth, or decayed teeth. In growing bone small doses of phosphorus, frequently repeated, can produce an increased osteogenesis. After the long-continued use of nitrate of silver, black silver-deposits may be found in the most diverse tissues of the body — in the skin, in the kidneys, in the intestinal viUi, and in the choroid plexus of the brain. The snake-poisons possess, in addition to their local irritant action, a paralyzing effect upon the nervous system and the heart. So after snake-bite we may have death from paralysis of the centre of respiration. Solutions of lead, when taken into the alimentary tract, may have a corrosive action on the mucous membrane, giving rise to inflammation, and producing such intestinal sj^mptoms as vomiting, diarrhoea, consti- pation, and gastric cramp, associated with such nervous symptoms as ansesthesias, motor palsies, convulsions, faintings, and unconsciousness. If lead be ingested continuously for a long time, general disturbances show themselves, such as derangements of digestion, intestinal colic, pain in the limbs, anaesthesia, motor palsies, disturbances of cerebral activity, and kidney-disease. These various lesions are undoubtedly de- pendent upon the dispersion and deposition of lead in the body, leading to the most wide-spread anatomical changes. The active poisonous principles of ergot {Secale cornntum) are spJiace- Knic acid and cornutine. When taken in large doses, as continuously in bread, this drug causes itching, pains, cramps in the extremities, and, later on, numbness and a feeling of cold in the tips of the toes and fingers. This condition may go on to more or less wide-spread gangrene and sloughing of the parts, with the formation of ulcers in the intestines [ergotism, itching disease). These results are attributed by von Reckling- hausen and Robert to peculiar changes in the arteries due to the action of the ergot. In long-continued poisonings, degenerations take place in the spinal cord (Tuczek). § 10. Poisons which cause changes especialli/ in the blood, and hence may be called blood=poisons, are partly gases and partly fixed substances which are absorbed. The latter are aljsorbed principally from the intes- tinal tract; they may, however, enter the body through wounds, or they may be injected directly into the blood-vessels. Sometimes these blood- poisons produce also a local action upon the tissues at the point of entrance ; again, there may be joined to the action on the blood a direct influence upon the nervous sj'stem, producing death under certain cir- cumstances, even before the action upon the blood has been recognized. Finally, it shordd be noted that the blood-changes induced by the poison may produce secondary diseases in the different organs, as, for instance, the"^ kidneys, the liver, the intestines, and the brain. 22 EXTERNAL CAUSES OF DISEASE. The n:ost important blood-poison is undoubtedly carlon-mouoxide gas, which causes an effect upon the blood, and very frequently produces more or less serious or deadly poisonings. Most frequently the poison- ing occui-s from the carbon monoxide contained in coal- or illuminating- gas. This gas may also be produced after the burning of gunpowder or gun-cotton. The action of the carbon monoxide taken in by breathing consists largely in its combination with the hismoglobiu, forming carbo-oxy- hfemoglobin. This combination decreases the amount of oxygen in the hsemogiobiu and hinders the taking up of oxygen by this substance, even when the respired air contains as low as 0.05 per cent, or 0.02 per cent, of CO (G-ruber). The blood-corpuscles are not changed in appear- ance by this poison. If a sudden addition of carbon monoxide reaches the nervous system, it may produce direct injury to it, giving rise to cramps and, later on, to paralysis (Geppert, Kobert). In cases of poison- ing lasting for a long time, the displacement of the oxygen in a large por- tion of the blood-corpuscles may produce tissue-asphyxia. If the poisoned individual does not die, he may suffer from disturbances of the nutrition of various organs of the body, especially of the nervous system. The poisoning itself is characterized by headache, tinnitus aurium, fainting, malaise, vomiting, giddiness, cramps, palsies, and coma. The blood itself turns a pale-violet or cherry-red color on account of the increase in cai-- bon monoxide, and the internal organs have a peculiar bright-red color. A second not infrequent form of poisoning is that produced by hydro- cyanic arid (CNH), which, in combination as potasskmi cyanide (CNK), is much iised in the arts. In general, hydrocyanic acid is found in unstable combination in the leaves, barks, and seeds of very many plants : bitter almonds, cherry- and peach-stones, apple-seeds, leaves from the common laurel, the rind of Prumts pndns, the root-bulbs of many of the Euphor- bia, flaxseed, etc. Hydrocyanic acid possesses a double action. In relatively small doses it exerts a paralytio influence upon the central nervous system, and death may be produced in a short time — even in a few seconds — by paralysis of the centres of respiration or of circulation. Besides this, there is an action upon the blood and tissues, robbing them of their ability to unite with and use oxygen (Geppert), so that these organs suffocate in the presence of oxygen. According to Kobert, there is formed a cyan-methaemogiobin which appears bright red in color and produces a bright-red appearance of the cadaveric lividity. Among the third class of poisonous substances which should be named in this c(5nnection is hydivf/pii sulphide (H2S\ which is formed in the vapors of sewers and dimg-pits, and which may produce sudden death by paralysis of the nervous sj^stem, when inspired in large amounts. By long contact with blood containing oxygen, as may usually be seen in decomposed corpses, sulphur-methgemoglobin is formed, the blood becom- ing greenish in color. Apart from their direct action on the nervous system, carbon mon- oxide, hydrocyanic acid, and hydrogen sulphide produce deleterious effects by lowering the functional powers * of the red blood-cells, through com- bination with the haemoglobin. * The words in the original text are—" die functionellen Lahmungen" ; but the latter is doubtless a misprint for " Leistungen."— Translator's Note. INTOXICATIONS. 23 Another large group of poisons injure the Mood chiefly, by destroying the red lylood-corimscles and forming methmmoglohin. By methsemoglobin we understand a combination of oxygen with the haemoglobin ; the amount of oxygen present in the combination being the same as in oxyhsemo- globin. The haemoglobin, however, has been bound up with the oxygen into a more stable chemical compound than oxyhaemoglobin. Such an action is produced by oxidizing substances, as ozone, iodine, sodium hy- pochlorite, chlorates, nitrites, and nitrates ; by reducing agents, as nascent hydrogen, palladium hydride, pyrogaUol, pyrocatechin, hydrochinon, and alloxantin ; and, finallj^, by substances which act differently from either of these, as aniline salts, toluidin, and acetanilide. In the change from haemoglobin to methsemoglobin through oxidizing agents, oxyhsemo- globin is present as an intervening stage. The production of methEemoglobin can take place as well in the blood-corpuscles as in the coloring-matter which has escaped into the blood-plasma ; but the destruction of blood-corpuscles and the escape of haemoglobin into the blood-plasma are not always followed by the forma- tion of methsemoglobin. In case of such a marked destruction of red blood-cells as occurs in poisoning from phallin, helvellio acid, and arse- niuretted hydrate, only a portion of the haemoglobin is changed into met- hsemoglobin. Haemoglobin and oxyhaemoglobin have a red color, met- haemoglobin a sepia-brown color. Dissolution of the red corpuscles and the formation of methaemogio- bin is seen after poisonings which have produced marked local tissue- changes, as, for instance, poisonings with acids, salts of the metals, and phosphorus ; but a great number of other substances have the property of attacking the blood and changing the coloring-matter. Phallin, a toxalbumin which is found in mushrooms {Amanita s. Aga- ricus phalloides), the helfellic acid, which occurs in fresh Helvella esculeitta and is lost if the fungus be dried, and ar sen ix retted hydrogen (AS.H^) have a very dissolving action on the red blood-corpuscles, and, in conse- quence, produce an increased formation of biliary pigment, as well as a deposition of the derivatives of the blood-coloring matter in the liver and kidneys. Potassium chlorate (CLO^K), pyrogaUol (C''H'^[0HJ3), hydradne (H^N-- NII2), toluylendiamine (CWl'NWl^GW), nitrolemol (C^H^NO'^), nitroglycerin (C''H'^[ON02]3), amyl nitrite (C-'H^iN02),ptmc acid (C'lPll^O-YOIL), aniline (C^H^NH^), carbon disulphide (CS^), are distinctive in their action, in that they sometimes cause the destruction of the red blood-corpuscles in the formation of methaemoglobin, and they sometimes do not. After a very large dose of potassiimi chlorate, death may occur in a very few hours, through destruction of the blood-corpuscles and the action of the potassium, with the development of vomiting, diarrhoea, dyspnoea, cyanosis, and weakening of the heart. The blood in these cases is of a chocolate-brown color. In more protracted cases of poison- ing with small doses we find the products of the destruction of the blood in the spleen, liver, marrow of the bones, and kidneys ; and the urine may show a reddish-brown to black color (methsemoglobin). The presence of delirium, numbness, coma, and cramps during the illness shows that the central nervous system is markedly affected. PyrogaUol produces sim- ilar symptoms. Hydrazine and phenyl hydrazine produce multiple ecchy- moses, besides the destruction of the red blood-cells, with the production of methaemoglobin. The main feature of toluyleudiamine-poisoning is the 24 EXTERNAL CAUSES OP DISEASE. breaking up of the red blood-corpuscles, which leads to the deposition of iron-containing pigment in the spleen, liver, and bone-marrovf. Accord- ing to Stadelmann, hemoglobin and methaemogiobin are not found in the urine, or, at least, only in small amounts. In picric-acid poisoning there is marked disturbance of the central nervous system, which is characterized by severe cramps, in addition to the changes in the blood and the production of methaemogiobin. In a similar manner, aniline and carbon disulphide not only cause changes in the blood, but also act harmf ally by paralyzing the nervous system. In the last group of blood-poisons, as the chief representatives, are to be named riciiie, derived from the seed of the castor-bean, and ahin, found in the seed of the Ahrus ])recatorius, which belongs to the Papil- ionaceae. The entrance of these poisons into the 'b\oo(!i prodnces a coagu- lation similar to that produced by the fibrin ferment. Ricine is very virulent, and may be absorbed from wounds and from the alimentary- tract, producing weakness, vomiting, colic, bloody dejecta, icterus, cramps, and anuria. In the intestine, at spots where the ricine has formed thrombi in the vessels, ulcers may be found. Abrin is also very poisonous, and, when introduced into the blood in doses of a few hundredths of a milhgram per kilo of the body-weight of the animal, can produce death (Robert). Upon the mucous membrane it produces, even when very dilute, coagulation in the blood-vessels, and, later on, inflammation. § 11. The last group of poisons, which are generally classed together as nerve= and heart=poisons, are principally characterized by the fact that notwithstanding the severity of the symptoms, which show them- selves in the form of irritations and palsies, anatomical changes are either not susceptible of being recognized, or at least they are not so in a manner that can be looked upon as characteristic in a given case of poisoning. This is especially the case when the poison produces death very quickly ; for during the course of protracted poisoning, or chronic poisoning from small doses extending over months and years, anatom- ical changes very easUy recognized are often found — a fact which shows that these poisons do not solely produce functional changes in the ner- vous system, but more frequently produce a damaging effect on the ceU- protoplasm, which finds expression in degenerations. Among the very numerous ^ofso^-s tvMch act especially upon the nervous system, and thus may produce death through its paralysis, belong, as the most important members: chloroform, ether, hyponitrous oxide, alco- hol, chloral hydrate, opium and its alkaloid morphine, cocaine, atropin, hyoscyamine, daturine (Stramonium atropin), nicotine, coniine, cicutoxin, santonin, camphor, quinine, veratrine, colchicine, aconitin, strychnine, cytisin, and curarine. As heart-poisons are to be especially noted : digitalin, heUeborin, and muscarine. Chloroform (CHCF) acts in an irritating manner when applied directly to the mucous membranes, and mav produce transitory inflam- mations. When it is inhaled, or when it is conveyed to the blood by means of the intestinal tract, there ensues, after a short period of exci- tation, a diminution of the irritability of the gray and the white matter of the brain. According to Binz, a slight coagulation of the protoplasm of the ganghon-cells is produced. Death may be caused by paralysis of the central nervous system, as well as through early stoppage of the heart INTOXICATIONS. 25 — the latter, liowever, occurring only when tlie heart ia abnormally weak or degenerated, though pei-haps also when the irritation produced by the chloroform upon the mucous membrane of the nose causes an unduly strong excitement of the inhibitory nerves of the heart. Finally, long- protracted exhibition of chloroform may produce degenerative changes in various organs, as the heart, kidneys, liver, the muscles, and the blood. Ether (diethjl ether, C-H\O.C-H"') acts similarly to chloroform, yet it is less poisonous and acts less detrimentally upon the functional activity of the heart. Hyponitrous oxide (N-0) acts especially upon the cerebrum, destroys sensation of pain, and paralyzes consciousness; later on, the action extends to the spinal cord, the meduUa oblongata, and the heart. Alcohol (C^H^OH), after temporarily producing excitement, acts as a depressant and paralyzant of the brain, and produces at the same time a dilatation of the arteries of the skin, so that in a drunken person a severe chilling through the skin can easily take place. Death can follow suddenly, in a manner similar to what is observed in apoplexy; more frequently it produces a gradually deepening loss of consciousness and sensorial perception, the breathing becomes slower, the pulse small, the countenance cyanotic ; complete coma and general paralysis close the picture. The immoderate iise of alcohol extending over months or years may produce, on the one hand, pathological accumulations of fat in the regions where fat is normally to be found, and, on the other hand, it may cause degeneration of the glandular organs, especially the kidneys and liver, followed by overgrowth of the connective tissue, with atrophy of the liver and kidneys, and, in addition, sclerosis and atheroma of the arteries, degenerations in the brain, etc. It is, however, impossible to say at the present time in what manner, how frequently, and to what extent these symptoms belong to the use of alcohol. It is certain that the drunkard frequently suffers from indigestion, diseases of the circula- tion, laryngitis, pharyngitis, bronchitis, and disturbances of the cerebral functions, and that the disease of the brain which is produced by alco- holism and is called delirium tremens is marked by twitchings of the muscles, obstinate sleeplessness, anxiety, and hallucinations. Chloral hydrate (CCF.CHO.H'^O) has a local irritating action on the mucous membranes, and a paralyzant action through the blood upon the brain, spinal cord, and heart, and thus produces sleep. When death occurs from an overdose, deep coma and relaxation of all tissues are observed, with oedema of the lungs. Opium and morphine (C^H^^NO^) produce depression of the functions of the brain, leading to sleep, though in some persons this is preceded by a condition of excitation. Large doses produce unconsciousness, muscular paralysis, slowing and weakening of the action of the heart, contraction of the pupils, slowing of intestinal peristalsis, diminution in the exchange of gases in the blood, and an inhibition of the normal irri- tability of the respiratory centres. There are no characteristic post- mortem lesions ; the blood is dark and liquid. Chronic opium-ingestion may produce disturbances in digestion, dizziness, sleeplessness, neural- gias, imbecility, impotence, anemia, hallucinations, tremors in the hands, fever, etc., which may vary much in different individuals. The system in chronic morphinism becomes accustomed to increasingly larger doses ; withdrawal of the drug produces severe nervous symptoms, and, under certain conditions, dangerous collapse. 26 EXTERNAL CAUSES OP DISEASE. Cocaine (C'H^iNO*) produces peripheral dulling of the sensibility of the terminal sensory nerve-filaments ; centrally, first irritation, then par- alysis. The chronic cocaine habit may produce symptoms similar to those seen in chronic morphinism. Atrojnn and Mjoscyamine (C'^H^sNO'), alkaloids which are found in the members of the order Solanacese (deadly nightshade, thorn-apple, and hyoscyamus), have a paralytic action on the peripheral nerve-fila- ments, and finally irritate and then paralyze the centres. A solution of atropin introduced into the eye produces dilatation of the pupil and paralysis of accommodation for near vision, through its action on the terminal fibres of the oculo-motor nerve in the iris. Atropin may further inhibit the secretion of glands (as the submaxillary) ; under its action, also, intestinal peristalsis ceases through deprivation of the neces- sary nerve-stimulus. Through the action of this poison on the brain we may have excitation, gaiety, laughter, leading even to insanity and mad- ness, followed by paralysis. Post-mortem examination is negative. Nicotine (C'°Hi*N-), a volatile alkaloid found in the tobacco-plant, acts upon both the peripheral and the central nervous system, producing nausea, salivation, vomiting, diarrhoea, dizziness, muscular weakness, headache, convulsions, delirium, and paralysis. Chronic nicotine-poison- ing may be followed by nervous diseases and disturbances of the heart's action. According to Vas, there is both in chronic-alcohol and nicotine poisoning a characteristic degeneration of the ganglion-cells, the chro- matin structure becomiag homogeneous. Coniine (C^H^'N), an alkaloid of hemlock, acts as a paralyzant of the periphei'al motor terminal nerve-fibres, irritating and then paralyzing the central nervous system. Cicutoxiii, a poisonous resin extracted from the water-hemlock {Vlaita virosa), causes nausea, vomiting, attacks of colic, palpitation of the heart, cramps, and unconsciousness. Santonin (C'^H'^0'') produces cramps originating in the brain and spinal cord, with benumbing of the sensorium, vertigo, vomiting, saliva- tion, and yellow vision, or xanthopsia, in which white is seen as yellow and blue as green. Quimne (C-'^H-^N'O^), the most important of the numerous vegetable alkaloids, found in the bark of cinchona and other plants of the same order, acts in a paralyzing manner upon the living protoplasm, and in relatively small dt)ses inhibits the functional capacity for work of the cerebrum. Large doses produce death by paralysis of the centres of respiration and of the heart. Aconitin, colchicine, and veratrine produce local irritations and, later, benumbing of the peripheral endings of the sensory nerves. On the central nervous system they act as irritants and finally as paralyzants. Strijclmine (C-^H-N'-O"'^), derived especially from the plant nux vomica, causes increased reflex irritabiUty of the nerve-centres, so that the slight- est external irritation produces tetanic convulsions. Death may occur in from ten to thirty minutes after the first attack of convulsions, and results through central paralysis — namely, of the vaso-motor centre. Curarine (C^^H->''N), the most active principle of the arrow-poison curari, which is probably derived from the cortical portion of the roots of many plants of the Strychnia family, paralyzes in small doses the terminal fibres of the musculo-motor nerves. Larger doses paralyze the central nervous system and the vaso-motor nerves, after a temporary excitation. INTOXICATIONS. 27 Digifalin and digitalein, two glucosides obtained from the foxglove, act locally as irritants, and also exercise, after absorption, an irritating action on the heart, vagus-centre, and muscular fibres of the blood- vessels, so that there is produced, by the slowing of the heart, an increase in blood-pressure. Larger doses produce headache, delirium, ringing in the ears, irregularity in the frequency of the heart's action, convulsions, and coma. Helleborin, a glucoside from hellebore, acts similarly to the prepara- tions of digitalis. Muscarine (C'H^^NO^), the poison of the fly-mushroom, acts as an irritant upon those peripheral nerve-filaments which atropin paralyzes. In poisoning by muscarine, death takes place not from paralysis of the heart, bat from the intense excitation of the inhibitory centres producing stoppage of its action. In general, after the ingestion of this poison, we have sahvation, vertigo, anxiety, nausea, vomiting, diarrhoea, eonvi^lsions, and finally unconsciousness. Small doses produce a condition similar to that seen in inebriation, with a state of excitation. In the foregoing summary of poisons, which, necessarily comprises but a superficial examination of a few out of the entire number of such agents, I have in general followed the arrangement in groups used by Kobert in his " Text- book on Intoxications." A deeper knowledge than that which we have at present concerning the physiological action of these poisons will probably lead in the future to another mode of classification. Loew * has lately attempted to make a classification of poisons according to their action on the manifestations of life — i.e., upon the Hving protoplasm. He divides them into two large groups — naim.e\y, general poisons, those which, in moderate concentration, act fatally upon the entire organism ; and special poisons, those which do not injure certain classes of organisms. The general poisons are characterized chiefly by their power to change the chemical character of the proteids out of which the living protoplasm is formed. Among these can be differentiated: 1, oxidizing poisons (ozone, chromic acid, manganic acid, hypermanganio acid, hypochlorites, hydrogen peroxide, chlorine, bromine, iodine, phosphorus, and arsenious acid) ; 2, poisons having a catalytic action (ethyl ether, chloroform, chloral, many carbohydrates, etc.), which transfer to the protoplasm the unstable condition of their mole- cules, and thus tend to produce chemical changes in the unstable (lahilen) albundn ; 3, poisons acting by the production of salts (acids, soluble mineral bases and caustic alkalis, alkaUne earths^ and salts of the heavy metals), which form chemical combinations in the proteid materials; 4, substitution-poisons (hydroxyl- amine, diamide, phenyl hydrazine, ammonia, carbolic acid, hydrocyanic acid, etc.), which even when greatly diluted interfere with the aldehyde- or amido-groups. Special poisons are classified as: 1, toxic proteids — i.e., (a) toxalbumins (produced by bacteria and poisonous to animals), (&) alexins and immunitoxins (produced in animals physiologically or pathologically, and poisonous for bacteria), (c) vegetable emyms (abrin and ricine, produced from phanerogams and the higher fimgi, and poisonous to animals), [d) animal enzyms (produced by cer- tain animals, snakes, fishes, and spiders, and poisonous to other animals); 2, organic bases (strychnine, atropin, curari, etc.) having an unknown action; 3, poisons worTiing indirectly, which interfere with the processes of respiration (carbon monoxide, sulphites), or act as poisons through decomposition (nitrites, iodine combinations), or act destructively through changes in the formative conditions of organized tissues (neutral salts of the alkalis, the alkaline earths, oxalates). * " Natiirliches System der Gifte," Miinchen, 1893. 28 EXTERNAL CAUSES OP DISEASE. 3. Origm of Diseases through Infection or Parasitism. — Miasms and Con- tagions. — Vegetable and Animal Parasites. § 12. As we have seen in §§ 8-11, there occur, in the intoxications, morbid -vital phenomena which are produced by definite chemical sub. stances, the mode and severity of their action being dependent upon the character of the poison and the dose employed — that is, if the idiosyn- crasies of the suVjects of the poisoning and the special mode of apphca- tion of the poison are not taken into consideration. In those diseases which arise from infection, and therefore are called infectious diseases, we have, on the contrary, to deal with dis- eased vital phenomena which, if we disregard the individual susceptibility of the infected person and the peculiar mode of entrance, into the body, of the infecting material, are dependent solely upon the character of the infecting agent; while the amount of the dose, if it possesses any signia- cance, has at least only a subordinate one. The explanation of this difference between intoxication and infection consists in the fact that, in the first case, intoxication, the poison does not increase within the body, while in infection the harmful substance in- creases after its entrance into the organism, so that amounts of infective material so small as to be utterly inappreciable by us suffice to produce the severest fatal diseases. The dose, or quantity, of infecting material has this influence, therefore, upon the succeeding illness — namely, that a larger amount makes the infection more probable ; that is, the reproduc- tion of the injurious material within the body takes place more rapidly, and the constantly increasing material of infection will therefore in a shorter time attain such proportions that pathological processes must develop in the tissues, and must at the same time be accompanied by recognizable symptoms. The injurious elements which are produced by infectious diseases always find their way from the outer world into the human organism, and cause an illness which may follow a pathognomonic course ; and from the peculiarities of this course it is possible to conclude that we are dealing with a specific variety of injurious infiuenee — one that behaves in an entirely characteristic manner. In pregnant women the infectious matter may be transmitted from the organism of the mother to her child in utero. If an infectious disease attacks a number of individuals in a given locality, it is termed either a pestilence or an epidemic. A study of professional observations shows that, in a certain number of cases, the noxious influence producing a certain infectious disease manifests its activity in certain localities, catising sickness among the people of a given district. In other cases contact with the diseased per- son, or proximitjr only, or using something which that person has used, or still other ways — as, for instance, through dejecta or sputum upon un- cleaned objects — may produce the disease. Finally, it may occur that infecting material is produced only occasionally in a given localitj'-, and only when a patient \'isits that particular region and by his presence leads to the production there of the infectious material. Out of the various conditions enumerated, occasion has been taken to divide the matters which are capable of producing infectious diseases into various groups and to designate these under particular names. If infectious INFECTION. — MIASMS AND CONTAGIONS. 29 material is connected with a certain locality it is called a miasm, and receives this name on the ground that the particular region produces the infectious material. If one particular region alone produces the disease it is termed a local miasm, and if present everywhere it is termed a ubiquitous miasm. To these miasmic diseases belong especially malaria, and also croupous pneumonia, articular rheumatism, many wound-inflam- mations, septic osteomyelitis, and ulcerative endocarditis. When the infection is carried dir-ectly from man to man, and spreads through houses, villages, cities, and countries, it is termed a contagium, and it is consequently understood that the place in which the organism grows is within the human body, or it may be also in some inferior ani- mal, while outside of the human or animal body neither production nor multiplication of the infecting material takes place. To such contagious diseases belong smallpox, measles, scarlet fever, diphtheria, erysipelas, pyaemia, phlegmon, typhus fever, relapsing fever, anthrax, hydrophobia, gonorrhoea, whooping-cough, influenza, many catarrhs of the mucous membranes, tuberculosis, syphilis, glanders, and leprosy. When an infectious material is characterized by the fact that it develops in a certain district only when a patient suffering from the disease chances to visit tliis particular locality and there gives rise to an outbreak of an epidemic, we have what is called a miasmatic=contagious disease ; the assuniption being warranted, under these circumstances, that the infecting matter had spread from the organism of the first patient, had then multiphed at some given spot, and finally had of itself, or with the help of certain local influences, attacked the resident popula- tion of the locaUty in an epidemic fashion. Such miasmatic-contagious diseases are cholera, typhoid fever, dysenteries, yellow fever, and the plague. The nature of the causes of these miasms and contagious diseases remained concealed from the older practitioners. If such an infectious disease made its appearance in the form of a plague or epidemic its cause was sought in cosmic and telluric conditions, and it was spoken of as a constitutio epiclemicu or a constitutio pestilens. Only within the last few decades has our knowledge of the etiology and nature of infectious diseases made true progress, and it has been shown that infectious dis- eases are parasitic diseases \rliose o)-idiich at the same time exert a solvent effect upon the red blood-corpuscles. The absorption of a part of the contents of the bowel, or of urinary ingredients, or of the constituents of bile, into the lymph or the blood, and their transference to va,rious tissues, constitute the chief foundation INTOXICATION AFTER INFECTION — ^AUTO-INTOXICATIONS. 51 of auto-intoxications. There are other substances, however, which orig- inate in the body without the aid of infection, and which may also exert a deleterious influence. Thus, for example, the reabsorption into the circulation, and the transportation to other localities in the body, of the remains of broken-down tissues and disorganized blood produce not only local disturbances, but also symptoms indicative of a general disorder — such, for example, as fever (aseptic fever) ; and in seeking for the causes of this deleterious influence we are obliged to assume that they consist in part of the unformed ferments or enzyms which develop in the tissues, and in part of the products of metamorphosis which result from fermen- tation, and also in a measure from some influence exerted by the living tissue-cells. The term auto -intoxication is not used with the same signification by all authors, for many give to it a broader meaning than has been given to it in the preceding paragraphs ; some even going so far as to include among the auto- intoxications the poisonings which are caused by pathogenic bacteria. In favor of this interpretation of the term the argument may be advanced that the poisons thus developed also emanate largely from constituents of the body. But it seems to me that such an extension of our idea of what the term auto-intoxi- cation should include is not useful or advisable ; for, after all, the primary cause of the chemical changes underlying the production of the poison does not reside within the body itself, but enters it from without ; or, in other words, the poisoning cannot take place without a previous infection. For these reasons it seems to me more correct to apply the name auto-intoxication only to those cases of poisoning which are caused by the products of metabolism within the body — a metabohsm brought about either by the influence of the activity of the cells of the organism, or by the activity, within the organism (in the intestine, for instance), of the non-pathogenic bacteria, which are always normally present. Chronic diseases, which seem to consist in the disturbance of most of the functions of the organism, are very often grouped together under the name of constitutional diseases. Samuel includes among constitutional diseases, last- ing anomahes of the blood, of the lymph-glands, and of the nerve-substance (neuropathic predisposition), rachitis, osteomalacia, multiple exostoses, weak condition of the muscles, relaxed articular ligaments, etc. Hoffmann * describes, under this heading, ansemias, hesmorrhagic diathesis (hsemophilia), hsemoglo- binsemia, rachitis, osteomalacia, chronic rheumatism, progressive ossifying my- ositis, multiple exostoses, obesity, gout, diabetes meUitus, diabetes insipidus, and Addison's disease. Nothnagel, in his '' Handbook of Special Pathology," under the heading of constitutional diseases, leaves out the blood-diseases and only includes rachitis, osteomalacia, gout, obesity, chronic rheumatism, arthritis de- formans, diabetes mellitus, and diabetes insipidus. From these examples one can see clearly enough that the ideas in regard to what conditions should be classed as constitutional diseases are very different. In the case of the above- named diseases we are really not deahng with constitutional anomalies, but with the sequelae of anomahes or diseases of certain tissues, so that the term con- stitutional disease is very frequently misused. Obesity and gout come nearest to meriting the designation of constitutional diseases. According to Bouchard, auto-intoxications are caused particularly by leuoo- maines — that is, by the products of beginning retrogressive metamorphosis of the albuminous materials, which, under normal circumstances, through the action of intra-organic oxidation, are used up in the formation of urea, and are then expelled. According to this view, auto-intoxications occur in diseases which are characterized by diminished oxidation energy — as, for example, in gout, rheumatism, many infectious diseases, chronic constipation, uraemia, dia- betes, and many nerve-diseases. According to Poehl, the ferment which keeps * "Lehrbuch der Constitutionskrankheiten," Stuttgart, 1894. 52 LOCAI, AND GENERAL DISEASES. the oxidation processes of the body at normal height is spermin, a base which is found in a variety of glands— the pancreas, the thyroid gland, the testicles, etc. § 20. The integrity and normal functional activity of many organs are dependent in a great measure upon the maintenance of the normal function of other organs, and it is necessary for the preservation of the normal condition of the entire organism that the individual organs maintain their proper functions. The general organism cannot be de- prived of the function of many of the individual organs for any length of time. In consequence of this interdependence of the individual organs very frequently the altered function of one organ — even though no actual intoxication be produced by the disturbance — has a preju= dicial influence on other organs, or even may threaten the entire system. The dependence of one organ upon another is shown in an especially striking manner in their relation to the vascular system and the blood. The vascular system and its contained blood have relations to all the tissiies, and accordingly diminution in quantity and diseases of the blood, as well as ixitliological alterations of the blood-vessels, verj' often produce diseased conditions in this or that tissue, or even in the entire body. If the amount of htemoglobin in the blood is diminished by a decrease in the number of red blood-corpuscles (oligocythaemia), or by some patho- logical 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 atten- dant fatty degeneration will result ; in fact, in exceptional cases, this deficiency of oxygen may produce death, by causing a paralysis of the nerve-centres. Should the arteries be closed by thrombi or emboli (compare § 17 and Section III.), or narrowed or actually closed by thichening of tlieir walls, as happens in the arterial disease known as arteriosclerosis (see Section II. of Special Pathological Anatomy), the regions supplied by the arteries thus affected become the seat of local deficiencies in nutrition and in oxy- gen-supply, of local asi^hyxia, and, later, of degenerative processes which very frequently end in the death of the tissues involved, and sometimes also of the connective-tissue framework of the organ. In the cerebrum and spinal cord the alterations in the blood-vessels tend to produce ischsemic softening processes (see Section 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 distm-bed, or it may even become entirely insufficient. In the kidney the secreting glandular parenchyma, together with a portion of the connective tissue, undergoes necrosis and atrophy, and the loss of these substances produces local or wide-spread shrinkings which are called, according to their size, embolic and arteriosclerotic atrophies. In the stomach ischsemia of the miicous membrane produces local ulcerations ; in the liver and in the muscles it induces atrophv ; in short, no tissue can withstand the effects of a long-standing bloodlessness or poverty of the blood. Consequently, narrowing or closing of the arteries INFLUENCE OP DISEASE OP ONE ORGAN UPON OTHER ORGANS. 53 by clots or by changes in their walls plays an exceedingly important part in pathology, and is not only the cause of aimmic necroses (see Sec- tion IV.) and luemorrhagic infarcts (see Section III.), but also of number- less in'ogressive 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-degeneration 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 Section VI.), the disturbances of the circulation through alteration in the blood-vessel walls, the disp)lacements and changing of the vascular channels, which result in part from the closing of old vessels dy proliferating endothelial cells or by thrombi, and in part from the forma- tion 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. The chronic infiammations of glandular structures make this very apparent, for in these organs proliferation of the endothelial cells of the blood-vessels often results in obliteration of their lumina. 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 wUl show themselves in the more remotety 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. If a portion of the lung 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 functionallj^ active. The effect of this is to produce first an overdistention of this part of the lung, and eventually a condition of atrophy due to the abnormal stretching of the tissues. By increase in the size of the liver compression is exerted upon neigh- boring organs ; diseases of the parenchyma of the liver are often 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 iirine 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. 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 dis- 54 LOCAL AND GENERAL DISEASES. ease of the lungs, is often followed by dilatation and liypertropliy 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 hypertrophy 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 inabihty 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- ments 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 pro- duces atrophy of the corresponding peripheral nerves" and the muscles supplied by them. Paralyzed extremities become atrophied. Diseased conditions in the region of the respiratory and vascular centres induce disturbances of the functions controlled by these centres. Injuries 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 circum- stances, first a rapid absorption of the hepatic glycogen into the blood, and then a secretion of a saccharine urine. Irritation of the periph- eral nerves may produce abnormal reflex sensations and movements, as well as circulatory disturbances, in other parts of the body. Paralysis of both vagi, or of the branches which are given off by them, and which are called the recurrent laryngeal nerves, may be brought about by in- flammatory processes or by pressure on the part of neighboring lymph- glands, etc. ; and the condition is one which may be followed by inflam- mation of the lungs, by reason of the fact that the accompanying paral- ysis of the laryngeal muscles permits the entrance of foreign substances into the lung during inspiration. Diseased conditions of the cutaneous nerves may caiTse the formation of inflammatory vesicles (herpes zoster), or even ulceration of the skin itself. The trophoneurotic diseases of the tissues are mentioned in the main text only cursorily, and their occurrence is set forth as only a possibihty. This is done for the reason that the relations of the trophic nerve-system to theindividual 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 hable, and attribute to_ the motor, secretory, sentient, sensory, and reflex nerves the power of estabhshing the necessary connection with the nerve-centres. Others attrib- ute the same power to special trophic nerves. Thus, for instance, muscidar atrophy, glandular atrophy, bone- and joint-atrophies (especially tabes ; com- pare the section relating to the pathological anatomy of the joints), diverse diseased conditions of the skin characterized by thinning, exfoliation of the epithelium, loss of hair, inflammation, etc., unilateral tissue-atrophies, certain forms of degeneration of the heart and also hypertrophic growths of the muscles, TKOPHONEUEOSES. — CESSATION OF CERTAIN GLAND FUNCTIONS. 55 the giands, 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 are produced both degenerative and hypertrophic tissue-changes and in- flammations; but most probably these are dependent not upon a condition of the tissues caused by the removal 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 distui'bances in circulation which have developed coincidently with the disturbances of innervation. An example of this is seen in the tissue- disturbances which are obsei'ved when the affected parts lose their sensibility. Many draw their conclusions as to the trophic influence of the nervous system upon certain organs from the fact that the development of the body in many respects is dependent upon a full development of the sexual organs. Later observations on the action of injections of the juices derived from the sexual glands into the human economy make it probable that these glands produce chemical substances whose absorption into the juices of the body has an in- fluence on other organs (compare ^§ 21-23). According to the observations of Singer* in urticaria, which develops in connection with disturbances in the intestinal function, the intestinal putrefaction is increased, which may be recog- nized by the presence in the urine of indican and ethyl- sulphuric acid. The same jDeculiarity may be observed in other forms of skin-diseases. § 21. When glands cease to perform their functions, or if a part of the function of a gland undergoes some alteration, various diseased con- ditions may result ; and we may explain them bj^ assuming that certain harmful products are retained in the system and undergo absorption (§ 19), or also that certain chemical substances which are of importance to the integritj' of the economj' are no longer produced. In harmony with these ideas we may establish a group of diseases which owe their origin to the lack of certain chemical substances which cease to be provided when certain gland=functions are arrested. If the lung be considered as a gland, one may include in this group the diminislied absorption of oxygen, with all its sequelee, which is brought about by various pathological conditions of the lung. To this group also belong those disturbances of the digestion which result from the permanent or temporary abolition of the functional activity of the glands of the stomach, as a result of which the gastric juice loses its peculiar digestive power on the ingested foods— a power which it owes to the pepsin, the mUk-curdling ferment, and the hydrochloric acid contained within it, and which is manifested in such acts as the coagulation of milk by the curdling ferment just mentioned, the solution of albumin and gelatin and their conversion into peptones by means of the pepsin, and the conversion of grape- and milk-sugars into lactic acid. In a sim- ilar manner we should place in this same group the disturbances occa- sioned by the suspension of the secretions of the accessory special glands of the alimentary tract. Thus, by the cessation of the production of the salivary secretions in the mouth, the action of the ptyahn, which changes starch into sugar, is arrested ; by the cessation of the pancreatic secre- tion, the peculiar effects which it is capable of prodiicing are not accom- plished (the following are the effects in question : by means of a diastatic ferment it changes swoUen-up starch into dextrine and sugar ; it emulsi- fies softened and fluid fats, partly separating them into glycerin and fatty acids ; through the contained trypsin it dissolves albuminoid bodies and gelatinous tissues, converts them into peptones, and then splits them * Wien. Klin. Wochenschr., 1894. 56 LOCAL AND GENERAL DISEASES. up) ; and, flually, by the abolition of the biliary supply, the antiseptic action of the bile in the intestinal canal is arrested. Finally, the diminution in the amount of urea formed in severe dis- eases of the liver-parenchyma shordd not be overlooked. It has been only within the last few years that the significance of the partially recognized disturbances in the functions of the pancreas, of the thyroid, and of the suprarenal capsules has received due consideration. These glands probably produce a secretion the admixture of which with the blood and the juices of the body is necessaiy for the preservation of the integrity of the organism. Consequently their absence causes pecu- liar diseases, which are known as diabetes, cachexia thyreopriva, myxadema, cretinism, and Addison's disease. Diabetes is a disease characterized by the presence of a large amount of grape-sugar in the urine (glucosuria), accompanied by a marked in- crease 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 [3-oxybutyric acid in the urine. At the same time grape-sugar and the acids just named are fouud 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, faintings, and finally arrest of consciousness (coma diabeticum) are apt to develop, and these conditions are probably attributable to intoxication by acids (Stadel- mann, Minkowski). The presence of sugar in the urine may be due to the fact that too much siigar has been taken into the body, so that a portion has entered the urine unchanged (alimentary glucosuria). Glucosuria 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 cerebrum (soften- ing, epilepsy, mental affections, severe psychical derangements, tumors, parasites), or of some form of poisoning (carbon monoxide, curari, mor- phine, strychnine, amyl nitrite, nitrobenzol), in which the liver probably gives up its glycogen into the blood more rapidly than normal, so that a hyperglycffimia is set up. Finally, glucosuria 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 administration of phlorrizin (von Mering). These alimentary, neurotic, and toxic glucosurias are, however, to be distinguished from the ordinary diabetes in that the cause of glucosiu-ia 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 sufficiently 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 (Hedon, Lepine, Arthaud, Butte, Grley, Thiroloix, Harley, Capparelli), this loss of power in the organism to oxidize the sugar brought into the body, or to store it up as glycogen or fat, is to be explained by a ^veaTcened functional action of DIABETES MELLITUS. 57 the pancreas. This conclusion is drawn from the fact that, after the total extirpation of the pancreas in dogs, a severe, and after a few weeks fatal, diabetes is produced, which is characterized, as diabetes is in the human subject, by polyuria, polydipsia, hyperglycasmia, glucosuria, a diminution 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, p-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 anatomical examination often fails to disclose a pathological condition of the pan- creas, so that we must content ourselves with the belief that the anatom- ical alterations which may underKe the functional disturbance of this organ are not sufi&ciently well marked for us to be able to demonstrate them. A precise explanation of the causal relations existing between diseases of the pancreas and diabetes cannot be given at the present time ; yet from the foregoing experimental researches we may deduce the hypoth- esis 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 destruction of j3-oxybutyrio acid, aceto-acetic acid, and acetone. As these substances are not always found in artificially produced pancreatic diabetes (Min- kowski), 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 (Minkowski). They may also accompany other diseases (poisonings, carcinoma, derangements of digestion), and are not always to be found in cases of diabetes. The appearance of diabetes after the total extirpation of the pancreas fur- nishes evidence that the pancreas has an especial function which is of the greatest importance in the normal consumption of sugar in the organism. Lepine is of the opinion that there is in the blood a glycolytic ferment which is derived directly from the pancreas, and that, in diabetic patients and in dogs from whom the pancreas has been removed, the cause of the meUituria is to be sought in a decrease in the amount of this ferment. According to Minkowski, Lepine's experiments are not sufficient for the support of this theory. A satis- factory 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 com- pletely extu'pated (Minkowski, Hedon) ; it recurs, however, as soon as the im- planted 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 phlorrizin produces in man and in most animals a marked glucosuria, 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 phlorrizin diabetes cannot be identified with the ordinary diabetes — that is, the pancreatic 58 EFFECTS OF SUSPENSION OF CERTAIN ORGANIC FUNCTIONS. diabetes as found in man. In dogs in whicli diabetes lias been produced bj' ex- tirpation of the pancreas, phlorrizin produces an increase in the amount of sugar excreted (Minkowski). § 22. Cachexia thyreopriva is a peculiar disease which is lyroduced by the loss or decrease or suspension of the function of the thyroid gland, these conditions resulting either from defective development or from pathological changes in the gland. To Kocher belongs the honor of having discovered the cause of this disease, he having observed that it followed the total extirpation of the thyroid gland. Numerous clinical observations and experimental researches which followed this discovery 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, especiallj'' during its growth, requires a thyroid gland capable of perform- ing its functions in a normal manner. Probably this gland produces a substance that serves a useful purpose in the metabolism of the body ; it is also possible that it changes or destroys deleterious substances cir- culating 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 sj-mptoms, which are characterized by the appearance of convulsions and cramps, and finally by palsies of the muscles, so that the condition has been called thyreoprival tetany. Young animals and the caruivora are especially sensitive, and dogs die mostly in a short time after the total extirpation of the thyroid. 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 antemia, manifests itself, and at the same time pale waxy swellings of the skin, especially of the face, appear, and there is a 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 partially the growth of the bones in their longitudinal axes. _ In thyreoprival tetany the body-temperature is raised ; in the cachexia 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 myxoedema (Ord) is a disease which is specially dependent upon changes in the thyroid gland. Myxoedema is a condition in which the external appear- ance of the patient reminds one of the thyreoprival cachexia ; there is the same peculiarly pale elastic swelling of the facial skin, M-hich does not yield to the pressure of the finger, and which may also be accom- panied by similar pale and dry swellings in other parts of the body. Later on, there is a decrease in intellectual power, which shows itself in an increasing difficulty in thinking and acting, also in dulness of tactile sensation, in retardation of muscular reaction, and in the monotonous, nasal character of the voice. Finally, marked general weakness and CACHEXIA THYREOPEIVA MYXCEDEMA CRETINISM. 59 often symptoms of actual mental derangement appear, and the fatal termination occurs under manifestations of increasing cachexia, antemia, and coma. So far as may be judged from the clinical and anatomical facts observed in patients affected with this disease, it is highly probable that cretinism, or rather the alterations in the structure and functions of the body which characterize this disease, is also dependent upon disturb- ances of the functions of the thyroid gland. Thus we know 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 in their general aspect remind one of those individuals whose growth has been stunted through a thyroidectomy having been performed upon them during childhood. The longitudinal 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 face, is pale, flabby, wrinkled, and pufEy, as if oedematously swollen. The mental faculties are always feeble, sometimes markedly so. The power of speech and of understand- ing words may be entirely absent ; and only those cases of cretinism which are 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 ip. the drinking-water, acts with a degenerating influence upon 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 epidemic cretinism, we might also term cachexia thjrreopriva operative cretinism. 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 observations and experimental researches which have been made (see the works of Horsley, Hofmeister, and de Quervain, in which are to be found summaries of the literature of the subject). Regarding the mode of action of the thyroid gland there are, however, many opinions. It is a striking- fact that very smaU remnants of the thyroid tissue suffice to prevent the evil effects of extirpation, and that the implantation of small portions of thjrroid tis- sue, provided they continue to hve in their new surroundings, exerts a curative influence upon tetanilla strumipriva and cachexias trum^ipriva (Vassale, Gley, Christiani, Leichtenstern, Hofmeister, and others). The same results have also been obtained by subcutaneous injections of the juices derived from the thyroid rf an animal, and by administering portions of the gland as food. Hofmeister asserts with positiveness that, in cases like those which have just been enumer- ated, the thyroid gland contributes to the juices of the body a chemical substance indispensable to the organism. As further corroborative evidence of the fact that cachexia strumipriva and myxcedema are closely related, we may mention the fact that in myxcedema the existence of degeneration of the thyroid gland has several times been demon- strated. That the clinical manifestations and the pathological changes observed 60 EFFECTS OF SUSPENSION OF CERTAIN OEGANIC FUNCTIONS. in the two diseases are very similar is a well-known fact. But a stUl more striking evidence of the dependence of myxoedema on disease of the thyroid gland is furnished by the fact that either the prolonged use of subcutaneous in- jections of thyroid-gland juice, or the habitual feeding of portions of the gland to the patient, exerts a strongly curative effect upon myxoedema (Murray, Vermeh- ren, Ord, Hellier, Kocher, Beadles, Laache). If the supposition be correct that endemic cretinism is dependent upon degeneration of the thyroid gland,, one may hope that this disease, if taken at its inception, may be cured by the suit- able administration of thyroid tissue. Very few characteristic post-mortem lesions are found in persons who have died from cachexia strumipriva or from myxoedema. The central nervous sys- tem shows no noteworthy changes, either in tetany (de Quervain) or in cachexia (Langhans, Hofmeister). In the year 1892 Langhans and Kopp described pe- culiar changes in the peripheral nerves. The conditions which they found are the following: single or multilocular vesicular cells (derived from the endoneurium) in the lymph-spaces of the endoneurium ; next, pecuhar flat or cylindrical or spindle-shaped bundles of fibres, changed in part, in the centre, to a hyaUne mass ; finally, on the inner surface of the perineurium, blood-vessels having a thickened homogeneous or concentrically striated adventitia. The importance of these discoveries in cachexia thyreopriva is, however, questionable, since Weiss has found the same condition in healthy dogs upon whom the extirpation of the thyroid had not been performed. According to Hofmeister, the kidneys and sexual glands show degenerative changes. The most remarkable of the characteristics shown after removal of the thyroid in early life, or after it has become diseased at an early period, is the arrest of the longitudinal growth of bones, dependent upon some disturbance of the process of endochondral ossification. According to Hofmeister, a similar arrest may be produced artificially by operation on rabbits. Another thing worthy of note is the fact that, according to the researches of Rogowitsch, Stieda, and Hofmeister, removal of the thyroid in young rabbits produces en- largement and a peculiar alteration of the hypophysis cerebri. The assertion, thought to have been established by of t-repeated experiment, that rabbits after extirpation of the thyroid do not have tetany, is, according to the investigations of Gley, which Hofmeister has confirmed, based on an error, arising from the experimenters having overlooked the fact that the rabbit always possesses supernumerary thyroid glands. If these are also removed, along with the regular glands, rabbits — like the majority of carnivora operated upon — die from tetany. § 23. Addison's disease is a peculiar affection which ends in death after a course, on an average, of two years, and vfhich 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 pigmentation of the skin, there occur loss of appetite, nausea, pain in the epigastrium, diarrhoea, 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, headache, dizziness, faintings, epileptic seizures, and a comatose condition. According to the comprehensive statistics compiled by Lewin, altera- tions of the suprarenal capsules are found in eighty per cent, of all typical eases of Addison's disease. Most frequently these organs are found to be changed into a caseous or a partly cheesy and partly fibrous mass. CACHEXIA THYREOPRIVA. — ADDISON'S DISEASE. 61 Other lesions whieh 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 com- plete 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. In the same category witli the pathological conditions which result from the withdrawal 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 the changes which occur are referable only to the organs of generation : menstruation ceases, and the uterus atrophies ; and yet there are cases on record in which it was observed that changes occurred in the pro- duction of adipose tissue and the growth of hair, and also in the general tem- perament. 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. U, on the contrary, boys are castrated the development of the body simulates 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 genitaha remain smaU, 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 cooks the growth of the comb is arrested. How the extirpation of the sexual glands affects the entire body has not been determiaed with certainty. It is generally supposed that, by means of this operation, the trophic influence which is exerted upon the tissues by the sexual glandg, through the nervous system, is withdrawn. It is, however, very im- probable that the sexual glands exert such a trophic influence through the nervous system, and the supposition, corresponding more closely to the actual circumstances, must rather be that there is produced in the sexual glands during development a chemical substance which exerts a definite influence upon the growth and development of the body. According to the opinion of Brown-Sequard, 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 ac- tion, 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. The literature ot Addison's disease is unusually rich (see works of Averbeck, Alexander, and Lewin), but nevertheless the very numerous clinical and exper- imental 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. Since in some cases of Addison's disease no lesions are found in the suprarenal capsules, the attempt has frequently been made to refer the disease to other localized pathological lesions — as, for instance, of the sympathetic nerves and ganglia ; but the conditions found up to the present time do not justify such a deduction. That there have been found in a few cases, even 62 EFFECTS OF ORGANIC DISEASES UPON THE ENTIRE ORGANISM. when correctly diagnosed, no degenerative lesions of the suprarenal capsules, cannot be used as an argument against the pathological importance of the de- generation of these glands in the etiology of Addison's disease^ since an appa- rently normal suprarenal capsule may have performed its functions in an abnormal manner. According to the experiments of Tizzoni, pathological conditions similar to those seen in Addison's disease can be produced in rabbits by the destruction of the suprarenal capsules : as, for example, abnormal pigmentation of the mucous membrane of the mouth, loss of strength, epileptic attacks, comatose conditions, and finally death. It is also of interest to note that in cases in which the animals died in consequence of the operation, Tizzoni found degenerative processes present in the spinal cord. Inflammatory and degenerative changes in the sernilunar ganglia and in other parts of the sympathetic system^ and also in the intervertebral gangha, have been found frequently in Addison's disease, and have lately been more fully described by Fleiner. They can be explained upon the hypothesis of an extension of the inflammation and degeneration 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 con- stant, while those of the nerves have been found in only a few cases. Alexander found that the suprarenal capsules contain a good deal of leci- thin, and he is, for this reason, disposed to beUeve that the disease of the supra- renal capsules is due to the fact that this substance, which is also present in a relatively large quantity in the central nervous system, is no longer produced. Abelous and Langlois, who performed experiments upon guinea-pigs by re- moving the suprarenal capsules, conclude from their researches that, by means of a pioison which they produce, the suprarenal capsules modify or destroy a poison that originates in muscles. 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, apecuhar hyaline substance is found, which by the chromic-acid solution is colored brown, in much the same manner as are the surrounding parenchyma-ceUs. It is there- fore possible that from these cells a peculiar substance is furnished to the blood. It should be stated, furthermore, that this substance is also found in arteries. It cannot be demonstrated in alcoholic preparations. IV. Fever and its Significance. § 24. 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 caUed 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 iodihj temperature; yet other symptoms usually accompany it, as, for example, increased fre- quency of the pulse, disturbances in the distribution of the blood, and altera- tions in the intercliancje 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 eifect of the infection when associated with symptoms of poison- ing ; 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 (Jiirgen- FEVEE. 63 sen), the bodily temperature maintains a mean height of 37.2-37.4° C. (98.8-99.3° F.). The normal variation in thermal condition 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 regulation of both phenomena that makes possible the normal constancy of body tem- peratui'e. 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, hj dilatation of the cutaneous arteries, and by an increase in the sweat-excretion. ■A .7-5 \M\T/\ III M ZOTM I u—k ~— -.-: . Fig. 3. — Temperature-curve in a continued remittent fever with a slowly increasing and a very gradually decreasing temperature (typhoid fever). 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 temperatti)-e of the body becomes more or less elerated above the normal (Figs. 3, 4, and 5). Elevations of temperature (taken in the rectum) to 38° C. (100.4° F.) are called hijpenwrmal; from 38° to 38..JO 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.) (evening), highly febrile ; while any temperature over 41° C. (105.8° F.) is called hyper- pyretic. Four periods may be distinguished in fevers. The first, called the pyrogenetic or initial stage, or stadium incrementi, comprises the time in 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. 4) — and is then gener- ally accompanied by a chill; sometimes it is longer (Fig. 3), extending over one or more days, and is then usually unaccompanied by a chill, but in some cases there may be repeated chills. G4 EFFECTS OF ORGANIC DISEASES UPON THE ENTIRE ORGANISM. 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-jioints, between which are found more or less marked re- missions. 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. 4), it is called crisis; if it occurs gradually (Pig. 5) 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).* In lysis the temperature falls gradually in from three to four or more daj^s, and may be either continuous or intermittent. Fig. 4. Fig. 5. i'ggSiEMIA. caU the state one of pathological hyperasmia or of pathological anasmia. These conditions are only in part caused by the same governing mechan- ism which determines the normal blood-supply of an organ. § 37. Hypersemia of an organ is caused, under pathological condi- tions, either by an increase of the arterial supply or by an obstructiou and hindrance to the venous outflow, and we distinguish, accordingly, an active or congestive (arterial) hypercemia and a passive or stagnation (venous) hypercemia. Active hyperasmia arises from an increase of the afflux of Uood {congestion), and is either idiopathic or collateral. The first of these plays the more important role, and depends upon a relaxation 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 atropin, brief interruptions of the blood-current), or, finally, by diminution of the piressure hearing on the vessels. Collateral hyperemia is merely the result of a diminished flow of blood to other parts. It arises fii'st in the imme- diate 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 hyperasmia is accompanied by more or less marlied 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 channels 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 with blood. Passive hyperasmia is a consequence of retardation or obstruction of the flow of Hood 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 particularly 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 hmgs, lead to a pulmonary stasis ; the latter not infrequently reaching a degree that makes the damming back of the blood appreciable in the right side of the heart as weU as in the veins of the corporeal circulation (cf . § 34). 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 en- largement 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 bodUy 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 con- traetUity — these forces being insufficient to drive onward the column of blood which presses against the walls of the vessel. An inadequate aspiration through the respiratory movements makes itself felt when res- ACTIVE AND PASSIVE HYPEE^EMIA. Ill piration is interfered with by inflammation or other disease processes in the lungs or the pleura. A further cause of local passive hypersemia consists in the narrowing or closing of particular veins, as occurs in compression, ligation, the for- mation of thrombi (§ 39), 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 maj^ choke the cerebral sinuses or the femoral or the portal vein, or a sarcoma of the pelvis may grow into the great pelvic veins. Should any single vein become occluded by any of the above pro- cesses, 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 obstacle 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 passage of the blood — as, for instance, is the case with the radicles of the portal vein, with the sinuses of the dui-a mater, with the femoral or with the renal veins — then a greater or less degree of stasis occurs in the area of dis- tribution of the vein affected. The effect of the obstacle to the cii-culation shows itself first in the portion of the vein which lies between the obstruction and the periphery, the blood-current in this part becoming slowed or entirely checked, while at the same time, through continued af&ux 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, the circulation will remain intact, and, through such channels as it still finds open to it, the blood wiU flow on to the heart ; and 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 communi- cating vessels capable of dilatation are at hand, the circulation will be arrested, and a condition of complete stasis (§ 42) or of thrombosis (§ 39) win be brought about in the area of distribution of the obstructed vessel. If the arrest of the blood in the area of distribution of a vein extends to the capfllaries, so that these become distended with blood, this will impart a reddisJi-Uue, cyanotic hue to the surrounding tissues, and a cer- tain amount of stmlUng will take place in them. Both active hyperemia and passive hyperemia, observed during hfe, 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 hypersemia 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 (miless 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 112 LOCAL HYPEREMIA AND LOCAL ANEMIA. sinks to the most dependent parts, and fills not only the veins, but finally also the capillaries. The phenomenon is known as post-mortem htjpostam, and the spots are known as death-spots or livid spots {livores). They ap- pear as early as three hours 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 appa- rent 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 insuificiency, 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 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 phe- nomenon, likewise designated as hypostasis, is particularly observed in the lungs (hypostatic 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 expe- dient, 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 circula- tion 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 distended with accumulated red blood-corpuscles. After a certain time the tongue begins to swell through infiltration with transuded fluid. The frog's tongue and the web of the frog's foot are also weU adapted to the study of the circulation during active hypersemia and during ansemia. According to the investigations of Landerer,-|- the wall of a capillary vessel embedded 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. In active hypersemia as well as in passive hypersemia, the tension of the tissues and the pressure upon them are increased; in ansemia both are diminished. § 38. Localized ansemia or ischsemia 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 ]iormal, then the cause of the ischemia is purely local ; if there is an insufficient quantity of blood in the whole vascular system, the local insufficiency may partly depend upon that. The pathological diminution in the afflux of hlood to an organ is some- times merely the result of an unusual increase in the normal resistance of the arteries — that is, of a contraction of the muscular tunics. In other cases abnormal obstructions — such as compression of the arteries, narrow- ing of the arterial lumen through pathological changes in the vessel-waU, deposits on the internal surface of the vessels, occlusion of the vessels by emboli (cf. § 18), etc. — act as hindrances to the blood-current. * Cohnheim, Virch. Arch., 40. Bd. t " Die Gewebsspannung," Leipzig, 1884. LOCALIZED ANiEMIA OR ISCHEMIA. 113 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 obstruc- tion to an immediate standstill. If, back of the point of constriction or occlusion, the artery be provided with connecting branches of relatively considerable size — so-called collateral arteries — the disturbance of the cir- culation is abated 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 occluded artery pos- sess no communicating branch in its area of distribution — if it be 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 becomes 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 distribu- tion of the artery in question. Frequently, however, after a short time has elapsed, an afflux of blood comes from neighboring capillaries. When the current and the pressure beyond a constricted point have 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 corpuscles, particidarly, cease to move, and collect in the veins and capillaries, and as a consequence the area supplied by the artery in question beeomes filled with blood once more; only not with circulating, biit with stagnant blood. The same thing occurs tvhen, 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 capil- laries. An accumulation of blood within the anaemic area maj^ also occur by reflux from the veins. This occtu's when the intravascular pressure within this area has sunk to nothing, and when neither the weight of the blood nor the venous valves oppose the reflux of the blood. A further cause of anaemia in an organ may be the abnormal conges- tion of other organs, as in that case the total mass of the blood would not suffice to supply the remaining organs adequately. Anajmia 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 appears dis- tinctly under these circumstances. The significance of a condition of ischasmia 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. § 3). Complete arrest of the blood-supply leads in a short time to death of the tissue involved. If blood come to flow anew among the degenerated and dying tissues in the area of distribution of an obstructed vessel, and stagnate there, extravasation of blood into the tissues may follow, and a hemorrhagic infarct (cf. § 47) be formed. The rapidity and completeness with, which a collateral circulation may be de- veloped 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 ischsemic. If these are numerous and distensible, the ischsemic area becomes very soon irrigated with an approximately normal volume of blood. If this is not the case the disturbance of the circulation corrects itself much more slowly, 114 COAGULATION, THROMBOSIS, AND STASIS. and stasis and increased pressure are found to extend farther back from the point of obstruction toward the heart, so that the collateral circulation becomes established through vessels situated farther back on the course of the blood, i.e., nearer the heart. In the further course of the process of reestablishing the cir- culation, 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 becomes permanent, and leads in turn to a permanent disten- tion 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 anasto- motic vessels may be demonstrated about six days after the ligation of an artery; and after the ligation 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. III. Coagulation, Thrombosis, and Stasis. § 39. 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 occur at a time when the red blood-corpuscles are still evenly distributed in the blood, and the whole mass of the blood become coagu- lated, the clots form dark-red masses — a condition in which the blood is termed cruor. If before coagulation, through the settling of the red cor- puscles, the mass divide itself into a substratum rich in red blood-corpus- cles and an upper fluid layer containing none and consisting exclusivel3' of the plasma ; and then if the latter coagulate, there will be formed soft gelatinous lumps, and also fibres, light yellow in color, elastic, with a Fig. 6. — Part of the border of a recent hsemorrhagic infarct of the lung, a, Interalveolar septa without nuclei, containing capillaries filled with deep-violet thrombi of homogeneous appearance ; 6, Septa showing nuclei ; c, Vein contain- ing a red thrombus ; d, Alveoli distended by a firm blood-clot ; e, AlveoH flUed with serous fluid, fibrin, and leucocytes. (Specimen hardened in Miiller's fluid, stained with heematoxyhn and eosin, and mounted in Canada balsam. Magni fled 100 diameters.) COAGULATION OF THE BLOOD. 115 smooth surface, aud not adherent to the vessel-waU, wliich are designated as lardaceaus clots or as fihrinmis deposits. Through the inclusion of red blood-corpuscles in these formations, they may exhibit in parts a red or reddish-black color ; but when an unduly large proportion of leucocytes are present, the color at such spots will border on white. If blood be dratvii from an artery or a vein and received into a vessel, within a short time coagulation will occur, transforming the whole into a soft coherent mass. If freshlj^ drawn blood be beaten with a solid body, in a short time stringy fibrin will be separated from the surface of the blood. If ivithin the body blood be extravasated in considerable quantity into the tissties — for instance, into the pericardium or into the lungs — coagula- tion may occur here likewise, and among the red blood-corpuscles stringy masses are formed (Fig. 6, d, e), whose fibres run in the most varying directions, crossing one another continually, and frequently also proceed- ing 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 fibrinogenie stibstance, of a ferment, and of certain salts, especially calcium salts, is indispensable, and that the fibrinogenie substance is an albuminoid body, belonging to the class of the globulins, which is present in the blood, while the ferment is prob- ably derived from the white (possibly also from the red) corpuscles of the blood, which either are dis- solved in the blood-plasma, or yield to it certain constituents of their mass. 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 preexisting in the alkaline solu- tion, which body is precipitated by the calcium salts present in the plasma ; and in the process of coagulation we must recog- nize two stages — to wit, the stage of the production of the ferment and the stage of the fei-menta- tive action or coagulation prop- er. According to Pekelharing, on the other hand, the fibrin- fennent is itself a calcium com- pound which has the power of carrying lime over to the fibrino- gen, whereby from the soluble fi- brinogen an insoluble albiimin- ous compound is formed, con- taining calcium, which body is fibrin. If coagulation of the blood within the heart and the vessels take place during life, or if a solidifying mass separate from the circulating blood, this process is called thrombosis and its product a thrombus. Pig. 7. — Section through a red throm- bus formed in one of the muscular veins of the thigh after ooclusion of the femoral vein, a, Fibrin threads ; 6, Leucocytes and granular bodies. (Specimen hardened in Miiller's fluid, and stained with hasmatoxy- lin. Magnified 250 diameters.) IIG THROMBOSIS. If coagulation or thrombosis occur in a mass of blood deprived of motion, there is formed a darl<-red thrombus (Fig. 6, c, and Fig. 7), which, like the reddish-black post-mortem clots, or like the coagula of extravasated blood (Pig. 6, d), contains all of the red blood-corpuscles ; the precipitated iibrin forming granules (&) and fibres (a). Immediately after its formation the 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 in extravasation. Fig. 8. Fig. 9. Fig. 8. — Section of a white thrombus extending through the vena cava in- ferior, and containing but few cells, a, Granular mass ; h, Granular and stringy tibrin in retif orm arrangement ; c, Threads of fibrin in parallel arrangement. (Preparation stained with hsematoxylia. Magnified 200 diameters.) Fig. 9. — Section of a mixed thrombus of the aorta, rich in cells, a, Red blood-corpuscles ; h, Granular mass ; c, Retif orm disposition of fibrin with numerous leucocytes ; d, Threads of fibrin in parallel arrangement. (Prepara- tion stained with hsematoxylin. Magnified 200 diameters.) As was observed by Baumgarten, who found the blood in the vessels between two ligatures still fluid after an interval of weeks, the mere stag- nation of a mass of blood within a vessel is not sufficient to cause coagu- lation. The (tause of the coagulation of blood that is not in circulation lies probably in part in the fact that certain portions of the mass of blood are no longer in contact with a living and inviolate vascular wall, which con- tact, according to Briicke, normally prevents coagulation. At the same time the production of a Lu-ge amount of fibrin-ferment may provoke co- agulation. This occurs, consequently, in vessels which have been ligated, when the endothelium is destroyed at the point of ligation. It takes place. furthermo]'e, 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 produced by the injec- tion of ruby-red blood (larJcfarievefi BJiit) whose cells are in part broken up. The fibrinous deposits from blood in circulation, which not iufre- COAGULATION OF THE BLOOD. 117 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, accordingly, between white, mixed, and laminated thrombi. With the microscope we may discern that these thrombi are composed (Figs. 8 and 9) of granu- lar and fibrous masses and of colorless and red corpuscles, which in vary- ing proportions and arrangement make up their structui-e. The colorless thrombi consist almost exclusively of granular masses (Fig. 8, a) and of fibrogranular fibrin, the latter displaying at one point (h) a retiform ar- rangement of its fibres, while at another point (c) they run more nearly in a parallel direction. Both the granidar masses and the fibres of fibrin contain only a scanty sprinkling of leucocytes. Other white thrombi con- tain more cells. In the mixed thrombi (Fig. 9), granular masses (b), more rarely hyahue 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 numerous — ^leucocytes (Fig. 9). The fibrogranular masses which enter into the structui-e of the thrombi consist doubtless 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 thi'ombi 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 (Bizzozero, Eberth, and Schimmelbusch) a broad, homogeneous, red stream in the axis of the blood-vessel (Fig. 10, 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 recognizable; in the peripheral stream, however, isolated white blood- corpuscles appear from time to time (Fig. 10, 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 allows the observer to make out indistinctly the blood-corpuscles of the axial stream (Fig. 11, 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. 11, d), and they finally come to occupy this zone in considerable numbers. If the current be still further retarded so that the red blood-corpus- cles become clearly recognizable (Fig. 12, a),, then, in the peripheral zone, alongside of the white blood-corpuscles appear blood-plates, which in- crease more and more in number with the progressive retardation of the 118 THROMBOSIS. flow, wMle the number of the leucocytes becomes again diminished. "When total arrest of the blood-current finally occurs, a distinct separa- tion of the corpuscular elements in the lumen of the vessel follows. Fig. 10. Fig. 11. Fig. 10. — Quickly flowing blood -stream, a, Axial stream; 6, Peripheral stream with iso- lated leucocytes, d. (After Eberth and Schimmelbusch.) Fig. 11. — Somewhat retarded blood-stream, a, Axial stream ; 6, Peripheral zone with nu- merous leucocytes, d. (After Eberth and Schimmelbusch.) Fig. 12. — Greatly retarded blood-stream, a, Axial stream ; 6, Peripheral zone with blood- plates; c, A considerable col- lectioh of blood-plates; d,di, White blood-corpuscles. (After Eberth and Schimmelbusch.) When, in a vessel in which the circulation is retarded, the intima is injured at a certain point by compression or by violence, or by chemical agents such as corrosive suijlimate, nitrate of silver, or strong salt-solu- tions, and yet the lesion of the vessel-wall does not cause a complete ar- rest of the blood-current, we may observe (Bizzozero, Eberth, Schimmel- busch) Wood-plates adhering to the vessel-wall at the injured point, and before long they cover the site of the injury in several'layers. Frequently more or less numerous leucocytes, or colorless blood-corpuscles, become lodged in the mass (Bizzozero), and their number is proportionate to their abun- dance in the peripheral 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 irregu- larity of the circulation, or of extensive lesion of the vascular wall, red ilood-corpuscles also may separate from the circulation, and become adher- ent to the intima, or to a layer of leucocytes previously deposited upon it. Not infrequently portions of the separated mass are swept away, in which case a new deposit of blood-plates is formed. Through a long-continued deposition of the elements of the blood the vessel may finally become com- pletely closed. Should a blood-vessel suffer a lesion, as above described, while the cur- rent of blood within it still remains swift, there is no adherence of blood- plates or of blood-corpuscles. When at any point blood-plates have become adherent in considerable numbers, they become, after a time, coarsely granular at the centre, and finally granular or homogeneous at the periphery, and become fused together into one compact mass. The final result of the process is the formation of a colorless blood-plate thrombus, within which more or less numerous ivhite blood-corpuscles may CONGLUTINATION AND COAGULATION. 119 be imprisoned. Eberth designates the sticking together of the blood- plates by the term conglutination ; their final fusion into a coherent throm- bus he calls viscous metamorphosis. If we compare the observations of Bizzozero, Bberth, and Schimmel- busch, as well as the recent observations of Lowit, on warm-blooded ani- mals, with the histological findings in thi-ombi 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 observ^ed in the lower animals, and we judge that their formation is directly de- pendent 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 would direct the blood-plates against the vascular wall — and upon local changes in the ivall of the vessel. Probably, too, 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 caiises plays the principal part in the forma^ tion of the thrombi, or that all three may concur equally in the process ; and, on the other hand, that one of the causes alone is not ordinarily 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 (Pigs. 8 and 9), seems to denote that fibrin-ferment is set free in the for- mation of the blood-plate thrombus, and that hence, iu the neighborhood of the conglutinated blood-plates, a process of coagulation occurs in the circumjacent peripheral zone of the blood-stream. If white blood-corpus- cles alone are floating in the latter, the coagulating mass remains color- less (Pig. 8) and includes a greater or less number of leucocytes ; while if red blood-corpuscles be circulating in the peripheral zone, or if the in- fluence of the ferment extend as far as the axial stream, mixed thrombi will be formed (Pig. 9). According to Eberth and Schimmelbusch, fibrin enters into the struc- ture of artificially produced thrombi in those cases where thrombosis was provoked by the action of strong silver-solutions or by the introduction of foreign bodies. Kohler, von Diiring, and Hanau are of the opinion that the formation of many thrombi — as, for instance, those occurring in subjects who are in a condition of marasmus (Kohler, Hanau), or after traumatism (von Diiring) — is to be ascribed to the toxic action of a ferment, and that local disturbances of the circulation merely determine the point of the coagula- tion. Vaquez is of the opinion that infection plays an important part in the formation of thrombi in cachectic subjects. According to Naunyn, Franken, Kohler, Plosz, Gyorgyai, Hanau, and others, by the introduction of ruby-red blood {lackfarbenes Blut), of solutions of hffimoglobiii, of the salts of gallic acid, of ether, and of other substances into the circulation, more or less extensive coagulation may be produced ; neverthe- less the results of the experiments are not constant (SchiflEer, Hugyes, Landois, Eberth), and coagulation may not occur. The probability of effecting coagu- lation is proportionate to the degree of disturbance produced in the blood by the substance injected. A. Schmidt seeks the cause of coagulation after such 120 BLOOD PLATES. — FIBRIN FERMENT. injections in the fibrin-ferment. Eberth holds any such fermentation coagula- tion to be, at present, questionable, because it may likewise be produced (Edel- berg) without fibrin-ferment, and because the solidified masses formed after such injections do not consist exclusively of fibrin, but also of " conglutinated blood-plates," of precipitated albuminoid bodies, and of disintegrated blood- corpuscles. Such injections, therefore, yield very diverse products, and conse- quently the experiments made in this manner possess only a limited value as a means of interpreting the mode of origin of thrombosis in the human subject. According to Arthus and Pag^s, blood, as it flows from a vein, 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 1 per cent, solution of calcium chloride be added, coagulation takes place in from six to eight minutes, and the calcium salts enter into the constitution of the fibrin-molecule. The fibrin-ferment can act upon the fibrinogen only iu the presence of calcium salts. Under the influence of the fibrin-ferment, and in the presence of calcium salts, the fibrinogen undergoes a chemical metamor- phosis which results in the formation of a calcium-albumin compound — fibrin. For the occurrence of coagulation it is not necessary to invoke ' the aid of any peculiar flbrinoplastic, globulinoid substance, but there is need merely of the presence of calcium salts. The ferment which induces the coagulation is formed by the disintegration of cellular elements. Bizzozero, some years ago, described as a new component of the blood cer- tain minute, fiat, homogeneous structures which he designated as blood-plates and regarded as identical with the hsematoblasts described by Hayem. Relying upon profound experimental research, he concluded that it was these which, in breaking up, induced coagulation, while he decHned to attribute this property to the white blood-corpuscles. Rausehenbach, Heyl, Weigert, Lowit, Eberth, Schimmelbusoh, Hlava, Groth, and others have since then taken a stand against this doctrine of Bizzozero, as part of them deny any connection between the blood-plates and the coagulation of the blood, and part of them (Weigert, Hlava, Halla, and Lowit) do not regard the blood-plates as constant morpho- logical elements of the blood, but rather as the debris 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 without doubt be followed by coagulation, thus showing that the blood-plates are at least not the only pro- ducers of fibrin. According to Groth, for example, the injection of large num- bers of leucocytes into the circulation produces thrombosis. According to Rausehenbach, the dissolution of leucocytes is constantly occurring in the blood; but by an inhibitory action of the organism the supervention of coagulation is prevented, and the flbrin-ferment is either destroyed or rendered ineffectual. In an essay published in the year 1875, Zahn first undertook a strict differ- entiation of the red from the white and the mixed thrombi, and showed that the first arose from coagulation of the blood, and the latter, on the other hand, from a deposit from blood in circulation. The colorless substance in the white and in the mised thrombi, Zahn, basing his opinion on experimental research and on direct observation of the process of thrombosis in the blood-vessels of the frog, regarded as formations which were produced from white blood-cor- puscles which had become separated from the blood-stream, then had become adherent to rough points on the vessel-waU, and finally had become fused together into a homogeneous or a granular mass. Up to a few years ago most authors coincided with these views, although since the investigations of Bizzo- zero, Lubnitzky, Eberth, Schimmelbusoh, and Lowit there can be no doubt of the existence of the blood-plate thrombus also, into whose composition the white blood-corpuscles enter in but unimportant proportions. Eberth and Schimmel- busch do not look upon this process as a coagulation — a physical change which they, in common with Eichwald, regard as a precipitation or a crystallization— but as a process peculiar to itself, as a conglutination and viscous meiamorpliosis CONGLUTINATION AND COAGULATION. 121 of the blood-plates. According to Eberth, the adhesion of the blood-plates to the vessel- wall follows only upon an irreparable alteration of the latter. The adhesion of the leucocytes is, on the other hand, a vital process. According to Lowit, the blood-plates are not a constituent of normal blood, but rather make their appearance under definite conditions, and are nothing more than globuhn precipitated in the form of plates. For their appearance very slight alterations in the circulation or in the composition of the blood suf- fice, and it is therefore difiS^cult to make observations upon blood ia circulation without causing them to appear ; it is nevertheless possible, with proper pre- cautions in iavestigating, to prove that the blood cu'ciilatiug through the mesen- tery of the mouse contains no morphological elements beyond the red and the white blood-corpuscles. Alterations of the vessel-wall and retardation 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 metamorphosis into a substance closely resembling ordinary fibrin, become comparatively insoluble, swell up, and take on a partly granular appearance. The fibrin derived from the blood-plates is very like ordinary fibrin in its capa- city for taking dyes, and the formation of a blood-plate thrombus is also, iadeed, a kiud 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 globuhn is precipitated in a granular condition. 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 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 vascxdar walls and retardation of the blood-current in cold-blooded animals lead to the formation of thrombi consisting essentially of leucocytes and capa- ble of transformation into granular masses. At the beginning of cell-deposi- tion we find the spindle-shaped leucocytes deposited with especial frequency. According to observations made by Wlassow, in my laboratory, I feel my- self justified in adopting the opinion that the blood-plates are a product of the red blood-corpuscles, and either are thrown ofE from the bodies of degenerating red blood-corpuscles, or are formed on the disintegration of the same. Wlassow studied both the early stages of thrombus-formation and also the behavior of the blood-corpuscles when treated with various fluids, and his observations in- dicate, on the one hand, that at the beginning of a thrombosis in circulating blood red blood-corpuscles do become adherent to the vessel-wall and may subsequently become changed and transformed into a granular mass, and, on the other hand, that a portion of the red blood-corpuscles — presumably those which are the oldest and are approaching their decadence — are extremely un- stable cells, out of which structures with properties corresponding to those of the blood-plates are readily formed. As to whether such structures are devel- oped under normal conditions, or whether, in the normal breaking down of the red blood-corpuscles, the colorless components of their structure enter imme- diately into solution, could not be decided; this much only could be demon- strated : that the most diverse influences caused a plasmosehisis (a splitting up of the blood-plasma), accompanied by a formation of the so-called blood-plates. A. Schmidt, in his work on the blood, published in 1892, wherein he collects the results of many years of study on coagulation, regards the fibrin-ferment or thrombin as a derivative of the hfe of the cells, which is developed from an in- active earher state, prothrombin, under the influence of certain zymoplastic sub- stances. In the same way he regards the fibrinogenous substance, or metaglobulin, as a product of the disintegration of cellular protoplasm. If this view be cor- rect, and if the investigations of Wlassow find further corroboration, then the generators of coagulation, as well as those of thrombosis, must aU 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 122 THROMBUS-FORMATION. directly proportional to tlie 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 coagiilation. 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 relative, depending upon the amount of ferment present. No value can therefore be ascribed to the fluidity of the blood in the diagnosis of the mode of death. § 40. Thrombosis occurs most frequently in cases of degeneration and inflammation of tlie intima of the heart and of the vessels, as well as under certain circumstances which, like compression, stricture, or dilata- tion of the vessels, fattj^ infiltration and fatty degeneration of the heart, stenosis and insufficiency of the valvular orifices, etc., cause a retarda- tion or an arrest of the circulation. If thrombi occur in cachectic indi- viduals, 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 re- Fig. 13.— Thrombus-formation in the heart as a result of inflammatory degeneration and aneurismal dilatation of the heart- waU. a, Inflammatory thickenmg of the endocardium; 6, Inflammatory degeneration of the myo- cardium ; e. Thrombus. (Two-thirds natural size".) VARIOUS FORMS OF THROMBI. 123 lations to the vessel containing them. Thus a parietal thrombus is one attached to the wall of the heart (Fig. 13, c) or of a vessel ; a valvular thrombus, one which is situated upon a valve of the heart or of a vein (Fig. 14, d). Either kind may consist only of dehcate, transparent, almost membranous and hyaline deposits ; and then, again, they are often thicker and tougher, and project into the Ixunen of the heart or blood-vessel, as the case may be. Their surface, in the latter case, often shows rib-like ridges of paler appearance than the other parts. If the lumen of a ves- sel becomes closed by a thrombus, the latter is spoken of as an obturat- ing thrombus (Fig. 14, a, h). The coagula first formed are designated as primary or autochthonous ; those subsequently deposited upon these, as induced thrombi. Through growth by accretion a parietal thrombus may become obturating. In such a case it not infrequently happens that a red thrombus is superadded to one originally white or mixed in color (Fig. 14, c), inasmuch as the thrombosis began in circulating blood, whUe later, after the closing off of the vessel, the blood became stagnant and the whole mass then coagulated. The opposite occurs when a red throm- bus, 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 appen- dages and in the recesses between the trabeculee caimeae, as well as on any diseased spot of the heart-wall (Fig. 13, c), that they establish themselves. Their formation starts in the deep in- tertrabecular recesses; but through continual accretions more consider- able coagulation-masses are formed, which project in the form of polypi above the general surface, and there- fore 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 sur- face is often ribbed. As a rare occur- rence, large globular or pear-shaped thrombi may become loosened, and then, in case they cannot pass the os- tium, they lie free in that chamber of the heart (most frequently an auricle) in which they had their origin. 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 Fig. 14. — Thrombosis of the femoral and of the saphenous vein, a, b, An obturating thrombus, of mixed coloring and laminated ; c, Eed thrombus with peripheral attachment ; d, Thrombus protruding from a valve. (Reduced one fourth.) 124 THROMBUS-POEjVIATION. size by tlie deposition of fresh layers of fibrin after they have been set loose. If coagulated 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. 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-degenerated intima, parietal thrombi, white, or of a mixed color, and superficially adherent, are formed in the aorta. In the veins thrombi occasionally are formed in the pockets of the valves (Fig. 14, cl), from which they gradually pro- trude 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 instance, a thrombus having its origin in one of the lesser veins of the lower extremity may grow up through the vena cava inferior iintil it reaches the heart. Thrombi of the smallest vessels arise most frequently in consequence of disease of the sitrrounding tissues, and especially after infections and toxic inflammations and necrotic processes, and they have, for the most part, a hyaline composition, though by proper technique ( Weigert's fibrin- stain) it may often be demonstrated that they are made up of stringy fibrin and blood-plates. They are found, furthermore, after superficial burns (Klebs, Welti, Silbermann) and after poisoning — for instance, poisoning with corrosive sublimate (Kauf mann) — especially in the lungs. They fre- quently exist in litem orrhagie infarcts (Fig. 6, c) which are already of a certain age. Thrombi, too, originating in the capillaries, may develop in the efferent veins, partly for the reason that through the obturation of a great number of capillaries the blood flows slowly into the veins, and partly, also, for the reason that disintegrating blood-corpuscles and blood-plates find their way to the veins in great numbers. As a matter of course, impermeability of the capillaries and constriction of the arteries, due to any other causes, produce thrombi in the first of these two ways. § 41. The first deposits in the formation of a thrombus are dehcate, transparent, or whitish layers. The fully formed thrombus is a com- pact, 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 process of con= traction, and thereby become firmer and more dry. In this way, in ease 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 eventually becomes calcified. This occurs both in valvular thrombi and in those located in the vessels. Chalky concretions in the veins, known as phlebo- liths, are formed in this way. Similar formations in the arteries, which occur, however, less frequently, we may call arterioliths. Shrinking and calcification constitute a comparatively favorable issue of thrombosis. Far less favorable are the various kinds of disinte- gration which frequently follow and are known as simple and as puriform or septic yellow softening. In the simple softening the central portion of the thrombi becomes converted into a grayish-red, gray, or grayish- SOFTENING AND ORGANIZATION PROCESSES IN THROMBI. 125 white gi-umous mass, consisting of broken-down and shrunken red blood- corpuscles, pigment granules, and colorless granular debris. If the soft- ening extends 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 softening d6bris are swept along into the circulation. This occurs both with heart-polypi and with venous thrombi, especially when the tip of a thrombus in a small vein projects into the lumen of a larger vein through which the blood stUl flows freely. A frequent result of such softening is the formation of emboli (cf. Fig. 2, page 41). In the yellow puriform or septic softening the thrombus breaks down into a yeUow or grayish-yeUow or reddish-yellow mass similar to pus, grumous, creamy, and foul-smelling, which along with pus-corpus- cles contains a great deal of a finely granular substance made up of fatty and albuminous detritus and micrococci. This mass acts as a destructive irritant, causing inflammation by its contact. As a result the intima be- comes cloudy, and a suppurative inflammation arises in the media and adventitia, as well as in 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 eventu- ally supervenes. If the puriform masses are carried along by the blood- current to other places, there too they lead to necrosis and septic disin- tegration of the tissues, and to suppurative inflammation, which affects not only the wall of the vessels, but also the circumjacent tissues. The process of puriform softening of a ve- nous or an arterial plug, coupled wath the infil- tration of the vascular wall, is denominated thrombo=phlebitis purulenta or thrombo=ar= teritis purulenta. The inflammation of the vessel-wall may start either in the softening thrombus or else in the parts adjacent to the vessel. In the latter case the softening of the thrombus either goes on simiiltaneously with the inflammation of the vessel-wall or else suc- ceeds it. These occurrences take place most fre- quently in the neighborhood of purulent foci. The most favorable issue of thrombosis is in the organization of the thrombus — that is, in its being replaced by vascularized connective tissue. The new connective tissue is developed from proliferating endothelial cells ; but if these have been destroyed, then plastic migratory cells arrive from the outer layers of the vessel-waU. The thrombus itself takes no part in the process of organization ; it is a lifeless mass exciting in- flammation in surrounding parts. In course of time the thrombotic mass becomes absorbed, and its place is taken by vascularized connective tissue (Fig. 16, cj). Fig. 15. — Eemains of a thrombus of the right femoral vein, termed three years before death, a, Obliterated portion of the vein (the right common iliac vein was likewise obliterated) ; 6, c, d, Bridles of connective tissue in the interior of the vein and of its branches; e, Eeoent thrombus. (Natural size.) 126 THEOMBI REPLACED BY VASCULARIZED CONNECTIVE TISSUE. The cicatricial tissue occupying the place of the thrombus shrinks more or less in course of time. Cicatrices 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 thickening of the wall of the vessel, or there may remain only threads and trabeculas (Pig. 15, h, c, d), which cross the lumen of the thrombosed vessel, so that the blood-current can once more pass the affected spot without serious impediment. It not infre- FiG. 16. — Portion of the edge of a pulmonary infarct with obliteration of the artery in the process of heaUng. a, Extravasated blood changed into yel- lowish granular masses ; 6, Necrotic interalveolar septa without nuclei; c. Newly formed connective tissue ; d, vascular granulation tissue within the alveoli ; /, An artery ; g, Vascularized connective tissue occupying the place of an embolus in the artery. (Specimen hardened in Miiller's fluid, stained with haematoxyhn, and mounted in Canada balsam. Magnified 45 diameters.)* quently happens, nevertheless, that the connective-tissue bridles crossing the lumen of the vessel cause a marked lessening of its calibre ; and this may proceed to a complete obliteration of the vessel, so that the blood- * Near the top of the cut, right and left, are structures marked e. No description of them is given in the original. They appear to represent newly formed vascular loops with nucleated endothehum, pushing their way into the granular masses, o, a. — Translator's Note. FORMATION OF EMBOLI. 127 vessels for a greater or less distance become converted entirely into solid fibrous cords. Pieces broken off from a thrombus and carried into an ai-tery and there wedged— so-called emboli— generally induce fresh deposits of fibrin upon their surface (Fig. 2, c, page 41). Afterwai-d they undergo the same changes as thrombi, and may either soften and break down or become shi-unken (Fig. 17, a) and calcified. If the emboli are non-infectious they generally become replaced hj vascular connective tissue (Fig. 16, g). In many cases this new formation of connective tissi^e leads to the oblit- eration of the artery (Fig. 16,/, g). 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 thiekenuig of the intima. In still other cases the lumen of the vessel is traversed by Fig. 17. — Remains of an emboHo plug of a branch of the pulmonary artery, a. Shrunken embolus traversed by threads of connective tissue ; 6, Bridles of connec- tive tissue crossing over the orifices of branch vessels. (Natural size.) Fig. 18. — Embolus of an intestinal artery with suppurative arteritis, em- bolic aneurism, and periarteritic metastatic abscess, a, h, c, d, e, Layers of the in- testinal wall ; /, Wall of the artery ; g, The embolus, surrounded with pus-corpus- cles, lying within the dilated and partially suppurating artery; h, Parietal thrombus ; i, Periarterial purulent infiltration of the submucosa ; Jc, Veins gorged with blood. (Specimen hardened in alcohol, stained with fuchsin, and mounted in Canada balsam. Magnified 30 diameters.) 128 STASIS OR STAGNATION OP THE BLOOD. bridles of connective tissue (Pig. 17, 6), which eitlier run separately, or, through mutual interlacings, 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. 18, 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 acti'^'e, congestive form the velocity of the blood-current is increased ; in the passive form — venous hypersemia — it is diminished. If the passive form become 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 standstill ; and that condition then obtains which is known as stasis or stagnation of the blood (Fig. 19). Inasmuch as fresh masses of blood from the ar- teries strive with each pulse-beat to force their way into the area of stag- FiG. 19. — Stasis from venous hyperseinia in the vessels of the cerium and of the papillae of the plantar surface of the toes in a man succumbing to valvu- lar disease, heart-failure, and arteriosclerosis. Deep-violet coloring and com- mencing gangrene of the toes. (Specimen hardened in Miiller's fluid, stained with alum carmine, and mounted in Canada balsam. Magnified 20 diameters.) CEDEMA AND DROPSY. 129 nation, 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 diver- gence of the nearest permeable artery (von Recklinghausen), and by this means a great portion of the fluids of the blood is pressed out of the capil- laries 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 (Fig. 19). 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-corpuscles 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 lieat and cold, irritation with acids or ivith alkalis, 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. According to von Recklinghausen, these agents accomplish their untoward results chiefly in abstracting water from the blood and from the vessel- wall. Possibly the composition of the blood-corpuscles and of the blood- plasma becomes, ftirthermore, so altered that the blood-corpuscles become less mobile (von Recklinghausen). The stasis which occurs in tissues which are taken from the interior of the body and exposed to the air is to be ascribed to evaporation. Through the operation of heat and cold, it is highly probable that changes occur not only in the vessel-wall, but also in the constitution of the blood. Many chemical agents so damage the vessel- walls that the frictional equation becomes greater, while at the same time the wall itself becomes more pervious. IV. CEdema and Dropsy. § 43. The unconflned fluid which permeates the tissues is essentially a transudation from the blood, though, under some circumstances, a por- tion of the juice contained in the cells and fibres may also pass over into the unconflned fluid of the tissues (Heidenhain). The exudation of fluid from the vessels is not a process of simple flltration, but is rather to be regarded as a process of secretion (Heidenhain) effected by means of the specific function of the capillary walls. The fluid secreted from the capillaries, which becomes mingled with the products of tissue-metabo- hsm, is absorbed by the lymphatics from the interstices of the tissues, and is returned to the veins through the ductus thoracicus. Bveiy increase in the transudation of the blood-fluids 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 lymphatics. This equilibration, however, has its limits ; with increased transudation from the blood-vessels we get a more or less permanent oversaturation of the tissues with the transuded fluid. That condition which is produced by this collection of fluid in the tissues is known as oedema or as dropsy, and we distinguish between a general and a limited dropsy according to the extent of the affection. CEdema extending over superficial portions of the body is known as anasarca or as hyposarca. 130 ANASARCA. — HYPOSARCA. — ^ASCITES. That portion of the Hood which is transuded from the vessels 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 circumstances, the formation of vacuoles (Pig. 20), due to the accumulation of drops of fluid within the cells or their derivatives. Fig. 20. — Longitudinal section through the oedematous muscle-fibres of the gastrocnemius of a subject with chronic oedema of the legs. (Specimen hardened in Flemming's acid-mixtuie, stained with safranine, and mounted in Canada balsam. Magnified 45 ~ diameters.) This may be most frequently demonstrated in tegumentary and in glandular epithelium, but becomes evident also in other tissue-elements, particularly in muscle-fibres (Pig. 20), whose fibrillBe become separated by drops of fluid. It may happen, moreover, that cells in oedematous tis- sues, particularly in the lungs and the serous membranes, become loos- ened from their attachment, and the fluid comes to contain an admixture of epithelial and endothelial cells in considerable numbers. Tissues which are the seat of oedema appear swollen, though the de- gree 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 oedema. Its appear- ance is then pale, it has a doughy feeling, and upon pressure with the fin- ger an indentation remains behind. An incision sets free an abundance of clear liquid and reveals the tissues thorouglily saturated 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 oedema, become filled with liquid, which, on pressure, escapes from a cut surface, mingled with air-bubbles. Par less capable of i-etaining fluids is the kidney ; consequently but little fluid flows off on section of an oedematous kidney, though the cut surface is moist and glistening. The amount of blood contained in oedematoustissues is variable, and their color is consequently so also. Such cavities of the body as are the seat of dropsical effusion contain at one time a considerable, and at another a very small amount of clear, generally hght-yeUow, rarely quite colorless, alkaline fluid, which occa- sionally contains a few flakes of fibrin (cf. the section on Inflammation). 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 pm-e 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 transudates 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, OEDEMA AND DROPSY. 131 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 consideration, and of the water contained in the cells and in the fibres — ^the tissue-fluid proper. This tissue-fluid may, under certain circum- stances, undergo considerable variations, 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) become greater, both blood and lymph 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 between the blood and the lymph is accomplished with the aid of a force inherent in the capillary cells ; that is, it is not a phe- nomenon of mere diffusion. The evidence of this lies in the fact that the pro- portion of salts or of sugar in the lymph is oftentimes greater than that in the blood. § 44. According to the etiology we distinguish four varieties of osdema — namely, the oedema of stagnation, inflammatory (edema, Jiydrmmic cedema, and the oedema ex vacuo. The oedema of stagnation is the result of a partial stagnation of the blood-circulation. If in any manner the outflow of venous blood be im- peded, if the obstacles impeding the blood-flow exceed a certain limit, the fluids of the blood then seek a lateral outlet and escape 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 increase of pressure in the veins the proportion of albumin rises (Senator) ; the fluid, furthermore, contains 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 do not so suffice, the fluid collects in the tissues and we have a condition of cedema 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 pressiu"e to which they are subjected. Obstruction to the flow of the lymph, as expeiiments in this Kne have shown, is not ordinarily succeeded by oedema. In the fii'st place, the lymph-vessels in the various parts of the body have elaborate anastomoses, 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, pro- vided 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 oedema, 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. * " Versuohe und Fragen zur Lehre von der Lymphbildung " [Essays and Queries Regarding the Theory of Lymph-formation] , Arch. f. d. ges. Physiologie, 49. Bd., 1891, and Verh. des X. internat. med. Cong., ii., Berlin, 1891. 132 DIFFERENT VARIETIES OF (EDEMA. Although lymphatic obstruction is not ordinarily sufficient to cause oedema of itself, yet it does increase an oedema already produced by ex- cessive transudation from the blood-vessels. The amount and the character of the fluid which escapes from the capillaries and the veins are not dependent merely upon the intravascu- lar pressure and the degree of obstruction to the blood-current, but also upon the constitution of the vessel-wall. Therefore not only disturbances of the circulation, but also changes in the vessel-ivall, and in the endothehum in particular, may lead to an increase or to a diminution of the transuda- tion. Indeed, as the outcome merely of long-continued obstruction aud the resulting imperfect renewal of the blood, but stiU more in consequence of chronic ischwinia, of imperfect oxygenation or of chemical changes in the Mood, or by reason of the effect of high or low temperatures or of traumatic lesions, etc., the walls of the vessels may become more pervious to the fluid as well as to the corpuscular elements of the blood. Just what changes the vessels suffer under these circumstances we are not able to state pre- cisely, but it is proper enough to suppose that injury to the endothelial cells and to the cementing substance between them is the most important part of the lesion. If through these influences oedema arise, then we may distinguish, according to the cause, toxic, infectious, thermal, traumatic, ischaemic oedema, etc., and such a di^dsion would have much to commend it. Hitherto the kinds of oedema here under considera- tion have generally been relegated to two groups, inflammatory oedema and cachectic oedema. Inflammatory oedema is most undoubtedly to be referred to an altera- tion in the wall of the vessel, and is seen both as an independent affection, in the shape of circumscril3ed 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 collat- eral oedema. Inflammatorj^ oedema is differentiated from the oedema of stagnation in that the transuded fluid holds far more albumin in solution and is much richer in white blood-corpuscles, and, furthermore, in that considerable coagula occur in it (cf. the section on Inflammation). 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 hydrsemic or cachectic oedema, it was long thought that hydraamia proper — i.e., diminution of the solids of the blood- — as well as hydrtemic 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 con- taining a larger amount of albumin. The vessel-walls are not, however, lifeless animal membranes, but are to be regarded as a living organ. Hydi-aemia, experimentally produced, is not, according to Cohnheim, fol- lowed by oedema ; and even when we succeed, through the production of hydrffimic plethora — i.e., through overfilling the vascular system with watered blood — in obtaining an increased transudation from the vessels, and eventually oedema, this oedema supervenes only after the proportion of watei' in the blood has become very large, and, moreover, it does not develop in the same localities where the so-called hydrfemic oedema in man develops. We are driven, then, to assume that the oedema of cachectic individuals, as weU as that of "nephritics" — i.e., of individuals whose renal function is imperfect — is due essentially to an alteration of the vessel- CEDEMA AND DROPSY. 133 walls, an alteration caused either by the hydrated condition of the blood or by a poison circulating in that fluid. Probably other lesions of the tissues should be considered in this connection (Landerer) — lesions which diminish the elasticity of the tissues. Under these conditions the hydnemia indeed favors the appearance ofcedema, but is not the sole cause thereof, nor does it determine the site of the same. Hydra3mic oedema is distinguished from inflammatory oedema by the facts that the transudate is less rich in albumin, and that it contains cor- puscular elements in smaller proportion. (Edema ex vacuo occurs principally in the cranial cavity and in the spinal canal, and arises in all cases where 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 Cohnlieim and Liehtheim, injection of aqueous solutions of salt into the vascular system of dogs * — hydration of the blood — does not produce oedema. 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, however, not universally — for instance, not in the extremi- ties. In an advanced state of hydrsBmic plethora the abdominal organs become oedematous, but never the extremities. Control-experiments recently made by Franeotte conftrm the observation that hydrsemic plethora artificially induced in the lower animals results directly in dropsy of the abdominal organs ; but Fran- eotte obtained oedema also of the skin and of the subcutaneous ceUular tissue. The view that the so-called hydreemic oedema is merely the result of an in- crease of the absolute amount of water in the blood is championed especially by von Recklinghausen and recently by Pisenti also. The distribution of the dropsy is, according to von Recklinghausen, essentially dependent upon bodily position, external pressure, obstructions to circulation, difference in innervation of the several vascular areas, and upon the consequent difference in the fulness of their vessels. I can subscribe to these opinions only in so far as they apply to the modify- ing factors named, not, however, as regards their general drift. Opposed to this are not only the experiments of Cohnheim above referred to, but also the fact that in nephritic as well as in cachectic subjects oedema not infrequently appears at a time when no hydrsemic plethora is present, and the further fact that, with hydrsemic plethora, oedema 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 oedema. According to Lowit, for the development of an oedema 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 limgs, which, moreover, must persist for a certain length of time. According to Heidenhain, the specific function of the capillary walls plays a controlhng 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 capdlaries and cause a discharge of tissue-fluids into the lymph has already been mentioned in § 43. Heidenhain has, however, found substances which, when injected, in- crease the transudation of water from the blood-vessels into the lymph. This may be accompUshed, 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-albumin ; and by these means the quantity of lymph flowing * Virch. Arch., 69. Bd. 134 HEMORRHAGE AND THE FORMATION OF INFARCTS. from tlie ductus thoraeicus may be increased from five to six fold. There is also a concomitant increase in the proportion of organic matter in the lymph. The exciting substance must then stimulate the function of those cells in the capillary walls which secrete the lymph. If we reason from these observations, it seems very probable that many skin-affections described as neuropathic, and character- ized by cutaneous hyperaemia accompanied by cedematous swelling — as, for ex- ample, urticaria, erythema nodosum, and herpes zoster — are to be regarded as intoxications 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. liasmorrhage and the Formation of Infarcts. § 45. By haemorrhage we understand tlie 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 once. The blood which has escaped from the capillaries is termed an extravasate ; at the same time, for the various forms of haemorrhage there are a great variety of names in use. If the hgemorrhagic foci are small and form more or less sharply defined, punc- tate, red or reddish-black spots, we designate them as petechice or ecchy- moses ; if they are larger and less clearly defined, as snggillations 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 Jimmorrhagic infarct. If the blood forms a tumor we speak of it as a hmmatoma, or a blood-tumor. Considerable hfemorrhages are always coupled with a pronounced alteration of the tissues ; not infrequently the tissue is broken down for a considerable distance (as may be the case with the brain). If the haemorrhage occur at the free surface of an organ the blood either escapes externally or is poured out into the cavitj^ surrounding the organ. Haemorrhage from the mucous membrane of the nose is called epis- taxis; vomiting of blood, Jicentateinesis; bleeding from the lungs, liiemoptoe or licmioptysis; from the uterus, metrorrhagia or menorrhagia (during menstruation) ; from the urinary organs, hcematuria. A collection of blood in the uterus is designated as luemafometra, in the pleural cavity as hcemotJiorax, in the tunica vaginalis testis as Juema- tocele, in the pericardium as hcemopericardium. Recent extravasations of blood have the color characteristic of arterial or of venous blood. Later, the extravasate undergoes various alterations, which are partiei^larly characterized by color-changes. Subcutaneous snggillations become first brown, then blue and green, and finally yellow. In course of time extravasates become absorbed again. (For more par- ticular treatment of this subject, see the chapter on Heematogenous Pig- ment-formation, iu Section IV.) Escape of blood from the vessels occurs in two different ways. Sud- den hfemorrhages are always connected with interruption in the continu- ity of the vessel-wall, and are therefore called haemorrhages per rhexin or per diabrosin. This is the only form of arterial haemorrhage. From the capillaries and the veins hemorrhage may occur, on the other hand, in still another manner — to wit, per diapedesin ; that is, by a process in which the blood passes through the vessel-waU without any previous rent in the same. In this case the blood-corpuscles make their way one after RUPTURE OF BLOOD-VESSELS. 135 another through the vessel-wall, while at the same time there is an escape of fluid ; yet not of unaltered blood-plasma, but of fluid less rich in albu- min (cf. § 44). Such hsemorrhages are often quite small and of inconsider- able extent ; in other cases the process continues for a longer time, and the infiltration of the tissues with red blood-corpuscles becomes very ex- tensive. Haemorrhages by diapedesis are not always small, and hsenior- rhages by rhexis not always great. Rupture of a capillai-y 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 hsemorrhage has taken place by rhexis or by diapedesis. In suitable objects the phenomenoii of diapedesis may be observed, imder the microscope. For this purpose we make use of the frog's m.eseiitery or of the web of the frog's foot (Cohnheim). 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.* Heringf 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-waU by pressui-e. Exhaustive investigations in regard to diapedesis of the red blood-corpus- cles, as well as in regard to the escape of other anatomical elements within the blood-vessels, have been carried on by Arnold.t He thought first that we must admit the presence of gaps in the endothehal tube at the points of exit of the corpuscular elements, and he designates these gaps as stigmata and stomata. He subsequently recognized the supposed openings to be but accumulations of the intercellular cement-substance between the endothelial cells. Under patho- logical conditions this cement-substance becomes softened and permits the pas- sage of the red blood-corpuscles. § 46. The causes of interruptions in the continuity of the vessel= walls are partly mechanical injury, partly increase in the intra vascular pres- sure, partly disease of the blood-vessels. Increase in the blood-pressure in the capillaries is suiJicient of itself to cause capiUary rupture without the aid of vascular changes, especially in cases of marked obstruction. Sound arteries and veins, on the other hand, cannot be dilated to the point of rupture by the mere rise of blood-pressure ; diseased or abnormally thin- waUed 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 permeaMlity of the vessel-ivalls. If the outflow of venous blood in a given vascular area is totally interrupted, diapedesis of the red blood-corpuscles from the capillaries and veins starts up here and there ; this is to be regarded as the result of the increase in intravas- cular pressure. The exodus of blood-corpuscles through vascular degen- eration 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 heemoi'rhage the condi- * Cf . Cohnheim, " Allgemeine Pathologie," I. Th., and Virchow's Arch., 41. Bd, t Sitzungsber. d. Wiener AJcademie, 1868, 57. Bd. t Virchow's Arch., 58., 62., and 64. Bd. 136 ACQUIRED AND CONGENITAL HiEMORRHAGIC DIATHESIS. tion is called one of hsemorrhagic diathesis, of which we recognize a congenital and an acquired form. Thecongenital h£emorrhagicdiatliesis and congenital haemophilia,* as has already been stated in §§ 30 and 31, belong to the hereditary dis- eases and have their cause probably in an abnormal constitution of the vascular walls, on account of which the aflieted subject has a marked disposition to bleed, and prolonged, uncontrollable haemorrhages follow after petty injuries. It is nevertheless possible that the constitution of the blood is also in some way altered. An acquired haemorrhagic diathesis attends those diseases known as scurvy, morbus maculosus Werlhofii, purpura simplex, pi^rpm-a (peli- osis) rheumatica, purpura hemorrhagica, and hemophilia and melaena neonatorum, and furthermore plays a part in many infectious diseases and intoxications — e.g., septicaemia, endocarditis, malignant pustule, spotted typhus, cholera, smallpox, the plague, acute yellow atrophy of the liver, yellow fe^•er, nephritis, phosphorus-poisoning, snake-bites, etc. — and also, finally, in pernicioiis anaemia, leucocythaemia, and pseud o-leucocythemia. The cause of the diseases named in the first group — in all of which the occurrence of haemorrhages in the skin, as well as in the mucous mem- branes, and in the parenchyma of other organs and tissues, constitutes a prominent symptom — is ordinarily supposed to lie in a general dis- turbance of nutritinH and circulation, although many 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 fre- quently been found in these latter affections also — that is, in purpura hemorrhagica and also in hemophilia neonatorum. In this connection we must refer particidarly to the investigations of Kolb, Babes, G-artner, Tizzoni, and Clio vannini, who have foiind in those suffering from these dis- eases 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 changes in the walls of the vessels, caused by localized growths of bacteria, partly by the injurious influence of toxic substances 2}i'o- duced by the bacteria themselves. In this case thej^ should in part be reck- oned among the hemorrhages of intoxication. The hemorrhages occurring in conditions of anemia are to be re- garded as a consequence of anemic 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 raso-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 menstrua- tion, many forms of nasal, intestinal, and bladder hemorrhage ; further- more, bleeding from the skin (stigmatization), from the breasts, from hemorrhoids, from wounds, etc. "Here also are to be reckoned a por- * The wording of the original text clearly makes these out to be two sepa- rate diseases; and yet it would seem as if the "and" should he supplanted by an " or," the text then reading — " congenital heemorrhagic diathesis or congenital hffimophiha." — Teanslator's Note. DISTUEBANCES IN THE CIRCULATION. 137 tion of those pulmonary haemorrhages 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 hypersemia and to the escape of blood in the lungs. Lastly, there occur in brain-disease — particularly in disease of the crura cerebri — gastric and intestinal haem- orrhages which are dependent upon the cerebral lesion. According to von Preuschen, the gastric and intestinal haemorrhages occurring during the first days of life, and known as melaena neonatorum, belong to this category, inasmuch as during labor haemorrhages and ecchymoses are not infrequently produced in the brain, in consequence of which the intestinal haemorrhages foUow. By others, on the contrary (Gartner), melsena neonatorum is classed among the infectious diseases. § 47. When an artery is suddenly closed by thrombosis, or by em- bolism, or by ligation, or by any other means, there occurs behind the obstructed point, as has 'already been stated in § 38, an arrest of the cir- culation, after the vessel has more or less emptied itself by the contrac- tion of its walls ; while from the point of obstruction back to the point of divergence of the nearest arterial branch the blood-pressure increases. If the branches of the artery behind the point of obstruction have free arterial communication with some other unobstnicted artery, this latter by becoming dilated is able to caiTy a supply of blood sufficient for the Fig. 21. — Part of the edge of an anaemic infarct of the kidney, a, Normal uriniferous tubules in a normal stroma; ffli, Normal uriniferous tubules in a stroma infiltrated with cells ; 6, Normal glomerulus ; c, Necrotic tissue without nuclei, with granular coagula in the tubules ; d, Necrotic glomerulus, swollen and with few nuclei ; e, Uriniferous tubules without nuclei, in a stroma with nuclei still persisting; /, Necrotic tissue with cellular, and, g, with hasmorrhagic infiltration. (Specimen hardened in Miiller's fluid, stained with hfematoxylin and eosin, and mounted in Canada balsam. Magnified 50 diameters.) 138 HEMORRHAGIC INFARCTS. area of distribution of the obstructed vessel, and the arrested circulation is thus restored. 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 anasmic 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 (Pig. 21, c, (I, g) no longer take the stain. If the area of distribution of the obstructed vessel have no arterial anastomoses, if the obstructed vessel be, to use Cohnheim's expression, a terminal artery, but if there remain, on the other hand, the possibihty of a scanty afflux of blood from adjacent capillaries or from the veins, a hsemorrhagic infarct may be formed. The capillaries of the region rendered anaemic bj' the obstruction become slowly filled once more with blood, which comes in part from the domain of adjacent vessels, in part from the veins, from which it 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 ; the blood consequently stagnates and the capillaries be- come filled fuller and fuller. Even in the event of a possible reflux of blood from the veins, the blood, of course, merely flows into the capilla- ries, but does not circulate through them. In consequence of the stagnation which arises from the lack of power to force the blood along, diapedesis eventually takes place. The escape of the blood is favored by the disorganization and necrosis of the tissues and of the vessel-tvalls — changes which result from the arrest of nutrition Fig. 22. — Part of the edge of a recent hseinorrliagic infarct of the lung, a, Interalveolar septa without nuclei, oontaining capillaries gorged with throm- botic masses, homogeneous in appearance and deep-bluish violet in color ; 6, Septa containing nuclei ; e, A vein with a red thrombus ; d, Alveoli completely filled with clotted blood ; e, Alveoh filled with serous fluid, fibrin, and leuco- cytes. (Specimen hardened in Miiller's fluid, stained with hsematoxylin and eosin, and mounted in Canada balsam. Magnified 100 diameters.) DISTURBANCES IN THE CIRCULATION. 139 or its reduction to almost nil — and it is further favored by the coagula- tion which occurs in the efferent vessels and renders impossible the onflow of the blood. The ultimate effect of the diapedesis is the permeation of the whole tissue with coagulated blood (Fig. 22, d), and the formation of a solid, recldish-Uack hemorrhagic focus, generally conical in shape. Embolic hmmorrhagic infarcts are to be found in the lungs (Fig. 22), but they are formed, after the embolic obstniction of an artery, only ivhen there is a tendency to stagnation of the j)ulmonary circulation ; while with a normal pulmonary circulation such circulatory disturbances as follow upon embo- lism are generally promptly allayed. In the corporeal circulation exten- sive haemorrhages from embolism are confined, almost exclusively, to the territory of the superior mesenteric arteiy, whose branches, although they are not terminal vessels, yet possess but few anastomoses. Ancemic in- farcts occur particularly in the spleen, in the heart, in the kidneys, and hi the retina, though haemorrhage is found in these also, along the bor- ders of the obstructed region, so that the bloodless foci have a hsemor- rhagic border surrounding them, or at least present hemorrhagic spots (Fig. 21, g). The necrotic tissue, furthermore, becomes satiu-ated with fluid, and may then swell (Fig. 21, d) and present granular or fibrous coagula in its interstices (Fig. 21, c). In case of the obstruction of arteries of the brain, or of those of the extremities, or of the central artery of the retina, haemorrhages 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 which are the first to die. After a time exudative inflammation arises in the neighborhood of ischeemic and of haemorrhagic infarcts, with the formation of a cellular (Fig. 21,/) or fibrocellolar exudate (Fig. 22, e) ; and this is followed by tissue-prolifera- tion (Fig. 16, c, d, page 126), by means of which the dead tissue, with its haemorrhagic infiltration, becomes absorbed (Fig. 16, «, b), and its place is taken by connective tissue. In his published works Virchow, who was the first to institute any profound experimental researches into the matter of thrombosis and emboUsm, left the question of the origin of the hsemorrhagio infarct still open, but he expresses the opinion that in the area of distribution of the obstructed artery the vascular walls sufEer certain alterations which render them more fragile and permeable. If a collateral circulation afterward become established, this secondary hyperse- mia causes exudation and extravasation. Cohnheim, who observed directly under the microscope the results of embohsm in the frog's tongue, demonstrated the retrograde flow of the blood in the veins, the refllhng 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 anaemia. 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 fields. The disorganiza- tion of the vessel- wahs he thinks also unnecessary for the production of infarc- tion, inasmuch as the stagnation suffices of itself, just as in venous obstruction, to explain the diapedesis. 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 haemorrhagic 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 stdl pervious portions of the implicated territory, it encounters resistance, becomes stagnant, and then escapes from the vessels. According to Klebs* emboli thrown into the circulation of the lower animals cause infarction ^ Schtceizer Arch. f. TJieirheilk. 28., Bd., 1886. 140 LYMPHORRHAGIA.— CHYLURIA. only when blood rich in ferment is thrown in after the embolus, or else when substances provoking coagulation become disseminated through the obstructing 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 inflammation are to be regarded as the cause of the hsemor- rhages. He furthermore regards the new-formed vessels consequent upon the in- flammation as the essential source of the haemorrhage, and views the coagula in the pulmonary arteries, not as emboli, but as thrombi of autochthonous origin. According to my own views, which are shared by the great majority of pathologists, there is no room to doubt the existence of embolic pulmonary in- farcts. They can only occur, it is true, 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. 22, a). Secon- dary thromboses in the vessels within the area of obstruction 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 essen- tial to the occurrence of the hsemorrhage. Hsemorrhages also occur frequently in the lungs, particularly in subjects with cardiac disease, merely as the result of impeded circulation ; these are not always inconsiderable, but are often, indeed, extensive, and, as they are limited to a circumscribed area, they have very much the appearance of embolic infarcts. They are generally, however, less sharply defined and less firm, so that they are for the most part easily disting^uishable 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 follows that lymph can be poured out from a lymphatic onty when the affected vessel lies on the external surface, or when a natural ca-\dty is at hand into which the lymph can flow, or when, by the same cause which effected the breach in the Ijonph-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 resistance. If after the wounding of a lymphatic vessel the aperture persists, so that there is a permanent flow of lymph escaping externally (as is the case in ulcers) or into one of the cavities of the body, we have a so-called lymph=fistula, through which considerable quantities of lymph may become lost. Most important and also most dangerous is a diiision of the ductus thoracicua, observed sometimes after traumatism, and occasionally also as the result of obstruction to 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 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 reddish emulsion, and contains, along with albumin, large quantities of fat subdivided into very minute globules. The phenomenon is coneequently known as chyluria. It occurs endemicaUy in certain tropical regions (Brazil, CHYLURIA. 141 India, the Antilles, Zanzibar, Egjrpt), -where it is caused by a parasite, the Filaria BancrofUi, which inhabits the abdominal lymph- vessels and there pro- duces 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 con- tained in the chylous urine. The connection between the chyluria and the in- vasion 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 (Soheube, Grimm) ; and in corroboration 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 ob- servation of Havelburg's, the urme coming directly from the ureter showed no admixture of chyle, although chyluria was present at the time. SECTION 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 disturbance of the fttnction of the tissue. Infiltrations of the tissues are characterized, on the other hand, by a deposit in them of iMtholoejical 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 tvith. The iniiltration is often only a result of preceding degenerative changes, or, on the other hand, it 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 gTowth, 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 development, so that it is either completely absent or at most only a mere rudiment 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 de- velopment, 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 du'arf 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 resul+ing atrophy are for the most pa.-t 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 142 KETROGRADE DISTURBANCES OP NUTRITION. 143 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. Among the extrinsic harmful influences which may lead to degenera- tions nearly all those should be mentioned which have been discussed in Section II. ThiTS an important part is played by disturbances of the cir- culation, 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 he more general and the entire organism may suffer. Thus the picture of a general disease may be produced by a degenerative or atrophic condition of the blood, which may show itself either by diminution of the red blood-corpuscles or of their hffimoglobin content, whereby a permanent condition of gen- eral aneemia 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 disordered 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 weakness and malnutrition, often associated with ansemia, leading to atrophy of the body as a 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. IF. Death. § 50. All life comes sooner or later to an end — to death. When this occurs at an advanced age, without preceding weU-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 it is preceded by symptoms 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 ob\d- ously impossible to draw any shai-jj line of separation between what may be called jDhysiological and pathological death. The causes of pathological death are those which have been discussed in Section II. as the causes of disease. A body is said to be dead all of whose functions have forever ceased. Death is, howe^^er, 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 all functions shall have ceased. Indeed, after life is irrevocably lost, many organs are still capable of performing 144 SIGNS OF DEATH. 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 cessa- tion of the functions of its various organs, into the state which we term death. The discontinuance of the functions of the heart, of the lungs, and of the nervous system results in almost immediate death of the entire 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 further nour- ishment of iJ-e 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 appearance. 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 ansmic it is pale. Furthermore, disease may material^ 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 iirst place, the temperature of the body falls, so that after a variable interval it reaches the temperature of the surrounding air. It should, however, 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 notches of cadaveric lividity, and depend upon the accumulation of the blood in the capillaries and veins of the more dependent portions of the skin. They are not observed in those pai'ts of the body subjected to pres- sure. 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 particularly 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 ap- pearance usually in from four to twelve hours after death, though it may PUTREPACTn':E CHANGES. — ^APPARENT DEATH. 145 occur almost immediately thereafter, or may not appear until twenty-four hours have elapsed. It usually is first noticed in the muscles 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 stri- ated. The contraction of these elements in the skin is the cause of the so-caUed goose-flesh of the cadaver. Putrefaction begins somewhat before the disappearance of rigor mortis. 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 putrefaction 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 skJTi, 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 eyeball loses its prominence, and darJi spots after a time develop in the sclera. These changes in the eye are due to evaporation and putrefaction. When the eyelids are not closed the resnlts of drying are very evident in the uncovered portions of the eyeball. Wherever the sMn has lost its epidermis the ex- posed tissues become dried. Under certain circumstances the evidence of life may be reduced to a min- imum, and a condition of apparent death may result which may be mistaken for death. Post-mortem hvidity, rigor mortis, and evidences of putrefaction are un- mistakable signs of death ; taut, since these changes do not appear until some time after death, an interval is left during which it may occasionally be doubt- ful whether death has actually taken place or not. To ascertain the truth with certaiuty under these circumstances it must tae determined by an appropriate examiaation whether the heart still beats, whether respiration is going on, whether the blood still circulates, and whether the nerves and muscles still re- main irritable. This condition of apparent death may occur imder a variety of circumstances, as, for example, in the course of cholera, in catalepsy, in hysteria, after great bodily exertion, after violent concussion of the nervous system, after profuse hsemon-hage, when respiration is suspended as the result of strangulation, hang- ing or drowning, in certain cases of poisoning, in lightning-stroke, after pro- longed exposiu-e to cold, etc. The duration of this condition is usually short, but it may occasionally persist for hotu-s or even days. III. Necrosis. § 51. By necrosis is understood a condition of local death, or death of single cells and groups of cells. As the result of necrosis there is always a cessation of the functions peculiar to the affected tissue. 146 NECROSIS. It is only occasionally that the necrosis of a cell-gronp 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 macroscopic appearance of the visible portions of the body inform us when a portioi] thereof becomes necrotic. Necrosis of a tissue is therefore evident upon anatomical examination only when certain changes in its structure have occurred either coinci- dently with its death or subsequently thereto. The immediate occurrence of such changes is met with occasionally in the case of traumatism, while the changes which develop later always make their appearance after the lapse of a certain length of time. It is customary to distinguish several forms of necrosis, according to the nature of the changes which take place. Histologically necrosis of a cell is very often indicated by its proto- plasm taking on a homogeneous appearance and by disintegration and disappearance of its nucleus. The chromatin of the latter — the substance which is stained by the nuclear dyes — forms small masses and granules which occasionally leave the nucleus and get into the cell-body, where they dissolve and disappear. In other cases the nucleus first loses its power of staining, and then gradually dissolves and disappears (Fig. 23, c), 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 I'endered ischfemic by the cutting off of the blood-supply in embolism of the arteries of these two organs, the nuclei of the cells of the spleen and of the kidney epithelium (Fig. 21, c) are very soon lost, and at the same time the affected tissues assume a dis- tinc^tly pale, cloudy, yellowish- white appearance, which makes it possilile to recognize the onset of necrosis even with the naked eye. Fig. 23. — Necrosis of the epi- thelium of the uriniferous tubes in a case of icterus gravis, a, Normal convoluted tubule ; b. Ascending looped tubule ; c, Convoluted tubule with necrotic epithelium ; d, Con- voluted tubule with only a part of its epithelium necrotic; e, Stroma and blood-vessels, as yet unaltered. (Preparation hardened in Miiller's fluid, stained with gentian violet, and mounted in Canada balsam. Magnified 300 diameters.) The injuries which lead to death of limited portions of the body may be classed in three groups. The first includes those which destroy the tissue directly through mechanical violence or through the action of chemicals. Thus, for example, a finger may be crushed by violence, sulphuric acid may destroy a portion of the skin, or bacteria may cause the destruction of glandular tissue in which they develop. The second NEUROPATHIC NECROSES. 14T group of injurious influences are of a thermal character. Elevation of the temperature of a tissue for any length of time to 54-68° C. results in its death. Higher temperatures act more quickly. Similarly, exces- sive cold can be borne for only a short time (cf. § 5). A third form of necrosis, characterized as anaemic 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 "vvhich residt 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 injuiy of anaesthetic and paralyzed portions of the body. The observa- tions thus far made upon man, and experiments upon animals, indicate that, at all events, an important part in the production of this form of' necrosis is always played by external injuries and by disturbances of the circulation, more particularly by spasm of the vessels. Again, all those conditions seriously affecting the circulation and leading to stoppage of the blood-supply — such as thrombosis, embolism,, closure of a vessel as the resiilt of lasting abnormal contraction, disease of its wall, or ligation, pressure on the tissue, inflammation, haemorrhage, etc. — may result in necrosis of the affected part ; nor is it necessary that the disturbance of the circulation be permanent, since a comparatively transient interference with the blood-supply may be followed by death of tissue. Whether or not htemorrhage 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. Hmmorrliagic infarction has thei'efore precisely the same significance as an anmuic necrosis comhined with hceiii- orrJiage. 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 Ijy degenerative changes in the tissue, it is termed indirect necrosis or necrobiosis. Mechanical, chemical, and thermal injuries and anffimia 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 under- goes a change, which terminates in stasis and coagulation of this fluid in the capillaries, as well as in the veins and arteries ; and as a resiilt 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 occurrence. 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 hydrsemia 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 comparatively slight injuries, more particularly of the extremities, in the aged and in those- who suffer from uncompensated valvular lesions of the heart. Further- more, disturbances of the nerves of the vessels, in so far as they lead to- impairment of the circulation, may afford a predisposition to necrosis- 148 SENILE AND JIARASMIC NECROSES. In the prostration incident to typlxoid fever, comparatively slight pressure on the hip, elbow, sacrum, or heel may be sufficient to bring about gan- grenous destruction of the skin and of the subcutaneous tissue. These forms are known as senile and marasmic necroses, 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, iipon the changes in the tissue which will resiilt 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 degenera- tion, inflammation, hemorrhage, etc. Under these circumstances, even when the progress of the necrosis is simple and is marked by compara- tively slight histological changes, the resulting structural changes may be very complex. The varieties of necrosis thus induced will be discussed in succeeding paragraphs. As the result of necrosis there is always inflammation of more or less intensiiij in the surrounding tissite (cf. Figs. 21 and 22), and it is most in- tense when processes of decomposition set up in the necrotic tissues. Through the formation of a zoue of inflammation the necrotic area is shut off from the surrounding tissue — is isolated and sequestered ; i:iud the inflummiition is accordingly spohen of as limiting or sequestering, and the dead tissue thus shut off is tei-med a sequestrum. A detailed de- scription of these inflammatory processes wiU be found in Section VI. If we exclude from consideration for the present the more special complications of necrosis — as, for example, the development of specific irritating materials — four sequelae are to be distinguished : 1. The dead tissue may be completely ahsorhed, or may be cast off from a surface, and its place talten hy newly formed normal tissue. This is spoken of as regen- eration. 2. The dead tissue is similarly removed, but, instead of the nor- mal tissue of the part being reproduced, simple connective tissue, the so- •called cicatricial tissue, more or less completely supplies the defect. 3. The dead tissue is only partially absorbed or cast off, and a sec[uestrmn of necrotic tissue remains, which may later become calcified, and which is in time surrounded by a dense connective-tissue capsule. 4. There is cijst- Jormation at the site of the necrosis, resulting from encapsulation of the dead tissue by connective tissue, absorption of the necrotic mass, and sub- stitution for it of a 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, and the reader is referred, for further details regarding it, to the chapter on Softening of the Braiu [in the volume devotedto special pathological anatomy]. The time required for the in duetion of necrosis after stoppage of the circula- tion varies with the different tissues. Ganglion-oeUs, renal epithelium, and the epithehum 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 JjTnph from the surrounding tissue ; and these changes are consequently absent COAGULATION NECROSIS. 149 when, for any reason, the circulation of the lymph in the diseased organ is stopped. Putrefaction is also a potent influence in inducing a rapid disintegra- tion and disappearance of the nuclei ; but Fr. Kraus has shown that portions of tissue preserved aseptically and out of aU contact with bacteria, in moist cham- bers 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 disappeared even after the lapse of from eight to fourteen days. It has been found by Goldmann that the disappearance of the nuclei occurs only in the presence of a consider- able degree of moisture, and may be prevented by desiccation of the tissue. § 52. When a tissue vrhieli is dead or dying contains coagulable materials and the necessary ferments, coagulation occurs, provided no conditions are present that may prevent such action ; and the term coagu= lation necrosis has consequently been applied to this variety of necrosis (Cohnheim, Weigert). Such coagulation may occur in liquids in which degenerating and disintegrating cells afford the necessary ferment, and we must consequently group among the eoag-ulation necroses the coagu- lation of the blood described in § 39 and the consequent formation of thrombi. As a rule, coagulation occiirs particularly in exudates from the blood-vessels in the course of inflammation. Here the coagulated mate- rial appears as flocks or as a false membrane, when the inflamed tissue is a mucous membrane (Fig. 24, «) or a serous membrane, or as granular or fibrillar masses lying in the liquid of the oedematous tissue. In inflammatory false membranes the fil)rin may be present as fine granules, as fibrils, as thicker fibres forming an interlocking framework, or as homogeneous masses. Fig. 25. Fig. 24. — Croupous membrane from the trachea, a, Transverse section of the membrane ; 6, Uppermost layer of the mucous membrane, with pus-cells, c?, ' scattered throughout its sub- ^^^HJIlC^^sg' stance; c. Fibrin threads and granules; d, Pus- ^^^^Pc>3 cells. (Magnified 250 diameters.) ^^ J Pig. 25. — Waxy degeneration of muscular fibres, from a case of typhoid fever, a, Normal muscular fibre ; 6, 6, Degenerated fibres, which have broken down into separate masses; c,c, Cells lying inside of the sarcolemma; d, Con- nective tissue infiltrated with cells. (Magnified 250 diameters.) _ A second form of coagulation is observed when dead cellular masses lying within the parenchyma of the body become infiltrated with lymph con- taining fibrinogen. Under these circumstances the cells become changed 150 CHEESY DEGENERATION. into finely granular masses (Fig. 23, e) or into hyaKne bodies (Fig. 25, b; Pig. 26, &), while at the same time they lose their nuclei. This variety of coagulation necrosis is most often met with in ischmmic infarctions of the kidney (Fig. 21) and spleen, already described in § 47, iu which the cells appear as finely granular masses, devoid of nuclei, between which — for example, in the lumina of the tubules, in the case of the kidney — fibril- lar and hyaline masses are found. It occurs also in many toxic and traumatic necroses of the glandular organs, and in the necrosis of muscle- tissue which results from thermal, traumatic, or chemical injuries. In the last-mentioned form of necrosis the muscle loses its striations, and its contractile substance becomes converted into shining, homogeneous material, which may later become broken into irregular hyaline masses (Fig. 25, V). A muscle which has undergone this change appears of a pale, grayish-red color, similar to the flesh of fish, and is more cloudy and drier than normal. Zenker has applied the name "waxy" to this variety of degeneration. Finally, similar processes of coagulation are of frequent occurrence in cellular inflammatory exudates, in which the cells of the tissue, as weU. as the exuded ingredients of the blood, undergo coagulation into irregu- lar granular or homogeneous masses devoid of nuclei. As the result of this process considerable masses of tissue may become wholly devoid of nuclei (Fig. 26, h) and appear granular (cf. Section VI.). The tissue which has thus died presents a grayish or yellowish-white appearance, which may be browner if it contains altered blood, or somewhat greenish if putre- factive changes have occurred. Fig. 26. — Section of a uvula after the destruction of its epi- thelial covering by diphtheria, a, Micrococci ; b, Mucous membrane which, is infiltrated and broken down into separate masses ; c, c, Parts infiltrated with small cells ; d, Fibrinous exudation ; e, Blood-vessels; /, Lymph-ves- sels containing cells and fibri- nous material. (Bismarck-brown preparation. Magnified 100 dia- meters.) Besides the cells, the interstitial connective tissue, the walls of vessels, hyaline membranes, etc., may become swollen as the result of imbibition of liquid, and may then coagulate into a homogeneous mass ; and at the same time granular, fibriUated, and hyaline products of coagulation may also be formed in the spaces between the fibres of a tissue. § 53. The term cheesy degeneration is applied in pathology to a change in the tissue as the result of which it comes to have the gross appearance of firm cheese or of softer cream-cheese. This term has been chosen solely because of the gross appearance of the product of the degen- eration, for it is known that the processes underlying it are not always the same. LIQUEFACTION NECROSIS. 151 In the first variety of cheesy degeneration — that which results in the formation of a firmer, dry, rather tenacious, yellowish-white, highly re- fracting material — we have to do with a special form of coagulation necrosis, which occurs most frequently in tissues rich in cells— as, for example, in tubercular tissue, in some very celMar tumors, and in lung- tissue infiltrated by the products of inflammation. The death of the tis- sue usually takes place rather slowly, so that the process has perhaps more the character of a gradually progressive degeneration, or necrobi= osis, than that of a true necrosis. Tissue tvhich has Ijecome completely cheesy is always devokl of nuclei. It is sometimes finely granular, at other times more homogeneous and shin- ing. In the transition of a tissue into these cheesy masses the change takes place in one of three ways : it either acquires a more and more homogeneous appearance and finally loses its nuclei ; or irregular small masses of homogeneous material (Fig. 27, a) form, which later become conglomerated ; or, finally, there is a disintegration of the cells, as the re- sult of which granules and fine granular fibres (fibrin) are formed, which then become agglomerated into a dense homogeneous mass. This last mode of formation is observed more particularly in cheesy exudates in the lungs, while the first is of frequent occurrence in tissues which have undergone hyperplasia as the result of chronic inflammation or of tuber- cle-formation (Fig. 27). Masses which were originally homogeneous may become granular after a time, as the result of further changes (Fig. 27, a). Fig. 27.— Tissue from a focus of tuber- I3r;f^f7'^^'2^?^*SJ^d cular disease, showing bacilli and a limited -» i-^ _ ,_ , z~^ _sj Fig. 28.— Section througli the epidermal and papillary portions of a cat's paw, a short time after it had been burned with fltdd seahng-wax. a, Horny layer of the epidermis ; 6, Rete malpighii ; c. 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 ; e. Epithelial cells lying between the papillas, the upper ones being swollen and elongated, while the lower still remain in a normal condition; /, Fibrinous network composed of epithelial cells (broken down so as to be no longer recognizable as such) and exudate ; g, An interpapdlary mass of cells which have become swollen and have lost their nuclei ; h, A part of a similar mass in which the cells have been entirely destroyed ; i, A papilla that has been flattened by pressure and that is infiltrated with cells; k, Solidified subepithelial exudate. (Carmine preparation. Mag- nified 150 diameters.) When a portion of the wall of the stomach is deprived of its circula- tion by plugging of the vessels, and dies in consequence, a rapid lique- faction of the dead tissue results from the action upon it of the gastric juice. In ana?mic necrosis of the brain the various histological elements of the brain-substance become broken up into smaller and smaller fragments, DRY GANGRENE. 153 some of which are absorbed, while others are dissolved in the lymph in- filtrating the dead tissue, so that ultimately, in place of the brain-sub- stance, there is a collection of clear, thin liquid. The failure of this liquid to coagulate probably depends upon the small content of the brain-sub- stance in coagulable material, and upon the absence from the lymph of any considerable quantity of fibrinogen. A similar condition is observed in other tissues also, as in the heart, where, in softening of this organ, the muscle-fibres undergo degeneration and disintegration, and are finally completely liquefied in the lymph of the tissues. But in this case there is the difference that coagulation of the muscle-substance at times precedes its solution. In inflammations which go on to suppuration there is invariably a lique- faction of the tissues of greater or less extent, and here it is not only the cells, rich in protoplasm, which succumb, but also the connective-tissue fibres, elastic fibres, nerves, etc. In inflammations which result in the formation of coagulable exudates and which lead to coagulation necrosis of the inflamed tissue, the coagu- lated masses as a rule subsequently undergo liquefaction, and, similarly, it is a common occurrence for thrombi to break down and become liquefied. § 55. Necrosis terminating in mummification, or what is usually called dry gangrene, occurs chiefly in parts of the body which are ex- posed to the air. Typical examples of dry gangrene are senile necrosis of the extremities, more particularly of the toes (Fig. 29) and feet, and gangrene of the toes or feet as the result of freezing. In the first of these the necrosis is the result of an impaired circulation (cf. § 42, Fig. 19) which is partly de- pendent upon weakness of the circulation as a whole and partly upon local changes in the blood-vessels. The necrosis which follows freezing is, on the other hand, the direct result of the excessive cooling of the tissues. Fig. 29. — Dry gangrene of the toes, caused by narrowing and closure of the arteries which supply these parts — arteriosclerosis. Since in both the senile gangrene, at the time when the part is actu- ally dead, and in that which results from exposure to cold the tissues are apt to be congested, and since there is diffusion of the blood-pigment throughout them, the affected parts come to have a reddish-black appear- ance, sometimes spoken of as Mach gangrene. At the same time desicca- tion occurs, progressing with greater rapidity in cases in which the epi- dermis has been lost, as occurs frequently in intense congestion and after freezing of a part. The tissues, as the drying progresses, at first become 154 MOIST GANGRENE. simply leather}', but later they become hard and friable and black. Micro- scopical examination shows the tissues to be much shrunken and the cells for the most part destroyed. When an extremity is anaemic at the time of its death, and when for any reason it does not later become penetrated by the blood, it remains pale, and is then said to be in a condition of white gangrene. In the changes which occur in the stump of the umbilical cord in the new-born we have a physiological example of dry gangrene. The gan- grenous tissue becomes separated from the neighboring healthy tissue by a zone of inflammation, spoken of as the line of demarcation. Dry gan- grene may sometimes develop out of moist gangrene as the result of desiccation. The terms moist gangrene and sphacelus are applied to necrotic tissues which have undergone decomposition and putrefaction. When the micro- organisms of putrefaction gain access to dead tissues, either directly from the air (as in necrosis of the skin or of the lung) or through the circula- tion (as may occur in the case of a neci'otic testicle or foot), and when the dead tissues are saturated with blood or with lymph, thej^ quickly begin to decompose. An exposed part which is well supplied with blood — the foot, for example — becomes of a dark blue-black color as the result of diffusion tkrough it of the blood-pigment. Bullae frequently form in the epidermis. When the gangrene is confined to the skin, the gangi-enous tissue is warm to the touch, particularly when there is much inflamma- tion in its neighborhood ; and hence the name hot gangrene has been applied to this variety. When in addition to the skin the deeper tissues are affected, so that the circidatiou in the dead tissue is quite stopped, the extremity is cool, and there is said to be cold gangrene or sphacelus. Tissues affected with moist gangrene and undergoing decomposition early give off a disagreeable odor and begin to disintegrate. Very trivial mechanical injuries are at times sufficient to cause loss of substance. The tissue is discolored, saturated with bloody liquid, very friable, and at times like tinder. Hand in hand with the changes which have been mentioned above, and which are easily recognizable by the unaided eye, decided chemical changes are going on in the tissues, changes which tend to their ultimate destruction. Under these circumstances gases not in- frequently form and give rise to what is called gangrenous emphysema. Whether this destruction of the tissue shall progress slowly or rapidly de- pends chiefly upon the nature of the affected tissue and upon the rapidity of the decomposition going on in it. Bones usually maintain their form for a long time in the midst of a focus of gangrene, while the soft parts disintegrate very rapidly. The microscope always reveals the presence of bacteria in tissues affected by this lesion (cf. the section on Schizomycetes). The blood-cor- puscles disappear early, becoming liquefied or disintegrating into granu- lar masses of blood-pigment. The cells of the tissue become cloudy, lose their nuclei, break down, and become liquefied. Muscle-fibres lose their striations and break up into smaU homogeneous masses. The medullary sheath of nerve-fibres coagulates into drops. Pat-cells disintegrate, and their contained fat is disseminated throughout the gangrenous mass in the form of smaU di'oplets. Connective-tissue fibres swell, become cloudy, lose their sharp contour, and gradually undergo solution. Tendons and cartilage resist for a long time, but eventually succumb to the same changes. In general it may be said that in gangrene there is a gradual MICROSCOPIC CHANGES IN GANGRENE. 155 solution of the solid elements of the tissues, as the result of which there is formed a dirty-gray, grayish-black, or grayish-yellow, opaque, more or less liquid mass, mixed with remnants of the destroyed tissue. There is, accordingly, a progressive disappearance of all the normal ingredients of the tissue, and a gradual development of formed crystalline elements, the product of the various chemical changes. Thus, for example, there may be found in gangfcnous tissue fat-needles, the so-called margarin crys- tals, fine acicular crystals of tyrosin, globules of leuein, rhombic plates of triple phosphate, black and brown masses of pigment, and crystals of haematoidin. Fig. 30. Fig. 31. Fig. 30. — Skeleton of a female dwarf, thirty-one years of age, 118 centime- tres in height, an idiot, and possessing a klinoeephalio skuh. All the disks 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 related to one another, the upper extremities alone being relatively somewhat short. Fig. 31. — Skeleton of a female dwarf, fifty-eight years of age, 117 centimetres m height, and with a long trunk and very short arm- and leg-bones. The disks of cartilage are still present ; the articular ends of the bones are thick. 156 HYPOPLASIA. Moulds may also occasionally develop on gangrenous tissue whicli is exposed to the air. Putrefaction, and consequently also gangrene, can only occur through the activity of micro-organisms, and for these a certain content of water is necessary. Accordingly, if thp tissues become dry, the development of the germs of putre- faction must cease, or at aU events become greatly delayed, and a similar delay in the process of disintegration results. The chemical end-products of the gan- grenous destruction of animal tissues are carbohydrates, ammonium sulpfide, hydrogen sulphide, valerianic acid, butyric acid, etc., and, finally, carbonic acid, ammonia, and water. IV. Hypoplasia, Agenesia, and Atrophy. § 56. 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, abnor- mally smaU individuals result, caUed dwarfs (Figs. 30 and 31), whose parts may be either fairly well proportioned (Fig. 30) or else unsymmetrically developed (Fig. 31). 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 extremities may be abnor- mally smaU, while the head develops to about the normal size, being then out of all proportion to the bodj-. When the maldevelopment is confined to a single part of the skeleton, or is here much more marked than else- where, a rudimentary condition of that part results. Thus, as the result of maldevelopment of the cranium, conditions of microcephalus (Fig. 32) and micrencephalns (Fig. 33) are induced ; 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, maldevelop- ment of the pelvic bones of one side may lead to asymmetry of the pel- vis (Fig. 34). Fig. 32. Fig. 33. Fig. 32.— Head of Helene Becker (microcephalic), at the age of five years. (From a photograph taken by A. Bckerinl868.) Fig. 33.— Bram of Helene Becker (microcephalic), who died at the age of eight years. (From von Bischoff.) This brain weighed 219 grammes (instead of 1377 grammes, as Vierordt claims that it should). EXAMPLES OF HYPOPLASIA. 157 Among the separate organs the central nervous system and the gen- ito-urinary system suffer perhaps most frequently from maldevelopment {Figs. 33 and 35), though the intestine, heart, lungs, and liver by no means escape. In Fig. 33 we have seen an example of abnormal smallness and retarded development of the whole brain ; but there are also cases in whicli one hemisphere alone suffers (Fig. 35), either wholly or in part. A part of the intestine may be so imperfectly developed as to form only a small and quite useless canal (Fig. 37, d) or to be merely a small solid cord (Fig. 37, e). The uterus not infrequently remains in an undeveloped state Fia. 34. — Hypoplasia of the os innominatiiin of the left side, resulting from coxitis which, from the period of childhood, had prevented the use of the left leg. (The reduction in size amounts to a httle more than one half.) (Fig. 36), and occasionally the entire group of female generative organs, both internal and external, may remain at the time of puberty in the un- developed condition of a young child. Among the organs of the urinary system a more or less complete maldevelopment of the kidney is not un- common. In the development 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. 38). The above-mentioned examples of hypoplasia, to which many others might be added, are all due either to causes operating within the develop- ing fcBtal organism itself, in which case they may be said to be inherited, or to external deleterious influences working upon normal tissues during 158 HYPOPLASIA. their developmental period. Thus, as causes of maldevelopmeut of the bones, we may mention disease of the thyroid gland (of. § 22), insufacient Fia. 35. — Hypoplasia and microgyria of the left cerebral hemisphere ; case of a deaf-mute, a, Eight hemisphere ; 6, left hemisphere ; e, occipital lobe, diminished in size and in a state of microgyria ; d, membranous cyst in the region of the parietal lobe. (Seen from above, after removal of the cerebeUum, Two-thirds natural size.) Fig. 36. — Hypoplasia of the uterus, with well-developed ovaries. (From an idiotic girl, eighteen years of age.) AGENESIA. ATROPHY. 159 nutrition (rachitis), disuse (Fig. 34), and inflammation. When portions of the body or single organs fail of all development, the condition is spoken of as agenesia. This de- pends upon an entire failure of development of the part in ques- tion from the very start, or upon a total destruction of the part after it has begun to develop (ef . the section on Malformations). Fig. 37. — Hypoplasia of the small intestine of a new-born child, a, A much-dilated portion ; &, c, rf, e. Por- tions that are much narrowed and wasted ; /, Normally developed small intestine. (Five-sevenths natural size.) The tissue composing hypoplastic organs or parts of organs is at times normal in structure ; but there is often associated with the abnor- mal smallness of the organ an imperfect organization of its integral ixirts, with failure of development of some of its more highly specialized ele- ments, so that associated with a hypoplasia of the entire organ there may be agenesia of some of its elements. Thus in hypoplasia 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- flbres, and at times portions of the brain may be represented by merely membranous masses (Fig. 35, d), in which ganglion-ceUs are entirely absent; and in hypoplasia of the lung (Fig. 38) there may occasionally be complete failure of development of the alveoli, the lung-tissue then consisting chiefly of rather vascular connective tissue in which bronchi, usually dilated, lie. Fig. 38. — Agenesia of the respiratory parenchyma of the left Ivng. The Inng consists of dense connective tissue in the midst of which dilated bronchi are found. (Horizontal section through the apex of the upper lobe. Natural size.) § 57. Atrophy is diminution in size of an organ as the result of dimi- nution in size and disappearance of its elements. It may occur at any period of life, and is, in fact, a very frequent residt of many different pathological processes. Within certain limits it may be regarded as a physiological process, since in advanced age a retrograde change in all the organs is of constant occurrence and is always associated with more or 160 ATROPHY. less diminution in their size. A few of the organs suffer a similar change even before old age — as, for example, the thymus, which becomes com- pletely 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. In the 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 in- dividuals, the brain or the glands of some of them undergoing the earhest and most rapid change. The most striking evidence of atrophy of an organ is its diminution in size. When the muscles atrophy (Fig. 39) the affected portions of the body become smaller; and in cases of extensive atrophy of the muscles of the extremities the impression is given as if nothing intervened between the skin and the bones. When the atrophy of an or- gan goes on symmetrically in all its parts its normal shape may be preserved. But it often progresses more rapidly in one part than in another, in which case great asymmetry of the organ may result, there being often deep pits upon its surface (Fig. 41) and cicatricial contractions (Fig. 44), so that the affected organ — for example, liver or kidney — may present a knobbed or granular surface. In cases in which the tissues undergoing atrophy are in any way prevented from contract- ing, 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 exceniric atrophy or osteoporosis (Fig. 40). In the lungs the alveoli become united into large air-spaces as the result of disap- pearance of the intervening alveolar walls. When atrophy affects glands and muscles there is often a change in then- color, though this is of but secondary importance, depending either upon an unusual distinctness of the pigment of the affected organ because of the disappearance of parts ordinarily over- shadowing 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 organs is the result of diminution in size and disapipearance of the structural elements of the tissues composing them. In the majority of the organs — more particularly glandular organs, mus- cle, and bone — the more highly specialized portions suffer, in undergoing atrophy, to a much greater extent than the connective-tissue framework which supports them. Indeed, it is not uncommon to find this latter tis- FiG. 39. — Juvenile muscular atrophy. (Case observed by de Souza.) ATROPHY OF BONE. 161 Fig. 40. — Exeentric atrophy of the lower ends of the tibia and fibula, with osteoporosis. (Natural size.) / Fig. 41. — Senile atrophy of the calvarium, with defect of the external table and of the spongy portion throughout the central parts of the parietal bones. 162 ATROPHY OF MUSCULAR TISSUE. sue quite intact, or even increased in amount, in an organ from which all the more highly differentiated parenchyma has disappeared. Thus in atrophic muscle-tissue (Fig. 42) the contractile substance within the sar- colemma frequently disappears entirely without the occurrence of any noticeable atrophy in the connective tissue between the muscle-bundles, the nuclei of which may be actually increased in number (Fig. 42, ci). Fig. 42. — Section of an atrophied muscle, from a ease of progressive mus- cular atrophy, a, a, Normal muscular fibres ; b, Atrophic muscular fibres ; e. Perimysium internum, the nuclei of which, at Ci, seem to be increased in uumber. (Preparation stained with Bismarck-brown and mounted in Canada balsam. Magnified 200 diameters.) In atrophy of the Mdney the epithelial cells of the urinary tubules (Fig. 43, /) become smaller and smaller, and ultimately disappear, the tubules then undergoing complete coUapse. A similar change occurs in the epithelium of the glomeriili, the capUlaries of which disappear. The same thing occurs in simple atrophy of the liver, in which the entire parenchyma of a lobe may disappear without any considerable 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 diminu- tion in the neuroglia, which is often actually increased in amount. Fi&. 43. — Senile atrophy of the kidney, a, a, Normal urinif- erous tubules; 6, Normal glo- merulus ; c, Stroma, with blood- vessels ; d, Atrophic glomerulus ; e. Small artery, with somewhat thickened intima ; /, Atrophied and collapsed uriniferous tu- bules. (Preparation hardened in alcohol, stained with alum carmine, and mounted in Canada balsam. Magnified 200 diam- eters.) In atrophy of bone it is the true bone-tissue which becomes diminished in amount, and in excentric bone-atrophy 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. DEGENERATIVE ATROPHIES. 163 lu 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 mthout any appreciable change in the structure of its component parts (Fig. 42), the atrophy being the result of a simple diminution in size of the vari- ous 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 the be- ginning and are frequently associated with deposits of pathological sub- stances in them. Thus a cell may become granular and undergo frag- mentation, or may swell up and iiquefj^, or droplets of fa,t or mucus may form in it, aU of these changes being indicative of degenerative processes in the protoplasm of the cell. The special varieiies of degenerative changes which occur in tissues will be treated of in the succeeding paragraphs of this section. Coincidently with changes in the protoplasm of the cell-body there may be similar degenerative changes in the nucleus, such as frag- mentation, change of shape, irregular distribution of the chromatin, dis- charge of the chromatin into the cell-bodj'^, and swelling and disappear- ance of the nucleus, all of which ultimately lead to destruction of the nucleus, and secondarilj^ of the cell itself. Degenerations thus ultimately leading to atrophy of the affected organ are of very frequent occurrence, particularly in glandular organs. Fre- quently inflammation is also a complicating factor in the production of these conditions. Not infrequently granules are met with in cells, of such appearance and under such conditions as to preclude the possibility of their being the result of degeneration and disintegration of the cells. These have been made the sub- ject of careful study by Ranvier and Ehrlich. The latter of these investigators has shown the presence in the white blood-corpuscles, under normal conditions, of granules giving distinct reactions Avith some of the anUine dyes. He is thus able to differentiate cells containing neutrophile grantdes (which stain with a neutral dye obtained by mixing acid fuohsin and methyl green) and ceUs contain- ing oxyphile granules (which stain with the acid dye eosin). Uuder pathological conditions, other leucocytes are also found containing basophile granules, stain- ing with the alkahne dyes. Besides these ceUs of the blood, large cells containing basophile granules in large numbers are sometimes found in the connective tissue of various organs, especially in cases in which there is also present a slight but chronic inflamma- tory process. These cells have been called "Mastzellen" (hterally " feeding cells") by Ehrlich. The exact significance of these and similar granules in ceUs is at present uncertain. Altmann, who by the use of special methods has demonstrated such granules in the greatest variety of cells, sees in them the morphological unit of living matter, and apphes to them the name hioblasts. Separate, independent bioblasts, such as the micro-organisms, he calls autohlasts, while those which are aggregated in cells he calls eytoWasts, and these latter he again divides, accord- ing to their location in the cell, into kart/oblasts and somatohlasts. This view would tppear, however, to be hardly in accord with the facts ; and the hypothesis of EhrUch, in which he is supported by Heidenhain and Lowit, would appear more probable — i.e., that these granules are of the nature of a secretion by the proto- plasm of the cells, and that the cells in which they are found may be regarded as in a measure unicellular glands. The investigations of Tettenhamer into the spermatogenesis of salamanders have shown the formation of acidophile granules from degenerating nuclei. Since these find their way into leucocytes as the re- sult of phagocytosis, they may be considered to represent the acidophile forma- 1C4 SENILE ATROPHY. tion of granules whieli takes place in these leucocytes later on. As regards the " Mastzellen," the opinions of different observers are at variance. Some (Browicz, Raudnitz) take them to be degenerating cells ; others (Neumann) be- lieve them to be transition stages of proliferating cells j while still others (Ehrlich Rosenheim, Korybutt-Daszkiewicz) look upon them as being cells which have been superabundantly supplied with food. It certainly militates against this last view that Ballowitz has found the " mast-cells " in hibernating animals, at the end of their winter's sleep, in almost the same number as at the beginning, and that "mast-cells" are often found in persons who have been in a state of cachexia at the time of death. § 58. The various atrophies may be separated according to their ori- gin into active and passive. The cause of the first lies in the inability 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 ceU, or such as is brought is of an improper kind, or harmful substances are contained in it which impair the nutritive function of the cell. Active atrophy is more particularly observed as a part of senile degeneration, but it occurs also under pathological conditions, especially in nerves, glands, and muscles (Pig. 39) whose function is interfered with. Clinicians are apt to prefer to the above another classification of the atrophies, distinguishing senile atrophy, atrophy dependent upon impaired nutrition, pressure atrophy, atrophy of disuse, and neuropathic atrophy. "X f~ln-7>p., ^^ ilfifk^ *K V Fig. 44. — Arteriosclerotic atrophy of the kidney. (Natural size.) Senile atrophy (Fig. 41) is partly active, partly passive, since it is not simply the result of gradually diminishing 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 organs, and is often more pronounced in one organ than in another. The bones, the kidneys, the liver, the brain, and the heart may all thus suffer a decided diminu- tion in their volume. The atrophy dependent 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^ody, and then affects the whole body, although even then the fat, the blood, the muscles, and the abdominal glands suffer most. Local atrophies may result from interference with the blood-sup- ply of limited regions (Fig. 44), and are a frequent result of disease of the Mood-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, PRESSURE ATROPHY. — ^NEUROPATHIC ATROPHY. 165 the result of simple atrophy, but of a variety 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 diminution in size of the thyroid gland, and in chronic lead-poisoning the extensor muscles of the forearm are apt to undergo atrophy. Pressure atrophy results from continued and moderate pressure upon a tissue. It would appear to depend both upon dii'cct injury to the tissue and upon interference with its cir- culation. Typical examples are : the atrophy of the liver which results from tight lacing and consequent pressure of the ribs upon the liver; and the disap- pearance of bone as the result of pressure of an aneurism (Pig. 45) or of an accu- mulation of liquid in the ventricles of the brain. Disuse atrophy occurs in muscles aud glands, as well as in bones, skin, and other tissues, and is due to non-use of the tis- sues in question. In the case of muscles and glands the. atrophy is essentially ac- tive, but as the result of their functional inactivity there is at the same time a con- siderable diminution in their nutritive activity and in the activity of the circula- tion in them. In the other tissues the atrophy is chiefly due to a loweiing of the nutrition of the unused parts, though it is impossible to quite ehminate from consideration a change in the power of assimilation of the cells. Wlien the dis- use is operative during the developmen- tal period, and the tissue is on that ac- count poorly nourished and undergoes but an imperfect development, the result- ing condition is properly regarded as one of hypoplasia (Fig. 34) ; and yet it is im- possible to sharply separate this condi- tion from one of atrophy, since in hypoplasia there may be also a dis- appearance of structui'es which had undergone a certain degree of de- velopment. Neuropathic atrophy is a result of diseased conditions of the nervous 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. As the result of disease of the nerves of one side of the face there may be unilateral neuropathic atrojjJiy of the face (Fig. 46). Unilateral affections of the brain during foetal life or dm-ing childhood may lead to atrophy of the opposite half of the body (congenital and infantile hemi- atrophy). Fig. 45. — Pressure atrophy of the spinal column, caused by the encroachment of an aneurism of the aorta. 166 CLOUDY SWELLING OF CELLS. Ill all these pathological alterar tions of neuropathic origin we very often have to deal not with true atrophies, but with various degenera- tive processes ; and the term atrophy as applied to them is only justifi- able to this extent, namely, that the ultimate result of the process is an atrophic condition of the affected parts. The causes of the degenera- tive processes are found in part in vaso-motor disturbances, in part in loss of function, and in part in sev- erance of the affected tissues, the nerves, from their centres in the spinal cord or brain. Fig. 46. — Facial liemiatropliy. (After Lichtheim and Borel.) V. Cloudy Swelling and Hydropic Degeneration of Cells. § 59. 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 hypertrophy with tendency to degeneration. At all events, the greatest weight is to be laid upon the degenerative character of the change. Histologically the process is characterized by the formation of fine granules within the bodies of the swollen ceUs — for example, in kidney epithelium, liver-ceUs Fig. 47. — Cloudy swelling of liver-cells. (Scraped from the out surface of the liver of a man who had died of sep- tiosemia ; examined in salt solution. Magnified 350 dia- meters.) (Fig. 47), or heart-muscle. Their microchemical reactions (solubility in acetic acid, insolubility in alkalis and ether) would indicate the albumi- nous 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 structure and form of the cell are lost. Thus in cloudy swelling of the tubular epithelium of the kidney (Pig. 48) the rod-like markings of its protoplasm and the cell-processes extending into the lumen of the tubule disappear, the cell becomes larger (&, c), and dark granules make their appearance throughout its substance. This change is to be regarded as a disorganization of the cell-protoiMsm f oUowing the absorption of liquid into its substance, and leading to a partial separation of its solid and liquid constituents. The mieleus not infrequently participates in these changes, undergoing a similar disorganisation. Recovery from a moderate degree of this degeneration is quite possi- ble, 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 HYDROPIC DEGENERATION OP CELLS. 167 Fig. 48. — Cloudy swelling of kidney epithelium, a, Normal epithelium ; 6, Epithelium beginning to be cloudy ; c, Advanced degeneration ; d, Cast-off degenerated epithehal cells. (From a preparation which had been treated with ammonium chromate. Magnified 600 diameters.) up into finely granular fragments. Fatty degeneration (cf. § 62) is fre- quently associated with the degeneration tinder discussion. Cloudy sweUing 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- caemia, 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. § 60. The term hydropic degeneration is very properly applied to a change frequently observed, in epithelial cells chiefly, whereby they be- FiG. 49.— Hydropic degen- eration of epithelial cells, from a carcinoma of the breast, a, Ordhiary epithehal cells ; 6, Hy- dropic ceUs, with bladder-like di-ops of fluid (physalides) in their interior ; c. Hydropic nu- clei; d, Enlarged nucleoli; e, Wandering cells. (The prepa- ration was hardened in Miiller's fluid and alcohol, then stained with Bismarck-brown, and finally mounted in Canada bal- sam. Magnified 300 diameters.) 11 168 LIPOMATOSIS. come swollen as the result of imbibition of liquid. The process is closely related to cloudy swelling, though the resulting disorganization of the cell is usually much less extensive. When epithelial cells undergo this degeneration the cell-contents appear clear, the protoplasm 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 mea- sure to resemble plant-cells (Fig. 49, &). Occasionally distinct vacuoles (6) are formed — i.e., globular drops of clear liquid in the cell-protoplasm. The nucleus (c) also becomes swollen, and may be indicated merely by a large globule with liquid contents. When muscle is the affected tissue, clear droplets of liquid appear between the fibrils, pressing them apart (Fig. 50 and Fig. 51, a, h), so that, when the disease is extensive, the for- mation of the clear round spaces may give to the muscle a distinctly bubbly appearance (Fig. 50). For a time the muscle-fibrils between these Fig. 50. — Hydropically degener- ated tnusciilar fibres, from the gas- trocnemius of a patient suffering from chronic oedema of the legs. (The preparation was first treated with Flemming's acid-mixture, then stained with safranine, and finaUy mounted in Canada balsam. Mag- nified 45 diameters.) drops may remain unchanged, but with a continuance of the process they degenerate and undergo liquefaction. Hydropic degeneration may be the result of cedema (Pigs. 50 and 51), or it may occur in inflammatory conditions or in ttonors (Fig. 49). When it results from inflammation its degenerative character is usually much more pronounced than when it occurs merely as an accompaniment of oedema, and it may then lead to complete disintegration of both the cells and the nuclei. In cedematous condi- tions the cells often remain alive for a very considerable time, notwithstand- ing their hydi-opie condition. Fig. 51. — Transverse section of a bundle of muscular fibres in a state of hydropic degeneration. a, Muscular fibres with smaU drops of fluid ; 6, Fibres with large drops. (The preparation was hardened in Miiller's fluid, then stained with heematoxylin, and finahy mounted in Canada balsam. Magnified 66 diame- ters.) VI. Lipomatosis, Fatty Atrophy, and Fatty Degeneration. § 61. 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 to 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. FATTY ATROPHY. 169 When the ingestion of fat oi- 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 of 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 universalis. 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. 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, etc. In counective-tissue cells and in the hepatic cells the fat is deposited in the form of small drops (Fig. 52, a, b), which soon coalesce to form larger drops, ultimately replacing the entire cell-body and converting it into a spheroidal mass of fat. Obesity may persist as a permanent condition until death, to which it may directly lead at times as the result of interference with the action of the heart. But it may also become less, as the result of diminished ingestion of food or in (ionsequence of improved metabolism, in which ease the fat stored up in the cells undergoes diminution, breaks up into smaller drops, and may ultimatelj' be entirely reabsorbed, the cell again assuming the shape and appearance of the connective-tissue cell. Occa- sionally with the disappearance of the fat there may occur a multiplica- tion of the nuclei of the cell. When the fat is removed from a tissue normally containing it, in the course of general marasmus, and its place is taken by serum, the tissue assumes a gel9,tinous appearance, and the resulting condition is spoken of as serous atrophy of fat=tissue. When pigment is deposited in atro- phic fat-ceUs, giving to them a yellowish or brownish color, pigment atropliy is said to have occurred. According to Volt, 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 pro- cess of synthesis with glycerin, or from albumin and carbohydrates. The im- portant factor in the metabolism of nutrition is not the oxygen of the blood, but the cell itself, whose protoplasm possesses the power to convert complex chem- ical compounds into simpler ones. The substances most readily lending them- selves to this change are the albumin brought to the cell in soluble form and the carbohydrates. Fat is, on the other hand, resistant, both that directly absorbed from the food and that formed ia the body. Now, when fat is supplied to the ceU in excess, or when the metabohc potential of the cell is lowered so that it is imable to further decompose the fat which it elaborates from the albumin brought to it, fat of necessity remains in its protoplasm. When these two in- fluences act in combination, the effect is, of course, greater. Improved nutritive conditions, exercise, and elevation of the body-temperature increase the metabolic activity of the ceUs, 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 production the metabohc 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 accmnulation of fat which is often noticed in ansemia is explained on the ground of diminution in the cell-mass of 170 FATTY DEGENERATION. the body, resulting in diminished 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 ceU occurs in two stages. In the first, the stage of ferment-action without oxidation, or of hydro- lytic separation, uric acid or analogous substances (urates and creatine derivates) are formed from the protoplasm, the carbohydrates at the same time being con- verted 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 metabohsm of proteids. The carbohydrates are in part oxidized, but the greater part of them, particularly during muscular inactivity, 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. § 62. When a cell contains fat which cannot be accounted for as hav- ing been formed from proteids or carbohydrates in the circulation, or as having been obtained from the ingested food, but which would appear to have been formed in the cell at the expense of its own protoplasm, the fat must be regarded as an expression of degeneration of the cell, and the term fatty degeneration is applied to the process from which it results. This degeneration may occur in the course of parenchymatous degen- eration as a later development, but it also frequently occurs without any such preceding condition, so that it must be regarded in reality as a split- ting up of the protoj^lasm of the cell with fat-formation. Cells which are in the condition of fatty degeneration always con- tain easily recognizable «!ro|JS of irregular size, colorless, highly refracting, insoluble in acetic acid, soluble in alcohol and in ether. Perosmic acid stains these droplets black. Their number and size vary greatly, though the largest rarely attain great size. Thus heart-muscle in a condition of fatty degeneration (Fig. 53) shows minute fat-droplets scattered through its substance, varying in number with the intensity of the process, but which seldom become conglomerated together to form large drops. Fig. 52. Fig. 53. • MM Fig. 52. — Fat-containing liver- ceUs. a, b, Fat-infiltration ; c, d, e, f, Fatty degeneration. (Mag- nified 400 diameters.) Fig. 53. — Fatty degeneration of the muscular tissue of the heart. (Magnified 350 diame- ters.) A similar appearance is presented by liver-cells (Fig. 52, c, d) and by the tubular epithelium of the kidney (Fig. 54, e, f) when undergoing fatty degeneration, though it should be said that here the fat-droplets are fre- quently of greater irregularity in size, and when the process is far ad- vanced in these organs many of the cells may become broken up into a fatty detritus composed of fine granules and minute fat-droplets. Fatty degeneration affects both connective-tissue cells and epithelium. When many cells closely associated are affected, the condition is usually readily recognizable with the naked eye ; the more readily, of course, the CAUSES OF FATTY DEGENERATION. 171 more intense the process, the less striking the color of the tissue involved, and the smaller its blood-content. Colorless, transparent tissues, like the iutima of the heart and of the vessels, assume an opaque, whitish appear- ance ; the cortical substance of the kidney becomes grayish, and when the process is intense, even yellowish white and opaque ; the heart-muscle be- comes yellowish, and even the skeletal muscles may come to have a pale yellowish-brown color. The cells contained in liquids — as, for example, those in pus — frequent- ly undergo extensive fatty degeneration, ending usually in the disinte- gration of the cell. The same is true of the cells of coagulated exudates. Fatty degeneration would appear to depend in part upon a change in the composition of the blood, and consequently in the nutritive sub- stance brought to the cells, and in part upon a lowered vitality of the cells themselves. An important part in its production is undoubtedly played "bj persistent diminution in the supply of oxygen to the cells (A. Fraenkel), which shows itself, in the first place, by an increased breaking down of albumin and a consequent increase in fat-production, and, in the second place, by the cireiunstance that it is then no longer possible for the fat so formed to undergo further oxidation. Since, in this process, the reproduction of albumin does not keep pace with the speed with which it is destroyed, a gradiial diminution of the albumin-content of the affected organs must necessarily follow. Fig. 54. — Section of a kichiey affected with fatty and amyloid degenera- tion, a, Normal loops of vessels ; 6, Loops affected with amyloid degeneration ; c, Patty glomerulus epithelium; Ci, Fatty capsule epithelium; d, Fat-drops at- tached to the outer surface of the capillaries ; e, Fatty epithehum in situ ; f, Cast- off fatty epithelium ; g, Hyahne soUdiflcations (urinary casts) ; h, Transverse sec- tions of casts composed of fat-drops; i, Amyloid artery; k, Amyloid capillary; i, CeUular infiltration in the connective tissue; m, Eound cells inside the uri- liiEerous tubules. (Magnified 300 diameters. The preparation was treated with MiiUer's fluid and perosmic acid, and then stained with methyl violet.) 172 FATTY DEGENERATION. On this account fatty degeneration is a frequent accompaniment of condi- tions jn'oducing general or local ancemia. Thus, if the power of the blood to appropriate oxygen is diminished by disease, as it is in anaemia, leu- cocythsemia, and coal-gas poisoning, and the processes of nutrition are thereby interfered with, fatty degeneration may occur in a great variety of organs. In cases of serious loss of blood, either from an ulcer of the stomach, or from letting blood too freely from a vein, or from an excessive nose-bleed, it sometimes happens that the patient laecomes blind either immediately after the bleeding or perhaps even several days later. In such cases the blindness is to be attributed to fatty degeneration of the cells of the retina and of the optic nerve in the region of the lamina crib- rosa, and this degeneration in turn is to be ascribed to the anaemia caused by the haemorrhage. It is also probable that in these cases the degenera- tive process is favored by spasm of the arterial vessels of the optic nerve and retina. Circumscribed areas of fatty degeneration are most apt to occur when a tissue receives an insufiBcieut supply of blood owing to some local lesion, or when the escape of venous blood from the part is retarded, so that re- newal of the blood cannot occur at the normal rate. Furthermore, fatty degeneration may occur in cells which have become detached from their normal nutritive surroundings and are undergoing necrotic changes. Various poisons may also bring about increased degeneration of albii- min and consequent fatty degeneration. Among such may be mentioned phosphorus, chloroform, iodoform, arsenic, sulphuric acid, nitric acid, and many of the toxic substances produced by the bacteria ; and fever would appear to act in a similar manner. In the case of fever it is possible that the degenerative change is in consideraWe part due to diminished supply of oxygen to the tissue ; but the presence of toxic substances in the blood at such times luidoubtedly contributes thereto. The decision as to whether fat which is found in cells is the result of degeneration of the eell-protoplasm, or whether it has merely been de- posited in the cell, is not, as a rule, attended with much difficulty. It is generally admitted that the fat resulting from degeneration is in small droplets which rarely become confluent, while the fat deposited in a ceU usually runs together to form large drops. While this is true of the fatty changes in most of the organs, it is not universally applicable. It holds for striated muscle, heart-muscle, smooth muscle, neurogUa-ceHs, etc., but in fatty degeneration of the kidney epithelium the drops wliich form as the result of the fatty degeneration are already somewhat larger, and in the liver the drops of fat which form as the result of degeneration are both small and large. This is particularly the case in phosphorus-poisoning. On the other hand, when the fat is merely deposited, and not formed as a resiilt of degeneration, the drops which first appear are small, and then when reabsorption of the fat sets in, the large drops break up into smaller ones. When the appearance of the fat as it occurs in cells does not afford the necessary indication as to its source, the location of the fatty cells may often serve to determine it. The occurrence of fat-droplets in cells which normally contain no fat, under circumsta.nces excluding the possi- bility of an increased transport of fat to them, is strong evidence that the fat in question has been formed from the albumin of the cell as the result of a degenerative change. Difficulty arises, then, practically only when the affected tissue is normaUy a fat-depot and is at the same time FAT-GRANULE CELLS. — CHOLESTERIN. 173 prone to fatty degeneration, as is notably the case with the liver ; and it is often very difficult to decide how much of the fat present in its cells has been deposited there and how much has been the result of degenera- tion. A fui'ther complication arises from the fact that degeneration-fat may at times be absorbed and then subsequently deposited in the same organ as infiltration-fat. According to A. Fraenkel, all processes which dimiaish the supply of oxygen to the tissues in so far tend to increase the waste of proteid substances and pre- pare the way for fatty degeneration. As the result of the lack of oxygen, he explains, a kind of necrobiosis of the cells occurs. The dead protoplasm is then subjected to the action of various ferments, and by them is spht up iato a nitrogen-containing substancej which is eliminated ia the urine, and a non- nitrogenous substance, fat, which remains in the tissues. Fraenkel bases this theory upon the results of observations in eases of phosphorus-poisoning, in which condition, as has been shown by Storch and Bauer, the consumption of oxygen is materially lowered and the waste of proteids increased ; and also upon the results of blood-letting, of hindrance to the respiratory absorption of oxygen, and of carbonic-oxide poisoning, in which conditions fatty-degenera- tive changes occur, and there is at the same time an increased ehioiination of nitrogenous substances in the urine. Fi-aenkel explains the occurrence of fatty degeneration in the course of fever also upon the theory of diminished oxygen- supply, insisting that during the febrile state the oxygen-carrying power of the hsBmoglobin is diminished, that the red blood-corpuscles disintegrate in large numbers, and that abnormal contraction of the arteries is present. The fact that in fatty degeneration the fat remains in the cell-body is ex- plained, according to Voit, not so much by lack of oxygen as by diminished metaboUc power of the ceUs, which are unable to further decompose it. Tissues which have undergone extensive fatty degeneration, and liquids in which the contained cells have degenerated, very often contain large cells com- pletely filled with fine fat-granules. These cells may properly be called fat- granule cells. They are to be regarded as only in part the result of fatty de- generation, and in many cases would appear to be wandering cells which have become increased in size and spheroidal owing to their absorption of fat lib- erated from other disintegrated cells. § 63. The fats which occur in the human body are mixtures of oMn, palmitin, and stearin. The first of these is liquid at the ordinary tem- perature, the second melts at 46° C, stearin a,t 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 palmitin and stearin separate in the form of fine star-shaped or feathery needles (Fig. 55, 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. 55, a), is frequently deposited in areas of fat-con- taining 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 which 174 PATHOLOGICAL DEPOSIT OF GLYCOGEN IN THE TISSUES. 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, in which the bile salts and soaps hold it in solution. 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. Fig. 55. — a, Cholesterin plates ; 6, A free cluster of margarin needles ; c, Needles inclosed in fat-cells ; d, Grass-like bundle of margarin needles. (Mag- nified 300 diameters.) Water, dilute acids, caustic alkalis, 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, be- ginning at their borders, and this color then slowly changes into violet. A weaker solution (3 parts sulphuric acid, 1 part water) causes a 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. Pathologically it is met with more particularly when these bodies are undergoing degeneration with fat-formation, or, in other words, in tis- sues and exudates which are in process of fatty degenei'ation. It is also occasionally formed in old echinococcus cysts. VII. Glycogen=deposit in the Tissues under Pathological Conditions. § 64. 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 foimd in the tissues as a hyaline siibstance somewhat re- sembling amyloid in appearance (Langhans). It is more often situated in the cell-bodies, but may also lie at times in the intercellular spaces of CHEMICAL CHARACTERISTICS OF GLYCOGEN. 175 the tissue, aud it is generally in the form of spherules of different sizes. In the cells these spherules usually lie rather near the nucleus. Although glycogen is soluble in water, there would appear to be, ac- cording to Langhans, some difference in the degree of its solubility when obtained from different tissues, that contained in the liver, kidney, mus- cles, pus-corpuscles, etc., being distinctly more easily soluble than that from cartilage-cells and pavement epithelium. Hardening of tissues in alcohol makes the contained glycogen distinctly less soluble. The glyco- gen contained in the liver at the time of death is quickly converted into sugai" by the diastatic ferment of the liver. Iodine causes glycogen to assume a broivnisJi-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 tinc- ture (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 (G-abritschewski), in cartilage-cells, and in almost all embrj^onic 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 dis- appear entirely. In diabetes there is a deposit of glycogen in the epitheUum of the kid- ney, particularly in that lining Henle's loops, in the isthmus of which the cells are commonly almost filled with it, leaving, after solution in water, clear spaces in the cell-bodies. The glycogen in the blood is also much increased in diabetes — both that within the corpuscles and that in the blood-plasma (Gabritschewski). In fresh inflammatory exudates glycogen may be present in the pus- cells. The leucocytes of the blood contain glycogen in excess, more par- ticularly in conditions of cachexia (Czerny). Glycogen has also been ob- served in tumors of various kinds, as, for example, in the epithelial cells of condylomata, in carcinomata and adenomata of the testicle, in endo- theliomata (Driessen), in myxosarcomata, enchondromata, sarcomata of bone, and more rarely, also, in those of 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, in tumors of the ovary, of the kidney, and of lymph-nodes. It is also absent from fibro- mata, lipomata, myxomata, osteomata, angiomata, leiomyomata, and from the tissue of the infectious granulomata (Langhans). 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 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. 176 MUCOUS AND COLLOID DEGENERATIONS. VIII. Mucous and Colloid Degenerations. § 65. Mucous degeneration has its physiological prototype in the pro- duction of mucus by the mucous membranes and mucous glands, and in the formation of mucus in the connective tissue of the umbilical cord, of ten- dons, of bursse, and of synovial membranes. In the umbilical cord the mucus occurs as a jelly-like matrix; in the joints, bursas, and tendon- sheaths it forms a stringy, clear liquid. The formation of mucus in mucous membranes takes place in epithelial cells, called beaker- or goblet-cells, whose cell-bodies are in great part occupied by clear substance, the mucus which has been elaborated at the expense of their protoplasm. In mucus-formation in mucous glands the epithelial cells swell, their centres become transparent, and the proto- plasm granules become reduced to small groups or strings. The so-called mucus-corpuscles of the salivary secretion, characterized by glassy trans- parent contents in which vibrating protoplasm granules are often pres- ent, are spheroidal cells which have undergone mucous degeneration. The 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 com- pletely destroyed. The formation of mucus occurs under pathological conditions in the same manner as normally. In catarrh of the mucous membranes (of. Sec- tion VI.) the stringy excretion which forms is chiefly the result of exces- sive 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 appear to be formed from the nuclein of their nuclei (Kossel). In mucous membranes containing cylindrical epi- tlieliiim the number of beaker-cells is greatly increased as the result of catarrhal inflammation, and the exudate often contains cells which have undergone complete mucous degeneration, and which appear as glassy masses often containing a few fine granules. Again, the cells may con- tain mucus in the shape of irregular drops of various sizes. 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 Fig-. 56. Fig. 57. Fig. 56. — Epithelial ceUs which have undergone mucous degeneration, from a cystadenoma of the ovary, a, CeUs which are only slightly affected ; 6, Cells which show a high degree of mucous degeneration. (Magnified 400 diameters.) Fig. 57. — Mucous degeneration of the connective tissue of the aortic valves. a, Fibrous tissue ; h, Tissue that has undergone mucous degeneration. (The section was made from a frozen specimen that had been treated with osmic acid; it was then mounted in glycerin. Magnified 350 diameters.) MUCIN. — PSEUDOMTJCIN. 177 beaker-cells (Pig. 56, a) and cells in which the entire cell-bodies have changed into mucus (Fig. 56, h). In some carcinomata a large part of the epithehal 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 be- longing to this class. It is here more particularly the intercellular matrix (Fig. 57, b) which undergoes the mucous change, becoming converted into a homogeneous, structureless mass. The cells themselves may re- main unchanged, may become fatty, or may also undergo mucous degen- eration, 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. The stringy, gelatinous material which results from mucous degenera- tion is no single chemical substance, since in it several different varieties of mucin and pseudomucin may be detected. The mucins — of which several kinds may be distinguished, according to their soui'ce, as siibmaxillary mucin, intestinal mucin, tendon mucin — • are nitrogenous substances, which dissolve or swell up in water, forming a stringy, mucous liquid. From such solution they are precipitated by acetic acid in the form of stringy masses which fail to redissolve in ex- cess of the acid, thus differing from the true albuminoids. They dissolve in neutral salt-solutions and in caustic alkalis and alkaline carbonates, gradually forming alkali albuminates in the latter. All mucins contain both nitrogen and sidphur, the percentage of carbon, oxygen, nitrogen, and sulphur varjdng somewhat in the different varieties. By proper treatment a carbohydrate, called animal gum (Landwehr, Hammarsten), may be separated from the mucins ; and mucin may there- fore appropriately be called a giycoproteid (Pfannenstiel). Pseudomucin is also soluble in water, appearing then as a mucous Uquid, from which alcohol throws it down in the form of stringy flakes, which are again soluble in water. Acetic acid does not precipitate it. On boiling with dilute mineral acids a carbohydrate is formed (as was the case with mucin) which reduces copper sulphate in alkaline solution (Pfannenstiel). According to Pfannenstiel, pseudomucin occurs in the proliferating glandular ovarian cystadenomata, and to a certain extent also in the papillary ovarian cystadenomata, and the peculiar gelatinous and mucous consistence of the contents of these cysts is due to its pi'csence. It is produced by the epithelium of these tumors (Fig. 56), and in forming this material these cells undergo changes analogous to those described in discussing the formation of mucin by epithelial cells. In all probability the gelatinous substance found in colloid cylindrical-cell carcinomata is a substance closely related to pseudomucin or metalbumin — i.e., there are several varieties of pseudomucin, of which the two mentioned are examples. The mucin-like substance contained in the synovial secretion, coagulated by acetic acid, differs, according to Salkowski, from nucleo-albuimn in that it con- tains no phosphorus, and from ordinary mucin in its different conduct with the mineral acids, since it is not converted by them on boiling into a reducing substance. 178 COLLOID DEGENERATION. In the blood, in the bone-marrow, in the spleen in leucsemia, and in excre- tions from the inflamed bronchi in bronchial asthma, sharp, slender, colorless octahedral crystals are not infrequently found. They are called, after their discoverers, Charcot's crystals or Leyden's crystals. Salkowski believes these to be composed of a substance closely related to mucin, but crystalline in form. Schreiner, on the other hand, declares them to be composed of the phosphate of a base newly investigated by him, which he describes as a decomposition product of albumin and perhaps nearly related to the ptomaines. Cursehmann believes these crystals to be formed from disinte- grating blood-corpuscles, and Ungar has been able to produce them artificiaUy by allowing sputum to stand in a moist chamber. § 66. Colloid degeneration js closely related to mucous degeneratioij, in that it too is the result of degenerative chacge iu an albuminoid body, namely, the protoplasm of the cell. Nothing is known with certainty as to its chemical nature. It is certainly formed from the protoplasm of the cell, and occui-s physiologically (in extra-iiterine life) in moderate degree in the thyroid gland. Here, at this period, it is found lying in the midst of the parenchyma of the gland (Fig. 58, c), in the form of variously sized spherules, which are somewhat crowded together, and which, on section, present a translucent appearance - '-i'' jli^ja! > ' ."' * : suggesting boiled sago or lard. ^ ., .^-"* ^^*» ' ','.."'. p They are usually of a yellowish or '•'"*'•"' ' J . . • ' ' brownish color, and of the consis- tence of firm jelly. :tv. • i ,^^ ^ t*. '*"'.." '• ' Fig. 58. — Colloid in a specimen a***' ^f 'I*' ' «■,, ' taken from an enlarged thyroid gland. a, Follicle filled with cells ; 6, Follicle •'3' * «.--'■'• r * « V- * ^ ., i '^ with a lumen ; c, c, Masses of colloid ; C- JtV *"■-. *'»f \ '7*' ,»' "^t^ d, Capillaries; e, Connective-tissue - ',a« J^ ^\ , '. »*t' \'"^'''5Cr septum, with artery. (Specimen i," *'** ;*^**' ''-' "*»•' " t' ^ stained with alum hasmatoxyUn. r 1* ' ■ _■''' „I_ Magnified 60 diameters.) When this colloid is pathologically increased in amount it may come to compose by far the greater part of the whole volume of the thyroid gland, and may cause it to be greatly enlarged (colloid goitre). Microscopically the coUoid of the thyroid gland possesses a homogene- ous appearance ; it contains but very few cellular elements, and these confined to the periphery of the mass, where the colloid is in process of formation. Occasionally a large mass will be made up of a number of smaller ones, or may be mottled with vacuoles. In the formation of col- loid, small, homogeneous, spheroidal masses first make their appearance in the cells of the thyroid, and these, as they continue to grow, may be discharged from the cell or may gather together into a single mass fill- ing the entire cell-body. As far as can be judged from a histological examination, colloid may also develop from masses of desquamated epi- thelial cells (Fig. 59, g), in which case the individual cells break down and form a single homogeneous mass. Colloid masses, in all particulars similar to those above described, are oc- casionally contained in the renal tubules of diseased kidneys (Fig. 59,/, h), and often in the follicles of the hypophysis cerebri (the pituitaiy body). In the tubules of kidneys which have undergone cystic degeneration such col- loid spherules are sometimes present in large numbers. Occasionally the LOCALITIES -WHERE HYALINE SUBSTANCE OCCURS. 179 connective tissue of the diseased and atrophied gastric mucous membrane may contain hyaline bodies similar to colloid. Colloid is distinguishable from mucus in that it does not swell or dis- solve in water, that acetic acid does not coagulate it, and that it is not made opaque by the action of alcohol or of chromic acid. Observations by Biondi, Langendorf, Podbelsky, and Hiirthle would indicate that a part of the colloid substance produced in the follicles of the thyroid gland finds its way into the lymphatics ; for at the points where these vessels come in contact with the glandular tissue, a melting- down of the epithelium takes place, and an opening is estabUshed be- tween the sacs which contain this broken-down material and the lym- phatic channels. Fig. 59. — Section of a con- tacted kidney, showing ar- teriosclerosis and masses of colloid in the \iriniferons tu- bules, a, TMekened artery ; 6, Wasted glomerulus ; c, Cap- sule of the glomerulus ; d, e, Atrophic uriniferous tubules ; /, Tubules with laminated col- loid casts in their interior; /loid substance is deposited in the affected parts, caus- ing them to increase in size and to assume a peculiar wax!/ appearance. It may occur in almost all the organs of the body, but is more frequently met with in the spleen, liver, kidneys, intestine, stomach, suprarenal bodies, pancreas, and in the tympli-giauds. It is encountered less often in fat- tissue, in the thj'roid gland, in the aorta, in the heart, in the muscles, in the ovaries, and in the uterus. When extensive it is readily recognizable by the naked eye, as the affected parts present a translucent waxy appearance {lardaceous degen- eration). In the spleen the change occurs most frecxuently in the region of the glomeruli, which may become completely changed into homogeneous, transparent areas I'esembling grains of boiled sago, whence this form of amyloid spleen has come to be called the sago-spleen. When the amyloid degeneration is present also in the spleen-pulp, more or less distinctly recognizable waxy lines and streaks appear on its cut surface. At times almost the entire substance of the spleen may be thus affected. The spleen is then enlarged and feels hard, and may look as if composed entirely of wax {lardaceous spleen). The changes in the appearance of the liver are similar in that here also, when the amyloid change is extensive, clear, translucent waxy areas appear, which may subsequently become confluent and lead to a consider- able enlargement and hardening of the liver. The liver-tissue lying be- tween the masses of amyloid substance may be redder than normal, or it may look pale and yellowish because of fatty degeneration in it. The kidney may also be increased in size and in firmness of texture as the result of amyloid degeneration, and may, at times, in spots or throughout its whole substance, present a similar waxy appearance. In other cases the waxy areas may be so small as to be invisible to the naked eye, and it may be only through the presence of other visible changes, REACTIONS OF AMYLOID SUBSTANCE. 181 especially of fatty degeneration, that one is led to suspect amyloid. In the intestine, also, the amyloid is rarely distinguishable without optical and chemical aids, and the same holds true of most of the organs in which amyloid is of rarer occurrence, as in fat-tissue, in the heart, in the larger arteries, the thyroid gland, etc. The substance which is deposited in amyloid degeneration forms for .the most part shining, Jiomogeneous viasses which develop & peculiar reac- tion with iodine and with some of the aniline dyes. Iodine in water, or, bet- ter, in a solution of potassium iodide, when poured over amyloid tissue, causes the amyloid substance to assume a dark mahogany-red color. In thin sec- tions, under the mi- croscope, this reaction differentiates the amy- loid substance very clearly from the psile- veUow suiTOunding tissue (Pig. 60, b). Fig. 60.— Section of an amyloid liver, show- ing the effects of stain- ing it with a solution of iodine, a, Normal liver- tissue;- b, Tissue that has undergone amyloid degeneration ; c, Glis- son's capsule. (Magni- fied 35 diameters.) In very weU-marked amyloid degeneration, when the tissues are of an almost wooden hardness, this reaction sometimes results in the produc- tion of a violet or bluish or green color ; and specimens which have been changed to a mahogany color by the action of iodine, when treated with dilute sulphuric acid or with solution of chloride of zinc, may similarly turn red, violet, blue, or green, or, on the other hand, the original mahog- any color may simply be intensified. This reaction is, however, often unsatisfactory. The aniline dye known as methyl violet or aniline violet colors amyloid substance ruby red (Pig. 61, b), while the healthy tissue is at the same time stained blue or deep violet (Pig. 61, a, c, e). Fig, 61. — Section of an amyloid liver after hein g treated with methyl violet and acetic acid, a, Elongated masses of liver-cells ; 6, Amyloid substance; c, Endothelium of the capillaries; e, Colorless blood-cor- puscles. (Magnified 150 diameters.) 182 LOCALITIES WHERE AJIYLOID SUBSTANCE IS DEPOSITED. Vircliow, the discoverer of amyloid substance, was the first to observe its peculiar reaction with iodine, from which he inferred that amyloid must be devoid of nitrogen and must be nearly related to cellulose or starch, since cellulose, when tre.itcd with iodine and concentrated sul- phuric acid, assumes an intense blue color, and similarly starch becomes of an ultramarine blue when treated with iodine alone. Virchow accord- ingly gave the name amyloid to the newly discovered substance. It was not until several years later that Friedreich and Kekule demonstrated that the so-called amyloid is in reality a nitrogenous substance of an albuminous natm-e. The peculiar reaction of amyloid substance makes it possible to detect its presence in the tissues in cases in which it is present in such smaU amount as to be quite in\'isible without the aid of iodine. In applying tlie test to fresh tissues, care should be taken to wash out the blood as perfectly as possible, since the color resulting from the combination of the red haemoglobin and the yellowish-brown iodine rather closely resem- bles the mahogany red of the amyloid. Amyloid is very resistant to acids and alkalis. It is not changed by al(v)hol and chromic acid, aud it is only slowly affected by the changes of putrefaction. Amyloid material is deposited in the framewor'k composed of blood- ivasels and connective tissue, and more particularly in the tvalls themselves of the smaller blood-vessels. Living cells are not affected by it. In connec- tive tissue the amyloid material would appear to be first deposited between tlie connective-tissue fibres. In the acini of the liver the amyloid material is found in close prox- imity to the capillary tubes. The endothelium (Fig. 61, c) is covered on its outer side by a more or less thick layer of homogeneous, glassy sub- stance composed whoUy of amyloid material. The hver-ceUs between the amyloid masses are either well preserved (Fig. 61, a) or they may be compressed and already undergoing atrophy. They often contain fat. The larger blood-vessels of the liver also at times show amyloid changes, more particularly in the media of the ai'teries. In the kidney (Pig. 62) the amyloid is found most abundantly in the walls of the vessels, the vessels of the glomeruM (Fig. 62, b) beir.g moder- ately swollen and homogeneous, aiid similar homogeneous deposits occur- ring also in the arteries (Fig. (32, /), veins, and capillaries (Pig. 62, k) of other parts of the kidney. In the mucous membrane of the intestine the amyloid deposit also occurs in the walls of the blood-vessels more i)articu]arly. In fat-tissue, which is often (extensively affected with amyloid disease, the waxj^ material is found both in the walls of the blood-vessels and in the connective-tissue stroma, so that at times the thin connective-tissue sheath of the fat-cells may be converted into a clear hyaline substance. In lymph-glands and in the spleen, as has been already said, it is the coiniective-tissue framework which is more espeoiall}' affected and which often becomes much thickened (Pig. 63, a, b). In striated muscle it is the perimysium intei-num and the sarcolemma which are involved. In glan- dular organs possessing a tunica propria — as, for example, the mucous glands and the kidney — this membrane may also be affected and swell to a very cf)nsiderable extent. The results of amyloid degeneration which make themselves appa- rent to the eye, and which in a measure account for the perversions of AMYLOID DEGENERATION. 183 \ -fl in, I Fig. 62. — Section of an amyloid kidney, a, Normal vascular loops ; 6, Loops affected with amyloid disease ; c, Fatty glomerulus epithelium ; Ci, Fatty capsule epitheHum ; d, Fat-drops lying against the outer surface of the capillaries ; e, Fatty epithelium in situ ; f, Desquamated and fatty epithelium ; g, Hyaline co- agulations (urinary casts) ; h, Transverse section of a east composed of fat- drops ; i, Amyloid artery ; k, Amyloid capillary ; I, Cellular infiltration of the connective tissue ; m, Round cells within the uriniferous tubules. (Magnified 300 diameters. Specimen treated with MiiUer's fluid, perosmic acid, and methyl violet.) function observed in cases of amyloid disease, are the pronounced change ill structure of the affected tissue, and the degenerative changes in the cells of tile affected organ. Amyloid disease, consequently, has a distinctly de- generative quality. The connective tissue itself is permanently changed, as the insoluble amyloid substance would appear never to be removed from it, and it is self-evident that the function of organs thus affected must be seriously impaired. The deposit of amyloid material in the blood-vessels leads to very considerable thickening of their walls, and at the same time to narrowing or even obliteration of their lumina, both of which conditions entail per- manent interference with the circulation. The amyloid masses compress the surrounding epithelial structures and cause them to atrophy, and at the same time, on account of the impaired circulation, they may undergo fatty degeneration. These changes are well seen in amyloid degenera- tion of the liver, in which the liver-cells are always more or less deformed and atrophied as the result of pressure, and are often in a condition of pronounced fatty degeneration. In the kidney, also, fatty degeneration of the tubular epithelium is a prominent characteristic of the amyloid change, though it should be remembered that other conditions occurring in association with the amyloid disease may contribute to this change, and that on that account the degree of fatty change is not to be relied 184 NATURE OF AMYLOID DEGENERATION. upon as indicative of the intensity of the amyloid disease, being often very extensive where the amyloid change is but slight. In the spleen and lymph-glands, also, the cells lying in the meshes of the swoUen trabeculae disappear as the result of atrophy and fatty de- generation (Fig. 63, /), and in c-JW muscles the contractile sub- stance diminishes 'pari passu with the increase of the amyloid material. Fig. 63. — Amyloid swelling of the reticulum of a lymphatic gland. (After Eberth.) a, Normal reticu- lum ; 6, Swollen reticulum ; c, Nu- cleus still unaffected; d, d, Degen- erated nuclei; e, Normal lymph- corpuscles ; /, Atrophic lymph-cor- puscles. (Magnified 350 diameters. Methyl-violet preparation.) Regarding the causes and nature of amyloid degeneration but httle can be stated with certainty. We know that it is of most frequent occur- rence in the various cachectic states, but we are wholly in the dark as to the precise perversions of nutrition which bring it about. The diseases with which it is most frequently associated are tuberculosis of the lungs and of the bones, syphihs, chronic dysentery, and leucaemia, and often in these diseases the most extensive amyloid degeneration will be found, while in the cachexia resulting from carcinoma it is but rarely observed. Occasionally it occurs without any discoverable preexistent disease, and observations by Cohnheim would make it appear that it may become well developed in from two to three months. Amyloid cinmge ivJiich is ividely distributed throughout the lody must re- sult from general causes. The amyloid substance itself does not exist in the blood, but the material from which it is formed is undoubtedly derived from the blood, and it would appear that the lowered vitality of the tissues re- sulting from general cachexia favors its formation. Perhaps in the con- ditions mentioned this peculiar amyloid substance results from the union of an albuminous material derived from the blood with some constituent of the tissues ; or, as the result of impaired nutrition, a peculiarly modified albuminous body may be separated from the albumin in the circulation Virchow and Kyber have drawn a parallel, and very properly as it seems to me, between amyloid degeneration of tissues and calcification. In both, a tissue of lowered vitality, because of impaired nutrition, becomes flUed with a sub- stance brought to it by the blood, and becomes intimately combined with sub- stances preexisting in the tissue. Wagner considers amyloid material to be the result of a retrograde metamorphosis of the albuminates, or more definitely as an intermediate stage between them and fat. Von Recklinghausen advances the hypothesis that in amyloid formation a homogeneous material is formed by the cells and, constantly washed by the lymph, swells and conglomerates, simi- larly to mucus, forming itself into small masses, reticula, membranes, or tubes. It has seemed to me that the amyloid material must be derived from the circu- lating blood, and I would venture the opinion that, as the result of the lowered metabolic power of the tissues, the substance thus derived cannot be converted, as under normal conditions, into nutritive matter, but lies in the tissues and undergoes metamorphosis into the peculiar material which we term amyloid. LOCAL AMYLOID INFILTRATIONS. 185 Czerny believes that the precursor of amyloid is to be found in tbe white blood- oorpuscles. § 68. The form of amyloid degeneration which we have thus far con- sidered is a disease which usually affects a number of organs of the body, or, if confined to one of them, is more or less uniformly distributed throughout its entire substance. There is, however, a form of amyloid change in which localized deposits of amyloid material occur either in the form of localized amyloid infiltrations of the tissues or as free concretions. Local amyloid infiltrations are met with in granulations which are rich in cells, ia chronically inflamed tissues, in cicatrices, and in hyper- plastic connective-tissue growths. They occur also in tumors in which other degenerative processes are in progress. In some cases only small particles of amyloid material are formed, and then frequently in the walls of the vessels ; but in other cases large masses are met with, composed almost entirely of amyloid substance and often almost as hard as wood. The amyloid substance is here also deposited in the basement substance of the tissue, though it is held by some authors (Rahlmann) that the ceUs of the tissue may also acquire a hyaline appearance and give the reactions characteristic of amyloid. Such local amyloid deposits have been found in the inflamed con- junctiva, in syphilitic scars in the liver, tongue, and larynx, in inflamed lymph-glands, in ulcers of bone, and in tumors of the larynx and stomach. Tumor-hke amyloid masses are also occasionally met with in the conjunc- tiva, tongue, larynx, and trachea under conditions in which it is impos- sible to establish any relationship between them and some inflammatory process, and where, besides, there is but little normal connective tissue in the vicinity of the amyloid masses. Freely lying amyloid concretions, or corpora amylacea, are most often found in the tissues of the central nervous system, especially in the spinal cord and in the ependyma of the cerebral ventricles. They occur also in the prostate gland. Those found in the nervous system are for the most part small, homogeneous, and somewhat shining particles (Red- lich), usually devoid of any definite nucleus (Pig. 64, c). In the prostate they are larger and usually show dis- tinct stratification (Fig. 64, a). Wag- ner and Langhans have observed corpora amylacea in carcinomata, and they have also been found in the lung (Friedreich, Zahn, Ziegler), in inflammatory areas, in bloodj^ extravasations, and in emphysema. Fig. 64.— Corpora amylacea. a, Laminated concretions from the prostate. (Magnified 200 diameters.) h, Corpus amylaceum from an old hemorrhagic infarction of the lungs, with hsematoidm crystals in the nu- cleus. (Magnified 2()0 diameters.) c, Corpora amylacea from the spmal cord. (Magnified 400 diameters.) These, local deposits of amyloid material and the amyloid concretions should not be considered as altogether similar to the progressive amyloid 186 HYALESTE DEGENERATION. change to which we apply the term amyloid degeneration. Some of them, it is true, give the characteristic amyloid reaction, and the coi-pora amylaeea of the nervous system, in particular, assume the characteristic blue color when treated with iodine and sulphm-ic acid. But, in the case of these bodies, we have to do with formations dependent essentially upon local conditions for their origin, and it can hardly be disputed that they are formed from the albumin of the affected tissue. The concretions of the prostate are. made up of degenerating epithelium or of fragments of the same matted together in layers, and it is probable that the similar bodies in the lung and in tumors are composed chiefly of fragments of degenerated cells, though in part, also, of albumin from the blood. Eed- lich considers the corpora amylaeea of the nervous system, which stain similarly to nuclei with hfematoxylin, to be made np of the nuclei of neurogiia-eells and to be a senile retrograde development of the tissue. Stroebe, however, believes them to be composed of fragments of swollen axis- cylinders, while Siegert believes them to have originated from cells. X. Hyaline Degeneration of Connective Tissue. § 69. Hyaline degeneration is naturally taken up next in order after amyloid degeneration, both because of the appearance of its product and because of its occurrence in connective tissue and in blood-vessels. But it does not give the reactions characteristic of amyloid. Wlien hyaline degeneration begins there is usually a degeneration of the walls of the smaller vessels (Fig. 65, a), as the result of which a hya- line material, strikingly similar to amyloid, but differing from it in reac- tions, is formed just externally to the endothelium of the vessels, making their walls thicker and narrowing their lumina, until the vessels may be- come very narrow tubes whose outline is made irregular by the presence of the hyaline material in theii- walls. Finally, the lumen of the vessel Fig. 65. Fig. 65.— Hyaline degeneration of the blood-vessels of an atrophiclymph- gland from the axilla, a, Vessels which have undergone hyaline degeneration, but still possess an open lumen ; 6, Obliterated vessels. (Specimen hardened in alcohol and stained with alum carmine and picric acid ; and the section mounted m Canada balsam. Magnified 200 diameters.) Fig. 63. — Hyaline degeneration of the connective tissue of the myocardium. a, Normal cof^nective tissue ; h, Connective tissue that has undergone hyalme degeneration ; c. Hyaline masses ; d, Transverse sections of normal muscle-cells ; e, Transverse sections of mu.scle-cells which are atrophic. (Preparation treated with hasmatoxyhn and neutral oarmme, and mounted in Canada balsam. Mag- nified 250 diameters.) CHANGES OBSERVED IN HYALINE DEGENERATION. " 187 may be completely obliterated, in which case its endothelium, which may have remained practically unaltered or may have even proliferated up to that time, disappears. Occasionally the hyaline substance is deposited in drop-like masses in the immediate neighborhood of the vessels, but with- out compressing their lumina. These changes are most frequently met with in the vessels of the glomeruli of the kidney and in those of the thy- roid, brain, lymph-glands (Fig. 65), choroid, and retina (in cases of lead- poisoning) (Oeller). Vossius and others have shown that the conjunc- tiva may be the seat of tumor-like growths, composed of adenoid tissue, in which the reticular basement substance becomes hyahne, swells, and ac- quires a knotty appearance, and in which the cells undergo atrophy. The mode of formation of these hyaline masses cannot be stated with positiveness, though it would appear likely that the walls of the vessels and the connective tissue become infiltrated with a hquid of some sort ■ which coagulates. It is possible, also, that the leucocytes and blood-plates furnish a portion of the hj'aline substance, and Oeller believes that red blood-corpuscles also participate in its formation. Occasionally, though rarely, hyaline degeneration typical in appear- ance is met with in fibrous connective tissue — as, for example, in the con- nective tissue of the heart, intestine, and thyroid gland^and may then cause a material increase in volume of the connective tissue of the organ (Fig. 66, 6). In the early stages of this process the connective tissue appears uniformly homogeneous and loses its fibrillar appearance ; later, distinct masses of hyaline material form, just as was described in connec- tion with amyloid degeneration. In this process everything included in the degenerated area degenerates and disappears — both parenchyma and connective-tissue cells. These changes are unquestionably closely related to those which occur in amyloid degeneration, both in appearance and in significance, for por- tions of the hyaline material may undergo conversion into amyloid, thus causing combinations of the two forms of degeneration. A second variety of hyaline degeneration of connective tissue, to which Virchow has applied the term sclerosis, occurs in old age as a rather fre- quent affection of the intima of the valves of the heart and of the arteries. It is also met with in strumous thyroid glands, in cicatrices, and in the connective-tissue stroma of tumors. As in the first-mentioned form of hyaline change, the tissue acquires a homogeneous appearance and becomes thickened and actually in- creased in volume to a certain extent. The contained cells, which are at first preserved, ultimately undergo fatty degeneration in most cases and disappear. Finally calcification of the h^-aline material may occur. The origin of this variety of degeneration is shrouded in even greater obsem-ity than that of amyloid degeneration. There can be no question as to its being a form of retrograde change, and since there is moderate increase in volume of the affected tissue, it is probable that a deposit of some sort occurs in it. Whether the mode of development of this variety of hyaline degeneration is the same as that of the first-described variety, differing from it only quantitatively, is questionable. The degenerated areas react similarly in both cases to staining solutions and reagents, al though to the naked eye the sclerotic areas appear to be less translucent than the others. The preparation pictured above (Fig. 66) was obtaiaed from the heart of a woman about fifty-five years of age, the greater part of which had undergone hyahne degeneration. Numerous hyaline plates and masses were found in the 13 188 CALCIFICATION. endocardium and pericardium. The muscle-tissue was in parts degenerated as shown in the figure. Associated with this condition in the heart there was exten- sive degeneration of the blood-vessels, particularly of the intestine, tongue, lungs, heart, and bladder. The peritoneum was also thickly bestrewn with hyaline masses. The fact that the smaller hyaline areas and the periphery of the larger areas gave no iodine reaction, while the central portions of the larger areas did so, appears to me to make the close relationship between hyaline and amyloid sub- stance unquestionable. And this is further supported by the fact that amyloid organs occasionally contain areas of hyaline degeneration. It would therefore appear permissible to advance the hypothesis that amyloid substance is formed from a hyaline albuminous body not reacting to iodine, but that the transition from the one to the other usually occurs very quickly. Litten* has made the observation that portions of amyloid tissue introduced into the abdominal cavity of animals undergo a change, in the course of several months, as the result of which they lose their power to react to iodine and methyl violet, although their transparence and homogeneity are preserved. From this it would seem that amyloid may at times be converted into hyaline material. Van Gieson's method of staining connective tissue is well adapted to the detection of hyaline. It consists of overstaining with haBmatoxylin, and of de- colorization and contrast-staining with watery solution of picric acid which has been made of a hght-red color by the addition of a few drops of acid-fuchsin solution. With this stain the hyaline material takes on a brilliant red color, while amyloid assumes a more orange color. XI. Calcification and the Formation of Concretions and Calculi. § 70. It is, on the w^hole, a rather frequent occurrence for crystals, or amorphous and granular masses, to be precipitated here and there in the body ; and w^hen such deposits are in sufficient amount to cause harden- ing of the affected tissue, the resultant condition is spoken of as petri= faction, or, when the deposited material consists of lime-salts, as calci- fication. Such deposit may occur in tissue which forms an integral part of an organ and which bears its normal relation to the surrounding tissues. In other cases it may form an incrustation around tissues which have been separated in some manner from their surroundings, or around foreign bodies which have found theii' way into the body from without, and have then become the centres of a process of incrustation. In the first case calcification of the tissue results ; in the second, free concretions and calculi are formed. It is to be remembered, however, that concretions which may have been at first free may occasionally be- come firmly attached to the tissues of the organ in which they lie by growth into them of some of the siirrounding tissue ; and, on the other hand, a portion of calcified tissue may gradually undergo separation from the siuTounding tissue and ultimately foi-m a free concretion. The cause of calcification is for the most part to le found in local changes ill the tissues, since the deposit of lime-salts usua% occurs in localities in which the tissue has already died or is in process of degeneration and necrobiosis. It looks as if dying tissue, which has undergone more or less modification, possesses a kind of attraction for the lime-salts in solu- tion in the body, and enters into intimate combination with them. Among the degenerating or dead tissues which are particularly prone to undergo calcification we may mention in particular connective tissue (§ 69) * "Ueber die Amyloiddegeneration," Deutsche med. Wochenschrift, 1877. CONCRETIONS AND CALCULI. 189 which has undergone hyaline degeneration ; such connective tissue being quite often encountered in the walls of the blood-vessels, in the endocar- dium, in an enlarged and degenerated thyroid, or in thickenings of the pleura or pericardium. It is common, also, in degenerative areas in the walls of blood-vessels, or in tumors, or in any other portion of the body in which hyaline and fatty degeneration are in progress ; in degenerating cartilage; in dead cell-bodies, as, for example, in dead ganglion-cells (Fig. 68) or kidney epitheliuih (especially in corrosive-sublimate, aloin-, or bismuth-poisoning) ; or in cii'cumscribed cheesy areas of considerable size. Calcification occurs, also, at times in tissues which have undergone much less degeneration and in which there are still living cells ; and under very exceptional conditions it may take place in tissues which show no recog- nizable change. This occurs more particularly in advanced age, when the lime-salts of the skeleton are undergoing more rapid absorption, in which case they may be deposited in the lungs as well as in the kidneys and in the mucous membrane of the stomach. The lime-salts are deposited in the form of small granules (Figs. 67 and 68), and preparations are occasionally met with in which the sepa- rate calcareous granules are still visible. Fig. 67. Fig. 68. Fig. 67. — Calcification of the media of the aorta. (Magnified 350 diameters.) Fig. 68. — Calcified ganglion-cells from the brain of a demented person affected with hemiplegia and with a dropsical effusion in the ventricle of one side. (Magnified 500 diameters.) As the result of conglomeration of these granules, larger masses and spherules may be developed (Fig. 68). More frequently, however, a more homogeneous deposit forms, in which it is impossible to distinguish the individual granules. Both cells and intercellular substance may undergo calcification, and when calcification is in progress the degenerated tissue comports itself somewhat differently toward certain stains than normal, unchanged cell- protoplasm or intercellular substance does. Thus hsematoxjdin imparts a dirty bluish-violet color to it, and it usually stains red with picrocar- mine. This applies, however, only to deposits of carbonates and phos- phates of lime, not to those of oxalate of lime. Calcification may aflbect small or large areas of tissue, causing, in the latter instance, distinct hardening of the tissue and a whitish coloration. At times such calcified areas are sharply separated from the surrounding tissue in the shape of spheroidal, spindle-shaped, or cactus-like masses (Fig. 69 and Fig. 70, a, b, c, d), being in reality concretions lying in the 190 PSAMMOMATA. tissue. Not infrequently these are of sufficient size to be readily visible to the naked eye. Such concretions occur physiologically in the form of stratified calcific spherules in the pineal gland and in the choroid plexus, and are then known as brain-sand {acervulus cerebri). Pathologically they are met with in various localities in the pia and dura mater, in tumors of these membranes (psammomata — Fig. 70), in cheesy areas (Pig. 69, b), and in nodular growths of connective tissue (Pig. 69, a). Fig. 69. Fig. 69. — Calcareous concretions, a, Concretions from an inflamed omen- tum; h, Calcareous glands from a tubercular lymph-gland that has undergone cheesy degeneration. (Magnified 200 diameters.) Fig. 70. — Section of a psammoma of the dura mater, with calcareous formations, a, Hyaline nucleated balls with an inclosed grain of calcareous material ; 6, Calcareous formations surrounded by a non-nucleated hyaline sub- stance encapsulated in an envelope of fibrous connective tissue ; c, Calcareous nodule surrounded by hyaline connective tissue ; d, Calcareous spieute in the con- nective tissue ; e, A calcareous spicule, with three separate concretions, embedded in the connective tissue. {Specimen hardened in alcohol and then decalcified in picric acid; the section stained with hsematoxylin and eosin. Magnified 200 diameters.) The formation of these bodies may perhaps be best described as it occui'S in the psammomata. Some of the cells of the tissue (Fig. 70, a, b, c) or a circumscribed area of connective tissue (Pig. 70, d) undergo hyaline degeneration, the nuclei being at first preserved, but later lost. In this way small hyaline spherical areas ai-e formed, and in these the deposit of lime-salts takes place. The more spheroidal concretions would appear to be formed from masses of degenerated cells, while the longer, spindle- shaped concretions seem to have their origin in the connective tissue, though it would seem that the spheroidal masses may also be formed in it. The variety of connective tissue Avhich undergoes this calcification is the ordinary white fibrous tissue, but concretions may also occasionally form in the connective tissue surrounding the blood-vessels. § 71. The ordinary petrifaction or calcification of the tissues results from a deposit of carbonate and phosphate of lime, to which occasionally magnesium-salts are added. In certain states of the body, however, a deposit of uric-acid salts takes place. This is notably the case in gout, in which an excess of uric acid accumulates in the body as the result of chronic disturbance of nutrition. GOUTY DEPOSITS. 191 Gout is usually inherited, though it may occasionally be acquired. It is of very frequent occurrence in England and in northern Germany, bat is rare in other localities, as, for example, in southern Germany. As to its ultimate cause we know practically nothing. It is characterized chiefly by the deposit in the body of urates (Fig. 71, b), particularly of sodium Pig. 71. — Deposits of urates in the knee-joint, in a case of gout, a, Condyles of the femur ; 6, Deposits of urates upon the cartilaginous surface. (Two-thirds natural size.) urate, with which small quantities of carbonates and phosphates are sometimes associated. The deposit of these salts is usually accompanied by symptoms of a very acute nature — pain and inflammation ; though at times, when the deposit takes place very slowly, there may be no charac- teristic acute attack. The kidnej^s and the skin and subcutaneous tissue are perhaps most often affected, though deposits may also take place in the tendon-sheaths, the tendons, hgaments, synovial membranes, and ar- ticular cartilages (Fig. 71), and may ultimately be found in nearly every organ of the body. The metatarsophalangeal joint of the great toe is a favorite site. The deposits consist for the most part of bunches of fine acicular crystals (Fig. 72) and lie usually in necrotic tissue, which fact has led Ebstein to infer that the urates cause necrosis of the tis- sue in which they have been de- posited. Fig. 72.— Deposit of needle- shaped crystals of urate of soda in the articular cartilage. (After Lan- cereaux. Magnified 200 diameters.) The areas in which this incrustation and necrosis have occurred are at first small, but soon cause inflammation and proliferation in the sur- rounding tissue. These areas, with the occurrence of fresh deposits, may 192 FREE CONCRETIONS. increase in size, and in tliis way often attain, after a time, considerable dimensions. These larger deposits are called tophi. I hey consist of white, plaster-like snbstance, and at times form large rounded masses, more especially in the joints and tendons (Fig. 73). In the joints the articu- lar cartilage looks at first as if it had been sprinkled over with plaster of Paris (Fig. 71, h), bnt with time the white substance penetrates deeper and deeper into it, until finally it may perme- ate the whole cartilage. In the kidney the necrosis of tissue and inflammatory condition consequent upon a deposit of urates may lead to induration and contrac- tion of the organ. The de- posit is more abundant in the medullary substance of the kidney, but is also met with in the cortex. According to Garrod and Ebstein, the acute ex- acerbation in gout depends upon excessive accumula^ tion of uric acid, either as the result of deficient excre- tion by the kidneys (Gar- rod) or because of local changes in the affected tis- sue (Ebstein). Pfeiffer ex- plains it by supposing that the deposits of salts depend simply upon the presence in excess, in the body-liquids, of a substance which is sol- uble with difficulty in them, and which therefore may very readily be deposited in various parts of the body, sometimes accumulating there in such quantity as to induce a localized necrosis. The symptoms of the attack are supposed to depend upon a temporary increase in alkalinity of the liquids of the body, en- abling them to dissolve and absorb a portion of the deposited salts, in the course of which procedure pain and inflammation are induced. Von Noorden, on the other hand, considers uric-acid formation and deposit to be a secondary phenomenon, caused by the presence of a localized fer- ment of some sort, and quite independent of the amount and condition of the uric acid forjned in other parts of the body. Fig. 73.— Gouty nodes of the hand Lancereaux.) (After § 72. Free concretions occur most often in ducts and in cavities of the body which are lined by epithelium, as in the intestine, in the ducts ENTEROLITHS. — BRONCHIAL CALCULI. — WALL-STONES. 193 of the glands pouring their secretions into the intestine, in the gall-blad- der, in the uiinary passages, and in the respiratory passages. The con- cretions occasionally met with in the lumina of vessels and in serous cavities might also be included in this gi'oup, although they are for the most part closely bound to the surronnding tissue. All free concretions have an organic basis or nucleus. Thus enteroliths which form in the intestine have a basis of inspissated isecus, or hairs (bezoar-stones, segagropilse), or indigestible vegetable material, or some- thing of the sort, in which phosphates of ammonia, magnesia, and lime, and carbonates are deposited in varying proportions, according to the nature of the food taken. The tartar of the teeth is formed by the de- posit of lime-salts in particles of food, miicus, or masses of bacteria, which collect upon the teeth ; and it is probable that the calculi which form in the ducts of the salivary glands and in the ducts of the pancreas originate primarily from a substance derived from the epithelium. Bronchial calculi result from the deposit of lime-salts in dried and thickened bronchial secretion ; and the stones found in arteries and veins, from calcification of thrombi. Gall-stones often seem to be made up entirely of crystalUne material ; but by the employment of suitable methods of examination it is always possible to show that they also contain a nitrogenous basis. They are for the most part spheroidal or faceted concretions of various sizes, whose cleavage suggests a crystalline structure. Several varieties of gall- stones are, in fact, distinguished according to the substance depos- ited in them. Thus there are gall-stones com- posed of cholesterin alone, or cho- lesterin and bUe-pigment, others of bilirubin, others of biliverdin and lime, and still others of ca.rbonate of Ume alone. The most frequent Fig. 74.— Faceted concretions from are the first two, and the calculi the gall-bladder. (Natural size.) composed of them have a ray-like, crystalline, and sometimes stratified cleavage, and are white or colored in proportion to theu' content of bile-pigment. If the cholesterin of one of these gall-stones be dissolved out by ether, it will be found that a rather yellowish substance remains, which pre- serves the shape of the original stone, and which, when embedded and cut for microscopic examination, will be found to consist of a delicate homogeneous material (Fig. 75) in which there are usually radiating spaces formerly occupied by the crystals, and which frequently shows concentric stratification. It is possible to demonstrate a similar ground- substance in other calculi after solution of their contained salts. There can, then, be no doubt that gall-stones also are the result of incrustation of an organic substratum in all probability derived from the mucous membrane of the bile-ducts and gall-bladder. Gall-stones are more apt to form in advanced life. Naunyn is very positively of the opinion that stagnation of the bile in the biliary passages is a universal cause of their formation, that this condition and disease of the mucous membrane lead to desquamation and degeneration of the epithelium, and 194 GALL-STONES. that in this debris the deposit of cholesterin and bile coloring-matters takes place. In conformity with this view is the fact demonstrated by Steinmann that albuminous substances are capable of precipitating lime from solutions in which it is present as chloride or sulphate, in the form of carbonate ; and he has shown that the shells of mollusks are produced by calcification, in this way, of mucous material elaborated by the mantle Fig. 75. — Transverse sec- tion of a small so-called cho- lesterin calculus after the re- moval of aU the cholesterin. (Magnified 15 diameters.) epithelium. When a concretion has once started, its growth continues as the result of fresh deposits of degenerated material which is incrusted with cholesterin and bile-pigment as before, and so on. At the same time the original softer nucleus of the concretion undergoes a change in that its sohd ingredients seem to be attracted to the denser periphery of the stone, while its organic ingredients may liquefy. This accounts for the occasional presence of a cavity filled with liquid in the centre of gall- stones. In time cholesterin fills this cavity and in great part replaces the bile-pigment in the remainder of the stone. Carbonate of lime may also be deposited. Gall-stones consequently occur where epitheliunLof the mucous mem- brane is degenerating, and it is probable that much of the cholesterin which composes these masses is derived from its protoplasm. The chalky deposits stained with bilirubin have their origin in the lime-salts secreted by the mucous membrane, and their precipitation would appear to be aided by the presence, in the secreted mucus, of the degenerating albu- minous material. Of course the cause of the epithelial degeneration is inflammation of the bile-passages, which may be brought about by stag- nation of the bile, or perhaps, also, by penetration of bacteria into the common duct. Finally, Ebstein has shown that the concretions and calculi found in fJie iirinarii passages are also composed of an albuminous stroma in which various ingredients of the urine have been deposited. These concretions are described, according to their situation, as occurring in the kidney or in the urinary passages leading from it. In the kidney they are, as a rule, small deposits which, as already alluded to in §§ 70 and 71, may form in the tissue of the kidney or in the lumina of the urinary tubules, in which latter case thej^ are interspersed with debris of the tubular epi- thehum. _ This is true, for the most part, of the calcifications which are observed in cases of poisoning by corrosive sublimate, bismuth, and aloin, URINARY CALCULI. 195 and, more rarely, in poisoning by phosphorus, potassium chromate, and oxalic acid. It is also true of at least some of the gouty deposits. Fur- thermore, concretions of uric acid are frequently met with in the uri- niferous tubules of children who have died during the first two weeks or so of life. They impart to the medullary portion of the kidney a distinct streaked, yellowish appearance, the condition being spoken of as uric- acid infarctimi of the new-born. The epithelium lining the tubules in which these concretions are found is for the most part well preserved, but in places slight desquamation and degeneration of the desciuamated cells will be found. In the lumiiia of the tubules are many small spher- ules (Fig. 76, b), radially striated, colorless, or slightly brownish, and com- posed chiefly of urates or of uric acid. On solution of the uric acid a fine delicate stroma remains (Fig. 76, c). If, as the result of the presence of these concretions, further desquamation and degeneration of the epithe- FiG. 76.— Uric-acid infarc- tion from a new-born child. Transverse section of a pyra- mid of the kidney, a, Collect- ing-tube of the papillary zone of the medullary portion, seen in transverse section and as yet in a normal condition ; 6, Dilated eoUecting-tubes filled with uric-aoid concretions ; c shows what remains in one of these tubes after the concre- tions have been extracted by the aid of water. (Speci- men hardened in alcohol, stained with hsematoxylin, and mounted in Canada bal- sam . The part at c was drawn from another specimen which had been allowed to soak for some time in water. Magni- fied 200 diameters.) lium takes place, leading to the formation of considerable albuminous degenerated material in the tubules, some of the smaller concretions may graduall}' grow, as the result of accretion, to stones of considerable size ; but this is unusual. Concretions may also form in the pelvis of the kidney, in the ureters, in the bladder, in the urethra, or even under the prepuce, in the form of sand, gravel, or calculi. The last-mentioned are spheroidal or oval in shape, as a rule, and may be smooth upon the surface, or rough, mulberry- like or coral-like (Figs. 77 and 78). When several stones lie together, their adjacent surfaces usually become faceted, as shown in Fig. 78. When they occupy the pelvis of the kidney, their shape not infrequently quite accurately represents the shape of the pelvis. Seen in section, urinary calculi are sometimes homogeneous, at other times distinctly stratified (Fig. 78) or tadially streaked, and often show a nucleus and several distinct zones of different appearance. Ebstein has shown that in these calculi, also, an organic substance, albuminous in nature, is left after solution of the varioits salts. In stratified calculi this stroma also shows stratification, often with radially disposed slits. 196 URINARY CALCULI. When stratification is absent, it is composed of a network of irregular construction, or, more rarei^y, of a homogeneous mass. There would seem to be little doubt that the crystalline bodies are deposited in this stroma, partly in the spaces and partly in its substance; and it is also most probable that the stroma itself is a product of the mucous membrane of the urinary passages, whose formation is assisted by the accumulation of debris and mucus consequent upon catarrhal inflammation or toxic degeneration of the epithelium. Fig. 77. Fig. 78. Fig. 77. — Coral-shaped stone from the bladder, composed of oxalate and phosphate of lime. (Natural size.) Fig. 78. —Transverse section of two stones from the bladder, closely fitted together, and composed of urate of soda and ammonio-magnesium phosphate. (Natural size.) What particular substances are deposited in any given case of stone- formation depends upon a variety of cii'cumstances. When the uric-acid diathesis is present coincidently with the condition of epithelial degen- eration necessary to the formation of a calculus, urates are usually de- posited. Decomposition of the urine, with formation of ammonio-mag- nesium phosphate, gives the condition necessary for the formation of a phosphatic calculus. Cystin calculi may form when cystin is excreted b}^ the kidneys as the result of peculiar metamorphoses of albuminous material in the intestine, brought about by bacteria (Baumann, von Udransky, Brieger). When a calculus has once begun to form, the irri- tation of the mucous membrane which it produces, and the decomposi- tion which results from stagnation of the urine, cause its further growth by fresii accretion, and in the same wa,j foreigti bodies which have in any manner found their way into the bladder may act as a nucleus for a cal- ridltS. Urinary calculi are classified according to the substances of which they are composed, as follows : 1. Calculi composed chiefly of uric acid or urates. Pure uric-acid calculi are for the most part small, hard. They are yellowish, reddish, or brownish in color. Calculi oj urates are rarely pure. They are usually covered on the surface by coatings of oxalate of lime and ammonio-mag-nesium phosphate. 2. Calculi composed chiefly of phosphates and carbonates. To this group helong calculi composed of calcium phosphate, ammonio-magnesium phosphate, and calcium carbonate. The last mentioned are rare. AU these calculi PIGMENT-FORMATION IN THE TISSUES. 197 are white or grayish. Those composed of the triple phosphate are soft and friable ; the others are hard. 3. Calculi composed of calcium oxalate. They are hard and rough. Their color is brown. 4. Calculi composed of cystin. These are soft, waxy, and brownish yellow. 5. Calculi composed ofxanthin. These are cinnabar red in color, smooth, and their fracture is earthy. Ebstein and Nicolaier succeeded ia producing urinary calculi artificially by feeding animals with oxamide, an ammonium derivate of oxalic acid, as the result of which concretions of a greenish -yellow color formed in the urinary passages of dogs and rabbits. These were found to be composed of oxamide and to have a concentrically stratified structure with radial striations. They possessed an albuminous stroma, which resulted from desquamation and necro- sis of the tubular epithelium induced in the excretion of the oxamide. XII. Pigment-formation in the Tissues. § 73. Pigment is normally present in connective and epithelial tissues in several parts of the body (autochthonous pigment). It lies mthin the cell-bodies and consists of yellow, brown, and black granules, or is diffuse, imparting its color to the cell-protoplasm. Among the epitlielial structures containing pigment maj' be mentioned the deepest layers of the rete Malpighii which in all the colored parts of the skin contain pig- ment, the hairs, the pigment epithelium of the retina, and many gaoglion-ceUs. In the skin the pigment granules are for the most part yellow and brown ; in the retina, black (melanin granules). When the skin is unusually dark, other layers of the rete Malpighii contain pigment also. Among the connective-tissue structures which may contain yellow or brown pigment granules are the cells of the pia, of the choroid, of the sclerotic, of the cutis vera, and of the heart- muscle. Under various physiological and pathological conditions this normal pigment, of autochthonous origin, may increase in amount. Thus during preg- nancy the pigment of the skin usiialhj in- creases more or less [chloasma uterinum), particularly in brunettes. In Addison's disease, which would appear to depend upon changes in the suprarenal cap- sules, decided pigmentation of the skin occurs as the result of increase of the normal pigment. In atrophic condi- tions of the heart-muscle there is usually increase of its pigment, and atrophy of the voluntary muscles is often accom- panied by an accumulation of yellow Pig. 79. — Large hairy pigmented mole over the lower part of the back and on the posterior aspect of the hip, with scattered spots of discoloration over the trunk and shoulders. (Prom Rohring.) 198 PIGMENT-FORMATION IN THE TISSUES. pigment in the fibres. In old persons the smooth muscle-fibres of the intestine always contain more or less pigment. The most intense grades of pathological pigmentation are met with in freckles, in pigmented moles {Fig. 79), and in various pigmented tumors (melanotic tumors). The amount of pigment may be so great as to impart a perfectly black color to the tissue. The pigment is for the most part contained in the cell-bodies, though it is occasionally in the intercellular substance also, and is composed of yellow, brown, or black granules. Occasionally cells are diffusely colored. In Addison's disease the pigment granules are situated partly in the epi- thelial cells lying next the connective tissue of the cuticle (Fig. 80) and partly in branched connective-tissue cells, some of the pigmented branches, as a rule, extending up between the epithelial cells. In pigmented spots in the skin and in melanotic sarcomata the pig- ment is to a great extent contained in large, specially differentiated con- nective-tissue cells, in part also in ordinary connective-tissue cells in the neighborhood of blood-vessels and in their walls. Fig. 80, A and B.— Pigmented cells of the skin, from a case of Addison's disease with cheesy tuberculosis of both suprarenal capsules, a, Pigmented epithelial cells from the deepest layer in a section made at right angles to the surface ; A, 6, Pigmented epi- thehal cells from a section made in a plane parallel with the sur- face ; B, h, Epithelial cells contain- ing no pigment ; Ci, c, Nucleated pigmented connective-tissue cells, the terminal processes of which push their way, in B, between the epithelial cells ; d, Pigmented ter- minal processes of cells. (Speci- men hardened in alcohol, stained with hsematoxyhn, and mounted in Canada balsam. Magnified 350 diameters.) So far as may be inferred from histological examination, the pigments which we have been de^criJmig are the result of a special Jcind of cell-actiiiti/, and we must suppose that many connective-tissue cells, ganglion-ceUs, and muscle-ceUs are able to form pigment out of the material brought to them. The pigment would appear to be formed for the most part where it is found, though it has been showh that it may at times be transported, and that the pigment of the skin in particular, as well as that of the hair, is, in part at least, formed in connective-tissue cells lying close under the rete Malpighii, and sending branching processes between its epithehal cells, from which the pigment is taken into the epithelial cells. It is even more difficult to determine the source of the material from which the pigment is elalwrated. The frequent proximity of the pigment to blood-vessels seems to indicate that its antecedents are derived from the blood, and many accept the theory without question that the pigment is derived from the coloring-matter of the blood. It is distinctly against this view, however, that when pigment is found in the neighborhood of VARIOUS FORMS OF PIGMENT. 199 vessels, these are not capillaries, as a riile, but arteries, from which escape of blood-pigment could hardly occur, and that any change in the blood itself, or in the neighborhood of the vessels, suggestive of breaking down of the blood-corpuscles and escape of pigment from them, is usually en- tirely lacking. The attempt has consequently been made to solve this question by chemical means, with the result that several facts have been discovered tending to show that the pigments are products of cell-activity and are formed from albuminous bodies. In the first place, it has been shown that the varioiis pigments differ to a considerable extent in composition. In the course of investigations in von Nencki's laboratory a brownish- black amorphous pigment containing a distinct but variable quantity of sulphur was separated from human hair. The pigment of the choroid was, on the other hand, shown to be devoid of sulphur. The metastases of a melanosarcoma, which had its origin in a pigmented mole of the skin, contained a pigment free from iron, but rich in sulphur, insoluble in alcohol, water, and ether, soluble in ammonia and alkaline carbonates. Von Nencki has named this pigment phymatorhusiit. Two other melant)- sareomata examined by von Nencki and Sieber, however, contained no phymatorhusin, and they are convinced that the pigment formed in Addison's disease is also different. Black pigment from a melanotic sar- coma of a horse was also iron-free and contained sulphur, though in smaller amount than the pigment from the human melanosarcoma. Von Nencki has called this Mppomelanin. Carbone also failed to find iron in a mel- anosarcoma, whUe Brandl and Pfeiffer, on the other hand, found in a melanosarcoma 3.7 per cent, of sulphur and 0.52 per cent, of iron, and Morner obtained 0.2 per cent, of iron from another. Finally, WaUach obtained a reaction for iron by treating portions of a melanosarcoma with aqua regia and potassium ferrocyanide. Nothing can be said with certainty as to the source of the material from which the cells form pigment. The mere fact that the pigment of melanotic tumors contains iron is no proof that it is derived from the hemoglobin, since tumors often contain disintegrated blood in addition to pigment. At all events, one finds here and there in melanosarcomata yellow granules which give the reaction of hemosiderin (cf. § 74), while the majority of the pigment granules do not. But, on the other hand, failure to obtain a reaction for iron does not prove that a given pigment is not derived from the blood, as after a time changes occur in iron-con- taining pigments which make it impossible to obtain a reaction for iron. The high sulphur content of many of the pigments makes probable their origin from albuminous substances, and their frequent proximity to the blood-vessels would suggest that this albuminous material is derived from the blood, perhaps from the globulin of red corpuscles. The pigment of the so-called chloromata is of a fatty nature (Lipoclirom), according to Krukenberg. These tumors have a light-green or dirty brownish-green color when freshly cut. It is quite likely that the coloring-matter of the egg-yolk and of the corpus luteum is also of this nature. During the past few years the origin of the pigment of the sMn has been the subject of much study and discussion among both anatomists and patholo- gists. Aeby was the first to express the behef that the epithehal ceUs themselves do not form pigment, but derive that which is found in them from wandering ■cells laden with pigment, which penetrate between the individual epithelial cells and then degenerate, the pigment and debris of the cells being taken up by the 200 PIC4MEXT-F0RMATI0N IN THE TISSUES. ejiitlielium. Accoi-ding: to von KoUiker, " the pigment of the hair and of the skin is derived from pigmented connective-tissue cells which send processes between the epithelial cells ot the deepest layers of the hair-bulbs and of the rete Mal- pighii, which processes divide and subdivide, penetrating deeper and deeper between the cells, and in some instances even passing into the bodies of the cells themselves and depositing their pigment there. These pigmented connective- tissue cells are always confined to the deepest layers of the rete." The pigment of the ganglion-cells and of the cells of the retina is formed in these cells them- selves. Eiehl and Ehrmann concur with von KoUiker in this opinion. Karg has arrived at much the same conclusion, as the result of the study of the effect of grafting white skin on the floor of an ulcer of the leg in a negro. In the course of from twelve to fouiteen weeks the grafted skin became quite black, like the skin of the rest of the negro's body. Examination showed fine pigmented processes, believed to be offshoots of connective-tissue cells, lying loetween the epithelial cells at a time when the epithelial cells themselves had not as yet become pigmented. Von Wild has also shown that in melanosareo- mata of the skin the pigmented connective-tissue cells penetrate between the epithelial cells. The pigmented skin of persons affected with Addison's disease shows similar pigmented connective-tissue cells, though these are not always to be found everywhere in such cases. Histological studies of the mode of formation of pigments in animals, which have been carried on chiefly on fishes, amphibia, and reptiles, have led to various conclusions. Thus Jarisch is of the opinion that the pigment of the skin and teeth of tadpoles is not derived from the blood, but is a product of the proto- plasm of the cells, while List thinks that he can trace the pigment of the skin of fishes and amphibia to disintegrated red corpuscles. According to Kromayer, the pigment of the skin of mammals is dei'ived from protoplasmic processes of the epithelial cells and represents a product of their degeneration. A curious pigmentation of the internal organs is met with in some domesticated animals, occasionally associated with melanosis of the subcutaneous tissue, in which the heart, lungs, intestine, etc., contain grayish or black spots, looking^ like ink-spots, in varying numbers, and which are produced by the presence of pigment in connective-tissue cells otherwise apparently healthy. Virchow has described, under the term ochronosis of cartilage, a peculiar pig- mentation of cartilaginous structures, tendon-sheaths and synovial membranes by an iron-free pigment, whose imbibition into the matrix of the cartilage im- parts to it a brownish or black color. He explains this on the supposition that blood-pigment has soaked into the stroma of the cartilage, and compares this form of pigmentation with that which occurs in freckles. It is probable that this condition is only a more pronounced form of the diffuse pigmentation especially noticeable in the costal cartilages of old persons. Occasionally this pigment is also deposited in granular form. § 74. Haematogenous pigment — that is to say, pigment whose origin from the blood-coloring watfer is certain — is derived usually from blood which has escaped from the vessels or has undergone coagulation in the vessels, and consequently (lepe)ids upon local changes. Occasionally, also, it may be traced to the absorption of hfemogiobin by the blood, or to changes in the blood as the result of which granidar pigment or haemo- globin gets into the plasma and when deposited gives rise to pigmentation of the tissue. Such deposits of blood-pigment have been called hcemo- chromatoses hy von Recklinghausen. Extravasations of blood quickly undergo changes which are visible even to the naked eye. In the skin "they are at first brownish, then blue,, green, and yellow. Where small hemorrhages have occurred in the sub- stance of a tissue, as in the peritoneum, pleura, or lung, reddish-brown or blackish spots will be visible long afterward. In bodies which are rapidly putrefying these areas may be slate-colored. Larger haemorrhages HAEMOGLOBIN. 201 into the tissues — for example, in the brain or in the lung — come to Jiave a rustj color after a time, and still later the affected spot shows ochre-yel- low, yellowish-brown, or brown pigmentation. Corresponding with aU these changes in color are physical and chemical changes in the haemo- globin and in the iron contained in it. When hemorrhages occur into the tissues or into any of the cavities of the body, a considerable quantity of the blood-plasma and of the cor- puscles is taken up unchanged by the lymph- vessels in the neighborhood. Other red corpuscles seem to have the hsemoglobin dissolved out of them, leaving the colorless stroma. This dissolved Juemoylobin diffuses itself into the surrounding tissues and gives rise to the changes in color of the tissues in the neighborhood of the extravasation. Part of this dissolved coloring-matter may be eliminated in the urine in the form of urobilin (urobiliniiria), but some of it is precipitated in the tissue in the form of Fig. 81.— a, Cells contain- ing amorphous blood-pig- ment ; a, Tliose in wMeh there are only a few larger frag- ments of red blood-corpus- cles ; b, c, Those in which these fragments are numer- ous, but quite small ; B, Rhombic plates and needles of hsematoidin. (Magnified 500 diameters.) granules and crystals. These latter are yellowish-red or ruby-red rhombic plates and needles of hmmatoidiii (Fig. 81), and are a frequent residuum of hsemorrhages. Part of the dissolved blood-pigment may be taken up by cells, in which it appears in the form of yellow and brown pigment granules. Still other blood-corpuscles disintegrate at the site of the haemorrhage and d!^J^^!5ft #1 Fig. 82. — Cells containing hsemosideiin and liamatoidin, from an old hsemor- rhagic focus in the brain, a, Cells containing hemosiderin ; 6, Cells containing haematoidin ; c, Fat-granule cells which have become clear ; d, Newly formed connective tissue. (Preparation hardened in alcohol and treated with potassic ferrocyanide, hydrochloric acid, and carmine. Magnified 300 diameters.) 202 HJ3M0SIDEEIN. form yellow and brown irregular masses. This is very frequent in large extravasations,- in tlie so-called hwmatomata. Pigment derived in any of these ways from the blood is very freqViently taken up by cells, and in this manner are formed the so-called Mood-corpuscle cells and piij- meiit-citrrying cells (Fig. 81, A, and- Pig. 82, a, b). When red blood-corpuscles are just beginning to disintegrate, the coloring-matter found is haemoglobin ; but this is quickly changed, and the yellow and brown masses and granules found both in the cells and l,ying free in the tissue are, as a rule, derivatives of heemoglobiti and not haemoglobin itself. These derivatives of haemoglobin are divided into two groups according as they contain iron or not, the former being called hceviosideriii, the latter hcematoidiii. Haematoidin, identical chemically with bilinibin, is a ruby-red or red- dish-yellow pigment, which occui's either in crystalline form or as irregu- lar granules, which may be quite amorphous or may be rather angular in shape, suggesting a I'udimentary and imperfect crystalline form. It is soluble in chloroform, carbon disulphide, and absolute ether, but in- soluble in water and alcohol. It would appear to be more abundant when the blood-pigment is not much exposed to the action of living cells, as in the centre of large extravasations and in hemorrhages into preformed cavities of the body, as, for example, into the pelvis of the kidney or into the subdural space. It may be produced artificially by introducing blood in glass cells under the skin or into the peritoneal cavity in such a way that the body-fluids may have access to it. Hsematoidin is found both in the cells and loose in the tissue. When it is contained in cells it has usuaUj'- got there as the result of phagocyto- sis, though occasionally, particularly in cartilage- and fat-cells, the hsemar toidin will have been absorbed while in solution, and have been deposited afterward in the solid form. Hsemosiderin, the derivative of htemoglobin containing iron, is met with in the tissues for the most part in the form of yellow, orange, or brown masses and granules, which deepen in color with time, and are usually contained in cells, sometimes in the very red corpuscles from which the haemoglobin has been absorbed. When treated with potassium ferrocyanide and dilute hydrochloric acid, hemosiderin becomes blue as the result of the formation of Prussian blue (Pig. 82, a) ; it becomes black when acted upon by sulphide of ammonium, iron sulphide being formed. Hemosiderin is formed, according to Neumann, more particularly when the extravasated blood, or that composing a thrombus in a vessel, is subjected to the action of the cells, and it is consequently more abun- dant in small extravasations and in the neighborhood of larger ones. The formation of hemosiderin may take place in the cells or in the intercel- lular spaces. That which is found in the cells may have been formed from fragments of disintegrated blood-corpuscles which have been taken up by the cells, or from dissolved hemoglobin which has infiltrated them, as is indicated by the occasional finding of both wandering and fixed cells whose bodies are stained diffusely yellow and which are stained blue by the Prussian-blue reaction. Furthermore, when hemoglobin is excreted by the kidneys, iron -containing pigment frequently forms in the tubular epi- thelium ; and cartilage-ceUs, which could hardly be supposed to act as phagocytes and take up solid fragments of blood-corpuscles, often con- tain granules of similar pigment, even when lying at some distance from a hemorrh^agic area. PSEUDOJMELANOSIS. 203 The free pigment and the pigmented cells, then, cause distinct and early pigmentation of the tissue in the neighborhood of an area of ex- travasated blood. But soon the pigmented cells find their way into the lymph-channels and form metastases along the course of the lymphatics and in the adjoining lymph-nodes (Fig. 83), in which at first the pigment is lodged in the bodies of the free lymphoid cells, but later may come to Fig. 83. — AcoTimtila- tion of cells containing pigment granules in the lymph-glands after the absorption of an ex- travasation of blood, a, Peripheral nodule ; h, Lymph-sinus ; c. Cells containing pigment granules. (Preparation hardened in Miiller's fluid, stained with car- mine, and mounted in Canada balsam. Magni- fied 100 diameters.) lie in the tissue-cells also. After a time htemosiderin is either destroyed and disappears, or changes into a pigment which no longer gives the reaction for iron. If hsemosiderin comes in contact after death with hydrogen sulphide it becomes black, and then causes the black and gray spots or diffuse patches spoken of as pseudomelanosis. This is observed most often in the intestine, in the peritoneum, and in suppurating wounds, since in these localities hydrogen sulphide is more apt to be formed in the course of putrefaction. The question whether heemosiderin granules may be converted into a pig- ment devoid of iron is differently answered by different authors. M. Schmidt and Neumann are of the opinion that the iron reaction of hsemosiderin is by no means constant, that it is quickly lost, and that it may even be absent from the first. The fact is that not infrequently the iron reaction is not obtained when the conditions are all such as to lead one to infer the presence of heemosiderin. If the pigment in such cases is not hsematoidin it must be supposed that the iron has disappeared from the hsemosiderin or has been converted into some form not sensitive to the Prussian -blue reaction, without thereby producing any change in. form or color of the pigment. Since the investigations of Vogel* the black pigment characteristic of pseudomelanosis has been believed by most authorities to be due to the formation of sulphide of iron as the result of the action of hydrogen sulphide upon the iron of the hsemoglobin. Perls f considers it to be sulphide of iron formed from the haematin of dissolved corpuscles, which results when simultaneously with the dis- integration of the corpuscles hydrogen sulphide is formed in the course of putrefaction. Grohe t behoves that as a result of putrefaction the iron is liber- ated from its combination in the hsemoglobin, and that when thus freed it readily combines with the hydrogen sulphide present. E. Neumann, § however, is of the opinion that pseudomelanin is not a product of putrefactive processes alone, but that it depends to a large extent upon local conditions which bring about a de- posit of iron-containing blood -pigment during life, and that this accumulated * "Path. Anat.,"i, p. 163. t Virchmd's Archiv, 20. Bd. f "Lehrbuch der allg. path. Anat.," i. § Ibid., 111. Bd. 204 HiEMOGLOBINiEIMIA. pigment is tlien later acted upon by the hydrogen sulphide o£ putrefaction. This view is supported by the fact that in pseudomelanosis almost all the black granules are contained in cells. § 75. When large numbers of red blood^corpuscles break down in the blood, haemoglobin or methsemoglobin may come to be dissolved in the plasma, or portions of broken-down corpuscles may be swept about in the circulation. This condition is most pronounced in poisoning by arsenic, toluylendiamine, potassium chlorate, and mushrooms, though it is observed also in many infectious diseases, in malaria, and in pernicious anaemia. Dissolved haemoglobin or metheemoglobin imparts a red color to the blood-plasma, and this condition is termed limnogloUncemia. When much dissolved haemoglobin is contained in the blood a portion of it may be excreted by the kidneys, giving rise to limmoglohinuria and methcemo- gloUnuria, in which case the urine is of a reddish color that ^'aries from a light brownish red to a decidedly dark red. This is especially the case in arsenic-poisoning, but occurs occasionally as the result of other influ- ences, as, for example, after exposure to cold (periodical haemoglobinuria). When the disintegration of the red corpuscles is not so complete, and fragrnents of them remain in the blood, as is the case not infrequently after burns, the fragments accumulate in the capillaries of the hver, spleen, lymph-nodes, and bone-marrow, and to a much less extent in some of the other organs. Sooner or later they are taken up by cells. In the liver, as the result of this increased supply of haemoglobin, there is considerable increase of functional activity, which is shown by the pres- ence of an increased amount of bile-pigment in the bile, and occasionally oxyhsemoglobin also may be present in it (Stern). At times, when the amount of haemoglobin brought to the liver is too great to be wholly dis- posed of in this way, one or other of the derivatives of haemoglobin may be deposited in the cells of the liver itself or in other organs, or may be eliminated by the kidneys. When organs are colored yellow, orange, or brown as the result of such deposits, the condition has been aptly named by von Recklinghausen hasmochromatosis. The derivatives of haemoglobin deposited in this way are the Same as those met with in other extravasations of blood, and consist partly of pig- ments free from iron and partly of hsemosiderin. The latter is a fre- quent cause of pigmentation of the tissues, and it is therefore permissible to speak of a ^jujinentation by hmmatogenous siderosis. These deposits of iron=containing pigment are most often met with in the liver, where they occur as yellow granules or masses in leucocytes and endothelial cells, in the plasma of the cap- illaries, in the liver-cells, and Fig. 84. — Infiltration of the tra- beculse of liver-cells with yellow heemosiderin granules (as at a), from a case of pernicious anaemia. 6, Cells in a condition of fatty de- generation. (Preparation treated with osmic acid and carmine, and mounted in glycerin. Magnified 250 diameters.) HiEMOCHROMATOSIS. 205 in the star-cells of Kupffer (Fig. 84). In pernicious malaria and per- nicious anaemia the majority of the liver-cells may contain such pigment, as the result of which the whole liver maj^ have a brownish color. When large quantities of broken-down corpuscles or of hsemoglobin derivatives are brought to the liver, they accumulate more especially at the periphery of the acini (Fig. 85, d, e), and in the periportal connective tissue, lying, as before stated, partly free in the capillaries, or in the tis- FiG. 85.— Hsemoehromatosis of the liver, from a man who died of morbus maculosus Werlliofli. a, Acini ; b, Peritoneum ; c, c. Branches of the portal vein ; d. Infiltrated periportal connective tissue ; e, Pigment deposited inside of the capillaries of the hepatic lobules ; /, Venute centrales. (Preparation hard- ened in alcohol, stained with carmine, and mounted in Canada balsam. Mag- nified 20 diameters.) sues themselves, and partly inside of leucocytes, hver-cells, connective- tissue ceUs, and the endothelial cells of the capillaries. The tissues thus infiltrated present a reddish-brown coloration distinctly visible to the naked eye. The pigment which is carried to the spleeti is found for the most part in cells lying loosely in the pulp, at times also in the fixed cells of the tissue. In the lymph-glands it lies chiefly in cells within the lymph-chan- nels. In the bone-marrow, where it is often present in large quantity, it is found in cells in the capillaries, in the capillary endothelium, and in the pulp-ceUs. In the Mdneys it is most abundant in the epithelium hning the con- voluted tubes, but is also met with in the lumina of the tubules, in the capsular epithelium, and in the endothelium of the capUlaries. When masses of haemosiderin are present in the circulation they are almost cer- tain to be found in the capillaries of the kidney. When hfemoglobin is 206 ILEMOSIDERIN. — HiEMATOIDIN. being eliminatecl by the kidney it is usually to be found in the lumina of some of the tubules. When pigmentation of the kidney is extensive, it may often be detected with the naked eye. A large part of the hfemosiderin which is found in the various organs has been brought to them in the form of granules or small masses, and is then, as a rule, contained in leucocytes in the capillaries. But, in addi- FiG. 86.— Haemato- genous deposit of iron in the kidiey, from a patient who died of per- nicious malaria (con- tracted in Bagamayo). a, Convoluted uriniler- ous tubules, the lining epithehal cells of which contain granules of iron and are sta,ined a pale- blue color ; 6, Iron granules in the lumen of the tubule; c, Straight uriniferous tubules; d, Glomerulus ; e, Capsule epithelium, also con- taining iron granules. (Preparation hardened in alcohol, treated with alum carmine, potassic ferrocyanide, and hy- drochloric acid, and mounted in Canada balsam. Magnified 150 diameters.) tion to this, solid particles of pigment would also appear to be formed in the cells themselves from material brought to them in solution. This view is sustained by the fact that, in applying the Prussian-blue reaction for the detection of iron, many of the cells which contain no definite granules nevertheless stain diffusely blue, indicating the presence of iron diffused through their substance. The iron-containing pigjment which thus infiltrates the cells would appear to be later excreted by them in the form of solid masses of pigment, though it is, of coui-se, possible that some of this diffuse coloration may have resulted from the solution of the iron vsuthin the cells. It is also suggested by the observations of a num- ber of investigators that colorless iron-containing material — albuminates, perhaps — may at times be present in cells in the body, since the iron re- action develops oftentimes many more iron-containing granules than were otherwise visible in the tissue. The deposit of iron=free pigments, licBmatoidin or bilimbin, is usually very scanty in cases of hsematogenous pigmentation, as the result of dis- integTation of blood-corpuscles in the circulation. Occasionally, however, pigment is met with in the various organs which fails to give the reaction for iron, and which it is reasonable to suppose has not contained iron at any time, though it should be i-emembered that after a time hsemosiderin fails to respond to this reaction. Von Recklinghausen has a,pplied the name Jimmofuscin to a form of pigment deroid of iron which occurs as yellow granules in the heart-musr cle and in smooth muscle-cells. It is occasionally so abundant in smooth muscle as to cause much swelling of the cells, and it is almost constantly H^MOPUSCIN. 207 present, according to Goebel, in some of the nmscle-eells of the outer layer of the muscularis of the jejunum in persons who have passed their eighteenth year. This pigmentation increases with age, and may ulti- matelj' become so abundant as to impart to the intestine a distinctly yel- low or brownish coloration. Similar pigment is also met with in the muscle-cells of blood-vessels and other muscular organs, in the cells of the connective-tissue sheaths of blood-vessels, and in the cells of gastric, intestinal, tear, sweat, and mucous glands. In the heart, pigmentation of the muscle-cells is of very frequent occurrence in old age, and is some- times so marked in atrophic conditions of the heart as to cause distinct coloration of its muscle. Marked pigmentation also takes place in volun- taiy muscle-tissue when it undergoes atrophy, though it is by no means constantly present. The nature and source of h^mofuscin are not determinable with cer- tainty by microscopic examination, though von Reckhnghausen and Groebel are both inclined to class the pigmentation caused by it, among the hiemochromatoses. It is uncertain whether the haemoglobin or some other ingredient of the blood furnishes the material from which h^mofuscin is formed. Experiments conducted in my laboratory by de Filippi show that iron preparations introduced into the system subcutaneously or by the intestine, in soluble form (Sehmiedeberg's ferratin), find their way in considerable quantity into the fluids of the body and into the blood, and are deposited particularly in the bone-marrow, spleen, and lymph-glands. The iron may be demonstrated microchemically, lying in intercellular spaces in the form of fine granules or small masses, or in solution diffused through the cells and in the walls of the blood-vessels. In the liver the deposit is chiefly observed in leucocytes, endo- thehal cells, and KupfEer's stellate cells in the blood-vessels, while the hver-eells. themselves, as a rule, contain iron only transitorily and in such a form as will permit us to detect it by microehemical means in only a few of the cells. According to the researches of Biondi, which were also made in my labora- tory, the conditions observed in chronic poisoning by toluyleudiamine, which brings about progressive disintegration of the red blood-corpuscles, are very similar to those just narrated, for here also the places where the iron is deposited are the bone-marrow, the spleen, the lymph-glands, and the vascular and connec- tive-tissue framework of the liver, whUe the Hver-ceUs themselves remain free. And, Anally, a similar residt is obtained when the ductus choledoohus of animals is Ugated, in which case iron-containing bile is forced to enter the blood. In man such iron-containing pigment is almost constantly found inside of the cells of the organs in question, though in most cases in very small quantity. This iron is, on the whole, to be considered as having originated from broken- down red blood-corpuscles, though it is possible also that at times an excess of iron is taken into the system. Biondi is of the opinion that when, under path- ological conditions, as is frequently the case, large amounts of iron are found not only in the connective-tissue cells of the above-mentioned organs, but in the hyer-ceUs as well, the inference is justifiable that there has been both abnormal disintegration of the blood-corpuscles and at the same time derangement of the function of the hver. It would appear that healthy Uver-eells limit their content of iron, giving up to the bde, to the blood, or to the lymph, any excess of it which nay be brought to them, so that it is only exceptionally and then only for a short time that they contain any iron which may be detected by microehemical tests. Under pathological conditions this abihty of the liver-cells to dispose of iron would appear to be impaired, as the result of which there occurs in them an excessive and persistent accumulation of iron. It is probable that the iron which is deposited in the above-mentioned organs inay later be of use in building up new tissue, more particularly in the elabora- tion of red blood-corpuscles. 208 JAUNDICE. In malaria two pigments result from tiie destruction of the red corpuscles by the micro-organisms of that disease. The one is formed by the Plasmodia themselves. It is black, gives no iron reaction, and lies in the bodies of the Plasmodia. Nothing is known as to its nature. The other is hsemosiderin, which passes into the plasma of the blood as the result of the destruction of the corpuscles, and is later deposited in the Uver, spleen, and marrow of the bones. When excessive destruction of the blood occurs, it may also lead to a condition of siderosis of the kidnej^s (Fig. 86) and to elimination of iron in the urine. The greenish coloration which is observed, in decomposing cadavers, in the neighborhood of blood-vessels fiUed with blood, is dependent upon the formation of sulphide of methaemoglobin through the action of the hydrogen sulphide upon the blood. § 76. A pathological pigmentation of the tissues by bile-pigment is designated jaundice or icterus. Icterus is a symptom which is frequently present in the course of a number of diseases of the liver, and is a fre- quent occurrence during the first few days of life {icterus neonatorum). Dming life the pigmentation known as jaundice is apparent ehieflj' in the skin, conjunctivas, and urine, but after death it may be detected also in the internal organs, the serous membranes, the lungs, kidneys, liver, in the subcutaneous and intermuscular connective tissue, in the blood- plasma, in clots in the vessels, etc. Fresh icteric colorations are yellow, but after a time the skin may assume an olive-green or dirty grayish- green color j and similar colorations are also met vnth in the internal organs, particularly in the liver and occasionaUj^ also in the kidneys. Jaundice results from the entrance of bile or of bile-pigment {bilirubin) into the blood and liquids of the body. During its continuance the urine contains bile-pigment also. These biliarj^ pigments have their origin in the liver, and jaundice is consequently a hepatogenous disease. It com- monly depends upon some diseased condition of the bihary passages or of the liver itself, as the result of which the outflow of bUe from the hver is impeded. The bile is then taken up by the lymphatics and blood-ves- sels. Such a condition may be brought about by catarrh of the bile-ducts ; by narrowing or obliteration of the bile-ducts by cicatrices, by gall-stones, or by tumors which may have originated in the gall-ducts themselves or in the tissue in their neighborhood, and which compress them ; by in- flammatory conditions, abscesses, connective-tissue growths, tumors ; or, finally, by congestion of the blood-vessels of the liver itself, which causes pressm'e upon or obliteration of the gall-ducts within the liver, and so pre- vents the outflow of bile through the gaU-capillaries and smaller gall-ducts. Wlien for any reason the bile is congested in the small gall-ducts of the Uver, the first thing which occurs, in aU probability, is an absorption of a certain amount of the bile by the Ij-mphatics of the liver. But as the process continues the bile accumulates more and more in the gall- capillaries and in the liver-cells themselves ; the latter circimistance being due, doubtless, to the inability of the liver-cells to dispose of the bile which they have formed (Pig. 87, a). If the process continues for any considerable time the dilatation of the gaU-capillaries may be very great (Fig. 87, &), so that ultimately they may burst and their contained bile may be discharged directly into the blood-capillaries (Fig. 87, g). Even in the early stages of jaundice, yellow (or green, in cases of sublimate fixation) granules may be seen in Kupffer's cells and in the endothelial cells of the capillaries, which often desquamate in consequence and lie free in the blood-vessels. Not infrequently such biliary congestion is fol- JAUNDICE. 209 lowed by degenerative changes, necrosis, inflammation, and connective- tissue growth. "When bile-pigment, either still in solution or in the form of granules or small masses, finds its way into the blood in the manner above de- ' ^> , ., ' O /A U c? ) o o.., z;^^' c Fig. 87. — Icterus of the liver, from a case of cancer of the gall-bladder, in which there was eoinpression of the ductus choledoehus. a, Jloderately dilated intravenous bile-ducts filled with bile ; 6, A large mass of bile-pigment in a widely dilated intravenous bile-duct ; c. Bile-pigment in the liver-cells ; d, di, Still firmly attached endothelial and Kupfler's cells, stained by granules of bile- pigment ; e, Desquamated endothelial ceUs stained with bile ; ./', Portions of pig- ment surrounded by cells ; g, Escape of pigment contained in the bile-ducts into a capillary. (Preparation hardened in corrosive subhm^ate, stained with alum carmine, and mounted in Canada balsam. Magnified 365 diameters.) scribed, the tissues of the body, being bathed constantly by bile-stained lymph, gradually absorb some of the coloring-matter and are colored by it. Solid particles which may be circulating in the blood, for the most part in cells, slowly accumulate in the spleen and in the bone-marrow. ^\iter a time the bile-pigment in solution iu the various liquids of the body becomes deposited as fine granules, or more rarely as rhombic or acicu- hir crystals, which have already been described as hsematoidin (Fig. 81). This crystalline deposit rarely occurs except in new-born infants, where the crystals form in fixed and wandering connective-tissue cells, in the liver-cells, and in the tubular epithelium ( >f the kidneys. In intense icteric conditions very many of the cells of the body come to contain bile-pig- ment. This is often accumulated in large amount in the lymph-glands (Fig. 88), to which it is, as a rule, carried by cells, and whose lymph-chan- nels may be so filled with the yellow gr-anides as to give to the whole gland a yellowish-brown cohn-. In the kidneys, which are active in eliminating the biliary ].iigment from the body in jaundice, there is also much pigmentation, particularly 210 JAUNDICE. of the secreting epithelium of the tubules, which often desquamates in consequence (Fig. 89, a). When casts of the urinary tubules are formed Fig. 88. — Icterus of the lymph-glauds, followiug au attack of jaundice due to obstructed outflow of bile (Fig. 87). «, Lymph -follicles with distended blood- vessels ; 6, Capsule ; c, Lymph-cliannels with cells which contain yellowish-green pigment granules (entirely free from iron). (Preparation hardened in corrosive sublimate, stained with carmine, and mounted in Canada balsam. Magnified 45 diameters.) -.0 (t Fig. 89. — Icterus of the kidney, following an attack of jaundice due to obstructed outflow of bile (Fig. 87). ri, Tubular epithelium containing yellowish- green granules: h, Large yellowish -gi-een urinary, cast ; c, Cast with pigment - cells entangled in its substance ; d, Desquamated epithelium containing bile- pigment granules. (Preparation hardened in corrosive sublimate, stained with carmine, and mounted in Canada balsam. Magnified 200 diameters.) JAUNDICE. 211 as the result of the degeneration of the tubular epithelium, these casts are usually colored by the bile-pigment (Fig. 89, b, o). Associated with the deposits of bilirubin in jaundice, there is always more or less deposit of hcemosiderin, chiefly noticeable in the bone-marrow, in the spleen, and in the lymph-glands, occasionally also in the liver, so that the pigmentation of the tissues depends in part upon the presence of an iron-containing pigment in this condition also. When unusual disintegration of red blood-corpuscles occia'S within the blood, hsematoidin or bilirubin is formed in association with hsemo- siderin, as was explained in § 75, and is deposited in various parts of the body. Such extrahepatic bUirubin-f ormation is, however, very slight, and is never sufficient alone to cause jaundice, so that a purely hcBmatogenous ictenis does not occur. The liver is the great elaborator of bilirubin, and the production of this substance is at times increased in the liver as the result of disintegration of red corpuscles. Jaundice, then, whicli follows hrealdng down of the blood, can only occur ivlien associated with changes in the liver which result in the passage of bile into the blood. According to the majority of authors (cf. Harley), the bile, when obstructed in its outflow, finds entrance to the blood only through the lymph-channels ; the chief reason for this opinion being that after ligation of the bile-ducts of animals jaundice does not occur unless the thoracic duct has also been ligated. Investigations which I have made on the Uvers of persons who have suffered from long-continued jaundice lead me to believe this opinion to be incorrect, and I beheve that in all cases of chronic and well-marked obstruction of the outflow of bUe there is also a direct entrance of the bile into the blood (Fig. 87), and that this depends upon inordinate dilatation and rupture of the intra-aci- nous gaU-capillaries. The question as to whether jaundice may be of haematogenous as well as hepatogenous origin has been under discussion and is still unsettled, notwith- standing numerous experimental investigations directed to its solution. Since, as a matter of fact, bdirubia may be formed in the tissues as the result of extravasation of blood, the likelihood of the occurrence of hsematogenous icte- rus would a priori seem quite plausible. Experiments made with arsenious acid, toluylendiamine, and potassium chlorate, to determine the result of the disin- tegration of red blood-corpuscles in the blood, have, however, shown that the derivative of the blood which forms and is deposited in the various tissues is hsemosiderin, and that the formation of bilirubin under these circumstances is confined to the Uver, which for the time being excretes an increased amount of iatensely pigmented bde. According to Miakowski and Naunyn, the urine of geese and ducks con- tains no bile-pigment after extirpation of the liver — a fact which would indicate that the transformation of blood-pigment into bile-pigment is ordinarily hmited to the liver. The inhalation of vapor of arsenic for a very few minutes is suffi- cient to produce in geese intense polychoUa and heematuria, the urine containing hffimoglobia in solution, fragments of red corpuscles, and bdiverdin. If, now, the hver of such a goose be extirpated, biliverdin quickly ceases to be present in the urine, and there is, at the same time, no biliverdin in the blood. It is thus evident that in arsenic-poisoning the formation of the bile-pigment which ap- pears in the urine must occur in the liver, in which broken-down blood-corpus- cles are found in large numbers. So far as may be inferred from the results of experiments which have been made up to the present time, it would seem that a purely haematogenous jaun- dice does not occur. The mere fact of the occurrence of jaundice in intoxica- tions, after ether and chloroform inhalations, transfusion, snake-bite, and in septicaemia, typhoid fever, yellow fever, paroxysmal hsemoglobinuria, etc., is in no wise proof that the jaundice in these cases is of haematogenous origin. There is, mdeed, in these conditions an increased destruction of red blood-oorpuscles ; but bdirubin is essentially a product of the liver, and its presence in the blood 212 ICTERUS NEONATORUM. may readily be accounted for on the supposition that a part of the bile pro- duced in excess in these conditions finds its way into the blood. In fact, Stadel- mann has shown that change in the density of the bile may bring about its absorption by the blood. Many theories have been proposed from time to time in explanation of •icterus neonatorum. Frerichs beheved it to be due to the passage of bile into the blood as the result of sudden diminution of intravascular tension in the liver after birth. Hofmeier supposes that the unusually large consumption of red corpuscles during the first few days of hfe leads to the production of a bile unusually rich in pigment^ and that some of this bile finds its way into the blood. Biroh-Hirschfeld beheves that this benign tjrpe of jaundice, which is not traceable to septic infection and is not dependent upon serious anatomical changes in the liver, is produced by an oedematous condition of the connective tissue of Glisson's capsule, which condition is brought about by stasis in the area of distribution of the vena portee and of what remains of the umbihcal vein. Silbermann attributes it to congestion of bile dependent upon dilatation of the liver-capillaries and of the portal vessels immediately after birth, and he also believes it to be associated with a greater breaking down of red corpuscles. I myself would venture the opinion that the absorption of bile under these circum- stances is referable not only to increased production of bile by the liver imme- diately after birth, but also to increased absorption of biUary coloring-matter from the meconium and its transportation to the Hver. According to E. Neumann, bilirubin crystals are frequently found in the fat- cells of the omentum, and at times also in the subserous fat, in the fat about the kidneys, beneath the pericardium, and in the mediastinum of new-bom children, even when they are not jaundiced; and he explains this by supposing that after death the biliary coloring-matter which was in solution in the tissue-fluids has crystallized out. In both children and adults biliary coloring-matter which has found its way after death, by diffusion, into the tissue surrounding the gall-blad- der may crystallize, more particularly in the fat-tissue. § 77. Pigmentation of the tissues by foreign substances introduced into the body from without occurs when substances possessed of color in themselves,^nd capable of resisting the action of the body-fluids, gain access in any manner to the tissues and remain there. The substances which may act in this way are naturally numerous, as are also the modes of their entrance into the body. The lungs are their most frequent channel of entrance, but they may also be taken in through the intestine or from wounds. Tattooing of the shin affords a familiar example of the introduc- tion of pigment through wounds. This staining is effected by rubbing insoluble granular pigments, such as lampblack or cinnabar, into slight wounds of the skin. The pigments penetrate into the wounds and intU- trate the tissue in their immediate neighborhood, part of the pigment re- maining there permanently, while some of it is carried to neighboring lymph-glands, which then participate in the pigmentation. The lungs and their lymph-glands are often intensely pigmented as the result of inhalation of particles of dust, more particularly coal-dust, soot, iron-dust, etc. They may become actually black in consequence of inhalation of coal-dust. A part of the dust inhaled is carried to the bron- chial lymph-glands, which often become quite black, and may undergo more or less softening when the pigmentation is excessive. When these glands are situated near blood-vessels, the latter may be secondarily in- volved in the pigmentation, and sometimes also in the softening, and in this way particles of the pigment may gaia access to the circulation and may be carried to remote organs, such as the liver, spleen, and bone-mar- row, where they may be deposited (cf. § 18). CYST-FORMATION. 213 Among the pigmentations wliich may result from absorption through the intestine we may mention the condition known as argyria, which is dependent upon the long-continued use of preparations of silver. The skin under these circumstances may assume an intense grayish-brown a coloration, and in a similar way the ^ ®':^ / : 8 internal organs may undergo pigraen | @ii^ g 1 tation to a greater or less degree. The fe SF^ J silver is deposited in the form of fine J |: ; i fe grains in the stroma of the tissues, * ©; ' r.;|^ more especially in the glomeruli and % ^ '-^ 3 | in the connective tissue of the medul- %, *« ' ® larypoi-tionof the kidneys (Fig. 90, &), «■ ^is.® v^ in the intiina of the larger vessels, in & f% /? f J the adventitia of the smaller arteries, J 'if '^ i S ® intheneighborhoodof mucous glands, «< § .fe i® £ in the papillae of the skin, in the eon % % %< g ® neetive tissue of the intestinal villi, ® © * ® |, and in the choroid plexus of the lat- t I ;^ S S £ eral ventricles. Deposits may also | I *! ® @ occur in the serous membranes, but ^ % i;' ® ^ epithelial tissues, the braiu, and the * % ^ » ^^ cerebral vessels escape. Extensive de- 1 ^^ ^ posits in the medullary portion of the ®© S kidney may lead to growth of dense *« « connective tissue, which then not in- •'^ s frequently undergoes calcification. *, «< Pig. 90. — Deposits of silver in the pyramidal portion of a rabbit's kidney, after the animal had regularly received fixed doses of a silver-preparation for a period of seven months (experiment of von Kahlden). a, EpitheUmn of the coUecting'-tnbes ; 6, Connective tissue filled with brown granules of silvei'. (Preparation hardened in alcohol, stained with hsematoxyhii, and mounted in Canada balsam. Magnified 5[f] diameters.) Iron particles taken into the body in large amount may also lead to pigmentation of the bone-marrow, spleen, and lymph-glands, though rarely to such an extent as to be visible to the unaided eye. XIII. Cyst-formation. § 78. A cyst is a circumscribed cavity which is shut off from the sur- rounding tissues by a connective-tissue membrane or by tissue of complex structure, and whose contents are different from this capsule. When a cyst comprises only a single such cavity it is called a simple cyst; when it is divided into a number of compartments it is said to be miiltilocular. The most frequent form of cyst is the so-called retention cyst, which results from the accumulation of secretion in a duct of a glandular organ, in the gland itself, or in anj* preexistent canal. They all have an epi- thelinl or endothelial lining. These cysts form in organs provided with an open duct, when oblitera,- tion of this outlet occurs in any part of its course, provided that actively secreting parenchyma still exists beyond the point of obhteration. They 214 RETENTION CYSTS. are accordingly met with in the sebaceous glands of the skin, in the hair- follicles, in the uterine glands, in the mucous glands of the alimentary- tract, in the epididymis (Fig. 91, c), in the urinary tubules, and less frequently in the gall-ducts and their glands, in the breast, in the pancreas (Fig. 92, 6), in the glands of the mouth, etc. Larger canals may also become cystic — as, for example, the ureters, the vermiform appendix, and the Fallopian tubes (Fig. 93, c). The obstruction of the duct neces- sary to cause a retention cyst may be brought about by accumulation of the secretion of the gland, or by cicatricial or neoplastic compression and quent obhteration. conse- FiG. 91. — Section of the testicle and epi- didymis, showing multiple cysts in the head of the epididymis, a, Testicle ; 6, Epididy- mis ; c, Cyst broken up into compartments. (Nearly natural size.) Closed glandular cavities, such as the follicles of the thyroid gland, of the ovary, or of the parovarium, undergo cystic degeneration when their walls pour out an inordinate amount of secretion. Similarlj'', remains of foetal canals or clefts — for example, those of the branchial clefts, of the urachus, or of Muller's ducts — may become cystic. Fig. 92.— Cyst of the pancreas, caused by dilatation of a branch of Wirsung^s duct, a, Glandular tissue ; &, Cyst ; c. Transverse section of an artery ; d, Longi- tudinal section of a vein. (Natural size.) Small cysts, such as are met with in mucous glands, vary in size up to that of a pea. Larger cysts, like those occurring in the liver and in the ovary, may attain the size of the fist or be even larger. The contents of cysts depend upon the natui-e of the tissue in which they are formed. Thus cysts of the hair-foUicles and of the sebaceous glands (afheromata) contain a semi-solid material, whitish, grayish, or brownish in color, composed chiefly of squamous epithelial cells, fat- globules, and cholesterin ; cysts formed in mucous glands contain clear, or, when cellular elements are also present, milky, mucous liquid. When RETENTION CYSTS. 215 haemorrhages take place into cystic cavities the blood imparts its color to the cyst-contents, making them red or brownish. Cystic Graafian follicles usually contain clear, more or less colored hquid ; cysts of the thyroid Pig. 93. — Dropsy of the Fallopian tube, with perisalpingitic and periovarian adhesions, a, Uterus ; 6, Uterine portion of the tube ; c,_ Abdominal end of the tube, in a condition of cystic degeneration and adhering to the neighboring parts; d, Ovary; e, Membranous adhesion. (Two-thirds natural size.) gland and of the kidney contain colloid material, or clear, though occa- sionally' cloudy, liquid. Betention cysts lined with endothelium may arise from blood-vessels, lymphatics, lymph-spaces, synovial membranes, or tendon-sheaths. Here also the nature of the cyst-contents depends upon its place of origin. Not infrequently the condition resulting in cyst-formation is caused by the shutting off of a portion of one of the cavities already named by a constriction. As enlargement of a retention cyst goes on it is quite necessary that the tissue composing its wall should also develop, for otherwise defects in its wall would result. Cyst-formation is, therefore, not an exclusively degenerative process. The epithelial or endothelial cells lining the cyst- waH are the first to show this development, but the connective tissue upon which these cells rest participates in it also, as a rule, and may even, despite the stretching, become increased in thickness. It should further be stated that cyst-formation is very frequently associated with the pathological development of new glandular tissue, and constitutes, there- fore, a secondary alteration in hjrpertrophic or tumor-like growths. Con- sequently it is sometimes impossible to distinguish between simple reten- tion cysts of preexistent gland-ducts and gland-vesicles, on the one hand, and those tumors, on the other, which are characterized by the presence of cyst-formations (the cystomata). Similarly, cysts lined with endothelium may originate from newly developed Ivmph spaces and ducts. 13 216 DEGENERATION CYSTS. A second variety of cyst comprises the cysts which result from de- generation, softening, and liquefaction of a portion of tissue. Cysts are formed in this manner in the brain, in enlarged thyroid glands, and even in tumors. They are usually Med with either a clear or a more or less cloudy hquid. A third kind of cyst results from the formation of a dense capsule of connective tissue about any foreign substance which may have found entrance into the body — as, for example, around a parasite. A fourth varietjr of cyst is formed by parasites which pass through a cystic stage in the course of their development in the body. SECTION y. Hypertrophy and Regeneration of the Tissues and Organs. I. General Considerations Concerning the Processes called Hyper= trophy and Regeneration, and the Cellular Changes that Accom= pany Them. § 79. By hypertrophy is meant an increase in the substance of a tis- sue or organ, brought about by an increase in or multiplication of its elements, in such a way that the structure of the hypertrophied tissue is similar to, or at leapt does not materially differ from, that of the normal. By regeneration is meant the process by which a loss of substance in a tissue is restored by a new tissue that is exactly lilie that which was lost, or at least that contains the same ele- ments which it had. Hypertrophy may result from a morbid impulse existing in the germ-plasm itself, or from an impulse originating during the life of the individual. Re- generation, on the contrary, is always secondary to a tissue- lesion, which, however, may oc- cur during either intra-uterine or extra-iiterine life. If an abnormal tissue-in- crease takes place dming the period of embryonic develop- ment or of extra-uterine growth, and if there are no influences discoverable which would seem to account for the tissue-growth, then we are disposed to regard it as the result of embryonic impulses, and so we call it hypertrophy of congenital origin. If the enlargement affects the entire body — for example, if a newly born child weighs 5 or 6 kg., or if an individual reaches the height of 180 or 200 cm. 217 t < ?' v -Jv'_ kr_" t ~ Fig. 94.- romatosa. -Elephantiasis femorum neu- 218 HYPERTROPHY AND REGENERATION. — this is called general giant groivth. If the growth affects only certain parts of the body — for example, the entire head or one half of it, or one extremity, as a finger, or the labia majora or minora — it is called a partial giant growth. Hypertrophic growths of the skin that lead to changes suggesting the skin-formation of the pachydermata are called elephantiasis (Figs. 94 and 95). In hypertrophy of a limb or of a fin- ger aU the elements of the part are uni- formly enlarged. In elephantiasis of the extremities the connectiA^e tissue of the skin and of the subcutaneous struetiu-es especially is apt to increase, though the development and structure of these growths show considerable variations in that the pathological new formation sometimes affects all the connective-tis- sue elements uniformly, sometimes single elements only — as, for example, the con- nective tissue of the nerves or the blood- or lymph-vessels — or at least takes its start from these. For this reason it has been customary to distinguish different varieties of elephantiasis, named, accord- ing to the structure of the hypertrophic P. ,^,JMjf 01-3" " tissue, elephantiasis neuromatosa (Fig. '-'Op^. ' "^^ 94), angiomatosa, lymphangiectatica (Fig. •■ -^ ■ ' s*™" 95), lipomatosa, etc. To what extent it is possible to ex- plain new growths by congenital impulse cannot be exactly determined, and in many cases it can be only surmised. In general the early appearance of the growth, as well as the history of heredity and the absence of possible external influences, speaks in favor of its congenital origin. Yet later influences which might bring about the growth do not disprove a congenital origin. For example, in the bones, especially of the head (Fig. 96), excessive bony growths occur whose beginning sometimes follows the operation of an external cause — as, for example, trauma or inflammation. Sometimes, on the contrary, it occurs without any such cause. Since in these cases, as we know by experience, the influences that determine the growth are not by themselves able to cause it, therefore we must explain the obsei-ved phenomena on the ground that the trauma, for instance, is merely the influence that starts up the new growth in a tissue already possessing congenital patho- logical impulses. Very recently, under the titles of acromegaly (Marie), j)achyaliria (von Recklinghausen), and ostioarthropathie hypertrophiante (Marie), there have been described certain peculiar enlargements of the tips of the extremities (Fig. 97), in some cases associated with enlargement of the face and with deformities of the spinal column. These cases had occurred for the most part in early or middle life, less often in later life, and had developed gradually. So far as anatomical investigation (by Arnold, Marie, Marinesco, Fig. 95. — Elephantiasis cru- ris lymphangiectatica. AKROMEGALY. PACHYAKEIA. 219 Thomson, Hoisti) has been able to make out, the change consists in an increase in all the tissues that go to make up the extremities and the face. In this increase the bones also take part, in that they grow thicker (Fig. 98) and at the same time may be the seat of rounded or pointed exostoses. On the other hand, up to the present, an increase in the length of the bones has not been demonstrated in this disease (von Recklinghausen, Arnold), and so the term pachyakria of von Recklinghausen is fittingly chosen. The cause and nature of these morbid phenomena are still ob- scure, and the above names are not used by aU authors with the same significance. In Germany the term akromegaly is applied to all forms of enlargements of the ends of the limbs which lead to a paw-like ap- pearance of the hands and a gigan- tesque appearance of the feet, while Marie, who first described these pathological manifestations, tries to draw a marked distinction be- tween akromegaly and osteoarthro- pathie hypertrophiante. He holds that in akromegaly the hands and feet are not deformed, but sym- metrically enlarged, and, indeed, that the thickening and broadening dim- inish at the ends, so that the terminal phalanges are only slightly thick- ened. On the other hand, he holds that in osteoarthropathie hypertrophi- ante the terminal phalanges are swollen so as to resemble drumsticks, and the articular ends of the bones are irregularly thickened. In the former case, moreover, the lower jaw is lengthened, in the latter case it is thick- ened. Marie believes that in many cases ost6oarthropathie hypertrophi- ante is a sequela of an inflammatory affection of the lungs and pleurae. Accordingly he calls it osteoarthropathie hypertrophiante pneumique, and he believes that the cause is to be found in a taking up of the toxic products of the body-fluids from the foci of inflammation in the lungs; _ so that the disease of the bones may be regarded as an infectious, toxic, hypertrophic inflammation. Some other authors regard akromegaly and osteoarthopathie hyper- trophiante as the result of a congenital predisposition (Virchow) ; others as the result of disturbances of the sexual organs (Freund) ; others as due to hypertrophy of the hypophysis (Henrot, Klebs) or to a persistence of the thymus gland (Erb, Klebs) ; still others believe them to be due to nervous influences (von Recklinghausen). Nevertheless none of these hypotheses is supported by anatomical and clinical observations. Finally, as a result of the investigations that have been made, it seems fair to assume that in the disease imder consideration we have to do not with excessive growth that can be compared with the partial giant growths, Fig. 96. — Leontiasis ossea, occur- ring in a boy the subject of general giant growth. (Observed by von Buhl.) 220 AKEOMEGALY. — PACHYAKRIA. Fig. 97. — Akromegaly, according to Erb and Arnold. (Ost^oarthropathie, according to Marie and Souza-Leite.) but with acquired morbid conditions, whicli develop either as independent diseases (akromegaly, pachyakria) or as secondary phenomena in the conrse of other diseases (osteoarthropathie hypertrophiante pneumique). The size of the entire body as weh as of its separate parts and organs is sub- ject to considerable variations within the normal physiological limits, according Fig. 98. — Skeleton of the hand with hypertrophied bones, from the case of akromegaly pictured in Fig. 97. (After Arnold.) CONGENITAL HYPERTROPHIES. 321 to race, family, and individual idiosyncrasy. The variation in the relation of the size of the separate parts and organs to that of the entire body is less great. A most excellent compilation of statistics bearing upon this matter is given by Vierordt in his book * as well as in his article, which was published some- what earher.f I select from the first mentioned the following data : The average height of weU-built individuals is, men 172 cm., women 160 cm.; of the newly bom, males 47.4, females 46.75 cm. The average body-weight in Europe is for man 65 kg., for woman 55 kg., for the newly bom 3250 grammes. The average weight of organs is as follows, the figures in parentheses being for the newly bom : brain, 1397 (385) grammes ; heart, 304 (24) ; lungs, 1172 (58)'; hver, 1612 (118) ; spleen, 201 (11.1) ; right kidney, 131; left kidney, 150 ; both kidneys, 299 (23.6); testicles, 48 (0.8); muscles, 29,880 (625); skeleton, 11,560 (445) grammes. Expressed in percentages of the body-weight we have the following figures, those in parentheses being for the newly bom : heart, 0.52 (0.89) ; kid- neys, 0.48 (0.88) ; lungs, 2.01 (2.16) ; stomach and intestinal canal, 2.34 (2.53) ; spleen, 0.346 (0.41) ; hver, 2.77 (4.39) ; braia, 2.37 (14.34) ; suprarenal bodies, 0.014 (0.31) ; thymus, 0.0086 (0.54) ; skeleton, 15.35 (16.7); muscles, 43.09 (23.4). _ The phenomena that have been described under the names osteoarthropathie hypertrophiante and akromegaly and pachyakria are clearly enough not a single disease. In one set of cases we have to do with a series of clinical symptoms that occur in the course of infections, such as tuberculosis and syphUis; while in another set of cases the eti- ology is unknown. It is a crypto- genetic disease. An excellent survey of the present status of the question is given in the works of Arnold. For the further consideration of general and partial giant growth and elephantiasis, see the chapter upon Single Malformations in Section Vlll^as well as the chapters upon the Pathological Anatomy of the Skin and the Bones. § 80. As has already been said in § 79, the hypertrophies that are the outcome of congenital impulses, and which occur with- out any discoverable cause, may affect not only whole sections of the body or entire organs, but, starting in some single tissue-ele- ments, may limit themselves to one or two kinds of tissues. This is manifested in an especially striking way ia the affection which is called ichthyosis, a pecu- liar anomaly of the epidermis in which the horny layers show a more or less marked hyper- trophy. Fig. 99. — Ichthyosis congenita. * Entitled " Anatomische, physiologisohe und physikahsehe Daten und TabeUen zum G-ebrauche fiir Medieiner," Jena, 1893. t " Das Massenwachsthum der Korperorgane des Menschen," Arch. f. Anat. «.P%s., 1890. 222 ICHTHYOTIG WARTS. — HTPERTBICHOSIS. In the form known as ichthyosis congenita one finds even in the newly- born a similar increase in the horny layer, and eases occur in which the whole surface of the body (Fig. 99) is covered with thick plates of horn, separated from one another by cracks and fissures. These plates consist of scales and lameUse which are pierced by the hairs, generally in an oblique direction, and they result from an increase in the normal epi- thehal processes of the skin. In other cases, at a later period — for instance, during the first year of life — circumscribed areas of thickening of the epidermis develop, which form iirm scales and plates, sometimes smaller, sometimes larger, giving the skin a rough or checkered appearance. The corium and the papillary layer generally are not involved in the ichthyosis. Nevertheless there are cases in which, in the areas of ichthyosis, the papillary layer is hyper- trophied, and in these cases the roughness of the surface is intensified {ichthyosis hystrix). If the change is confined to smaU, limited spots, then circumscribed warts with rough epithelial covering are formed, and these may be called ichthyotic ivarts. In rare cases there are developed still more extensive layers of epithelium over the hypertrophied papillae, whose scales are arranged perpendicularly to the layers of the skin ; and Fig. 100, Fig. 101, Fig. 100.— Comu euta- neum, removed from back of hand. (Natural size.) Fig. 101. — Cornu euta- neum, removed from arm. (■Natural size.) these sometimes reach such dimensions that they are called epidermal horns (Figs. 100 and 101). In very rare cases hj'pertrophic epithehal growths without known cause occur on the surface of the mucous membrane of the mouth, and there is a peculiar disease known as Mach hairy tongiie, which is characterized by the formation of a black or brown epithelial growth over the papillae filif ormes. By the hypertrophic develop- ment of hair in situations where only woolly hair, or even no per- manent hair at all, should occur, there is brought about an abnormal hairiness over a larger or smaller area of the body, which is known as hypertrichosis, and this is ex- plained either as a persistence or abnormal development of the pri- mary or down-like hairs, or as a pathological development of the secondary hairs. Excessive growth Fig. 102.— Head of a hairy individ- ual, a woman. (From Hebra.) HYPERTROPHY PROM OVERWORK. 223 of the nails leads to tlieir pathological overgrowth, to hyperonycJiia, which is often followed by onychogryphosis, or claw-like deformities of the nails. It must, however, be noted that pathological increase of the nails is gen- erally an acquired disease. An abnormal overgrowth of the internal organs is of very rare occur- rence, and is to be regarded reaRy as au anomaly of growth and not as the result of intra-uteriue influences, and it generally is so limited that we may class it among the individual variations in regard to extent of development. The brain and spinal cord are the commonest seat of such pathological enlargement, and it consists, as far as we know, in an increase sometimes of all the elements of the organs, sometimes only of certain of the tissue-elements. § 81. Hypertrophies of the tissues from causes operating during extra=uterine life are brought about most often by an increase in the work that the tissues and organs are called upon to do ; but they may result, too, from other causes. Hypertrophy from overwork is oftenest met with in muscles and in glands, but may occur in other structures. If the heart is called upon to do an extra amount of work, by reason of special valvular or aortic con- ditions, and if these conditions exist for a considerable length of time, then that part of the heart-muscle upon which this extra work falls suf- fers a more or less marked hypertrophy, and in this way the total bulk of the organ may reach double the normal, or even more. Pig. 103. — Transverse section of a heart, with hypertrophy of the left ven- tricle in insufflcienoy and stenosis of the aortic valves, a, Left ventricle ; h, Right ventricle. (Natural size.) Similarly, striated muscle, also the muscular layers of the bladder, the ureters, the uterus, the intestine, and the blood-vessels, may become hypertrophied from a persistent increase in their activity. 224 COMPENSATORY HYPEETROPHY. Of the glands, it is the Iddneys and the liver especially that are capable of changing their size to suit functional needs, and correspondingly it is these glands that are most liable to undergvo hypertrophy. If one kidney becomes destroyed, the other is capable of undergoing such an enlargement that it may reach approximately the same weight that the two kidneys together originally had. In the same way, the liver, after destruction of part of its parenchyma by disease, is capable of compensating for its loss by a hypertrophy of the remainder. This advantageous increase is called com- pensatory hypertrophy, because by it the normal function of the organ is restored. One may apply the same term also to muscle-hypertrophy, if by means of it lost function is restored. In the case of some other glands, as the salivary glands, ovaries, testicles, and mammae, compensa- tory hypertrophy either does not occur at all or takes place only under special circumstances, as, for instance, when from loss of one part of the gland the work of the rest is increased. For example, it is possible that, in the case of a nursing woman who has lost one mamma, the greater demands made iipon the other may resxdt in an increase in its activity and a greater development of its secreting parenchyma. However, the loss of one ovary or testicle in adult life can hardly result in an increased activity or hypertrophy of the remaining one. In the case of the thyroid gland, extirpation of the larger part of it is generally not followed by any material hj'pertrophy of the piece remaining. On the other hand, the hypophysis suffers an enlargement which must be regarded as com- pensatory. In the case of the lungs, an increase in the activity of one portion, after loss or destruction of other parts, is generally followed only by a permanent distention, which, indeed, may even go on to atrophy. On the contrary, if during embryo life a faulty development of one lung takes place, the other may become the seat of a compensatory growth ; and in the case of total failure of one lung to develop, this enlargement of the other may reach a very marked extent. Other tissues also behave in a similar way, and it may be stated as a general rule that compensa- tory development of a tissue is more nearly complete the younger the in- dividual is. In the same way, compensatory development of the kidneys is more marked in young than in old persons. In the case of the brain, a compensatory growth of one part, after loss of another, is possible only during the developmental period. In tissues that are in constant use a lessening wear may lead to hypertrophy. For instance, a diminished desquamation of the epidermal layer of the skin leads to a pathological thickening of it." If the incisor teeth of _ rodents are no longer normally worn down, by reason of the destruction of an opposing tooth or the obUque position of the teeth, they may grow to be very long and curved (Fig. 104). In the same Fig. 104. — Hypertrophy of incisor tooth of a white rat, occurring by reason of oblique posi- tion of the jaw. (Natural size.) way, finger- or toe-nails may reach an abnormal size, by reason either of absence of wear or of their being left uncut. Organs which undergo a temporary enlargement and then again become smaller may become HYPERPLASIA. 225 liypertropMed from a failure to diminish in size after the natural in- crease. For example, the uterus, after pregnancy, may remain abnor- mally large, from involution failing to take place. Under some circum- stances the removal of a normal pressure from a tissue may result in a new growth of tissue. For instance, the inner layer of the skull be- comes thicker when the brain atrophies in early life or fails to develop. In atrophy of the kidneys a hypertrophy of the surrounding fat fre- quently takes place. Among the commonest causes of pathological new growth are fre= quently repeated or persistent irritations of the tissues, of mechanical or chemical nature, associated with disturbances of circulation. Conse- quently these may be regarded as belonging to the chronic iniiaminatory processes (cf. chapter on Chronic Inflammations). For example, frequently repeated mechanical irritation of the skin may lead to the condition called callous formation or corns, a condition which is characterized by massive thickening of the epidermal layer of the skin, partly also by pathological changes in the papillary layer and the eorium. The frequently repeated inspiration of dust may result in a de- velopment of connective tissue in the lungs, and the irritation which the gonorrhceal secretion from the urethra brings about may lead to a growth of the papiUas of the epidermis in the neighborhood, and so to the appear- ance known as condylomata. Frequently recurring inflammation involv- ing considerable areas of skin often leads to thickening of the nature of elephantiasis, and ichthyotic hypertrophy of the epidermis may result from the same cause. Epithelial tissues and also connective tissues may develop hypertrophic growths by the influence of bacteria which grow in them and produce there certain chemical products — for example, tubercle- bacflli and actinomycosis. In many cases hypertrophic new growths are developed without our being able to discover any cause for them, and where we cannot assume a congenital impulse. For example, extensive hypertrophy of the lymph- glands occurs, and also of the other lymphadeuoid structures, as the spleen, the cause of which is entirely unknown to us. In the same way we are ignorant of the cause of the very common hjrpertrophy of the thyroid gland, and must turn to hypotheses to explain the condition. § 82. If an oi-gan is the seat of a hj'-perplasia it frequently is the case that all parts of it do not take equal part in the hyperplasia. For ex- ample, if a gland is enlarged, we find that in one case this is the result of an increase in the gland-substance proper ; in another, of an increase in the connective tissue. In the first case we should call it a glandular, in the second a fibrous hyperplasia. Other organs also, made up of different tissues, behave in a like way. The inequality in the relation of the two tissues to each other may go so far that while the one is markedly hj^per- trophied, the other not only may not be increased, but, indeed, may even be atrophied. In this latter case it is for the most part the specific tissue- elements that atrophy, such as ganghon-cells, nerves, gland-cells, muscles, etc., while the connective-tissue elements are increased. The chronic in- flammations are a very common cause of such a localized hyperplasia of connective tissue (see chapter on this subject). They play an important part in pathology, and only too often hyperplasia of the connective tis- sue, with atrophy of the parenchyma, follows in their train. The same rule holds for regeneration as for hyperplasia. If a part 226 REGENERATION. — HETEROPLASIA. of a tissue is destroyed, the regeneration which ensues is often incom- plete. The capacity for regeneration which the tissues and organs of the human organism possess is limited. Large pieces of tissue which are lost cannot be restored — as, for example, an extremity, a finger, or a piece of brain. The highly organized tissues, and especially their specific elements, possess only a slight capacity for regeneration. G-anghon-cells, for example, probably never are regenerated in adults, and glandular epi- thelium only if the loss is slight, and if within the tissue (gland sacs or tubes) gland-cells stOl remain intact. If an injury has happened to a gland, and in consequence its continuity is broken, the wound is repaired not by gland-tissue, but by connective tissue, a pathological process that is called cicatrization. The epithelium of the skin and of the mouths of glands has more capacity for repair than the glandular epithelium itself and ganglion-cells, for it is capable of being regenerated to a very considerable extent. Of aU the connective-tissue structures, the periosteum especially is distin- grdshed by its great power of regeneration, while cartilage shows but little of this power. If from some embryonic impulse a tissue is produced the elements of which are in themselves normal, but do not correspond to the structure of the mother-tissue, it is called a heteroplasia. In this sense a cicatrix in an organ — for example, in the liver — is a heteroplasia — a term that one employs to indicate that in the area in question connective tissue is present, together with undeveloped epithelial elements, and not true liver- tissue. Even in relation to the connective tissue of the liver we may still call it heteroplasia, inasmuch as it materially differs in structure from the normal connective tissiie of the organ. The same thing holds good for connective-tissue hyperplasia of the organs generally, especially for that which develops after inflammation. In consideration, however, of the close relationship of the tissues to one another, it is generally not reck- oned among the heteroplastic tissue-growths. The tumors nre the real iijpe of lieieroplastk growths. They represent new growths, which, while they maj' resemble the mother-tissue upon which they grow, nevertheless possess peculiarities which distinguish them from the tissue upon which they are developed, and justify us in regarding the tumor as a heteroplastic structure. § 83. Changes in tlie cells themselves are always the initial phe- nomenon of hypertrophy and regeneration, changes which lead first to enlargement of the cells and then to multiplication of them. In the further development of the new growth the basement substance formed by the cells may be increased. In hypertrophy the increase may be due entirely to enlargement of the cells, or there may be at the same time a multiplication of them ; and accordingly a distinction is made between simple hypertrophy, or hyper- trophy in the narrower sense, and a vumerical hypertrophy, or hyperplasia. For instance, a muscular organ, such as the uterus or heart, may materi- ally increase in size simply from enlargement of its muscle-ceUs. More- over, in glandular hj^ertrophy an increase in size may occur in the same way from enlargement of the' cells ; though in these cases, if the hyper- trophy is of considerable extent, there always occiirs in addition a new cell-formation, so that the process has to be caUed a hyperplasia in the histological sense. CELL-DIVISION. — SUBDIVISION OP THE NUCLEUS. 227 Under special cireumstanoes regeneration also may consist of simple enlargement of pt-eexisting cells, or of restitution of parts of cells that have been lost (regeneration of axis-cylinder processes of ganglion-cells). In the ease of a loss of considerable portions of a tissue there always occurs a multiplication of the cells by division, in addition to enlargement of them. Cell-division leading to a formation of new tissue is always character- ized hy peculiar prelimincinj changes in the nuclei and protoplasm ; that is, peculiar changes take place in the nuclei which enable us to predict the coming division of nucleus and cell, even in its preliminary stages. The completely developed nucleus of a ceU possesses a peculiar struc- ture which may be clearly made out on microscopic examination with a high power, and after the proper manipulation. A nucleus at rest con- sists of an outer shell, or memhrane, and the nuclear contents. This latter seems to consist of two parts : one a denser, more highly refracting nuclear substance, the other the nuclear fluid. The nuclear fluid forms a colorless mass, and is also spoken of as the intermediate substance. To the nuclear substance belong, in the first place, the nuclear corpuscles; in the second place, scattered granules and threads, which often form Sifranie- ivorlc (Fig. 105) which is clearly visible after proper treatment, and may be stained by the agents which color nuclei. The nuclear framework is that part of the nucleus which undergoes a series of typical changes of form in the subdivision of the nucleus — -changes which result in the separation of the nucleus into two masses of equal size. The process of nuclear division is often called karyoki= nesis {icapvov, kernel of a nat; Kivrjatg, movement), referring to these changes of form. Flemming, having in mind the skein-like structure of the nucleus when in process of division, has given to it the name mito= sis or karyomitosis (iMrog, thread). The solid substance of the nucleus, which is colored by nuclear-staining dyes, is called nuclein or chromatin (Flemming). If one studies the process of division of nucleus and cell in men or in other mammals, one is able to appreciate a series of preliminary phe- nomena in the nucleus at the commencement of division, which consist essentially of an increase of the chromatin, the substance which takes up the dye. In many nuclei the chromatin forms granules or lumps of various sizes (Fig. 106), which arrange themselves in a net-like framework. In other cases the chromatin is distributed throughout the nucleus uniformly in masses of about equal size (Fig. 107). In still others the small granules are arranged in waving rows (Fig. 108). It is probable that the uniform distribution of the chromatin particles precedes the heaping up of the lumps and granules in the framework, and is followed by the formation of the rows of granules. In the further course of the mitosis there are formed, in the next place, smooth, dense threads which stain darkly, and which are arranged in the form of a mass oj interlacing fine threads (Figs. 109 and 110). Up to this time the nucleolus is still visible (Figs. 105 to 109). Now, however, it disappears (Fig. 110) and probably takes part in the formation of the mass of threads. At the same time the membrane loses its capacity for being stained (Figs. 109 and 110), and later on it disappears entirely. By reason of the threads growing shorter and thicker, the knotted mass of fine threads (Figs. 109 and 110) develops into one of coarser threads, whose elements subdivide (Fig. Ill) later on into separate portions which 228 KABYOKINESIS. are called nuclear segments (Hertwig) or chromosomes (Waldeyer). Since the latter arrange themselves in the equatorial portions of the nucleus with their angles pointed toward the centre, there appears, if one looks at it from the pole (Figs. 105 to 120), a figure like a wreath, and later on star-shaped, and which is called the mother-star (Figs. 113 and 114). Fig. 105. Fig. 106. Fig. 107. Fig. 108. Fiff. 109. Fig. 110. Fig. 111. Fig. 112. m w .^ Fig. 113. Pig. 114. Fig. 115. Fig. 116. "^•^ W ^%M~ m \ li Fig. 117. Fig. 118. Fig. 119. Fig. 120. ! ^^^ ment of a mesenteric gland (from Flemming). a, ^ lOy -^^ ^ (a> Largeleucocytes; 6, Small leucocytes ; c,Karyomi- }^ \ rf'^Tv ^ ^ &ri^ toses ; A, Direct division of the nucleus, or nuclear ~i~1*l"I\i'»^^'^ \ ^^ fragmentation, the significance of which is still -^ ^ (^i. "> unkQ0wn;e, Cells which contain, about the nucleus, "> f"^ c ^ granules whose meaning is unknown. (Prepa- ^ n i^ l""" ^c ration treated with Flemming's acid-mixture and Q ~n i^^ii^ > Jj stained with safranine and gentian violet. Magni- 3"^%-* fr U r /™ fied 400 diameters.) o ^ ._^^ ^^ ^ ^^^ Mitotic division is the one which leads to the formation of viable cells. In how far amitotic division (fragmentation of the nuclei) is followed by cell-division is hard to tell, but there is no doubt that the leucocytes with broken-up nuclei represent for the most part elements undergoing retro- grade metamorphosis. Consequently the transformation of uninuclear into multinuclear leucocytes would have to be regarded as an evidence of their death. Not infrequently in pathological conditions an increase in. leucocyte-for- mationtsk&s, place, and this may occur not only in the germ-centres, but alsO' in other situations. This increase may lead to a temporary increase of the leucocytes of the blood — to a leucocytosis — as, for example, in the course of many infectious diseases, as pyaemia, erysipelas, pneumonia, pleurisy, peritonitis, in which especially the polynuclear cells are increased in number. It must, however, be noted that an increase of the leucocytes of the blood is no proof of an increased production, for the cells may be transferred from the lymphadenoid tissue into the blood in larger num- bers. In the chronic disease called leitra'iiiia, the eosinophile cells of the blood are increased, and there apx)ear in this fluid mononuclear white and red cells which are not normally present in the blood. Since in leucaemia sometimes the spleen, sometimes the lymph-glands, sometimes the marrow, and in some cases all these organs together, show a condition of hyper- trophy with increased cell-production, it is likety that the leucocytes pres- ent in the blood also for the most part come from these organs. Large mononuclear forms with neutrophile granules are chai'acteristic of mye- logenic leucasmia (BhrKch). In the lymphatic and splenic forms the uni- nuclear lymphocytes are increased. The new formation of the red bIood=cells occurs (Bizzozero, Neu- mann, Flemming) by mitotic division of nucleated young forms of red blood-cells. In adult men the seat of this growth is limited to the bone-mar- row, and this also holds good (Bizzozero) in the case of mammals, birds, reptiles, and tailless amphibia, while in tailed amphibia and in fishes the spleen also has a share in it. In embryos the development and multipli- cation of red blood-ceUs takes place in the entire vascular system ; later, it is limited to the spleen, the liver, and the marrow, and finally to the latter alone. 15 250 NEW FORMATION OP THE RED BLOOD-CELLS. Neumann claims tbat the multiplication of the young forms of the red blood-cells takes place in the lymphoid marrow, without more defi- nitely indicating the situation. According to Bizzozei'o and Denys, it takes place only within the vessels of the marrow, and the complete de- velopment of the red cells is carried out in the same situation. The trans- formation of the nucleated into non-nucleated cells takes place, accord- ing to most observers, by disappearance of the nucleus. Rindfleisch and Howell hold that the nucleus passes out of the cell. According to Ma- lassez, the cell separates off from the nucleus. The origin of the nucleated red cells has not yet been satisfactorily explained. According to Bizzozero, the young red corpuscles are cells of a peculiar kind which always contain haemoglobin and have no color- less periphery. Denys, Lowit, and HoweU, on the contrary, assume that they arise from nucleated colorless cells without liEemogiobin, which, according to Denys, proliferate within the vessels of the marrow, while LiJwit believes that the colorless antecedents of the red cells, dividing by mitosis, and which he calls erythroblasts, occur as well in the lymph- glands and spleen as in the marrow, and as well in the vessels as in the meshes of the reticulated tissue. F'lemming, who agrees with Bizzozero regarding the hasmoglobin of the nucleated young red blood-cells, is inclined to assume that the young forms which are present in later life are direct descendants of those of the embryo period, while Neumann believes that this hypothesis is not sufficient to explain all the phenomena of later life, as, for example, the replacing of the fatty marrow containing no nucleated red cells by blood- forming Ij'mphoid mari'ow, and the formation of blood in entirely newly produced marrow. He finds himself driven to the assumption either that a development of the nucleated blood-cells takes place from the leucocytes of the blood which are carried to the marrow after birth by the arteries, or that the cells arise from the tissue-elements of the mari-ijw. In the increased blood-formation which takes place after loss of blood, as well, also, as in severe chronic anaemias and in leucaemia, nucleated red blood-cells occur also in the circulating blood outside the marrow, while imder normal conditions thej^ are not found there. The fatty mar- row acquires in this way once more, in part, the character of lymphoid marrow, and this transformation is completed by disappearance of the fat, by a widening of the blood-vessels with an increase in their contents, and by an increase in the number of the colorless corpuscles of the marrow. Ehrlich * and Einhorn f distinguish among the leucocytes of the normal blood : (1) small lymphocytes with relatively large nuclei that stain deeply, and with little protoplasm ; (2) large lymphocytes with large nuclei that stain faintly, and with more protoplasm ; (3) mononuclear transition forms with irregular nuclei ; (4) jpolynuclear neittrophile leucocytes with polymorphous nuclei, or with several nuclei andneutrophile granules (granules which stain with a neutral dye, obtained by mixing acid fuchsin with basic methyl green), these forming about 70 per cent, of all the white cells of the blood, and migrating in purulent inflammations ; and (5) eosinophile cells, whose protoplasm contains numerous granules which stain with acid dj'es (eosin). * Zeitschrift filr l;lin. Med., i.; Charitd-Amudeii, 1884; Verhandl. der Phys. ■Gesellsch. zii Berlin, 1878-79 ; and Deutsche med. Wochenschr., 1883. t '■ Ueber das Verhalten der Lymphooyten zu den weissen Blutkorperchen," I.-D., Berlin, 1884 ; ref. " Fortsehritt der Med.," iii. NEW FORMATION OP TRANSVERSELY STRIATED MUSCLE-FIBRES. 251 According to Quincke, the life of a red blood-cell is probably about two or three weeks ; but tms estimate seems too small in view of some other observations, which indicate that a dog manufactures about 20 grammes of blood a day. As soon as the red cells are incapable of performing their function th ey are taken up by white blood-cells and eliminated from the blood-current, and this takes place by preference in the spleen and liver as well as in the marrow and lymph-glands. The red cells inclosed in the colorless cells (pulp-cells, marrow-cells), or their de- generation-products, are changed to colored or colorless iron compounds, which may be demonstrated microchemicaUy sometimes in soluble, sometimes in granular form. A part of these iron compounds is later on taken up into the blood in the spleen and marrow, and probably also in the liver, and is used again in the formation of new red blood-cells. Another part of the iron, on the contrary, is excreted through the liver-cells. Lowit distinguishes two separate forms of colorless blood-corpuscles, leucoblasts and erythroblasts, which, he thinks, have an entirely different mean- ing and do not pass from one form into the other. The leucoblasts are the lymphoid cells with chromatin arranged in lumps, and which do not suffer division by mitosis, but are changed to multinuclear leucocjrtes by fragmenta- tion of the nucleus. The erythroblasts are the colorless youthful forms of the red blood-cells, which undergo mitotic division and differ from the lymphoid cells by the homogeneous character and slight contractility of the protoplasm. He claims that the transformation into cells eontaioing hsemoglobin takes place partly in the blood, partly in the marrow. Flemming considers Lowit in error, and claims that a transformation of colorless erythroblasts into red cells does not follow from Lowit's observations: he calls attention to the fact that nucleated red cells are generally absent, and that leucocytes that do not go on to form red cells suffer mitotic division. Neumann also is.imable to agree with Lowit. Howell claims that the marrow contains numerous colorless erythroblasts, which change in the marrow first into nucleated red cells, and, later on, into the non-nucleated form by extrusion of the nucleus. Hayem is of the opinion that the red blood-cells arise from biconcave, non- nucleated discs, the blood-plates, which he accordingly calls hasmatoblasts. He considers that the blood-plates develop into colorless lymph-corpuscles, which are set free from the lymph before they come into the blood. Cadet and Pouchet hold opinions Kke the above, but the latter thinks that the nucleated red cells are formed by direct transformation of leucocytes. Malassez thinks they come from buds from nucleated ceUs of the marrow. According to Denys, with whom also E. H. Ziegler agrees, the red corpuscles have a pecuhar origin. In birds they are formed from the wall of the venous capillaries of the bone-marrow, which have a germinal area for red cells, in the shape of a cellular coating of many layers, which gives up into the blood-stream cells which then come to contain haemoglobin. Fo^ and Salvioli advance the hypothesis that the large cells of the marrow, with central lobulated nucleus, produce red cells by the development of a bud from the nucleus, which comes to be surrounded by hyahne substance, then is constricted off, and finally comes to contain haemoglobin. § 93. The new formation of transversely striated muscle=fibres starts from portions of old muscle-fibre ; and if, after injury to a muscle, the intermuscular connective tissue goes on to active growth, it forms, later on, only connective tissue, or probably also the sarcolemma of the new fibres, but never new contractile muscle-fibres. After injury of a muscle, the first signs of formative activity appear in the muscle-nuclei. These stretch out lengthwise and then (Steudel, Nauwerck) divide into a varying number of pieces. Already on the second day mitotic division of the nuclei may begin (Pig. 141, a, b), which seems to be the only way in which the tissue multiplies ; and under favorable conditions this takes place quite actively after the second day. 252 NEW FORMATION OP TRANSVERSELY STRIATED MUSCLE-FIBEES. The behavior of the contractile substance of the muscle differs very materially according to the nature and extent of the injury. In the case of traumatic, as well as of toxic and ischtemic injuries, it suffers frag- mentation into larger and smaller portions, so that the muscle-ceUs come to lie in spaces of various sizes in the midst of the debris of the muscle- fibres. Crushing and tearing can bring about a wide separation of the parts of contractile substance. The ends of the pieces of fibre then be- come sometimes pointed, sometimes oblique, transverse, or with irregular edges. Not infrequently, also, after a short time, the ends become split into several pointed filaments (Fig. 141, a). Fig. 141. — Portions of musole-flbre, from wounds of muscle at various stages of regenerative growth, a, Pointed ends of a muscle-fibre with nuclear-divi- sion figures, three days after being torn across; 6, Proliferated muscle-nuclei transformed into cells rich in protoplasm, of which one is in process of mitotic division; c. Piece of a muscle-fibre eight days after tying across a muscle; d, Giant cells which inclose a necrotic piece of muscle, from a muscle -cicatrix twenty-six days old; e,/. Muscle-fibres ending in masses of protoplasm (mus- cle-buds) — e from a ten-days-old, / from a twenty-one-days-old cicatrix; g, Muscle-fibre dividing, from a forty-three-days-old cicatrix. (Preparations hardened in Flemming's acid-mixture, stained with safranine, and mounted in Canada balsam. Magnified 350 diameters.) The mitotic division of the muscle-nucleus takes place not only in the case of nuclei that rest upon living fibres (a), but also in the muscle-cells (6) lying free in the spaces between the fibres that have separated from one another, and is followed in both cases by the development of large mul- tinuclear cells, which lead to the formation of multinuclear protoplasmic masses on the ends of the muscle-fibres (e, /), as well as in the body of the fibres (c). Between these and the transversely striated muscle-sub- stance there is no sharp line of demarcation. There occurs, therefore, ivitli muUipJicafiou of the nuclei, a growth of the sarcoplasm of the muscle- fibres, and this becomes clearly visible ; and it is probable that the musele- fibriUffi also may suffer a transformation again into sarcoplasm. The muscle-ceUs that are not connected with living contractile sub- stance become transformed into large epithelioid cells with a large nucleus (b), which again is changed, by continued nuclear division, into multi- HYPERTROPHY OP STRIATED MUSCLE. 253 nuclear masses of protoplasm [d) ; and a cicatrix of from eight to thirty days, consisting of growing connective tissue, may possess such giant ceils in large number, which often contain (d) debris of the old fibres. The new muscle-fibres are developed from the sarcoplasm rich in nuclei which appears in the continuity and at the ends of the muscle-fibres, and is associated with the formation of numeroiis large nuclei ; and by its mcrease in bulk it forms a growth in the muscle, which has been called lud-formation by Neumann. With the transition of the sarco- plasm into muscle-fibrillae there appears gradually a longitudinal and, later on, also a transverse striation, an indication that the organic struc- ture of the plasma has completed its development in the way charac- teristic of muscle. The greater part of the muscle-cells groivitig without connection with liv- ing muscle-fibres die. Yet it must be uoted that they last a long time, so that in many muscle-cicatrices of eight to forty days one can often find large numbers of masses of protoplasm rich in nuclei, which, under some circumstances, may form long continuous bands or whole rows of sepa- rate pieces of protoplasm. There is also no doubt that a part of these cells are, under favorable circumstances, transformed into transversely striated muscle-substance ; and this occurs either by the formation of independent new muscle-fibres, or by union with old muscle-fibres or mus- cle-buds. According to Volkmann, the non-continuous muscle-growth takes place by preference when the contractile substance is destroyed, without destruction of the protoplasm itself — for example, in typhoid fever — ^while the budding is observed after cutting through of the muscle. The buds springing from their ends or from their sides may form a simple prolongation of the muscle-fibre, frequently deviating from its original direction (/). Often there occur fibres split up into two or three parts [g), so that the old fibres branch as they pass into the muscle-scar. As far as we know, this splitting up occm-s very early — often, indeed [a), before the proliferating muscle-nuclei have formed much sarcoplasm — so that the proliferation appears first in the products of the division of the fibres. As a result of this fission, cicatrices in muscle often contain a larger number of muscle-fibres than were originally present in the area in question. The regeneration of muscle-tissue after injury requires favorable con- ditions as far as nourishment is concerned. Active inflammatory pro- cesses hinder it. On the contrary, nerve-influences are not essential to it, and consequently it takes place even if the corresponding nerves are destroyed. Hypertrophy of striated muscle takes place by enlargement of the separate muscle-fibres, and yet a proliferation of the fibres may also be associated with this. A new development of cardiac muscle seems to occur only to a very limited extent. To be sure, after injuries to the heart, nuclear-division figures may appear in the muscle-cells. Nevertheless, even after a few days, these can no longer be demonstrated, and the wound heals with ordinary scar-tissue. Foci of degeneration of the cardiac muscle heal in the same way by cicatricial connective tissue. If the heart=muscle is for any reason hypertrophied, this increase in size takes place by enlarge- ment of the muscle-cells ; whether or not a proliferation of the cells also is present is not yet positively known. A new formation of smooth muscle occurs, as does regeneration, 254 REGENERATIVE NEW FORMATION OF NERVE-FIBRES. after traumatic or toxic and isclaseinic degeneration. It occurs also in hypertrophic new formation of muscle-tissue — for example, in tumors — and is initiated by a mitotic division of the nuclei of the muscle-cells, which is followed by cell-division. According to both experimental work and observations upon the muscle-tissues of man, the reproduction of the fibres is shght, while after injuries and focal degeneration it ceases again after a short period. Thus, for example, defects in the muscularis of the stomach and intestine or of the bladder are repaired, for the most part, only by connective tissue. New muscle-tissue probably arises only from old muscle-tissue. Hypertrophy of the smooth muscle-fibres is a phenomenon which, within certain limits, very often occurs. In the gi-avid uterus the size of the muscle-cells reaches five to ten times the ordinary. Of the other organs, the bladder most often shows a considerable hypertrophy of its smooth muscle. § 94. Regenerative nevi^ formation of the nerve-elements of the central nervous system by new formation of ganglion-cells, as far as is known, does not occur in man and mammals in post-embryonic life. After injuries or focal lesions, to be sure, nuclear-division figures may appear in neighboring ganglion-cells, but these do not seem to lead to cell-division and new formation of ganglion-ceUs. According to the in- vestigations of Stroebe, on the contrary, divided nerve-fibres may grow somewhat lengthwise, and this holds good for the fibres of the pyramidal tract and of the posterior roots, both of which, after being cut through, grow out into the cicatricial tissue which develops at this point, the former in a downward, the latter in an upward direction. But a complete res- toration of the nerve-tissue does not occur, and a traumatic defect in the spinal cord is really replaced by connective tissue, partly by neurogha. It is not yet known whether the loss of separate nerve-fibres of the brain and spinal cord may, under favorable circumstances, be entirely restored again by the growing out of the axis-cylinders — for instance, if the sup- porting tissue be left intact. Regenerative and hypertrophic growths of the neuroglia are phe- nomena which frequently occur in morbid affections of the nervous sys- tem, and either foUow close upon degenerative changes in the nervous elements or upon destruction of the neuroglia itself, or they appear with- out such antecedents, and then take their origin partly in the period of development. They lead to a multiplication of the spider- and brush- cells, and at the same time, also, to an increase in the fibrillary elements of the supporting tissue, and under some circumstances a thick feltwork of fine fibres (sclerosis) may be formed which no longer contain any nerve-elements. Regenerative new formation of the nerve-fibres of the peripheral nervous system occurs very often, and is present in all those cases in which the continuity of a nerve-fibre is interrupted or partly destroyed by any influences whatsoever. For its accomplishment, however, it is necessary that the ganglion-cell whose process forms the nerve-fibre iu question be preserved. If a nerve has been divided by cutting, the axis-cylinders, as well as the medullary sheaths, in the distal portion, undergo degeneration, in the course of which the sheaths break up into granular debris, which is later on absorbed. During the destruction of the nerve-fibres the nuclei situ- REGENERATIVE NEW FORMATION OF NERVE-FIBRES. 255 ated beneath the sheath of Sehwaun go on to grow with the formation of mitoses, and form cells rich in protoplasm, which may take up into themselves the products of the destruction of the nerve-fibres (Stroebe). Of the central portion of the nerve only the peripheral extremity de- generates, up to the next Ranvier's node, or the next but one. The regeneration of the nerve begins a few days after the operation, in the proximal portion, and, indeed, according to Ranvier and Stroebe, in the very neighborhood of the incision ; according to Vanlair, on the contrary, at a distance of from 1.5 to 2 cm. from it. The first change consists in a swelling of separate axis-cylinders in the peripheral parts of the nerve-bundles of the central portion, which is later on followed by a splitting off of from two to five or more new axis- cylinders. The new axis-cylinders arising from the splitting up of the old ones grow in a longitudinal direction (Fig. 142, a, h), and form, within the sheath of Schwann, whole bundles (Fig. 142, c, and Fig. 143, e) of new nerve-fibres, which for the most part fill the entire lumen of the old nerve-tubes, and, indeed, stretch it, and, more rarely, also inclose remains of the old fibres (Fig. 143, /). According to Vanlair, they may even break through the old sheath of Schwann, and then either go on further in the endoneurium, or push through the perineurium of the nerve-bun- dles into the epineurium. Fig. 142. — Old and newly formed nerve- fibres, from an amputation stump, in longitudinal section, a, b, Old nerve-fibres, from which sev- eral young nerve-fibres have grown; c, Neuri- lemma, with young nerve-fibres. (Preparation hardened in Miiller's fluid, stained by Weigert's method (medullary sheath stained black), and mounted in Canada balsam. Magnified 200 dia- meters.) In this way there are formed, on the lower end of the proximal portion of the nerve, a large number of new nerve-fibres, which originally con- sist only of the newly formed axis-cylinders, but immediately (Stroebe) suiTOimd themselves with a medullary sheath which, by reason of the ir- regularity of its development, gives to the nerve-fibres a varicose appear- ance (Fig. 142, c). Later, the fibres acquire a neurilemma sheath — that is to say, a connective-tissue shell, which probably is formed from the nerve-corpuscles concerned in the growth. If a nerve is entirely severed, and with no possibility of a union of its cut ends — as, for example, occurs in all amputations of extremities — then there is developed in the region of the cut end a germ-tissue spring- ing from the connective tissue of the nerve, which later on changes into connective tissue. Originally free from nerves, this connective tissue be- comes traversed by young nerves which grow out from the nerve-stump, and which, arranged in small bundles, or scattered, grow into the cica- tricial tissue and pierce it in every direction (Fig. 144). Often the growth of nerves is so extensive that knob-like or clubbed swellings — known as amputation neuromata — arise on the ends of the nerves (Fig. 144). 256 REGENERATIVE NEW FORMATION OP NERVE-FIBRES. If a nerve is divided, but, after the division, lias been again united, or if the division has been incomplete, the nerve-fibres which gi-owout from the proximal portion, piercing through the connective tissue which is Pig. 143. Fig. 144. Fig. 143. — Cross-section of a nerve-bundle of the median nerve, just above a wound made four months previously, a, Perineurium ; 6, Endoneurium; c. Cross-section of a vessel 5 d. Old unchanged nerve-fibre ; e, Bundle of newly formed nerve-fibres ; /, Newly formed nerves, with remains of the old fibres inside the same sheath. (Preparation hardened in Miiller's fluid, stained with neutral carmine, and mounted in Canada balsam. Magnified 200 diameters.) Fig. 144. — Amputation neuroma of sciatic nerve in longitudinal section (amputation of the nerve nine years before), a, Nerve ; h, Neuroma. (From a preparation hardened in Miiller's fluid. Magnified 3 diameters.) formed in the neighborhood of the wound, may in part, or all, find their way into the peripheral portion, where, in the meanwhile, the nerve-fibres have perished. According to the investigations of Vanlair, the growth of a nerve in process of regeneration amounts to 0.2-1.0 mm. per day, according to the nature of the tissue in which it lies. Single young nerve-fibres may burrow into the old empty sheaths of Schwann (Vanlair), but the major- ity of them press into the epineurium (Vanlair) and perinem'ium, and in this situation grow toward the end-organs. Separate fibres also pass by the ends of the nerves, and grow toward the periphery either along the old nerves, or by an independent route of their own. Finally, many fibres which have left the old route are lost in the tissues. In the lower half of the intermediate portion the nerve-strands have already begun to separate into bundles again, and with the formation of a perineurium METAPLASIA OF THE TISSUES. 257 about the latter, the regenerated nerve may take on more and more the structure of a normal nerve. The above-described process of regeneration requires for its accomplish- ment weeks or even months, and sometimes is not complete even after sev- eral months. According to Eichhorst, toward the end of the first month, generally, the fibres of the central ti-unk have pierced the cicatrix. In the course of the third month, usually, the regeneration is complete. As is evident from the description, the peripheral portion of a divided nerve is not regenerated from itself, but is furnished with nerve-fibres from the central portion. Vanlair calls this neurotization. This process is repeated in all cases in which a divided nerve is regenerated, and, indeed, even if the severed nerves are muted immediately, or if only the nerve-fibres and not the connective-tissue structures are divided. The difference between th e two cases consists in this only : that in the first instance the young nerve has to gTow through a tolerably ex- tensive area of embryonic and cicatricial tissue, while in the latter case this intermediate area is absent, or, at least, is very thin, so that the growing axis- cylinders are entirely within the nerve. The views of different authors concerning the formation of axis-cyHnders in severed nerve-fibres are very diverse. Waller, Schiff, Bindfleisch, Cornil, Ban- vier, Eichhorst, Vanlair, and others beheve that it occurs through a longitudinal fission of and an outgrowth from the old axis-cylinders of the central portion. According to PhiUppeaux, Vulpian, Bemak, Leegard, Neumann, Dobbert, Dasz- kiewicz, and others, the new fibres originate in the peripheral end, and, indeed, according to Leegard, from the nuclei of the neurilemma ; according to Bemak, by longitudinal division of the old axis-cyUnders that have remained intact; according to Daszkiewicz, from the remains of the old axis-cylinders broken up transversely ; according to Neumann and Dobbert, from a protoplasmic mass which has developed in advance by a chemical metamorphosis of the medulla and the axis-cylinder. According to Cattani, new axis-cyHnders develop in de- generated nerves in the interior of a nucleated protoplasmic mass which, in the degenerated fibres, fills the sheath of Schwann. Nasse, Giinther, Schon, and Steinbriick claim that the axis-cylinders origi- nate from the old fibres of both ends ; Lent, Einsiedel, Weir Mitchell, Beneke, Grluck, and von Biingner, that they come from the nuclei of the sheaths of Schwann of both portions ; while, according to Laveran and Herz, they spring from white blood-corpuscles ; finally, Hjelt and Wolberg think they arise from the ceUs of the perineurium. Those authors who are of the opinion that after nerve-division the axis- cyhnder in the peripheral portion remains intact assume also that, in regenera- tion, a reuniting of the central and peripheral axis-cyhnders takes place by means of an intermediate piece. Wolberg holds that this takes place by means of strands of spindle-cells which arise from the perineurium. He beheves, however, that also a heahng by first intention is possible, in the sense that the cut surfaces of severed axis-cyhnders and sheaths of Schwann are immediately united. According to my observations upon regenerating nerves, the process of re- generation as it is above described is firmly estabhshed. I am supported partly by my own observations, partly by those of Stroebe, whose admirable prepara- tions, in my opinion, admit of no other interpretation. III. Metaplasia of the Tissues. § 95. By metaplasia of a tissue is understood a process by which mi already completely formed tissue, is transformed into another without a cellu- lar intermediate stage — that is, an embryonic tissue or formative tissue. Such a transformation occurs only in structures that are closely related to one another, especially, therefore, in the connective tissues. In this 258 METAPLASIA OF THE TISSUES. group, under pathological conditions, all the forms may be transformed one into another without the appearance of any intermediate growth — a phenomenon which is not startling, for, indeed, it occurs normally. If mucous tissue is changed to adipose, then the star-shaped tissue-cells change to roimd adipose cells by taking up fat, while the mucous base- ment substance disappears. In the same way, lymphadenoid tissue, after disappearance of the lymphatic elements, may change to adipose tissue by the taking up of fat in the cells of the reticulum. The cellular and gelatinous bone-marrow also behaves in the same way. By disappearance of the fat, adipose tissue may take on the appear- ance of mucous tissue, and at times, also, may contain nuclei. If the basement substance of hyaline cartilage becomes fluid, so as to form a mucilaginous jelly, or if it becomes completely dissolved, then the carti- lage-cells (Fig. 145, a) set free in this way change to stellate cells anas- n'niiiiFpffiTfmifill c_ 'JlOw'iL a ^ ')f^ ^ p(f%^^m^y^ L" Fig. 145. — Metaplasia of cartilage in reticular tissue, in arthritis fungosa. a, Hyaline cartilage ; 6, Tissue consisting of branching cells ; c, CartUage-coUs set free by solution of the cartUage basement substance and passing over into mucous-tissue cells. (Magnified 400 diameters.) tomosing with one another (c, i), so that a tissue is formed which cor- responds in its structure to mucoid tissue or to the reticular tissue of bone-marrow. By taking wp of fat the latter may become adipose tissue ; by storing up of round cells in its meshes it becomes cellular marrow- tissue. If the basement substance of hyaline cartilage becomes fibrous, and if it changes at once to a glue-producing material, then connective- tissue cartilage is produced. If the cartilage-cells lose their characteristic nature, and if they become flat connective-tissue cells, then the cartilage changes into ordinary connective tissue. If portions of the cartilage change to medullary tissue, then other parts of it may at the same time be transformed into bone, in which case the basement substance is changed into a gelatinous material and impreg- nated with lime-salts, while the cartilage-cells are transformed into bone- ceUs, in the neighborhood of which the basement substance of the bone forms the bone-corpuscles. If connective tissue changes directly into METAPLASIA OF THE TISSUES. 259 bone (Fig. 146), then in the first place a condensation of the basement substance (6) takes place, and later on a storing up of lime (c), in the com'se of which the connective-tissue cells (d) come to lie in indented spaces or bone-corpuscles and become bone-cells (di). Fi&. 146. — Bone-formation from con- nective tissue. Cross-section through a bone-trabecula in process of forma- tion from an ossifying fibroma of the periosteum of the upper jaw. a, Con- nective tissue ; b, Thickened tissue, form- ing the groundwork of the new bone ; e, Lime-deposit ; d, Connective-tissue cells; di, Bone-corpuscles. (Prepara- tion hardened in alcohol and cut with- out decalcifying, stained with hsema- toxyUn, and mounted in Canada balsam. Magnified 200 diameters.) If connective tissue is to be transformed into mucous tissue, then the fibrillse disappear, and there appears in their place a gelatinous mucus. If numerous lymphatic round ceUs establish themselves in a fibrillated connective tissue, and if at the same time a breaking up or a disappear- ance of the connective-tissue fibres takes place, while the connective-tis- sue cells persist, and unite to form a reticular tissue by the development of processes, then in this case a lymphadenoid tissue may be developed from it. Metaplasia of connective tissue is to be distinguished not only from simple degeneration, but also from the processes of growth. Prom the former no new tissue arises, but the old tissue perishes. In the latter it is a question of a new tissue, rich in cells, and taking its origin in cell- division. Metaplasia stands, in a certain sense, midway between the two. A new tissue, to be sure, is formed, but ceU-gTowth is not present, or at least is a minor matter. In many ways the process is allied to the retrogressive changes ; for example, the change into mucous tissue is a process very similar to mucous degeneration. Moreover, the new tissue is not infrequently a perishable one. On the other hand, one often enough observes developmental pro- cesses following upon metaplasia. Sometimes the condition of the blood- vessels has the greatest intluence upon the subsequent course of events, since a good vascular supply for the tissue suffering metaplasia favors a further development of it, while its absence, on the contrary, encourages retrograde metamorphosis. In mucous membranes the seat of chronic inflammation — for example, of the uterus and the respiratory tract — it not rarely happens that the cylindrical epithelium in places changes to pavement epithelium, a phe- nomenon which is known as epithelial metaplasia. The transformation takes place in this way : the regenerating epithelium changes its char- acter after repeated loss of the original epithelium. In the stratified pavement epithelium of a mucous membrane, moreover, a Jiorny degen- eratimi of the upper layer of cells may take place, and, indeed, not only in sitxiations which normally possess pavement epithelium — for example, in the urinary passages — ^but also in those where it has developed patho- logically, as in the nose and uterus. SECTION yi. Inflammation and the Associated Processes of Repair. I. Acute Inflammation and its Various Forms. § 96. Inflammation is essentially a local tissue=degeneration com= bined with pathological exudations from the blood=vesseIs, caused by some injurious agency, with whick are associated, sornetimes earlier, some- times later, tissue-proliferations leading to regeneration or to hypertrophy. In acute inflammation the exudation is generally associated with a pronounced hyperemia, which begins even before the exudation, and in- troduces it. As a resiilt of the combination of hypersemia and exudation, the inflamed tissue is reddened and swollen. If it is situated on the surface of the body, wliere the tissues are cool, the increased supply of warm blood from the deeper parts produces local increase of temperature. If the tissue contains sensory nerves, the sensation of pain sets in at the same time with the changed conditions in the inflamed area. Redness, swelling, increased heat, and painfulness of the inflamed tissue are phenomena which even in antiquity the physicians regarded as signs of inflammation ; and rubor, tumor, calor, and dolor were des- ignated by Celsus, at the beginning of our era, as the cardinal symptoms of inflammation. To the four was then added a still further symptom — functio laesa, altered function of the inflamed tissue. The causes of inflammation may be attributed to mechanical, thermic, electrical, or chemical actions, and also to the injiuence of parasites. It is a common characteristic of aU these injurious agencies to produce at first a local tissue-degeneration , which in a certain degree of extent and of intensity is associated with disturbances of the circulation and' of the vascular secretion. The causes of inflammation are not specific injurious agencies ; but, rather, every injurious agency may produce inflammation, if, on the one hand, its action is sufficiently intense to induce certain disturbances of circu- lation with tissue-degeneration, while at the same time it does not act strongly enough to destroy the tissue and stop the circulation. Most causes of inflammation reach the human organism from the out- side, but excitants of inflammation may also be formed in the iuterior of the body. Bacteria which have penetrated into the tissues very often produce at first, from the substances present in the body, products whose action induces inflammation. Then, moreover, substances that excite in- flammation can develop in the organism even without the aid of parasites ; for example, i£ tissues die in large masses from any cause — e.g., as a re- sult of ischsemia — or if, in consequence of disturbances of the processes 260 ACUTE INFLAMMATION AND ITS VARIOUS FORMS. 261 of assimilation (gout), abnormal products of metabolism are deposited in the tissues. The exciters of inflammation can act upon the tissues both from the external parts of the body and also from the lymphatics and the blood, and one can accordingly distinguish ectogenoiis, lymphogenous, and Juema- togenous inflammations. Through the extension of inflammations to the neighboring regions there arise inflammations by continuity; the transfer of the producer of inflammation from a focus of inflammation through the lymph- or blood-stream leads to metastatic inflammations. If noxious substances are discharged bj^ the excretory organs, excretory inflammations may arise. When a local injury to tissues has reached such a degree as to pro- duce the exudation characteristic of inflammation, there is usually pres- ent a congestive hyperasmia, on account of which the blood flows with increased quickness through the dUated channel. After a short time there occurs, however, on the other hand, a lessening of the speed of the circulation, which ends in a slowing of the blood=current. The first disturbances of the circulation, which find their expression in the congestive hypera?mia, can be due either to an irritation or a paraty- sis of the vaso-motor nervous system, or to a direct action on the walls of the vessels, particularly those of the arteries, which has as a restdt a dilatation of the channel. Although these very often precede the inflam- matory exudations, they stiU form no essential characteristic of inflamma- tion, but occur very often when an inflammatory exudate does not f oUow them. The circulatory disturbance characteristic of inflammation is shown only when the slowing of the bIood=current and the patholog= ical exudation from the vessels set in. As has been demonstrated, prin- cipally by the researches of Cohnheim, Samuel, and Arnold, the slowing of the blood-stream in the widened channel and the pathological exuda- tion are caused by a niodiflcation of structure, an alteration of the vas= cular walls ; while this induces both a lasting dilatation and an increase of the adhesion of the blood to the waU of the vessel, together with an. increase of resistance from friction, and lastly an increased permeaMlitij of the vascular walls. In the capUlaries the lasting dilatation is chiefly the result of relaxation of the connective tissue surrounding them, while the thin- ness of the capillary walls makes this tissue bear a great part of the pres- sure upon them. The tissue-lesion which leads to the phenomena of inflammatory dis- turbance of circulation and exudation affects generally all parts of the tissue, but may, under certain conditions, be conflned to the vascular walls, particularly when it is a case of hsematogenous inflammation, in which the injurious agency acts from the blood. However, the tissue in the region adjoining the capillaries must soon become involved in associ- ated suffering. The tissue-changes which are established by the excitants of inflammation are sometimes only transient, and not easUy, or not at all, recognizable even by microscopical examination ; at other times they are serious, so that they can be easily recognized even by macroscopic inspec- tion. The latter is particularly the case when a considerable time has passed since the occurrence of the damage. In the subsequent progress there are often added to the lesions established by the causes of inflammar tion other tissue-changes, which are produced by the inflammatory dis- turbances of circulation and by the collection of exudate in the tissues. If in any tissue the cause of inflammation has led to that alteration 262 ACUTE INFLAMMATION AND ITS VARIOUS FORMS. of the vessels wMcli is the requisite antecedent of the inflammatory dis- turbance of secretion — i.e., the formation of inflammatory exudate — and if as a result of this there is already evident a slowing of the blood-cm-- rent, the circulation in the capillaries is performed in an irregular way, and there is here and there stagnation, or transient or permanent cessation of flow. Since, in this event, the colorless blood-cells often remain attached to the walls, while the red blood-corpuscles are carried on, there occurs in the capillaries a more or less marked increase of the colorless blood= corpuscles as compared to the red. In the veins, in which one can distin- guish in the normal circulation an axial red stream and a cell-less plasmatic peripheral zone, more or less numerous leucocytes pass over into the peripheral plasmatic zone when there is a certain degree of slowing of the circulation. Still greater slowing of the circulation results in the pass- ing over of blood-plates and of red blood-corpuscles into the peripheral plasmatic zone, and finally the difference between the axial stream and peripheral zone may be entirely lost. When leucocytes have passed over into the peripheral zone they either roU along further or attach themselves to the vein-wall, either to roll on again further after a time or to remain permanently attached. If this occurrence leads to a marked accumulation of leucocytes along the walls of the veins, the appearance is called marginal disposition of the color- less corpuscles (Pig. 147, d). Related to the accumulation of leucocytes in the capillaries and to the marginal disposition in the veins is the emigration of the leucocytes from the vessels involved (Fig. 147, d, e), and there occurs simultaneously a pouring out of fluid from the vessels. Fig. 147. — Inflamed human mesentery, a, Normal trabecula of mesentery ; 6, Normal epithelium ; c. Small artery ; d, Vein with peripheral colorless blood- corpuscles; e, Colorless blood-corpuscles, emigrated or emigrating; /, Des- quamated epithelium; /, Polynuclear ceU ; g, Extra vasated red blood-cor- puscle. (Osmie-acid preparation. Magnified 180 diameters.) INPLAMMATOEY DISTURBANCES OP THE CIRCULATION. 263 The emigration of the colorless blood=corpuscles is an active pro- cess, which is accomplished by the amoeboid movement of the cells, and it also occurs independently under normal conditions. The cause of the enormous outpouring, as it is observed in inflammations, is doubtless a change in the vessel-walls, which is favored by the circumstances that the leucocytes attach themselves to these walls and also ,pass through them. According to the researches of Arnold, Thoma, and others, the places where the wandering out occurs are the cement lines between the endothehal cells, and in the inflammatory vascular alteration a partial widening of these spots occurs. The emigration is accomplished in such a manner that the leucocyte first sends a process through the vessel- wall and then flows after the process with the rest of the cell-body, until finally the whole mass lies outside of the vessel. Arrived here, the leu- cocytes may remain stationary at first, but generally they wander further, when the direction of the excursion is generally settled by chemotaxis — i.e., the attraction or repulsion due to chemical substances present in solu- tion in the tissue-juices. Possibly chemotactic influences sometimes exert an influence both on the leucocytes situated at the periphery and on those which are at a standstill in the capillaries. The leucocytes that have mi- grated from the vessels are chiefly polynuclear forms that make up about 70 per cent, of the colorless corpuscles in the blood. Their number is sometimes large, sometimes only small. The pouring out of the fluid exudate, whose composition always varies more or less from that of the normal tissue-lymph and is distin- guished by a relatively high proportion of albumin, is a process which is also to be referred to an alteration of the vessel-walls, in consequence of which the secretory function of the latter suffers a disturbance. It takes place simultaneously with the migration of leucocytes ; may also, however, begin even before it, or occur in cases in which emigration of leiicocytes is lacking or remains within very narrow Umits. The composition of the cruciate is dependent in every case partly on the peculiar property of the vessels affected — which always varies according to the formation of the tissue to which they belong — partly on the degree of vascular alteration ; and it is to be admitted that the quantity of albumin is larger the more the vascular wall is injured. If the extravasated fluid contains flbrinog- enous substances and fibrin-ferment, and if, on the other side, no influ- ences opposed to such a change are acting, coagulation — i.e., a separa= tion of the fibrin, which is generally deposited in the form of filaments and granules — may occur in the exudate. If the alteration of the vessels is of a very high degree, or if at the same time the stasis is pronounced, red blood=corpuscles may emerge from the vessels along with the fiuid, either by diapedesis or by rhexis. The diapedesis takes place, according to Thoma and Engelmann, espe- cially at the places where leucocytes have previously passed through the wall of the vessel, and the escape of red blood-corpuscles by the same route may follow very quickly. Since the red blood-corpuscles are not motile, their escape must be regarded as a passive process which is per- formed under the influence of pressure within the capillaries. The escape of blood=plates into the exudate can occur both in exu- dates which are rich and in those which are poor in cells, but occurs principally in exudates that are distinguished by their rich proportion of fibrin and red blood-corpuscles, while the leucocytes are fewer in number. 264 INFLABOIATORY DISTURBANCES OF THE CIRCULATION. The clinical significance of the term inflammation (phlogosis) has, on the whole, changed little in the course of time, since the cardinal symptoms of in- flammation brought forward by Celsus, and accepted by Galen, are recognized as such at the present day. Just so much the more do the views differ about the differentiation of the essential from the accidental in the symptom-complex of in- flammation, and about the accurate determination of its real nature. A com- parison of the expressions concerning these points on the part of recent authors (Virchow, von Recklinghausen, Cohnheim, Samuel, Thoma, Neumann, Strieker, Heitzmann, Grawitz, Leber, Metschnikofl:, and others) shows that no single one defines inflammation in the same way as any other, or judges in exactly the same way the individual phenomena of inflammation. The definition which I have given above can accordingly not lay claim to universal recognition ; yet since its advancement * it has met with no opposition, and I believe I may therefore dare to hope that it finds acceptance by other pathologists also. Formerly one believed that one should discern in hypersemia the most essential symptom of infiammation. Eokitansky maintained that every inflam- mation was characterized by a dilatation of the capillary vessels, slowing of the blood-stream, and stasis, which was caused by a thickening of the blood through the effusion of serum, and by an adhesion of the red blood-corpuscles one to another. Henle, Stilling, and Rokitansky attributed the dilatation of the vessels and the slowing of the blood-stream to a paralysis of the vessel-nerves, the cause of which, according to Henle and Rokitansky, is an increased excite- ment of the sensory nerves ; while according to Stilhng, the cause is a paralysis of these nerves induced by the infiammatory irritant. Eisenmann, Heine, and Briicke sought to attribute the distm'bances of the circulation to a primary spasm of the vessels, which is brought about by irritation of sensory nerves, and which produces, behind the contracted places, slowing of the current, irregular circula- tion, and finally even stasis. Vogel, Emmert, Paget, and others, on the other hand, attributed the dilatation of the vessels and the stasis to an abnormal at- traction of the tissues for the blood. In opposition to these opinions, however, one must maintain that all the changes of circulation produced by contractions and paralysis of the vessels certainly precede or accompany the inflammatory — i.e., the circulator^' — disturbances which lead to the formation of exudate, and may have a modifying influence on the course of the inflammation, but that they do not belong to the essence of inflammation, and therefore may either be lacking or be present in it, without the accompaniment of inflammatory exudate. Rokitansky sought to explain the pouring out of fluid from the vessels in inflammation by the assumption that with the dilatation of the vessels there occurred also a thinning and an increased permeability of the vascular wall. Vogel, C. Emmert, and Paget, on the other hand, made this phenomenon also dependent on an increased attraction between the blood and tissue parenchyma or juices. Virchow, on the other hand, beheved (1854) that a part of the exu- date — that which collects in the tissue-crevices and is poured out on the free surfaces of the body — is the result of mechanical pressure in the vessels — i.e., is pressed-out blood-serum ; while a part, which is chiefly derived from the " irri- tated " cells, is to be considered as the product of an increased attraction on the part of the tissues for the blood-constituents. Of the cells that collect in the in- flamed region, he believed that all originate from a proliferation of the tissue- cells occurring in consequence of the action of the inflammatory irritant. The recognition that the formation of exudate is to be referred to an injury to the vessel-walls we owe chiefly to Cohnheim, whose researches in various directions were completed by Samuel, Arnold, Thoma, Binz, and others. Cohn- heim also showed that in inflammation th e colorless corpuscles emigrate and form an essential constituent of the inflammatory exudate. Dutrochett and Waller t already in the years 1842 and 1846 had described * Cf. Ziegler, " Historisches und Kritisches iiber die Lehre von der Entziind- ung," Beitr. v. Ziegler, xii., 1892. f " Rech. anatomiques et physiologiques sur la structure interne des animaux et des vegetaux et sur leur moti'lite," Paris, 1842, p. 214. t Philosoph. Magaz., xxis., 1846, pp. 271. 398. INFLAMMATORY DISTURBANCES OF THE CIRCULATION. 265 the escape of colorless corpuscles from the circiilatiiig blood. The observation, however, fell into complete oblivion tiU Cohnheim. rediscovered the occurrence in 1867. As follows from the researches of Schklarewsky,* the peripheral disposition of the colorless blood-corpuscles in the veias is a purely physical phenomenon. If one makes hquid, in which finely pulverized substances of varying speoifie gravity are suspended, flow in tubeSj at a oertaiu degi'ee of retardation of the current the specifically hghter bodies pass over to the peripheral zone ; and when the rate becomes still slower, the heavier bodies also enter this zone. For the emigration of the colorless corpuscles to occur, it is necessary, according to the researches of Binz, Thoma, and Lavdowsky, that they be capa- ble of motion and of adhering to the vessel- wall. According to these authori- ties, therefore, the emigration of the colorless blood-cells is not a purely passive, but at least ia part an active process. If one reduces the motility of the colorless corpuscles by irrigation of the mesentery with a 1.5 per cent, solution of salt (Thoma), or if one lowers their vital activity with quinine or iodoform (Binz, Appert, Kemer), the emigration is also inhibited. Pekelharing, on the other hand, beheves that one should accept the view that quinine, oil of eucalyptus, and sahcylic acid produce a narrowing of the veins, restrict the increase of permeability of their walls, and thus reduce the extravasation of colorless corpuscles ; a view which is rejected, however, by Disselhorst, who observed a dilatation of the veins after irrigation of the tissues with quinine, carbolic acid, sahcyhc acid, and sublimate. As there occurs in this case a retardation of the current after a transient acceleration, without the emigration of the leucocytes that pass out into the peripheral zone ; and as, on the other hand, leucocytes from blood-vessels that have been irrigated for an hour with quinine are still of complete vitality (Eberth), Disselhorst is of the opinion that the drugs men- tioned so change the inflamed vessel -wall that an accumulation of the leucocytes that pass by either cannot occur at all, or can do so only with difficulty. Very probably a lesion of the vascular wall is not absolutely necessary for the emigration of leucocjrtes (Thoma). Since vaso-motor disturbances of the circulation can produce migration (von Recklinghausen, Thoma), a slowing of the blood-stream, the abihty of the colorless corpuscles to perform amoeboid movements and to adhere to the wall of the vessel, and their disposition to remain in the peripheral zone of the stream, probably furnish all the conditions necessary for this migration. Possibly differences in the watery content of the tissues (Thoma) also exert some influence, since an increased amount of water increases amoeboid movement. It is also possible that the presence in the tissue- fluids of substances having chemotactio action may lead to migration of leuco- cytes which remain attached to the inner wall of the vessel {vide § 105). According to the researches of Arnold, Thoma, and Engelmann, a soft cement substance lies between the borders of the endothelial cells, and this substance suffers a change in the circulatory disturbances associated with cell- migration — a change which may sometimes be recognized in the histological examination in the form of numerous circumscribed widenings of these inter- cellular areas (Engelmann). If leucocytes pass through these parts of the vessel in large quantities, the cement substance becomes still more permeable, and soon permits red blood-corpuscles also to pass through in quick succession (Thoma). Under normal conditions, wandering ceUs are found in many tissues (von Recklinghausen), and wander from there partly into the lymph-vessels (Hering, Thoma), sometimes also into the blood-vessels (Bubnoff, Schulin, Ranvier, Senftleben), or to the surfaces of mucous membranes, to which they penetrate between the epithelial cells. About collections of lymphad^noid tissue in the mucous membrane they may constantly be found in abundance, and wander from there to the surface through the epithelial layer. According to observa- tions of Kunkel and Siebel, a few of them may also reach the free surface of the alveoU of the lungs. The discharge of fluid from the capillaries and veins was regarded by Cohn- heim and Hering as a process of filtration, which is modified in inflammation 16 * Pfluger's Arch., 1. Bd. 266 INFLAJMMATORY DISTURBANCES OP THE CIRCULATION. by the alteration of the vessel-walls in such a manner that a liquid abnor- mally large in quantity and rich in albumin transudes. According to the re- searches of Heidenhain, however, the formation of lymph is not a simple filtra- tion process, but a process of secretion, which is caused by a peculiar property of the living vessel- waU; and accordingly the inflammatory exudate is depen- dent on a change of the functional action of the vessel- walls, especially of the endothehum (of. § 44). The inflammatory disturbances of the circulation and the formation of ex- udate may be most easily followed on the transparent membranes of the cold- blooded animals, especially on the mesentery or the extended tongue or the spread-out web-membrane of the frog. On the frog's mesentery, which has been spread out on a suitable object-stand, circulatory disturbances and inflam- mation develop from simple contact with the air and the drying that results ; the tongue and the web-membrane must be cauterized in order to become in- flamed. By the employment of suitable apparatus, the circulation of the blood and the formation of infl.ammatory exudate can be observed with the microscope on the thin membranes of mammals also (mesentery of rabbits, wing-membrane of bats), and observations made in this manner show that the phenomena which occur agree completely with those observed in the frog. § 97. The cellular and fluid extidates secreted by the vessels collect first in their neighborhood, but soon spread out in the vicinity, mass them- selves in the lynqjh-spaces of the tissties, and thus form a tissue=infiltrate (Fig. 149, &, and Fig. 151, p). When the exudate is abundant, it can spread out and infiltrate also the neighboring sound tissue that has not been injured by the cause of the inflammation. This infiltration may be so considerable as to produce new disturbances of circulation and Fig. 148. — Section through the border of a bhster. a, Horny layer of the epi- dermis ; 6, Rete Malpighii; c. Normal papillse ; d, Swollen cells, some of the nuclei of which are stUl visible, but pale, while others have been entirely de- stroyed; e, InterpapiUary epithelial cells, the deep ones intact, while in the upper layers they are drawn out lengthwise and are somewhat swollen, without nuclei; /, Total liquefaction of the cells ; g, InterpapiUary cells without nuclei, swoUen, and raised from the cutis ; h, Total degeneration of the interpapUlary cells which are separated from the cutis ; i, Flattened papillse iaflltrated with cells ; h, Coagulated exudate (fibrin) lying under the lifted epitheUum. (Car- mine preparation. Magnified 150 diameters.) PARENCHYMATOUS AND INTERSTITIAL INFLAMMATION. 267 nutrition, and thus increase the area of tissue-degeneration aiid inflamma- tory exudation. When exudate is present in a tissue, it may he absorbed in part ty the tissue-elements themselves, so that they swell up and not rarely contain drops of fluid, which are ordinarily called vacuoles. There often occurs, also, a complete dissolution of the tissue=elements in tlie exudate, especially of the connective-tissue cells (Fig. 148, d, f), and not seldom, also, of the intercellular substance. In this way both brain- and miiscle-tissue, as well as ordinary connective tissue, may be complete^ liquefied in the course of an inflammation. If dead ceUs become saturated with lymph containing fibrinogen, and fibrin-ferment is formed, a coagulation may precede the liquefaction of the infiltrated tissue ; in which case the cells are transformed partly into homogeneous masses without nuclei, and partly into granules and fila- ments (Fig. 150, c, d). If the exudate within an organ — e.g., a gland — is chiefly in the sup- porting tissue, while the specific parenchyma appears little altered, the form of the inflammation is designated as an interstitial inflammation (Fig. 149, &). On the other hand, if the degeneration of the specific tis- sue — e.g., of the epithelium of the uriniferous tubules (Fig. 150, c, d) of the kidney, of the liver-cells in the liver, of the contractile substance in the muscles — is promi- nent, and these parts appear saturated with exudate, one caUs the condition paren= W^^^^^^^^^^^^$?^§^- chymatous inflammation. M^^^^^^^^^^^^Ziw^^^^^i^^ Fig." 149. — Eecent intersti- tial hepatitis, a. Normal liver- tissue ; 6, Small-celled infil- tration of the periportal con- nective tissue. (Hsematoxj'lui preparation. Magnified 80 dia- meters.) If the seat of an inflammation is the surface of an organ, one calls it a superficial inflammation (Fig. 151). If the exudate can gain free ac- FiG. 150. — Parenchymatous ne- phritis, with necrosis of the epithe- lium of the nriaiferous tubules, in ic- terus gravis, a, Normal convoluted tubule; 6, Ascending loop; c. Convo- luted tubule with necrotic epithe- Uum ; d, Convoluted tubule with epithehum partly intact, partly ne- crotic ; e, Stroma with blood-vessels. (Preparation hardened in MuUer's fluid, stained with gentian violet, and mounted in Canada balsam. Magnified 300 diameters.) 268 INFLAIVBIATORY EFFUSIONS. cess to the siirface, and flows from it mixed with particles of cast-oii tis- sue (Pig. 151, d, e, f, fi, h), the inflammation is called a catarrh. If the pouring out of a liquid exudate on the surface of the skin or of a mucous membrane is impeded by coherent, horny epithelium (Pig. 148_, a), and there form under this cover circumscribed collections of fluid, in which the deep soft layers of epithelium dissolve (Pig. 148, d, /, g), the lesions thus formed are called vesicles and blisters. When the exudate from serous surfaces collects in the cavities of the body, there are formed in them inflammatory effusions, which not rarely reach a considerable bulk, distend the affected cavity, and compress the organs contained therein. Fig. 151.— Superficial catarrhal inflammation of a brouclius. a, Ciliated cells; «!, Deep cell-layers ; 6, Goblet-cells ; c, Markedly mucoid cells ; ci. Mucoid cells with mucoid nucleus ; d, Desquamated mucoid cells ; e. Desquamated cili- ated cells ; /, Layer of drops of mucus ; /i. Layer of stringy mucus and pus-cor- puscles ; g. Excretory duct of a mucous gland filled with mucus and cells ; h, Desquamated epithelium of the excretory duct ; i, Intact epithelium of the ex- cretory duct ; h, Swollen hyaline basement membrane ; I, Connective tissue of the mucosa, partly infiltrated with cells; m, Dilated blood-vessel; n, Mucous gland fiUed with mucus ; %, Lobule of a mucous gland without mucus ; o. Migrating cell in the epithelium ; p, Cellular infiltration of the connective tissue of the mucous glands. (Preparation hardened in Muller's fluid and alcohol, stained with aniline brown, and mounted in Canada balsam. Magnified 120 diameters.) If an organ is in a condition of inflammation, it is customary to ex- press it by adding the termination "itis" to the Greek name of the organ. In this way are formed, for example, the terms endocarditis, myocarditis, pericarditis, pleuritis, peritonitis, encephalitis, pharyngitis, keratitis, orchitis, oophoritis, colpitis, metritis, hepatitis, nephritis, amyg- dalitis, glossitis, gastritis. The ending "itis" is sometimes affixed to the Latin names. One says, e.g., conjunctivitis, tonsillitis, and vaginitis. If LEUCOCYTES IN INFLAMMATORY EXUDATES. 269 one wishes to denote that the serous covering or the neighborhood of an organ is ioflamed, one places before the Greek name with the termina- tion "itis" a "peri" or "para." Thus are formed the words perimetritis, parametritis, periproctitis, perityphlitis, paranephritis, perihepatitis. JFor isolated forms of inflammation there are also in use special names ; thus one calls inflammation of the lungs, pneumonia; inflammation of the arch of the palate and tonsils, angina. Since Cohnheim taught us to recognize the migration of colorless blood- corpuscles en masse as an important part of inflammation, and showed that they might serve as a new source of origin for the cells present in the exudate, the question of the origin of the cells present in the exudate of fresh inflammations has been many times the subject of discussion. While some regarded aU ceUs present in the exudate as extravasated leucocytes, others beheved that the leucocytes coming from the blood formed only an accidental component of the exudate, and that the cells contained in it for the most part have originated on the spot from the tissue "irritated" by the cause of the inflammation. Strieker is of the opinion that the swelling and hardening of the tissue in inflammation are not caused by the coUection of exudate, but by a swelling of the cell-retieulum which traverses the tissues, and that it is a phenomenon of gTowth of the cells and their prolongations characterized by swelling. The cellular exudate — ^i.e., the pus — he accounts for partly by a segmentation and division of the ceUular reticulum swoUen from the inflammation, partly by a transforma- tion of the connective-tissue fibrils into pus-corpuscles. Heitzmann considers the inflammatory tissue-changes as a reversion of the tissues to the embryonal condition, and beheves that the hving material is not contained in the cells only, but ioflltrates the entire ground substance, and increases, in the progress of an inflammation, with the hquefaction of the ground substance. Connective tis- sue, cartilage, and bone become resolved in inflammation into those elements from which they are formed — i.e., into celts — which then immediately reproduce their like. Grawitz beheves that both the ceUular infiltrate and the pus occur without any participation of the leucocytes worth mentioning. Everywhere in the tissues cells which he caUs slumber-cells he latent in large quantities, not affected by our nuclei-staining dyes and therefore not recognizable (only from 5 to 10 per cent, of the tissue-ceUs, according to him, are known to us), but which in inflammation awake, increase in size, respond to nuclei-staining dyes, and therefore again become recognizable. After what an unprejudiced careful examination of inflamed tissue exhibits, there can be no doubt that the description of the origin of the inflammatory in- filtrate given by Strieker, Heitzmann, Grawitz, and their pupils, does not corre- spond to the conditions as they actually exist. The cells that accumulate in the tissues in acute inflammations in the first hours and days are leucocytes derived from the blood, and this is true especially of all cells which tear the character of polynuclear and mononuclear leucocytes. A tissue-growth occurs, it is true, almost always in the course of inflammation, hut it is able to produce a large quantity of cells only in the course of several days (cf . § 101), and these cells do not possess the characters of lymphocytes. A doubt about the origin of the cells exists only in regard to a part of the mononuclear forms, because proliferating tissue can produce cells which appear very hke the larger forms of mononuclear leucocytes and have not yet been certainly distinguished from them. § 98. Both the local tissue-degeneration and the exudation may appear very differently in different cases, and one can distinguish conformably different forms of inflammation. If the exudate consists principally of fluid, while the cellular compo- nents are comparatively insignificant, it is called a serous exudate. If this is within a tissue — for example, the cutaneous and subcutaneous tis- sues or the kidneys (Fig. 152, a) — it leads to inflammatory oedema. 270 SEROUS CATARRH. — MUCOUS CATARRH. Escape of fluid on the surface of a mucous or serous membrane gives the picture of a serous catarrh ; locali^ied collection of fluid beneath the horny layer of the epidermis, with the liquefaction of the soft layers of epithelium, leads to the formation of vesicles and blisters with clear con- tents (Pig. 148, d, /). Fig. 152. — Inflammatory cedema of the kidney, with catarrh of the urinif- erous tubules (from a man who died of suppurative mediastiaitis and pleuritis with nephritis on the tenth day after the beginning of the Ulness). a, Stroma distended by fluid, and infiltrated with granules and filaments of fibrin and separate fat-droplets ; 6, Capillaries ; c, EpitheUa of the convoluted tubules, in parts shghtly fatty and desquamating ; d, Desquamated epithelial cells in a looped tubule ; e, Granular and fatty detritus in a looped tubule, whose epithe- hum remains, but is cloudy ; /, Hyaline cylinder (cast) in a convoluted tubule ; g, Eound cells. (Glycerin preparation treated with osmic acid. Magnified 350 diameters.) If the fluid exuded on the surface of a mucous membrane is associ- ated with marked mucoid change of the superficial epithehum (Pig. 151, 1), c, ci) and of the m_ucous glands (u), there is a mucous catarrh (Pig. 151, d, f, /i). If a marked desquamation of the epithelium of the mucous membrane, with or without mucoid change, occm-s, there is a desquania= tive catarrh, and it may occur not only in mucous membranes, but also in the respiratory parenchyma of the lungs, on serous surfaces, in the kidney-tubules (Pig. 152, c, d), etc. In desquamative catarrh, if the secretion is mixed with much epithe- lium, it is cloudy and contains a large number of cells, which consist, ac- cording to the source of the catarrh, sometimes of mucoid cylindrical and ciliated cells (Pig. 153_, .3, 6), sometimes of squamous epithelium {11, 12, 18, 19). At the same time there generally are found also round cells (Pig. 153, 1, 2, 7, 9, 10,^ 13, 20), and often also bacteria (4, 14, 15, 16, 17, 21). If the deposition of fiibrin, or coagulation, occurs in a liquid exudate, there are formed fibrinous and sero=fibrinous exudates, which are often also called croupous. They occur chiefly on the surface of serous or mucous membranes and in the lungs, but masses of fibrin can also be FIBRINOUS EXUDATES IN rNFLAJOIATION. 271 deposited within tissues infiltrated witli exudate (Fig. 152, a, and Fig. 156, I), as well as in lymphatic vessels (Pig. 156, Ji). Fibrinous exudates on mucous surfaces form whitish patches and co- herent membranes, which sometimes lie upon them only loosely, some- times are firmly attached to the under surface. In the serous cavities the deposits of fibrin float in the form of flakes in the fluid exudate, or attach themselves firmly to the surface of the membranes. These de- (.s<(P Fig. 153. — Catarrhal secretion of various mucous membranes. A, Secretion from mucous membranes with cylindrical epithelium. ; B, From the mouth ; C, From the urinary bladder. 1, Round cells (pus-corpuscles) ; 2, Large round cells with bright nuclei from, the nose ; 3, Mucoid cylindrical cells from the nose ; 4, Spirillum from the nose ; 5, Mucoid cells with cilia from the nose ; 6, Goblet-cell from the trachea ; 7, Round cells with mucoid masses from the nose ; 8, Epithe- lial cells containing pus-corpuscles from the nose ; 9, Fatty cells in chronic catarrh of the lar3mx and pharynx ; 10, Cells from sputum containing coal- pigment ; 11 and 12, Squamous epithelium from the mouth ; 13, Mucus-cor- puscles ; 14, Micrococci ; 15, Bacteria ; 16, Leptothrix buccahs ; 17, Spirochaete dentkola; 18, Superficial ; 19, Middle layer of bladder epithehum ; 20, Pus-cor- puscles; 21, Schizomycetes. (Magnified 400 diameters.) posits consist at times only of smaU, attached granules and flakes, which give to the affected surface a cloudy, duU, rough, or even granular ap- pearance ; at other times they consist of larger yellowish or yellowish-red tough membranes, which often give the surface a felted or villous ap- pearance (cor villosum, pericarditis villosa). In the lung croupous in- flammation leads to the filling of the alveoli with a coagulated mass, as a result of which the lung acquires a firm consistency. The formation of croupous membrane on mucous surfaces occurs only if the epithelium is already desquamated and the connective tissue, in 272 FIBRINOUS EXUDATES IN INFLAMMATION. part at least, exposed ; but tissue covered with epithelium may be coated over with coagulated fibrin extending from spots free from epithelimn. The desquamation of epithelium fol- lows, in such a case, sometimes gradu- ally, sometimes, quickly, through the lifting up of whole layers of epithe- lium (Fig. 154, h), which are either stiU well preserved or already degen- erated or necrotic (Fig. 163, h) and infiltrated with exudate (Fig. 156, a). ^-^ •?9 ^ *■" .iTS^ 7^ Fig. 156. — Section of a uvula inflamed and covered witli a stratified fibrin membrane, from a case of diphtheritic croup of the pharyngeal organs, a. Super- ficial layer of coagulation, consisting of epithelial plates and fibrin and dotted with numerous balls of cocci ; 6, Second layer of coagulation, which consists of a close-meshed reticulum of fibrin inclosing leucocytes ; c, Third layer of coagu- lation, lying on the connective tissue, and consisting of a wide-meshed reticulum of fibrin inclosing leucocytes ; d, Connective tissue infiltrated with cells ; e. Infil- trated boundary-layer of tbe connective tissue of the mucous membrane ; /, Mass of red blood-corpuscles ; g, Congested blood-vessels; ft. Lymphatic vessel dis- tended with fluid, flbriti, and leucocytes; i, Excretory duct of a mucous gland distended with secretion ; S, Transverse section of a gland ; I, Reticulum of fibrin in the superficial layers of connective tissue. (Preparation hardened in Miiller's fluid, embedded in ceUoidin, stained with hsematoxylin and eosin, and mounted in Canada balsam. Magnified 50 diameters.) In the lungs the fibrin generally forms an irregularly arranged retic- ulum (Pig. 158) composed of very fine or coarser filaments, and inclosing leucocytes, red blood-corpuscles, and desquamated epitheUum. In the fii-st stages of fibrin-formation there are also sometimes found filaments which 274 HiEMORRHAGIC EXUDATE. are arranged like a necklace and consist of rows of corpuscles. Accord- ing to the researclies of Hauser, the first deposit of the fibrin reticulum may start from the dead epithelial cells of the alveoli, whose thin plates are infiltrated at the same time with a delicate reticulum of fibrin. Fig. 157. — Adhesive pericarditis. Section through the epicardium, a, and the fibrin membrane, b ; c, Dilated and congested blood-vessels ; d, Round cells which infiltrate the tissue ; e, Lymphatic vessel filled with cells and coagula ; /, Formative cells within the deposit. (Preparation hardened in Miiller's fluid and stained with hasmatoxylin. Magnified 150 diameters.) In the kidneys deposits of fibrin may occur in the form of fine fila- ments or fibrinous masses in the uriniferous tubules and in the glomerular- capsule. In the lymphatic glands fibrin filaments form principally within the honph-passages. Haemorrhagic exudate — i.e., exudate which contains red blood-cor- puscles in large quantities — occurs particularly in connection with the deposit of fibrin (Fig. 154, d, and Fig. 158). Thus croupous pulmonary exudate always contains a larger or smaller number of red blood-corpus- f~^ ^ cles, and in the same way, in f "^ - ^* fibrinous pericarditis and pleu- / y^^"!'=-,#'^^^^ ritis, large quantities of red blood- ' *~ corpuscles quite often escape. Haemorrhagic inflammations oc- cur also not rarely in the central nervous system, in the lymphat- ic glands, in the skin, and in the kidneys. Fig. 158.— Croupous hepatization of lung. Alveolus tilled with an ex- udate consisting of fluid, red and colorless blood-corpuscles, and epi- thelial cells. (Preparation first in- jected ana then stained with hema- toxylin. Magnified 80 diameters.) The serous, fibrinous, and sero-fibrinous inflammations may be caused both by thermic and chemical influences and by bacteria, but are most often the result of infection, especially of infection with the Diplococcus- INFILTRATION OF THE TISSUES WITH SMALL CELLS. 275 pnemnonim and the Bacillus diphtherim. The former causes particularly croupous inflammatioEs of the lungs and the pleurae, the latter fibrinous inflammations of the pharynx, palate, and respiratory passages. Hauser recently emphasizes that the fibrin-formation extends from cells — e.g., from pulmonary epitheha or leucocytes — which are at the centre of the de- posit of fibrin. So far as I have observed, this actually occurs ; stiU I have gener- ally seen, in the centre of radiating rods of fibrin, only bright forms without nuclei, which, as I beUeve, originate not from leucocytes or tissue-ceUs, but fi'om red blood-corpuscles, and are probably partly identical with the forms described as blood-plates. § 99. When the inflammatory exudate consists principally of leuco- cytes, there is an infiltration of the tissues with small cells (Pig. 159, d, e, /), which may at times be so crowded as to obscure the structure of the tissue. If leucocytes with fluid exudate appear in large quantities on the surface of a mucous membrane or an external wound, a white fluid is seen on the affected part, which is called pus, and has given occasion Fie. 159. — ^Purulent bronchitis, peribronchitis, and peribronchial broncho- pneumonia (from a child aged fifteen months), a, Purulent bronchial contents ; b, Mucoid bronchial contents ; c, Ci, Bronchial epithehum infiltrated with round cells and partly raised up,(c2) ; .:v?'^^^^^iaiSJ^M:J^S^iffi sist in the newly formed connective tissue and then generally become calcified. Coagulated exudates in the lung are generally soon liquefied and absorbed; yet their removal in this man- ner may be associated with connective-tissue prolifera- tion, which terminates in induration of the lung. Fia. 172.— Formation of granidations within a fibrin- ous deposit in pericarditis sev- eral weeks old. a, Epicardium; 6, Deposit on the epicardium, consisting' of granulation tis- sue, d, and fibrin, c. (Prepa- ration hardened in Midler's fluid, stained with hsematoxy- lin and eosin, and mounted in Canada balsam. Magnified 45 diauieters.) Masses of coagula within the vessels, which are termed thrombi, give rise, when no infection intervenes, to an inflammatory proliferation of the vessel-walls, a proliferating vascuhtis — i.e., a process which is as- sociated with cell-migration, and which exactly corresponds to the inflam- matory proliferation of the serous membranes. It is entirely immaterial whether the thrombus has been caused by a preceding inflammatory pro- cess or by any other conditions ; for the presence of the coagulated mass is itseK sufficient to jaroduee inflammation and tissue-proliferation. The first change which is introduced in the replacement of the throni= bus by connective tissue is here also the appearance of fibroblasts (Fig. 173, li), which arise from the vessel-wall, and later, with the aid of vessels that grow in from the vessel-wall and its neighborhood, form an embry- onal tissue that is finally converted into connective tissue. The complete replacement of an obstructing thrombus or embolus results in the oblitera- tion of the lumen of the vessel by vascular connective tissue (Fig. 175, jr). Replacement of a peripheral thrombus, on the other hand, results in fibrous thickening of the wall. Owing to incomplete replacement and liquefaction of the part not replaced, there arise strings and threads of connective tissue, which cross the lumen of the vessel. Calcification of the parts of thrombi which are not replaced by connective tissue leads to the formation of vascular calculi. Necrotic tissues, which cannot be sequestrated and discharged ex- ternally, are also replaced by vascular connective tissue that becomes changed into cicatricial tissue ; and this replacement is accomphshed in the same way as in the case of the fibrinous exudates and thrombi. A REMOVAL OP TISSUE-NECROSES. 291 preliminary condition for this replacement is that the necrotic tissue shall contain no substances (bacteria) which hinder a tissue-pro- FiG. 173.— Devel- opment of embryonal tissue in a thrombosed femoral artery of an old man, three weeks after Ugation. a, Me- dia; b, Elastic boun- dary-layer j c, Intima thickened by old chronic inflammatory processes; d, Coagu- lated blood; e, Cellular infiltration of the me- dia ; /, The same of the intima; g, Eound cells, partly withia the thrombus, partly be- tween the latter and the intima; h, DifEer- eitt forms of formative cells. (Preparation hardened in alcohol, stained with hfema- toxylin, and mounted in Canada balsam. Magnified 300 diame- ters.) liferation and produce severe inflammation. For the rest, it is immate- rial how the necrosis has occurred, and whether the necrotic tissue is free Fig. 174. — Border of a recent hsemorrhagic infarct of the lung, a, Non- nucleated alveolar septa, whose oapiUaries are filled with hyahne thrombi ; 6, Nu- cleated septa ; c, Vessels filled with red thrombi ; d, di, AlveoU fiUed with coagu- lated blood; e, Fibrino-cellular exudate in the alveoli. (Preparation hardened in MiiUer's fluid, stained with hematoxylin and eosin, and mounted in Canada balsam. Magnified 100 diameters.) 292 REMOVAL OP TISSUE-NECEOSES. from exudate or is infiltrated with exudate or blood (Fig. 174, d, di). Under these conditions the first phenomenon leading to healing is the following: the inflammatory infiltration (e) in the neighborhood of the necrosis becomes associated with a tissue-proliferation, which pro- duces granulation tissue, and this in turn grows toward the necrosis (Fig. 175, d, e), pushes it aside, and replaces it. If this process is not disturbed by any influence, even extensive tissue-necroses may disappear in the course of weeks or months, and be replaced by connective tis- sue. It may also happen, however, that certain tissues resist absorption (e.g., bone ; cf . Fig. 181), or that the development of granulations stops so early that the remainder of the necrosis persists and then becomes calcified. When, owing to an inflammation or an ischasmia within an organ, only the more sensitive elements die — for example, the epithelia or the muscle-cehs — while the connective tissue is preserved, the absorption of the necrosis is performed quickly, and in a short time there develops a Fig. 175.— Peripheral portion of a healing infarction of the lung, a, Blood- extravasation changed into a granular, yellowish mass ; 6, Necrotic alveolar septa without nuclei ; c, Newly formed connective tissue ; d, Vascular granulation tis- sue within the alveoH ; e, Fibroblasts within alveoli containing the residue of the hajmorrhage ; /, Artery ; g, Vascular conneetive tissue formed within the artery at the place of the embolus. (Preparation hardened ia Miiller's fluid, stained with haematoxylln and eosin, and mounted iu Canada balsam. Magnifled 45 diameters.) EMPYEMATA. FOREIGN BODIES. 293 scar or callus of connective tissue (Fig. 176, e), in which the specific tissue- elements are lacking. Pus is quickly absoried 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 neighbor- hood, and this leads to the formation of an abscess membrane. The camtj may be obliterated by the absorption of the pus and by the growing together of the granulating abscess membrane ; and so the abscess may heal, leaving a scar behind. Incomplete absorption may lead to thicken- ing of the pus, and later to calcification of the residue. If the thickening of the pus, however, does not occur, the 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 granula= tton 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 con- nective tissue in the same way as are tissue-necroses or masses of fibrin. Fia. 176.— Callosity of heart. Section through a muscle trabeculum that has undergone fibroid degeneration, a, Endooardium ; 6, Transverse section of normal muscle-cells ; c, Connective-tissue hyperplasia rich in cells ; d, Atrophic muscle-cells in hyperplastic connective tissue ; e, Dense connective tissue without nuclei or muscle-cells ; /, Veins, in whose neighborhood a few muscle-cells stiU remain ; g, SmaU blood-vessels ; h, Small-celled infiltration. (Preparation stained with hsematoxylin. Magnified 40 diameters.) 294 PHAGOCYTOSIS. — CHEMOTAXIS. III. Phagocytosis Occurring in the Course of Inflammations, and the Formation of Giant Cells around Foreign Bodies Chemotaxis. § 105. When small foreign bodies, or portions or particles of devital- ized tissue, are found in the human body, there is very often a marked assetnbling of cells at their place of deposition. These are, first, leucocytes which have migrated from the vessels, but later also tissue-cells that Jiave become motile, that are proliferating, or that come from an already established centre of proliferation, wander into the neighborhood of the foreign body or the remains of devitaUzed tissue. According to the researches of Leber, Buchner, Massart, Bordet, Ga- britschewsky, and others, it is certain that this assembhng 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 devital- ized tissue ; but doubtless other conditions also exert an influence in de- termining 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 phenom- enon which is termed phagocytosis. If one observes the process 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 granules of soot — one sees that the motile cells pour their protoplasm, if one may use the expres- sion, around the foreign bodies, and absorb them completely into their Fig. 177. — Granular cells in a focus of degeneration of the brain, a, Blood- vessel with blood ; 6, Media ; c, Adventitia with lymphatic sheath ; d, Unchanged gha-oells ; e, Fatty gha-cells ; /, Binuclear glia-cells ; g, Sclerosed tissue ; h, Round cehs ; hi, Round cehs with single droplets of fat ; 7i2, Fatty-granule spheres ; fe, Pigmented-granule spheres. (Teased preparation treated with osmic acid. Magnified 300 diameters.) PHAGOCYTOSIS. — CHEMOTAXIS. 295 protoplasm by the union of the pseudopodia extended over the bodies. Among the foreign bodies that have penetrated from the outside, which are particularly often taken up by the leucocytes 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 infections 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 debris of tissues one finds most often fat-droplets (Fig. 177, 111, In) and products of the destruction of the red blood-corpuscles (Fig. 177, h, Fig. 179, c, and Fig. 180). These products of destruction may be taken up by the cells until they are stuifed with them and converted into large granular forms that are terraed fattif-granule spheres and jjig- mented-granule spheres. Besides fat and blood-pigment, other fragments of tissue also — as, for example, particles of the contractile substance of muscle-eeUs 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 luxui-iant prohf eration — fibroblasts, osteoblasts, sarcoblasts, etc. If an inflammatory exudation runs its course at the same time as the prohferatiou, and if the proliferating tissue contains leucocytes, these may also he taken up dy the jAagocytes (Fig. 178, a, b, c). Fig. 178. — Phagocytes from granulat- ing tissue with included leucocytes and their fragments, a, Eound fibroblast with two leucocytes; 6, Swollen spindle-shaped connective-tissue cell with one leucocyte ; c, d, e, Fibroblasts with, fragments of leu- cocytes. (Preparation hardened in sub- limate, stained with Biondi's staining mix- ture, and mounted in Canada balsam. Magnified 500 diameters.) The substances taken up by the phagocjd;es may be partly dissolved and destroyed within the cells ; and this is true particidarly for the leu- cocytes, which gradually disappear inside of the cell-protoplasm of the phagocytes (Fig. 178, c, d, e), but it also holds equally for various fragments Fig. 179.— Mass of pig- mented-granide spheres in a lymphatic gland, a, Lymph-node; 6, Trabec- ule of the lymphatic gland; c^ Lymph-passage with pigmented-granule spheres. (Preparation hardened in alcohol, stained with carmine, and mounted in Canada bal- sam. Magnified 80 dia- meters.) of tissue, except blood-pigment (Fig. 179, 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 according to 296 PHAGOCYTOSIS. — CHEMOTAXIS. their vital properties and the condition in which they entered the cells, are sometimes dissolved and destroyed, but sometimes, on the other hand, re- main 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. 179, c) and later also the blood, from which they are deposited principally in the 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 leiicocytes 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 osteoclasts under physiological conditions (Fig. 180, 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 gradual dissolution of soluble substances (e.g., strands of catgut, fragments of dead muscle-fibres). It sometimes hap- pens that mononuclear cells take up small foreign bodies into their in- terior, and after this, by di^dsion, their nuclei become polynuclear. This is observed most often after the inclusion of bacteria (lepra, tuberculo- sis), which still multiply within the cells. Fig. 180. — Dog's hair encapsulated in subcutaneous tissue, a, Hair ; 6, Fi- brous tissue ; c, ProUferatrag granulation tissue ; d, Giant cells. (Preparation hardened in alcoliol, stained with Bismarck brown, and mounted in Canada balsam. Magnified 66 diameters.) When a foreign body in the tissues cannot be absorbed it is sur- rounded by granulation tissue that changes later into connective tissue (Fig.180, h, c), and in this way becomes encapsulated. The proliferation may be very slight, however, about smooth, completely insoluble sub- stances (glass beads). The phenomena of chemotropism or chemotaxis — i.e., the attraction or repul- sion of freely motile cells by substances soluble in water — were first observed by Strahl and Pfeffer, who made researches particiilarly on myxomycetes, infusoria, bacteria, seminal filaments, and swarming spores. Eesearches of Leber, Buch- ner, Massart, Bordet, Gabritschewsky, and others have shown that the leuco- cytes may also be attracted (positive cliemotropism 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 bacterial cells (Buchner) —which even after great dilution (according to Buchner, the protein of pyocya- PHAGOCYTOSIS. — CHRONIC INFLAMMATIONS. 297 neus is still active in a dilution of 1 to 3000) are positively chemotaotic. Ac- cording to Buchner, this property belongs also to gluten-casein from wheat- paste and legumin, glue from bones, and alkali albuminate from pease, while ammonium butjrate, trimethylamine, ammonia, leucin, tyrosin, urea, and skatol exhibit negative chemotaxis. Phagocytosis is a vital phenomenon that has been long known and has many times been made the subject of investigation. Von Recklinghausen, Poniick, Hoffmann, Langerhans, Slavjansky, von Ins, Ruppert, Langhans, Rindfleisch, and others conducted such experiments in the sixties and seventies, and described par- ticularly the relations of cells to granules of dust and the disintegration products of the blood. In the year 1874 1 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 phagocy- tosis is a vital function of cells, which in the first place is directed to the taking up of nutriment. But since a phag'ocytosis is also observed in cells which give off substances to the excreta (e.g., in the renal epithelia) ; since, also, wanderiug ceEs 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 dii'ected also partly to the excretion of certain substances. Since the year 1883 MetsohnikofE has occupied himself in a particularly thor- ough fashion with phagocytosis (hehas also introduced this-name) , and has demon- strated 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 comtat waged hy the cells against intruders or dis- ease producers. This view is, however, completely erroneous and finds no support in the actual conditions. Metschnikoff, in putting forward his definition of in- flammation as a battle of phagocytes against disease producers, pays no atten- tion to those phenomena which have been termed inflammation 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 recognized on aU sides as inflammation, it is apparent that legitimate inflammations occur in which no phagocytosis is present ; so that phagocytosis does not even form an inseparable concomitant of inflammation. For the rest, it is to be remarked that phagocytosis is a phenomenon that often occurs in the course of even non- inflammatory processes (e.g., within tumors). Finally, one cannot see in phago- cytosis any appearance of a struggle, since in the taking up of cinnabar or soot or fragments of red blood-corpuscles or pus-corpuscles every possibility of re- sistance 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. (§ 26 and Section IX. contain more on this subject.) IV. Chronic Inflammations. § 106. Inflammation is naturally an acute process, but various condi- tions 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 in the course of an acute inflammation changes occur which prevent a rapid healing. As may be deduced from the forego- ing, all large defects of tissue and tissue-necroses, as well as large masses of exudate that are difficult to absorb, act in this way. When necrotic masses 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. 181, a), and maintain a constant inflammation. 298 e:HRONIC IXFLAMMATIONS. When a large superficial defect of the integument is produced by a burn granulations develop, but it 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- fluences. Thus, for example, re- peated inhalation of dust may cause chronic inflammation of the lung; repeated friction of the skin, chronic inflammation of the skin ; repeated pathologi- cal alterations of the stomach- contents, inflammation of the stomach. In the canals of the body in which concretions tovm, these may also be a cause of lasting tissue-lesions. When unfarorahle nntritire conditions exist in a tissue — e.g., great congestion — these may also enable even slight external influences, that under normal conditions produce no inflam- FiG. 181.— Necrosis of fifteen years' duration in the lower part of the diaphysis of the femur, a, Sequestrum; 6, c, Edges of the opening in the thickened bone. (Alcohol preparation. Eeduced to two-thirds natural size.) mation or one that soon stops, to set up ulceration without any tendency to heal. In this way, for example, chronic ulcers of the leg may occur. Infections are also a frequent cause of chronic inflammations, espe- cially those by Ixtcteria and moulds, which multiply in the body and so con- stantly produce new inflammatory irritation. The inflammations which they cause are distinguislied from others chieflj' by having often a pro- gressive character, and by causing metastases by way of the lymphatic vessels and the blood. Finally, chronic intoxications form a last cause. They act particularly on the kidneys and liver, and may be attributed either to the introduc- tion into the organism, through the intestinal canal or the lungs or even the integument, of substances that are injurious to the organs affected or to others ; or to the production in the body itself, by disturbances of the processes of metabolism, of injurious substances, so that there is a chronic a uto-intoxication. § 107. The forms of chronic inflammation are determined partly by their fundamental causes, partty by the nature of the tissue affected. The remains of acute processes, as they are seen in fibi-inous exudates and tissue-necroses, lead, when not complicated by specific infectious, to CHRONIC INFLAMMATIONS. 299 an inflammatory tissue=proliferation. For the rest, inflammatory hypertrophies of connective tissue restilt from various chi-onie irrita- tions of the tissues. So, for example, chronic irritation of the lung by the deposition of stone-dust may lead to a connective-tissue hypertrophy in the Pig. 182.— Section of a stone-cutter's lung with bronchopneumonic fibrous nodules, a, Group of fibrous nodules; 6, Normal lung- tissue; c, Pulmonary tissue, thickened, but still containing bronchi, vessels, and a few al- veoli. (Preparation hardened in spirit and stained with pic- rocarmine. Magnified 9 dia- meters.) lung, which is essentially characterized by the formation of circum- scribed nodules (Fig. 182, «)> hut occurs also partly in the form of a diffuse hypertrophy (c). Continued irritating conditions in the neigh- borhood of the oriflces of the urogenital apparatus, where they are main- tained by the discharge of irritating secretions, often lead to the forma- tion of acHiuinate condylomata — i.e., to hypertrophy of the papdlfe, in which the inflamed and infiltrated papilla?, with their vessels, enlarge (Fig. 183, a) and often also divide into branches. The epithelium covering the papillEe is also apt to become hypertrophic. Pig. 183. — Condyloma acumi- natum, a, Enlarged and branch- ing papillae; 6, Epidermis. (In- jected preparation, stained with hsematoxylin. Magnified 20 dia- "" '^ meters.) Repeated continued mild inflammations of the skin and subcutaneous tissue, which are caused by mechanical lesions (scratching), by parasites, or by any other continued ir-ritation, may also often, when they acquire a considerable extent, lead to diffuse connective-tissue hypertrophy, whiuli 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. 184), may be caused both by non-specific irritations — e.g., by inflammations 'which run their course in the neighborhood of chronic ulcers — and by specific infections, as the syphilitic and tubercular. Chronic catarrhs of mucous membranes are sometimes caused by specific infections (gonorrhoea, tuberculosis), sometimes by a non-specific 300 CHRONIC INPLAIVIMATIONS. injury (concretions, pathological changes in the contents of stomach and intestine), sometimes by continued distui-bances of the circulation (con- gestions). Chronic abscesses generally result from acute abscesses, and have the same etiology, but may, however, also develop more gradually, and are then caused by special infections, generally tuberculosis or actinomycosis. They are usually limited externally by a con- nective-tissue membrane covered with granu- lations, and may increase in si^ie partly by the secretion of pus from the abscess-wall, partly by the destruction of the waU and its neigh- borhood. Enlargement advancing toward the deep-lying parts leads to the formation of burrowing or congestive abscesses. Their growth is reaUy always to be ascribed to the persistence of the infection. Perfora- tion into neighboring tissues leads accord- ingly, also, to new infectious inflammations. The tubercular 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 Section IX.). Chronic ulcers are generally caused by specific infections (tuberculosis, syphilis, glanders), but non-specific harmful factors also lead to chronic ulceration in tissue which is specially susceptible to such ulcer- ation. Thus chronic congestions in the vas- cular system of the leg may interfere 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 ad- FiG. 184. — Periosteal hyperostosis of the tibia, at the base of a chronic ulcer of the leg. (Re- duced to three-fifths natural size.) vances at other parts, the ulcer is termed serpiginous. Active growth of granulation tissue in an ulcer leads to the formation of an ulcus eleva- fum hypertrophicum ; dense, callous, gristly induration of the edge and base leads to the formation of an ulcus callosum, or iiidolens, or atmicum. Chronic granulation growths (granulations) which persist as such a longer or shorter time, without undergoing conversion into connective 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 tliese infections, often pro- duce spongy growths and tumor-like formations, they are also called CHRONIC mPLAMMATIONS. 301 Fig. 185. — Transverse section througli the mucosa and submucosa of an atrophic large intestine, a, Glandular layer reduced to one half its height ; 6, Musoularis mueosse ; c, Submucosa ; d, Muscularis ; e, Mucous membrane entirely atrophied. (Magnified 30 diameters.) fungous granulations or care luxurians, and infectious granulation tumors or granulomata. They show all the special peculiarities that enable one to recognize, from the strncture, the development and life-his- tory of the granulation formations, as well as their special etiology (of. Fig. 186. — Induration and atrophy of the renal tissue in chronic nephritis. a, Thickened and fibrous Bowman's capsule ; &, Normal glomerular vessels ; c, Griomerulus whose vascular loops are partly impermeable and homogeneous, and its epithehum mostly lost ; d, Completely ruined glomerulus ; e, Homogeneous mass of coagulation, studded with nuclei, and consisting of exudate and epithe- lium ; /, Desquamated glomerular epithelium ; g, Epithehum from the capsule ; h, Collapsed urinary tubule with atrophic epithelium ; i, Collapsed tubule without epithelium ; h, Hyperplastic connective-tissue stroma ; I, Collection of smaU cells ; m, Norma], somewhat dilated urinary tubule; n, Aiferent vessel ; o, Vein. (Al- cohol preparation, stained with alum carmine and mounted in Canada balsam. Magnified 250 diameters.) 18 302 CHRONIC INFLAMMATIONS. Section 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 is 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 with continual desquamation, while the connective tissue remains, or they decay at the same time as the connective tissue on which they are situated imdergoes necrosis and destruction. The final result is a mucous membrane (Fig. 185) 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 hsematogenous 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 intoxications. They begin either acutely or more insidiously, and are characterized by atrophy and degeneration of the glandular tissue (Fig. 186, h, i), by hypertrophy of the connective tissue (Fig. 186, a, k, and Fig. 187, 6), by ceUular infiltration, by the formation of granulations (Fig. 186, I, and Fig. 187, e), by obliteration of old vessels (Fig. 186, c, ' ' ' .': in the hands and feet, although , » ^ ^ , ' ^ - , » ' ■ '• ' ; they may also develop iu other - ' _ ^ - - ' ■ • ' parts of the skeleton. » ". •' : Fig. 199.— Section through a •■ ■ ; . elioudroma of the ribs. Cartilage • » ' f •'''*» ' .' containing many cells: a. Small; 6, * • - ; • Large. (Preparation stained with # "■ • ' ' '' hematoxylin and carmine, and • - . • mounted in Canada balsam. Mag- nified 80 diameters.) » CONNECTIVE-TISSUE TUMORS. — OSTEOMA. 317 The tissue of an enchoudi'oma is usually that of hyaline cartilage (Fig. 199) ; less often is it composed of reticular or fibrocartHage. Still there are often fibrous patches in the hyaline cartilage. The periphery is often composed of fibrous tissue, which constitutes a sort of perichondi'ium. The number, size, form, and arrangement of the cells vary greatly in different enchondromata, and also in the same tumor. Certain ones con- tain many cells (Fig. 199), 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 individual ceUs are scattered abotit in a regular manner. All the varieties of car- tilage which exist normally may be found 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 suiTound it as a whole. What was said in § 91 holds good here with reference to the method of develop- ment. Sometimes cartilage forms the matrix, sometimes bone-marrow, or periosteum, or bone, or one of the forms of connective tissue. Cartilagi- nous tumors growing from cartilage have been denominated ecchovdroses. The tissue of enchondromata is often subject to retrograde meta- morphoses. 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 tissue (§ 127, Fig. 236), thus giving rise to a chondromyxoma ; or the intercellular substance under- goes 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, or genuine done may be formed, so that the name osteochondroma must be employed in designating such a growth. By excessive proliferation of the cells of the cartUage, sarcomatous tissue may resrdt, and the neoplasm becomes a chondrosarcoma (ef. § 127). An euehondroma is tisuaUj^ a lieuign growth, although in certain cases of mixed tumors metastases niay occur. (e) Osteoma. § 115. An osteoma is a tiunor consisting of bone. Tumors of this natm-e are generally found in connection with the osseous system (Figs. 200-202), 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 diffusely spread out it is called a hyperostosis. If it 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 to old bone are of four sorts : movahle periosteal exostoses, which are surrounded by the ■'issues of the periosteum, but are separate from the bone ; parosteal oste- omata, which have their seat near a bone ; disconnected osteomata, which are jemoved to some distance from any bone and are situated in tendons and muscles ; and finally, heterop>lastic osteomata, which occur in the lungs, meninges, diaphragm, skin (very rare), parotid gland, etc. The teeth, too, may have excrescences. If they are formed from the enamel they are called dental osteomata; if from the dentine, odoutoiuata. 318 (:ONXE( 'TI VE-TISSUE TUMORS. — OSTEOMA. Fig. 200.- ■one sixth. -Multiple etauxneous exostoses of the frontal bone. (Reduced about The latter come from a hyper- plastic development of the pulp during the formation of the tooth. We can divide osteomata into hard or ehurneous {osteoma dunim or ehiirneum) (Figs. 200 and 202) and softer spongy forms [osteoma sponejiosum' or meduJlare) (Pig. 201). The former consist of a firm, com- pact tissue like the cortical portion of the shafts of long bones, and have very narrow nutrient canals (Pig. 202) ; the latter are made up of thinner and more delicate masses of bone-tissue with wide medul- laiy spaces, imitating in their structure the cancellous tissue of bones. Fig. 201. — Cartilaginous exos- tosis of the upper diaphysis of the tibia. (Eeduced about one third.) CONNECTIVE-TISSUE TUMORS.^ — OSTEOMA. 319 Sometimes the surface is regular and smooth, so that the whole tumor has the appearance of a ball or a knob on a stem ; or it may be irregular, rough, and warty, so that it has no definite shape (Fig. 201). The former Pia. 202. — Ebumeous osteoma of occipital bone, seen in a frontal section. a, Osteoma; h, Wall of cranium. (Eight-ninths life size.) is the ease with the ivory-like nodules which most commonly appear as exostoses on the skull (Figs. 200 and 202), while the latter is true of the spongy exostoses and the disconnected and heteroplastic osteomata, such as are observed, for instance, in the falx of the dura mater. 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. 200) 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 epiph- yses or points of insertion of tendons, or both together, are the favor- ite seats. Such growths are evidently to be referred to an inherited dis- position, on the part of the points affected, to overgrowth, or else to a disturbance in the development of the skeleton. Sometimes a transmitted tendency can be proved (cf. § 31). The bony tissue is developed partly through the formation of osteo- blasts, as described in § 91, partlj- through the metaplasia of formed tis- sues (§ 95). 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 mai-row. If an exostosis develops in such a manner that cartilage is first formed from the periosteum or the mar- row, and then bone develops out of this, we apply to this the term ciirti- laginous exostosis (Fig. 201). But if this intermediate stage of cartilage 320 CONNECTIVE-TISSUE TUMORS. — ANGIOJIA. is wanting, and the exostosis develops directlj^ from the proliferating periosteum, then we term the growth a connective-tissue exostosis (Figs 200 and 202). 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 hyper- ostoses, osteophytes, and exostoses, as well as of a part of the parostoses and disconnected osteomata. Scales of bone which in rare cases form in the mucoiis membrane of the air-passages are best explained as errors of development. The formations of bone which occur in the deltoid muscle and in the adductors of the tliigh from constant caiTying of a miisket and horseback-riding must be looked upon as tumors which owe their origin to a local congenital predisposition ; for the connective tissue belonging to muscles shows itself possessed of qualities which, as a rule, belong only to the periosteum and bone-marrow. The so-caUed myositis ossificans — that peculiar disease of the muscles which is characterized by a progres- sive ossification, in chUdhood, of their connective tissue — is to be inter- preted in the same way (cf. Pathological Anatomy of the Muscles). (/) Angioma. § 116. Under the name angioma are grouped those new growths in the structure of which blood-vessels or lymph-vessels constitute such cm importunt part us to determine the character of the tumor. The vessels of such a tumor are only in part of new formation ; the remainder are old vessels which have been more or less changed, these changes consisting of dilatations and hypertrophies of the vessel-walls. Vascular tumors which arise from l)lood-vessels are called haeman= gioinata, or angiomata in the restricted sense of this term ; while those which arise from lymph-vessels are called lymphangiomata. HEemangioma simplex, or telangiectasia, are terms used to describe a formation in which there are an abnormal nun/her of nornud blood-vessels, or abnonnallu broad blood-vessels, or capillaries and veins whose structure, in part at least, is abnormal. Such formations are commonly found in the skin. They are usually congenital, but grow after birth. They are called vascular naevi (ncevi vasculosi), and are often found in places where foetal clefts have closed (fissural 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 deserve the name of tumor. In these not only the skin, but also the subcutaneous tissue, may be the seat of the disease ; and in them, furthermore, the ectatic vessels are separated by connective tis- sue of new formation, and the tumor presents itself either as a sharply defined growth or merely as a thickening of the skin. The smooth nffivus is a superficial substitution of another tissue for that of the skin. The color of the affected part is either bright red {na'vus flammeus) or bluish red (nceviis vinosus). Usually the line of demarcation l)etween healthy and affected skin is not a sharp one. On the border of the chief mark or in its neighborhood are often little circumscribed red spots, presenting some- times the appearance of outrunners from the centre of the disease. The red color is produced by dilated vessels fall of blood, which, situ- ated either in the corium or in the subcutaneous tissue, form little sacs of blood. More rarely than in the skin do we find similar angiomata in CONNECTIVE-TISStJB TUMORS. — ANGIOMA. 321 glands (the breast), in bones, and in the brain and spinal cord and their membranes. On the other hand, we often find analogous alterations of the vessels in tumors — e.g., in gliomata or sarcomata. The vascular changes consist for the most part of circumscribed dila- tations of preexisting or neiv-form.ed capillaries (Fig. 203). The dilatation is either fusiform or cylindrical or sacculated or spherical, or one of the endless possible combinations of these different forms. The larger blood- cavities communicate with one another by means of anastomosing capil- laries of normal or moderately increased lumen. The vessel- walls are tMn ; that is, in comparison with normal capillaries, they are only slightly thickened. ''% '' ' f . N- ' . ^'• -■ ^ Jjv\ ^ / 1 ""■^ ' * 1 \ ', ^ '.>v , / , ■ , , / ',"' ^ ' ^ ,- / / 'K' '. ' ' J /.' v Fig. 203. — Dilated capillaries from a telangiectatic tumor of the brain, all tke attached portions of tumor-tissue having been shaken off in water. (Magni- fled 200 diameters.) Simple hypertrophic angioma is a term applied to a tumor composed of capillaries with dilated lumina and greatly thickened walls. It is most frequently found in the skin and subcutaneous tissue, where it produces a swelling much like a wart and often of about the same color as normal skin. The size of the vessels in this variety of angioma is not so great as in that already described ; the vessels are, however, so numerous that in section they seem to lie side by side (Fig. 204), with but very little intervening tissue. The vessel-wall is disproportionately thick and rich in cells (Fig. 204), like the wall of an arteriole. In rare cases it is seen that the endothelia have become changed into cells rich in protoplasm, which protrude more or less into the lumen. If the vessel is empty and contracted as much as possible, and these cells happen to be disposed radially, the appearance presented is much like that of a section through 19 322 CONNECTIVE-TISSUE TUMORS. — ^ANGIOMA. the duct of a sweat-gland. The similarity is made even more striking by the fact that the tumor is composed of several nodules or lobules bound together by connective tissue, each of which is made up of a coil of hyperplas- tic vessels. Moreover, the lobules do actually sometimes inclose the duct of a real sweat-gland (Fig. 204). If the ectasia is limited to a group of veins, while the capillaries belonging to them are slightly or not at all affected, we have an angioma simplex venosum Fig. 204. — Section tbrougli an angioma simplex hypertrophicum cutaneum et sub- eutaneum. In the middle of the section is the duct of a sweat-gland cut transversely. (Preparation stained with alum carmine and mounted in Canada balsam. Maguifted 200 diameters.) seu varicosum. The dilatations of the veins are partly cylindrical, partly bottle-shaped, partly sacculated, the waUs of the dilatations being easily distinguishable and sometimes even rather thick. The cavernous angioma, or tumor cavernosus, consists of a system of wide, variously sliaped cavities (Pig. 205) separated from one another hy mere connective-tissue iMrtitions. Fig. 205. — Angioma cavernosum cutaneum congenitum. a, Epider- mis ; &, Corium ; c. Cav- ernous blood-spaces. (Preparation stained with heematoxylin. Mag- nified 20 diameters.) The partition- walls of the cavities are formed of nucleated connective tissue or of a tissue composed of spindle-cells, and at certain points there are openings by means of which communication may take place between two adjoining blood-cavities. The tissue is very like that of the corpora cavernosa of the penis. The cavities are lined with endothelium. Cavernous tumors are usually situated in the skin and in the subcu- taneous tissue, and they are sometimes found here at the time of bu-th (Fig. 205). They may also develop in these localities from simple angi- omata by continual widening of the already ectatic blood-vessels. They generally occur in the form of raised patches of a bluish-red color, and sometimes the patch has a rough surface {ncevus prominens). If the cav- ernous formation extends to any distance in the skin and subcutaneous tissue, we may have a deformed condition — suggesting elephantiasis — of the parts which are thus involved. Among the abdominal organs the Uver (Fig. 206) is most frequently the seat of cavernous tumors, which here form reddish-black foci, not ele- vated above the surface and not compressing the hepatic tissue, but simply CONNECTIVE-TISSUE TUMORS. — ANGIOMA. 323 playing the part of a substitute for this tissue. In this locality cavernous tumors are not congenital ; they develop first in advanced life by varicose dilatation of single capillaries in an acinus, in association with a simul- taneous atrophy of the liver-ceDs (Fig.. 206). In the beginning there is no growth of the vessel-waUs. Later, several capillaries unite to form a single cavity through partial atrophy of the separating walls. If the pro- cess extends to the border of an acinus, the periportal connective tissue forms a capsule for the other- wise iU-deflned territory. Not in- frequently the phenomena of new tissue-formation make their appear- ance at this stage. Fig. 206. — Section through the mar- gin of a very small cavernous angioma of the liver, at a time when this margin was ill process of active growth. (Car- mine preparation. Magnified 150 dia- meters.) Cavernous angiomata are very rarely found in the kidneys, spleen, uterus, intestine, bladder, muscles, bones, etc. Fig. 207. — Angioma arteriale plexiforme of the frontal and angular ar- teries of both sides. 324 CONNECTIVE-TISSUE TXUMOES. — ANGIOMA. A cirsoid aneurism, or angioma arteriale racemosum, or angioma arteriale plexiforme (Pig. 207), is a condition in which the arteries of a whole group are dilated, tortuous, and thickened, so that they form a eon- A^olution 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 congenital in origin ; others appear to be acquired, and develop in consequence of a traumatism. § 117. Angioma lympliaticum, or lymphangioma, is composed of a tissue the greater part of which is made up of dilated lymph-vessels (Fig. 208). The different forms are : lymphangioma simplex, or telangiectasia lynvphatica ; lymphangioma cavernosum ; and lymphangioma cystoides. The fluid contained in the cavities is usually a clear and bright lymph, but sometimes it is milky. In the simple lymphangioma the lymph-vessels to a greater or less distance are dilated, and their walls are usually thickened. In the cav- ernous lymphangioma (Fig. 208) the vessels are still more increased both in number and in size, while the intervening tissue is diminished in quan- FiG. 208. — Lymphangioma cavernosum suboutanetim. a, Ectatie lymph- vessels; 6, Fibrous tissue; e, Fat; d, Larger blood-vessels; e, Cellular tissue. (Preparation stained with alum carmine and mounted in Canada balsam. Mag- nified 20 diameters.) tity, 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 between the dilated lymph-vessels is, according to the part from which the tumor springs, connective tissue, or fat (Fig. 208, c), or muscle, or some other tissue. Sometimes this tissue includes foci of lymphadenoid tissue (e). Moreover, it may present the signs of active proliferation. CONNECTIVE-TISSUE TUMORS. — ANGIOMA. 325 Lymphangioinata are sometimes congenital, sometimes acquired. As a congenital phenomenon ectasia of the lymph-vessels is observed in dif- ferent forms, particularly in the tongue {niacr aglossia), in the palate, in the Ups {macrocheilia), in the skin (ncevus lyniphaticiis), in subcutaneous tissue, in the neck (hygroma colli congenitum), in the vulva, etc. Lymphan- giectasia of the skin is often also an acquired disease, as, for instance, in the thigh or the scrotum. Sometimes the lymphangiomata form large, weU-deflned tumors (Pig. 208), which fluctuate. If the cavernous develop- ment of the subcutaneous lymph-vessels spreads over large areas of the skin, conditions outwardly resembling those of elephantiasis maj^ result. In such eases the intervening tissue usually takes part in the hypertrophic growth. If the superficial dilatations in a cutaneous lymphangioma burst, lymphorrhcea may result. Ectasia of the lymph- vessels is often accom- panied by connective-tissue hyperplasia of the skin or some other organ. In very rare cases chylangiomata, containing chyle, appear in the course of the lymph-vessels of the intestine or mesentery. Cystic lymphangi- omata of the peritoneum are also extremely rare. Certain peculiar pathological formations in the skin, which are some- times congenital and sometimes develop in the early years of Ufe, and which are described as pigmented usevi, lentigines, ephelides, and fleshy warts, belong, according to their micro- scopical structure, to the lymphangio- mata. The pigmented nmvi [ncevi pigmentosi) (Fig. 209) form larger or smaller plaques situated on the same level with the sur- rounding skin (ntevus spilus), or raised above it like warts (naevus prominens, naevus verrucosus), and often studded with hairs (naevus pUosus). They are pale brown or dark brown or black (Fig. 209), and are usually covered bj'' normal, less often by hypertrophied epi- dermis. They are usually small, but they may be as large as an ordinary plate, and in rare instances they may cover a large part of the body. Lentigines appear at any time after birth, and on any part of the surface of the body; and when once formed they remain for life. They closely resemble the little pigmented nsevi, and form well- defined spots of a yellow or brown or al- most black color, and as large as a pin- head or larger. FrecMes, or ephelides, are ill-defined, angular, pale-brown spots not elevated above the surface, which appear in the early years of life on face, hands, and Fig. 209. — Large, hard pigmented naevus of the back, buttocks, and thighs, with scattered smaller pigmented spots ou the upper part of the body. (After Rohring.) 326 CONNECTIVE-TISSUE TUMORS. — FLESHY WAKTS. seldom elsewhere, and which either remain permanently or in com-se of time disappear. The pigmentation is favored by the sunlight. Fleshy warts (verrucce carnece) are non-pigmented, well-defined, smooth or slightly roughened (Fig. 210) or very uneven papillary growths caused by a normal or hypertrophic epithelium (Fig. 211, a). Fig. 210. — Section through a slightly uneven fleshy wart, a, Epidermis ; &, Cutis ; the cellular new growth at c is in the cutis ; at e, in the papilte. (Prep- aration stained with aniline brown. Magnified 10 diameters.) In all of the pathological formations just described the connective-tis- sue framework incloses masses of cells, either in round groups or drawn out into bands. They lie partly in the papillsB and partty in the corium, Fig. 211. — Section through two papilte of a papillomatous fleshy wart. a. Thickened horny layer of epidermis ; 6, EpitheUal pearls; c, Rete Malpighii; d. Nests and strings of cells in the papiUse; di, Nests and cells in the reticular layer ; e, Connective tissue. (Preparation stained with carmine. Magnified 50 diameters.) CONNECTIVE-TISSUE TXBIOES. — MYOMA. 327 and are more abundant in those cases where the growth is elevated above the surface of the skin. In the pigmented growths these cells contain the pigment, usually in the form of yellow and brown granules, but also diffused throughout the substance of the cells. So far as can be judged from the position and arrangement of the cell-masses, it seems probable that the cells are pathologically developed from the endothelial cells of the lymph-vessels ; so that the growth can be reckoned with the lymphangiomata, and, under the name lymphangioma hypertrophiaim, it may well be placed by the side of the heemangioma hypertrophicum. In consideration of the marked endothelial prolifera- tion which takes place in these cellular n^vi, they might be classed among the endothehomata or among the lymphaugiosarcomata (cf. § 124) ; but the Umited character of their growth militates against this classification. (g) Myoma. § 118. 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 myomafa Icevicelliilares, occur most frequently in the uterus, less often in the muscular layers of the alimentary canal or in those of the urinary tract. They are rounded nodular tumors hke the fibromata. In exceptional cases they are found in the skin and sub- cutaneous tissue, where they form smaR 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). If the new growth takes place in muscular organs it proceeds from the muscular layer, forming in its development bundles of muscle-fibres (Fig. 212) interwoven in various directions, and giving, therefore, in sec- FiG. 212.— Section through a leiomyoma, showing the nuclei cut both longitudiually and transversely. (After Perls.) tion a variety of views. In the skin and subcutaneous tissue, as far as there are any observations on the subject, the new growth of muscle-fibres has its origin in the muscularis of the vessels (Fig. 213), which not only becomes thickened (e), but gives off separate outrunners of muscular cells (b). This new formation of muscular tissue may easily be associated with the pathological foi-mation of blood-vessels (a), so that tumors result, to which the name angiomyomata applies (Fig. 213). According to the ob- 328 CONNECTIVE-TISSUE TUMORS. — ^MYOMA. servations of Jadassohn, myomata of the skin may also spring from the erector muscles of the hairs — the arrectores pilorum. 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. For example, most of the myomata of the uterus are myoiibromata. 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 houi's in 20 per cent, sulphuric acid, or for twenty to thirty minutes in 34 per cent, potassic hydrate. In a longitudinal section the muscular fibres are best recognized bj' the staff -like nuclei (Fig. 212 and Fig. 213, h), 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 centre of each of these areas is the nucleus cut transversely (Fig. 212). Fig. 213. — Subcutaneous angiomyoma of the back, a, Cavernous blood- vessels ; muscular strings cut longitudinally at 6, transversely at c ; d, Connec- tive tissue ; e, Artery with hypertrophied muscular layer; /, Group of lymph-cells. (Preparation hardened in alcohol, stained with hffimatoxyhu and eosin, and mounted in Canada balsam. Magnified 50 diameters.) Leiomyomata are thoroughly benign tumors. 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 is also common. A myofibroma may become a pure fibroma by atrophy of the muscular fibres. CONNECTIVE-TISSUE TUMORS. — MYOMA. 329 A rhabdomyoma (Zenker), or myoma striocellvlare (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 fibres form nucleated bands of various widths, which show a transverse (Fig. 214, a, 6, c) and in places also a longitudinal striation (e, /). The ill-de- veloped forms consist of narrow bands without transverse striation {d) ; of spindle-cells with long-drawn-out thread-Kke processes without trans- verse striation {g) or with partial striation (/) ; and also of rounder cells of different sizes, which show either a radial or a concentric striation [h, i). Besides these there are also cells which possess no especial characteristic, so that it is impossible to decide whether they are yoimg undeveloped muscle-ceUs or simple cells of the connective tissue. The bands as well as the spindles are usually in bundles, and interwoven among themselves. It is usually not possible to demonstrate 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 sar- colemma. Fig. 214. — Cells from a rhabdomyoma. (After Ribbert and Wolfensberger.) a, 6, c, Fibres of various sizes with transverse striation ; d, Small nucleated fibre ■without striae ; e, Spiadle-eell with longitudinal strisB ; /, Spindle-cell with longi- tudinal and transverse striae ; g, Spiadle-cell, non-striated, with elongated processes ; h, i, Round cells with concentric and radial striation. Rhabdomyomata occur most frequently in the kidney or in its pelvis, in the testicle and in the uterus ; seldom in other localities, as, for exam- ple, in the vagina, bladder, muscles, subcutaneous tissue, mediastinum, oesophagus, etc. Thej' form nodular tumors of varying size, and if situ- ated on the surface of a mucous membrane the new growth is polypoid or papillomatous in shape. In the kidney and testicle they either form well-defined nodules or else they cause the destruction of the whole organ. The gi'owth of these tumors is dae apparently to misplaced portions of embryonic muscle-tissue, and consequently the condition is generally con- genital. But these tumors may first develop at an advanced age. Some- times another tissue — e.g., cartilage — is included in the tumor. Moreover, fairly well-developed muscular fibres are found in complicated tumors of the testicle and kidney. 330 CONNECTIVE-TISSUE TUMORS. — GLIOMA. If a tumor contains only a few cells which can be definitely recognized as muscle-fibres, while most of the cells have no specific character, it is usually called a myosarcoma. {h) Glioma and Ganglionic Neuroglioma. § 119. Qliomata are tumors which grow from the cells of the stroma of the central nervous system, and which, when fully developed, consist essen- tially of these cells. In the brain thej' 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 pathological tissues, suffice to convince the eye that a real tumor is present. When they occur va. the spinal cord these tumors are most apt to arise in the neighborhood of the central canal, and may spread over a considerable 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- sistency ; sometimes they are grayish white and of firmer consistency ; 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. GUomata which contain much blood often exhibit hsemorrhagic foci. Fatty degeneration, softening, and destruction of the tissue are also common occurrences. A section of a fuUy developed glioma shows under the microscope a network of extremely delicate glistening fibres (Fig. 215, 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 fiuid, it is easy to detect that these nuclei belong to cells that are characterized by the great number of fine branching processes which they possess, and which extend in every direction (Fig. 215, A). The cells closely resemble normal ganglion-celLs, although at times they are much larger, / ^ and, in some instances, more spherical in shape. A few of them contain two, three, or even four nuclei. Fig. 215. — Glioma of the cerebrum. A, Cells is- olated by teasing, and stained with carmine ; B, Section from the same tumor after hardening in Miiller's fluid. (Prepara- tion stained with aniline brown and mounted in Canada balsam. Magni- fied 350 diameters.) Investigations with reference to the development of gliomata have proved that the glia-cells are the mother-cells of the tumor. The gan- CONNECTIVE-TISSUE TUMORS. — GLIOMA. 331 glion-cells do not take any part in the proliferative processes. The abun- dance of cells in a glioma varies greatly. Sometimes the cells preponder- ate decidedly, and then at other times the stroma is the more prominent part of the texture. A simultaneous proliferation of the cells of the peri- vascular connective tissue produces a gliosarcoma. The vessels are often developed to a very great degree, and in some places they may be ectatic. Gliomata usually occur singly, and do not furnish metastases. Their etiology is unknown. Some gliomata probably originate from imperfectly developed portions of the brain and spinal cord. Traumatism may fur- nish the exciting cause for their development. Certain highly cellular tumors which develop in the retina, and whose elements closely resemble the cells of the nuclear layer (KornerscMcht), are classed among the gliomata. As their growth advances they break through in part into the retrobulbar space, and in part forward through the cornea and sclera. They are apt to recur after extirpation, and they cause metastases. The cells of which they are composed are round, some with and some without processes. It is open to doubt whether these tumors shoidd be classed with the gliomata. They ought rather to be reckoned among the sarcomata. Neuroglioma ganglionare (Pig. 216) is a term apphed to those new growths which arise in the central nervovs system, are composed of hyper- plastic glia-tissiie, ganglion-cells, and nerve-fibres, and constitute either ill- defined swellings of the larger masses of the brain or cii'cumscribed nodular enlargements of small sections of this organ. When examined Fig. 216. — Section from a nodular neurogUoma ganglionare of the central convolution of the cerebrum. A, Portion of the tumor which is rich in ganglion- cells J B, Portion eontaining nerve-fibres ; C, Jelly-like portion, a, Ganglion- eeUs in groups; b, Individual ganglion-cells ; e, GangUon-oeUs with two nuclei ; d, Nerve-fibres with medullary sheaths; e, Glia-oells ; /, Blood-vessel. (Prepa- ration treated by Weigert's method and mounted in Canada balsam. Details completed from another preparation which had been stained with hsematosylin. Magnified 300 diameters.) 332 CONNECTIVE-TISSUE TUMORS. — NEUROMA. by the naked eye the affected portions of the brain may still appear to be fairly normal ; but as a general rule the distinction between gray and white substance is fainter than normal, and the tissue is throughout white or grayish white or spotted white and gray, and at the same time more or less hardened. These masses are chiefly made up of more or less dense glia-tissue con- taining a certain number of nerve-fibres {d ) and ganglion-cells {a, b, c), not only in the region of the cortex, but also in that of the white sub- stance. Probably all such formations must be regarded as the result of a dis- turbance of the embryological development of the brain — that is, as local cerebral malformations, which have undergone further development after birth. (i) Neuroma. § 120. The tumors called neuromata are observed most often in the ends of amputated nerves, where they form at times quite large swellings, which are either separated from the surrounding tissues by more or less sharply defined limits or are united to them without any such distuict line of separation . From their origin they have received the name of amputation neuromata (Fig. 217, b). The development of these neuromata is explained in the following manner: After the nerves are cut off, more or less connective tissue forms on the stump, and at the same time the axis-cylinders divide and grow out in length. In this manner the scar-tissue becomes supplied with nerves, which at first have no sheaths, but which very soon become covered with fibrous sheaths and ultimately with med- ullary ones. The mass of nerves penetrat- ing into the granulation tissue may be very great, so that the connective tissue, after a certain length of time, may contain a rich supply of nerves, which, radiating from the end of the old nerve, spread through the fibrous tissue in eveiy direc- tion (Fig. 217, b). We have here, there- fore, an instance of the useless regenera- tive growth of a nerve-stump — a growth which exceeds the physiological necessi- ties of the nerve and so forms a tumor- like mass. Another form of neuroma develops spontaneously in the course of a nerve, without any outside provocation. This tumor owes its origin to an increase of the Fig. 217.— Amputation neuroma of the ischiatic uerve (nine years after amputation). Longitudinal section, a, Nerve ; h, Neuroma. (Drawn from a preparation which had been hardened ia Miiller's fluid. Magnified 3 dia- meters.) CONNECTIVE-TISSUE TUMORS. — NEUROMA. 333 connective tissue of the nerve, usually of the outer, more rarely of the inner layers of the endonemium ; as a result of which the nerve-bundles, at the point where the tumor is developing, are inclosed in a more or less thick layer of connective tissue, usually of a loose sort (Fig. 218, b, d) ; or these bundles are split open by the growth of connective tissue into separate individual fibres. Sometimes the perineurium is also involved in the pro- liferative process. "Where nerves lie together in a large bundle the epi- neurium as well as the endoneurium and perineuriiim of the smaller nerve-bundles may be affected by this process, but this is usually not the case. Fig. 218. — Nerves from a cirsoid neuroma whieh involved the cheek and lower jaw and presented a close resemblance to elephantiasis, a, b, Nerve, the outer layers of whose endoneurium have undergone decided proliferation ; the nerye-flbres proper occupy the axis of the entire mass ; c, Nerve with markedly proliferated endoneurium and separated nerve-fibres ; d, Thickened nerve show- ing a small bundle of nerve-fi.bres at the left end ; e, Loose connective tissue, rich in nuclei, lying between the nerves and containing fat-tissue. (Preparation hardened in Flemming's solution, stained with safranine, and mounted in Can- ada balsam. Magnified 8 diameters.) These tumors, structurally considered, are not neuromata, but fibro- mata of the nerves. A number of them are usually present at the same time, and they may occur in all the peripheral nerves, although, as a rule, they are limited to a definite area of nerve-distribution. The nodules are sometimes situated along the nerve-trunk, sometimes on the finest branches, usually of the cutaneous nerves. These soft connective-tissue nodules, which are scattered about through the skin in smaller or larger numbers, are termed multiple fibromata of the sldn. The finest nodules are demonstrable only with a microscope, but the usual size is from that of a pea to that of a hazel-nut. Individual tumors may reach the size of a man's fist, the nerve-fibres being quite lost sight of in the great mass of connective tissue, whose continued growth may even cause them to waste away entirely. In addition to this formation of well-defined nodules there may also be, throughout the area of distribution of the affected nerves. 334 CONNECTIVE-TISSUE TUMORS. — LYMPHADENOMA. a diffuse tJiiclcening of the nerve-fibres, due to hypertrophtj of the connective tissue. And finally, with the conditions mentioned may be associated a hypertrophic thickening of the connective tissue of the skia proper and of the subcutaneous tissue, resulting ra alterations of the skin not unlike those observed in elephantiasis. A third form of neuroma is the cirsoid neuroma (Bruns) or plexiform neuroma (Verneuil), a tumor which is characterized by the circumstance that in the domain of several nerve-branches a convolution of twisted and interwoven, thickened and nodular nerves takes place (Pig. 219). An examination of the individual cords reveals this also to be a fibromatosis of the nerves, the excessive growth of the endoneurium resulting partly in a diffuse thickening of the nerve-fibres, partly in a nodular one. But in this case attention should be directed to the fact that the nerves in the territory involved are not only thickened, but also actually increased in length, and consequently rendered tortuous; and, furthermore, that the nerves are increased in number, so that the sum total of the nerves situated in the skin and subcutaneous tissue is greater than it should be under normal conditions. The conditions here, therefore, are those of a genuine neuroma,, a neuroma verum. Most of the nerves in this tumor are medullated (neuroma myelini- cwm). It is difficult to deter- mine to what extent tumors of this nature contain nerve-fibres which are non-meduUated (neu- roma amyehnicum) ; neverthe- less cases have been reported in which most of the fibres were found to be non-meduUated. Cirsoid neuromata occur on the head, body, and extremities, and are usually characterized hjgross alterations of the skin which re- mind one strongly of elephantiasis. Fig. 219. — Cirsoid neuroma of the sacral region. (Prom a draw- ing by P. Bruns.) The nodular, twisted, and interwoven nerves are dissected out at a, while at h they are still covered by connective tis- sue. (Life size.) Neurofibromata and cirsoid neuromata do not cause metastases, but in certain cases neuromata take on a sarcomatous and consequently a mahg- nant character. Hereditary transmission and congenital predisposition have been proved to be concerned in both forms of neuromata. {h) Lymphadenoma and Lymphosarcoma. § 121. The term lymphadenoma is applied to growths which repre- sent a proliferation of lymphadenoid tissue — a proliferation which may lead to a considerable increase in the size of the lymphadenoid organs already existing in the body. Generally several such organs are affected at one LYMPHADENOMA. — LYMPHOSARCOMA. 335 time, as in the case of an entire group of lymph-glands ; and when this is the case the process may extend, like a general disease of the body, over a smaller or larger portion of all the lymph-organs. The lymphatic glands, under these circumstances, increase in size until they are as large as a hazel-nut or a walnut, or even larger. In consistency these enlarged glands are soft, and their cut surface presents a white medullary appear- ance. The follicles of the spleen become transformed into nodules of con- siderable size. The tonsils attain the dimensions of more or less extensive tumors. The lymph-follicles in the mucous membranes stand out more prominently above the sui-face, and may also attain the proportions of considerable nodules. The increase in biTlk is chiefly due to a continuous increase in the number of the free cells which have only one nucleus. A few scat- tering multinuclear cells may also occasionally be observed. The lymphadenoid character is preserved in the newly formed tissue, but the distinctions between tha cortical follicles and the reticulating medul- lary cords on the one hand, and the lymph-sinuses on the other hand, are lost ; and the trabeculge of the connective-tissue framework, as well as the capsule of the gland, become infilti-ated with round cells. At the same time all trace of a germinal centre in the lymph-nodes ceases to be recognizable. The cause of the development of lymphadenomata is unknown, and the whole formative process is difficult to explain. The alterations which take place in the structure of the gland are opposed to the view which regards this process as a simple hypertrophy. No definite proof has been brought forward in favor of an infective origin ; in fact, no para- sites have ever been demonstrated in these structures. So we are com- pelled to reckon the aifection among the tumors. It is of interest to note that in part of the cases the growth of adenoid tissue is associated with an increase of leucocytes in the blood ; while in another portion of the cases only cachectic and ansemic conditions are established. Accordingly two separate processes are recognized — a leu- camic hjmphadenoma or adenia, and a pseudoleucmnk or simple adenia (Hodgkin's disease). The term lymphosarcoma is apphed to a proliferative process origi- nating in the lynipliadenoid tissue of the lymphatic glands, the spleen, the ton- sils, and the mucous monhrane of the pharynx, palate, stomach, and intestinal canal; the new tissue thus developed exhibiting the characteristics of lymphadenoid tissue — that is to say, a reticulated framework which in- closes cells of the character of lymphocytes. The distinction between lymphosarcoma and lymphadenoma rests, in the first place, on the fact that in the former, as the new growth of tissue progresses, it does not limit itself to the lymphadenoid organ, but breaks through into the neigh- boring structures ; and, in the second place, on the further fact that, in the former, metastases occur either by way of the lymph-channels or by that of the blood-vessels, according to whichever of the two gives way and permits the entrance of portions of the new growth. The new growths due to proliferative processes going on in the mucous membranes may form very large swellings, which break down and form ulcers. When the lymphatic glands undergo proliferation, a large mass of conglomerated nodules consisting of lymph-glands may be formed. Here, too, we may have necrosis as a result of obliteration of tie vessels. 336 CONNECTIVE-TISSUE TUMORS. — SAECOMA. The etiology of lymphosarcoma is unknown ; it may be looked upon as a particular form of sarcoma (cf. § 123). It is impossible to draw the line sharply between lymphosarcoma and lymphadenoma ; in fact, the former maj'' develop from the latter. According to their structure we can differentiate hard and soft forms of lymphosarcoma, the latter being characterized by a stronger develop- ment of the reticulum, often also by the formation of fibrous connective tissue. Enlarged lymphatic glands are often called lymphomata, this term being ap- plied to entirely different aif actions of the glands; therefore to lymphadenoma, to lymphosarcoma, and also to those enlargements which are caused by infec- tion with the bacilli of tuberculosis or of typhoid fever, or with the virus of syph- ilis. If the use of this term is insisted upon, it should always be accompanied by a word which indicates what kind of lymphoma is meant. Lymphadenoma and lymphosarcoma are commonly called malignant lymphoma. (I) Sarcoma. § 122. A sarcoma is a connective-tissue tumor in which the cellular ele- ments are much more prominent than the intercellular substance, not only on account of their nimiber, hut often also iy reason of their size. The sarco- mata are therefore closely related to undeveloped connective tissue, and a comparison between sarcoma and embryonic tissue is by no means far- fetched. Sarcomata always develop in one of the tissues belonging to the group of connective substances — that is to say, in formed or unformed connec- tive tissue, in cartilage, in bone, in miicous tissue, in a lymphatic gland, or in adipose tissue. The transformation into tumor-tissue takes place by growth and multiplication of the existing cells. The cells usually divide by mitosis, and the faster the tumor grows the more numerous are the mitoses. Besides the typical mitoses there are atypical forms of all sorts ; sometimes also nuclei broken into fragments. When fully developed, sarcomata form tumors which are separated from the surrounding tissues by more or less sharply defined limits. They may grow in smj part of the body where there is connective tissue, but they are found in certain regions far more frequently than in others. For example, they are found much oftener in the skin, fascise, intermus- cular connective tissue, bone, periosteum, brain, and ovaries than in the liver, lungs, intestine, and uterus. The development and form of the cells vary considerably in different sarcomata. The intercellular substance is sometimes scanty,, soft, or even like tough mucus ; at other times it is more abundant, and resembles in character rather the basic structure of the developed normal connective substances. The amount of the intercellular substance has a marked influence upon the consistence and color of the tumors. The medullary variety presents a marrow-white or grayish- white cut surface, and is rich in cells and poor in intercellular substance. A hard and dense tumor is poorer in cells and richer in fibrous intercellular tissue. Such tumors shade by insen- sible gradations into fibromata. Varieties upon the border-line are called fibrosarcomata. The cut surface of a sai-coma presents throughout pretty nearly the same appearance, iinless retrograde changes or an un- equal distribution of blood-vessels cause differences. It is usually uni- CONNECTIVE-TISSUE TUMORS. — SAECOJIA. 337 formly smooth and of a milk-white color ia the medullary forms, or clear gi-ayish white and somewhat translucent, or of a bright grayish red or grayish brown, in the firmer varieties. The hard varieties are of a bril- liant-white or yellowish- white color. The development of blood-vessels varies in sarcomata. Sometimes the vessels are remarkably numerous and broad — in fact, ectatic [telangiectatic sarcomata). Usually the vessels have walls easily distinguishable from the tumor-substance, but the tumor-ceUs themselves may also constitute the outer cells of the walls of the vessels ; and in such a case the cells of the walls of the vessels also take part in the growth of the tumor. Lymph- vessels have not been demonstrated in sarcomata. Ketrograde changes — such as fatty degeneration, mucoid degenera- tion, liquefaction, cheesy degeneration, necrosis, haemorrhage, gangrene, ulceration, etc. — are common occurrences in sarcomata. Sarcomatous tumors may be divided into three classes. The first of these includes the simple sarcomata — sarcomata in the narrower sense, that is, tumors which are formed according to the type of foetal connec- tive tissue, and which show, therefore, a more or less even distribution of the cells, without any formation of separated foci or groups of cells. The second class includes those sarcomata which show a particular ar- rangement and grouping of the individual elements, so that in appearance they resemble the epithelial tumors. The third class is characterized by secondary changes in the cells, the intercellular substance, and the blood-ves- sels, which give to the tumor a peculiar appearance. The etiology of sarcomata is not a simple one. They occur oftener in youth than in old age. Some develop in foetal life and owe their origin to some local malformation. Sometimes they develop as the result of a trauma. A parasitic origin has not been demonstrated. Usually there is a single primary tumor ; but multiple primary sarcomata are sometimes observed, as, for example, in the skin and in the bone-marrow. The softer tumors lead to metastases. § 123. Simple sarcomata include both the soft medullary forms and those of a fii-mer consistency, which shade off insensibly into the fibro-sarcomata and the fibromata. Among these forms several sub- ordinate varieties may be distinguished, according to the character of the cells. Small round'°celled sarcomata are very soft, rapidly growing tiimors, which develop especially in the connective tissue of the Mmbs and sup- porting framework of the body, and also in the skin, testicles, ovaries, and lymphatic glands. The cut surface of a section of one of these growths appears milky white, and sometimes shows caseous or softened areas. If scraped the surface yields a milky fluid. The structure is very simple. The tumor is composed almost wholly of round cells and vessels (Fig. 220). The cells are small and frail ; they have very little protoplasm, and a spherical or slightly oval, rather large and bladder-hke nucleus (c), which seems to be more highly developed than the nuclei in lymphatic elements. Between the cells lies a very scantj^ amount of granular and delicately fibrUlated intercellular substance. The vessels traverse the masses of cells in the form of very thin-waUed canals. If the tumor be examined at its very margin of growth among the muscular fibres, its tissue will be found to present an aggregation of round cells (Fig. 220, h, c) in the connective tissue lying between the muscles. Often in close prox- 20 338 CONNECTIVE-TISSUE TUMORS. — SARCOMA. imity to the cells of the tumor there are lymphatic elements whose nuclei {d) stain more deeply than those of the tumor itself. Fig. 220. Fig. 221. -a Fig. 220. — Section through the margin of a sarcoma of the intermuscular connective tissue of the neck, a, Normal muscle cut transversely ; ai, Atrophied muscle cut transversely ; 6, Bound cells of the sarcoma growing between the muscle-fibres ; c, Mature tumor-tissue^ d, Bound cells of the character of white blood-corpuscles. (Carmine preparation. Magnified 300 diameters.) Fig. 221. — Section from a lymphosarcoma of the mucous membrane of the nose, after shaking it about in water to free it from the greater number of its cells, a, Beticulum ; 6, Cells of the reticulum ; c, Bound cells ; d, Blood-vessel with actively growing cells. (Carmine preparation. Magnified 300 diameters.) A second form of round-celled sarcoma is called lymphosarcoma. This tumor imitates in structure the lymphatic glands, at least to this extent : that the stroma, which holds together large numbers of round cells, is composed of a vascular reticulum (Fig. 221, a), a part of which, at least, is made up of branching and anastomosing cells (&). These re- lations are easily made clear by shaking a section in a test-tube. Macroscopically the tumor has the same appearance as other small round-celled sarcomata,, and is as malignant as they are, both by reason of its rapid growth and by reason of the fact that it forms metastases. Lymphosarcomata occiu' most frequently in the lymphatic glands or the lymphadenoid tissue of the mucous membranes, but they are also found in other situations (cf. § 121). Large round-celled sarcomata occur in the same localities where the small round-celled sarcomata are found, but their cells are much larger than those of the latter. These two forms of tumors resemble each other closely, although the large-celled variety is not so soft as the small-celled. The cells are richh? supplied with protoplasm, and possess large bladder- like oval nuclei (Fig. 222). Many of the cells have two nuclei, some more than two. Between the cells is a reticulated intercellular substance (Fig. 222), in which both spindle-shaped and branching cells unite to form an alveolar network in whose meshes the large round epithelioid cells lie. For this reason such tumors have been called large round^celled alveolar sarcomata (Billroth). The vessels are for the most part thin-walled. In certain forms of large round-celled sarcomata the cells are of vary- ing size (Fig. 223), and among them are many long or irregularly shaped CONNECTIVE-TISSUE TUMORS. — SARC05IA. 339 cells, so that the tumor may well be called a sarcoma with polymorphous ceils. The nuclei, too, vary much in size (Fig. 223) in these tumors, and there may be a large number of them in a single cell (e) (multinucleated giant cells). Fig. 222. 'K Fig. 223. ^4- ..«* r. :- ^ c- d Fi&. 222. — Section from a fungoid large round-celled sarcoma of the skin of the leg. (Carmine preparation. Magnified 400 diameters.) Fig. 223. — Section of a sarcoma of the breast, with variously shaped ceUs. a, Connective tissue : 6, Sarcomatous tissue ; c, Smaller ceUsj d, Cells with hyper- trophic nuclei^ e, Multinuclear cells. (Preparation stamed with Bismarck brown. Magnifled 300 diameters.) The large round-celled sarcomata and the sarcomata with polymor- phous cells are in general not so malignant as the small round-celled ones ; but nevertheless they do give rise to metastases. Spindle=celled sarcomata are among the commonest of tumors. They are usually much denser than the round-celled varieties, but they may also be of a soft mediiUary character. A cut section usually appears grayish or yellowish white and somewhat translucent, or it may present a more or less reddish hue, by reason of its vascularity. Medullary tumors whose cells have undergone fatty degeneration may have a pure- white color. In general these tumors are much less malignant than the round-celled ones, but their character in this respect varies according to theii" location and their richness in cells. According as the cells are large or small, we may distinguish large spindle=celled and small spindle-celled sarcomata. By teasing small bits of the tumor-tissue some of the cells may be isolated, and in this way very long spindles may occasionally be obtained (Fig. 224). The cells lie side by side, arranged in bundles, which in a section may be cut transversely or obUquely or longitudinally — a proof that they are inter- woven in different directions. This arrangement of the spindle-cells in bundles is often very strik- ing. In other cases it is entirely absent, and for considerable distances the spindles will be found to lie in the same dii-ection. Sometimes the direction of the spindles is determined by the direction of the blood-ves- sels — i.e., the individual bundles build each a sheath about its own blood- vessel. Between the spindle-cells there may be a very little intercellular sub- stance, or it may not be possible in the section to demonstrate any inter- 340 CONNECTIVE-TISSUE TUMORS. — SARCOMA. cellular substance. In other cases it is more abundant and of a fibrillary character. In such cases the cells have less protoplasm, so that often it is scarcely possible to demonstrate any protoplasm around the nucleus and the processes at the poles of the cell seem to spring directly from the nucleus (nuclear fibres). Such varieties are dense and hard. They form the connecting-link between sarcomata and fibromata, and are called fibrosarcomata. Fig. 224. Pig. 225. A i >' y- Fig. 224. — Spindle-cells from a large spindle-celled sarcoma of the cheek. (Teased preparation. Magnified 400 diameters.) Fig. 225. — Cells from a medtdlary giant-celled sarcoma of the tibia. (Prep- aration stained with hsematoxylin. Magnified 400 diameters.) Sarcomata with polymorphous cells are also found among the spin- dle-celled sarcomata. They contain spindle-shaped, triangular, and pris- matic cells, and also star-shaped cells and cells which are quite in-egular in shape (Pig. 225). Bach cell has the shape which fits most perfectly into the space allotted to it. Both in polymorphous-celled and in spindle-celled sarcomata are found more or less numerous giant cells (Figs. 223 and 225), so that the name of giant=celled sarcoma may properly be applied to these tumors. They develop most often from some part of the osseoiis system, but they are found in other parts of the body also (Fig. 223). § 124. Sarcomata vi'hich present an organoid structure are usually found among those forms called alveolar sarcomata and tubular sar= comata. These growths are connective-tissue tumors in which the cells, especially the larger ones, are arranged in gi'oups, so that it is possible to distinguish a vascular strotna and separate aggregations of cells. In many oases the peculiar alveolar and tubular structure of the tumor is a direct result of the particular locality from which it origi- CONNECTIVE-TISSUE TUMORS. — SAECOMATA. 341 nates, the large tumor-cells springing from particular cells of the con- nective tissue. Sometimes the large epithelioid tumor-cells plainly re- sult from a proliferation of endothelial cells (Fig. 226, d, e), and hence these tumors have been called also endotheliomata. If it can be demonstrated that they arise from the endothelium of the lymph- vessels, many authors apply the name angiosarcoma, or, more correctly, lymphangiosarcoma, to them. Such tumors occur in the serous membranes of the large cavities of the body, and in the membranes of the central nervous system, partly Fig. 226.— Section through an endothelioma of the pia mater and cerebral cortex, difEusely spread out over tlie surface of the brain and spinal cord, a, Pia mater on the surface, b, in a sulcus, of the brain ; c, Cortex ; d, e, Endothelial growths in the subarachnoid spaces ; /, g, h, Endothehal growths in the pial sheaths of the cortical vessels; i, Longitudinal section through a vein. (Prep- aration hardened in MuUei-'s fluid, stained with hsematoxylin, and mounted in Canada balsam. Magnified 30 diameters.) as limited and well-deflued, partly as iU-defined and flat sweUings. Where the dehcate membranes of the brain are involved, it is perfectly evident that the elements which contribute to the formation of the tumor are the endothelial cells, which clothe the connective-tissue trabeculae, and which swell up and multiply, so that in the subarachnoid tissue, and in the pia (Fig. 226, d, e), formations are produced which remind one of ducts and alveoli of glands, or even of solid club-shaped and racemose gland-struc- tures — formations which present a strong resemblance to what is observed m adenomata and carcinomata. If the growth extends to the pial con- 342 CONNEOTIVE-TISSUE TUMORS. — SARCOMATA nective-tissue sheaths wliich envelop the vessels of the cortex, we may- have also, in these new localities, bands and nests of large epithelioid cells (Fig. 226,/, gr, A). In a similar manner the endothelial cells of the dui-al lymph-vessels may take on a proliferative activity and convert the lymph-vessels into gland-like canals or even into solid cords of cells (Fig. 227, c, d), thus pro- ducing a peculiarly constructed endothelioma, one having considerable resemblance to a tubular carcinoma. The endothehomata of the pleura, peritoneum, and mamma show nearly the same structure. Fig. 227. — Endothelioma of the dura mater, a, Stroma of connective tissue; 6, An aggregation of small round cells ; c, Nests and cords of cells, resulting from the proUferation of the endothelium of the lymph-vessels ; d, Cord of endo- thelial cells with a lumen ; e, Area of fatty degeneration in a nest of endothelial cells ;/. Cord of cells, gradually mixing with the bordering connective tissue on the right. (Preparation hardened in Miiller's fluid, stained with hsematoxyhn, and mounted in Canada balsam. Magnified 25 diameters.) In a second class of alveolar and tubular sarcomata the gi'owth pro- ceeds from the cells of the walls of the blood-vessels and neighboring tissues. Accordingly the name angiosarcoma (Waldeyer, Kolaezek), or, more correctly, luemaiujiosarcoma, has been given to them. Even in endotheliomata of the pia mater the observation may be made that the proliferative processes in the region of the cerebral cortex are con- fined in large degree to the adventitia of the arteries (Fig. 226, /, g, h), thus leading to the production of cords of cells which completely surround the vessels. But there are also other forms of tiimors in which this peri- vascular deposit of proliferating cells is characteristic of the tumor throughout its whole extent. The tissue of the tumor, in typical cases, is almost wholly composed of a tangle of vessels (Fig. 228, a, a) whose walls are surrounded by heavy masses of cells, which extend even as far as to the endothelium (6). Such a tumor, therefore, is made up essen- tially of thick-waUed cellular tubes, which partly foUow an independent course and partly unite with other tubes by anastomoses, thus giving rise to a complicated mass of twisted and interwoven cords of cells {plexiform angiosarcoma). CONNECTIVE-TISSUE TUMORS. — SARCOMATA. 343 In a typically developed tumor of tMs kind the masses of ceUs show a cylindrical arrangement ; but this arrangement may sometimes be dis- turbed. Thus, for example, two contiguoiis cords of cells may become merged into one, and some of the vessels may undergo obliteration. If the remaining vessels with their surrounding connective tissue form a Pig. 228. — Section through a nodular angiosarcoma of the thyroid, a, a, Ves- sels in section ; 6, Perivascular cellular cylinder in cross-section, showing numer- ous mitoses ; c, Granular masses with scattered cells between the cellular cylin- ders. (Preparation hardened in Flemming's mixture, stained with safranine, and mounted in Canada balsam. Magnified 80 diameters.) network, or if the process of proliferation has filled out the spaces left between the walls of a capillary network, the fully developed tumor may present an alveolar structure. However, it should be mentioned here that in both endotheliomata and angiosarcomata the alveolar and the tubular structure may be wholly lost in places, through the diffuse man- ner in which the proliferation takes place. Angiosarcoma occurs in the brain, kidney, testicle, lympha- tic glands, breast, skin, bone, thyroid, and liver, although it i_.^S:4, '"'*l^»'S^^fl^^f#^;Sit_6 is a very rare occurrence in the two situations last named. Pig. 229.— Section through an alveolar sarcoma of a lymphatic gland, a, Stroma; b, Nests of cells; c, AlveoH with cells lying free within them. (Preparation hardened in MiiUer's fluid, stained with alum carmine, and mounted in Canada balsam. Magnified 100 diameters.) 344 CONNECTIVE-TISSUE TUMORS. — SAECOMATA. Alveolar sarcoma develops by no means rarely in fleshy warts or moles or birthmarks. In such formations there are, in the corium or in the papUlse, peculiar nests of large cells, which proliferate actively when a sarcoma begins to develop. As these nests of ceDs probably represent pathologically developed lymphatic vessels (cf. § 117, Pig. 211), these sar- comata may properly be reckoned among the endotheliomata. More- over, alveolar sarcomata in which a connective-tissue vascular stroma (Fig. 229, a) incloses nests of large cells (1), c) are also observed in the bones, lymphatic glands (Fig. 229), and other organs. The term angiosarcoma is not used with the same meaning by all authors. Waldeyer introduced the name for tumors springing from the adventitia of blood-vessels. Kolaczek has extended its use so that it shaU include also those which spring from the lymph- vessels. It certainly is more correct, as well as more practical, to employ the name only for those tumors to which it was origi- nally given, and to apply the name endothehoma to tumors starting from endo- thehum. If, however, the application of the term be insisted upon for both classes of tumors, the hmiting adjective ought never to be omitted ; the tumor then being designated either as a hssmangiosarcoma or as a lymphangiosar- § 125. Among the secondary changes which a sarcoma may undergo, and which give to it a distingiiishing peculiarity, the formation of pig- ment may be mentioned as the most important. This change, which char- acterizes the melanosarcomata, is oftenest observed in sarcomata of the skin and eyeball, and the tumors thus affected present a brown or black, or sometimes also a spotted appearance. Melanotic sarcomata are malignant tumors, which form metastases and often affect, by means of secondary nodules, many of the organs of the body, of the skin, and of the muscles. Sometimes the primary tumor is only faintly pigmented or pigmented in pai't, whUe the secondary nodules are almost black. Pigmented sarcomata of the skin grow usually from moles and pig- mented warts (cf. § 124), and iisuaUy belong, therefore, to the alveolar group of sarcomata (Fig. 230) ; but the alveolar structure is not always typical, being usually more or less obsciured by an even distribution of the newly formed cells. The pig- ment wMch exists in yellow and brown granules or as a diffuse staining of certain cells (cf. § 73) lies often chiefly in the perivascu- lar tissues (Pig. 230, e). There it is embedded in small connective- tissue cells. It may also be de- posited in the large tumor-ceUs (&), Fig. 230. — Section through a mel- anotic alveolar sarcoma of the skin. a, Sarcoma-cell of an epithehal char- acter, containing one nucleus ; ai. The same, with more than one nucleus; 6, CeUs containing pigment ; e, Stroma containing blood-vessels and pig- ment. (Preparation stained with haematoxyhn. Magnified 300 diame- ters.) CONNECTIVE-TISSUE TUMORS. — SARCOMATA . 345 and in different places may be found in almost all the different cells. If the pigmentation is very pronounced, the cells may degenerate and fall to pieces. In certain rare cases tumors develop which present on fresh section a bright-green appearance, becoming dirty green on exposure to the light. To these tumors the name of chloroma has been given. According to the reports which have been published thus far, these tumors usually de- velop in the periosteum of the skuU, and are made up of round cells lying in a reticulated stroma. They belong, therefore, to the round-ceUed sarcomata, and especially to the group designated lymphosarcoma. Von Eecklinghausen classes this tumor with the lymphadenomata, of which he considers it a variety. According to Chiari and Huber, the green color is due to the presence in the cells of small shining spherules which give the mierochemical reaction of fat. The disappearance of the color in alcohol lends support to this statement. On the other hand, von Reck- hnghausen claims that the color is parenchymatous. A further peculiarity of sarcomatous as well as flbromatous and myxomatous tumors is the possible formation, within the tumor, of cu'- cumscribed areas of calcification, which resemble the sand-like particles found in the brain ; and from this circumstance some authorities have felt warranted in calling such tumors psammomata {acermdomata, sand- tumors). They are found chiefly in the membranes of the central nervous system and in the pineal gland, where they form nodular tumors ; and if these concretions are present in sufficient numbers, their existence may readily be made out, even with the naked eye, through their white color and through the resistance encountered by the knife when a section is made. The hme concretions form either round bodies with concentric layers (Fig. 231, a, b, c), as they occur normally in the plexus in the form of brain-sand ; or they are more lanceolate {d) or nodular (e). As has been already mentioned in § 70, the basic substance of the concretions is formed partly of connective tissue which has undergone hyaline degen- eration (d, e), partly of degenerated cells (a, &, c). Fig. 231. — Section of a psam- moma of the diira mater, a, Hyaline nucleated globule including a con- cretion ; 6, Concretion with non-nu- cleated hyaline border^ lying in fi- brous tissue ; c, Concretion with hya- line border; d, Lanceolate concre- tion in connective tissue ; e, Lanceo- late formation containing three con- cretions. (Preparation hardened in alcohol, decalcified in picric acid, and stained with hsematoxylLn and eosin. Magnified 200 diameters.) Sometimes deposits of lime take place in the basic substance of cel- lular sarcomata of bone (Fig. 232, c, d ), giving rise to a hardening of the tumor similar in appearance to ossification. As the hardened portions fionsist purely of calcified connective tissue, and lack entirely the struc- ture of bone, these tumors must not be reckoned with osteosarcomata. 346 CONNECTIVE-TISSUE TUMORS. — SARCOMATA. The better plan is to give them the name of petrifying sarcoma {sarcoma petrificans). Fig. 232. — Petrifying large-celled sarcoma of the tibia, a, Polymorphous- tumor-cells; 6, Alveolar stroma; c, Trabeculae of the stroma with small cal- careous concretions; d, Petrified bands of the stroma. (Preparation hardened in MiiUer's fluid and alcohol, stained with hsematoxyhn and eosin, and mounted in Canada balsam. Magnified 365 diameters.) § 126. Finally, there are certain sarcomata which are characterized by the mucoid or hyaline degeneration of a portion of the tumor. If, as a result of this, peculiar bands of cells, aggregations of cells interrupted here and there by clear hyaline spaces, and hyaline masses in elongated or branching forms are developed, the tumors in which such changes take place are by many authorities called cylindromata — a name which has also been given to cancers in which similar hyaline alterations occur. Sometimes even the ordinary soft, cellular forms of sarcoma present a more than usually translucent appearance, and a cut surface which yields a mucous or somewhat cloudy fluid. This condition is due to the existence of a mucoid degeneration, which may be recognized by the swoUen state of the cells, as well as by the formation of drops in their interior. In hardened preparations this mucoid degeneration can no longer be made out easily. The cells are shrunken (Pig. 233, &), and separated from the stro- ma (a) by a clear zone. Sometimes one may come across a few nuclei which are much swollen (c) and quite bright, but. their surroundingprotoplasm will be found to have wholly disappeared through mu- coid degeneration. FiG.233.— Sarcoma myxomatodes. a, Stro- ma ; 6, Sarcoma-cells separated from the stro- ma by a clear area (partly the result of shrink- age in chromic acid and alcohol): c, Swollen nucleus without protoplasm. (Preparation stained in hfematoxyhn. Magnified 400 dia- meters.) CONNECTIVE-TISSUE TUMORS. — SARCOMATA. 347 Sometimes this mucoid degeneration is evenly distributed through- out the parenchyma of the tumor ; in other cases it occurs in patches, so that degenerated areas alternate with others which are stiU in a healthy condition. Frequently this form of degeneration gives rise to hyaline balls and branching hyaline figures, between which the cells which have escaped appear in bands that present a multitude of shapes. Those tumors which appear in section, even to the naked eye, as partly hyaline and partly grayish white sometimes present a peculiar combination of sarcmiatotis and myxomatous tissue. The latter consists of a mucoid groundwork and a network of anastomosing cells (Fig. 234, a). The sar- Fig. 234. — Section through a myxosarcoma (cylindroma) . a. Mucous tissue : h, Strings of cells j c, Fibrous tissue. (Preparation stained with carmine and mounted in glycerin. Magnified 250 diameters.) coraatous portion, on the other hand, is made up of branching columns and rows of cells pressed close together (b), which often anastomose and give the tumor a peculiar appearance. From their mode of construction such tumors must be called myxosar- comata. The anatomical reason for the existence of the plugs and cords of cells is not always discoverable. There is no apparent connection with the distribu- tion of the blood-vessels, for these run at times in the very directions in which the cords of cells are absent (Fig. 234, c). According to von Recklinghausen, the cords of cells may lie in lymph-vessels and lymph-spaces, while the connective tissue which intervenes presents a wholly homogeneous aspect. Fig. 235. — Cluster of blood-vessels hav- ing hyaline sheaths and hyaline processes ; from a cylindroma, a, Small blood-vessel ; 6, Layer of cells resembling epithelium, upon a hyaUne bulb-like process. (From Sattler. Magnified 200 diameters.) 348 CONNECTIVE-TISSUE TUMOES. — MIXED FORMS. Hyaline degeneration occurs relatively often in angiosarcomata, and in these growths the connective tissue and blood-vessels, as well as the perivascular masses of cells, may in part be transformed into a hyaline substance (Fig. 235) ; as a result of which the tissue is made up of mul- tiform cords and masses of cells, and hj'^aline masses iu which few or no cells are to be found. A part of the cylindromata are therefore to be reckoned among the angiosarcomata, of which they form a group that is characterized by hyaline degeneration. (m) Mixed Forms of the Connective-tissue Tumors. § 127. Various combinations of different sorts of tissue-formations have been described in the preceding paragraphs. Speaking literally, there are no tiunors which are composed of a single kind of tissue. In the first place, in every tumor of any size there is a new formation of blood-vessels, and those tumors, such as chondroma, osteoma, sarcoma, myoma, and myxoma, which are not made up of connective tissue have nevertheless a certain amount of it in their structure. The reason why such tumors are not spoken of as mixed tumors is because in them one kind of tissue is insignificant when compared with the other, and also because it exists to a certain degree only for the benefit of the other. When this relation is changed, so that the lesser tissue forms an integral part of the tumor, and its presence affects the character of the tumor, then the name mixed tumor is applied, and the name of one kind of tissue is made an adjective to qualify the other, or from the names of the two tissues a compound name is formed. If, for example, the vessels are very abundant and at the same time large or cav- ernous, as often happens in a glioma or a fibroma, the tumor is spoken of as a glioma or a fibroma — as the case may be — telangiectodes or cav- ernosum. If fatty and mucous tissues coexist, the tumor is called a lipoma myxomatodes or a Upomyxoma. Finally, a combination of cartilage and sarcoma is called a chondrosarcoma. Combinations of cartilaginous and mucous tissues, or of cartilaginous and sarcomatous tissues, occur frequently in the parotid (Fig. 236). Most of the tumors which develop in this region are chondro- myxomata or chondrosarco- mata or chondromyxosarco- mata. Tumors of the fas- ciae or of the intermuscular connective tissue are often Tig. 236.— Chondromyxo- sarcoma of the parotid, a, CartUage-tissue; 6, Sarcoma- tissue; c, MucoTis tissue; d, Cartilage in process of de- generation and change into sarcomatous and mucous tis- sue. (Preparation hardened in alcohol, stained with car- mine, and mounted in Canada balsam. Magnified 80 dia- meters.) CONNECTIVE-TISSUE TUMORS. — ^MIXED FORMS. 349 made up of connective tissue, sarcomatous tissue, mucous tissue, and adipose tissue ; and, in addition, the tumor is often of a telangiectatic character. Such a composite growth may be due to the fact that from the outset the tumor develops along different lines; or, in other cases, the connective tissues, after undergoing certain secondary changes, may pass from one form to another in the same group. Thus, for example, in chondrosar- comata of the parotid gland, the sarcomatous tissue or the mucous tissue is wont to traverse the cartilaginous tissue in cords or bands (Fig. 236, 6) ; and in some places the cartilage changes directly, in other places gradu- ally, into mucous tissue (c) or into sarcomatous tissue (&) ; and where this takes place the groundwork of the cartilage gradually disappears {d) and is replaced by a mucoid groundwork containing proliferating spindle- shaped and star-shaped cells. Combinations in which there is development of bone occur in those tumors which spring from bone. There are two forms of tumors in which such a formation of bone occurs, namely, the osteochondroma — i.e., a union of bony and cartilaginous tissues — and the osteosarcoma or osteofibroma — a union of osseous and sarcomatous or fibrous tissues. Fig. 237. — Osteoid sarcoma of the ethmoid bone, a, Sarcoma-tissae ; 6, Os- teoid tissue ; c, Plate of old bone ; d, Vascular fibrous tissue. (Preparation hardened in Muller's fluid, stained with heematoxylin and eosin, and mounted in Canada balsam. Magnified 45 diameters.) The osteosarcoma and the osteofibroma may arise from any bone in the body; they develop usually from the periosteum. A characteristic feature of these tumors consists in the formation of bony trabeeulse by means of condensation changes in the basic substance (Fig. 237). The new-formed bony groundwork may calcify immediately upon its forma- tion, so that the tumor becomes permeated with hard bony trabeculfe. But it occasionally happens that the calcification fails to take place (Fig. 237, b), while the trabeculas still preserve the characteristics of osteoid tis- sue ; in which case it is perfectly proper to give to the growth the name of osteoid sarcoma. 350 CONNECTIVE-TISSUE TUMORS. — ^MIXED FORMS. The osteochondroma is a hard tumor and is usually found in connec- tion with the long bones ; either growing out from some one portion of the bone or developing all around it as if the latter were a shaft pierc- ing it. The starting-point for the development of these tumors is espe- cially the periosteum, bat the bone-marrow may also take part in the for- mation of cartilage and bone. Except in parts where pure cartilage may exist, it is not possible to cut through one of these tumors when fully developed, and they often grow to considerable size. When it is sawed through, the surface may be very like a sawed surface of solid bone. Only by careful observation can one distinguish the white bony sub- stance from the more translucent cartilage. If the new growth has taken place at the same time in marrow and periosteum there wiU be found in the latter situation a cartilaginous tissue (Fig. 238, g) thickly traversed by trabeculae of bone (h), arranged for the most part at right angles to the surface of the old bone, but also united in many places by transverse offshoots. The cartilage also contains little clefts and canals which hold the scanty blood-vessels and a little connective tissue. In the cortical layer of the bone (a) are seen a greater or less number of Havers- ian canals, dilated and filled with cartilage (e) even to the smallest cleft and to every canal which harbors a blood vessel, while this cartilage itself is Fig. 238. — Section through an osteoid chondroma of the humerus, a, Cor- tical layer of the humerus; 6, Medullary caYity; c, Periosteal new growth; d, Normal Haversian canals ; e. Dilated Haversian canals flUed with cartilage con- taining at /new-formed bone ; g, CartUage formed from periosteum contaimng bone-trabeculse, h; i, Cartilage formed from the marrow-tissue with new-formed bone-trabeeulee, k; I, Old bone-trabeculae ; m, Remains of medullary tissue. (Magnified with a hand magnifying-glass. Preparation decalcified with picric acid and double-stained with hsematoxylin and carmine.) EPITHELIAL TUMORS. — ADENOMATA. 351 traversed in places in its central portions with new-formed bone-trabeculse (/). In the place of the fat-containing bone-marrow (6) is found a vas- cular cartilage which also contains numerous little trabeculffi of bone {k). If an active growth of sarcoma-tissue takes place in an osteochondroma, as may happen in its outer layers, there will be developed an osteochon- drosarcoma. 2. Tumors whose Structure Comprises Ujjithelium as well as Connective Tis- sue and Blood-vessels. — Epithelial Tumors. (a) Preliminary Remarks. § 128. In the case of the tumors described in the last chapters, we had to do with those new growths which arise from some tissue of the con- nective-tissue group — a tissue, therefore, which came from the middle germ-layer. In the development of the tumors which are to be described in the following paragraphs the epithelia — that is, the derivatives of the upper and lower germ-layers — are also directly involved. In fact, it is the very tissue which is formed from these layers which gives to these tumors their special character. They are therefore properly included under the general term of epithelial new growths. AH the tumors belonging to this category consist in part of epithelial cells, in part of vascular connective tissue. The latter forms the stroma — ^the framework which gives shelter and support to the epithehal elements. The pattern upon which these tumors are constructed is to be found in the various glandular organs, whose different stages of development are in many particulars mimicked by the tumors. To a large extent, there- fore, they resemble the various glandular organs of the body; but the degree of this resemblance varies greatly in different tumors, and on this ground we may make a division into two great classes. The first of these classes comprises the adenomata — that is, tumors which imitate with a certain degree of perfection any one of the normal gland types. The tiunors of the second class — ^the carcinomata — do not ordinarily reach any such perfection of imitation, or at least not through- out the whole new growth. Usually only the first stage of gland-forma- tion is followed — the mutual ingrowing of epithelium and connective tis- sue — and this process is repeated over and over again. In this way — that is, by the multiphcation of epithelial cells — cell-nests and plugs and cords of cells are formed, and these are continually being sheathed about by the growing connective tissue. The result of the process is a neoplasm whose connective-tissue stroma incloses multiform spaces filled with epi- thelial cells. These epithelial cells, however, do not arrange themselves iu a layer along the wall of the space, as in an adenoma, nor do they leave any free space — a lumen — between themselves ; but they are packed to- gether as soM, irregularly arranged cell-masses. The epithelial cystomata must be mentioned as an especial variety of the epithelial tumors. They are characterized by the formation of large spaces which are lined with epitheUum and filled with fluid. Carcinomata are malignant tumors which grow into the neighboring tissues, sooner or later penetrating into the lymph- and blood-vessels, and forming metastases. It must be remarked, however, that the malignancy varies according to the location of the carcinomata. They usually ap- pear singly, but sometimes two carcinomata of the same variety, or two of different varieties, develop at the same time in the same individual. 352 EPITHELIAL TUMORS. — ^ADENOMATA. Adenomata and cystomata are usually benign tumors, but there are examples of adenoma, as well as of cystoma, which, not only in structure, biit also in method of growth, approach very closely to the carci^iomata! They are doubtless transition forms between adenomata or cystomata on the one hand, and carcinomata on the other ; and consequently a sharp boundary-hne between adenoma and cystoma on the one hand, and car- cinoma on the other, cannot be drawn. Moreover, an adenoma or a cys- toma originaHj'' benign may in its growth assume the characteristics of a carcinoma. The development of this character of mahgnancy announces itself chiefly by the fact that the tumor breaks into the surrounding tis- sues. At the same time there is often noticed a more active and likewise a more atypical growth of epithelial cells. The defluition of the terms adenoma and carcinoma, just given, is founded on the anatomy and histogenesis of these tumors ; and I maintain that this is the only rational definition which the anatomist can accept. Inasmuch, also, as tumors which arise solely from cells belonging to the middle germ-layer may correspond exactly to other tumors in whose formation epithelial cells certainly take a part, and even constitute the characteristic part of the growth, any defi- nition which rests solely on an anatomical basis must necessarily be unsatisfac- tory. The definition of carcinoma as a tumor of alveolar type, in which a con- nective-tissue stroma contains cells in the form of nests, makes it impossible to draw any liae of distinction between alveolar sarcomata and carcinomata. This purely anatomical definition of careiaoma has brought us to the point where the question is widely discussed whether a carcinoma arises only from epitheUal structures, or whether it may not come also from connective tissue. Such a discussion becomes at once fruitless if the histogenesis of these tumors is accepted as a basis of classification. As a result of such a method of classifica- tion, only those tumors merit the name of carcinoma in which epithelial cells take an active part in the growth in the manner described above, while the connective-tissue tumors, which are anatomically similar but genetically very different, are called alveolar sarcomata. (6) The Adenomata and their Helations to Glandular Hypertrophies and Carcinomata. § 129. The well'defined adenomata are benign tumors which spring from glands, and usually present the aspect of nodular tumors sharply separated from the surrounding tissues. They may develop in the large glands — as, for example, the liver, kidneys, and breast — or in the small glands — like the sweat-glands, for example. On the whole, they are by no means common, certainly not if the adenocarcinomata (§ 130) and the adenocystomata (§§ 136 and 137) are separated from them and classified by themselves. The new growth consists of a tissue which in its structure closely re- sembles a normal gland (Figs. 239 and 240), but yet differs from it in the following respects : it does not reproduce all the anatomical character- istics of the fiilly developed gland, nor does it possess the power to per- form the functions of the gland which it imitates. Adenomata may be divided into two groups according to their histo- logical construction — that is, according to whether they are patterned upon the type of a tubular gland or upon that of a racemose or alveolar gland. Upon this basis we may recognize an alveolar adenoma (Pig. 239) and a tubular adenoma (Fig. 240). Either of these forms may de- velop into an adenoma papilliferum by a more active growth of the epi- thelium and by the formation of connective-tissue papillae which rise up EPITHELIAL TUMORS. — ADENOMATA. 353 Fig. 239. — Alveolar adenoma of the breast, a, Terminal alveoli of gland; 6, Ducts of gland: c, Connective-tissue stroma. (Preparation, hardened in Miiller's fluid and alcohol, stained in alum carmine, and mounted in Canada balsam. Magnified 30 diameters.) Fig. 240. — Tubular adenoma of the breast, a. Branching and dilated glandular ducts, cut longitudinally ; 6, The same, cut transversely ; c, Stroma. (Preparation hardened in alcohol, stained with alum carmine, and moiinted in Canada balsam. Magnified 30 diameters.) from the inner surface of the walls of the tubes and alveoli of the gland (Fig. 241, c). The development of an adenoma begins with the proliferation of the epithelium of the gland, and is speedily followed by the formation of glandular sprouts. The surrounding connective tissue, under these eir- 354 EPITHELIAL TUMORS. — ADENOMATA. ■cumstances, is penetrated by these new-formed glands, and may itself also take on a more or less decided proliferative activity, wlucli results in the Fig. 241. — Adenoma tubulare papilliferum of the kidney, a, Connective- tissue stroma; 6, Glandular tubules with diverticula; c. Tubules with markedly developed papillary excrescences. (Preparation hardened in Muller's fluid, stained with hsematoxylin, and mounted in Canada balsam. Magnified 30 diameters.) formation of new tissue. In fully formed adenomata the connective-tis- sue stroma may be either well developed (Fig. 239, c, and Fig. 240, c) or only poorly developed (Fig. 241). Adenomata occur in the breast in the form of nodular tumors, which vary in size from that of a hazel-nut to that of a man's fist ; sometimes they are even larger. On section they appear to be made up of lobules ; Fig. 242. — Section of a benign polyp of the large intestine, with develop- ment of new gland-tissue, a, Cross-section of glandular tubule ; 6, Branchitig glands, cut longitudinally ; c. Stroma rich in cells. (Preparation hardened in alcohol, stained with alum carmine, and mounted in Canada balsam. Magnified 80 diameters.) EPITHELIAL TUMORS. — ADENOr.IATA. 355 the texture is rather firm and tough ; and here and there dilated liimiua of the glands may be seen. Adenomata of the kidney, liver, and testicle present a less-developed stroma and are therefore softer. Adenomata with papillary growths are especially soft. Fig. 243. — Hyperplasia of the mucous membrane of the uterus, a, oi, Sections of glands ; 6, Connective tissue of the mucous membrane; c, Blood-vessels. Section through a bit of tissue ob- tained by curetting the ute- rus. (Specunen hardened in alcohol, stained with Bis- marck brown, and mounted in Canada balsam. Magni- fied 150 diameters.) The adenomata form a group of tumors which cannot be sharply dif- ferentiated from simple hyperplastic glandular growths, nor from other tumors of a similar character. Indeed, there appear, in the mucous mem- brane of the intestine and uterus, new growths which, from the glands contained in them (Figs. 242 and 243), resemile adenomata, and which are reckoned ly many writers, on account of the limited, area of their groivth, among the adenomata. Nevertheless they ought rather to be called glandular hypertrophies. In the intestine they occur as the result of chronic inflam- mation and ulcers, but are also sometimes found in a mucous membrane which shows no traces whatever of previous inflammation or ulceration. If these growths develop in consequence of a destructive process in the mucous membrane, we must look upon them as a manifestation of repro- ductive activity, which does not lead, however, to the restoration of normal mucous membrane, but rather to the formation of tumor-like, often poly- poid, masses of tissue. The glands belonging to these masses of tissue are formed, it is true, according to the pattern of normal tubular intes- tinal glands, with tall cylindrical epithelial cells ; but 'they are often shaped in an abnormal fashion (Fig. 242, 5), and in particular abnormally branched, so that we may speak of them as representing, in a certain sense, atypical glandular new formations. Sometimes in these tumors a certain number of glands also undergo dilatation, andpapillary excrescences (Pig. 244, c) develop from the walls of these dUated portions ; both of which phenomena belong to the altera- tions which are also observed in adeno- mata. Fig. 244. — Section of a glandular polj^p of the stomach, with papillary excrescences in some of the dilated glands, a. Gland- tubules with cylindrical epithelium; 6, Stroma infiltrated with cells ; c. Papilloma- tous growths inside of a gland which has undergone cystic degeneration. (Hsema- toxyliu preparation. Magnified 300 dia- meters.) 356 EPITHELIAL TUMORS. — ADENOMATA. If the signs of previous ulceration are wanting in the intestine which is the seat of glandular polyps, we must regard these growths as hijper- fropMc productions, whose cause is usually past finding out. In the uterus such glandular growths occur for the most part in later life, and usually present the characteristics of hypertrophic new formations of tissue, either following upon inflammatory processes or occurring independently of them. At the same time attention should be called to the fact that so long as menstruation continues, there occurs, at the time of the men- strual flow, a partial destruction of the mucous membrane, followed by increased growth of the epithelium and connective tissue; so that the beginning of the growth, under these circumstances, is sometimes to be considered as a reparative process. The glands developing under these circumstances (Fig. 243) are sometimes normally formed, and sometimes abnormally branched, or provided with papillary excrescences. Tumor-like growths resembling adenomata rarely develop inside of glands ; but in the course of chronic inflammations atypical new growths of gland-tissue often occur (cf. Fig. 187), and the only reason why they are not, as a rule, confounded with adenomata is because they evidently belong among the regular phenomena of an independent and distinct dis- ease. But there are glandular formations in glands which are with diffi- culty distinguished from the adenomata. In the prostate, for example, in old age, there is an increase in size, accompanied by an actual increase in the amount of glandular tissue; and under these circumstances one Fi6. 245. — Section through the growing margin of a tubular adenoma des- truens or carcinoma adenomatosum of the stomach (somewhat schematic), a, Mucosa; 6, Snbmucosa; c, Muscularis; d, Serosa; e, New growth proceeding from the mucosa and infiltrating the other layers. A round-cell infiltration ap- pears in parts in conjunction with the development of tubules. (Preparation hardened in alcohol, stained with hsematoxyUn, and mounted in Canada balsam. Magnified 15 diameters.) EPITHELIAL TUMORS. CARCINOMATA. 357 may eutertain considerable doubt as to whether the condition should be termed a glandular hyperplasia or an adenoma. The same dif&culty exists in regard to the distinguishiug characters of carcinomata and adenomata, and it often becomes a matter of individ- ual judgment whether a certain tumor shall be classed as belonging to the former or to the latter of these two varieties of tumors. In the first place, we sometimes observe in the intestinal tract adenomata which, ac- cording to their structure, must be called tubular adenomata (Fig. 245), but which, at the same time, in contradistinction to the adenomata already described, present a most marked degree of malignancy and break into the surrounding tissues in the same way as a carcinoma generally does, grow- iag from the mucosa into the submucosa, and so on into the muscularis of the intestine or the stomach, as the case may be (Fig. 245, e) ; in a word, the new growth often penetrates the entire thickness of the intestinal wall or the stomach-wall at a time when the portion of the tumor which projects into the intestine or into the stomach is stiU quite small. If, in judging of such a tiimor, we attach the chief importance to its histological struc- ture, we may appropriately give it the name of adenoma destruens or carcinomatosum or malignum ; but if its behavior toward the surround- ing tissues or its chnical course be chiefly considered, we shall probably prefer to call the tumor a carcinoma adenomatosum. It should be fur- ther mentioned that tumors which in structiu'c begin like adenomata may later, both in the matter of structure and as regards their relation to surrounding tissues, be precisely like the cancers, and so constitute a special variety of carcinoma (cf. § 130), for which the term adenocarci- noma might with fitness (in view of the origin of the growth) be adopted. Finally, it should be stated that adenomata are closely related to the group of epithelial cystomata (cf. §§ 136 and 137) and often form the first stage in the development of the latter. Consequently there are tumors which, from their origin, merit the name of adenocystoma. (c) Carcinoma. § 130. Carciaomata develop either from a mucous membrane or from the skin or from a gland, the growth beginning in epithelial multiplica- tion, in which the cells usually divide by mitosis. In many cases the epitheUal structures first formed possess the characteristics of a gland. This is true of a great part of the carcinomata of the intestinal tract (cf. § 129), and also of the rarer cases of carcinoma of the body of the uterus. The structures first formed are glandular tubides, more or less atypical in form, and hned with simple cylindrical epitheliimi (Fig. 245, e). These tubules push their way in an outward direction from their point of ori- gin — that is, from the mucous membrane — into the siirrounding tissues. In rare cases this form of growth maj^ be thoroughly maintained for a long time. More often, however, a more active proliferation of the epi- theUum takes place, resulting in the formation, at one time, of many lay- ers of epithelium in the glandular tubules (Fig. 246, a, h), at another of solid masses and columns of cells (Fig. 247, b). The mode of develop- ment of the tumor is therefore very much like that of an adenoma, from which it is distinguished, however, by the increased proliferative activity of the epithehal cells and by the more markedly atypical manner in which this activity shows itself — characteristics which justify the use, as applied to this tumor, of the term adenocarcinoma. In the intestinal tract it is 21 358 EPITHELIAL TUMORS. — CARCINOMATA. Fig. 246. — Tubular adenocarcinoma of the rectum, a, b, Epithelial gland- tubules : c, C|, Stroma ; d. Collection of leucocytes in the gland-tubules. (Prep- aration hardened in alcohol, stained with alum carmine, and mounted in Canada balsam. Magnified 80 diameters.) the commonest variety of carcinoma, although cancers are common enough here in which from the beginning the epithelial multiplication takes place in compact cell-groups. Cancers of the sMn and of the mucous membranes which are covered Fig. 247. — Adenocarcinoma fundi uteri, a, Stroma; 6, Carcinomatous pro- cesses ; c. Single cancer-cells. (Magnified 150 diameters.) EPITHELIAL TUMORS. — CARCINOMATA. 359 with stratified epithelium are usually characterized, in theii* development, by the formation of compact nests and colunms of cells (Fig. 248, /, g), which spring from the superficial epithelium («), or from the sebaceous glands or the hair-follicles, and penetrate next into the clefts or spaces of the neighboring connective tissue. Fig. 248.— Section through a cancer of the skin in an early stage of develop- ment, a, Epidermis; b, Corinm; c, Subcutaneous connective tissue; d, Seba- ceous gland ; e, Hair-follicle ; /, Cancerous plugs connected with the epidermis ; g, Cancerous plugs lyiag deeper in the tissues ; h, Proliferating connective tissue ; i (above and on the right side). Epithelial pearl; i (below). Cross-section of a sweat-gland. (Preparation stained with Bismarck brown. Magnified 20 cUameters.) In these instances, accordingly, the carcinomatous new formation appears from the outset in a pure type ; that is, the proliferation of epi- thelial cells shows characteristics which are in general recognized as be- longing to the carcinomata and as being typical of them. The skin, however, is sometimes the seat of cancers whose columns of cells possess a central lumen. Such a tumor, on section, presents the picture of elon- gated and often anastomosing gland-tubes. But cancers like this are rather rare. Cancers which spring from the glands, breast, liver, kidney, pancreas, salivary glands, ovary, testicle, etc., usually display, even in the early stage of their growth, solid masses of epithelium, which, arising from parts of the glandular tissue, penetrate into the connective tissue of the vicinity. In aU these organs, however, other cancers develop which more closety re- semble the adenocarcinomata in their formation of structures like gland- tubules and alveoli — i.e., structures like those which have already been described when we spoke of intestinal carcinomata. The epithelial growth proceeds usually by mitotic cell-division, and in aU cell-nests of growing carcinomata — provided retrogressive changes have not set in — a greater or less number of karyokinetic figures may be found. 360 EPITHELIAL TUMORS. — CAECmOMATA. The connective tissue, in the beginning of the carcinomatous develop- ment, sometimes shows no appreciable change. Oftener, however, it shows indications of growth, and usually there are also infiltrations of leucocytes (Fig. 249, h), which may, in certain spots, lie in large masses in the tissue. Very often these leucocytes penetrate into the columns of epi- thelial cells. Here they cease to live, being destroyed by the epithelial cells, which doubtless utilize them for their own nourishment. If a cancerous growth has begun to develop, it spreads with greater or less rapidity into the neighborhood. This spread of the growth is especially rapid in the case of cancers of a mucous membrane, where the breaking through into the submueosa is followed by a rapid diffusion of the cancerous new growth in the interstitial spaces of this layer. Hence, in cancers of the intestine, not only the submueosa, but the muscularis and serosa as well (Fig. 245, e), are soon studded with the cell-nests of the tumor, and at once begin to proliferate activety. This diffusion of the growth takes place chiefly along the course of the lymphatic channels, but a break into blood-vessels — more especially veins — is by no means a rare occurrence. In a similar manner cancer of a gland extends its de- velopment into the neighboring tissues after its growth has proceeded beyond the particular region of its origin ; and it may spread far be- yond the site of the first centre of growth. So, for example, in the growth of a carcinoma of the breast (Fig. 249), the connective tissue surround- ing the gland becomes studded with round or spindle-shaped or cord-like Fig. 249. — Section through a segment of a carcinoma of the breast (drawn, with the aid of a basic lens), a, Nipple ; 6, Tissue of the mammary gland; c, Skin; d, Outlet-ducts of the gland; e, Carcinomatous masses occupying the position of glandular tissue ; /, Lobules of fat already iniUtrated with cancer; g, Portion of skin also infiltrated with cancer ; h, Carcinomatous cell-nests in the nipple ; i, Normal lobules of the gland ; k, Infiltration of small cells in the con- nective tissue. EPITHELIAL TUMORS. — CARCINOMATA. 361 foci of cancer-cells («,/, g,h); and the cancerous growth penetrates into the surrounding fat-tissue (/), into the skin {g), and often also into the papiUsB of the nipple (h). The channels along which the cancerous growth spreads are the lymph spaces and vessels, and only a very short time is required before secondary nodules, quite separate from the original focus of the disease, make their appearance in the course of the efferent lymph- vessels. The newly produced epithelial cells of the individual cell-nests, usually referred to in fully developed carcinoma as cancer-cells, show in general in their characteristics their origin from epithelium. They are relatively large and have large bladder-like nuclei. Very often, too, it is possible to recognize the character of the epithelium from which the cancer has sprung. Thus we may find, in cancer of the intestine, cylindrical epithelial cells, and in cancer of the skin characteristic cells of stratified epithelium. In many parts of the tumor, however, the characteristic cell-form is lost. When the cells develop in the inter- stices of the connective tissue in the form of plugs and columns, it is un- avoidable that they should press upon one another, and that their shapes should undergo considerable altera- tions (Pig. 250). As a consequence of this the single cells, when isolated, pre- sent the greatest variety in their forms. This has led some authorities to speak of a polymorphy of cancer=cells ; and it is hterally true that the cancer-cells appear in a very great variety of shapes. But it must not be forgotten that this richness in the forms of the cells of a tumor affords no certain proof of its cai-cinomatous nature ; in fact, irregularly shaped cells are even more likely to belong to a sarcoma. In glands carcinoma forms nodular tumors sometimes sharply limited, sometimes losing themselves, without definite boundai-ies, in the surround- ing tissues into which they send out offshoots. In mucous membranes these new growths stand out prominently in the form of fungoid or papillomatous masses, or they are spread out more flatly along the sur- face. At an early period of their growth they penetrate into the submu- cosa, and may extend even deeply into the surrounding tissues. Cancers of the skin behave in a similar manner, but their growth is usuaUy not so rapid as that of cancers of mucous membranes. Degeneration in the new growth often causes ulcers. § 131. Different kinds of carcinomata have been established in accor- dance with their varying characteristics — such, for example, as the differ- ences in the localities where they may begin to grow, and in the tissues from which their first development may commence ; differences in the form and composition of the cells and in their mode of arrangement ; differences in the manner in which the epithelial cells infiltrate the con- nective tissue ; and, finally, differences in the amount and character of the connective-tissue stroma. Many of these distinctions, however, have to-day lost much of their significance. So, for instance, the designation Fig. 250. —Epithelial plug from a cancer of the skin. (Magnified 250 diameters.) 362 ■ EPITHELIAL TUMORS. — CARCHSfOMATA. of certain cancers of the skin and mucous membranes as epithelial can- cers, or epitheliomata, possesses only this value — namely, that in this way the site and anatomical characteristics of a tumor maybe conveniently designated, whereas formerly the term was used to indicate a distinction between epithelial and connective-tissue cancers. Other terms, such as carcinoma medullare, carcinoma simplex, carcinoma scirrhosum, by which it was intended to characterize the structure -of diiiei-ent carcinomata, especially those springing from glands, also possess only a hmited value ; for a carcinoma does not show the same structure in all its parts or in all its phases of development. In general the form of a cancer depends on the nature of the parent- tissue from which it springs ; that is to say, in its growth the cancer re- peats, with little change, a certain group of foi-mations that are normally present in the parent-tissue. From mere a priori reasoning it would seem most natural to divide the carcinomata into two great groups — namely, those which start from the epithelium of a sm-face and those which de- velop from the epithelium of a gland. Theoretically one can adopt a classification like this, but in practice it is not possible to follow it in aU cases without resorting to an exact histological examination. For example, a cancer of the skin springing from sebaceous glands shows in general the same characteristics as one which springs from the hair-foUicles or the epidermis ; and in the alimentary tract it is scarcely possible to make a division of carcinomata according to their origin from the surface epi- thelium or from that of the glands of Lieberkiihn. Consequently, in the consideration of carcinomata in general, it is best simply to select certain chief types, which are distinguished by well-marked anatomical differ- ences. 1. Flat-celled epithelial cancer commonly occurs in the skin as sMn- cancer or sJcin-cancroicl (Fig. 248), and forms a warty or a nodular tumor or a fiat thickening of the skin, all of which forms are characterized by the development of large cancerous cell-nests, made up of large, polj'- moi-phous, flat epithelial cells. Degeneration of the new growth forms cancerous ulcers. Upon scraping the cut surface of the tumor, which shows plainly its alveolar structure, a knife drawn across it scrapes up a gruel-like fluid containing plugs of cells and single epithelial cells. Within the plugs the cells are often arranged concentrically, like the layers of an onion (Fig. 250). These balls of cells may become horny and form epithelial pearls. Such tumors are usually called Jiorny cancroids. The cancer-cells of skin-cancers are derivatives of the cells of the epidermis as well as of the sebaceous glands and the hair-foUicles. Flat-celled cancers occur also in those mucous membranes which are covered with similar epithelium — e.g., in the mouth, pharynx, oesophagus, bladder, vagina, and uterus. 2. Cylindrical epithelial cancer occurs, in the first place,in themucous membranes, and most often in that of the intestine ; it also occurs, but more rarely, in the mucous membrane of the gall-ducts, gall-bladder, re- spiratory passages, and uterus. In the last situation it arises only in those portions which are covered with cylindrical epithelium, as cancers of the vaginal portion, or of the vagina, are for the most part flat-ceUed. It forms soft nodular, sometimes papillary tumors, which are generally classed among the encephaloid growths. Furthermore, this variety of cancer also develops in glands where it EPITHELIAL TUMORS. — CARCINOMATA. 363 forms likewise nodular tumors, from whose cut surface an abundant nulky fluid can be scraped. Cyliniirical-celled cancers resemble adenocarcinomata in their charac- ter (Figs. 246 and 247). From their appearance and from their mode of origin they might be caUed medullary adenocarcinomata. 3. Besides the adenocarcinomata, we also find, both in mucous mem- branes and in glands, medullary cancers whose feebly developed stroma contains only solid cancer-nests, without any central lumen. To such growths we apply the term medullary carcinoma. 4. Carcinoma simplex is a term given to a form of cancer which fre- quently grows in glands and forms rather hard nodular tumors. The cut surface appears of a bright grayish-white color, and somewhat translucent. Connective-tissue stroma and cancer-cell nests are, at least in some portions, by reason of their different colors, easily distinguish- able. This is especially the case if by fatty degeneration the ceU-nests have become white or yellowish white. A rather abundant milky juice can be scraped from the cut surface. The tumor has a strong fibrous stroma (Fig. 251, a), which contains meshes of different shapes and sizes filled with epithelial cell-masses. Fig. 251. — Section of a carcinoma simplex of the breast, a, Stroma; 6, Plugs of cancer-cells; c, Single cancer-cells; d, Blood-vessel; e, Infiltration of tke stroma with, small cells. (Preparation stained with hematoxylin. Magni- fied 200 diameters.) Such earcinomata are especially common in the breast, but are less often found in the pancreas and kidney. 5. A scirrhous carcinoma, or scirrhus, is one in which the cancer-cell nests are relatively small and scanty, and separated from one another by tough fibrous stroma, which gives a hard and tough consistence to these tumors. No strict line of division can be drawn between scirrhus and carci- noma simplex. On the contrary, in a single tumor one portion often 364 EPITHELIAL TUMOKS. — CAKCINOMATA. presents the appearances of carcinoma simplex, and another portion the appearances of scirrhus (cf. Fig. 249) — i.e., in one portion of the tumor the cancer-cell nests may be rather abundant and large and the stroma insignificant, while in another portion the nests are small and the stroma well developed. The hardness which is characteristic of scirrhus is best marked in those portions in which (as in Fig. 249, g, h) very small spindle- shaped cancer-cell nests are scattered throughout the connective tissue. This hardness may also owe its existence to the fact that fatty degenera- tion and absorption of the cancer-cells have left nothing behind but the tough connective-tissiie stroma, which looks very much like scar-tissue. In this manner a soft cancer, by retrograde changes in the cancer-cells and corresponding proliferation of the connective tissue, may come to possess a scirrhous character. This happens very often in ulcerating can- cers of the stomach and intestine. Hard cancers, rich in connective tissue, occur chiefly in the breast and stomach, less often in the testicles, ovaries, and kidneys. 6. Gelatinous carcinoma, or alveolar or colloid cancer, occurs in the form of nodules or as a diffuse infiltration. It is found most frequently in the intestinal tract or in the breast, more rarely in the ovary, etc. Its tissue is noticeable on account of its great transparency ; for the stroma, instead of inclosing the more opaque cancerous ceU-nests, contains trans- parent colloid masses, both large and small. This transparence is often observable on the surface of the tumor — for example, in colloid cancers of mucous membranes, which develop in the form of fungoid or of papil- lomatous or of more diffuse growths, as the case may be. In coUoid can- cers of the breast the transparent nature of the tumor is only discovered after it is cut into. Often only a part of a tumor displays this character, while the rest of it appears grayish white or grayish red, like an ordinary carcinoma. The gelatinous character of the tumor is due to a mucoid or coUoid degeneration of the cancer-ceU nests (Fig. 252) — a change which begins by the formation of clear drops within the cancer-cells (d). In the cylin- drical-ceUed cancers goblet-cells are commonly formed. Later, these cells degenerate and are destroyed, and the drops flow together, or unite with larger aggregations of the material, already formed, to constitute a single homogeneous mass. In this way all the cancer- cells throughout large areas may be destroyed, so that of formed ele- ments nothing remains Fig. 252. — Grelatinous carcinoma of the breast. a, Stroma ; 6, Plugs of can- cer-cells ; c, Alveoli without cancer-cells ; d, Cells con- taining colloid masses. (Preparation stained with heematoxylin. Magnified 200 diameters.) but the stroma. In other parts nests of cells stOl remain within the coUoid mass (6), and there may be still other portions which are quite free from colloid degeneration. EPITHELIAL TUMOES. — CARCESTOMATA. 365 7. A myxomatous carcinoma (carcinoma myxomatodes) is a cancer ia which the stroma undergoes a change into mucous tissue (Fig. 253). Under certain circumstances a like degeneration overtakes the cancer-cells (Fig. 253, d ), so that the tissue becomes quite translucent and gelatin- like. If the cells of the connective tissue likewise undergo destruction, Fig. 253. — Myxomatous carcinoma of the stomach, a, Plugs of cancer-cells; b, Connective-tissue stroma ; c, Stroma of mucous tissue ; d, Cancer-cells which have undergone mucous degeneration. (Preparation stained with hsematoxylin. Magnified 200 diameters.) the colloid areas will finally contain no cellular elements whatever. This variety of cancer occurs in the same situations where the gelatinous car- cinoma is found. 8. Another relatively rare form of carcinoma may develop in the fol- loAving manner : the elements of the growth first undergo hyaline degen- eration, and at the same time the hyaline substance and the masses of cells arrange themselves in groups in a peculiar manner. The pictures pre- sented by sections of a carcinoma which has gone through these changes remind one of those seen in the sarcomata called cylindromata, when they have similarly undergone hyaline degeneration. Carcino- mata like this have accordingly been reckoned among the cylin- dromata, and called carcinomata cylindromatosa. In a certain number of the cases the hyaline Fig. 254. — Carcinoma showing hyaUne degeneration of the epithehal cells (carcinoma eyhndromatosum). a, CeU-nest without hyaline-degener- ated areas; b, CeU-nest with a few hyaline globules; c, c, CeU-nests in which the cells have been forced into net-hke forms by the abundant for- mation of hyaUne globules. (Magni- fied 150 diameters.) 366 EPITHELIAL TUMORS. — CAECINOMATA. degeneration involves the epithelial cells, and accordingly hyaline glob- ules develop in the midst of the cell-nests (Pig. 254, b). These globules may at last become so numerous as to press the epithelial cells together in trabeculse arranged like netting (c). In other cases the hyaline degen- eration involves the connective tissue, and it may happen that columns of cells growing in the lymph- vessels may be separated from one another only by hyahne connective tissue. Cancers in which there are spots which show hyaline degeneration are observed not only in the skin and intestine, but also in glands. 9. Giant-celled carcinoma (carcinoma giganto-cellulare) is a name which may be applied to a form of carcinoma in which a part of the can- cer-cells reach an extra large size. In some of the cases these large ceUs are simply hypertrophic cells which reach an extraordinary size without undergoing any other particular change in appearance, except, perhaps, that they may have several or many nuclei (giant cells). In other cases the enlargement of the cells is due to a mucoid or dropsical degeneration (Fig. 255), which causes the cells (6), as weU as their nuclei (c) and nucleoh, to become very much swoUeu. The protoplasmic granules appear to be pushed apart by the fluid, and in the cells (&) and nuclei (c) clear drops free from granules are formed. Such cells are called physalides by some authors. Fig. 255. — Enlarged dropsi- cal cancer-cells from a carci- noma of the breast, a, Ordinary cancer-cells ; b, Dropsical cells containing in their interior clear drops of fluid : c. Swollen nu- cleus ; dj Swollen nucleolus ; e, Wandermg cells. (Preparation hardened in Miiller's fluid, stained with Bismarck brown, and mounted in Canada balsam. Magnified 300 diameters.) 10. Melanocarcinoma is the last variety of cancer which requires men- tion. It forms gray or brown or black tumors. The pigment lies partly in the stroma, partly in the cancer-cells. Melanocarcinoma is much rarer than melanosarcoma. "We should also mention, in this place, the pearly tumors or cholesteatomata — ^i.e., tumors or tumor-like products wMoh are characterized by the formation of shining- white pearly bodies. The pearls are made up of cells hke scales, which are packed together in concentric layers in the form of httle balls, some of which inclose cholesterin. The most typical formations of this sort occur in the pia mater and ia the brain-substance proper, where they form either sohtary tumors possessing a connective-tissue capsule and resembling dermoid tumors, or multiple glistening nodules or larger round masses lying free in the pia and brain. Many authors* * Cf. Virchow, Virchoui's Arch., 8. Bd.; Eppinger, Prager Vierteljahrsschr., 1875; Gross, " Contrib. k I'etude des tumeurs perles," Paris, 1885; Eberth, Virch. Arch., 49. Bd. ; Chiari, " Cholesteatome des Riickenmarkes," Prager med. Wochensehrift, 1883; Glaeser, "Untersuch. ii. das Cholesteatom und ihre Ergeb- nisse fur die Lehre von der Entstehung der Geschwulste," Virch. Arch., 122. Bd.; Buzzi, " Cholesteatom," Mittheil. a. d. JDermat. Klin. d. Charite, 1888. EPITHELIAL TUMORS. — CAECINOSLi.TA. 367 regard them as endotheliomata ; others hold the view that they are of epithelial origin. As the scales in every respect resemble cornifled epidermis-cells, and as, according to my own observation, the ceU-masses may contain hairs either free or growing in hair-follicles, I am of the opinion that the pearls are of epider- mal origin, and that accordingly these growths spriag from cutaneous tissue which in foetal life has found its way either into the pia or into the brain-sub- stance, as the case may be. The same may be said of similar formations which are found in the pelvis of the kidney,* in the connective tissue of the testicle, the parotid gland, the ovary, etc., in the auditory canal, and in the cavities of the mastoid process and middle ear.f In all of these cases we have to do not with tumors but with epithelial collections in preexisting spaces, the epithelial desqua- mation (excepting when it occurs within a tumor) being caused by inflammatory processes. § 132. A cancer grows first in the particular organ where it originates (Fig. 256, a, &), but often extends to the neighboring organs. The specific tissues — such as parenchymatous gland-cells, muscle-fibres, and bones — atrophy under the pressure of the growing tumor, while the connective tissues take on active proliferation under its influence. If epithelial germs from a carcinomatous focus find their way into a lymph- or blood-vessel, a metastasis forms at the point where these germs lodge and develop. This occurs very often in the affected organ Fig. 256. — Primary carcinoma of the fiver (a), with multiple metastases (ft) within the hver itself. (Reduced more than one half in size.) itself (Fig. 256, h). In other cases these germs appear very early in the lymph-vessels outside of the organ primarily affected (cf. Pig. 192), or in the nearest lymph-glands. Often, too, the proliferating epithelial cells manage to get into the blood-current, and are swept away by it. Thus, * RoHtansky, " Lehrb. d. pathol. Anat.," iii., 1855; and Beselin, Virch. Arch., f Kipp, Arch.f. Augen- u. Ohrenheilk.,\v.; Lucae, Arch.f. Ohrenheilh., i., 1873; Steinbriigge, Zeitschrift f. Ohrenheilh., viii.; Wendt, Arch. d. Reilk., xiv., 1873; von Troltsch, " Lehrb. d. Ohrenheilk." 368 EPITHELIAL TUMORS. — CARCINOMATA. for example, in cancers of the intestinal tract very often epithelial cells break into some branch of the portal vein and are carried to the liver, where they develop into metastatic nodules. By multiplication of the transplanted cells a ceU-nest is formed (Fig. 257), which sweUs out the vessel into which the cells have floated, while the iiver-ceUs are compressed and undergo atrophy. Then with the as- sistance of the vascular and connective-tissue system of the Hver, which develops a connective-tissue stroma and new blood-vessels, a secondary nodule is formed which resembles in all points of its structure the parent-growth from which it originated. The columns of hver-cells in its vicinity are either displaced and compressed, or the cords of cells be- longing to the secondary growth push their way directly through the liver-cells. The latter happens in this way : the growth of the cancer- nodule takes place mostly on the periphery in the open capillary vessels (Pig. 258), so that the blood-capillaries are filled one after another with cancer-ceUs. As the latter develop the liver-cells atrophy and disappear. Fig. 257. '/°N r/ t Fi&. 257. — Section tkrough an aggregation of very young cancer-ceUs, lodged like an embolus within a capUlary of the liver. The parent-growth was an adenocarcinoma of the stomach. (Preparation staiued with heematoxyliii. Magnified 300 diameters.) Fig. 258. — Metastatic cancerous development in the liver-capiUaries, follow- ing upon carcinoma of the pancreas. Within the capillaries, both cancer-cell nests and connective tissue have developed. (Preparation stained with alum carmine and mounted in Canada balsam. Magnified 250 diameters.) The epithelial elements of the metastatic cancer-nodules are to be re- garded as purely derivatives of the cells transplanted from the primary nodule. The tissue in which the secondary nodule is located furnishes only the vascular and connective-tissue portions of the new growth. § 133. Retrograde changes occur extensively in carcinomata, and often terminate in the destruction of a part of the new growth. Not a few of the cells found in the juice scraped from the cut surface of a cancer are almost always fatty-degenerated or necrotic, and this is especially true of EPITHELIAL TUMORS. — CARCINOMATA. 369 soft, rapidly growing tumors. If the fatty degeneration is considerable the portions affected have a white opaque appearance, and may disinte- grate into a gruel-like mass which either thickens into a caseous material or becomes absorbed. If only the cancer-cells are affected by the fatty degeneration, as is usually the case, the alveolar contents are then espe- cially prominent, by reason of the contrast between their dull- white color and the more gray or grayish-red or shining-white stroma. In tumors which are located superficially in an organ, or stand up above the level of the surface of the body, the absorption of the disinte- grated cancer-cells causes a central depression, a hollow — the umbilica= tion of cancer. In cancers which have a firm stroma, and in which a hyperplasia of the connective tissue keeps pace with the wasting away of the cancer-cells, the original cancer-nodule may in this way change into a firm mass of connective tissue which contains few or no cancer-ceU nests. This occurs with special frequency in scirrhus of the breast and of the stomach. Miicons degeneration and dropsical degeneration have already been re- ferred to in § 131. Partial amyloid degeneration of the stroma has been seen a number of times. Calcification is most often seen in skin-cancer, but is quite rare anyway. Necrotic changes in carcinoma, and the ulcers resulting from them, are of great importance, since in this way even large new growths may be destroyed. Cancer-nodules in the intestine, for instance, are destroyed in this manner, so that in a short time after the nodule has formed, its place may be taken by an ulcer which presents scarcely a trace of the ' preceding tumor. If the ulceration has not progressed too far, a little of the old tumor may remain in the form of nodules and papillary growths at the bottom and along the margins of the ulcer ; but if the ulceration has advanced stiU further, the bottom of the ulcer presents a smooth and clean appearance, and seems to consist only of hard connective tissue, while the edges form an elevated wall about it, at times studded with papillomatous or nodular growths. Sometimes, finally, the margins are also destroyed, and the ulcer then appears like a non-carcinomatous one with indurated base. Even a section may at times leave us in doubt as to whether cancer-cell nests still exist in the tissue or not. Carcinomata of the skin or of the breast or of other subcutaneous glandular organs may undergo superficial necrosis and form ulcers just as do the cancers of mucous membranes. In the floor of the ulceration there is always to be found a greater or less degree of inflammatory inflltration, and a new formation of connec- tive tissue results, which sometimes reaches very considerable proportions. Sometimes quite extensive growths of granulation tissue develop in the ulcer, and rise like fungous growths above the level of the surrounding surface. They are distinguished from other granulations chiefly by the cancerous cell-nests which they contain. § 134. The etiology of cancer has not been satisfactorily cleared up by such investigations as have been made up to the present time. According to the result of histological investigation, the growth of a cancer is due to the pathological penetration of epithelium into connec- tive tissue. The cause of this process may be looked for in a diminution of resistance offered by the connective tissi^e, or in an increase in the proliferating power of the epithelium, or in a simultaneoiis exhibition 370 EPITHELIAL TUMORS. — CARCINOMATA. of botli. The last corresponds best to the conditions actually observed. The idea of a diminished resistance of the connective tissue to the ad- vancing epithelial cells is supported not only by the histological appear- ances of sections made through cancerous nodules in the early stages of development, but also by the fact that cancers occur most often in ad- vanced age and at a time when it can be demonstrated that atrophy of the tissues has set in. In support of an increase in the power of multi- plication of the epithelial cells may be mentioned their luxuriant growth, which exceeds even that observed in regenerative processes ; in fact, in a given area more nuclear mitotic figures may be found in growing cancers than in simple regenerative new growths. At the same time there occurs what may be termed a metaplasia of the epithelium, in that the newly formed cells possess morphological and physiological characters other than those of the epithelium from which the new growth springs. The cause of the increased prohf erative activity on the part of the epi- thelium, and of its change into cells which remind one more of embryonic epithelium, is not known. In part of the cases (cf. § 109, Pig. 190) the can- cerous development foUows immediately wpon chronic irritations (action of concretions upon mucous membranes, or of dirt upon the skin), or upon ulceration and the formation of cicatrices (ulcers in the stomach and in- testine, lupus cicatrices in the skin), or upon the development of granula- tion growths (lupus carcinomata), in all of which processes the epithelial cells are in part subjected to altered conditions of nutrition, and in part are displaced, so that often they are lodged among the deeper layers of the tissues. There can be very little doubt that these changes, together with the altered character of the connective tissue, give rise to the de- velopment of a cancer. Nevertheless it is impossible to say why pre- cisely similar conditions at one time produce a carcinoma and at another do not. In modern times, and especially quite recently, the idea has bemi ad- vanced, by a nimiber of authors, that cancer may be a parasitic affec- tion. Some have looked for the cause in Schizomycetes, others in Protozoa. In support of this hypothesis it may be said that there are doubtless both Schizomycetes and Protozoa which, when they become colonized in the body, cause proliferation of the tissues. Quite lately the further state- ment has been made that in cancer-cell nests there are often found lying inside the cells structures of various shapes which resemble Protozoa, and especially coccidia. But the finding of all these organisms does not warrant the conclusion that true cancer is really a parasitic affection. So far as the presence of parasites has been definitely demonstrated, it has always been in growths which cannot be called genuine cancers; and, further- more, the spherical, oval, spindle-shaped, and sickle- shaped hyahne and granular bodies which have been described as occurring in cancer may be otherwise interpreted. They are partly products of retrograde meta- morphosis, such as cornification, colloid degeneration, and fatty degen- eration of the epithehum ; partly products resulting from the reception of leucocytes into the epithelial cells, followed by a degeneration and dis- integration of the leucocytes ; partly products of a nuclear division which is pathological, atypical, or in one way or another distorted; and partly products of an altered cell-division or of the inclusion of one cancer-cell in another. EPITHELIAL TUMORS. — CYSTOMATA. 371 (d) Epithelial Cystomata. — Cystadenoma and Cystocardnoma. § 135. The tumors which may be grouped together under the name epithelial cystomata have this in common : they all contain cysts which are visible to the naked eye. It is advisable to separate the cystomata from the simple cysts, which result from the retention of secretion in preexisting tubes or cavities lined with epithelium. The distinguishing characteristic, and the one which determines the diagnosis, is the fact that in cystoma there is an actual new formation of tissue; and, further, it is a fact to which attention should be called that the differences which are observed in this new formation of tissue afford sufficient grounds for dividing cystomata into different forms. The number of cavities in a cystoma varies greatly, and from this starting-point we may make a division into one-chanibered or unilocular cystomata, and many-cliamhered or multilocular cystomata. Sometimes the number of chambers is so great that it would be well-nigh impossible to count them (cf. Figs. 259 to 271). Epithelial cystomata occur most frequently in the ovaries, mamm^, testicles, hver, and kidneys — rarely in the sldn. Multilocular cystomata of the ovary very often form extensive tumors, which weigh from ten to twenty kilogrammes or more, and which are composed of cysts of different sizes (Fig. 259). Usually the Fig. 259. — Cystoma of the ovary — partly of the simple variety, partly of a papillary character, a, Smooth-waUed cysts; 6, Papillary growth which has broken through a cyst-wall. (It is soft and covered with the ordinary cyhndrical epithelium of mucous membranes.) There were metastatic nodules in the peri- toneum. (Eeduced by about one third.) 372 EPITHELIAL TUMORS.— CYSTOMATA. arrangement of the parts is sucli that numerous httle cysts lie close be- side a few larger ones (Fig. 259) ; the httle ones sometimes projecting outward from the walls of the larger cysts, sometimes forming more com- plicated combinations among themselves. In rare cases the whole tumor is made up of small cysts, so that the section presents a honeycombed appearance (Fig. 260). Usually the tumors possess portions where the tissue resembles fine sponge, and other portions where it is more hke marrow, both of these portions being lo- cated here and there between the cystic masses; but the amount of such tissue may be slight. The walls of the cysts now under con- sideration are smooth and ghstening, sometimes more like a smooth, stretched mucous membrane, sometimes more like a serous membrane. The cysts contain a fluid which is either clear or clouded by white flakes and granules, or colored red or brown by blood or blood-pigment. Sometimes this fluid is tenacious and plainly mucoid in character; at other times it is more serous, like the fluid of a transudation. According to Pfannen- stiel, the mucoid character of the cyst- contents is due to the presence of pseu- domucin (cf. § 65). Fig. 260. — Section of a part of a multiloc- ular cystoma of the ovary. (Reduced about one sixth.) A second variety of ovarian cystoma which also is of rather common occurrence, and which may greatly resemble in external appearance the form already described, is to be distinguished from it by the presence, in Fig. 261. — Portion of a papUlary cystoma of the ovary, seen in section. (Drawn from a specimen hardened in chromic acid. Four-fifths life size.) EPITHELIAL TXMORS. — CYSTOIVL^TA. 373 some or all of its cysts, of papillary groivths (Fig. 261), which sometimes are very small and sometimes are enormously developed, and which, under certain circumstances, may lill up most of the lumen of the cyst, or may even break through and appear upon the outer surface of the tumor (Fig. 259,.&). In order to separate the two forms, the name simple cystoma may be given to the first, and papillary cys= toma to the second. Many authors call the latter cystoma proliferum. The cystomata which occur in the testicle are usually of the smooth- waUed multUoeular variety (Fig. 262), whose cysts reach only a moderate size. Cystomata in the liver occur usu- ally in the form of single cysts or of small groups of cysts scattered here and there throughout the hver-sub- stance (Fig. 263, d) ; but the cysts which develop may also attain a considerable size (c) ; it is also possible for the liver- tissue to be replaced throughout large areas by a tissue made up wholly of cysts (Fig. 263, e, c). Fig. 262. — Section through an adenocystoma of the testicle of a four-year-old boy. (Life size.) Ipf^il^ Fig. 263. — Multilocular cystoma of the liver, seen in section, a, Parenchyma of the liver ; 6, Membranous 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; /, Portal vein; g, Hepatic artery. (Two-thirds life size.) 22 374 EPITHELIAL TUMORS. — CYSTOMATA. -'■'^"■W& Fig. 264. — Cystoma of the kidney, in section. (Eleven-fourteenths life size.) Cystomata of the kidney are usually large tumors made up of cysts which vary from a pea to a walnut or even a hen's egg in size (Fig. 264), and between which at most only a trace of kidney-tissue can be demon- strated. However, cases are also seen in which the cysts are all small, so that the surface of a section of the kidney presents a porous appearance Fig. 265. — Transverse section of one-half of a congenital cystic kidney, with small cysts (from a new-bom child). The kidney measured 12.5 cm. in length, 9 cm. in breadth, and 5 cm. in thickness. The cortex presented throughout a spongy appearance, with small cavities. In the medullary portion, on the other hand, there were very few cysts. (Life size.) EPITHELIAL TUMORS. — CYSTOIHATA. 375 (Fig. 265) ; and yet one can still recognize, in such a section, the general anatomical features of the organ. The cystic tumors which appear in the breast have a general resem- blance to those which occur in the ovaries, but they differ in two respects : the cysts belonging to the former are usually smaller, and the interven- ing tissues are more strongly developed. Moreover, that form of cystic tumor which is associated with the formation of papillary excrescences occurs far more frequently in this locality, and the accompanying prohf- eration of the connective tissue of the breast often lends a peculiar aspect to the new growth, in consequence of which many of these cystic tumors of the breast are apt to be classified, according to the character of the tissue, as cystosarcomafa, cystofibromata, and cystomyxomata. However, there are also cases in which the breast is the seat of a papillary cystoma (Pig. 265), whose structure follows exactly that of the ovarian cystomata ; and consequently these tumors must be separated from the connective- tissue group and reckoned among the epithelial tumors. Fig. 266. — Papillary cystoma of the breast, a, Stroma ; 6, Smooth- walled, cysts j c, Cysts studded on the inside with papillary growths ; d, Cysts completely filled with papillary growths ; e, Small encysted papillary growths ; /, Adenom- atous growths ; g, Nipple of the breast. (Eeduced in size by about one third.) In rare cases papUlary cystomata appear in the skin in the form of "well-defined nodules, which vary in size from that of a walnut to that of an apple. The interior of the cysts is closely filled with papillary excres cences, and these may also at times break through so as to appear on the outside of the cyst. These tumors probably develop from atheromata of the skin or of the subcutaneous tissue — i.e., from sebaceous cysts, which are formed by the dilatation of epithelial canals in the skin, such as the ducts of hair-follicles or sebaceous glands, or pathological inversions of the epithelium {Epitlieleinstulpungen) in the corium or subcutaneous tis- sue. Furthermore, papillary cystadenomata i:iay also have their origin in the remains of branchial fissures. 376 EPITHELIAL TUMORS. — CYSTOMATA. § 136. The development of a cystoma proceeds from the preexisting glandular tissue, so far, at least, as one may judge from the anatomical investigation of suitable specimens. Cystomata which develop out of a depot of retained secretion, and in which the proliferative process estab- lishes itself only at a later date, are of the single-chambered variety, whether the cyst-cavity be smooth- walled or studded with papiUse ; for, under certain circumstances, the development of papiUee takes place only after the cyst has existed for a long time. The multUocular smooth- walled and papUlary cystomata generally spring from patho- logical glandular new gi'owths (Pig. 267) — i.e., from adeno- mata, — and they may therefore be appropriately termed adeno- cystomata. The alteration of the ducts of the glands into Fig. 267.— Section of a papillary cystadenoma of the ovary. (Prep- aration hardened in MiiUer's fluid, stained with hsematoxylin, and mounted in Canada balsam. Mag- nified 40 diameters.) cysts is a result of retention, and the secretion so retained varies accord- ing to the nature of the cystoma. The development of adenoeystomata of the ovary takes place either in malformed or in normal ovaries, and is characterized by the formation of tubular glands (Fig. 267) which closely resemble the embryonic tubular glands of the ovai-y. It is not impossible that remains of these foetal glands form the starting-point for the new growth, but this has not yet been proved. In favor of the existence of a local congenital predisposi- tion to such a growth may be mentioned the fact that ovarian cystomata often appear on both sides. The smooth cysts are lined with simple cy- Hndrical epithelium, the cells of which are of varying height and often present appearances of mucous degeneration. Cystoma-formation in the Mdneys, so far as it affects the whole kidney, is usually referable to some disturbance in development, and accordingly most of the cases observed are in the new-born or in very young childreu. The predecessors of the cysts are, in the first place, atypicaUy formed tubules (Nauwerck, Hufschmid, von Kahlden), in which papillary excres- cences may often be observed. Furthermore, a more or less decided pro- liferation of connective tissue can l)e made out in the vicinitj'' of these tubiiles (von Kahlden). Besides the tubules, Mueller's capsules may also, through the influence of retained secretion, undergo dilatation into cysts ; and iinder these circumstances we may take it for granted that urine con- stitutes the chief, if not the sole, contents of the cysts. As cystomata of the kidney may also develop in later life, it is probable that atypical tubules may develop in kidneys which are not in any manner malformed, and they may later, through the medium of retained secretion, become transformed into cysts. Pathological proliferation of the walls of the gaU-ducts furnishes a EPITHELIAL TUMORS. — CYSTOMATA. 377 basis for the development of cysts in the liver; and, as a result of thii? proliferation, at different points numerous gland-tubules appear in the periportal connective tissue. The fully developed cysts are lined with q, simple epithelium. The histological examination furnishes no grounds for the belief that these tumors originate in some congenital malforma- tion. The nearest suggestion of such an origin lies in the coincident appearance of cystomata of the hver and kidney. Gystomata of the. testicle usually develop from gland-tubules which are hned with cylindrical (less often squamous) epithelium, and whose struc- tiu-e is materially different from that of the normal tubules of the testicle. It is probable that the adenomatous growth usually occurs in pathologi- cally developed testicles ; and as pointing to this conclusion, the following facts may be mentioned : first, that these growths occur at an early age ; second, that other pathological tissues — as, for example, cartilage — are found quite frequently in the adenomata and adenocystomata of the tes- ticle (cf. § 137) ; and third, that the character of the epithelium varies (Fig. 272). The development of a multilocular cystoma begins in the breast with an atypical growth of new gland-tissue, which presents the characteristics of tubular glands. The epitheUal lining of the tubules is composed of a sim- ple cylindrical epithelium, whose height varies in different cases. The connective tissue may be only very sUghtly developed, so that the neo- plasm presents the appearance of a pure adenoma ; but it is just here in the breast that the growth of glandular tissue is often accompanied by a marked growth of fibrous tissue, which gives to the tumor the character- istics of an adenofibroma (cf. Fig. 196). The development of papillary excrescences, which may occur either in simple or in multilocular cystomata, and which have been classified by some authorities as a special group of papillary cystomata, begins either immediately upon the formation of new glands, or else takes place only after the cysts have become fully developed. In the latter event simple retention cysts may form the basis from which the papillary growths spring. If papillary excrescences develop in an adenoma whose glands pre- sent no cystic dilatations, an adenoma papilliferum. wiU be formed (cf. Fig. 241). The development of cysts leads to the formation of a cystoma papilliferum. The papilla3 which are found in ovarian cysts are usually slender single-stalked or branched structures (Fig. 268, a), and are made up of a connective tissue very rich in nuclei. In some cases the papillse are very thick and plump. They are usually covered with a tall cylindrical epithelium (Fig. 268, c), whose cells have the form of mucus-generating goblet-cells, and produce a secretion which can be drawn out like tough mucus, and which contains many cast-off epithelial cells (d) that have undergone mucous degeneration. Other cystomata have cubical epithe- lium, and stiU others ciliated epithelium. Finally, in some papillary ovarian cystadenomata the epithelial lining of the cysts consists of strati- fied cylindrical epithelium (Fig. 269). In these cases, which are not alto- gether rare, the new growth of epithelium decidedly preponderates. Fre- quently, as a result of this, the cysts become filled with a marrow-like growth, which gives to the neoplasm, even under naked-eye inspection, a peculiar medullary or encephaloid appearance. As long as ovarian cystomata have a. simple epithelial lining they are 378 EPITHELIAL TUMORS. — CYSTOMATA. benign tumors ; but when they begin to develop papillae somewhat vigor- ously they may already be looked upon as possessing a certain degree of local malignancy, inasmuch as at this stage the papillae may break through on the surface (Fig. 259, 6), and may even, under certain circumstances, r J** — ~ - f C -^ -^ -r \I V _- J. ^- .d f > " ' -T' ^r^ *^ *" *^ FiG. 268. — Papillary cystoma of the ovary, a, Stroma with papiUse ; 6, Gland- tube with small papiUse ; c, TaU cyhndrical epithelium which lines the cyst-cavities and covers the papillae ; d, Mucus filled with cells, in the interior of the cysts. (Preparation hardened in Muller's fluid, stained with hsematoxyUn and eosin, and mounted in Canada balsam. Magnified 150 diameters.) spread over the peritoneum. When the development of epithelium becomes more pronounced, the malignancy in turn increases, and this change is shown in two ways: the growth invades to a greater and greater degree the broad ligaments, permeating the tissues like an infiltration, and causing cauliflower growths to appear upon them ; and, in the second place, it gives rise to metastases in the peritoneum or elsewhere. According to its be- havior the tumor must be classed as a malignant papillary cystadenoma or as a papillary cystocarcinoma. It is a remarkable circumstance that the metastases sometimes show in their structure the characteristics of an ordinary carcinoma. Papillary cystomata may manifest in the breast the same behavior which they do in the ovary ; but in the former region the cystomata with slender branching papilla are on the whole rare. The epithelial lining in these forms of tumor is iisually strongly developed, and consists of sev- eral layers of a stratified epithelium, which gives a medidlary appearance to the contents of the cysts (Fig. 266, c, d, e). This abundant growth of the epithelium indicates in this case, also, the degree of malignancy of EPITHELIAL TUMORS. — CYSTOMATA. 379 Pig. 269. — Section from a papillary adenocystoma of the ovary, a, Stroma ; 6, Epithelium; c, d, Papillse. (Preparation hardened in Miiller's fluid and alco- hol, staiaed with hsematoxyUn, and mounted in Canada balsam. Magnified 80 diameters.) Fig. 270. — Intracanalicular fibroma of the breast (cystoma papilliferum). a. Dense fibrous tissue lying between the canals ; 6, Pericanalicular tissue, rich in cells ; c, d, e, Nodular intracanalicular growths, cut longitudinally ; /, Intra- canalicular growths, cut transversely. (Preparation hardened in alcohol, stained with alum carmine, and mounted in Canada balsam. Magnified 25 diameters.) 380 EPITHELIAL TU5I0RS. — CYSTOMATA. the tumor, — a malignancy which finds its expression in the formation of cancerous metastases, so that the tumor merits the name of malignant papillary cystadenoma or papillary cystocarcinoma. If, in an adenoma of the breast, the pericanalicular connective tissue develops with especial activity (see the pericanahcular fibroma repre- sented in Fig. 196), it often happens that this connective tissue forces its way somewhat abruptly into the lumen of the gland-tubules in the form of thick prominences (Pig. 270, c, d, e), and in this waj'^ forms a peculiar kind of papillary cystoma, in which the mass of the papillse which grow into the glands and into the cystic dilatations of the glands is so great that it seems just to describe the tumor as an intracanalicular papillary fibroma or as &p)apillary cystofibroma. The intracanalicular papillary fibromata appear usually in the form of small nodular tumors whose individual nodes are made up of a group of glands modified, in the manner described above, by a new growth of connective tissue. The growth has usually definite limits, but in certain Fig. 271. — Papillary cystoma or intraoanalicular papillary fibroma of tlie breast, laid open by a longitudinal incision. (One-half life size.) cases it takes on a more vigorous development, and in that event wide cystic cavities are developed which become filled with nodular and poly- poid or compressed leaf-like fibrous excrescences (Fig. 271). Such cysts are for the most part quite numerous, but there are cases in which the entire growth is composed of only a few cysts, or even of only one cyst. If polypoid and papillomatous excrescences in a cyst press hard against EPITHELIAL TUMORS. — TEBATOMATA. 381 the cyst- wall they may break through it, and may even perforate the over- lying skin and appear on the outer surface of the body. The polypoid growths of the cystomata just described often show an abundance of cells in the new growth of connective tissue, or they may present portions where the tissue appears to be myxomatous in character ; and on this account the tumors have been classified among the sarcomata or among the myxomata, as the case may be, and the names pcqnUart/ cystosarcoma and cystomyxoma have been given to them. The leaf-like structure which these tumors exhibit on section, by rea- son of the compression of the polypoid excrescences which grow within the cysts, has led to the application of the term sarcoma jjliyllodes. 3. Teratomatu mid their Relations to Monogermiiud and Bigerminal Im- plantations and to BenHiins of Fwtal tStrtictures. § 137. The term teratoma or teratoid tumor is applied to a peculiar sort of new growth, which usually presents a complicated structiu-e, and Fig. 272. — Congenital adenocystoma of the testicle, with formation of pig- ment and cartilage. (Section from Fig. 262.) a, Connective-tissue stroma; b, Simple cubical epithelium ; c. Stratified cylindrical epithelium ; d, Stratified ciU- ated cylindrical epithehum; e, Pigmented epithelium hning a gland- tubule; /, Pigmented connective-tissue cells ; g, Focus of cartilage in connective tissue ; h, Focus of cartilage in a gland-tubule. (Preparation hardened in Miiller's fluid, stained with haematoxyhn, and mounted in Canada balsam. Magnified 100 diameters.) 382 EPITHELiIAL TUMORS. — TERATOMATA. consists, at least in part, of tissues which do not normally occur at the site where the tumor is found. As already mentioned, tumors containing cartilage frequently occur in the parotid and testicle, and similar tumors have been observed in other organs which normally contain no cartilage — e.g., in the breast and thyroid gland. Rhabdomyomata are found oftenest in the kidney, tes- ticle, and uterus, and these organs have normally no striated muscle. Osteomata are sometimes found in intermuscular connective tissue and in the mucous membrane of the air-passages, at a distance from any part of the skeleton. The testicle is sometimes the seat of cystomata whose gland-tubules and cysts (Fig. 272) are lined with simple cubical (6) or cy- lindrical epithelium, in some parts stratified (c), in other parts provided with cilia (d), and in very rare cases also pigmented (e). These tumors may also contain foci of cartilage, which are usually found lying in the connective tissue (g), but maj^ also, under certain circumstances, be found in the cystic cavities (/?-). Finally, the connective tissue also may contain pigment (/). The cysts which are found in the neck also contain not infrequently cartilaginous foci in their walls, and sometimes also lymphadenoid tissue. In the sacral region congenital tumors are found which contain gland- tubules, as well as various sorts of connective-tissue formations. These and many other similar appearances are very striking, and jus- Fig. 273. — Portion of the wall of an ovarian dermoid cyst, a, Wall of the cyst ; 6, Projecting portion made up of fatty and cutaneous tissues; c, Hairs ■ d, Teeth. (Life size.) ^ .r ; > ' EPITHELIAL TUMORS. — TEKAT01VLA.TA. 383 tify US in giving such growths a special place among the tumors, and in classing them with the formations known as teratomata. But there are stiU. other formations to which the term apphes even more strongly, since in these are found not only different kinds of tissues, but even more or less complete organs, such as skin, hairs, nerves, muscles, bones, glands, rudimentary portions of intestine, etc. Such structures are found oftenest in tumors which are known as dermoid tumors (Fig. 273) — that is, cystic tumors whose limiting mem- brane repeats more or less perfectly the structure of the skin, so that under stratified epidermis a corium with its papiUte is found, and often also, underlying this, a layer of subcutaneous adipose tissue. In many cases the membrane contains structures which are the special attributes of the skin, such as sweat and sebaceous glands and hair-f olHcles ; and here and there locks of long blond hair are seen (Fig. 273, c). The cyst contains usually a fatty, unctuous material, the product of the epider- moid hning of the cyst, and in it fat, cast-off epithelial scales, and hairs are foimd. Sometimes teeth (Fig. 273, d) are found here and there in the wall of the cyst. The specimens found are occasionally perfectly typical forms of teeth, and the base upon which they rest may be either connective tis- sue, bone, or cartilage. Other sorts of tissue-formations, such as nerves, muscles, and intestine, are very rarely found. Dermoid cysts are oftenest found in the ovary, more rarely in the testicle, in the peritoneum, in the region of the base of the brain, in the neck, in the orbit, etc. Sometimes they are encountered in the shape of very small cysts not larger than a pea ; but usually they are of consider- able size — as large as the fist, or even, in some cases, as large as a man's head. In the ovary they are often associated with the formation of a cystoma. These gi-owths plainly grow very slowly, and may be carried about for years and even for decades. When sufficiently large they may set up enough proliferative activity in the neighboring tissues to cause adhesions to take place between the tumor and neighboring organs. Closely related to the dermoid cysts are the hairy polyps which are found in the mouth and pharynx, and which may inclose in their connec- tive-tissue framework all sorts of tissue-formations. Of a similar nature, also, are the cystic formations which appear in the skin or under the skin in different portions of the body, but especially in the neck and in the median line of the back, and which are lined with stratified squamous epithelimn [dermatocysts). These contain no hairs, but in the neck they are often combined with pathological new formations of cartilage. Other growths which should also be reckoned among the teratomata are cysts with cylindrical epithelium, at times ciliated, which have been observed in the subcutaneous tissue, especially in the neck and the fore- head, as well as within certain organs, and especially in the tissues of the peritoneum, in the subperitoneal tissue, and in the mediastinum. Teratomata of a complicated structure — that is, those formations which with the dermoid cysts make up the real teratomata, in the nar- rower sense of the term — are most often found in the sacnd region; but they hkewise occur in other parts of the body, as, for instance, in the neck, in the face, and also in internal organs. They may be made up of the most diverse tissues : connective tissue, fat, cartilage, bone, muscle, peripheral nerves, central nerve-substance, cysts lined with epithelium, and tubular glands. Sometimes rudimentary or fairly well-developed 384 EPITHELIAL TUMORS. — TERATOMATA. organs, extremities, portions of backbone, intestine, nerves, portions of the central nervous system, etc., are also found in these formations. § 138. The formations described in § 137 can be explained only on the supposition that at the time of development germinal fragments have been misplaced, or else that remains of foetal formations have persisted. The latter is the correct explanation for many cysts of the neck, and for those which occur in the peritoneal and subperitoneal regions, the testi- cle, and the mediastiniim, where remains of the branchial clefts or of the foetal urogenital apparatus have heen preserved. The best explanation to give of all those formations which contain cysts or sohd masses of tis- sue in places where such structures existed at no time of the develop- ment, is to consider them in the light of a transposition of tissues. It is an open question whether we have to do, in such cases, with autochtho- nous or with heterochthonous implantations — i.e., with monogerminal or with bigerminal implantations. If a teratoma be found to contain very diverse tissue-formations which at least in part may be identified as representing rudiments of Organs or perhaps even fully developed organs, which, however, are superfluous for the individual in whom they are found, we may consider such a tumor as a heterochthonous teratoma or as a bigerminal implantation — i.e., as a rudimentary twin which is more or less completely enveloped by the well-developed twin (cf. Double Monsters, § 157). On the other hand, if the teratoma contains only diverse tissues and cysts whose production does not necessarily imply the existence of a second individual, the tumor is to be looked upon as an autochthonous teratoma or as a monoger- minal implantation. The origin of a particular formation of tissue may be inferred from its structure, as a given tissue can be derived only from the same or a closely related tissue. Cartilage and bone indicate the presence of con- stituent portions of the skeleton, or more particularly of the respiratory apparatus. Striated muscular fibres can come only from the germs of the muscular system, and in the same manner nerve-tissues come only from some part of the peripheral or central nervous system. If gland- formations are present in whose structure we can recognize certain par- ticular glands, we are sure of their origin, since they must have been de- rived from those glands. The cysts, which so often represent teratoid formations, or form parts of teratoid tumors, may originate from various sources; and by means partly of the nature of the epithelium and partly of the site of the growth it is possible to determine their exact source of origin. Cysts which are lined with stratified squamous epithelium, and whose waUs present the same characteristics as the skin, must be regarded as derniatocysts, which spring from the ectoderm. Cysts with cylindrical and with ciliated epithelium, according to the site which they occupy, may have come from rudimentary gland-structures or from the medul- laiy canal ; and hence they may be divided into adenonjsts and wijeloci/sts. In the abdominal cavity cysts may arise from portions of the intestine which have become isolated through constriction, and similarly rudiments of the intestine which have developed from bigerminal implantations may change into cysts. These are called eiifproc>/sts. The pathological de- velopment of tymph-vessels in a cyst may lead to the formation of lymph- cysts lined with endothelium. Excessive dilatation of blood-vessels leads to the formation of Uood-eysts or luemntocysfs. EPITHELIAL TUMORS. — TEEATOMATA. 385 The transposition of the germs of tissues in most cases can be in- ■ ferred only from the structure of the resulting growth, while the mech- anism of the original process cannot, as a rule, be made out. iL_L.ii_-'T And yet there are also eases in which the changes are demon- strable. So, for example, in the cases where a hernia of the spinal cord in the sacral region retui-ns to its proper place (von EeckUnghausen), adipose {Fig. 274, i) and muscular tissues (Fig. 274, Jc) may find their way into the spinal canal and into the arachnoid space, and grow around the nerves. Arnold saw a transposition of adipose, cartilaginous, glandular, and glial tissues at the lower end of the trunk of the body, in a case of myeloeyst with com- plete defect of the lumbar, sacral, and coccygeal portions of the spinal column. If a tissue is transplanted it may remain unchanged, or gradually be destroyed in its Pig. 274. — Spina bifida occulta, with myolipoma inside the vertebral canal. (Sagittal section about 1 cm. to the left of the median line. Eeduced about one half. Copied from von Recklinghausen.) a, Abnormally haiiy skin; b, Fibrous covering which forms the posterior waU of the sacral canal, with a sht-like open- ing at c; d, Spinal cord; e, Conus medullaris, lying in the second sacral verte- bra (2) instead of in the second lumbar vertebra ; /, Cauda equina ; g, Dura mater; h, hi, Eecurrent left anterior nerve-roots of the third and fourth lumbar nerves ; i, Fat ; Ic, Muscular tissue ; IV, Fourth, and V, fifth lumbar vertebrae ; 1-4, Sacral vertebrse. abnormal situation and its place be taken by other tissue. Or from this ircmsplanted tissue, bi/ further growth, a heterotopic tuDwr may develop. According to the observation of various authors (Arnold, Balin, Lesage, Legrand, Bird, von Bergmann, Maas, Ziegler, and others), it cannot be doubted that lipomata, fibromata, dermoid cysts, and hairy polyps may arise within the cavities of the skull and vertebral column, as a result of the retrogression of clefts and hernias in these parts. Accessory suprarenal capsules, whether lying within the kidneys or elsewhere — e.g., in the broad ligaments (Marchand) — may not onlj^ per- sist, but may form the starting-point for various tumor-formations. In the same way tumors may develop in supernumerary ( abgesprengteii) thyi'oid or mammary glands. A cancerous growth has often been observed to start in branchiogenic cysts ; and from isolated portions of the rudimen- tary epithelial dental membrane not only dental cysts but malignant tumors (cancers) may arise. SECTION yiii. Disturbances of Development and the Resulting Malformations. I. General Considerations in regard to Disturbances of Development and the Origin of Malformations. § 139. 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 character- istics which the embryo has received by transfer of inheritable paternal or maternal characteristics which were in the ascendant at the moment of the union of the sexual elem,ents, which are to be regarded as the car- riers of inherited characteristics. It follows that not only the character- istics proper to the species, but also the special peculiarities of the individ- ual, 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 without an influence from the environment, in that the embryo of necessity receives nourishment and warmth from the maternal organism, and is exposed to mechanical influences on the part of its envelopes and the uteiTis. 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 imrticular type, which experience has shown recvu'S 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 is 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 oiiginates from a single indi- 386 MALF0R5IATI0NS. — INTERNAL AND EXTERNAL CAUSES. 387 vidual, while a, double malformation or a double monster is one whicli is made tip from two individuals. 2Ialforniations may arise in two ways : from internal causes and from ex- ternal causes. 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- 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 (ef. § 32). It is also possible that disturb- ances 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, bat did occiu- in remoter ancestors, whUe 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 (polydactylism), pigment spots of the skin, abnormal hairiness, harelip, and certain patho- logical conditions of the nervous system, as, for example, fibromata of the peripheral nerves. Under external causes of malformations the first to be considered are jarrinfjs,2)ressHre, and disturbances in the siqjply of oxygen and nourishment. 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 fcEtus and to extru- sion of the egg than to the development of a malformation. Infectious diseases 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 where the amniotic fluid is in small qtiantity. Deformities of the extremities — as, for example, club-foot, flat-foot, and club-hand — not rarely show signs of pressure having been exerted (Fig. 278). Prom 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. The amnion is formed at the time when the embryo sinks into the yolk which is then lying under it, and arises from the extra-embryonic portion of the somatopleure, which forms folds anteriorly, posteriorly, and laterally, and surrounds the em- bryo. Prom the coalescence of these folds over the dorsum of the embryo the latter comes to be in a cavity, whose envelope, the amnion, is con- 388 MALF0R1LA.TI0NS. — ^INTERNAL AND EXTERNAL CAUSES. Fig. 275. — Malformation of the head, due to adhesions of the membranes to the frontal region (close adhesions of the placenta to the uterus), a, Cutaneous sac inclosing a vascular, spongy tissue containing abundant cysts ; 6, Eye ; c, Distorted lip ; d, Funnel-shaped depression lined with mucous membrane ; e, Eight, ft, left ala nasi; /, Fibrous bands. (Reduced to three-fourths natm'al size.) nected with the embryo at the umbilicus. The amniotic sac contains at first but little fluid, whicli later increases in amount. A disturbance of embryonic development may arise from abnormal adhesions between the embryo and the amnion, and also from, jiressnre of the amnion npon the embryo, this pressure being due to insufficient dilatation of the amniotic cavity. Adhesions are not rarely demonstrable even at the birth of the child, Fig. 276.— Malformation of the face, caused by amniotic adhesions and pressure (asymmetry of the face), a, Misshapen nose; h, h, Rudimentary openings between the eyelids ; c, Ci, Clefts in the upper hp and alveolar process of the upper jaw; d, Intermaxillary bone with prominent lip; e, Oblique facial fissure, closed so as to make a fur- row by scar-tissues. MALFORMATIONS. — INTERNAL AND EXTERNAL CAUSES. 389 being found as connecting bands and threads (Figs. 275, /, and 276) ; and their relations to the malformed portions leave no doubt that they stand in causal relation to the malformation. Such adhesions may cause grave malformations of the cranial (Pig. 275) or of the facial (Fig. 276) portions of the skull. Not infrequently portions of extremities are snared off by amniotic threads (Fig. 277). How far these attachments of the amnion to the foetus are to be re- ferred to primary adhesion and union, and how far to inflammatory pro- cesses appearing later, is still the subject of controversy. If a portion of an extremity — for example, a finger — is caught in a loop of such a uniting band, and then the band put on the stretch, by accumulation of the amniotic fluid, the portion included in the loop will be snared (Fig. 277) and eventually amputated. At an early embryonic period ampu- tated portions may be absorbed. What gi'oss deformities may appear on the head as a result of amni- otic adhesions is shown in Figs. 275 and 276, and from these cases it may readily be inferred what the effect of adhesions on other parts of the head maybe. It is not rare at birth to find adhesions no longer apparent, and only a scar-like appearance to mark the affected spot (Fig. 276). According to Dareste and Geoffroy-St. Hilaire, an abnormal snugness of the amnion exerts also a damaging influence on the embryo. So it is also claimed that abnormal tightness of the cephalic cap of the amnion is capable of causing the malformations known as anencephalia and ex- encephalia (§ 145), cyclopia (§ 146), and cebocephalia or arrhinencephaHa Fig. 278. Fig. 277. — A hand stunted by amniotic adhesions ; ring-finger snared off f middle and index fingers grown together and distorted. (Reduced one sixth.) Fig. 278. — A hand stunted and misshapen by pressure ; thumb wanting ; hand fiattened : great bending and shortening of the forearm. (Reduced one fifth.) 390 TYPICAL AND ATYPICAL MALFORMATIONS. (§ 146) ; while abnormal tightness of the caudal cap leads to stunted de- velopment of the lower extremities (§ 150). Marchand refers also phoco- melia to pressure exerted at an early period. Finally, clefts which occur in the anterior abdominal and thoracic walls (§ 148) 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, wluch may follow from a variety of causes, but is doubtless often to be classed with the spontaneous or primary malformations. The period at which the damaging influences exert themselves natu- rally varies much, and so, also, does the extent of the damage. The earlier the damage occurs the more extensive it generally is. Malformations in the ]nore restricted sense arise mostly in the first three 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 ap- pearance are more nearly allied to those acquired after hirtU. Some malformations are typical — that is to say, they always reappear in the same form ; while others, again, are entirely atypical, so that often the most astonishing anomalies of form arise. The latter are mostly the result of harmful influences operating secondarily from without, while the former may be regarded as chiefly due to internal causes. External influences, however, may also cause typical deformities. The damaging influences which afEect the normally constituted embryo in the process of development play in the etiology of malformations a more prominent rdle than inheritance or primary germ- variation. This comes about from the general use of the term malformation in the sense only of gross anatomical depar- tures, such as arise through external, causes ; while the pathological pecuharities which pass by inheritance from the parents to the child, and the primary germ- variations, manifest themselves much less by changes in the outward form than by deficient or perverted function of the tissues or predisposition to diseases, etc. — departures whose anatomical basis can be found only by painstaking study, or is wholly insusceptible of anatomical demonstration. 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 f agrees with him in general, although he admits the possibility of a primary abnormality. In hens' eggs he produced malformations by temperature variations of the incubator, and also by varnishing the shells. Dareste t made similar experiments, 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. Gerlaeh, Fol, Warynsky, Eichter, Roux, and Sohultze have experimented in this direction, and have sought, with some success, to produce malformations in hen embryos by locahzed influence of radiant heat, variations of temperature, varnishing 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 destruction of one of the divisions formed by the primitive streak, the other continued its development 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 replaced 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. ^ " Hist. gen. et partic. des anomalies de I'organisation chez I'homme et les animaux," Paris, 1832-37. t " Untersuch. iiber die Entstehung der Missbildungen," Berhn, 1860. t " Recherches sur la production artiflcielle des monstruosites," Paris, 1877. SINGLE AND DOUBLE MONSTERS. 391 Scliultze experimented on tlie eggs of amphibia. Tliey normally assume a position in which the darkly pigmented protoplasm of lighter speeifle gravity lies above, and the heavier clear protoplasm, rich in yolk granules, lies below. Malformations may be produced by placing the eggs in an abnormal posi- tion and preventing their resuming the normal position; and the degree of malformation stands in direct relation to the size of the angle which the attrac- tion of gravity makes with the abnormally placed axis of the egg. By turning the egg through an angle of 180° in the two-ceU stage a double monster is regu- larly produced. By the same, turning in the eight-cell stage, development is completely stopped. All this shows that gravity is another influence capable of causing disturbances of development, and that these disturbances arise from displacements consequent upon a sinking of the heavier and a rising of the Kghter constituents of the egg. 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 minimum of development without perishing at an early period, unless maintained as a sort of parasite upon another foetus developing at the same time (cf. § 157). § 140. Single malformations maj^ conveniently be divided, accordini^ to the sort of departm-e which characterizes them, into five groups. As arrests of development, or monsters due to defective develop- ment, are classed aU those malformations in which the whole or a part of the body is abnormaDy 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 smaUness of the brain; defects in the septa of the heart; absence and dwarfing of the ex- tremities, etc. Where parts of the body or organs are normally formed by the union of distinct centres of develojjment, 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 development 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 pro- cesses of the fii-st branchial arch to unite or to form a union with the in- termaxillary process gives rise to clefts in the facial portion of the head. If the lateral halves of the earlj^ spinal cord fail to unite, a duplex cord results. 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 kidneys are more or less united, and the eyes may be more or less completely merged into a single organ. Such mergings of organs arise in two ways : from secondary union 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 ahnormal size of in- dividual parts, sometimes by multiplication of their number. An extremity 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 392 SINGLE AND DOUBLE MONSTERS. growth). These are examples of increase in size of members. A multipli- cation of the number of parts occurs notably in the glands of the breast the spleen, the suprarenal capsules, and the fingers. The supernumerary organs or members are mostly smaller than the normal ones. Malformations occm*, also, through an abnormal disposition of parts {monstra per fdbricam alienam). Under this head are included certain anomahes of the thoracic and abdominal organs which are characterized by abnormal positions of the organs, and also in part by the changes in relations between individual parts. In this class belongs the transposi- tion 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 the instances of transposition of the vascular trunks should be reckoned under arrests of development. A fourth group of malformations is caused by the presence of tis- sues in unusual situations and the persistence of foetal structures, as already spoken of in §§ 137 and 138. Finally, a fifth group includes malformations exhibiting a mixture of the sexual characteristics, 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 to the female. A part of these malformations are arrests of development ; others are to be regarded as cases where from the original bisexual em- bryonic formation the organs of both sexes have attained developmeint, whereas normally the structures characteristic of one sex, instead of de- veloping, dwindle away and persist only in a very rudimentary form. § 141. Double monsters [monstra duplicia) are instances of a duplica- tion 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. According to the older theories, double monsters arose from a grow- ing together of two embryos in the uterus (Meckel, Gurlt, Geoffroy-St. Hilaire). It was indeed supposed that where there were two separate and distinct eggs the membranes might disappear at the point of contact and then the two foetuses blend. This view is now abandoned. All double monsters come from a single egg, and develop from a single germinal vesicle. According to Kolliker, the first evidence of embryonic development appears as a white, circular, opaque spot, the embryonic area. The ecto- derm of the bUaminar blastodermic vesicle becomes thickened by enlarge- ment of the cells, and forms this embryonic area. Later, the embryonic area takes on a pyriform shape. Its posterior and sharper extremity be- comes rounded and thickened and drawn out into a wedge-shaped appen- dage. This is the earliest trace of the primitive streak, and consists of a thickening of the ectoderm at the same place where the mesoblast is also found, and spreads itself out between ectoderm and entoderm over the SINGLE AND DOUBLE MONSTERS. 393 whole of the embryonic area. After the primitive streak has been present for a time in the embryonic area, the medullary groove forms in front of it. At the same time the embryonic area becomes differentiated into a paraxial portion about the medullary groove and an outer lateral por- tion. The various parts of the body are formed by the progressive de- velopment of these two portions. 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 gi-eater or less extent. A second possibility is the formation within a single embryonic area of two primitive streaks and two medul- lary grooves, which either remain separate or partially merge one into another. A third case would be where 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 struc- tures 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 suppose a duplication of parts of the blastodermic vesicle or of the embryonic area. The only question is how far it may be possible for a doubling 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 merg- ing can take place at an early stage. This question cannot be definitely settled at present. There is, however, every likelihood that embryonic areas in process of formation may merge one into another. About the causes of duphcation of the embryonic elements in the blastodermic vesicle we have thus far no knowledge. According to Fol, double and multiple monsters arise from anomalous impregnation of the ovum by two, three, or more spermatozoa ; but other observations (Born) tend to show that ova impregnated by two or more spermatozoa do not develop at aU. The views of the authors as to the formation of double monsters vary greatly. Some (Forster, Virchow, Oellacher, Ahlfeld, and Gerlach) advocate the theory of a division. Others (Sohultze, Panum) hold that more or less com- pletely divided elements reunite. According to Rauber, two or more primitive streaks arise in one embryonic area, and later come ia contact at some point and merge more or less one into the other. This is called the theory of radiation. Marehand holds that generally two embryonic germs are formed, and that they blend together. The duphcation, according to him, is referable to conditions existing before the beginning of the medullary groove — that is, to conditions of the ovum itself, or of its impregnation, by which there are preformed two distinct centres for the formation of medullary grooves. Born has noted that those fish eggs which develop into double formations produce a normal and single first furrow, exactly hke those from which a smgle embryo springs. Probably the second furrow runs as it does in the ordinary eggs. As in the ordinary egg the first furrow divides the germinal material into a right and a left, or an anterior and a posterior half (Eoux), it follows that 33 394 SPECIAL MALFORMATIONS IN MAN. in tliose eggs destined to develop into double formations the first division must liave another significance. Probably a full haM of the qualities of the mother-' germ pass in congruent arrangement into each of the halves, and the division into right and left, or anterior and posterior, does not take place until the second divi- sion occurs. In most of the double monsters among the fishes, more or less of the posterior portion of the body is single ; which gives color to the theory that between the two plans in accordance with which the first divisioH can take place, there must be something like an intermediate plan, in accordance with which one part of the nuclear material subdivides in a congruent manner, while the other subdivides differently. Eggs which show a primary threefold or a quadruple division — in which prob- ably an excessive impregnation has taken place — perish. In recent years successful experiments have been made in the production of double monsters from the eggs of animals. They were conducted by Gerlaoh, O. Schultze, and Born. Gerlaeh produced double monsters (anterior duphca- tion) from hens' eggs by varnishing them before incubating, and leaving only a V-shaped spot in the region of the primitive streak free. Schultze produced double monsters by tirrning frogs' eggs through an angle of 180° (cf. § 139). Born succeeded in uniting together portions of the larvse of amphibia, not only of the same kind, but also of different species and families (rana esculenta with bombinato rigneus and with triton). From aU 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 Man. 1. Arrests of Development in a Single Individual. (a) Arrest in the Development of all the Embryonic Elements. § 142. Arrest in the development of all the embryonic elements mani- fests itself in two ways. If the disturbance is very marked, further de- velopment 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. When a foetus dies it remains unchanged only for a short time; sooner or later it undergoes various changes. In the majority of eases it is expelled from the uterus along with its membranes (abortion). In the earliest periods of development the embryo may disappear by absorp- tion. The fate of the membranes in this case varies. Usually they are expelled; in some cases they remain and undergo various 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 foetus. The chorionic viUi may degenerate in a peculiar manner, then gi-ow and produce club-shaped and globular, bladder-like, translucent structures (Fig. 279), which give the egg the appearance of a bunch of grapes, and furnish a wan-ant for the name by which it is known — grape-cluster mole. The Uttle sacs have a diameter of from two to twelve or more millimetres, and hang from slender stems, which are attached to other sacs or directly to the chorion. Their tissue consists of myxomatous tis- GRAPE-CLUSTER MOLE. 395 sue with few cells and fibres, which are separated by greater or less quantities of mucilaginous fluid. The death of a foetus in an advanced stage of development results, provided it be not expelled, in the formation of a lithopaedion. This occurs most frequently in cases of extra-uterine preg- nancy, where the foetus oc- cupies an abnormal site, as in the peritoneal cavity, in a Fallopian tube, or in an ovary. If a f cetus so placed dies at such an advanced state of development that it cannot be absorbed, it may be carried in the ma ternal organism for years. Not infrequently its form is perfectly retained (Pig. 2S0), and the whole foetus becomes enshrouded in an envelope of connective tis- sue. In other cases the foe- tus, in the course of time, becomes converted into a partially fluid mass, which contains the osseous re- mains, as well as fat, cho- lesterin, 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 ele- ments that remain. AU of these forms are included in the term lithopaedion, but they are subdi\'ided under three heads (Kiichenmeister). The f cetus may be mum- mified, but easily shelled out from calcified membranes [lithocelyplios). Or the foetus, while yet alive, may become adherent at a number of points with the membranes, and later these points become calcified, while the remaining parts undergo mummification [Utlweeh/pJiopced ion). Or, again, the membranes may ruptm-e and the foetus be discharged free into the peritoneal cavity, and later become incrusted with hme-salts (UthopcedioH in the narrower sense). A second form of general arrest of development shows itself in dwarf= growth — that is, a general diminution in the size of the body [microsomia or nanosomia). Sometimes the proportion between individual parts is not maintained, and the head especially is sometimes disproportionately large. Fig. 279. — Portion of a mole, presenting the form of a bunch of grapes. (Natural size.) 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 defor- mities 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. 396 DEFICIENT DEVELOPMENT. — RACHISCHISIS. ^-"^Z -j-y^^.^.-jji. Fig. 280. — Foetus 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 end of a Fallo- pian tube into abdominal cavity. (Reduced one third.) (6) Deficient Closure of the Cerebrospinal Canal and the Accompanying Malforma- tions of the Nervous System. § 143. The spinal column originates from bilateral halves, and it is only by the union of these that the spinal canal is formed. If for any reason this union fails to take place, there arises the condition known as rachischisis. Where closure of the canal fails throughout its entire length the con- dition is called rachischisis totalis or holorachischisis (Fig. 281). The ver- tebrae form a shallow furrow posteriorly, covered in the main only by a thin, transparent membrane, though rarely rudiments of the spiaal cord may show as whitish bands and lines. The delicate envelope which lies in the furrow and covers the dura mater lining the bones, is the ventral portion of the pia mater spinaUs. In the lateral portions there may usually be seen in the pia whitish bands which represent the ligamentum denticulatum. More or less extensive rudiments of the nerve -roots may have formed ; in which case they will be seen lying beneath the pia and dura mater. They are in general less DEFICIENT DEVELOPMENT. — RACHISCHISIS. 397 Fig. 281. — Cranioracliiselusis, with total absence of the brain and spinal cord. The skull is covered by irregular skin-like masses, the spinal furrow with a deheate envelope (pia mater). Under this envelope, in the lowest portion of the spinal furrow, a few whitish lines are to be seen. Kypholordotic bending and shortening of the spinal column. (Eeduced one sixth.) well marked in proportion to the smoothness and thinness of the pia mater and the paucity of spinal cord rudiments. Of the arachnoid there are usually present only scattered threads and bits of membrane spread out between the pia and the dura mater. A partial rachischisis [mero- vacMschisis) is far more fre- quent than the total variety, and affects mostly the sacro- lumbar or less often the upper cervical portion of the spine. The intervening portion is sel- dom affected. The dorsal sur- FiG. 282. — Rachischisis par- tiahs. (After von Recklinghau- sen.) a, Outer skin with hairs; 6, Spinal cord, laid bare by dissec- tion; c, Area nieduUo-vasculosa; d, Cranial, di, caudal polar fur- row; e, Zona epithelo-serosa ; /, Zona dermatica with hairs; g. Space between dura mater and pia; h, Anterior, hi, posterior nerve-roots ; i, Ligamentum den- ticulatiun. 398 DEFICIENT DEVELOPMENT. — RACHISCHISIS. face of the vertebral bodies whose arches have remained rudimentaiy is mostly covered by a mass of velvety red tissue (Pig. 282, c) (von ReckUng- hauseu) closed in by a delicate integument; though the amount of this tissue may be ^^ery small, or may even be wanting. External to this tissue- mass, which is not everywhere equally abundant, and which decreases at the sides, com es usually a delicate, transparent, vascular skin (Fig. 282, e) ; next, a zone of skin with an epidermis, but somewhat thinner than the normal skin, and often bearing abundant hairs (Pig. 282, /) ; then, finally, comes the normal skin. According to von ReckUnghausen, the soft red tissue-mass (c) lying in the median line is the rudiment of the malformed spinal cord, and is an extremely vascular tissue, containing often more or less abundant parts of the spinal cord, as nerve-fibres, ganglion-cells, and glia-cells, and is therefore appropriately called a rea medullo-vasculosa (von Recklinghausen ) . The area medullo-vascidosa 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 (Polgruhe — von Recklinghausen) (d, ch). VentraUy this is next to the spinal cord (b) ; in lumbosacral rachischisis caudally it is con- nected 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 prominent zone border- ing this and covering the rudiments of the posterior 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 {g), bounded on its deeper side by the dura mater and the external layer of the arachnoid ; so that this space is in reaUty the ventral portion of the subarachnoid space, and, as is normal with this space, is crossed by the ligameutum denticulatum (i) and the nerve-roots (h, hi), which, in the region of the area medullo-vasculosa, lose themselves in the pia-like tissue. The origin of racMschisix is ascribed by authors to various causes : accumulation of fluid within the vertebral canal ; pressure from without and infolding of embryonic membranes : and faulty separation between the neural canal and the epidermal layer of the skin. According to von Recklinghausen, the fault lies in agenesia or hypoplasia of the dorsal ridges from which the vertebral arches are to be formed, and the malformation of the spinal cord is also to be referred to the earliest embryonic period, being due to under-development of the blastoderm. The defects of skin, muscles, and fascite are attributed to the same cause. In the earliest embryonic period the medullary groove is formed by the throwing up on either side of the median line of wall-like eminences. The neural canal is formed by a converging growth of these and their uniting posteriorly. These masses of cells lying by the side of the canal develop into an envelope which surrounds the neural canal and forms at first a membranous and not articulated vertebral column. In this arise, in the beginning of the second month, discrete cartilages, from which in the further course of develop- ment the vertebral bodies and arches are formed, while between them are devel- oped the intervertebral disks and ligaments. The cartilaginous vertebrae are not complete until some time in the fourth month, and until this time the dorsal eovering_ of the neural canal is formed by the membranous vertebral column. The cartilaginous vertebrse are replaced by bone in the course of development. DEFICIENT DEVELOPMENT. — RACHISCHISIS. 399 The spinal cord and the brain are formed from the medullary tube. The portion that is to form the brain changes at an early period into three vesicles. The anterior of these, the forebrain, develops laterally the eye-vesicles. The middle portion grows forward and upward, dividing into the first secondary vesicle and the second secondary vesicle. From the first secondary vesicle arise the cerebral hemispheres, the corpora striata, the corpus caUosum, and the for- nix. From the second secondary vesicle arise the optic thalami and the floor of the third ventricle. The middle primary vesicle, or midbrain, forms the corpora quadrigemina, while the third dififerentiates into a fourth and a fifth secondary vesicle, from which are developed respectively the pons and cerebellum, and the medulla oblongata. The cerebral portion of the neural canal is inclosed in the prevertebral plates of the head. These make the primordial membranous skull, whose basal portions become cartUage in the second month of foetal life. In the third month the absal cartilages and also the membranous vault begin to ossify. § 144. If fluid accumulates in the suharaclinoid space in a case of par- tial rachischisis, provided the pia mater is intact and does not allow of its escape, this membrane is made to protrude posteriorly in the form of a globular tumor, known as a myelomeningocele (Fig. 284). Frequently Fig. 283. — Spina bifida sacralis. (After Froriep and Forster.) Girl of nine- teen 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. these cases are included under the head of spina bifida, a characteriza- tion in general use for all those cases in which a hernia-like tumor pro- jects through a defect in the vertebral canal (Fig. 283). In harmony with its mode of formation, the myelomenin- gocele may be capped by an area meduUo- vasculosa (Fig. 284, c) ; but this may be Fig. 284.— Myelomeningocele sacralis in sagittal section, a Httle to the left of the me- dian line. (After von Eecklinghausen.) a, Skin ; 6, Spinal cord ; hi, Column of the cord ; c. Area medullo-vasculosa ; d, Cranial, di, caudal polar groove ; e, Piainater; f, Arach- noid, somewhat separated from the pia ma- ter; /i, 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 lumbar nerve, running free in the arachnoid sac ; k, Sacral nerve-roots between the arachnoid and pia; I, Filum terminale. entirely wanting, or reduced to little scattered patches of vascular tissue. The skin of the neighborhood extends from the sides more or less ex- 400 DEFICIENT DEVELOPMENT. — RACHISCHISIS. tensively on to the walls of the tumor. The dm-a mater is never present on the dorsal portion of the tumor. By the elevation of the deformed region the spinal cord (5) is pulled outward posteriorly (ii). The nerve- roots pass in part through the cavity of the sac {i, ii), in part they are attached to its wall, and run there between the pia and the arachnoid. Occasionally, also, a nerve (h) may spring from the column of the cord as it courses through the sac. In virtue of the fact that the sac is formed by an accumulation of fluid in the subarachnoid space, it is called a hydromeningocele or a hydroracMs externa circumscripta ; but inasmuch as the spinal cord is pressed outward and protrudes, the condition is also spoken of as a myelocele, and it is cus- tomary to designate the whole condition as a myelomeningocele. If there be a deficiency of the bony wall of the vertebral column at some point, and the dura mater be there abnormally yielding, a localized accumulation of fluid in the subarachnoid space causes a more or less ex- tensive hernial bulging into the neighboring soft parts, which, when it attains sufficient dimensions, appears in the form of a sac. If the spinal cord takes no part in the tumor it is called a meningocele. Like the myelomeningocele, it is most commonly found in the sacral region, where defects of the spinal canal, in the form of holes and clefts in the verte- bral arches, or even in the bodies of the vertebrae, occur most frequently. For example, it is not rare for the hiatus sacralis to extend up to the third sacral vertebra, owing to a broad cleft in the arch of the fourth sacral vertebra. Usually the sac of a meningocele protrudes posteriorly {meningocele pos- terior), and may either be concealed in the soft parts (spina Nfida occulta) or raise the skin above the surface ; but instances also occur where the cysts press forward into the pelvis {meningocele anterior). With a defect in the wall of the vertebral canal a hernial protrusion of the pia mater may also be produced by a dilatation of the central canal of the spinal cord, causing a larger or smaller portion of the spinal cord, together with its membranes, to assume the form of a cystic tumor, called a myelocystocele, a hydromyelocele, or also (in England) a syringomye- locele. According to von Recklinghausen, the wall of these sacs is formed, in the main, of the spinal membranes, but is lined on the inner sxu-face by a cylindrical epitheUum, and has at some part of its inner surface an area meduUo-vasculosa — 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 majority 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 iodies of the verteirm, lead- ing often to shortening of the trnnl;; sometimes affecting only the dorsal region, and sometimes including also the lumbar region. There is often, also, ecstropliy 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 furthermore be combined with meningoceles, producing myelocystomeningoceles. Von Recklinghausen holds that, in the production of the various forms of hernial protrusion of the pia mater from the vertebral canal, the primary disturbances are always the local defect in the bony verte- DEFICIENT DEVELOPMENT. — RACHISCHISIS. 401 bral canal and the deficient development of the dura mater, which latter is often entirely wanting at the seat of protrusion. TariLfQ believes that in some cases the cause of the spina bifida lies in a vascular hyperplasia of the primitive cord. The cysts push up from some distance below the surface, and, if they attain sufBcient size, raise the skin. In rare cases their top may reach the surface. Smaller ones remain buried in muscle and fat beneath the fascia of the back {spina bifida occulta, cryptomero- rachischisis). As to the origin of myelocystoceles and myeloeystomenin- goceles, one cannot, according to von Recklinghausen, ascribe as a cause either the persistence of the connection between the neural canal and the epiblast, or an interposition of foetal membranes between the primi- tive cord and the epiblast, or an excessive stretching of the meduUary groove-wall through bending of the axis of the embryo. According to him, the myelocystocele is a deficient growth in the long axis of the ver- tebral column, characterized anatomically by shortness of the column, by failing of vertebrae or portions of vertebree, by separation of bony wedges from the bodies of the vertebrae, and by unilateral defects in the arches. The medullary tiibe then, pursuing its normal development, becomes too long for the vertebral canal, and consequently undergoes 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 in- fluences may give rise to one or more of these anomalies. Where the protrusion shall take place depends on where the wall of the spinal canal is yielding — i.e., where clefts exist. It can take place posteriorly, laterally, or anteriorly. Most frequently the protrusion lies posteriorly and at one side of the median line. At the summit of the sac one membrane, which may be looked upon as the dura, is always want- ing. The growth of myelocystic and meningocystic sacs is to be attrib- uted to congestive and inflammatory transudation. Occasionally marks of inflammatory change are found, consisting in thickenings of the pia and adherent membranes and threads in the interior of the sac. In cases of rachischisis there is not infrequently, according to von Keeklinghausen, a division of the spinal cord into two parts {diastema- tomyelia), usually where the rachischisis is total — that is, where generally only rudiments of spinal cord ai-e indicated. "Where there is partial ra- chischisis such rudiments 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 where each cord-half shows an H-shaped area of gray matter. The duplications of the cord in spina bifida and rachischisis are to be regarded not as true douhle formations with duplication of the cord-substance ; they represent only a divergence, a faiilty union of the elementary symmetrical cord-halves. In rare cases there is duplication of the central canal without external division of the cord (Wagner, Schiippel, Pick). The human vertebral column is (Wiedersheim) an organ in process of retro- gression, and the pelvic girdle is proportionately thrown into prominence. This is evidenced by the fact that embryos of 9-10 mm. in length have thirty-eight vertebrae, while in the adult man there are only thirty-three or thirty-four. When the embryo is six weeks old the thirty-sixth to the thirty-eighth vertebra 402 DEFICIENT DEVELOPMENT. — CRANIOSCHISIS. coalesce into a single mass, in whicli the thirty-flfth also joins later. According to Eosenberg, the first sacral vertebra unites with the sacrum later than the second, and the second later than the third. As development becomes higher therefore, the pelvis becomes more prominent anteriorly and sacral vertebrte disappear. The number of the latter varies between four and five. A decrease in the number of lumbar and dorsal vertebraB is not rare, and coalescence between them, as also partial defects of vertebras, occur. (On increase of the number of vertebrse and formation of a tail, see § 153.) § 145. The cleft-formations and hernial sac-formations which have been described in § 144 all occur in corresponding forms, also, in the cephalic portion of the neural canal, and lead to a series of malforma- tions, some of which persist in post-embryonic life. In the most exaggerated forms the bony portions and the skin of the cranial vault are wanting (Figs. 281 and 285), and the surface of the base of the skull is covered only by a tegumentary layer of vascular, spongy tissue, usually containing scattered haemorrhages, and beneath which there may be rudiments of brain-substance. Modifying the term used in ra- chischisis to suit the condition as found here, we may call this tissue the area ceretro-vasculosa. Fig. 285. Fig. 286. Fig. 285. — Anencephalia et acrania. (Reduced one half.) Fig. 286. — Cranioschisis with encepha- lomeningocele. The cleft-formation may be confined to the cranial vault, but frequently it includes vertebral arches as well (Fig. 281), and extends to a greater or less distance down the back. The deficiency in the cranial vault is called acrania and cranioschisis, and when combined with a vertebral cleft it is called craniorachischisis. In this latter condition the vertebral column is usually stunted and bent so that the head is drawn sharply backward and the face turned upward (Fig. 281). In these malformations the stimted development of the forehead, and the great prominence of the eye resulting therefrom, give the appearance of a frog's head {frog foetus). The abnormalities in the individual bones of the cranium are by no means always the same ; and between cases where the cranial vault and DEFICIENT DEVELOPMENT. — CBANIOSCHISIS. 403 walls are entirely wanting and cases of microcephalus, where the vault is properly closed, but the cranium abnormally small, there are the most various intermediate gradations (Figs. 285 and 287). Similarly the brain- substance present varies in amount and in the extent to which it has reached development into recognizable portions of brain. If there is no microscopically recognizable portion of brain-substance present the case is called one of total anencephalia ; where the deficiency is only partial it is called partial anencephalia. If the ^ rudiment of brain is '-l^— -=^ f small, and confined to '' ^2^-"= - the posterior portions which are inclosed in the cervical vertebrte, it is also called de= rencephalia. Fig. 287.— Partial agenesia of the bones o£ the cranium in anence- phalia. a, Defect; 6, Occipital portion of skull; c, Parietal bone; (i, Frontal bone. (Re- duced one flfth.) The tegument covering the base of the skull is often only a mass of spongy tissue of slight or moderate thickness. But sometimes sacs (Fig. 275, ft, and Fig. 285) protrude from the opening between the rudimentary parietal and the occiput or the frontal bone (Fig. 287, a, &, p, d), consisting of a vascular connective tissue containing cystic cavities and occasionally also rudiments of brain-substance. Sacs which contain only meninges with cysts are called meningoceles ; those containing also brain-substance are called enceplialomeningoceles (cf. § 146). Geoffroy-St. Hilaire, Forster, and Panum regard acrania and anen- cephalia as due to an abnormal accumulation of fluid in the cerebral vesi- cles — a hydrocephalus — occurring before the fourth f CEtal month. Dareste and Perls oppose this view, drawing attention to the circumstance that in acrania the base of the skull is mostly arched inward and not pressed outward, and seek for the cause of this condition in a pressure acting on the skull from without (Perls) and exerted by the cephalic cap of the amnion, lying snugly against the cephalic bend and liindering the development of the cranium. LebedefE looks for the cause of acrania in an abnormally sharp curvature of the body of the embryo, occurring where the cephaUc end of the embryo has elongated abnormally, or the cephalic envelope has lagged behind in development. Through the sharp curvature the change of the meduUary plate into the neural canal is supposed to be prevented, or the already formed canal to be destroyed again. This would explain the absence, later, of the brain, together with its membranous and bony coverings. Lebedeff sup- poses the cystic formations which are found lying on the base of the skull to result from folds of the medullary plate which become sunk in the mesoderm and then snared off. It is very likely that acrania is not always due to a single cause ; and whUe in one case the influences brought forward by Perls and Lebedeff, 404 DEFICIENT DEVELOPMENT. — CRAKIOSCHISIS. or adhesions to the membranes (Fig. 275), may have checked the devel- opment of cranium and brain, yet in other instances the malformation must probably be ascribed to a primary agenesia ah-eady determined in the germ. § 146. Where the cranium is in general properly closed, but presents partial 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 cephaloceie (Fig. 288). Defects of ossification (Ackermann), 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. 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 ap- proach the brain in volume. Where accumulation of fluid in the sub- arachnoid space has caused only the arachnoid and pia to protrude, the tumor is a meningocele ; where brain-substance also protrudes, it is a meningo=encephalocele. A protrusion of brain-substance and pia with- out accumulation of fluid is called an encephalocele ; if the protruding brain-substance contains part of a ventricle fiUed with fluid it is called a hydrencephalocele. These brain-hernias appear mostly in the occipital region {hernia occip- italis) close above the foramen magnum (Fig. 288), at the root of the nose, and at the lower end of the frontal suture {hernia syncipitalis) ; but they occur also in the region of the temple, at the base of the skull, in the orbital fissure, and elsewhere. Marked stunting in the development of the anterior of the three cere- bral vesicles may leave the cerebrum single (St. Hilaire's cyclencephalia ov cyclocephalia), while at the same time a deficient separation of the ocular vesicles takes place. Where the stunting is very marked, only a single eye may be formed in the middle of the forehead, or there may be two rig. 288. Fig. 289. Fig. 288.— Hydrence- phalocele occipitalis. Fig. 289. — Synophth- almia or cyclopia. united together and lying in a single orbit (Fig. 289) ; and this malfor- mation is called cyclopia or synophthalmia, andarrhinencephalia (Kun- drat). The nose is also stunted, and present only as a cutaneous tag at- tached above the eye and devoid of honj foundation {ethmocephalia). Where the eyes are separate, yet abnormally close together, the nose in general may be normal, but at the root it is very small {cebocephalia). MALFORMATIONS OP THE FACE AND NECK. 405 In the severer forms of the malformation the ethmoid and the nasal septum may be wanting, and the upper lip and palate cleft in the median line, or laterally on one or on both sides (Kundrat). In the milder forms the forehead is merely reduced in size and pointed like a wedge. Fifi. 290. — Cranial cavity of a synophthalmiis microstomus opened by a frontal section (viewed from behind), a, Skin and subcutaneous tissue ; 6, Cra- nial vault; c, Dura mater; c7, Ten- torium; e, Arachnoid; /, Poste- rior surface of the cerebrum, consisting merely of a thin-walled sac covered with pia mater; g, Tumifled border of the cerebral sac; h, Subarachnoid space be- hind the cerebral sac ; i, Cavity of the cerebral sac, communicat- ing with the subarachnoid space by the enlarged transverse fis- sure ; k, Section through the cor- pora quadrigemina ; I, Section through the cerebellum; m, The atlas. (Four-fifths -natural size.) In the severest grades of these malformations the cerebrum consists of a sac (Fig. 290, )') occupying more or less of the cranial cavity and fiUed with a clear fluid ; where the sac does not lie against the cranial waU the intervening space is taiien up by fluid distending the subarachnoid space [h). In milder instances only individual portions of the brain are want- ing in development, those mostly afl'ected being the olfactory nerve and olfaetory bulb, the corpus caUosum, a part of the convolutions, etc. The optic thalami are often blended together. The chiasma and optic tracts may be either wanting or present. The corpora quadrigemina (Jc), the pons, the medulla oblongata, and the cerebellum (Z) are usually unaffected. (c) Malformations of the Face and Neck. § 147. The development of the face is subject not infrequently to dis- turbances leading to more or less marked malformations, which may ap- pear alone or be combined with malformations of the cranial portion of the head. Where 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 malfor- mations 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=paIatoschisis). This mal- formation establishes a communication between the mouth and the nasal cavity (Fig. 291). The hard palate, where it abuts against the vomer, is 406 MALFORMATIONS OF THE FACE AND NECK. cleft in the median line where it meets the soft palate. In the alveolar pro- cess 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 (Fig. 291) or unilateral, primary and hereditary or sec- ondarily acquired, one of the causes of the latter condition being amni- otic adhesions (Fig. 276). Frequently the cleft involves only Special portions of the region above mentioned, as the upper lip {harelip, labium leporinuni), or, what is rarer, only the hard or only the soft palate. The mildest degree is indicated by a 7iotc]i or a cicatricial line in the Up, or by a hifurcation of the uvula. Pig. 291. Fig. 292. Fig. 291.— Double clieilo- gnatho-palatoschisis. Fig. 292.— AgnatMa synotia (Guardan). and Prosoposchisis (Fig. 276, e) is the term applied to a cleft running obliquely from the mouth to an orbit. It is usually associated with mal- formations of the brain. Morian distinguishes three varieties. The first commences on the upper lip as a harelip, passes into the nostril, thence around the ala nasi toward the orbit, and may extend even beyond the orbit. The second variety begins hkewise in the region of a harelip, but extends outward from the nose toward the orbit. The third variety ex- tends from the corner of the mouth outward through the cheek toward the canthus of the eye, and divides the superior maxillary process exter- nally to the canine tooth. A fraiisoerse cleft of the cheek also occurs, cours- ing from the corner of the mouth toward the temporal region. Median facial clefts also occur, and may involve the nose and upper jaw, and also the lower jaw, or even extend as far down as the sternum. 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. Where the inferior maxiUary 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. 292), and the appearance presented is as if the lower half of the face had been cut away ; the ears MALFORMATIONS OP THE FACE AND NECK. 407 are sometimes so close to each other as to touch {synotia). Usually the superior maxillary processes are also imperfectly developed, and fre- quently the ear is misshapen. Malformations of the mouth, as abnormally large size Imacrostomia), abnormally small size {microstotnia), closure [atresia oris), and duplication [distomia), are all rare. Where the embryonic external branchial clefts or internal branchial pockets fail in part to close, flstulffi opening either externally or inter- nally, or closed cysts, remain. The former condition is called fistula colli congenita. The mouths of the external fistulge are generally found at the side of the neck, more rarely approaching, or actually in, the median line; those offjthe internal fistulas open into the pharynx, trachea, or larynx. Frequently slight remains of the branchial pockets form merely diverticula of the latter organs. The flstulse are mostly clothed with a mucous epithelium, sometimes cUiated, originating, therefore, from the visceral branchial pockets — according to von Kostaneoki and von Mielecki, mostly from the second. In rare cases a complete branchial fistula is found, having both an external and an internal opening. The branchial cysts which arise from the branchial pockets are some- times clothed with mucous membrane (ciliated epithelium), are filled with fluid, and receive the name of hydrocele colli congenita ; sometimes they are hned with an epidermal covering, contain masses of epidermal cells, and are therefore reckoned among the atlieromata and dermoid 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. 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 ven- trally in the primitive throat-waU. The single rudiment, called the frontal process, is a prolongation downward 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-hke depressions or branchial pockets. The frontal process and the first branchial arch form the borders of the great primitive mouth, which has a diamond shape. In the course of development the first branchial arch sends out two processes, of wliich the shorter appUes 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, produces 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 processes, pro- duces the borders of the nostril and the nasal furrow. The lateral nasal processes are the lateral portions of the skull, and develop within themselves later the ethmoid labyrinth, the cartilaginous roof, and the sides of the anterior por- tion of the nares. At a certain stage they form with the superior maxillary process a fissure running from the nasal furrow to the eye, and called the lach- rymal 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 development, 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 ante- riorly and progresses backward. 408 FAULTY CLOSURE OP THE ABDOMINAL AND THORACIC CAVITIES. 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. {d) Faulty Closure of the Abdominal and Thoracic Cavities, and the Accompanying Malformations. § 148. The construction of tlie body-form from the flat embryonic lay- ers 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 tiibes, one of which is the abdominal wall, the other the alimentary caual (Hertwig). 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 abdominal wall produce a tube whose interior finally communicates only at the parietal umbilicus, by means of a tubular prolongation, 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 intes- tinal furrow closes to form a tube which is in com- munication at only one point — namely, at the vis- ceral umbilicus (within the above-mentioned com- munication of the abdom- inal cavity) — with the cavity of the umbilical vesicle, the channel be- tween the two being called the omphalomesenteric duct. The omphalomesen- teric duct becomes oblit- erated in the sixth week. The complete closure of the abdominal cavity fol- lows in the eightk week. Arrests of develop- ment 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 re- gion of the umbilicus, where the closure is latest. Where faulty develop- ment of the abdominal wall at this point — leav- FiG. 293. — Hernia funiculi umbilicalis. thirds normal size.) (Two- FAULTY CLOSURE OF THE ABDOMINAL AND THOEACIG CAVITIES. 409 ing the abdominal cavity closed over a gi-eater or less area onlj^ by peri- toneum and the covering of the umbilical cord (the amnion) — gives lise to hernial protrusion over this area (Pig. 293), 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. The anterior abdominal walls may entirely or almost fail to unite — conditions called lissura abdominalis, gastroschisis completa, and thoracogastroschisis, and characterized by the undeveloped abdominal coverings not having been separated from the amnion, but running into it. The greater bulk of the abdominal contents then lie in a sac com- posed of peritoneum and amnion ; or the peritoneum may be wanting also. The iimbilical cord is also often wanting, and the umbUical vessels run to the placenta without joining one another. 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. Where 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. Where the urinary bladder prolapses through a cleft in the abdominal wall, the condition is known as ectopia vesicae urinariae. Clefts of the abdominal wall, whether total or partial, are not infre- quently complicated by clefts of the parts lying behind the abdominal wall. Where 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, the condition is called fissura or ecstrophia or inversio vesicjE urinariae (Fig. 294, c). Sometimes the pelvic girdle and the lu'ethra are also cleft, converting the latter into an exposed trough (Fig. 294, e). The eesti'ophy is then said to be compli- cated with fissura genitalis and epispadias. Where an abdominal fissure, or an abdominal fissure together with ecstrophy of the bladder, is complicated with fissiu'C of the intestine, the condition is called fissura abdominalis intestinalis or vesico=intestinalis. The intestinal fissure is situated in the ctecum or in the beginning of the colon, and the mucous membrane of the intestine protrudes in the same manner as the posterior wall of the bladder ; and hence it is called ecstro- phia 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 gener- ally the appearance of a glove-finger, and either ends blindly or is at- tached at the umbilicus, sometimes being dilated at the ends. It may be adherent in the umbilical ring and its mucous surface may protrude [ectopia infcsiini, adenoma umWicale). In very rare cases a cyst lined with mucous membrane is found in the abdominal wall (a remnant of the omphalomesenteric duct). Umbilical hernia and clefts in the upper part of the abdominal wall are often combined with craniorachischisis, while ccsti'Ophy 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. 24 410 MALFORMATIONS OF THE EXTERNAL GENITALIA. \..d&^ Fig. 294. — Fissura abdominis et vesicae iirinariae, in a girl eighteen days old. a, Border of the skin ; 6, Peritoneum ; c, Bladder ; d, Small bladder-cavity com , posed of the trigone ; e, Trough-like \irethra ; /, The labia minora. (e) Malformations of the External Genitalia and of Parts belonging to the Anal Region, caused iy Arrested Development. § 149. Malformations of the external genital organs maj' be associated 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 Fig. 295. Fig. 296. Fig. 295. — Hypospadias, associated with a stunted penis. (Eeduced one fourth.) Fig. 296.— Epispadias. (After Ahlfeld.) MALFOBJIATIONS OF THE EXTERNAL GENITALIA. 411 region, and, as a rule, is associated with defects in the internal genital organs (Pig. 297). A rare condition is a duplication of the penis or of the penile urethra, one canal giving passage to the urine, while the other communicates with the sexual organs. A dwarfed condition of the penis, resembling the cUtoris, is more common. It is usually associated with hypospadias, the urethral opening being beneath the glans, the body or the root of the penis (Fig. 295), or, in extreme cases, behind the scrotum (hypospadias perineoscrotalis). The same degrees of hypospadias may exist in penises otherwise normal, being due simply to a more or less complete covering of the sexual furrow from which the urethra normally develops. Epispadias (Pig. 296) is the term applied to the condition in which the urethra opens upon the dorsal aspect of the penis. It is less common than hypospadias, and results from an incomplete or retarded closing of the pelvic cavity, of such a character that the cloaca is divided into an anal and a genital portion (Thiersch). Sometimes the two penile halves may remain separate, with or without ecstrophy of the bladder or an in- complete closure of the abdominal cavity. The prepuce is siibject to the following anomalies : it may rarely be entirely absent, or, more frequently, abnormally short ; often it is hypertrophied, and this hypertrophy may be associated with a stenosis of the orifiee, so that it cannot be retracted (hypertrophic phimosis). Deficient development of the scrotum is usually associated with re- tention of the testis in the abdominal cavity or in the inguinal canal, and causes the external genitals to look like those of the female — a result which is heightened when the penis is small or ill developed. In the female the clitoris and the labia majora and minora may be deficiently developed ; epispadias and hypospadias may also occur, the former associated with ecstrophy and, perhaps, incomplete closure of the ab- domen (Fig. 294). In hypospadias the urethra opens into the vagina. The urethra may be absent in either sex (Pig. 297). In young females the bladder may open directly into the vagina. Urethral atresia can also occur in either sex, and results from a local de- fective development or an obhteration of the orifice. An acciimulation of urine may, in these cases, cause extreme dila- tation of the bladder (Pig. 297). Fig. 297. — Complete absence of the tirethra and external genitals, with extreme distention of the abdomen by an accumu- lation of urine in the bladder; and com- pression and dwarfing of the lower extrem- ities. (In the posterior wall of the bladder there were rudiments of tubes and ovaries.) An abnormal narrowness of the urethra may exist in a portion of its course or throughout its whole extent. Its lumen maj'' be compro- mised by a hypertrophy of the colliculus seminalis. 412 SIALFORMATIONS OF THE EXTREMITIES. Occasionally the urethra opens by multiple orifices, and sometimes there is a blind canal in the glans penis, lying beside the normal urethra. An allantoic cloaca, due to arrested development, may persist at birth and form a common outlet for the bladder and intestine. Frequently the bladder is divided, the rectum not existing, and then the ileum' opens directly into the cloaca. In less anomalous cases there is merely a failiu-e in the separation of the intestinal outlet from the urogenital sinus — i.e., from the genital and m-inary orifices. Since the external depression which forms the anus is wanting in these cases, they are designated as atresia ani, and, according to the association of the intestine with the neighboring structures, they are classed as atresia ani vesicalis, nrethralis, or vaginalis. When the rectum communicates neither with the urogenital sinus nor with the cutaneous anal depression, the condition is called atresia simplex. In such cases the rectum is often imperfectly developed. (/) Malformations of the Extremities due to Arrest of Development. § 150. The extremities appear first as thickenings of the cutaneous plates of the embrj'o, which after elongation become divided off into the component divisions of the extremities by shallow furrows. Defective development of the extremities is 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. Aiiieliis. The extremities are either aU entirely wanting or are rep- resented by mere stumps or wart-like rudiments (Fig. 298). 2. Peromelns. All the extremities are dwarfed. 3. PJwcomehis. The hands and feet are developed, but are attached directly to the shoulder and pelvis respectively. 4. Micromelus (microbrachius, micropus). The extremities are fully differentiated, but remain abnormally small (Fig. 299). 5. Ahrnclmis and a pus. Absence of the upper extremities with well- developed lower extremities, or vice versa. 6. PerobracMus and pteropus. 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. 8. tSj/nipus, sirenoriielia, symmyelia. The lower extremities are coales- cent in a position of semi-rotation around their axes, so that their ex- ternal aspects are in contact (Figs. 300 and 301). The pelvis is usually absent, as are also the external genitals, bladder, urethra, and anus. The feet may be entirely wanting {stjmpus apiis) and only a few toes be pres- ent (Fig. 300), or in other cases (Fig. 301) a single foot (synipus monopus) or both feet {sympus dipiis) may be present. 9. Of the single bones, the radius, fibula, patella, clavicle, and scapula are those most frequently absent. 10. Acliirus and jjerochirus. The absence or dwarfing of the whole JIALPOKMATIONS OP THE EXTREMITIES. 413 Fig. 298.— Amelus. Fig. 299.— Micromelus with cretinitic faeies. Fig. 300.— Sympus apus. Fig. 301.— Sympus dipus. 414 MALFORMATIONS OP THE EXTREMITIES. hands and feet is rare. More frequently individual fingers or toes are wanting or stunted [perodactylus), or coalesce with others (syndactylus) (Fig. 302, Fig. 303, c. Figs. 304 and 805. Cf. also § 139, Figs. 277 and 278, page 389). Fig. 302. Fig. 304. Fig. 305. Fig. 302. — Malformation of the right hand (peroehirus) "with coalescence of the fingers. (After Otto.) a, Supernumerary thumb; 6, Thumb proper; c, Dwarfed index-finger ; d, Middle finger; e, Ring-finger ; /, Little finger. Fig. 303. — Bones of the peroehirus depicted in Fig. 302, shown in their dor- sal aspect. (After Otto.) a-f, Same as in Fig. 302; g, Ulna; h, Radius; 1, Os naviculare ; 2, Os lunatum ; 3, Os triangulare ; 4, Os pisiforme ; 5% Os multan- gulum majus superfluum ; 5', Os multangulum ordinarium ; 6, Os multangulum minus ; 7, Os capitatum ; 8, Os hamatum. Fig. 304.— Peropus dexter. (After Otto.) a, Great toe ; 6, Little toe. Fig. 305. — Bones of the foot depicted in Fig. 304, in the dorsal aspect, a, Big toe ; 6, Little toe ; c, Rudiment 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. ABNORMAL POSITIONS OF EXTREMITIT5S. 415 2. Abnormal Positions of the Internal Organs and of the Extremities. § 151. Of the abnormal positions of tlie internal organs, the most im- portant 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 malpo- sition of the heart alone, or, more rarely, of only the abdominal organs. Other malpositions affect most frequently the abdominal 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 ab- dominal cavity {ectopia interna seu abdomiiialis testis ; cryptorchismus), or in the inguinal canal {ectopia inguinalis), or at the external ring {ectopia puhica), or, finallj-, at some point between the latter situation and its normal position {ectopia cruroscrotalis, perinealis, or cruralis). Abnormal positions of the intestine, especially of the large intestine, are not rare. Among the abnormal positions of the extremities congenital luxations are of particular interest. They are most common at the hip, more rare at the elbow, shoulder, and knee. Von Ammon, DoUinger, Grawitz, and Kronlein regard them as the result of arrested development. At the hip the acetabular socket remains small and imperfect, and the head of the femur is more or less incompletely developed, so that it is readily displaced, usually backward (luxatio iliaca). At birth the ligamentum teres is always intact, but stretches when the limb is used, and may be ruptured. The capsule is at first intact, but the continued pressui-e be- tween the bony surfaces may cause it to become perforated, in which case a new joint may be formed by the proliferation of the surrounding tissues. Abnormal positions of the feet and hands are to be attributed some- times to disturbances of development, sometimes to mechanical causes. The most important is congenital club=foot (pes equinovarus), which, according to Eschricht, is due to arrest of development leaving the foot in its foetal position, with malformation of the bones and their articular surfaces. He describes the feet as lying at first with their dorsal sur- faces against the abdominal wall of the foetus. This position gradually passes into the normal through a revolution around the axis; but even at birth this rotation is not completed, the toes being still turned inward, and this persists until the act of walking gradually completes the change. In club-foot this foetal position is exaggerated, the inner edge of the foot is abnormally raised, and the whole foot is in a position of plantar flexion. The shapes of the bones and joint surfaces are also abnormal, the collum tah being especially elongated (Htiter, Adams). If the children learn to walk, they tread upon the outer edges of the feet, which are flattened by the pressure, while the whole foot is more strongly inverted. 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 posi- tions known as pes calcaneus and pes valgus may be produced. They are characterized in part by a strong dorsal flexion, in part by a twist- ing, of the foot. Frequently the evidences of the pressure to which the feet have been subjected are seen in an atrophic condition of the skin and the relative positions of the bones. 416 GENERAL AND PARTIAL GIANT GROWTH. The position of the liand 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. § 152. A malformation known as general giant growth is the result of an excessive growth of the whole body, which may take place in utero or in after-life. New-born children weighing more than twenty-two pounds are on record. During extra-uterine life growth far beyond the usual maximum may take place. Partial giant growth (cf. § 79) may also take place in utero or after birth, and usually affects portions of the extremities or the head. Dur- ing 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 extremities are the seat of this growth the condition is usually designated as elephanti- asis. 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 they assume the form of a neoplasm. The same is true where the parts affected belong to the face ; the lips, cheeks, and tongue being not infrequently 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 sometiines multiple. The bones of the head — those of the skull as well as those of the face — may be the seat of hypertrophy, which may be so extensive as to cause a deformity of one or both of these regions, a condition known as leontiasis ossea (Fig. 96, p. 219). Circum- scribed 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 may result in the formation of atypical, frequently multiple, masses of bone. § 153. 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 siippressed 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 shoul- der 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. 306). The number of fingers may reach nine or ten. SUPERNUMERARY FINGERS AND TOES. 417 Supernumerary fingers (polydac- tylism) on a simple hand, where the extra fingers are attached at the radial or ulnar side of the hand, or intercalated between the normal fingers, are more common than a duplication of the whole hand (Fig. 307). Similar anomalies oc- cur on the lower extremities (Pig. 308). Frequently the duplication involves only the first, or the first two, terminal joints of the fingers (Fig. 307). When attached to the edge of the hand the Fie. 306. — Polydactyhsia with duplica- tion of the hand. (After Lancereaux.) fingers may be well developed, or they may be mere rudiments. Occa- sionally they appear as small pedunculated fibrous tumors. In the fully developed supernumerary fingers the phalanges may articulate with the metacarpal or metatarsal bones of neighboring fingers, or with super- numerary bones of the hand or foot, which in turn may articulate with supernumerary carpal or tarsal bones. Fig. 307. Fig. 308. Fig. 307.— Polydactylism and syndactylism of the left hand. (Reduced one fifth.) Fig. 308. — Polydactylism and syndactylism of the right foot. (Reduced one fifth.) 418 TRUE AND FALSE HERJIAPHRODISM. Polydactylism is sometimes inherited, sometimes the result of iatra- 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 axillae to the inguinal regions ; but they may, rarely, be in other places — e.g., the axilla, shoulder, abdomen, back, or thigh. They are usually small, but may acquire functional activity when pregnancy takes place. Supernumerary nipples may reach as high a number as ten. 3. The formation in men of breasts resembling those of women (gynae= comastia) is rare in well-developed men with perfect sexual organs (see Hermaphrodism, § 155) ; but it not infrequently happens that the male breast suffers moderate enlargement at puberty. 4. Supernumerary bones and muscles are of frequent occurrence. Extra vertehrce 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 taUs containing bones, there are, according to Virchow, two forms 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, are usually the result of an elonga- tion or separation of the vertebree rather than of the presence of super- numerary bones. /Supernumerary ribs in the neck or loins, as weU as a forking of the ribs, are not rare. Supernumerary teeth also occur. 5. 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. § 154. The internal sexual organs develop from a primitive sexual gland lying near the Wolffian body, and a sexual passage, the duct ofMiillei; which are at first identical in the two sexes. The latter lies close to the Wolffian duct, both terminating in the lower end of the urinary bladder or urogenital sinus (Kolliker). 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 Woffian body, which becomes the epididymis, another small portion forming the vasa aberrantia testis (organ of Giraldfes), whUe the chief bulk of the organ disappears, and the Wolffian 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 duets of Miiller, which coalesce at then- lower ends, develop the vagina, uterus, and FaUopian 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 mam- malia (and probably in man) by a thickening of the peritoneal epithehum, which becomes the germinal epithelium of the organ (Waldeyer), while the mesoderm also proliferates. Whether the seminal tubules are derived from the peritoneal TRUE AND FALSE HERJIAPHRODISM. 419 epithelium (Bornhaupt, Egli), or whether they are derived from the Wolffian body (Waldeyer), is still a mooted question (KolUker). The ova spring from the germinal epithelium. The environing cells of the Graafian follicle are re- garded by Waldeyer as also derived from the germinal epithelium, while KoUi- ker thinks they are probably derived from the Wolffian body. The significance of the pedunculate and non-pedunculate hydatids, situated in varying numbers near the globus major, is not as yet fully determined (K61- liker). According 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 relations to the Woffian body, inasmuch as occasionally a vas aben-ans of the epididymis communicates with it. At first the testis lies within the abdominal cavity, in front of and internal to the primordial kidney, close to the lumbar vertebrae. As the primordial kidney disappears, the testis comes into intimate relations with a band of tissue, the gubemaeular cord, which passes from the lower end of the primordial kidney to the internal inguinal ring. In the third month of foetal life the processus vagi- nalis, a pouch of the peritoneum, pushes its way through the inguinal canal into the scrotum, which is formed from the integument. Meanwhile the gubemae- ular cord has passed down behind the processus vaginalis into the scrotum, binding the latter to the epididymis, which was formed from a part of the primordial kidney or Wolffian body. Then the testis, covered by peritoneum, follows the course of this band, reaches the internal ring during the seventh month, and at birth is usually situated within the scrotum. The processus vaginalis is obliterated soon after birth, but frequently only imperfectly, and occasionally remains patent. 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 (Kolliker) or in the walls of the uterus (Beigel). Riedel holds that they persist throughout life in about one third of the cases, consisting of a strand of cylindrical epithelium surrounded by muscu- lar tissue, or of a mere muscular bundle lying in front and to the side of the uterus and vagina. The ducts of Miiller at first open into the urinary bladder immediately in front of the Wolffian ducts, while the ureters have their insertions higher up. The lowest portion of the bladder, designated as the urogenital sinus, progresses in its development more gradually than the surrounding structures, which be- come urethra and vagina ; but finally the urinary and sexual organs are so far separated that the vestibule is all that they have in common. Inasmuch as the vagina develops into a wider channel than the tii'ethra, the m-Qgenital sinus, which at first was a part of the urinary bladder, becomes a continuation of the vagina, into which the smaller urethra opens. The uterus becomes differentiated from the vagina, in the fifth month, by the development of an annular ridge. The hjTuen is formed from the ridge which marked the junction of the vagina with the urogenital sinus or vestibulum vagina?. In the female the gubernacular cord becomes the round and ovarian liga- ments. As the Wolffian body disappears, the ovary approaches the inguinal canal and assumes an oblique position. The jjeritoneal covering of the Wolffian body becomes the broad ligament. As the Wolffian duct disappears, the guber- naculum joins the ducts of Miiller, near the point where the Fallopian tube is attached. A processus vaginalis is formed similar to that in the male, but is usually subsequently obliterated ; though occasionally the ovary may descend to, and, in extreme cases, be situated in, the labimn majus. 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 sexual tubercle just in front of the cloaca, and two lateral sexual folds. Toward the end of the second month the tubercle becomes more prominent and its lower surface is furrowed. In the third month the cloaca becomes divided to form the anal and genito-urinal orifices. In the male the genital tubercle develops into the penis, the glans becoming recognizable in the third month, and 420 TRUE AND FALSE HEKJMAPHEODISM. the furrow closing to form a tube (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 urogenital sinus. In the female the sexual folds do not unite, but form the labia majora ; the genital tubercle becomes the cUtoris; the edges of its furrow, the labia minora. § 155. The fact that the sexual organs of both sexes develop from struc- tures that are originally common to both, and which contain the begin- nings of all the organs of both sexes, makes it a priori probable that mal- formations might result through an unequal development of the organs on the two sides of the body, or through a simultaneous development of organs peculiar to the two sexes, or, finally, through a lack of harmoni- ous 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 hermaphro- dism (Pig. 309). 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 blend- FiG. 309. — Hermaphrodismus verus lateralis. (After Obolonsky.) a, Ure- thra; 6, Prostate; e, CoUiculus seminaHs: d, Hymen; e, Urogenital canal; /, Bladder ; g, Vagina ; h. Uterus ; hi, Left uterine horn ; i, Left tube ; ii, Infundi- buhf orm extremity of left tube ; h, Left ovary ; I, Ovarian ligament ; m, Left round ligament; n, Eight tube; o, Right testis; p, Epididymis; q, Right vas deferens ; r, Right round ligament. (About one-half natural size. Specimen in the pathological collection of the German Pathological Institute in Prague.) TRUE AND FALSE HERMAPHRODISM. 421 ing 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 inebs: I. Hermaphrodismus verus, or androgynes. Of these there are three possible varieties : 1. Hermaphrodismus verus hilateraUs, 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. Accord- ing to Klebs, no certainly authentic ease 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 hermaphroditic ex- ternal genitals and possessed of a vagina, uterus, and Fallopian tubes. 2. Hermaphrodismus verus uniJateralis. Cases in which both sexual glands are present on one side, while only one is present on the other side of the body. No au.thentic ease of tliis malformation is on record. 3. Hermaphrodismus verus lateralis. These are cases in which there is an ovary on one side, a testis on the othei-. They have been frequently described in human beings (Rudolph, Stark, Berthold, Barkow, H. Meyer, Klebs, Messner, and others), but usually without exact microscopical ex- amination. In the cases where that has been undertaken, ovarian struc- tures had not been made out with certainty until Obolonsky made a his- tological study of a case in the collection of the German university iu Prague, and established the fact of a testis on the right (Fig. 309, o) and an ovary {Ic) on the left side. The broad ligament on the right side con- tained a testis (o), an epididymis [p), a vas deferens {q), a rudimentary tube (ji), and a round ligament ()■)■ The left broad ligament contained an ovary (k) with an ovarian ligament (I) and a well-developed tube (i). There was also a uterus [h), vagina {g), and a prostate (6). According to pubHshed 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 sexual 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 WoMan duct have developed in females. In male false hermaphrodites the external genitals are frequently mal- formed and approach the female type, Avhile in the female they resemble the male (Fig. 310). This resemblance is brought about in the male where 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 depres- sion at the root of the penis between the scrotal halves. In the female the male genitalia are simulated by a development of the clitoris into a 422 TRUE AND FALSE HERMAPHRODISM. sort of penis, a union of the labia, and narrowing or even closing of the ostium vaginse. The vagina and urethra may have a common opening or separate openings be- neath the penile clitoris. Malformation of the external genitals does not necessarily imply malfor- mations in other portions of the sexual apparatus. 1. Pseudohennaphro- dismus masculinus occurs in three varieties : First, PseiidoJiermaph- rodismus masculinus in- ternits. The external geni- talia belong to the male type, and the prostate is also developed, but is usu- FiG. 310.— External gen- italia of a female false her- maphrodite with vaginal stenosis, a, Clitoris resem- bling penis; 6, Labia ma- jora. (Five-sixtlis natural size.) ally pierced, generally at the coUiculus seminalis, by a canal which com- municates with the urethra and passes above into a rudimentary or more or less well-developed vagina, and occasiona.lly uterus, and even tubes. The male organs may be well developed or more or less malformed. Second, pseudoliei-inaphrodismus masculinus completus or externus et in- ternus. Vagina, uterus, and tubes af e present, either more or less com- pletely developed or in a rudimentary state, and the external genitalia 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 and a vagina. Sometimes the vestibule and vagina are separate. In rare cases the ex- ternal genitals appear normal, but the penis contains two canals, one, the upper, being the urethra, the other the sexual passage. Where the ducts of Miiller are highly developed the vasa deferentia are frequently defec- tive, and sometimes the vesiculas seminales are wanting. Third, pseiidohermaphrodism us masculinus externus. Only the external genitalia depart from the male type, resembling more or less perfectly 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 feminiints also occurs in three varieties, but is rarer than masculine false hermaphrodism. Itl pseudohermaphrodismus femininus internus rudiments of fheWo^SAa-n 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 external genitalia resembling those of the male (Pig. 310). DOUBLE MALFORMATIONS. 423 Pseudohermaphrodismus femininus extermts et internus, where the ex- ternal genitals resemble the male and there is a persistence of parts of the WolfBan ducts, has been recorded in only two cases (Manee, 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. 5. Double Malformations. (a) Complete Duplication of the Axial Structures. § 156. Varieties in which both divisions develop uniformly. 1. Homologous twins result when both divisions develop unhindered. They always are of the same sex, each forming its own amnion, though where the two come in contact an absorption may take place. They possess, almost without exception, a common placenta. 2. Thoracopagi are forms in which the trunks — i.e., thoraces and abdomens — are coalescent (Fig. 311). They are also called omplialo]_mgi, because they possess a common navel and umbilical cord. Varie- ties of this maKormation are distinguished accord- ing to the extent of the coalescence. Xipliopagi are united only at the ensiform car- Os^{ Fig. 311. — Thoracopagus tribrachius tripus. The hand of the third arm, common to both halves, has two dorsal surfaces^ and the laterally distorted fingers possess nails on both sides. The third foot has eight toes. Fig. 312.— Cranio- pagus parietalis. 424 DOUBLE MALFOBMATIONS. tilage by a bridge of that tissue. The peritoneum extends into the bond between the two halves. (The well-known Siamese twins belonged in this division.) Sternopagi have a common thorax; the sternum is either double or single ; the heart also either double or single, but malformed. The intes- tinal tract is in part common to both halves, in part divided. The liver is double, but the two portions are connected by bridges of hepatic tissue. If of the upper extremities two coalesce, the malformation is designated as thoracopagus iribrachius (Fig. 311). If the coalescence involve two lower extremities and the pelvis, it is designated as thoracopagus tripus. The coalescence may include not only thorax and abdomen, but also the head {prosopo-thoracopagus, or cephalo-thoracopagus, or syncephalus (Fig. 318, p. 428). Since in these cases por- tions of the brain and cephalic ver- tebrae may also be coalescent, they might also be classed with the double malfor- mations with only partial duplication of the axial structures (of. § 158). The liver of the right twin is usually transposed, which is sometimes the case with the other viscera. The common extremities often show distinct traces of the union of two extremities— e.g., extra toes (Fig. 311) or two dorsal surfaces to the hand (Fig. 311). Thoracopagi are among the most common double malforma- tions. 3. Craniopagi are twins united by their heads ; according to the site of union, they are designated as cranio- pagus frontalis, parietalis, or occipitalis. They are rare. 4. Ischiopagi (Fig. 313) are united by the pelves. The spinal column and pelvis are duplicate, the latter forming a single, wide ring in which the sacral bones stand opposite to each other. This pelvis carries either four or two extremi- ties. Fig. 313. — IscLiopagus. (From Levy.) In preparing the classification of double malformations, I have, in the main, followed the work of AhKeld,* and the chapters on this subject in Perls's "Ahge- meine Pathologie." Forster and Marchand group these malformations into monstra duplicia catadidyma or dupUcitas anterior, monstra duplicia anadidyma or duplicitas posterior, and monstra duplicia anacatadidyma or duplicitas parallela. In the last group they include also the parasitic thoracopagi and the rhachipagi. The group duphoitas anterior contains both symmetrical and asymmetrical pygopagi, ischiopagi, dieephalus, diprosopus ; and the group duplicitas pos- terior, the symmetrical and the parasitic forms of oraniopagus, syncephalus, and dipygus. § 157. Varieties in which the two divisions do not develop uni- formly. * " Die MissbUdungen des Mensohen," Leipzig, 1880. DOUBLE MALPORBIATIONS 425 Among these, two groups may be distinguislied. In the first group the nourishment of one twin is cut off. It dies without suffering modi- fications in form. In the second group one of the twins assumes the nourishment of the otlier ; the latter, which is called the ■parasite (while the former is designated as atitosite), then suffers more or less in its de- velopment. The retrograding parasite may become more or less incorporated with the autosite, or it may be connected with only the placenta of the latter. The following forms are distinguished : 1. Foetus papyraceus. This form results from a too intimate rela- tionship between the umbihcal vessels in the common placenta of distinct twins, where, anastomoses being established, one twin receives nourish- ment at the expense of the other, which eventually dies. The amniotic fluid then ceases to be formed, and the dead fcetus is compressed by the one which continues to develop, and becomes flat and thin. In other cases the death of one twin may be occasioned by haemorrhage into the chorionic villi, or by toi-tion, kinking, or compression of the umbilical cord. 2. Acardiacus (Figs. 314 and 315). Malformations in which the heart fails to develop are invariably very imperfect products. The rudimentary foetus may be connected with the normal twin only by the placenta, or it may be more or less intimately and extensively united with it (cf. Tera- tomata). In the former case the acardiac foetus is designated as an allan- toic ov placental ixirasite, and its umbihcal vessels communicate with those of its twin, the heart of the latter maintaining the circulation in both. Claudius, Forster, Ahlfeld, and others explain the production of acardi- Fig. 314. Fig. 315. Fig. 314. — Acardiacus acephalus, show- ing a rudimentary development of the lower extremities (acardiacus amorphus). -Acardiacus acormus. (After a, Head ; 6, Rudiment of the Fig. 315. Barkow.) left upper extremity ; c. Rudimentary in- testine; d, Artery; e, Vein. 426 DOUBLE MALFORMATIONS. acus by a tardy and insufficient development of the allantois of one foetus which, not being able to reach the chorion, attaches itself to the allantois of the other foetus. The heart, when the blood-current becomes reversed faUs to develop at all, or remains rudimentaiy. The lungs, trachea, peri- cardium, diaphragm, sternum, vertebrse, and ribs also fail to develop, or attain only a rudimentary development, which is the case, also, with the liver and upper extremities. The viscera of the abdominal and pelvic cavities usually show the greatest development. The subcutaneous con- nective tissue frequently attains a marked development, resulting in the formation of irregular masses of tissue (Fig. 314). Acardiacus occurs in various forms : (a) Acardiacus aniorplms, which is rare, is an irregular mass covered with skin and containing only rudiments of organs. (5) Acardiacus acormus. In this the head is more or less developed (Fig. 315), but the trunk is wanting or rudimentary. It is very rare. (c) Acardiacus acephalus (Fig. 314). There is no head ; the thorax is rudimentary, while the pelvis and its adnexa are more or less well devel- oped. It is the most common variety of acardiacus. Subvarieties are : acephalus sympus, a. monopus, a. dipus, a. monobrachius, a. dibrachius, and a. paracephalus. The latter possesses a rudimentary skull. 3. Thoracopagus parasiticus results when, in a case of thoracopagous twins, one foetus suffers such deficient development that it forms a sort of appendage to the other. The union includes the ensiform process and that portion of the abdomen extending from it to the umbilicus, and the parasite is therefore frequently designated as epigastriiis. It rarely pos- sesses a full complement of body parts. In the majority of cases it is an acardiacus acephalus or acormus, whose vascular system blends with that of its host. This malformation is rare. 4. Epignathus (Fig. 316) is a prosopo-thoracopagous parasite united to its twin at the mouth of the latter, from which it projects as an amorphous mass of cartilage, connective tissue, glandular and intestinal structures, cerebral tis- sues, teeth, bone, muscle, ajjid hair-producing skin with an external cutaneous envelope. In very rare cases the epignathus springs from some other sit-e — e.g., the orbit. 5. Teratomata is the name given to tumors made up of a number of various tissues, tliis com- plexity of structure distinguishing them from other neoplasms. Some of them contain rudiments of skeletal parts — e.g., a spinal column, a pelvis, etc. — together with rudiments of various normal or- gans and tissues, as the intestine, brain, various glands, and nervous and muscular tissues. Others contain various tissues, such as muscle, cartilage, skin, bone, glandular structures, cysts, etc., none of which, however, are so formed or grouped as to represent rudimentary organs or skeletal structures. The former kind are certainly to be regarded as dwarfed parasitic twins {acardiaci amorphi) which Fig. 316. Epig- ^^® intimately united to their hosts. The latter nathus. (After Lan- kind are difficult to classify. It is probable that cereaux.) at least some of them are the result of an erratic DOUBLE JIALFORSIATIONS. 427 disturbance in the development of a single fmtus (compare also § 137, ou pp. 381, et. seq.)- From this point of view, epigastrius and epignathus are to be regarded as teratomata when they fall short of a certain degree of differentiation and development. Teratomata are most frequently formed at the sacrum (sacral teratomata, or teratoid sacral tumors). If they resemble a foetus iu their external appearances it is easy to recognize them as the results of twin-formation. The tumor is then called an epipygus. The diagnosis is more difficult where the tumor is a shapeless mass, and depends then upon a careful anatomical (and microscopical) study (cf. the preceding pages and § 137). It must not escape attention that just in the sacral region tumors of ordinary connective-tissue types and epithelial tumors are of not infrequent occurrence in the new-born. 6. Inclusio foetalis. The teratomata just referred to often show an intimate union of the parasitic twin with its host. When the teratoid tumors lie more deeply within the substance of the well-developed indi- vidual they are designated as inclusions and are classified as follows : (a) Inclusio ahdominalis [engastrius). (&) Inclusio subciitanea. (c) Inclusio mediastinalis. {d) Inclusio cerebralis {teratoma glandulce pinealis). (e) Inclusio testiculi et ovarii. Perls regards the views of Claudius with reference to the origin of acardiacus, which have been accepted by Forster and AhEeld, as inadequate. He assumes, with Panum,* that other factors — e.g., constriction occasioned by the membranes and cord — may cause stunting of one of the foetuses, in which case, provided there be anastomoses with the vessels of the other normal foetus, the latter assumes the nourishment of the stunted foetus. He supports this view ou the observation (Orth) that in a single foetus decapitation may be occasioned in this way. (&) Partial Duplication of the Axial Structures. § 158. The later in the developmental chain of events a duplication of the axial foetal structures takes place the less wiU be the duplication in the resulting product. The most common are duplications at the cephalic end of the foetus {terata catadidyma, chqjlicitas anterior). Duplication at the caudal end is more rare [terata anadidyma, dnplicitas piosterior). Karer than either are duplications affecting both extremities of the foetus [tercda anacatadidyma). Duplicitas anterior is most frequently met with in the malformation designated as diprosopus (Pig. 317), iu which the face is more or less dupli- cated, as represented by the varieties diprosopus clistomus, diophthalmus, triophtliahnus, tetropMhalmus, diotus. The minimum degree of duplication is that of the liypophysis (Ahlfeld). Bieephalus is the name, given to cases in which the head and upper end of the vertebral column are duplicated ; and, according to the number of upper extremities present, they are specified as diceptJialus dihracMus, tribracMus, and fetrabracJiius. The last possesses two hearts and two lungs and is viable. In very rare cases one half remains rudimentary {diceplialus parasiticus) . *Virch. Arch., 72. Bd. 428 DOUBLE JIALFORMATIONS. If the division of the foetal structure extends to the pelvis, so that the two halves are united only by the sacrum and coccyx, the resulting pro- Fig. 317. Fig. 318. Fig. 317. — Diprosopus distomus tetrophthalmus diotus. Fig. 318. — Cephalothoracopagus or syncephalus with Janus-head. Both anterior and posterior faces are malformed, having only one eye, and a nose resembhng a proboscis situated above the eye. duetion is called pygopagus. If twins are united only at some circimi- scribed portion of the vertebral column, and are separate both anteriorly and posteriorly to that point of union, the malformation is called rachi= pagus or duplicitas parallela. Teratomata occurring at the sacrum are probably in part rudimentary, acardiao, parasitic pj^gopagi. Duplicitas posterior of uniform development is rare in man. In the least marked cases it amoimts merely to a duplication of the end of the spinal column, the pelvic bones and organs, and the external genitaha. In more marked cases the lower extremities show more or less duplication. In extreme cases the whole spinal column and back are double, the head uniting the two bodies (syncephalus). The head may be simple or show evidence of duplication, such as a double face (t7a7M(s-head or Janiceps, Fig. 318). If, as is often the case, the thoraces are also to some extent united, the Janiceps may be considered as a cephalo-thoracopagus (§ 156). In the higher degrees of division only those axial structures which are situated farthest forward — for example, the brain and cranial verte- brte — remain undivided, and consequently there is no sharp line of sepa- DOUBLE ]\IALFORJLA.TIONS. 429 ratiou between synceplialus and a duplication with complete division of the axial structures. The two faces are usually unequally developed [Janiceps asymmetros), and frequently neither is well formed (Fig. 318). If one of the twins is retarded in its growth a Jamis parasiticus results. Cases in which there is a duplication of the posterior portion of the spinal column and the pelvis, while the head is simple, are called dipygus. A uniform development of the two portions is very rare in such cases, so that dipygus imrasiiicus usually results (Figs. 320 and 321). The parasitic portion is more highty developed the nearer its situation to the cephalic end of the autosite, so that if it have a thorax and upper extremities it usually springs from the mouth, neck, or chest V'1 Fig. 319. — Dipygus parasiticus. (After Schenk von Grafenberg.) Parasite springing from thorax of the autosite. (Fig. 319). If it have only lower extremities they arise from the pelvis (Figs. 320 and 321) {polymelia). The parasite is always acardiae and is included in the vascular system of the autosite. The rudiments of the parasite may lie beneath the skin of the autosite, forming a teratoid tumor. In very rare cases the duplications are restricted to portions of the pelvis and its contents — e.g., the genitalia and anus. Fig. 320. — Dipygus parasiticus. (After Lancereaux.) Parasite arising from the pelvis of the autosite. Fig. 321. — Dipygus parasiticus. (After Liesching.) 430 TRIPLE MONSTERS. (c) Triple Monsters. § 159. Complete division of the germ at the earliest period into sev- eral parts may give rise, if development be not checked,, to homologous triplets. They lie within a single chorion, and there may be either a single amnion, or each foetus may have its own amnion. Frequently one or two of the triplets are malformed (acardiacus). Where a complete division has taken place and then one of the halves undergoes a further partial division, there are produced within a single chorion a double monster and a simple foetus. This Bombination is not very rare. A three-headed monster (tricephalus) arises from partial division of an already partially divided germ. It is very rare. SECTION IX. Fission-fungi which Exist as Parasites and the Dis= eases Caused by Them. I. General Considerations in Regard to the Schizomycetes or Pis- sion=fungi. 1. General Biology of the Fission-fungi. § 160. The Scliizomycetes or fission=fungi, also frequently called collectively bacteria, belong to the protophytes — i.e., to the very smallest, 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 disintegi-ated cell-products of the tissues only with the greatest trouble — i.e., only by the use of different reagents or methods of staining. The fission-fungi throughout are devoid of chloropJiyl 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 differ- ences are used to group the bacteria into different genera. The cocci, often also called micrococci, constitute the first genus of fission-fungi, and constantly occur as spherical or oval cells, and were formerly often called spJioerobacteria (Cohn). Six forms of growth can be distinguished accord- ing to their grouping in the process of reproduction : double cocci or diplo- cocci, chain-cocci or streptococci, clustered cocci or staphylococci, tablet-formed cocci or merismopedia, pacTiet-shaped cocci or sarcince, 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. 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 thii'd genus. Screws with short, wide turns are called spirilla, those with drawn-out turns vibrios, those with a long, narrowly twisted screw spirochaete. All of the bacteria as yet referred to occur either in one single form of growth or in a verj'' limited cycle of forms of growth, and may there- fore be grouped together as monomorphic or oligomorphic bacteria. 431 432 FISSION-FUNGI. — GENERAL BIOLOGY. Cohn, to whom we are indebted for the fundamental investigations of the bacteria, united under this term exclusively these oligomorphic organisms. Recently, however, there have been also organisms classified as bac- teria which have in their ontogenesis a long series of forms of growth — i.e., forming spherical cells as well as rods and screws — wluch can be con- sequently called pleomorphic bacteria. Here belong, namely, the water- fungi which go by the names cladothrix, deggiatoa, and crenothrix. The fission-fungi are aU made up of a plasma, or cell-contents, sm*- rounded by a cell-membrane, both, according to Nencki, consisting for the most part of an albuminous substance, or mycoprotein. According to observations of Schottelius and others, it is possible with good lenses to differentiate in the inside of the bacUli oblong bodies, in the inside of cocci round bodies, which are probably to be interpreted as cell-nuclei. These bodies differ optically from the cell-protoplasm, and divide in two before the division of the cell takes place. According to Nageli, Zopf, and others, many fission-fungi possess a membrane consisting of cellu- lose, or at least of a carbohydrate 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! In 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 oscOlatory 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 divi- sion 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, leptotlirix) ; according to the sec- ond method, colonies in a plane are formed {merismopedia) ; according to the third method, colonies are formed in a solid body (sarcince). 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-division 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 zoogloea. The jelly is formed out of the cell-membranes of the fission-fungi, and, according to Nencki, 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 more- over, when they are put into fresh nutrient solutions, they can produce a new generation. Most frequently the spore-formation is endogenic — i.e., the spore arises inside of a cell, especially in bacilli, and is developed out FISSION-FUNGI. — GENERAL BIOLOGY. 433 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 ar- throspores, 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 morphological peculiarities. Babes and Ernst, by special methods of staining with Loffler's methy- lene blue, haematoxyiin, and Platner's nuclear black, have found in the in- terior of different bacteria, granules which, according to their behavior, probably bear some relation to the cell-division and to the spore-forma- tion. 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. § 161. The fission-fungi, owing to the absence of chlorophyl 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 cae- sium 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, salicyUc acid, phenol, etc. The fission-fungi derive their nitrogen from albuminous matter; more- over, from those compounds which are designated as amines (methj'lamine, ethylamine, propylamine), amido-acids (asparagin, leucin), and amides (oxamide, urea) ; and also from the ammonia salts, and partly also from nitrates. The albuminates are changed into peptones, previous to their as- similation, by a ferment given off from the fission-fungi. Free nitrogen cannot be assimilated as such. Nitrogenous and non-nitrogenous com- pounds are not only assimilable as such, but also in combination. The fission-fungi can derive their nitrogen from ammonia and nitric acid only in the presence of organic carbon compounds. 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 present, all further growth ceases ; stUl many fission-fungi are able to dispense with water temporarily. Spores suffer very little from the effects of drying. Some of the fission-fungi are restricted, for their nourishment, mainly or exclusively to dead organisms or to solutions of organic matter, and belong, therefore, to the saprophytes. Others are also able to derive their nutrition from living animals or plants, and are therefore to be reckoned among the parasites. If the fission-fungi get into water containing no nutritive material, many of them die in time. 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 oxj'gen is cut off. The 434 FISSION-FUNGI. — GENERAL BIOLOGY. fii'st of these are called obligatory aerobes, the second facultative anaerobes, the third obligatory anaerobes. Facultative anaerobes prodiice in part fermentation by their multi- plication in the absence of oxygen ; but, according to the investigations of Fliigge and Liborius, fermentative phenomena seem also often to be absent. Pathogenic bacteria, according to Liborius, are facultative or obligatory anaerobes. Carbon dioxide has no influence upon the development of many bac- teria, as, for example, upon the typhoid-fever bacilli and upon the Fried- lander pneumonia-bacilli. Upon others, on the contrary, it has an in- hibitory action, as, for example, Bacillus indiciis, Proteus vulgaris, and Bacillus phosphorescens, the bacilli of anthrax and of cholera, the pus- cocci, and others (C. Frankel). The baciUi 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 antliracis the vimlence can be weakened by sunlight (Arnold, G-aillard). Anthrax-spores die out when exposed for a long time to light and air (Arloing, Roux). According to G-eisler, the green, violet, and ultra-violet are the rays which are particu- larly injurious to them. According to Nageli, Hauser, Buchner, Zopf , and others, different con- ditions of nutrition act in modifying the form and dimensions of the fission- fungi. For example, bacilli cultivated in different nutrient solutions have different lengths as well as different thicknesses. In many varieties, more- over, 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 properties can also change under different modifications of nutrition. The temperature of the medium surrounding the bacteria acts gen- erally in such a way that when there is a fall the vital processes become weaker and slower, and finally cease, whereas with elevation of the tem- perature they rise to a certain maximum, and at a slight excess above this suddenly cease ; still higher temperatures kill the fungi. The maxi- mum of permissible temperature lies at a different height for different fungi, and, according to Nageli, is also partially dependent upon the char- acter 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 temperatm-es. The rigidity due to cold develops in the individual forms at different temperatures. The most favorable temperature for the Bacillus anthracis lies between 30° and 40° C. ; at temperatures above 44° C. a,nd below 15° C. there is cessation of development. Many bacilli form spores only at high tem- peratures. Boiling water and steam at 100° C. kiU aU bacteria and bacterial 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 temperature of 60-70° C, provided it be kept up for a very long time. Anthrax-bacilli multiply within certain limits more and more slowly the lower the temperature is. Between 30° and 40° C. growth and spore-formation FISSION-FUNGI. — GENERAL BIOLOGY. 435 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. BeV)w 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 baciUi are de- stroyed at a temperature of 140° C. at the end of three hours. The temperature penetrates the objects to be disinfected so slowly in hot air that objects of mod- erate dimensions, such as a small bundle of clothes, pillows, and such things, are not disinfected after three or four hours' exposure to a temperature of 140° C. (Wolffhiigel). Anthrax-spores die in hoiling water in two hours, in confined steam in ten minutes ; but the spores of the garden-earth bacillus (garden-earth contains usually a pecuUar bacillus) are not kiUed in this time. The action of steam at 105° C. for a period of ten minutes kills all spores. Watery vapor is more effective when in motion than when it is confined. It then kills all spores in from ten to fifteen minutes, and penetrates very well into the objects to be disinfected (Koch, Gaffky, Lofler). In disinfecting with boiling water, attention must be weU given that the heating lasts a long time — i.e., tiU all parts are heated up to 100° C. According to Arloing and Duclaux, anthrax-bacilli die in from twenty-four to thirty hours when exposed to the direct rays of the sun ; spores in from six to eight weeks. § 162. If fission-fungi find themselves in a medium which suits them, their multiplication can still be brought to a standstill provided the fluid contain substances which hinder their growth or even kill them. This effect is produced by many substances — sublimate, lysol, carbolic acid, iodine, etc. — even in comparatively great dilution. Other substances 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 bacteria are killed. Spores are much more resistant than the vegetative forms. 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 amoiint of acid in the nutri- ent fluid. As a 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 biityric-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 putre- faction of albumin, since the products, such as phenol, indol, skatol, phenyl acetic acid, phenyl propionic acid, etc., hinder the further develop- ment of the bacteria. The fission-fungi are less sensitive to alkalis, and many of them can bear a tolerably high degree of alkalinity in the nutri- ent 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 nu- 436 FISSION-FUNGI. — GENERAL BIOLOGY. trient material— i.e., with an insufficient amount of water. The fact that fruit preserved in sugar, and salted and dried flesh, do not become foul depends upon this. Pood-stuffs can also be preserved by depriving them of water and by the addition of substances which are dissolved in the tissue-fluids, and in this way increase the proportion of solid matter. The limit at which development takes place is reached at a much higher degree of humiditj^ for the flssion-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 repelled by chemical substances dissolved in water. The bacteria swimming around in the fluid consequently collect together at places where there are chemical substances which attract. Typhoid-fever bacilli and eholera- spiriUa, for example, are attracted by the juice of a potato (Ali-Cohen). Potassium salts, peptone, and dextrine also act by attraction, but the in- dividual bacteria behave differently toward these substances (Pfeffer). Free acids, alkalis, 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-organ- isms, and fission-fimgi, budding fungi, and mould-fungi can crowd one another out. If, for example (Nageli), fission-fungi, yeast-fungi, and mould-fungi are introduced together into a solution of sugar, the flssion-fungi alone increase and cause lactic-acid fermentation. If to the same solution 5 per cent, of tartaric acid is added, the budding fungi alone multiply and cause alcoholic fermentation. If 4 or 5 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 development 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 only multiply and produce acetic acid 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. Often a large number of fission-fungi develop in one culture-fiuid, and it often seems as if they favored one another's growth ; still a reciprocal crowding out occurs among the flssion-fungi themselves. Thus, for ex- ample, cocci can be supplanted and destroyed by bacilli, or one form of bacillus by another. This would happen where either the composition or the temperature of the mitrient fluid is more favorable for one or for the other, or also where one species of bacteria forms products which act injuriously upon the other, or where one form grows more rapidly than the other and in this waj^ takes away the necessary nutrient material from the competitor. According to the investigations m ade by Pasteur, Emmerich, Bo uchard, Woodhead, Blagovestchensky, and others, the antagonism between 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 sus- ceptible animal is hindered. Thus, for example, the development of the anthrax-bacilhis can be hindered by a simultaneous inoculation with ery- sipelas-cocci (Emmerich) or with the Bacillus pyocyaneus (Bouchard). FISSION-FUNGI. — GENERAL BIOLOGY. 437 Substances which are specially adapted to hinder the growth of the bacteria, or to kill them, are usually called antiseptic substances. The knowledge of their action is of great practical interest, as it is possible in this way with their aid to render solid or fluid bodies and also human tissues free from bacteria, or at least to hinder the development of bacteria in them and so to protect the body in question from the injurious action of the bacteria. For therapeutic and hygienic purposes, sublimate, lysol, carbolic acid, and preparations of iodine are the antiseptics chiefly used. § 163. The growth and nmltipUcation of the fission-fungi are uniformly accompanied iy considerable changes in the tissues or fluids upon which they feed. For not only is material taken away bj^ osmosis and used to build up new fungus-cells, but at the same time extensive destructive chemi= cal metamorphoses take place, which affect the assimilated substances, as well as also the substances outside the cells, and lead to a decomposi- tion of the complicated organic conipounds into simpler bodies. These metamorphoses are due to the vital activity of the protoplasm, and can be regarded as fermentation processes. As to whether the decomposition in fermentation takes place inside the cells or on their surface is not yet decided, but the latter is the more probable. In the decomposition caused by the fission-fungi there are numerous products formed, which vary according to the character of the nutrient fluid and the form of the fission-fungus. A fission-fungus can only pro- duce fermentation when an adequate fermentative material is present for it. Many fungi can do this as well in the presence as in the absence of oxygen. In some of them paucity of oxygen is essential. Fermentation is unknown in some of the fission-fungi. The fermentations caused by the fission-fungi constitute essentially much of the decomposition going on every day on a large scale. Thus, for example, they are the cause of the stinking pi utref action of albumin; they change milk into lactic acid {sour milJc); mannite, dextrine, glycerin, sugar of milk, starch, and lactic acid into butyric acid (fermentation of sauerkraut) ; sugar into a gummy slime [so-called " langer Wein "); alcohol into acetic acid / tirea into carbonate of ammonia. In the putrefaction of albumin, peptones and similar bodies are first formed ; then afterward alkaloidal bodies, so-called ptomaines, as, for example, the putrid poison of Panum, sepsine (Bergmann, Schmiede- herg), coUidine (von Nencki), peptotoxin, neuridine, neurine, choline, tetanin, ethylendiamine, cadaverine or peutamethylendiamine, putrescine or tetramethylendiamine, substances resembling gadinin and muscarine (Brieger) ; then next, nitrogenous bases : leucin and tyrosin, amine, methyl-, ethyl-, and propylamine ; moreover, organic fatty acids : formic acid, acetic acid, propionic acid, butyric acid, valerianic acid, palmitic acid, margaric acid, lactic acid, succinic acid, etc. ; furthermore, aromatic prod- ucts : indol, phenol, cresol, pyrocatechin, hj'drochinon, hydroparacumaric acid, and para-oxyphenyl acetic acid (von Nencki, Salkowski, and Brieger) ; finally, sulphuretted hydrogen, ammonia, carbon dioxide, and water. Besides the bodies enumerated above, there result from the growth of numerous pathogenic bacteria albuminous bodies which act in a poison- ous manner upon the human and animal organism, and are therefore called toxalbumins. The products named are formed partly by hydration, partly by reduc- tion, partly by oxidation. 438 FISSION-FUNGI. — GENERAL BIOLOGY. Along with the fermentative action the fission-fungi also give off dis- solved substances -which produce decomposition, are known as unformed ferments, and may be separated from the fungi. The unformed diasta- tic ferments convert starch and cane-sugar, and perhaps, also, lactose and cellulose, into grape-sugar, and the insoluble peptone-producing albu- minous substances into peptone. In consequence of this, mUk may undergo an alcoholic fermentation, and insoluble albuminoid masses may undergo putrefaction. According to the investigations of Winogradsky, there are also Ucing bacteria in the soil ivliich are able to form nitrous and nitric acid out of am- monia; and he calls these, accordingly, nitrifying or nitro=bacteria. Along with the nitrification of nitrogen there takes place simultaneously a de- struction of the earthy alkali carljonates, 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 ceUs from the salts of carbonic acid. There takes place, therefore, as a result of the -^dtal activity of these organisms, a synthesis of organic material out of inor- ganic 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, they 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 (bleed- ing bread) ; moreover, bandages and piis sometimes turn blue in conse- -quence of the presence of the Micrococcus cyaneus. On the surface of boiled eggs exposed to the air in a moist place there appears usually very quickly a yellow- coating, formed by the Micrococcus luteus. 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 repi'oduction of the bacteria. Fermentation and pidrefaction can only occur where the fungi concerned live, and the extent of the decomposition is conditioned upon the number of fungi. One specific fungus form does not occur alone in every decom- position, and a single fungus form often causes not alone one kind of decomposition. The ordinary stinking putrefaction of albuminous sub- stances develops under the influence of different bacteria, but especially under that of Proteus. According to Cohn, the cocci do not produce putrefaction, but decompositions of another kind. Butyric-acid fermen- tation is said to be brought about mainly by the Clostridium butyricum. Anthrax-bacilli produce ammonia in nutrient fluids. In putrefying sub- stances are found, for the most part, many kinds of fission-fungi. According to Nageli, it is possible by cultivation to change the prop- erties of a fission-fungus in such a way that it will no longer be able to bring about the decompositions which it previously caused, but it will cause some other fermentation. According to him, it is possible, for example, to change by cultivation, in meat-extract containing sugar, the fission-fungus which causes lactic-acid fermentation in such a way that when it is reintroduced into milk it causes an ammoniacal decomposition, -and it only regains the power of producing lactic acid after many genera- tions. Accordingly the physiological properties of a fission-fungus are capable of a change within certain limits ; or, at least, with changes in the conditions of life, different properties predominate. FISSION-FUNGI. — GENERAL BIOLOGY. 439 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 fermenta- tion and putrefaction depend upon the presence of very small organism s. Almost at the same time (1857) Cagnard-Latour observed the multiplication of yeast- cells in alcoholic fermentation. The observation made by Schwann was subse- quently corroborated by Helmholtz. H. Schroeder and von Dusch then showed that by filtering through cotton-wool the air admitted to a fluid capable of fer- mentation, 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 hypotheses upon the cause of fermentation, especially upon the alcoholic fer- mentation caused by the yeast-fungi. Certain authorities have sought to bring these processes in immediate relationship to the life of the cells causing the fer- mentation ; 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,t the ceUs 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 com- pound. According to Pasteux,t fermentation is dependent directly upon the life of the fermentative cells. It only occurs when free oxygen is lacking to the cells, so that these have to take the oxygen from the chemical compounds in the nutrient fluid (cf. § 161). In this way the molecular balance of the latter is de- stroyed. According to von NencM, also, anaerobiosis is to be regarded as the cause of the different Mnds of fermentation. Since the fermentative organisms derive their oxygen not out of the air, but out of the nutrient substance, there appear constantly also reduction products — alcohol, butyric acid, etc. — along with the end-product, carbon dioxide. According to Nageli's molecular-physical theory,^ fermentation is a transfer of molecular motion from the living protoplasm to the material undergoing fer- mentation. This motion is present in the molecules, groups of atoms, and atoms of all substances. The compounds forming the living protoplasm remain them- selves unchanged, but by the transfer of molecular motion they destroy the equipoise in the molecules of the fermenting substance, and these become disin- tegrated. 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 decomposition of the dissolved albumin circulating in the organism is attributable to a fermentative activity of the cells. Pasteur has shown that fruit and leaves possess fermentative properties under suitable conditions. As already remarked, the amount of oxygen present has considerable efllect upon the decomposition caused by fission-fungi. Pasteur states that fungi that grow in the presence of oxygen produce principally oxidation; those, on the contrary, that grow without oxygen produce decomposition without oxidation. Hoppe-Seyler if corroborates the fact that the presence of an abundance of oxygen retards the decomposition of sugar into alcohol and carbon dioxide by yeast, while at the same time volatile acids are formed in abundance. If bac- teria develop in an albuminous fluid with abundant access of oxygen, all of * Poggend Annal., 29. Bd., ref . in Sehmidfs Jahrb., 1866. t Cf. Hoppe-Seyler, Pfluger'>s Arch., 12. Bd., 1875, and "Physiol. Chemie." % Ann. de Chim. et de Phys., tome 58, 1860, et tome 64, 1862; Comptes rend, de VAcad. des Sciences, tomes 45, 46, 47, 52, 56, 80 ; and Duclaux, " Ferments et maladies," Paris, 1882. § Abhandl. d. Bayr. Akad., Math.-physih. Kl, iii., 76, 1879. II " Physiologic des Sauerstoffwechsels," Leipzig, 1881. IT " Ueber den Einfluss des Sauerstoffes auf Gahrungen," Strassburg, 1881. 440 PATHOGENIC FISSION-FUNGI. those substances vanish which constitute an important part of the products of decomposition in the presence of a paucity of oxygen — namely, indol, hydropar- acumaric acid, sulphuretted hydrogen. The oxygen must therefore act by in- ducing oxidation, and the products of fermentation suffer further changes. Along with fermentation and putrefaction which result from fimgi, 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 sub- stances, also ammonia. This form of decomposition takes place under con- ditions where 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 tnouldering. 2. General Considerations concerning the Pathogenic Fission-fungi and their Behavior in the Human Organism. § 164. As has been already explained in §§ 13 and 14, there are among the fission-fungi numerous species which are capable of producing disease processes in the human organism, and they are thei'efore called patho- genic fission=fungi. The first condition of such action is evidently that the bacteria concerned must possess properties enabling them to multi- ply in the tissues of the Mving human body. They must consequently find in the tissues the suitable nutrient material, and in the body-temper- ature the warmth, necessary to their growth. The tissues, moreover, must not contain substances which are a hindrance to their growth (cf. §§ 26 and 29). 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. 322, c), necrosis, inflammation (e), and new growth of tissue, while the toxins and toxalbumins produced by them cause manifestations of poisoning. But in individual cases the disease process assumes different forms, 5 Vt-^ Fig. 322. — Section through a vocal cord of a child with streptococcus colonies upon and in the epithelium, a, Epithelium; b, Connective tissue of the mucous membrane ; c, SwoUen, degenerated epithelium, in part devoid of nuclei ; d, Layer of cocci ; e, Eeaetive small-cell infiltration, partly inside the degenerated epithelium, partly in the connective tissue. (Magnified 200 diameters.) PATHOGENIC FISSION-PUNQI. 441 in that the distribution of the bacteria in the organism and their local action, as well as the production of poisons, differ greatly iu the different forms of bacteria. In many of them the local action upon the tissues comes to the front ; in 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 foci (cf. § 18) ; 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 feet us during pregnancy, since the placenta forms no certain filter against pathogenic bacteria. This has been proved, for example, for anthrax-baciUi (Straus, Cliam- berland, Marehand, Malvoz, Latis, Birch-Hirsohfeld, Perroncito), for the bacilli of symptomatic anthrax (Arloing, Cornevin, Thomas), for the bacilli of glanders (Loffler, Mallet, Cadeac), for the spirilla of relapsing fever (Albrecht, Spitz), for the bacilli of typhoid (Eberth, Neuhaiiss, Reher, Chantemesse, Widal, Ernst), and for the pneumococcus (Netter, Foa, Bor- doni-Uffreduzzi). According to certain observations of Malvoz, Birch- Hirschfeld, and Latis, changes in the placenta, such as haemorrhages, 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 haderia which succeed in multiplying in the human body die out again, in many cases, in a short time, and the diseases caused by them pro- ceed to recovery (cf. § 27). Nevertheless it also not infrequently happens that they are x>reserved for a long time in the body, and either continuously cause disease processes, or, on the other hand, remain in a state of inac- tivity, so that no disease processes of any kind are recognizable till, after a shorter or longer period of latency, a lively multiplication tal-es place, and along with it new manifestations of disease shoiv themselves. Not infrequently a secondary infection associates itself with an infec- tion already existing. The relation between the two infections is either that the second occurred accidentally after the first became established, or, on the other hand, that the way was prepared by the first infection for the subsequent one (cf. § 14). Finally, double infection, where 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. § 165. Each pathogenic fission-fungus has a specific action upon the tissues of the hxmian 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 tliat the species of the pathogenic fission-fungus can be recognized with certainty. 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 become changed through external circumstances ; that is to say, may 20 442 PATHOGENIC FISSION-FUNGI. become weakened so that they either lose entirely the power to produce processes of disease in the organism, or at least can only cause 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 ex- tent, why a certain infection does not always run the same course, and, moreover, why alongside of severe attacks light ones also occur. On the other hand, it affords us the possibility of obtaining material for inocula- tion from attenuated cultures of bacteria, by means of which slight de- gi-ees of infection and also slight degrees of intoxication can be produced, which protect the organism from severe infection or cure an infection that has already taken place (cf. § 29). Attenuation of the pathogenic properties of a fission=fungus can be effected by allowing higher temperatures, oxygen or light, or chemical 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 artij&cial media to bring about attenuation; in others, such as the bacUlus of chicken-cholera, prolonged exposure of the culture to the air suffices to bring about an attenuation. If it is desii-ed to preserve the virulence of the pneumococei 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). 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 10 minutes' heating at 55° C. (Toussaint), or by heating at 52° C. for 15 minutes, or at 50° C. for 20 minutes (Chauveau) ; moreover, the same re- sidt is also obtained liy the action of oxygen at high pressure (Chauveau). The bacilli weakened by the influence of high temperature for a short time, regain their virulence very quickly by recultivation ; the bacilli, on the contrary, which have been weakened at lower temperatures, remain atten- uated througb 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 re- production. Moreover, the bacilli can be weakened without killing them Ity weak solutions of sublimate, thymol, eucalyptus-oil, nitrate of silver, etc. The addition of cai-bolic acid in the proportion of 1 : 600 to the culture- fluid permits of the development of anthrax-bacUli, but destroys their ■\drulenee in twenty-nine days (Chamberland, Roux). In the same way attenuation is obtained by addition of bichromate 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. The poison of rabies, which kUls rabbits in a short time on inocula- tion, may be a,ttenuated by drying at temperatures of 22-26° C. (Pas- tern-). According to Protopopoff, it is mainly the higher temperature which prodiices the attenuation. EXAMINATION OF FISSION-FUNGI. 443 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. It is possible to make hypotheses only 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 artifi- cial 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 superiority. 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 (Fliigge). 3. General Considei-ations in Regard to the Examination of Fission-fimrji. § 166. If bacteria are suspected in any tissue-fluid or in the parenchyma it is first sought to discover them by microscopic examination. Occasion- ally this succeeds merely by looking at a drop of the fluid or of a smear- preparation of the tissue-juice diluted with salt-solution or distilled water. lu 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 purpose methylene blue is used by preference, the solution consisting of a 1 per cent, solution of the dye in a 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 violet, or aniUne-water fuchsin, or aqueous methyl violet, and the color subsequently removed with weak acids or with iodine and alcohol (G-ram's method). lu this way it is often brought about that only the bacteria remain stained, some- times even certaia 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 bacteria uni- formly in a solution of gelatia or agar previously warmed, and pouring out some of the mixture vipon horizontal glass plates. The fluid contain- ing the bacteria is obtained either by scraping the tissue or by rub- bing up pieces of tissue in sterilized salt-solution. The gelatin- and agar- solutions are liquid at higher temperatures and solid at lower. When 444 exajmination of fission-fungi. the solutions become solidified the individual bacteria or spores become developed at points separated from one another. By a proper application of the method varied colonies are subsequently obtained in the layer of gelatin spread out on the plate (Fig. 323). The colonies often differ from one another in appearance, even when ex- amined with the naked eye. If the colonies are sufficiently separated from one another a small amount is to be ta,ken 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, 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 trans- parent medium contained in a test-tube (Plate I., Figs. 1-3). r^TCTnr.TTOSH^IT'iaBKrTSTTMW /:-:::..;^ V0;3:::r/c:^; Fig. 323. — Gelatin plate containing colonies of small baciUi. These colonies are peLicle-like, with somewhat sinuous margins. Also small, round white col- onies of cocci are present. Obtained from the exudate of a purulent peritonitis. (Diminished by one tMrd.) 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 peculiarities show them- selves which make it possible for the practised observer to recognize the form of bacteria. Still it will occasionally happen that a thorough micro- scopic examination of the colonies will also have to be made. It goes without saying that all the above manipulations must be car- ried out with care, and that care must be had for the absolute cleanliness of the instruments that come into use — of the glass plates and test-tubes, — and that the nutrient media must be free from bacteria. Suitable pro- cedures are easiest learned in laboratories specially arranged'for the pur- pose. The long-continued heating of the instruments used or their sub- jection to high temperatures plays an important r61e. The necessary guidance is furnished in the various books on bacteriological methods of examination which have appeared recently. 35iegler, General Pathology. Plate 1. p 1. Stab-culture of 2. Stab-culture of ' Staphyloeocciis Pyogenes Bacilli of Swine Erysipelas Aureus in Agar-Agar. in gelatine. 3. Stab-culture of Cholera Spirilla in gelatine. *. Culture of Tubercle Bacilli upon coagulated blood serum (after Koch). are of Anthrax Bacilli upon a boiled potato. Culture of Staphylococcus Pyogenes Citreus upon a boiled potato. EXAiMINATION OF FISSION-FUNGI. 445 Infusion of meat containing peptone and gelatin is most usuallj'- em- ployed for making plates. TMs 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 temperatui-es. For stroke- and stab-cultures sometimes this same gelatin is used (Plate I., Pigs. 2 and 3), sometimes a jelly made of a mixture of watery extract of meat, peptone, and agar-agar (Plate I., Fig. 1), sometimes blood-serum that has been brought to coagulation by warming (Fig. 4). For stab-cultui'es the jelly is allowed to solidify with the test-tube in a perpendicular position (Pig. 3), for stroke-cultures in an oblique posi- tion (Fig. 4). Sterilized bouUlon is often used for cultures. The inoculated nutri- ent media are either kept at room-temperatm'e or at higher temperatures of 30-40° C. in an incubating-oven. The latter, however, is only possible with agai'-agar, blood-serum, and potatoes, as the gelatin that is used be- comes fluid at the temperatm-e 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 is necessary to use agar-agar plates and to do away with gelatin. Occasionally small pieces of tissue are excised and introduced directly into the nutrient solution. If it be 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 fi'om the under surface of a cover-glass and is inoculated from a previ- ously purified cultm-e 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 cavitj^ in the slide — which may be efilected by sticking on the cover-glass with oil or vase- line — 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 pe- culiarities have been sitfiieiently studied in this way its development in the animal body is tested. As experimental animals those most usually em- ployed are rabbits, dogs, guinea-pigs, rats, mice, and sjnall birds. Bacteria to be tested are introduced sometimes under the skin, sometimes directly into the blood-current, sometimes by inoculation into tlie inner orga,ns, sometimes by inhalation into the lungs, sometimes 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 aninial may, under certain conditions, die, even if the bacteria do not increase at all in its body ; for the poison- 446 THE DIFFERENT FORMS OF FISSION-FUNGI. ous substances ready-formed in the culture and introduced by inocula- tion 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 other- wise in animals. In other cases the pathogenic fission-fungi which occm* in man or certain animals are, it is true, pathogenic for the experimental animals, but the morbid process shows a different localization and a differ- ent course. In still a third case the experimental animals 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. II. The Different Forms of Fission=fungi and the Infectious Diseases Caused by Them. 1. The Cocci and the Morbid Processes Caused by Them, {a) Forms of Growth of the Cocci. — Saprophytic Coed. § 167. The cocci or coccacei (Zopf) are bacteria that always occur ex- clusively in the form of round or oval or lancet-shaped cells, and under no condition form rods. In their multiplication by division they often form aggregations of ceUs hanging together, and it is customary to des- ignate these by special names, according to the character of the different forms that appear. Since certain forms of cocci are speciaUj"- apt to de- velop in definitely shaped aggregations, many authors have found occa- sion to make different species and subspecies accordingly. Many of the cocci multiply by transverse division of the spherical cell after it has become somewhat elongated. If in this case the spheres re- sulting 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. 324, b). If rows of cocci in a plane result from the con- Fig. 325. Fig. 326. Fig. 324. \ ■©>"» "„■■ Fig. 327. Fig. 324. — Streptococcus from a purulent peritoneal exudate of puerperal peritonitis, a, Separate cocci ; h, Diplococci ; c, Streptococci. (Magnified 500 diameters.) Fig. 325. — Micrococcus colonies in a blood-capillary of the fiver, as the cause of metastatic abscess-formation in pysemic infection. Necrosis of the fiver-ceUs. (Magnified 400 diameters.) Fig. 326. — Cocci grouped in tetrads (merismopedia), from a softening infarc- tion of the lung. (Magnified 500 diameters.) Fig. 327.— Sarcina ventriculi. (Magnified 400 diameters.) SAPROPHYTIC COCCI. 447 tiuuous division of the cells they are called streptococci (Fig. 324, c) or tonila-chains. Masses of cocci united into a regiilar granular colony, and held together by a gelatinous substance which is derived from the membrane of the cocci, are called zooglcea, and the cocci which often ap- pear ia this form, micrococci (Zopf) or heaped cocci (Fig. 325). For some of the forms belonging here the name staphylococci (Ogston and Rosen- bach) or grape-cocci has come into use. Forms which, on the nutrient material, make round masses — recognizable as such even to the naked eye — and which contain, in a thick, gelatinous, cax-tilage-like membrane, one or more closely packed coccus colonies, are called ascococci. Zopf introduced the name merismopedia, or tablet-cocci, for cocci which remain for a long time united in a four-celled tablet (Fig. 326). Others regard such bacteria as micrococci. The cocci that go by the name sar= cin^e are characterized by dividing in three directions of space, so that compound cubical packets (Fig. 327) of round cells are formed from tetrads. The names given above, which are used, as has been said, to designate different species, have only a limited value, and only to this extent : they represent the appearance corresponding to the forms of growth which characterize various kinds of cocci that differ very greatly from one another in their cultures as well as in their physiological properties. StUl they are expedient for understanding quickly the manner in which a form of bacterium appears in any nutrient medium, such as a human being. The term micrococcus, moreover, is used by most authors for all the different cocci, and is not restricted to the staphylococcus. 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 Cien- kowski, van Tieghem, and Zopf, the Coccus mesenterioides, leuconostoc, that makes a frog-spawn-hke coating on sugar or parsnips, forms arthro- genic 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 decom- position. Many of them also produce pigment. 2Iicrococcus urece (Pas- teur, 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 Pfliiger 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 lufeus, the Micrococcus auranfiacus, the Sarcina hitea, the Micrococcus cyane- us, and the Micrococcus molaceus, which produce yeUow, 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 liamatodes (Babes) is said to be the cause of red sweat, and produces red-colored zooglcea masses. Sarcina ventriculi (Fig. 327) 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 spher- 448 THE DIFFERENT FORSfS OF FISSION-FUNGI. ical 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 ceUuJose. Micrococcus tetragenus {merismopedia) 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 hsemorrhagic softening foci in the lungs, and forms tetrads in multiplying, the cells of which are held to- gether 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. Micrococcus fceiidus is described by Rosenbach as having been found in carious teeth. In the intestinal tract Brieger and Escherich have found cocci. In the cavity of the mouth cocci are always to be found along with bacilli. (6) Pathogenic Cocci. § 168. The pathogenic cocci cause mostly diseases which run an acute course in human beings and in animals, and at present there are already quite a number that are weU known and have had their action upon tis- sues studied. They are able to act deleteriously upon the tissues and to excite inflammation in them mainly by the excretion of certain poisonous substances {toxins or toxalhmnins) . In the first place there is a group of cocci which occur especially in suppiu'ative processes, and are, moreover, the cause of the suppuration ; they may therefore be called pus=cocci. A given suppurating focus con- tains sometimes only one single form of coccus, sometimes two or more of them. One which occurs oftenest is the staphylococcus pyogenes aureus (Ogston, Rosenbach, Krause,, Passet). This coccus tends to form cloudy or aggregated or grape-shaped colonies in animal tissues (Fig. 325, Fig. 328, c, ci, and Fig. 329, d), or it may form swarms; but it not infre- quently forms diplococci and tablet-cocci, and torula-chains. It can be stained with different aniline dyes, and retains the stain by Gram's method. It grows on gelatin, agar-agar, and potatoes even at room-temperature, and forms whitish colonies that afterward turn golden yellow on places exposed to the air (Plate I., Fig. 1). The gelatin around the colonies becomes slowlj^ liquefied. By inoculation of pure cultures suppuration can be produced in mice, rabbits, and guinea-pigs. In man the presence of large quantities of staphylococci (Fig. 328, c, a, and Fig. 329, d) causes necrosis of tissue (Fig. 325 and Pig. 328, 6), and subsequently inflammation (Pig. 328, d,e) and suppuration (Pig. 329, e,f), which finally run on to abscess-formation (Pig. 329, g). In the skin it can cause those forms of inflammation which are termed acne, eczema, furuncle, and cuta- neous and subcutaneous abscesses, which are all characterized by suppura- tion and destruction of tissue. It can penetrate into the cutaneous and subcutaneous tissues through wounds, as well as by wa}^ of the hair-fol- licles or the ducts of the cutaneous glands. In the interior of the body it can cause suppuration of the various tissues. It has been observed frequently in suppuration of the bones and joints {osteomyelitis and peri- ostitis infectiosa), as well as in purulent injiammation of the lung, liver (Fig. 328), pleura, peritoneum, muscle, endocardium, myocardium, Iddney, etc. Ac- PATHOGENIC COCCI. 449 FiGt. 328. — Metastatic aggregation of micrococci in the liver, a, Normal lobule ; 6, Necrotic lobule ; c, ci, Capillaries and veins flUed with, micrococci ; d, Periportal small-cell infiltration; e, A collection of small round cells partly inside, partly outside a vein into wliioh a venula centralis filled with micrococci opens. (Preparation stained by Gram's method with gentian violet and with vesuvin, and mounted in Canada balsam. Magnified 40 diameters.) ;^5a ^-i^S Fig. 329. — Endocarditis pustulosa caused by Staphylococcus pyogenes aureus, a, Tissue of the posterior segment of the mitral valve ; &, Threads of tendon ; c, Pustular protuberance of the upper surface of the mitral valve ; d, Staphy- loccoccus pyogenes aureus; e, Staphylococci intermixed with pus-corpuscles; /', Pus-corpuscles with cocci ; g, Small abscess. (Preparation hardened in alcohol, treated by Gram's method and subsequently stained with vesuvin, and mounted in Canada balsam. Magnified 60 diameters.) 450 THE DIFFERENT FORMS OF FISSION-FUNGI. cording to investigations of Ullmann, the staphylococcus is very often present in large numbers in the air, especially of rooms much used. In many cases, as can be proved, it gets into the inside of the tissues through wounds, and is taken up by the lymph-vessels and veins iii whose neighborhood and in whose walls it has settled, and then is con veyed farther by the blood-current. The suppurations in the internal organs bear, therefore, the character of metastatic processes, and the terin pycemia following infection of wounds is applied to them. In other cases the infection starts from the air-passages or from the intestinal tract, especially where ulcers furnish a portal of entrance. In still other cases the portal of entrance cannot be made out. This is true, for example, in many cases of endocarditis and myocarditis, suppura- tive or septic osteomyelitis and periostitis, suppurative pleuritis, etc., in which the process is one of cryptogenetic infection. According to the observations referred to above, the Staphylococcus pyogenes aureus causes mostly circumscribed suppurations ; stiU its vit-u- lenee is not always the same, and hence the multiphcation of these bac- teria in the tissues does not always lead to suppuration, but often merely to light transitory inflammations. In course of time the cocci iisually die out, after which the process heals. Under certain circumstances, how- ever, they seem able to remain for a long time — weeks or even months — in the tissues. Staphylococcus aureus is able to cause the suppurations above men- tioned as well alone as in company with other cocci. Staphylococcus pyogenes albus (Rosenbach) corresponds under the microscope with the staphylococcus just described, but appears white in cultures. Its action upon the human and animal organisms is the same as that of Staphylococcus pyogenes aureus, and is observed alone as well as in company with the latter in foci of suppuration. Staphylococcus pyogenes citreus (Passet) is also a pus-producing fis- sion-fungus ; it occurs, however, more seldom than the first two. It forms citron-yeUow colonies (Plate I., Fig. 6). Micrococcus pyogenes tenuis, a coccus first observed by Rosenbach in abscesses, is somewhat larger than staphylococcus, and forms cultures almost as clear as glass on agar-agar. It seems to occur seldom. Streptococcus pyogenes (Ogston, Rosenbach, Krause, Passet) is char- acterized by a tendency to form chains of from four to ten links or more, and also diplococci. The individual cocci are somewhat larger than the cells of the yellow staphylococcus. Staining succeeds very well by Gram's method (Fig. 330). On gelatin plates it forms only very small, slightly elevated colonies that grow slowly, appearing yellow or brownish under the microscope. On agar-agar the colonies are cloudy and not transparent. In gelatin stab-cultures it forms small whitish, almost transparent col- onies. It produces, on subcutaneous inoculation into animals, sometimes only transitory, insignificant inflammation (rabbits), sometimes a small area of suppuration. Healthy rabbits bear even intravenous injection. If the valves of the heart are previously injured it is possible sometimes to produce endocarditis (Fliigge, Wyssokowitsch). The streptococcus is often observed in human beings, and causes sup- puration and sero-purulent and fibrinous exudates which have the ten- dency to spread over large areas, so that wide-spread cloudy, purulent, gelatinous infiltrations, phlegmonous influimiiations, and purulent oedema PATHOGENIC COCCI. 451 result. It eau penetrate from wounds or from the puei-peral uterus into the tissues; but such iufiammations can also occur, irifJiaiit any observable changes at the portal of eutrunve, iu suhcutaneous, iutermuscular, medias- tinal, peripharyngeal tissues, in the seroiis and mucous membranes or the subniucosa of the nose and its adjoining cavities, in the submucosa of the stomach, etc. The strept()('oc<'i lie in the foci of inflanuuation partly free in the tis- sues (Fig. 331) and partly in the cells (Fig. ^30, b). The former is espe- cially observable Avhere the cocci peneti-ate into the tissues (Fig. 331, a). In the region of the coccus invasion the tissues in time succumb to necro- sis (c), and finally are destroyed, becoming disintegrated and liquefied. If a tissue becomes the seat of suiDpuration, out of su(!h foci the pro- ducts caused by the process of decomposition are taken up by the juices of the body, and often lead to morViid conditions of the entire organism. Cocci themselves often get into the ch-culation and transfer the process to other organs. If the infection of a wound leads to a metastatic or embolic inflamma- tion and suppuration accompanied l)y fever, the process is called pyaemia. If a general disense with severe symptoms on the part of the nervous system appears, with disturbance of the regulation of tempei'ature and blood-circnlation, often acc(mipanied, also, by diari-hu-a, etc., without the format-ion of metastases, the disease is classed as septicaemia or sep= thaemia. Both terms ai'e (MiUective, since a metastatic inflammation accom- panied by fever is not necessarily brought aliout by one single form of bacterial infection, and the mauifestations of septicaemia are not always caused l)y the same noxious agent. The essence of si^jifica niia is a poisiniiiig of the. orgaiiisni by toxins^ toxul- bumins, ferments, and other products of bacterial decomposition — /.''., it is a septic intoxication. As these products differ according to the stage of the putrefaction as well as according to the nature of the putrefactive agent, it follows that the intoxication cannot ahvays be t-a.used by the same sub- stance. Simultaneously with the intoxication, infection, of the blood with micro-organisms can also take place ; but this is not ne(!essary, and it is possible to distinguish between a si'ptic intoxication, pure and simi)le, on the one hand, and a ba<-terial septiccemia, on the other. Moreover, the manifestations of septicmmia may be combined n-ith pi/wmic inflammation, a combination that has given rise to a disease that has been designated septicopyaemia or pyosepthaemia. ^..._ X- FiG. 330. — Streptococcus pf/oge- ^?~^fmi]'f^^^-^i'.i from a phlegmonous inflam- "—f ^\v-3/f7i>>//rTA^-'--^'-.Ji^'' matory focus of the stomach, a, -iJ-'-i'-.- r?'#){. ■'#)^^=^''''---x Leucocytes; &, Leucocytes with _- -. c^.a ■„ ;/ r..-- ,\ -,.^. -. ,-^l.^,/ -.-=^ streptooocci inside; -•. Free strep- j ti':0;-;y/:--'®''-V (pi'%f}'''^^'^''^-\'' tocooci. (Preparation hardened in ^'^'~^''l'.Il^'^^^se::;^^^^>'-s'''^^ alcohol, stained t)y Gram's method, ' 3^^:pss=c- ^---^^==f^y^-^^ V;^ ,^; -^_ ^ and mounted in Canada balsam. / 'gkA ['f-^r^ yj,----' -^ ^^ \ Magnified 500 diameters.) X \my/ 'v^' -< Septic blood-])oisouings ftdlow most frequently from wounds and from foci of suppuration situated in the parenchyma of the tissues, but the putrid substance producing the intoxitjation may l)e taken up from the 452 THE DIFFERENT FORMS OF FISSION-PUNGI. intestines or the lungs. The anatomical changes in the infected wounds are often insitiuificant and scarcely recognizable. ^;:-'V-vAtfv:^-. Fig. 331. — 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 poisoning. (The phlegmon of the wall of the chest developed two days after the finger was injured, and the intermediate lymph-vessels of the arm showed no evidences of being involved.) a, Perimysium internum full of streptococci ; b, Transversely cut muscular fibres, still intact ; c. Transversely cut muscular fibres which are beginning to degen- erate ; d, Muscular fibres into which the cocci have penetrated. (Preparation treated with gentian violet and vesuvin, and mounted in Canada balsam. Mag- nified 350 diameters.) If the first iuflaniniatory processes start in the de^jth of the body they are characterized as cryptogenetic pyaemia and septicopyaemia. The bacteria producing them get into the tissues from the intestinal canal or the lung, or from the skin, or from any small wound, and are thence con- veyed with the blood-current or the juices to anj'' particular place with- out leaving behind any demonsti'able change. As is seen from the foregoing, suppurative processes may be produced in man as well as in animals by different bacteria, and not infrequently many forms of bacteria are contained simultaneously in a focus of suppiu-ation. Be- sides the pus-cocci proper, the gonococcus, the Diplococeus pneumonia, the Bacillus typhi abdominalis, the actinomyces, and the glanders-bacillus can also produce suppui'ation. According to Flugge, the streptococci which occur in suppuration do not all belong to the same species. Thus Flugge found a strepto- coccus in a necrotic focus in a leucsemic spleen (Streptococcus pyogenes malignns) that closely resembles the ordinary Streptococcus pyogenes under the microscope and in cultures, but kills mice and rabbits in a few days when introduced by subcutaneous inoculation; at the same time producing not only local inflamma- tion at the point of inoculation, but also metastatic inflammation, and appear- ing as well in the blood. Different authors have used the term septicmmia also for hacterial infections of the blood which can be produced experimentally by inoculation of animals, and which are characterized by the fact that the bacteria multiply in the blood. It would be more proper to apply the term bactericemia to such processes. THE DIFFERENT FORMS OF PATHOGENIC COCCI. 453 § 169. streptococcus erysipelatis is the cause of the inflammation of the skin and mucous membranes called erijsipelas. According to Pehleisen, it may be cultivated upon the meat-inf usion-peptone-and-gelatin mixture ; and the cocci from cultures produce typical erysipelas wheu inoculated into human beings. The fission-fungus of this disease, moreover, may be inoculated into rabbits (Ziegler, Fehleisen), and produces an inflam- mation radiating from the point of inoculation. It is killed in one min- ute by 3 per cent, solutions of carbolic acid or by a 1 : 1000 corrosive- sublimate solution (Fehleisen). The cocci get into the skin through small wounds, and thence into the lymph-vessels (Fig. 332, a, h), but occasionally also into the blood- current. Fig. 332.— Colonies of Strep- tococcus erysipelatis .- a, in a lymph- vessel, 6, in part composed of thickly packed spheres, in part of torula-chains ; c. Neighbor- hood of the lymph- vessel, with pale tmstaiaable nuclei ; d, Vein ; e, Perivenous cellular infiltra- tion, of tissue; /, Accumulation of cells in the lymph-vessel. (Section of rabbit's ear two days after LQoeulation with erysipelas-cocci, treated with gentian violet, and mounted in Canada balsam. Magnified 250 diameters.) Observed in hving beings, erysipelas runs its course in the form of a reddening and swelling of the skin extending at the periphery and accom- panied by a febrUe condition. In some cases vesicles are formed in the skin, and under certain circumstances individual portions of the skin be- come even gangrenous. The cocci that spread in the lymph-vessels form first torula-chains (Fig. 332, a) and afterward colonies that fill the lymph-vessels more or less fully (Fig. 332, b, and Fig. 333, Ji, i) and not infrequently spread over the contiguous connective tissue (Fig. 333, ](). In the area of a larger bacterial invasion and in its neighborhood the tissue usually degenerates and often becomes devoid of nuclei — necrotic (Fig. 332, c, and Fig. 333, 1, h)- At the same time an inflammation occurs in the neighborhood which is connected directly or indirectly with the tissue-lesion caused ty the bacteria. Consequently it either represents a reaction dependent upon the degeneration of tissue, or is to be regarded as an alteration of the vessel- walls by the products formed by the bacteria. It leads to a dense cellular infiltration of the tissue (Fig. 332, e, and Fig. 333, m, mi). A Uquef action of the cells can take place in the epithelium (Fig. 333, e, /, M Fig. 335. — Diplococcus ptieumonia of Weichselbaum ffi® ^ '■'/// ,^^\-, ^^^ Frankel. a, Cocci without a capsule; 6, Single %"^ (l/ ®5X1® cocci and double cocci ta a gelatinous envelope; c, Chain-cocci with a gelatinous envelope; d, Colonies of cocci. (Magnifled 500 diameters.) According to the observations of Fraukel, Weichselbaum, and others, it is the cause, in a large number of cases — according to Weichselbaum, 71 per cent. — of the lung-affection called croupous pneumonia, in which the lung is the seat of an acute inflammation which is ushered in by a congestive hyperaemia. In the course of the disease the alveoli over large areas become filled with a coagulated exudate which consists of des- quamated epithelium, leucocytes, 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 characteristics of catarrhal bronchopneumonia — processes, therefore, which encroach upon the lung-tissue by extension from the bronchi, and which are characterized by the appearance of an exudate partly serous, partly cellular. The cocci are found during the disease principally in the inflamed area of the lung, but they maj^ also be met with in neighboring areas — in the pleura, and, iinder certain circum- stances, in the pericardium , in the peritoneum, in the meninges (A. Frankel, Fo&,, Bordoni-Uffreduzzi, Weichselbaum, Ortmann), in the cavities adja- cent to the nose, in the cellular tissue of the neck, in the mediastinum, in the submucous tissue of the soft palate and throat, even in the conjunc- tiva (Weichselbaum) ; and in all of these localities they cause inflammatory changes. Occasionally they may be found in the 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 through- out the body. They may cause a serofibrinous inflamm ation in the meninges, the pleura?, the pericardium, and the peritoneum, and under certain con- ditions they may also cause seropurulent and fibrinopurulent inflamma- tion, without the appearance simultaneously of a pneumonia. They can, furthermore, cause inflammation of the endocardium, of the kidneys and of the joints (Samter), and are also found in abscesses (Haegiei-, Ortmann, Samter). 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 cerebral and cerebrospinal meningitis (Weichselbaum) the maxillary cavity, the tympanic cavit}', 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. In cover-glass preparations the cocci, as weU as their capsule, stain well with fuchsin and gentian violet dissolved in aniline water. If the cocci stained with gentian violet are treated with a solution of iodine and alcohol they retain the stain. They will not grow on gelatin at ordinary room-temperatm-e, 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 THE DIFFERENT FORMS OP PATHOGENIC COCCI. 457 suggest the deposit of dew on a cover-glass (Frankel) and consist of diplococci and chain-cocci witliout capsules. The growth is, however, scanty, and easily dies out. Cultures do not succeed on potatoes. Inoculated upon rabbits, guinea-pigs, and mice, they multiply in the form of capsule-eocci, 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 to forty-eight hours after subcutaneous inoculation, with symptoms of septi- caemia. If pure cultures are injected into the pleural cavity of rabbits a pleurisy results, as well as a splenization of the lung in which the paren- chyma 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 vii-ulence 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 pneumonice belongs to those bacteria whose physiological char- acteristics are very variable. Fo& distinguishes, according to the principal places in which they are encountered, a pnemnococcus and a meningococcus. According to Emmerich, in bouillon-cultures there is formed a sediment at the bottom con- taining some resistant forms which remain capable of development for months. Rabbits may be rendered completely immune (Emmerich) by repeated injections of much-dHnted cultures (five thousand times diluted) of increasing vu-ulence, so that 30 oc. of cultures of full virulence are borne without any striking dis- turbance. The injected bacteria are killed in the course of a few days. The serum of immunized rabbits can cure pneumococciis infection in rabbits and mice. The Diplococcus pneumonia, it is true, is the most frequent, but not the only cause of croupous pneumonia. In a smaU percentage of cases a streptococcus occurs in pneumonic lungs that resembles very closely the Streptococcus pyogenes — ^possibly it is identical with it. Cases also occur in which the exudate contains the Staphylococcus pyogenes aureus, also the alhus, sometimes alone, sometimes along with diplococci. Furthermore, a part of the cases are to be referred to the invasion of the Bacillus pneumonice of Friedlander (cf . § 178). Staphylococci and streptococci appear particularly in pneumonias occurring in the course of pyaemic infections. In the course of other infectious diseases, as, for example, typhoid fever, croupous pneumonia may be caused by the specific bacteria in question (tjrphoid-bacilli). Bronchopneumonias — i.e., inflammations of the lungs arising from inflam- mations of the bronchi or from inspiration of inflammatory irritants from the au'-passages — have a very varied etiology, and are partly attributable to the entrance of the Diplococcus pneumonia or of staphylococci and streptococci into the lungs, and partly to other specific infections the causes of which are unknown, as measles and whooping-cough ; often also to mixed infection and to the inspi- ration of foul substances, etc. BUebs, and subsequently Eberth and Koch, published papers upon the oc- currence of cocci in croupous pneumonia. More thorough investigations, how- ever, were first made by Friedlander, Frobenius, A. Frankel, Weichselbaum, Talamon, Senger, Poa, Bordoni-UfEreduzzi, and others. § 172. The pathogenic significance of the bacteria above mentioned is proved by experiments upon animals ; and although the biology of these bacteria, in some cases, is only incompletely known, still there is no ques- tion as to then* etiological connection with the diseases concerned in the majority of cases. 458 INFECTIOUS DISEASES OF ANIMALS CAUSED BY COCCI. In another category of infectious diseases cocci have been often ob- served and described, it is true, and also pronounced to be the cause • but at the present time there is nothing certainly known about them, and it is very likely that many of the bacteria found stand in no sort of rela- tion to the diseases concerned, and constitute only secondary colonizations. To this category belong the cocci found in variola, varicella, scai-latina, morbilli, influenza, yellow fever, acute yellow atrophy of the liver, and mycosis fungoides. Among the infectious diseases occurring in animals there are also a number supposed to be caused by cocci ; thus the cattle-pest, the pleuro- pneumonia of cattle, the myofibroma of horses ( Johne), and the pneumonia of horses (Perroncito). Various affections can be produced experimentally in animals by the inoculation of cocci — e.g., the Micrococcus tetragenus, the staphylococci, streptococci, and the Diplococcus imeumoniae.. Infections Diseases of Animals said to be Caused by Cocci. 1. According to Poels and Nolan,* 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 cultm-es injected into the lungs of rabbits, guinea-pigs, dogs, and cows cause pneumonic changes. Cornil and Babes found various bacteria in the exudate. 2. According to Semmer and Archangelski,f the microparasite of cattle-pest is a micrococcus. According to Metschnikoff and Gamaleia,t it is a bacillus. The disease is anatomically distinguished by inflammation of the intestiual tract, bearing partly a croupous and diphtheritic character, as well as by swell- ing and sometimes even by necrosis of Peyer's plaques. 3. According to Schutz,^ the epidemic lung-disease of horses, infectious pneu- monia, is caused by an oval coccus, which is not identical with the Diplococcus pneumonicB of Frankel or the Bacillus pneumonia of Friedlander, and conse- quently not identical with the fission-fungus described by Perroncito || in the pneumonia of horses, and held to be identical with the Diplococcus pneumonice. 4. According to Schutz,1T Sand and Jensen,** and Poels,ff 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, more- over, the lymph-glands pertaining 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 inoculation (Schiitz). 5. According to Hess and Borgeaud,tt the infectious inflammation of the udder which is designated yellow Oalt, and which occurs in cows, goats, and sheep, is caused by a streptococcus. 6. Babes found in hemoglobinuria of cattle — a disease that occurs in epi- * Fortschr. der Med., 1886. t CentralM. f. d. med. Wiss., 1883, and D. Zeitschr. f. Thiermed., xi. t CentralM. f. JBakt, i., 633. § " Die Ursachen der Brustseuche des Pferdes," Archiv f. loissensch. ii. prakt. Thierheilk., 1887, and Virch. Arch., 107. Bd., 1887. II Arch. ital. de biol, vii., 1886. IT " Der Streptococcus der Druse der Pferde,'' Arch. f. loissensch. u. praM. Tliierheilk.,^ xiv., 1888, and Zeitsch. f. Hygiene, in. ** " Die Aetiologie der Druse," Deutsche Zeitsch. f. Tliiermed., xiii. tf " Die Mikrokokken der Druse der Pferde," Fortsch. d. Med., vi. Jt " Eine contagiose Euterentziindung, gelber Q-alt genannt," Schweizer Arch, f. Thierheilk., 30. Bd., 1888. THE BACILLI AND THE MORBID PROCESSES CAUSED BY THEM. 459 demies in Rumania — a coccus resembling the gonococcus, wliicli lie regards as the cause of the disease.* 7. According to Semmer, Friedberger, and Mathis,f the distemper of dogs is also caused by a coccus, which can be cultivated pure and which causes the dis- temper in dogs when it is inoculated subcutaneously. 8. The foot-and-mouth disease of cattle, according to Klein, is caused by a streptococcus t which, on niitrient gelatin, blood-serum, and agar-agar-peptone bouillon, slowly develops colonies in the form of closely aggregated small points or drop-like spots. In recent years, Sehottelius§ and Kurth|| have also found a streptococcus in the organs of animals sick of the foot-and-mouth disease; but the bacteria described do not correspond with one another, and the patho- logical significance is doubtful. Johne has published a review of the works published up to the present time on foot-and-mouth disease.il 9. According to Rivolta and Johne,** and Eabe,tt 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 tis- sues in round or grape-eluster-like colonies. These quickly become surrounded by a hyaline capsule, and are therefore to be reckoned as ascococci (Micrococcus ascoformans). The tumefaction consists, similarly to that of actinomycosis, of connective tissue, inclosing small foci of prohferation, which break down into pus. The foci harbor the fungi. They seem to develop oftenest in the sper- matic cord, after castration. They appear, however, in other parts of the body.K 10. According to Eberth§§ and M. Wolef |{|| a large number of the gray par- rots {Psittacus 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 Uver and their neighborhood, where they cause necroses of the liver-cells, but no suppuration. 11. According to Eberth, H IT some of the pseudotuberculous processes occur- ring in guinea-pigs represent a chronic suppuration that is produced by cocci, and that sometimes leads to metastases in other organs. 2. The Bacilli and the Morbid Processes Caused bp Them. (a) Vegetative Fwms and Method of Multiplication of the Bacilli. — Non-pathogenic Sapi'ophytic Bacilli. § 173. At pi'esent all those bacteria which form rods by their growth and reproduction are classed under the term bacilli. Consequently the microbacferia (according to the classification of Cohn), as well as the des- mobacteria designated bacilli, are included under this conception. * " Sur I'hemoglobiuurie bacterienne du boeuf," Compt. rend, de I'Acad. des Sciences de Paris, cvii., 1888; Virch. Arch., 115. Bd.; and Annal. de VInstit. de Pathol, a Bucarest, 1890. f Gentralbl. f. Bakt, iii., 343. t Gentralbl. f. d. med. Wiss., 1886. § " Ueber einen bakter. Befund bei Maul- u. Klauenseuche," Gentralbl. f. Bakt., xi., 1892. II " Bakt. Untersuch. bei Maul- u. Klauenseuche," Arb. aus dern Beichsgesund- hesitamt, viii., 1893. H Deutsche Zeifsch. f. Thiermed., xix., 1893. ** Deutsche Zeitsch. f. Thiermed., xii., and Beiicht iiber das Veterinarwesen im Konigr. Sachsen f. das Jahr 1885. ft Deutsche Zeitsch. f. Thiermed., xii. ii Kitt, " Der Micrococcus ascoformans und das Mykofibrom des Pferdes," Gentralbl. f. Bakt, iii., 1888. H Virch. Arch., 80. Bd. |||| Virch. Arch., 92. Bd. nil Virch. Arch., 100. Bd. 460 THE BACILLI AND THE MORBID PROCESSES CAUSED BY THEM. 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 for some time, or if the division between the differ- ent parts is not easily recognized, there result long jointless rods or threads (Fig. 337, i). If the divided rods remain hanging together they form chains of rods (Fig. 336, c, and Fig. 337, c). In many forms of bac- teria the ends are blunt, in others rounded or even pointed. Fig. 337. Fig. 336. — Bacillus subtilis in different stages of development. (After Praz- mowski.) a, Separate rods; 6, Rods with flagella; c, Chains of rods; d, Separate cells with spores; e, Chains of rods with spores; /1-/5, Germination of spores. (Magnified 800 diameters.) Fig. 337. — Clostridium hutyricum. (After Prazmowski.) a, Short rods; 6, Long rods; c, Chains of rods; d, Cells with spores; 61-67, Germination of spores. (Magnified 800 diameters.) In many bacilli resting stages as well as swarming stages are observed, in which the flagella serve as organs of locomotion (Fig. 336, 6). The flageUa are situated sometimes at the ends, sometimes on the sides of the rods, and may occur in large numbers. In many baciUi endogenic spore=formation is observed (Fig. 336, d, e, and Fig. 337, d), in which the spoi-e sometimes lies in the middle, some- times in the end of tlie cell. Not infrequently the spores appear in jointed threads. The germination of spores results in the formation of new rods (Fig. 336,/i-f5, and Fig. 337, ei-ei). 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. 337, d), and this has been taken as ground for establishing a special group, Clostridium. Numbers of authors, 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 amylobader, and these offer good exam^Dles of the processes which come under consideration in this connection. Bacillus subtilis is a fission-fungus whose spores are very widely dis- tributed in the air, and consequently is met with on various objects. It can be obtained by leaving an infusion of liay open in the incu- bator. Cultivated upon slices of potato or upon dung of herbivorous ani- mals, it forms whitish-yellow clumps ; on liquids, thin and thick pellicles. It requires oxygen for its development. The fully grown cells (Fig. 336, a) are 6 |U long. The snake-like motions sometimes seen are produced by one or two flageUa (b). The THE BACILLI AND THE MORBID PEOCESSES CAUSED BY THEM. 461 growtli 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 ill their interior glistening, sharply contoured spores {d, 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 germination the spore (Fig. 336, /1-/5) becomes pale and loses its glistening appearance and its sharp contour. Then at each pole a shadow appears, while the spore be- gins 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 produces swarming staves. The empty spore membrane may remain preserved for a time after the exit of the embryo. Bacillus butyricus {Bacillus amylohacter of van Tieghem, Vibrioii luty- riqiie of Pasteui-, Clostridium Jyutijricum of Prazmowski) possesses staves of 3 to 10 /i in length, and also produces threads and chains of rods. In spore-formation the cells become spindle-shaped or club-shaped and tad- pole-shaped (Fig. 337, d), and then produce one or two glistening spores. In germination after absorption of the spore membrane a germinal tubule protrudes from one of the two poles (Fig. 337, ei-e?). This becomes pro- longed and forms new staves by segmentation. Bacillus dutijricus needs no oxygen for its development, and produces butyric-acid fermentation, with evolution of carbonic-acid gas, in solutions of starch, dextrine, sugar, or glycerin. In starch or glycerin or nutrient fluids containing cellulose the bacilli stain blue with ioditie. § 174. Saprophytic bacilli caxise many kinds of fermentation by their growth in nutrient fluids ; many of them also form pigments. • Bacillus prodigiosus grows on potatoes and bread, as weU. 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 de- velops only where oxygen is present. In the growth in milk the color- ing-matter is contained in the fat-droplets. The bacilli themselves are always colorless. Bacillus f luorescens liquefaciens produces in gelatin whitish cultures, and in the neighborhood of these the gelatin becomes liquefied, while the gelatin in the more remote surrounding portions fluoresces with a yellow- ish-green color. 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 (Fliigge). Bacillus acidi lactici causes fermentation of sugar of mUk in lactic acid, and produces coagulation of casein. The cultures obtained in gela- tin are of a white color. Bacillus caucasicus {Bispora 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 a round spore. By their growth in the milk the milk-sugar is probably converted into glucose, while 462 PATHOGENIC BACILLI. — ANTHRAX. 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, 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 cidtivated in meat (Carbone) asthylendiamine, gadinin, and trimethylamine, of which the fii-st two bases are poisonous for ani- mals. According to observations of Bordoni-Uffreduzzi, Fo^, Bonome, and Banti, certain bacilli closely resembling the proteus of Hauser seem to be pathogenic for human beings and capable of causing blood infection as well as intestinal affections. Bacillus aceticus {Mycoderma aceti.) 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- nine 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, sometimes general infection. According to Kossel, it is pathogenic for children and causes inflammation. Bacillus saprogenes was discovered in foul-smelling secretions by Rosenbach, who showed that the bacilli cause a foul-smelling putrefaction in meat. Bacillus ureae, a short, rather broad rod, is often found, according to Leube, in old urine, and converts the urea into carbonate of ammonia. A fission-fungus from the cavitj'^ of the mouth, described as Leptothrix buccalis, forms long, thin, not visibly jointed threads, which are often mixed with cocci, and form masses that stain violet when treated with iodine and acids. According to observations of Tratibe, Leyden, and Jaffe, it also occurs in gangrenous lung-tissue. Porster, 0. Graefe, and Cohn observed it in concretions of the tear-passage. It is assumed by many authors to be the cause of caries of the teeth. Very likely lepto- thrix represents merely the thread form of different bacteria. Foiiaerly Bacterium termo was named as one of the most familiar forms of bacteria. It was described as a small rod, somewhat constricted in the middle, from 1 to 1.5 p. in length ; sometimes ghstenipg, sometimes black, according to the focussing of the microscope ; sometimes at rest, sometimes in more or less active motion. According to Hauser, however. Bacterium termo merely repre- sents a form of growth of proteus, and can therefore no longer be regarded as a separate species. (6) Pathogenic Bacilli. § 175. Bacillus anthracis (Bacteridie 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 inocu- .lated into a susceptible animal organism. The anthrax-bacilli (Fig. 338) are from 3 to 10 |U long and from 1 to 1.5 ^ broad. In the 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. 338 and 339), more seldom slightly concave PATHOGENIC BACILLI. — ANTHRAX. 463 or even convex (Johne). According to Serafini, Giinther, and Johne, they possess a gelatinous capsule, which can be best made visible in dried prep- aration by staining with methylene blue (Giinther). They can be culti- vated upon blood-serum, upon gelatin, in bouillon, on slices of potatoes 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° C. Development is impossible at a temperature below 150 C. and above 43° C. ; it is also impossible in the absence of oxygen. Fig. 338.— Section of liver with capillaries containing numbers of anthrax-bacilli and a few leuco- cytes. (Preparation treated with gentian violet and vesuvin. Mag- nified 300 diameters.) If the conditions above mentioned are present, the staves grow in length (Fig. 339), 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 only by treatment with iodine or with some coloring-material (Fig. 339). Ten hours later the clear contents of the threads become granular, and at regular intervals bright glistening bodies become apparent, which enlarge into strongly refractive spores (Fig. 339). Later on, the threads disintegrate and the spores become free. Fig. .339. — Anthrax-bacilli containing spores, and free spores that have escaped from the bacdli. (Cover-glass preparation treated with fuchsin and methylene blue, from a culture of the bacUh on a potato, under the stimulation of heat in an incubator.) According to Bref eld, 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. Swarming is not observable dui-ing the entire process of development ; the bacilli are always motionless. The anthrax-bacilli easily die under the influence of high temperatures, when subjected to drying, and in the presence of a nutrient medium which has become putrefied. The spores, on the contrary, are very resistant, and consequently are the ordinary medium of the transfer 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 464 PATHOGENIC BACILLI. — ANTHRAX. 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. If the bacilli or spores get into the blood they multiply and produce the staves above described, which can be readily observed in a drop of blood taken from a vessel and stained with gentian violet. On decolor- izing the preparation by Gram's method it will be found that these staves retain the stain. Sections of hardened organs show that they are present in large numbers in the capillaries, 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, especially in the spleen- pulp. If an infection of the blood takes place during pregnancy the infection may go over to the foetus. If anthrax-bacilli or their spores get through little wounds of the skin ^Sk'Wy^rii^'ifJ^ .. r tfM^-^^ ' Fig. 340. — Section through an anthrax-pustule ten days old, extirpated from the arm of a man. a, Epidermis; 6, Corium; c. Papillary body, csdematous, swollen, fiUed with exudate and bacilli; A, External layer of the corium iniU- trated with cells; di. The same containing bacilli; e. Deeper layers of the corium containiag bands of cells; /, Tissues of the skin interspersed with bacilli and cells; g, Bloody exudate on the sm'face containing baciUi; h, Hair-follicle j i, Sweat-gland coil. (Preparation hardened in alcohol, treated with gentian violet, iodine, and vesuvin, and mounted in Canada balsam. Magnified 35 diameters.) PATHOGENIC BACILLI. — AKTHRAX. 465 in humau beiugs tliey develop a somewliat elevated pustule witli arched or flattened surface (Fig. 340), usually from six millimetres up to several centimetres in diameter. The pustule is red or possibty more of a yellow- ish color. It is often, in time, covered with vesicles, or after the loss of epithelium it becomes moist ; and by the drying of this exudate, which is often bloody, a scab is formed (Fig. 340, g). Infection takes place in per- sons 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 of the pus- tule is sometimes little changed and sometimes red and swoUeii, and may be occupied by small yellowish or bluish-red vesicles (W. Koch). If the process remains local the sloughing pustule may be thrown off. Infec- tion of the blood is followed by fatal consequences. In rare cases infec- tion shows itself in a wide-spread, intense cedematous swelling of the tis- sues without the formation of a circumscribed pustule. In the region of a fully developed anthrax-pustule (Fig. 340) the corium {d, di) and papillary body (c) become permeated by a cellular serous and bloody exudate as well as by bacilli. The bacilli lie in the external portions of the corium (f?i) and in the papillary body (c) ; but they can penetrate into the deeper layers of the corium (/). In the region of the papillary body (r) the exudate is sanguinolent. Vesicles filled with bloody fluid resTilt if the exudate extends up to the epithelial 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 {g) appears on the surface. Fig. 341. — Section from a portion of an anthrax-pustule where the tissues contained bacilli. (Preparation treated according to Gram's method with gentian violet and then colored afterward with vesuvin. Magnified 350 diameters.) The cellular infiltration has its seat mainly in the corium {d, di, 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. 339). The taking up of vigorous, strong bacilli into the cells does not take place ; consequently the infiuence of the cells upon the devel- opment of the bacilli — if any such influence exists at all — cannot lie in this act of " devouring " on the part of the cells. If infection with anthrax-spores takes place in the intestinal canal the lesions are itsually located in the region of the small intestine, more seldom in the stomach and large intestine, and disease foci are formed which resemble in a general way the pustules on the skin, and which con- sist of reddish-black or reddish-brown hemorrhagic foci the size of a lentil or bean, with a grayish-yellow or greenish-yellow discolored sloiigh in the middle. In other cases the crests of the folds of the mucous membrane are swollen and show hfemorrhagic infiltration, and the most prominent 466 PATHOGENIC BACILLI. — ^ANTHRAX. parts show evidences of sloughing. The mucosa and submucosa are infil- trated with blood in the region of the foci ; the surrounding tissue is cedematous and hyperaemic. In these foci, as well as in their surround- ings, the tissue contains bacilli, especially in the blood- and lymph- vessels, and they may be equally well seen in the swollen lymph-glands. According to observations of Eppinger and Paltauf, primary lung in- fection occurs by inhalation of anthrax-spores, usually proving fatal in from two to seven days. Individuals that have to handle the hair of ani- mals that have died of anthrax are specially exposed. Rag-sorters' disease, occurring in the rag-sorters in paper-factories, is, iu a part of the cases, ac- cording to Eppinger and Paltauf, 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 pleiira, and in the broncjhial 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 tissues, and swelling of the lymph-glands. It may also lead to forma- tion 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 in- testines 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 bacUli at 42-43° C. (Toussaint, Pasteur, Koch) it is 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 before 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 inocula- tion with bacilli that wiU kill guinea-pigs, but not strong rabbits, sheep and cattle can be rendered immune, but not mice, guinea-pigs, or rabbits. Practically, liowever, this protective inoculation cannot be employed, be- cause 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. — 10-15 per cent. — die from the pro- tective 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- bacilh can, while retaining their full virulence, be permanently deprived of the power of producing spores by cultivation in bouillon to which a small amoimt (1 : 2000) of potassium permanganate or cai-bolic acid (1-2 : 1000) has been added. The bacilli of anthrax only develop at a temperature above 15° C, and in the presence of oxygen. In the body of an animal buried more than one metre deep, no spores can form. According to Johne,* they do not develop in the animal body even at higher temperatures. This, however, can take place very readily, according to Koch, if, in burying animals dead of anthrax, the blood ^ Bericht uber das Veterinanvesen im K. Sachsen pro 1885. PATHOGENIC BACILLI. TYPHOID FEVER. 467 and secretions (urine) get on the surface of the ground, where the temperature in summer goes above 15° C. Pasteur's assertion * that earthworms bring the spores of the bacilli in their intestinal canal up to the surface from the bodies of animals that have been buried, and deposit them with their excreta, is declared by Koch to be improb- able, and unnecessary for the explanation of the spread of anthrax, since in burying the bodies the surface-layers of the soil become contaminated. Koch bases his statement upon experiments made to test this point. It is evident from Koch's investigations that the transfer by earthworms does not play the r61e attributed to it by Pasteur, but the possibihty is not entirely excluded. BoUiuger was able to detect the presence of the bacilli — by means of inocula- tions — in only one specimen among seventy-two earthworms taken from pas- tures where anthrax prevailed.! According to Koch, anthrax-baciUi can be cultivated on potatoes and alka- line or neutral infusions of hay, on cold infusions of pea-straw, on mashed bar- ley and mashed wheat, in the juice of turnips, wheat, leguminous seeds, and numerous dead plants, in the presence of a sufncient quantity of water. Con- sequently the bacilli grow and develop 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 eotogenic bacillus. 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. § 176. The Bacillus typhi abdominalis (Fig. 342) is a fission-fungus which appears mostly in the form of plump staves 2 to 3 /^ long, with rounded ends growing out into long pseudothreads in cultures. It is recognized as the cause of typhoid fever. When examined alive in cul- tures it shows lively independent locomotion, caused by from eight to twelve flagella which are attached ^ to the sides of the staves as well as to the ends. ^ "^ <^ '^

vated pure by Gaffky. A. Pf eiffer showed its pres- ^/ ^ ^ cp '^ ence in the dejecta of typhoid patients, and Ms '^ observations have been corroborated often since Fig. 342. — Bacillus (Prankel, Simmonds, Seitz, Chantemesse, Widal, of typhoid fever. and others). According to Seitz, Hueppe, Neu- (Magnified about 800 mann, and others, it may also be present in the diameters.) urine of typhoid patients. It may be well stained in cover-glass preparations with gentian violet, alkaline methylene blue, and Bismarck brown. The bacilli stained with gentian violet become decolorized by treatment with iodine according to Gram's method. The detection of the bacilli 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 baciUus 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 is scarcely recognizable with the eye. But if the sur- face 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. * Bulletin de VAcad. de Med., 1880, No. 28. f Arh. a, d. path. Inst, zii Miinchen, 1886. 37 468 PATHOGENIC BACILLI. — TYPHOID FEVER. Od gelatin and agar-agar the bacilli form wliitish-gray flat cultures of irregular shape. Gelatin is not liquefied. Milk in which the bacilli are grown is not changed externally. Cultures floui-ish 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 not spores, but are degeneration forms occurring especially where the cidtm-e contains an acid (Buchner), in the presence of which the staves become relati^'ely long. The polar granules represent con- densed protoplasm, and consequently stain in fresh preparations more quickly with the anUine dyes than do the other parts. The clear, color- less 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 for- mation of hollows in the ends of the staves, due to retraction of the tube of protoplasm on the death and drying of the baciUi. The polar granules become changed in position to the middle portions by this retraction. Consequently spore-formation has not been proved to exist. In moist earth (Grancher, Deschamps), in pure and impure water, typhoid-bacilli may remain aliv6 for weeks. They do not die out for many weeks in artificial Seltzer water (Hochstetter). In privy- vaiilts and fiscal masses, or in earth saturated with ftecal matter, they may sm-vive, under certain circumstances, for weeks and months (Finkler, Uffelmaun, Karhnski). Inoculation of the bacilh in animals used ordinarily for experimental purposes does not produce a disease corresponding to typhoid fever in man. Stdl experiments of Sirotinin, Beumer, Peiper, and others have shown that the typhoid-bacilli produce active toxins and toxalbumins (Brieger) which kdl animals in larger doses, causing hyperasmia 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. Outside of the human body the bacilli have been found, as already stated, in the dejecta of typhoid patients, and they have been found, fur- thermore, in suspected water (Chantemesse, Widal, Beumer, Thoinot, Martinotti, Barbacci) and in the soil (Mace, Uffelmann). The bacilli or their spores get into the human organism probably with the drinking-water and food ; stiU an infection through the lungs is not to be excluded. According to the results of the anatomical examination, 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, that is extraordinarily rich in cells (Fig. 343, ai, &i), and appears in the form of flat or somewhat elevated and rounded areas above the inner surface of the intestines. Occasionally cellular inflam- matory foci limited in area occur also in the muscularis (ci) and in the serosa (di). A part of the infiltrated tissue usually sloughs and is then cast off, so that ulcers are formed. In another part the swelling may subside by the absorption of the infiltration. The swelling of the lymph-glands, which is also due to the accumula- PATHOGENIC BACILLI. TYPHOID PEVEK. 469 tiou of cells and fluid, either ends in i-ecovery by the absorption of tlie in- filtration, 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. Fig. 343. — Typhoid fever. Section through the edge of a swollen Peyer's plaque, a, Mucosa; 6, Submucosa; c, Musoularis interna; d, Muscularis ex- terna; e, Serosa; ai, 6i, ci, ^i, e,i The different layers of the intestine infiltrated; /, /, Sections of a Lieberkiihn's gland; g, Folhele. (Preparation hardened in alcohol, stained with Bismarck brown, and mounted in Canada balsam. Magni- fied 15 diameters.) According to recent investigations, the bacilli are usually distributed to other parts of the body, and it is probable that the inflammatory exu- dates 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 mind that inflammations due to inhalation of irritating substances very often occur in the kings of typhoid patients, and also that secondary infections with cocci start from the ulcers and maj' 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. The bacilli have often been discovered in the liver (GafEky, E. Frankel, Cygnaus, Simmonds), also in the gall-bladder (Chiari). The bacilli do not usually circulate in the blood; nevertheless, Neuhauss and Riitimeyer were able to cultivate them fi'om the blood of roseola patches. According to Seitz, Neumann, Faulhaber, and others, they may often be found in the kidneys. They have been observed by others (Chantemesse, "Widal, Curschmann) in the central nervous system, by Ebermaier in the inflamed periosteum, by Tavel in the inflamed testicle, by Valentini in purulent plemitic exudate, by A. Frankel in the exudate in peritonitis. According to Quincke, they st^em to be almost constantly ■470 PATHOGENIC BACILLI.— CROUPOUS PNEUMONIA. present iu the marroAv of bones. Xeuliauss was able to find them in the spleen of a fcEtus four mouths old whose mother was suffering from typhoid fever and had an abortion. Reher, Eberth, Chautemesse, Widal, and Ernst make similar statements. Since the typhoid-bacilli produce active toxins and toxalbumins, the morbid jjhenomena are to be referred largely to poisoning. The cultures of typhoid-bacilli show few characteristic properties, and are consequently difficult to distinguish from other widely distributed bacteria. Thus their properties are very similar to those of the Bacillus coli communis (at. § 177). As a differential 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 iu from twenty-four to forty-eight hours at 37° C. § 177. The Bacillus coli communis, or the Bacterium coli commune (Escherich), is a fission-fungus constantly present in the abdominal canal of man as weU as mammalian animals. The bacilli are staves 2 to 3 ,« long and .3 to .4 /i thick. They are capable of locomotion by means of flageUa, which may number as high as twenty on one staff (Bunge, Luksch, Giin- ther). The baciUi 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, the shade of maize or pease (G-iiuther). Spore-forma- tion does not occur. The bacilli cannot be stained by Gram's method. The Bacillus coli 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. § 176). Formerly it was regarded as a harmless saprojihyte of the large intestines, but it can no longer be doubted, according to recent investigations, that pathogenic properties are also attributable to it. Thus, under suitable conditions, such as perfo- ration or incarceration of the intestines, or impacted faeces, it may get into the peritoneal cavity and cause purulent inflammation, or at least take part with other bacteria in the production of inflammation. It gets, more- over, not infrequently, into the gall-ducts and gall-bladder, and seems capable of causing inflammations of varying intensity. Moreover, the bacillus has also been found, in some cases of septic disease, in the exu- date of the membranes of the brain ; furthermore, in pericarditis, pyelitis, cystitis, bronchopneumonia, strumitis, and scarlatinal angina. 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 consequently the two forms may pass over into each other. Still, at present the opinion prevails that the two bacdh are to be entirely separated from each other (cf. 5 176). As there are other bacilli that much resem- ble the Bacillus coli, and often are not to be distinguished with certainty from it, it may well be assumed that the publications on the Bacillus coli have not always dealt with the same bacterium. § 178. The Bacillus pneumonias is a bacillus discovered by Fned- lander and Frobenius ; it is capal)le of producing croxipous xineumonia, but PATHOGENIC BACILLI. — CROUPOUS PNEUMONIA. 471 is present only in a limited nnmber of cases of tliis disease (cf. § 171). More- over, it has also been found in the nasal secretion and in inflammations of the middle ear. The bacilli lie in the alveolar exudate, as well as in the pleuritic exu- dates that form at the same time as the inflammation of the lungs. They appear sometimes in the form of staves (Fig. 344, &), sometimes in the form of oval cells («), 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 reckoned with the cocei. Fig. 344. — Bacillus pneuinonice of Friedlander. a, Oval cells and rows of cells with gelatinous capsule ; b, Staves with gelatinous capsule. (Magnitied 500 diameters.) The bacilli possess a hyaline, mucin-like capsule, soluble in alkalis, in- soluble in acetic acid, which forms a common sheath around the chains of the baciUi (Fig. 344). Independent motion has not been observed. The bacillus loses its color when stained with gen- tian violet and treated with iodic? and alcohol, and maybe easily distinguished in this way from the dip- lococcus. In order to stain it along with the capsule in sections, Friedlander recommends the employment of an acid solution of gentian violet, consisting of 50 parts of concentrated alcoholic solution of gentian A'iolet, 100 parts of distilled water, and 10 paits of acetic acid. After staining for twenty-four hours the sections are 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 oral and staff-shaped cells possess no capsule. Stab-cultures in gelatin are nail-shaped (Fig. 345), this appearance being due to the fact that the bacilli form a knob- shaped prominence at the entrance of the canal of inoc- ulation. This is a peculiarity that the pneumonia-ba- cilli share with nianj' other bacteria. On blood-serum they form gray transparent colonies, on agar-agar grayish- white, on potatoes grayish-white or \ellowish- -irhite, creamy colonies. Spore-formation is not ob- served. Rabbits are almost entirely refractorj^ to inocula- tion of the lung ; mice, on the contrary, die with pleu- risy and disseminated pneumonia in from eighteen to twenty hours after injection of the bacilli into the lung, and the exudate as well as the blood are found to con- tain bacilli with gelatinous capsule, some lying free, some inclosed in cells. A typical lobar pneumonia can- not be produced in the ordinary experimental animals. Fig. 345. — Nail-shaped stab-culture of Friedlander's pneumococcus in gelatin. 472 PATHOGENIC BACILLI. — DIPHTHERIA. Neumann * found, in a case of pneumonia that occurred in the course of an attack of variola, a bacillus which he regards as identical with that which has been described by Schon as occurring in vagus-pneumonia of rabbits, and which is called by Fliigge Bacillus pneumonicus agilis. Affanasiew t found, in ten cases of whooping-cough, in the mucus that was coughed up, a small bacillus which he regards as the cause of whooping-cough. Ssemetschenko t published a similar discovery. § 179. A bacillus was described in 1892 by R. Pf eiffer as the influenza- bacillus, and the discovery has been frequently corroborated since (Weich- selbaum, Kruse, Baumler, and others) ; it is regarded as the cause of the infliienza. In individuals vrho are sick of influenza it is found in the eatarrhally affected air-passages, occasionally also in the lungs. The small bronchi may contain enormous numbers of the bacilli in pure culture. It is assumed that the multiplication of these organisms in the respiratory tracts causes inflammation, and that at the same time they produce poi- sons which on being absorbed cause the morbid phenomena peculiar to influenza. Canon states that the bacilli go over into the blood. The influenza-baciUi are very small, thiu staves with rounded ends, which lie separate or joined in twos, and may be stained with the usual aniline dyes, but r-ot by Gi'am's method. They maj^ 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 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 weakness of the muscles and dyspncea. § 180. The Bacillus diphtherise is a bacillus, first accurately studied by Loffler, which is found in the croupous membrane that occurs in diph- theria, and is very probably the cause of diphtheria. In the internal organs, such as the spleen and lymph-glands, the bacilli are either entirely absent or they are present in such small numbers that they can only be detected by methods of cultivation (Frosch). They have the same length as the tubercle-bacUli, but are about twice as thick and are often swollen at the ends. Their substance has a granular appearance. For staining it is best to use a staining solution of 30 ccm. of a concentrated alcoholic solution of methylene blue in 100 ccm. of potas- sium-hydrate solution of .0001 per cent, strength. After staining, the sections are put into .5 per cent, acetic acid for a few seconds and after- ward treated with alcohol. The bacilli are often segmented in stained preparations. The diphtheria-bacilli grow best, according to Loffler, on a mixture of 3 parts calf's or sheep's blood-serum and 1 part neutralized calf- bouillon to which 1 per cent, peptone, 1 per cent, grape-sngar, and .5 per cent, salt have been added ; or upon blood-serum or agar-agar with 10 per " Zuv Kenntniss des Bacillus pneumonicus agilis,^'' Zeitsch. f. Min. Med., xiii., 1887. t "Aetiolog. u. klin. Bakteriologie des Keuchhustens," St. Petersh. med. Wochensch., 1887. t " Zur Frage der Keuchhustenbakterie," St. Pefersh. med. Wochensch., 1888. PATHOGENIC BACILLI. — DIPHTHERIA. 473 cent, glycerin or nutrient bouillon containing sugar (Kolisko, Paltauf, Kitasato). They form grayish-white colonies. They require a tempera- ture above 20° C. for their development. Loffler found the dried bacilli still capable of living after one hundred and one days. Roux and Yersin succeeded in obtaining cultures of the baciUi, that were still virulent, from a three months' old diphtheritic membrane that was dry and had been protected from the light. Spore-formation has not been observed. Guinea-pigs inoculated subcutaneously with cultures of the baciUi (Loffler, Roux, Yersin) die in two or three days. At the point of inocu- lation there is found a whitish deposit and hfemorrhagic oedema. The point of inoculation contains bacilli ; the internal organs, on the contrary, are free. In rabbits, chickens, and pigeons, the introduction of cultures into the trachea through a wound is followed by the formation of a pseudomem- brane. Inoculations of the conjunctiva in rabbits and of the vagina in guinea-pigs, is also followed by the formation of a false membrane. In young rabbits a simple smear upon the conjunctiva, which need hardly be injured, suffices to prodiiee death with high fever and nervous phe- nomena (Babes). Roux, Yersin, Loffler, Spronck, and others observed subsequent paraly- sis in pigeons and guinea-pigs that had survived inoculation. Roux and Yersin assert that intravenous injection of filtered cultures — i.e., bouil- lon-cultures containing no bacUli — causes, in guinea-pigs and rabbits, a severe illness characterized by paralysis, and fatal consequences in two or three days. Loffler obtained a substance precipitable with alcohol from cultures of the diphtheria-bacilli which he had treated with glycerm. When it is repeatedly thrown down and purified with alcohol from solution it forms a whitish precipitate, that causes an inflammatory hsemorrhagic oedema and necrosis of the skin when injected in aqueous solution under the skin of rabbits in small doses (.1 to .2 gramme.). According to the investigations of Brieger and C. Frankel, the substance which the bacilli produce is a poison that closely resembles the toxalhumins in its chemical relations, and in the pure state is fatal to experimental animals, in a dose of 2. .5 mg. to 1 kg. of the weight of the animal, often taking effect only after weeks or months. The circumstance must also be mentioned that Guinochet obtained a poison from cultures of the bacilli in urine. Locally the poison produces inflammation ; when taken up into the juices of the body, it produces an exudate in the pleurse, nephritis, fatty degeneration of the liver, and paralysis. According to Proskauer and Wassermann, the organs and blood of animals dead of diphtheria from inoculation contain a very poisonous toxalbiimin that kills animals on inoculation in from six to twenty-one days. Sheep are very susceptible to diphtheria intoxication. 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. § 98, Figs. 155 and 156). The croupous membranes constitute the most strili- ing feature. They are spread over the throat usually in hmited flat patches, more rarely uniformly over larger areas, or they may form a continuous lining upon the larynx and air-passages. Underneath the croupous membrane the epithelium is mostly lost, the connective tissue of the mucoiis membrane hypera?mic, infiltrated, and swollen. In severe 474 PATHOGENIC BACILLI. — DIPHTHERIA. 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 internal organs the kidneys especialty 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 cedema- tous swelling and foci of small-cell infiltration — conditions which are to be regarded as consequences of the intoxication. The lungs are not notably changed by the diphtheria poison ; stUl bronchopneumonias often occur which are due to inhalation of the irri- tating contents of the bronchi, or to an extension of the bronchial inflam- mation upon the respiratory parenchyma. The inflammatory irritants that get into the lungs in this way are usually not the diphtheria-bacilli, but products of the specific exudate which often inclose bacteria, espe- cially cocci, that have become lodged secondarily. Recently attempts have been made by different experimenters to cure diph- theria after it has broken out, and to make children poison-proof against diph- theria poison, by the injection of an antitoxin. The investigations made by Behring and Ehrhch in this direction have been to a certain extent successful. Sheep, goats, and horses susceptible to diphtheria may be rendered immune by inoculation with cultures in which the baeUli have been attenuated or killed; and the blood, also the mhk, of the animals that have been made immune con- tain an antitoxin which neutralizes the effect of the toxins when injected into the body of an infected animal in certain amounts, and which is able, as they believe, to make human beings and animals poison-proof. Judging from the most recent experiments in this direction, favorable results may indeed be ob- tained in human beings suffering from diphtheria, but it is impossible as yet to forecast the proportions that these favorable results may assume. According to Lofler, von Hoffmann, Roux, Yersin, Babes, and others, bacilli designated as pseudodiphtheria-hacilli 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 that the two bacilli are varieties of one kind. § 181. The Bacillus tetani (Kitasato) is a fine, slender bacillus which is widely distributed throughout the superficial layers of the earth, and is to be regarded as the cause of tetanus. According to observations of Nicolaier made in 1885, it is often possible, in mice, guinea-pigs, and rabbits, by a subcutaneous inoculation of earth taken from the super- ficial layers, to obtain tjqsical tetanus with fatal termination. The demonstration was first made by Rosenbach in the j^ear 1886 that the bacilli found in traumatic tetanus and those found in tetanus due to frost-bite in human beings, in the region of the seat of injury, were one and the same, and that when inoculated into guinea-pigs and mice they cause genuine tetanus. Since then this discovery has been often corroborated. 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 allomng the PATHOGENIC BACILLI. — MALIGNANT (EDEMA. 475 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- cultures in an atmosphere of hydi-ogen. The bacteria growing along with the tetanus-bacillus are killed by the heating, while the tetanus- bacUlus is preserved. The tetanus-bacillus (Kitasato) is anaerobic and grows very well in an atmosphere 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 1.5-2 per cent, grape-sugar accelerates the growth. The most favorable temperature is between 36° and 38° C. It forms long, thin, bristle-Uke staves that produce spores on one end which 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-forma- tion. 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 ba- cilli, and guinea-pigs especially are very sensitive to it. The blood or transudate from the thoracic cavity of an animal infected with tetanus, although free from baciUi, causes tetanus when inoculated into mice. It is consequently to be assumed that in tetanus it is a matter of intoxica- tion 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 purified poison gives no reaction for albumin, and consequently does not belong to the toxalbumins, as was formerly assumed by Brieger and Frankel. The Bacillus oedematis maligni (Viirion septique of Pasteur) is an anaerobic 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 3 to 3.5 ii long and 1 to 1.1 jj. broad, and often form long pseudothreads. They are similar to the anthrax-bacilli, but are somewhat more slender and rounded on the ends, not sharply cut across, and are occasionally motile. In spore-formation a swelling de- velops from one part of the rod, as in Bacillus Mtyricus, so that spindle- shaped and tadpole-shaped forms result. The bacillus is motile and possesses fiagella 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 1 or 2 per cent, of grape-sugar is a specially favorable medium (Pliigge). Nutrient gelatin and blood- serum are liquefied, the latter with the production of gas. 476 PATHOGENIC BACILLI. — TUBERCULOSIS. The bacillus can be readily obtained by sewing up garden-earth under tlie skin of a guinea-pig and by taking care that the air does not find ac- cess to the point of inoculation. The subsequent multiplication of the bacilli causes a progressive cedematous swelling of the subcutaneous tis- sue. At a more advanced stage the baciUi spread upon the serous mem- Ijranes, in the spleen, and in other organs. Mice, guinea-pigs, horses, sheep, and swine are susceptible to the bacilli ; cattle are not (Arloing, Cliauveau). According to the observations of Brieger, Ehrlich, Cliauveau, Arloing, and others, the oedema-bacilli also occasionallj' develop in the tissues of human beings, especiallj^ when the tissues are poorly nourished and the bacilli by any accident^ — e.g., by puncture of a hypodermatic syringe — get into the depth of the tissues. They lead to a gangrenous process which is combined with bloody oedema and the development of gas. According to Vaillard and Vincent, tetanus does not follow inoculation of tetanus-V^acilli deprived of poison. Consequently it must be assumed that the bacilli can only multiply in the tissues of man and animals and lead to poison- ing when special conditions 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. According to investigations of Kitasato, Tizzoni, Cattani, Baquis, Behring, and others, susceptible animals may be made immune from tetanus, or, more properly speaking, poison-proof against the poison of tetanus. The blood of animals that have been rendered poison-proof possesses the property of de- stroying the poison of tetanus, and consequently it is possible to immunize sus- ceptible animals with the curative serum obtained from this blood, or to cure tetanus that has already broken out in man or animals (cf. § 29). According to Kolb, Babes, Tizzoni, and Giovannini, the diseases designated as purpura hemorrhagica and as hceniophilia neonatorum are to a certain extent caused by a special kind of bacillus that is also pathogenic for animals (cf . ^ 46). Pianese is of the opinion that chorea is caused by a bacillus. § 182. The Bacillus tuberculosis is the cause of the infectious disease which is very frequent as well in man as in the domestic mammalia, and which is usually called tuberculosis, but is also sometimes called Pearl disease {Pevlsiicht) in animals. The tubercle-bacilli, discovered and thoroughly investigated by Koch in the year 1882, form narrow staves (Fig. 346), 1.5 to 3.5 /' in length, that are often slightly curved. Aniline dyes (fuchsin or gentian violet), in aqueous solution witli the addition of an alkali or carbolic acid or aniline, are suitable for staining them. The ti^- .;,^/ :.:t- . ^ bacilli once stained retain the dye ^ *^ ^. '^ ^- r-^' even when the preparation is decolor- \ ^ '^ ^, \ii '%-'' ized with dilute sulphuric or nitric "■}\ '%>^ ' ^ 3 acid, or with hydrochloric acid and c>- ■'■"> ■ \ \sr-~X v ^ . alcohol. K:;; ^ "'^- Fig. 346.— Tubercle-bacilU. Sputum ' ^ of a man sufEering from tuberculosis of '\« ''^ ' ^ -0 the lung, spread in a thin layer on a cover- ■y I ^ , I ''•^' ^^ \ glass and stained with fuchsin and methy- ^ " . , -^ ° lene blue. (Magnified 400 diameters.) The decolorized preparation can then be stained with another color (Fig. .346). PATHOGENIC BACILLI. TUBERCULOSIS. Hi 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 forniei-ly 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 bodj'--temperature and in the presence of oxygen upon solidified blood-serum, upon blood-serum gelatin, upon nutrient agar, and in bouillon ; they multiply, however, veiy slowly, so that only on the seventh to tenth day, or even later, cul- tui'es appear at the point of iuocrdation in the form of dull-white flakes resembling httle scales. Larger cultures form on the surface of solidified blood-serum white, irregularly shaped, dull coatings (Plate I., Fig. 4). According to Xocard, Roux, and Bischoff, the growth of the bacUli is gi'catly aided by the addition of from 4 to 8 per cent, of glycerin. Paw- lowsky succeeded in cultivating them on potatoes in sealed glass tubes. At temperatures below 28° C. and above 42° C. the growth of the bacilli ceases. Sunlight kills the bacilH in a short time (Koch). If the baciUi from pure cultures are inoculated into experimental ani- mals, tuberculosis is produced in these ; and the infection succeeds as well by inoculation under the skin or in the abdominal cavity or in tlie ante- rior chamber of the eye as by inhalation of an atomized suspension of the ciilture and by injection of the bacilli into the veins. Guinea-pigs and cats are specially susceptible ; dogs, rats, and white mice, on the con- trary, are less so. The tubercle-bacilli very Hkely find outside of the body of men or animals only very rarely a suitable nutrient medium for development ; that is to say, they grow almost exclusively as parasites, extremely seldom as saprophytes. The infection of human beings and of animals occurs from the taking up of the tubercle-baciUi from the lung or intestinal tract, or from wounds. 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 and theii' spores are spread mainly by the sputa, under certain ctmditions also by the faeces and by the urine ; furthermore, from tuberculous ulcers of the skin or tuberculous organs taken from living or dead persons. Since the bacilli are tolerably resis- tant, they may remain preserved here, under certain conditions, for a long time, and can become mixed with the respired air as weU as with 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 demonstrably dis- eased (Hirschberg, Ernst). For the occm-rence of an infection there seems to be required a certain predisposition, which lies partly in circumstances which affect the entire constitution of the individual, partly in accidental local lesions existing at the time of the infection. That tuberculosis occurs as a disease of fami- lies speaks for the former ; that tuberculosis occasionally follows directly upon other morbid affections, such as tissue-lesions and inflammation, speaks for the latter ; and, as further corroborative evidence, should be 478 PATHOGENIC BACILLI. — TUBERCULOSIS. mentioned the circumstance that the bacilli by no means always develop on inoculation. If the bacilli succeed in developing and multiplying in any tissue of the human body, they lead by a series of changes to the formation of cel- lular nodes or tubercles, which remain devoid of blood-vessels, and which, when they have arrived at a certain stage of development, die out again. According to the investigations of Baumgarten, the first effect of the development of the bacilli in a tissue may be a hyperplasia of the fixed cells of the tissue (Fig. 347), which begins with karyomitoses {c, d) and leads to the formation of epithelial-like protoplasmic cells, 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 clumps of epithelial cells [a) which form little knot-like foci at the point where the bacilli multiply (Fig. 347), and at these foci the bacilli lie partly between the cells, partly in the cells themselves (Fig. 347). Fig. 347, Fig. 348. J<~ %t '( , / ^,x• Fig. 347. — Tissue-changes produced by a recent invasion of the tuberole- baciUi. (Diagrammatic, after Baumgarten.) a, Hyperplastic connective tissue; 6, Cross-section of a blood-vessel; e, Karyomitoses in the connective tissue; d, Mitoses of an endothelial cell of a vessel ; e, Emigrated leucocytes. (Magnified 350 diameters.) Fig-. 348. — A giant cell containing bacilli with necrotic centre, from a tuber- cle. (Preparation stained with gentian violet and vesuvin, and mounted in Canada balsam. Magnified 350 diameters.) 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 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 i-eticulum of the tubercle. These exuberantly growing cells have for the most part one or two nuclei (Fig. 347, a, and Fig. 349, b) ; but usually cells containing several or many niielei (giroit cells) also appear (Fig. 348, Fig. 349, a, and Fig. 3.')0, c), and these often inclose a very considerable number of large, oval, vesicular nuclei, as well as bacilli (Fig. 348 and Fig. 350, c). The aggregation of large cells, when it has reached the summit of its development, may become somewhat sharply marked off from the sur- rounding tissue by a thick crowding together of the cells lying at the periphery. Despite the extraordinary exuberance of cell-growth which affects PATHOGENIC BACILLI. — TUBERCULOSIS. 479 the connective-tissue cells, as well as tlie cells of the vessel-waRs lying in the morbid area and the universally present epithelial cells, a new forma- tion of capillaries does not take place within the nodule. Sooner or later there takes place an inflammatory alteration of the vessels (Fig. 347, b) lying in the diseased area, due to the presence of the multiplying bacilli, and this brings about an emigration of colorless Uoocl- corpuscles (e). According to observations of Baumgarten, the time at which the emi- gration of cells begins seems to vary according to the method of the in- vasion of the bacilli, and probably also according to the character of the infected tissue. It takes place earliest when the tissue is at the same time injured by any other harmful substance — e.g., by trauma. If a large-celled nodule has been formed by excessive cell-reproduction the emigration of cells leads first to an accumulation of small round cells in the periphery (Fig. 349, c), later to a general infiltration with round cells, which can be- come so extensive that the large cells may become entirely hidden. A large- celled tubercle becomes in this way a lymphoid or small-celled tubercle. If the emigration of ceUs takes place very early the tubercle assumes from the start the character of a small-celled focus. The growth of cells may fall so much behind the emigration that a large-celled nodule is not present at any stage of develop- ment of the tubercle, but constantly a small- celled nodule, in which the reproduction of large cells is either en- tirely absent or takes place only at a late stage. Fig. 349.— Tubercle from a fungous granula- tion of bone, a, Giant cell ; 6, Epithelioid cells ; •c, Lymphoid cells. (Prep- aration hardened in Miil- ler's fluid, colored with Bismarck brown, and mounted in Canada bal- sam. Magnified 250 dia- meters.) With the emigration of cells there is usually combined a serous exu- dation, and fibrin may be deposited in the tubercle itself as well as in the neighborhood. The tubercle arrived at the height of its development forms a small, gray, translucent, cellular 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 cells die out. The small cells die out first; their nuclei become shrunken or break up and disintegrate. Later, the large cells also die out, become pale and homogeneous, lose their nucleus, and becom.e glistening hj^aline flakes (Fig. 350, ai). In the giant cells at this stage may be seen not infrequently a partial necrosis. 480 PATHOGENIC BACILLI. — TUBERCULOSIS. whicli may be recognized by a diminution in the staining power of the protoplasm (Fig. 350), an appearance which was pointed out by Weigert a few years ago. The nuclei are consequently situated more especially in that part where the protoplasm still remains alive, and they occupy sometimes a side (Pig. 350), sometimes one pole, sometimes the entire circumference of the giant cell (Fig. 348), or sometimes also the centre. The bacilli are often accumulated especially at the boundary between the dead and the living tissue (Fig. 348), but they may also lie in the portions which are devoid of nuclei (Fig. 350). Finally, the whole cellular tissue yr^. J.-V yx-^™-».n,7* ™«M, ^»-(-t7^-TO« jijQ 35()_ — Tissue from a focus of tubereu- n. * » Icir disease, showing bacilli and a limited area ^**^ of cheesy degeneration, a, Granular cheesy L, *<^ t V ^ material ; ai, Cheesy material in the form of ' , M ' small separate aggregations ; 6, FibroceUular ^" J tissue; c, Partly necrotic giant cell with ba- * ( illi ; d, Cellular tissue invaded by bacilli ; c, t , •*" A similar invasion in tissue that is necrotic ; ^ ■"< 4 ^ y ■> ' ^ /, Bacilli inclosed in cells. (Preparation e^' , * ^ ■'» ' '«-