Cornell 1Hntv>et:8tt\> Xtbrarp OF THE 1Rew Jflorfc State College of agriculture fta i.\.ak.. L3.ra.lisi Cornell University Library RB 111.Z73 1908 General pathology, 3 1924 003 512 534 Cornell University Library The original of this book is in the Cornell University Library. There are no known copyright restrictions in the United States on the use of the text. http://www.archive.org/details/cu31924003512534 GENERAL PATHOLOGY BY DR. ERNST ZIEGLER Professor of pathological anatomy and of general pathology in the university of freiburg ix breisgau TRANSLATED FROM THE ELEVENTH REVISED GERMAN EDITION (ol-STAY FISCHER. JENA, 1905) EDITED AND BROUGHT UP TO DATE BY " ALDRED SCOTT WARTHLN, Ph.D., M.D. PROFESSOR OF PATHOLOGY AND DIRECTOR OF THE PATHOLOGICAL LABORATORY IN THE. UNIVERSITY' OF MICHIGAN, ANN ARBOR, MICHIGAN WITH 604 ILLUSTRATIONS IN BLACK AND IN COLORS NEW YORK WILLIAM WOOD AND COMPANY MDCCCCVIII Copyright, 1908, By WILLIAM WOOD AND COMPANY. AUTHOR'S PREFACE TO THE ELEVENTH EDITION. In the preparation of this new edit ion I have endeavored to utilize as fully as possible the researches of the last several years, and, in so far as these have given us new facts and represent actual advances in our knowl- edge of pathological processes, to incorporate them into the contents of the book. It lias become almost impossible to review the great mass of literature concerning the pathogenic micro-organisms, their life history, and their effects upon the human organism; but I hope that the essential and established results of recent investigations have not escaped me, and that I have estimated them at their proper worth. 1 may mention with especial emphasis the researches of Schaudinn on the spirochete and the parasites of malaria; also those of other authors on the trypanosomata, various pathogenic bacteria, the agglutinins, precipitins, cytolysins, and hemolysins, as well as the numerous investigations and theoretic observa- tions that, based upon Ehrlich's side-chain theory, have been carried out concerning the toxic action of bacterial products and the formation of antitoxic and antibacterial substances. During recent years an immense amount of literature concerning tuberculosis has appeared; but ourprevious views concerning its etiology and genesis have not been materially altered. Koch's view as to the difference between human and bovine tuberculosis is applicable only in so far as certain differences in the characteristics of the two strains of bacilli are concerned. For all these differences it is true that bovine tuberculosis is communicable to man, and the domestic animals may be- come infected from tuberculous human beings. Yon Behring's publica- tion that infants may be easily infected through milk containing tubercle bacilli has only confirmed well-known views. The attempt of von Behring to refer all cases of tuberculosis to an intestinal infection occurring in infancy is doubtless an error, and is not likely to destroy the belief that tuberculosis is most frequently an air-borne 'nfection and enters primarily through the lungs. The researches concerning the etiology, genesis, and morphology of neoplasms have likewise been numerous and extensive; nevertheless, any expectations of a great advance in our knowledge of the etiology of neo- plasms are doomed to disappointment. The attempts to establish a para- sitic etiology for tumors have entirely failed, and the extensive statistics that have been amassed concerning the distribution of carcinoma have IV AUTHOR S PREFACE TO THE ELEVENTH EDITION. led to results that can be regarded only as antagonistic to the parasitic theory. Of greater value have been the researches on the histogenesis of tumors; yet I find in these essentially only a confirmation and a more thor- ough grounding of our older views. I cannot bring myself to the accept- ance of all the latest views,for example, the assumption that the prelimi- nary condition of tumor development is to be found in the isolation, disconnection, and misplacement of germinal anlage or of single cells during embryonal or extrauterine life (Kibbert, Borrmann), or that the epithelial cells of a carcinoma can become transformed into connective- tissue cells (Krompecher). Significant advances in the theory of fatty degeneration and glycogen deposit are also to be noted ; and although many problems must still wait a solution, our knowledge concerning these processes has been greatly furthered through the labors of recent years. The long discussion over the significance of the cells appearing in the tissues during the course of inflammation has at last reached certain conclusions. The questions still unsettled are of minor importance. The arrangemeut of the book is left, on the whole, as iu the last edition ; but I have not simply inserted the new facts and views, many sections having been entirely recast to agree with the additions. The number of illustrations has been increased from 586 to 604. The bibliography has been given a careful revision and brought up to the autumn of this year. E. ZlEGLEE. Freiburg im Breisgatt, December, 1904. EDITOR'S PREFACE. Ixthe translation of the last (eleventh ) edition of Ziegler's "General Pathology" the editor has endeavored to carry out the same plan followed in the preparation of the tenth edition, viz., to given simple and con- sistent English rendering of the text and spirit of the original, suitable to the needs of the medical student. The original matter has been given without change or omission. So rapid, however, has been the progress of pathological knowledge that, in the three years elapsing since the book left Ziegler's hands, numerous important facts have been estab- lished and new theories advanced. in order, therefore, to bring the work up to the present date, the results of recent investigations, in so far as they have proved to be of value or of interest, have been inserted into the book in the form of additions to the paragraphs in tine print. Such interlardments include recent observations on theeffectsof Roentgen irradiation, heredity, phagocytosis, opsonins, blood-plates, thrombosis, necrosis, cloudy swelling, fatty degeneration, calcification, regeneration, inflammation, malignant neoplasms, tuberculosis, syphilis, relapsing fever, spirochfetse, protozoa, etc. In subject-matter the work has thus been brought up to the date of issue. The bibliography lias also been revised, and the most important contributions of the last three years in- cluded. Through these changes and additions the editor hopes and be- lieves that the present edition will become an adequate English repre- sentative of the original German work. It seems fitting here to pay an American tribute to the memory of the author, Geheimer Hofrat Ernst Ziegler, Professor in the University of Freiburg, who died on the 30th of November, 1 i>0.~>, in the fifty-seventh year of his age. His fame rests upon his text-book rather than upon his investigations, although these included a number of important contribu- tions. Passing through eleven editions, translated into English, French, and Italian, the " Ziegler " became a familiar and final authority wherever the study of pathology was prosecuted. Devoting his life to the per- fecting of the work, constantly improving it in material and illustrations, the author made of it a splendid example of a scientific text-book prac- tically free from subjectivity, one-sidedness, and prejudice. To this one achievement alone the students of medicine during the last twenty-five years owe a large part of their medical culture, and in this respect its influence upon the recent development of medicine can hardly be esti- VI EDITOR'S PREFACE. mated. Within late years there has been fostered somewhat a tendency toward the disparagement of the writing of text-books as compared to the prosecution of research work, but of the intrinsic worth of a text- book such as the oue under consideration there can be no question. Truly, as great a service as that of pure investigation is rendered by the calm and judicious spirit, who, without prejudice, wisely sifts the great mass of collected investigations and brings from them a tangible order and scheme. And upon such a service rests the great reputation of Ziegler's text-book. Aldeed Soott Waethik. Anx Aeboh, Michigan, September, 190tf. Note. — Because of the difference in the size of the page it lias been found necessary to reduce slightly some of the illustrations. In such cases the magnification or ampli- fication lias been changed to meet the amount of reduction. CONTENTS. PAGE Introduction, ............ 1 CHAPTER I. Extrinsic Causes and Congenital Anlage op Disease. I. The Extrinsic Causes of Disease, ........ 4 1. The Origin of Disease through Deficient Supply of Food and Oxygen, through Fatigue. Heat and Cold, Changes of Atmospheric Pressure and Electrical Influences, ........ 4 2. The Origin of Disease through Mechanical Influences. . . . 16 3. The Origin of Disease through Intoxication, . . . . .IS 4. The Origin of Disease through Infection or Parasitism, . . . 30 II. Congenital and Inherited Anlage of Disease, . . . . . .44 1. Immunity, Predisposition, and Idiosyncrasy . . . . .44 2. Diseases Arising from Congenital Pathological Anlage, . . .48 CHAPTER II. The Spread and Generalization of Pathological Processes throughout the Organism. Autointoxications and Secondary Diseases. T. General Consideration of the Different Forms of the Distribution and Gen- eralization of Pathological Processes in the Organism, . . . CV.i II, Metastases and Embolism and Their Significance in the Development of Lymphogenous and Hematogenous Diseases, ..... 04 IIP The Sequela? of Local Organic Diseases, ....... 72 JV. Autointoxications and Disturbance of Internal Gland Secretion. . . 7."> V. Fever and Its Significance, ......... 90 CHAPTER III. The Protective and Healing Forces of the Human Organism. The Acquiring of Immunity. I. The Natural Protective Contrivances, Protective Forces and Healing Powers of the Human Organism, and Their Action, .... 97 II, The Acquiring of Immunity against Infections and Intoxications. Pro- tective Inoculation, . . . . . ■ ■ -111 III. The Active Substances of Acquired Immunity. Ehrlich's Side-chain Theory . ■ • ■ .118 CHAPTER IV Disturbances in the Circulation of the Blood and of the Lymph. I. General Disturbances of the Circulation Dependent upon Changes in the Function of the Heart, Changes in the General Vascular Resistance, and Changes in the Mass of the Blood, 124 Vlll CONTENTS. II. Local Hyperaemia and Local Anaemia, III. Coagulation, Thrombosis, and Stasis, IV. (Edema, V. Haemorrhage and the Formation of Infarcts VI. Lymphorrhagia, , PAGE . 130 . 135 151 . 15S . 165 CHAPTER V. Retrograde Disturbances of Nutrition and Infiltrations of Tissues I. General Considerations Concerning the Retrograde Disturbances of Nutri- tion and the Tissue-infiltrations, II. Death of the Organism, .... III. Necrosis and Gangrene, IV. Hypoplasia, Agenesia, ami Atrophy, . V. Cloud}' Swelling and Hydropic Degeneration, VI. Lipomatosis, Atrophy of Fat-tissue, and Fatty Degeneration, VII. The Deposit of Glycogen, ..... ... VIII. Mucous Degeneration, ......... IX. Formation of Epithelial Colloid and Epithelial Hyaline Concretions, X. The Pathological Cornification of Epithelium, ..... XL Amyloid Degeneration and the Amyloid Concretions, XII. Hyaline Degeneration of Connective Tissue, and the Hyaline Products ol Connective-tissue Cells, ........ XIII. Petrifaction of the Tissues and the Formation of Concretions and Calculi XIV. The Pathological Formation of Pigment, . . . . . ' . XV. The Pathological Absence of Pigment, ..... XVI. The Formation of Cysts it;, 168 170 ISO 190 193 204 207 209 212 21-1 222 226 23S 257 258 CHAPTER VI. Hypertrophy and Regeneration. Results of Transplantation. Metaplasia. I. General Considerations Concerning the Processes Known as Hypertrophy and Regeneration, and the Accompanying Cellular Changes, . . 262 II. The Processes of Hyperplasia and Regeneration in the Various Tissues, . 2S5 III. The Results of Transplantation and Implantation (if Tissues and Organs, 309 IV. The Metaplasia of Tissues, ......... 314 CHAPTER VII. Inflammation. I. The Early Stages of Acute Inflammation, .... . . 31.9 II. The Termination of Acute Inflammation in Healing. .... 345 III. The Inflammatory New-formation of Tissue, Healing of Wounds, Sub- stitution of Exudates and Tissue-necroses by Connective Tissue, . 350 IV. Chronic Inflammations, . . . . . . . . 365 CHAPTER VIII. Tumors. I. General Considerations . 371 II. The Different Forms of Tumors, 385 1 . Tumors Derived from Connective Tissue or the Supporting Framework, (a) Fibroma, ........... 385 (b) Myxoma, . . ... ... :-;S5 O) Lipoma, .......... 387 (rl) Chondroma 389 O) Osteoma .... 391 CONTENTS. (/) Hemangioma and Lymphangioma, ...... 394 lg) Myoma," . 398 (/() Glioma, and Neuroglioma Ganglionare, ..... 40!) (i) Neuroma and Neurofibroma, . . . . . .413 (k) Sarcoma, . . . . . . . . . .416 The Epithelial Tumors, 419 (a) General Remarks, . . ...... 439 (6) Papillary Epithelioma, Adenoma, and Cystadenoma, . . 440 (c) Carcinoma and Cystocarcinoma, ...... 4.55 The Teratoid Tumors and Cysts, ....... 485 CHAPTER IX. Disturbances of Development and the Resulting Malformations. I. General Considerations Regarding Disturbances of Development and t' Origin of Malformations, ...... . . 498 II. Tie Different Forms of Malformations in Man, ...... .506 1. Arrests of Development in a (Single Individual, . ... .506 (a) Arrest of the Development of the Entire Embryonal Anlage, . .506 (6) Defective Closure of the Cerebrospinal Canal and the Accom- panying Malformations of the Nervous System, . . . 508 (c) The Malformations of the Face and Neck, . . . .517 (<0 Faulty Closure of the Abdominal and Thoracic Cavities and the Accompanying Malformations, ...,., 5120 (e) Malformations of the External Genitalia and Anus, due to Ar- rested Development, ........ 523 (/) Malformations of the Extremities, due to Arrested Development, 525 2. Abnormal Position of the Internal Organs, ...... 530 3. Malformations, due to Excessive Growth or Multiplication of Organs or Body-parts, ......... 531 4. True and False Hermaphrodism, ........ 535 5. Double Monsters, .......... .539 (a) Classification of Double Monsters, ...... 539 (6) The Chief Forms of Double Monsters, 540 CHAPTER N. The Pathogenic Fission '-'unci and the Diseases Caused by Them. I. General Considerations Legarding the Schizomycetes or Fission-fungi, . 549 1. General Morphology and Biology of the Fission-fungi, . . :549 2. General Considerations Concerning the Pathogenic Schizomycetes and their Behavior i . the Human Organism, . . . . . . ,5,58 II. The Different Forms of Bacteria and the Infectious Diseases Caused by Them, ............ ,5(53 1. The Cocci or Sphserobacteria and the Morbid Processes Caused by Them, (a) General Considerations Regarding the Cocci, .... 563 (b) Pathogenic Cocci, . . . ... . . . . .565 2. The Bacilli and the Polymorphous Bacteria and the Pathological Processes Produced by Them, ...... 5S6 (a) General Considerations Regarding Bacilli and the Polymorphous Bacteria, . 586 (b) The Pathogenic Bacilli and Polymorphous Bacteria, . . . 5S9 3 The Spirilla and the Diseases Caused by Them, . . . . 670 (a) General Remarks upon the Spirilla, ...... 670 (6) The Pathogenic Spirilla 671 CHAPTER XL The Yeasts and Moulds and the Diseases Produced by Them, . 077 CONTENTS. CHAPTER XII. The Animal Parasites and the Diseases Produced by Them. I. Protozoa, ...... II. Vermes. Worms. .... A. Platyhelmintb.es, Flat-Worms, 1. Trematoda. Sucking-Worms, 2. Cestoda. Tape-Worms. B. Nemathelminthes. Round-Worms, JIT. Arthropoda 1. Araclmida, ..... '2. Insecta, ..... PAGE 689 7 1 6 716 716 7l»l 7.'!4 748 7-1 S Index, 757 LIST OF ILLUSTRATIONS. PAGE 1. Lightning-figures on the shoulder, breast, and ami 14 2. Multiple emboli in the branches of the pulmonary artery 65 3. Fat-embolism of the lungs ' 66 4. Fat-embolism of the kidney 67 5. Thyreoprival cachexia 82 6. Myxcedema S3 7. Same case after treatment with thyroid extract 83 S. Female cretin 84 9. Temperature chart of a continuous remittent fever 91 10. Temperature chart of a continued fever with rapid rise and Fall 92 11. Temperature curve of an intermittent fever 92 12. Lardaceous clot from the cadaver 135 13. Recent hemorrhagic infarct of the lung 136 14. Bundles and stellate clusters of fibrin threads or rods 137 1 5. Red thrombus 1 3S 16. Laminated mixed thrombus rich in cells 139 17. White thrombus poor in cells 13(1 18. Rapid blood-stream 140 19. Moderately slow blood-stream 140 20. Greatly retarded blood-stream 140 21. Polypoid heart thrombi 1 44 22. Thrombosis of femoral vein 115 23. Remains of a thrombus of femoral vein 146 24. Obliteration of pulmonary artery by connective tissue 147 25. Remains of embolic plugs in pulmonary artery 1 17 26. Embolism of intestinal artery with purulent arteritis 14S 27. Stasis from venous hyperemia 1 50 28. Stasis oedema of the papillary bodies 152 29. Hydropic connective-tissue cells 152 30. CEdema of muscle I 53 31. Inflammatory oedema of the papillary bodies 153 32. Hemorrhage into skin 159 33. Traumatic cerebral hemorrhage 160 34. Hemorrhagic infarct of the lung. 164 35. Necrosis of kidney epithelium 171 36. Peripheral portion of an anemic infarct of kidney I 72 37. Coagulation-necrosis of mesenteric lymph-gland 174 38. Waxy necrosis of striped muscle 1 75 39. Caseation-necrosis of tuberculous focus 175 40. Fibrin-containing tubercle of the lung 176 41. Liquefaction-necrosis 177 42 Dry gangrene of the toes ■ 178 43. Skeleton of a female cretin, thirty-one years of age 181 44. Skeleton of a female dwarf, fifty-eight years of age 181 45. Head of Helene Becker (microcephalia) 182 46. Brain of Helene Becker 1 82 47. Hypoplasia and microgyria of left cerebral hemisphere 182 48. Hypoplasia of uterus 183 49. Hypoplasia of the small intestine 1S3 50. Sections of ovary at different ages 184 51. Juvenile muscular atrophy 185 52. Excentric atrophy of lower end of tibia and fibula 186 53. Senile atrophy of skull-cap 1 87 LIST OF ILLUSTRATIONS. 54. Section through atrophic muscle 187 55. Senile atrophy of the kidney 188 56. Arteriosclerotic contracted kidney 18S 57. Pressure-atrophy of spinal column 189 58. Hemiatrophia facialis IS!* 59. Cloudy swelling of liver-cells !90 60. Cloudy swelling of kidney-cells 191 61. Hydropic degeneration of carcinoma-cells 191' 62. Hydropic degeneration of muscle-fibres 192 63. Transverse section of hydropic muscle 192 64. Fat tissue from the panniculus of the heart 193 65. Lipomatosis of calf-muscles 194 36. Spinal muscular atrophy with lipomatosis 195 67. Skin with sweat-glands 195 68. Fatty infiltration of liver 196 69. Fat-granule cells 197 70. Fat-containing liver-cells 199 71. Fatty degeneration of heart-muscle 199 72. Anaemic and fatty necrosis of the myocardium 190 73. Fatty degeneration, vacuolar degeneration and necrosis of heart-muscle 200 74. Marked chronic fatty degeneration of heart 20O 75. Fatty degeneration of kidney epithelium 201 76. Cholesterin plates and margarin needles 204 77. Glycogen degeneration of the renal epithelium in diabetes 205 78. Mucoid degeneration of epithelial cells 207 79. Mucoid degeneration of epithelial cells, from a cystadenoma of ovary 20S 80. Mucoid degeneration of connective tissue 208 81. Colloid degeneration of thyroid 209 82. Secretion of colloid in the thyroid 209 S3. Urinary tubules filled with colloid • 210 84. Colloid concretions 210 85. Hypertrophic prostate with concretions 211 86. Amyloid spleen 21-1 87. Amyloid liver treated with iodine 215 88. Amyloid degeneration of splenic follicles and splenic pulp 216 89. Amyloid liver 217 90. Amyloid kidney 218 91. Corpora amylacea 220 92. Hyaline degeneration of the connective tissue of a colloid goitre 222 93. Hyaline degeneration of connective tissue in a tuberculous bursa 223 94. Hyaline degeneration of blood-vessels 223 95. Hyaline degeneration of the connective tissue of (he myocardium 223 96. Calcification of the media of the aorta 227 97. Calcification of the media of the femoral artery 227 98. Calcified cerebellar vessels 228 99. Calcification of necrotic lung 228 100. Hyaline degeneration and calcification of the connective tissue of the renal papilla; 229 101. Calcification of epithelium of urinary tubules 229 102. Concretions of lime salts 230 103. Section of psammoma of dura mater 230 104. Deposit of urates in knee-joint 231 105. Deposit of needle-shaped crystals of sodium urate 231 106. Gouty nodules of hand 232 107. Faceted stones from gall-bladder 233 108. Section of cholesterin stone 234 109. Uric-acid infarction of kidney 234 1 10. Coral-like urinary calculus 235 1 1 1. Calculi of sodium urate and ammonium-magnesium phosphate 235 1 12. Incrusted lead-pencil from bladder 236 I 13. Large hairy na>vus on back and buttocks 238 1 14. Pigmented cells from skin in Addison's disease 239 1 15. Cells containing amorphous piernont. Crystals of hrematoidin 243 116. Hemosiderin- and haematoidin-containing cells 244 1 1 7. Deposit of pigment-cells in a lymph-gland 245 118. Infiltration of liver-rods with hcemosiderin 246 LIST OF ILLUSTRATIONS. 119. Hemochromatosis of the liver 247 120. Hemosiderosis of the bone-marrow 248 121. Hematogenous hemosiderosis of kidney of pernicious malaria 219 122. Icterus of liver due to compression of common duct 2.31 123. Icterus of kidney 2.53 124. Deposit of cinnabar in tattoo 255 125. Argyria of rabbit's kidney 256 126. Vitiligo endemica 257 127. Multiple cysts in epididymis 2.39 128. Dilatation cyst of pancreas 2.59 129. Hydrops tube 260 130. Elephantiasis femorum neuromatosa 2(52 131. Elephantiasis cruris lymphangiectatica 263 132. Ichthyosis congenita (microscopical) 263 133. Ichthyosis congenita 264 134. Cornu cutaneum from back of hand 264 135. Cornu cutaneum from arm 264 136. Head of a bearded woman 26.3 137. Leontiasis ossea 26.3 138. Hypertrophy of left ventricle 267 139. Hypertrophy of incisor-tooth of a white rat, due to disuse ' 268 140. Elephantiasis scroti 268 141. Acromegaly 269 142. Skeleton of hand from case of acromegaly 270 143. Cutaneous portion of a laparotomy wound 273 144. Healing of intestinal ulcer 274 145. Scar of muscle and tendon 27.3 146. Edge of embolic scar 276 147-157. Nuclear changes in cell-division 280-2S2 158. Atypical karyokinetic figures 2S2 159-162. Giant-cells from an osteosarcoma 283 163. Proliferating adipose tissue 283 164. Regeneration of the epithelium of the bile-ducts 286 165. Healing blister 286 166. Development of blood-vessels 289 167. Two vessels of papillary body, with proliferation of endothelium 290 168. Proliferating periosteum four days after fracture of bone 291 169. Isolated cells from wound-granulation 292 170. Development of connective tissue from fibroblasts 292 171. Scar from skin, two years old 293 172. Periosteal formation of cartilage 293 173. Endosteal formation of bone from osteoblasts 294 174. Formation of osteoid trabecule in the proliferating periosteum 291 175. Formation of bone upon old bone by deposits of osteoblasts 29.3 176. Section from a germ-centre of a mesenteric lymph-gland 298 177. Regeneration of striped muscle 301 178. Sclerotic tissue from the posterior columns of spinal cord 304 179. Old and newly formed nerve-fibres 305 180. Cross-section of nerve-bundle from median nerve four months after wound. . 30.5 181. Amputation-neuroma 306 182. Skin-transplantation of about four and a half days 311 183. Periosteal formation of bone 31.5 184. Formation of bone from connective tissue 315 185. Periosteal formation of cartilage 316 186. Tracheotomy wound in cricoid cartilage 316 187. Metaplasia, of cartilage into reticular tissue 317 188. Metaplasia of cartilage into osteoid tissue 317 189. Inflamed human mesentery 322 190. Meningitis recens purulenta 327 191. Hematogenous staphylococcus myositis 327 192. Section through the edge of a blister 32S 193. Parenchymatous hepatitis 328 194. Mucous catarrh of a bronchus 329 195. Purulent desquamative catarrh of trachea 331 196. Catarrhal secretions of different mucous membranes 332 197. Acute hemorrhagic-fibrinous inflammation of trachea 333 XIV LIST OF ILLUSTRATIONS. PAGE 198. Croupous membrane from trachen 333 199. Section of diphtheritic membrane 334 200. Croupous tracheitis 335 201. Traumatic fibrino-purulent peritonitis 335 202. Fibrinous pleuritis 335 203. Fibrino-purulent diplococcus pleuritis 336 204. Croupous pneumonia 337 20.5. Purulent bronchitis, peribronchitis, and peribronchial bronchopneumonia. . . 339 206. Section of a small-pox pustule 339 207. Embolic abscess of intestinal wall 340 208. Suppuration and necrosis of the mucosa of the intestine in dysentery 341 209. Phlegmon of subcutaneous tissue 342 210. Necrosis of the epithelium of the epiglottis 343 211. Bacillary diphtheritis of colon in dysentery 344 212. Section of uvula in diphtheria 344 213. Diphtheritic necrosis of a mesenteric lymph-gland 34.5 214. Phagocytes from granulation tissue 346 215. Isolated cells from a wound-granulation 350 216. Scar tissue fifteen days old 351 217. Tissue from a scar sixty-five days old 352 218. Plasma-cells and klasmatocytes 353 219. Dog's hair encapsulated in subcutaneous tissue 353 220. Cross-section of blood-vessel from the deeper layers of the skin 354 221. Granulation tissue from open wound 356 222. Healing of incised wound of skin 358 223. Cutaneous portion of a laparotomy scar 359 224. Beginning organization of pericardial exudate 360 225. Granulation-tissue formation on the pleura in pleuritis 860 226. Organization of pericardial exudate 361 227. Intraseptal and intra-alveolar development of connective tissue in the lung. . 361 228. Development of formative tissue in a thrombosed femoral artery 362 229. Edge of organizing hemorrhagic infarct of lung 362 230. Fibroid area in heart-muscle 363 231. Necrosis in lower portion of femur 365 232. Changes in lung and pleura in chronic purulent pleuritis 366 233. Stone-cutter's lung 367 234. Condyloma acuminatum 367 235. Periosteal hyperostosis of the tibia 368 236. Section through mucosa of atrophic colon 369 237. Induration and atrophy of kidney tissue in chronic nephritis 369 238. Hyperplasia of connective tissue and proliferation of bile-ducts in chronic "hepatitis 370 239. Tissue from mammary cancer with many division-figures 372 240. Fungoid carcinoma of body of uterus 373 241. Papillary adenoma of rectum 373 242. Primary carcinoma of gall-bladder 377 243. Primary carcinoma of liver 380 244. Metastases in periglandular lymph- vessels of axillary region 381 245. Metastases of carcinoma in portal vein and liver capillaries 381 246. Metastatic sarcoma of liver 382 247. Recurrent sarcoma of femur 383 248. Hard fibroma of ear-lobe 385 249. Section ot oedematous fibroma of uterus - 385 250. Fibroma pericanaliculare mamma' 3X0 251. Cells from a myxoma of the periosteum 388 252. Section ot a myxosarcoma 388 253. Lipoma of the shoulder region 389 254. Lipomyxoma of the back 390 255. Periosteal chondroma of finger-phalanx 391 256. Section of chondroma of libs 301 257- ( 'hondromyxosarcoma parotidis 302 258. Periosteal chondroma of calcaneus 392 259. Osteochondroma of humerus 393 260. Ivory-like exostosis of parietal bone 394 261. Exostosis cartilaginea of tibia 395 202. Ivory-like osteoma, of parietal bone 390 LIST OF ILLUSTRATIONS. 203. Osteoma of dura mater 396 264. Osteochondroma of humerus 397 265. Teleangiectasis of abdominal panniculus 398 266. Dilated capillaries from a telangiectatic tumor of the brain 399 267. Angioma cavernosum cutaneum congenitum 399 268. Angioma cavernosum hepatis 400 269. Angioma simplex hypertrophicum 401 270. Angioma simplex hypertrophicum cutaneum et subcutaneum 401 271. Angioma cavernosum hypertrophicum -102 272. Angioma arteriale plexiforme 403 273. Weeping subepithelial lymphangioma of skin 404 274. Lymphangioma cavernosum subcutaneum 405 275. Large hairy pigmented naevus 400 276. Lymphangioma hypertrophicum 406 277. Lymphangioma hypertrophicum 407 27S. Section through two papilla? of a fleshy wart 407 279. Myoma of uterus 409 280. Angiomyoma subcutaneum dorsi 410 281. Cells from rhabdomyoma ta 411 282. Glioma cerebri 413 283. Section of a glioma cerebri 414 284. Neuroglioma ganglionare 415 285. Amputation neuroma of sciatic nerve 417 286. Nerves from a cirsoid neuroma 418 287. Cirsoid neuroma of sacral region 418 288. Sarcoma of intermuscular septa of cervical muscles 421 289. Lymphosarcoma of nasal mucosa 121 290. Large round-celled sarcoma of skin 422 291. Sarcoma of mamma 422 292. Spindle-cells from a large spindle-celled sarcoma of cheek 423 293. Cells from a myelogenous giant-cell sarcoma 423 294. Giant-cell sarcoma of upper jaw 424 295. Endothelioma of pia mater 426 296. Endothelioma dura? matris 427 297. Endothelioma of pleura 427 298. Endothelioma of mamma 428 299. Hemangioendothelioma of kidney 429 300. Angiosarcoma of thyroid 430 301. Angiosarcoma of testicle 430 302. Chondrofibroma of parotid 431 303. Melanotic alveolar sarcoma of skin 432 304. Melanotic sarcoma of skin 433 305. Metastasis of a melanotic sarcoma of skin 434 306. Endosteal osteosarcoma of the humerus 434 307. Sarcoma ossificans 435 308. Osteoid sarcoma of the ethmoid bone 435 309. Petrifying large-celled sarcoma of tibia 436 310. Section of a psammoma of dura mater 436 311. Myxoangiosarcoma of parotid 437 312. Papillary epithelioma 439 313. Senile horny wart 440 314. Papillary epithelioma of larynx 441 315. Papillary epithelioma of bladder 441 316. Papillary epithelioma of bladder 442 317. Adenoma tubulare of intestine 444 318. Adenoma tubulare of stomach 441 319. Adenoma mamma? tubulare 44:_> 320. Adenoma mamma? alveolare 44.5 321. Papillary adenoma of the kidney 446 322. Fibroma intercanaliculare mamma 1 447 323. Section of cystadenoma ovarii papilliferum 448 324. Adenocystoma of bile-ducts 449 325. Portion of a multilocular adenocystoma of the ovary 449 326. Section of an adenocystoma of testicle 449 327. Multilocular adenocystoma of liver 450 32S. Cystoma of kidney* 450 XVI LIST OF ILLUSTRATIONS. 329. Adenocystoma ovarii partim simplex partim papilliferum 451 330. Portion of an adenocystoma papilliferum ovarii 451 331. Cystoma papilliferum ovarii 152 332. Papillary adenocystoma of ovary 453 333. Intracanalicular papillary fibroma of mamma 454 334. Section of carcinoma of the lip 461 335. Beginning cancer of portio vaginalis uteri 462 336. Development of adenocarcinoma of colon 463 337. Developing adenocarcinoma of stomach 463 338. Cystocarcinoma of mamma 464 339. Tubular adenoma of mamma with beginning carcinoma 464 340. Carcinoma placentare of uterus 465 341. Horny carcinoma of tongue 468 342. Carcinoma of skin 468 343. Adenocarcinoma recti tubulare 469 344. Adenocarcinoma fundi uteri 479 345. Carcinoma simplex mamma" 470 346. Acinous carcinoma of mamma. .- 471 347. Tubular scirrhous cancer of breast 171 348. Segment of a cancer of breast 472 349. Mucoid carcinoma of breast 473 350. Development of a mucoid cancer in atrophic gastric mucosa • . 474 351. Carcinoma mucosum mammae 474 352. Carcinoma with hyaline drops # 175 353. Enlarged hydropic cancer cells. . . ~ * 47.1 354. Carcinoma myxomatodes 476 355. Adenosarcoma malignum of kidney 476 356. Cystocarcinoma papilliferum mamma" 1 7 S 357. Cystocarcinoma papilliferum ovarii 479 358. Papillary cystocarcinoma of mamma? 479 359. Colloid carcinoma of thyroid 480 360. Section of enlarged axillary lymph-gland with beginning metastases of carcinoma 481 361. Metastatic cancer-cell in liver-capillary 482 362. Metastatic cancer in liver from primary carcinoma of the pancreas 182 363. Carcinoma metastases in the uterine mucosa 4S3 364. Metastatic carcinoma in the diploe of the skull-cap 483 365. Adenoma-like snaring-off of portions of mucosa of small intestine 4S7 366. Adenoma-like remains of Wolffian body in the uterine wall 48s 367. Portion of the wall of a dermoid cyst of the ovary 490 368. Section of a prominence in a multilocular dermoid 491 369. Congenital adoneevstoma of testicle 293 370. Teratoma of testicle 194 371. Malformation of head due to amniotic adhesion 199 372. Malformation of face due to amniotic adhesion .~>00 373. Hand stunted by amniotic adhesion 501 374. Deformity and stunting of hand due to pressure 501 375. Lithopaedion ">07 376. Craniorachischisis 509 377. Spina bifida sacralis 509 378. Myelomeningocele sacralis 510 379. Anencephalia et acrania 513 380. Cranioschisis with exencephalus 513 381. Partial agenesia of the cranium 5 1 :; 382. Hydrencephaloccle occipitalis .514 383. Encephalomeningocele nasofrontalis ">I4 384. Synophthalmia or cyclopia 515 385. Frontal section of cranial cavity in synophthalmus microstomus 515 386. Wolf's jaws 518 387. Agnathia and synotia 518 388. Hernia funiculi umbilicalis 521 389. Fissura abdominis et vesica' urinaria? 522 390. Hypospadias 523 391. Epispadias 523 392. Complete absence of urethra and external genitals ,504 393. Amelus 526 LIST OF ILLUSTRATIONS. 394. Micromelus 526 395. Sympus apus 526 396. Sympus dipus 526 397. Defect of femur and fibula 527 398. Perodactylism and syndactylism 527 399. The same hand illuminated by Roentgen rays 527 400. Perochirus • ' 527 401 Skeleton of perochirus 527 402. Peropus 528 403. Skeleton of peropus 528 404. Polydactylism 533 405. Polydactylism of new-born 533 406. Polydactylism and syndactylism of left hand 533 407. Polydactylism and syndactylism of right foot 533 408. Hermaphrodismus verus lateralis 536 409. External genitalia of a female pseudohermaphrodite 537 410. Acardius acephalus 540 411. Acardius pseudoacormus 540 412. Pygopagus 5 42 413. Ischiopagus 542 414. Dicephalus dibrachius dipus 543 415. Diprosopus distomus tetrophthalmus diotus dibrachius 543 416. Craniopagus parietalis 54 I 417. Cephalotiioracopagu.-j 54 1 418. Thoracopagus tribrachius tripus 545 419. Polymelos 546 420. Polymelos 546 421. Pygopagus parasiticus 546 422. Thoracopagus parasiticus 546 423. Thoracopagus parasiticus 547 424. Epignathus 547 425. Gelatin plate with colonies of bacteria 561 426. Streptococcus from a purulent peritoneal exudate 563 427 Micrococcus-colonies in liver-capillary 563 428. Cocci grouped in tetrads 563 429. Sarcina ventriculi 563 430. Streptococcus tracheitis in scarlatina 566 431. Streptococcus pyogenes from phlegmon of stomach 566 432. Streptococcus erysipelatis in lymph-vessel 566 433. Section of skin in erysipelas bullosum 567 434. Erysipelas of head in child of one month 567 435. Beginning streptococcus phlegmon on trunk 568 436. Streptococcus phlegmon of muscle 569 437. Streptococcus infection of petrous bone 569 438. Metastatic hrematogenous streptococcus pneumonia 570 439. Parietal endocarditis of left auricle, due to streptococci 571 440. Erythema multiforme caused by streptococci 571 441. Marked streptococcus infection of kidney 572 442. Diplococcus pneumoniae 575 443. Diplococcus pneumonia in early stage 576 444. Multiple abscssses of skin caused by staphylococci 578 445. Miliary abscesses of kidney caused by staphylococci 579 446. Staphylococcus osteomyelitis of the calcaneus 580 447 Gonococci in urethral secretion 582 448. Urethritis gonorrhoica 582 449. Bacillus subtilis in different stages of development 586 450. Clostridium butyricum 586 451. Anthrax-bacilli in liver capillaries 590 452. Anthrax-spores 590 453. Anthrax pustule 591 454. Portion of anthrax pustule, containing bacilli 591 455. Typhoid bacilli from a pure culture 594 456. Typhoid bacilli with flagella 594 457. Typhus abdominalis. Section of Peyer's patch 595 458. Tetanus bacdli with terminal spores 603 459. Bacillus pneumoniae 606 LIST OF ILLUSTRATIONS. 460. Nail-shaped stab-culture of pneumonia-bacilli in gelatin 600 461. Influenza-bacilli from sputum 607 462. Diphtheria-bacilli from a pure culture 609 463. Pest-bacilli 6113 464. Tubercle-bacilli 615 465. Tubercle from a fungoid granulation tissue of bone 616 466. Giant-cell containing tubercle-bacilli 616 167. Tuberculosis of pleura 617 468. Large-celled tubercle with fibrin 617 469. Caseous necrosis of tuberculous granulation tissue 618 470. Miliary tubercle of omentum 61S 471. Fibrocaseous tubercle of lung 619 472. Fibrous tubercle in thickened synovial membrane 619 473. Lupus of skin with atypical proliferation of epithelium 626 474. Tuberculous granulation tissue from the synovial membrane of the knee ... 627 475. Large solitary tubercle of pia mater cerebelli 627 476. Tuberculous induration of the lung 628 477. Tuberculous induration of the lung 62N 478. Encapsulated caseous focus in lung, with induration 629 479. Encapsulated caseous focus in lung 629 4S0. Tuberculous cavity in tibia 630 481. Tuberculous ulcer of intestine 63 1 482. Beginning pulmonary tuberculosis without catarrh 631 4S3. Beginning pulmonary tuberculosis in child of two years 632 484. Eruption of tubercles in a lymph-gland 633 485. Tuberculosis of veins in neighborhood of a tuberculous retroperitoneal gland 634 486. Hicmatogenous miliary tuberculosis of liver 635 487. Tuberculosis of omentum 635 4SS. Proliferation of pleura in " pearl-disease " of cattle 637 489. Initial sclerosis 642 490. Section of syphilitic initial sclerosis 642 491. Condyloma latum ani 643 492. Meningoencephalitis syphilitica gummosa 644 493. Syphilis of the skull-cap 644 494. Gumma hepatis 646 495. Syphilitic ulceration of larynx 647 496. Congenital syphilitic induration of liver 647 497. Changes in lung in congenital syphilis 64N 498. Tissue, from a leprous nodule 650 499. Giant-cell containing lepra-bacilli 650 500. Section of leprous nodule of skin 650 501. Leontiasis leprosa 65 1 502. Lepra amesthetica ulcerosa 652 503. Lepra anaesthetics, mutilans 653 504. Glanders of cat's testicle 655 505. Section of rhinoscleroma • . . 658 506. Hyaline cells and spherules from rhinoscleroma ' 658 507. Actinomyces hominis 660 508. Actinomycosis of the tongue 660 509. Actinomyces druse surrounded by giant-cells and pus-corpuscles 660 510. Actinomycosis of lung 661 511. Frontal section of nose and upper jaw of a cow affected with actinomycosis. . 662 512. Spirillum rugula and spirillum undula 670 513. Cholera-spirilla 671 514. Stab-culture of cholera-spirilla in gelatin 073 515. Stab-culture of the Finkler-Prior spirillum 675 516. Saceharomyces ellipsoideus 678 517. Fresh favus-mass consisting of hyphse 67.8 518. Thrush, from tongue of man dying of typhoid fever 678 519. Section through a thrush-covered oesophagus of a small child 679 520. Mucor corymbifer in fructification 6S1 521. Hyphse of Aspergillus fumigatus, with conidia-bearers 68! 522. Culture of Trieophyton tonsurans 687 523. Amoeba coli mitis 689 524. Amo?ha dysenteria- 690 525. Cercomonas intestinalis 69 1 LIST OF ILLUSTRATIONS. XIX PAGE 526. Trichomonas hominis 691 527. Trichomonas vaginalis 691 528. Lamblia intestinalis 692 529. Spirochete obermeieri from the blood of a patient suffering with relapsing fever 693 530. Portion of tissue and isolated cells from a splenic follicle in case of typhus recurrens 693 531. Trypanosoma sanguinis murium 696 532. Trypanosoma Lewisi in various stages of developmenl 696 533. Section of a bile-duct filled with eoccidia 701 534. Goccidia from the bile-ducts of a rabbit's liver 701 535. Epithelioma contagiosum 702 536. Parasites of epithelioma contagiosum 703 537. Miescher's sacs from muscle of hog 703 538. Cycle of development of Coccidium schubergi 704 539. Plasmodium malaria? of quartan fever 70S 540. Plasmodium vivax of vernal tertian fever 700 541. Plasmodium pra?cox of tropical malaria 700 542. Anopheles claviger 71(1 543. Ookinete of pernicious malaria in intestinal wall of mosquito 710 544. Oocyst of pernicious malaria, filled with sporozoites 711 545. Cycle of development of Proteosoma 713 546. Balantidium coli 715 547. Distoma hepaticum 717 548. Eggs of Distoma hepaticum 717 549. Development of the liver-fluke 71S 550. Distoma lanceolatum 718 551. Distoma spathulatum 710 552. Distoma westermanni 710 553. Distoma haematobium 720 554. Eggs of Distoma haematobium 720 555. Head of Taenia solium 722 556. Half-ripe and ripe segments of Taenia solium 722 557. Two proglottides with uterus 722 558. Segment of Taenia solium, with mature sexual apparatus 723 559. Eggs of Taenia solium 723 560. Cysticercus cellulosae 723 561. Cysticerci of Taenia solium 72 t 562. Portion of a Taenia saginata 725 563. Head of Taenia saginata 725 564. Segment of Taenia saginata 725 565. Mature T;enia echinococcus 72X 566. Wall of echinococcus cyst with brood-capsules 728 567. Echinococcus hydatidosus 729 568. Portion of an Echinococcus multilocularis 730 509. Bothriocephalus latus 732 570. Head of Bothriocephalus latus 732 571. Middle portion of a proglottis of Bothriocephalus latus 733 572. Eggs of Bothriocephalus latus 733 573. Free embryo of Bothriocephalus latus 733 574. Ascaris lumbricoides 735 575. Egg of Ascaris lumbricoides 735 576. Oxyuris vermicularis 737 577. Eggs of Oxyuris vermicularis 738 578. Male of Anchylostoma duodenale 730 579. Head of Anchylostoma duodenale 730 580. P]ggs of Anchylostoma duodenale 730 581. Anguillula intestinalis 74 1 582. Female of Anguillula stercoralis 741 583. Triocephalus dispar 743 5S4. Egg of Tricocephalus dispar 743 585. Sexually mature trichinae 74 I 586. Encapsulated muscle-trichina' 745 587. Filaria or Dracunculus medinensis 746 588. Embryo of Filaria bancrofti, known as Filaria sanguinis hominis 746 5S9. Female itch-mite 749 XX LIST OF ILLUSTRATIONS. 590. Scabies 74!) 591. Leptus autumnalis 750 592. Acarus folliculorum hominis 750 593. Ixodes ricinus 750 .594. Cephalic end of Pentastoma denticulatum 750 595. Male of Dermatophagus communis 752 59G. Male of Dermatocopt.es communis 752 597. Female of Pediculus capitis 753 598. Male of Pediculus pubis 753 599. Female of Pediculus vestimentoruin 753 600. Larva of Anthomia canicularis 753 601 . Larva of Musca vomitoria 753 602. Larva of Lueilia macellaria 753 603. Larva of Dermatobia cyaniventris 753 604. Gastrophilus equi 754 GENERAL PATHOLOGY. INTRODUCTION. The life of an organism is revealed only through its vital manifesta- tions and activities. Physiology, the science of the normal or healthy life, teaches us concerning these activities. At the same time it shows us that the vital functions are performed according to definite laws hav- ing their foundation in the structure of the organism. Changes in this organic structure, manifesting themselves in vital phenomena differing from those regarded as normal, form the material basis of disease or abnor- mal life. The return to the normal condition is regarded as the sign of recovery or healing. A permanent cessation of all vital functions leads to death. Tem- porary interruptions of the vital activities without the loss of the possi- bility of a return to the normal state may be seen in the condition of apparent death or in congelation, which may be followed either by death or by a return to life (anabiosis). When there are present pathological changes in the tissues, arising either before the appearance of pathological symptoms or persisting after their cessation, so that at any time a new outbreak of the latter may take place, the disease is spoken of as latent. The entire science of disease is embraced by Pathology. As its first task there falls to it the determination of the causes and origin of pathologi- cal processes, these two divisions constituting etiology and pathogenesis. A second task lies in the investigation of the anatomical changes under- lying the pathological alterations of function ; and the branch of the science to which this field is assigned is known as pathological anatomy or anatomical pathology. Since the structure and finer organization of the different tissues vary according to their functions, and as we cannot conceive of vital manifestations without a material substratum for them, it is reasonable to assume that pathological manifestations of life must likewise be the expression of material changes in the tissues concerned. Moreover, experience has taught us that in the case of any pathological alteration of function of any tissue or organ, there may be demonstrated in the latter changes of structure, in part even macroscopically, while at other times they can be made out only with the aid of the microscope and by means of especial histological methods of investigation. A third field of labor belonging to pathology is concerned with the observation and interpretation of the symptoms of disease as seen in the patient, and this branch of general pathology is designated clinical pathology, pathological physiology, physiological or biological pathology. Its facts are ascertained in part by simple observation and examination of the pa- tient, and in part through the utilization of especial physical and chemical 1 1 2 INTRODUCTION. methods of examination. A successful application of the results obtained by the methods of clinical or biological pathology requires iu the first place a knowledge of the pathological-anatomical chauges present, as well as of their etiology and pathogenesis. As a further help to the in- terpretation of disease a knowledge of the chemical processes taking place in the living organism under the influence of the vital activity of the cells and the unformed ferments separable from them is essential. This knowledge is specialized in the science of pathological chemistry or chemical pathology. In conjunction with anatomical pathology this field of pathology offers the possibility of a complete understanding of the origin and course of pathological processes, as well as of their nature and significance, The extensive and many-sided domain of Pathology demands its practical division into various branches according to especial points of view. A knowledge of clinical pathology is best gained at the bedside or in the clinic, and from especial courses, lectures, and text-books. Like- wise chemical pathology demands an especial theoretical and practical training. In this text-book General Pathology will be considered as including etiology, pathogenesis, and pathological anatomy. Chemi- cal Pathology will be touched upon only in so far as is necessary to the understanding of the anatomical changes occurring in diseased organs. The first part of the work, General Anatomical Pathology, concerns itself with the causes, origin, nature, and course of disease-processes without reference to the individual clinical forms of disease. Iu the second part, Special Anatomical Pathology, the pathological processes occurring in the individual organs and tissues are considered with especial reference to the anatomical and histological changes occurring in them. Literature. (Pathological Anatomy and Chemistry. ) American Text-Book of Pathology, Philadelphia, 1901. Aschoff und Gaylord; Cursus der pathologischen Histologie, Wiesbaden, 1900. Barlow: Elements of Pathological Anatomy and Histology, London, 1903; Manual of General Pathology, 1904. Birch-Hirschfeld : Patholog. Anatomic, 1S96-1S97; Allgem. Pathologie, Leipzig, 1892. Bollinger: Atlas und Grundriss d. pathol. Anatomic, Miinchen, 1S96-1S97. Bouchard: Traite de pathologie generale, Paris, 1895-1901. Chantemesse et Podwyssowzki: Les Processus generaux, Paris, 1901. Coats: Manual of Pathology, London, 1895. Coyne: Anatomie pathologique, Paris, 1903. Cohnheim: Vorlesungen iiher allgemeine Pathologie, Berlin, 1S82. Cornil et Ranvier: Manuel d'histologie pathologique, Paris, 1901-1902. Cruveilhier : Anatomie pathologique (Atlas), Paris, 1842. Delafield and Prudden: Pathological Anatomy, New York, 1904. Diirck: Atlas und Grundriss d. pathol. Histologie, Miinchen, 1900-1903. Graupner und Zimmermann: Technik u. Diagnostik am Sektionstisch, Zwickau, 1898. Hallopeau ct Apert: Traite elementaire de pathologie generale, Paris, 1904. Hammarsten: Physiolog. Chemie, Wiesbaden, 189G. Karg und Schmori: Atlas der pathologischen Gewebelehre, Leipzig, 1893. Kaufmann: Specielle patholog. Anatomie, Berlin, 1904. Klebs: Die allgemeine Pathologie, i., Jena, 1886, und ii., 1889. Krehl: Pathologische Physiologic, Leipzig, 1904. Lancereaux: Traite d'anatomie pathologique, i.-iii., Paris, 1877-1889. INTRODUCTION. i Lazarus-Barlow: A Manual of General Pathology, London, 1899. Lukjanow: Grundziige einer allgemeinen Pathologie der Zelle, Leipzig, 1891; Grund- ziige einer allgemeinen Pathologie des Gefasssystems, Leipzig, 1894; Grundziige einer allgemeinen Pathologie der Verdauung, Leipzig, 1899. Neumeister : Physiologische Chemie, Jena, 1897. Nicolle-Diinschmann: Grundziige d. allgemeinen Mikrobiologie, Berlin, 1903. v. Noorden: Pathologie des Stoffwechsels, Berlin, 1893. Orth: Lehrbueh der speciellen pathologischen Anatomie, Berlin, 1893-1903. von Recklinghausen. Allgemeine Pathologie des Kreislaufs u. der Ernahrung, Stuttgart, 1883. Ribbert: Pathologisehe Histologie, Bonn, 1901; Die Lehre von dem Wesen der Krankheit in ihrer geschichtlichen Entwickelung, Bonn, 1899; Specielle Pathologie, Leipzig, 1902. Rumpel und Kast: Pathologiseh-anatomische Tafeln, Hamburg, 1892-1903. Schmaus : Grundriss der pathologischen Anatomie, Wiesbaden, 1904. Stengel: Text-book of Pathology, Philadelphia, 1906. Thoma: Lehrbueh der patholog. Anatomie, Stuttgart, 1894. Tripier: Traits d'anatomie pathol. g6ne>ale, Paris, 1904. Virchow: Die Cellularpathologie, Berlin, 1871. Weichselbaum : Grundriss der pathologischen Histologie, Wien, 1892. Wells: Chemical Pathology, Philadelphia, 1907. Woodhead: Practical Pathology, London, 1892. CHAPTER I. The Extrinsic Causes and the Congenital Anlage of Disease. I. The Extrinsic Causes of Disease. 1. Origin of Disease through Deficient Supply of Food and Oxygen, through Fatigue, Heat and Cold, Changes of Atmospheric Pressure, and Electrical Influences. § 1. From his birth to his death man is constantly exposed to the in- fluences of the world surrounding him, many of these external influences being favorable to the normal exercise of his functions, while others are unfavorable. As long as the human organism is able to offset these influences, through independent changes of its relations to the external world or through adaptation of its functions to external conditions, it will remain in health. If his regulating mechanism no longer suffices for successful opposition to unfavorable external influences, and if he cannot escape these or change, his conditions of life, man becomes ill or dies. For its preservation the body needs first of all a certain amount of food, water, and oxygen ; and though it may exist for a short time with- out these, an insufficient supply of oxygen, food or water beyond a certain limit and after a certain time must of necessity lead to disease or death. A total deprivation or diminution of the supply of oxygen to the tissues may take place at any period of life, either because of a lack of oxygen in the surrounding medium, or some obstruction to the entrance of the oxygen of the air into the lungs or blood, or inability on the part of the blood to take up a sufficient amount of oxygen. The fcetus in utero may be insufficiently supplied with oxygen as a result of diminished supply to the mother, premature separation of the placenta, disease of the placenta, or compression of the cord, whereby the interchange, of gases between the maternal and foetal blood is hindered. After birth an insufficient supply of oxygen may be due to hindrances to respiration, or the child may be so weak that its respiratory movements are insuffi- cient to expand the lungs. When the supply of oxygen is completely shut off, as may happen from the entrance of water or other fluid into the respiratory tract or from closure of the air-passages, the affected individual dies in a very short time from choking or suffocation. Animals confined in closed chambers die as soon as the oxygen of the air reaches two or three, per cent by volume, the normal volume percentage being 20.8 (01. Bernard, P. Bert). If the, supply of oxygen is not wholly shut off, but only greatly diminished, as in the case of carbon-monoxide poisoning, in which the firm combination of carbon monoxide, with the haemoglobin prevents the taking up of oxygen by' the red blood-cells, death by suffocation may DEPRIVATION OF OXYGEN, FOOD, AND WATER. 5 take place only after several days. In gradually increasing hindrances to the entrance of oxygen and resulting accumulation of carbonic acid in the blood, as in cases of narrowing of the lumen of the larynx through inflammatory exudates, compression of the trachea from goitre, weaken- ing or obstruction of respiration, etc., a condition of breathlessness, cyanosis, convulsions, and disturbances of consciousness is produced, which is termed asphyxia. If the taking up tof oxygen is diminished in only a slight degree but for a long time, as in the case of a lessened number of red blood-cells in oligocythemia, degenerative processes characterized by increased de- struction of albumin and by fatty changes may occur in the tissues and organs, and these may lead not only to disease but under certain condi- tions to death. Total deprivation of food and water leads to a rapid loss of body- weight, inasmuch as the fat and albumin continue to be decomposed; death finally ensues. According to Lehmann, Muller, Munk, Senator, and Zuntz, the total amount of oxidation in cases of starvation does not fall below that of the same individual in the fasting state under the same conditions. A marked decomposition of albumin and loss of water take place. In animals death occurs after the loss of about forty per cent of the body-weight, about, one-half of the loss being due to the waste of muscle. The fat disappears most rapidly; even as much as ninety-three per cent may be lost. The other organs show diminution of substance in the following order: liver, spleen, testicles, muscles, blood, intestines, skin, kidneys, and lungs. The heart, nervous system, and bones show the least loss of weight ; but destruction of bone-tissue does take place during starvation, as is shown by the increase of calcium and phosphoric acid, in the urine, following ingestion of water. In the blood there is a rapid diminution of the leucocytes (Lueiani) ; the red blood-cells, on the other hand, may be relatively increased in number. The organs of animals dying from starvation show simple atrophy of the tissue-elements, par- ticularly of the liver (Lukjanow), hyperemia, scattered hemorrhages, degenerations, and inflammatory changes, especially in the intestine, liver, kidneys, and nervous system. tin the case of total deprivation of food and water, death occurs in an after from seven to twelve days ; bodily exercise hastens the end, ingestion of water may delay it markedly, so that some individuals have been enabled through the use of water to endure a period of total absti- nence from food for thirty days or longer, without dying or suffering permanent harm. The consumption of water leads to an increased ex- cretion of nitrogen in the urine. Life may be maintained for a long time upon insufficient nourish- ment, but a wasting of the body takes place which may lead to a condi- tion of extreme emaciation, marasmus, or cachexia, and finally to death. The same thing happens when the composition of the food is unsuitable and only a portion of the necessary food-elements is present in sufficient amount, so that the body is starved either in albumin, fat, salts, or water. Dogs deprived of all nitrogenous food die in from thirty-one to- thirty-four days (Magendie). When the food is abundant but poor in albumin, there occur after a time fin dogs after six weeks) loss of appe- tite and repugnance toward the proffered food, with impairment of diges- tion and assimilation (Munk). This is especially the case when the food is lacking in fat, less so -when albumin or the carbohydrates are wanting. 6 THE EXTRINSIC CAUSES OF DISEASE. It is very probable that the lessened absorption is chiefly due to diminished secretion of the digestive juices, this being capable of quantitative de- monstration in the case of the bile. The fseces are finally nearly desti- tute of bile. An insufficient supply of iron for a long period gives rise to anreniia and general disturbances of nutrition. If for experimental purposes an animal well supplied with food is to= tally deprived of water, there is a rapid loss of body-weight followed in from eight to twelve days by death. The pathological changes found in the different organs are similar to those resulting from starvation. They are caused partly by lack of water and insufficient absorption of food, and partly by the retention of harmful products of metabolism. Cow's milk has a very email iron-content. According to Purst, milk ash contains 0.53 per cent of iron, white of egg 0.57, beef 0.7, peas 0.88, potatoes 1. 18, apples 1.4, yolk of egg 1.65, lentils 2.0, plums 2.54, rye flour 2.54, spinach 3.35, lettuce 5.31, strawberries 5.89, tea 9.29, beef blood 9.79 per cent. Literature. (Results of Diminished Supply of Oxygen, Food, and Water. ) Ahlfeld: Der Uebergang der intrauterinen Athmung zur extrauterinen, Marburg, 1891. Beneke: Grundlinien der Pathologic des Stoffwechsels, Berlin, 1874. Bischoff und Voit : Die Gesetze der Ernahrung des Fleischf ressers, 1860. Coen: Sull' inanizione acuta. Bull, delle Scienze Med. di Bologna, ser. vii., vol. i., 1890. Daddi et Treves : Observations sur l'asphyxie lente. A. ital. de biol., xxviii., 1897. Dennig: Bedeutung der Wasserzufuhr fur den Stoffwechsel. Zcit. f. Ther. , i., 1898. Dreyfus-Brissac : De l'asphyxie non toxique, Paris, 1883. Ehrlich: Das Suuerstoffbedliriniss des Organismus, Berlin, 1885. Frankel: Einliuss d. verminderten Sauerstoffzufuhr. Virch. Arch., 67 Bd., 1876. Halliburton: Lehrb. der chemischen Physiologic 1 und Pathologie, Heidelberg, 1896. Hofmann: Lehrbuch der gerichtl. Medicin, Wien, 1895. Hoppe-Seyler: Stoffwechsel bei Sauerstoff mangel. Festschr. d. Assist, f. Virchow, Berlin, 1891. Krehl: Die Athmung. Pathol. Physiologic, Leipzig, 1898. Lehman, Miiller, Munk, Senator, und Zuntz: Untersuchung an zwei hungernden Menschen. Virch. Arch., 131 Bd., Supplement, 1893. Luciani: Das Hungern (iibersctzt von O. Frankel), Leipzig, 1890. Lukjanow: Veriind. d. Zellkerne unt. d. Eintl. d. Hungerns. Arch, des Sc. biol., vi und vii., 1897 u. 1898. Meltzer and Norris : On the Influence of Fasting upon the Bactericidal Action of the Blood. Jour, of Exp. Medicine, 1899. Monti: Alterat. del sist. nervoso nell' inanizione. Arch. ital. de Biol., xxiv., 1895. Miiller: Stoffwechseluntersuchungen bei Krebskranken. Zcitschr. f. klin. Med., xvi , 1889. Miihlmann: Russische Literatur fiber die Pathologie des Hungerns (zahlreiche und vielseitige Untersuchungcn). Centralbl. f. allg. Pathol., x., 1899. Munk: Leber die Folgen einer ausreichenden aber eiweissarmen Nahrung. Virch Arch., 132 Bd., 1893. v. Noorden: Pathologie des Stoffwechsels, Berlin, 1893. Ottolenghi: Osserv. sperim. sul sangue asfittico. Arch. p. le Sc. Med., xvii., 1893. Peri: Alterations du syst. nerv. prod, par l'inanition. Arch. ital. de Biol., xviii., 1892. Pernice und Scagliosi: Wirkung d. Wasscrent.ziehung. Virch. Arch., 139 Bd., 1S95 (Lit.). Penzoldt u. Fleischer: Einliuss von Respirationsstorungen. Virch. Arch., 87 Bd., 18H2. Runge : Die Krankheiten der ersten Lebcnstage, Stuttgart, 1893. Statkewitsch: Verauderungen d. Muskeln u. Drilsen b. Hungern. Archiv f exp Path., 33 Bd., 1894. § 2. An unusual demand upon the functional activity of an organ for an extended period of time leads sooner or later to a state of ex- FATIGUE. 7 haustion, which is, iu part, due to the consumption of cell-substance, and in part to the formation of toxic products of metabolism, wherebv the organ is incapacitated for further extended activity. Most often the results of overwork are manifested in the muscles and nervous system in the form of such symptoms as soreness and stiffness of the muscles, mental excitement, sleeplessness, heavy feeling in the head, loss of appetite, great weakness, unnatural sweating, and sometimes fever. Overwork of the heart leading to exhaustion may cause death. This may occur either when the heart is for a short time taxed to the extreme limit of its power or when for a longer period it works slightly under its maximum capacity. If the exhausted tissues are permitted to rest and supplied with an abundance of nourishment, the loss of cell-material due to the excessive activity will be replaced, the products of metabol- ism, which are hindering the functional activity of the tissue, will be removed, and the part restored to its normal condition. If a tissue is frec[uently subjected to excessive functional demands, and if the periods of rest are too short to admit of its complete restora- tion, there will result ultimately a condition of permanent functional in- sufficiency, a chronic exhaustion, which may under certain circumstances manifest itself in a degeneration or atrophy of the affected organ. For example, a muscle through overwork may become atrophic, and a brain too constantly stimulated to activity without proper periods of rest may finally reach such a state of weakness and exhaustion that it is incapable of performing even its normal function. Through rest and properly regulated nourishment such a brain may recover ; but beyond a certain limit of exhaustion the functional insufficiency may become permanent and eventually manifest itself in anatomical changes. A very severe over-stimulation of the nervous system, even for a very short time, may under certain conditions lead to a paralysis of its functions, which, in case the heart and respiratory apparatus are af- fected, may cause death, but in the majority of cases is of a transitory nature. Overwork of any organ is more cprickly followed by fatigue and functional insufficiency in the case of impaired nutrition. Fatigue and insufficiency of the heart are most frequently observed when the general nutrition is lowered, as in cases of fever, or when there is deficient oxy- genation of the blood, as in poorly compensated heart lesions or pulmo- nary diseases. It is very probable that overwork lowers the resistance of the body to various infections. When the functional demands upon a muscle or gland are only mod- erately increased, and if the nutrition is good and in proportion to the increase of labor, the affected tissue becomes hypertrophied, aud is thereby enabled to perform the increased work permanently. A permanent diminution or cessation of activity causes in organs that normally perform a definite and constant function (muscles and glands) a loss of tissue- substance (atrophy). Literature. ( Overexertion and Fatigue. ) Abelous: Coutrib. al'etude de la fatigue. Arch, de Phys., v., 1893. Blake and Larrabee : Observations upon Long-Distance Runners. Boston Med. and Surg. Jour., 1903. 8 THE EXTRINSIC CAUSES OF DISEASE. Bouveret : La neurasthenie, Paris, 1891. Brauus: Die Neurastbenie, Wiesbaden, 1891. Carrieu: De If fatigue etde son influence pathogenique, Paris. 187S. Edinger: Neue Tbeorie iiber die Ursacben einiger Nervenkrankheiten, Leipzig, 1894. Erb: Die zunekmende Nervositiit uuserer Zeit, Heidelberg, 1893. DeFleury: Patbogenie de l'epuisement nerveux. Rev. de Med., 1896. Guerrini: Action de la fatigue sur les cellules nerveuses. Arcb. ital. de Biol, xxxii., 1899. Kraepelin: Zur Ueberbiirdungsfrage, Jena, 1897 (Lit.). v. Krafft-Ebing: Lehrbuch der Psychiatrie, 1893; Gesunde u. kranke Nerven, 1895. Krehl u. Romberg': Bedeutung d."Herzmuskels u. d. Herzganglion. f. d. Herztkatig- kcit. Arcb. f. exp. Path., 30 Bd., 1892. Leyden: Herzkiaukbeiten in Folge v. Ueberanstrengung. Zeitschr. f. klin. Med., xi., 18S6. "_ Marfan: Fatigue et surmenage. Path. gen. publ. par Bouchard, i., 1895. Mosso: Die Ermildung, Leipzig, 1893. Seitz: Ueberanstrengung d. Herzens. D. Arcb. f. klin. Med., xi., 1873, u. xiii., 1874 (Lit.). Williams and Arnold: Tbe Effects of Violent and Prolonged Exercise upon the Heart, Phil. Med. Jour., 1899. Ziehen: Neurasthenic. Eiilenburg's Realencyklop., xvii., 1898 (Lit,). § 3. High temperatures may act, either through local destruction oj tissue (burning) or through overheating of the entire body. The latter conditiou is possible only when the body is exposed to an increased tem- perature for such a time that it cannot protect itself from overheating by increased heat-dispersion. In dry air of from 55-60° C. (131-140° F.) the most profuse perspiration is no longer able to protect the body permanently from overheating, and in a moist atmosphere the same is true at even lower temperatures. If the human body is subjected to high temperatures, it may become ■overheated, and the condition known as heat-stroke may result. The pulse-rate is increased, the respiration very rapid and labored, the pupils are dilated, and finally death may occur as iu the case of the animals made the subject of experiment. The occurrence of heat-stroke is favored by heavy bodily labor, interference with heat-dispersion through 'impermeable clothing, or by a lack of water in the body. The direct action of the rays of the sun upon the head may cause cerebral and meningeal irritation, a condition characterized by hy- peremia and inflammatory exudations, and known as sun-stroke or insolation. The local effects of heat upon the skin, burns, are, according to the intensity of the heat and the time of its duration, either hyperemia, (burn of first degree), formation of a blister (second degree), tissue- eschar (third degree), or carbonization (fourth degree). The heat pro- duces local changes in the tissues, and kills them at a certain height of temperature or after a certain time of exposure to its action. When a large part of the surface of the body, about one-third, is burned, the affected individual usually dies, even though the burn is only of a. slight degree and eschars are not formed. The anatomical find- ings in fatal cases of superficial burns would indicate, when death has not resulted very quickly from the severe shock to the nervous system and the overheating of the body, that the cause of death is to be sought in the changes in the blood and in disturbances of the circulation. The blood-changes consist in the loss of a portion of its water and in destruc- tion of the red blood-cells, or in such injury to them as to diminish their function and to give rise at the same time to a deposit of the products of destruction and of hemoglobin in the liver, spleen, and kidneys. The THE EFFECTS OF HIGH AND LOW TEMPERATURES. 9 changes are further characterized by a tendency on the part of the blood to stasis, hemorrhages, and intravascular coagulation, through which vessels of both the pulmonary and the systemic circulation may be ob- structed, so that local tissue-degenerations and necroses may occur in cer- tain organs, as, for example, in the kidneys, liver, mucosa of the stomach and intestine, bones, and soft parts. It is also probable that poisonous products are produced which have an injurious action, particularly upon the nervous system, liver, and kidneys. Low temperatures act in the same manner as high ones, in part through local injury and death of tissues, in part through refrigeration of the entire body. Severe and lasting lowering of temperature causes tissue death ; after mild chilling there occur, as the result of tissue-de- generation, thrombosis, hypersernia, and exudations which are relatively rich in leucocytes. A very short refrigeration at the freezing-point is sufficient to produce degenerative changes which are quickly followed by regenerative proliferation on the part of the cells remaining uninjured. Epithelial thickenings may be produced (Fuerst) by repeated slight re- frigerations (as well as by repeated slight increase of temperature). The tips of the extremities, nose, and ears are the most easily frozen. After repeated drillings of mild degree inflammatory redness and swell- ing of the skin, associated with severe itching, often occur (chilblains, perniones). If the temperature of the entire body be markedly lowered, a condi- tion of general paralysis results from the diminished excitability of the tissues, the nervous system and heart being especially affected. The sensorium becomes dulled, the heart-beat and respiration gradually grow weaker, and finally cease entirely. If the body be again warmed, be- fore the excitability of the tissues is wholly lost, the power of movement in the limbs is gradually restored, and after a time consciousness re- turns. In man, instances of complete recovery have been observed, even after refrigeration of the body to from 24-30° C. (75-86° F.). Besides the more severe forms of local or general lowering of the tis- sue temperature there may occur, as harmful pathogenic influences, mild general or local chillings, the so-called colds, as the result of which dis- ease-phenomena may manifest themselves partly at the seat of chilling, partly in organs in distant parts of the body. For example, after wide- spread refrigeration of the skin there may occur diarrhoea, catarrh of the respiratory tract, or disease of the kidneys; after local chilling of the skin, painful affections of the deep-seated muscles. The exact relation between these phenomena and the refrigeration is unknown (the oft-re- peated hypothesis that they are due to hyperemia of the internal organs caused by the chilling of the body-surface has not been proved), but there is no reason on this account to deny the existence of diseases caused by cold. Though many diseases formerly attributed to "catching cold " have been shown to be of infectious origin, there yet remain a number of diseased conditions for which we know no other etiology than that of refrigeration. Conditions of the body in which the skin is hypersemic and the perspiratory function active favor the taking of cold. Many in- dividuals appear to possess a predisposition on the part of certain tissues to the effects of refrigeration ; in one person certain muscles, in another the mucous membranes will be affected. According to the view of many writers, refrigeration of the body increases the susceptibility to infection, so that, for example, the patho- genic bacteria which may be present in those cavities of the body acces- 10 THE EXTRINSIC CAUSES OF DISEASE. sible from without may, after suck refrigeration, be able to exert their injurious influences upon the tissue. If rabbits are placed in well- ventilated incubators at a temperature of 36-40° C. (96.5-104° F.), their body temperature will rise to 39-40° C. (102.3-104° F.), the respira- tion and pulse being at the same time greatly increased in frequency. A very marked elevation of body temperature may lead in one to three days to death through paralysis of the nervous and muscular systems, the chief symptoms being a marked increase of both respiratory and cardiac activity. If the increase of body temperature is not greater than 2-3° C. (3-5° F.), the animals may, if properly nourished, live from ten to thirty days or even longer, but they will lose in weight and ultimately die, showing before death a gradually increasing diminution of haemoglobin and of red blood-cells. De- generative changes, particularly fatty degeneration, occur in the liver, kidneys, and heart muscle. During the experiment there is an increased production of urea. The fact that man dies so frequently after an extensive superficial burn of the skin has been explained in various ways. Billroth, Foh, Mendel, and others believed the cause of death to lie in a suppression of the perspiration and the resulting accumula- tion of toxic substances in the blood; while others, as B. Sonnenburg and Fall;, sought the cause in a reflex lowering of the vascular tone. In the foudroyant cases, according to Sonnenburg , the overheating of the blood causes a paralysis of the heart. Ponfick, Klebs, von Lesser, and others, on the other hand, are of the opinion that the fatal issue is due to injury and destruction of the red blood-cells. Silbermann, Welti, and Sal- violi also seek the cause of death in an injury to the blood, emphasizing, however, not so much the destruction of the red blood-cells as the occurrence of stasis and coagula- tion of the blood in the vessels of different organs, which are interpreted as resulting from the changes in the blood. On the other hand, Kijanitzin, Parascandolo, Sca- gliosi, and Dorn hold that there is formed in the bodies of burned individuals a poison which has an injurious action upon the nervous system and also upon the liver and kid- neys. Wilms seeks the cause of death partly in a loss of the water of the body and partly in the absorption of poisonous products from the burned area. According to Pfliiger and others, all the vital processes may be brought to a stand- still through refrigeration, without its being impossible for a recovery to take place from the apparent death. This may happen even when the animal is frozen to a solid mass. Preyer also holds the opinion that the continuity of life may be wholly inter- rupted by refrigeration, and designates subjects who are thus "lifeless," but still capa- ble of living, as anabiotic. Frogs are said to remain capable of life for many hours, even though the temperature be reduced to —2.5° C.,at which temperature the heart is frozen. According to the investigations of Koch, such anabiosis of solidly frozen animals is possible when only a portion of the water contained in the body of the ani- mal is frozen and when the thawing process takes place slowly. In the case of rapid thawing, strong diffusion currents are set up between the water coming from the ice- crystals and the concentrated albuminous solutions of the blood and the tissues; and these currents may exert a damaging effect upon the latter. According to the investigations of J, Dewar (Proc. of the Royal Soe., London, 1900), the seeds of wheat, barley, mustard, peas, and pumpkins do not lose their ger- minative power when put into liquid hydrogen; that is, in a temperature of —250°. Further, the protoplasm under these conditions was not changed by the cold. Not only do the heat-rays of the sun-light or the arc-light affect the human body, but their chemically active violet and ultraviolet rays have also an important action upon its tissues. According to Young, Beclard, Schnetzler, Godnew, and others (for literature see Sack, I.e.), the processes of growth and regeneration are carried on more rapidly under the influence of blue and violet rays than under ordinary con- ditions. According to Finsen, variola-lesions in the skin run a much more favorable course when protected from the violet rays by means of red glass. According to the investigations of Maklakow the violet and ultraviolet rays of the arc-light can produce a peculiar erythema of the skin, even when the heat-rays are excluded (Widmark). Finsen holds that "sunburn" is produced chiefly by the violet and ultraviolet rays. Bacteria in plate-cultures are killed within a short time by exposure to the ultraviolet rays of the arc-light. According to the investigations of Godnew, Finsen, Mbller, and others, the violet and ultraviolet rays penetrate the skin, but are absorbed by the blood. Basing his views upon these facts, Finsen has attempted to treat skin diseases, espe- cially lupus, cancer, vascular nsevi, acne, etc., with the ultraviolet rays of the sun and the arc-light, and has been very successful with the latter method. Fresh cases of lupus were healed by it in a relatively short time. The heat-rays are excluded by means of the interposition of quartz lenses and chambers of running water. A hollow lens of quartz through which water is flowing is pressed firmly against the affected area in order to exclude the blood which absorbs the ultraviolet rays. The irradiation, when ROENTGEN RAYS. 11 continued for about an hour, causes first an inflammation, leading after twelve hours or more to the formation of a blister. Later, scar tissue develops in the area so treated. According to investigations by Dreyer, and confirmed by Neisser and Halber- staedter, infusoria, bacteria, and animal tissues when impregnated with erythrosin (solution of 1: 1.000-1: 4,000) become sensitized to red and yellow rays, so that these rays act upon them in the same manner as the violet and ultraviolet. Since the red and yellow rays possess a greater power of penetration into the tissues, a more marked and deeper effect of irradiation can be obtained by the previous treatment of the tissues with solutions of erythrosin. Roentgen-Rays, acting upon the skin for some time, cause in the exposed por- tions, at point of entrance and exit, degenerative changes affecting chiefly the epithelium, but also the connective-tissue cells. These are followed by inflammatory processes. Clinically these changes show themselves usually about fourteen days after the exposure, and reach their acme after some weeks. The hair and finger-nails may be lost. If tissue-necrosis occurs, the healing of the resulting ulcer is very slow and difficult. The Roentgen-rays have also been used with some success in the treatment of lupus and carcinoma of the skin. Exposures of 30 to 60 minutes are given, and repeated two or three times. After one or two weeks the cancer shows an inflammatory reaction. Healing of the neoplasm takes place through the destruction of the carcinoma cells, which are especially susceptible to the action of the rays; and the resulting ulcer heals through the formation of scar-tissue and a. regeneration of the epidermis. In the case of carcinoma of the mamma a certain amount of destruction of the neoplasm may be accomplished, but not to the extent of a complete cure. Recent cases have been observed of cancer developing in skin frequently exposed to Roentgen-rays. According to investigations by Heineke and Warthin, the experimental irradiation of rats, mice, guinea-pigs, rabbits, and dogs causes, even after fifteen-minute exposures, a marked destruction of the lymphoid cells of the spleen, bone-marrow, and lymph- nodes. The disintegration of the lymphoid cells is evident almost immediately after the exposure, and persists for some hours. After single exposures regeneration is rapid, but after prolonged or repeated exposures the spleen may finally become practically devoid of lymphoid cells. In exposures of this degree the death of the animal usually takes place within ten days, after it has exhibited marked symptoms of intoxication. Small animals maybe rendered blind by prolonged exposures. In the use of Roentgen- rays as a curative agent in leukaemia it has been shown that the size of the spleen may be greatly diminished, the white-cell count brought down to normal, the general condi- tion improved, and the life of the patient extended by one to two years. Wurthin has shown that this improvement is due wholly to the destructive action of the rays upon the white cells of the blood-cell-forming organs, and that the essential disease-process is not cured. He has also emphasized the dangers of an intoxication arising from the products of proteid disintegration, and has shown the occurrence of extensive degeneration and calcification of the kidneys in cases so treated. His investigations show also that slight changes occur in the renal epithelium as the result of short ex- posures. Capps believes that a leukotoxin is produced in the sera of animals exposed to the rays. Scholz, Seldin, Philipp, HaJberstaedter, and others have demonstrated the production of azoospermia in man and animals by means of Roentgen irradiation. Numerous cases of sterility in Roentgen-ray operators have been observed. Bardeen found that the death of spermatozoa is hastened by irradiation, and that spermatozoa injured by short exposures to Roentgen- rays, but still capable of fertilization, may cause the development of monsters from ova fertilized by them. He concludes that nuclear material may be so influenced by exposures to the rays that after a latent period it may show marked abnormalities in development. Foersterling warns against the Idangers of irradiation in young children. Edsatt has reported an instance of death following Roentgen irradiation, and the present tendency is to regard the rays as agents capable of producing serious damage to the animal organism. BecquereURays act similarly to the Roentgen. Tissue-degenerations and in- flammations appear in the second or third week after the exposure and reach their acme in 20-30 days (Halkin, I.e.). Slowly healing ulcers may be formed. Some success has been obtained with the rays in the treatment of cancer of the skin and lupus. _ Accord- ing to Pfeiffer, Friedberger, and Scholtz the rays are bactericidal, and a portion of the active rays can penetrate the tissues to a depth of several millimetres. Roentgen and Becquere'l rays are not, like light, heat, and electricity, especial forms of undulations of the ether.'but consist of extremely minute particles of matter, electrons, which are given off into space with great rapidity. In the case of the Roentgen-rays the projecting power is the electrical energy supplied to the Roentgen tube. The Becquerel rays represent a property of certain bodies designated by Becquerel as radio-activity. In 1896 this investigator discovered that uranium and its salts give off rays that act upon photographic plates in the dark and are capable of penetrating bodies impervious to 12 THE EXTRINSIC CAUSES OF DISEASE. light. In 1898 Madame Curie succeeded in separating from pitchblende two radio- active bodies which were named radium, and polonium. In 1S99 a third radio-active body (actinium) was discovered by Curie and Debieme. Radium has been produced in a pure form and has been the most carefully studied. It is a new element, the salts of which are radio-active in the highest degree and project electrons into space at a velocity of 160,000 kilometres per second, at the same time giving off heat-rays. The air about it becomes ionized, that is, becomes a conductor for electrical discharges. The action of radium upon the tissues is similar to that of Roentgen-rays. According to Hinstedt (Ann. der Physik, 1903), numerous springs, hot ones in particular, are radio-active, and it is not improbable that their special action is in part dependent upon this property. Literature. (Effects of Sigh and Low Temperatures.) Alonzo: Alteraz. delle fibre nervose in seg. al congelamento. A. p. le 8c. Med., xiii., 1S89. Ansiaux: La mort par le refroidissement, Bruxelles, 1889. Bardeen: A Review of the Pathology of Superficial Burns, Johns Hopkins Hosp. Rep., vol. vii. Dittrich.: Ueber Hitzschlag. Zeitschr. f. Heilk., xiv., 1S93 (Lit.). Dohm: Path. Anat. d. Todes nach Hautverbrennung. D. Zeitschr. f. Chir., 60 Bd., 1901. Finsen: Leber die Bedeutung d. chem. Strahlen des Lichtes f. Medizin, Leipzig, 1S99. Fraenkel: Befunde bei acut. Todesfallen nach Hautverbrennung. Pent. med. Wochensehr. , 18S9. Fuerst: Verilnd. d. Epidermis dureh leichte Warme- und Kalteeinwirkung. Beit. v. Ziegler, xxiv., 189S. Gottstein: Klimatische Einfliisse als Krankheitsursache. Ergebn. d. allg. Path.,iv., Wiesbaden, 1899. Grawitz: Widerstarjdsfahigke.it lebender Gewebe. Deut. mod. Wochensehr., 1897. Hochhaus: Gewebsveriind. nach Kalteeinwirkung. Virch. Archiv, 154 Bd., 189S. Jacubasch: Sonnenstich u. Hitzschlag, Wien, 1881. Keferstein: Der Erfrierungstod, Berlin, 1893. Kijanitzin: Lrsache d. Todes nach Hautverbrennung. Virch. Arch., 131 Bd., 1S93. Kisskalt: Disposition, Erkaltung u. Abhartung. Milnch. med. Wochensehr., 1900; Die Erkaltung. Arch. f. Hyg., 39 Bd., 1901. Koch.s: Wirkung der Kalte und Anabiose. Biol. Cent.. 1890. u. xv.. 1895. Krieg-e: Hyaline Veranderungen der Haut durch Erfrierungen. Virch. Arch., 116 Bd., 1889. Laloy: Scheintod u. Wiederbelebung als Anpassungan Kalte. Biol. Cbl., xx., 1900. Le Noir: Agents physiques. Pathol, gen. publ. par Bouchard, i., 1895. Lefevre: Reactions consec. aux refrigerations. Journ. de phys., ii., 1900. Lesser: Leber die Todesursachen nach Verbrennungen. Virch. Arch.. 79 Bd., 1880. Markusfeld u. Steinhaus: Todesursache nach Verbriihung. Cent. f. allg. Path., vi., 1895. Masehold: Sonnenstich u. Hitzschlag. Eulenburg's Realencyklopadie, xxii., 1899. Neisser u. Halberstaedter: Lichtbehandlung nach Dreyer. D. med. Woch., 1904. Obernier: Der Hitzschlag. Bonn. 1889. Parascandolo: Alterat. du syst. nerveuxdans les briilurcs. Arch, de phys., x., 1S98. Pfliig-er: Die allgemeinen Lebenserscheinungen, Bonn, 1889. Pictet: L'Emploi des basses temper. Jahresber. liber 1S93 v. Hermann, ii., 1895. Ponfick: Todesfillle nach Hautverbrennungen. Berl. klin. Woch., 1876, 1S77. u. 1S83. Preyer: Leber Anabiose. Biol. Central!)., xi., 1891. Rischpler: Histol. Veranderungen nach der Erfrierung. Beitr. v. Ziegler, xxviii., 1900. Ruhemann: 1st Erkaltung eine Erkrankungsursache? Leipzig, 189S. Sack: Wesen d. Finsenschen Lichtbehandlung. Munch, med. Wochensehr., 1902. Salvioli: Causa della morte per scoltatura. Virch. Arch., 125 Bd., 1891, u. Arch. ital. de Biol., xv., 1891. Scagdiosi: Sonnenstich. Virch. Arch., 165 Bd., 1901; Hautverbrennung. D. med. Woch., 1903. Schmidt, E.: Lichttherapie. Zeitschr. f. arztl. Fortbildung, i.. 1904. Schmidt u. Markuse: Verand. der Haut nach Finsenschen-Bestrahlungen. A. f Derm., 64 Bd., 1903. radio-activity: atmospheric pressure. 13 Silbermann: Ursachen d. Todes nach Hautverbrennungen. Virch. Arch., 119 Bd., 1890. TJschinsky: Wirkung der Kalte auf verschiedene Gewebe. Beitr. v. Ziegler, xii., 1892. Wegner: Abkiihlung blossgelegter Organe. v. Langenbeok's Arch., xx., 1876. Welti: Todesursache nach Hautverbrennungen. Beit. v. Ziegler, iv., 1889; Cent. f. allg. Path., 1890. Werhovski: Wirkung erhohter Eigenwiirme. Beitr. v. Ziegler, xviii., 1895 (Lit.). "Wilms: Zur Pathologie der Verbrennung. Grenzgeb. d. Med. u. Chir., Bd. viii., 1901. Ziegler: Wirkung erhohter Eigenwiirme. Verh. d. Congr. f. inn. Med., 1895. (The Effects of Radio-activity. ) Apolant: Wirk. v. Radiumstrahlen auf die Karcinom d. Mause. D. med. Woch., 1904. Bardeen: The Action of Roentgen Rays upon Spermatozoa. Amer. Medicine, 1906. Capps: On the Production of a Leukotoxin by Roentgen Irradiation. Trans. Assoc, of Amer. Phys., 1906. Caspari: Bedeutung des Radiums. Zeitsschr. d. diat. Chir., viii., 1904. Edsall: Dangers of Roentgen Irradiation. Jour. Amer. Med. Assoc, 1906. Fittig: Behandlung d. Kareinome mit Roentgenstrahlen. Beitr. v. Bruns, 42 Bd., 1904. Halkin: Einfluss der Becquerelstrahlen auf die Haut. A. f. Derm., 65 Bd., 1903 (Lit.). Heineke: Einwirk. d. Roentgenstrahlen auf inn. Organe. Munch, med. Woch., 1904. Perthes: Einfluss der Roentgenstrahlen auf das Karcinom. Arch. f. klin. Chir., 71 Bd., 1903. Scholtz: Einfluss der Roentgenstrahlen auf die Haut. Arch. f. Derm., 59 Bd., 1902; Roentgenstrahlen. Eulenburg's Jahrb., ii., 1904; Wirk. d. Radiums. D. med. Woch., 1904. Warthin: The Effects of Roentgen Rays upon the Blood-forming Organs. Inter- national Clinics, Jan., 1906; ibid. With Especial Reference to the Treatment of Leukemia. Physician and Surgeon, 1907 (Lit.); Action of Roentgen Rays upon the Kidney. Am. Jour, of Med. Sciences, 1907 (Lit.). Weber: Die heutige Kenntnis d. Radioaktivitat. D. med. Woch., 1904. § 4. A sudden lowering of atmospheric pressure, as in the case of mountain-climbing and balloon ascents, may cause conditions of great exhaustion, with marked palpitation of the heart, unconsciousness, ir- regular breathing, and sometimes vomiting, and bleeding from the gums and lips. These symptoms depend essentially upon a lack of oxygen (P. Bert), the capillaries of the lungs being unable to take up sufficient oxygen from the highly rarefied air. Kronecker believes that they are to be referred to disturbances of the pulmonary circulation. According to the investigations of Schumburg and Zuntz, it appears that a given amount of labor calls for a greater amount of oxygen at an increased ele- vation than at a lower level. The symptoms of mountain-sickness appear at a lower elevation than those of balloon-sickness, owing to the demands made upon the muscles in the former case during the climbing. During the building of the Gorner Grat Railway it was found that at a height of 2,700-3,000 metres the capacity of the laborers was diminished to a third. According to the researches of Egger, Miescher, and others, a sojourn in high altitudes leads, after a short time, to an increase in the number of red cells and a greater haemoglobin-content of the blood. Schaumann and Eosencpiist hold that the same phenomenon may be observed in animals confined for some time in bell-jars at a lower atmos- pheric pressure. Other authors (Schumburg, Zuntz, Gottstein) oppose this view, and maintain that the phenomenon is due either to a thicken- ing of the blood from loss of water and to changes in the distribution of the blood, or to changes in volume of the measuring-apparatus ; they endeavor to explain the favorable effects which many individuals expe- 14 THE EXTRINSIC CAUSES OF DISEASE. rience from a residence at high altitudes by certain stimulating influ- ences (greater exposure to sun's rays) -which affect the nervous system and cause increased metabolism. According to Marti, intense and pro- longed irradiation of the body stimulates the formation of red blood-cells and to a lesser degree also that of the hrenioglobin. A sojourn in diving-bells or caissons, such as are employed in build- ing operations beneath the water, in which the atmospheric pressure is increased, under certain conditions, as high as four atmospheres or even greater, causes a slight difficulty in breathing and a relatively unimpor- tant increase of the pulse-rate. If a change be made quickly from the compressed atmosphere to air of ordinary pressure, there may occur within an hour a condition of great fatigue, tightness of the chest, ring- ing of the ears, cramps in the muscles, pains in the joints and limbs, haemorrhages from the nose, ears, and lungs, dilatation of the pupils, and under certain conditions paralysis, coma, delirium, and even death after an interval of from one to twenty days. The cause of these phenomena is probably to be found in the obstruc- tion of blood-vessels of the spinal cord by bubbles of nitrogen that has been ab- sorbed under the high pressure (Hoche). According to experimental investiga- tions of Heller, Mager, and von Schrot- ter, the blood, after rapid removal of pressure, contains free gas (almost ex- clusively nitrogen), so that free gas circulates in the blood. In fatal cases associated with paralysis areas of de- generation (Nikiforoff) are found in the white columns of the spinal cord, in which individual nerve-fibres present marked changes in the form of swelling of the axis-cylinders, and disintegration of the medullary sheaths, with the for- mation of vacuoles in the place of the nerve-fibres that have been completely destroyed. If the gray matter is in- volved, the ganglion-cells may also de- generate. Changes in the electrical condition of the atmosphere and in the magnetic state of the earth have no demonstrable influence upon the human body; on the other hand, electric discharges, as lightning-stroke, may cause, in part, local lesions of the skin resembling burns (Pig. 1), hsem- orrhages in the skin, and burning of the hair, aud, in part, lesions of the whole body. Under certain circumstances lightning-stroke causes lacera- tion of internal organs, as, for example, of the heart and liver. The most frequent and important effect of lightning-stroke is a paralysis of the nervous system, which gives rise to a severe dyspnoea, which may be fatal immediately or after a few minutes or hours, or may gradually pass away after several hours, days, or weeks. Only rarely do individual nerve-trunks remain permanently paralyzed. A ti-ansitory paralysis may occur when the electrical discharge has not passed through the body, but has descended in its neighborhood. In individuals who have been struck by lightning there may be found Fig. 1.— Lightnlng-flgures on the shoul- der, breast and arm of a woman struck by lightning. ELECTRIC CURRENTS. 15 slight or severe burns of the skin corresponding to the points of entrance and exit of the current, and various injuries to the tissues in the course of its path through the body. The marks of the burn are for the greater part red, and form peculiar branching zigzag lines, the so-called lightning figures (Fig. 1), which are esseutially a hyperemia, and soon disappear if the burns are not severe. The passage of powerful electric currents of high tension, such as are generated by dynamos, through the human body, as may happen when an individual is placed in a circuit or comes into contact with an uninsulated conductor, may give rise to severe disturbances or cause death. According to Kratter, the lower limit of danger occurs at a ten- sion of about five hundred volts. Alternating currents are much more dangerous than continuous ones of the same strength and tension. When the effects are not fatal, the injured person is suddenly rendered uncon- scious, this condition lasting for a few minutes or several hours, and for several days afterward symptoms of vertigo, prostration, headache, and palpitation of the heart may persist (Kratter). At the points of contact more or less severe burns are produced. In fatal cases, death takes place suddenly or rarely after ten or thirty minutes. The autopsy findings, aside from the burns at the points of contact, are evidences of suffocation and hyperveuosity of the blood, stasis of the blood within the thoracic vessels, and often small scattered haemorrhages which are due partly to the direct action of the current. The cause of death is paralysis of the centre governing the respiration or the heart's action. Literature. (Effects of Changes of Atmospheric Pressure and of Solarization. ) Bert, P. : La pression barometrique, Paris, 1878. Egger Veranderungen d. Blutes im Hochgebirge. Congr. f. inn. Med., Wiesbaden, 1893; u. Arch. f. exp. Path., 39 Bd., 1897. Gottstein- Klimat. Einflilsse als Krankheitsursachen. Ergebn. d. allg. Path., iv., Wiesbaden, 1899; Vermehrung der rothen Blutkorp. im Hochgebirge. Munch. med. Woeh., 1899. . _. _ , 1onr TT . Heller Mager, Schrotter: Mitth. ilbcr Caissonarbeiter. Kim. Woch., 1895; Unter- such. liber d. Wirkung rascher Veranderungen d. Luftdruckes. Pfluger's Arch., 67 Bd., 1897; Luftdruckerkrankungen, Wien, 1900. Hoche: Luftdruckerkrankung d. Centralnervensystems. Berl. klin. Wochenschr., 1897. Kronecker: Die Bergkrankheit. Deutsche Klinik, Bd. xi., 1903. Leyden- Durch plotzl. Verminderung d. Barometerdrucks entsteh. Ruckenmarksafiec- tion. Arch. f. Psych., ix., 1879. Loewy u Zunz: Einfluss d. verdilnnt. Luft. Pflliger s Arch., 189 1. _ Marti: Wirkung der Hautreize und Belichtung. Verb. d. Congr. f. inn. Med., Wies- baden, 1897. , , iOA( Mercier: LTufluence dc l'altitude. Arch, de phys., vi., 1894. Miescher: Bezieh. zwiscli. Meereshohe u. Beschaftenh. d. Blutes. Corrbl. f. scnweiz. Aerzte, 1893. Mosso: Der Menschauf den Hochalpen, Leipzig, 1899. Nikiforoff Veranderungen d. Ruckenmarks in Folge schneller Herabsetzung des barometrischen Druckes. Beitr. v. Ziegler, xii 1892. _..,,,. M , or Schaumann u. Rosenqvist ; Blutverand. im Hohenkhma. Zeit. f. klin. Med., dt> Schumburg und Zunz: Einwirkung des Hochgebirges. Pfluger's Arch., 63 Bd., 1896. Snell: Compressed- Air Illness, London, 1896. Wolff: Einfluss des Gebirgsklimas auf d. Mensehen, Wiesbaden, 18J5. Zunz- Puthogenese der durch Luftdrucksunderungen erz. Krankheiten. lortschr. d. Med., xv., 1897. 16 THE EXTKINSIC CAUSES OF DISEASE. (Effects of Lightning and of Electrical Currents. ) D'Arsonval: L'energie electrique. Path. gen. publ. par Bouchard, i., Paris, 1895. Dillner: Ueber die Wirkung des Blitzes. In.-Diss., Leipzig, 1865. Ebertz: Ueber Blitzverletzungen. In.-Diss. , Tubingen, 1892. Ereund: Wirkung der Polentladung hochgespannter Induktionsstrome. Akad. d. Wiss., Bd. cix., 1900. Jellinek: Verand. im Nervensystem durch Blitz u. Starkstrome. Virch. Arch., 170 Bd., 1902; Elektropathologie. Stuttgart, 1904. Kratter: Wirkung d. Blitzes. Vierteljahrsschr. f. ger. Med., 1891; Tod durch Elek- trieitiit, Wien, 1896 (Lit.); Elektrische "Verungiuckungen. Eulenb. Jahrb., vi., 1896 (Lit.). Iiiman: Blitzschlag. Deutsch. med, Wochenschr., 1885. Mills and Weisenburg : The Effects on the Nervous System of Electric Currents of High Potential. Univ. of Penn. Med. Bull., 1903. Prevost et Battelli: La mort par les decharges electriques. J. de phys., i., 1899. Vincent : Contrib. a l'hist. niedicale de la foiidre, Paris, 1875. 2. The Origin of Disease through Mechanical Influences. § 5. Traumatic influences of various kinds leading to concussion, bruising, and laceration of tissue are of very frequent occurrence, and act partly through the tearing aud destruction of tissue, partly through changes in tissue-organization not recognizable to the naked eye, and partly through lesions and ruptures of the blood- and lymph-vessels, and through irritation and paralysis of nerves. The sequelae are partly necrosis and destruction, of tissue, partly disturbances of circulation, inflam- mation, and regenerative proliferations. Frequently repeated mechanical traumatisms of slight degree, such as rubbing, may give rise to congestive hypenemia and inflammations, which may lead further to hyperplastic growths of tissue. If large quantities of insoluble dust particles are con- tinuously taken into the lungs indurations of the pulmonary tissue may develop in consequence. As a result of prolonged pressure and diminution of space, atrophy of an organ or tissue may occur (corset-liver). After a single or after frequently repeated trauma, there may de- velop under certain conditions at present unknown to us, malignant new- formations of tissue called tumors. Trauma may further pave the way for an infection, either in that the wound caused by the trauma is in- fected at the time of injury or is secondarily infected from without ; or that micro-organisms were previously present in the body under conditions in- hibiting their growth, and these find in the injured tissues a suitable soil for growth, so that to the trauma an infection is joined. Traumatic influences affect, first of all, the external parts of the body; but it may happen, either with or without visible injury to external parts, that internal organs may be injured, and' the internal lacerations, necroses, and hemorrhages thus produced, may be followed, not only by inflammations and reparative tissue pro- liferations, but also by malignant neoplasms, and by infective proc- esses. Mechanical lesions (also thermal, electrical, and corrosive) run a spe- cial course, if through the local injury the nervous system becomes in- volved. Such involvement occurs either through the direct action of the trauma upon the central nervous system ; or, by the stimulation of the sensory or sympathetic nerves, the central nervous system may be so affected that a number of additional nervous symptoms follow. If the direct concussion of the cranium is followed by paralysis of the cerebral function and unconsciousness, the condition is termed commotio cerebri or cerebral concussion. This term is especially used shock: traumatic neuroses. 17 when the trauma has produced no visible changes in the structure of the brain, or at least none of any size or importance. Excessive stimulation of the peripheral nerves may cause a reflex in- hibition or paralysis, involving chiefly the functions of the heart and respiratory apparatus ; the symptoms thus produced being collectively designated as shock. The most frequent causes of shock are injuries to the spinal column, abdominal cavity, and scrotum, less frequently to the extremities and thorax. Further, shock may be caused by light- ning-stroke, burns, corrosions of the skin, fear, and psychical emotions through whatever avenue of perception they may be called forth. In- dividuals whose nervous systems are in a certain condition of excitement are especially liable to shock ; conditions of narcosis and drunkenness inhibit its occurrence. Shock is characterized chiefly by weakened energy on the part of the heart and irregular breathing, which lead to a decrease in the inter- change of gases in the tissues and to a lowering of the temperature (Roger). The consciousness is usually preserved, the skin and visible mucous membranes are pale, the pulse is small and markedly quickened, often irregular and intermittent. Further, the individual suffering from shock may be either excited, groan, shriek, and complain of a fearful anxiety associated with dyspnoea (erethistic shock) ; or he may lie quiet, with sunken countenance, and ex- hibit evidences of great weakness of both sensory and motor functions {torpid shock). In severe cases death takes place from the stoppage of the heart and cessation of respiration. Shock, in being due to the over-stimulation of the peripheral nerves, is closely allied etiologically to the phenomenon known as syncope ; but the last-named condition differs essentially from shock in that its chief symptom is a transitory loss of consciousness, while the functions of the heart and respiration show no marked disturbance. Syncope is, further, usually preceded by prodromal symptoms, such as dizziness, ringing in the ear, and darkening of the visual field, these being absent in shock. Not infrequently, following an injury to some part of the body, there may arise a more or less pronounced functional disturbance of the ner- vous system, which may often persist long after the local injury has healed, so that such disturbance is in no way dependent upon anatomical changes in the peripheral or central nervous system, but must be re- garded as a purely functional disturbance of psychical origin. Such condi- tions are termed traumatic neuroses or accident nervous diseases, and are characterized chiefly by subjective but in part also by objective symp- toms. To the first belong especially pains not definitely localized at the seat of injury, as headache, pain in the chest, backache, difficulty in movement, general lassitude, inability to perform mental labor, dul- ness of perception, disturbances of sight, flashes before the eyes, dizzi- ness, restless sleep, loss of appetite, and disturbances of digestion. With these last symptoms are associated psychical depression of a hypochon- driacal or melancholic character, irregularly placed areas of cutaneous anaesthesia, enfeeblement of the senses of taste, hearing, and smell, motor paralysis, cramps, and hyperesthesia, concentric narrowing of the visual field, ' pareses, muscular spasms, tremors, acceleration of the pulse, and tendency to sweating. All of these phenomena depend essentially upon a psychical shatter- ing of the perceptive life, a psychoneurosis which is less often due to the trauma and the associated psychical shock than to the resulting anxi- 18 THE EXTRINSIC CAUSES OF DISEASE. ety over health and business matters. The condition in part partakes of the nature of hysteria, as characterized by a disturbance of the normal relation between the mental and bodily processes ; in part of hypochon- dria, as recognized by the spontaneous occurrence of abnormal sensa- tions; and in part of a neurasthenia, which reveals itself by the produc- tion of abnormal pathological sensations through relatively slight stimulation or exertion. If the will no longer controls the motor centres, hysterical paralyses arise; if the normal control and inhibition of the •will are lost, so that unreasonable will-stimuli are created and influence the muscles, hysterical twitchings, contractures, or convulsions take place. If a nervous stimulus arising in the sensory tract fails to reach the con- sciousness, there follows a hysterical anaesthesia ; if there arise in the consciousness the images of expected or feared sensations, and if these images are intensified into actual subjective stimuli of consciousness, hysterical pains and neuralgias result (StriimpeH). Bosenbach designates as kinetoses those diseases which arise when energetic and continuous movements of the body in one direction are changed into the opposite direc- tion, so that a shifting of the internal organs results. In this class belong the patho- logical phenomena observed in seasickness, and in the conditions caused by see-sawing, whirling, movement in a vertical direction, and sudden stoppage of motion. As a result of the rapid change in direction of bodily motion, the molecules which are moving in the line of the primary direction are forced to move in the opposite direction; and, ac- cording to Rosenbach, such a change is sufficient to cause more or less important molec- ular disturbance. He explains the symptoms of seasickness, as, for example, the ab- normal secretion of the stomach, the increase of intestinal peristalsis, the vomiting, etc., as the results of purely mechanical influences on the tissues, and believes that the liver, intestine, brain, and nerve-plexuses are similarly affected through mechanical in- fluences acting upon their protoplasm. On the other hand, Binz refers seasickness to an acute ana-mia of the brain which causes the nausea and vomiting. A horizontal position and the administration of a water solution of chloral hydrate, which dilates the arteries of the head, have a favorable action upon the condition. Literature. ( Effects of Trauma.) Binz: Ueber die Seekrankheit. Centralbl. f. inn. Med., 1903. Bruns: Unfallsneurosen. Eulenburg's Jahrb. , viii., 1898 (Lit.). Fischer: Ueber den Shock. Samml. Win. Vortr. v. Volkmann, No. 10. 1870. Freund: Traumatische Neurosen. Samml. klin. Vortr., No. 51, Leipzig, 1892. Groeningen: Ueber den Shock, Wiesbaden. 1885. Hdber: Shock durcli Reizung seroser Haute. Arch. f. exp. Path., 40 Bd., 1897. Jolly: Traumatische Epilepsie. Char. -Ann., xx., 1895. Lejars: Les agents mecaniques. Path. gen. publ. par Bouchard, i., 1895. Oppenheim : Die traumatischen Neurosen, Berlin, 1892. Roger: Choc nerveux. Arch, dephys., v., 1893, vi., 1894. Rosenbach: Die Seekrankheit, Wien, 1896; u. Eulenburg's Realeneyklop, xxii., 1899. Sachs u. Freund: Die Erkrankungen des Nervcnsystems nach Unfallen, Berlin, 1899. Seeligmuller : Unfallnervenkrankheiten. Encyklop. Jahrb. der ges. Heilkunde, 1893 (Lit.). Stern. Die traumatische Entstehung innerer Krankheiten. Jena, 1900 (Lit.). Striimpell: Traumat. Neurosen. Miinch. med. Woch., 1889; Verb. d. XII. Congr. f. inn. Med., 1893. 3. The Origin of Disease through Intoxication. § 6. By poisoning or intoxication is meant that impairment of health, caused by the injury to a tissue, which certain substances, by virtue of their chemical nature, are able to produce under certain conditions. Such sub- POISONS. 19 stances are termed poisons, and are derived partly from the mineral kingdom, partly from the vegetable, and partly from the animal king- dom. They may occur in a natural state or they may be produced artificially from inorganic or organic substances. Many of the most important poisons are products of either plaut or animal life, and are formed either within the tissues of the plant or animal, or from their food-supply by the transformation of substances which are either inert or possess an entirely different action. The most important poisons belonging to the mineral kingdom or which are produced from minerals are : metallic mercury, chlorine, bromine, iodine, sulphur, and various combinations of these substances, different combi- nations of arsenic, antimony, lead, barium, iron, copper, silver, zinc, potassium, sodium, chromium, etc. Of the poisons containing carbon, which are artificially produced, the most important are: chloroform, chloral hydrate, ether, alcohol, iodoform, carbon bisulphide, hydro- cyanic acid, potassium cyanide, oxalic acid, nitroglycerin, amyl nitrite, petroleum, carbolic acid, nitrobenzole, picric acid, and aniline. It may be observed in this connection that modern chemistry is constantly pro- ducing new substances, some of which are poisons. Of the poisons produced by plants of the higher order, those of chief im- portance are: the vegetable alkaloids, such as morphine, quinine, colchicine, atropine, hyoscyamine, veratrine, strychnine, curarine, solanine, nico- tine, digitaline, santonin, aconitine, cocaine, coniine, muscarine, and ergotine, all of which in relatively small doses may cause poisoning. The lower forms of plant life, especially bacteria, produce an extraordi- nary variety of both poisonous and non-poisonous s%ibstances, out of the food material in which they develop. Some of these substances are similar to the vegetable alkaloids, others to the ferments, and are therefore desig- nated toxic cadaveric alkaloids, toxic ptomains, toxins, and toxenzymes (com- pare § 11). It may happen that the blood, flesh, or any organ of a healthy animal may acquire poisonous properties through the presence in it of poisonous products of bacterial growth. Such diseases due to bacterial poisons in the food are known as botulisiuns, sausage, meat, fish, and cheese poisoning. These conditions are to be explained, in part, by the growth of bacteria (B. botulinus) in the food-stuff and the formation of poisonous products, true toxins (§ 11) ; in part by the fact that germs were present in the tissues of the animal before death, the animal being slaughtered while diseased, and the use of its flesh as food causes either poisoning or the same disease as that affecting the animal. Under cer- tain conditions foods which are not spoiled may already contain bacteria, and these may develop in the intestine of the individual eating the food and cause poisoning through the production of toxins, or enzymes. According to Lombroso, the disease pellagra, which is of common occurrence in Italy, Eoumania, and Greece, is caused by the eating of decomposed corn. The disease kakke or beri-heri, which is endemic in Japan, is regarded by Miura and Yamagiva as due to the extended use of rice which has been spoiled in drying. Among the animals which normally produce poisons within certain tissues of their bodies, the best known are: serpents, toads, salamanders, fish, mussels, oysters, scorpions, Spanish flies, and many stinging insects. Certain forms of sea-fish are poisonous at all times, others only at certain periods, and observations have been made particularly of such fish found in Japanese waters. According to Saotschenko, the poison of many poisonous fishes is secreted by certain 20 THE EXTRINSIC CAUSES OF DISEASE. skin-glands found at the roots of the dorsal and caudal fins, and may he found also in the eggs of such fish. According to Remy, Miura, and Takesaki, the poison is secreted in the sexual glands alone in the case of the poisonous fish belonging to the family Gymnodontes (tetrodons). According to Mosso, there is found in the blood-serum of eels a toxic substance (ichthytoxin) which, when introduced into the small intestine of animals experimentally, causes symptoms of poisoning and may kill the animal. According to M. Wolff, the liver of mussels (Mytilus edulis) contains the poison; its action, according to Sehmidtmann, Yirchow, Salkowski, and Brieger, is similar to that of curare. Brieger has also shown that from the poisonous mussels there can be ob- tained basic substances closely related to ptomains, the basic products of decomposi- tion. To what extent the causes of the production of poisons in poisonous fishes and mollusks are to be ascribed to normal and to what extent to pathological processes of life cannot at the present time be always decided. From the fact that the mussels and oysters are poisonous only in certain places where the water is impure, and as the starfish found in the same localities are similarly affected, it is probable that the poison- ous action of these mollusks may in part be due to their contamination with bacteria or to the occurrence of certain diseased conditions. The venom of serpents is formed exclusively in the poison-glands lying in the upper portion of the corner of the mouth. It is a green or yellowish fluid and its activity is not influenced by drying or by preservation in spirits. Snake venom, the poison of spiders and toads and of the blood of the eel and murcena, riein (obtained from the seed of the castor-oil bean), and abrin (from the seed Abrus preca- torius) show properties similar to those of the bacterial toxins (compare §11). Snake- poison and that of the blood of the eel have also a hemolytic action. It is difficult to give an exact definition of poison and poisoning, since the action of the substances considered in this connection varies greatly according to the dose and attenuation, as well as the method of introduction into the tissues of the body. The most powerful poisons when introduced in minute doses may not only be harmless, but may exert a beneficial or curative effect. On the other hand, substances which are not usually classed with the poisons, such as the non-corrosive sodium salts, when in- troduced into the body in large quantities or in concentrated solutions, may produce effects which must be regarded as of the nature of poisoning. Further, poisons in cer- tain dilutions (phenol) may serve as food-material. Literature. (Intoxication. ) Binz, B6hrn, Liebreich: Arbeiten deutsch. Pharmakologen a. d. J. 1865-1889, Ber- lin, 1890. Frohner: Lehrb. d. Toxicologic f. Thierarzte. Stuttgart, 1890. Hildebrandt: Compendium der Toxicologic, Freiburg, 1S93. Kionka: Vergiftungen. Ergebn. d. allg. Path., vi., Wiesbaden, 1901. Kobert: Lehrb. der Intoxicationen, Stuttgart, 189S; Compend. d. Toxicologic, Stutt- gart, 1894. Kunkel: Handb. d. Toxicologic, i., Jena, 1S99. Lewin: Nebenwirkung d. Arzneimittel, Berlin, 1899; Die Pfeilgifte. Virch. Arch., 138 Bel., 1894; Toxicologic, Wien, 1897; Cumulative Wirkung. Deut. med. Woch., 1899. Loew: Natiirliches System der Gifte, Munchen, 1893. Oppenheimer: Toxine u. Antitoxine, Jena, 1904. Roger: Intoxications. Path. gen. publ. par Bouchard, i., Paris, 1S95. v. Wyss; Lehrbuch der Toxicologic, Wien, 1895. (Poisoning by Spoiled Foods. ) Bertarelli: Gegenw. Stand, der Pellagrafrage. Centbl. f. Bakt., xxxiv., 1904. Bollinger: Ueber Fleischvergiftung. Zur Aetiologie d. Infectionskrankheiten, Mun chen, 1881. Butter u. Huber: Die Massenerkrankungen in Wurzen, 1877. Arch. d. Heilk., xix. Ceni: Gli Aspergilli nell' Et. della Pellagra. Riv. sper. di fren., xxviii., 1902. v. During: Pellagra. Eulenburg's Realencyklop., xviii., 1898. van Errnengem: Des intoxications alimentaires, Bruxelles, 1895; Botulismus. Zeit. f. Hyg., 26 Bd., 1897. POISONS. 21 Flinzer: Massenerkrankung in Chemnitz, 1879. Vierteijahrsschr. f. ger. Med., xxxiv., 1881. Husemann: Ostreismus (Austernvergiftung). Eulenburg's Jahrb., vii., 1897 (Lit.). Kaensche: Krankheitserreger bei Fleischvergiftung. Zeit. f. Hyg., xxii., 1896. Lombroso: Die Lehre von der Pellagra, Berlin, 1898. Nauwerck: Wurstvergiftung. Deut. med. Wochenschr., 1886; Wurtt. Correspbl. f. Aerzte, 1886. Scheube: Die Krankh. d. warmen Lander, Jena, 190.3. Schneidemuhl: Botulismus. Centralbl. f. Bakt., xxiv., 1898 (Lit). Siedamgrotzky : Leber Fleischvergiftung. Vortr. f. Thierarzte, iii. ser., 2 H., 1880. Silberschmidt: Fleischvergiftung. Zeitschr. f. Hyg., 30 Bd., 1899. Vaughan: Milk- and Cheese-poisoning. Zeit. f. phys. Chem., 1886; Journ. of Amer. Med. Assn., 1887. Yamagiva: Zur Kenntniss der Kakke. Virch. Arch., 156 Bd., 1899. (Animal Poisons. ) Aron: Experimentelle Studien iiber Schlangengift. Zeitschr. f. klin. Med., 1883. Arustamoff: Leber die Natur des Fischgiftes. Centralbl. f. Bakt., x., 1891. Bren.ni.ng: Die Vergiftung durch Schlangen, Stuttgart, 1895 (Lit.). Brieger: Miesmuschelvergiftung. Biol. Centralbl., vi., 1886, u. Deut. med. Woch., 1885. Calmette: Venin des serpents. Ann. de l'lnst. Past., vi., 1892; viii., 1894; ix., 1895. Fischel u. Enoch: Zur Lehre von den Fischgiften. Fortschr. d. Med., x., 1893. Husemann: Fischgifte. Eulenburg's Realencyklop., 1895; Schlangengifte, ib., xxi., 1899; Thiergifte, *., xxiv., 1900. Karlinski: Zur Pathologie der Schlangenbisse. Fortschr. d. Med., viii., 1890. Kaufmann: Ueber 63 Falle von Giftschlangenbissen. Correspbl. f. Schweiz. Aerzte, 1893. Lamb and Hanna: The Poison of Russell's Viper. Journal of Pathology, viii., 1902. Langer: Das Gift der Honigbiene. Arch. f. exp. Path., 38 Bd., 1897. v. Linstow: Die Giftthiere, Berlin, 1894. Lustig: I microorganismi del Mytilus edulis. A. p. le Scienze Med., xii., 1888. Mitchell: Researches upon the Venom of the Rattlesnake, Washington, 1884. Mitchell and Reichert: Venoms of Poisonous Serpents, Washington, 18S6, ref. Biol. Central., vii., 1888. Miura u. Takesaki: Zur Localisation des Tetrodongiftes. Virch. Arch., 122 Bd., 1890. Miura u. Sumikawa: Schlangengift. Centralbl. f. allg. Path., xiii., 1902. Mosso: Un venin dans le sang des murenides. Arch. it. de Biol., xii., 1888; u. Arch. f. exp. Path., xxv., 1888; Du venin qui se trouve dans le sang de l'aiguille. Arch. it. de Biol., xii., 1889. Nowak: Et. des alter, prod, paries venins des serpents et des scorpions. Ann. de lTnst. Past., 1898. Oppenheimer: Toxine und Antitoxine, Jena, 1904. Ragotzi: Wirkung des Giftes der Naja tripudians. Virch. Arch., 122 Bd., 1890. Roger: Intoxications. Path. geh. publ. par Bouchard, i., Paris, 1895. Salkowski: Miesmuschelvergiftung. Virch. Arch., 102 Bd., 1885. Saotschenko: Atlas des poissons veneheux, St. Petersburg, 1887. Scheube: Die Krankheiten der warmen Lander (Ophidismus), Jena, 1903. Schmidt: Leb. d. Natur des Fischgiftes. Verhandl. d. X. int. med. Congr., ii., Ber- lin, 1891. Starcke: Gift der Larven des Kafers Diamphidia locusta (Blut aufiosendes Pfeilgift der Kalachari). Arch. f. exp. Path., 38 Bd., 1897. Thesen: Vergiftung durch Muscheln. A. f. exp. Path., 1902. Virchow, Martens, Lohmeyer, Schulze, u. Wolff: Miesmuschelvergiftung. Virch. Arch., 104 Bd., 1886. Virchow: Miesmuschelvergiftung. Berl. klin. Woch., 1885. Vollmer: L~eb. d. Wirkung d. Brillenschlangengiftes. Arch. f. exp. Path., 31 Bd., 1892. Wehrmann: Et. du venin des serpents. Ann. de l'lnst. Past., xii., 1898. Wolff, M.: Miesmuschelvergiftung. Virch. Arch., 103 Bd., 1886; u. 110 Bd., 1887. Zardo: Microorganisme isole du Nytilus. A. ital. de Biol., xxxvi., 1901. See § 12 for literature of Ptomains and Toxins. 22 THE EXTRINSIC CAUSES OF DISEASE. § 7. Poisons may be divided according to their action into three groups : first, those producing local tissue-changes ; second, those acting injuriously upon the blood; third, those affecting chiefly the nervous system and the heart without producing recognizable anatomical lesions. The poisons which cause marked local lesions injure primarily the tissues with which they first come into contact upon entering the body. If such poisons are diffused by means of the body-fluids, the most diverse organs and tissues may be injured; but their action is usually limited to that organ in which they are stored up or through which they are excreted, especially the liver, intestine, and kidneys. The primary seat of injury is most often the mucosa of the upper portion of the intestinal tract and the respiratory passages, but in many cases the skin is first affected. Very frequently poisons, which are em- ployed for disinfecting, are brought into contact with wounds for the purpose of killing bacteria or preventing their growth, and in this way may cause local changes or may be absorbed and damage the internal or- gans or the entire body. The first great group of poisons belonging to this class are those which cause marked tissue-changes at the primary point of contact, which are similar to those of burns, and for this reason have been designated caustics or corrosives. If the action of a caustic reaches its most char- acteristic severity, the affected tissue will be wholly destroyed and con- verted into either a dry, hard eschar, or under certain conditions into a moist, soft slough. If the action is of moderate intensity as the result of a less concentrated solution of the caustic agent, or of incomplete action of the chemical even when applied in strong solution or in substance, or because the tissue itself is more resistant as in the case of the skin, the changes produced are much less severe, and are characterized by red- ness, swelling, inflammation, and haemorrhages. Very diverse changes are often found in the same organ, such as local sloughing (necroses), haemorrhages, inflammations, and small swellings due to local hyperaemia. If the changes have existed for some time, the local eschars are sur- rounded by a more or less marked inflammatory zone, which in the case of certain caustics may be of very limited exent. The substances belonging to the class of caustic poisons are: first, the corrosive acids, sulphuric, nitric, hydrochloric, phosphoric, oxalic, arsenic, arsenious, osmic acetic, lactic, trichloracetic, carbolic, and salicylic acids; and further, the corrosive combinations of the alkalies and alkaline earths, potassium and sodium hydroxide (watery solutions of KOH and NaOH), caustic ammonia (solution of NH, in water), ammonium carbonate, caustic lime, and barium sulphate. Belonging in this class are also certain corrosive salts, chiefly of the heavy metals, such as salts of antimony (tartar emetic and antimony trichloride), salts of mercury (corrosive sublimate and red precipitate), nitrate of silver, zinc chloride, zinc sulphate, copper sulphate and copper acetate, aluminum acetate, potassium chromate and bichromate, and chloride of iron. The poisons belonging to this class derived from animals are: cantharidin, from the beetle Li/tla vesicatoria; phrynin, the secretion from the cutaneous glands (parotid) of the toad; the secretions from the poison-glands of snakes and scorpions; the secre- tion of the sting-gland of bees, wasps, and hornets; the secretion of the salivary glands of stinging-gnats, flies, and gad-flies; and the secretion of the poison-glands of the maxillary palpa? of spiders (tarantula) — all of which cause local necrosis, or haemorrhage and inflammation. Many of the higher plants produce in their blossoms, seeds, stems, or roots substances which, when brought into contact with the tissues, cause local irrita- tion and inflammation, as, for example, daphne, different forms of Ranunculus, varie- ties of anemone, Primula obconica (pubescent portion), marsh-marigold, different varieties of Calla, dragon-root, Croton tiglii (from the seeds of which croton-oil is obtained), buckthorn (Rhamnus cathartiea), black elder (Rhamnus frangula). The nature of the local changes which these substances and many others not POISONS. 23 mentioned here produce is naturally very varied, and is dependent partly upon the activity of the poison, and partly upon the location and manner of application. The mineral acids, solutions of caustic potash and mercuric chloride, when concentrated, cause marked tissue-eschars, associated with hemorrhagic inflammations, especially when taken into the stomach. Through the action of acids there is a marked with- drawal of the alkaline constituents of the body fluids, leading to disturbances of res- piration and circulation. The venom of snakes causes visually severe local inflamma- tions and haemorrhages, which often extend far beyond the region of the bite, and sometimes may cause also a widespread gangrene. There are also snake-venoms which produce only insignificant local changes, the general symptoms of poisoning being much more prominent. The volatile or gaseous poisons, which in the form of gas or vapor cause local irritation of the tissues, affect chiefly the mucous membranes of the eye and respiratory tract (irrespirable gases). To this class belong especially the fumes of ammonia, chlorine, sulphurous acid, nitric oxide, nitric dioxide, nitric tri- oxide, osmic acid, formalin, and mustard-oil. The intensity of action of these poisons is very varied, often causing only a transitory hyperaemia, but being able also to give rise to tissue necrosis and severe inflammation. The irritation of the respiratory tract gives rise to coughing and a spasmodic narrowing of the glottis which may interfere with breathing. To the local irritation and inflammation caused by these poisons at the primary seat of contact may be added further effects upon internal organs. After the absorption of these poisons into the fluids of the body, those organs suffer most in which the poison is stored up or elaborated, though organs of the most varied structure may be affected, as well as those not concerned in the excretion of the poison. In the case of certain poisons, the changes at the point of entrance are very slight and often not recognizable, the important anatomical lesions occurring first in other tissues, to which the poison has been carried by the blood. Finally, a given poison may act also as a nerve and heart poison, so that clinically the effects of this action are much more promi- nent than the local lesion. In poisoning with corrosive sublimate, cell necrosis takes place in the secreting part of the kidneys, and there is also severe inflammation of the colon. The salts of chromic acid, cantharidin, and many acids cause more or less marked degeneration and inflammation in the secreting portion of the kidney and in the urinary passages. >^-* Phosphorus, arsenic, antimony, and pulegon, which have but slight corrosive action, produce tissue-degenerations, particularly fatty degeneration, and also haemor- rhages, in the kidneys, liver, heart, muscles, bone-marrow, and capillaries of different organs, these changes being particularly marked in cases of phosphorus poisoning. According to Meyer, the cause of the tissue-degenerations in phosphorus poisoning is to be sought in its action upon the cardiac nervous system and the consequent dis- turbances of circulation. Tischner believes that there is a lesion of the peripheral nervous system. If an individual is exposed for months or years to the fumes of yellow phosphorus, there may take place an inflammation of the jaw bones leading to necrosis, but only when the occurrence of inflammatory changes is favored by other causes, such as putrid decomposition in the mouth or the presence of decaying teeth. The long-continued use of silver nitrate may be followed by a deposit of black granules of silver in the most diverse tissues, the skin, kidneys, intestinal villi, and the choroid plexus. The venom of snakes possesses, in addition to its local effects, a paralyzing action upon the nervous system and heart, and may cause death through paralysis of the respiratory centre. Soluble salts of lead when ingested may cause irritation and inflammation of the intestine, with such symptoms as vomiting, diarrhoea, constipation, cramps in the stomach, associated with such nervous phenomena as anaesthesia, motor paralysis, convulsions, vertigo, and loss of consciousness. When ingested continuously for a long time, lead gives rise to anaemia (Jores), general disturbances of nutrition, intes- tinal colic, pains in the limbs, anaesthesia, motor paralysis, cerebral disturbances, and kidney disease. These disturbances are without doubt dependent upon the distribu- tion and deposit of lead throughout the body, leading to anatomical lesions of varied nature. The active principles of ergot (Secale cornutum), sphacelinic add and cornutin, when taken in large doses, or when repeatedly eaten in bread, cause itching, pain, and cramps in the limbs, followed by numbness and feeling of cold in the toes and finger tips, and finally there may also occur a more or less extensive gangrene of these parts (ergotism, " Kribbelkrankheit-' ) , at the same time ulceration of the intestine may occur. In cases of chronic poisoning, degenerations of the spinal cord take place (Tuczek). The feeding of chickens with ergot causes gangrene of the comb through 24 THE EXTRINSIC CAUSES OF DISEASE. the production of stasis and hyaline thrombosis in the blood-vessels. In animals fed for a long time with ergot degenerative changes are found in the "entral and peripheral nervous system, in the blood-corpuscles, and in the endothelium of the blood-vessels (Grigorjeff). Literature. (Poisons Producing Local Tissue- Changes.) Bettmann: "\Yirk. d. Arseniks auf Blut und Knoehenmark. Beitr. v. Ziegler, xxiii., 1898. Brouardel: Les paralysies arsenicales. Arch, de med. exp., viii., 1896 (Lit.). Coen e D'Ajutolo: Avvelenamento cronico di piombo. Beitr. v. Ziegler, iii., 1888. Eichhorst: Ueber Bleilahmung. Virch, Arch., 120 Bd., 1890. Erlicki u. Rybalkin: ArseniklahmuDg. Arch. f. Psych., xxiii.. 1892. Fraenkel u. Reiche: Nierenveraud. nach Sckwefelsaurevergiftung. Virch. Arch., 131 Bd., 1893. Geyer: Hautverand. bei Arsenicismus. Arch. f. Derm., 43 Bd., 1898 (Lit.). Goetze: Die Bleivergiftung, Wiirzburg, 1893. Grigorjeff: Mutterkornvergiftung. Beitr. v. Ziegler, xviii., 1895. Griinfeld: Mutterkornvergiftung. Dorpater Arbeiten, kerausgeg. v. Kobert, viii., 1892. Hartmann: Exper. L'ntersuchungen iiber Chromsaurenephritis. Inaug.-Diss., Frei- burg, 1891. Husernann: Arsenaussehlage u. Arsenvergiftung. Encvklop. Jahrb., v., 1895; Bleigicht, ib., 1897. Ipsen: Salpetersiiurevergiftung. Vierteljahrssehr. f. ger. Med., vi., 1893. Jacobj : Das Sphacelotoxin. Arch. f. exp. Path., 39 Bd., 1897. Janowski: Die Ursachen derEiterung. Beitr. v. Ziegler, xv., 1S94. Jores: Chron. Bleivergiftung. Beitr. v. Ziegler. xxxi., 1901. Kaufmann: Die Sublimatintoxication, Berlin, 1888; u. Virch. Arch., 117 Bd., 1889. v. Kahlden: Die Aetiologie und Genese der acuten Nephritis. Beitr. v. Ziegler, xi., 1892. Kobert ; Lehrbuch der Intoxieationen, Stuttgart, 1893. Kocher: Zur Kenntniss der Pliosphornekrose, Berlin, 1893. Kockel: Wirk. v. Dampfen salpeteriger u. Untersalpctersaure. Vierteljahrssehr. f. ger. Med., 1898. Krysinski: Pathol, u. klin. Beitrage zur Mutterkornfrage, Jena, 1888 (Lit.). Langerhans: Verand. der Luftwege nach Carbolsaurevergiftung. Dcut. mcd. Woch., 1893. Lanz: Pathogenese der mercuriellen Stomatitis, Berlin, 1897. Lesser: Verand. des Verdauungskanals durch Aetzgifte. Virch. Arch. 83 Bd., 1881. Leutert: Sublimatvergiftung. Fortschr., xiii., 1895. Lewiu: Arsen. Eulenburg's Realencyklopfldie, ii.. 1894. Lindemann: Verand. des Stotl'wechsels durch Pulegon. Zeit. f. Biol., 39 Bd., 1900. Maier: Bleivergiftung. Virch. Arch., 90 Bd., 1882. Meiser: Wismuthvergiftung. Inaug.-Diss., Freiburg, 1892. Meyer: Wirkung des Phosphors. Arch. f. exp. Path., xiv., 1881. Model: Primula obconica. Mlinch. med. Woch., 1904. Miiller: Arsenmelanose. Arch. f. Derm., 25 Bd., 1882. Muir: Arsenical Poisoning. Journal of Pathology, vii., 1901. Neuberger: Wirkung des Sublimates auf die Nieren. Beitr. v. Ziegler, vi., 1889. Pistorius: Acute Arsenikvergiftung. Arch. f. exp. Path., 16 Bd., 1882. Riess : Phosphorvergiftung. Eulenb. Realencyklop., xix., 1899. Schultze: Leber Bleilahmung. Arch. f. Psych., 16 Bd., 1885. Steinhaus: Verand. d. Netzhaut durch Phosphor. Beitr. v. Ziegler, xxii., 1897. Tischner: Unters. z. Pathol, d. Leber. Virch. Arch., 175 Bd., 1904. TTllmann: Localisation d. Quecksilbermetalle im Organismus. Arch. f. Derm., Er- ganzh., 1893. Welander: Absorption und Elimination des Quecksilbers. Arch. f. Derm., 25 Bd 1893. Westphal: Ueber Encephalopathia saturnina. Arch. f. Psych., 19 Bd., 1888. Winternitz: Allgcmeinwirkung ortl. rcizender Stoffe. Arch. f. exp. Path., 35 Bd., 1895. Ziegler u. Obolonsky: Wirkung des Arseniks u. des Phosphors. Beitr. v. Ziegler. ii., 1888. See also § 6. BLOOD-POISONS. 25 § 8. The poisons which affect the blood chiefly, and are therefore termed blood-poisons, are partly gases and partly fixed substances. The latter are absorbed chiefly from the intestine, but they may also enter the body through wounds, or they may be injected directly into the blood-vessels. Some of the blood-poisons may also produce local lesions in the tissue at point of entrance; further, there may be joined to the action on the blood a direct effect upon the nervous system, which under certain con- ditions may cause death before the action upon the blood is recogniz- able. Finally, it should be emphasized that the blood-changes produced by the poison may cause numerous secondary changes in different or- gans, for instance, in the kidneys, liver, intestine, and brain. Carbon monoxide, hydrocyanic acid, potassium cyanide, and hydrogen sulphide form combinations with haemoglobin giving rise to carbon-mon- oxide-haemoglobin, cyan-mettueinoglobin, and sulphur-methaemoglobin, thereby inhibiting or destroying the functional capacity of the red blood- cells. They also produce an effect upon the nervous system which is most marked in the case of hydrocyanic acid and potassium cyanide. These poisons in very small doses paralyze the central nervous system, producing death almost immediately through paralysis of the centres of respiration and circulation. Potassium chlorate, toluylendiamin, hydrazin, nitrobenzol, nitroglycerin, amyl nitrite, picric acid, phallin (a poison obtained from the mushroom, AgaricusphaUoides), helvellic acid (poison of Helvetia esculenta), extractum fllicis maris cethereum, arseniuretted hydrogen, and other substances cause destruction and haemolysis of the red blood-cells and lead in part to the for- mation of methsemoglobin, that is, to an oxygen combination of haemo- globin, the oxygen content of which is the same as that of oxyhemo- globin, but in which the oxygen is bound more firmly than in the latter. Certain bacterial products which are called bacterial hcemolysins have also a specific action upon the red blood-cells, leading to the production of haenioglobinaeniia. The best known are those occurring in infec- tions with the tetanus bacillus and staphylococcus and are known as tetanolysin and staphylolysin. When the blood of an animal is introduced into the blood stream of man or of an animal of another species, specific hcemolysins become active, that is, poisons which cause haemolysis of the foreign red blood-cells. Carbon-monoxide -poisoning most often results from the carbon monoxide in coal- or illuminating-gas, but may occur under other conditions, as in the case of vapors produced by gun-powder or gun-cotton. The effects of the inhalation of carbon mon- oxide result from the combination of the gas with the haemoglobin of the blood and the formation of carbon-monoxide-hsmoglobin. The amount of oxygen combined with the haemoglobin is thereby decreased, and the taking up of oxygen is reduced, even when the respired air contains only 0.0.5 per cent or even 0.02 per cent of CO (Gruber). The red blood-cells themselves present no changes. A rapid supply of carbon monoxide to the nervous system may cause direct injury to the nerves, giving rise to convulsions and later to paralysis {Geppert). In cases of long-continued poisoning the displace- ment of the oxygen from the greater portion of the red cells leads to tissue-asphyxia. If the affected individual does not die, there may result, in addition to the poisoning, severe disturbances of nutrition, occurring especially in the nervous system. The poisoning itself is characterized by headache, tinnitus aurium. vertigo, malaise, vomit- ing, fainting, convulsions, paralysis, and coma. The blood, as a result of the presence of carbon monoxide, becomes a bright violet or cherry-red color, so that the hyperamic skin and internal organs also appear bright red. Hydrocyanic acid (CNH) is found in unstable combination in the leaves, bark, and seeds of many plants (bitter almonds, cherry- and peach-stones, apple-seeds, leaves of the laurel, bark of Prunus padus, tubers of many of the Euphorbiacefe, flaxseed, etc.). Potassium cyanide (CNK) is used in many of the technical arts. The action of both 2G THE EXTRINSIC CAUSES OF DISEASE. of these poisons upon the blood is the formation of cyanmethaemoglobin, which gives the blood a bright red color and produces a bright red post-mortem lividity. Hydrogen sulphide {H-. Nencki, Otto, Angerer, and others also found in decomposing tissues similar cadaveric alkaloids, which in experiments upon animals were partly in- ert, and partly toxic, producing in the latter ease symptoms of poisoning similar to curare, morphine, and atropine. To von Nencki (1876) is due the honor of being the first to obtain a cadaveric alkaloid in its pure form and to establish its formula; this was accomplished in the case of collidin, obtained from decomposing glue and albumin, its platinum salt crystallizing in fiat needles. Following v. Nencki, Etard, Gautier, and Baniitaiin, and especially Brieger, have studied ptomains, the last named having obtained a large number of them in a pure state and determined their physiological action. For instance, Brieger obtained from fibrin peptone a poison (p'eptotoxin) which in animals causes symptoms of paralysis and ultimately death. From decom- posing horse-flesh lie extracted three substances crystallizing in needles, namely, neuridin, neurin, and cholin, the second of which is markedly poisonous, and, like muscarine, causes salivation, disturbances of circulation and respiration, contraction of the pupils, and clonic convulsions. From fish-flesh he obtained, besides neuridin, three other poisonous bodies: ethylendiamin, a substance similar in its action to muscarine, anil a substance called gadinin. From decomposing glue and cheese he obtained the poison neurin, and from decomposed yeast dimethylamin. The majority of ptomains are not found in fresh tissues, and it is therefore very probable that they are derived from the splitting of chemical combinations present in the tissues. Thus it is probable that cholin is formed from the splitting of lecithin, and by the further decomposition of cholin the poison neurin is formed. Cholin and neuridin are, according to Brieger, demonstrable even in the fresh human brain. After the poisonous nature of part of the ptomains had been made known through the researches mentioned above, there was developed the hypothesis that the toxic symp- toms observed in infectious diseases could be entirely, or in a great measure, ascribed BACTERIAL INFECTION. 39 to the action of the toxic ptomams. Through the investigations of recent years (Roux, Yersin, Buchner, Brieger, C. Fraenkel, Pfeiffer , Ehrlich, Wasserrnann, and others) it has been shown that besides the ptomains there occur specific bacterial poisons, which are characteristic for the given bacterial species. These were first regarded as active albumin bodies and were called toxalbumins. Brieger and Fraenkel hold the view that they are formed by the action of bacteria from the albumins of the body juices. Buchner, on the contrary, believes that they are produced by the bacterial cell itself. Investigations on the poisons formed in diphtheria, tetanus, cholera, typhoid fever, pneumonia, and tuberculosis have shown that the so-called toxalbumins are not albumin bodies, and have led to the differentiation of different poisonous substances as given in the text above. The toxins, in the strict sense, may be compared, according to their origin, with the enzymes formed by the body cells (pepsin, trypsin, ptyalin) which produce hydro- lytic splitting. On the other hand, the endotoxins clinging to the cells may be com- pared with the expressed juice of yeast known as zymase (Buchner), which is able, in the same way as the living protoplasm of the yeast-cell, to excite an alcoholic fermenta- tion in fluids containing sugar. Toxins and enzymes are mixed with albuminous substances which up to the present time have not been separated from them. This explains why they were earlier regarded as albuminous bodies. Brieger, who first characterized the toxic substances as toxalbumins, has himself prepared toxins that gave no albumin reaction. According to the views of Ehrlich, only those substances are poisons that possess a chemical affinity for some element of the body and through their union with this cause an injurious action that may be recognized clinically (toxophorous affinity). A toxin or haptin is, according to him, a poison which possesses two specific atomic groups, a haptophore group which permits the union with the body cells through the haptophorous group of the latter, and a toxophore group which exerts the poisonous action. If in any poison the specific action of the toxophore group is lost, while the haptophore group remains, there arise toxoids or non-poisonous haptins which may anchor themselves to the body cells but are no longer poisons. Finally, there occur also primary bacterial products (in diphtheria), the toxons (Ehrlich), that is, poisons which have the same haptophore group as toxins but a less active toxophore group. Since the intracellular toxins, the endotoxins (typhoid bacilli, cholera spirilla, B. pyocyaneus, pus cocci), are stored up in the bodies of the bacteria, the bacterial cell- substance is the most active. In old cultures the poisons pass over into the fluid, but they probably no longer represent the primary endotoxin, but a modification of the same. Cholera spirilla, typhoid bacilli, and pneumococci form endotoxins, which on the death of the bacteria are in part set free, and become active as such, or act in a. modified form at the same time with the bacterial proteins. Anthrax and tubercle bacilli probably form no true toxins, but contain poisons of another kind whose action is combined with that of the bacterial proteins. The importance and the course of an infection depend, therefore, upon the char- acter of the cells possessing receptors for the given toxin. In tetanus it is the nerve- cell; in diphtheria and tuberculosis the connective-tissue cell. Diphtheria poison does not injure the skin of the mouse, while the one-hundredth or one-thousandth part of the same dose will produce tissue-necrosis in the guinea-pig (Ehrlich). Aggressins: When bacteria are grown in the pleural or peritoneal cavities, in pleural or peritoneal exudates, blood-serum, or even in distilled water, there is formed a substance which, when the non-toxic sterilized culture fluid is inoculated at the same time with a sublethal dose of the bacteria, neutralizes the protective powers of the body and permits the growth of the bacteria. These substances have been called aggressins, and may be regarded as serving the bacterial organism in the same way that the opsonins protect the animal body. (Bail: Arch. f. Hyg., 1905.) Literature. (Bacterial Infection and Intoxication.) Baumgarten: Der gegenwartige Stand der Bakteriologie. Berlin, klin. Woch.,1900. Bouchard: Actions des produits secretes par les microbes pathogenes, Paris, 1890; Theorie de l'infection. X. intern, med. Congr. i. Berlin, 1891; Les microbes pathogenes, Paris, 1892. Brieger: Bakteriengifte. Zeit. f. Hyg., xix., 1S95; Diphtherie u. Tetanus. Deut. med. Woch., 1890; Fleischvergiftung, ib., 1897. Buchner: Ueber Bakteriengifte, Munch, med. Woch., 1893. 40 THE EXTRINSIC CAUSES OF DISEASE. Canon: Bakteriologisehe Blutuntersuchungen an den Leichen. Cent. f. a. Path., XV., 1904. Chantemesse: Le sol, l'eau et l'air. Traite de Path, gen., II., Paris, 189(3. Charrin: L'infection. Traite de Path. gen. publ. par Bouchard, ii., Paris, 1896. Debierre: Les maladies infectieuses, microbes, ptomaines, leucomaines. Paris, 1888. Duclaux: Ferments et maladies, Paris, 1882; Le microbe et les maladies, Paris, 1S86. Phenomenes generaux de la vie des microbes. Ann. de l'Inst. Pasteur, i., 1S87; Les matieres albuminoi'des, ibid., v., 1891; Traite de Mikrobiologie, Paris, 1899. van Ermengem: Les intoxications alimentaires. Bruxelles, 1895. Fischer: Aetiologie der Fleischvergiftungen. Z. f. Hyg. 39 Bd., 1902. Flexner: The Pathology of Toxalbumins. Baltimore, 1897. Flugge: Die Mikroorganismen, Leipzig, 1896. Forssmann : Bakterologie u. Botulismus. Centralbl. f. Bakt.. xxix.. 1901. Gaffky u. Paak: Wurst- u. Fleischvergiftung. Arb. a. d. Kais. Gesundheitsamte, vi., 1S90. Gamaleia: Les poisons bacteriens, Paris, 1892. Gautier : Sur les alcaloides derives de la destruction bacterienne ou physiologiques des tissues animaux, ptomaines et leucomaines, Paris, 1SS6. Germano: Uebertragung der Infektion durch die Luft. Z. f. Hyg., 26 Bd., 1897. Halban: Resorpt. d. Bakt. bei localer Infection. Jahrb. d. K. Akad., Wien, 1S96. Hildebrand: Eindringen pathog. Mikroorganismen von d. Lunge aus. Beit. v. Zieg- ler. ii.. 1887. Hueppe: Naturwissensch. Einfiihrung in die Bakteriologie. Wiesbaden. 1896 Husemann: Fleischvergiftung. Encykl. Jahrb., v., 1S95; Ptomaine. Eulenb. Encykl.. xix., 1S98. Janowski: Die Ursachen der Eiterung (Lit.). Beitr. v. Ziegler. xv., 1894. v. Kahlden: Sepsis. Eulenburg's Realencyklop.. xxii.. 1899 (Lit.). Koch: Lntersuchungen tiber Wundinfectionskrankheiten. Leipzig, 1SS7. Kruse: Die Krankheitserregung, Leipzig, 1896. Lenhartz: Die septischen Erkrankungen, Wien, 1902. Levy: Sepsinvergiftung. Arch. f. exp. Pathol., 34 Bd., 1S94. Loftier: Die gesehichtliche Entwickelung der Lehre von den Bakterien, Leipzig, 1S87. Neisser: Durcbgangigk. d. Darmwand f . Bakterien. Zeit. f. Hyg., xxii., 1896 (Lit.). Notzel: Infection granulirender Wunden. Fcytsch., xvi., 1898. Oppenheimer: Bakteriengifte. Handb. d. pathol. Mikroorganismen, i., Jena, 1903. Panum: Das putride Gift, die Bakterien, die putride Infection und die Septikamie. Virch. Arch., 60 Bd.. 1874. Pawlowsky : Zur Frage der Infection. Zeit. f. Hyg., 33 Bd., 1900. Petruschky: Krankheitserreger u. Krankheitsbild. Z. f. Hyg., 36 Bd.. 1901. Romer: Infection vom Conjunctivalsack aus. Zeit. f. Hyg., 32 Bd., 1S99. Roth: Duichlassigkeit d. Schleimhaute u. d. auss. Haut fi'ir Bakterien. Zeit. f. Hyg., iv., 1888. Roux et Vaillard: Contr. a 1'et. du tetanos. Ann. de l'Inst. Pasteur, 1893. Roux et Yersin: Contr. a 1'et. de la diphtheric Ann. de l'Inst. Pasteur, 1SSS and 1890. Runge: Die Krankheiten der ersten Lebenstage, Stuttgart, 1893. Schirnmelbusch u. Ricker: Bakterienresorption frischer Wunden. Fortschr. d. Med.. 1895. Simmonds: Bakteriolog. Blutuntersuchungen an der Leiche. Virch. Arch., 175 Bd., 1904. Treutlein: Milzbrandinfektion. Cent. f. allg. Path., 1903. Vaughan and Novy: The Cellular Toxins, 1902 (Lit.). Virchow: Traumatismus u. Infection. Virch. Arch., 162 Bd.. 1900. Wassermann : Wesen der Infektion. Handb. d. pathol. Organismen, i., Jena, 1903. Woodhead: Bacteria anil their Products, London. 1891. See also § 6 and § 10. S 12. The pathogenic moulds (eumycetes) and the budding fungi belong, as do the schizomycetes, to the non-chlorophyllaceous thallo- phytes. They occur in the human organism in the form of jointed or non-jointed and sometimes branching threads or hyphce, and short oval cells, (he so-called conidia. The eumycetes may be divided into the moulds, the fungus of thrush, and the cutaneous mould-fungi. At times they form fructification organs of peculiar structure. The single cells are much larger than those of the schizomycetes, so that they may be s INFECTION BY YEASTS AND MOULDS. 41 seen with lower magnifying power. Outside of the body the moulds de- velop as velvety films of different colors, on the surface of many organic substances and fluids, from the carbon-compounds and salts of which they derive their nourishment. The yeast-fungi are found chiefly in fluids con- taining sugar, and are the cause of the alcoholic fermentation of the same. The spores or conidia, which represent resistant reproductive cells, are for the greater part formed in special organs of fructification, but may also be developed by a simple process of constriction of the ends of the hyphaB, and pass into the air from the surface of the mould-film, and may be widely scattered by the air-currents. Likewise, yeast-cells may be carried about in the air, in the case of the evaporation of a fermenting fluid and the conversion of its residue into dust. The moulds may, as do the bacteria, produce poisonous substances in the nutritive media in which they multiply, usually first outside of the human body, and when these are taken in with the food symptoms of intoxica= tion are produced. For example, the chronic disease, known as pellagra or maidism, which occurs particularly in Italy, Spain, southwestern por- tion of France, and Roumania, and is characterized by gastro-iutestinal disturbances, changes in the skin, spinal and cerebral functional disturb- ances, and general marasmus, is, according to the view of many writers, the result of the eating of corn which has been spoiled through the growth of Aspergillus fumigatus and flavescens or Penicittium glaucum. According to Ceni the active poisonous substances are produced in the spores of the fungi. As parasitic agents causing disease the moulds and the yeasts cause only local infections characterized by tissue degeneration and inflamma- tion. The moulds develop in regions accessible from without, in the skin, the ear, mouth cavity, lungs, etc. They usually occur first as sapro- phytes in cerumen, necrotic lung tissue, etc., but they may also pene- trate into living tissue. The thrush fungus occurs chiefly in the epithelium of the upper layer of the mucosa of the alimentary tract, but often penetrates into the con- nective tissue and causes inflammation. Hematogenous metastasis is rare. The cutaneous moulds multiply in the epithelium of the skin and cause inflammation (favus, herpes tonsurans, pityriasis versicolor, erythrasma). The yeast fungi develop most frequently in the stomach, particularly after the eating of fermenting fruit juices. In cases of glycosuria they may multiply in the urinary bladder and excite there a fermentation. Within the tissues they develop only rarely, and cause there local inflam- mations of varying character. Yeast-like budding fungi occur also in a granulomatous and suppurative process affecting the skin andinternal organs (blastomycetic dermatitis, blastomycosis, sac- charomyeosis, coccidioidal granuloma, etc.). The majority of the cases have oc- curred in America. The parasites involved cannot at present be definitely classified. By some writers (Ricketts) they are believed to belong to the genus Oidiurrj (oidiomy- cosis). Blastomycetes are supposed to be the cause of a peculiar suppurative disease in horses. Literature. (Infection by Moulds and Yeasts.) Bestarelli: Stand der lehagrafrage. Cent. f. Bakt., xxxiv.. 1904. Buschka: Ueber Hefenm^kosen. Klin. Vortr., No. 18, Leipzig, 1898. Busse: Pathogene Hefen und ir.chimmelpilze. Ergebn. d. allg. Path., v., 1900. 42 THE EXTRINSIC CAUSES OF DISEASE. Cao: Oidien u. Oidiomykosen. Zschr. f. Hyg., 34 Bd., 1900 (Lit.). Ceni: Aspergillus fumigatus. Beitr. v. Ziegler, xxxv., 1904. Ceni u. Besta: Aspergillus fumigatus und flavescens u. d. Bez. z. Pellagra. Cent, f, allg. Path., xiii., 1902. Dubreuilh: Les moisissures parasitaires de l'homme. Arch, de med. exp., 1891 (Lit.). Leber: Die Entstehung der Entziindung. Leipzig, 1891. Lonibroso: Die Lehre von der Pellagra, Berlin, 189S. Neusser: Die Pellagra, Wien, 1887, Paltauf und Heider: Der Bacillus maidis u. s. Bez. z. Pellagra. Med. Jahrb., 1SS9. Pick: Stand der Dermatomvkosenlehre. Arch. f. Derm., xxix., 1S94. Podak: Aspergillusmykosen. Virch. Arch.. 139 Bd., 1S95 (Lit.). Ricketts: Oidiomycosis. Journal of Med. Research, 1901. Sanfelice: Pathogene Blastomyceten. Zeit. f. Hyg., xxi., 1896. Saxer: Pneumonomykosis aspergillina, Jena, 1900. Siebenmann: Die Schimmelmykosen des Ohres, Wiesbaden, 1890. Sternberg: Pathogene Hefen. Beitr. v. Ziegler, xxxii., 1902. Toulerton: Pathogen. Action of Blastomycetes. Journ. of Path., vi, 1S99. Tuczek: Klin. u. anatom. Studien iiber Pellagra, Berlin, 1893. § 13. The production of disease by animal parasites is most fre- quently brought about by the introduction of mature parasites, larvae, or eggs iuto the intestinal tract through the medium of the food and drink or by unclean Augers. This is particularly true of those parasites whose habitat is in the intestine or the tissues located within the body ; such parasites are accordingly designated as Entozoa. Parasites living in the outer tissues, as the skin, are termed Epizoa; they remain either on the surface of the skin or penetrate into the same from without. The passage of parasites from the intestine iuto the internal tissues and the changes thereby produced constitute the condition which is usually called, after the designation first used by Heller, an invasion-disease . The animal parasites for the greater part produce only local changes, but they can also cause symptoms of a general disease, particularly when the parasites increase in the body and are present in great numbers in the blood or certain tissues, or when they produce toxic substances. The parasitic protozoa are partly harmless parasites, which develop in the secretions of the mucous membranes without causing pathological changes. Other forms, on the contrary, can penetrate into the living tissues, increase inside of cells, and give rise to local morbid changes, characterized chiefly by peculiar new-formations of tissue (coccidia- dis- ease of the rabbit's liver, epithelioma contagiosum). Certain forms, which are probably to be classed as Sporozoa, increase in the blood, as inhabitants and destroyers of the red blood cells, and are the cause of the infectious disease known as malaria. Others still (trypanosomata) inhabit the blood-plasma. It is not impossible that other infectious dis- eases, for example, small-pox, are caused by parasites belonging to the Protozoa. The parasitic worms (Nematodes, Cestodes, Trematodes) occur in man, partly in the adult and fully developed sexual state, and partly in the larval state. In the first case they are for the greater part intestinal jjarasites, which obtain nourishment from the intestinal contents, rarely sucking the blood from the intestinal mucosa. Fully developed worms are also found in other regions, as in the blood- and lymph-vessels, bile passages, lung, pelvis of the kidney, and in the skin. The eggs or fully developed larvse produced in the body by parasitic worms are either cast out with the dejecta or, through active wandering or metastasis through the blood or lymph, finally reach other organs of the body, where they pass the first stage of their development. Here they remain, however, INFECTION BY ANIMAL PARASITES. 43 in a larval condition, and do not reach sexual maturity. The larva; are capable of further development only when they have been taken into a new host, or have been again eaten by the same host. The worms which reach their sexual maturity in the human body are taken in as larvae through the food and drink. Their first stage of de- velopment is passed in the great majority of cases in animals whose flesh is used for food ; in other cases in certain of the lower animals not used as food. Others develop in water or damp earth or even in the human intestine, so that the embryos or eggs, which pass off with the dejecta, develop at once in case they are again introduced into the intestinal tract of man. The worms which occur in man only in the larval condition (hydatids) develop from eggs which have come from sexually mature worms, which inhabit different animals. They are taken into the intestinal tract usu- ally in the food or drink, but under special conditions eggs capable of development may be contained in the dust of the air, and, being inhaled and finally reaching the intestinal tract, complete the first stage of de- velopment. The intestinal parasites for the greater part produce only slight dis- turbances, though they may cause mechanical irritation of the intestine. The presence of blood-sucking worms in large numbers (Anchylostoma duodenale) can cau.se anaemia. Some also produce poison (Bothrioceph- cdus) . Those parasites which enter the tissues may cause in their vicinity mild inflammation and proliferation of tissue, which may produce more marked clinical symptoms when the number of the parasites (trichina- larvce) in the tissues is very great. Others are of pathological impor- tance, in that they reach a large size (ecMnococcus cysts) and thereby crowd aside and compress the neighboring structures. Otherwise their pathogenic significance depends essentially upon their location. A parasite situated in the muscles or subcutaneous tissue may cause very slight symptoms, while one in the eye, medulla oblongata, heart, or blood-vessels may cause severe disturbances, and under certain conditions death. The parasitic arthropoda (Arachnida and Insects) come to the human body partly from the outer world, partly from infected animals, and partly from infected human beings. They belong almost wholly to the Epizoa, which have their habitat in and upon the skin and accessible mucous membranes (lice, bedbugs, fleas, mites) or only occasionally take their nourishment from the skin (gnats, gad-flies, flies), a few multiply either in the skin (itch-mite) or upon its surface ( lice). Flies and gad- flies occasionally lay their eggs upon the mucous membranes or surfaces of wounds, and from the eggs so laid larvae may develop. The larva of an arachnoid (Pentastoma dentieidatum) is alone found in the internal organs. In so far as these parasites penetrate into the tissues, they cause irritation and inflammation ; the bite of insects that suck blood is also followed by an inflammation in the neighborhood of the puncture. Attention has recently been directed to the possibility that mos- quitos, stinging flies, gad-flies, bed-bugs, lice, etc., maybe the conveyers of an infection, in that bacteria or protozoa may by chance be attached to their bodies, or that in the act of sucking blood of an infected man or animal they may take up into their bodies either bacteria or protozoa and later convey them to other individuals. So far as experience goes, the danger of such conveyal is not very great in the case of the majority of the infectious diseases, since the bacteria thus taken up die after a 44 THE EXTRINSIC CAUSES OF DISEASE. time ; yet it i.s probable that such conveyal does take place, as, for ex- ample, in plague, infection with pus-cocci, and anthrax. This method of conveyal is of chief importance in malaria, in that the plasmodia taken from the blood of infected individuals by mosquitoes (anopheles) undergo further development in the body of the mosquito and produce a new generation, which through the bite of the mosquito is transferred to another individual, so that the spread of malaria is accomplished through mosquitos. Similar conditions exist, also in the case of the tsetse-fly disease and Texas fever of cattle, the latter being conveyed by ticks. Further, it is claimed by Manson, Sonsino, and others that the infection of man with the filaria is also brought about through the agency of mosquitos. Of the parasitic protozoa there should be mentioned also the Amoeba dysenteric, the cause of one form of dysentery in man; the Trypanosoma evansi, the cause of surra; Tr. brucei, the cause of the tsetse-fly disease or nagana; Tr. gambiense the etiological agent in human trypanosomiasis or sleeping-sickness; and the Trichomonas as a probable causal agent in catarrhal conditions of intestine or genitourinary tract. Supposed protozoan parasites have also been described as the causal factors of small- pox, scarlatina, tick-fever in man, rallies, syphilis, tumors, etc., but convincing proofs are not yet at hand. A protozoal origin is also assumed by some writers for yellow- fever, partly because of the fact that the causal agent of this disease is conveyed by a mosquito, Stegomyia fasciala (Reed and Carroll'), Literature. ( Origin of Disease through Animal Parasites. ) Blanchard: Parasites animaux. Path. gen., ii.. Paris, 189(3. Braun: Die thierischen Parasiten des Menschen, Wurzburg, 1893. Celli: Die Malaria, Berlin, 1900. Golg-i: Malariainfcction. Arch, perle Sc. med., x., 1886, and xiii., 1889; Arch. ital. de Biol., ix. and xiv., 1890; Beitr. v. Ziegler. iv., 1889, and vii., 1890; Zeitschr. f. Hyg., x., 1891. Grassi: Die Malaria, Jena,, 1901. Howard: Mosquitos, New York, 1901. Huber; Bibliographic der klin. Helminthologie, Munchen, 1891—1895. Laveran: Du pahidisme et de son hematozoaire, Paris, 1891. Laveran et Mesnil: Trypanosomes et Trypanosomiasis, Paris, 1904. Leuckart: Die thierischen Parasiten des Menschen, 2 Aufh, 1879-1897. Liihe: Krgebnisse der neueren Sporozoenforsehung. Cent. f. Bakt.. xxvii. and xxviii., 1900. Mannaberg- : Die Malariaparasiten, Wien, 1893; Die Malariakrankheiten, Wien, 1899. MuMing: Uebertragung von Krankheitserregern (lurch Wanzen u. Blutegel. Cent, f. Bakt., xxv., 1899. Nuttal: Die Mosquito-Malariatheorie. C. f, Bakt., xxv. and xxvi.. 1899; die Rolle der Insecten, Arachnoiden u. Myriapoden als Trager bei der Vcrbreitung von durch Bakterien u. thier. Parasiten verursachten Krankheiten. Hygien. Rund- schau, ix., 1899, ref. Cent. f. Bakt., xxvi., 1899. Reed: Etiology of Yellow Fever. Pan-Amer. Cong,, 1901; Amer. Med., 1901: Med. Rec, 1901' Sch.neidemu.h.1: Die Protozoen als Krankheitserreger, Leipzig, 189S. TJhlworm: Ccntralbl. f. Bakt. u. Parasitenkunde, 1887-1900. II. Congenital and Inheritable Anlage of Disease. 1. Immunity, Predisposition, and Idiosyncrasy. £ 1 4. Toward the injurious agents capable of producing disease differ- ent individuals show very different powers of resistance, and such differ- ences are exhibited particularly in the case of the infectious diseases and many poisons. When an individual is not susceptible to a given infec- tion in- poison, the property thus manifested is designated as immunity and as insusceptibility to poison; but if an individual is easily infected by a pathogenic microorganism, we assume that he possesses a predisposition CONGENITAL AND INHERITABLE DISEASES. 45 to the given disease. If influences of any kind having no effect on ordi- nary individuals are able to throw certain persons into a pathological condition, this phenomenon is explained through the assumption of an extraordinary sensitiveness, an idiosyncrasy. Immunity and predisposition represent the opposite behaviors of an organism toward external injurious agents, but at the same time they cannot be sharply separated from each other. In very many cases the immunity is not absolute but only relative, so that the individual con- cerned may be made ill through a given harmful agent, for example, a pathogenic microorganism or a poison, when the agent acts in its char- acteristic manner and strength. On the other hand, the predisposition to a disease may be but slight, so that the latter occurs only under es- pecial conditions. An absolute immunity or insusceptibility is possessed by man against many of the microorganisms pathogenic for animals, for example, the bactei'ia of swine plague, swine erysipelas, and symptomatic anthrax, and this may rest upon the fact that the character of his tissue and tissue juices does not admit a localization and multiplication of the given bac- teria, or that the poisons produced by the latter are not poisonous for man. The human race is very susceptible to smallpox, vaccinia, measles, and influenza, so that the great majority of human individuals in the course of life acquire these diseases. In the case of other diseases, as scarlet fever, pneumonia, typhoid fever, diphtheria, the susceptibility seems much less, but it is not possible to determine exactly to what extent the greater rarity of these diseases is dependent upon the fact that the individuals not affected are not exposed to the infection. In the case of many infectious diseases, there is a greater suscepti- bility shown in childhood than in old age; as, for example, diphtheria, whooping-cough, and scarlet fever. Further, there are also variations in the degree of susceptibility at different times, as, for example, an in- dividual may be exposed at certain times to measles without becoming infected, while at other times under similar conditions he may contract the disease. In the case of many pathogenic organisms there appears to be neces- sary for the entrance of infection a certain favoring condition or temporary increase of susceptibility. As evidence of this may be taken the fact that in the human alimentary canal, especially in the mouth and throat, as well as in the respiratory tract, pathogenic organisms (streptococci, staphylococci, pneumococci, tubercle bacilli) may be present without the occurrence of an infection. It may also happen that cholera spirilla may increase abundantly in the intestine without causing marked symp- toms. Such occurrences may be explained in part by a decrease or loss of virulence on the part of such bacteria, but this explanation cannot be applied to all cases. In many instances it must be assumed that the harmlessness of the bacteria is due to the ability of the tissues to hinder their entrance into the deeper parts. In some cases this may depend upon the structure and organization of the tissue, in other cases chemical substances may have a determining influence (see § 29). In favor of the first assumption lies the fact that tissue-lesions, which permit of the entrance of bacteria, bring about an infection. A wound, therefore, in whatever way produced, forms a local predisposition, and the disease, in such cases, bears the character of a wound=infection. Infections caused by pus-cocci, tubercle bacilli, tetanus bacilli, glanders, and an- thrax bacilli are often of this character. 46 THE INTRINSIC CAUSES OF DISEASE. Other causes leading to an increased predisposition to infection are less easily recognized. It appears that severe chilling, " taking of cold," or hunger may have this effect ; also changes in the tissues due to preceding infectious or non-infectious local or general diseases (see § 11, Secondary Infections '). In the case of intestinal infections (typhoid, cholera ), gastro- intestinal disturbances, diminished acidity of the stomach contents, over- loading of the intestines, retention of the contents, etc., play an impor- tant role. Not infrequently it is impossible to determine what causes have favored the production of an infection at a given time. Special predisposition or special lessened resistance of the organ- ism is also not infrequently shown to other injurious agents than those of infectious nature. Certain individuals are less able than others to stand external high temperatures, particularly if at the same time bodily labor is performed. Of the soldiers on a march only a fraction may suffer from heat-stroke, although all are under the same conditions. The altitude at which different, individuals, during mountain ascents and bal- loon voyages, become sensible of the deficiency of oxygen, varies greatly. The effects of chloroform anaesthesia differ greatly in different individ- uals. Many persons become exhausted through physical or mental la- bor at a time when in other individuals, under like conditions, no trace of such exhaustion is discoverable ; and such influences operating daily upon a brain, in cases of especial predisposition, may lead to diseased conditions. Occasionally certain individuals show a sensitiveness toward particu- lar external influences, which is wholly anomalous to that usually ob- served, so that symptoms of disease may be caused by influences which ordinarily do not affect, the majority of mankind. Such a peculiar sen- sitiveness is designated idiosyncrasy. It is exhibited particularly in reference to certain chemical substances, in that certain articles of food or drink regarded as harmless act upon such persons as poisons. The eating of fresh fruit or sugar or salad produces, in certain individuals, nausea and vomiting. Others have an aversion to partaking of dishes prepared from liver or kidneys, and become ill if they overcome this aversion and eat these foods. Others still, after eating crawfish, lobster, strawberries, raspberries, morels, or asparagus, are affected with urti- caria, a disease characterized by an eruption of itching wheals, colic, and vomiting. Not a few persons are unable to drink boiled milk without unpleasant results therefrom. Alcohol, eveu in very small doses, may in certain individuals cause marked excitation, or narcosis, or remarka- ble disturbances of the vaso-motor system. The drinking of cocoa may cause cardialgia and dyspeptic symptoms. Doses of morphine or chloro- form, which are borne by the majority of mankind without injury, may cause in certain individuals severe symptoms or even death. Some in- dividuals show a high degree of sensitiveness, on the part of the mucous membranes of the respiratory tract, to the pollen of certain grasses, so that during the time of the hay-harvest the inhalation of the pollen which is widespread through the air gives rise to a catarrhal condition of the nose and conjunctiva, often of the larynx, trachea, and bronchi, which in severe cases may be associated with asthma and fever. These conditions are known as hay-fever, hay-asthma, or as pollen-diseases. According to the investigations of Dunbar, the pollen contains a substance that may be extracted, and, when injected subcutaneously into those dis- posed to this disease, causes the characteristic symptoms of intoxication. Disinfecting fluids, corrosive sublimate or carbolic acid, in solutions PREDISPOSITION AND IDIOSYNCRASY. 47 which are ordinarily borne without discomfort, may, when applied to the skin of certain individuals, cause not only local disturbances of sen- sation and inflammation, but under certain conditions may excite an eczema that spreads over a large part of the body. On what the peculiar idiosyncrasy in individual cases depends is not clear. In many cases an especial excitability of the nervous system or of certain parts of the same may be regarded as the cause of the phenom- enon. In the case of an idiosyncrasy toward chemically active sub- stances, it may be assumed that the affected cell-protoplasm contains atomic groups which combine with the given substance. The great importance of the part played by natural predisposition and immunity in the origin of infectious diseases has not only been made evident by the study of the spread of epidemics among men and animals, but has received also abundant confirma- tion by numerous experimental investigations. If, for example, a mixture of different bacteria be injected into an animal, only a part of these will develop and produce tissue- changes; the others die. If the same mixture be injected into an animal of a different species, the bacteria which develop are not the same as those in the first case. Further, a certain form of bacteria, which when inoculated into a certain species of mouse in- variably causes death, may, when inoculated into another mouse of different species, be without effect. Mice are very susceptible to anthrax, rats are nearly immune. The poison of the so-called septicaemia of rabbits kills with absolute certainty rabbits and mice; guinea-pigs and rats are immune to it, while sparrows and pigeons are suscepti- ble. The spirilla of relapsing fever may be successfully inoculated only into apes. Gonorrhoea, syphilis, and leprosy cannot be successfully inoculated into any of the lower animals with the exception of apes. In the case of a natural antitoxic immunity the toxins that may enter the organism may remain as perfectly harmless material in the body, and only relatively late are split up in the process of metabolism. In such cases the avidity between the toxin and the body cells, their receptors respectively, may be entirely wanting or very slight. When not entirely wanting, an increase of the dose may produce intoxication. An immunity against small doses may arise through the anchoring of the poison (for ex- ample, tetanus poison) to tissue elements whose changes do not produce symptoms of disease; or antitoxins may be present which render the toxins inert. The especial diseases to which the new-born so frequently succumb are, aside from the conditions acquired during intra-uterine life, dependent partly upon a pathological weakness of the entire organism (especially in case of premature birth), and partly upon the surrounding conditions. Asphyxia, which is of such frequent occurrence, may arise either as the result of bodily weakness or of pathological influences exerted dur- ing delivery. Infectious diseases may be acquired through the stump of the cord or through the accessible mucous membranes and respiratory tract during birth. Heemor- rhages are dependent partly upon traumatic influences exerted during birth, partly upon disturbances of circulation and upon infections. Nurslings and also older children are more susceptible to many infections than adults; particularly so in the case of whooping-cough, diphtheria, measles, scarlet fever, and tuberculosis. In the intestine of nursing infants, bacilli, tubercle bacilli in particular, are very easily taken up into the lymph-vessels; the skin of infants also offers less resistance to the entrance of pus-cocci than that of older individuals. Young dogs may be easily infected with anthrax while old ones cannot. In this connection it should be noted that the slight susceptibility or the immunity of many adults is de- pendent upon the fact that they owe their immunity to attacks of such diseases during childhood. Further, it should be remarked that children are more exposed to certain infections, for instance, tuberculosis, than are adults. In later life haemorrhages, softening of the brain, cardiac degenerations, cancerous growths, and the formation of gall-stones are of especially frequent occurrence. The disease of the arteries known as arteriosclerosis, and also gout, may appear even in the late years of middle life. The predisposition in old age to certain diseases depends in part upon degenerative processes, associated with premature senility of the tissues: in part also upon the fact that certain influences, which the years bring with them, grad- ually accumulate, so that finally the changes which they produce become so prominent that they lead to functional disturbances; and thereby to recognizable morbid condi- tions. Moreover, it is to be remarked that many pathological symptoms of old age are secondary diseases, which become apparent only after other tissue-changes have reached a certain degree. For example, senile haemorrhages, senile gangrene, degenera- tions of the brain and heart are dependent upon disease-processes occurring in the arteries. 48 THE INTRINSIC CAFSES OF DISEASE. The predisposition of the sexes to certain diseases depends, in the first place, upon the especial structure and function of the sexual apparatus. The conditions of preg- nancy and the puerperium offer an especially favorable field for many diseases, as, for example, for infection through wounds. Moreover, different relations of the sexes to many diseases may be explained by differences in the modes of labor and in the habits of living of the two sexes. Differences of predisposition of different races are shown particularly in regard to malaria and dysentery, toward which the negro in general shows less susceptibility than the European. Malarial parasites may be present in the blood of the former without giving rise to symptoms of disease. Literature. (Predisposition and Immunity. ) Bourcy: Predisposition et immunite. Pathol, gen., i., Paris, 1895. Charcot: Lecons sur les maladies des vieillards, 1808. Dunbar: Zur Ursache u. Heilung des Heufiebers. Miinchen, 1903; D.med. Woch., 1903. Ehrlich.: Experimented Untersuchungen tiller Immunitat. Deut. med. Wochenschr., 1891. Emmerich: Die Ursachen der Immunitat. Arch. f. Hyg., xii., 1891. d'Espine et Picot: Manuel pratique des maladies de 1'enfance, Paris, 1889. Galli-Valerio: Immunity, e resistenza alle malattie, Mil., 1897. Goenner: Heufielier. Correspbl. f. Sehweizer Aerzte, 1897. von Hansemann: Die anat. Grundlage d. Disposition. Deutsche Klinik, i, Berlin, 1903. Henoch: Vorlesungen iiber Kinderkrankheiten, Berlin, 1890. Hirsch: Handbuch der historisch-geographischen Pathologic Berlin, 1881-1886. Hueppe: Naturwissensch. Eirifiihrung in die Bakteriologie, Wiesbaden, 1890. Jousset: Traite de l'acelimatement et de l'acclimatation, Paris. 1884. Lode: Beeinfhissung d. Disposit. z. Infect, (lurch Warmeentziehung. Arch. f. Hyg., 28 Bd., 1S90. Lubarsch: Untorsuch. lib. d. Ursachen d. angebor. u. erworbenen Immunitat, Berlin, 1891; Zur Lehre von den Geschwulsten u. Infectionskrankheiten, Wiesbaden, 1899. Maggelsen: I T eber die Abhangigkeit der Krankheiten von der Witterung, Leipzig, 1890. Marfan: Le surmenage. Pathol, gen. de Bouchard, i., Paris, 1895. Martius: Pathogenese innerer Krankheiten, Leipzig, 1899 and 1900; Krankheitsursache u. Krankheitsanlage. Verb, der Dtseh. Ges. d. Naturforscher, Leipzig, 1898. Muller: Die Krankheiten d. ueibl. Korpers in ihren Bezieh. z. d. Geschlechtsfunc- tionen, 1888. Riess: Heufieber. Realencyklop., 1896 (Lit.). Eunge: Die Krankheiten der ersten Lebenstage, Stuttgart, 1893. Stockvis: Vergleichende Rassenpathologie und Widerstandsfahigkeit des Europiiers in den Tropen. Verh. d. X. internat. med. Congr. i. Berlin, 1891. Zeehuisen: Leber Immunitat und Idiosynkrasie. Arch. f. exp. Path., 35 Bd., 1895. •2. Inheritable Diseases Arising from Congenital Pathological Anlage. § 15. Among the morbid conditions arising from congenital anlage, and which either appear spontaneously or are developed through any external influence whatsoever, there may be distinguished different groups; namely, one in which the body as a whole — the constitution — is involved ; another in which only a part of the body as a system or an organ is affected; and, finally, a third in which only a part of an organ presents functional or anatomical changes of a pathological nature. It must be noted that there is no sharp dividing line between these groups, inasmuch as local pathological changes may be associated with constitu- tional conditions. Further, it is often very difficult or impossible to de- termine exactly what part the anlage and what part extrinsic causes have PATHOLOGICAL CONDITIONS DUE TO INTRINSIC CAUSES. 49 taken in the production of such pathological conditions, inasmuch as the force of the external influence which has called the pathological process into activity cannot be estimated with certainty. Among the constitutional diseases arising from intrinsic causes are to be mentioned, first, the development of dwarfs and giants, dis- turbances of growth, the first of which is marked by an under-develop- ment of all the parts of the body, both of the skeleton and the soft parts, while the second is characterized by a growth exceeding that of the ordinary individual. It cannot be doubted that both dwarf and giant growths are often purely dependent upon a congenital anlage; but the same effects can be produced, at least in so far as the in- hibition of growth is concerned, by harmful influences exerted dur- ing the period of development and growth. It cannot always be told with certainty whether an abnormal bodily growth is dependent upon a congenital anlage or upon pathological influences during the period of growth, as, for example, defective development or disease of the thyroid gland. The same difficulty is presented in cases in which the body has at- tained full development of stature, but manifests a general feebleness of constitution, as shown by its inability to withstand a great variety of external influences. Such condition may arise either from congenital defective and weak anlage or from harmful influences which have attacked the developing body during intra- or extra-uterine life; or further, congenital weak anlage and external weakening influ- ences may have affected the development of the individual in an equal measure. A further constitutional peculiarity, which is founded upon a spe- cial congenital anlage, is corpulence (obesity, adipositas, lipomatosis uni- versalis), a condition in which fat is deposited in an excessive amount, either in the tissues normally containing fat, or further, in regions which normally contain no fat, as, for example, beneath the endocardium or between the muscles. The increased deposit of fat is ultimately to be referred to a disproportion between fat-production or fat-supply and fat- consumption, the pathological increase of fat being at one time depend- ent upon an abnormal increase of fat-production, at another on a de- crease of fat-consumption. Daily experience teaches that the energy with which metabolism goes on in the body differs greatly, and changes also at the different periods of life, so that the normal amount of nour- ishment tends at one time to fatten, at another time does not. In the pathological condition termed obesity, which in part rests upon a congenital tendency, the energy of the protoplasmic forces of destructive metamorphosis is weakened, so that an abnormal amount of fat is deposited, even when only a moderate or even a decreased amount of nutritive material is supplied to the tissue. Gout, like obesity, is also a constitutional disease, which is chiefly dependent upon a congenital anlage and is produced essentially by in- trinsic causes. The exact nature of the disease is not yet known. It is characterized by deposits of uric acid in the tissues. According to Gar- rod and Ebstein, the acute attacks of gout are caused by an accumula- tion of uric acid which has its origin either in the kidneys or in local conditions. On the other hand Pfeiffer holds that the essential feature of the gouty tendency consists in the fact that the uric acid is produced in a form which is soluble only with difficulty. According to von 50 THE INTRINSIC CAUSES OF DISEASE. Noorden, the formation and deposit of uric acid is only a secondary process, which is induced by the presence of a certain ferment having only a local action, and is consequently not dependent upon the amount or character of the uric acid formed in other parts of the body. Pathological changes arising in single systems and organs from congenital anlage may occur in any part of the body, and may involve an entire system or organ, or only a part of one. In the skeleton there may occur abnormal development of single parts, as, for example, an abnormal smallness of the extremities (micro - melia) or of the head (microcephalus) in contrast to the size of the trunk ; an abnormal over-development of a bone or group of bones (macrocephalus, macrodactylism, giant growth of a finger, entire foot, or of an extremity) ; malformations of the extremities (cleft-hand, cleft- foot, etc.). Occasionally supernumerary bones, as carpal bones or phalanges, may develop, giving rise to supernumerary fingers. Fur- ther, there may be developed atypical formations, such as bony out- growths (exostoses, hyperostoses), which may extend over the skeleton to a greater or less extent, originating either spontaneously or following some traumatism. In the muscular system there occur particularly pathological bony formations, either single or multiple (myositis ossificans), which, in the period of childhood, occasionally lead to a progressive stiffness of the muscles, through the transformation of muscle into bony plates. In the vascular system there occur either gross anatomical changes, such as abnormal branching of the arteries, pathological development of the heart, or finer changes, which reveal themselves through some abnormal action on the part of the circulatory apparatus or through a tendency to haemorrhages (hcemophilia) which take place spontaneously, that is, without, our being able to demonstrate the action of some in- jurious influence upon the heart or blood-vessels. During the development of the central nervous system there may occur primary disturbances, which in part may manifest themselves only through some pathological disturbance of function or some special predis- position to disease, while others are distinguished by gross anatomical changes, such as abnormal smallness of the brain (micrencephalon) or of the spinal cord (micromyelia), defective development or absence of par- ticular parts (see chapter on malformations), misplacement of the gray matter (heterotopia of the gray substance), abnormal formation of cavi- ties (syringomyelia), or abnormal formations of neuroglia. These dis- turbances may involve the functions of the sensory organs and the motor centres, and even to a greater extent the psychical processes. The mor- bid conditions known as idiocy, epilepsy, periodic and circular insanity, hysteria, neurasthenia, as well as paralysis, mania, melancholia, and dementia, may have their origin in a congenital predisposition. Re- cently the tendency to crime has also been ascribed to a congenital pre- disposition, and Lombroso, in particular, has endeavored to prove that the man who lives only through crime and for crime, the Homo delin- quens, is a congenital criminal — that is, a man who suffers from bodily and mental abnormalities, who possesses other physical and psychical characters than the normal man or even than one who is simply men- tally unbalanced, in that he presents the symptoms of a form of degener- ation tending in a well-defined direction. According to Lombroso, a subnormal development of the anterior half of the cranium, associated with a corresponding lack of development of the anterior portion of the PATHOLOGICAL CONDITIONS DUE TO INTRINSIC CAUSES. 51 cerebrum, in connection with an over-development of the posterior por- tion, produces a feebler development of the intelligence and of the moral sense, and favors a strongly developed instinct-life. Benedikt even goes so far as to maintain that the criminal possesses a peculiar configuration of the cerebral convolutions, similar in type to those of beasts of prey. The views of Lombroso and Benedikt have met with much opposi- tion, and have been attacked as incorrect. There can be no doubt that there does not exist a degenerate species of the human race, which is characterized by such anatomical peculiarities as to make it possible for us to distinguish a class of Homo delinquens from that of Homo sapiens. All the somatic peculiarities regarded as characteristic of the criminal type — as, for example, the beast-of-prey type of cerebral convolutions, slightly developed frontal brain, receding forehead, massiveness of the lower jaw, prognathia, asymmetry of the cranium, marked prominence of the arms superficialis and arcus frontalis, pathological conformations of the skull, etc. — while relatively frequent in criminals, are also far from being infrequent in normal men. On the other hand, it is not to be doubted that the tendency to crime is very frequently dependent upon a congenital predisposition having its seat in some special organization of the central nervous system. In this respect the criminal resembles the insane individual ; further, mental diseases — for example, epilepsy and hysteria — are often observed in criminals. Pathological cerebral functions may develop primarily in individuals possessing such morbid predispositions — that is, without external influ- ences playing any part in the production of the disturbance, so that the person concerned may manifest pathological disturbances of cerebral functions without the concurrence of any external injury, either during the period of development and growth or later. On the other hand, in other cases, external influences — such as mental work, sorrow, care, psychical irritation, disease, etc. — are the causes which give rise to the particular illness — that is, to the occurrence of pathological brain or spinal-cord functions. In these cases the inherited tendency consists only in an abnormal weakness, a predisposition to disease of the central nervous system, so that insignificant influences which would produce no recognizable effects upon a normal individual are sufficient to excite the morbid phenomena. Since many influences, as diseases, infections, psychical irritations, are adequate under certain conditions to produce mental diseases in individuals who must be regarded as normal, it is clear that in many instances it is difficult and often impossible to deter- mine what part the intrinsic causes — the inherited predisposition — and what part the extrinsic causes have had in the production of a disease of the central nervous system. In the case of the peripheral nerves, it is especially their connective- tissue elements which often take on a pathological activity of growth under the influence of intrinsic causes. This activity may manifest it- self partly in the form of diffuse thickenings (fibromatosis of the nerves), which are situated either along the course of those nerves large enough to be dissected with the knife or along the finer nerves, often in large numbers through the entire nervous system, and occasionally involving the entire territory of the peripheral nerves, the skin being most fre- quently affected (multiple fibromata of the skin). In individual cases the fibromatosis of the nerves is associated with an increase in the num- ber of nerve-fibres, so that within a given area of nerve -distribution there will be found a great increase of nerve-fibres, thickened through a 52 THE INTRINSIC CAUSES OF DISEASE. pathological increase of the endoneurium and for the greater part twisted and wound into serpentine forms (cirsoid neuroma, plexiform neuroma). Among the congenital pathological conditions of the visual appa- ratus are to be mentioned in particular dyschromatopsia and achroma- topsia, congenital partial or total color-blindness, which are frequently spoken of as Daltonism, and are characterized by a want of perception for certain colors (most frequently for red and green) or for all the colors. In this same category belongs further the typical pigment degen- eration of the retina, in which there occurs a peculiar spotted, black pigmentation of the retina, associated with a diminution of central sharpness of vision and light-perception, with a narrowing of the visual held. Finally, certain forms of myopia, also albinism (absence of pig- ment in the choroid), the latter condition also involving the structures of the skin, are to be considered in this connection. Of intrinsic conditions of the auditory apparatus deaf -mutism is of chief importance ; this condition, in part at least, is dependent upon a primary disturbance of development. Further, certain malformations of the external ear fall into this class. In the skin and subcutaneous connective tissue new-growths may develop from congenital anlage, consisting of proliferations, sometimes of connective tissue, at other times of epithelium. They often involve particular parts of the skin, as the cutaneous nerves, blood-vessels, lymph-vessels, or the adipose tissue. When occurring as extensive thickenings of the skin and subcutaneous tissue, they constitute the foundations of the conditions known as fibromatous, neuromatous, tuemangiomatous, lymphangiomatous, and lipomatous elephantiasis. As circumscribed growths they are known as birth-marks, fleshy moles, lentigines, freckles, and tumors of the blood- and lymph-vessels. The epithelial hypertrophies give rise to those conditions designated as fish- scale disease or ichthyosis, ichthyotic warts, and cutaneous horns. In addition to the pathological conditions which have been mentioned, there are also malformations of the body (see chapter on malforma- tions) or also of internal organs which must be regarded as primary — i.e., which are not produced by injurious influences exerted upon the developing foetus. Finally, many forms of tumors (see chapter on tumors) are to be placed in this class, particularly those which are found to be already developed at birth or which develop during childhood. Literature. (Diseases Arising from Intrinsic Causes.) Anton: Die Aufgahen d. Psychiatric u. d. Lehre v. d. Vererbung v. Nervenkrank- heiten, Wien, 1892. Baer: Der Verbrecher in antbropologischer Beziehung, Stuttgart, 1803. Benedikt: Anat. Studien an Verbreckergehirnen, Wien, 1879 ; Cent. f. d. med. Wiss., 1880. Charcot: Maladies des vicillards, gouttes et rhumatisme. CEuv. compl., vii. , Paris 1890. Conn: Studien liber die angel). Farbenblindheit, Breslau, 1879. Crocq: [/unite de la diathese et l'heredite morbide. Rev. de med., 1893. Ebstein: Die Fettleibigkeit, Wiesbaden, 1882;' Natur und Behandlung der Giclit, Wiesbaden, 1882; Beitr. z. Lehre von der harnsauren Diathese, Wiesbaden, 1891; Die Stellung der Fettleibigkeit, der Gicht und der Zuckerkrankheit ini nosolog. System. Deutsch. med. Woch., 1898. Fere:* Nervenkrankheiten und ihre Vererbung, Berlin, 1890. Le Gendre: L'heredite. Pathol, gen. publ. par Bouchard, i, Paris, 1895. THE INHERITANCE OF DISEASE. 53 Grassmann: Erblichkeit der Psychosen. Zeitschr. f. Psych., 52 Bd., 1895. Haeckel: Anthropogenic, 1891. Kisch: Die Fettleibigkeit, Stuttgart, 1888, and Eulenburg's Realencyklop., Art Fettsucht, 1895. Kolisch: Wesen und Bebandlung der uratisehen Diathese, Stuttgart, 1895. Koller: Erblichkeitsstatistik der Geisteskrankheiten. Arch. f. Psych., 27 Bd., 1895. Kurella: Cesare Lombroso und die Naturgeschichte des Verbrechcrs, Hamburg, 1893. Lee: De l'obesite, Paris, 1886. Locher-Wild: Ueber Familienanlage und Erblichkeit, Zurich, 1874. Lombroso: Der Verbrecher, i.-iii. (init Bilderatlas), Hamburg, 1891-1895. Lombroso u. Ferrero: Das Weib als Verbrecherin und Prostituirte, Hamburg, 189-1. Minkowski: Die Gicht, Wiea, 1903. v. Noorden: Pathologie des Stoffwechsels (Fettsucht, Gicht), Jena, 1893. Pfeiffer: Das Wesen der Gicht, Wiesbaden, 1891. Schaeffer: Fotale Ohrformen bei Erwaclisenen. Arch. f. Anthropol., xxi., 1892. Sernoff: Die Lehre Lombroso's. Biol. Centralbl., xvi., 1896. Virchow: Descendenz u. Pathologie. Virch. Arch., 103 Bd., 1886. Wagner: Die Krankheitsanlage. Deutsch. Arch. f. klin. Med., 23 Bd., 1888. Wiedersheim : Der Bau des Menschen, Freiburg, 1902. See also § 17. § 16. The origin of congenital pathological anlage — that is, of diseases in which extrinsic influences are either entirely absent during both intra- and extra-uterine life, or are of significance only as a source of irritation sufficient to excite into development pathological tendencies already present in the body — maybe explained in two ways: Either the pathological peculiarities of the individual concerned are inherited from the ancestors, or they are developed from the seed, i.e., from the individual sexual nuclei that have copulated or from the segmentation nucleus resulting from their union. The inheritance of pathological qualities is a fact clearly shown by clinical observations, inasmuch as many of the examples of diseases due to intrinsic causes which are cited in § 15 also appear as inheritable characteristics in certain families. In some cases these characteristics are transmitted from the parents to the children, in other cases the grandchild may exhibit pathological peculiarities of the grandparents, the parents themselves remaining exempt ; finally, in other cases the pathological peculiarity may be manifested in individuals of the collat- eral branches, as from uncle to nephew. Dwarfishness and giantism are pathological peculiarities which frecxuently characterize certain families. Six fingers, cleft-hand and cleft-foot, hare-lip, dextrocardia, birth-marks, multiple exostoses, fibromatosis of the nerves, and multiple neurofibro- mata may appear in families for many successive generations. Congenital haemophilia is also an inheritable condition, which is ordinarily transmitted through the daughter to a male grandchild, the daughter not showing the disease. There may occur, however, a direct transmission of haemophilia from parents to children. Partial or total color-blindness also occurs as an inheritable family disease, especially affecting the male members, and like haemophilia is transmitted through the female line, which does not suffer, to the male descendants. The typical pigment-degeneration of the retina, myopia, deaf -mutism, cer- tain forms of progressive muscular atrophy, and polyuria (Weyl) are also inheritable. According to Gairdner and Garrod, in about ninety per cent of the cases of gout there is a family history of the disease. Of the pathological conditions of the nervous system many are in- heritable; to these belong especially periodic and circular insanity, epilepsy, hysteria, congenital insanity, and to a somewhat less extent 54 THE INTRINSIC CAUSES OF DISEASE. melancholia, mania, delusional insanity, and alcoholism. Progressive paralysis, the deliriums, and the conditions of nervous exhaustion are but slightly influenced by heredity (Kraepelin). Hageu estimates the number of hereditary insane at 28.9 per cent, Leidesdorf at 25 per cent, Tigges at over 40 per cent of all cases, while Forel holds that 69-85 per- cent have hereditary taint. In the most severe forms of hereditary degeneration the pathological condition itself is inherited, but more frequently the predisposition to disease is alone inherited and the morbid condition itself is developed through the action of extrinsic harmful influences upon the central ner- vous system. The character of the disease in the descendants may be the same as in the ancestors (identical heredity). More often the charac- ter of the disease is changed (transformational heredity), not infrequently in the sense that the severity of the condition increases from generation to generation (degenerative heredity). According to Morel, there may appear, for example, in the first gen- eration, nervous temperament, moral depravity, excesses; in the second, a tendency to apoplexy, severe neuroses, alcoholism ; in the third, psychi- cal disturbances, suicidal tendency, intellectual incapacity; finally, in the fourth, congenital idiocy, malformations, and arrests of development. The occurrence of inheritable diseases is by no means remarkable ; it is a well-known fact that in a family not only the peculiarities of race, but also of that particular family are inherited, and that very often the characteristic qualities of either parent or of both recur in the children. As a hypothesis for the explanation of heredity, it is only necessary to assume that the peculiar quality under consideration represents not merely a somatic change accidentally acquired during the life of the an- cestor, but much rather a quality of the ancestor developed from a con- genital anlage. Diseases which in a normal individual arise only un- der the influences of some external injurious influence are never in a true sense inherited (compare § 17), but only those pathological conditions existing in the germ are to be regarded as examples of true inheritance. If a certain disease, as, for example, a mental disease or myopia, is the product of a special inherited predisposition plus the effect of injurious influences which have acted upon the body during life, only that part cau be transmitted which has its seat in some peculiar congenital anlage, but not that caused by external influences — the acquired condition can- not be inherited. In direct inheritance — i.e., in that form of inheritance in which parental qualities are transmitted to the child — the transmission of nor- mal as well as of pathological qualities is possible only when both sexual cells, in the condition in which they combine, contain the potentialities of the characteristics of both parents, in so far as these characteristics are transmissible. The product of the union of the sexual cells — the segmentation-cell — must, therefore, contain within itself both the pa- ternal and maternal qualities. Since the sexual cells do not represent a product of the body developing during the course of life, but are rather to be regarded as independent structures, which at an early period of development are separated from the other parts of the body (that is, from the somatic cells) into special organs, where, protected and nourished by the body to which they belong, they lead an independent existence; the only possible explanation for the phenomenon of inheritance is found iii the hypothesis that the individual sexual cells contain, from the time of their origin onward, the potentialities of the same qualities which appear THE INHERITANCE OF DISEASE. 55 in the body in which they dwell. Both the sexual cells and the body itself, therefore, inherit in general the same qualities from the ancestors. Since iu the act of fructification only the nuclei of the sexual cells — that is, parts of the same — come to copulation, we are compelled further to assume that the nuclei are the bearers of inheritable qualities, and the peculiarities of the individual arising from the combination of the sex- ual nuclei have their foundation in the organization of the nuclei. The appearance in the descendants of normal or pathological char- acters belonging to the collateral relatives (uncle, great-aunt, or cousin), but which are not present in the parents, is known as collateral inheri- tance. This phenomenon is explained by the hypothesis that the sexual cells, in their origin, received characteristics which the bodies of the parents did not receive, or which, at least, did not undergo development and manifest themselves in the parental bodies, whereas iu certain rela- tives they did become manifest. The appearance in an individual of normal or pathological character- istics which were wanting in the parents, but were present in the grand- parents or great-grandparents, is known as atavistic inheritance. This phenomenon is explained by the hypothesis that given characteristics of the grandparents or great-grandparents were transmitted to the sexual cells of the son, or of the son and grandson, without developing in the body of the first, while the quality thus remaining latent became again manifest in the grandson or great-grandson. The attempt has been made to give to the atavistic mode of transmis- sion — which is of frequent occurrence and is usually confined to the immediate generations of ancestors — a wider significance in pathology. Thus it has been proposed to explain the occurrence of many newly aris- ing pathological conditions, which appear similar to certain somatic qualities possessed by remote animal species in the ancestry of man, as a reversion to the type of these ancestors. For example, microcephalus and micrencephalus have been explained as a reversion to the ape type ; and Lombroso is inclined to regard the homo delinquens as an atavistic phenomenon. There can be no doubt that certain writers have gone too far in this respect and have mistaken certain acquired pathological for- mations or new germ- variations (compare § 17) for atavistic conditions. Aside from the question of reversion to the type of the nearest genera- tions of ancestors, atavism plays but an insignificant part in pathology, and it can really be employed only in the explanation of pathological formations in which the tissues show a certain fluctuation of behavior, so that not rarely formations arise which in phylogeny or ontogeny rep- resent stages of the then normal conditions. In this category belong, for example, the occurrence of certain forms of the ear, supernumerary ribs, nipples, or mammary glands, and the development of certain muscles which are found in the most closely related mammals. It is held by many writers that in individual cases, acquired pathological conditions may, under certain circumstances, be transmitted to the descendants. Some even affirm the possibility of hereditary transmission of deformities caused by inj ury, and regard such transmission as proved in certain cases. In support of their view they believe that they can refer to the hereditary transmission of birth-marks, malformations of the fingers, myopia, mental diseases, predisposition to tuberculosis, etc., as examples, ac- cording to their assumption, of diseases which appeared in the first instance as ac- quired, and which were then transmitted to the descendants. Further, they hold that they can point to observations on animals, of which numerous accounts are found in the literature, as giving evidence that injuries may cause deformities which are later transmitted to the offspring. 56 THE INTRINSIC CAUSES OF DISEASE. An unprejudiced examination, however, of the material collected in support of this view shows that observations which establish the hereditary transmission of patholog- ical characteristics acquired in the individual do not exist. The alleged proofs are found in part to be based upon inaccurate observations, in part upon incorrect inferences drawn from accurate observations. For example, the assumption that the occurrence of a birth-mark in a child in the same region of the skin as that in which the mother has a scar is a proof of inherited deformity is wholly in the wrong, inasmuch as birth- marks and scars represent two entirely different pathological processes. If, among the descendants of a man who suffered from some form of mental disease and who showed this disease only after a certain age through the perversity of his actions, there appears an inheritable disease of the central nervous system, or if we note a similar occurrence in the case of myopia, we cannot conclude from such observations that the disease of the ancestor was purely an acquired condition. The term acquired, in the biological sense, can be applied only to that which in the course of the life of an individual arises purely from extrinsic influences, but not to a quality, the anlage of which existed al- ready in the germ-cell, although this quality did not become manifest until excited to development by extrinsic influences. Should there appear in a family inheritable men- tal diseases or hereditary myopia, the first case of such diseases may have already been due to some pathological alteration of the germ, although no manifestations of the dis- ease occurred until some of the outside influences of life excited it to activity, and so rendered possible the recognition of the pathological condition. The particular patho- logical condition in this case cannot, therefore, be regarded as a purely acquired disease. The observations of Brown-Sequard that guinea-pigs, in which epilepsy has been experimentally induced, can transmit the condition of epilepsy, have been shown by Sommer to be incorrect, in that the condition is not a true epilepsy, but a reflex epilepsy, and is not transmitted. Against the occurrence of an inheritance of acquired pathological conditions is the simple consideration that the human race, which is exposed to so many injurious influ- ences, and whose individual members sutler so frequently from disease and mutilations, would very soon arrive at a state of extreme misery and stunted growth and would eventually perish were only a small part of the acquired diseases transmitted lo the descendants. Further, the origin of man and animal forms reproducing through ger- minal cells is in itself an argument against the possibility of the transmission of qualities acquired by the individual. The act of fructification — that is, the first step leading to the production of a new indi vidua! — is accomplished by the copulation of the sexual nuclei — that is, of the nuclei of the ovum and spermatozoon. According to the researches of the last decades, there can be no doubt that these nuclei are the bearers of the hereditary characteristics of the parents, and that the individuality of the copulating nuclei is inherent in the or- ganization of the same. It is impossible to conceive in what manner processes taking place in the body cells can produce in the sexual nuclei, which lie within special cells in the sexual glands, such alterations of organization that the}' shall contain in poten- tial form the acquired characteristics of the body and transmit them, after copulation has occurred, to the descendants. Delage was able to fructify non-nucleated portions of the eggs of echinoderms, annelides, and mollusks with spermatozoa (merogony). He regards the union of the nucleus of the spermatozoon with the protoplasm of the egg as the essential feature of fructification. Tins is not applicable to the ordinary method of fructification, but only shows that in exceptional cases the entrance of the spermatozoon into the protoplasm of the egg is sufficient for the setting-up of further development, and that the nucleus of the spermatozoon entering into the egg without uniting with the nucleus of the lat- ter exercises an especial influence upon the protoplasm of the egg. Darwin in his time represented the view that acquired characteristics could be transmitted to the descendants, and endeavored to make such phenomena intelligible by the theory that molecules from all the cells of the body contribute to the formation of the germ-cells, and that, consequently, alterations of the organism can be trans- mitted to the germ cell. Nevertheless, there occur in the writings of Darwin state- ments which not only do not agree with this opinion, but directly contradict it. At the present time the views with regard to the inheritance of disease generally accepted are that there is no true inheritance of infections and that gross structural dis- turbances cannot be inherited. The only possible inheritance of conditions acquired by the parents is that of conditions acting both upon the somatic tissues and germ-cells of the parents. Chemical and physical conditions acting within the body or from with- out may cause changes in the constitution of somatic and germ-cells. The occurrence of such changes in the germ-cells is clearly shown in the effects upon the progeny of paternal or maternal alcoholism, plumbism, and experimentally with abrin. It is a INHERITANCE OF PATHOLOGICAL CONDITIONS. 57 well-known fact that in the case of the birth of monsters there is often obtainable a history of some infection in one of the parents before conception took place. Bardeen's experiments regarding the changes in embryos arising from ova fertilized by sper- matozoa that had been injured by Roentgen irradiation are very suggestive. Adami has applied the side-chain theory in explanation of heredity. According to this view there may be also a true inheritance of morbid conditions due to modifica- tions in the biophoric molecules through the interaction of their side-chains. Recently much discussion has been waged over the principles of heredity involved in Mendel' a lam, Gallon's law, and De Vries' tlieory of mutations (see literature). Literature. (Inheritance of Pathological Conditions.) Adami: Heredity in Relation to the Development of Morbid States. Ref. Hand- book of Med. Sc, 1902; Osier's Modern Medicine, 1907. Bateson: Mendel's Principles of Heredity, London, 1902. Bernhard: Familiare Erkrankung d. Centralnervensystems. Virch. Arch., 126 Bd., 1891. Bolling-er: Ueber Vererbung von Krankheiten, Stuttgart, 1SS2. Brown-Sequard: Arch, de phys., i., 1868, ii., 1869, iii., 1870, iv., 1872 (giebt an, dass kunstlicb erzeugte Epilepsie bei Meerschweinehen auf die Jungen ubergehen konne). Couvelaire: La dysostose cleido-cranienne. J. de phys., i., 1899. Darwin, C. H. : Die Ehe zwischen Geschwisterkindern und ihre Folgen, Leipzig, 1876. Dejerine: L'h6redite dans les maladies du systeme nerveux, Paris, 1SS6. Delage: Etude sur la merogonie. Arch, de zool. exper., 1S99. Deutschrnann: Vererbung v. erworb. Augenaffectionen. Zehnder's kl. Monatsbl., xviii., 1880. Dietrich: Die Bedeutung dcr Vererbung fiir die Pathologic, Tubingen, 1902. Fischer: Ueber hereditare multiple Exostosenbildung. Dtsch. Zeitschr. f. Chir., xii., 1880. Galton: Natural Inheritance, London, 1889; Proc. Roy. Soc, 1897. Grandidier: Die Hamophilie, ii Aufl., 1877. Griesing-er : Die Pathol, u. Ther. der psych. Krankheiten, 7 Aufl., 1892. Gutzmann: Vererbung v. Sprachstorungen. Deut. med. Woch., 1898. Hag-en: Statist. Enters, uber Geisteskrankheiten, 1876. Ueber die Verwandtschaft des Genies mit dem Irresein. Allg. Zeitschr. f. Psych., xxxiii. Henle: Handbuch der rationellen Pathologie, i., Braunschweig, 1846. Herrmann: Die Vererbung v. path. Zustanden beim Pferde. Vortr. f. Thierarzte, viii., 1, 188.5. Hossli: Geschichte und Stammbaum der Bluter von Tenna, Inaug.-Diss., Basel, 1885. Israel: Angeb. Spalten der Ohrlappehen. Virch. Arch., 119 Bd., 1890. Mayer: Spalthand u. Spaltfuss (durch 4 Generat. vererbt.). Beitr. v. Ziegler, xxiii., 1898. Morel: De riieredite morbide progressive, Paris, 1867. v. Nathusius: Die Vorgange der Vererbung bei den Hausthieren, Berlin, 1891. Pearson: Law of Ancestral Heredity. Proc. Roy. Soc, 1S98; Law of Reversion. Ibid., 1900. _ Reinecke: Erblichkeit der multiplen Wachsthumsexostosen. Beitr. v. Bruns, viii., 1891. Roth: Die Thatsache der Vererbung, Berlin, 188.5. Der gegenwartige Stand der Frage der Vererbung erworbener Eigenschaften. Wiener Klinik, 7 H, Wien, 1890. Saury: Etude clin. sur la folie he'r^ditaire, Paris, 1886. Sioli: Vererbung von Geisteskrankheiten. Arch. f. Psych., xvi., 1885. Sommer: Die Brown-Sequard 'sche Meerschweinchenepilepsie. Beitr. v. Ziegler, xxvii., 1900. Thoma: Lleber einige senile Veranderungen des Korpers, Leipzig, 1884. Virchow: Gesammelte Abhandlungen, Frankfurt, 1856; Virch. Arch., 103 Bd., 1886. De Vries: Die Mutationstheorie, Jena, 1901. Weil: Die hereditare Form des Diabetes insipidus. Virch. Arch., 95 Bd., 1884. Zander: 1st die Polydaktylie theromorphe Varietat oder Missbildung? Virch. Arch., 125 Bd., 1891. ' 5S THE INTRINSIC CAUSES OF DISEASE. Ziegler: Konnen erworbene pathologische Eigensehaften vererbt werden u. wie entstehen erbliche Krankheiten u. Missbildungen? Beitr. v. Ziegler, i., 1886; Die neuesten Arbeiten iiber Vererbungs- u. Abstammungslehre u. ihre Bedeutung f. d. Pathologie, ib., iv., 1888. See also § 15 and § 17. § 17. As has been explained in § 17, inherited diseases are always such as have at the very first developed from intrinsic causes, that is, from certain anlage in the germ-cells ; or at least are diseases in which the predisposition thereto is a congenital characteristic. Conversely, the statement may be made that all normal or pathological qualities in the germ-cells are inheritable. The first appearance of new pathological characteristics which are inheritable may be dependent upon the fact that as a result of sexual procreation — i.e., of the union of two sexual nuclei, one of which is the bearer of the transmissible qualities of the father, the other of those of the mother — new variations are constantly arising, so that the child is never exactly like one parent ; but, on the other hand, in addition to the qualities which the parents offer, it possesses also new qualities. Even if we assume that the sexual nuclei at times contain in potential form exactly the same characteristics as those of the parents, the product re- sulting from the copulation of these nuclei would present a certain degree of variation. In such a case, however, the differences between the children of such parents would be but slight. As a matter of fact, the different products of the same parents may show an infinite variety, by reason of the fact that the germ-cells themselves contain further a mixture of the transmissible characteristics of the paternal and maternal ancestors, and that this mixture is never the same in the individual germ-cells. In accordance with this is the fact that the children of a certain fam- ily always present important differences in both physical and mental qualities. A marked resemblance occurs only in the case of twins aris- ing from one egg — i.e., when the process of development of both chil- dren has started from the same act of copulation. The embryonal variations resulting from the mixture of two indi- vidually different hereditary tendencies can find their expression in the most varied qualities of the body and mind of the developing child. If these do not deviate in a marked degree from the characteristics which the different members of the family show, the conditions are regarded as normal and ordinarily receive no especial attention. If, on the con- trary, important differences of character are produced, the occurrence attracts greater attention; and, according to the value which it has for the individual concerned, is regarded at one time as something favor- able, at another time as something unfavorable, something pathological. When small, weak parents produce children who develop into large and strong individuals, or when the intellectual capacity of the children sur- passes that of the parents, the occurrence is regarded as favorable. If, as actually happens, a genius in any branch of human knowledge or skill suddenly appears within a family, without any evidence of an especially marked mental development in the ancestors, the phenomenon would attract general attention and be regarded as a fortunate event. But if, on the other hand, strong parents beget children who are weak or physically defective, or if they show a mental development inferior to that of their parents, or if they show a complete stunting of a part of their mental faculties, the newly appearing variation is regarded as abnor- mal, pathological. THEORIES OF INHERITANCE. 59 If we consider the experiences which the pathology of man and ani- mals fnrnishes, the assumption seems fully warranted that of the transmissible pathological conditions and predispositions, very many, perhaps the majority, are referable to a variation of the germ based upon the amphimixis. For example, the group of hereditary patho- logical conditions and predispositions of the central nervous system, hereditary myopia, haemophilia, pigmentation of the retina, and poly- dactylism may arise in this manner. If such abnormal characteristics show themselves repeatedly in the children of the parents, who are them- selves normal and have healthy ancestors, it may be assumed that the germ-cells of the parents, though individually normal, have through their union given rise to a pathological variation. This hypothesis be- comes substantiated when one or both parents produce normal offspring through copulation with other individuals. Besides the variations which are the result of normal sexual repro- duction, it is very probable that pathological germ- variations which lead to the development of transmissible pathological qualities may also arise through the action of injurious influences upon the sexual nuclei or the segmentation nucleus ; or else that the process of copulation — that is, the union of the sexual nuclei — has been disturbed in some manner. The injurious substance may be a body-product, or it may come from without, and at the same time also produce its harmful effects upon the body. Consequently, in these cases we may speak of the germinal ac= quisition of a transmissible pathological characteristic through the action of an extrinsic injurious influence. This does not mean, however, as has been accepted by many, that the tissues of the body, under the influence of extrinsic harmful influences, first suffer changes in themselves, and then transfer these changes to the germ-cells. It is to be believed, rather, that the harmful influence acts directly upon the sexual nuclei or the segmentation-nucleus, producing in these a change of some kind, which later leads to a pathological development of the individual developing from the impregnated egg. It is a matter of no importance, so far as the nature of the resulting pathological variation is concerned, whether the somatic tissues also suffer changes, or of what nature such changes may be. If a transmissible pathological characteristic arises, it may, in case it does not affect life or prevent reproduction, actually be transmitted, al- though this does not necessarily follow. The chances that a particular characteristic will be transmitted are greatest when both parents possess the same quality, as, for example, when both parents are affected with hereditary deaf -mutism or with near-sightedness. If the characteristic is wanting in one parent, there is produced most frequently a new germ- variation, in which the pathological characteristic fails entirely to mani- fest itself, and in the following generations may completely disappear. If several descendants are begotten, the pathological characteristic, in case it is not wholly lost, may show itself in only a few of the descend- ants, and in these in either a modified or in an aggravated form. Not rarely it happens that the characteristic remains latent in one generation — that is, is confined to the sexual cells, and appears again in the second generation. There seems to me to be no doubt that, through the copulation of two sexual nuclei possessing different hereditary tendencies, variations may be produced, and that among these there may be some which are to be regarded as pathological. It is more difficult to answer the question whether, besides these, there are not also transmissible variations of a pathological nature, which arise through influences which affect the 60 THE INTRINSIC CAUSES OF DISEASE. nuclei of the ova or of the spermatogonia, the spermatocytes or spermatosomes, or the segmentation-nucleus; and further, if we accept the existence of such variations, with what frequency do they occur. Weismann holds the opinion that the basis of transmis- sible variations is to be found, not in the amphimixis, but rather in the direct action of ex- ternal influences upon the sexual nuclei. Starting from the assumption that the variable cells or cell-groups derived from the germ (by him designated as hereditary pieces or determinates) are represented in the germ-plasma by special particles, which are formed by the grouping together of a number of Ufe-trophdblasts or biophores (molecular groups which represent the smallest units of life), and which he calls determinants or determin- ing pieres, he believes that he is warranted in ascribing the transmissible variation primarily to the changes produced by external influences in the determinants or group of determinants contained within the nuclear chromatin, so that finally the hereditary pieces or determinates derived from them also suffer changes. He believes that such an influence might be exerted by excessive nourishment of a determinant, causing it to grow more rapidly. For example, he regards it as possible that many congenital mal- formations (for example, an increase in the number of fingers and toes) can be referred to a reduplication of the determinant-groups caused by increased supply of nourish- ment. According to Weismann, the amphimixis has only a secondary influence in the origin of a permanent variation, in that it mixes in constantly new manner the varia- tions dependent upon the changes in the determinants, but does not in itself produce new variations. "The deviations which the determinants suffer through unequal con- ditions of nutrition constitute the material out of which, through amphimixis in con- nection with selection, the visible individual variations are produced, through whose increase and combination new forms arise." I agree with Weismann in so far as the assumption that the appearance of a new variation of pathological nature is in part to be referred to changes in the determinants contained within the sexual nuclei, due. to the direct action of extrinsic influences. I do not, however, believe that there is sufficient ground for attributing, as. does Weis- mann, the formation of new separate parts to an over-nourishment of single groups of determinants. Such a dependence of the germ-plasma upon the surrounding nutritive material seems to me scarcely conceivable, and is opposed to all views hitherto held re- garding the nutrition of cells. Not only quantitative but much rather qualitative changes of the food-material would appear to be necessary in order to produce changes in the organization of the determinants. Further, I hold that the amphimixis has not only a secondary but. much more a primary significance with regard to the origin of pathological variations, in the sense that it itself is able to produce new variations. Finally, it seems to me that we cannot at the present wholly set aside the hypothesis of Nageli, according to which the idioplasm is capable of altering its own condition, from within outward, in certain fixed directions and according to certain fixed laws, and thus may produce new characteristics. Literature. (Theories of Inheritance. ) Ackermann: Meehanismus u. Darwinismus in der Pathologic Halle, 1SS4. Adami: New York Medical Journal, June 1, 1901; Osier's Modern Medicine, 1906. van Bemmelen: Die Erblichkeit erworbener Eigensehaften. Biol. Centralbl x 1891. Bigelow: Heredity. Reference Handbook of Med. Sciences, 2d ed. Bonnet: Die stummelschwanzigen Hunde. Beitr. v. Ziegler, iv., 1S88. Boveri: Gesehlechtl. erzeugter Organismus ohne mtitterl. Eigensehaften. M nied Woch., 1SS9. Broman; Ueber atypische Spermien. Anat. Anz., xxi., 1902. Darwin: Das Variiren der Thiere u. Pflanzen, Stuttg., 1873; Die Abstammung des Menschen, Stuttgart, 1S73; Ges. kl. Schriften v. Ch.. Darwin, her. v. Krause, Leipzig, 1886. Origin of Species; The Descent of Man. Delage: La structure du protoplasma et les theories sur l'here^lite, Paris, 1S95. Eimer: Die Entstehung der Arten, Bd. i.. Jena, 1SSS. Emmery: Gedanken zur Descendenz- u. Vererbungstheorie. Biol. Centralbl., xxiii , 1903. Galton: Hereditary Genius, London, 1892. Haecker: Die Anatomie der vaterliehen und der mutterlichen Kernsubstanz vom Ei bis zu den Fortpflanzungszellen. Biol. Cbl., xx., 1902. Hallervorden: Biologische Interferenz u. Erblichkeit. Virch. Arch., 144 Bd., 1S96. Hartog-: Grundziige d. Vererbungstheorieen. Biol. Cbl., xviii., 1898. PLACENTAL TRANSMISSION. 61 Hegar: Der Geschlechtstrieb, Stuttgart, 1894. Hertwig, 0.: Das Problem d. Befruehtung u. d. Isotropie des Eies, eine Vererbungs- theorie, Jena, 1884; Exper. Studien am thierischen Ei vor, wahrend u. nach d. Befruehtung, Jena, 1890; Entwickelungsgeschichte, Jena, 1893; Preformation oder Epigenese? Zeit- u. Strcitfragen der Biologie, i., Jena, 1894. Israel: Angeborene Spalten der Ohrlappchen. Virch. Arch., 119 Bd., 1890. Klaatsch: Das Problem d. Vererbung m. Rucks, auf d. Pathol. Munch, med. Woch., 1898. Kolliker: Bedeutung d. Zellkerne f. d. Vorgange d. Vererbung. Zeit. f. wiss. Zool., xlii., 1885. von Leudenfeld: Variation und Selektion. Biol. Cbl., xxiii., 1903. Minot: Vererbung u. Verjiingung. Biol. Centralb., xv., 1895. (See also Original Papers in English.) v. Nageli, C: Mechanisch-physiol. Theorie der Abstammungslehre, Miinchen, 1884. Ortmann: Ueber Keim variation. Biol. Cbl., xviii., 1898. Plate: Ein moderner Gegner der Descendenzlehre. Biol. Cbl., xxi., 1901. v. Rath: Vererbung von Verletzungen. Biol. Centralbl., xiii., 1893; Telogonie, ib., xv., 1895. Ribot: Die Vererbung, Leipzig, 1895. Rohde: Gegenw. Stand d. Frage nach d. Entstehung u. Vererbung individ. Eigensch., Jena, 1895. Romanes: Die geistige Entwickelung d. Menschen, Leipzig, 1893; Darwinist. Streit- fragen, 1895. Roux: Der Kampf der Theile im Organismus, Leipzig, 1881; Entwickelungsmechanik des Embryo, Miinchen, 1885; Die Entwickelungsmechanik der Organismen, Wien, 1890. Sanson: L'hereVlite normale et pathologique, Paris, 1893. Schaffer: Fotale Ohrfonnen u. Erblichkeit ders. Arch. f. Anthrop., xxi., 1892; Die Vererbung, Berlin, 1898. Schlatter: Gedanken uber die Vererbung. Biol. Centralbl., xvi., 1896. Spencer: Unzulanglichkeit d. natiirl. Zuchtwahl. Biol. Centralbl., 1893, 1894. Waldeyer: Befruehtung u. Vererbung. Verh. D. Naturforsch., Leipzig, 1897. Weismann: Aufsatze tiber Vererbung, Jena, 1892; Das Keimplasma, Jena, 1892; Allmacht der Naturziichtung, Jena, 1893; Aeussere Einflijsse als Entwickelungs- reize, Jena, 1S94; Neue Gedanken zur Vererbungsfrage, Jena, 1896; Ueber Ger- minalselection, Jena, 1896. Wiedersheim: Der Bau des Menschen, Freiburg, 1902. Wilkens: Vererbungslehre auf Grund thierziichterischer Erfahrungen. Zeitschr. f. Thiermed., 18 Bd., 1891; Vererbung erworbener Eigenschaf ten. Biol. Centralbl., xiii., 1893. See also §§ 15 and 16. § 18. Besides the inheritable pathological conditions mentioned above, there appears to be a hereditary transmission in the case of the infec= tious diseases ; but this is in reality not a true form of inheritance, and is more properly designated as postconceptional intrauterine infection. If pathogenic micro-organisms enter into the blood-stream of a preg- nant woman they may be carried into the vessels of the maternal placenta, and finally may pass through the foetal placenta into the body of the foetus. Such a transmission has been positively demonstrated in many infections (staphylococcus, streptococcus, pneumococcus, typhoid fever, tuberculosis, anthrax, smallpox, syphilis, and others) through the pres- ence of the micro-organisms or of characteristic changes in the tissues of the feetal organism. In many cases, for example, in tuberculosis and anthrax, the path which they have taken may be demonstrated since the placenta also shows characteristic pathological changes. Up to very recently it has been assumed that besides a placental transmission there might occur also a germinal transmission, that is, an infection of the sexual cells before or during the fructification. Further, it has also been taken for granted, that, through infection of the fructifying spermatosome, an infection of the ovum without that of the maternal organism may occur, and such a mode of infection has been regarded as established, particularly in syphilis. Up to the present time 02 PLACENTAL TRANSMISSION OF INFECTION. however, this mode of transmission has not been proved by unquestioned observations to occur in man and the mammals, and its occurrence even in syphilis has also been thrown into doubt (Matzenauer). According to our present knowledge we may say definitely that the transmission of infections through the placenta to the foetus in utero has been positively demonstrated and occurs in different infectious diseases. Infections of the ovum or of the sperm before or during fructification are indeed possi- ble, but it has not yet been positively demonstrated in the case of man and the other mammals that a further development into a viable foetus is possible in the case of an ovum in which the agents of infection have produced characteristic changes. This is true not only in the case of acute infections, but also in such chronic ones as tuberculosis and syphi lis. According to the views of Matzenauer, in no case of hereditary syphilis can mater- nal transmission be excluded; and there are no clinical observations that speak for a pure paternal spermatic infection of syphilis. The fact that the mothers of children showing hereditary lues are immune toward syphilis (Colles' law) cannot be explained by the hypothesis that the mother has received syphilis toxins from the child syphil- ized from the father and in consequence has produced antitoxins (Finger), but can be explained only on the ground that she herself was infected with syphilis. That the mother often shows no syphilitic changes cannot be taken as an argument against the latter view, since syphilis may often be present with complete absence of symptoms. Literature. (Transmission of Infectious Diseases to the Foetus.) Birch.-Hirsch.feld: Die Pforten d. placentaren Infection d. Fotus. Beit. v. Ziegler, ix., 1891. Blurner: Congenital Typhoid. Jour. Amer. Med. Assn., xxxv. Charrin et Gley: Rech. sur la transmission hereditaire de 1'imrnunite. Arch, de phys., vi., 1894. Condorelli: Vaiuolo intrauterine in un feto, Catania, 1890. v. During-: HereditSre Syphilis. Eulenb. encyklop. Jahrb., v., 1895 (Lit.). Eberth: Geht der Typhusorganismus auf den Fotus liber? Fortschr. d. Med., vii , 1889. Ehrlich: Leber Immunitiit durch Vererbung und Saugung. Ztschr. f. Ilyg., xii., 1892. Ernst: Intrauterine Typhusinfection einer lebensfahigen Frucht. Beit. v. Ziegler, viii., 1890. Finger: Die Vererbung der Syphilis, Wien, 1898 (Lit.). Fournier: L'heredite syphilitique, Paris, 1891. Kockel u. Lungwitz: Placentartuberkulose beim Rind. Beit. v. Ziegler, xvi., 1894. Latis: Lebergang des Milzbrandes von der Mutter auf den Fotus. Beit. v. Ziegler x., 1891. Inibarsch: Leber die intrauterine Lebertragung pathogener Baktericn. Virch. Arch 124 Bd.,1891. Maffucci: Leb. d. Verhalten d. Embryo gegen Infection. Centralbl. f allg Path v., 1894. Matvoz: Transmission interplacentaire des microorganismes. Ann. de 1'Inst Past 1888 and 1889. Morse : Foetal and Infantile Typhoid. Arch, of Fed., 1900. Neumann: Vererbung der Syphilis. Arch. f. Derm., xxiv., 1892. Porak: Du passage des substances a travel's du placenta. Arch, de med. exp., 1894. Schrnorl u. Geipel: Tuberkuloseder mensch. Placenta. Munch, med. Woch., 1904. Schmorl u. Kockel: Tuberk. der menschl. Placenta. Beit. v. Ziegler, xvi., 1894. Straus et Chainberland : Transmission des maladies virul. de ia mere au foetus Arch, de phys., 1883. Warthin: Tuberculosis of the Placenta. Journal of Infectious Diseases, 1907. Warthin and Cowie: Tuberculosis of the Placenta. Journal of Infectious Diseases 1904. Wassermann: Erbl. Lebertrag. d. Infektionskrankh. Handb. d. path. Mikroorg Jena. 1903. Wolff: Leber Vererbung von Infectionskrankheiteu. Virch. Arch., 112 Bd., 1888. CHAPTER II. The Spread and Generalization of Disease through= out the Organism. Autointoxications and Sec= ondary Diseases. I. General Considerations Concerning the Spread and Generalization of Pathological Processes in the Organism. § 19. If through the action of any injurious agent, a local tissue- change is produced, there occurs first a primary local disease or organ- disease, which is accompanied by a disturbance of function of the affected part. If the injurious agent passes into the body-juices and into the blood without causing noticeable changes at the point of en- trance, while within the body it gives rise to local changes, the result- ing condition may be designated as a solitary or multiple lymphogenous or hematogenous local disease or organ-disease. Local diseases may during their entire course remain confined to the organ originally affected, yet very frequently they lead to further sec- ondary diseases of organs or to a general disease. The first method by which disease-processes spread throughout the body is through metastasis, by means of which there are very frequently formed, not only solitary, but innumerable foci of disease throughout the body. Not infrequently there may occur such a generalisation of disease by way of the blood and lymph -channels (tuberculosis, suppurations, and car- cinomatous growths) that the majority of the organs will be found to contain metastases, and show correspondingly more or less easily recog- nized functional disturbances. A second method of the spread of disease occurs in those diseases in which in the primary foci there are formed toxic products which, taken up into the lymph and blood, produce such changes in different organs that they must be regarded as intoxications by poisonous substances arising from diseased foci. This intoxication is, as shown in § 12, of very com- mon occurrence in the infectious diseases, and leads not only to secondary degenerations of organs, but much more to the picture of a more or less severe general disease, as shown by general disturbances of metabolism, fever, and disturbances of the central nervous system. A third form of the spread of disease processes throughout, the body becomes possible by reason of the fact that the integrity and normal functional capacity of many organs are to a great measure dependent upon the function of other organs ; and, further, upon the fact that the organism needs, for the preservation of its normal condition, the perfect functional working of its organs, and in the case of many organs cannot permanently dispense with their functions. There is, therefore, a large group of local and general diseases which arise as the result of the imperfect functional activity of this or that organ. 63 64 THE GENERALIZATION OF DISEASE. A fourth mode of origin of secondary diseases is through autointoxica- tion — that is, through a poisoning of the organism by substances which arise in the body itself through its own activity (metabolic poisons). The place of origin of these substances is in part the intestinal tract (enterogenous poisons), and partly the tissues (histogenous poisons). The cause of the poisonous action of these products of metabolism lies partly in the fact that they are produced in an increased amount or are retained within the body as a result of disease of certain glands; partly also that they are not transformed to non-poisonous bodies, as is the case under normal conditions. In conditions of disturbed metabolism poisons foreign to the normal body may be produced. A. fifth method by which the animal or human organism may be injured is the production of symptoms of disease through the impairment and loss of function of those glands producing an internal secretion which is of impor- tance to the organism. In this category belong especially the thyroid, hypophysis, pancreas, adrenals, liver, and sexual glands. Since in the disease of the glands just named intoxication plays also an important role, this group of processes is closely connected with that of the fourth mode of generalization of disease. II. Hetastasis and Embolism and Their Significance in the Etiology of Lymphogenous and Haematogenous Diseases. §20. The transportation, through the blood or lymph-stream, of a disease- producing agent, and the production of disease at the point of deposit of such agent, is termed metastasis. This is one of the most common modes of the spread of disease throughout the body. Ordinarily the term metas- tasis is applied particularly to those cases in which the transportation of a given substance is followed by easily recognizable clinical and anatom- ical manifestations of disease, especially those of inflammation or tumor- formation, so that we are accustomed to speak of metastatic inflammations and metastatic tumors. There is, however, no good reason for not includ- ing also under metastasis those cases of transportation of corpuscular elements through the lymph or blood stream in which the changes pro- duced by the transportation are less striking, and are recognizable only through a more careful anatomical or microscopical investigation. The term metastasis indicates further that the substance deposited has arisen from some other known place within the body. If the source of the transported material is not known, or at least cannot be definitely located, we are accustomed to speak of lymphogenous and hematog- enous deposits and diseases. The same designation is also applied to deposits of known origin. The significance of metastasis is in all cases dependent upon the properties of the transported body. Insoluble bland foreign bodies of small size may have little effect upon the tissue; soluble and chemically active substances may, on the other hand, produce important tissue changes. Bacteria capable of reproduction may give rise to a disease which corresponds in general to that produced at the primary focus of infection. Tumor- cells capable of growth may develop into a secondary tumor. The size of the transported body is of essential importance in hematogenous metastasis, in that small bodies may pass all the blood- vessels, even the capillaries, while larger ones will be carried only through those vessels whose lumen is sufficiently large to admit them. When the latter have by any means obtained entrance to the arteries of METASTASIS AND EMBOLISM. 65 Fig. 2.— Multiple emboli in the brandies of the pulmonary artery, after thrombosis of the right auricle, a, Arteria! branch; b, embolus; c, embolus with secondary thrombosis. the the greater or lesser circulation and are carried along by the blood- stream, they will become lodged at those divisions of the vessels where the vessel-lumen is too small to admit them, and will thereby more or less completely obstruct the vessel. This occurrence is designated by the special term embolism ; the body blocking the vessel is called an em- bolus or a vessehplug (Fig. 2, b, c). The effect of embolism is in gen- eral the more or less complete obstruction of the vessel, partly through the embolus itself, partly through an associated coagulation of the blood. As a result of such obstruction there is an interference with the circulation, which may vary greatly in different cases, in that behind the point of obstruction there may be established either a complete or partial compensatory circulation, or in other cases such a compensation may be en- tirely wanting. When the compensa- tion is incomplete or wholly absent, the area of tissue supplied by the ob- structed vessel undergoes degeneration or dies. Both lymphogenous and hemato- genous metastasis usually occur in the direction of the normal current, but under special conditions a transporta- tion in the opposite direction may take place — retrograde metastasis. Such a change of current in the lymph-vessels occurs when the normal escape of lymph from the region involved is hindered through stoppage of lymphatics, and the lymph is forced to seek other outlets. A similar condition may occur in circumscribed areas of the peripheral blood- vessels. In this way clots arising in the right heart or in the large veins of the body may be transported into the peripheral veins ; par- ticularly under conditions in which there occur backward waves of blood which gradually force the clots back into the smaller veins. According to the experimental investigations of Arnold upon dogs, foreign bodies (wheaten grits), which were too large to pass the capil- laries, when introduced into the jugular or craral veins, as well as into the longitudinal sinus of the dura mater, were carried by retrograde metastasis not only into the main trunks, but also into the smallest branches of the veins of the liver, kidneys, heart, extremities, dura mater, pia mater, and orbit, as well as into the posterior bronchial veins. In the case of a defect in the septum of the heart, bodies circulating in the blood may pass directly from one side of the heart to the other, and thereby give rise to a crossed or paradoxical embolism. § 21. The substances which may be transported in the process of metastasis may be conveniently divided into six groups, this classifica- tion being based partly upon the origin, partly upon the character of the transported body, and partly upon the effects of the metastasis. In the first group are placed insoluble lifeless substances composed of very small particles, which enter the body from without, and which may be designated collectively as dust. The majority of these substances enter the body in the respired air, and pass from the lungs into other tis- sues. A smaller part may enter the tissues directly through accidental or intentional wounds (tattoo). Most frequently these substances are particles of soot, coal- and stone-dust, more rarely metal, porcelain, to- 5 60 THE GENERALIZATION OF DISEASE. baceo, hair or other kinds of dust. In tattooing of the skin, lampblack, india-ink, ultramarine, cinnabar, and other granular pigments are used. The behavior of the tissues of the body toward such substances -will be treated of elsewhere ; it is only necessary to mention here that these forms of dust, sometimes in a free state, sometimes enclosed within cells, are deposited first in the tissues nearest the point of entrance, further in the lymph-vessels and lymphatic glands. In the latter location they may remain for a life-time ; but in cases of excessive deposit they may be carried beyond the lymph-glands, especially in those instances in which the glands, because of the great deposit, undergo softening and give rise to inflammation and proliferation of the tissues in their neigh- borhood. Very often as a result of such changes the affected glands be- come confluent with and break into neighboring veins. This event is es- pecially likely to happen at the hilum of the lungs, whereby the contents of the gland ultimately, sometimes slowly, at other times more rapidly, gain entrance to the vessel-lumen and are carried away by the blood- stream. In the case of the lungs, dust may be deposited directly in the vessel-walls and gradually penetrate as far as the intima. Further, the particles from a broken-down lynipk-gland can again enter the lymph- stream, and, if not again arrested by some lymphatic glaud, may reach Fig. 3- Fat-embolism of the lungs (Flemming's solution, safranin). a. Arteries tilled with blackened masses of fat ; b, fat-droplets in capillaries ; c, veins ; d, cells in the alveoli. X 1(X). the blood-stream. It is also conceivable that softened lymph -glands may break directly into the thoracic duct. As numerous experiments have shown, the dust gaining entrance to a blood-vessel remains but a very short time in the circulation. Large amounts artificially introduced into a vein disappear in a few hours from the circulating blood. The greater part collects in the capillaries of the liver, spleen, and bone-marrow, partly free and partly within leucocytes, in the former case adhering to the surface of the endothelium. After a short time the leucocytes containing the dust particles wander out from the vessels, so that the dust collects more and more in the tissues, where it is held for a long time, partly in wandering-cells, partly in fixed cells, METASTASIS AND EMBOLISM. 07 and partly free, and under certain conditions may remain here during the lifetime of the individual. In the mean time a part is carried in the lymphatics to other regions and there deposited, particularly in the por- tal and coeliac lymph-glands. According to the researches of Kunkel and Siebel, still other cells containing dust-particles may reach the surface of the body-cavities, either through the capillaries of the lungs, the paren- chyma of the tonsils, and probably also from the lymphoid tissue of the intestines, and in this way be discharged externally. From the liver the dust -particles may be passed out in the bile. According to observations which may be not infrequently made on inflamed organs, wandering leucocytes are able to take up a great number of the particles lying in the tissues and transport them from the lungs, intestinal tract, and other organs to the surface, and in this way clear the tissues. The second group is composed of portions of the body itself, which occasionally may be transported through the blood-stream; namely, tissue-detritus, parenchymatous cells, and dead, coagulated, and broken-up constituents of the blood. Of the elements arising from the destruction of tissue, fat-droplets (Fig. 3, a, b, and Fig. 4, a, b) most often find their way into the circulation; particularly when through trauma or some other pathological process, as, for example, haemorrhage, the tissues are destroyed. This occurs most frequently in cases of crush- ing, destruction, and violent agitation of fat-tissue, as may happen in the case of the different panniculi adiposi and the bone-marrow ; but fat may also enter the circulating blood through destruction of liver-tissue. The parenchymatous cells most frequently entering the circulation are liver-cells, syncytial placenta-cells, portions of chorionic villi, and bone- marrow cells. Ordinarily these are carried into the pulmonary arteries and capillaries, but through retro- grade metastasis they may be carried into the veins, and through paradoxical embolism into the ar- teries and capillaries of the system- ic circulation. Embolism of liver- cells and bone-marrow giant-cells is caused by traumatic and toxic in- juries and hemorrhages of the affected tissues. Placental - cell emboli, in the form of syncytial giant - cells, have been observed especially in puerperal eclampsia, but occur also in the course of normal pregnancies. Pulmonary emboli of small portions of the chori- onic villi have also been observed. In diseased conditions of the intima of the heart or blood-vessels, degenerated endothelium, broken-down and degen- erated masses of connective tissue of the intima, portions of the valves, and material of similar nature may gain entrance to the blood-stream. Frag- ments and disintegrated portions of blood-corpuscles may enter the circula- tion from hemorrhagic foci or may arise within the vessels themselves, in the case of degenerative changes produced in the blood through the influence of various harmful agents. Coagulated masses of blood enter the circulation when a thrombus — i.e., blood coagulated in the vessels (see Chapter IV. ) — breaks loose, either in toto or in fragments. The fate of the last-named substances is for the chief part dependent Fig. 4.— Fat-embolism of the kidney (Flernming's solution, safranin). a. Glomeruli with lat in the capillaries ; h, fat-droplets in the intertubular capil- laries. X 100. 68 THE GENERALIZATION OF DISEASE. upon their size and physical properties. All fragments of much greater diameter than the lumen of the capillaries become lodged in the bifurca- tions of the arteries (Fig. 2, a, b) and usually occlude the same. This occurs most frequently in the case of dislodged thrombi or of fragments of such ; on the other hand, fat-droplets usually pass into the capillaries, where part remain, while others pass through and later become lodged in some other place. Since the fat occasionally passes first into the veins of the body and thence to the heart, the fat-droplets collect, especially in the capillaries of the lungs (Fig. 3, b) ; but they may also pass through the lungs into the capillaries of the greater circulation, and are then found especially in the intertubular and glomerular capillaries of the kidneys (Fig. 4, a, b), and also to some extent in the capillaries of other organs. Capillary fat-embolism causes a noticeable disturbance of the circulation only when of extensive occurrence; iu this case it may lead to the production of oedema of the lungs. Furthermore, the fat disap- pears in the progress of metabolism, or is conveyed into the neighboring tissues. Parenchymatous cells (in so far as the entrance into the circulation of small living cells of the character of lymphocytes and myelocytes is not concerned) become lodged in the capillaries or smaller arteries iu the case of arterial metastasis. The latter is especially true of liver-cells when entering the circulation en masse. At the place of lodgment their presence may lead to a heaping-up of blood-plates and a hyaline coagula- tion. The cells themselves do not multiply, lint they may remain pre- served for a certain length of time, according to Lubarsch, as long as three weeks. They then gradually die, the protoplasm dissolves, the nuclei swell or shrink, and finally lose their chromatin. The point of lodgment of loosened thrombi or fragments of thrombi depends upon the path which they take, as well as upon their size. Since thrombi may be formed in the systemic veins, right heart, and pulmonary arteries, as well as in the pulmonary veins, left heart, and systemic arteries (see Chapter IV. ), it is possible for embolism to occur in any of the arteries of the greater or lesser circulation. Very often the emboli iodge at the bifurcation of arteries, forming the so-called riding or straddling emboli (Fig. 2, e). Through retrograde metastasis emboli may be carried from the vewe cav;e or larger veins into the smaller veins. Defects in the septum of the heart may lead to the pro- duction of a paradoxical embolism. Small fragments of thrombi, dead red blood-cells or fragments of such, endothelial cells undergoing disintegration or fatty degeneration, etc., meet the same fate as dust-particles. They may remain free or be taken up by cells; they are soon removed from the circulation and col- lect especially in the spleen, liver, and bone-marrow, where they un- dergo further changes and are destroyed. The products resulting from the destruction of red blood-cells may persist for a long time in the or- gans named, as colored deposits. The third group of substances producing metastases is composed of living cells, which, originating from proliferating tissue=foci and hav- ing gained entrance to the circulation through direct rupture into the blood-vessels, or having entered the lymphatics, are carrried to other or- gans. This process may be observed in the case of tumors growing by infiltration. The metastasis of living cells from such a tumor leads through 1 he proliferation of the transported tumor-cells to the produc- tion of metastatic daughter-tumors, which in the case of lymphogenous METASTASIS AND EMBOLISM. 69 metastasis develop first in the lymph-vessels and lymph-glands, bnt in the ease of direct rupture int. the blood-vessels arise in that part of the vascular system to which the tumor-cells are carried by the blood. The metastasis usually occurs in the normal direction of the blood- and lymph- streams, but retrograde transportation may also occur', whereby a tumor which has broken into one of the systemic veins may give rise to metas- tases in the region drained by smaller branches of other systemic veins. Retrograde metastasis is not infrequently observed in the lymphatic sys- tem, when closure of the efferent lymph-channels has produced a change in the direction of the lymph-current. In the fourth group may be placed all those processes characterized by the entrance of vegetable or animal parasites into the circulation. If under such circumstances these organisms do not find conditions suit- able for their development, they are quickly eliminated from the blood- stream and destroyed under the influence of metabolic processes. But if they are able to reproduce themselves anywhere, they will give rise to the production of metastatic foci of infection, which are located partly in the vascular system, but also partly extending thence into the neigh- boring tissues. The secondary foci in the case of bacterial invasion have in general the same character as that of the primary. If an em- bolus contains organisms capable of producing tissue-necrosis, inflam- mation, and putrid decomposition, there will occur, along with the embolism and the accompanying disturbances of circulation, suppuration and sloughing — that is, there will be a repetition of the same processes occurring at the original seat of infection. As the fifth group of metastatic processes may lie classed together those cases in which constituents of the human body having under- gone solution are transported in the soluble state and again deposited in a solid form ; and also those in which extrinsic substances are taken up by the body in a soluble form and are then deposited in the tissues in a solid state. Of the first class there occurs most frequently the entrance of bile-pigment into the circulation within the liver, so that this may permeate through the most varied tissues, and give to them a yellowish color (icterus). Not infrequently iron-containing derivatives arising from the destruction of red blood-cells in the circulation are carried to the spleen, bone-marrow, live]-, ami kidneys and form there pathological deposits of iron (hsematogenous siderosis). Fat can be split off from the fat depots in the form of soluble soaps and carried through the blood to different organs where it is again taken up by the cells and changed into neutral fat. When preparations of silver are, for medicinal purposes, introduced into the body through the gastro -intestinal tract for long periods of time, there may occur a deposit of fine granules of silver in the connective tis- sue of the skin, in the glomeruli, medullary pyramids of the kidneys, intima of the large arteries, adventitia of the small arteries, in the neigh- borhood of mucous glands, connective tissue of the intestinal villi, in the choroid plexus of the cerebral ventricles, and in the serous membranes. Tissues showing such a deposit have a grayish-brown color. The fact that the epithelial tissues and the brain are not affected shows that there is a selective action on the part of the tissues, and that this selective action differs essentially from that which is seen in the case of a metastatic deposit of corpuscular elements. It may therefore be as- sumed that the chemico-physical character and the functional activity of the tissues coming into contact with substances in solution exert a deter- 70 THE GENERALIZATION OF DISEASE. mining influence upon the separation and precipitation of .such sub- stances. As a sixth, group of metastatic processes may be classed the entrance of air into the circulation. If in any manner a large amount of air gains entrance to the right heart, an event which occurs especially in case of injury to the large veins lying in the neighborhood of the thoracic cavity, or more rarely from the opening of a vein, for example, of a stomach- vein, through ulcerative processes, the air mingling with the blood forms a foamy mass, which the contractions of the heart are scarcely able to drive onward. As a result the left heart receives little or no blood, the aortic pressure falls, and the affected individual quickly dies. Should the air enter the circulation in small amounts or intermit- tently, it may be carried by the blood-stream in form of air-bubbles and circulate through the entire body. Larger amounts may lodge for a time in the vessels of the major or minor circulation, obstruct their lumen, and cause disturbances of the circulation, which may give rise to func- tional disturbances of the brain and respiration. If these conditions do not cause death, the air is after a time absorbed. If the lung-tissue be ruptured through trauma or through violent coughing, screaming, or vomiting, etc., air may be forced into the con= nective=tissue spaces and lymphatics, and may extend through these into all parts of the lungs, pleurae, and the mediastinum, as well as into the skin. The conditions thus produced are termed emphysema of the skin, of the subcutaneous tissue, of the mediastinum, etc. Under cer- tain circumstances the air may spread through a large area of the sub- cutaneous lymph-vessels and connective-tissue spaces, whereby the skin presents an inflated appearance and when pressed upon produces a crackling sound. According to Siebel and Kunkel, granules of cinnabar and indigo injected into the blood-stream of a frog are quickly taken up by leucocytes, and after one to two hours no more free granules are to be found in the circulating blood. After twenty-four hours the leucocytes containing pigment-granules have disappeared from the circula- tion, and lie for the greater part clumped together in the capillaries, the greatest num- bers being found in the capillaries of the spleen, liver, bone-marrow, and the lungs, while they occur in smaller numbers in the capillaries of the kidneys, and in still smaller numbers in the capillaries of the heart-muscle. Even after two hours free pigment and cells containing granules are found outside of the vessels, and after a few days they have almost wholly disappeared from the ves- sels. The granules lie then partly in -wandering-cells, partly in fixed cells, as well as in the free cells of the splenic pulp (Ponflck) and bone-marrow. They may be found in these organs for weeks afterward (Hoffmann, Langerhans). In both frogs and dogs some of the granule-eontainiug cells find their way into the lumen of thealveoli and bronchioles and so pass out of the body. In the liver the pigment-particles for the greater part adhere for a short time to the endothelium of the liver-capillaries and may be taken up by the endothelial cells ( Browicz, Heinz) ; another part is found in leucocytes, which later wander out from the vessels into the tissues. Thence they are for the greater part taken up into the lymphatics of the liver and ultimately reach the lymph-glands. A part of the granules finally pass out with the bile, but by what course they reach the bile-vessels is not known. In dogs the pigment-granules also collect in the tonsils and are carried to the surface through the epithelium by the leucocytes which have taken them up. According to the observations of Jadassohn (" Pigmentverschleppung aus der Unut," Airh.f. Derm., 24 Bd., 1892) and Schmorl(" Pigmentverschleppung aus der Haut," Gentralbl. f. allg. Path., 4Bd., 1893), both normal and pathological pigment may be transported from the skin to the lymph-glauds— in other words, a. pigment-metastasis may take place. According to Leioin (Arch. f. exp. Path., 40 Bd., 1897), if the outflow of urine from the bladder be hindered, small foreign bodies can pass into the kidney-pelves, and thence into the urinary tubules, lymph-vessels, and veins, and into the general circula- tion. METASTASIS AND EMBOLISM. 71 Literature. (Metastasis of Bust.) Arnold, J. : Staubinhalation u. Staubmetastasen, Leipzig, 1885; Die Geschicke des eingeathmeten Metallstaubes im Korper. Eeitr. v. Ziegler, viii. , 1890. Browicz: Phagocytose der Lebergefassendothelien. A. f. mikr. Anat., 58 Bd., 1902. Buxton: Absorption from the Peritoneal Cavity. Journal of Medical Research, 1907. Heinz: Phagocytose der Lebergefiissendothelien. A. f. mikr. Anat., 58 Bd., 1901. v. Kupffer; Sternzellen der Leber. Munch, med. Woch., 1899. MacCallum: Absorption from the Peritoneum. Johns Hopkins Hospital Bulletin, xiv., 1903. Muscatello: Aufsaugungsvermijgen d. Peritoneum. Virch. Arch., 142 Bd., 1895. Oekonomides: Ueber diechronischen Bronchialdrusenaffectionen. Inaug. -Diss., Basel, 1882. Ponfick: Ueber die Shicksale korniger Farbstoffe im Organismus. Virch. Arch., 48 Bd., 1809. v. Recklinghausen: Virch.. Arch., 28 Bd. ; Allgem. Pathol, d. Kreislaufs, Stuttgart, 1883. Siebel: Ueber das Schicksal von Fremdkorpern in der Blutbahn. Virch. Arch., 104 Bd., 1886. Sticker: Staubkrankheiten. Eulenburg's Realencyklop., xxiii., 1900 (Lit.). Sulzer: Durchtritt corpuscul. Gebilde durch d. Zwerchfell. Virch. Arch., 143 Bd., 1896. Weigert: Kohlenstaubmetastase. Fortschr. d. Med., i., 1883. Weintraud: Ueber Kohlenstaubmetastase. Inaug. -Diss., Strassburg, 1889. (Embolism of Fat and of Parenchymatous Cells. ) Arnold: Uebertritt v. Knochenmarkzellen ins Blut. Virch. Arch., 140 Bd., 1895. AschofF: Capillare Embolie von riesenkernhaltigen Zellen. Virch. Arch., 134 Bd., 1893. Beneke: Fettembolie. Beitr. v. Ziegler, xxii., 1897. Colley: Fettembolie nach gewaltsamer Gelenkbeugung. Zeitschr. f. Chir. , 36 Bd., 1893. Ebstein: Lipamie u. Fettembolie bei Diabetes. Virch. Arch., 155 Bd., 1899. Flournoy: Contrib. a l'etude de l'embolie graisseuse, Strassburg, 1878. Graham: Fat Embolism. Jour, of Med. Research, 1907. Haemig: Fettembolie des Gehirns. Beitr. v. Bruns, 27 Bd., 1900. Hamilton: Lipajmia and Fat Embolism. Edinburgh Med. Journal. 1879. Hess: Beitr. z. d. Lehre v. d. traumatischen Leberrupturen. Virch. Arch., 121 Bd., 1890. Jurgens: Fettembolie u. Metastase v. Leberzellen. Tagebl. d. Naturf.-Vers. in Ber- lin, 1886. Klebs: Multiple Leberzellenthrombose. Beitriige v. Ziegler, iii., 1888. Leusden: Puerperale Eklampsie. Virch. Arch., 142 Bd., 1895. Lubarsch: Parenchymzellenembolie. Fortschr. d. Med., xi., 1893; Zur Lehre von den Geschwulsten u. Infectionskrankheiten, Wiesbaden, 1899. Maximow: Parenchymzellenembolie. Virch. Arch., 151 Bd., 1898. v. Recklinghausen: Allgem. Pathologie d. Kreislaufs, Stuttgart, 1883. Ribbert: Fettembolie. Oorrespbl. f. Schweizer Aerzte, 1894. Schmorl: Embol. Verschleppung v. Lebergewebe. Deut. Arch. f. klin. Med., 42 Bd., 1888; Organbefunde bei Eklampsie. Cent. f. allg. Path., ii. ; Enters, lib. Puerpe- raleklampsie, Leipzig, 1893. Scriba: Fettembolie. Deut. Zeitschr. f. Chir., 1879. Turner : Hepatic Cells in the Blood. Trans, of the Path. Soc. of London, 1884 Virchow: Berl. klin. Woch., 1886, No. 30; Virch. Arch., 5 Bd. ; Ges. Abhandlungen, 1856. Warthin: Pulmonary Emboli of Liver-cells and Bone-marrow Giant-cells. Med. Mews, 1900. Zenker • Schussverletzungd. Leber mit Verschleppung v. Lebergewebe. Deut. Arch, f. klin. Med., 42 Bd., 1888. 72 THE GENERALIZATION OF DISEASE. (Retrograde and Paradoxical Metastasis.) Arnold: Ueber ruckliiuflgen Transport. Vircli. Arch., 124 Bel., 1891. Bonome: Trasport.o retrograde degli emboli e embolia croeiata. Arch, per le Sc. Med., xiii., 1889. Bouma: Retrograder Transport im Venensystem. Virch. Arch., 171 Bd., 1903. Cohn: Klinik der embolischen Getasskrankbeiten, Berlin, 1860. Cohnheim: Vorlesungen i'lber allgemeine Pathologic, Berlin, 1882. Ernst: Rucklauf. Transport in Herz- u. Lebervenen. Virch. Arch., 151 Bd., 1898. Hauser: Embol. Verschleppung v. Thromben a. d. r. Herzen in Kijrperarterien. Munch, med. Woch., 1888. Lui: Due casi di embolia retrograda. Arch. p. le Sc. Med., xviii., 1894. v. Recklinghausen: Venose Embolic u. retrograder Transport. Virch. Arch., 100 Bd., 1885. Ribbert: Retrograder Transport im Venensystem. Cbl. f. allg. Path., 1897. Schmorl: Leberruptur mit embol. Verschleppung v. Lebergewebe. Dent. Arch. f. klin. Med., 42 Bd., 1888. Vierth: Rucklaufige Metast. in den Lymphbahncn.' Beitr. v. Zicgler, xviii., 1895. Vogel :. Retrograde Metastase innerh. d. Lymphbahu. Virch. Arch., 125 Bd., 1891. Zahn: Paradoxe Embolic. Vircli. Arch., 115 Bd., 1889; Geschwulstmetastase, ib., 117 Bd., 1890. (Air Embolism.) Couty: Etude exper. sur 1'entree de Fair dans les veines. Gaz. med. de Paris, 1876. Bamsch: Ueber Unterhautemphysem bei Bronchopneumonie. Deut. med. "Woch., 1891. Fischer: Lufteintritt in die Venen walirend eincr Operation. Deut. C'hir. , Lief. 18, 1885. Frantzel: Unterhautemphysem bei Erkrank. d. Respirationsapparates. Deut. med. Woch.. 1885. Hare: Entrance of Air into Veins. Therapeutic Gaz., 1889; Amer. Jour, of Med Sc., 1902. Hauer: Erscheinungen im gr. u. kl. Kreislauf bei Luftembolie. Zeit. f. Heilk., xi., 1890. Heller, Mager, u. v. Schrbtter: Arterielle Luftembolie. Zeit. f. klin. Med.,33Bd., 1897. Husemann: Luftembolie. Eulenburg's Jahrb., viii., 1899. Jiirgensen: Lufteintritt in d. Venen. Deut. Arch, f. klin. Med., 31 Bd. ; Luft im Blute, ib.. 41 Bd., 1887. Panum: Exper. Beitriige zur Lehre von der Embolic. Virch. Arch., 25 Bd., 1862. Passet: Ueber Lufteintritt in die Venen. Arbeiten a. d. path. Institut zu Munchen, 1886. Senn: Entrance of Air into Veins. Trans. Amer. Surg. Assn., 1885. Wolf: Luftembolie. Virch. Arch., 174 Bd., 1903. III. The Sequelae of Local Organic Disease. § 22. Secondary diseases which arise as the results of patho= logical conditions of individual organs occur with great frequency as the result of pathological changes in the blood and circulatory apparatus. The circulatory apparatus and the blood therein contained bear cer- tain relations to all the body-tissues, and accordingly diminution in amount and pathological alterations of the blood, as well ax changes in the blood-vessels, often give rise to diseased conditions of (his or that tissue or of the entire organism. If the haemoglobin- content of the blood is decreased through a diminution in number of the red blood-cells (oligocythsemia), or through a pathological condition of the same, or if the haemoglobin through the action of carbon monoxide is rendered in- capable of taking up the oxygen of the air, the body-tissues will no longer receive a normal amount of oxygen ; consequently there will arise, in case the amount of oxygenation falls below a certain point, disturb- THE SEQUELS OF LOCAL DISEASES. 73 ances of nutrition, as the results of which there occur very frequently conditions of fatty degeneration, and under certain circumstances death through paralysis of the nervous centres. Should an artery become narrowed or closed through thrombosis or em- bolism, or thickenings of its trails, as in the case of the arterial disease known as arteriosclerosis, there will arise in the region supplied by the affected vessel a local deficiency of food supply and oxygen, local as- phyxia, and later degenerative processes, which frequently end in the death of the specific parenchymatous elements, at times also of the con- nective-tissue framework. In the brain and spinal cord the vessel -changes lead to ischemic proc- esses of softening, which frequently result in paralysis, and not rarely in death. In the heart there results a diffuse fatty degeneration or local softening of the heart-muscle, giving rise to disturbances of cardiac ac- tivity or often even to complete insufficiency. In the kidneys the secret- ing glandular parenchyma, together with a portion of the connective tissue, undergoes necrosis or atrophy ; and the loss of these substances gives rise to local or widespread contractions, which, according to their origin, are designated as embolic or arteriosclerotic atrophies. In the stomach ischsemia of the mucous membranes gives rise to local ulcerations; in the liver and muscles to atrophic conditions. No tissue can withstand the harmful effects of a long-continued anaemia, and con- sequently the narrowing and closure of arteries, through the formation of clots or through changes in the vessel-walls, play a very important role in pathology; and are not only the causes of anazmic necrosis (see Chapter V.) and hemorrhagic infarction (see Chapter IV. ), but also of numerous progressive atrophies of organs. In the pathogenesis of the last named, arteriosclerosis has an especially important part, since in old age it is of very common occurrence, and gives rise to tissue-degenera- tions in organs of the most different structure. As evidences of such degenerative processes, the majority of the affected organs show later areas of scar-tissue, in which the specific parenchyma has disappeared while the connective tissue has increased. The active participation of the vascular apparatus in all inflamma- tory processes (see Chapter VII. ), the disturbance of circulation through the alteration of the vessel-walls, the shifting and changes of the vascular channels which result from the closure of old vessels by proliferation of en- dothelium or through thrombosis, as well as from the formation of new vessels, make easily comprehensible the fact that in all chronic inflamma- tions the specific cells dependent upon a regulated nutrition undergo degeneration and are frequently replaced by connective tissue of a lower grade than normal. A profuse watery discharge from the intestines may deprive the or- ganism of water.. If, as a result of stenosis of the oesophagus or pylorus, a sufficient amount of food is prevented from entering the intestinal tract, or if the stomach and intestine are no longer able to digest the food brought to them and to prepare it for assimilation into the body juices, the organism as a whole becomes poorer in albumin and fat. If the heart is no longer able to force onward with normal strength the blood coming to it, there will arise in various organs changes due to venous stasis. If the respiration is hindered or imperfect, the composi- tion of the blood suffers changes. Collection of fluid in the thoracic cavity causes compression of the lungs; interference with expiration, with free inspiration, leads first to distention of the lung and later to 74 THE GENERALIZATION OF DISEASE. atrophy. If a part of the lung has been rendered useless by chronic in- flammation, the inspiratory enlargement of the thorax affects only that portion of the lung which is capable of functionating, and this part be- comes over-distended and in consequence finally atrophic. Diseases of the parenchyma of the liver often give rise to disturbances of the circulation of blood through the organ, and stasis throughout the portal circulation with resulting ascites. Should the pancreas be de- stroyed or if it is no longer able to produce its ferments (proteolytic trypsin, amylolytic diastase, and the fat-splitting and emulsifying steap- siu) there results an imperfect metabolism of albumin, carbohydrates, and fat. Hindrance to the outflow of urine from the ureters renders difficult the secretion of the kidneys and leads to their atrophy. The loss of a, large portion of the renal parenchyma is followed by increased blood-pressure in the aorta, increased action of the heart, and hypertrophy of that organ. An increased resistance in the pulmonary circulation due to diseased con- ditions of the lungs is often followed by dilatation and hypertrophy of the right heart. Obstruction to the flow of blood through the aortic opening leads to hypertrophy' of the left ventricle. Stenosis and insufficiency of the mitral valve cause a stasis of blood backward through the lungs to the right heart. This may be compensated for through hypertrophy of the right ventricle, or may extend farther back into the veins of the sys- temic circulation. An oblirpie position of the pelvis leads to curvature of the spine. Stiff- ness and immovability of a joint cause atrophy of the muscles moving the joint, the atrophy being due to inactivity. Diseases of the nervous system may give rise to functional disturbances and anatomical changes in any organ of the body — in glands, muscles, skin, bones, lung, heart, intestine, etc. These changes are to be referred partly to stimulation, partly to inhibition or arrest of nervous impulses, and partly to amesthesia (anaesthetic tissues being especially liable to in- jury). Destruction of the large ganglion-cells in the anterior horns of the spinal cord leads to the atrophy of the corresponding peripheral nerves and muscles. Paralyzed extremities become atrophic. Diseased condi- tions in the region of the respiratory and vasomotor centres lead to dis- turbances of respiration and circulation. After injury to certain por- tions of the medulla oblongata, after concussion of the brain and spinal cord, through the presence of tumors in the brain, after psychical affec- tions, after poisoning of the nervous system, there is caused under certain conditions a rapid withdrawal of the glycogen of the liver into the blood- stream and the excretion of sugar in the urine. Stimulation of periph- eral nerves may produce abnormal reflex sensations and movements as well as circulatory disturbances in other parts of the body. Paralysis of both vagi or of their branches, the recurrent laryngeal nerves, through inflammatory changes or through pressure from neighboring lymph- glands, etc., may be followed by inflammation of the lungs, in that the accompanying paralysis of the laryngeal muscles favors the entrance of foreign bodies into the lungs during inspiration. The so-called trophoneurotic diseases of thetissues are not mentioned above, for the reason that the trophic relations of the nervous system to the individual tissues arc not yet clear, and the views of different authors as to the dependence of the tissues upon the nervous system vary greatly. Many authors ascribe to the trophic action of the nervous system a far-reaching influence upon the conditions of the tissues, and seek the nerves forming the connections with the nerve-centres, partly in the motor, secretory, AUTOINTOXICATION. 75 sensory, and reflex nerves, as well as in special trophic nerves. Thus, for example, muscular atrophy, glandular atrophy, atrophy of the bones and joints (in tabes and syringomyelia), different pathological conditions of the skin characterized by thinning, exfoliation of the epithelium, loss of hair, inflammations, etc., unilateral tissue- atrophies, necroses, also hypertrophic proliferations of muscles, glands, skin, or bones, etc., are all referred to affections of the nerves. It cannot be doubted that both degenerative and hypertrophic tissue-changes and inflammations often occur as sequent to disturbances of innervation, but these most probably are not the direct result of the removal or change of nerve-influences affecting the tissues, but are rather the results of increased or decreased functional activity of the tissue, or of injuries, inflammations, or disturbances of circulation, which have de- veloped in connection with the disturbances of innervation — for example, in connection with the loss of sensibility. Golz and Ewald, after completely destroying the thoracic and lumbar portions of the spinal cord of dogs, were able through great care to pre- serve uninjured the skin of the animals thus operated upon ; they are, therefore, op- posed to the theory of the existence of trophic centres and nerves. Literature. {Trophoneurotic Tissue -changes. ) Baldi: Action trophique du systerne nerveux. Arch. ital. de biol., xii., 1889. Charcot: Lecons sur les maladies du systerne nerveux. (Euvres completes, i.-iii. Dejerine et Leloir: Alter, nerv. dans cert, cas de gangrene. Arch, de phys., 1881. Durdu.fi: Exp. Unters. z. Lehre v. d. trophischen Nerven. Cbl. f. allg. Path., v., 1894. Frankel: Neurotische Angiosklerose. Wien. klin. Woch., 1896. Golz u. Ewald: Hund mit verkurztem Rl'ickenmark. Pfluger's Arch., 63 Bd., 1896. Harbitz: Oni de patologisk-anatom. Forundringer af neurotrofisk oprindelse, Chris- tiania, 1900. Hochenegg: Ueber symmetrische Gangriln, Wien, 1886. Joseph: Neurotische Hautgangritn. Arch. f. Derm., 31 Bd., 1895. Kopp: Trophoneurosen der Haut, Wien, 1886. Kriege: Vasomot. Storungen d. Haut bei traumat. Neurosen. Arch. f. Phys., 22 Bd., 1890. Leloir: Rech. clin. et anatomo-pathol. sur les affections cutanees d'origine nerveuse, Paris, 1883. Pitres etVaillard: Gangrenes massives d'origine nevrotique. Arch, de phys., v., 1885. v. Recklinghausen: Allg. Pathol, des Kreislaufs und der Ernuhrung, Stuttgart, 1883; Multiple Fibrome d. Haut, Berlin, 1882; Akromegalie. Virch. Arch., 119 Bd., 1890. Rosenbaum: Symmetrische Asphyxie. Eulenburg's Jahrb., ii., 1892. Schlesinger: Syringomyelic, Wien, 1895. Schwimmer: Die neuropathischen Dermatosen, Leipzig, 1883. Springer: Dactylite hypertrophique symetrique. Rev. denied., vii., 1887. Weir Mitchell: Des lesions des nerfs et de leur consequences, 1874. Ziegler: Ursachen d. pathol. Gewebsneubildungen. Internat. Beitr. Festschr. f. Vir- chow, ii., Berlin, 1891. IV. Autointoxications and Disturbances of Internal Secretion. § 2.3. Autointoxication or self-poisoning may take place in a variety of ways. In the first place, poisonous products of metabolism of normal character and produced in normal amounts may fail of proper ex- cretion, and, being carried over into the juices of the body, may be retained in the same. Secondly, the physiological production of poisonous substances may be pathologically increased. Thirdly, it may happen that poisonous products of metabolism, which normally are decomposed and thereby rendered harmless, may, as a result of a local or general meta- bolic disturbance, escape such destruction, Finally, it may also happen that, as the result of pathological changes or cessation of the functional 7G THE GENERALIZATION OF DISEASE. activity of certain organs, poisonous substances may appear in the blood eriods of fever, each paroxysm having an initial period, a fastigium, and a defervescence. In the infectious disease known as febris recurrens there is first a continuous fever, which after a few days falls by crisis ; after about a week or so a second rise of temperature occurs, which may be followed by a second stage of apyrexia, and thisbyathird period of fever. Many diseases — such as typhoid fever, pneumonia, measles, relapsing FEVER. 93 fever, etc. — are characterized by a typical temperature-curve ; others — as pleuritis, endocarditis, diphtheria, tuberculosis, phlegmon, etc. — have no typical course of fever. The elevation of the body=temperature in fever is dependent pri- marily on an inn-case in heat-production through increase of the chemical changes occurring in the body. The respiratory interchange of gases — the excretion of carbonic acid and the taking-up of oxygen — is increased, a proof that the oxidation-processes and with these also the heat-produc- tion are increased. At the same time the excretion of nitrogenous elements in the urine (urea, uric acid, creatinin) is increased — on the average about from seventy to one hundred per cent, under certain conditions even as much as threefold. There is also an increased destruction of the albu- minoid substances of the body, the albumin of the organs, even in the latent period of the fever. The increase of heat-production varies in different fevers, but in gen- eral does not reach that degree which can be produced by excessive muscle-action and over-feeding with albumin. It is at its highest point at the time of the initial chill, in that the violent muscular contractions thereby produced may increase the production of heat. The second cause of the elevation of the body-temperature is deficient heat-dispersion. At the height of the fever the patient as a rule gives off more heat than the normal individual, but this dispersion is not suffi- cient to offset the excessive heat-production. Heat-production is con- stantly increased ; heat-dispersion is irregular. In the initial stage the cutaneous vessels are contracted as a result of stimulation of the vasomotors, the skin is pale, the heat -dispersion slight, nude]' certain conditions even less than normal. Chills occur when, through the contraction of the peripheral arteries, the supply of blood, and consequently the heat-supply, to the cutaneous nerves is suddenly diminished, while in the interior of the body the tem- perature is rising. In the second stage of fever the skin is often hot and reddened, and in certain diseases sweating occurs; but the increased heat-dispersion thereby produced is not sufficient to lower the temperature to the uor- mal. The increased excitability of the vasomotors or the deficient irri- tability of the vaso-dilators is also present during this period, and as a result the skin-temperature, as well as the heat-dispersion, varies greatly. The skin is at times pale and cold, at other times red and hot, and the hands may be cold while the trunk is hot. The centres governing heat- dispersion are therefore acting faultily. In the period of defervescence the relations of heat-dispersion and heat -production are changed in favor of the former. The cutaneous ves- sels become dilated, the skin gives out a great amount of heat from the abundance of blood circulating through it, and when the critical fall of the fever occurs there is usually profuse sweating. The cause of fever is not known with certainty, yet this much can be said, that fever is most frequently the result of the entrance of a harmful agent into the fluids of the body. In many cases this harmful agent arises demonstrably from a local focus— for example, from erysipelatous and phlegmonous inflammations of the skin. Experimentally, fever may be produced by very different procedures — for example, through the infu- sion into the vessels of an animal of blood from one of another species, through the injection of animal or vegetable substances that are begin- ning to decompose, and through numerous infections. In man, the infec- 04 THE GENERALIZATION OF DISEASE. tious diseases, which are regarded as due to specific micro-organisms mul- tiplying in the body, are in particular characterized by fever. It is probable that the parasites multiplying within the body cause an increased tissue -destruction, either directly or through the production of unformed ferments, and that at the same time substances are produced which act as poisons upon the central nervous system. The action of the latter may be assumed to be of such a nature that, on one side, the activity of the muscles and glands, and consequently the heat-producing metabolism, are increased; while, on the other hand, through the dimin- ished and disturbed functions of the nerves governing sweating, as well as of the vasomotors, the processes of heat-dispersion fall behind those of heat-production. Further, though the organism makes an effort to regulate the temperature, it is no longer able to maintain it at the nor- mal level, because of the disturbances of the regulating apparatus. What share in the increase of body-temperatnre is due to the direct ac- tion of bacteria and of the ferments formed by them, or what share is due to the increase of metabolism, through the stimulation of the nerves as well as by disturbance of heat-dispersion, cannot at present be deter- mined. It is, however, certain that the factors vary in different cases. That under certain conditions, changes in the nervous system without contamination of the tissue-juices are in themselves sufficient to cause a feverish increase of temperature, is shown by the fact that fever may occur in epileptic attacks, in the periods of excitation occurring in the course of progressive paralysis, after severe frights, after the passage of a catheter into the bladder, etc. According to the investigations of liichet, Aronsohn, and Sachs, a marked increase in body-temperature with increase of the respiratory interchanges of gases and increased ex- cretion of nitrogen (Aronsohn and Sachs) may be produced in animals by a puncture which passes through the cerebral cortex and strikes the corpus striatum. The same phenomenon may be produced also by elec- trical stimulation (Aronsohn, Sachs) of the same portion of the brain. Nevertheless, fevers dependent upon nervous disturbance are rare, and are overshadowed in importance by those caused by infection. The rise of temperature in fever is usually accompanied by an in= crease in the frequency of the pulse-rate ; but in some cases this effect of the elevation of temperature may be so greatly modified through stimulation of the vagus — as, for example, in basilar meningitis — that I he pulse-rate may be lowered. The pulse is at one time full and bound- ing, at another time small because of weakened contractions of the heart. The impairment of the contractions of the heart-muscle is dependent partly upon the constant high temperature, partly upon poisonous sub- stances, which are produced by the morbid processes peculiar to the es- pecial disease, and which exert a harmful influence upon the muscle- substance of the heart or upon the nervous system. In diseases accompanied by fever there is usually a marked sensation of illness with a heavy feeling in the head. In severe fevers there occur clouding of consciousness, symptoms of excitation and depression, hal- lucinations, delirium, apathy, involuntary evacuations, tremors of the hands, convulsions (in children), etc. The muscles of the body become weak and not infrequently painful. Digestion is decidedly impaired ; the appetite for food is slight, but on the contrary there is great thirst ; the mouth is dry. There is an increased frequency of respiration ; after the appearance of muscular weakness the respiratory movements are superficial. The excretion of urine is usually diminished ; the amount FEVER. 95 of urea in the urine is increased, while that of sodium chloride is dimin- ished. In prolonged fevers there is marked wasting of the body, in that a large portion of the albuminous material and fat of the body is de- stroyed. To what extent these symptoms in individual cases are dependent upon the increase of temperature or to what extent upon the damage to the organism caused by the specific morbid process, it is difficult to say, but the marked effects upon the nervous system must for the greater part be regarded as a result of the infection and intoxication. Death results most often from cardiac insufficiency, but it may be brought about also by the severity of the infection and the intoxication, by the wasting of the strength, as well as by an excessive elevation of temperature to 43°, 44°, or 45° 0. (109.4°, 111.2°, and 113° F.). It should, however, be remarked that under certain conditions very high temperatures may be borne for a length of time without fatal results, and that the death following very high temperatures cannot be ascribed to the abnormal temperature alone, but is rather to be regarded in part or wholly as the result of the infection (see § 3). The questions concerning the nature of fever, which Galen designated as Color prater naturam, have been much advanced during the last decades by numerous clin- ical and experimental investigations. From these we have learned of the associated disturbances of metabolism, the increased consumption of oxygen, the increased excre- tion of nitrogen and carbon compounds, as well as of the disturbances of the heat-dis- persion. If we, in spite of this knowledge, do not yet possess a full understanding of all the morbid processes which in a given case may cause fever, we may attribute this to the fact that, the causa efflciens of fever is not a single entity, but may be one of many different factors, and that the feverish elevation of the body-temperature does not always occur in exactly the same manner. The increase of the tissue-changes and oxidation-processes within the body is not always brought about in the same way. Further, the disturbance of heat-dispersion through radiation from the skin and the evaporation of water is not always the same, but changes, not only in the course of one febrile disease, but also in different forms of fever. Correspondingly, the role played by the nervous system in the occurrence of the feverish increase of temperature is not the same in every case. According to Aronson, the essential feature of fever is a pathological increased stimulation of the heat-centres whereby the motor-trophic ap- paratus of the body muscles is excited to an increased production of heat and to changes in the heat-dispersion. The different types of fever are determined by the different kinds of stimuli, which in the infectious diseases are especially manifold. The founda- tion type is an elevation of the body-temperature in the absence of any other disease of the body, and caused solely by a direct mechanical, electrical, or chemical stimulation of the heat-centre. According to Senator, there is, in fevers, no harmony between the regulation of heat and metabolism ; and we must therefore assume that heat is developed through other processes than those leading to the production of urea and carbonic acid. According to Herz, heat is set free by the changes in the arrangement of the molecules of the cell-protoplasm, which occur in many of the cells in fever patients, and which lead to the destruction of protoplasm. Further, heat may be liberated by processes of swelling and coagulation of the protoplasm, while at the same time the diminished ac- tivity of the regenerative processes in fever occasions a loss in the storing-up of latent heat. On the other hand, Kreld and Matthes are of the opinion that oxidation forms the sole source of heat. Literature. (Fever.) Aronson: Das Wesen des Fiebers. B. med. Woch., 1902. Aronson u. Sachs: Beziehungen d. Gehirus zur Korperwiirme u. zum Fieber. Pfliiger's Arch., 37 Bd., 1885. Bouchard: Lecons sur les auto-intoxications dans les maladies, Paris, 1889. Cohnheim: Vorlesungen fiber allgemeine Pathologic, ii., Berlin, 1882. 96 THE GENERALIZATION OF DISEASE. Finkler : Pfliiger's Arch., xxvii.; Ueber das Pieber, Bonn, 1882. Franke : Die rnenschliche Zelle, Leipzig, 1893. Gangolphe ut Uourmont; La iiOvre consec. a 1' obliteration vasculaire. Arch, de med. exp., iii., 1891. Girard: L 'influence du cerveau sur la chaleur animale. Arcii. d. phys., viii., 1886. Glax: Ueber die Wasserretention im Pieber, Jena, 1894. Guyon: L'hyperthermie centrale, consec. aux les. du cerveau. Arch. med. exp., 1891. Hammerschlag : Bezieh. des Fibrinferraentes zum Pieber. Arch. f. exp. Path., 27 Bd., 1890. Herz: Lntersuchungen fiber Warme und Fieber, Wien, 1893. Jurgensen: Die KQrperwarme des gesunden Menschen, Leipzig, 1878. Rrehl: Patbologische Physiologie, Leipzig, 1898. Krehl u. Matthes: Bntstebung der Temperatursteigerung des fiebernden Organ- ismus. Arch. i. exp. Path., 38 Bd., 1897 (Lit.); Eiweisszert'all, ib., 40 Bd., 1898. Leyden: Respiration im Fieber. Deut. Arch. 1. klin. Med., v., vii., 1870. Lieberrneister : Pathol, u. Ther. d. Fiebers, Leipzig, 1875; Specielle Pathol, Leip zig, 1887. Lb-wit : Die Lehre vom Fieber, Jena, 1897. Loewy: Stofiwechseluntersuchungen im Fieber. Virch. Arch., 126 Bd., 1891. May: Der StofEwechsel im Fieber. Zeitschr. f. Biol, 30 Bd., 1893. Mosso: Influence du systeme nerveux sur la temperature animale. Arch. ital. de biol, vii., 1886; Virch. Arch., 106 Bd. ; La doctrine de la fievre et les centres thermiques cerebraux. Arch. ital. de biol., xiii., 1890. Murri: Sulla teoria della febbre, Fermo, 1874. Naunyn: Experimentelles zur Lehre vom Fieber. Arch. f. exp. Path., xviii., 1884 (Lit.). v. Noorden: Pathologie des Stoffwechsels, Berlin, 1893. Rabe: Die modernen Piebertheorieen, Berlin, 1894. RosentLal: Warmeproduction im Fieber. Biol. Cbl, xi.. 1891. Roussy: Rech. exp. sur la pathogenie de la fievre. Arch, de phys., ii., 1890. Sarb6: Ueber hysterisches Fieber. Arch. f. Psych., 23 Bd., 1891". ScLultze: Warmehaushalt nach dem Wiirmcstich. Arch. f. exp. Path., 43 Bd., 1899 Senator: Unters. liber den fieberh. Process, Berlin, 1873; Arch. f. Anat. u. Phys., 1872. Stern: Warmeregulation im Pieber. Zeitschr. f. klin. Med., 20 Bd., 1892. Xlghetti: Das Fieber. Jena, 1895 (Lit.). TJnverricb.t : Leber das Fieber, Leipzig, 1898. Volkniann u. Genzrner: Septisehes u. asept. Wundfieber. Samml. klin. Vortr, , No. 121, 1877. Welch: On the General Pathology of Fever, Philadelphia, 1888. Wunderlich : Das Verhalten der Eigemvarme in Ivrankheiten, Leipzig, 1870. Zunz: Ueber den StofEwechsel fiebernder Thiere. Arch. f. Psych. 1882. CHAPTER III. The Protective and Healing Forces of the Human Body. The Acquiring of Immunity. I. The Natural Protective Contrivances, Protective Forces, and Healing Powers of the Human Organism, and their Action. § 29. The human organism is not entirely defenceless against the many harmful influences to which men during the course of their lives are exposed. It possesses various protective contrivances and pro- tective forces, by which it is able in many cases to ward off the injuri- ous agent, or at least rapidly to counteract its harmful influence, so that a disease may be either wholly prevented or confined to a slight local lesion of much less severity than the disease usually produced by the particular injurious agent. As the mode of action of different injurious influences varies greatly, so does the manner of defence likewise vary greatly. The protective forces may act at very different times — that is, sometimes even before the tissues have been damaged, at other times after the injurious action has reached a certain stage, and threatens, either through direct extension or through metastasis, or through poison- ing of the body-fluids, or through disturbance of function, to spread further through the body. When the environment of the body becomes relatively cold or rela- tively warm, those regulating functions are brought into play through which the organism can increase or diminish heat-production and heat-dis- persion, and in this manner protect itself within certain limits against the influence of the external temperature. If these regulating functions are imperfectly performed, as in consequence of alcoholic intoxication, the individual may more easily die from the effects of cold than when under normal conditions. We cannot speak of special protecting contrivances against gross mechanical influences ; yet it is to be noted that the tissues by virtue of their physical properties are fitted to offer resistance to numerous forms of traumatism without receiving injury. If small, firm bodies, such as dust-particles, reach the mucous membrane of the respiratory or intes- tinal tracts, the epithelium forms a protective barrier against their en- trance into the tissue -spaces. Further, if ciliated epithelium is present, the dust-particles may be carried away by the movements of the cilia, or they may become surrounded by the mucus produced by the epithelium and mucous glands, and in this way are transported out of the body. Not infrequently there appear cells on the surface of the mucous membrane which encompass the dust-particles, and, taking these up into their substance, are carried away with the secretion of the mucous mem- brane. This phenomenon, known as phagocytosis, is observed on the mucous membranes of the pharynx and respiratory tract and in the alveoli of the lungs. The active agents participating in it are not only 7 97 98 THE PROTECTIVE POWERS OF THE RODY. the wandering-cells which pass from the tissues to the surface, and are derived chiefly from the blood-vessels and also from the nodes of lymphadenoid tissue in the mucous membrane, but epithelial cells as well. The peculiar phenomenon of phagocytosis depends upon the fact that the cells can, by movements of their protoplasm, take up little par- ticles, which, like insoluble dust, exert no harmful influence upon the cell-protoplasm. If these cells laden with dust pass outside of the body, the taking-up of the dust by the cells appears to be a useful activity which aids in the cleansing of the organs from dust. If the dust-laden cells, on the other hand, as happens particularly in the lungs, pass into the lymph-channels and are deposited along their walls or are carried to the lymph-glands — that is, if a metastasis of the dust-containing cells into the internal organs takes place — the taking-up of dust by these cells appears in a less favorable light ; and we can regard this act as a useful phenomenon only through the consideration that the infiltration of the pulmonary connective tissue and lymph-glands witli dust is less harmful than the deposit of dust on the inner surface of the alveoli. When dust-particles, free or enclosed in cells, reach the lymph -glands, they are arrested and deposited in the cells of these glands, so that the lymph-glands may be regarded as trustworthy filters, which guard the blood and the internal organs from the entrance of dust. Against the action of poisons the human body is able to protect itself in various ways. In the case of corrosive poisons the homy layer of the epidermis and the mucus of the mucous membranes offer a certain pro- tection ; and under certain conditions a marked increase in the produc- tion of mucus — in the stomach, for example — may greatly diminish the harmful effects of a corrosive fluid. Through a transudation of fluid from the blood-vessels on to the surface of the mucous membrane a caustic fluid may be so diluted as to modify its action. On the other hand, the injurious substance may be thus spread over a greater surface, and thereby cause a more widespread damage to the tissue. On many poisons, abrin, ricin, the toxins of cholera, tetanus, and diphtheria, and snake-venom, the digestive juices have such an influence that doses invariably fatal when injected under the skin may be borne with impunity when taken by the mouth. According to Ransom, guinea-pigs are able to withstand, when administered by the mouth, an amount of tetanotoxin equivalent to three hundred thousand times the minimal fatal dose. According to Nencki and others, this neutralization of the poison is produced by the digestive enzymes, at one time chiefly through the pepsin, at another time through the trypsin and the mixture of the pancreatic juice with the bile. It is probable (Nencki) that the digest- ive enzymes cause a slight change in the molecules of the toxin, similar to the change of albumin into albumose ; and the products arising from the toxins may accordingly be termed toxoscs or toxoids. The intestinal enzymes have no neutralizing influence in the case of sausage-, meat-, fish-, beau-, pea-, etc., poisoning produced by the Bacillus botulinus ; and, therefore, after the eating of such infected foods severe and fatal intoxi- cations may occur. In the case of those poisons which after their entrance into the body- juices act injuriously upon the blood or the nervous system, a favorable counter-action on the part of the organism may be given partly by a rapid excretion of the poison through the kidneys, liver, intestine, pan- creas, salivary glands, mammary glands, sweat glands, and lungs ; partly through their transformation into combinations soluble with difficulty, which NATURAL IMMUNITY. 99 are thus stored up indifferent organs (liver), and partly through a change of the poisons into combinations that are relatively harmless and easily soluble, which are then taken up into the circulation and excreted, and partly through a chemical change of the poison. Of natural immunity against poisons or natural resistance to poisons we know but little at present, yet there is no doubt that many poisons are poisonous only for certain organisms, and it is probable that man is re- sistant to many poisons which are injurious to certain animals. The same thing holds true especially of the toxins (§ 11), such as are formed by bacteria or by higher animals (snakes) and plants (ricin and abrin). If we consider that many animals are only slightly or not at all suscepti- ble to poisons which have marked action upon the human body — for example, the hedgehog is immune or resistant to cantharidin and the bite of poisonous snakes respectively ; birds are immune against atropine and opium ; goats against lead and nicotine ; while dogs, rats, or other ani- mals used for experiment show a disproportionately greater resistance to bacterial poisons or plant-alkaloids than does man — so it is very prob- able that the reverse is also true. The natural immunity of man against many of the infectious diseases of animals must depend upon a resistance to the toxins produced by the particular bacteria. According to Ehrlich, this resistance to poisons may be explained by the theory that the particular toxin possesses no chemical relationship to any one of the body elements. A relative immunity may therefore depend upon the fact that the healthy individual possesses already a certain amount of antitoxin (for example, against diphtheria toxin). Fromm has recently briefly summarized our knowledge concerning the chemical protective resources of the animal body in intoxications. Inorganic poisons are rendered harmless chiefly by three kinds of chemical action — oxidation, reduction, and combina- tion with a protective body with liberation of water. Phosphates and sulphides are oxidized so that phosphoric acid and sulphuric acid arise which are neutralized and excreted. The iodates and chlorates are changed into the easily soluble and less poisonous iodides and chlorides which are then excreted. The metallic salts and metallic oxides are converted into albuminates (the salt-like combination of metallic oxide and albumin) or into sulphides. Inorganic acids are combined through alkalies and changed into less poisonous salts. Organic poisons are transformed into non-poisonous substances through oxida- tion, reduction, the liberation or the taking up of water. Often several reactions follow one another; usually the product arising through oxidation or reduction is combined to one or more other substances with the liberation of water. Such protective sub- stances are represented particularly by the sulphates arising through the disintegra- tion and oxidation of albumin, by glycocoll arising in the breaking down of albumin, glycuronic acid arising through the oxidation of the carbohydrates, and perhaps also urea. Poisonous acids of the fat series are oxidized to carbonic acid and water. Phenol and those bodies which through oxidation pass directly into phenol are through a combination with sulphuric acid made soluble, harmless, and capable of being excreted; for example, phenol is excreted as potassium-phenol-sulphate; benzoic acid and its oxidation products and those substances that are transformed directly into benzoic acid or their derivatives are combined by glycocoll; trimethyl carbinol, naphthol,and chloral hydrate appear in the urine combined with glycuronic acid, chloral hydrate after its transformation into trichlorethyl alcohol. Literature. (The Action of Digestive Juices upon Toxins.) Charrin: Action des sues digestifs sur les poisons microb. Arch. d. phys., x., 1898. Fraser: Remarks on the Antivenomous Properties of the Bile. Brit. Med. Journ., 1,897. 100 THE PROTECTIVE POWERS OF THE BODY. Fromm : Die chemisehen Schutzmittel d. Thierkorp. bei Vergift unseen, Strassburg, 1903, (Lit.). _ Nencki, Sieber 11. Schournow: Entgiftung d. Toxine dureh Verdauungssafte. Ctbl. f. Bakt., xxiii.. 1898. Ransom: Das Schicksal des Tetanusgiftes nach seiner intestinalen Einverleibung. Deut. med. Woch., 1S9S. § 30. Against the infections and intoxications caused by parasites the human organism possesses various protective contrivances ami powers of defence; and these play a very important role in the diseases caused by bacteria. In the first place, man possesses a natural immu- nity against many of the micro-organisms pathogenic for animals (for example, swine plague, swine-erysipelas, cattle-plague, symptomatic anthrax ), so that the given micro-organisms are not able to reproduce "within the body, either because they do not find in human tissues the necessary conditions of life, or because the presence of certain chemically active substances hinders their increase or kills them directly. Further, immunity may also rest upon the simple fact that the poisons produced by given bacteria in a given organism are inactive because no chemical affinity or relationship exists between the poisons and any one of the body elements. For the protection of the body against the pathogenic micro=organisms there are available certain protective forces, which, according to their action, maybe divided into four groups: the first hin- dering the entrance of bacteria into the tissues; the second hindering the unlimited local spread (it those bacteria which have gained entrance and have begun to multiply; the third preventing the entrance of bac- teria into the blood and their metastasis; the fourth hindering intoxica- tion, or at least weakening it, and reducing it to a low degree. For the prevention of the entrance of pathogenic bacteria into the tissues the same properties of tissues are effective as those hindering the entrance of dust ; and in such capacity the protective epithelium and the mucus play a very important role. In the respiratory tract the move- ments of the ciliated epithelium also furnish protection, and in the stomach the poisonous action of the gastric juice upon many pathogenic bacteria is an efficient means of defence. There can be no doubt that many patho- genic bacteria are not able to penetrate into the tissues, not only through the uninjured external skin, but also through an unwounded mucous membrane, without some assistance favoring colonization and reproduc- tion, aud that the stomach secretion not infrequently hinders the activity of the bacteria (pneumococcus, cholera spirillum), or even kills them. It appears also that the mucus secreted by the mucous membranes not only can envelop the bacteria, hinder their entrance into the tissue, and favor their removal, but that — -what is of much greater importance — the mucus acts upon the bacteria, causing them to degenerate, either in that it contains substances which are injurious to the bacteria or in that it offers an unfavorable medium for the growth of the bacteria. In this way, according to Sanarelli and Dittrich, pus-cocci, cholera-spirilla, and pneumococci gradually lose their virulence and die in the mucus of the mouth-cavity, while diphtheria-bacilli and tubercle-bacilli apparently are not injured by mucus. In the secretions of the vagina and uterus, various kinds of bacteria likewise soon die. In the intestine the bacteria normally present there (B. coli communis, B. lactis aerogenes) afford an effective protection against the multiplication of any pathogenic bacteria that may happen to be present; for example, against diphtheria and tetanus bacilli and against cholera-spirilla, while, PROTECTION AGAINST INFECTION, 101 on the other baud, the development of staphylococci and streptococci does not appear to be hindered by them. Not every pathogenic organism, therefore, which gains a foothold upon the skin or upon any of the accessible mucous membranes or gains entrance into the intestines or the lungs produces an infection. It has been shown through repeated investigations that in normal individuals there not infrequently occur in the upper respiratory passages and mouth- cavity not only harmless bacteria — i.e., those which cannot reproduce in human tissues — but also those which can. undoubtedly produce disease, as, for example, cocci which cause suppuration or those which are able to cause croupous inflammation of the. lung. It must, therefore, be granted that bacteria which are found upon the mucous membranes and have perhaps multiplied there often die and are carried away without having produced infection. This occurs especially in the case of the cocci above mentioned, and tubercle-bacilli, as well as in the case of cholera-spirilla which suffer when brought into contact with the acid secretions of the stomach. Finally, it may also be assumed that of the pathogenic bacteria entering the alveoli of the lung in the inspired air, many do not reproduce, but die. When bacteria have succeeded in gaining- entrance locally and have begun to multiply — no matter whether they have passed through the epithelium without the aid of any other influence (typhoid-bacilli, cholera-spirilla), or whether they have passed into the connective tissues through the medium of small wounds (tetanus-bacilli, pus-cocci, tubercle- bacilli) — if they produce further effects either through local destruction of tissue or through the poisoning of the fluids of the body, there may be brought into action on the part of the body certain counter=influences which either hinder the further development of the bacteria or weaken or even completely destroy the poisons produced by them. The first-named restraining influence must naturally depend upon local conditions, either upon vital tissue -processes or upon the effects of chemical substances. As previously mentioned, the development of bacterial colonies gives rise to local tissue-degenerations, inflammation, and tissue-proliferations — all of which are processes in which the amount and composition of the fluids found in the affected region, as well as the cells themselves, are changed. Since in some of these cases a destruction of the bacteria has been observed, and the infection not infrequently comes to an end through the complete disappearance of the bacteria, the death of the latter must be regarded as dependent upon local conditions. Many writers ascribe the prevention of the further spread of the infection and the destruction of the bacteria, in local foci of growth, to the activity of cells which collect at the seat of infection and take up the bacteria into their protoplasm — that is, to phagocytosis is ascribed the most important role in the protection of the body against bacterial in- vasion. According to Metschnikoff and others, the, amoeboid cells of the body carry on a fight against the foreign invaders and endeavor to over- come them and destroy them. Such a characterization of the phenomena of phagocytosis is not supported by the actual facts, and can be regarded only as a poetical manner of expression by which consciousness and will- power are attributed to the amoeboid cells of the body (the leucocytes and the proliferating tissue-cells) — which attributes it is evident do not exist. Scientifically considered, the gathering of the cells at the infected focus and the resulting phagocytosis represent simply an expression of certain processes which are natural to the amceboid cells, and which are 102 THE PROTECTIVE POWERS OF THE BODY. dependent upon the fact that the cells under the influence of mechanical, chemical, and thermal influences perform certain definite movements. We know through numerous investigations that the motile cells of the body are in part attracted, in part repelled or paralyzed by means of chemical substances in certain concentrations of solution (see the Chapter on Inflammation) ; and, further, that contact, with hard bodies can stim- ulate them to the sending-out of protoplasmic processes. Such phenomena are designated as negative and positive chemo= tropismus or chemotaxis and as tactile irritability. We must assume that the bacteria multiplying within the tissues act upon the amoeboid cells through the chemical substances which they produce, sometimes re- pelling or paralyzing, sometimes attracting, in the latter case affording conditions favorable for phagocytosis. The bacterial proteins arising from the bodies of dead or dying bacteria and passing over into solution in the body juices have, in particular, a positive chemotactic action upon the phagocytes. The remit of the taking-up of bacteria into cells depends in a particular case partly upon the properties of the devouring cells, partly irpon the properties of the microparasites, and can result as well in the death and dissolution of the parasite, as in the death of the cells ; or in a symbiosis of the cells with the parasites, the latter living within the cells un- changed and giving rise to no disturbance. In the first-named case the phagocytosis may be regarded as a curative process which hinders the multiplication and spread of the bacteria. In the second and third cases, on the contrary, the jdienomenon is useless for the prevention of the spread of the parasites ; indeed, there are cases (leprosy and to some extent also tuberculosis) in which the parasites find favorable conditions for development inside of the cells, increase within them, and finally cause their destruction. If the cells containing bacteria remain pre- served for a length of time, they may wander with the enclosed bacteria to other parts of the body, in this way effecting a metastasis. Phagocytosis is therefore only of slight significance as a protective force in a certain number of cases ; yet it cannot be doubted that the phagocytes in certain infections take up, not only dead or dying, but also living bac- teria not yet injured by other agents, and can cause their death.'" The collection of great numbers of cells in the infected tissue may, through the close packing of the lymphatics, offer a certain mechanical hindrance to the spread of bacteria, yet the protection so afforded is frequently in- sufficient. If bacteria, either free or enclosed in cells, pass from the lymph-ves- sels into the lymph=glands, the latter act as filters, as in the case of dust, and retain the bacteria; but the protection which they offer is sufficient only when the bacteria so collected in the lymph-glands are hindered in their reproduction and are killed by the influence of their surroundings. The destruction may be accomplished under the influence of phagocytosis, but in many cases phagocytosis is possible only when the bac- teria, are weakened or have already been killed. Further, the taking-up of living bacteria by the cells is not always followed by destruction of the bacteria, but there very frequently takes place an intracellular multipli- cation of the bacteria. More important than phagocytosis for the prevention of the spread of bacteria and other microparasites is the influence exerted by certain chemical substances in solution in the tissues. Since the saprophy- tic, non -pathogenic bacteria, when injected into living tissue, are killed PROTECTION AGAINST INFECTION. 103 within a very short time, we must assume that in the tissues there are present chemically active substances which are poisonous for many bacteria and can cause their rapid destruction. Further, siuee many pathogenic bac- teria ordinarily increase only locally (tetanus-bacilli, diphtheria-bacilli, cholera-spirilla) and after a certain time perish within the infected area, without spreading further through the body, it is very probable that the tissues of the body also contain substances which are poisonous for many pathogenic bacteria and prevent their spread. The phenomena observed in local infections speak also for the fact that such substances at times are formed in increased amounts or are aided in their action by newly-formed poisonous substances. It is, furthermore, probable that the crowding of cells which takes place in the infected tissue or in its neighborhood leads also to an increase in the production of these poison- ous substances, and may thereby hinder the spread of the bacteria ; nev- ertheless, attention should be drawn to the fact that in many infections the spread of bacteria through the tissues comes to a standstill in places where there has been no crowding together of cells. It is also a fact that in many infections the spread of bacteria through the body by metastasis is either wholly wanting (tetanus, diphtheria) or at least is insignificant in comparison with the local infection, and is usually fol- lowed by relatively insignificant local changes. The explanation of this fact is to be sought, not so much in the assumption that local tissue- changes, through the formation of special chemical substances or through the aid of mechanical substances or through the aid of mechanical hin- drances — such as that afforded by a wall of cells — hinder the entrance of bacteria into the lymph and blood, but much more in the fact that there are present in the lymph and blood itself certain forces which are able to in- jure and weaken the bacteria taken up into these fluids or to destroy them. (See paragraph below on opsonins.) The hostile action of the blood on bacteria has been ascribed to the phagocytic action of the leucocytes ; and this theory is supported by the fact that such a phagocytosis can be demonstrated very frecpiently in acquired infections or after the artificial introduction of bacteria into the blood; and, further, by the fact that the bacteria within the blood, en- closed in cells, may often be carried out of the blood-vessels and deposited in different organs — for example, the spleen, liver, bone-marrow, and the kidneys — and there destroyed or excreted from the body. These observations do not warrant the conclusion that phagocytosis forms a protection against the spread of bacteria in the lymph and blood ; in- deed, in those very cases in which a transportation of bacteria through the blood does not take place, phagocytosis is also absent ; while on the contrary, the entrance of bacteria into the blood, and the multiplication of the same inside of the blood-vessels, is very often accompanied or fol- lowed by phagocytosis. Here, again, phagocytosis is of the nature of a secondary phenomenon which occurs when there are present in the blood bacteria or protozoa, that are not able to prevent themselves being taken up into the bodies of the leucocytes — that is, they exert a positive at- traction on the phagocytes. When bacteria are taken up by cells, they either die or continue to multiply inside of the cells, according to their properties and their con- dition at the time of the phagocytosis. Tire forces which, are able to hinder the development of bacteria in the blood are believed by the majority of writers to depend upon the presence of antibacterial chemical substances, which are designated 104 THE PROTECTIVE POWERS OF THE BODY. alexins (Buchner) or mycosozins ( Hankin). According to Buchner, with whom the majority of authors are in harmony, there is formed a fer- ment-like body, an enzyme (cytase [Metschnikoff ] ) , which, through the aid of an intermediate body (amboceptor), exerts its destructive action upon the bacteria. The leucocytes themselves are probably the chief producers of this protective body, and the leucocytosis observed in the blood in the course of many infections may therefore increase the protective power (see opsonins below). So far as conclusions can be drawn from the behavior of the human and animal organisms in infections diseases, we may assume that in the blood of man there are always present protective chemical substances, that is, alexins, particularly so against bacteria which never or only exception- ally enter the blood ; and that others, on the contrary, are produced only during the course of an infection, so that not until a certain stage of the infection does an inhibition of the development of the bacteria, through the formation of antibacterial substances, occur. In favor of such hypothesis speaks the fact that many bacteria (typhoid-bacilli, cholera- spirilla, pus-cocci) possess at first their full virulence when distributed through the body by the blood, but later suffer a loss of virulence and finally die. The means of protection which the organism possesses against the poisons produced in the tissues by bacteria are to be found, first, in the possibility of a rapid excretion of the poisons by the kidneys, or, under certain circumstances, also by the stomach, intestine, and skin; and this action may in certain cases suffice to prevent a fatal poisoning. Further, in certain infections in which true toxins are formed there is an antagonistic action on the part of the organism, in the sense that these poisons are made ineffective through the action of counter poisons, the so-called antitoxins. ( See § 31 and § 32. ) The antibacterial properties of the blood and lymph against certain bacteria have been demonstrated conclusively by the experimental investigations of various writers. These experiments have shown that the bactericidal action of the blood of a given ani- mal is exerted only upon certain forms of bacteria and never upon all; and that this action is subject to individual variations. According to the investigations of Fodor, Petruschky, Nuttal, Ogata, Buchner, Beh- rimj, Nissen, Pansini, and others, the blood and the serum from dogs, rabbits, and white rats are capable of rendering the anthrax-bacillus harmless, and even of killing it; but this action is a limited one, so that after the introduction of a large number of the bacilli into the blood taken from the vessels, the bacilli after a time begin to multiply. Defibrinated blood of dogs and rabbits can destroy the cholera-spirillum and typhoid- fever bacillus; but, on the other hand, has no effect upon the different pus-cocci, and against proteus; the same is true also with regard to the blood-serum. Human blood or blood-serum can kill typhoid-bacilli, diphtheria-bacilli, and the bacilli of glanders. Von Baumgarten and Walz, as well as A. Fischer, oppose the view that there are chemically active substances in the blood, and explain the natural immunity of the tissues and the blood against certain bacteria as due wholly to the inability of the bac- teria to find there the necessary chemical conditions for growth and multiplication. They regard the fact that different bacteria which have been passed into the blood or blood-serum do not develop at all. or show but partial or delayed growth and a great diminution in numbers when cultivated upon plates, as in no manner speaking for the presence of bactericidal substances in the blood. According to their view, the second transplantation into another culture-medium causes a disturbance of the processes of assimilation and osmosis. There arise in consequence plasmolytic changes in the bacteria present in the serum; during the pouring of the plates the already injured cells die from disturbances of assimilation. On the other hand, it is to be noted that .1. and //. Kossel have demonstrated that certain products of animal cells (nucleinic acid, protamine) possess bactericidal properties. The alexins of the blood serum are made inactive through heating to 55° C, and are very susceptible to the action of sunlight (Buchner), and they can also be BACTERICIDAL SUBSTANCES: OPSONINS. 105 destroyed by living bacteria and their decomposition products. They resist pepsm. The addition of salt to the serum lowers their sensibility to heat. By means of a 90- per-cent sodium sulphate solution there may be obtained from dog serum a precipitate which remains active when dried at 70° C. The bactericidal action finds its analogy in the globulicidal and hsemolytic action of the serum; that is, its capacity to destroy and dissolve the red blood-cells of an animal of a different speci.s. According to the investigations of Ehrlich and his students the bactericidal and globulicidal antibodies contain two components, one thermolabile, which is destroyed by heating to 55-60" C, and a thermostabile , which resists heating. Both must act to- gether in order to bring about the death of bacteria or the dissolution of the red blood- cells. Ehrlich designates the thermostabile component as the immune body or inter- mediate body (Bordet "as the substance sensibilatrice"). the thermolabile as the com- plement (earlier designated the addiment). To the immune body he ascribes two haptophorous side-chains, one the cytophile, which unites with the cell (bacterial cell, red blood-cell), for which it possesses a chemical affinity, and a complementophile , which combines with the complement. It is therefore an amboceptor, which carries over the action of the complement to the cell. Buchner's alexin is identical with the thermola- bile component, the complement of Ehrlich (Bordet). That a union of the immune body with red blood-cells and bacteria, respectively, does take place has been demon- strated by the investigations of Ehrlich, Morgenroth, Hohn, Trommsdorff, von Dungern, and others. Iiankin, Kanthack, Denys, Hahn, Lowit, and others assume, on the ground of experimental investigations, that the alexins are produced by the leucocytes. Kossel holds it as possible that the nucleinic acid present in the leucocytes in relatively rich amounts plays a role in the destruction of the bacteria. Noesske believes that the eosino- phil cells of the bone-marrow in particular produce bactericidal substances. It is not possible at the present time to draw a definite conclusion as to the part played by the colorless cells of the blood in the defence against infections. According to Bitter, the bactericidal substance found in organs — that derived from the lymph-glands, spleen, and thymus — is to a certain extent different from that of the blood and the blood-serum, and therefore does not originate wholly in the blood. It is certain that the bactericidal action of the blood is not the only protective influence which can oppose the spread of an infection, or wholly prevent it, and confer immunity. According to observations of C'zaplewski, anthrax-bacilli in an infected organism, which have been taken up into leucocytes, degenerate as a rule more slowly than those lying free in the blood and tissue-juices. It appears, therefore, as if under certain conditions the cells afford to the bacteria which they enclose a certain degree of pro- tection from the bactericidal substances of the tissue-fluids. The antitoxins which render the bacterial poisons harmless are usually formed first during the course of the infection; but, according to the investigations of Wasser- mann, Abel, Eischl, von Wunschheim, and others, the serum of healthy men also con- tains such substances. Serum which contains the antitoxin against a certain toxin — as, for example, that against the diphtheria-toxin — can lie a good culture-medium for the given bacteria; the antitoxin does not destroy the bacteria. Animals refractory toward diphtheria contain in the blood serum no diphtheria antitoxin, but according to Wassermann about 80 per cent of human individuals have in their blood a not insignificant amount of antitoxin. The immunity of the animals depends therefore not upon the presence of the antitoxin, but on a lack of affinity between the poison and the tissue-cells (Ehrlich and Wassermann). It is possible to produce in mice a fatal intoxication with the blood of apparently healthy fowls that have been injected with large doses of tetanus toxin. Opsonins. The protective function of phagocytosis has in recent years been accorded a position of great importance through the discovery by Wright and Doughs (1902) of the presence in the blood and other fluids of the body of certain substances, called by them opsonins, which render various bacteria susceptible to the phagocytic action of leucocytes. It is now apparently an established fact that certain special substances, normal and immune, act upon the bacteria and change them in such a manner that they are readily taken up by polynuclear leucocytes in vitro. Opso- nins ca])able of acting upon a variety of bacteria occur in normal blood. They appear to be the most important antibodies in infections with streptococci, staphylococci, pneumococci, micrococcus melitensis, gonococci, meningococci, the bacilli of plague, dysentery, anthrax, tuberculosis, typhoid fever, the colon bacillus, cholera spirillum, etc. Whether this wide range of opsonic action is dependent upon a common opsonin or upon a variety of specific opsonins is not yet determined. Specificity of the opsonins probably does not exist. Various researches suggest that they may be a constant 106 THE PROTECTIVE POWERS OF THE BODY. quantity. They are to a certain extent thermolabile , being partly destroyed at 60-65 C. Bacteria first treated with normal serum and then exposed to this temperature are taken up as under normal conditions. The opsonic power of the blood is increased in recovery from infection, and it can also be artificially increased by immunization with living attenuated bacteria, dead bacteria, or proteid constituents of the bacterial cells. The opsonic index is the relative influence of a patient's blood upon phagocy- tosis as compared with that of normal individuals. It is determined by mixing in a capillary tube equal parts of the patient's serum, a suspension of leucocytes, and an emulsion of the bacteria against which the index is taken. Control tests are made in the same way with normal serum. The mixtures are incubated for a time, thin smears are made, dried, and stained, and the average number of bacteria taken up by the leucocytes is estimated. Regarding the index of the normal blood as unity, the average number of bacteria in the leucocytes of the patient's serum divided by it will be the opsonic index. 75-100 leucocytes are usually counted. A low opsonic index is taken as indicating the presence of an infection or of a low degree of resistance to it, while a high index indicates a high degree of resistance to a recovery from infection. Literature. {The Protective Power of the Body against Infection.) Afanassieflf: Bedeutung d. Granulationsgewebes bei Infectionen. Beitr. v. Ziegler, xxii., 1897. Arloing: Un mot sur l'immunite' naturelle. Arch, de med. exp., 1890; Les virus, Paris, 1891. Arnold: Der Kampf d. menschl. Organismus mit d. Bakterien. Akad. Rede, Heidel- berg, 1888. Baurngarten: Der gegenwartige Stand der Bakteriologie. Berl. klin. YVoch., 1900; Die naturl. Schutzmittel geg. Infection, ib., 1900; Verhandl. d. D. path. Ges., ii., Berlin, 1900. Behring: Infection und Desinfection, Leipzig, 1894; Infectionsschutz u. Immunitat. Eulenb. Jahrb., ix., 1900. Behring u. Nissen: Bakterienfeindl. Eigenschaften verschied. Blutserumarten. Zeit. f. Hyg., viii., 1890. Besredka: Pouvoir bactericide des leucocytes. Ann. de l'Inst. Pasteur, xii., 1898. Bitter: Ueb. d. bakterienfeindlichen Stoffe thierischer Organe. Zeit. f. Hyg., xii., 1891. Bordet: Rech. sur la phagocytose. Ann. de l'Inst. Pasteur, 1896. Brock: Resorptionsvermogen der Haut. Arch. f. Derm., 35 Bd., 1898 (Lit.). Buchner: Ueber die bakterien todtende Wirkung des freien Blutserums. Centbl. f. Bakt., v., vi., 1889; Ueber die bakterientodtende Wirkungen d. Blutes u. Blut- serums. Arch. f. Hyg., x., 1890, ref. Cbl. f. Bakt., ix.; Htilfskrafte d. Organ- ismus gegen Krankheitserreger. Munch, med. Woch., 1894; Bakteriengifte und Gegengifte, ib., 1893; Naturl. Schutzeinrichtungen, ib., 1899. Charrin: Les defenses naturelles de l'organisme, Paris, 1898. Czaplewsi: Enters, lib. d. Immunitat der Tauben gegen Milzbrand. Zeit. f. Hyg., xii., 1892. Emmerich, u. Tsuboi: Die Schutz- u. Heilkrafte des Blutes. Verh. d. XL Kongr. f. inn. Med., Wiesbaden, 1892; Microbicide Wirkung des Blutserums. Cbl. f. Bakt., xiii., 1893. Fischer, A.: Die Empfindlichkeit d. Bakterienzelle u. d. bactericide Serum. Zeit f. Hyg., 35 Bd., 1900. Fischi u. v. Wunschheim: Schutzkrafte im Blute d. Neugeborenen. Zeit. f. Heilk., 1S95 (Lit.). v. Fodor: Die Fahigkeit d. Blutes, Bakterien zu vernichten. Cbl. f. Bakt., vii., 1890. Friedenthal : Function der weissen Blutkorperchen. Biol. Cbl., xvii., 1S97 (Lit.). Gabritchewsky: Pathologie der Spirochateninfection. Cbl. f. Bakt., xxiii., 1898. Hahm Naturliche Immunitat. Handb. d. path. Organismen, iv., Jena, 1904 (Lit.). Hankin: Ueber den schtitzenden Eiweisskorper der Ratte. Cbl. f. Bakt., ix., x., 1891; Ueber den Ursprung und das Vorkommen von Alexinen im Organismus, ib., xii., 1892. Hugenschrnidt: Defense de la cavite buccale. Ann. de l'Inst. Pasteur, 1896. Jacob: Schutzkraft d. Leukocyten. Zeit. f. klin. Med., 32 Bd., 1897. Jetter: Backtericide Eigenschaften des Blutserums. Arb. a. d. path. Inst, zu Tubin- gen, i., 1893. Jurgelunas: Durchgiingigkeit des Granulations-Gewebes. B. v. Ziegler, xxix., 190 1. BACTERICIDAL SUBSTANCES: OPSONINS. 107 Kendratieff: Selbstschutz ties thier. Organismus. Arch. f. exp. Path., 37 Bd., 1896. Kossel: Lymphzellcn. Deut. med. Woch., 1894; Baktericide Zellbestandtheile. Zeit. f. Hyg., 27 Bd., 1898. Krosing: Bakterienfeindliches Verhalten d. Scheidenseorete. Deut. med. Woch., 1S94. Kruse: Bemerkungen tlber Infection, Immunitat, und Heilung. Beitr. v. Ziegler, xii., 1893. Kiister: Fragen der pathol. Pflanzenanatomie. Biol. Cbl., xx., 1900. Lowit: Bezieh. d. Leukocyten zur baktericiden Wirkung. Beitr. v. Ziegler, xxii., 1897. Lubarsch: Die bakterienvernichtenden Eigenschaften des Brutes. Cbl. f. Bakt., vi., 1889; Unters. ub. die Ursachen der angeborenen und erworbenen Immunitat, Ber- lin, 1891; Ausscheidung der Spaltpilze. Ergebn. d. a. P., vi., 1901. Manfredi: Bedeutung d. Lymphgangliensystems. Virch. Arch., 155 Bd., 1899. Marchand: La phagocytose des streptocoques. Arch, de med. exp., x., 1898. Marmorek : Theorie der septischen Krankheiten, Stuttgart, 1894. Metsehnikoff : Die Lehre v.d. Phagocyten. Handb. d. pathog. Organismen, iv., Jena, 1904. Mills: Action de la salive et du sue gastr. sur les bacteries, Bruxelles, 1896. Mosse: Kommen der Zelle antibakt. Eigensch. zu? Zeit. f. klin. Med., 36 Bd., 1898. Moxter: Wirkungsweise der bakterienauflos. Substanzen. Cbl. f. Bakt., xxvi., 1899; Beziehung d. Leukocyten zu den bakterienaufibsenden Stoffen. Deut. med. Woch., 1899. Neisser: Durchgangigkeit der Darmwand fiir Bakterien. Zeit. f. Hyg., xxii., 1896. Nissen: Bakterienfeindl. Eigensch. d. Blutes. Zeitschr. f. Hyg., vi., 1889. Noesske: Eosinophile Zellen bei Infectionskrankheiten. Zeit. f. Chir., 55 Bd., 1900. Notzel: Infect, granul. Wunden. Forschr. d. Med., xvi., 1898. Nuttal: Bacillenfeindl. Einflusse des thier. Korpers. Zeit. f. Hyg., iv., 18S8; Bak- terienvernichtende Eigenschaften des Blutes. Cbl. f. Bakt., iv., 1889. Ogata: Ueber die bakterienfeindliche Substanz des Blutes. Cbl. f. Bakt., ix., 1891. Pekelharing : Zerstorung des Milzbrandvirus iin Unterhautbindegewebe. Beitr. v. Ziegler, viii. , 1890. Petruschky: Der Verlauf der Phagocytencontroverse. Fortschr. d. Med., viii., 1890; Einwirkung des lebenden Froschkbrpers auf den Milzbrandbacillus. Zeit. f. Hyg., vii., 1889. Podwyssozki: Die Reservekrafte des Organismus, Jena, 1894. Sanarelli: Die Ursachen der naturl. Immunitat gegen Milzbrand. Zeit. f. Bakt., ix., 1891; Defense de l'organisme contre les microbes. Ann. de 1'Inst. Pasteur, vii., 1893. Stern: Ueber die Wirkung des menschlichen Blutes und anderer Korperflussigkeiten auf pathogene Mikroorganismen. Zeit. f. klin. Med., 18 Bd., 1890; Neuere Ergebnisse auf dem Gebiete der Immunitatslehre. Cbl. f. allg. Path., v., 1894 (Literaturiibersicht). Strasburger: Die Bedeutung d. normalen Darmbakterien. Mimchen. med. Woch., 1903. Walz: Baktericide Eigenschaften des Blutes, Braunschweig, 1899. Wassermann: Personl. Disposition gegen Diphtheric Zeitschr. f. Hyg., xix., 1895. Werigo: Les globules blancs comme protecteurs du sang. Ann. de 1 Inst. Pasteur, vii., 1893; Developp. du charbon chez le lapin. lb., viii., 1894. Wyssokowitsch: Schicksal der ins Blut injic. Mikroorganismen. Zeitschr. f. Hyg., i., 1886. Ziegler: Ursachen und Wesen der Immunitat des menschlichen Organismus gegen In- fectionskrankheiten. Beitr. v. Ziegler, v., 1889; Schutzkrafte des menschlichen Organismus. Akad. Rede, Freiburg, 1892; Die Lehre von der Entziindung. Beitr. v. Ziegler, xii., 1892. See also Literature to §§ 31 and 32. {Opsonins.) Barratt: Proc. Roy. Soc, 190.5. Bulloch: Lancet, 1905; Practitioner, 1905. Cole and Meakins: Johns Hop. Hosp. Bull., 1907. Cowie ami Chapin: Jour, of Med. Res., 1907. Dean: Proc. Roy. Soc, 1905. Hamilton: Jour, of Infect. Dis., 1907. Hamilton and Horton: Ibid., 1906. Hektoen: Jour. Amer. Med. Ass., 1906; Jour, of Infect. Dis., 1906, 1907. Horton: Jour, of Infect. Dis., 1906. 108 THE PROTECTIVE POWERS OF THE BODY. Jeans and Sellards: Johns Hop. Hosp. Bull., 1907. Klien: Ibid. Lawson and Stewart: Lancet, 1905. Moss: Johns Hop. Hosp. Bull., 1907. Rosenow: Jour, of Infect. Dis.. 1907. Rotch and Floyd: J. Anier. Med. Ass., 1907. Ruediger: J. Amer. Med. Ass., 1905, 1906. Russell: Jour. Inf. Dis.. 1907. Simon: Jour, of Exp. Med., 1906. TunniclifT: Jour, of Infect. Dis., 1907. Walker: Jour. Med. Res., 1907. Wright: Med. Chir. Trans., 1905; Lancet, 1905; Jour. Amer. Med. Ass., 1907; Prac- titioner, 1908. Wright and Douglas: Proc. Roy Soc, 1903, 1904; Lancet, 1904. § 31. The healing=powers of the human body are furnished by those life-processes which are able to compensate for the disturbances and changes caused by disease, and to render harmless or to remote any harmful agent that may still be present in the body. If portions of tissue have been destroyed, the healing consists essentially in the removal of the changed and dead tissue, and its replacement by new tissue. When from any cause the temperature of the body becomes abnor- mally low or abnormally high, compensation may be effected in such a way that through the suitable regulation of the heat-production and heat-dispersion the temperature of the body may be brought back to the normal. If through trauma a portion of tissue is destroyed, the organism may repair the defect either through the local production of new tissue (regeneration) or by a corresponding increase in other similar tissues (compensatory hypertrophy). If poisons enter the body and produce symptoms of intoxication, healing can follow only through the rapid excretion of the poison, or its destruction or neutralization within the body ; while at the same time the damaged tissues, under the influence of normal nutrition, again return to their normal state, existing defects being properly compensated. In infections the healing processes follow directly upon the action of the protective forces; indeed, the action of the latter constitutes the first stage of healing; the protective and healing processes are in part identical. In many infectious diseases the healing influence of protective sub- stances already present in the affected body is supplemented by the ap= pearance of new substances foreign to the normal organism, which as bactericidal substances and as antitoxins antagonize both the infection and the intoxication. The bactericidal antibodies are formed by the tissue-cells which through the infection have been placed under altered conditions of life; they spread throughout the tissue-juices, and thus hinder the further extension and multiplication of the bacteria. They are formed particularly in typhoid fever, cholera, and plague, and show constantly a certain specificity in that they influence primarily those bacteria through whose vital activities they have arisen. This specificity is, how- ever, not absolute, inasmuch as they can act upon closely related species. Antitoxins are formed in those infections in which toxins are pro- duced. The action of the toxin takes place in this manner (Ehrlich) : the poison molecule combines through a haptophorous side-chain with the haptophorous group of certain cells, while the toxophorous side- chain of the poison exerts its influence in a specific manner upon the affected cells, so that we may regard the antitoxins as representing noth- ing more than an excess of haptophorous side-chains of the cell-substance sus- antitoxins: specific bactericidal substances. 109 ceptible to the poison, that are given off into the blood-serum and into the body- juices, and combine the corresponding haptophorous side-chains of the toxin. The haptophorous group of the toxin is thereby prevented from carrying over its toxophorous group to the cells and thereby becoming active. Toxin and antitoxin combine according to fixed quantitative relations. Antitoxins are formed against the poison of diphtheria and tetanus, the pyo- cyaneus poison, ricin, snake-poison, the poison of eel-blood, and certain mushroom poisons. Since the antitoxins of snake-venom (Calmette) and that of the pyocyaneus toxin {JY assermann) are more easily destroyed than the poisons themselves, it is possible in a mixture of the two, when the combination has lasted but a short time, to destroy by heating to a certain degree the antitoxin alone, so that the toxin again becomes active. The virulence of the toxin of diphtheria is weakened with age, through the fact that the toxophorous group in part becomes inactive. If the favorable course and the healing of an infectious disease depend essentially upon the production of antitoxins, the bacteria concerned may still be preserved and increase in numbers; only the harmful action is averted. After a certain time they also die. According to investigations by R. Pfeiffer, confirmed by Sobemheim, Dunbar, Loeffier, and others, there is found in the blood-serum of animals made immune against typhoid-bacilli or cholera-spirilla, or of human individuals suffering or convalescing from typhoid fever and cholera, a specific bactericidal substance (f/sogenous substance of C . Fraenkel). The addition of such a serum to a virulent bouillon-culture of these bacteria so changes the latter that the bacteria when inoculated into the peritoneal cavity of an experimental animal rapidly disintegrate into little spherules and are finally dissolved. Burdet has shown that a fresh human' serum is active also in the test-tube outside of the human body. When heated to 56° C. this activity is lost (inactivation) but it may be restored again through the addition of normal serum (reactivation). According to the investigations of Gruber, Durham, Pfeiffer, Kotle. Sobemheim, Widal, C. Fraenkel, and others, the blood-serum of individuals ill, convalescing, or en- tirely recovered from, typhoid or cholera exerts a damaging influence upon typhoid- bacilli or cholera-spirilla respectively; this influence being of such a nature that in bouillon-cultures the bacteria so affected become motionless, clump together, sink to the bottom-'of the vessel, and are destroyed. When the serum is added to a hanging drop of bouillon-culture, the rapidly moving vibrios at once become motionless and collect in little heaps. Gruber believes that this phenomenon is to be explained by a swelling and bursting of the membrane of the bacterial cell, and assumes that this phange enables the alexins to destroy the bacteria present in the body. He therefore designates the active substances in the serum as agglutinins, and believes that to these may be attributed the chief agency in the healing of infectious diseases and in the pro- duction of immunity against the same. Pfeiffer, on the contrary, denies the occurrence of any swelling of the cell-membrane, and explains the phenomenon as due to an in- hibition of development, and designates the active substances, the nature of which is wholly unknown, as specific paralysins. After Gruber had demonstrated the peculiar action of the blood-serum of typhoid-fever patients, Widal {Sem. medicate, Paris, 1896) proposed that this action of the blood-serum on cholera-spirilla and typhoid-bacilli respectively be utilized as a diagnostic aid during the course of an attack of typhoid. Numerous "clinical investigations have demonstrated that it is possible, during the course of the attack or for a long time (several months) afterward, to make a diag- nosis of typhoid from the action of the blood-serum upon cultures of typhoid bacilli (W idol's reaction). (See § 33.) According to Kraus, there is present in the blood of animals artificially immunized against cholera and typhoid fever a body, which, on the addition of such a serum to a clear bacteria-free filtrate of cultures of cholera or typhoid bacilli, produces in the latter a clouding and later a precipitation, thus acting as a precipitin. (See § 33.) The protective substances which appear in the blood in the course of infectious diseases are not always formed at the same place; in pneumonia they are said to be produced in the bone-marrow (Wassermann); in cholera and typhoid fever in the spleen (Pfeiffer and Marx); in " Rinderpest '■' in the liver (Koch). They are to be regarded as specific secretory products arising in response to specific stimuli. The bactericidal immune=bodies are, according to their physical and chemical properties, to be regarded as ferments (theyare neither globulins nor albumins). The immune-bodies combined with the bacterial cells during bacteriolysis may be set free after the solution of the bacterial protoplasm, and again become capable of action. 110 THE PROTECTIVE POWERS OF THE BODY. It has often been assumed that the fever occurring in infectious diseases is a pro- tective process favoring the destruction of bacteria; and it is not impossible that in individual cases it may exert such a favorable influence. Thus, for example, it is con- ceivable that a parasitic micro-organism, growing well at a temperature of 37-38° C, will not thrive at a temperature of 40-41° C so that high-fever temperatures may hin- der its power of reproduction. The conclusion should not, however, be drawn from this that fever is a useful phenomenon which always favors the counterbalancing of pathological disturbances. Even in those cases in which the metabolic processes occur- ring during the fever exert an injurious influence upon the bacteria, this is not to be taken as proving the usefulness of fever. We can only say that a. part of the morbid processes occurring during an infectious fever leads to a formation of decomposition- products which may possess antibacterial or antitoxic properties. Literature. (Bactericidal Substances and Antitoxins.) Banti: Sulla distruzzione dei batteri nell' organismo. Arch. p. le Sc. Med., xiii., 1SS9. Biedl u. Kraus: Ausscheidung d. Mikroorganismen durch Driisen. Zeit. f. Hyg., xxvi., 1897. Bitter: Metschnikoff's Phagocytenlehre. Zeit. f. Hyg., iv.. 1888; Bakterienfeindl. Stoffe thier. Organe, ib., xii., 1892. Bordet: Action des serums preventifs. Ann. de l'lnst. Past., 189G; Mecanisme de 1 'ag- glutination, ib., 1899. Bordet et Genon: Substances sensibilatrices des serums antimicrobiens. A. d. l'lnst. Past., 1901. Bouchard: Les microbes pathogenes, Paris, 1892. Brieg-er: Antitoxine und Toxine. Zeit. f. Hyg., xxi., 1,896. Conradi: Bildung baktericider Stoffe bei der Autolyse. B. v. Hofmeister, i., 1901. Denys et Havel: La part des leucocytes dans le pouvoir bactericide du sang. La Cellule, x., 1893. Durham: On a Special Action of the Serum. Journ. of Path., iv., 1896. Eichel: Wachsthumsverhaltnisse verschied. Bakterien im Fieber. Virch. Arch., 121 Bd., 1S90. Foerster: Die Serodiagnostik d. Abdominaltyphus. Fortschr. d. Med., 1897 (Sam- melref. ). Fraenkel, C; Agglutinine bei Typhus abdom. (Widal'sche Probe.) Deut. med. Woch., 1897 (Lit,). Gamaleia : Destruction des microbes dans les organismes Kbricitants. Ann. de l'lnst. Past., 1883. Golgd: II fagocitismo nell' infezione malarica. Arch. ital. de Biol.,xi., 1889. Gruber: Immunitat geg. Cholera u. Typhus. Wien. med. Woch., 1896; Theorie der Immun. (Agglutinine). Munch, med. Woch., 1897; Serumdiagnostik d. Typhus, ib.; Theorie der Agglutination, ib., 1899. Halm: Bezieh. d. Leukocyten z. baktericiden Wirkung d. Blutes. Arch. f. Hyg., 25 Bd., 189.5. Jetter: Baktericide Eigensch. d. Blutserums. Arb. a. d. path. Inst, zu Tubingen, i., 1893. Loewy u. Richter. Ileilkraft des Fiebers. Virch. Arch., 145 Bd., 1896 (Lit.), v. Klecki: Ausscheidung d. Bakt. durch d. Nieren. Arch. f. exp. Path., 39 Bd., 1897 (Lit.). Melnikow: Bedeutung der Milz bei Infectioneu. Zeit. f. Hyg., xxi., 1896 (Lit.). du Mesnil: Gruber-Widal'sche Serumdiagnostik. Munch, med. Woch., 1897. Nissen: Bakterienvernichtende Eigenschaften des Blutes. Cbl. f. Bakt., iv., 1889. Oppenheimer: Toxine und Antitoxine, Jena, 1904. Pawlowsky: Heilung des Milzbrandes durch Bakterien u. das Verhalten der Milz- brandbacillen im Organismus. Virch. Arch., 108 Bd., 1SS7; Bemerk. tib. d. Mittheilung v. Emmerich u. di Mattei: Ueber Vernichtung der Milzbrandbacillen im Organismus. Fortschr. d. Med., vi.; Infection u. Immunitat. Zeit. f. Hyg., 33 Bd., 1900. Pernice u. Scag-liosi: Ausscheidung d. Bakt. a. d. Organismus. Deut. med. Woch., 1892 (Lit.). Pfeiffer (Kolle, Vagedes): Fin neues Grundgesetz d. Immunitat, etc. Deut. med. Woch., 1896; Specifische Immunitatsreaction der Typhusbacillen. Zeit. f. Hyg., xxi., 1896 (Lit.); Weitere L T ntersuchungen ub. specifische Immunitatsreaction. IMMUNITY. Ill Cbl. f. Bakt., xx., 1S9G (Lit.); Wirkung und Art. d. aktiven Substanz d. pra- ventiven u. toxischen Sera. Ibid., xxxv., 1904. Roger: Elimination des poisons. Path. gen. de Bouchard, i., Paris, 1895. Ruffer: Destruct. des microbes par les cellules amceboides. Ann. de l'lnst. Past., v.. 1891. Sherrington: Exper. on the Escape of Bacteria with the Secretions. Journ. of Path., L, 1893 (Lit.). Tsuboi: Die Schutz- und Heilsubstanz des Blutes, Wiesbaden, 1892. Wassermann : Pneumokokkenschutzstoffe. Deut. med. Woch., 1899. Williamson: Leukocyten bei Pneumokokkeninfektion. B. v. Ziegler, xxix., 1901. Widal et Sicard: Le serodiagnostie. Ann. de l'lnst. Past., 1897 (Lit.). Ziegler: Die Ursachen d. pathol. Gewebsneubildungen. Internat. Beitr., ii., Festr. f. Virchow, Berlin, 1891; Ueb. d. Zweckmassigk. d. pathol. Lebensvorgange. Munch. med. Woch., 1896. See also § 30, § 32, and § 33. II. The Acquiring of Immunity against Infection and Intoxication. Protection through Inoculation. § 32. The acquiring of immunity against a particular infectious disease is a phenomenon whose frequent occurrence has long been known through clinical observations. This fact has been established chiefly by the observation that the great majority of men suffer but one attack of such widespread infections as measles, smallpox, whooping-cough, scar- let fever, and diphtheria, and that after such attack they are spared by the disease, even when they expose themselves under the most varied conditions to the danger of infection with its poison. The knowledge of this fact is very old, and early in the eighteenth century it had led, in the Orient, to attempts to obtain immunity against the natural contagion of smallpox by the inoculation of material from smallpox pustules. In the latter part of the eighteenth century Jenner discovered that the dis- ease known as cowpox — i.e., a milder form of pox, which is an attenuated form of human smallpox — afforded protection against the true smallpox. As a result of this observation, since the beginning of the year 1796, at first by Jenner himself, afterward by the physicians of all civilized countries, artificial inoculations of cowpox have been carried out upon millions of human individuals, with the result that through such inoculation a high degree of immunity against the true smallpox has been secured to the inoculated; so that at the present time, in all countries where vaccina- tion is universally practised, the occurrence of widespread epidemics of smallpox, once so frequent, is very rare, and the disease no longer as- sumes the character of a dangerous pestilence. The investigations of the last decades with regard to the causes and origin of infectious diseases, which have covered such an extraordinarily broad field, have shown that the acquiring of immunity against a cer= tain infectious disease through one attack of the given disease oc- curs in different infectious diseases, especially in those running an acute course; and represents sometimes a transitory, at other times a per- manent peculiarity of the individual concerned, which in pregnant women may be transmitted to the foetus in utero. These observations have also shown that the single or repeated inoculation of attenuated pathogenic bacteria — that is, of bacteria which on account of their slight virulence produce a disease that, in contrast to the natural infection with bacteria of full virulence, is relatively insignificant, often localized to a limited area — can also confer immunity against the corresponding dis- ease. Further, it has been demonstrated that the injection of certain 112 THE PROTECTIVE POWERS OF THE BODY. chemical substances produced by the bacteria is sufficient to confei immunity against certain infections. Immunity through the inoculation of attenuated specific disease- germs may Vie produced, for example, against anthrax, symptomatic anthrax, chicken-cholera., diphtheria, and swine-erysipelas. The weak- ening of the virulence of bacteria may be produced either by the action of high temperatures or chemical agents, or by the action of the air alone ; further, it may also be produced by the inoculation of the bacteria into certain animals or through their long-continued cultivation on artificial media. Inoculation is, in general, carried out by injecting subcutane- ously first markedly attenuated, then less attenuated, and finally fully virulent bacteria together with their products. According to the investigations of numerous authors, immunity in animals may also be produced by the injection of sterilized cultures in which the bacteria are completely killed — as, for example, against Ameri- can hog-cholera, symptomatic anthrax, diphtheria, the infectious disease produced experimentally in rabbits by the injection of the Bacillus pyo- cyaneus, and the infection produced in guinea-pigs by cholera-spirilla. A third form of artificial immunization, which Raynaud attempted as early as 1S77, but was first securely established by Behring in 1890, can be produced by the injection into man or an experimental animal of blood=serum taken from animals which were previously susceptible, but have been rendered immune by means of inoculations. The most extensive and at the same time the most successful attempts thus far made have been carried out with diphtheria and tetanus; that is, in dis- eases in which intoxication through toxins forms the most striking fea- ture. Moreover, successful exxjeriments with the blood-serum of immu- nized animals, in the case of cholera, swine-erysipleas, anthrax, typhoid fever, and plague, have been reported. The specific protection which the blood-serum affords may be secured, not only by injection before infection occurs, but also after infection "Nas already taken place ; so that the serum may be designated not only a protective serum, but also a healing serum. For both protection against and for Ihe cure of a certain infection a definite amount of serum is necessary, the precise amount depending, on one hand, upon the se- verity of the infection, and On the other, irpon the activity of the serum itself, which increases with the completeness of the immunization of the originally susceptible animal furnishing the serum. If the serum is not injected until after infection has occurred, the amount of serum must be so much the greater the longer the lapse of time after the beginning of the infection. In the case of true bacillary diphtheria, the injection of curative diphtheria-serum has now been carried out in thousands of cases, of both severe and light forms ; and there is without any doubt a beneficial influence exerted upon the course of the disease, as shown by a rapid improvement of the patient's general condition (rapid establishment of euphoria, fall of fever, improvement in the pulse), as well as by the favorable course pursued by the local disease. In tetanus a definite cur- ative action of serum has been demonstrated in the case of experimental animals, guinea-pigs, and mice ; but the results in man have not yet been fully determined. The blood-serum of immunized animals exerts its beneficial action, without doubt, through the presence of a counter-poison, an antitoxin, which neutralizes the poisons produced by the bacteria. In the case of IMMUNITY. 113 the patients treated by a given antitoxin, there is produced a poison- immunity against the corresponding bacterial poison — as, for example, against the rtoison produced by the diphtheria-bacilli, in those patients injected with diphtheria-antitoxin — and this immunity is to be ascribed to the presence of a definite amount of antitoxin in the blood. Besides the antitoxins, the blood-serum of immunized animals or human beings may also contain bactericidal substances, which injure or kill the bacteria themselves ; and this is said to occur especially in cholera and typhoid infections. In the case of immunization by means of attenuated cultures or by sterilized chemical bacterial products, the antibodies are produced as new substances within the organism, and this process has been designated active immunization (Bhrlich) ; in the case of the injection of immu- nizing serum the antitoxin already formed is introduced from without, and this may be spoken of as passive immunization. It is probable that in the last case no new-formation of antitoxin occurs after the injection. For tlie foundation researches in regard to inoculation with attenuated cultures of bacilli cultivated outside of the body, we are indebted to Pasteur, who, in 18S0, demon- strated the fact that chickens could be immunized against chicken-cholera through the inoculation of cultures of chicken-cholera bacilli, that had been weakened through long exposure to the air. Since that time numerous experiments have been carried out with other forms of bacteria, especially with attenuated cultures of the bacilli of anthrax and symptomatic anthrax. Good results have been obtained from inoculations against the symp- tomatic anthrax of cattle. Less favorable are the results in inoculations against an- thrax, in that some of the animals die from the effects of the protective inoculation, while others are not rendered absolutely immune against a new anthrax infection. Sheep and cattle may be made immune against anthrax ; most expediently (Koch) by first inoculating them with attenuated cultures of anthrax-bacilli, which will kill mice but not guinea-pigs, and then with those which will kill guinea-pigs but not large rabbits. As vaccine against symptomatic milliner, there may be used cultures of the bacillus attenuated through heat or such chemical agents as sublimate solutions, thymol, eucalyptol, and silver nitrate; and by such inoculations cattle maybe rendered im- mune. At the present time heat (Hess, KM) is most commonly used in the preparation of the vaccine. The infected muscle of an animal dying with symptomatic anthrax is chopped tine, triturated with one-half its weight of water, and pressed through a piece of linen cloth. Finally, the fluid is again Altered through a moistened piece of fine linen. The virulent material is then spread in thin layers upon glass plates or flat dishes, and transferred to a dry chamber at a temperature of 32-35° 0. When thor- oughly dry the virus is scraped off and removed in the form of powder. When it is desired to give inoculations, the virus is triturated with double its weight of water and the fluid evaporated in a thermostat. By raising the temperature to 100° C. for six hours a weak vaccine is obtained ; at a temperature of 85° C. for six hours a stronger one. For the immunization of cattle, about 0.5 gm. of the weaker virus in a dilute water solution is injected into the subcutaneous tissue of the animal's tail, and after eight to twelve days the stronger solution is similarly injected. According to observations of C'hauveau and others, protective inoculations may also be made by the injection of virulent bacteria in very small quantities, or in such a manner that the life of the animal shall not be endangered. In the ease of sympto- matic anthrax this may be accomplished by the injection of very small doses into the extremity of the animal's tail; such injections not causing a fatal illness, but only a local disturbance. According to Afanassieff, it is possible to render animals immune by inoculating the granulating surface of a wound with a virulent culture. Cattle may also be immunized against contagious pleuropneumonia, (Hchiitz) by in- jecting the tissue-juices from the lung of an animal dying from this disease into the tip of the tail. There is produced in this way a circumscribed inflammation, or, at least, one which is confined to the tail ; after recovery from which the animal is im- mune to both natural and artificial infection with this disease. Hogs may be rendered immune against inoculation with virulent bacilli of swine- 114 THE PROTECTIVE POWERS OF THE BODY. erysipelas (Pasteur), by using, as vaccine, cultures attenuated by successive inocula- tions" in rabbits. According to Emmerich, rabbits may also be made immune against the bacilli of swine-erysipelas through the injection into the ear-vein of a small quan- tity of a virulent bouillon-culture diluted with fifty times its volume of water. Animals susceptible to diphtheria may be rendered immune against this disease, according to Behring, by the injection of cultures of diphtheria-bacilli which have been weakened in virulence by exposure for sixteen hours to iodine trichloride (1 : 500). Two cubic centimetres of such a culture are injected into the peritoneal cavity; after three weeks this injection is repeated with a diphtheria-culture (0.2 c.c.) which has been washed four days in bouillon containing iodine trichloride (1 : 5,500). After this, f idly- virulent cultures are injected in increasing doses. Protective inoculations against rabies were first carried out in cases resulting from bites by rabid animals, particularly in France (Pasteur Institute), Russia, and Italy. As inoculation-material, the spinal cord from rabbits which have been infected with rabies is used after it has been dried in dry air at a temperature of 23-25' C. ; the viru- lency of the cord being gradually lost after about fifteen days of the drying-process. According to Protopopoff, it is the temperature, and not the drying (Pasteur), which lessens the virulence. According to Marx, the micro-organisms of rabies have already been weakened in the body of the rabbit. Small portions of a rabbit's cord thus weak- ened in virulence are triturated in sterilized chicken-broth and injected subcutaneously into the bitten individual ; at first pieces of cord greatly reduced in virulence are used, then those of gradually increasing virulence. According to the view held by Pasteur, the spinal cord contains both the microbes of the disease and the specific poison formed by them ; if the latter spreads through the body more rapidly than the microbes, it con- fers an immunity against a subsequent spread of the microbes, and affords protection to the nervous system in particular. In order to confer immunity it is, therefore, necessary to introduce as large a quantity as possible of the chemical poison. Accord- ing to the reports of the Institutes in which the Pasteur inoculations against hydro- phobia have been carried out, it must be acknowledged that these inoculations have been successful in preventing cases of hydrophobia. Immunity against cholera may be produced, in both man and animals (Ilaffline, Pfeiffer, Kolle, Voges, and others), by the injection of sterilized or attenuated cultures of cholera-spirilla; this immunity (which is of short duration) depends upon the forma- tion of specific bactericidal anti-bodies in the blood (see Voges, 1. c). On the other hand, we do not yet possess a specific remedy by which the life of any animal or man in- fected witli cholera may be saved. Immunity against typhoid feeer may be secured in man by the subcutaneous injec- tion of sterilized cultures of typhoid-bacilli (Pfeiffer, Kolle) ; and the establishment of the immunity may be recognized by the fact that the blood-serum of the individual so inoculated is found, after a few days, to contain bactericidal substances. Attempts at immunization in cases already ill with typhoid (Brieger, Wassermann, O. Fraenkel) have up to the present time been unsuccessful. According to the reports published by Koch (British Medical Journal, 1897; Deut. med. Wbchen., 1897, No. 10; Centralbatt f. Ball., xxi.. p. 520) of the investigations which were carried out during the winter of 1896-1897 with regard to the cattle-plague in Cape Colony, cattle may be immunized against " Sinderpest" by subcutaneous in- jections of 10 c.c. of the bile taken from animals dying of the disease; the condition of immunity becoming established at the latest by the ^enth day. According to the re- port of Professor Winkler (" Landwirthschaftl. Bezirks-Verein Giessen," August, 1900) hogs and cattle may be immunized against foot-and-mouth disease through feeding with milk of animals which are affected by the disease or have recently recovered from it. Loeffler and Uhlenhuth (Conlralblatt f. Ball., xxix., 1901) have also reported successful protective inoculations with a serum against the foot-and-mouth disease. In the year 1890 Koch made the discovery that cultures of tubercle-bacilli contain an active substance, "tuberculin," which, when injected into tuberculous individuals, causes a rise of temperature and to some extent local inflammatory changes in the neigh- borhood of tuberculous foci. It was at first hoped that in tuberculin a remedy for tuberculosis had been found, but the many trials made with it upon human beings and animals have shown that it indeed produces after repeated injections an immunity against the toxic action of tuberculin, but does not hinder the multiplication of tubercle- bacilli and the consequent spread of the disease. Further, the local inflammation caused by the tuberculin leads to favorable results only under special conditions, but, on the other hand, often causes actual harm (through the metastasis of bacilli). Never- theless, Koch's discovery has proved of great importance. In the first place, it is of practical value in the diagnosis of tuberculosis, in that tuberculin injections do not ex- cite fever in normal individuals. Inoculations for diagnostic purposes are now used very extensively in cases of suspected tuberculosis in domestic animals. Moreover, the reports published by Koch gave a great stimulus to further investigations with re- HEALING SERA: VACCINES. 115 gard to immunization by means of inoculation with bacterial toxins; and these investi- gations have led to the discovery of the antibodies of diphtheria, tetanus, cholera, and typhoid fever. Small doses of tuberculin appear also to have a favorable influence upon the course of tuberculosis. In 1897 Koch ("Ueber neue Tubereulinpriiparate," Dent, med. Woch., 1897) suc- ceeded in obtaining from highly virulent cultures of tubercle-bacilli a substance which he claims is able to immunize against all of the constituents of the tubercle- bacillus. To obtain this substance young cultures of tubercle-bacilli are dried in a vacuum-exsiccator and then triturated. The product obtained by trituration is mixed with distilled water and centrifugated. The active substance is contained in the muddy precipitate thus obtained (designated by Koch as T. It.). This is again dried and tritu- rated, dissolved in water to which twenty per cent of glycerin is added for the purpose of preservation. (The preparation is manufactured by Meister, Lucius, and Brunning, at Hochst-on-the-Main, Germany.) The fluid preparation contains 10 rugm. of solid substance in every cubic centimetre, and when it is to be used should be diluted with physiological salt solution. Through the use of large doses animals are said to become immunized in from two to three weeks. In the treatment of tuberculosis in man the dose should begin at ^-^ mgm. and gradually be increased up to 20 mgm., the injections being given every other day. According to the observations so far published, the T. R. preparation does not appear to exert a curative action upon tuberculosis in man. The blood=serum treatment of diphtheria, i.e., the employment of the antitoxins contained in the blood of an animal immunized against diphtheria as a means of curing that disease when it is already contracted, or as a protection against such infection, is a discovery which we owe to Behring. The favorable effects of the method discov- ered and proved by him through experimental investigations have been confirmed by thousands of observations. In the treatment of diphtheria patients a large quantity of the serum (one thousand immunizing units) is usually injected at one time beneath the skin of the thigh. The term "normal serum" — i.e., a serum having the value of one immunization unit — is used by Bel/ring to designate a serum which, when mixed with a quantity of diphtheria poison equal to ten times the minimal fatal dose and then injected in (he amount of 0.1 c.c. into a guinea-pig of from 200 to 300 gm. weight, will surely protect that animal from diphtheria. Sheep and horses are especially adapted for the prepara- tion of the serum. Tt is prepared and sold in doses of from five hundred to three thousand immunization units. If culture-filtrates of the tetanus=bacillus are weakened by the action of chemi- cal agents (iodine trichloride or iodine combined with potassium iodide), it is possible through repeated injections of such filtrates of increasing virulence to produce im- munity in animals against tetanus (Kitasato, Behring, Tizzoni, Buelmer). The blood of such immunized animals contains an antitoxin which affoi'ds a sure protection to experi- mental animals against tetanus. The antitoxin treatment of human beings suffering from tetanus has not given satisfactory results (see Kohler and Schlesinger, I.e.), not even in cases of relatively early injection of the antitoxin, though it appears to be effective if administered before the appearance of the tetanus. Susceptible animals and human beings may be immunized against bubonic plague by means of sterilized cultures of the pest-baciilus (Tersin, Haffkine, Kolle); and it ap- pears that in the blood-serum of immunized animals (the horse, for example) there are present anti-bodies which render the serum utilizable for both protective and curative purposes. Animals may be made immune against snake-poisons by means of inoculations of very small doses of such poison continued for some length of time (Calmette, Tsahisto- witsch); and the blood-serum of such immunized animals is also found to possess an antitoxic action against the given poison, so that it may be used as a healing-serum. In Brazil, Mexico, Africa, etc., various methods involving the use of snake-poison itself are employed for the immunization of individuals against a snake-bite, fir for curing them after they have been bitten (drinking of the secretions of the poison- glands, rubbing of the diluted poison into small wounds of the skin, etc.) (Brenning). According to the investigations by Ehiiich, mice may be made immune against ricin, to which they are extremely susceptible, by mixing very small doses of ricin with their food and then afterward injecting additional small doses subcutaneously. The appearance of the immunity occurs on the sixth day after the administration of the ricin, so that upon this day the animal can withstand a dose thirteen times as great as at the beginning. Through continued systematic inoculations the animal becomes immune to a dose eight hundredfold as strong. The immunity is produced by an anti- toxic body, antiricin, which neutralizes the poisonous action of ricin. Vaccines. Since Wright's discovery of the opsonins, bacterial vaccines have been extensively employed in the treatment of certain infections. The vaccines are prepared by cultivating the'given organism on agar-agar, suspending the growth in salt-solu- 116 THE PROTECTIVE POWERS OF THE BODY. tion, and heating to 05 c -80° C. for an hour to kill the bacteria. The emulsion of dead bacteria is then injected. Immediately following the injection the opsonic index falls for a time, the so-called negative phase. This is followed in a day or two by a rise in the index to or above its original height, the positive phase. Considerable doubt has been thrown upon the opsonic index as a reliable guide in the progress of an infection ; but man}' clinicians have obtained gratifying results in the treatment with bacterial vaccines. The conditions most amenable to this treatment are localized inflammations caused by staphylococci, streptococci, pneumococci, gonococci, and the tubercle-bacil- lus. As the method of treatment is still in the experimental stage, it is too early to make definite statements concerning its value. Attempts have been made to treat thyroidism with a specific serum (Rogers, Beebe). Experimental immunity to Spirillum obermeieri can be. produced by the injection of filtered blood in which the spirilla have died out (Novy). Experimental immunity can be obtained in experimental cerebrospinal meningitis (Flezuer). Literature. {Acquiring of Immunity against Infections and Intoxications.) Afanassieff: Bedeutung des Granulationsgewebes bei Infection. Beitr. v. Ziegler, xxii., 1897. Arloing-, Cornevin, et Thomas : Le charbon symptomatique, Paris, 1887. Babes: Studien tiber die Wuthkrankheit. Virch. Arch., 110 13d., 1887. Baumg-arten : Phagocytenlehre. Beitr. v. Ziegler, vii., 1890; Jahresber., 1891-98. Beck: Untersuclningen liber Tetanus. Zeit. f. Hyg., xix., 1895. Beclere, Ch.am.bon, et Menard: Immunite vaccinale. Ann. del'Inst. Past., 1890. Beebe: Nucleo-proteid Immunity. Brit. Med. Jour., 1900; Serum-treatment of Ex- ophthalmic Goitre. Trans. Ass. Amer. Phy., 1900. Bet-ring: Die Ursachen der Immunitat von Batten gegen Milzbrand. Cent. f. klin. Med., 1888; (andKitasato)Diphtherie-Immunitatu. Tetanus. Deut. med. Woch., 1890; Die Blutserumtherapie, i., ii., Leipzig, 1892; Die Blutserumtherapie bei Diplitherie u. Tetanus. Zeit. f. Hyg., xii., 1892; Immunis. u. Heilung bei Tetanus, ib,, xii., 1892; Die Geschichte der Diphtherie, 1893; Gcsamm. Abhandlugen z. atiol. Therapie, Leipzig, 1893; Infection u. Desinfeclion, Leipzig, 1894; Leistungen u. Ziele der Serumtherapie. Deut. med. Woch., 1895; Immunitat. Eulenburg's Bealencyklop., 1890; Antitoxintlierapeutischc Probleme. Fortschr. d. Med., 1897; Ileilprincipien. Deut. med. Woch., 1898. Bitter: Verbreitung d. "Vaccins u. d. Impfschutzes im Korper. Zeit. f. Hyg., iv., 1888; Pestigung v. Thieren gegen Toxine des Tetanus, ib., xii., 1892; Schutzimpf. gegen Pest, ib., xxx., 1899. Bonome: Transfusion von Blut u. Serum immunis. Thierc. Fortschr. d. Med., ix., 1891. Bordet: Serum antistreptococcique. Ann. del'Inst. Past., 1897. Brenning: Die Vergiftungen durch Schlangcn, Stuttgart, 1895. Brieg-er, Kitasato u. Wassermann: Immunitat und Giftfestigung. Zeit. f. Hyg., xii., 1892. Brieg-er u. Ehrlich: Die Milch immunisirter, Thiere. Zeit. f. Hyg., xiii. 1893. Buchner: Immunitat u. Inimunisirung. Munch, med. Woch., 1889, 1897, 1899; Bakteriengifte u. Gegengifte, ib., 1893; Sehutzimpfung. Handb. d. spec. Ther., i., Jena, 1894. Calmette: Vem'ns, toxines et antitoxines. Ann. del'Inst. Past., 1895; Venins des ser- pents et serum antivenimeux, ib., 1897. Calmus et Gley: Immunite contre le serum d'anguille. Ann. de l'lnst. Past., 1899. Charrin: L 'immunite. Arch, de phys., v., 1893; Traite de path. g§n., ii., Paris, 1890. Chauveau: Theorie des inoculations preventives. Rev. de med., 1887; Mecanisme de rimmunite. Ann. de l'lnst. Past., ii., 1888; Proprietes vaccinales des microbes ci-devant pathogenes transformer en microbes d'apparencesaprogene. A. denied, exp., i., 1889. Corbette: The Action of Antitoxins. Journ. of Path., vi., 1899. Delius u. Kolle: lnfluenzaimmunitiit (lasst sich nicht erzielen). Zeit. f. Hyg., 24 Bd., 1897. Deutsch.: Origine des anticorps typhiques. Ann. del'Inst. Past., 1899. Dieudonne: Sehutzimpfung u. Serumtherapie, Leipzig, 1895. IMMUNITY. 117 Ehrlich : Ueber Ricin u. Antiricin. Deut. med. Woch., 1891; Fortschr. d. Med., xv 1897: Die Werthbemessung d. Diphtherieheilserums. Klin. Jahr., 1897- Immii- nitat durch Vererbung u. Siiugung. Zeit. f. Hyg., xii., 1892; Zur Kenntuiss d. Antitoxmwirkung. Fortschr. d. Med., 1897. Emmerich: Ursache der Irnmunitat, Heilung von Infectionskrankheiten. Munch med. Woch., 1891; Infection, Immunisirung u. Heilung bei krup. Pneumonie Zeit. f. Hyg., xvii., 1894. Emmerich and Low: Bakteriolytische Enzyme als Ursache d. erworb. Immunitat u Heilung von Infectionskrankheiten. Zeit. f. Hyg., 31 Bd , 1899 Engelmann: Semmtherapie des Tetanus. Miinch. med. Woch. 1897 (Lit ) Ferran: L'mocul. preventive contre le cholera-niorbus, Paris, 1892. Finger : Immunitat u. Phagocytose beim Rotz. Beitr. v. Ziegler, vi., 1889. Flexner: Exper. Cerebrospinal Meningitis and Its Serum Treatment. Jour, of Exp Med., 1907. ' Fliigge: Abschwilehung virulenter Bakterien u. erworb. Immunitat. Zeitsehr. f. Hyg., iv. (Arbeiten von Smirnow, Sirotinin u. Bitter), 1888. Foa: Sur 1'infection par le diplococcus lanceolatus. Arch. ital. de biol., xx., 1893. Foa u. Bonome: Ueber Schutzinnpfungen. Zeitsehr. f. Hyg., v., 1889. Fraser: Immunization against Serpents' Venom. Brit. Med. Journ., i., 1896. Frisch: Die Behandlung der Wuthkrankheit, Wien, 1887. Galeotti: Immunit. u. Bakteriotherapie gegen Cholera. Cbl. f. allg. Path., vi., 1895 (Lit.). Gamaleia: Etude sur la vacinnation charbonneuse. Ann. de l'lnst. Past., 1888. Ganghofner: Die Serumbehaudlung der Diphtheric, Jena, 1897. Gay: Vaccination and Serum Therapy against the Bac. of Dysenterv, Univ. of Penn. Med. Bull., 1902. Giinther: Die Blutserumtherapie. Deut. med. Woch., 1893, Referat. Hess: Rauschbrand. Thiermed. Vortrage, 1 Bd., 4 II., Halle, 1888; Die Schutzimp- fungen gegen Rauschbrand im Kant. Bern in d. J. 1882-89, Bern, 1884, 188(5 and 1889. Hdgyes: Lyssa, Wien, 1897. Issaeff: Kunstliche Immunitat gegen Cholera. Zeitsehr. f. Hyg., xvi., 1894. Kitt: Der Rauschbrand. Cbl. f. Bakt., i., 1887; Gefliigelcholera u. deren Schutzimp- fung. Deut. Zeit. f. Thiermed., xiii. ; Cbl. f. Bakt., i. 1887. Kitasato: Heilversuche an tetanuskranken Thieren. Zeitsehr. f. Hyg., xii., 1892. Klemperer: Immunisirung u. Heilung bei Pneumokokkeninfection. Berl. klin. Wocli., 1891. Knorr: Entstehung d. Tetanusantitoxins. Fortschr. d Med., xv., 1897. Koch: Milzbrandimpfung, Berlin, 1882: Mittheil. a. d. K. Gesundheitsamte, Berlin, 1884; Neue Tuberkuhnpraparate. Deut, med. Woch., 1897, No. 14. Kdhler: Serumtherapie des Tetanus (Statistik). Miinch. med. Woch., 1898. Kolle: Active Immunisirung gegen Cholera. Cbl. f. Bakt., xix., 1896 (Lit,); Bakter- iologie der Beulenpest. Deut. med. Woch., 1897 (Lit,). Kossel: Behandlung der Diphtheric mit Diphtherieheilserum. Zeit, f. Hyg., xvii., 1894; Antitoxinwirkung. Berl. klin. Woch., 1898. Landau: Diphtherieheilserum. Eulenburg's Encyklop. Jahrb., vi., 1896 (Lit.). Ldffler: Zur Immunitiitsfrage. Mitth. a. d. K. Gesundheitsamte, i. ; Immunisirungs Heilversuche gegenliber d. Infection mit Milzbrand-, Tetanus- u. Diphtheric- Bacillen. Cent. f. Bakt., ix., 1891. Ldffler u. Abel: Specilische Eigenschaften d. Schutzkorper. Cbl. f. Bakt., xix., 1896. Longcope: A Study of the Bacteriolytic Serum-complements in Disease. Univ. of Penn. Med. Bull., 1902. Lydtin u. Schottelius: Der Rothlauf der Schweine, Wiesbaden, 1885. Maiselis: Durch Ueberstehen v. Infectionskrankheiten erworb. Immun. Virch. Arch., 137 Bd., 1894. Maragliano : La sicroterapia nella tubereolosi, Milano, 1897. Marx: Theorie der Schutzimpfung gegen Tollwuth. Deut. med. Woch., 1900. Metschnikoff: Etudes sur rimmunite. Ann. de l'lnst. Past., 1890, 1891, 1894, and 1895; Rech. sur rinfluence de l'organisme sur les toxines. lb., 1897, 1898. Mosny: Vaccination et guerison de 1'infection pneumonique. Arch, de med. exp., 1893 (Lit.). Novy : Studies on Spirillum Obermeieri. Jour, of Infect. Dis., 1906. Oppenheimer: Toxiue u. Schutzstoffe. Biol. Cbl., xix., 1899 (Lit.). Pasteur: Sur la rage. Ann. de l'lnst. Past., i., 1887; Lettre aM. Duclaux. lb., ii., 1888. Pearce and Jackson: Production of Cytotoxic Sera by Inject, of Nucleoproteids. Jour, of Infect, Dis., 1906. Perroncito : Studieu uber die Immunitat gegen Milzbrand. Cbl. f. Bakt., v., 1889. IIS THE PROTECTIVE POWERS OF THE BODY. Petruschky: Immunitat des Prosches gegen Milzbrand. Beitr. v. Ziegler, iii., 1888; Wissensch. Grundlage d. Serumtherapie. Samml. kliu. Vortr., No. 212, Leipzig, 1898. Pfeiffer: Immun. Wirkung m. Choleraarnbozeptoren belad. Choleravibrionen. D. rued. Wool., 1903. Pfeiffer u. Kolle: Schutzimpfung gegen Typhus. Deut. med. Woch., 1896. Raynaud : Role du sang dans la transmission de l'immunite vaecinale. Compt. Rend. , t. 84, 1877. Rodet: L 'attenuation des virus. Rev. de med., vii., 1887, and viii., 1888; Les inocu- lations vaccinales, L'immunite acquise, ib., viii., 1888, et ix., 1889. Roger: Schutzimpfung gegen Rinderpest. Zeit. f. Hyg., 35 Bd., 1900. Roux: Immunite centre le charbon symptomatique confere par des substances solu- bles. Ann. de l'lnst. Past., 1888; De l'immunite. Ib.,1891; Les serums antitox- ines. II)., 1894. Roux et Borrel: Tetanus cerebral et immunite. Ann. de l'lnst. Past., 1898. Roux et Chamberland : Immunite oontre la septicemic confere par des substances solubles. Ann. de l'lnst. Past., 1887; Immunite centre le charbon. Ib., 1888. Stephens and Meyers: Action of Cobra Poison on the Blood. Journ. of Path., v., 1898. Stern: Ergebnisse auf d. Gebiete der Immunitatslehre. Cbl. f. allg. Path., 1894; Wirkung d. menschlichen Blutserums auf die exper. Typhus-Infection. Zeit. f. Hyg., xvi., 1894 Steuer : Serumbebandlung d. Tetanus. Cbl. f. d. Grenzgeb. d. Med., iii., 1900. Taruffi: Heilung des Tetanus traumaticus durch Antitoxin. Cbl. f. Bakt. xi., 1892. Tavel: Beitr. z. Blutserumtherapie d. Tetanus. Corrbl. f. Schweizer-Aerzte, 1894. Tschistowitsch : L'immunisation contre le serum d'anguille. Ann. de l'lnst. Past., 1899. Vaughan and Novy : The Cellular Toxins, 1902. Vog-es: Die Choleraimmuuitat. Cbl. f. Bakt., xix., 1896 (Lit.). Wasserman: Immunitat. Eulenburg's Jahr. , iv., 1894; Zeit. f. Hyg., xxii., 1890; Serumtherapie. Deut. med. Woch., 1897; Klinstl. Immunitat. Berl. klin. Woch., 1898; Seitenkettenimmunitat. Ib., 1898; Neue Versuche auf dem Gebiete der Serumtherapie. Deut. med. Woch., 1900; Naturliche u. kiinstliche Immunitat. Z. f. Hyg., xxxvii., 1901. Wechsberg : Nattirl. Immun. a. bakterizide Heilsera. Z. f. Hyg., xxxix., 1902. Weigert: Arbeiten zur Tueorie der Antitoxinimmuuitat. Ergebn. d. allg. Path., iv., 1899. Welch: The Huxley Lecture. Bull, of the Johns Hopkins Hosp., 1902. Yabe: Etude sur l'immunite de la tuberculose, Paris, 1900. Yersin: La Peste bubonique. Ann. de l'lnst. Past., 1897. See also §S 30, 31, and 33. III. The Active Substances of Acquired Immunity. Ehrlich's Side- chain Theory. § 33. Acquired Immunity depends upon the presence of specific anti- toxic and bactericidal antibodies. The process is seen in its simplest form in the production of antitoxins, a phenomenon most familiar to us in the healing of diphtheria and tetanus. According to the views of Ehrlich, only those substances are poisons that possess a chemical affinity for some element of the body and through a combination with this exert a harmful action recognizable clinically. A congenital immunity to poison may, therefore, depend upon the fact that the poison finds in the immune-body no element with which it can react chemically, or the element so affected suffers no damage in a clini- cal sense. In acquired immunity to poison the poisonous action of the toxin is prevented through the formation of an antitoxin. The complex protoplasmic substances, when considered as chemical structures, consist of (Ehrlich) a governing-nucleus ox central-group (cen- tral riii//). and of various side-chains. These side-chains can combine with the side-chains of albuminous nutritive substances, and so bring about an assimilation of the latter. They thus have the significance of receptors EHRLICU S SIDE-CHAIN THEORY. 119 or of a haptophore group which combines with a haptophorous group of the albuminous food-material. In the same way toxins are anchored through their haptophorous group to the receptors of the cell-protoplasm , thus enabling the toxophorous group of the toxin to exert its action upon the cell-protoplasm and to injure the vital powers of the cells. As the result of the combination of the toxins with the receptors, por- tions of the protoplasmic albumin-molecule are rendered incapable of functionating. If the life of the cell and its power of compensation are not damaged, there is produced only a functional disturbance of the cen- tral-group without any definite injury to it; and the cell may again re- place the side-chains and even form them in excess, throw them off, and give them to the blood. Such detached side-chains or receptors constitute an antitoxin. The antitoxin is, therefore, no new substance, but one nor- mally present, which under certain conditions is rnoduced in an increased amount and given off into the blood, and, circulating there, combines the toxin present in the blood to form a harmless body, and so prevent its action upon the cells. The same substance in the living body, which as a con- stituent of the cells renders intoxication possible, becomes the cause of healing when set free into the blood-stream (von Behring). The bactericidal action of the blood=serum, a phenomenon occurring in certain infectious diseases (typhoid fever, cholera, plague), is depend- ent upon the combined action of two substances. One of these is a ferment- like body found in the tissue -juices, and particularly in the blood-serum of the normal organism. It is very labile and is destroyed by heating to 55° C. Buchner has designated this substance as alexin, Ehrlich as complement (earlier as addiment), and Metschnikoff as cytase. It alone is not able to injure the bacteria, but needs for this action the coop- eration of an intermediate-body, the amboceptor or immune-body of Ehrlich (substance sensibilatrice of Bordet). The amboceptors are occasionally formed first during the course of an infection, and are specific for that infectious disease (specific immune- bodies), that is, they are active only in that disease in the course of which they are formed. They possess two haptophore groups, one of which (cytophile group) combines with a receptor of the bacterial proto- plasm ; the other (complementophile group) combines with a haptophore chain of the complement, so that the zymotic group of the latter can act upon the bacterial cells. The amboceptor is less susceptible to heat than the complement and is not destroyed by heating to 60° C. The bactericidal sera act, in the first place, in such a way as to cause the death and solution of the bacteria, in that the specific immune-body, the amboceptor, carries over to the bacteria the digestive action of the normal body -juices, in the complement, so that the bacteria are in part dissolved. Such sera contain, therefore, bacteriolysins. A second action is shown by them in the phenomenon of agglutination, in that specific substances contained in the serum, the agglutinins, combine with the bacterial cells and cause a characteristic clumping of the bac- teria contained in a uniform suspension. The agglutinins are less sus- ceptible to heat than are the lysins and are not changed at 56° 0. Finally, bactericidal immune-sera cause also the phenomenon of pre- cipitation, in that certain substances contained in the same, precipitins, or coagulins, form chemical combinations with certain substances given off from the disintegrating bacterial bodies and coagulate or precipitate them. If an active bactericidal serum be added to a clear fluid which contains such albuminous substances of the bacterial cells, there is quickly produced a flocculent precipitate. 120 THE PROTECTIVE POWERS OF THE BODY. Precipitins -withstand beating to 56° C. and may be dried without losing their potency. According to Ehrlich, tbe receptors for a toxin represent only a hap- topborous group of the cells with whose haptophorous chain the toxin has combined. Pie designates the same as a receptor of the 1 order. On the other hand, the receptor of the cells for the nutritive albumin-molecules contains a haptophorous and a zymophorous group, the latter of which causes a fermentative disintegration of the anchored albumin-molecule. This is designated as a receptor of the II order. The receptor for bacteri- olysin contains a haptophorous group for the anchoring of the ferment- like complement and a receptor for the combining of the disintegration products of bacteria, so that the former can act upon the latter. The receptors thrown off by the cells are designated by Ehrlich as haptins, and he distinguishes: a haptin of the I order, the antitoxin, which combines the toxin to form a harmless body; haptins of the II order, the agglutinins, precipitins, or coagulins, which, after their union with the albumin of the bacteria, cause agglutination, coagulation, and precipita- tion through the action "f the zymophorous group; and haptins of the III order, or baeteriolysins, which as amboceptors cany over the fer- mentative action of the complement to the bacteria. Under especial conditions there appear in the tissue-juices, particularly in the blood, substances that act upon the red blood-cells or tissue-cells or the soluble albumins of the human and animal organism in the same manner as the antibodies described above. According to their action they are classed as haemolysins (globulicidal immune-sera), cytolysins, precipitins, and agglutinins. They arise when into the body of an ani- mal there is introduced the blood, lymph, milk, or tissue from an animal of a different species (Bordet, Tschistowitsch, Kraus, von Dungern, Wassermann, Ehrlich, Morgen- roth, Landsteiner, Uhlenhuth, and others). The blood-serum of a guinea-pig injected repeatedly with defibrinated rabbit's blood is able to dissolve quickly in vitro the red corpuscles of the rabbit, while normal guinea-pig's blood does not possess such a power. The action of haemolysins or of a globulicidal immune-serum corresponds in all respects to that of the baeteriolysins, and the researches concerning the nature of the haemolysins (Ehrlich, Morgenroth) have aided essentially in the explanation of the mechanism of the process of bacteriolysis. The immune-body or amboceptor appearing in globulicidal serum shows a great specific affinity for the corresponding erythrocytes; it will combine with them at 0° ('. and, when thus separated from the complement left in the serum, is not in itself able to dissolve the red blood-cells. The complement will not combine with the red cells without the immune-body. When the immune-body or amboceptor is present, the complement may, at a higher temperature, be carried by the amboceptor over to the red cells and cause their solution. After intraperitoneal injections of laked blood of the same species, the so-called isolysins may be formed, that is, the blood-serum of the animal injected acquires the power of dissolving the red cells of another individual of the same species. Cytolysins or cytotoxins arise through the injection of foreign cells into an organ- ism, for example, after the injection of ciliated epithelium, spermatozoa, leucocytes, renal epithelium, adrenal cells, brain-substance, pancreas-cells, placenta-cells, and carcinoma-cells. In the case of ciliated epithelial cells and spermatozoa the action of the cytolysins contained in the serum can be recognized outside of the body in the rapid cessation of movement (tricholysin, spermolysin). Cytolysins act in the same manner as the tuemolysins. Precipitins arise in the blood-serum as a specific reaction of the body after the subcutaneous, intraperitoneal, or intravenous introduction of foreign albuminous substances. A serum containing precipitins has the power, when added to the albumin solution used in the injections, of causing in the latter a precipitate. A'. Kraus has demonstrated this action first for cholera-spirilla, that is, for the substance of the bacterial cell brought into solution. The serum of goats previously treated with injections of cholera-spirilla or with the bacterial substance causes a precipitate in filtrates of cholera-cultures that contain no bacilli. This property of the bacterial precipitins may be used in diagnosis. According to the investigations of Tschistowitsch, Bordet, Wassermann Schiitze PRECIPITINS AND AGGLUTININS. 121 Ehrlich, Mc-genroth, Myers, Uhlenhuth, von Dungern, and others, such precipitins are also formed after the injection of foreign blood, milk, inflammatory exudates, fresh and dried flesh, etc.; and through the aid of this method it becomes possible to dis- tinguish from one another not only the red blood-cells of different species, but also flesh, milk, semen, etc.; that is, the precipitating serum of an animal A, that has been treated with an albumin of an animal B of another species, will precipitate the albumin of B, but not that of a third species. This reaction of albumin obtained by biological methods (biological method of differentiating albumins, Wassermann and Schiitze) is so extremely sensitive that the specific test for albumin is possible even at a dilution of 1:100,000. The precipitin reaction has found its most important application in the examination of blood-stains, but it is also of use in the differentiation of different kinds of meat, milk, etc., and can be applied also to the differentiation of plant-albumins. The reaction is specific for the albumin of different species of animals and for man, between the albumins of different elements of the body, as, for example, between chicken-blood and the white of a chicken-egg, there exist only quantitative differences. An antiserum to human blood will precipitate also urine containing albumin, puiulent exudates, ascitic fluid, seminal fluid, etc.; so it may be inferred that the various fluids of the body contain the same receptors as those of the blood-serum. In the examina- tion of spots, stains, etc., the first thing to be determined is the presence of blood (guaiacum test, Teichmann's test, spectroscopic examination). When this is de- termined, the biological test, properly handled, gives very certain results, particularly when the animal used for the production of the serum is not closely related. An anti- serum for human blood gives only a very weak reaction with ape's blood (particu- larly that of anthropoid apes); and similar conditions exist between the horse and the donkey, and between the chicken and pigeon. For the demonstration of the presence of human blood or albumin, the serum of rabbits properly treated beforehand can be used to best advantage, but that of the horse, sheep, or goat may also be employed (according to von Dungern, cold-blooded animals produce no precipitins). To produce the antiserum (Uhlenhuth) .5-10 c.c. of a dilute solution of albumin derived from human tissues or blood are injected into a rabbit at intervals of several days, until a test of blood taken from the vein of the ear, made about five days after the last injection,, shows the serum to be active. It is very strange that the time in which this change in the serum occurs varies greatly with individual animals. When the serum has attained its full .strength, the animal is anaesthetized, the thorax opened, and a cut made into the heart. The blood flowing into the thoracic cavity is taken up by a pipette and collected in a sterilized glass graduate. The serum when separated is filtered through a Berkefeld filter and when ready for use must be perfectly clear. The albuminous material to be tested is dissolved in physiological salt-solution. A serum of high potency may contain precipitins that act not only upon homo- logous albumins, but also upon heterologous. Uhlenhuth recommends, therefore, a marked dilution (1: 1,000) of the fluid to lie examined, which, moreover, must be per- fectly clear. To 2.0 c.c. of the dilute fluid 0.1 c.c. of the antiserum is added, and in the presence of homologous albumin a cloudy precipitate forms at once or after one or two minutes. Agglutinins that cause clumping through their functional molecule-groups may be combined first with bacteria, but also after that with red blood-cells.. Agglutinable substances and agglutinins possess specific combining haptophore-groups (ELsenberg and Volk, Wassermann). In the agglutinable substance the functional group is more labile and more easily destroyed than the haptophore-group; this is true also of the agglutinin (Wassermann). Through external influences the functional group may be lost, and from the agglutinin there is produced an agglutinoid, which is no longer able to cause agglutination, and through its combination with the agglutinable substance is able to prevent the occurrence of agglutination in the presence of agglutinin. As has been mentioned above (^ 31), agglutination has been observed chiefly in the case of cholera-spirilla, typhoid-bacilli, pyocyaneus, colon, and tubercle bacilli. Immune-agglutinins are produced during the process of immunization by an increased formation and setting free of groups' that under certain conditions occur in slight amount even in normal serum. Agglutination can be applied to the diagnosis of the given disease, but it must be remembered that the serum of healthy individuals causes agglutination (in typhoid fever even in dilutions of 1 : 20, while the serum of persons having the disease will agglu- tinate at a dilution of 1: 50); and that a serum can also agglutinate to a greatet or less degree other bacteria than the one coming under the influence of its agglutination power. The serum of typhoid patients or of those immune to typhoid acts upon many colon- species even in high dilutions. The precipitable substance in culture-fluids is, according to Wassermann, identical 122 THE PROTECTIVE POWERS OF THE BODY. with the agglutinable substance in the bacterial cells; that is, the substance present in the uninjured bacterial cells, combining in agglutination with the agglutinating serum, is, in the culture-fluids, dissolved out of the bacteria, set free in the same, and gives there a specific precipitate with the serum. Agglutination and dissolution of the bacteria, according to Wassermann, Ehrlich, Morgenroth, etc., are not caused by the same substance, as is believed by von Baum- garten and Gruber to be the case. Agglutinins and amboceptors or immune-bodies are two bodies distinct from each other and do not have the same haptophorous group in common. The immune-body needs for its action the complement, the agglutinin does not. The agglutinin is made up of separate or partial agglutinins, and a bacterial agglu- tinin may, therefore, vary in its constitution according to the biological qualities of the animal in which it is produced. Two varieties of bacteria (typhoid-fever and colon- bacilli) may also possess a number of partial agglutinins in common. It, therefore, becomes necessary {Wassermann), when applying agglutination-tests for the purpose of diagnosis, to work always with such dilutions as possess a limit of action not far from that obtained by titration for the given bacterial species (the limits of potency of any serum may vary greatly). A positive agglutination is, therefore, decisive as pertaining to that species with which the animal producing the serum was previously treated. The production of antitoxin plays the most important role in the healing of diphtheria and tetanus; the success attending the prophylactic and therapeutic use of these antitoxins has already been mentioned in § 32. Antitoxins are also produced in the course of infections with the staphylococcus, streptococcus, pneumococcus, intoxi- cations due to Bac. botulinus (sausage-poisoning) and the Bac. pyocyaneus, but the results of the therapeutic applications of these are at the present time uncertain. Antitoxins are also produced in poisoning with ricin, abrin, crotin, pollen-toxin, mushroom-poison, snake-venom, eel-poison, and the poison of toads and spiders. The toxin is not destroyed by the antitoxin. When snake-venom (Calmette) is mixed with antitoxin so that the mixture becomes harmless to animals, and if the more thermolabile antitoxin be destroyed by heating to 68° C, the mixture again becomes poisonous. The same thing may be demonstrated in the case of the toxin and anti- toxin of the Bac. pyocyaneus. According to Wassermann, the substance of the central nervous system chiefly affected by tetanus is able to combine with the tetanus toxin alter the manner of an antitoxin and so render it harmless. Tetanus toxin rubbed up with the brain sub- stance of a normal rabbit becomes so weakened that guinea-pigs can bear ten times the fatal dose without damage. According to Ransom, the tetanus-poison injected in fatal doses into pigeons is demonstrable in all organs except the central nervous sys- tem, with which it has entered into chemical combination. Therapeutic attempts with bactericidal sera have up to the present time not given such good results as those of antitoxic sera. In the first place, the bactericidal sera have no influence upon an existing intoxication. Further, an action upon the bacteria present is also impossible when the injected serum finds no free complement in the blood of the patient or when the amboceptor from animal blood (horse blood) does not combine with the complement of human blood. The agglutinins, precipitins, etc., can in turn produce in the organism anti-anti- bodies, antiagglutinins, antiprecipitins, etc. Hypersusceptlbility or anaphylaxis. Animals may react to certain toxic or foreign substances in one of two ways, either by an increased resistance or immunity or by an increased susceptibility (hypersusceptlbility or anaphylaxis). According to Theobald Smith, Otto, Rosenau and Anderson, Gay and Southard, etc., there occurs a remarkable toxic action in guinea-pigs as the result of an injection of a small dose of horse-serum (.0001-. 1 c.c), followed after ten days or two weeks by a second injection of relatively large amount (5 c.c), the reaction being characterized by severe symptoms with death within one hour. This reaction is specific in that guinea-pigs sensitized with horse-serum do not react to the second injection of other proteid substances, and vice versa. The reaction following a second injection of the same proteid in guinea- pigs appears to be common to all higher forms of albuminous substances (white of egg, hamioglobin, milk, extract of peas, bacterial proteids, etc.). Simpler albuminous substances, such as peptone, seem to have slight sensitizing and poisonous properties, while lower nitrogenous compounds as leucin and tyrosin possess none at all. Hyper- susceptlbility in the guinea-pig may be transmitted by the female to the offspring. The hypersusceptibility may persist for a long time (Rosenau and Anderson). The hypersusceptlbility produced in guinea-pigs to second injections of bacterial proteids resembles that produced by second injections of horse-serum. It is significant that the period of incubation in a number of infectious diseases corresponds to the ten to fourteen days required to sensitize animals to a foreign proteid. (For literature see Anderson and Rosenau, Jour, of Med. Res., July, 1908.) ACQUIRED IMMUNITY. 123 Literature. {Acquired Immunity, Ehrlich' 1 8 Side- Chain Theory.) Aschoff: Ehrlich's Seitenkettentheorie, Jena, 1902 (Lit.). von Baumgarten: Phagocytenlehre. B. v. Zieg., vii., 1S96; Jahresber., 1891-1904; Die Hamolyse. Festschr. f. Jaffe, Braunschweig, 1900; B. klin. Woch., 1901. Bordet: Les serums hemoly iiques. Ann. de l'Inst. Past., xiv., 1900; Mode d'action des serums cytolytiques. Ibid., 1901. Charrin: L'immunite. A. de phys., iv., 1893; Traite de path, gen., ii., Paris, 1S96. Corbette: The Action of Antitoxins. Jour, of Path., vi., 1899. vonDungem: Globulicide Wirk. d. tier. Organismus. Munch, med. Woch., 1899; Imrnunseruin gegen Epithel. Ibid., 1S99; Beit. z. Immunitatslehre. Ibid., 1900; Die Antikorper, Jena, 1904; Bindungsverhaltnisse b. d. Priicipitionsreaktion. Cbl. f. B., xxxiv., Orig., 1903. Ehrlich: Ueber Toxin und Antitoxin, Berlin, 1901; Munch, med. Woch., 1903; Schutzstoffe des Blutes. D. med. Woch., 1901; Verh. d. Ges. d. Naturforsch., Leipzig, 1902. Ehrlich und Morgenroth: Hamolysine. Berl. klin. Woch., 1900; Wirkung und Entstehung d. aktiven Stoffe im Serum nach d. Seitenkettentheorie. Handb. d. path. Mikroorg., iv., 1904. Emmerich: Bakterolyt. Wirkung d. Nucleasen u. Nucleasenimmunproteide. C. f. B., xxxi., 1902, Orig. Engel: Leitfaden u. klin. Untersuch. d. Blutes, Berlin, 1902. Friedberger : Die baktericiden Sera. Handb. d. path. Mikroorg., iv., Jena, 1904. Gruber: Zur Theorie der Antikorper. Mtinch. med. Woch., 1901. Hauser: Serodiagnostische Methode. Munch, med. Woch., 1904. Joos: Mechanismus der Agglutination. Z. f. Hyg., 40 Bd., 1902. London: Cytolytische Theorie d. Immunitat. C. f. B., xxxii., Orig., 1902. Lowit: Niederschlagsbildung bei d. Agglutination. C. f. B., xxxiv., Orig., 1903. Manwaring: The Application of Physical Chemistry to Serum Pathology. (Various papers.) Studies from Rockefeller Institute, vi., 1907. Marx: Einfuhrung in die Serodiagnostik. Z. f. Tiermed., vi., 1902. Metschnikoff: Sur les cytotoxines. Ann. de l'Inst. Past., 1900; Immunitat bei Infektionskrankheiten, Jena, 1902; Die Lehre v. d. Phagocyten. Handb. d. path. Mikroorg., Jena, 1904. Moxter: Immunserum gegen Spermatozoen. D. med. Woch., 1900. Muir: The Action of Hamiolytic Sera. Lancet, 1903. Muller: Antihamolysine. Cbl. f. Bakt., xxix., 1901. Neisser und Wechsberg: Wirkungsart baktericider Sera. Mtinch. med. Woch., 1901. Noguchi: The Thermostabile Anticomplementary Constituents of the Blood. Jour. of Exp. Med., 1906. Oppenheimer: Toxine und Schutzstoffe. Biol. Cbl., xix., 1899 (Lit.). Pfeiffer, I..: Die moderne Immunitatslehre. Z. f. Hyg., 43 Bd., 1903. Piorkowski: Die spezifischen Sera. C. f. Bakt., Ref., xxxi., 1902. Proscher und Pappenheim: Die theoretischen Grundprinzipien der Immunitats- lehre. Fol. haem., i., 1904. Sachs: Die Hamolysine u. ihre Bed. f. d. Immunitatslehre. Ergeb. d. a. Path., vii., 1902; Hamolysine d. normalen Blutserums. Miinch. med. Woch., 1904. Silberschmidt: Ergeb. a. d. Immunitatsforschung. Korr. f. Schw. Aerzte, 1902. Uhlenhuth: Prazipitine. Eulenb. Jahrb., ii., 1904 (Lit.). Vaughan and Wheeler: The Effects of Egg-White and Its Split Produets on Animals. Jour, of Inf. Dis., 1907. Wassermann: Natiirl. u. ktinstl. Immunitat. Z. f. Hyg., 37 Bd., 1901. Agglutinine u. Prazipitine. lb., 42 Bd., 1903; Die Grundziige d. Lehre v. d. Immunitat u. Serumtherapie. Z. f. arztlich. Fortbildung, i.. 1904; Giebt es ein biologisches Differenzierungsverfahren f. Menschen- u. Tierblut mittels der Prazipitine? Deut. med. Woch., 1904; Entstehung und Wirkung d. aktiven Stoffe im Immun- serum. C. f. B., xxxv., Ref., 1904; Antitoxische Sera. Handb. d. path. Mikro- org., iv., Jena, 1904. Weigert: Arbeiten z. Theorie d. Antitoxinimmunitat. Ergebn. d. allg. Path., iv. 1899. Ziegler, K.: Serumdiagnose verschied. Blutarten. Cbl. f. a. Path., xiii., 1902 (Lit.). CHAPTER IV. Disturbances in the Circulation of the Blood and of the Lymph. I. General Disturbances of the Circulation Dependent upon Changes in the Function of the Heart, Changes in the General Vascular Resistance and Changes in the flass of the Blood. § 34. The mass of blood is kept constantly in motion by means of the rhythmical contractions of the auricles and ventricles of the heart. The blood, as it is driven into the elastic tube of the aorta toward the periph- ery of the body, meets a significant degree of resistance, which is caused by the friction in the innumerable divisions aud subdivisions of the arterial system. This resistance occasions a relatively high pressure throughout the entire arterial system, which iu the human femoral artery equals that of about 120 mm. of mercury. After passing through the capillaries the blood arrives in the veins with very little velocity, and stands in the veins under a very slight pressure, which varies according to the location of the vein, and is greatest where a high column of blood rests upon the lumen of the vein. In the great venous trunks in the neighborhood of the thorax the pressure is usually negative, espe- cially duriug inspiration, as the thorax during this stage of respiration aspirates the blood from the veins lying outside of the chest. Only dur- ing forced expiration does the positive pressure in the veins rise some- what higher. Assuming the mass of the blood to be constant, the degree of pressure within the aorta, at any given moment, is dependent upon the work of the heart and the resistance in the arterial system. The latter in turn is dependent upon the variations in the total diameter of the combined cross-sections of the blood-vessels, due to the elasticity and contractility of the arteries. In the major circulation the arterial tone is very pro- nounced ; in the lesser circulation it is slight, the blood -pressure in the pulmonary artery being only from one-third to two-fifths that in the aorta. Both the heart and the arteries are under the influence of the nervous system, which regulates their activity. The activity of the heart consists in rhythmical contractions of its musculature; aud its normal efficiency xiresupposes that the heart-mus- cle, and also the cardiac ganglia, are sound. Every disease of the heart, therefore, in so far as it diminishes the contractile capacity of the heart- muscle and lessens the activity of the ganglion-cells, and in so far as a lessened functional activity of certain parts of the cardiac muscle is not compensated by an increased activity of other parts, will diminish the functional capacity of the heart. In many cases in which the functional capacity of the heart- muscle is impaired, certain anatomical changes, such as fatty degeneration and necrosis of its cells, can be demonstrated ; in other cases no anatomical 124 IMPAIRMENT OF CARDIAC FUNCTION. 125 changes can be made out, especially in those cases in which the diminu- tion of working-capacity follows the exhaustion caused by excessive overexertion. This may occur when the heart is forced to work for some time only slightly above the normal, but under unfavorable condi- tions, as, for example, in cases of elevation of the body-temperature ; as well as in cases when for a short period it is overworked to an excessive degree. Under certain conditions disturbances of nutrition and intoxi- cations, such as occur in the infectious fevers, as well as a sudden diminution in blood-supply from the obstruction of a coronary artery, may cause an insufficiency of the heart within so short a time that the heart-muscle presents no recognizable anatomical lesion. The work of the heart may also be made difficult at times through the formation of adhesions between the epicardium and pericardium, and between the lat- ter and the contiguous pleura, in consequence of which the contractions of the heart are hindered. Through the collection of fluid in the pericardial sac in the course of certain diseases, further, through marked deformities of the thorax causing an abnormal smallness of the thoracic cavity, and through a high position of the diaphragm, the diastolic dilatation of the heart and the free afflux of blood from the veins may be hindered to such an extent that the ventricles receive too little blood. If, following pathological processes in the heart-valves, there result rents or distortions of the flaps or adhesions between them, or if in case of dilatations of the heart and the valvular orifices the valve-flaps become relatively too short, there may arise those conditions of the auricular and ventricular orifices known as insufficiency and stenosis. The former condition is characterized by a failure of a valve to close completely during the diastole of the auricle or ventricle lying behind the given valve; the second condition, by the fact that during the contraction of the auricle or ventricle the valvular orifice does not suffice for the passage of the blood through the opening. The effect of a stenosis is that of opposing additional obstacles to the out- flow of the blood during systole. In aortic and pulmonary insufficiency the blood regurgitates, during the ventricular diastole, back from the great vessels into the ventricles ; in mitral and tricuspid insufficiency the systole of the ventricle causes a regurgitation into the corresponding auricle. Finally, there are not infrequently formed in the heart masses of coagula, which under certain conditions — in case they lie near the orifices — may on the one hand interfere with the proper closing of the valves, or on the other cause a narrowing of the ostium. As the result of all the above-mentioned pathological conditions, the efficiency of the heart's function is impaired, so that in a given time too little blood passes into the arterial system, the aortic pressure conse- quently falls, and the velocity of the blood-current is diminished ; while in the venous system the blood collects more and more, and the venous pressure rises. There is consequently an inadequate filling of the arteries throughout the entire body, varying, indeed, according to the degree of contraction maintained in individual arterial systems, while both veins and capillaries are, on the other hand, overfilled with blood. There develops, therefore, a condition of general venous hyperemia, which in some parts may become so marked that the tissue, because of the en- gorgement of the capillaries with venous blood, acquires a blue-red, cya- notic appearance. When the difference in pressure between the arterial and venous systems becomes reduced to a certain minimum, the circula- 126 DISTURBANCES OF THE CIRCULATION. tion comes to a standstill, while the right side of the heart becomes greatly distended with blood. Should the contractions of the heart from any cause become weak and imperfect, the pulse-wave also becomes small. If the rate of the heart- beat becomes diminished in frequency, the arterial system empties itself to a greater extent than normally during the pause between the systoles. If the impairment of cardiac efficiency involves the left heart essen- tially, as is the case, for instance, in valvular disease of the left side, the disturbance of circulation is manifest first in the systemic arteries, as well as in the pulmonary vessels. In stenosis of the aortic valves, the arteries, if the heart's action re- main unchanged, fill but slowly and incompletely (pulsus tardus). In aortic insufficiency a normal or even an increased amount of blood is thrown into the arteries during systole (pulsus celer), but a part of this flows back again during diastole. In both cases the left ventricle be- comes more and more distended, the emptying of the left auricle is hin- dered, its cavity also becomes dilated, and finally the blood is backed up in the pulmonary veins. Owing, however, to the low pressure in the pulmonary circulation, the blood is readily dammed back upon the right ventricle, and the blood stasis may finally extend beyond this into the right auricle and into the systemic veins. Valvular lesions at the mitral orifice produce similar effects upon those portions of the circulatory apparatus lying behind the left auricle, as in such cases there is produced also a condition of pulmonary stasis, with a rise of pressure in the pulmonary arteries and veins ; while the left ventricle either receives too little blood (stenosis) or during its con- traction drives a portion back into the auricle (insufficiency). In valvular lesions of the orifices of the right heart the damming back of the blood is limited to the veins of the systemic circulation, while in the pulmonary circulation both pressure and velocity are diminished. Further, the pressure in the aorta also falls, since the left side of the heart receives too little blood. The damming back of the blood in the great systemic veins may manifest itself by venous pulsations in the neighborhood of the thorax, in- asmuch as retrograde waves of pressure proceeding from the heart may pass through the veins toward the capillaries, distending the veins to such an extent that the venous valves, particularly those of the jugular bulb, are rendered inadequate. The essential condition of the transmis- sion of the venous pulsation is the insufficiency of the venous valves. In the case of imperfect function of the valve in the jugular bulb, a slight pulsation may be observed even during normal action of the heart ; but when the veins are distended, and particularly in the case of tricus- pid insufficiency, the pulsation becomes much stronger and extends further toward the periphery. If the tricuspid is adequate the venous pulsation (presystolic) is only the expression of the rhythmical occur- rence of a hindrance to the outflow of blood from the veins (negative or normal venous pulse). In tricuspid insufficiency the contraction of the right ventricle forces blood back through the tricuspid opening into the right auricle and into the veins beyond, giving rise to a systolic venous pulsation (positive venous pulse). If in a heart affected with a valvular lesion the chambers lying be- hind the lesion become distended with blood, the muscular walls of these chambers, in case they are otherwise normal, may by an increased ac- tivity compensate for the valvular lesion within certain limits. In the IMPAIRMENT OF CARDIAC FUNCTION. 127 course of time there results an increase iu the volume of the heart-mus- cle, a hypertrophy of the heart-muscle, which enables the heart to carry on its increased work for an indefinite period. Such compensation fre- quently becomes inadequate, with the result that the aortic pressure is permanently lowered, while the venous pressure, on the other hand, is abnormally high. There is, at the same time, the danger that the heart- muscle may in time become exhausted, or that a very slight illness may render the heart insufficient. Thus, for example, a prolonged quicken- ing of the heart's rate, by shortening the diastolic periods of rest, may cause cardiac exhaustion and insufficiency. Arrest of the heart's action finally follows, with great accumulation of blood in the heart, since the heart is no longer able to drive onward the mass of blood entering it. An increase of the heart's action — that is, an increase in the fre- quency of the heart's contractions, these at the same time remaining strong and complete — causes an increase in arterial pressure and an in- creased velocity of the blood-current. When increased demands are fre- quently made upon the left side of the heart — as frequently happens in heavy bodily labor, conditions of luxurious living, abnormal irritability of the cardiac nerves, etc. — the left ventricle may become hypertrophic and act permanently with greater force. Inasmuch as the qiiickening of the blood-stream causes the right heart to receive a greater amount of blood during diastole, a hypertrophy of the right ventricle is usually found in connection with the hypertrophy of the left ventricle. Lessening of the mass of blood or general anaemia from the loss of blood leads temporarily to a fall of pressure in the aorta ; but if the loss o f blood was not excessive, the blood-pressure rises again, as the vessels adapt themselves to the changed conditions, and, as the result of the stimulation of the vasomotor centre through local anaemia, show a greater degree of contraction. "Under normal conditions the mass of blood is quickly increased through the absorption of fluids, and later by a re- generation of the blood. Similarly, in anhydrasmia — i.e., a diminution of the water of the blood — the arterial pressure is lowered and the blood- current slowed. After severe haemorrhages the arterial pressure is low- ered for a greater length of time, the circulation is slowed, and the pulse, because of the lessened stimulation of the vagus-centre (Cohnheim), is frequent and small. In the case of lasting diminution of the blood-mass — i.e., the condi- tion known as chronic anaemia, which occurs under varying conditions — the vascular system is imperfectly filled, the blood-pressure lowered, and the blood-current slowed. Both heart and blood-vessels adapt them- selves to the new conditions and become diminished in volume. In the case of a marked deficiency of haemoglobin, degenerations of the heart- muscle, particularly fatty degeneration, frequently occur. Increase in the mass of the blood, through the injection of blood or salt-solution into the blood-vessels, is followed in animals by only a tem- porary increase in pressure and in the velocity of the blood- current. A return to the normal is brought about, partly by the dilatation of a part of the vascular system, particularly in the abdomen, and partly through the elimination of the surplus from the vessels. If the mass of blood, as the result of some especial predisposition or of high living, conies to stand in an abnormally high porportion to the body-weight, if there exists a permanent plethora, the pressure in the aorta becomes perma- nently raised, the work of the heart is permanently increased, and there develops a corresponding hypertrophy of the heart. 12S DISTURBANCES OF THE CIRCULATION. When the arterial blood-pressure is raised there occurs an increased giving-off of fluid from the blood, and thereby a concentration and diminution in the amount of the venous blood; in lowering of the blood-pressure the amount of fluid given oft is diminished and eventually an increased taking-up of fluid occurs. This change in the venous blood is under normal conditions compensated for in the lungs: in the first case, through a taking-up of lymph from the lymphatics; in the second case, through a giving-off of lymph to the lymphatics (Hess: " Beeinflussung des Fliissigkeitsaus- tausches zwischen Blut u. Oeweben durch Schwankungen des Biutdruckes." D. Arch. f. klin. Med., Bd. 79, 1903). § 35. Increase, of the general vascular resistance may occur in either the greater or the lesser circulation, and results in an increased pressure behind the point of increased resistance, and a diminished press- ure beyond it. In the systemic circulation the hindrance may lie either in the main vessel, the aorta, or in the arterial branches, whose degree of contraction maintains and governs the normal pressure in the aorta. Vascular con- traction involving a great number of arteries and their branches, and sufficiently well marked to increase the blood-pressure, is generally a temporary phenomenon, passing off with the relaxation of the arterial tension. Nevertheless, a permanent increase in the aortic pressure with consequent hypertrophy of the left ventricle does occur ; and this cannot be explained otherwise than as the result of the contraction of the lumen of the smaller arteries. Transitory arterial contraction and increase of pressure occur particularly through an increase of the amount of car- bonic acid contained in the blood. A permanent increase of aortic- pressure is, on the other hand, a result of chronic diseases of the kidney, in which the secreting parenchyma is destroyed. Inasmuch as the por- tion of the vascular system which is thus cut off is much too small to cause such an increase of pressure throughout the whole aortic system, since the vessels leading to other organs might become correspondingly dilated, it must be assumed that in the case of contracted kidney some other hindrance to the circulation occurs throughout more extensive vascular areas. This hindrance would most naturally be sought in the apparatus which normally serves to keep the aortic pressure at its proper height, namely, in the smaller arteries of the body. "Whether the condi- tion is caused by nervous stimuli arising in the kidney, or by the action of retained urinary substances upon the vasomotor centres or directly upon the vessel -walls, or whether the heart is excited by nervous stimuli to increased action, we are not at present able to say. Increase of resistance in the aorta may result from stenosis of this vessel, as occurs in rare cases at the isthmus, or from congenital narrow - ings of the whole aorta, large aortic thrombi, or from extensive disease of the vessel-wall, in consequence of which the intima is rough and nodu- lar, the entire vessel rigid, inelastic, and unyielding ; or, finally, from a general dilatation of the vessel, whereby eddies are formed in the blood- stream. Lowering of the total resistance in the systemic circulation is pos- sible through the relaxation of the tone of a large part of the arteries, and this event may happen when the vasomotor centre is paralyzed, or when the cervical cord is divided or partly destroyed through any other process. Since the blood, in this case, flows abnormally quickly from the arteries into the veins, the difference in blood-pressure between the arteries and veins is lessened, the current becomes slower, the heart re- ceives too little blood during diastole, and, finally, the circulation may come to a standstill. INCREASED BLOOD-PRESSURE. 129 Increase of the resistance in the pulmonary circulation occurs most frequently as the result of disease of the lungs and pleura. Adhesions of the pleura, as well as spinal curvatures, which hinder the expansion of the lungs and their change of volume during inspiration, thereby de- priving the circulation of an efficient aid, may cause such increase of pulmonary resistance. Of great influence, moreover, are such affections of the lung as idiopathic emphysema, retractions and indurations of the lung, and destruction of lung-tissue — all of which lead to the oblitera- tion of a portion of the pulmonary capillaries ; further, compression of the lung through pleural exudate; and, finally, compression of the pul- monary arteries by aortic aneurism or by tumors. If the hindrance is only slight, the blood may make for itself a new passage to the left heart without any increase of pressure ; the rate of the current in the blood-vessels which are unobstructed alone being increased. Greater obstacles cause an increase of pressure in the pulmonary artery and the right heart, and if the condition persists for some time the light ventricle through increased exertion may become hypertrophic. This can occur, however, only when the heart-muscle is adequately nourished and when the mass of the blood is not diminished to correspond to the diminution of the area of the pulmonary vessels. If the right heart is not able to overcome the obstacles in the pulmonary circulation, the blood is dammed back upon the right heart, and eventually upon the systemic veins. An increase of the pressure in the right side of the thorax hinders the en- trance of the venous blood into the right heart, and causes an accumula- tion of blood in the systemic veins. A sudden increase of pressure may cause a retrograde flow of blood into the neighboring veins. According to the investigations of Romberg, Pastier, Bruhns, and Mailer, pneumo- cocoi, diphtheria-bacilli, and the Bacillus pyocyaneus injure the circulatory apparatus of the rabbit (leaving out of the question the dilatations of the heart that occur particu- larly in diphtheria) , in that they cause paralysis of the vasomotor centres in the medulla. This paralysis leads to a diminution of the arterial blood-pressure and to a change in the distribution of the blood. The splanchnic vessels become overfilled, the vessels of the brain, skin, and the muscles become empty. The heart is not concerned in this disturbance of the circulation. In general, it is affected secondarily as a result of the deficient flow of blood due to the vasomotor paralysis. A central paralysis of the vaso- motors is also responsible for the circulatory disturbances occurring in the acute infec- tions; and is the chief cause of the failure of the circulation. The observation that hypertrophy of the heart follows different diseases of the kidneys has been interpreted in various ways. Some writers seek the cause in an in- crease of the volume of the blood (Traube, Bamberger), others (Senator, Ewakl) believe it to be due to the changed character of the blood, while others (Gull and Sutton) ascribe it to a widespread change in the walls of the small arteries. Buhl holds that it is due to the over-nourishment of the heart. According to the investigations made up to the present time, there can be no doubt that the hypertrophy of the heart in diseases of the kidney is dependent upon an increase of the aortic pressure. This increase is best explained by an increase of the resistance in the small arteries of the entire body, due to the contraction of the small arteries. This contraction must be brought about either through the direct action of the urinary substances contained in the blood or by some reflex stimulus from the kidneys, or finally by some influence exerted upon the vasomotor centre. It is possible that the heart also may be excited to increased activity. Literature. (Disturbances of the Circulation. ) Bamberger: Ueber Morbus Brightii. Saminl. klin. Vortr., No. 173, 1879. v. Basch: Allgem. Physiologie u. Pathologic des Kreislaufs, Wien, 1892. 9 130 DISTURBANCES OF THE CIRCULATION. Cohnheim: Vorlesungen tiber allgem. Pathologie, Berlin, 1882. Gull and Sutton: Med.-chir. Transact., lv., 1852. Janowski: Diagnost. Bedeutung der Pulsuntersuchung. Klin. Vortr., Nos. 192, 193, Leipzig, 1897. Jurgensen: Erkrankung d. Kreislauforgane, Insufficienz des Herzens, Wien, 1899. Krehl: Pathologische Physiologie, Leipzig, 1904. Ldwit: Ueber die Entstehung des Lungenodems. Beitr. v. Ziegler, xiv., 1893. Lukjanow: Allgemeine Pathologie des Gefasssysterns, Leipzig, 1894. Mackenzie: The Venous and Liver Pulses. Journ. of Path., ii., 1893. Passler u. Roily: Die Kreislaufstorung im Kollaps bei akuten Infektionskrank- heiten. Munch, med. Woch., 1902. Romberg, Passler, Bruhns u. Muller: Kreislaufstorung bei acuten Infections- krankheiten. Deut. Arcli. f. klin. Med., 64 Bd., 1899. Rosenbach: Herzkrankheiten. Eulenburg's Realencyklop. ; Einfluss der Raumbe- sehrankung in der Pleurahohle auf den Kreislauf. Virch. Arch., 105 Bd., 1886. Thoma: Patholog. Anatomie, i., Stuttgart, 1894. Yogt: Exp. Untersueh. tlber anat. u. funkt. Veritnd. d. Herzens bei Entzlindung des Herzbeutels u. bei Verschliessung der Kranzarterien, Moscow, 1901. II. Local Hyperaemia and Local Anaemia. § 36. To the blood is assigned the function of supplying all the or- gans and tissues of the body with nourishment. The cells and cellular structures of which the various tissues are composed are able to maintain their existence without the advent of fresh nutritive material only for a short time ; and for this reason the majority of the tissues are supplied with blood-vessels, and those not possessing vessels of their own are placed in the most intimate connection with vascular structures. The demands of the different tissues for blood are not always the same, and there is consequently in the various tissues a corresponding increase or decrease in the afflux of blood and in the amount of blood contained within an organ or tissue at any given moment. An organ rich in blood is designated as hyperaemic ; one poor in blood as anaemic. The regulation of the amount of blood which an organ receives under physiological conditions is brought about by a change of the resistance in the afferent arteries ; and this change is effected entirely through a variation in the calibre of the arteries. Since the total mass of the blood in the body is not sufficient to fill all the vessels at the same time, an extra supply of blood to one organ is possible only by supplying a less amount of blood to other parts. The change in the calibre of an artery is determined, aside from the blood-pressure, by the elasticity of the artery-wall and the degree of contraction of its smooth muscle-fibres. These fibres are the regulating element; their activity is dependent partly upon influences affecting them directly, and partly upon ner- vous influences from the intravascular plexuses and from the vasomotor centres in the medulla oblongata and in the spinal cord, some of these stimulating, others inhibiting the muscular action. When the departures from the average blood-supply of any part of the body overstep the physiological limits, or if such variations arise without physiological causes, or are unduly prolonged, the condition is spoken of as pathological hyperaemia and pathological anaemia. These conditions are in part brought about by the same regulating mechanism which governs the normal blood-supply of an organ. Hyperaemia of an organ is caused under pathological conditions either by an increase in the arterial supply or through an obstruction and damming-back of the venous outflow ; and there are distinguished, accordingly, two forms, an active or congestive (arterial) hypercemia and HYPEREMIA. 131 a passive or stagnation {venous") hyperwmia. Active hyperaemia arises through an increase of the afflux of Wood (congestion), and may be either idiopathic or collateral. The first of these plays the more im- portant role. It depends upon a relaxation of the muscular tunics of the artery, which may be brought about either by paralysis of the vaso- constrictors (neuroparalytic congestion), or through a stimulation of the vaso- dilators (neurotic congestion), or through direct weakening and paralysis of the muscles (as, for instance, by heat, bruisiug, action of atropine, brief interruptions of the blood-current), or, finally, through a diminution of the external pressure exerted upon the vessels. Collateral hyperaemia is merely the result of a diminished flow of blood to other parts. It oc- curs first in the immediate neighborhood of the parts whose blood - supply is lessened ; later, the blood may be driven also to such other more distant organs as may require it. Active hyperemia is characterized by a more or less marked redness and swelling of the part, which are very striking in tissues rich in blood-ves- sels. The blood flows through the widened channels with increased velocity, and gives to the tissue the color of arterial blood. Superficial tissues which are exposed to cooling become as a result of the increased blood-supply warmer than the neighboring tissues which are less richly supplied. Passive Hyperemia arises through the retardation or obstruction of the flow of blood from the veins. A general passive congestion of the systemic veins occurs in those cases in which, through weakness of the heart's ac- tion, valvular insufficiency or stenosis, or obstructions to the pulmonary circulation, the emptying of the large veins into the right heart is hin- dered. In the pulmonary circulation stagnation of the blood-stream may be brought about by any cause hindering the outflow of blood from the lungs, particularly valvular lesions of the left heart, weakness of the left side of the heart., and, more rarely, obstructions in the systemic arteries. Not infrequently such a stasis of the pvdmonary circulation may reach such a degree that the blood is dammed back into the right heart, and into the veins of the systemic circulation (see §§ 34 and 35). Local passive congestion may arise directly from the fact that the progress of blood through the veins is not adequately supported by the activity of the muscles and the aspiration of the blood from the veins dur- ing the inspiratory enlargement of the thorax. The absence of the first factor is most apparent in the case of the branches of the inferior vena cava; as, for example, in individuals who pass a large part of their time sitting or standing without active bodily exercise, so that the emptying of the deep-seated venous branches into the vena cava is dependent al- most wholly upon the activity of the vein -walls, which by virtue of their elasticity and contractility work against the pressure of the column of blood resting upon them. The absence of the inspiratory aspiration of the venous blood may, on the other hand, make itself felt in disturbance of inspiration through inflammation or other disease-processes of the lungs or pleura. A further cause of local passive hyperemia consists in the narrowing or closing of individual veins, as in the case of compression, ligation, formation of thrombi (§ 38), and the invasion of the veins by new- growths. For example, the pregnant uterus or a pelvic tumor may com- press the pelvic veins, a thrombus may obstruct the cerebral sinuses or the femoral or portal veins, or a sarcoma of the pelvis may grow into the large pelvic veins. 132 DISTURBANCES OF THE CIRCULATION. When through the above-mentioned processes or through ligation, single veins become occluded, the effect of the occlusion is often very insignificant, inasmuch as the veins concerned may possess free commu- nication with other veins, so that but slight obstruction is offered to the outflow of the blood. If, on the other hand, the occluded vein possesses no collateral communications, or very small ones which are inadequate for the passage of the blood — as, for instance, is the case with the main divisions of the portal vein, the sinus of the dura mater, the femoral and the renal veins — there results a more or less marked passive congestion in the area supplying the given vein. The effect of an obstacle to the outflow of blood shows itself first in that portion of the vein lying between the obstruction and the periph- ery, the blood-current becoming slowed or checked entirely, while at the same time there follows a progressive filling and dilatation of the veins through the continued afflux of blood from the capillaries. If through the counteractive effect of the increasing tension of the elastic and con- tractile vein-walls the obstacle is overcome, the circulation is main- tained, and the blood flows toward the heart through the channels which it still finds open. Not iufrequently the small veins thus called upon to perform this increased labor become gradually much dilated, and are converted into larger veins. When the obstacle cannot be overcome and communicating vessels capable of dilatation are not present, the circula- tion comes to a standstill, and a condition of stasis (§ 40) or thrombosis (§ 38) is produced in the obstructed vessel and its tributaries. If the congestion within a venous area extends to the capillaries, so that they become overfilled with blood, the affected tissue becomes blue- red or cyanotic, exhibiting at the same time a certain degree of swelling. Both active and passive hyperemia, observed during life, may, after death, show a very different appearance, and not infrequently disappear entirely. This is especially the case in the active hyperasniias of the skin, in part also in those of the mucous membranes. This is dependent upon the fact that the tissues, put upon the stretch by the dilatation of the capillaries, contract upon the latter, after the stoppage of the cir- culation, and by their counter-pressure drive the blood from the capil- laries into the veins. In this way a tissue which was red during life may become pale after death. On the other hand, tissues which during life were pale or at least showed no especial redness, may after death take on a blue-red color. This takes place particularly upon the sides and back of the trunk (in those parts not pressed upon by the body- weight), on the neck, and the posterior aspects of the extremities of cadavers lying upon their backs; and is to be explained by the fact that after death the blood sinks to the most dependent parts of the body, and fills not only the veins, but finally also the capillaries. This phenome- non is known as post-mortem hypostasis, and the areas of discoloration as " death=spots " or livores. They appear within about three hours after death, and are the more pronounced the greater the amount of blood contained in the skin and subcutaneous tissues at the time of death. In the internal organs post-mortem hypostasis is particularly notice- able in the pia mater, the dependent veins being usually more markedly distended with blood than those situated higher. In the lungs the set- tling of the blood causes an engorgement not only of the veins, but also of the capillaries. If the general circulation during life, as a result, of cardiac insuffi- ciency, is imperfect, and there results a general passive congestion, the AN.EMIA. 133 blood may also collect in the dependent portions of the body, partly be- cause it is not driven out of them, and partly because it sinks into these parts from those situated on a higher level. This phenomenon is also known as hypostasis, and occurs particularly in the lungs {hypostatic congestion). For the observation of the circulation and its disturbances during life the tongue or the web of the curarized frog, properly spread upon a glass plate, may be used (Cohnheim, VircJi. Arch., Bd. 40). This may be done in a very simple manner by draw- ing the frog's tongue over a cork ring, which is cemented to a glass plate, and fasten- ing it to the sides of the ring with pins. The pulsating arterial current and the con- tinuous venous stream possess a clear zone of Mood-plasma, in both the normal and the quickened circulation. If, through the ligation of the efferent veins of the tongue, passive congestion is produced and the current slowed, the plasma-zone in the veins is lost, and both veins and capillaries become greatly distended with accumulated red cells. After a certain time the tongue swells as the result of an infiltration with trans- uded fluid. According to the investigations of wn Lunderer ("Die Gewebsspannung," Leipzig, 1884), the wall of a capillary vessel embedded in tissue supports only from one-third to one-half of the blood-pressure. The remaining portion is borne by the tissues, which afford an elastic resistance, and thereby maintain the tension which is necessary to keep the blood in motion. In both active and passive hyperemia both the tissue-pressure and the tissue-tension are increased ; in amemia they are diminished. § 37. Local anaemia or ischa?mia, the lack of proper blood-supply to a tissue, is always the result of a diminution iu the afflux of blood. If the total mass of the blood is normal, the cause of the antemia is purely local ; if there is a general poverty of blood, the local anaemia, in part at least, is secondary. The pathological diminution in the blood=supply to an organ is at times merely the result of an abnormal increase of (he arterial resistance, due to the contraction of the circular muscular coat. According to Strieker, Steinach, and Kahn, the capillaries also possess a power of con- tractility which is under the influence of the nervous system. In other cases pathological obstructions — such as compression of the arteries, narrow- ing of the arterial lumen through pathological changes in the vessel-walls, deposits on the inner surfaces of the arteries, occlusion of the vessels by emboli (see Fig. 2, p. 65 ), etc. — may act as hindrances to the blood- stream. The immediate result of the' narrowing of an artery is always a slow- ing and diminution of the blood-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 is provided with large arterial communicating branches — the so-called arterial collaterals — the disturbance of the circu- lation may be compensated by an increased afflux of blood through the collateral arteries ; and this compensation is the more complete the larger and the more distensible are the collaterals. If the narrowed or occluded artery possesses no collateral branches in its area of distribution — if it is a so-called terminal artery — the slowing or cessation of the circulation be- yond the point of obstruction or occlusion cannot immediately be done away with, and the affected vascular area becomes partly or wholly emp- tied of blood, in that, through the contraction of the arteries and the pressure of the tissue on the capillaries and veins, the blood is almost wholly driven out of the area supplied by the obstructed artery. Fre- quently there occurs after a time an afflux of blood from the neighboring capillaries. When the current and the pressure beyond a constricted point have 134 DISTURBANCES OF THE CIRCULATION. sunk to a certain minimum, the driving force gradually becomes unable to propel the mass of blood. The red corpuscles, in particular, cease to move, and collect in the veins and capillaries, so that the area supplied by the artery in question becomes again filled with blood ; only not with cir- culating, but with stagnant blood. The same thing occurs when, after com- plete occlusion of a terminal artery, the blood slowly and under low press- ure enters the vessels of the affected area from small arteries incapable of adequate enlargement, or merely through anastomosing capillaries. Finally, an accumulation of blood within the anaemic area may also oc- cur by a reflux from the veins. This takes place when the intravascu- lar pressure within this area has sunk to nothiug in the arteries and capillaries, while in the veins a positive pressure exists. A condition of passive congestion in the veins favors such a reflux. A further cause of ana3mia of one organ may be found in the abnor- mal congestion of other organs, as in that case the total mass of the blood is not sufficient to supply adequately the remaining organs. Such an anaemia is designated collateral ancemia. All ancemie tissues are characterized by paleness. At the same time they are flabby, not turgescent, and show their individual color more distinctly. The significance of ischaemia lies especially in the fact that, on ac- count of the need of the tissues for a continuous supply of oxygen and food-material, the persistence for a certain length of time of the condi- tion of imperfect blood-supply brings about tissue-degenerations (compare § 1). Total arrest of the blood-supply leads in a short time to the death of the tissue involved. If the blood conies to flow anew into the degen- erating and dying tissues in the area of distribution of an obstructed ves- sel, and there stagnates, an extravasation of blood into the tissue may take place, leading to the formation of a hemorrhagic infarct (compare §44). The rapidity and completeness of the development of a collateral circulation after the occlusion of an artery depends upon the size and distensibility of those vessels which are in communication with those of the anaemic area. If these are numerous and dis- tensible, the anaemic area is soon again supplied with an approximately normal volume of blood. If this is not the case the disturbance of the circulation is more slowly com- pensated; and the stasis and increased pressure are found to extend farther back from the point of obstruction toward the heart, so that a collateral hyperemia occurs in ves- sels situated farther back toward the heart. In the further course of the process of re-establishing the circulation the resulting increase of volume and velocity remains confined to such vessels as communicate with the area of the obstructed artery, that is, confined to the capillary and arterial anastomoses, where the increase of volume and velocity become permanent. This leads further to a lasting dilatation of the vessels concerned, and at the same time to an increase in the vessel-walls, not only in thickness, but also in length, as is evident from the increased tortuosity of the vessels. Accord- ing to Nothnagel, the phenomenon of the increase in thickness of the walls of the anas- tomosing arteries may be demonstrated in the case of rabbits in about six days after the ligation of an artery ; and after the ligation of large vessels in their continuity, the small arteries which carry on the collateral circulation become changed in the course of a few weeks, into quite capacious, thick-walled arteries. Literature. (Local Disturbances of Circulation. ) Baldwin: Multiple Anaemic Infarction of the Liver. Jour, of Med Research 1902 (Lit.). Bier: Entstehung d. Collateralkreislaufs. Virch. Arch., 147, 153 Bd., 1897, 1898 (Lit.). Cavazzani: Sur la genese de la circulation collaterale. Arch. ital. de biol., xvi., 1892. Conn : Klinik der embolisehen Gefiisskrankheiten, Berlin, 18(30. Cohnheim: Vorles. fiber allgemeine Pathologie, Berlin, 1882. Hektoen: Embolism of the Coronary Arteries. Med. News, 1892. COAGULATION AND THROMBOSIS. 135 Krauss: Der Verschluss der Vena Cava sup. u. d. Vena Cava inf. Iuaug. Diss., Tu- bingen, 1894 (Lit.). Lowit: RiickUlufJge Blutstromung. Centralbl. f. alig. Path., viii., 1897. Lukjanow: Allgemeine Patbologie des Gefasssystems, Leipzig, 1894. Marchand: Gehirnembolie. Berl. klin. Woehenscbr., 1894. Mogling: Zur Kenntn. des bamorrhagischen Infarktes. Beitr. v. Ziegler, i., 1886. Nothnag-el: Die Entstehung des Oollateralkreislauf s. Zeitsch. f. klin. Med., xv., 1888. v. Recklinghausen: Pathologie des Kreislaufs u. der Ernahrung, Stuttgart, 1883. Reimar: Embolie der Art. centralis Retinaj. Arcb. f. Augenheilk ., 38 Bd., 1899. Saveliew: Gehirnarterienembolie. Vircb. Arcb., 135 Bd., 1894. Steinach u. Kahn: Kontraetilitat u. motor. Innervat. d. Kapill. Pflllff. A., 97 Bd., 1903. b Talma: Leber collateral Circulation. Pfliiger's Arch., 23 Bd., 1880. Thoma: Pathologiscbe Anatomie, i., Stuttgart, 1894. Virchow: Oertliche Storungen des Kreislaufs. Handb. d. spec. Path., i., Erlangen, 1854. III. Coagulation, Thrombosis, and Stasis. § 38. Upon the death of the individual the blood contained in the heart and great vessels sooner or later coagulates in part, and there arise those formations which are known as post-mortem clots. If the clotting oc- curs at a time when the red blood-cells are still evenly distributed in the blood, the whole mass of the blood becomes coagulated, forming soft, dark-red masses of coagulum which are known as cruor. If before the clotting there occurs, through the sinking of the red cells, a separation of the blood into two layers — a substratum rich in red blood-corpuscles, and an upper fluid layer containing none and consisting only of the plasma — then, if the latter coagulate, there will be formed soft, gelat- inous, light-yellow, elastic lumps and stringy masses having a smooth surface and not adherent to the vessel-wall, which are known as lardace- /', " '" "'IK -^f 4^-wM^ Bto. 12. — A tardaceous clot from the cadaver. (Formalin, hematoxylin, and eosin.) X 500. ous clots or as fibrinous deposits. These contain the same fibrin threads (Pig. 12) and scattered red and white blood-cells. Through the inclu- sion of red cells in these formations, they may present in parts a red or reddish-black color ; if large numbers of leucocytes are present, they may have a whitish color. When blood is drawn from an artery or vein and received into a vessel, coagulation will occur within a short time, as the result of the adhesion of the fluid to the sides of the receptacle. The entire blood-mass be- comes changed into a soft coherent mass. When freshly drawn blood is 136 DISTURBANCES OF THE CIRCULATION. beaten with a solid body, the surface of the latter becomes covered m a very short time with felt-like fibrin. If within the body large quantities of blood pass oid into the tissues— as, for example, into the pericardium or into the lungs— coagulation may occur here likewise, and the extravasated blood may in this way acquire a firm consistency (Fig. 13, d). Under certain conditions there may be formed within the heart or blood-vessels during life, firm deposits, which in part are similar to cruor, and in part to the fibrin-masses formed by whipping the blood. These formations are known as thrombi, and the process which leads to their formation as thrombosis. According to their color they may be distin- Fi(5. 13. and eosin.) Coagulated blood in a fresh hemorrhagic infarct of the lung. (Muller's fluid ; hematoxylin a. Alveolar septa without nuclei, containing capillaries filled with dark bluish-violet, homo- geneous thrombus-masses; b, septa containing nuclei; c, vein tilled with red thrombus; d, d lt alveoli rilled with firm blood-clots ; e, alveoli tilled with" serous fluid, tlbrin, and leucocytes. X 90. guished as red, colorless or white (that is, yellow or grayish-white), anc? mixed, thrombi. The coagulation of the blood is a peculiar process, difficult of exact interpretation. Histologically, it is characterized, both in extravascular clotting (Fig. 13, d, d t ) and in intravascular as well (Fig. 14), by the formation of little rods and threads between the red cells, at one time ar- ranged in a meshwork, at other times in stellate or fascicular groups around centres. These little rods and fibres are known as fibrin ; and are in part smooth and shining, in part covered by little granules, or partly interrupted by granules, or are composed entirely of such collected together. Besides the threads there occur also free granules, granular masses, and blood-plates of varying size and form; and not infrequently . such formations lie in the centre of the fibrin-stars. At times the stellate and fascicular forms of fibrin are found arranged about leucocytes or at- tached to endothelial cells of the intima of the vessel. In the red blood-cells there occur here and there degenerative appear- ances, in the form of plasmolysis, plasmorrhexis, and plasmoschisis. In plasmolysis or erythrocytolysis there occurs a passage of soluble substances from (he red cells into the blood plasma, so that the red cells become smaller, and the so-called microcytes and red blood-cell "shadows" are produced. At the same time individual cells may become swollen. In plasmorrhexis or eryth rocytorrhexis and in plasmoschisis or erythro- cytosehisis, blight, shining globules arise from the red cells, or the latter COAGULATION AND THROMBOSIS. 137 become covered with little prickle-like projections, or come to resemble mulberries, or send out protoplasmic processes. Through the snaring- off of these prominences round, disc-like, angular, or thread-like bodies are formed, which are partly homogeneous and partly finely granular, and not infrequently enclose larger shining bodies. Finally, the red cells may break up into disc-like or globular pieces, and finally into granules. The formations known as blood-plates are for the greater part peculiarly formed products of plasmorrhexis and plasmoschisis of the red cells; and it is possible to distinguish among them those which are colorless, those con- taining haemoglobin, and homogeneous and granular forms. In fresh coagula, changes cannot usually be demonstrated in the color- less corpuscles of the blood; but in the later course of the process degenera- tive appearances are found in these also; and products may thereby be produced resembling those arising through the disintegration of the red blood-cells designated as blood-plates. Between the destruction of the red blood-cells, respectively the formation of the blood-platen, and, the coagulation of the blood, both extra- and intra- vascular, there exist undoubtedly close relations; that is, coagulation is set into action through the occurrence of change's in the red cells as above described. According to our present knowledge, it must be assumed that many red cells, probably the oldest ones, very easily suffer such changes, so that, for example, adherence to a diseased por- tion of the vessel-wall, which is prevented by the normal condition of the intima, is sufficient to cause a disintegration of certain red cells, with formation of blood-plates, and later coagulation and thrombus-forma- tion. The origin of coagulation has also been regarded as due to plas- molysis and plasmorrhexis of the leucocytes; further, similar degenera- tions of the endothelium may also induce coagulation. The possibility that the endothelial cells play a certain part in the origin of coagulation cannot be excluded, but it must be emphasized that the degenerative changes ordinarily preceding coagulation cannot be demonstrated in these cells. The facts brought forth, particularly by Hauser and Zenker, that the fibrin-threads not infrequently are attached to endothelial cells, or leucocytes, or to the remains of such cells, do not prove that these are the exciters of coagulation, or that they offer material for the formation of fibrin; inasmuch as the deposit of the fibrin upon these cells may be due to purely mechanical causes. The chemical processes concerned in coagulation can- not at present be explained. It is assumed that for its oc- currence the presence of a fibrinogenic substance, a fer- ment (thrombin), and certain salts, particularly calcium salts, is necessary; and that the fibrinogenic substance is an albuminoid body belonging to the globulins, which is present in the blood-plasma, while the ferment is produced by FIG. U.— Bundles and star-shaped clusters nt fibrin Tne CellS. According to A. threads within a blond-vessel. (Fibrin stain.) Prepara- Schmidt, thrombin is derived lion taken from an inflamed tracheal mucous membrane. ~ , , , x sno. from a parent-substance, pro- mm WW M ^ 13S DISTURBANCES OF THE CIRCULATION. FIG. 15.— Section through a ret] thrombus funned in one of the veins of the thigh-muscles, after occlusion of the femoral vein. (Muller's fluid ; hematoxylin.) a, Fibrin -threads; h, leucocytes and granular masses. X 260. thrombin which becomes active under the influence of a sijmox>lastic sub- dance. By means of the thrombin there is formed, in an as yet unknown manner, from the globulins pre-existing in the alkaline solution, a greatly swollen albuminoid body, which is precipitated by the * calcium salts contained in the plasma. In the process of coagulation we must, therefore, recognize two stages, namely, the stage of the production of the fibrin-ferment, and the stage of the action of the ferment or coagulation proper. Morawitz is also of the opinion that fibrin-ferment arises through the cooperation of several substances, thrombo- f/en, thronibolcinase, and calcium. The substance designated as thrombokinase is identical with the zymoplastic substance of Selimidt and behaves in the same way as a ferment. The red thrombus is formed under such conditions us the com- plete stoppage of the circulation or a, marked slowing of the Mime, and comprises the total mass of the red cells (Fig. 15). The precipitated fibrin forms granules (Fig. 15, b) and threads (a). In fresh clots in small vessels, it is not infrequently possible to demonstrate after death, by means of special methods, the presence of bundles and star-shaped clusters of fibrin-rods (Fig. 14), which radiate from centres of coagula- tion. In such cases, however, it is often impossible to distinguish with certainty to what extent the coagulation is intravital or to what extent post-mortem. Such form of coagulation is most frequently observed in inflamed tissues, and the conclusion is warranted that changes in the blood occurring in such inflammatory areas are the cause of this variety of fibrin-formation. Since these thrombi often enclose very few red blood-cells (Fig. 11) and thereby present a pale appearance, it is evident that the red blood- cells for the greater part must have become disinte- grated. Immediately after its formation the red thrombus is soft and rich in the fluids of the blood ; biter it becomes tougher, denser, and more dry, as the fibrin contracts and squeezes out a portion of the fluid. At the same time it becomes paler, brownish-red or of a rust-color, inasmuch as the blood-pigment undergoes changes similar to those occurring in ex- travasations. The cause of the ante-mortem intravascular coagulation is to be found either in an increase in the production of fibrin-ferment or fibrinogenic substances or in a diminution of the power possessed by the normal vessel- wall of inhibiting coagulation. Under certain conditions the more marked ad- hesion of the blood to a degenerated area in the vessel-wall may in itself be sufficient to induce coagulation. This occurs accordingly in ligated vessels, when the endothelium at the point of ligation is injured; but in the case of a slight injury to the vessel -wall and the blood, clotting may not take place (Baumgarten). THROMBOSIS. 139 White, mixed, and often distinctly laminated thrombi arise in the flowing Mood, and consist of masses of yellowish color, or of various shades of red, or of alternating layers of red and white. The micro- scopical examination shows them to consist of granular and thread-like masses (Pigs. 16 and 17), leucocytes, and red cells, which in varying pro- aM m, 0jM FiO. 16.— Section Croraamixed thrombus rid in Fig. 17.- cells. (Mifller's Quid, hematoxylin.) a,B.edblood- ing but lev? colls; h, granular masses; e, reticular fibrin con- a, Granular mas taining many leucocytes: d, threads ol fibrin in ing a net-like ret: parallel arrangement. X 200. arrangement. Is. tMQller's fluid ; hematoxylin.) ssps; /», flbrogranular fibrin form - i ; c, fibrin-threads in parallel portion and arrangement make up their structure. White thrombi may consist almost entirely of granular masses (Fig. 17, a ) and fibro-granu- lar fibrin, which in some cases is arranged in a meshwork (b), in others in fibres running nearly parallel (e) which enclose few leucocytes, in other cases the number of cells may be much greater. In mixed thrombi (Fig. 16), granuhir fibrin (6), more rarely hyaline masses, thready fibrin (c, d), and red blood-cells (a), in varying proportion and in alter- nating stratification, constitute the thrombus-mass, and all of these ele- ments enclose more or less numerous, often many leucocytes. The color- less portions of mixed thrombi consist essentially of fibrin, fluid, and leucocytes, but they often contain also numerous decolorized red blood- cells. The fibrogramdar masses which form part of the structure of the thrombus are composed of precipitated fibrin. The granular and hyaline masses, on the other hand, probably arise directly from the products of the plasmoschisis and plasmorrhexis of the red blood=cells, in particular from the bIood=plates. In large thrombi they often show a coral-like arrangement. The causes of the formation of white and mixed thrombi are es- pecially: changes in the intima of the heart and the vessels and diseases of the vascular apparatus, that lead to a general or local slowing or irregularity of the blood-stream. The formation of thrombi may he studied directly, in suitable subjects, undci the microscope, both in the case of cold-blooded and warm-blooded animals; and the observations made in this line, especially by Bizzozero, Eberth, Schimmelbusch, and Lbivit, have led to very important results. When the blood flows with normal velocity through a blood-vessel, there may be 140 DISTURBANCES OF THE CIRCULATION. i (*,Ss a ^, . b m # 3 1'IG. IS. a ,1 fig. 19. seen under the microscope a broad, homogeneous red stream in the axis of the blood- vessel (Fig. IS, a), while at the sides there lies a clear plasma-zone (b) free from red colls. This may be observed in the arteries, veins, and large capillaries, but is best seen in the veins, while in the small capillaries, which are just large enough to permit the pass- age of the red cells, this difference between the axial stream and plasma-zone is not present. In the axial stream the differ- ent constituents of the blood- stream are not recognizable; in the plasma- zone there appear, from time to time, white blood- corpuscles (Fig. IS. , also blood-plates (b), which in- crease more and more in number with the progressive retardation of the current, while the leuco- cytes again become diminished in numbers. When total arrest of a distinct separation of the corpus- -T Fig. IS. -Rapidly Bowing blood-strean '», marginal zone with isolated leucocyte and Schimmelbusch.) Axial stream (After Ebertl Fig. 19.— Moderately slow hlood-st \ peripheral zone with numerous Iberth and ScMmmelbuseh.) pain. G, Axial leucocytes, '/. Fig. 20. - Markedly slow current, a, Axial strea ipheral stream with blood-plates; c, collectionot bli tJ, , c, d, connec- tive-tissue cords in the lu- mina of the vein and its branches ; e, fresh thrombus. (Natural size.) SEQUELAE OF THROMBOSIS. 147 In case of marked contraction, the fibrin, blood-plates, and the red blood-cells may become changed into a firm mass, which may remain in Fir. 24.— Obliteration of a pulmonary artery by connective tissue after embolic plugging of its lumen. (Miiller's fluid, hematoxylin, and eosin.) a. Artery wall; /j, connective tissue filling the vessel-lumen; c, fi, newly formed blood-vessels. X 45. this condition for a long time, become firmly adherent to the vessel-wall, and finally undergo calcification. This may occur in both valvular heart -thrombi and thrombi located in the vessels. The chalky concre- tions formed in this manner in the veins are known as phleboliths ; those occurring more rarely in the arteries as arterioliths. Contraction and calcification are relatively favorable sequelae of thrombosis. Much less favorable are the more frequent processes of de- generation occurring in thrombi, which are known as simple and as puri- form or yellow septic softening. In simple softening the central portion of the thrombus becomes changed into a grayish-red, or gray, or grayish-white grumous mass, consisting of disinte- grated and shrunken red corpuscles, pigment-granules, and colorless, gran- ular debris. If the softening extends to the superficial layers, and if there is at the same time a certain strength of blood-current in the neighborhood of the thrombus, the products of disin- tegration may be swept along into the circulation. If thereby larger pieces become loosened and transported by the blood-stream, arterial emboli will be produced (see Fig. 2). In the yellow puriform or septic softening the thrombus breaks down into a yellow, or grayish-yellow, or reddish -yellow, pus-like, grumous, creamy, and at times foul-smelling mass, consisting of pus-corpuscles and a large amount of finely -granular substance, composed of fatty and albuminous detritus and micrococci. Fig. 25.— Remains of embolic plugs In a branch of the pulmonary artery, a. Con- tracted embolus traversed by connective-tissue threads; ft, cords of connective-tissue crossing the orifices of branch vessels. (Natural size.) 148 DISTURBANCES OF THE CIRCULATION. This mass acts as a destructive irritant upon the surrounding tissues, giving rise to inflammation. As a result the intima becomes cloudy, and there arises a purulent inflammation in the media and adventitia, as well as in the tissues about the vessel. After a short time all the vascu- lar coats become infiltrated and present a dirty-yellow or grayish-yellow appearance. A suppurative destruction of the tissues filially results. If puriform masses are transported by the blood-stream to other parts of the vascular system, they will give rise to metastatic foci of necrosis and septic disintegration of the tissues, and purulent inflammation, in- volving not only the vessel-wall but also the neighboring tissues. The process of puriform softening of a venous or arterial thrombus, associated with a purulent infiltration of the vessel-wall, is designated thrombophlebitis purulenta or thrombo=arteritis purulenta. The in- flammation of the vessel-wall may take its start either in the softening thrombus or in the tissues adjacent to the vessel. In the latter case the pear swol- len, though the degree of swelling depends essentially upon the structure of the affected tissue. The skin and the subcutaneous tis- sue are able to take up into their lymph - spaces large quantities of fluid, so that an extremity may become enormously swollen through oedema-. In this condition --""" it is pale, possesses a doughy Fig. 29.— Hydropic connective-tissue cells from the Consistence, and T)itS OU subcutaneous tissue of a case of chronic cedema due lo r\ ■ ■ • stasis. (K. Ziegler, l. c.j. x 400. pressure. On incision an CEDEMA. 153 abundance of dear fluid escapes, showing the tissues to be thoroughly saturated with fluid. The lung behaves in a similar way. Owing to its limited space it cannot become greatly distended, but it contains great numbers of cavi- ties filled with air, which, in the advent of cedema, become filled with fluid, which on pressure escapes from the cut surface, gen- erally mingled with air-bubbles. (Edematous swellings of the kidney, which may become very marked, are caused especially by the retention in the dilated urin- ary tubules of the water of the urine secreted by the glomeruli. In the connective tissue between the tubules largf lect but rarely. The amount of blood contained in cedematous tissues is varia their color varies accordingly. Body-cavities which are the seat of a dropsical effusion contain at one time a large, at another time only a small amount of a clear, usually Fig. 30. — Longitudinal section of oedematous muscle-fibres from the calf muscles in a case of chronic oedema of the legs. (Flemimng's solution, safranln.) X 45. imouuts of fluid col- e, and Fig. 31. — Infiammalory oedema of the papillary bodies, with elevation of the epidermis from the papillary bodies by an' inflammatory exudate, from a case of phlegmon of the thigh. (K. Ziegler, 1. a). f tli due to calcification, arteries. oblite ation of their a warm or hot gangrene, the latter designation being used when the gan- grenous area is kept warm by the blood flowing through the neighboring tissues. Gangrene may be caused by external injuries, heat, cold, corrosives, crushing, pressure, infection, etc., as well as by disturbances of the cir- culation. GANGRENE. 179 Gangrene due to disturbance or arrest of the circulation occurs not infrequently in old. people (senile gangrene), involving the extremities, particularly the toes, feet, and legs. It is usually of the dry variety, aud is dependent partly upon general disturbances of the circulation and partly upon disease of the arteries of the extremities (calcification, ossi- fication, thickening of the intima, thrombosis, embolism) (Fig. 42). The dying parts appear bluish-black as a result of the venous stasis. Gangrene from cold affects chiefly the tips of the extremities, nose, and ears, and is characterized by changes similar to those described above. Gangrene from heat is confined to the area directly affected by the heat. Pressure=gangrene or decubitus (bedsore) occurs in marasmic indi- viduals, most frequently upon the sacrum and the heels, both of which regions are exposed to pressure when the individual lies upon his back. The bedsore begins with the formation of bluish-red spots, within whose area the tissue dies, and through the agency of bacteria undergoes de- composition and finally disintegrates. The gangrenous area may be of large extent, especially when over the sacrum ; the bone may be laid bare over a large area through the destruction of the overlying soft parts. Toxic gangrene occurs chiefly in ergot poisoning as a result of the contraction of the small vessels and formation of thrombi. The tips of the extremities are usually affected. Infectious gangrene occurs particularly in different infections of the skin and subcutaneous tissue, and may be associated with gas-formation. In the form known as foudroyant gangrene different varieties of bacteria have been found ; the bacillus of malignant oedema, an anaerobic bacil- lus (Welch, E. Prankel, Hitschmann and Lindenthal ), proteus (Hauser), and bacterium coli. Infections associated with putrid gangrene may occur in the internal organs, but affect, chiefly the lungs and intestines. A so-called neuropathic gangrene occurs when a tissue affected with either sensory or motor paralysis is wounded or subjected to continued pressure. It is dependent partly upon circulatory disturbances and partly upon infection. Gangrene resulting from the withdrawal of the influence of trophic nerves has not yet been demonstrated. Symmet- rical gangrene, which affects corresponding parts of the extremities and has been regarded by many as a neuropathic disease, is dependent upon changes in the blood-vessels ; likewise, the perforating ulcer of the foot (mal perforant du pied), which begins as a callosity following me- chanical influences, and is characterized by an accompanying gangrene which rapidly penetrates into the deeper tissues, is dependent upon the closure of an artery of the foot. In moist gangrene the tissues break down with a varying degree of rapidity, the fascia3 resisting for the longest time. As crystalline prod- ucts of the chemical changes there may be found needles of fat and tyrosin, spherules of leucin, coffin-lid crystals of triple phosphate, and crystals of hajmatoidin. If the gangrene comes to a standstill, the gan- grenous tissue becomes sequestrated through the formation of a zone of demarcation — that is, becomes separated from the living tissue, and under favorable conditions may be thrown off from the body. In the case of necrotic portions of bone a very long time is required for seques- tration. Extension of gangrene (through infection or continued circu- latory disturbance) leads sooner or later to death, especially if toxic sub- stances or bacteria are taken up into the blood or lymph. Literature. (Necrosis and Gangrene ) Albrecht: Pathol, d. Zelle. Ergebn. v. Lubarsch, vii., J 902. Arnheim: Coagulationsnekrose d. Kernschwund. Virch. Arch., 120 Bd., 1S90. ISO THE RETROGRADE CHANGES. Balser: Ueber Fettnekrose. Virch. Arch., 90 Bd., 1882. Cliiari: Ueber die sog. Fettnekrose. Prager med. Woch., 1893. Condorelli : Istio-patologia del nucleo nelle contusioni, Catania, 1891. Dejerine et Leloir: Alter, nerv. dans cert, cas de gangrene. Arch, de phys., 1881. Dietrich: Verim. asept. aufbewahrter Organe. Verh. d. D. path. Ges., vi., 1904. Ellis: (X-Ray Necrosis) Lit. Amer. Jour, of Med. Sc, 1903. Falta: Gangraena senilis. Zeitschr. f. Heilk., xx., 1899. Flexner: Fat necrosis. Jour, of Exp. Med., 1897; Focal Necrosis. Johns Hopkins Hosp. Rep., 1897. Frangois: Essai sur les gangrenes spontanees, Paris, 1S32. Frankel: Ueber die Gasphiegmone, Hamburg, 1893; and Miinch. med. Woch., 1899. Goldschmidt: Gangrene symetrique (endarteriteobliterante). Revue denied., vii., 1887. Goldmaim: Veranderungen aseptisch aufbewahrter Gewebsstucke Fortschr. d. Med., vi., 1888; Reiskorperchenhaltiges Hygrom der Sehnenscheiden. Beitr. v. Ziegler, vii., 1890. Haga: Spontane Gangran. Virch. Arch., 152 Bd., 1898. Hauser : York. v. Mikroorg. in leb. Geweben. A. f . exp. Path., xx., 1886. Hitschmann u. Lindenthal : Gangrene foudroyante. Sitzb. d. Ak. d. Wiss. , Wien, 1S99. Hochenegg: Ueber symmetrische Gangran u. locale Asphyxie, Wien, 1886. Israel: Anam. Nekrose d. Nierenepithelien. Virch. Arch., 123 Bd., 1S91; Biolog. Studien.ib., 141 Bd., 1S9.5; 147 Bd., 1897; Tod d. Zelle. Berl. klin. Woch., 1897. Jacoby: Bedeutung d. Fermente f. d. Pathologie. Cbl. f. a. P., xvi., 1902; Wirkung d. intracellularen Fermente. Beitr. z. chem. Phys., iii., 1903. Kaufmann: Die Sublimatintoxication, Breslau, 1888. Virch. Arch., 117 Bd., 1889. Kraus : Im abgestorb. Gewebe auftretende Veranderungen. Arch, f . exp. Path., xxii., 1886. Langerhans: Ueber multiple Fettgewebsnekrose. Virch. Arch., 122 Bd., 1891. Le Count: Focal Necrosis. Jour, of Exp. Med., 1S97. Lesser: Anat. Veranderungen d. Verdauungskanales durch Aetzgifte. Virch. Arch.; 83 Bd., 1880. Liegros: Rech. hist, sur les gangrenes gazeuses. A. de med. exp., 1903. Levai: Mai perforant du pied. Zeit. f. Chir., 49 Bd., 1899. Mallory: Focal Necrosis. Jour, of Exp. Med., 1898; Necroses of the Liver. Jour. of Med. Research, 1901. Muller: Ueber die Bedeutung der Selbstverda.uung. XX. Kongr. f. inn. Med., 1902. Neuberger: Wirkung des Sublimates auf die Nieren. Beitr. v. Ziegler, vi., 1889. Obolonsky u. Ziegler: Wirkung d. Phosphors auf Leber u. Nieren. Beitr. v. Ziegler, ii., 1887. Obernddrfer: Koagulationsnekrose d. Muskelfaser. B.v. Ziegler, xxxi., 1902. Peiper: Eiterige Schmelzung der Gewebe. Virch. Arch., 118 Bd., 1889. Pfitzner: Zur pathologischen Anatomie des Zellkerns. Virch. Arch., 103 Bd., 1886. Rath.: Bakteriologie der Gangran. Cbl. f. Bakt., xxv., 1899. Raynaud; Del'asphyxie locale etde la gangrene symetrio.ue des extremit^s, Paris, 1S62. Reed: Focal Necrosis. Amer. Jour, of Med. Sc, 1895. Rischpler: Histol. Veranderungen nach der Erfrierung. Beitr. v. Ziegler, xxviii. 1900. Salkowski: Ueber Autolyse. Deutsche Klinik, xi., Berlin, 1903 (Lit.). Schmaus: Zelltod. Ergebn. d. allg. Path., iii., Wiesbaden, 1897. Schmaus u. Albrecbt: Ueber Karyorrhexis. Virch. Arch., 13S Bd., 1895 (Lit.); Die kiisige Nekrose, ib., 144 Bd., Supplh., 1896; Coagulationsnekrose. Deut. med. Woch., 1899. Seitz: Blutung, Entziindung u. brandiges Absterben des Pankreas. Berlin, 1892. Sternberg: Endarteritis u. spontane Gangran. Virch. Arch., 161 Bd., 1900. Tesdorpf: Symmetrische Gangran. Arch. f. Psych., 33 Bd., 1900. Tomasczewski: Malum perforans pedis. Miinch. med. Woch., 1902. Verworn: Allg. Physiologic, Jena, 1897; Derkornige Zerfall. Prllig. Arch., 63 Bd., 1896. von Wartburg: Spontane Gangran. B. v. Bruns, 35 Bd.; Das Mai perforant. Ibid., 36 Bd., 1902 (Lit.). Weigert: Pathologische Gerinnungsvorgange. Virch. Arch., 79 Bd.; Coagulations- nekrose mit besonderer Beriicksichtigung der Hyalinbildung und der Umpragung geronnener Massen. Deut. med. Woch., 1885; Weisse Thromben. Fortschr. d. Med., v., 1887; Coagulationsnekrose oderlnspissation. Cbl. f. allg. Path., ii., 1891. Weiss: Venenspasmus. Wien. med. Presse, 1882; Symmetr. Gangran. Wien. med. Klin., 1882. Wells: Experimental Fat Necrosis. Jour, of Med. Research, 1903. IV. Hypoplasia, Agenesia, and Atrophy. § 51. Hypoplasia, or the defective development of anlage, may affect HYPOPLASIA. LSI either the body as a whole or only single organs or parts of organs, and may occur either during the period of intra-uterine development or later during the period of post-embryonal development, When either the entire skeleton or at least the greater part of it is under-developed, and especially if the bones do not attain their normal length, the affected individual is abnormally low in stature, and is called a dwarf (Pigs. 43 and 44). The individual parts may be fairly well pro- portioned (Fig. 43), or they may be unsymmetrically developed (Fig. Fig. 43. Fig. 43.— Skeleton of a female cretin, thirty-one years of age, 118 cm. in height, with klinocephalic skull. The cartilage sutures of the diaphyses of the long bones and pelvic bones still show ; as does also the frontal suture. The individual parts of the skeleton are, on the whole, in the proper proportion, the upper extremities alone being relatively short. Fig. 44.— Skeleton of a female dwarf of fifty-eight years of age, 117 cm. in height, with very short extremities, and long trunk. The cartilage sutures are still present; the articular ends of the bones are thick. 44). For example, the trunk may be of normal size, while the extrem- ities are abnormally short (Fig. 44) ; or both the trunk and the extrem- ities may be abnormally small, while the head is of normal size, and consequently appears relatively too large for the small body. When the lack of development affects individual parts of the skeleton exclusively, or if it is more marked in certain parts than elsewhere, there results a 182 THE RETROGRADE CHANGES. stunting of individual portions of the body. For example, defective de- velopment of the cranium gives rise to mierocephalus (Fig. 45) and micrencephalus (Fig. 46) ; through defective development of the humerus or of the bones of the hand there re- sults a shortening of the upper arm or of the hand ; and through hypo- plasia of the lateral masses of the sacrum the transverse diameter of the pelvis becomes diminished. Of the individual organs the central nervous system (Figs. 40 Fig. 45.— Head of Helene Becker (microcephalic), at age of Ave years. (From a photograph taken by A. Ecker, in 1868.) ^teiLll^J^ Fig. 46.— Brain of Helene Becker (micro- cephalic) who died at the age of eight years. (After von Bischoff.) This brain weighed 219 gin. (instead of 1,377 gni., according to Vierordt). and 47), and the genito-urinary tract in particular suffer very frequently a stunting of development, although the intestines, heart, lungs, liver, Fig. 47. — Hypoplasia and .microgyria of the left cerebral hemisphere, from a deaf-mute, a, Rio-ht hemisphere ; h, left hemisphere ; c, occipital lobe presenting a condition of microgyria ; il, membranous cyst in tbe region of the parietal lobe. (Seen from above, after removal of the cerebellum. natural size.) Two-thirds HYPOPLASIA : AGENESIA. 183 etc., do not escape similar disturbances of growth. For example, the entire brain (Fig. 46), or only one of the hemispheres, or a part of the latter (Fig. 47, c, d) may fail of complete development. The intestine Fig. 48. — Hypoplasia of the uterus with well-developed ovaries, hut without ripe follicles. From a cretin, twenty-eight years of age. may in part be represented by a thin canal incapable of functionating (Fig. 49, d), or even by a solid cord (Fig. 49, e). The uterus not iufre- cpiently remains in an undeveloped state (infantile) (Fig. 48), and occa- sionally at the time of puberty the ovary (Fig. 50, e), or the entire inter- nal generative apparatus, and at times also the external organs may remain in the undeveloped state of the young child. A more or less marked hypoplasia of the kid- ney is not rare. In the de- velopment of the respiratory tract the alveoli of a portion of the lung may wholly fail to de- velop. The above - mentioned ex- amples of hypoplasia, to which many others might be added, arise partly through intrinsic causes inherent iu the germ, and are therefore inheritable, and partly through the action of extrinsic? injurious influ- ences upon normal anlage dur- ing the course of development. For example, the growth of the bones may be influenced and retarded by imperfect function of the thyroid gland or disuse, and inflammation. Total failure of por- tions of the body or of single organs to develop is known as agenesia. This condition is dependent either upon the non-formation of the anlage, or upon the destruction of the latter after they have begun to develop. (See chapter on Malformations. ) Fig. 49.— Hypoplasia of the small intestine of the new-born child, «, Greatly dilated portion ; /i, c, d, e, portion showing great narrowing and stunting ; /, normally developed portion. (Five-sevenths natural size.) 1S4 THE RETROGRADE CHANGES. The tissue composing hypoplastic organs or parts of organs, though of less bulk than normal, may present no abnormalities of structure. In other cases there may be associated with the smallness of size a disturb- ance of internal organization, so that often the more highly specialized elements of the organ fail of development, the hypoplasia being at the same time associated with an agenesia of individual parts. Thus, for example, in hypoplasia of the ovary (Fig. 50, e) the development of the ova and the ripening of the follicles may fail in part; in hypoplasia of the brain there may occur at the same time a defective development of the gan- Fig. 50.— Cross sections of ovaries at different periods of life. (Hematoxylin and eosin.) a, h, e, d, Normal ovaries; a, girl of Ave years; b, twenty-three years; c, twenty-nine years; and d. twenty-one years ; e, hypoplastic ovary of girl of twenty-seven years ; /, o\ senile ovaries from women of eighty and eighty-three years of age. (Natural size.) glion-cells and nerve -fibres, and at times portions of the brain may con- sist only of membranous masses (Fig. 47, d) in which no ganglion-cells are present. In hypoplasia of the lung there may be under certain con- ditions a complete failure of development of the alveoli, so that the lung-tissue consists merely of a very vascular connective tissue through- out which lie the bronchi, the latter in the course of time usually be- coming dilated. Literature. (Hypoplasia and Agenesia.) Forster: Die Missbildungen des Menschen, Jena, 1865. Hertz : Ueber Ilemiatrophia facialis progressiva. Arch, f . Kinderheil. , vii. , 1887. Hektoeri: Anatomical Study of a Short-limbed Dwarf. Amer. Jour, of Med. Sc., 1903. Mehnert: Die. individuelle Variation d. Embryo. Morph. Arb. v. Schwalbe, v., 1896. Paltauf, A. : Ueber den Zwergwuchs, Wien, 1891. Rahlmann: Mikrophthalmus u. Hemimikrosoma, Stuttgart, 1897. Vierordt: Anatomische, physiologiscke u. physikalische Daten u. Tabellen, Jena, 1888. See also Chapter IX. ; : g 52. Atrophy is a diminution in the size of an organ due either to a diminution in size or disappearance of its individual elements. It may occur at any period of life, and is a very common result of many path- ological processes. Within certain limits it may be regarded as a physi- ological phenomenon, in that in old age there constantly occurs a certain degree of retrograde change in all the organs, associated with a diminu- tion in their size. Certain organs undergo such an atrophy with partial or total loss of their functional power, even before old age, as, for exam- ple, the thymus, which atrophies completely even before the end of the period of growth ; and the ovary (Fig. 50, /, g), a part of whose ova are discharged during the period of sexual activity, the remainder being ATROPHY. 185 destroyed. In old age the lymphadenoid tissues, the muscles and bones, in particular, suffer atrophy, though the tissue-changes of senility vary greatly in different individuals, so that often other tissues, the glandular organs or the brain, show the most marked atrophy. The atrophy of an organ is characterized chiefly by its diminution in size. In atrophic conditions of the muscles (Fig. 51) the affected por- tions of the body become smaller, and in extreme cases the extremities appear as if consisting only of skin and bones. When the atrophy of an organ is uniform throughout, its normal shape may be preserved ; but if the atrophy progresses more rapidly in certain parts than in others, the surface of the organ may show local de- pressions (Fig. 53) and cicatricial con- tractions (Fig. 56), so that the organ, for example, the liver or kidney, may present a knobbed or granular appearance. When tissues which are undergoing atrophy are prevented from contracting, as in the case of the bones and lungs, the external form is preserved. In the case of bone, the medullary spaces and the Haversian canals become enlarged, and a condition results which is known as excentric atrophy or osteoporosis (Fig. 52). In the lungs the alveoli become confluent into large air- spaces as the result of the disappearance of the intervening walls. In atrophy of the glands and muscles there occurs frequently a change of color, though this is of secondary importance. Either the normal pigmentation of the affected organ is brought out more dis- tinctly by its atrophy, or associated with the atrophy there is a deposit of pigment (brown or pigment atrophy), or finally the change of color may be dependent upon the changed blood-content of the atrophic tissue. The diminution in size of atrophic organs is the result of a diminution in size and dis- appearance of the histological elements com- posing them. In the majority of the or- gans, particularly in the glands, muscles, and bones, the specific cells which perform the especial function of the affected or- gan, are affected in atrophy to a far greater degree than the supporting connective-tissue framework. Indeed, it may be frequently observed that the connective-tissue elements may be wholly preserved, or even increased in number, while the more high- ly specialized elements have disappeared. Thus, for example, in atrophic muscle (Fig. 54) the contractile substance within the sarco- lemma («) may disappear to a very great extent (b) without the occur- rence of any atrophy whatever of the connective tissue between the muscle-bundles. The nuclei (c,) of the connective tissue may even be increased in number. -Juvenile muscular atrophy, observed by ue Souza. ) 186 THE RETROGRADE CHANGES. Iii atrophy of the kidney the epithelial cells of the urinary tubules (Fig. 55, a) become smaller (/) and may finally wholly vanish so that the tubules collapse. Likewise, the, epithelium of the glomeruli (d) is lost, while the capillaries become obliterated. The same thing occurs in simple atrophy of the liver, in that all the liver cells of a lobule may disappear without any perceptible decrease of the supporting reticulum. Likewise the ganglion cells of the brain and spinal cord may atrophy without, the neuroglia being diminished. Not infrequently the latter may become increased. In atrophy of the bones the true bone-tissue becomes diminished. In atrophy of the bone-marrow the total mass of free marrow-cells is diminished. The supporting cells may in consecpience take up an in- creased amount of fat ; but, on the other hand, the fat in the cells of the marrow may also vanish, so that free spaces which be- come filled with fluid are formed between the support- ing cells. In atrophy of the lymph - glands and of the spleen the free cells in particular dis- appear and in parts are com- pletely absent. The changes leading to atrophy may take place with- out the occurrence of any apparent change of structure in the individual tissue-ele- ments (Fig. 54), so that the condition of atrophy is reached essentially through a loss of volume of the in- dividual parts. Both the cell -body and the nucleus may become smaller; and the latter change may lie ob- served particularly in the liver in cases of starvation - atrophy (Lukjanow). This form of atrophy is known as simple atrophy, and is to be distinguished from the degenerative atrophies, in which the tissue-elements during the x>rogress of the atrophy show changes in their structure, and frequently contain pathological substances. Thus a cell may become granular, and undergo fragmentation, or may swell up and licpiefy, or there may be formed within the cell drops of fat or mucus ; all of these changes signifying degenerative conditions of the cell -protoplasm. These processes are classed as special forms of degeneration and will be discussed in the paragraphs of the following section. Degenerative changes can occur at the same time in the nuclei, as shown by fragmen- tation, distorted shape, clumping of the chromatin, diffusion of chro- FIG 53.— Excentric atrophy of the lower end of the tibia aDd fibula, with osteoporosis. (Natural size.) ATROPHY. 1S7 matin into the cell-protoplasm, swelling and liquefaction of the nucleus. All these processes lead ultimately to the disappearance of the nucleus and the destruction of the cell. The degenerations leading ultimately to a condition of atrophy of the affected organ are of verv frequent occurrence, particularly in glandular FIG. 53.- -Senile atrophy of the skull-cap, with defect o[ the external table and the spongy portion throughout the central portion of both parietal bones. organs. The process is often complicated by the occurrence of inflam- mation. According to their genesis the forms of atrophy may be classed as active or passive. In the former the cell is no longer able to make use of the food brought to it ; in the latter the food is either not supplied to the cell in sufficient quantity or in the proper form, or harmful sub- stances are brought to the cells which impair their function. Active Fig. 54.— Section of an atrophic muscle, from a case of progressive muscular atrophy. (Mtiller's fluid, Bismarck brown.) o, Normal muscle-fibres; b, atrophic muscle-fibres; c, perimysium internum, the nuclei of which, at c,, seem to be increased in number. X 2(H). atrophy is particularly a part of senile degeneration (see above), but it occurs also under pathological conditions, especially in the case of nerves, glands, and muscles (Fig. 51) whose functional activity is not called into play. The clinician ordinarily prefers another classification of atrophy; 1SS THE RETROGRADE CHANGES. namely, senile atrophy, atrophy due to impaired nutrition, pressure atrophy, atrophy of disuse, and neuropathic atrophy. Senile atrophy (Fig. 53) is partly active, and partly passive, in that it is not simply the result, of the diminishing vital energy of the cell, but also depends in part upon the narrowing and obliteration of the vessels conveying nour- ishment to the cells. It may occur in all the organs, but is often more marked in one organ than in another. The bones, kidneys, liver, brain, and heart may undergo a marked loss of volume. Atrophy due to impaired nutrition may result in the first place from an insufficient supply of food to the body as a whole, or from extensive loss of the fluids of the body. In these cases the whole body is affected, though the fat, blood, muscles, and the ab- dominal organs suffer to a greater extent than the re- maining tissues. Local atrophies may result from local disturbances of circulation, and are the frequent sequela? of diseases of the arteries in which the vessel lumen is narrowed (Fig. 56). Further, they are of frequent occurrence as a result or a part of inflammatory processes; but it should be noted that in these cases the condition is not of the nature of a simple atrophy, but rather of various degenerative changes leading to the death of the cells and of the tissues. At times atrophy results from the presence of deleterious substances in the blood. For example, iodine causes a diminution in the size of the Fig. 55.— Senile atrophy of the kidney. (Alcohol, alum- carmine.) a, Normal urinary tubules; b, normal glomeru- lus; c, stroma with blood-vessels; ■»*"-«>«*ji ing of nver-ceiis (scraping appearance, as it covered with dust, while at the same t D e m ]iver e of "a man'dying time their normal structure (filamentous, granular, of septicaemia, examined alveolar) and form are lost. Thus, for example in in normal salt solution.) ... » ,, . . , . . ' . 1 ' x 350. cloudy swelling of the kidney-epithelium the rod-like markings of the protoplasm are lost (Fig. 60, a), as are also the cell-processes projecting into the lumen of the tubules. The swollen cells (b, c, d) are larger, more plump, and contain dark granules. This change is to be regarded as a disorganization, of the proto- plasm following an absorption of fluid, and leads to partial separation of CLOUDY SWELLING. 191 the solid and liquid constituents of the protoplasm. At the same time the nucleus swells and undergoes disorganization. Recovery is possible at a certain degree, and the cells may be re- stored to their normal condition. In other cases the cell-body is de- K$rW Ifffv Fig. 60.— Cloudy swelling of kidney epithelium. (Chromic acid, ammonia, glycerin.) a, Normal epithelium ; b, beginning cloudy swelling ; c, advanced stage of cloudy swelling : u\ desquamated degen- erated epithelium. /. 600. stroyed, breaking up into granular fragments. Fatty degeneration very often accompanies cloudy swelling. Cloudy swelling may occur in the cells of any of the parenchymatous organs, as the liver, kidneys, or heart, during the course of the majority of the infectious diseases, particularly in scarlet fever, typhoid, small- pox, erysipelas, diphtheria, septicaemia, etc. The affected organs pre- sent a cloudy, dull-shining, often gray appearance ; in marked cases the organ may appear as if cooked, the blood-content is very slight, the con- sistency doughy, and the finer details of structure are lost. It is not improbable that autolytic processes (see paragraph 49) play a role in parenchymatous degeneration (Landsteiner). Orgler regards it as an autolysis accom- panied by an increase of the water-content. The granules which become visible and show double refraction he regards as protagon, which, during autolysis, is either pre- served because of its slight solubility or during the course of the process is precipi- tated in the form of granules. Literature. (Cloudy Swelling.) Albrecht: Pathol, d. Zelle. Verb. d. D. path. Ges., v., 1903, u. vi., 1904. Arnold: Feinere Strukturen der Leber. Virch. Arch., 166 Bd., 1901. Benario: Die Lehre von der trilben Sc.h wellung, Wiirzburg, 1891. Galeotti: Ueber die Granulationen in den Zellen. Monatsschr. f. Anat., .xii., 1895. Landsteiner: Ueber Trubeschwelhing. B. v. Ziegler, xxxiii., 1903. Lukjanow: Grundzilge einer allgem. Pathologic der Zelle, Leipzig, 1891. Orgler: Chemische Nierenuntersuchungen. Virch. Arch., 176 Bd., 1904. 192 THE RETROGRADE CHANGES. Schilling': Verhalten der Altmann'schen Granula bei der trilben Schwellunc Virch Arch., 135 Bd., 1894. s ' Schmaus u. Bohm: Befund in der Leber bei Phosphorvergiftung Vircli Arch 152 Bd., 1898. Theohari: Structure des cellules gland. ;i l'etat pathol., Paris, 1900. Verworn: Per kOrnige Zerfall. Pfli'iger's Arch., 63 Bd., 1896. Virchow: Cellularpathologie. Arch., 8. Bd., 1855; lieizung u. Reizbarkeit lb 14 Bd.. 1858. Waldeyer: Veranderungen der quergestr. Muskelfasern. Vircli. Arch., 34 Bd., 1865. Zenker: Ueb. d. Veriinderung d. willkiirlichen Mrjskeln bei Typhus abdom., Leipzig, :s64. § 54. Hydropic degeneration is that form of degeneration frequently observed in cells of different kinds, whereby they become swollen through the i m b i b i t i o n of fluid. When epithelial cells undergo this change the cell-contents appear clear, the granules of the protoplasm are pressed farther apart by the fluid, often being crowded into a ring at the periphery of the cell; the cells thus coming to resemble plant-cells to a cer- tain extent. Vacuoles (Fig. 61, L) — that is, globules of clear fluid — may often be formed within the cells. The nucleus (c) also swells and be- comes changed to a large blad- der-like vacuole containing clear fluid. In muscles show- ing hydropic degeneration clear droplets of fluid appear between the fibrilla?, pushing the latter apart (Figs. 62 and 63, a, b). Through an abundant formation of such drops the muscle hbres may acquire in places an appearance of foam-like bubbles CFiff. 02"). At first the muscle fibres between these drops remain preserved, but finally they undergo fragmentation and lique- faction. Hydropic degeneration of cells may be the result of cedema (Figs. 62 and 63) ; it occurs also in inflam- matory foci (Fig. 41, cZ) and in tumor- Fir,. 61.— Hydropic degeneration of epithelial cells from a carcinoma of the breast. (Miiller's fluid, aniline brown, i a. Unchanged epithelium; ?*. hydropic cells containing bladder-like drops of tluid [physahdes]; c, hydropic nuclei ; d, enlarged nucleoli ; c, wandering cells, x mil). Fig. '6&— Hydropic degeneration of muscle-fibres from the calf "muscle in chronic oedema of the leg. (Flemming's solution, safranin.) X 15. Fig (B.— Transverse section of a muscle bundle showing hydropic degeneration oM* fibres. Midler's fluid, I, vmatoJvMnT a M use ,, cells (Fig. 61). In the case of inflammation the degenerative character of the process is more marked than in the case of cedema ; and a complete liquefaction of the cells and nuclei may result. In oedema the cells in spite of their hydropic condition, may remain alive for a lone time. FAT DEPOSIT AND FATTY DEGENERATION. 193 VI. Fat Deposit and Fatty Degeneration. § 55. Fat, in a form that can be demonstrated microscopically, is widely distributed throughout the human and animal organism. It ap- pears most prominently in the subcutaneous and subserous tissues and the bone-marrow; in these regions characteristic adipose tissue develops at a certain time during embryonal development or during childhood. Less prominent, and in part visible only on microscopic examination, is the fat present in various glands, also in ganglion-cells, cartilage -cells, leucocytes, surface epithelium, duct epithelium, endothelium, etc. The fat of adipose tissue occurs in the connective-tissue cells in which it is deposited, in the form of droplets that often become confluent, so that the fully developed fat-cell appears as a fat-spherule surrounded by r J- . j • j ■ -"r- "'- -*-"'"."""--. '' ' ■ rl"*" i - ■ . - ■ Fig. 64. — Adipose tissue from the panniculus of the heart. (Formalin, hEematoxylin, and Sudan III.), a, Fat tissue; 6, muscle; c, muscle infiltrated with fat tissue. X 40. a cell-membrane containing a nucleus. Jn preparations mounted in Canada balsam the fat-drop is represented by a clear vacuole (Fig. 65, c). Sudan III. and Scharlach-roth stain fat a yellowish-red (Fig. 64 ), while treatment with osmic acid, which is reduced by the fat, causes the fat-drops to become blackened (Fig. 67, c). The fat contained in the special adipose tissues of the body is a stored-up fat which the organism, incase of necessity, may use for its preservation, and it may, therefore, be designated as a supply of fat designed for consumption or temporary fat. Its abundance may be regarded as an indication of the condition of nutrition ; when this is good the adipose tissues are well developed, in cases of starvation and in chronic marasmus they may vanish entirely. There occurs an atrophy of fat-tissue, in which 1 lie' fat -cells contain only small droplets of fat- or 13 194 THE RETROGRADE CHANGES. no fat at all, in the latter case reverting to the type of ordinary connec- tive-tissue cells. The atrophic fat-lobules often take on a pale yellow color through the formation of pigment in the cells (yellow atrophy of adipose-tissue). Through t>he collection of fluid between the atrophic fat- cells the fat-tissue (most frequently in the cardiac panniculus) becomes translucent, resembling myxomatous tissue (serous atrophy of adipose tissue). Hypertrophy of adipose tissue leads to the condition known as obesity, adipositas, or lipomatosis. It is dependent primarily upon an excessive food-supply ; but there are frequent individual exceptions to this rule, since in many people an increased formation of panniculus does not take place, no matter how rich the food-supply. Again, an abundant deposit of fat occurs in some individuals when the food-supply M d xl i<>iP-W>f^ AT "«g£S ..;i>;?=4 f\J t^:yv/--^'fr i Fig. 65. — Lipomatosis of the calf muscles, associated with atrophy. (Miiller's fluid, carmine.) o, Trans- verse section of normal fibre ; a u of atrophic fibre ; a 3 , transverse section of sarcolemma tube containing disintegrated contractile substance ; ft, connective tissue ; c, fat-tissue. X 60. does not exceed the normal. In such cases the cause of the lipomatosis must be sought in an inability on the part of the organism to destroy the fat brought to it or arising normally within it. In general lipomatosis the deposit of fat takes place first in the normal fat-depots, and then later in places that normally contain no fat, for ex- ample, in the connective tissue of the muscles, in the myocardium, and even beneath the endocardium. A local lipomatosis may occur in various regions of the body, for example, in an arm, the front of the neck, nape, etc., and leads to deformities of the affected regions resembling elephan- tiasis. When occurring in circumscribed masses or nodules the con- dition is classed with the fatty tumors known as lipoma.ta (see Lipoma). A. local lipomatosis occurs also as a peculiar disease of the muscles in which without the agency of extrinsic causes but as the result of a con- genital anlage the muscles, particularly those of the calves of the legs, increase greatly in size (Fig. 65, c) through the development of adipose tissue in the perimysium internum. At the same time they become weaker, since many of the muscle-fibres (Fig. 65, a, a v a.,) may disappear (atrophia Musculorum lipomatosa pseudohypertrophica). Finally, in other FAT DEPOSIT. 105 cases adipose tissue may develop secondarily in places where other tissue has disappeared, for example, within muscles (Fig. 66, c) that have be- come atrophic as the result of disease of the anterior horn of the spinal Fig. 66.— Spinal muscular atrophy with lipomatosis, in ascending atrophy of the anterior norns of the spinal cord. (Miiller's fluid, Bismarck brown.) Section from the calf muscle, a. Transverse section of atrophic muscle-tlbres ; b, perimysium ; c, fat-tissue ; d, artery ; e, vein. X 60. cord or in the case of lymph -glands that in old age have lost, for the greater part, their lymphocytes. The fat of the glandular organs occurs ordinarily in small, even very minute droplets, but in the case of a great abundance of the fat larger droplets may be formed. The sebaceous glands, Meibomian glands, lachrymal glands, and adrenals are especially rich in fat. It oc- Fig. 67. — Skin with sweat glands, from the sole of the foot. (Osmic acid.) a, Thick gland coils with fine fat droplets; b, slender gland coils without fat droplets; c, fat drops lying about the gland coils. X 390. curs to a lesser extent in the testicles and ovaries; still less in the salivary glands, thyroid and sweat glands (Fig. 67, a). The kidneys have the least fat-content of any of the glands. During the period of functional activity (testicles and ovaries) and in advanced age the fat-content is, in general, somewhat increased. In the testicles and ovaries the fat is 198 THE RETROGRADE CHANGES. found both in the epithelial cells and in the connective tissue. Further, the fat-content of the glands is very constant and but slightly dependent upon the condition of the general nutrition, so that it does not disappear during starvation (Traina). This glandular fat may then be designated as the permanent fat or intrinsic fat. The liver holds an especial position among the glands in so far as fat is concerned. As do the other glands it contains constantly a certain number of fine fat-droplets which do not vanish during starvation. In Fig. 68.— Fatty liver from a case of pulmonary tuberculosis. (Flemming's solution, safranln.) a. Central portion of the liver-lobule ; <>, peripheral zone containing fat ; c, periportal connective tissue. X 30. addition there also occurs a temporary storage of fat which, beginning in the periphery of the lobule, extends toward the centre as aprogessive filling of the liver-cells with fat-droplets (Fig. 68, b) ; and, finally, the liver-cells may become completely changed into fat-cells, so that the par- enchyma acquires a straw-color. Fatty infiltration of the liver may result from excessive food-supply, but is much more frequently observed in marasmic individuals, particu- larly in consumptives whose panniculus is atrophic. Inability on the part of the liver to destroy or to give off again the fat brought to it from the intestine or from the fat-depots appears to be the cause of this phenomenon. Muscle-fibres, surface epithelium, the epithelium of different gland-ducts, cartilage-cells, connective-tissue ceils, vascular endothelium, leucocytes, lympho- cytes, etc., show a variable content of fat ; but all contain fat without show- ing any changes that can be regarded as degenerative in nature. In individual cases it is evident that the fat-content is dependent upon an abundant supply of fat from the intestine or of transportation of fat from the fat-depots, especially in those cases in which the leucocytes or the vascular endothelram (particularly that in the liver) are rich in fat. In still other cases there are definite functional conditions (the muscles) during which a rich supply of fat appears. The spleen and the lymph-glands, with the exception of the mesen- teric glands, to which fat may be brought from the intestine, contain but FAT. 197 little fat ; on the other hand, the thymus is relatively rich in fat, particu- larly at the time of its greatest development. All animal fats are mixtures of olein, palmitin and stearin, that is, of combina- tions of oleic acid' (dsHaiOj), stearic acid (CisH S eO s ) and palmitic acid (CioHsaOs) with the trivalent alcohol glycerin (C 3 Hr,[OH] 3 ) to form neutral esters, the so-called triglycerides. Whether taken in as free fatty acids, as neutral fats, or as soaps, the process of absorption is always the same; they appear constantly in the form of neutral fats in the channels through which absorption takes place. In close relationship to the body-fats stand the lecithins (combinations of each single molecule of glycerin-phosphoric acid with two molecules of fatty acid and the complex of an ammonium base, cholin), the protagons, and the cholesterins , substances which occur in small amount in the most varied tissues, but abundantly in the myelin of the brain and the peripheral nerves. Cholesterin occurs also in the bile. The breaking-down of all the components of the lecithins containing neutral fat leads first to the formation of fatty-phosphoric acid, which is then split into fatty and glycerin- phosphoric acids. The fat contained in the human organism is derived primarily from the food-fat taken up in the intestine. In the early weeks of life, when the intestine of the nursing infant is still abnormally permeable, the finest fat-droplets are taken up as such and carried through the lymph- stream into the blood. In later life the taking up of unchanged fat through the intestinal epithelium proba- bly takes place to a very slight degree or not at all, that is, the fat is, for the greater part, split up in 'the intestinal canal, and through the combination of the fatty acids with the alkali present in the intestine there are formed soaps soluble in water, which are absorbed by the epithelium. Even in the intestinal epithelium these soaps are changed into spherules of neutral fat (just as absorbed peptone is again changed into albuminate). The glycerin necessary for this change is absorbed di- rectly from the intestine, where it is present in a free state arising from the splitting of the neutral fats. In the entrance of the fat into the cells of the fat-depots the fat-molecule is again split up and then reconstructed within the cells. According to Arnold, the entrance of fat into the cells is associated in many cases with a certain activity of the plasmosomes, and is therefore connected with the cell- granules, which he regards as the morphological products of the function of the plas- mosomes. In the intracellular fat-formation, designated by him as granular fat- synthesis, which occurs in leucocytes and lymphocytes, also in endothelial cells, connective-tissue cells, cartilage-cells, epithelial and gland cells, soap is taken into the cells in a soluble form and there undergoes a granular change into fat. The fat- droplets appear at the site of the antecedent granules. In this manner there arise in part the so-called fat-granule cells, leucocytes and lymphocytes closely packed with fat-droplets, that occur frequently in areas of necrosis and inflammation, particularly in the central nervous system (Fig. 69, a). According to Arnold the uniform size of the fat-droplets speaks in favor of such an Jorigin. Such granule-cells may also be formed through phagocytosis ; that is, the amoeboid cells may take up through their protoplasmic movements fat-droplets lying free in the tissues (in softening of the brain and spinal cord they arise through the disintegration of the medullary sheaths). In the event of such occurrence, chemical and morphological changes in the material taken up are not excluded. The carbohydrates form a second source of fat-formation in the organism, but the chemical processes attending the formation of fat from carbohydrates have not been determined. It is probable that the amount of fat so formed is relatively mueh less Fig. 69.— Fat-granule cells in an ansemie area of softening in the brain. (Marchi's fluid.) a, Fat-granule cells; b, blood-vessels. X 280. 198 THE RETROGRADE CHANGES. than the fat taken in as such from the food. It is still a question as to whether fat can lie formed in the body from albumin. Since many facts speak for the transformation in the animal body of certain groups of the albumin-molecule into glycogen or grape- sugar, the theoretical possibility of the formation of fat from albumin cannot be denied (Kraus). Of the fats and lecithins present in the organism, those containing oleic acid alone reduce osmium tetraoxide to a black osmium hydroxide, so that treatment with osmic acid or Flemming's solution does not show the presence of palmitin and stearin. On the other hand , Sudan III and Scharlach-roth (ponceau) stain all the fats. Literature. (Fatty Infiltration:) Arnold: Fettkornchenzellen und Granulalehre. Anat. Anz., xxviii., 1900; Granulare Fettsynthese. lb., xxiv., 1904; Feinere Struktur der Leber. Virch. Arch., 16 Bd., 1901; Fettumsatz und Fettwanderung in der Cornea. C. f. a. P., xiv.. 1903; Gra- nulare Fettsynthese. Munch, med. Woch., 1903; Fettumsatz und Fettwanderung. Virch. Arch., 171 Bd., 1903. Ascnoff: Fettgehalt foOler Organe. Cbl. f. allg. Path., viii., 1S97. Connstein: Resorption u. Assimilation der Fette. Med. Woch., 1900. Ebstein: Die Fettleibigkeit und ihre Behandlung, Wiesbaden, 1892. Erb: Dystrophia muscularis progressiva, Leipzig, 1891. Fischer: Lipamie u. Cholesteramie. Virch. Arch., 172 Bd., 1903 (Lit.). Fischler: Exper. erz. Fettsynthese am tiberleb. Organ. Virch. Arch., 174 Bd., 1903. Flenirning-: Bildung u. Rlickbildung d. Fettzelle im Bindegewebe. A. f. mikr. Anat v vii., 1870; u. V. A., 52 Bd., 1871; Hypothesen tiber Fettresorption. Munch, med. Woch., 1898. Gaule: Das Auftreten von Fett in den Zellen. Arch f. Anat., 1890. Gautier: Die Ernahrung der Zelle. Biol. Cbl., xiv., 1894. Hagemeister: Fettbildung u. Fettschwund in Abhang. von Zirkulation. V. A., 172 Bd., 1903. Herter- Fettspaltung u. Fettaufbau im Gewebe. Virch. Arch., 164 Bd., 1901. Herxheimer: Fettinfiltration u. Fettdegeneration. Ergebn. d. allg. Path., viii., 1904 (Lit.). Kaufhiann: L'origine de la graisse. Arch, de phys., viii., 1896. Kisch: Die Fettleibigkeit, Stuttgart, 18SS; u. Eulenburgs Realencyklop., art. Fett- sucht, 1895. Kischensky: Fettresorption im Darmrohr u. Fettransport. B. v. Ziegler, xxxii., 1902. Lee: L'obesite, Paris, 1886. Lindemann: Leber pathologische Fettbildung. Beitr. v. Ziegler, xxv., 1899 (Lit.). Munk: Fette u. Fettsauren. Eulenb. Realencykl., vii., 1895. Nasse: Fettzersetzung u. Fettanhaufung im tierischen Korper. Biol. Cbl., vi., 1S86. v. Noorden: Pathologic des Stoffwechsels, Berlin, 1893; Die Fettsucht, Wien, 1900. Oertel: Kritisch-phys. Besprech. d. Ebstein'schen Beh. d. Fettleibigkeit, Leipzig, 1885. Pawlow: Die Arbeit der Verdauungsdriisen, Wiesbaden, 1898. Preiss: Pse\idohypertrophie der Muskeln. Arch. f. Psych., xx., 1889. Reuter: Durchtritt v. Fett durch Darmepithel. Anat. Anz., xix., 1901. Rumpf: Fettgehalt des Blutes u. einiger Organe. Virch. Arch., 174 Bd., 1903. Thaler: Fett u. Krystalle im menschl. Testikel. B. v. Ziegler, xxxvi., 1904. Traina: Fett u. Granula bei Marasmus u. Hungerzustanden. B. v. Ziegler, xxxv 1904. Voit: Physiologie des allg. Stoffwechsels. Hermanns Handb. d. Physiol., vi., 188P Ursachen der Fettablagerung im Korper, 1884, u. Biol. Cbl., vi., 1S86. Winternitz: Verhalten von Jodfetten im Organismus. Z. f. ph. Chem., 24 Bd., 1897, See also § 56. § 56. Fatty degeneration or fat-metamorphosis is that condition of the cells in which fat-droplets appear in the protoplasm in such a manner as to indi- cate a change in the chemico -physical cell-structnre. In a part of the cases this change may be inferred from the appearance of the cells, in that frag- mentation, disintegration (Fig. 70, e, /), and separation of the cells from their substratum may be demonstrated. FATTY DEGENERATION. 199 The views of Virchow were formerly accepted, to the effect that in lipomatosis there occurred a deposit of fat from the blood and tissue- juices; while, on the other hand, in fatty degeneration there took place a formation of fat from the albumin of the degenerating cells. Becent investigations make the latter view doubtful. Although the possibility of a formation of fat from albumin cannot be denied, it has not yet been p roved that this is the case in the so called fatty degeneration of the cells. In many cases what we call fatty degeneration is only the expression of a molecular physical deconstitution of the cells, a fat-metamorphosis, in which the fat contained in the cells in a form that can- not be recognized micro- scopically is separated out into the form of visible drop- lets. Therefore, an increase in the actual fat-content of the cell does not occur in fatty degeneration. Eenal cells that on microscopical ex- amination show no fat may, nevertheless, contain twenty per cent of fat. Should fatty degeneration occur, so that the fat becomes visible in the form of droplets, the total fat-content is not increased (Rosenfeld, Kraus). A process similar to that taking- place within the body occurs during the autolysis of tissue preserved aseptically in the incubator, fat-droplets becoming visible in such tissues (Hansen, Wentscher, Kraus, Muller, and others). When fat as such is Fig. TO. — Fat-containing liver- cells, a and fo, Fat-infiltration ; c, d, e, /, fatty degeneration. X 400. Fig. 71.— Fatty degeneration of the heart-muscle. X 350. Fig. 72. — -Amemic and fatty necrosis of the myocardium 85 hours after tin- closure of a coronary artery. (Flemming's solution, safranin.) ' a, Necrotic; b, fatty muscle fibres; c, con- nective tissue with leucocytes containing fat. X 300. not present in the cells it may arise through a chemical deconstitution of the lecithin, cerebrin, and protagons (myelin) contained in the cells. A second source of the fat appearing in fatly degeneration is the fat brought to the affected cells by the blood and tissue-juices, arising either from 200 THE RETROGRADE CHANGES. Fig. 73.— Fatty defeneration, vacuolization, and disor- ganization of tbe heart-muscle in a patient dying from pneu- monia and nephritis. (Flemming's, safranin. ) a. Trans- verse section ot normal muscle-cell ; h, muscle-cell in a statu of iatty defeneration ; muscle-cells with vacuoles; ) occurs in in- toxications and infections as the result of cell-in- jury through toxic action. Chronic fatty degeneration of the heart-muscle (Fig. 71, l>) is seen in valvular lesions, pulmonary emphysema, general ancemia; in the renal SStlSftSl , jniHufL . M : a m limm Willi ■ i '(in,i, m 1 \\mm m ■fa mi . mi®"- IvMm Fig. 74.— Marked tatty degeneration (chronic) of the ueai muscle. (Flemming's solution, safranin.) a. Normal musel h, muscle which has undergone fatty degeneration. X 80. FATTY DEGENERATION. 201 epithelium of consumptives it occurs partly as the result of a diminished supply of oxygen, and partly as the action of toxic substances. Ex- perimental investigations have shown that a long-continued elevation of the body temperature leads to a fatty degeneration of different tissues (heart, kidneys, and liverj. A mild grade of fatty degeneration cannot be seen with the naked eye. The more severe forms of the degeneration give an opaque whitish color to colorless tissues, as, for example, the intima of the blood-vessels and heart-valves, which frequently show patches of fatty metamorphosis. The cortex of a kidney showing fatty degeneration becomes grayish or fee ■■: *B ..auiSa *&■* m. m,& dp V -Fatty (leg ■neratiort of the renal epithelium, from a ease of chronic pulmonary tuberculosi (Formalin, hematoxylin, Sudan 111.) X .'100. yellowish in color. In the heart-muscle the yellowish discoloration of fatty degeneration, particularly when the change is localized in small foci (Fig. 74, b), stands out very prominently ("tiger-heart''). The questions relating to fatty degeneration have during recent years been the subject of diligent researches, and these have shown that the teaching of Virchow of the formation of fat from the albumin of the body can no longer be accepted. The conclusions resulting from recent investigations are embodied in the text above. It is not always possible to decide whether the fat present corresponds to a physio- logical or pathological condition. We can no longer accept the view that fine droplets of fat within the cells signify a pathological condition, since most glands contain small fat-droplets, and other tissues, for example, muscle-fibres, also contain fat-droplets under normal conditions. In favor of a pathological condition speak an increase of fat-content beyond normal limits and a focal occurrence of the fatty change. In fat transportation the fat may appear in the blood in the form of large or small droplets (lipaania). This is most marked in the case of fat-metastasis due to traumatic lesions of adipose tissue leading to fat-embolism. K may occur, however, under other conditions, as after the abundant absorption of milk or of pure fat from the intestinal canal. Large fat-drops that remain in the vessels disappear slowly, in part associated with an increase of the fat-content of the neighboring tissue. Further, proliferations of the vessel- wall may occur at the site of the embolism, not only after the direct introduction of fat into the blood-vessels, but also after feeding with fat, as in the administration of cod-liver oil (Witttig). If fasting dogs are fed with mutton-tallow, there is a deposit of mutton-tallow in the fat depots, if they are then poisoned with phosphorus, oleum pulegii, or phloridzin, their livers, which show fatty degeneration as the result of the poisoning, are found to contain mutton-fat in abundance in addition to the animal's own fat (Rosenfehl). 202 THE RETROGRADE CHANGES. According to Leick and Winckler, the mutton-fat under these conditions is found also in the fatty heart-muscle. In dogs fed with iodopin and afterward poisoned with phosphorus, the iodized fat passes into the liver. In animals devoid of adipose tissue no fatty degeneration occurs in the liver after poisoning with phosphorus or phloridzin (Rosenfeld, Fibiger). In the case of aseptic autolysis of the liver outside of the body Waldvogel has recently made thorough chemical and histological investigations that seem to show that fatty and fat-like products of disintegration may arise in hico; and there occurs an increase in those bodies which, related to albumin, have a fat-like (jecorin, lecithin, protagon) or fatty character (fat-acids, neutral fat). In phosphorus-poisoning {Wald- vogel and Tintemanri) protagon and jecorin appear as disintegration-products of al- bumin (the lecithin present is for the greater part transformed into substances which after the acetone precipitation make up the residue of the substances soluble in ether). A similar disintegration of the albumin-molecule occurs in autolysis. According to Dietrich, a formation of fat does not occur in autolysis. In degenerating cells (kidney, inflamed lung, adrenals, corpus luteum, etc. ) doubly refractive droplets similar to fat are found, but they stain only slightly with osmic acid. They are regarded by various authors (Albrecht, Kaiserling, Orgler, etc.) as myelin, similar in character to the myelin of the nerve.-ffbres. It is also probable that protagon appears in this form. Such droplets also appear in the autolysis of cellular tissnes. The kidneys may contain less fat than normal and yet show much fat- both to t lie naked eye and on microscopical examination, as the result of the liberation of the fixed fat in fatty degeneration. The invisible fat is set free and becomes visible. The condition of fatty degeneration, which is a well-established anatomical entity, may be defined, therefore, as an infiltration of fat from outside into cells degenerating through the influence of poisons or other injurious agents (liver, heart '.-muscle, ■pancreas) or as a setting free of the invisible intracellular fat through autolysis (kidneys, spleen, muscle). Literature. (Fait)/ Degeneration and Autolysis.') Albrecht: Myelinogene Stoffe im Zellleben. Yerh. d. D. path, ties., vi., 1904. Beneke: Fettembolie. Beitr. v. Ziegler, xxii., 1897. Binz u Schulz: Kohlenoxydgasvergiftung. Arch. f. exp. Path., xiv., 1881. Dietrich: Experiments z, Prage d. fettigen Degeneration. Munch, med. Woch., 1904. Dietrich u. Hegler. Verand. asept. aufbew. Organe. Arb. a. d. p. Inst, in Tubingen iv., 1904. Ehrlich: Das Sauerstor'fbediirfnis des Organismus, Berlin, 1885. Fibiger: Die Entwickelungd. fettigen Degeneration. Nord. med. Ark., 1901. Fischler: Fettgehalt in Niereninfarkten. O. f. a. P., xiii., u. V. A., 170 Bd., 1902. Frankel: Einfluss d. verminderten Sauerstoffzufuhr auf den Eiweisszerfall. V A 67 Bd., 1S76. Handwerck: Verb. d. Fettkorper zu Osmiumsaure u. Sudan. Z. f. wiss. Mikr., xv 1898. Kaiserling- u. Orgler: Myelin in Zellen. Virch. Arch., 167 Bd., 1902. Kraus, Ribbert, Albrecht, Schwalbe, Rosenfeld, Orgler, Dietrich, Miiller: Fett degeneration u. Fettinnltration. Verh. d. I), path. Ges., vi., Jena, 1904. Krehl: Fettige Degeneration des Herzens. D. Arch. f. Win. Med., 51 Bd., 1893. Landsteiner: Triibe Schwellung. Beitr. v. Ziegler, xxxiii., 1903. Leick u. Winckler: Herkunft d. Fettes bei Fettmetamorphose d. llerzfleisches B.f. exp. Path., 48 Bd., 1903. Leo: Fettbildung u. Fetttransport bei Phosphorvergiftung. Zeitschr. f. phys. Chemie ix., 1885. Lindemann: Ueber pathologische Fettbildung. Beitr. v. Ziegler, xxv., 1899 (Lit)- Wirkung des Oleum Pulegii. A. f. exp. Path., 32 Bd., 1896, u. Z. f. Biol., 39 Bd., 1900; Das Fett des normalen u. des fettig entarteten Herzmuskels. Z. f. Biol 38 Bd., 1899. FATS: CHOLESTEKIN. 203 Lubarsch: Fettdegeneration u. Fettinfiltration. Ergebn. d. allg. Path., iii., 1897; Verfettung u. Fettembolie. Jahrb. v. Eulenburg, ii., 1903. Lukjanoff : Vorles. uber die allgem. Path, der Zelle, Leipzig, 1893. Lummert: Tierische Fette. Pfljgers Arch., 71 Bd., 1898. Michaelis : Milchsekretion. A. f. mikr. Anat., 51 Bd., 1898. Miiller: Bedeutung der Selbstverdauung. Kongr. f. inn. Med., xx., 1902. Ribbert: Morphol. u. Chem. d. fettigen -Degeneration. D. med. Woch., 1903. Rosenfeld: Organverfettungen. Kongr. f. inn. Med., xix., Wiesbaden, 1901. Ruage: Die Krankheiten der ersten Lebenstage (akute Fettdegeneration), Stuttgart, 1893. Sacerdotti: Knorpelfett. Virch. Arch., 159 Bd., 1900. Sata: Fettbildung durch verschiedene Bakterien. Cbl. f. allg. Path.,xi., 1900; Ueber das Vork. von Fett in der Haut u. in einigen Driisen. Beitr. v. Ziegler, xxvii.; Fett in patholog. Geweben. lb., xxviii., 1900. Schmaus: Vork. d. osmierten Fettes in d. Leber bei Phosphorverg. Munch, med. Woch., 1897. Starke: Ueber Fettgranula. Arch. f. Anat. u, Phys., 1895. Steinhaus: Morphologie der Milchabsonderung. Arch. f. Anat., 1892. TJnna: Nachweis d. Fettes in der Haut. Monatsh. f. prakt. Derm., 1898. Waldvog-el: Autolyse u. fettige Degeneration. Virch. Arch., 177 Bd., 1904. Waldvogel u. Tintemann : Phosphorvergiftung. Cbl. f. allg. Path., xv., 1904. Wells: The Relation of Autolysis to the Histological Changes Occurring in Necrotic Areas. Jour, of Med. Res., 1906; The Relation of the Thyroid to Autolysis, etc. Jour, of Biol. Chem., 1907. Wentscher: Eigenleben menschl. Epidermiszellen. Beitr. v. Ziegler, xxiv., 1898. Werhowsky: Wirkung erhohter Eigenwarme. Beitr. v. Ziegler, xviii., 1895 (Lit.). Weyl u. Apt: Fettgehalt pathologischer Organe. Virch. Arch., 95 Bd., 1884. Ziegler u. Obolonsky: Arsenikvergiftung u. Phosphorvergiftung. Beitr. v. Ziegler, ii., 1888. .See also § 55. § 57. The fats which occur in the human body consist almost entirely of a mixture of the glycerin -esters of oleic, palmitic, and stearic acids which are designated olein, palmitin, and stearin. The first is fluid at ordinary temperatures, the second melts at 46°, the third at 53° C. Since the body-fats contain varying proportions of olein, palmitin, and stearin, they vary in consistency and melting-point. If after death the fat-containing tissues of the body are cooled below the melting- point of the contained fat, the stearin and palmitin may separate and form fine stellate or feathery needles (Fig. 7(3, b, c, d), which are commonly called margarin needles, and which, according to the con- ditions, are found sometimes in fat-cells, at other times free in the tissue -fluids. Cholesterin occurs in the form of delicate rhombic plates (Fig. 76, a), the edges and corners of which are often notched. These may be found wherever there are formed masses of detritus containing fat, aris- ing from degenerating cells or extravasations of blood, as in the diseased tunica vaginalis of the testis, in a dilated sebaceous duct or gland, or in a softened area of degeneration in the wall of a diseased aorta. When the substance in which the cholesterin plates are formed is fluid, these may often be visible to the naked eye as little glistening scales. Cholesterin (C, 7 H,,0) is a constant constituent of the bile, and is furnished by the mucous membrane of the gall-bladder and bile-ducts, and held in solution by the bile salts and soaps. It is found also in the medulla of the nerve-fibres, and in small amouuts in the blood, where it is held in solution by fats and soaps. According to Burchard traces of cholesterin are found in all the organs. Cholesterin is insoluble in water, dilute acids, caustic alkalies, and cold alcohol ; it is soluble in boiling alcohol, ether, choloroform, and benzol. 204 THE RETROGRADE CHANGES. When treated with a mixture of five parts of concentrated sulphuric acid aud one part of water the edges of cholesterin crystals take on a carmine-red color, which gradually passes into violet. Sulphuric acid da/,/ -e? m m FIG. 76.- w Cholesterin plates ; h, free cluster of margarin needles ; c, needles enclosed within fat-cells ; d, grass-like bunch of margarin needles. X 30(1. and water mixed in the proportions of three to one give a violet color to the edges of the crystals. Concentrated sulphuric acid containing a trace of iodine colors the crystals violet, blue, green, aud red. The origin of cholesterin is not known with certainty. It is probable, that it is an intermediate product in the decomposition of albumin. Cor- responding to this view, it is found under those pathological conditions in which albuminous substances break down with the formation of fat. Literature. (Oholesterin.) Hoppe-Seyler: Handb. d. pbysiol. u. path.-chem. Analyse, v. Anfl. Munk: Art. Cholesterin. Eulenburg's Realencyklop. u. Eulenburg's Jahrbuch, i., 1891. ' Windaus: Ueber Cholesterin, Freiburg i. B., 1908. VII. The Deposit of Glycogen. §58. Glycogen (C 6 H 10 OJ n is a, carbohydrate which is readily con- vertible into sugar; and in the body is formed chiefly from the carbohy- drates of the food, but may also be formed from albumin and gelatin. ' In the tissues of the body, glycogen is found as a hyaline substance, most often within the cells, but occasionally in the tissue-spaces. It usually occurs in the form of spherules or lumps of different sizes. In the cells these spherules are most frequently found in the neighborhood of the nucleus. Glycogen is soluble in water, but the solubility of that found in dif- ferent tissues varies (Langhaus) ; that found in the liver, kidneys, mus- cles, and pus-corpuscles is more easily soluble than that of cartilage- cells and surface epithelium. Fixation of the tissue in alcohol renders the glycogen less soluble in water. After death the glycogen of the liver is quickly converted into sugar through the action of a diastatic ferment. Glycogen becomes brownish -veil when treated with iodine. Through a. GLYCOGEN. 20.5 method given bv Best, glycogen may also be stained red with tannine (Pig. 77, b, c).' Glycogen is present in almost all the tissues of the embryo, also in the f 03tal membranes at an early period of development ; and in the adull body in the liver-cells, muscles, heart-muscle, cartilage-cells, in the sur- face epithelium of various organs, in the leucocytes, and in the blood- serum (Gabritschewski). During starvation the glycogen of the liver is diminished, and under pathological conditions may wholly disappear. Glycogen appears in pathologically increased amount, particularly in dia- betes, chiefly in the blood and in the kidneys. The epithelium of the Fig. 77. — Glycogen degeneration of the renal epithelium in a case of diabetes. (Compare Gierke, 1. c. ) a. Normal tubules; b, epithelium with early stage of glycogen deposit; c, advanced glycogen deposit with epithelial destruction. X 300. renal tubules in certain areas contains in part large numbers of small drops (Fig. 77, b), and in part also large drops (c). Since this deposit leads finally to a destruction of the cells, the condition may be desig- nated as a glycogen degeneration of the cells. Glycogen occurs also within inflammatory foci (also in infectious pro- liferations of granulation-tissue [Gierke]), usually first in the poly- uuelear leucocytes, but also in the so-called epithelioid cells, fibroblasts, and the syncytial giant-cells developing from these, further also in the tissue bordering upon the inflammatory area. Glycogen is also found in many tumors, eareinoniata and sarcomata. It is difficult to determine the significance of the glycogen appearing under pathological conditions. Since glycogen is abundant in embryonal tissues and in quickly growing tumors, Brault is of the opinion that its appearance is a sign of an increased proliferative cell activity; but the presence of glycogen in large amounts in pus-cells does not agree with this theory. Moreover, in tumors it is not found in the legions of most active cell proliferation. According to Gierke, glycogen appears by preference in those tissues deprived to a certain extent of the circulation. A certain 206 THE RETROGRADE CHANGES. parallel exists between the occurrence of fatty degeneration and glycogen deposit. Both changes are found, for example, in inflammatory foci and at the edge of necrotic areas. In both cases degenerating cells are present that are able to take up both fat and glycogen, but can no longer change them. According to Wolff, the leucocytes circulating in the normal blood also contain glycogen, but this glycogen is very easily soluble, and therefore difficult to demonstrate. In many infections and inflammatory exudates the glycogen of the leucocytes becomes less soluble and can therefore be more easily demonstrated. The iodophile hyaline substance contained in the tissues is not a pure glycogen, but is most probably a combination of glycogen with an albumin-like substance. To avoid the solution in water of glycogen in fresh preparations, a syrupy solution of iodine in gum (Ehrlich) or iodine-glycerin (Barfurth) may be used in this investiga- tion. Sections of tissues hardened in alcohol are best treated (Langlwns) with a dilute tincture of iodine (1 part tincture iodine to 4 parts absolute alcohol) , and then cleared in oleum origani in which the reaction is preserved for a long time. . The reaction is also preserved for a long time in hard Canada balsam. For the staining of glycogen with carmine, Best gives the following method: the sections are first stained with hema- toxylin and are then stained for three-fourths to one hour in a mixture of two parts of a solution of carmine (carmine 1.0 grm., ammonium chlorate 2.0 grms., lithium car- bonate 0.5 grm., aq. dest. 50 grms., brought to a boiling-point, after which there is added 20 c.c. of liq. amnion, caust.), 3 parts of liq. am. caust. and 6 parts of methyl alcohol. They are then decolorized for a few minutes in a mixture of 2 parts methyl alcohol, 4 parts absolute alcohol, and 5 parts water, and finally mounted in Canada balsam. Literature. ( Glycogen. ) Barfurth: Histochem. Untersuch. iiber das Glykogen. Arch. f. mikr. Anat., 25 Bd., 1885. Best: Ueber Glykogen, inspes. bei Entzundung. Beitr. v. Ziegler, xxxiii., 1903. Brault: Glycogenese dans les tumeurs. Arch, des sc. med., 1896; La production du glycogene dans les tissus qui avoisinent. Arch. geh. de m£d., 1899; Le pronostic des tumeurs. L'ceuvre med.-chir., 1899. Butte: La fonction glycogenique du foie dans quelques maladies. Arch, de phys., 1891. Czerny: Zur Kenntn. d. glykogenen u. amyloiden Entartung. Arch. f. exp. Path., 33 Bd., 1893. Driessen: Unters. iiber glykogenreiche Endotheliome. Beitr. v. Ziegler, xii., 1892. Ehrlich: Glykogen im diabetischen u. im norm. Organismus. Zeit. f. klin. Med., vi., 1883. Fichera: Verteilung der Glykogen bei Glykosurie. Beitr. v. Ziegler, xxxvi., 1904 (Lit.). G-abritschewski: Glykogenreaction im Blute. Arch. f. exp. Path., 28 Bd., 1891. Gierke: Glykogen in d. Morphologie d. Zellstoffwechsels. B. v. Ziegler, xxxvii., 1905. Hammarsten : Physiologische Chemie, Wiesbaden, 1899. Kaminer: Glykogengehalt der Leukocyten. Verh. d. anat. Ges., 1902; Z. f. klin. Med., 47 Bd., 1902. Katsurada: Glykogen unter pathol. Verhaltnissen. B. v. Ziegler, xxxii., 1902. Loeper: Le glycogene dans le sang. A. de med. exp., 1902. Lang-hans: Glykogen in pathol. Neubildungen u. Eihauten. Virch. Arch., 120 Bd., 1890. v. Mering: Zur Glykogenbildung in der Leber. Pflugers Arch., xiv., 1877; Ueber Diabetes mellitus. Verh. d. VI. Congr. f. inn. Med., Wiesbaden, 18S7. Nebelthau: Glykogenbildung in der Leber. Zeit. f. Biol., 28 Bd., 1892. Pfluger: Glykogen. Pflugers Arch., 90 Bd., 1903 (Lit.). Reich: Glykogen Reaktion des Blutes. Beitr. v. Bruns, 42 Bd., 1904 (Lil .). Wolff: Zur Los. d. Glykogenproblems. Z. f. klin. Med., 51 Bd., 1904. MUCOID DEGENERATION. 207 VIII. flucous Degeneration. In the umbilical cord the b § 5ft. flucous degeneration has its physiological prototype in the production of mucus by the mucous membranes and mucous glands, and in the formation of mucus in the connective tissue of the umbilical cord, tendons, bursfe, and synovial membranes, mucus occurs as a jelly-like matrix ; in the joints, bursse, and tendon-sheaths it forms a clear, stringy fluid. In the epithelium of the mucous mem- branes the mucxis appears first in the gob- let-cells (Fig. 78, a), forming a clear sub- stance which stains with hematoxylin. In mucous glands, during the process of mu- cus formation, the epithelial cells swell, their central portions become clear, and the granules of the protoplasm are re- duced to small groups or strands. The so-called mucous corpuscles of the saliv- ary secretion, which are characterized by glassy, transparent contents and vibrating protoplasmic granules, are round cells which have undergone mucous degener- ation. The mucus formed from the protoplasm of the cells may be discharged, and the cells remain intact, or in other cases they may be destroyed. Mucus is produced in the same way under pathological conditions as under nor- mal (Fig. 78, a). In catarrh of the mucous membranes there is an increased formation of mucus by the cells of the superficial epi- thelium as well as those of the glands. In addition the pus-corpuscles may also undergo mucous degeneration, the mucin being formed from the nuclein of the nuclei (Kossel). In mucous membranes covered with cylindrical cells the number of goblet-cells is increased, and in the secre- tion there are found cells which have undergone complete mucous degen- eration — that is, tf%v have been converted into glassy masses containing few granules. Other cells contain the mucus in the form of drops of varying size. The epithelium of pathological tissues may also undergo a mucous degeneration, in a manner similar to that occurring in normal tissues. Thus the epithelial lining of cysts of the ovary and of intestinal tumors may often contain numerous goblet-cells (Fig. 7ft, a), and cells which have undergone total mucous degeneration (b). In the so-called gelat- inous or mucoid carcinoma (colloid carcinoma) a large part of the epi- thelial cells suffer a mucous metamorphosis. Of the connective tissues, which may suffer a mucous degeneration and thereby acquire a gelatinous, transparent appearance, may be mentioned fibrous connective tissue, also cartilage, bone, adipose tissue, bone-mar- row, and sarcomatous tissue. In these tissues it is chiefly the ground- FIG. 78.— Formation of mucus within the epithelial cells of an adenomatous polyp of the small intestine. (Alcohol, hematoxylin.) a, Epithelium with dark-stained (hematoxylin) drops of mucus within the cells ; />, free mucus ; c, leucocytes in the epithelium. X 3IIU. 208 THE RETROGRADE CHAiSIUES. substance (Fig. 80, b) which undergoes mucous change and is converted into a homogeneous, structureless mass. The cells may remain un- changed, or may become fatty, or also undergo mucous degeneration. In the last event the entire tissue ultimately forms a hyaline mass, in FIG. 79.— Epithelial cells which have undergone mucous degeneration, from a eystadenoma of the ovary. a. Cells showing slight, change ; b, cells showing marked degree of mucous change. ■'. 400. FIG. 80.— Mucous degeneration of the connective tissue of the aortic valves (osmic acid, glycerin), a. Fibrous tissue ; b, myxomatous tissue. X 350. which only scattered fibres of connective tissue, or single cells or groups of cells are left to suggest the original tissue. The stringy, or gelatinous material, which results from mucous de- generation, does not represent a single chemical substance ; in it there may be found different varieties of mucins as well as of pseudomucins. The mucins (submaxillary, intestinal, and tendon mucin) are nitro- genous substances somewhat resembling albumin. They dissolve or swell up in water forming a stringy, mucous fluid, from which they may be precipitated iu a stringy form by means of alcohol or acetic acid ; but differ from the true albumins in the fact that the precipitate is not redis- solved in an excess of the acid. The precipitated mucins are soluble in neutral salt-solutions, caustic alkalies, and alkaliiie carbonates ; and are gradually converted into alkali-albuminates in case of solution by the last, named. All mucins contain nitrogen and sulphnr; their content in carbon, oxygen, nitrogen, and sulphur varies in the different forms. Pseudomucin also dissolves in water, forming a. gelatinous fluid, from which it may be precipitated in stringy masses by alcohol. The precipitate redissolves in water. Solutions of pseudomucin are not pre- cipitated by acetic acid. Pseudomucin is found particularly in ovarian cystomata, and is the cause of the gelatinous character of the cyst-coutents. It is produced by the epithelium of these tumors (Fig. 79) ; and in its formation the same changes take place in the cells, as in the formation of mucin from epithelium. In all probability the mucous substance present in gelat- inous carcinomata is a body closely related to pseudomucin or metalbu- jtiin — that is, there are different varieties of pseudomucin (Pfannenstiel), of which the two mentioned are examples. Through proper treatment the mucins inaj r be split into a carbohydrate, animal gum (Landwehr, Hammarsten), and mucin may therefore be designated a glycoproteid (Pfannenstiel). The pseudomucins when treated with dilute mineral acids likewise split oil a carbohydrate which reduces copper sulphate in alkaline solution (Pfan- nenstiel). EPITHELIAL HYALIN. 209 The mucin-like substances, precipitable by acetic acid, which occur in the synovial fluid, differ, according to Salkowski, from nucleoalbumin in the absence of phosphorus. From ordinary mucin they are distinguished by their different behavior with mineral acids; when boiled with dilute hydrochloric acid no reducing substance is obtained. Mbtjakoff has obtained from the gelatinous contents of an ovarian cyst a mucin-like substance which he has named •paramecin. It differs from pseudomucin chiefly in the fact that without previous boiling with dilute acids it reduces copper oxide in an alka- line solution. Literature. (Mucous Degeneration. ) Eichwald: Die Kolloidentartung dei 1 Eierstocke. Wttrzburger med. Zeitschr. , 1864. Hammarsten: Studien ilber Mucin u. mucinahnlichc Substanzen. Pfliig, Arch., 80 Bd,, 1885. Hoppe-Seyler: Handb. d. phys. u. pathol.-chem. Analyse, 5. Avifl. Hoyer: Nachweis d. Mucins durch F&rbemethoden. Arch. f. mikr. Anat., 26 Bd., 1890. Kossel: Ueber Schleim und schleimbildende Btoffe. Deut. med. Woch. Landwehr: Ueber Mucin, Metalbumin, u. Paralbumin. Zeitschr. f. viii. ; Ueber die Bcdeutung des tliier. Gummis. Pfluger's Arch., Bd., 1887. Leath.es: Beitr. z. Chemie d. Ovarialmucoide. Arch. f. exp. Path., 43 Bd. Mitjukoff: Ueber das Paramucin. Arch. f. Gyn., 49 Bd., 1895. Pfaunenstiel : Pseudomucine d. cystischen Ovarialgeschwillste. Arch. f. Gyn., 38 Bd., 1890. Salkowski: Zur Kenntniss der Synovia. Vircli. Arch., 131 Bd., 1898. Struiken: Histol. u. Histochemie d. Rectumepithels u. d. Schleimzellen, Diss., Freiburg, 1893. 1891. phys. Chem., 39 Bd., u. 40 1899. Inaua IX. Formation of Epithelial Colloid and Epithelial Hyaline Concretions. £ 60. The epithelial formation of colloid is a process closely related to the epithelial production of mucus; it consists partly in a secretion of Fig. SL Fig. 83. Fig. 8L— Colloid in enlarged thyroid gland. (Alcohol, hematoxylin.) a. Follicle filled with cells; b, fol- licle showing lumen ; c, masses of colloid ; d, capillary ; e, connective-tissue septum with artery. X 60. Fig. 82.— Secretion of colloid in the thyroid. (After Bozzi.) a, Colloid; b, secreting cells with granules. colloid by gland-cells, and partly in a conversion of entire cells into col- loid. Physiologically, colloid is found in the thyroid (Fig. 82), where it U 210 THE RETROGRADE CHANGES. -Dilated urinary tubules filled with colloid, fluid, ha-matoxylin, and eosin.) X 250. appears in the form of hyaline, rather firm, colorless, or slightly colored, jelly-like masses, which in the first place fill the follicles (c), but from these may extend into the lymph-vessels of the thyroid. Pathological collections of colloid occur both in normal gland-tissue and in newly-formed gland- ular-tissue of pathological nature. The accumulation causes a more or less marked „, , , .,;,..,. ,„,,,, distention of the follicles, ' *$' . Viiil /g^*-**^ and thereby leads to an en- largement of the affected gland, which is known as colloid goitre or bronchocele. The typical secretion of colloid is characterized by the formation of homoge- neous granules and spherules in that portion of the epithelial cells next to the lumen of the follicle (Fig. 82). Some of the cells may be completely filled with these gran- ules. In excessive and atypical formation desquamated cells may be- come converted into the hyaline substance of colloid. The colloid of the thyroid is found on microscopical examination to be homogeneous ; and according to its appearance it may be designated epithelial hyalin. As a rule it incloses no cellular elements, but de- generating cells may be found in it. Alcohol and acetic acid cause no clouding, or precipitation in the form of threads, as happens in the case of mucin when so treated. By means of Van Gie- son's staining meth- od the colloid is stained orange-red, while the connec- tive tissue takes a fuchsin-red. It must be noted that the contents of the thy- roid follicles, which are designated col- loid, are not always of the same charac- ter. At one time the substance is firm, at another soft or even fluid, or at least is readily soluble in Fig. 84. varium. parovarium -Colloid concretions in the cystic dilated tubules of the paro- (Formalin, Van Gieson's stain.) a, ft, Gland-tubules ot the o; c, cysts containing colloid concretions (d) . X 80. water. In prepara- tions fixed in alcohol a granulation or cleavage may be caused by con- traction ; and the staining reactions are not always the same. The chemical nature of the thyroid colloid is not fully kuown, and it is probable that the contents of the follicles are of variable composition. It is most probably an albuminoid body which is combined with iodothy- rin, the active principle of the thyroid gland. EPITHELIAL HYALIN : COLLOID. 211 Epithelial hyalin is also found in the glands of the hypophysis cere- bri, in the urinary tubules of diseased kidneys (Fig. 83), in the prostate (Fig. 85, d), in cysts of the parovarium (Fig. 84, d), in the glands of the stomach, and more rarely in other glands. In the last-named organs the hyalin occurs in the form of a uniformly homogeneous mass completely Fig. 85.— Section from a hypertrophic prostate with concretions. (Mutter's fluid, hematoxylin, and eosin.) ft, Stroma ; /j, glands ; c, dilated glands ; d, concretions. X 45. filling the gland-lumen, or often as hyaline, in part laminated concre- tions (Fig. 84, d, and Fig. 85, d) of more or less firm consistency. It must not be assumed that the last-named formations are identical in their chemical composition with thyroid colloid. The only thing which they possess in common is this: they both represent transformed protoplasm of gland-cells — a substance which is hyaline, possesses a certain firmness, and does not react to chemical reagents in the same manner as does mucin. These concretions may also undergo changes which necessitate, on their part, a different behavior toward microchemical reactions. This is particularly true of the prostatic concretions, which not infre- quently show, when treated with iodine, a reaction that has been taken as evidence that they are composed of amyloid material (see § 63). It may be proved, both in the case of prostatic concretions and of renal colloid, that they represent cell-material which has become changed into hyaline substance. In the case of renal colloid, however, it is only under especial conditions that the participation in its formation of albu- min derived from the glomeruli may be excluded. Colloid is a collective term which is applied to a great variety of formations that possess only certain physical attributes in common. There is a very great difference of opinion among authors as to the application of the term. Under colloid degeneration, for example, von Recklinghausen places mucous, amyloid, and hyaline degenerations; including under the last-named epithelial colloid-formation, hyaline degeneration of connective tissue, as well as hyaline coagulation-necroses and hyaline thrombi. Mar- chand gives the term a more limited application, but includes under colloid certain forms of epithelial mucin-formation (particularly in tumors), and also hyaline forma- tions in connective tissue. Inasmuch as colloid is not a definite chemical entity, and as its staining-reactions do not differentiate it sharply from other hyaline substances, it seems to me most expedient to apply the term only to those hyaline products of epithe- 212 THE RETROGRADE CHANGES. lium which do not possess the characteristics of mucin. I have, therefore, also classified as colloid those epithelial concretions which on account of their reaction with iodine (brown or blue color when treated with dilute iodine solutions) have hitherto been re- garded as amyloid bodies. If objection is made to the classification of these formations as colloid, they may be placed under the heading of epithelial hyalin. As epithelial hyalin (keratohyalin?) may be classed also the hyaline granules and spherules described by Russet, Klein, and others, and which are found especially in can- cer cells. They stain intensely with fuehsin, and also with Gram's method or with Weigert's fibrin stain. It should be noted further that similar bodies of varying size and form have been observed in the epithelium during the development of a vaccination pustule (Iliickel), and have been by many regarded as parasites. Literature. (Colloid.) Biondi: Beitr. z. Structur u. Function d. Schilddrilse. Berl. kliu. Woch., 1888. Bozzi: Untersucli. uber die Schilddrilse. Beitr. v. Ziegler, xviii,, 1895. Bubnow: Chemische Bestandtheile der Schilddrilse. Zeitschr. f. phys. Chem., viii., 1883. Ernst: Ceber Hyalin u. seine Bezieh. z. Koiloid. Virch. Arch.. 130 Bd., 1892. Hrickel: Die Vaccinekorperchen. Beitr. v. Ziegler, Supplh., 1898. Hiirthle: Seeretionsvorgange in d. Schilddrilse. Pflilg. Arch. f. d. ges. Phvs., 56 Bd., 1894. Klien: Russelsehe Fuehsinkorperchen. Beitr. v. Ziegler, xi., 1892. Lang-endorf: Beitr. z. Kenntn. d. Schilddrilse. Arch. f. An.. Supplh., 1889. Marchand: Kolloidentartuug. Eulenburg's Realencyklop., 1895. Pianese: Histol. u. Aetiol. d. Garcinoms. Beitr. v. Ziegler, Supplh., 1896. Podbelsky: Kolloid in den Lymphgef. d. Schilddrilse. Prager med. Woch., 1892. Pratt: Goitre. Kef. Handb. of Med. Sc, 1902. v. Recklinghausen: Allg. Pathol, des Kreislaufs u. der Ernahrung, Stuttgart, 1883. Reinbach: Bildung des Kolloids in Strumen. Beitr. v. Ziegler, xvi., 1894. Russel: Characteristic Organism of Cancer. Brit. Med. Journ., ii., 1890. Virchow: Die krankh. Geschwlilste, iii. Bd., und Ueber d. eigenthi'iml. Verhalten al- buminoser Fliissigkeiten bei Zusatz von Salzen. Vi:\ Arch., 6 Bd., 1854. Wolfler: Der Bau des Kropfes, Berlin, 1883. X. The Pathological Cornification of Epithelium. § til. The cornification of the surface epithelium over the entire skm is a physiological process, characterized essentially by the fact that the cells in the outer strata of the prickle layer of the stratum germina- tivum undergo a horny change. This cornification takes place first at the periphery of the cells and in the processes binding the cells together, -while at the same time the inner portions of the cell and the nucleus shrink, so that the cells become changed into thin, flat, horny scales. This horny substance or keratin is a very resistant modified albuminoid body of homogeneous composition, and is capable of resisting digestion by the gastric or pancreatic juices. As accompanying phenomena of cornification there appear in the cells of the prickle layer peculiar hyaline granules and spherules resembling colloid, which stain intensely with nuclear stains and are known as kera- tohyalin (Waldeyer). In those areas of the skin possessing a thick horny layer, there is formed a sharply limited layer of such keratohyalin -con- taining cells ; this layer is known as the stratum gramdosum. In those places where the horny layer is thin, the stratum granulosum is imper- fectly developed and exhibits breaks of continuity. Pathological cornification may occur, in the first place, as a wide- spread or localized increase of the horny layer, resulting in a condition of hypertrophy of the horny layer of the epidermis (see Chapter VI., § 7ti), CORNIFICATION, 213 or hyperkeratosis. This phenomenon may be primary — that is, due to intrinsic causes inherent in the anlage of the skin (ichthyosis, lichen pilaris) — or may be acquired as the result of external influences, mechani- cal lesions, infections and inflammations (callosities, corns). Further, there may occur disturbances in the process of cornification of the skin, so that certain pathological manifestations recognizable by the naked eye may make their appearance, such as desquamation of the skin. Such changes are included under the term parakeratoses. They occur especially as sequehe or concomitant phenomena of infections of the epidermis, and of inflammations of the coriuin and papillary body, sometimes without any recognizable cause ; and in these cases either the process of cornifica- tion or of the formation of keratohyalin, or both, is disturbed. Finally, pathological cornification often occurs in regions where normally it either does not occur at all or but to a slight extent. In the skin the cor- nification may extend to the ducts of the sebaceous glands and to the hair-follicles (ichthyosis) or to the sweat-glands (porokeratosis). Fur- ther, pathological cornification occurs not infrequently in the mucous membrane of the mouth, giving rise to white thickenings of the epithe- lium or to hair-like formations (hairy tongue). Horny change may be observed also in the mucous membrane of the middle ear, in the mastoid cells, in the descending urinary passages, and in these places it may lead to the formation of shining white scales (formation of cholesteatornata). Cornification of cancer cells is very frequently seen, particularly in cancer's of the skin, in which the horny scales are found usually in the form of round masses resembling onions or pearls. Similar horny prod- ucts are also found in cholesteatornata of the pia and brain. The pathological formation of horny substance in the mucous mem- branes or in tumors takes place either simply through cornification of the cell-membranes with contraction of the cell, or it may be combined with the formation of keratohyalin as in the case of typical cornification. The formation of keratohyalin and the cornification of eifithelial cells often occur irregularly distributed, particularly in cancers. Literature. (Cornification.) Best: Verhornung des Bindehautepithels. Beitr. v. Deutschmann, 34 H., 1898. Bostrom: Piale Epidermoide. Cbl. f. allg. Path., viii., 1897. Brosin : Die schwarze Haarzunge, Leipzig, 1888. Denoir: De la langue noire, Paris, 1878. Dinkier: Schwarze Haarzunge. Virch. Arch., 118 Bd., 1888. Ernst: Bezieh. d. Keratohyalins zum Hyalin. Virch. Arch., 130 Bd., 1892 (Lit.); Normale Verhornung. "Arch. f. mikr. Anal, 47 Bd., 1896; Pathol Verhornung. Beitr. v. Ziegler, xxi., 1897 (Lit,). Haug: Das Cholesteatom d. Miltelohrriiume. Cbl. f. allg. Path., vi, 1895. Joseph: Porokeratosis. Arch. f. Derm., 39 Bd., 1897. Leloir: Leukoplakie buccale. Arch, de phys., x., 1887. Mertsching : Keratohyalin u. Pigment. Virch. Arch., 110 Bd., 1889. Nehrkorn: Meningeale Perlgeschwulst. Beitr. v. Ziegler, xxi., 1897. Posner: Schleimhautverhornung. Virch. Arch., 118 Bd., 1889. Unna: Ilandb. d Hautkrankheiten, Leipzig, 1883; Die Histopathologic der Haut- krankheiten, Berlin, 1894; Wesen der Verhornung. Munch, med. Woch, 1896. Wassmvtth: Hyperkeratosis diffusa. Beitr. v. Ziegler, xxvi., 1899. 214 THE RETROGRADE CHANGES. XI. Amyloid Degeneration and the Amyloid Concretions. § 62. Amyloid degeneration is a peculiar degeneration of the con= nective tissue of the blood=vesseIs, characterized by a deposit of an albuminoid substance (amyloid) in the affected part, so that the tissue in- creases in mass and at the same time acquires a peculiar, glassy, homoge- neous appearance. The degeneration may occur in almost all the organs of the body; but is especially frequent in the spleen, liver, kidneys, in- testine, stomach, adrenals, pancreas, and the lymph-glands. It is more rarely observed in adipose tissue, thyroid gland, aorta, heart, muscles, ovaries, uterus, and in the urinary passages. Extensive deposits of amyloid may be recognized by the naked eye, as the affected parts present a translucent appearance resembling bacon (Jardaceous degeneration). In the spleen the change occurs most frequently in the follicles, which in a certain stage of the degeneration may become converted into homo- geneous, translucent bodies (Fig. 86, b) resembling grains of boiled sago, wherefore this form of amyloid spleen is known as sago spleen. When the amyloid change occurs throughout the spleen-pulp it may be recog- nized on the cut surface of the organ as more or less distinct spots or streaks. Ultimately the greater part of the substance of the spleen may become affected. The spleen is thus enlarged, its consistency becomes beculte. Pig. 86.— Amyloid degeneration of the splenic follicles and neighboring tissue. (Miiller's fluid hematoxylin, and eosln.) a. Transverse section of splenic artery; b, amyloid areas; c, pulp; d, tra- very hard, and the organ under certain conditions may be completely transformed into a bacon-like substance (Jardaceous spleen). The liver, in cases of well-marked amyloid degeneration, is increased in size and of a firmer consistency. On section, the liver-tissue is found to be replaced to a greater or less extent by translucent, lardaceous masses, between which the remains of the liver-tissue appear as brown- ish or yellowish (from abundance of contained fat) areas. AMYLOID. 215 The kidney, in cases of extensive amyloid change, is likewise enlarged and hardened, and on section shows hyaline, lardaceous spots and streaks of firm consistency. More frequently there is found a white, fatty, swollen, or normal-sized kidney, in which only here and there may be seen small hyaline granules or streaks, or the presence of amyloid may be recognized only after the tissues have been treated with iodine. In the intestine and lymph-glands the degeneration usually cannot WMffiSMM* Fig. 87. — Suction from un amyloid liver, treated with iodine, solution. X 35. be recognized without the aid of the microscope and chemical reagents; and the same thing is true in regard to the other organs which are more rarely affected, such as adipose tissue, heart-muscle, the great blood- vessels, the thyroid gland, etc. The substance which is deposited in amyloid degeneration forms chiefly shining, homogeneous masses, which exhibit a characteristic re- action with iodine as well as with various aniline dyes. Iodine dissolved in water, or better in a solution of potassium iodide, and poured over the affected tissue, stains the amyloid substance a dark brownish-red (mahog- any brown). In thin sections, under the microscope, the amyloid appears: a bright brown-red (Fig. 87, 6) while the remaining tissue is of a straw- yellow color (a). In marked amyloid degeneration, when the tissues are of a wooden hardness, the iodine reaction sometimes gives a blue or green color. Pre- parations which have been changed to a mahogany brown through the action of iodine become still deeper brown when treated with dilute sul- phuric acid or with a solution of zinc chloride, or they may become bright red, violet, blue, or green. This reaction is, however, imperfect in the majority of cases. Methyl violet stains amyloid a ruby red (Fig. 88, a, b), while the nor- mal tissue takes a blue or dark blue-violet. Because of the peculiar reaction with iodine, Virchow was led to re- 216 THE RETROGRADE CHANGES. gard the amyloid substance as a non-nitrogenous body closely related to cellulose or starch, inasmuch as cellulose when treated with iodine and concentrated sulphuric acid becomes bright blue, and starch similarly treated gives an ultramarine color. Virchow accordingly gave the name amyloid to the newly discovered substance. Several years later Fried- reich and Kekule showed that amyloid is a nitrogenous body of an albu minous nature. According to the investigations of Krawkow amyloid is a firm combination of ckondroitin-sulpburic acid with an albumin. The peculiar reactions of amyloid enable us to detect its presence in the tissues when it is present in such small amounts as to be otherwise practically invisible. In the microscopic examination of fresh prepara- tions care should be taken to wash out the blood from the piece of tissue, since the color resulting from the combination of the blood and the iodine may be deceptive. Amyloid is very resistant to acids and alkalies. Alcohol and chromic acid do not affect it ; and it is also very resistant to putrefactive changes. Fig. 88 — Amyloid degeneration of the splenic follicles and pulp. (Alcohol, methyl ylolet, hydrochloric" acid.) a, Follicle showing marked degeneration ; b, pulp showing beginning degeneration. X 300. Amyloid is deposited in the ground- substance of the connective tissue of the Mood-vessels, especially in the walls of the small vessels. Living cells are not affected. In the connective tissue the amyloid substance appears first between the fibrillar. In the acini of the liver the amyloid is found along the capillaries. The endothelium (Fig. 89, c) is covered on its outer side by a thick layer of a homogeneous, glassy substance, which in part maybe broken up through numerous clefts into lumpy masses (c) of amyloid material. The liver-cells between the amyloid masses are either intact (a) or com- pressed (h), or already atrophic, or may have wholly disappeared. They very often contain fat. The afferent blood-vessels of the liver particularly the media of the arteries, may also show amyloid deposits. ' In the kidneys (Fig. 90) the amyloid is found particularly in the vessel-walls. The capillaries of the glomeruli (b) may be greatly thick- ened and homogeneous; likewise the arteries (?'), the veins, and the capillaries (/<■) of other parts of the renal parenchyma may show amyloid AMYLOID. 217 deposits. In the intestinal mucosa the deposit is also found particularly in the walls of the blood-vessels. In fat-tissue, which is occasionally extensively involved, the amyloid substance is found partly in the vessel- walls, and partly in the connec- tive tissue, and the membranous sheath of the fat-cells may be entirely converted into a hyaline mass. In the spleen the connective-tissue tra- becule (Fig. 88, a, b) and the vessel-walls are especially likely to be affected, and may suffer a marked thickening (b). In striped "muscle the perimysium internum and the sarcolemma are involved. In glandu- lar organs possessing a tunica propria, as, for example, the mucous Fig. 89.— Amyloid degeneration of the liver. (Alcohol. Van Gieson's.) a, Liver-cells, in part containing fat: b, compressed liver-cells; c, amyloid. X 240. glands and the kidneys, this membrane may become affected and greatly thickened. The results of amyloid degeneration upon the functions and vitality of the affected organ are shown, through anatomical investigation, most prominently in the marked change of structure on the one hand, and on the other hand in the associated degeneration and the disappearance of the cellular elements. Amyloid disease is eminently degenerative in character. The connective tissue itself is permanently changed, as the practically insoluble amyloid is never removed from it. The deposit of amyloid substance in the tissues of the blood-vessels leads to a very marked thickening of their walls, and to a narrowing or even obliteration of their lumina (Fig. 90, b), and in this way to a per- manent disturbance of circulation. The amyloid masses may compress neighboring epithelial structures (Fig. 89) and cause them to atrophy. Often there is associated a fatty degeneration of the epithelium (Fig. 90, e, f), particularly in the kidneys; but this change is not to be referred wholly to the disturbances of circulation caused by the amyloid deposit. It is more likely that the fatty degeneration, at least in part, is a path- ological process running parallel with the amyloid disease, and caused by the same conditions producing the latter. Consequently, in some 218 THE RETROGRADE CHANGES. cases the amyloid change may be slight, while the fatty degeneration is very marked. In the spleen and lymph-glands the lymphoid cells lying in the meshes of the thickened reticulum (Fig. 88, «) disappear as the result of atrophy and fatty degeneration. In muscles the contractile substance diminishes in proportion to the increase of the amyloid deposit in con- nective tissue. Amyloid deposit is usually a sequela of cachexia due to chronic ulcer- ative tuberculosis of different organs, chronic suppuration (for example, of the bones), syphilis, or chronic dysentery. In the cachexia of carcinoma it is but rarely observed. In rare cases the degeneration occurs without being associated with any of the above-mentioned diseases. According to investigations by Czerny, Krawkow, Lubarsch, David- sons, Maximow, Kowak, Petrone, and Schepilewsky amyloid may be produced experimentally in the spleen, liver, kidneys, and intestines of various animals, rabbits, chickens, doves, mice, and dogs, through the ^JkmMk { Fir. 90. —Section of an amyloid kidney. (Muller's fluid, osmie acid, methyl violet.) a, Normal vascu- lar loops; it, amyloid vascular loops; c, fatty glomerular epithelium ; r,, fatty capsular epithelium ; d, f at- drops lying against the outer surface of the capillary walls ; c, fatty epithelium in situ ; /, desquamated and fatty epithelium ; (/, hyaline coagula (cast); h, transverse section of a cast composed of fat-drops ; »', amyloid artery ; k, amyloid capillary; Z, cellular infiltration oC the connective tissue; m, round cells will i in the" tubules. X 300. production of suppurations lasting several weeks. Amyloid may de- velop also in horses that are inoculated with diphtheria bacilli. Suppura- tive processes caused by staphylococci and oil of turpentine appear in particular to favor the formation of amyloid. In a number of cases amy- loid was also successfully produced through injections of decomposed bouillon, dead cultures of staphylococci, rennet-ferment, and pancreatin (Schepilewsky), when the inflammation produced by these agencies ran a somewhat chronic course. Krawkow observed the beginning of amy- loid formation after three days, Kowak after eight days. The origin of the amyloid substance has not yet been definitely deter- mined. The results of experimental investigation vary greatly, the de- generation being often absent in cases of chronic suppuration (particu- AMYLOID. 219 larly in dogs). It is probable that the blood brings to the tissues some substance which is changed into amyloid at the site of deposit. It has been many times shown that as the antecedent of amyloid there is found a hyaline substance in the tissues, which does not give the amyloid reac- tions. Similar observations have occasionally been made in man. The material from which amyloid arises is formed, perhaps, by disintegrating pus-cells or tissue-cells at the seat of the primary disease and thence enters the blood-stream. According to KrawTmw, there are found normally in the wall of the horse's aorta, in the ligamentum nucha; of cattle, in the stroma of the spleen of calves, and in the mu- cous memhrane of the stomach, combinations of chondroitin-sulphuric acid which are closely related to amyloid. According to Neuberg, amyloid proper is a basic albumin in the process of metamorphosis combined with chondroitin-sulphuric acid. From this last-named combination the basic albumin body may be easily differentiated chemically. Literature. (Amyloid.) Abraham: Ueber eigenthiimliche Pormen amyloider Entartung. lining. -Diss., Frei- burg, 1891. Browicz: Herkunft d. Amylsubstanz. Bull, de 1'ac. des sc. d. Craco vie, 1901. Burchardt: Amyloidfiirbung (Gentianaviolett, Salzsiiure). Virch. Arch., 117 Bd., 1889. Czerny: Zur Kenntn. d. glykogenen u. amyloiden Entartung. Arch. f. exp. Path., 31 Bd., 1893. Davidsohn: Exper. Erzeugung von Amyloid. Virch. Arch., 150 Bd., 1897; Erken- nung zweier Stadien der Aniyloidentartiing. Ibid., 155 Bd., 1899. Eberth: Die amyloide Entartung. Virch. Arch., 80 Bd., 1880. Edens: Histopathologic lok. u. allg. Amyloiddegeneration. B. v. Ziegler, xsxv., 1904. Friedreich u. Kekule: Zur Amyloidfrage. Virch. Arch., 16 Bd., 1859. Grandis et Carbonne: Reaction de la substance amyloide. Arch. ital. de biol., xiv , 1891. Grig-orieff: Resorptionsfahigkeit d. Amyloids. Beitr. v. Ziegler, xviii., 1895. Henning-s: Zur Statistik u. Aetiologie der amyloiden Entartung. Inaug.-Diss., Ber- lin, 1880. Hjelman: Studier ofver Amyloidin jurens. Inaug.-Diss., Hclsingfors, ref. Cbl. f. allg. Path., ii., 1891. Jiirgens: Eine neue Reaction auf Amyloidkbrper. Virch. Arch., 65 Bd., 1375. Krawkow: Exper. Erzeug. v. Amyloid. Cbl. f. allg. Path., 1895: Arch, de med. exp., 1896; Ohemie der Amyloidsubstanz. Arch. ('. exp. Path., 40 Bd., 1897. Kiihne u. Rudnew: Zur Chemie der amyloiden Entartung. Virch. Arch., 33 Bd., 18G5. Kyber: Die amyloide Degeneration, Dorpat, 1871; Virch. Arch., 81 Bd., 1880. Eevene: (Chondroidin-sulphuric Acid), Med. Rec, 1900. Iiindemann : Jodschwefelsaurereaction u. Amyloid (Krystalle). Cbl. f. allg. Path., 1897. Lubarsch: Exper. Erzeugung von Amyloid. Virch. Arch., 150 Bd., 1897; Hyaline u. amyloide Degen. Ergebn. d. allg. Path., iv., Wiesbaden, 1899. Maximow: Experimentell hervorger. Amyloidentartung. Virch. Arch., 153 Bd., 1898. Neuberg: Amyloidentartung. Verb. d. D. path. Ges., vii., Jena, 1904. Neumann: Ueber Amyloiddegeneration des Fettgewebes. Centralbl. f. alii;. Path., i., 1890. Nowak: Aetiologie der Amyloidosis. Virch. Arch., 152 Bd., 1898. Petrone: Degen. amyloide experimentale. Arch, de med. exp., 1898. Babe: Amyloidentartung bei Thieren. Jahresber. d. K. Thierarzneischule z. Han- nover, 1883-84. Schepilewsky : Exper. Erzeugung amyloider Degeneration. Cbl. f. Bakt., xxv., 1899. Schmidt: Amyloidentartung. Verb. d. D. path. Ges., vii., Jena, 1904. von Schrotter: Chemie d. Amyloiddeg. in Ott, Chem. Path. d. Tuberculosa, Berlin, 1903. Tarchetti: Exper. Amyloidentartung. D. A. f. klin. Med., 75 13d., 1903. Tschermak: Stellung d. amyloid. Subst. Zeitschr. f. phys. Chem., XX., 1875. Virchow: Ueber eine im Gehirn und Ruckenmark des Menschen aufgefundene Sub- stanz mit der chemischen Reaction der Cellulose. Vir. Arch., 6 Bd., 1854. Wichmann: Die Amyloidentartung. Beitr. v. Ziegler, xiii., 1893. Ziegler: Amyloide Tumorbildung in der Zunge und im Kehlkopf. Virch. Arch 65 Bd., 1875. 220 THE RETROGRADE CHANGES. § 63. The form of amyloid degeneration just considered is a disease, which usually appears as a multiple affection of several organs, or, if confined to a single organ, appears as a diffuse change extending through- out the whole organ. There is, however, a localized form of amyloid deposit, appearing either as a local amyloid infiltration of the tissues or in the form of free concretions. The local amyloid infiltrations occur in part in very cellular granu- lations (conjunctiva) and in tissues showing chronic inflammatory proc- esses ; and in part in scars and in hyperplastic proliferations of connec- tive tissue. They are also found occasionally in tumors in which other retrograde changes have begun. In certain cases only small deposits are found in the affected tissues, usually in the vessel-walls. In other cases larger nodules consisting almost wholly of amyloid may be formed, and these may acquire a wooden hardness. Here also the amyloid substance is deposited in the ground-substance of the tissue; but it has been claimed by some authors ( Rablmann ) that the cells of the tissue may acquire a hyaline appearance and give the amyloid reactions. Such local formations of amyloid have been found in the inflamed conjunctiva, in syphilitic scars of the liver, tongue, and larynx, in in- flamed lymph-glands, in the urinary bladder, ulcers of the leg, and in tumors of the larynx and stomach. Tumor-like nodules of amyloid also occur in the conjunctiva, tongue, larynx, lymph-glands, and trachea under conditions in which it is impossible to establish any relationship between them and inflammatory processes, and where besides the hyaline masses there is but little normal connective tissue present. According to Burow, Mauasse, von Schrotter, Zahn, and others, such nodules may arise also from connective-tissue tumors. Free amyloid concretions or corpora amylacea occur most frequently in the tissues of the central nervous system, especially in the substance of the spinal cord, and in the ependyma of the ventricle. They are found also in the prostate. In the nervous system they appear as small (Fig. 91, c), dull-shining, mostly homogeneous bodies, more rarely consisting of a nucleus and an outer shell (Eedlieh) ; in the prostate they form larger (Fig. 91, a) bodies which usually show a dis- tinct stratification. Corpora amy- lacea have also been found in car- cinomata (Wagner, Langhans), and have been repeatedly observed in the lung, where they occur in in- flammatory areas, hemorrhagic extravasations (&), and in em- physema. The local deposits of amyloid and the free amyloid concretions cannot be regarded as being wholly of the same nature as the progressive amyloid de- generation of connective tissue. Some of them indeed give characteristic amyloid reactions, and the corpora amylacea of the nervous system, in particular, become blue or brownish- © Fig. 91.— Corpora amvlaoea. o, Laminated pros- tatic concretions. X 200. f>. Corpus amylaeeum from an old hemorrhagic Infarct of the lung, with htematoidin crystals in its nucleus. X «S00. c, Corpora amylacea from the spinal cord. X 400. LOCAL FORMATION OF AMYLOID. 221 violet when treated with iodine and sulphuric acid. But, in the ease of these bodies, we have to do with formations which are dependent essen- tially upon local conditions for their origin; and which are derived in part from epithelium, and in part from connective-tissue cells. They are, therefore, to be regarded partly as modified epithelial hyalin (§ 60), and partly as modified connective-tissue hyalin (§05;. The prostatic concretions are formed through the fusion of masses of degenerating epi- thelial cells or of fragments of the same (epithelial colloid, § 60) ; and the similar bodies found in the lungs and in tumors are composed essen tially of the products of disintegrated cells, though in part also of albu- min derived from the blood. The corpora amylacea of the nervous sys- tem arise probably from fragments of swollen axis-cylinders to which, perhaps, remains of the changed medullary sheath still cling. Literature. (Local Formation of Amyloid and Amyloid Concretions.) Askanazy: Lokale Amyloidbildung in d. Darmmuskulatur. Verh. d. D. path. Ges., vii., 1904. Burk: Amyloidtumoren d. Thyreoidea mit Metastasen. C. f. a. P., xii., 1901. Burow: (Larynxtumoren.) v. Langenbeck's Archiv, xviii., 1867. Ceci: Corpusculi amilacei dell' encefalo e midollo spinale. Atti de Lincei, ix., 1881. Eiger: Zur Amyloidfrage. Cbl. f. allg. Path., xi., 1900. Friedreich: Corpora amylacea in den Lungen. Virch. Arch., 9, 10 BiL, 1850. Fumagalli c Krach : Degen. amiloide della congiuntiva. Arch, per le >Sc Med., xix., 1895. Glockner: Tumorformiges Amyloid d. Larynx. Virch. Arch., 160 Bd., 1900. Grawitz: (Nase and Luftrohre des Pferdes.) -Virch. Arch., 94 Bd., 1883. Herxheimer: Amyloidtumoren d. Kehlkopfes u. d. Lunge. V. A.. 174 Bd., 1903. Hildebrand: Corpora amylacea in einem endostalen Sarkom. Virch. Arch., 140 Bd., 1895. Hippel: (Augenlid.) Arch. f. Ophthalm., 25 Bd. Hueter: Amyloidbildung in Kehlkopf. Fcstschr. f. Orth, Berlin, 1903. Johanni: Amyloidtumoren d. Kehlkopfes u. d. Trachea. A. f. Lar., xiv., 1903. Kraus: (Zunge, Augenlid, Trachea, Leber.) Zeitschr. f. Heilk., vi., 1885; vii., 1886. Langhans: Corpora amylacea der Lunge. Virch. Arch., 38 Bd., 1867. Leber: (Augenlid.) Arch. f. Ophthalm., xix. and xxv. Manasse: Tumorformiges Amyloid des Larynx. Virch. Arch., 159 Bd., 190(1. Posner: Ueber Prostataconcretionen. Zeitsch. f. klin. Med., 16 Bd., 1889. Rahlmann: (Augenlid.) Arch. f. Augenheilk., x.; Virch. Arch.. 87 Bd., 1882. Redlich.: Die Amyloidkorperchen des Nervensystems. Jahrb. f. Psych., x., 1891. Rumschewitsch.: Hyaline u. amyloide Entartung d. Bindehaut. Arch. f. Augenh., 25 Bd., 1892. Saltikow: Amyloidtumoren der Luftwege. A. f. Lar., xiv., 1903. Schmidt: Amyloidtumoren d. Zunge. Virch. Arch., 143 Bd., 1896. Siegert: Fnters. iib. d. Corp. amylacea. Virch. Arch.. 129 Bd., 1892. Stilling: Entstehung von Concrementen der Prostata. Virch. Arch., 98 Bd., 1884. Stratz: Amy]. Degen. e. L T teruspolypen. Zeitschr. f. Gebh., xvi., 1889. Stroebe: Reparat. Vorgange bei Heilung von Ruckenmarksvrunden. Beitr. v. Zieg- ler. xv.. 1894. Tschistowitsch: Amyloidtumoren d. Retroperitonealdriisen. V. A., 176 Bd., 1904. Vossius: Amyloide Degeneration der Conjunctiva. Beitr. v. Ziegler, iv., 1889. Zahn: Corpora amyloidea der Lunge. Virch. Arch., 72 Bd., 1878. Ziegler: Amyloide Tumoren der Zunge und des Kehlkopfs. Virch. Arch., 65 Bd., 1875. 222 THE RETROGRADE CHANGES. XII. Hyaline Degeneration of Connective Tissue and the Hyaline Products of Connective=tissue Cells. § 64. Under the head of hyaline degeneration of connective tissue may be grouped those changes in which the fibrous ground-substance of the connective tissue of the blood-vessels acquires a hyaline character without giving the specific reactions of amyloid (Fig. 92). The change may involve nor- mal connective tissue (Fig. 92), or that altered by inflammation, as well as the newly formed connective tissue of inflammatory new-growths and of tumors. It is dependent partly upon local and partly upon general disturbances of circulation. Hyaline degeneration is found most often in the connective tissue of the thyroid (Fig. 92, b) ; the valvular endo- cardium; hitima of the arteries; the entire wall of the smaller vessels, particularly of the brain and spinal cord ; the lymph-glands (Fig. 94, a, b); glomeruli of the kidney; the connective tissue and blood-vessels of connective tissue tumors of the dura mater (psamnioma), parotid, and submaxillary glands (angiosarcoma) ; the connective tissue of corneal scars; the peripheral portions of tuberculous nodules; the connective tissue of tuberculous tendon-sheaths and bursa? mucosa? (Fig. 93, b). Hyaline degeneration of connective tissue possesses uo specific staining reactions, as does amyloid. Staining with Van Gieson's (acid fuchsin and picric acid) gives to hyalin in the great majority of cases an intense fuchsin red ; but this re- action is sometimes want- ing. It is probable that the degeneration of con- nective tissue known as hyaline represents a va- riety of degenerative con- ditions. By many authors hyaline coagula of exu- dates, occurring in the tissues, are included in this group. In many cases (thick- ening of the heart-valves or of (he intinia of ar- teries) the tissue appears on microscopical examin- ation to be very thick and dense, and from this fact the condition has been designated sclerosis. The cause of the thicken- The gradual disappearance S 66), or softening even to a-e Fkj. 92.— Hyaline degeneration of the connective tissue of a olloid goitre. (Alcohol, Van Gieson's.) a, Follicles containing oiloid: fr, hyaline connective tissue ; c, blood-vessel. X 300. ing and homogenous character is not known. of the nuclei, the subsequent calcification ^se< the point of complete disintegration (for example in sclerotic area the intinia), the sequestration of the altered tissue from the normal (for example, in the degenerated portions of the walls of the bursse), all point (o the fact that the process is essentially degenerative in character In other cases the appearance of the hyaline tissue resembles closely associated with the hyaline that of amyloid degeneration, and there is CONNECTIVE-TISS HE 1 I VALIN. 22S change a pronounced increase of bulk, particularly so in the case of hyaline degeneration of the small vessels of the central nervous system, glomeruli, and the lymph-glands (Fig. 9J= ; a, b), more rarely in the hyaline degeneration of the connective tissue it- self. There occur, more- over, though very rarely, certain forms of hyaline degeneration involving several organs, the heart (Pig. 95, h, c), serous membranes, intestinal wall, etc., with the for- mation of glassy masses, which in part give the amyloid reaction, and in part do not. In prolif- erations of the conjunctiva there have been frequently observed hyaline degenerations of the reticular ground-substance with nodular thicken- ings of the same ; and these changes give the amyloid reaction only in part. It may therefore be assumed that there is a form of hyaline de- generation of the connective tissue, which is closely related to amyloid, and may become changed into the latter (see § 62) ; and that it arises Fig. 93.— Hyaline degeneration of the connective tissue of the wall of a tuberculous bursa. (Mutter's fluid, hematoxylin, ami eosin.) a, Fibrous connective tissue ; h, hyaline connective tissue. X 40. J'rfv Fir,. 94. Fir. 95. Fig. 94.— TTyaline degeneration of the blood-vessels of an atrophic axillary lymph-gland. (Alcohol carmine.) a. Hyaline vessel with open lumen ; /), obliterated vessel. X ~00. Fig. 95. — Hyaline degeneration of the connective tissue of the myocardium. (Alci carmine.) a, Normal connective tissue; h, hyaline con nective tissue; c, hyaline mas section of normal muscle-cells, of atrophic (r). X 250. hoi, hematoxylin. 5es ; tl, transverse through the deposit of a hyaline probably derived from the blood. insoluble albuminous body which is The preparation shown in Pig. 95 was taken from the heart of a woman of fifty five 3 r ears of age, the greater part of the heart- wall presenting a hyaline degeneration. In both endo- and pericardium there were numerous hyaline nodules and flattened masses. The muscle tissue was in part degenerated, as shown in the figure. Associ- ated with this condition there was extensive degeneration of the blood-vessels, par- ticularly of the intestines, tongue, lungs, heart, and urinary bladder. The peritoneum was also thickly covered with hyaline nodules. The fact that the small areas and the periphery of the larger ones gave no iodine-reaction, while the central portions of the larger areas did so, appears to point conclusively to a close relationship between hyaline degeneration and amyloid. A similar ease lias been described by Steinhaus. 224 THE RETROGRADE CHANGES. Literature. (Hyaline Degeneration of Connective Tissue.) Alzheimer: Kolloidentartung des Gehirns. Arch. f. Psycli., xxx., 1898. Arndt : Entartung der Hirngefasse. Virch. Arch., 41 Bd., 1867. _ Best; Ueber die regressivenErnahrungsstonmgen (hyaline Concretionen)beibandfdrmi- ger Homhauttriibung, Hamburg, 1900. Birch-Hirschfeld : Degenerat. Processe in Homhautnarben. Graefe s Arch., 48 bd., 1899. Eppinger: Hyaline Entartung d. Hirngefasse. Vierteliahrsschr. f. prakt. Heilk., Prag, 1875*. Ernst- Hyalin u seine Beziehungen zinii Kolloid. Virch. Arch., 130 Bd.. 1892. Grawitz: Amy! u. hyal. Neubildung in d. Nasenschleimh. e. Pferdes. Virch. Arch., Holschewnikoff: Hyal. Degen. der Hirngefasse. Virch. Arch., 112 Bd., 1888. Lubarsch: Albuminose Degenerationen. Ergebn. d. allg. Path., 1895. Lubimoff: Kolloiddegeneration d. Hirngefasse. Arch. f. Psych., iv., 1874. Oeller: Hyal. Gefassdeg. im Auge (Bleivergiftung). Virch. Arch., 86 B<1., 1881. Rahlmann: Hyaline u. amyloide Deg. d. Conjunct. Virch. Arch.. 87 Bd., 1882. Rumschewitsch: Arayl. u. hyaline Degen. d- Bindehaut. Arch. f. Augenhk., 35 Bd , 1892. WJ!1 i Steinhaus: Hyalin- u. Amyloidinflltration im Zirkulat. ■ u. Digestionsapp. L. I. Isl. Med., 45 Bd., 1902. Stilling: Amyloide u. hyaline Degen. d. Milz. Virch. Arch., 103 Bd., 1886. Vossius: Hyaline Degeneration d. Conjunctiva. Beitr. v. Ziegler, v., 1889. Wieger: Hyaline Entartung der Lymphdrlisen. Virch. Arch., 78 Bd., 1879. v. Wild: Amyloide u. hyal. Degen. d. Bindegewebes. Beitr. v. Ziegler, i., 1886. Ziegler: Ursachen d. Nierenschrumpfung. Dent. Arch. f. klin. Med., 25 Bd.. 1878. §65. Hyaline products of connective=tissue cells arise in the first place from spherical masses of flat connective-tissue cells arranged in con- centric layers, which, in a manner similar to the eornifieation of epi- thelial cells, become changed into a hyaline substance containing no nuclei. These formations occur most frequently in the meninges, the choroid plexus, and the pineal gland, and in the new-growths arising in these re- gions. Through subsequent calcification they lead to the formation of laminated concretions of calcium salts ( see § 60, Fig. 103). Another kind of hyaline formation probably owes its origin to a secre- tory activity of the connective-tissue cells. This may be designated secretory connective-tissue hyalin, but it must be noted that under this term there is included a variety of different formations, and that, as in the production of colloid, the cells as a whole way be converted into hyaline products. Further belong here certain granules and spherules of hyaline ap- pearance which stain especially intensely with fuchsin, though staining also with methyl violet, gentian violet, etc. ; and which are known as fuchsinophile bodies. They are also often called Russel's bodies from the fact that they were described closely by Russel, who regarded them as parasitic fission-fungi. Fuchsinophile bodies are found both in normal and in slightly altered tissues (adrenals, various mucous membranes — as that of the stomach — in the bruin, spleen, and lymphadenoid tissues), also in inflamed tissues (particularly the mucous mem- branes, for example, of the stomach), inflammatory new-growths (polypi of the stomach) , and in connective-tissue tumors. They are partly intracellular, sometimes in great numbers, and partly extracellular. They are to be regarded as cell-products, probably of the nature of a cell-secretion, or formed as the result of the disintegration of the cells. Of their genesis and their composition nothing definitely is known: it is possible that CONNECTIVE-TISSUE IIYALIN, 225 they have a close relationship with the mast-cells. Those occurring in the brain and spinal cord are generally classed with the corpora aniylacea (§ 63), even when they give no specific iodine reaction. Finally, there should be considered in this connection the larger hyaline spherules and casts of tubes (changed blood-vessels) resembling epithelial colloid, which are not infrequently seen in sarcomata (see Endothelioma and Angiosarcoma), inasmuch as these formations are also to be regarded as products either of a secretory or of a degenerative process on the part of cells. The significance of the granules of eosinophile and mast-cells, as well as the neu- trophile granules of the leucocytes (which stain with a neutral dye obtained through a mixture of acid fuchsin and basic methyl green), cannot be positively stated at the present time. Ehrlich, Heidenhain, and Lowit regaril the granules of the leucocytes as secretory products of a specific metabolism of the cells in which they are found, so that these cells may be looked upon as unicellular glands. On the other hand , Weiden- reich regards the eosinophile cells as lymphocytes that have taken up the fragments of disintegrated red blood-cells, their nuclei in this process assuming the polymorphous form. Arnold regards the cell-granules which may be demonstrated by means of especial stains in leucocytes, pus-corpuscles, bone-marrow cells, and also in other cells, not as granules of secretion, but as representing changed structural elements of the cell aris- ing out of a metamorphosis of the plasmosomes — that is, the microsomes of the cell- cytoplasm (see § SO). Acidophile cells may be transformed into basophile, or the reverse may occur; these phenomena are to be regarded as the expression of different stages of development with changes in the physico-chemical properties. Hesse has expressed a similar opinion. The formations described in £§ 64 and 65 as connective-tissue hyalin are undoubtedly pathological products, which differ from each other in so far as their mode of origin and their chemical composition are concerned. Since we do not yet know the nature of the processes leading to these hyaline formations, there is nothing to do but to group them according to definite points of view. Von Recklinghausen gives to the term hyalin a much more comprehensive meaning than I do. He includes under the head of hyaline degeneration different pathological changes which I have placed under other heads. He defines hyalin as an albuminous body which stains intensely with eosin, carmine, picrocarmine, and acid fuchsin; is homogeneous and strongly refractive; is but slightly changed by acids; and in its re- sistance to alcohol, water, ammonia, and acids resembles amyloid, but does not give the iodine reaction. As hyalin he includes epithelial colloid and the hyaline products of connective tissue cells, as w 7 ell as hyaline degeneration of the ground substance of the connective tissue, also hyaline thrombi, and the hyaline coagula of inflammatory exu- dates, and hyaline tissue-necroses. According to this author, all of these formations result from the fusion of the elements of neighboring cells. From their external appearance, all of these products may be properly designated hyalin; but the following varieties must be recognized : epithelial hyalin (colloid, kera- tohyalin), connective-tissue hyalin (hyaline degeneration of the ground-substance of connective-tissue, hyaline products of cells, and cells which have become hyaline), blood-hyalin (hyaline thrombi), exudative hyalin (hyaline coagula of exudates on mu- cous membranes, serous surfaces, inflamed connective tissue, in the urinary tubules, tubercles, etc.), and hyaline tissue-necroses. In the case of connective-tissue hyalin a distinction must be made between the hyalin formed as a secretion in the cells (closely related to epithelial colloid, in its mode of origin), and hyaline degeneration of the ground-substance of connective tissue. Literature. (Hyaline Products of Connective-tissue Cells and Leucocytes; Cell- granules. ) Altmann: Die Elementarorganismen u. ihre Beziehungen zu den Zellen, Leipzig, 1890. Arnold: Ueber Granulafarbung lebender Leukocyten und Gewebe. Virch. Arch., 157 Bd., 1899; 159 Bd., 1900; Farbenwechsel der Zellgrauula. Cbl. f. allg. Path., x., 1899; Vitale Granulafarbung in Knorpelzellen, Muskelfasern, und Ganglienzel- len. Arch. f. mikr. Anat. , 55 Bd., 1900; A. f. mikr. Anat., 55 Bd. u. Anat. Anz. , xxiv., 1903. Ballowitz Ehrlich'sche granulirte Zellen bei winterschlafenden Thieren. An. Anz., vi., JP91. IT) 226 THE RETROGRADE CHANGES. Ehrlich: Physiol, u. Pathol, d. versch. Formen d. Leukocyten. Zeitschr. f. klin. Med., i., 1880; Granulirte Bindegewebszellen u. eosinophile Leukocyten. Arch. f. Anat., Phys. Abth., 1879; Untersuch. z. Histologic d. Blutes. Gesch. Mittheil., i., 1891. Galeotti: Die Granulationen in d. Zellen. Monatsschr. f. Anat., xii., 1895. Goldmann: Malignes Lymphom. Cbl. f. allg. Path., iii., 1892. Hansemann: Hyaline Zellen in Magenpolypen. Virch. Arch., 148 Bd., 189V Heidenhain: Histol. u. Physiol, d. Dunndarmsclileimhaut. Pfltiger's Arch., 23 Bd., Suppl., 1888. Hesse: Granula der Zellen des Knochenmarkes. V. A., 167 Bd., 1902 (Lit.). Klien: Russel'sche Fuehsinkorperchen u. Altniann'sche Granula. Beitr. v. Ziegler, xi., 1892. Ldwit: Neubildung u. Beschaffenheit d. weissen Blutkorperchen. Beitr. v. Ziegler, x., 1891. Imbarsch: Fuchsinkorper u. Corp. amylacea. Ergebn. d. allg. Path., 1895. Marwedel: Verand. d. Knochenmarks bei eiterig. Entziind. Beitr. v. Ziegler, xxiii., 1897. Neumann: Mastzellen bei path. Verand. im Gehirn. Virch. Arch., 122 Bd., 1890. Prus: Fuchsinophile Degeneration. Cbl. f. allg. Path., vi., 1895. Ranvier: Traite technique d'histologie, Paris, 1875-1888. Rosenheim: Mastzellen im Nervensystem. Arch. f. Psych., 17 Bd., 1886. Russel: Characteristic Organism of Cancer. Brit. Med. Journ., ii., 1890. Saltikow: Hyaline Korper in Magenpolypen u. and. Gew. Virch. Arch., 153 Bd., 1898. Sanfelice: Experim. Erzeugung d. Russel'schen Korperchen. Cbl. f. Bakt., xxiii., 1898. Schreiber: Markzellen (Klasmatocyten). Munch, med. Woch., 1902. Tettenhammer : Entstehung d. acidopliilen Leukoeytengranula. Anat. Anz., viii., 1893. Thorel: Hyaline Korper in Magen- u. Darmschleimhaut. Virch. Arch., 151 Bd., 1898. Touton: Russel'sche Fuchsinkorp. u. Goldmann 'sche Kugelzellen. Virch. Arch., 132 Bd., 1893. Wolff: Bedeutung der eosinophilen Zellen. Beitr. v. Ziegler, xxviii., 1900 (Lit.). See also § 64. XIII. Petrifaction of the Tissues and the Formation of Concretions and Calculi. § 66. It is, on the whole, of rather frequent occurrence for firm crys- talline, or amorphous, granular masses to be deposited in various parts of the body-tissues; and when such deposits are of such extent as to cause hardening of the affected tissue, the resulting condition is known as petrifaction, or when the deposit consists of lime-salts (particularly phosphates) as calcification. The deposit may occur, in the first place, in a tissue which forms an integral element of an organ, and which bears its normal relation to the surrounding tissues. In other cases it takes place in portions of tissue which have been loosened from their surroundings; or insoluble sub- stances which have become changed into a firm state; or, finally, in foreign bodies which have entered the body from without, and form the centres of a process of incrustation. In the first case there arise petrifactions of the tissues ; in the sec- ond, free concretions and calculi. It is to be noted, however, that un- der certain conditions free concretions may become firmly attached to the tissues of the organ in which they lie, by means of tissue-prolifera- tions extending into or surrounding them. On the other hand, a calci- fied portion of tissue may in the course of time gradually become loosened from its surroundings and ultimately form a free concretion. A deposit of lime salts occurs in the form of very fine colorless gran- ules (Fig. 96) which when treated with silver (von Kossa) take on a black color (formation of silver phosphate) (see Figs. 97, h, 99, and TISSUE-PETRIFACTIOX. 227 96.— Calcification of the media of the aorta. X 350. 100, B, b). When lying closely crowded together they become con- fluent, and thus give rise to the formation of chalky foci (Fig. 97, b) that are usually not sharply circumscribed, but may form also circum- scribed spherical concretions (Fig. 98). In the blood-vessels the calcification may begin either in the connective tissue, muscle-fibres, or in the elastic tissue. The cause of tissue-petrifaction is to be found chiefly inlocal tissue-changes, in that the deposit of lime-salts usually occurs in places where the tissue has already died or is in process of degeneration and necrobiosis. For example, lime salts may be deposited in pulmonary infarcts fFig. 99), thrombi, in necrotic foci arising during the course of inflammations, also in dead cells, particularly renal epithelium (Fig. 101, d, e), and liver- cells (von Kossa ) that have been killed as the result of intoxications ("mercuric chloride, lead, aloin, bismuth, copper salts, iodine, and iodo- form). A very frecpient antecedent to the deposit of lime-salts is the occurrence of hyaline defeneration of connective tissue, often associated with a deposit of fat. This occurs, for example, in the thickened intima of the blood-vessels and heart -valves, in the media of the medium-sized arteries, particularly in the extremities, in inflammatory new-formations of connective tissue (for example, in the serous membranes), in the con- nective tissue of the kidney pyramids of old people (Fig. 100, A, B), Fig. 97. — Calcification of the media of the femoral artery. (Silver preparation.) b, media; e, adventitia. X 40. and in degenerated thyroid glands. In dying adipose tissue (fat necrosis in the neighborhood of the pancreas) chalky soap may be formed. The hyaline character of the degenerated connective tissue shows well both in staining with Van Gieson's and with simple hematoxylin. In the case of the latter stain the calcified connective tissue (with the excep- tion of that fully calcified) becomes a diffuse dark blue color (Fig. 100, A, c). The same staining reaction occurs also in the case of calcified nec- rotic cells (Fig. 101, d, e). This reaction holds good only for the deposit of carbonates and phosphates, but not for the oxalates of lime. In rare cases there may occur a deposit of lime-salts in organs which 228 THE RETROGRADE CHANGES. show but slight changes— for example, in the lungs. Since in part of such cases there is found at the same time a more rapid absorption of the skeleton (senile atrophy of the bones, destruction of the bones by tumors), this deposit is regarded as metastatic in nature, due to the over- loading of the blood with lime-salts. Even under these circumstances the immediate cause of the calcification is local, and is dependent upon Fig. 98— Caicitled vessels in the cerebellum. (Alcohol, ba'niatoxytin. X 100, retrogressive changes — in the lung tissue (senile atrophy, obliteration of vessels, venous congestion) ; and the increased absorption of the skeleton is but a favoring factor. According to investigations of Kockel and Kischensky the elastic lamellos of the small and medium-sized vessels in particular become calcified, but the elastic fibres and capillaries of the alveolar septa are also involved. The calcification may affect either small or large areas, and in the latter case causes a hardening and white coloration of the tissues. Oc- casionally it appears in the form of sharply circumscribed spherical, or §MS Fie. 99. -Calcification of ; week; necrotic lung old. ( Kormalii periphery of r treatment.) hemorrhagic infarct six 100. nodular (Figs. 102 and 10:1 a, b, c), or long spicule-like formations (Fig. 103, d), or as cactus-like formations, and there arise in consequence concretions lying within the tissue that occasionally may be recognized even with the naked eye. Under physiological conditions such concre- tions are found in the form of laminated chalky spherules in the pineal gland and the choroid plexus, forming here the so-called brain-sand CALCIFICATION. 229 (acervulus cerebri). As pathological formations they occur in different regions of the outer and inner meninges ; in many tumors of the same (psammoma or sand tumors, Fig. 102), also in caseous masses (Fig. 102, b) or in indurated connective tissue (Fig. 102, a). The origin of these Wfr t^M-'l EST l!lg£3^4$tflH A B Fig. 100. — Hyaline degeneration and calcification of the connective tissue or the kidney papillae. A, Stained with hematoxylin and eosin. B, Treated with silver nitrate, a. Collecting tubules; I), blood-vessel; c, connective tissue showing hyaline degeneration and calcification. X 300. formations may be best studied in the psammomata and is ordinarily to be referred to a transformation of tissue cells (Fig. 103, a, b, c), or of fibrous connective tissue (d) into a hyaline mass that may at first still contain nuclei (a), and later loses them (b, e), and then takes up lime- salts. Spherical concretions arise chiefly from hyaline masses formed from cells (a, o, c) ; and spicules (d) arise through the calcification of hyaline connective tissue, but spher- ical concretions (e) may arise also in hyaline connective tissue. The con- nective tissue which undergoes de- generation and calcification is usually ordinary connective tissue, but cal- careous spicules and round concre- tions may develop also in degener- ated vessel w;il Is. A true formation of bone or ossification may follow the calcifica- tion of a tissue, either as the result of a new tissue-formation, or of a metaplastic development of osseous tissue. This has been observed most frequently in the media of calci- fied blood-vessels of the extremities, but it may occur also in calcified lymph -glands, in the neighborhood of calcified necrotic areas in the lungs, and in thickened serous mem- branes, etc. Fig. 101.— Calcification of the epithelium of the kidney-tubules following sublimate poison- ing. (Alcohol, hematoxylin.) Patient died seven days after the poisoning, a. Normal tubules; /), tubule with desquamated epithe- lium ; c, tubule with desquamated and necrotic epithelium possessing no nuclei ; d, e, tubule with degenerated and calcified epithelium. '300. 230 THE RETROGRADE CHANGES. According to the investigations of Gierke, calcifying tissues (foetal bones, the enamel anlage of the dentine, sand bodies of the choroid plexus, placental calcifications, calcified ganglion-cells) contain more or less iron, and there occur also iron-containing cell-necroses (epithelial casts in sublimate poisoning) which stain like calcified tissue, '&£») Fig. 102. Fig. 103. FIG. ] 02. — Calcareous concretions, a. Concretions from an inflamed omentum; 7>, calcareous masses from a tuberculous lymph-gland which had undergone caseation. X 200. Fig. 103. —section from a psammoma of the dura mater, with concretions. (Alcohol, picric acid, hasmatoxylin, eosin.) a. Hyaline nucleated spherule with enclosed calcareous granule; &, calcareous con- cretion with hyaline non-nucleated capsule, embedded in fibrous connective tissue; c, calcareous concre- tion surrounded by hyaline connective tissue; d, calcareous spicule in connective tissue; e, calcareous spicule containing three separate concretions, embedded in the connective tissue. X 175. but are not calcified. Tn other cases (fully developed bone in extrauterine life, calci- fied thrombi and calcified vessels) iron is not present. Elotz (Jour, of Exper. Med., 1905, 1906) suggests that the formation of calcium soaps is the first step in the formation of pathological masses of calcification, these soaps later undergoing a transformation into the less soluble phosphate and carbonate. Wells (Jour, of Exper. Med., 1905) found but minute traces of calcium soaps in calcifying matter. It is, therefore, probable that calcium-soap formation may be an important step in the process of pathological calcification, but is not an c" ■ The especial affinity of calcium for cartilage, hyaline connective tissue, e present lie explained. essential one . 1 c. , canuOt tit Literature. {Calcification of Tissues, and Formation of Concretions in the Tissues.) Arnold: Ban uiid Entwickelung der Psammome. Virch. Arch., 52 Bd., 1871. Aschoff: Verkalkung. Ergeb. d. a. Path., viii., Wiesbaden, 1904 (Lit.). Diemer: Kalkablagerung in d. Serosa des Herzens. Zeit. f. Heilk., xx., 1899. Ernst: Ueber Psammome. Beitr. v. Ziegler, xi., 1892. Friedlander : Verkalkung dor Ganglienzellen. Virch. Arch., 88 Bd., 1882. Golgi: Bau und Entwickelung der Psammome. Virch. Arch., 51 Bd., 1870 Gottschalk: Ueber die Einwirkung des Aloinsauf die Nieren. Inaug. -Diss Leipzig 1883. Kaufmann: Die Sublimatintoxication, Berlin, 1888; Virch. Arch., 117 Bd., 1889. Kischensky: Kalkablagerungen in Lunge und Magen. C. f. a. P., xii., 1901. Kockel: Kalkinerustation d. Lungengewebes. Deut Arch, f.klin. Med., 64 Bd., 1899. v. Kossa: Ki.inst.lich erzeugbare Verkalkungen. Beitr. v. Ziegler, xxix., 1901. Leber: Conjunctivitis petrificans. v. Gr.:efe's Arch., li., 1900." Leutert: Die Sublimatintoxication. Fortschr. d. Med., xiii., 1895. Levi: iTntersuchungen fiber den Bau und die Entstehung der Concretionen in Psam- momen der Dura mater u. der Kalkplattchenin der Arachnoidea spinalis Inaug - Diss., Freiburg, 1890. Litten: Der hftmorrhag. Infarkt, 1879; Verkalkungen in d. Nieren. Virch Arch 83 Bd., 1881. Mallory: Calcareous Concretions in the Brain. Journ. of Path., ii., 1894. Meyer: Structur und Entstehung der Sandkorper. Virch. Arch., 143 Bd., 1890. DEPOSITS OF URIC ACID. 231 Neuberg-er : Ueber die Wirkung ties Sublimates auf die Niere. Beitr. v. Ziegler, vi., 1889; Ueber Kalkablagerung in den Nieren. Arch. f. exp. Path., 27 Bd., 1890. Paltauf: Ueber Phosphorvergii'tung. Wien. klin. Woch., 1888. Bey: Ausscheidung u. Resorption des Kalks. Arch. f. exp. Path., 35 Bd., 1895. Kicker: Verkalkung und Steinbildung. Ergebn. d. allg. Path., iii., 1897. Roth: Verkalkung der Purkinje'schen Zellen. Virch. Arch., 53 Bd., 1879. Saikowsky: Veranderungen im Organismus durch Quecksilber. Virch. Arch., 37 Bd., 1866. Schujeninoff: Muskel verkalkung. Zeit. f. Heilk., xviii., 1897. Steudener: Zur Kenntniss der Sandgeschwiilste. Virch. Arch., 50 Bd., 1870. Virchow: Kalkmetastasen. Virch. Arch., 8 u. 9 Bd. ; Die krankhaften Geschwiilste, ii., Berlin, 1865; Verkalkung abgestorbener Gehirnzellen. Virch. Arch., 50 Bd., 1870; Cyanquecksilbervergiftung. Munch, med. Woch., 1888. Werra : Folgen d. vorilbergeh. u. dauernd. Verschlusses d. Nierenarterie. Virch. Arch., 88 Bd., 1882. Wildbolz : Kalkkonkremente in der Haut. A. 1 Derm., 70 Bd., 1904. Zanda . Entwickelung der Osteome der Arachn. spinalis. Beitr. v. Ziegler, v., 1889. See also § 68. § 67. The more common petrifactions consist of deposits of phosphate of lime, sometimes of carbonate ; with these some magnesium salts may be mixed. Under especial conditions there occur also deposits of uric- acid salts ; par- ticularly in the /¥ disease known as gout, winch is a chronic disturb- ance of the gen- eral nutrition characterized by a uric-acid diathe- sis leading to a deposit of uric acid in the tis- sues. Gout is usually inherited, and but rarely acquired ; it occurs most fre- quently iu certain regions, as, for example, in Eng- land and in North Germany ; and is very rare in other countries, as in South Germauy. Of the ultimate cause of the disease we have as yet no positive knowledge. It is characterized chiefly by the deposit in the body of uric-acid salts, chiefly sodium urate, with which small quanti- ties of carbonate and phosphate r-viv -~ r W~" r '"•' « H- •■"?r- , ' 7 '""[i''C" rV/ lf\ u1 ' Ibneare sometimes associated (Fig. 101:, h). Tbe deposit of these salts takes place usually during acute, typical paroxysms characterized by pain and in- flammation, but very great de- partures from a typical course may occur. The deposits are found in the kidneys, skin, subcutaneous tissue, tendon sheaths, tendons, ligaments, FIG. 304. — Deposits of urates in the knee-joint, in a ease of gout, a. Con- dyles of the femur; b, urate deposits on the cartilage. Two-thirds natural size. Fig. i 05. —Deposits of needle-shaped crystals of sodi- um urate in the articular cartilage. (After Lancereaux.) X 180. THE RETROGRADE CHANGES. bursse, and articular cartilages (Tig. 104), but may finally be present in almost all the organs. The metatarsophalangeal joint of the great toe is a favorite site of deposit, and often the first part affected. The de- posits consist essentially of clusters of fine slender needles (Fig. 105), in whose neighborhood the tissues are degenerated or necrotic ; and from this it may be assumed that the urates entering the tissues in solution give rise to the necrotic changes in the latter. The areas of necrosis and incrustation are at first of small size, but occasion inflammation and tissue-proliferations in their neighborhood. Later, with the occurrence of other paroxysms the deposits become larger, so that large nodules (the so-called tophi) are formed. These consist of white, plaster-like masses, and under certain conditions may form marked nodular thick- enings in the joints and ten- dons (Fig. 106). In the joints the articular cartilages at first appear as if sprinkled over with plaster - of Paris (Fig. 104, b), but later the white masses penetrate deeper and may permeate the entire articular cartilage. In the kidneys the tissue-necrosis caused by the uric acid, and the resulting inflammation may lead to contraction and induration of the organ. The deposit affects chiefly the medullary pyramids, but is found also in the cortex. According to Garrod and Ebstein the acute paroxysms in gout depend upon an ex- cessive accumulation of uric acid, either as the result of deficient excretion by the kid- neys (Garrod) or of local changes (Ebstein). Accord- ing to Pfeiffer the gouty pre- disposition is due essentially to the fact that the uric acid in the body-fluids is produced in a form which is soluble with difficulty, and tends to be deposited in the tissues where it may collect in. such quantity as to cause a localized necrosis. The symptoms of the gouty paroxysm are supposed to depend upon an increased alkalinity of the body-fluids caused by especial con- ditions, as a result of which there follows a partial solution of the de- posited uric acid, in the course of which process attacks of pain and symptoms of inflammation are produced. On the other hand, von Noorden regards the formation and deposit of uric acid as a secondary process, due to the local action of a special ferment, and quite inde- Fig. 10e.— Gouty nodes of the hand. (After Lancereaux.) CONCRETIONS. 232 pendent of the the body. amount and condition of the uric acid in other parts of Literature. (Gout and Gouty Deposits.) Aschoff: Exper. Harnsaureablagerungen. Verb. d. pathol. Gesell., ii., Berlin, 1900. Berkart: Path, of the Gouty Paroxysm. Brit. Med. Journ., i., 1895. Cantani: Specielle Pathol, u. Ther. der Stoffwechselkrankheiten, ii., Berlin, 1880. Charcot: Maladies des vieillards, goute et rheumatismes. OEuvres conrpl., vii.. Paris, 1890. Duckworth: Trait e dc la goutte, Paris, 1893; Die Gicht, Leipzig, 1894. Ebstein: Die Natur u. Behandlung d. Gicht, Wiesbaden, 1882; Verhandl. d. VIII. Congr. f. inn. Med., Wiesbaden, 1880; Beitr. z. Lelire v. d. harnsauren Diathese, Wiesbaden, 1891. Ebstein u. Sprague : Beitr. /,. Analyse glchtischer Tophi. Vircli. Arch,, 125 Bd., 1891. Freudweiler ; Exp. Unters. iiber das Wesen d. Gicht. Dent. Arch. f. Win. Med., 03 lid., 1900. Garrod: Die Natur und die Behandlung der Gicht, Wilrzburg, 1801. His: Wirkuug des sauren barns. Natrons. Dent. Arch. f. Kolisch: Wesen und Behandlung der uratisehen Diathese, Kionka: Vogelgicht. Arch. f. exp. Path., 41 Bd., 1900. Lievison: Die liarnsaure Diathese, Berlin, 1893. Iakhatscheff ; Uratablagcrung nacli Ureterunterbindung. klin. Med. Stuttgart, Beitr. 07 Bd. 1895. 1900. Ziegler, xx., 1890. Minkowski: Pliys. u. Pathol, d. liarnsaure. Arch. f. exp. Path., 41 Bd., 1898. Mordhorst: Entstehung der Uratablagerungen. Vircli. Arch., 148 Bd., 1897. v. Noorden: Pathologie des Stoffwechsels, Berlin, 1893 Pfeiffer: Das Wesen der Gicht, Wiesbaden, 1891. Riess: Gicht. Eulenburg's Realcncyklop., 1895. Rindfleisch : Bildung u. Rilckbildung gicht. Tophi. Vircli. Arcli., 171 Bd., 1903. 8 6.8. Free concretions are formed in the first place in the various ducts and cavities of the body which are lined by epithelium, as in the intestines, in the ducts of the glands pouring their secretions into the in- testine, in the gall-bladder, urinary passages, and respiratory tract. In a certain sense the concretions formed in the blood-vessels and serous cavities might also be included in this group, although they are for the greater part firmly united In the surrounding tissues. All free concretions possess an organic base or nucleus. Thus en- teroliths which form in the intes- tines have a nucleus of inspissated fasces, or foreign bodies which have been swallowed, such as hairs (bezoar stones or cegagropilw) , or indigestible portions of vegetable food, etc., in and about which phosphates (ammonium -magne- sium phosphate and calcium phos- in varying proportions according the mouth-cavity incrustations of phaie), and carbonates arc lo the nature of the food in<; deposilei jested. J the teeth, known as dental calculi or tor/or, are formed by the deposit of lime-salts in masses consisting of mucus, cell-detritus, and bacteria. In the same way there are formed in the ducts of the salivary glands and pan- creas oval or spherical faceted, or irregularly nodular, glandiform concre- tions, through the calcareous impregnation of a substance derived from the epithelium of the gland. 234 THE RETROGRADE CHANGES. Fici. 108.— Section through a small eholesterin stone after removal of the eholesterin. X 13. Bronchial calculi are formed by the calcification of thickened bronchial secretion; the stones found in veins and arteries (phleboliths and arterio- liths) from the calcification of thrombi; prostatic calculi through the cal- cification of the so-called amyloid concretions; navel stones through the retention and incrustation of desquamated epithelium, hairs, and other substances which may enter the navel - depression. The biliary calculi and (/all-stones found in the bile passages and gall-bladder are in part small granules, and partly larger spherical, oval, or faceted stones (Fig. 107), which on fracture appeal' to consist purely of crystal- line masses. By the em- ployment of proper methods it may be shown that these stones also possess a nitro- genous ground-substance. According to their essen- tial composition gall-stones may be classed as eholesterin, eholesterin - pigment, bilirubin, biliverdin-calcium, and calcium carbonate stones. The first two varieties are the most common ; they present a rayed, crys- talline, often laminated fracture ; and vary in color and in their mottling according to the amount of bile-pigment present. When no pigment is present they may be color- less and translucent. If the eholesterin be dis- solved out of a eholesterin stone by some suitable method, it will be found that the form of the stone is preserved, and a del icate, for the greater part yellow- ish, mass remains. This, when carefully embedded and cut into sections, is found under the microscope to consist of a delicate, ho- mogeneous substance (Fig. 108) whichshows concentric stratification and radiating clefts or spaces which were formerly occupied by the crystalline masses. A sim- ilar ground-substance may be demonstrated in other calculi after solution of their calcium salts. There can, therefore, be no doubt that gall-stones are also the result of the incrustation of an organic substratum, which is in all probability derived from the mucous membrane of the biliary passages and the gall- FlG. 109.— Uric-acid infarct of the new-born. (Alcohol, haema- toxylin. Drawn from a preparation that had been washed in water.) Transverse section through the pyramid of the kidney. a. Transverse section of unchanged collecting tubule from the papilla; o, dilated collecting tubule tilled with uric-acid con- cretions; c, remains of concretions after washing with water. X 300. CALCULI. 235 bladder. Gall-stones occur especially in advanced years ; stagnation of the bile favors their formation. Inflammations of the mucous membranes of the bile-passages (angiocholitis) lead to desquamation and destruction of the epithelium (eventually also to escape of leucocytes), and in the products derived from these pathological changes bilirubin and choles- terin are deposited. When once a concretion is formed it increases in size through the deposit of new products of cell-disintegration which be- come encrusted with cholesterin, pigment, and calcium. According to Naunyn the originally soft nucleus of the concretion undergoes a change, in that it separates into fluid, and into firm, granular masses of pigment- calcium and crystals of cholesterin which are deposited upon the outer crust, so that the stones may at times contain a cavity filled with the fluid. In the course of time this cavity may again be filled with cholesterin ; and also the pigment and calcium in the remaining portions of the stone FIG. no. no. in. PIG. 1 10.— Coral-shaped stone from the bladder composed ol calcium oxalate and phosphate. Natural size. FlO. 111.— Transverse section of two stones from the bladder, closely fitted together, and consisting of sodium urate and ammonium- magnesium phosphate. Natural size. may be gradually replaced by cholesterin. Further, calcium carbonate may also be deposited. The cholesterin masses from which the concretions are formed are derived chiefly from the disintegration of epithelial cells : likewise, the lime-salts combining with bilirubin are also furnished by the mucous membrane. The urinary calculi, gravel, and stones are also composed of an organic ground-substance, an albuminous stroma, in which the various constituents of the urine may become deposited. According to location we may distinguish calculi of the kiduey and those of the descending urinary passages. In the kidneys the deposits may form only small granules lying in the tissue itself, or in part also free in the lumen of the urinary tubules, in the latter place lying in the products derived from the disintegration of necrotic epithelial cells. This is true in the first place of the calcifications which, as mentioned above, occur iu the necrosed renal epithelium after poisoning with corrosive sublimate, bis- muth, aloin, copper-salts, iodine, phosphorus, potassium chromate, and oxalic acid. The same thing is true of some of the gouty deposits. Finally, belongs here the so-called uric-acid infarct of the new-born, a con- 236 THE RETROGRADE CHANGES. dilion characterized by the appearance of yellowish-red stripes in the medullary pyramids. The condition is not infrequently seen in children dying during the first five weeks after birth. The epithelium of the tubules is usually well preserved, but in places desquamation and disin- tegration of single cells may be found. The lumina of the tubules are tilled with very small, colorless or yellow granules of urates or uric acid, which at times show fine radiating lines (Fig. 109, b). Ou solution of these granules a delicate stroma remains (e). If as the result of the presence of the infarct further changes in the epithelium of the tubules are produced, leading to the formation of albumi- nous material iu the tubules, single granules may under certain conditions develop through accretion into large stones, but this occurrence is rare. In the pelvis of the kidney, ureters, urinary bladder, urethra, and under the prepuce concre- tions may be formed, either as sand, gravel, or stones. The last-named are oval or spherical, and may be smooth or rough and nodular, not infre- quently resembling a mulberry or mass of coral (Figs. 110 and 111). When several stones lie close- ly together, their surfaces may become faceted (Fig. 111). Those found in the kidney pelvis may form casts of the cavity and of the calyces. When examined in section, urinary calculi are sometimes homogeneous, at other times distinctly stratified (Fig. Ill) or show radiating lines. Not infrequently there may be seen a nucleus and several zones of different appearances. The crys- talline masses lie partly in the spaces of the stroma, and partly in the latter itself; and it may, therefore, be assumed that the stroma is a product of the mucosa of the urinary passages, and that its formation follows catarrhal inflammations or toxic necroses of epithelium when these lead to the collection of mucus or cell-detritus in the tubules. What substances are deposited in a. given case in the products of the mucous membrane depends upon the existing conditions. When the condi- tions favoring stone-formation are associated with a uric-acid diathesis, or if the excretion of uric- acid salts by causing tissue-necrosis has at the same time produced the conditions favoring the development of concretions, the deposits in the organic ground-substance will consist chiefly of urates. Decomposition of the urine with forma- tion of ammonium-magnesium phosphates leads to the production of calculi consisting chiefly of this substance. Cystin calculi may be formed when cystin is excreted by the kidneys, as the result of pe- culiar metamorphoses of albumin in the intestine, due to the action of bacteria (Baumann, von Udransky, Brieger). When once a stone is formed, the irritation which it causes upon that portion of the mucous membrane with which it comes in contact, as well as the decomposition of the retained urine, favors its further growth by accretion. Likewise, foreign bodies (Fig. 112), which have in any way entered the bladder Fig. IDi. — IncTusted lead- pencil, 12cm. long, taken from the male urinary bladder. Reduced ,V CALCULI. 2:>7 from without, may lead to the formation of calculi, through the irritation which they excite in the mucous membrane of the bladder. Intestinal calculi are much more common in horses and cattle than in man; since undigested vegetable material and hairs which have been licked off are of frequent oc- currence in I he intestinal canals of these animals and form the starting-point of such concretions. The true stones, which occur especially in horses, are rather hard masses consisting chiefly of magnesium phosphate ; the false stones consist of hairs and vege- table fibres which are more or less encrusted. Occasionally balls are found which con- sist almost wholly of hair (cegugropili or bezoar stone*). In ruminating animals they are found chiefly in the rumen or reticulum ; in hogs, more frequently in the small intestine. According to Schuberg, the enteroliths of herbivorous animals consist chiefly of car- bonates; those of carnivorous, of phosphates. The composition of those found in man varies according to the food ingested. Urinary calculi are classified according to their composition as follows; 1. Calculi composed chiefly of uric acid or writes. Pure uric-acid calculi are usually small, yellow, reddish, or brownish in color, and hard. Stones consisting of urates are rarely pure. They are usually covered on the surface with a coating of calcium oxalate and ammonium-magnesium phosphate. 2. Calculi composed chiefly of phosphates and carbonates. To this class belong stones composed of calcium plwsphate, ammonium-magnesium phosphate, and calcium carbonate. The last two varieties are rare. All these calculi are white or grayish-white. The triple phosphate stones are soft and friable, the others hard. 3. Stones composed, of calcium, oxalate. These are hard and rough, and of a brown color, 4. Cystin calculi. These are soft, waxy, and of a brownish-yellow color. 5. Xanthin calculi. These are cinnabar-red in color, smooth, and have an earthy fracture. Ebstein and Nicolaier succeeded in experimentally producing urinary calculi by feed- ing animals with oxamide, an ammonium derivative of oxalic acid. The greenish-yellow concretions thus produced in the urinary passages of dogs and rabbits consisted essen- tially of oxamide ; on section they presented a concentric laminated structure showing radiating striations. They were found likewise to possess an albuminous stroma, which was derived from the necrosis and desquamation of epithelium caused by the action of tin' oxamide during excretion. Literature. (Free Concretions. ) Baumann u. v. Udransky: Ueber das Vorkommeu von Diaminen, sog. Ptomainen bei Cystinurie. Ber. d. Deutseh. chem. Ges., xxi. ; Zeitschr. f. phys. Chem., 1889. Brieger u. Stadthagen: Ueber Cystinurie. Berk klin. Woch., 18K9. Cushing: (Gall-stones Lit.) Bull. Johns Hopkins Hosp., 1898. Ebstein: Die Natur 11. Behandlung der Harnsteine, Wiesbaden, 1884. Ebstein u, Nicolaier; Kiinstl. Darstellung von harnsauren Salzen in der Form v. Spharolithen. Virch. Arch., 123 Bd. ; Exper. Erzeugung von Harnsteinen, Wies- baden, 1891. Fauconneau-Defresne : Traite de l'affection calculeuse du foie et du pancreas, Paris, 1851. Fiirbringer: Nephrolithiasis, Calculi renum, Nierenconcremente. Deut med. Woch., 1890. v. Genersich: Hiirte der Concremente. Virch. Arch., 131 Bd., 1893. Hahn: Nabelconcremente. Bcitr. v. Brims, xxvi., 1900 (Lit.). Leube: Darmsteine. Ziemssen's Handli., vii. Lewis and Simon: Oystinuria with Diaminuiia. Amer. Journ. of Med. 8c. , 1902. Mayer: Gallensteinbil'dung. Virch. Arch., 136 Bd.. 1895. Mester: Beitr. z. Kenntniss der Cystinurie. Zeitschr. f. phys. Chem., xiv., 1889. Moreigne: La cystinurie. Arch, de med. exp., xi., 1899. Naunyn: Pie Gallensteinkrankheiten. Verb. d. X. Congr. f. inn. Med., Wiesbaden, 1891; Klinik der Cholelithiasis, Leipzig, 1892. Posner: Studien fiber Steinbildung. Zeitschr. f. klin. Med., ix. and xvi. 238 THE TtETROGKADE CHANGES. Ribbert: Path. Anat. d. Wurmfortsatzes (Bildung v. Kofhsteinen). Virch. Arch., 132 Bd., 1898. Schuberg: Bau u. chem. Zusammensetzung v. Kothsteinen Virch. Arch., 90 Bd., 1882. Sbattock: Calculi of Calcium Oxalate from a Cyst of the Pancreas. Journ. of Path., iv., 1896. Smith: Concretions and Calculi. Ref. Handb. of Med. Sc, 1901. Solg-er: Ablagerungen im Knorpel. Arch. f. mikr. Anat., 34 Bd., 1889. Spiegelberg-; Harnsaureinfarkt d. Neugeborenen. Arch, f, exp. Path., 41 Bd., 1899. Steinmann: Schalen- und Kalksteinbildung. Bur. d. Naturf. Oes. zu Freiburg, iv., 1889. Stroebe: Arbeiten ilber Bildung freier Concremente. Cbl. f. allg. Path., i., 1890 (Lit.). Studensky: Zur Lehre von der Bildung der Harnsteiue. Deut. Zeitschr. f. Chir., vii., 1877. Tross: Pacettirte Speichelstcine. Beitr. v. Ziegler, viii., 1890. XIV. The Pathological Formation of Pigment. § 69. Both connective and epithelial tissues hi various parts of the body contain normally an autochthonous pigment, which lies within the cells, and consists either of yellow, brown, or black granules, or forms a. diffuse yellow or brown coloration of the cells. These autochthonous pig- ments are known as melanin, lipochrome, and haemofuscin. In the epithelial tis- sues the pigment is found particularly in the lowest layers of the rete Malpighii, which contains pigment in all the pig- mented portions of the skin, also in the hairs, in the pigment-epithelium of the retina, and in many ganglion-cells. In the pigment- cells of the skin the granules are chiefly yellow and brown; in the epi- 1 helium of the retina they are black. In marked pigmentation of the skin other cells besides those of the rete Malpighii contain pigment. Among the connective- tissue cells, which most frequently con- tain yellow or brown pigment-granules, are the cells of the choroid, sclera, co- vium, heart-muscle, muscularis of the in- testine, and pia. The normal autochthonous pigments may be increased under various physiol- ogical and pathological conditions. For example, during pregnancy the pigment of the slcin is usually more or less increased (chloasma uterinum), particularly in bru- nettes. In Addison's disease, a general disease leading to cachexia and which is dependent upon pathological conditions of the adrenals (see § 26), there occurs a decided pigmentation of the skin as a re- sult of an increase of the normal pigment. Not infrequently spots of a bronze color appear in the mucous membranes of the mouth. Further, in atrophic conditions of the heart there is usually an increase of the normal heart-pigment. Yellow pigment-granules also Fir;. 113.— Large bairy pigmented aiole over the bark ami buttocks, with scattered spots of pigmentation over trunk and shoulders. (After Rob ring.) THE PATHOLOGICAL FORMATION OF PIGMENT. 239 appear in the voluntary muscles in conditions of atrophy ; and in old per- sons the smooth muscle of the intestine always contains more or less of a yellow granular pigment, so that sometimes the outer surface of the in- testine may show a' yellow or yellowish-brown coloration. The most intense grades of pathological pigmentation are met with in freckles, lentigines, pigmented moles (Fig. 113) and pigmented warts, and in blade melanotic tumors (see Chapter VIII.). The amount of pigment may be so great as to give the tissues a pure black color. The pigment lies for the greater part inside of tissue-cells (chromato- phores), more rarely in the intercellular substance. It is composed of yellow, brown, or black granules; not infrequently individual cells may be diffusely pigmented. In Addison's disease the pigment-granules are found partly in epithelial cells, especially in those lying directly upon the connective tissue (Fig. 114, A, a, I), and B, «), and part- ly in branched connective-tis- ,\ sue cells (A, c, c„ d), from which pigmented processes ex- tend up between the epithelial cells (B, c). In the pigmented spots of the skin and in melanotic sar- comata the pigment is partly contained in especially differ- entiated connective-tissue cells of large size, and partly in ap- parently normal cells of the given tissue, very often in the connective-tissue cells in the neighborhood of the vessels FIG. 111.— -1, and 7i, Pigmented cells of the skin from J? ■ +i n t ±u i a ease of Addison's disease with caseous tuberculosis of ana 111 Tlie Cells 01 lUe vessel- both adrenals. (Alcohol, carmine.) a, Pigmented epi- walls thelium cells from the deepest layer, in a section cut at '" rigbt angles to the surface. A, h, Pigmented epithelial In the ganglion-cells the cells from a section made parallel to the surface. B, h, ■ , • j e \ Epithelial cells containing no pigment; c,c ly nucleated pigment IS COinpOSeu 01 DrOWll pigmented connective-tissue cells, the processes of which, o'viiiiilpQ in Jl, push between the epithelial cells; d, pigmented » ra ' cell-processes. > 350. The pigments just described arc produces of a specific cell- activity ; and we must suppose that many connective-tissue cells, gan- glion-cells, aud muscle-cells are able to form pigment from the material brought to them. In the majority of cases the pigment appears to be formed in the places where it is found ; yet different investigations make it probable that the pigment may at times be transported. The pig- ment of the epidermis and of the hairs, at least in part, is not formed in the epithelial cells themselves, but in branched connective-tissue cells (Fig. 114 A, c, d, and B, c) which lie just beneath the rete, and send processes between the epithelial cells, through which the pigment is transferred to the latter. The fact that the pigment is often found particularly a) unit the blood- vessels would seem to indicate that the material from which it is formed is derived from the blood, and many authors accept without question the view that the pigment is a derivative of the coloring-matter of the blood. Against this view is the fact that neither in the blood nor in the neigh- borhood of the blood-vessels are there present evidences of an escape of the red blood-cells or of a disintegration and solution of the same. It 240 THE RETROGRADE CHANGES. is, therefore, very probable that the pigment is formed either from the circulating albumin or from the albumin of the cells. The attempt has been made to solve this problem by means of chemi- cal investigations; and the results obtained up to the present time favor the theory that the pigment is a product of cell-activity, and is formed from albuminous bodies. The different, forms of melanin, in which group the pigments of the skin and choroid are usually placed, are, ac- cording to the investigations of von Xencki, Sieber, Abel, Davids, and Schmiedeberg, nitrogenous bodies rich in sulphur, but vary greatly in composition. According to Schmiedeberg these differences depend upon (heir mode of origin, inasmuch as these pigments represent the filial prod- uct of a long series of metamorphoses of albumin ; and in their formation may be compared to the development of humus. The genuine albu- minous bodies do not furnish the material for the building up of this final product (Schmiedeberg), but it is derived from sulphur-containing bodies formed by the splitting-up of the albumins, and from which cer- tain carbon-containing groups have already been split off, so that there arise combinations which in proportion to their carbon-content are very rich in sulphur, and from these the melanins are formed. Iron may be present, in small amounts in masses of melanotic pig- ment, but is usually absent and is not necessary to the production of melanin. In the (use of a very abundant formation, melanin may be excreted in the urine. Lipochrome is the term applied to the coloring-matter of adipose tissue, corpora fntea, ganglion-cells (Rosin), and of the greenish tumors known as chloromata ( Krukenberg). Of the origin and nature of this pigment nothing definite is known. Haemofuscin (von Recklinghausen, Goebel) is the iron-free, yellow- ish granular pigment found in heart-muscle, smooth and striped muscle, in the cells of the glands of the stomach and intestine, in the lachrymal, mucous, and sweat glands, the seminal vesicles, and adrenals. Accord- ing to von Recklinghausen, this pigment is derived from the blood, but it has not yet been established that it is a haemoglobin-derivative. The sulphur-content (Rosenfeld) makes it not unlikely that the haemofuscin granules belong to the melanin group. It is a striking fact that when treated with " fat-stains " the hsemofusein-granules are found to be fat- containing just as lipochrome stains as fat ( Lubarsch ). According to '«» Kolliker, "the pigment of 1 1 1< - hair and epidermis is derived from pigmented connective-tissue cells which lie just beneath the deepest layers of 1 he epithelium of the hair-bulbs and of the rule, and scud processes between the del- icate cells of these layers. These processes divide into long tine ramifications which lie in the intercellular spaces and may even penetrate into the cells themselves, and in this way transfer their pigment to the latter." The pigment of the ganglion cells and of the cells of the retina arises, on the other hand, in the ectodermal cells themselves. Eiehlund Ehrmann agree with ?" ft ».%• Fig. 110. — Cells containing haemosiderin and basmatoidin from an old hemorrhagic focus in tbe brain (Alcohol, Berlin-blue reaction.) a, Cells containing hemosiderin ; h, cells containing bsematoidin • c fai- granule cells which have become clear; r/, newly formed connective tissue, x 3011. remains of disintegrated red blood-cells which have been taken up bv the cells, or from dissolved haemoglobin which lias been absorbed bv the cells. In favor of the latter mode of formation is the diffuse yellow color seen in both wandering and fixed cells, which becomes blue when the Berlin-blue reaction is applied. Further, when haemoglobin is excreted through the kidneys, iron-containing pigment-granules form in the renal epithelium; and moreover fixed cells, as cartilage -cells, for example HEMATOGENOUS PIGMENTS. .M5 which could hardly be supposed to act as phagocytes and take up frag- ments of red cells, often contain granules of hemosiderin, even when lying outside of the immediate neighborhood of the extravasate, The free pigment and the pigmented cells cause a distinct pigmenta- tion of the extravasate and its immediate neighborhood. The pigmented cells soon pass into the lymph-vessels and a metastasis of the pigment takes place, as a result of which the pigment is found in the lymph-vessels and their neighborhood, and in the lymph-glands where it is found first in the free cells of the lymph sinus (Fig. 117). Later it may be taken up by the fixed tissue-cells. In the course of time the hemosiderin is de- stroyed and disappears. The view which is held by many, that heniosi- derin is changed into a black melanin, is not supported by the actual facts. The brownish - black granules in 'the lungs, which have been explained as due to such a change, are found through high magnifica- tion (Neumann) to consist of one or several minute particles of carbon surrounded by a coating of hemosiderin. Tf hemosiderin is brought into contact with hydrogen sulphide it be- comes black; and as the result of such reaction there may be produced in the cadaver black and green spots or a more diffuse discoloration, which are known as pseudomelanosis. It is observed most often in the intestine, peritoneum, and in suppurating wounds, since in these regions hydrogen sulphide is more likely to be formed in the course of putrefac- tion. Fig. 117.— Accumulation of pigment-containing cells in the lymph-glands after resorption of an extravasate of blood. (Midler's iiuid, carmine.) a. Cortical node; o, lymph-sinus; c, cells con- taining pigment-granules. X 100. Arnold has recently declared that, both in hematogenous and exogenous siderosis (see § 71), the iron-granules of the sideroferous cells (leucocytes, connective-tissue cells, liver-cells, etc.) are not iron-granules which have been taken up from without through phagocytosis, or which have been precipitated within the cells, but are changed cell- plasinosomes which have taken up the iron, convened it. and combined it with them- selves. The statements made in the main text (£§ TO and 71) as to the genesis of a por- tion of the sideroferous cells harmonize with Arnold's view, but it must be affirmed that a formation of sideroferous cells through phagocytosis also occurs, both in case of extra vasates and haemachromatoses due to intravascular destruction of the red blood- cells. Pseudomelanosis is not produced, as many authors believe, by the action of hydro- gen sulphide upon the blood, but is formed by the action of hydrogen sulphide upon hiemosiderin. According to the investigations of Zeller, Arnold, and Ernst, black pig- ment, may also be former! during life, through the action of bacteria which produce hydrogen sulphide. Pseudomelanosis of the human hsemolymph-nodes (WartJtin) may occur in colon-bacillus infections as the result of the action of H 2 S in the blood upon the htemosiderin deposited in the glands following an excessive hfemolysis. 246 THE RETROGRADE CHANGES. Literature. (Hmmatogenous Pigment*. ) Arnold: Siderof ere Zellen. Anat. Anz, xvii. ; Virch. Arch., 161 Bd., 1900. Borst: Melanose ties Pericardii urns (Epithelpigmentirung). Vircli. Arch., 147 Bd., 1897. Cordua: Ueber den Reaorptionsmechanismus von Blutergiissen, Berlin, 1877. Diirck: Veranderungen d. Blutungen im Centralnervensystem. Virch. Arch., 130 Bd., 1892. Ernst: Pseudomelanose. Virch. Arch.. 152 Bd., 1898 (Lit,.). Gabbi: Le cellule globulifere nel loro rapporti alia fisiologia del sangue, Firenze, 1891. Lan.g-h.ans: Resorption der Extra vasate u. Pigmentbildung. Virch. Arch., 49 Bd. 1870, Milner : Pigmentbild. in e. extraduralen HSmatome. Virch. Arch., 174 Bd., 1903. Miihlmann: Pigmentmetamorphose der rothen Blutkorperchen. Vircli. Arch., 1~6 Bd., 1891. Neumann, E.: Beitrage zur Kenntniss der pathologischen Pigmente, ib., Ill Bd. , 1888, 177 Bd., 1904; Das Pigment der braunen LungeninduratioD, ib., 161 Bd., 1900. Perls: Naelnveis von Eisenoxyd in gewissen Pigmenten, ib., 39 Bd., 1807. auincke: Deut. Arch. f. klin. Med., 25, 27, and 33 Bd. Schmidt: Verwandtschaft d. hamatogeneu u. autochthoncn Pigmente. Vircli. Arch., 115 Bd., 1889; Hamorrhagie u. Pigmentbildung. Ergebn. d. allg. Path., iii., 1897. Skrzeczka: Ueber Pigmentbildung in Extruvasaten. Beitr. v. Ziegler, ii., 1888. Virchow: Die pathologischen Pigmente. Virch. Arch., 1 Bd., 1847. Vossius : GiTinliche Fiirbung der Cornea naeh Traumen. Graefe's Arch. , 35 Bd., 1889. Warthin : Pseudomelanosis of the Etemolymph Glands. Amor. Jour, of Med. (5c. 1904. Zeller u. Arnold: Pseudomelanotische Abscessc. Virch. Arch., 139 Bd., 1895. Ziegler: Untersuehungen liber die Herkuuft der Tuberkclelemente, Wiirzburg, 1875. § 71. When large numbers of red blood-cells break down in the circulating blood, a portion of the dissolved haemoglobin or methsemo- globin may pass into the plasma, or, on Ihe other hand, fragments of red cells may be carried about in the circulation. Such a destruction of red cells occurs to a marked degree in poisoning with arsenic, toluylendia- inin, potassium chlorate, and morels; to a lesser degree in other diseases, such as many infectious, malaria, pernicious anaemia, and in overheating of the body. The passage of haemoglobin or mel haemoglobin into the blood-plasma leads to the condition of hcemoglobin- cemia, in which the blood- plasma is colored red. When the amount of dissolved hae- moglobin in the blood is large, a portion may be excreted through the kidneys, giving rise to Juemoglobinuria or meth- (Bmogldbmuria, in which con- ditions the urine may present a bloody appearance, or a color varying from a clear brownish- red to a dark reddish-black. This occurs particularly in the case of the first-named poisons, but also occasionally after the action of other injurious influences as example, after exposure to cold (periodical hemoglobinuria). When formed products arise from the disintegration of the red cells, as, for example, after extensive burns, they collect first in the Fie. 118,— Infiltration of the cells of the liver- yellow hemosiderin granules, from a case of i anemia. (Osmlc acid.) o, Hemosiderin; b state of fatty degeneration. < 250. for HEMATOGENOUS PIGMENTS. 247 capillaries of the liver, spleen, lymph-glands, and bone-marrow, and to a less extent in other organs; and are sooner or later taken up by cells. As the result of au increased supply of haemoglobin to the liver the functional activity of this organ is increased, so that the amount of bile- pigment in the bile may be much greater than normal ; and under certain conditions oxyhemoglobin may appear in the bile (Stern). When the blood-destruction is very great, the liver may not be able to dispose of Fig. 119.— Hemochromatosis of tb_ of the portal vein; (.(.infiltrated periportal central veins. X 30. . lAleoho onueetive tis c, branches er-acini ; /, all the blood-pigment brought to it; and in consequence derivatives of haemoglobin are deposited, partly in the liver and partly in other organs, or may be in part excreted by the kidneys. In this way there may arise a more or less extensive hemochromatosis of different organs, the cells of which show an ochre-yellow or brown color. The derivatives of haemoglobin deposited in this way are partly iron- free pigments and partly hemosiderin ; but the latter is particularly a frequent cause of pigmentation of tissues, and it is, therefore, proper to speak of a pigmentation by hematogenous siderosis. These deposits of iron-containing pigment are chiefly in the liver, where they appear partly in the form of yellow granules and lumps, which are for the greater part enclosed in leucocytes lying within the liver-capillaries. Further, they are found also in the form of tine yellow granules, which give the iron-reaction, in the endothelial cells of the capillaries (to which the stellate cells of Kupffer belong), and in the liver-cells (Fig. 118, a). In many diseases, as, for example, pernicious malaria or pernicious anasmia, the majority of the liver-cells contain such pigment, so that the liver through the presence of so much iron takes on a characteristic yellowish-brown color. When large quantities of (he products of the disintegration of red 248 THE RETROGRADE CHANGES. blood-cells are brought to the liver, they accumulate particularly in the periportal connective tissue and in the periphery of the acini (Fig. 119. d, c). The lumps or granules of iron-containing pigment lie either free in the capillaries, or in the tissue; or are enclosed within leucocytes, liver-cells, connective-tissue cells, or the capillary endothelial cells. The infiltrated area, presents to the naked eye a reddish -brown, rusty color. The iron-pigment which is carried to the spleen is deposited chiefly in the pulp within free cells; but granules are also found in the fixed cells. In the lymph-glands the iron granules are found chiefly in the free cells of the lymph -channels. In the bone-marroio retained hemosiderin (Fig. 120) is found partly in free cells lying within the capillaries, and partly in the endothelium, also partly in the marrow-cells; the number of iron-containing cells may be very marked. In the kidneys the hemosiderin granules are most abundant in the epithelium of the convoluted tubules (Fig. 121, a), but they are also found in the luniiua of the urinary tubules (b), in the epithelium of Bowman's capsule (e), and in the endothelium of the capillaries. If small particles of hemosiderin are present in the circulating blood, they will usually be found in the kidney-vessels. When haemoglobin is ex- creted by the kidney, drops of this substance will be seen lying in the tubules. In cases of marked deposit of pigment the kidney may show a distinct pigmentation even to the naked eye. The hemosiderin, which is found in the different tissues, has been brought to them in the form of small lumps or granules, and is contained chiefly in leucocytes. On the other hand, another part of the iron-gran- '*w£ '1* «| -*& &*x *r & % t * 4b «* «s <*• "t a*^ « * * 9 1 * % « *** > * • i » ? Fir:, lai.— Hemosiderin deposit in the bone-marrow (mixed fatty and lymphoid marrow) in icteni"! (Alcohol, carmine, Berlin-blue, reaction.) X 300. ' ules is precipitated in solid form within the cells from substances brought to them in solution. Since the cells (liver-cells, kidney epithelium, en- dothelium of the blood-vessels, and the cells of the lymph-glands, bone- marrow, and spleen) not infrequently show a diffuse bine color after the iron-test has been applied, the iron must be diffused throughout the cell - protoplasm, and is probably converted later into the granular form. It is also possible that the diffuse coloration may arise in part from a solu HEMATOGENOUS PIGMENTS. 249 tion of iron within the cells. According to the observations of different authors it is assumed that besides the colored deposits of pigment, color- less granules of an iron-albuminate may be present in the cells. This theory is supported by the observation that more pigment granules are visible after the iron reaction has been applied, than could be seen before. The deposit of iron-free pigments, hcematoidin or bilirubin is not of frequent occurrence in hsemochromatosis, but occasionally yellow gran- ules which do not give the iron reaction are found in the organs named above; and it may, therefore, be assumed that the pigment in part may be constantly free from iron. By the majority of authors (sec Qeyer, toe. eit.), the mottled pigmentation of the skin, "which develops in chronic arsenic poisoning, and which is due to the deposit of small yellowish-brown pigment granules in the corium and epidermis (similar to the pig- mentation of Addison's disease), is to be classed with the hemochromatoses. It is to be referred to the degenerative influence of arsenic upon the " bone-marrow and the FIG. 121.— Haematogenous deposits o( iroa in the kidney in pernicious malaria (contracted in Baga- mayo). CAlcobol, carmine, Berlin-blue reaction.) fl. Convoluted tubules, whose epithelial cells contain iron granules and are stained diffusely blue; b, iron-granules in the lumen of the tubules ; c, straight tub- ules ; ci, glomerulus ; e, epithelium ot the capsule, containing iron-granules. X 150. blood. It should be noted, however, that the pigment does not give the iron reaction, imd that, according to other observations, pigment in epithelium which is derived from hemoglobin is not permanent; and that no increased destruction of the red blood-cells occurs in the affected individuals (Mnir). The organism supplies its need for iron through the assimilation of the iron compounds found in the iron-containing articles of food. The iron contained in the iron preparations used for medicinal purposes is absorbed from the small intestine, in particular from the duodenum. Iron absorbed in excess is in part stored up as hemo- siderin in the spleen, bone-marrow, and lymph-glands, or temporarily in the liver; and in part excreted through the kidneys, liver, and large intestine. In malaria two pigments are formed as a result of the destruction of the red cells by the malarial parasite. One of these is formed by the malarial Plasmodium itself, is contained within the parasite, is black, and gives no iron reaction. Its nature is not known. The second pigment is hemosiderin, which passes into the blood-plasma as the re- sult of the destruction of the red blood-cells, and is deposited in the liver, spleen, and bone-marrow. In cases of marked destruction of the blood there may occur also a side- rosis of the kidneys (Fig. 121), and an excretion of iron in the urine. The green color which is nhsemed in the neighborhood of blood-containing vessels in de- composing cadavers is to be referred to a formation of sulphur-methemoglobin through 250 THE RETROGRADE CHANGES. the action of H 2 S on oxyhemoglobin (Ebppe-Seyler, Harwich). In the absence of oxy- gen, sulphur-hemoglobin is formed, which possesses a dark-red color (Earnack). Literature. (Hccmochromatosis ; Iron Absorption; Deposit and Excretion.) Afanassiew: Toluylendiaminvergiftung. Zeitschr. f. klin. Med., vi. ; Slit Hiimoglo- binurie und Ikterus vcrbund. Vergiftungen. Virch. Arch., 98 Bd., 1884. Alexander: Bisengehalt d. Milz- u. Lymphdrtissen. Inaug.-Diss., Freiburg, 1895. Auscher et Lapicque: Accumul. d 'hydrate ferrique dans l'organisme. Arch, de phys., viii. , 1896. Arnstein: Ueber Melan&mie und Melanose. Virch. Arch., 61 Bd., 1874. _ Baserin: Eisengehalt der Galle bei Polycholie. Arch. f. exp. Path., xxiii., 1887. Biondi: Ablagerung von Hemosiderin bei Hiimatolyse. Beitr. v. Ziegler, xviii., 1893 (Lit.). Bostrom: Intoxication durch die essbaie Morehel, Leipzig, 1882. Browicz : Phagocytose d. Lebergefiissendothelien . A. f. mikr. An., lx., 1902. Cloetta : Bisenresorption im Darm. Arch. f. exp. Path., 38 Bd., 1897. Dutton : Iron in the Liver and Spleen in Malaria. Jour, of Path., v., 1898. de Filippi : Unters. iiber das Ferratin. Beitr. v. Ziegler, xvi., 1894. Futcher : Hemochromatosis with Diabetes Mellitus. Am. J. of the Med. Re., 1907. Gaule: Resorption des Eisens. Deutscb. med. Woch., 1896. Geyer: Die chron. Hautveriluderungen bei Arsenicisinus. Arch. f. Derm., 43 Bd., 1898 (Lit.). Grimm: Urobilin im Ham. Virch. Arch., 132 Bd., 1893. Harnack: Einflussd. Schwefelwasserstoff s auf d. Blutfarbstoff. Zeit. f. phys. Chem., 20 Bd., 1898. Heuss: Keratosis u. Melanosis nach Arsengebrauch. Correspbl. f. Schweizer Aerzte, 1894. Hintze: Hiimoohromatose. Virch. Arch., 139 Bd., 1895. Hochhaus u. Quincke : Bisenresorption u. Ausscheidung im Darm. Arch. f. exp. Path., 37 Bd., 1896. Hofmann: Eisenresorption u. Ausscheidung. Virch. Arch., 151 Bd., 1898. Hoppe-Seyler: Abscheidung des Urobilins in Krankheiten. Virch. Arch., 114 Bd., 1891. Hunter: Action of Toluylendiamin. Journ. of Path., Hi., 1895. Jacob: Ueber Siderosis. Inaug.-Diss., Freiburg, 1895. Kober: Ueber das Eisen in diatetiseher Ilinsicht. Ueut. med. Woch., 1894. Kobert: Argyrie u. Siderosis. Arch. f. Derm., 1893. Kunkel: Farbstoff im Ham. Virch. Arch., 79 Bd. ; PigmentinrJltration, ib., 81 Bd., 1880. Marchand: Giftige "Wirkung d. chlors. Salze. Arch. f. exp. Path., 22 and 23 Bd., 1886, 1887. v. Mering-: Das chlorsaure Kali, Berlin, 1885. Minkowski u. Naunyn: Ikterus durch Polycholie. Arch. f. exp. Path., 21 Bd., 1886. Moroni: Siderosi epatica. Arch, per le Sc. Med., xvii., 1893. Muir : Arsenical Poisoning. J. of Path., vii., 1901. Muller: Arsenmelanose. Arch. f. Derm., 25 Bd., 1893. Nasse: Die eisenreichen Ablagerungen im thierischen Korper, Marburg, 1889. Nathan: Aufnahme u. Ausscheidung d. Eisens d. Eisensoniatose. Deut. med. Woch. 1900. Neumann: Bilirubinkrystalle im Blute neugeborener und todtfauler Frilchte. Arch. d. Heilk., x., 1869; Das melaniimische Pigment. Virch. Arch., 116 Bd., 1889. Nielsen: Melanosis arsenicalis. Monatsh. f. prakt. Derm., xxiv., 1897. Opie: HSmochromatosis. Journ. of Exp. Med., iv., 1899. Peters: Eisenablagerungen bei versch. Krankheiten. Deut. Arch. f. klin. Med., 32 Bd., 1882. Ponfick: Hamoglobinamie. Berl. klin. Woch., 1877, 1883. auincke: Zur Pathologie des Blutes. Deut. Arch. f. klin. Med., 25, 27 and 33 Bd. ; Pemiciose Auainie. Klin. Vortr., No. 100, 1876; Eisentherapie. Klin. Vortr., No. 129 Leipzig, 1895. Scheimpnug: Beitr. z. pathol. Histologic des Darms. Zeitschr. f. klin. Med., ix., 1885. Schurig: Sehicksale des Hilmoglobins im Orgamsmus. Arch. f. exp. Path., 41 Bd.. 1898. ICTERUS. 251 Stadelmann : Der Ikterus, St'ittgart, 1891. Stern: Ueber das Auftreten von Oxyhamoglobin in der Galle. Virch. Arch., 123 Bd., 1891. Sttthlen: Eisengehalt versch. Organe bei Anamie. Deut. Arch. f. klin. Med., 54 Bd., 1895. Tedeschi: Das Eisen in d. Organen normaler u. entmilzter Thiere. Beitr. v. Ziegler, xxiv., 1898. Weidenreich. : Schicksal d. r. BlutkOrperchen. Anat. Anz.,xxiv., 1903. Wyss: Ueber Arsenmelanose. Correspbl. f. Schweizer Aerzte, xx., 1890. Zahn: Ueber Pigmentinfiltration der Knorpel. Virch. Arch., 72 Bd., 1878. Zaleski: Eisengehalt der Leber. Zeitr. f. phys. Chem., x., 1886; Zur Eisenfrage. Virch. Arch., 104 Bd., 1886; Ausscheidung des Eisens. Arch. f. exp. Path., xxiii., 1887. § 72. Icterus or jaundice is a pathological pigmentation of the tissues due to the presence of bile-pigment. Icterus is a symptom which occurs in the course of numerous diseases of the liver, and is of frequent occur- rence even iu the first days of life (icterus neonatorum). The pathological pigmentation which characterizes icterus is apparent during life, particularly in the skin, conjunctiva, and in the urine; in the cadaver the internal organs— the serous membranes, lungs, kidneys, liver, the subcutaneous and intermuscular tissues, the blood plasma, clots lying in the vessels, etc. — may show an icteric coloration. In recent cases the icteric color is yellow; in long-standing cases the skin takes on an olive-green or dirty grayish-green color, while similar color- 'if £fd?**'? v > ft! Wm U.J, Fig. 132.— Obstructive icterus of the liver, due to compression of the ductus choledochus by a cancer of the gall-bladder. (Sublimate, alum-carmine.) a, Intra-acinous bile-capillaries, moderately dilated and filled with bile ; 6, widely dilated intra-acinous bile-capillary, containing large mass of pigment ; c, bile- nigment in the liver-cells d, d u endothelium stained with bile-pigment; e. desquamated endothelium stained with bile-pigment ; /, pigment mass surrounded by cells ; g, rupture of the pigment contained in a hile-capillary into a blood-capillary, with bile-stained cells in the neighborhood. X 365. ations occur in the internal organs, particularly in the liver, and occa- sionally in the kidneys. Icterus results from the entrance of bile — that is, of bile-pigment (bilirubin) -into the Mood and fluids of the body. During such a condition the urine excreted contains elements of the bile, particularly the bile- pigments. 252 THE RETROGRADE CHANGES. Icterus is a hepatogenous disease, inasmuch as the bile-pigments have their source in the liver. As the result of disease processes in the biliary passages or in the liver itself the normal outflow of the bile is hindered, and the bile is then taken up into the lymphatics and blood-vessels of the liver. Such a damming back of the bile may be caused, for exam- ple, by a narrowing or closure of the large bile-ducts through the forma- tion of scar-tissue, through gall-stones wedged in the lumen, or through tumors developing in the bile-ducts themselves, or arising outside of the ducts and compressing them ; or through inflammatory processes, ab- scesses, connective-tissue growths, or tumors of the liver which compress or pull upon, or completely obliterate the smaller bile-ducts, and in this way hinder the outflow of blood from the smaller bile-ducts and capil- laries. In the case of a stasis of bile within the liver-lobules the intercellular bile -capillaries first become dilated and may become filled with large bile- thrombi (Fig. 122, a, h). The dilatation affects also the blind side branches extending toward the capillaries, and these finally may be broken through, leading to a separation of the liver-cells (Fig. 122, g), also to cell necrosis, so that the bile eventually gains entrance into the perivascular lymph-channels and thence also directly into the blood. Further, the bile-pigment is heaped up in granules within the liver-cells themselves (c), and the endothelium of the blood-capillaries (d, d lt e) also becomes stained with bile. Since there occurs in the liver-cells a double secretion, an external one through the bile-ducts of bile-acids and bile-pigment, and an internal one into the blood-vessels of sugar and urea, it appears reasonable that a passage of bile into the blood may occur not only through stasis of the bile, but also as the result of pathological conditions of the liver-cells due to infections and intoxications. ~\Ve may therefore distinguish, in addition to icterus due to bite stasis or stasis parapedesis (Minkowski), other forms of icterus due to toxic and, infectious parapedesis of the bite (paraehotia, Pick) ; and there are probably many forms of icterus formerly referred to as catarrh of the bile-passages that may be explained in this way. It is also possible that disturbances of innervation and of the circula- tion of the liver may be sufficient to bring about an escape of bile into the intra-acinous lymph -channels or into the blood, so that a nervous paraehotia may also be distinguished. When bile-pigment, either in solution or in the form of granules and lumps, obtains entrance to the blood, the tissues of the bod// become grad- ually permeated with bile-stained lymph, and thereby acquire an icteric color. If phagocytes containing granules or lumps of bilirubin are present in the circulating blood, they may accumulate here and there, particularly in the spleen and the bone-marrow. After a time the bile-pigment held in solution within the tissue-lymph may become pre- cipitated as solid particles of bile-pigment, chiefly in a granular form, but rarely in a crystalline (the latter form occurs almost entirely in 1 lie new-born, in which the crystals are found in the fixed and wandering cells of the connective tissue, in the liver-cells, and in the renal epithe- lium). The crystals are in the form of rhombic plates and needles, similar to those of haunatoidin (Fig. 115). In severe cases of icterus very many of the tissue- cells contain pigment, and, as a result of the metastasis of cells containing pigment, accumulations of the latter in the lymph -glands may occur. In the kidneys in which bile-pigment is being excreted there likewise ICTERUS. 25: ! •x'wu-s an excretory pigmentation, particularly of the epithelium of lb..- urinary tubules (Fig. 123, a, «!), wnich in consequence may become desquamated. If, as the result of the damage done to the secreting cells through the excretion of the bile-pigment, there are formed, as is usually the case, hyaline casts— that is, hyaline coagula in the albumin-contain- ing urine in the tubules— these likewise become colored by the bile-pig- ment (Fig. 123, b, c). Associated with the deposits of bilirubin in icterus there is always a deposit of hemosiderin which may become so abundant, particularly in the bone-marrow (Fig. 120); spleen, and lymph-glands, and occasionally also in the liver, that the pigmentation of the organs named is dependent in part upon iron-pigment. %«i fit -<&*?*.., C ti%& / ,£) -m^} ®/A fl ':iF©Vi>® ©2" gp # -'%r *&&mwi m ^m:m a Via. 123. —Icterus of the Sidney in obstructive jaundice. (Sublimate, carmine.) a. Tubular epi- thelium containing yellowish-brown granules ; 6, large casts stained yellowish-green ; c , cast containing pigmented cells ; d, desquamated epithelium containing bile-pigment granules. X 200. When an increased destruction of red blood-cells takes place within the blood-vessels, hsematoidin or bilirubin, in addition to hemosiderin, is formed in different parts of the body (see § 71) ; but the formation of bilirubin outside of the liver is very slight and is not sufficient to cause any extensive icteric coloration of the tissue, so that a purely hwmatoge- nous jaundice does not occur. The liver is the great elaborator of bilirubin, and in cases of increased destruction of the blood-cells the liver-function is increased and there is an increased production and excretion of bile- pignieut. An icterus due to increased destruction of blood-cells can occur only when at the same time there are present in the liver such changes as cause a passage of the bile into the blood. The question as to whether there is a hsematogenous as well as a hepatogenous jaundice has long been an object of discussion, and remains unsettled at the present lime, in spite of numerous experimental investigations directed toward its solution. Since, as a matter of fact, bilirubin may be formed in the most different kinds of tissue from extravasated blood, the occurrence of a hematogenous icterus would a priori ap- pear very probable. Experimental investigations as to the results of the destruction of 25-1 THE RETROGRADE CHANGES. red cells in the circulating Wood, particularly through the action of arsenic, toluylen- diamin, and potassium chlorate, have shown that the derivatives of blood-pigment which are formed in the tissues and there retained for a long time are essentially iron- containing pigments (hsemosiderin), while the production of bilirubin is practically con- fined to the liver, which for the time being secretes an increased amount of richly pig- mented bile. According to the investigations of Minkowski and Naunyn, the urine of geese and ducks after removal of the liver contains no bile-pigment— a fact which would indicate that the transformation of blood-pigment into bile-pigment is ordinarily confined to the liver. The inhalation of arseniureted hydrogen for a few minutes is sufficient to produce in geese in a very short time an intense polycholia and hematuria, the urine containing haemoglobin in solution, disintegrating red cells and biliverdin. If the liver from such a goose be removed, the biliverdin quickly disappears from the urine, and no trace of bile- pigment can be demonstrated in the blood. It is therefore evident that in arsenic- poisoning the formation of the bile-pigment is confined to the liver, in which organ leucocytes enclosing iron-containing iragments of broken-down red cells are found to be present. In so far as it is possible to judge from the experimental investigations which have been made up to the present time, a pure luematogenous jaundice does not appear to occur. The mere fact of the occurrence of jaundice after intoxications, inhalation of ether and chloroform, transfusion of blood, snake-bite, septicaemia, typhoid fever, yel- low fever, paroxysmal hemoglobinuria, etc., cannot be taken as proof of the existence of a hematogenous jaundice. There is, indeed, in these conditions an increased destruc- tion of red blood-cells; but bilirubin is essentially a product of the liver, and if jaundice occurs it can be due only to the fact that a portion of the bile-pigment, which is pro- duced in excess, has found its way into the blood. According to von Kupjfer and Pfeiffer, the bile-capillaries terminate in intracellular secretory vacuoles; from these, according to Nauwerck, Stroebe, and Browicz, delicate intracellular secretory canaliculi are given oil', forming a netwi rk around the nucleus. According to Nauwerck, the internal secretion of the liver also takes place into very delicate intracellular canaliculi. Schiifer describes small nutritive canaliculi within the liver-cell communicating with the blood-capillaries. Arnold opposes the view that any preformed system of canals exists within the liver cells. In the icterus occurring so frequently in the new-born (Schmorl) there occurs both a diffuse and a scattered yellowish coloration of the brain limited to the neighborhood of the nuclei, while in later life the brain, even after a long-continued icterus, remains free from pigment. With the nuclear icterus there are also found ganglion-cells stained with bile. Literature. (Icterus.) Abramow u. Samoilowicz: Pathogenese d. Ikterus. Virch. Arch., 17(i Bri., 1904. Arnold: Feinere Struktur der Leberzellen. Virch. Arch., 166 B<1., 1901. Auld; Hematogenous Jaundice. Brit. Med. Journ., i., 1S96. Birch.-Hirsch.feld: Die Entstehung der Gelbsucht neugebor. Kinder. Virch Arch 87 Bd., 1882. Browicz: Intracellulare Gallengange, etc. Deut. med. Woch., 1897; Cbl. I', allg. Path., 189S; Lebercapillaren. Bull. del'Ac. dessc. de Cracovie, 1900. Biirker: Ort d. Resorption d. Gallc. A. f. Phys., 83 Bd., 1901. Dastre et Florescu: Pigments biliaires. Arch, de phys., ix., 1S97. Eppinger, H. : Pathogenese des Ikterus. B. v. Ziegler. xxxi., 1902, und xxxiii., 1903. Halter u. Lauterbacher: Ilesorptionsikterusbeim Frosch. Beitr. v. Ziegler, x., 1891. Harley: Pathology of Obstructive Jaundice. Brit. .Med. Journ., 1892; Leber u. Galle wahrend dauernden Verschlusses von Gallon- und Brustgang. Du Bois-Reymond's Arch., 1893. Hofmeier: Die Gelbsucht der Neugeborenen. Zeitschr. f. Gebh. u. Gyn., viii., 1882, Ivannovics: Exp. Enters, lib. Ikterus. Z. f. Heilk., 25 Bd.. 1904. Kiener etEng-el: Pathogenic de l'ictere et ses rapports avee l'urobilinurie. Arch, de 1>hvs., x., 18S7. Kunkel: Ueber das Auft.reten verschiedener Farbstoffe im Harn. lb.. 79 Bd.. 1880. Lesage et Demelin: L'ictere du nouveau-ne. Rev. de med., 1S98. Lowit: Bildung des Gallenfarbstoffs in d. Froschleber. Beitr. v. Ziegler, i\\, 18,89. Minkowski: Die Storungen der Leberf unction. Ergebn. d, allg. Path., Jahrg ii 1897. EXTRINSIC PIGMENTS. 255 Minkowski u. Naunyn: Pathologic d. Leber u. d. Ikterus. Arch. f. exp. Path., xx i., 1SSG. Nauwerck: Leberzellen u. Gelbsucht. Munch, med. Woch., 1897. Neumann: Abscheidung von Bilirubinkrystallen aus dem Blute in den Geweben. Arch. d. Heilk., viii., 1S67; Bilirubinkrystalle im Blute der Neugeborenen u. todt- fauIerFriichte. lb., ix., 1868; ib.,xvii., 1876; Ikterus neonatorum. Virch. Arch., 114 Bd., 1888. Orth: Ueb. d. Vorkommen v. Bilirubinkrystallen bei neugeb. Kindern. Virch. Arch., 63 Bd., 1875. Pick: Entstehung d. Ikterus. Wien. klin. Woch., 1S94; Wesen d. Ikt. Prag. med. Woch., 1895. Quincke: Beitrage zur Lehre vom Ikterus. Virch. Arch., 95 Bd., 1884; Ueber die Entstehung der Gelbsucht Neugeborener. Arch. f. exp. Path., xix., 1885. Roger: Physiol, norm, et pathol. du foie, Paris, 1893. Runge: Die Krankheiten der ersten Lebenstage, Stuttgart, 1893. Schafer: Nutritive Channels within the Liver Cells. Anat. Anz., xxi., 1902. Schmorl: Ikterus neonatorum. Verh. d. D. path. Ges., vi., 1904. Silberrnann: Die Gelbsucht der Neugeborenen. Arch. f. Kinderheilk., viii., 1887. Stadelmann: Der Ikterus, Stuttgart, 1891. Stern: Ueber die norm. Bildungsstatte desGallenfarbstoffs. Arch. f. exp. Path., xix., 1885. Szubinski: Struct ur der Leberzellen. Beitr. v. Ziegler, xxvi., 1899. Wertheimer n\ Lepage : Absorption des pigmentes dans le foie. Arch, de phys., 1897. § 73. Pigmentation of the tissues through substances introduced into the body from without occurs when substances possessing a color of their ow r n gain entrance in some manner to the tissues, where they are able to remain for some time without suffering changes. The number of such substances is large, and the manner of entrance varied. The most common avenues of entrance are the lungs, wounds, and intestinal tract. The Fig. 13i.— Deposit of cinnabar in tattooed skin. (Alcohol, alum carmine.) c, cinnabar. X 80. Epithelium ; l», corium ; most familiar pigmentation through wounds is tattooing of the skin, which is frequently practised by individuals of civilized as well as of uncivil- ized nations. The method of tattooing colored figures, etc., consists in the intro- duction of insoluble granular pigments, such as carbon, india-mk, cin- nabar, sepia, burnt sienna, ultramarine, chromate of lead, etc. , into slight wounds of the skin. The pigments are rubbed into the wounds, whence they penetrate and infiltrate the tissue in their immediate neighbor- hood. A portion of the pigment remains in the corium (Fig. 124, c) ; 256 THE RETROGRADE CHANGES. 6 » <5> 9 another portion is carried to the lymph-glands, which thereby become pigmented. The lungs and their lymph-glands may become intensely pigmented through the inhalation of colored dust, such as coal-dust, soot, iron-dust, etc. Through the inhalation of coal-dust the lungs may become wholly black. When coal-dust is taken into the lungs in the respired air a portion of the pigment is carried to the peribronchial lymph-glands, which in consequence may become black. When the deposit is very abundant the lymph-glands may undergo softening and give off the pigment into the lymph-stream. If the glands are situated in the neighborhood of a vein, the pigment-deposit and the softening may involve the vein- wall, so that finally particles of coal-dust may pass into the blood- stream, and be carried to other or- gans, the spleen, liver, and bone- marrow (see § 21). From the intestine only soluble sub- stances are absorbed, and a perma- nent pigmentation can therefore oc- cur, only when these are precipitated in the tissue in a solid form, which is at the same time either black or possessing some color. The most fre- quent of such pigmentations is that known as argyria, which is due to the long-continued use of silver-prepara- tions. In this condition the skin may show an intense grayish-brown discol- oration, and the internal organs may also present more or less pigmenta- tion. The silver is deposited in the ground-substance of the tissues in the form of fine granules, more especially in the glomeruli, and the connective tissue of the medullary pyramids (Fig. 125, b), the intima of the great ves- sels, adventitia of the smaller ones, in the neighborhood of the mucous glands, the papillae of the skin, con- nective tissue of the intestinal villi, and in the choroid plexus of the lateral ventricles. Deposits may occur also in the serous membranes, but the epithelial tissues, the brain, and the cerebral vessels escape. Exten- sive deposits of silver pigment in the medullary portion of the kidneys may lead to the formation of hyaline connective tissue, which mav undergo calcification. Under especial conditions iron, when taken into the body iu excessive amounts, may be deposited in the bone-marrow, spleen, and lymph- glands; but the pigmentation thus produced is only rarely visible to the naked eye. In lead-poisoning there may be seen a. grayish- black discolor- ation of the gums, which is due to the deposit of granules of sulphide of lead in the connective tissue of the mucous membrane. They are pro- duced through the action of hydrogen sulphide upon the lead, which is present in solution in the mucous membrane. Fig. 135.— Deposits of silver in the pyramidal portion of a rabbit's kidney, after seven months' administration of silver salts (experiment by von Ivuhlden.) (Alcohol, hematoxylin.) a, Epithe- lium of the collecting tubes; b, connective tissue with brown silver granules. X 500. THE PATHOLOGICAL ABSENCE OF PIGMENT. Literature. (Argyria.) Behrend: Argyrie. Eulenburg's Realencyklopadie, 1894. Frommarm: Eiu Fall von Argyria. Virch. Arch., 17 Bd., 1859. Jacobi: Aufnahme der Silberpriiparate iu dea Organismus. Arch. f. exp. Path., • 1878. Jahn: Argyrie. Beitr. v. Ziegler, xvi., 1894. v. Kahlden: Ablagerung des Silbers in den Nieren. Beitr. v. Ziegler, xv. , 1894. Kobert: Ueber Argyrie u. Siderosis. Arch. f. Derm., 25 Bd., 1898. Levin: Ueber locale Gewebe- Argyrie. Berlin, klin. Woch., 1886. Riemer: Ein Fall von Argyrie. Arch. d. Heilk., 16 Bd.. 1875. Buge: Ueber den Bleisaum. Deut. Arch. f. klin. Med., 58 Bd., 1898. Warthin: Argyria. Kef. Handb. of Med. Be, 1901. XV. The Pathological Absence of Pigment. 8 74. The absence of pigment occurs, in the first place, as a congeni- tal condition, and is then termed albinism or leucopathia congenita. In a part of such cases the absence of ..,,, ,.,,.,,..,..;..,.... ..,, ; pigment extends over the entire body ^;r ' — '•.*. (albinism/us universalis, Kakerldken, albi- nos) ; in other cases it is restricted to cer- tain portions of the skin ( [albinismus par- tialis). In those parts of the skin which are destitute of pigment the hairs likewise may contain no pigment, and appear '. white or yellowish-white (poliosis or leu- cotrichia congenita universalis, et circum- scripta). In universal albinism the pig- ment of the retina, choroid, and iris may also be wanting, so that consequently, the choroid, from the amount of blood which it contains, appears red, and the iris, ac- • ; cording to the angle of observation and the degree of illumination, will appear either bluish-white or red. On micro- scopical examination no pigmented cells can be found. A second form of absence of pigment is that condition which is known as vitil- igo or leucopathia acquisita. This oc- curs later in life, either as a secpiela to certain well-known diseases (scarlet fever, typhus, recurrent fever), or as a symptom of an epidemic disease of unknown eti- 1 ology (vitiligo endemica), or finally with- \ out any recognizable cause. The forma- ;■ tion of white spots, within which the hairs | are also white (leucotrichia acquisita cir- cumscripta), takes place usually symmet- rically, and may extend over the greater Fig. 126.— Vitiligo endemica (after a photo- „ nrT 'e +],„ hod v (Tip- 126"l The white graph received from Professor Munch.) P' ur IJ1 uie uou J ». rl fe- '-">■ inenmie 17 258 THE RETROGRADE CHANGES. areas are surrounded by a border of more deeply pigmented skin ; and this suggests that with the disappearance of the pigment at one point the pigment is transferred to adjacent parts. The loss of color in the hairs (even as in old age) begins always in the root, no more pigment being- transferred from the hair-papilla to the hair-bulb. Finally the pigment- cells of the papilla disappear altogether. A third form of loss of pigment is associated with traumatic or infec- tious inflammations of the skin, particularly in syphilitic exanthemata and in leprosy ; this condition is known as leucoderma. In scars of the skin which remain white, the newly formed tissue replacing the defect does not possess the power of producing pigment ; and consequently represents a colorless cicatrix covered by epithelium. Not infrequently such a scar may be surrounded by a pigmented border. In mild forms of inflammation, in which the tissue of the skin suffers no loss (syphilis), the disappearance of color may immediately follow the inflammation, or not until later, in which case there may occasionally occur a preceding stage of increased pigmentation. According to Ehr- mann the lack of pigment in such cases is to be explained either by the fact that no chromatophores are present in the corium to furnish pigment to the epithelium, or the changed epithelium is not able to take up the pigment from the latter when present. The pigment which still remains in the cutis may then be absorbed. According to Munch, vitiligo is of common occurrence in Turkestan, and is consid- ered by the natives (Sarts) to be contagious, so that they isolate the individuals affected with this disease and confine them with lepers in enclosed courts. It is probable that in the literature vitiligo endemica has been many times mistaken for lepra maculosa, and has been described under the designation "white leprosy of the Jews." Literature. (Absence of Pigment. ) Behrend: Canities (Poliosis). Eulenburg's Realencyklop., 1894 (Lit.). Beigel: Bcitr. z. Gesch. d. Albinismus part. u. d. Vitiligo, Dresden, 1864. Ehrmann: Ilauteutfiirbung durch syph. Exantheme. Arch. f. Derm., Ergzh., 1891. Jadassohn: llautentfarbung. Vierteljahrsschr. f. Derm.. 1880; Pigment verscniep- pung. Arch. f. Derm., 1892. Landois: PI5tzliclies Ergrauen der Haupthaare. Virch. Arch., 35 Bd., lSlJG. Marc: Pathogenese der Vitiligo. Virch. Arch., 136 Bd., 1894. Munch: Lepra u. Vitiligo im Siiden Russlands, Kiew, 1884-86. Norris : An Extensive Case of Vitiligo. Univ. of Penn. Med. Bull., 1902. Schmorl: Pigmentverschleppung. Cbl. f. allg. Path., v., 1894. XVI. The Formation of Cysts. § 75. A cyst is a circumscribed cavity which is shut off from the sur- rounding tissues by a connective-tissue membrane or by tissue of a more complex structure, and possessing contents differing in nature from the capsule. Cysts may occur in any tissue. When composed of but a sin- gle chamber, the cyst is called a simple cyst ; when divided into a number of compartments, it is known as a multilocular cyst. The most common form is the so-called retention-cyst, which arises from the accumulation of secretions in preexisting spaces ichiclt are lined with epithelium or endothelium. In glands provided with an open duct, retention-cysts will be formed as the result of the obstruction of the duct, provided that actively- CYST-FORMATION. 259 secreting epithelium still exists behind the point of obstruction. Such cysts are of frequent occurrence in the sebaceous glands, hair-follicles, uterine glands, mucous glands of the intestinal tract, tubules of the epidi- dymis (Fig. 127, c), urinary tubules; less frequent in the biliary passages, in the breast, pancreas (Fig. 128, b), in the glands of the month, etc. Larger open canals, such as the ureters, vermi- form appendix, and tubes (Fig. 129, e), may also undergo cystic dilatation as the result of the collection of secretions. The obstruction of a given duct may be due to accumulation of secretion, to the formation of adhesions (Fig. 129, e), cicatricial obliteration, compression, or constriction of its lumen. Closed glandular cavities and tubes, such as the follicles of the thyroid aud the glandular tubes of the parovarium, may also become cystic when their walls produce an abnormal amount of secre- tion. Likewise, the remains of fetal passages and clefts, as, for example, re- urachus, Midler's ducts, etc., may also Fig. 127.— Section ol tbe testicle and epididymis, with multiple cysts in the head of the epididymis, a. Testis ; b, epididy- mis ; c, multilocular cysts. Slightly reduced. mains of the branchial clefts, become cystic. Small cysts, such as those developing in mucous glands, vary in size from a millet seed to that of a pea. Larger cysts, such as occur in the liver and ovaries, may attain the size of a fist and even larger. The contents of cysts depend upon the nature of the tissue in which they are formed. Thus the cysts of the sebaceous glands and hair-folli- cles (atheroma) contain a pultaceous, white, or grayish-white, more rarely brown, mass, which consists essentially of squamous cells, in part show- ing cornification, and also of fat-globules and cholesterin. The cysts oc- curring in mucous glands contain a mucous fluid which is either clear, or white and cloudy, as the result of the presence of cellular elements. FIG. 128. -Pancreas cyst, due to dilatation of branches of Wirsung's duct, transverse section of artery ; d, longitudinal section of vein. a. Gland-tissue ; b > cysts ; c. Natural size. Hamiorrhage into a cyst from the cyst-wall gives a red or brown color to the contents. When great numbers of cells are present in the cyst-con- tents, this may become converted into a semi-solid fatty mass, which 260 THE RETROGRADE CHANGES. may undergo calcification. Cysts of the thyroid and kidneys contain colloid masses, or a clear though occasionally cloudy fluid. Retention=cysts lined with endothelium may develop from blood- and lymph- vessels, lymph-spaces, bursas, and tendon-sheaths. Here also the content of the cyst is dependent upon its place and mode of origin. As retention-cysts increase in size the stretching of the cyst-wall would ultimately lead to a defect in the continuity of the wall if no new formation of tissue took place. Cyst formation is, therefore, not purely a degenerative process; such a new formation of tissue takes place first in the epithelial or endothelial lining of the cyst, but the connective- tissue elements of the wall also increase, so that in spite of the stretching m^M Fu:. 189.— Hydrops of the Fallopian tube, with perisalpingitic and periovarian adhesions n Uterus • 6, uterine portion of the tube : c, abdominal end of tube, showing cystic dilatation and adhesions 'with the neighboring parts; d, ovarium ; e, membranous adhesion. Two-thirds natural size. the wall of the cyst becomes no thinner, and under certain conditions may even increase in thickness. Moreover, cyst formation is often associated with a pathological formation of new glandular tissue, and in this way constitutes a secondary change in hypertrophic or tumor- like growths. It is, therefore, sometimes impossible to draw a sharp line between the simple cystic dilatations of preexisting gland-canals and gland-spaces, and those tumors, the cystomata, which are characterized by cyst formation (see Cystoma). Endothelial cysts may also develop out of newly formed lymph- spaces and lymph-vessels. A second form of cyst is the degeneration=cyst, which arises through the partial disintegration and liquefaction of a tissue. Cysts formed in this manner occur in the brain, hypertrophic thyroids, and in tumors. They may contain a clear or cloudy, or at times hemorrhagic exudate. A third form of cysts results from the formation of a connective- tissue capsule around foreign bodies, which have found entrance to the tissues, as, for example, about a bullet; or also about necrotic areas or haemorrhagic extravasates. A fourth variety of cysts is formed by parasites which pass through CYST-FORMATION. 261 a cystic stage in the course of their development in the body, and are likewise surrounded by a connective -tissue capsule. Literature. (Retention- Cysts.} Aschoff: Cysten. Ergebnisse d. allg. Path., II. Jahrg., Wiesbaden, 1897 (Lit.). Bard et Lemoine : De la maladie kystique essentielle des organes glandulaires, Paris, 1890. Cliiari: Genese der sog. Atheromcysten. Zeitschr. f. Heilk., xii., 1891. Franke: Blutcyste der seitlichen 'Halsgegend. Deut. Zeitschr. f. Chir., 28 Bd., 188s (Lit.). Henries: Angeb. Auswuchse am Halse. Arch. f. Kinderheilk., ix., 1888 (Lit.). Hess: Ueber cine subcutane Flimmercyste. Beitr. v Ziegler, viii. , 1890. Kiihue: Pathol. Histologic der Oystenbilclung. Vireh. Arch., 158 Bd., 1899. Marchand: Cysten. Eulenburg's Realencyklop., 1894 (Lit.). Nordmann : Galaktocele. Vireh. Arch., 147 Bd., 1897. Philippson: Anatomische Untcrsuchungen uber Nierencysten. Vireh. Arch., Ill Bd., 1888. v. Recklinghausen: Ueber die Ranula, die Cyste der Bartholin 'schen Druse und die Flimmercyste der Leber. Vireh. Arch., 84 Bd., 1881. Richard: Geschwiilste der Kiemenspalten. Beitr. v. Bruns, iii., 1888. Sabourin: La degenerescence kystique du foie et des reins. Arch, de pliys.. x., 1882. Sasse : Cysten der Mamma. Arch. f. klin. Med., 54 Bd., 1897. Terburgh: Ueber Leber- und Nierencysten. Inaug.-Diss. v. Freiburg, Leiden, 1891. Torok : Entstehung der Atheromcysten. Monatsschr. f. prakt. Derm., iii. Virchow: IJic krankhal'ten Geschwi'ilste, i., Berlin, 1803. CHAPTER VI. Hypertrophy and Regeneration. Results of Tissue^ Transplantation. Metaplasia. I. General Considerations Concerning the Processes Known as Hypertrophy and Regeneration, and the Accompanying Cellular Changes. § 76. In a general sense, hypertrophy is an increase in the size of a tissue or organ, due either to an increase in the size or in the number of the in- dividual elements, in such a way that the structure of the hypertrophic tissue is like that of the nor- mal, or at least does not differ essentially from it. In a more limited sense hy- pertrophy is an increase in size due to an enlargement of the in- dividual elements alone; the en- largement due to an increase in the number of the individual ele- ments being designated as hy- perplasia.. Hypertrophy may result from morbid impulses inherent in the germinal cells, or from influences acting during the life of the individual. If an abnormal tissue-in- crease occurs during the period of embryonal development, or of extra-uterine growth, and if no influences are recognizable that would account for the in- creased growth, the condition may be explained as the result of a congenital predisposition, and may lie designated as a hypertrophy due to a con= genital anlage. If the en- largement affects the entire body, for example, if a newly born child weighs 5-8 kgm., or if an individual should reach the height of 180-200 cm., the condition is called a general giant growth. When the en- largement affects only individual parts of the body, as, for example, the entire head or one-half of it, or one extremity, or a finger, or the vulva it is called a partial giant growth. The giant growth of several parts of one side of the body is designated a half giant growth ; one involving 262 Elephantiasis femorum neuromatosa. HYPERTROPHY AND HYPERPLASIA. 203 all the body-parts is very rare. Hypertrophic growths of the skin and subcutaneous tissues, leading to a disfigurement suggesting the appear- ance of the skin of the pachyderniata, are known as elephantiasis (Figs. 130, 131). In hypertrophic growth of an ex- tremity or of a finger all the elements of the same are uniformly enlarged. In elephantiasis of the extremities the connective tissue of the skin and sub- cutaneous structures is especially likely to become increased; but the develop- ment and structure of these growths vary greatly. In one case all the con- nective-tissue elements may be uniform- ly increased, in another case only indi- vidual elements; as, for example, the connective tissue of the nerves, blood- or lymph-vessels ; or at least, the path- ological new-formation takes its start from these. It is therefore possible to distinguish different forms of elephan- tiasis according to the structure of the hypertrophic part: elephantiasis neuro- matosa, (Fig. 130), angiomatosa, lymphan- giectatica (Fig. 131), lipomatosa, fibrosa, etc. If, as a result of some peculiar pre- disposition of the skin, there occurs a hypertrophy of the horny layer of the epidermis (Fig. 132, c), so that the skin becomes covered with horny plates, scales, or even with spines, the condition is designated ichthyosis. -Elephantiasis cruris lymphan- giectatica. ',■-'.',->':'" •'.•".;''" i if Fir,. 134 — Cornu iutaneum, Fii from bark of hand. (Natural fr size.) 135.— Ci ran cutaneum, (Natural size.) TISSUE-HYPERTROPHIES OF CONGENITAL ORIGIN. 265 Next to the enlargements associated with general or partial giantism the bones most frequently undergo a form of hypertrophy corresponding to the cougenital elephantiasis of the skin. The head is usually affected, the bones of which may undergo a very marked enlargement (Fig. 137), leading to a deformity in which the patient's head comes to resemble that of a lion, hence the name leontiasis ossea. Further, there often develop upon the skull or other bones of the body circumscribed bony growths knowu as exostoses, which are inherited and not dependent upon extrin- sic influences. In the internal organs hypertrophic processes dependent purely upon intrinsic causes are rare; but the brain, for example, may reach an abnormal size. It cannot always be definitely stated to what extent hypertrophy of the tissues is to be attributed to a congenital predisposition, inas- much as many extrinsic influences are able to produce proliferations of tissue similar to those due to Fig. 130.— Head of a hairy individual, a woman. (Alter Hebra.) Fig. 137.- Leontiasis ossea. occurrinK in a boy af- fected with general giant-growth. (Observed by Hull] ) intrinsic causes. For example, cutaneous horns and elephantiasis-like thickenings of the skin may develop as the result of inflammation. In general, the early appearance of a hypertrophic growth, the hereditary nature of the pathological peculiarity, and the absence of any external etiological factor, speak for the congenital nature of the condi- tion. The fact that later influences may apparently cause the growth does not preclude the existence of a congenital predisposition. Thus the excessive bony growths of the head above mentioned may follow trauma or acute inflammations. External influences may therefore be the excit- ing cause of the proliferation, but not the primary cause of the same ; since we know by experience that the given injurious influences are able to produce such changes only in tissues possessing a special predisposi- tion. Not infrequently an abnormal tendency to excessive growth may show 260 THE PROGRESSIVE CHANGES. itself in a premature development of certain organs, the structure remaining normal. The external and internal sexual organs are most frequently affected. Girls, even in the first years of life, may show a development of breasts and external genitals and a growth of hair corresponding to that of the sexually ripe woman ; and menstruation may be established at this early period. The size of the entire body as well as of its separate parts and organs shows con- siderable variation within physiological limits, according to the race, family, and indi- vidual. The variation in the' relation of the size of single parts and organs to that of the entire body is less marked. The average height of the body in well-built individuals is. according to Vierordt ("Daten u. Tabellen flir Med.," Jena, 1893), as follows: Men 173 cm., women 100 cm. ; of the new-born, males 47. 4 cm., females 40.75 em. The average body-weight in Europe is for men about 05 kgm., that of women about 55 kgm., that of the new-born about 3,250 gm. The average weight of the internal organs is as follows, the figures in parentheses being for the new-born: Brain 1,397 (385) gm., heart 304 (24) gm., lungs 1,172 (58) gm., liver 1,012 (118) gm., spleen 201 (11.1) gm., right kidney 131, left kidney 150 gm., both kidneys 299 (23.0) gm., testicles 48 (0.8) gm., muscles 29,880 (625) gm., skeleton 11,560 (445) gm. Expressed in percentages of the body-weight the figures for adults and new- born are (the latter in parentheses): Heart 0.52(0.89), kidneys 0.48 (0.88). lungs 2.01 (2.16), stomach and intestines 2.34 (2.53), spleen 0.346 (0.41), liver 2.77 (4.30), brain 2.37 (14.34), adrenals 0.014 (0.31). thymus 0.0080 (0.54), skeleton 15.35 (10.17), muscles 43.09 (23.4). Literature. (Tissue- Hypertrophy of Congenital Origin.) Arnheim: Congen. halbseitige Hypertrophic. Virch. Arch., 154 Bd., 1898 (Lit.). Baas: Das Hornhauthorn. Gbl. f. allg. Path., viii., 1897. Bartels: Abnorme Behaarung. Zeit. f. Ethnol, viii., 1896; Affenmenschen, ib., xvi., 1884. Behrend: Hypertrichosis. Eulcuburg's Realcnoyklop., 1896 (Lit.). Brandt: Hundemenschen. Biol. Cbl., xvii., 1897. Bruns: Leber Rankenneurom. Virch. Arch., 50 Bd. ; Beitr. z. klin. Chir. , 1891. Busch.: Riesenwuchs der Extremitaten. Arch. f. klin. Chir., vii., 1860. Carbone: Ictiosi congenita. Arch, per le Se. Med., xv., 1892. Caspary: Ichthyosis congenita. Vierteljahrsschr. f. Derm., xiii., 1886. Chiari: Leber Hypertrichosis. Prag. mod. Woch., 1890. Demme: Halbs. Muskelhypertrophie. 27. Jahresber. d. Jenner'seheu Kinderspitals, Bern, 1890. Ecker: Leber abnorme Behaarung des Menschen, Braunschweig, 1878. Esmarch. u. Kulenkampff: Die elephantiastischen Formeii, Hamburg, 1885. Esoff: Ichthyosis. Virch. Arch., 69 Bd., 1877. Ewald: Hypertrophic der Hand. Virch. Arch., 50 Bd., 1872. Fischer: Riesenwuchs der Extremitaten. Deut. Zeitschr. f. Chir., xii., 1880. Friedrich.: Halbseitige congenitale Kopfhypcrtrophie. Virch. Arch., 28 Bd., 1863. Fuchs : Riesenwuchs bei Neugeb. (6100 und 7550 gm.). Munch, med. Woch., 1903. Hornstein : Halbseitiger Riesenwuchs. Virch. Arch., 133 Bd., 1893. Hu.rth.le u. Nauwerck : Fibroma mollusc, u. congen. Elephantiasis. Beitr. v. Zieg- ler, i., 1886. Jacobson : Lniverseller Riesenwuchs. Virch. Arch., 139 Bd., 1895. Jordan: Pathol. -anat. Beitr. ■/,. Elephantiasis congenita. Beitr. v. Ziegler, hi., 1890. Kiwull: Zur Casuistik der halbseiligen Gesichtshypertrophie. Fortschr. d Med viii. , 1890. Klein: Pubertas praecox. Deut. med. Woch., 1899. Kussmaul : Geschlechtliche Fruhreil'e. Wurzb. rued. Zeitschr., 1863. Lesser: Hypertrichosis anomalis. Z. f. klin. Med., 41 Bd., 1900. Mitwalsky: Hauthorner der Augenadnexa. Arch. f. Derm., 27 Bd., 1894. Nonne: Elephantiasis congenita hereditaria. Virch. Arch., 125 Bd., 1891. Poisson: Hyperostose diffuse des maxillaires superieures. Seni. med., 1890. Poumayrac: El. sur 1 'hypertrichosis, Bordeaux, 1893. v. Reckling-hausen : Die multiplen Fibrome der Haut, Berlin, 1882. Rona: Ichthyosis im Junglingsalter. Arch. f. Derm., xxi., 1889. Spietschka:' Leber Elephantiasis congenita. Arch. f. Derm., xxiii.. 1891. ACQUIRED HYPERTROPHY. 2G7 Trelat et Monod: I)e 1 'hypertrophie unilaterale. Arch. gen. de med., 1869. TJnna: Keratoma palmare et plant, congen. Vierteljalirssehr. f. Derm., x., 1883. Virchow: Handbucb. der spec. Pathol., i., 1854; Die krankhatten Geschwiilste, 1865. Wiedersheim : Der Bau des Menschen, Freiburg, 1893. § 77. The hypertrophies of the tissues due wholly to extrinsic influences without the aid of a congenital predisposition owe their origin either to an increase in the activity of the tissue, to diminished use, defective retrograde change, or finally to prolonged or frequently repeated mechanical, chemical, and infectious irritations of the tissues. Under certain conditions the removal of pressure may also give rise to a localized hypertrophy. Hypertrophy from overwork is most f recjuently observed in the case of muscles and glands, but may occur also in other tissues. If the heart is called upon to do an extra amount of work as the result of diseased con- 138.— Transverse section of a heart showing hypertrophy of the left ventricle, resulting from aortic stenosis and insufficiency, a. Left, h, the right ventricle. Reduced A. ditions of the valves, aorta, or kidneys, and if such conditions exist for some time, that part of the heart-muscle upon which the extra work falls suffers a more or less pronounced hypertrophy (Tig. 13S), so that as a result the mass of the heart may reach threefold that of the normal. In a similar manner the striated muscles, and the unstriped muscle of the bladder, ureters, uterus, intestine, and blood-vessels may become hypertrophic as the result of persistent increase in their activity. As the result of an increase of the supporting strain from whatever cause the bones may become thickened, and the bony trabecular of the medullary portion become increased iu size. Of the glands, the kidneys, and liver in particular are able to change their size according to the functional demands, and may consequently present a marked hypertrophy. Should one kidney be destroyed the remaining one may become so enlarged that it may reach approximately 268 THE PROGRESSIVE CHANGES. Fig. 139.— Hypertrophy of an incisor tooth of a white rat, tue result of an oblique position of the jaw. (Natural size.) the same weight that the two kidneys together originally possessed. Likewise the liver after a destruction of a part of its parenchyma through disease may make good its loss by a hypertrophy of the remain- ing tissue. Since in this way a compensation for the defect and a restoration of the normal function is brought about, such a tissue-increase may be ap- propriately designated compensatory hy= pertrophy. The same term may also be applied to muscle-hypertrophy, if through it functional disturbances are compensated. A similar compensatory hypertrophy is said to occur also in the case of adrenal tissue. In the case of other glands, such as the salivary glands, ovaries, testicles, and mam- mary glands, such a compensatory hyper- trophy either does not occur at all, or takes place only during the period of development. The loss of an ovary or testis in adult life can hardly result in an increased activity or hypertrophy of the remaining organ. Extirpation of the larger part of the thyroid gland is nut fol- lowed by any pronounced hypertrophy of the remaining portion; but, on the other hand, the hypophysis undergoes an enlargement which must be regarded as compensatory. In the case of the lungs, an increase in the activity of one portion after the loss of other parts re- sults usually in a permanent overdistention which may lead eventually to atrophy. On the other hand, if during embryonic life a de- fective development of one lung takes place, the other lung may undergo a compensatory growth, which in the case of total agenesia of one lung may reach a very pronounced degree. For the other organs the general principle may be applied that compensatory hypertro- phy is the more perfect the younger the indi- vidual. In the case of the brain a compen- satory growth of one part after the loss of another is possible only during the early stages of development . Hypertrophy from lessened use occurs in the case of tissues which are subjected to a constant use. Thus, for example, a dimin- ished desquamation of the horny layer of the epidermis leads to its pathological thickening. If, as the result of the destruction of an op- posing tooth or an oblique position of the teeth, the incisor teeth in rodents are not worn down by use, they may grow out into long and curved tusks (Fig. 139). Likewise the, finger- and toe-nails may reach an ab- normal siae either from lack of wear or from being left uncut. Hypertrophy due to de= fective retrograde change occurs in organs which period of physiological growth undergo a diminution 140.— Elepbatiasis scroti in a Samoan nineteen yearsof age. (Af- ter Utlieinann, Deutsche mat. Wo- clir., 1895.) Fig chens after a definite, in size. For ex- ACQUIRED HYPERTROPHY. 269 ample, the uterus after pregnancy may remain abnormally large as the result of a failure of involution. The thymus gland, which should begin to atrophy after the tenth year of life, may persist for a much longer period than normally. In bones whose configuration has been brought about under the influence of the surroundings by means of an alternation of build- ing-up and tearing-down, a lessening of pressure may be followed by hypertrophy. In idiots whose brains are deficient in size there is very often seen a hyperostosis of the inner surface of the base of the skull (Chiari). A unilateral hyperostosis of the skull is associated with a unilateral hypoplasia of the brain. Frequently repeated or long-protracted mechanic cal, thermal, chemical, or infectious irritations give rise to proliferative proc- esses leading to tissue-hy- pertrophies, which accord- ing to their etiology and course must be regarded as chronic inflammations; and such new-formations of tissue may therefore be regarded as an inflammatory tissue=hy= pertrophy. They are char- acterized very often by the fact that, in the enlargement of the organ, not all of its parts are equally involved in the hypertrophy ; but certain individual elements, usually the connective tissue, occasion- ally also the epithelium, undergo hyperti'oj)hy to an especial degree, so that the structure of the organ (skin, gland, etc.) is no lunger wholly typical. If the skin is frequently subjected to mechanical irritation and press- ure, as, for example, the toes through an ill-fitting boot, there may arise in consequence thickenings of the horny layer of the epidermis, known as callus or corn (claims). Prolonged irritation of the skin in the neigh- borhood of the genital openings, caused by gonorrhoea! discharges, may cause a marked elongation and branching of the papilla? with an accom- panying thickening of the epithelium, leading to the formation of the warty, cauliflower-like growths known as venereal warts or condylomata acuminata. Chronic inflammations of the corium and subcutaneous tis- sue, due to infection or to animal parasites (Filaria Bancrofti), not infre- quently give rise to extensive fibrous hypertrophies of the tissue known as elephantiasis (Fig. 140). Such elephantiasic hypertrophies of the tissue may attaiii extraordinary proportions. In a similar manner there may occur in the bones, as the result of chronic infectious processes (syphilis. FIG. 111. —Acromegaly, according to Erb arid Arnold, (osteo- arthropathy, according to Marie and Souza-Leite.) 270 THE PROGRESSIVE CHANGES. for example), extensive hypertrophies characterized by an increased formation of bone-substance. In the majority of cases of those tissue-hypertrophies which appear during the course of life as acquired formations caused by external influ- ences, the causa efficiens may be recoguized with more or less certainty; but there are also many cases in which, at the present time, this is either wholly impossible or possible only to a limited extent. For example, there occur enlargements of the spleen, and of the lymphadenoid tissue of the lymph-glands and of the lymph-nodes in the mucous membranes, which are of the nature of hypertrophies, whose causes we are unable to recog- nize. Very imperfect, also, is our knowledge concerning the etiology of the enlargements of the distal portions of the extremities (Fig. 141), resem- bling partial giant-growth, which have been described as acromegaly (Marie), pachyakria (von Becklinghausen ), and osteoarthropathie hyper- trophiante (Marie). In a part of these cases there are an associated en- largement of the bones of the face and deformities of the spinal column. These changes appear usually in youth or middle age, rarely iu old age, and show a gradual development. So far as anatomical investigations have been able to throw light upon this cpiestion, the pathological change consists in an increase of all the tissues of the terminal portions of the extremities and of the face, in particular of the bony parts, in that the bones become thicker (Fig. 142) and at the same time become the seat of rounded or pointed exostoses. On the other hand, an increase in the length of the bones has not yet been demonstrated with certainty in this disease (von Recklinghausen, Fig. 142.— Skeleton of the hand, with hypertrophic hones, from the case of acromegaly pictured In Fia 141 (After Arnold.) Arnold). The disease suggests those changes which are seen as the re- sult of certain intoxications or infections, for example, syphilis, but it is not possible at the present time to assign to it any definite cause. The cause and nature of these pathological phenomena are as yet obscure; and the tenns mentioned above are not. used by all authors with the same meaning. In Ger- many the designation acromegaly is applied to all forms of enlargement of the ends of ACQUIRED HYPERTROPHY. 271 the extremities which lead to a paw-shaped deformity of (he hands and a gigantesque appearance of the feet, while Marie, who first described these conditions, attempts tc draw a sharp line between acromegaly and osteoarthropathie hypertrophiante. He holds that in acromegaly the hands and feet are not deformed, but are symmetrically enlarged, the thickening and broadening diminishing toward the tips of the extremities, so that the terminal phalanges of the fingers and toes are but slightly thickened, while, on the other hand, in osteoarthropathie hypertrophiante the terminal phalanges are enlarged so as to resemble drumsticks, and the articular ends of the bones are irregularly thickened. In the first affection the lower jaw is lengthened, in the latter it is thick- ened. Marie believes that in many cases osteoarthropathie hypertrophiante is a sequela of inflammatory affections of the lung", and pleurae, and designates the con- dition accordingly as osteoarthropathie hypertrophiante pneumique, and holds that the connection between these processes is to be found in the taking up into the body- fluids of poisonous products from the inflammatory foci in the lungs, so that the affec- tion of the bones is to be regarded as an infectious toxic hypertrophic inflammation. By other authors the causes of acromegaly and osteoarthropathie hypertrophiante are to be sought in a congenital predisposition (Virchow), in disturbances of the sexual function (Fremiti), in a diseased condition of the hypophysis (Henrot, Klebs, Tamburini, von Hansemann, Benda, Stevens), in persistence of the thymus (Erb, Klebs), or in nervous influences (rem Recklinghausen); but none of these hypotheses is adequately supported by anatomical and clinical observations. The frequent association of acrome- galy w'ith tumors of the hypophysis of different kinds has been definitely determined, but the character of the tumors in some cases would indicate an increase of function, in other cases a diminution or loss of the same. Cagnetto is therefore of the opinion that a primary disturbance of metabolism underlies the condition of acromegaly, so that both the bones and the hypophysis are stimulated to hyperplastic proliferation. Although the investigations made up to the present time do not permit a positive conclusion as to the nature of these conditions, they show that they do not represent an excessive growth similar in nature to a partial giant growth, but are acquired diseased conditions, which develop either as independent diseases (acromegaly, pachyakria), or as sec- ondary phenomena in the course of other diseases (osteoarthropathie hypertrophiante pneumique). The cause of the nodular hypertrophy of the thyroid gland, occurring so fre- quently in many regions, is wholly unknown. Literature. (Compensatory Hypertrophy of Glands and of the Heart.) Beresowsky: Compensatorische Hypertrophic d. Schilddriise. Beitr. v. Ziegler, xii., 1892. Bizzozero: Accrescimento e rigenerazione nell' organismo. Arch. p. le 8c. Med., xviii., 1894. Bostrbm: Beitr. z. path. Anat. d. Niere, Freiburg, 1884. Bozzi: Untersuch. iiber die Schilddriise. Beitr. v. Ziegler, xviii., 1895. Eckhardt: Compensat. Hypertrophie der Nieren. Yirch. Arch., 114 Bd., 1888. Galeotti u. Villa-santa: Komp. Hypertrophie d. Niere. B. v. Ziegler, xxxi., 1902. Grawitzn. Israel: As above, ib., 77 Bd., 1879. Hodenpyl: Apparent Absence of the Spleen with General Compensatory Lymphatic Hyperplasia. Med. Rec, 1S98. Horwath: Die Hypertrophie des Herzens, AYien, 1897. Krahe: Comp. Hyp. d. Speicheldriisen. Inaug.-Diss., Bonn., 18S8. Leichtenstern: Comp. Nierenhypertrophie. Berl. klin. Woeh., 1881. Nothnagel: Ueber Anpassungen u. Ausgleichungen bei pathologischen Zustanden. Zeitschr. f. klin. Med., x., 18S5; xi., 1886; xv., 1888. Perl: Comp. Nierenhypertrophie. Virch. Arch., 56 Bd., 1872. Podwyssozky: Exp. Enters, lib. die Regeneration d. Driisengewebe. Beitr. v. Ziegler, i., 1SS6. Ponfick: Zur Pathologie der Leber. Virch. Arch., 118, 119, and 138 Bd., 1889-1894. v. Recklinghausen: "Pathologie des Kreislaufes u. d. Ernahrung, Stuttgart, 1887. Ribbert: Comp. Nierenhvpertrophie. Virch. Arch., 88 Bd.: Compens. Hypertr. d. Geschlechtsdriisen. Ib., 120 Bd., 1890; Compens. Hypertrophie u. Regen. Arch. f. Entwickelungsmeehan., i., 1894. Rogowitsch: Verand. d. Hypophyse nach Entfernung d. Schilddriise. Beitr. v. Ziegler, iv., 1889. 2/2 THE PROGRESSIVE CHANGES. Sacerdotti: Ipertrofia compens. dei reni. Arch, per le Sc. Med., xx.; Virch. Arch., 146 Bd., 1896. Se.lmch.ardt: Compensat. Hypertrophie d. rechten Lunge. Virch. Arch., 101 Bd., 188.5. Simmonis: Compensat. Hypertrophie d. Nebennieren. Virch. Arch., 153 Bd., 1S9S. Stieda: Verhalten d. Hypophyse nach Entfernung d. Schilddriise. Beitr. v. Ziegler, vii., 1890. Stilling: Compensat. Hypertrophie der Nebennieren. Virch. Arch., 118 Bd., 1899. Tangl: Ueb. c'.. Hypertrophie u. d. phys. Wachsthiun des Herzens. Virch. Arch., 116 Bd., 1883. Velisch: Compens. Hypertrophie d. Nebennieren. Virch. Arch., 154 Bd., 1898. Wollmann: Ein Fall von Agenesie der Lunge. Inaug.-Diss., Freiburg, 1891. Ziegler: Crsachen d. pathol. Gewebsneubildungen. Intern. Beitr., Festschr. f. Vir- chow, ii., 1891. Zielonko: Stud. lib. die Hypertrophie des Herzens. Virch. Arch., 62 Bd., 1865. (Acromer;:tly, Pachyakria, Osteoarthropathie Sypertrophiante, and Hyper- trophy of the Skull.) Arnold: Akromegalie, Paehyakrie oder Ostitis. Beitr. v. Ziegler, x., 1891; Beitr. zur Akromegaliefrage. Virch. Arch., 13.5 Bd., 1893. Bamberger: Knochenverand. bei chron. Lungen- u. Herzkrankh. Zeit. f. Id. Med., xviii., 1890. Benda: Akromegalie. D. med. V\'och., 1901. Brooks: Acromegaly. Archives of Neurology, New York, i., 1898. Cagnetto: Bez. zw. Akromegalie u. Hypophvsistumoren. Virch. Arch., 176 Bd., 1904. Chiari: Basale Schadelhyperostose bei Idioten. Verh. d. path. Ges., ii., Berlin, 1900. Erb: Leber Akromegalie. Dent. Arch. f. kl. Med., 42 Bd., 1888. Freund: Leber Akromegalie. Samml. klin. Vortr., Nos. 329-30, Leipzig, 1SS9. Friedreich: Hyperostose des gesammten Skeletes. Virch. Arch., 43 Bd., 1863. Fritsche u. Klebs: Ein Beitrag zur Pathologie des Riesenwuchses, Leipzig, 1884. Holsti: Akromegalie avec autopsie. Festkrift fr. Pathol. Anatom. Institutet Helsing- fors, 1890. Israel: Der AkromegaL Knauerauf. Virch. Arch., 164 Bd., 1901. Lefebvre: Des deformat. osteoarticulaires consee. a des mal. de 1'app. pleuropulmo- naire, Paris, 1891. Marie: iSur deux cas d'akromegalie, hypertrophie singuliere non congenitale des ex- tremites et cophalique. Rev. de med., vi., 1880; De l'osteoarthropathie hypertro- phiante pneumique. lb., x., 1890. Marie et Marinesco: Sur l'anatomie pathol. de l'akromegalie. Arch, de med. exp., iii., 1891. Minkowski: Leber einen Fall von Akromegalie. Berl. klin. Woch., 1887. Oestreich: Riesenwuchs und Zirbeldriisengeschwulst. Virch. Arch., 157 Bd.,1899. Bauzier: Osteoarthropathie hvpertrophiante d'origine pneumique. Rev. de med., xi.. 1891. v. Becklinghausen: Leber Akromegalie. Virch. Arch., 119 Bd., 1890. Schmidt; Akromegalie. Ergebn. d. allg. Path., v., 1900 (Lit.). Schtitte: Path. Anat. u. Aetiol. d. Akromegalie. Cbl. f. allg. Path., ix., 1898 (Lit.). Souza-Leite: De l'akromegalie, Paris, 1890. Spillmann et Haushalter: Osteoarthropathie hypertrophiante. Rev. de med., x. 1890. Sternberg: Die Akromegalie. Wien, 1897. Stevens: Case of Acute Acromegaly. Brit. Med. Journ., 1903. v. Strtimpell: Zur Pathologie d. Akromegalie. Deut. Zeit. f. Nervenheilk., xi., 1897. Thomson: Acromegaly with the Description of a Skeleton. Journ. of Anat., xxiv., 189'. Verstraeten: L'akromegalie. Rev. de med., ix., 1889. Virchow: Leber Akromegalie. Berl. klin. Woch. and Deut. med. Woch., 1889. § 78. Regeneration is tjaat process through which tissues which hare been destroyed are restored. Under especial conditions this restoration may REGENERATION AND REPAIR. 273 be brought about by an enlargement of existing parts of cells (regenera- tion of axis-cylinders'), but it is usually the result of new-formation of cells, which irise in all cases through the division of preexisting cells. Begeneration presupposes that the injured tissue is capable of pro- liferation, and is, moreover, a phenomenon which is in all cases depend- ent upon extrinsic causes. In the fully developed organism in which the different tissues and organs have reached their ultimate differentia- tion, each tissue can produce only new tissue of its own or a closely related kind. The specificity of the tissues is of so decided a nature that epi- thelial cells can never give rise to connective tissue, nor can the latter ever produce epithelium. Ectodermal cells cannot produce intestinal epithelium ; kidney epithelium can produce only cells having the charac- ter of kidney epithelium, but never liver-cells or those of mucous glands, or connective tissue. Muscle-tissue can arise only from muscle-cells. Nerves and neuroglia can never arise from connective tissue. Only cells which are very closely related to each other can arise from the same parent-tissue or pass into each other. Thus the connective tissue of the periosteum can produce either ordinary connective tissue, cartilage, or bone — that is, tissues which are closely related to each other, and which Fig. 143.— The skin-portion of a laparotomy wound sixteen days old (Miiller's fluid. Van Gieson's). (j, Epithelium, b, eorium; c, subcutaneous adipose tissue ; d, se.ar in eorium ; e, new epithelium: /, scar in adipose tissue. X 38. may be regarded as different modifications of the connective-tissue substance. In tissue defects in which only single cells are lost (as, for example, iu the loss of single"connective-tissue cells), or in the case of a more extensive destruction of cells without an interruption in the continuity of the connective 18 274 THE PROGRESSIVE CHANGES. tissue of the blood-vessels (as the loss of localized areas of the surface epi- thelium, or a group of gland cells or of pulmonary epithelium), a com- plete regeneration, a restitutio ad integrum, may take place, aud the tissue be restored to a condition corresponding in all respects to that existing before the injury. After all injuries in which the continuity of the 0.0./ r< Fig. 111. — Healing ulcer of the small intestine, with formation of new gland-tubes in the proliferating submucosa (Midler's fluid, hematoxylin), a, Mucosa; b, submucosa ; c, d, muscularis ; e, serosa ;/, re- mains of the flour of tue ulcer not yet covered over with epithelium ; {/, overhanging edge of the ulcer; 7t, portion of floor of ulcer covered with epithelium ; i, newly formed glands in the submucosa ; k, deep crypt lined with epithelium. < IS. mesodermal supporting tissue is broken, either with or without an associated injury to tissues of ento- and ectodermal origin, the regeneration is incomplete; in that, at the point of injury there is formed a tissue which departs more or less from the normal structure of the affected part, and shows a more or less marked loss of functional capacity as compared to the normal tissue. In general this tissue is a new formation of connective tissue, designated as a scar (Fig. 143, d) or cicatricial tissue, in individual organs (as in the heart-muscle) also called a callosity, the new connective tissue resembling other formations of connective tissue, but not wholly identical with them. In the course of time it comes through a gradual change more and more to resemble normal tissue. Defects of the skeleton are replaced by scar-tissue which arises from the periosteum and endosteum, and by virtue of the peculiar properties of these tissues there develops a new-formation of bone-tissue within such scars, the structure coming to resemble closely that of normal bone. In many cases the cicatricial tissue consists purely of vascularized, con- nective tissue (Fig. 143, d), which later becomes enriched only through the ingrowth of nerve-fibres and the gradual development of elastic fibres. Scars bordering upon ectodermal or entodermal tissue may become cov- ered by a new-formation of epithelium (Fig. 143, e). Occasionally the structure of cicatricial tissue may undergo a further development in that specific tissue formations either grow into it secondarily or are preserved in it as remains of preexisting structures. The first process occurs most frequently in scars of the mucous membrane of the intestine (Fig. 144), and of glands in the neighborhood of their excretory ducts, and in scars of muscle (Fig. 145). In defects of mucous membranes which are REGENERATION AND REPAIR. 275 j t jplaced by scars formed through the proliferation of connective tissue (Pig. 144, b, f ), the surface is first covered with epithelium (7/, h, Jc), later there develop epithelial in- growths which bear the character of tubular glands (i). Gland-ducts (bile-ducts, ducts of the salivary glands) may grow into the develop- ing scar-tissue, and. form new tubes or only solid cords of cells. Such a new-formation of gland-ducts may occur not only in the neigh- borhood of traumatic injuries, but also in the course of hematogenous inflammations of the glands in question. A new-formation of gland-tissue proper in the neighborhood of scars is, on the other hand, want- ing in the case of the majority of glands (liver, kidneys, testicles, ovaries, thyroid, mammary glands, and lungs). Only in the case of the salivary glands does the de- velopment of the newly formed ducts lead to the formation of gland-lobules. In muscle-scars (Fig. 145) new muscle-fibres (d) grow from the ends of the old ones (a), and pen- etrate into the scar-tissue, so that the scar becomes gradually re- placed by muscle. The preservation of remains of specific tissue-elements in the area of cicatrization may be observed in the case of both muscles and glands, especially in the periphery of traumatic injuries and anaemic necroses (Fig. 140), and in most cases also in infectious foci of dis- ease. The preserved gland-remains within the sear usually present an atrophic condition (Fig. 14f>, b), but islands of normal tissue (d ) may also be enclosed, and there arises the possibility that such may undergo a compensatory growth. In inflammatory processes in glandular organs which are char- acterized on the one hand by the destruction of the specific paren- chyma, and on the other by a new- formation of connective tissue having the character of scar-tissue, there are often seen in the diseased area new-formations of scar-tissue con- FIG. 145. —Scar of muscle and tendon, thirty-two days old (Flemming's solution, Van Gieson's). <(, old muscle; h, tendon; c, scar; d, newly formed muscle-fibres. X 100. 276 THE PROGRESSIVE CHANGES. taming atrophic remains of the gland-tissue, and between these, island^_ of uninjured gland-tissue in a condition of hypertrophy. u The mass of the scar is only rarely equal to the mass of the tissue . lost, and there persists after the loss of considerable amount of tissue a more or less marked tissue defect. Over circumscribed areas of the surface of the skin, mucous membranes, or of glands, the brain, etc., such a defect gives rise to a cicatricial depression. Numerous cicatricial defects in an organ may occasion an atrophy of the same characterized by an irregular configuration of the surface. The loss of the tissues en masse of larger portions of the body, as, for example, a toe or a toe-joint, is in man never again replaced. Such de- fects are only closed in by scar-tissue which on the superficial parts of the body becomes covered with surface epithelium. The regenerative capacity of tissues is in man and the mammals slight on the whole. This is dependent upon the fact that the individual tissues show a very high degree of differentiation, and that also in the event of proliferation they do not lose this differentiation to such an extent as to revert to so embryonal a state that, like the cells of the embryonal anlage, they are able to produce different forms of tissue. In spite of this limitation the regenerative powers of the tissues in general are sufficient to restore the continuity of the tissues and to preserve intact the external covering of the • \ : F) m .... ''".".v...... ... m^^S;mmmM m ■ a I : >.v-?---:i.:- a.- mmm&mm \, - m PIG. 146.— Peripheral zone of an embolic, sear (MUller's fluid, htematoxylin and . eositi). o, Scar show- ing: obliterated glomeruli, but no tubules ; /'.indurated tissue with atrophic tubules, the glomeruli being preserved ; c, normal cortical tissue ; c7, island of normal tubules in the sear. V 30. body. If, as the result of a local loss of tissue, the life of the organism be endangered through the inability of the local tissues to restore the lost part, there exists in the case of many organs and tissues (liver, kidneys) the power of compensating for such a loss through the growth of the remaining normal tissue. In the lower animals the power of tissue-regeneration is much greater than in the case of the mammals; and further is much greater in the earlier stages of ontogenesis, so that, in many animals (tritons, ascidians, echinoderms, teleosts), the first two or even the first four segmentation cells still possess the power of forming an entire embryo. Insects possess during the larval state a very marked power of regeneration, which later is lost. In the case of protozoa each animal may quickly supplement itself through divi- sion. In the case of the fresh-water polypi small fragments of the body may develop again into the entire animal. The angle-worm is able to replace either its tail or head end when these a-re cut off. The wood-louse can replace its feet and antenna', the snail REGENERATION AND REPAIR. 277 its tentacles and anterior extremity, crabs and crayfish their claws and legs. Salaman- ders are able to restore their legs, eyes, and tails, and lizards and slow-worms their tails, when these are broken off. In the case of frogs, snakes, and fishes, on the other hand, the power of regeneration diminishes as the scale of animal life is ascended, yet this does not happen equally in the case of all animals, and animals closely related to each other may show very different capacities for regeneration. Further, in the same animal the regenerative power is not the same in all organs; for example, in tritons the regenerative capacity of the internal organs is slight. Moreover, the power to form a new portion of the body, as a tail or extremity, for example, does not prove that all the tissues of the portion of the body in question possess an especial capacity for pro- liferation. In crayfish and crabs the regeneration of the claws and legs takes place only from certain places; in injuries occurring to other points, the new extremity is thrown off only at that place where a new-formation is possible. In tritons, fractures of the bones heal very slowly, although they are able to reproduce their extremities. § 79. The cause of the celNproliferation underlying all hyperplastic and regenerative new-formations of tissue varies according to the condi- tions tinder which the proliferation occurs. If the new tissue-growth leading to hypertrophy takes its origin from the anlage of the organism concerned or of a portion of the same, no new stimulus is necessary for its appearance; the attainment of the abnormal size is dependent only upon the condition that the new-formation of tissue does not lead to hindrances to growth, before the full limit of development is reached. When the proliferation appears first at a later period, something addi- tional is necessary to cause an increase of the normal tissue-formation or to start again into activity the cell-proliferation which becomes quiescent at the close of the period of growth. In the case of both hyperplastic and regenerative proliferation the "stimulus" may consist simply in the removal of hindrances to growth. Experience teaches that the majority of the cells of the body possess the power in a given case to divide, even those (connective-tissue cells, gland- cells, muscle-cells) in which the processes of cell-division wholly cease for long periods of time. This cessation of proliferation may be ex- plained by the assumption that the firm combination of the cells with each other and the formation of the intercellular cement inhibit further multiplication. It is also possible that chemical and unknown vital influences act in the same manner. Injuries and degenerations of the tissues of the most varied kinds can, through the loosening of the cells, and throtigh physical and chemical changes in the intercellular cement substance and of the tissue-fluids, cause such changes that all hindrances to the growth and division of cells are removed. In addition to the removal of hindrances to growth there may be present at the same time a formative stimulus, which increases both the reproductive capacity and the tendency toward reproduction. Further, such a stimulus may act independently — that is, without the removal of the influences inhibiting growth — and this event is to be assumed in those cases in which after the loss of a portion id' an organ the remaining portion (liver, kidney) undergoes a compensatory hyper- trophy. The stimuli which are able to excite growth and cell-division are known only in part. In those cases in which their action may be recog- nized they appear to be identical with the stimuli which excite or increase functional and nutritive activity. In the case of the muscles hypertrophy is brought about by increased contraction following nervous excitation. Liver and kidney tissue undergo proliferation when, as the result of a loss of a large area of gland-tissue, the remaining portions are obliged to 278 THE PROGRESSIVE CHANGES. do an increased amount of work — that is, they must out of the circulating blood produce and secrete those substances which, if life is to be preserved, must be given off either externally or within the body. Whether there exist still other formative stimuli cannot be said with certainty at the present time. An increased supply of blood and nutrition, which has been believed by many to act as a formative stimulus, is not in itself sufficient to excite a new-formation of cells and tissue; it gives rise only to an increased deposit of fat. The cells of the body are not fed, they feed themselves ; and an increase of nutrition depends upon the activity of the cells. An increase of the temperature of the tissues may hasten the process of cell-division and thereby further tissue-prolifera- tion ; but it is doubtful if it can directly excite proliferation in a resting- tissue. The local action of heat, which has been observed to be followed by proliferation (for example, in the skin), produces in the first place changes of a degenerative nature, so that the occurrence of proliferation may be also explained as due to the removal of influences inhibiting growth. Whether there are chemically active substances capable of exciting pro- liferation, besides those present normally in the body, cannot be decided at the present time. The fact that slight irritation of the skin (painting with iodine) can cause proliferation without preceding degenerative changes makes this appear probable. But it is more probable that, in spite of the negative findings, slight tissue-changes of a degenerative nature do occur, and that through these the inhibitory influences are weakened. Moreover, it must be noted that even the hypertrophy of muscles and glands following increased activity cannot be absolutely regarded as the direct result of a nervous or chemical stimulus, but rather must we assume that with the increased labor there is an excessive consumption of cell- elements which excites regenerative processes, the latter leading not only to a restoration of the parts lost, but also to an increased building-up of the cell-mass and formation of new cells. Literature. (Regeneration. ) Aschoff: Regeneration u. Transplantation. Ergebn. d. allg. Path., v., 1900. Bard: La specificite cellulaire. Arch, de phys., vii., 1886; Intern, med. Congr., Berlin, 1890; De l'induction vitale mi influence specifique a distance des elements cellulaires les nus sur les autres. Arch.de med. exp., 1890; La specificite cellu- laire, Paris, 1899. Barfurth: Zur Regeneration de.- Gewebe. Arch. 1. mikr. Anat., 37 Bd., 1891; Regen- eration d. Keimbliitter bei Aniphibien. Anat. Hefte, Wiesbaden, 1893; Regenera- tion u. Involution. Ergcbn. d. Anat., Wiesbaden, 1893-1900; Rogen. bei Wir- beltierembryonen. Handb. d. Entwickelungsl., iii., 1903. Beneke : Die TJrsachen der Thrombusorganisation. Beitr. v. Ziegler, vii. , 1S90. Bizzozero: Accroissement et regeneration dans 1'organisme. Arch. ital. de biol., xxl. 1894; Arch, per le Sc. Med., xviii., 1894; Influence de la temperature Arch ital' de biol, xxvi., 1896. Caporaso: Sulla rigeneraz. del midollo spinale della coda dei Tritoni. Beitr v Zieg- ler, v., 1889. s Carnot: Les regenerations d'organes, Paris, 1899. Carriers : Studien liber die Regeneration der Wirbelthiere, Wurzburg, 1880. Cattani: Ueber die Reaction der Gewebe auf sperifische Reize. Beitr. v. Ziegler vii 1890. Coen: Verandenmgen d. Haut nach Einwirkung von Jodtinctur. Beitr v Ziegler ii., 1887. " ' Cohnheim: Vorlesungen Uber allgemeine Pathologic, 1882. Colucci, F. : Intorno alia rigenerazione degli arti e della coda nei Tritoni, Bologna, 1885. Delage: La structure du protoplasme, Paris. 1895. REGENERATION AND REPAIR. 279 Demarquay : De la regeneration des organes et des tissus, Paris, 1874. Fraisse : Die Regeneration von Geweben u. Organen bei Wirbelthieren, Berlin, 1885. Gotte: Ueber Entwickelung u. Regen. des Gliedmaassenskelets der Molche, Leipzig, 1879. Gruber, A. : Beitrage zur Kenntniss der Physiologic und Biologic der Protozoen. Berichte der Naturf. Ges. zu Freiburg i. B.', 1886; Biol. Cbl., iv., 1886. Harrison: Regeneration of the Tail of the Frog Larva. Bull, of Johns Hopkins Hosp,, x., 1899. Hansemann: Studien liber die Specifieitilt, den Altruismus und die Anaplasie der Zellen, Berlin, 1893; Ueber die Specificitat der Zelltheilung. Arch. f. mikr. Anat., 43 Bd., 1894. Herbst: Formative Reize. Biol. Cbl., xv., 1895. Klaatsch: Stand der Keimblattfrage. Milnch. med. Woch., 1899. Kolliker: Die embrvonalen Keimblatter und die Gewebe. Zeitschr. f. wiss. Zool., 40 Bd., 1884; 42 lid., 1885. Lick: Einil. d. art. Ilyperamie auf die Reg. A. f. klin. Chir., 67 Bd., 19(12. Marchand: Bez. d. path. Anat. z. Entwiokelungsgeseb. Verb. d. Deut. path Ges ii., 1900. Martinotti: Ueber Hyperplasie u. Regeneration der driisigen Organe in Beziehung auf ihre Functionsfahigkeit. Cbl. f. allg. Path., i., 1890.' Merkel: Bcmerkungen iib. d. Gewebe beim Altern. Verb. d. X. intern, med Congr Berlin, 1891. Minot: Vererbung u. Verjiingung. Biol. Cbl., xv., 1895. Morgan: Earthworm Regenerating a Tail in Place of a Head. An. Anz., xv., 1899. Morpurgo: Sur les rapports de la regeneration cellulaire avec paralysie vaso-motrice. Arch. ital. de biol., xiii., 1890; Sulla neoproduzione degli element! cellulari di animali nutriti dopo un lungo digiuno. Arch, per le Sc. Med., xiv., 1H90; Ueber den physiol. Zellneubildungsprocess wiihrend der Inanition. Beitr. v. Ziegler iv., 1889. Pekelharing: Ueber Endothelwucherung in Arterien. Beitr. v. Ziegler, viii., 1890. Penzo: Influenza dclla temperatura nella rigenerazione. Arch, per le Sc. Med xvi 1892. Podwyssozki, Jun. : Regeneration der Drtisengewebe. Beitr. v. Ziegler, i ii , 1886-87. Rand: Regenerat. and Regulat. in Hydra viridis. Arch. f. Entwickelungsmeeh viii ix., 1899. v. Recklinghausen: Allg. Path. d. Kreislaufs u. d. Ernahnmg, 1883; Ueber Akro- megalie. Virch.. Arch., 119 Bd., 1890. Ribbert: Das patholog. Wachsthuni d. Gewebe, Bonn, 1896; Umbildungen. Virch Arch., 157 Bd., 1899. Roemer: Ueber den formativen Reiz der Proteine Buchner's. Berl. klin. Woch., 1891 • Chem. Reizbarkeit tbier. Zellen. Virch. Arch.. 128 Bd., 1892. Roux, W. : Der Kampf der Theile im Organismus, Leipzig, 1881 ; Ueber die Specifi- cation der Furchungszcllen und liber die bei der Postgeneration und Regeneration anzunehmenden Vorgange. Biol. Cbl., xiii., 1893. Samuel; Die Regeneration. Virch. Arch., 50 Bd. ; Die histogeuetische Energie und die Symmetric des Gewebswachsthums, ib., 101 Bd ; Das Gewebswachsthum bei Storungen d. Circulation, ib., 108 Bd. ; Gewebswachsthum bei Storung d. Inner- vation,^., 113 Bd. Schultz : Das Yeihalten d. Regen. z. Embiyoualentwickelung. Biol. Cbl., xxii., 1902. Sokoloff. Bedingungen d. Bindegewebsneubildung in doppelt unterbund. Gefassen. Beitr. v. Ziegler, xiv., 1893. Thoma: Ueber Gefass- und Bindegewebsneubildung in der Artericnwand. Virch. Arch., 93, 95, 102, 105, and 112 Bd. ; Beitr. v. Ziegler, xi., 1891. v. Wagner: Ueber d. Verhaltniss d. Ontogenese zur Regeneration Biol. Cbl., xiii., 1893. Weigert: Die Virchow'sche Entziindungstheorie. Fortschr. d. Med., vii., 1889; Zur pathol. Histol. des Neurogliafasergewebcs. Cbl. f. allg. Path., i., 1890; Neue Fragestellungen. Deut. med. Woch., 1896. Weismann: Das Keimplasma, 1892; Aeussere Einfliisse als Entwickelungsreize, Jena, 1894 ; Thatsachen u. Auslegungen in Bez. auf Regeneration. Anat. Anz. , x v. , 1899. Welch: Adaptation in Pathol. Processes. Am. Journ. of Med. Sc. , 1897. Wolff: Das Gesetz der Transformation der Knochen, Berlin, 1892. Ziegler: Die neuesten Arbeiten liber Vererbung u. Abstammungslehre. Beitr., iv., 1888; Die Ursachen der pathol. Gewebsneubildungen. Intern. Beitr., Festschr. f. Virchow, Berlin, 1891 ; Die Reparation der Gewebe nach Verletzungen. Deut. med. Woch., 1900. See also §§ 80-87. 2S0 THE PROGRESSIVE CHANGES. § 80. The division of the nucleus and cell=body, upon which process the formation of new tissue depends, may occur in the first place through holoschisis (Flemming), or direct segmentation (Arnold) — that is, through a transverse constriction of the elongated nucleus and proto- plasm without an increase or characteristic grouping or movement of the chromatin elements of the nucleus. It appears, however, that the direct division of the nucleus leads to a new-formation of tissue — that is, to the production of cells which are able to form new tissue — only when it is connected with that form of cell-division known as karyokinesis or mm \%a :S Fig. 147. FIG. 14X. Fn.' 14 Fig. 147. — Enlarged nucleus. Increase in the chromatin framework. Fig. 148.— Thick, open skein, with segmentation of the threads into chromosomes ; the nucleolus and nuclear membrane have disappeared. Fig. 149. — Grouping of the completed chromosomes into a star- or wreath-form. karyomitosis (Flemming) or as indirect segmentation (Arnold), which is characterized by an incrca.se of the nuclein or chromatin (Flemming), and a definite cycle of changes of form and 'movements on the part of the latter. Usually karyomitosis follows atypical course, as in the normal growth of tissue, but deviations from this are not infrequently seen in pathologi- cal new-formations. A resting necleus consists of an outer covering, the nuclear membrane, and the nuclear contents. The latter is composed of a colorless nuclear fluid and the nuclear substance. To the nuclear substance belong the nu- cleolus and scattered, granules and threads which often form a frameioork staining with nuclear stains. When the nucleus undergoes division, there usually occurs in the first place, an increase of the chromatin, and the chromatin framework becomes more distinct (Fig. 147). The nuclear substance then forms a close skein, which with the disappearance of the nuclear membrane and the nucleolus becomes changed into an open skein with thick threads (Fig. 148), wiiose individual components divide themselves into nuclear seg- ments (Ilertwig) or chromosomes (in man these number eighteen ) (Figs. 148, 149). These segments then group themselves in the equatorial plane of the nucleus with their angles directed toward the centre, forming, when viewed from the polar aspect, a wreath -like figure (Fig. 140), and later a star-like figure, lying in the equatorial plane, which has been desig- nated the mother-star (Figs. 150, 151), or the equatorial plate (Flem- ming). Sooner or later two poles become visible in the so-called polar field that is, Iwo extremely small spherules, which are known as the polar or central corpuscles or the centrosomes. At first, these lie closely together, KARYOKINESIS. 281 but later separate from each other and act as centres about which the nuclear elements group themselves. Between these there is formed the nuclear spindle (Figs- 152, 153) which consists of fine threads which do not stain with nuclear stains, and converge in the polar corpuscles. In M -7, rife Fig. 15o. & gm Fig. 153. Fig. 154. Fig. 15 Fig. 150.— Completely developed mother-star ; polar view. Fig. 151.— Mother -star ; equatorial view. Fig. 152.— Stage of metakinesis. Single loops visible, their angles pointed toward the pole ; delicate spindle-figure within the nucleus. Fig. 153.— "Daughter-star ; side view (nucleus barrel-shaped); spindle-figure in the nucleus and the radial arrangement of protoplasm are visible. Fig. 154.— Daughter-stars separated ; the upper one presenting polar aspect, the lower one a side view. Fig. 155.— Daughter-skein with fine threads (above), and with lattice-work (below). Completed di- vision of the protoplasm. the neighborhood of the polar corpuscles themselves the granules of the protoplasm present a radial arrangement, giving rise to figures (Fig. 153) which are known as ray-figures, stars, or attraction-spheres. In the following stage of division of the nucleus, a movement takes place among the chromosomes leading to the formation of loops, whose angles are directed toward the pole. Later the loops divide in halves which, follow- ing the direction of the spindle-fibres, move toward the poles and form two stai'S (Figs. 152-151) which are known as daughter-stars. From the star-figures the daughter-star passes successively through the thick-skein and then the fine-skein stage (Fig. 155, upper part) which finally changes into the nuclear framework (Fig. 155, lower part). During the later stages of the process of division a new nuclear membrane is formed. In the stages of the segmented skein, or later as may be seen in the 2S2 THE PROGRESSIVE CHANGES. large nucleated cells of cold-blooded animals, there occurs a longitudinal splitting of the chromosomes (Fig. 156). In the change of position of the chromosomes known as metdkinesis the halves of the split threads sepa- FIG. 158. Fig. 156. — Mother-star, with chromosomes split longitudinally. (After Rabl). Fig. 157.— Metakinesis. The halves o* the chromosomes are separating from each other ami turning toward The poles. (After Rabl.) rate from each other (Fig. 157) so that each daughter-star receives half of the substance of each chromosome. The division of the cell=protoplasm usually takes place at the time the daughter-star changes into the ordinary nuclear condition, and con- sists in a constriction and separation of the protoplasm (Fig. 155). It is probable that a complicated interrelationship exists between the nucleus and cell-protoplasm ; but the nucleus is to lie regarded as tlie more highly organized substance, as the centre of cellular potentiality. The nuclei are also the bearers of heredity, while the protoplasm governs the relations of the cell with the outer world. Variations from the typical karyokinesis may consist in the first place in the occurrence of a pluripolar division in place of the bipolar, so that two to six or more nuclear spindles and a correspondingly increased number of equatorial plates (Fig. 158, a) maybe formed. Further, in place of the simple mother-star there may be formed a complicated figure out of the chromatin loops, from which several daughter-stars may be evolved. Not infrecjuently there occur asymmetrical, divisions of the nucleus (Fig. 158, 6, c), par- ticularly in tumors, but occasionally also in regenerative or inflammatory new-for- mations of tissue. There also not infrequently occur divisions of the nucleus which are char- acterized by abnormal size, abnormal rich- ness in chromatin, and manifold variations of form. As types of such division are the large oval or bean-shaped (Fig. 159), knobbed or convoluted, lobulated and branched (Fig. 160), wreath-shaped, linked, basket-shaped (Fig. 161), and otherwise-shaped nuclei. Finally, there are occasionally found in the cells more or less extensive, indis- tinctly-outlined heap's of granular and lumpy chromatin (Fig. 162). Fig. 158. ', C, asymt -n. Pluripolar division-figure ; letrical division-figures. ATYPICAL CELL-DIVISION. 283 Such nuclear forms, with the exception of the polynuclear leucocytes, are found particularly in the cells of the bone-marrow, spleen, and lymph-glands, and also in tumors which arise from the bone-marrow or periosteum, but have been also observed elsewhere, particularly in sar- comata. Certain of these forms are appearances due to contraction, and have nothing to do with cell-division. In other cases these changes of size and form precede a division of the nucleus through constriction of certain portions, this process occurring sometimes with, sometimes with- out an increase of the chromatin -substance. Arnold has designated the division by constriction with increase of the chromatin as indirect frag- mentation, that without such increase as direct fragmentation. Indirect fragmentation differs from mitosis or indirect segmentation in the lack Fig. 159. Fig. 160. Fig. 161. Fig. 159. — Cell with oval, slightly knobbed giant-nucleus, rich in chromatin. Fig. 160.— Cell with tabulated giant-nucleus. Fig. 102.— Cell with large masses of chromatin. Beitriirju von Ziegler, VII.) Fig. 161. — Cell with basket-shaped giant-nucleus. All these cells from a sarcoma of hone. {Stroebe. of an orderly arrangement of the chromatin in threads and in the irregu- larity with which the separation of portions of the chromatin results in new nuclei. Variations in the division of the cell-protoplasm occur most fre- quently, either in a total failure of the protoplasm to divide after the divi- sion of the nucleus lias taken place, or in the delayed division after that of the nucleus. These phenomena are ob- served in both mito- tic and amitotic divis- ion of the nucleus, and lead to the for- mation of multinu- clear giant = cells (Fig. 103), which are designated as plas- modial giant-cells. Cells of the spleen and bone-marrow and of tumors arising from the bones show this phenomenon with especial frequency. Proliferating fat-cells likewise often form rajc*,^.*^.^.. Fig. 163.— Proliferating adipose tissue from the subcutaneous pannic- nlus, twenty-six days after cauterization with trichloracetic acid (forma- lin, hematoxylin), a, Multinuclear fat-cells; b, proliferating connec- tive tissue. X 300. 284 THE PROGRESSIVE CHANGES. rnultinuclear giant-cells (Fig. 163, a). Besides this form of rnultinuclear: giant-cell there also occur those formed by the confluence of cells, which are known as syncytial giant=cells. (Compare also the sections on Inflammation and Tuberculosis. ) The significance of the nuclear corpuscles (nucleoli) is still a matter of dispute. Flemming and Pfitzner believe that they are different from the nuclear framework, while others regard them as much-thickened nodal points of the fibrils of the frame- work. In what way they are again formed after the division of the nucleus is not known . The spindle-figure, whose fibres stain but slightly with nuclear stains, is derived, according to Flemming and Hertwig, from the achromatic substance of the nuclear framework, while Strasburger believes that it arises from the cell-protoplasm. The centrosomes or polar corpuscles, which are always present in nuclear segmenta- tion, are found also in resting-nuclei; but, up to the present time they have been demon- strated only in a part of the cells, most frequently in lymphocytes and the giant-cells of the bone-marrow. At the same time the investigations of von Kblliker, Flemming, M. Heidenliain, Boveri, and others make it probable that the centrosomes are present in all cells, lying sometimes in the nucleus, sometimes in the protoplasm, where on account of their small size they can be demonstrated only with difficulty. (The cen- trosomes do not stain with the ordinary nuclear stains, but with acid aniline dyes, as acid fuchsin, safranin, ; nd with iron-hsematoxyl'n.) Whether they are elements of the protoplasm or of the nucleus has not yet been decided. According to van Bene- den, Boveri, and Rabl, the mitosis of the nuclear substance is to be referred to a direct dra wing-apart, starting from the divided centrosomes and brought about by the agency of the achromatic fibres. According to M. Heidenhain, the central corpuscles are sharply circumscribed granules which possess the power of assimilation, of growth, and of multi- plication by budding, whereby they are accustomed to form groups. Either alone or united in groups, they can form the central point of insertion of a system of con- tractile fibres (spindle-figures, microsome rays), and consist of a specific substance (in a chemical sense) which is not present elsewhere in the cell. Literature. (Cells mill Cell-division.) Arnold: Kerne u. Kerntheilungen in den Zellen des Knochenmarkes. Virch. Arch., 93 Bd., 1SS3; Ueber Kern- und Zelltheilungen lei acuter Hyperplasie der Lymph- driisen und der Milz. lb., 95 Bd., 1884; Theilungsvorgange an den Knoehenmark- zellen. lb., 97 Bd., 1884; Ueber Kerntheilung und vielkernige Zellen Ib.,9SBd., 1884; Theilungsvorgange an de:i Wanderzellen. Arch. f. mikr. Anat., xxx., 1SS7; Kern-u. Zelltheilungen in der Milz. Ib.,xxxi., 1888; Structur und Architektur der Zellen. lb., hi., 189S; Flemming und die M it osenleh re. Anat. Anz., xvi., 1899. Bardeleben: Karyokinese. Eulenburg's encyklop. Jahrb., i., 1891. Bizzozero: Ueb. die Regeneration. Cbl. f. d. med. Wiss., 1886 (Lit.). Bonnet: Syncytien, Plasmodien u. Symplasma in der Placenta. Mon. f. Gebh., 1903. Boveri: Ze'llenstudien I— II, 1887-88; Das Problem d. Befruchtung, Jena, 1902. Burger: Was sind die Attraktionspharen? Anat. Anz., vii., 1892. Cornil: Multiplication des cellules de la moelle des os. Arch, de phys., x., 1SSS. Demarbaix: Division et degene>escence des cellules geantes. La Cellule, v., 18S9. Denys : La cytodierese des cellules geantes et des petites cell, incolores de la moelle des os. La Cellule, 1885; Division des cell, geantes de la moelle des os d'apres les tra- vauxde Arnold, Werner, L6 wit et Cornil. Anat. Anz., iii., 1888; La Cellule v. 1889. Eberth: Virch. Arch., G7 Bd.; Kern- und Zelltheilung wahrend der Entzvindunf u. Regeneration. Internat. Beitr., Festschr. f. Virchow, ii., Berlin, 1891 . Fischer: Eixirung, Farbung und Bau des Protoplasmas, Jena, 1899. Flemming, W. : Kerntheilung. Arch. f. mikr. Anat., xvi., 1879: xviii., 1880" xx. 1882; xxiv., 1884; Virch. Arch., 77 Bd.; Zellsubstanz, Kern- und Zelltheilung' Leipzig, 1S82; Ueber Zelltheilung. Verh. d. anat. Gesellsch., Munchen. 1891; Beitrage zur Kenntniss der Zelle. Arch. f. mikr. Anal., xxix., 1887; Theilune u! Kernformen bei Leukocyten. lb., xxxvii., 1891 ; Aniitotische Theilung ini Blasen- epithel des .Salamanders. lb., xxxiv., 1890; Attraktionsphare u Zentralkorper Anat. Anz., 1891. Frenzel: Zur Bedeutung der amitotischen Kerntheilung. Biol. Cbl.. \i., 1891 Fuerst: Verand. d. Epith. durch Warme u. Kalte (Riesenzellen (lurch directe Kern- theilung). Beitr. v. Ziegler, xxiv., 1898. HYPERPLASIA AND REGENERATION. 2S5 Galeotti: Chromatin in den Epithelzellen der Carcinome. Beitr. v. Ziegler, xiv., 1893- Erzeugung von Unregelmassigkeiten d. karyokinet. Processe. lb., 1893; xx.', 1896' Gruber, A.: Biologie der Infusorien. Ber. d. Naturf. Gesellsch. zu Freiburg,' 1886 ; Einflusslosigkeit des Kerns auf Bewegung, Ernahrung u. Wachsthum einzelliger Thiere. Biol. Cbl., iii., 1883; Zeitschr. f. wiss. Zool., xxxviii., 1883. Hacker: Autonomie d. vaterl. u. mutterl. Kernsubstanz. Anat. Anz., xx., 1902. Hansemann: Ueber asymmetrische Zelltheilung in Epithelkrebsen u. deren biologi- sche Bedeutung. Virch. Arch., 119 Bd., 1890; Ueber pathol. Mitosen. lb., 123 Bd., 1891; Stud. tib. d. Specifitat, d. Altruisnms u. d. Anaplasie der Zellen, Ber- lin, 1893. Heidenhain, M.: Zentralkorper. Arch. f. mikr. An., 43 Bd.. 1894. Hertwig, O.: Bildung, Befruchtung, u. Theilung d. thier. Eies. Morph. Jahrb., i., 1875; iii., 1877; iv., 1878; Ei- u. Samenbildung bei Nematoden. Arch. f. mikr. Anat., xxxvi., 1890; Die Zelle und die Gewebe, Jena, 1893. Hess: Ueber Vermehrungs- u. Zerfallsvorgange an den grossen Zellen in der acut hyperplastischen Milz der Maus. Beitr. v] Ziegler, viii., 1890. Klemensiewicz: Mitose u. Amitose. Beitr. v. Ziegler, xxxiii., 1902. Kolliker: Handb. d. Gewebelehre, Leipzig, 1889. Krafft: Histogenese des Callus. Beitr. v. Ziegler, i., Jena, 1886. Krompecher: Die Mehrtheilung. Cbl. f. allg." Path., v., 1894; Die mehrfache Kern- theilung, Wiesbaden, 1895; Mitosen mehrkerniger Zellen. Virch. Arch., 142 Bd., 1S95: Zelltheilung. C. f. a. P., 1902. Lowit: Neubildung u. Zerfall weisser Blutkorperchen. Sitzber. d. K. Akad. d. Wiss. in Wien, 92 Bd., 1885; Neubildung u. Beschaffenheit d. weissen Blutkorperchen. Beitr. v. Ziegler, x., 1891; Amitotische Kerntheilung. Biol. Cbl., xi., 1891; Cbl. f. allg. Path., i., 1890. Meves: Ueber eine Art der Entstehung ringformiger Kerne, Kiel, 1893. Nauwerck u. Steudel: Regeneration d. quergestreiften Musculatur. Beitr. v. Zieg- ler, ii., 1888. Nedjelsky: Amitotische Theil. in path. Neubild. Beitr. v. Ziegler, xxvii., 1900. Pfeffer: Bedeutung der Amitose. Ber. d. K. Sachs. Ges. d. Wiss. z. Leipzig, 1899. Pfltzner: Arch. f. mikr. Anat., xxii., 1883; Morph. Jahrb., xi., 1885. Podwyssozky: Regeneration d. Driisengewebe. Beitr. v. Ziegler, i., ii., 1886-88. Rabl: Ueber Zelltheilung. Morph. Jahrb., x., 18S5; Anat. Anz., 1888, 1889. Reinke: Untersuchungen uber das Verhaltniss der von Arnold beschriebenen Kern- formen zur Mitose und Amitose. Inaug.-Diss., Kiel, 1891. Retzius, G.: Studien iiber die Zelltheilung, Stockholm, 1881. Roux, W. : Ueber die Bedeutung der Kerntheilungsfiguren, 1883. Schlatter: Stand der Zellenlehre. Biol. Cbl., xix., 1889. Schottlander: Ueber Kerntheilungsvorgange in dem Endothel der artificiell entziin- deten Hornhaut. Arch. f. mikr. Anat., xxxi., 1888. Schwarz: Zur Theorie der Kerntheilung. Virch. Arch., 124 Bd.. 1894. Strasburg-er : Zellbildung u. Zelltheilung, Jena, 1890; Ueber den Theilungsvorcang der Zellkerne u. d. Verhaltniss der Kerntheilung zur Zelltheilung. Arch. f. mikr. Anat., xxi., 1882; Die Controversen d. indirecten Kerntheilung. lb., xxiii., 1884; Das Protoplasma u. die Reizbarkeit, Jena, 1891. Stroebe: Kerntheilung u. Riesenzellenbildung in Geschwulsten u. im Knochenmark. Beitr. v. Ziegler, vii., 1890; Cellulare Vorgange u. Erscheinungen in Geschwulsten. Hi., xi., 1891; Vorkommen und Bedeutung der asymmetrischen Kaiyokinesen. lb., xiv., 1893. Verworn : Die physiolog. Bedeutung des Zcllkerns. Pnilger's Arch., 51 Bd., 1892. Waldeyer: Ueber Karyokinese. Deut. med. Woch., 1886, 1887. Weismann: Das Keimplasma, Jena, 1892. Wilson: The Cell in Development and Inheritance, New York, 1897. Zander: Ueber d. gegenwiirt. Stand der Lehre v. d. Zelltheilung. Biol. Cbl.. xii., 1892. Ziegler, H. E.: Biologische Bedeutung der amitotischen Kerntheilung. Biol. Cbl, xi.. 1891. II. The Processes of Hyperplasia and Regeneration in the Various Tissues. § 81. The morphological changes in the regeneration and hyperplasia of epithelium are relatively simple. The karyomitoses (Fig. 164, a-d) show for the chief part a typical course. The division of the protoplasm takes place either in the later stages of the process of nuclear division or 286 THE PROGRESSIVE CHANGES. follows after the same. Giant-cells may arise through failure of the protoplasm to divide. Epithelium arises only from epithelium, and, moreover, the different varieties of epithelium do not pass over into one another. It is to be noted, however, that under certain conditions — for example, in cases of inflammatory irritation of long standing — the regen- erating epithelium may change its character, so that pavement epithelium may occasionally be de- veloped in places which originally possessed strat- ified ciliated columnar epithelium. This may occur, for example, in the case of cicatrization of ulcers in the trachea. De- fects of ciliated columnar epithelium are in the first place repaired by low col- umnar or flat cells which later become changed into high columnar cells. Small losses of substance in the superficial epithelium are usually quickly replaced through regenerative growth of the neighboring cells (Fig. 165, (/, d v d,). In such cases it may be seen that the epithelium bordering upon the defect quickly pushes over the denuded surface and begins to proliferate. The division of the nucleus and cell-protoplasm takes place not only on the edge of the defect, but also at some distance from it. In the intestine the loss of the superficial epithelium is quickly made good by a proliferation of the epithelial cells situated in the deep parts of the crypts of Lieberkuhn. Likewise glandular epithelium — for example, in the liver or kidneys — is quickly restored after loss, pro- vided the structure of the tissue — that is, of the basement membrane Fie. 164. —Regenerative proliferation of tlie epithelium of bile-duets, in the neighborhood of a wound of the liver rive days old (Flemmlng's solution, safranin). a. Enlarged nueJeus of epi- thelial cell, with increase of chromatin ; /<, epithelial cell with mother-skein; c, epithelial cell with mother-star; J, epithelial cell with daughter-skein ; f, connective-tissue cell with daughter- star. X 400. 4 J" a b c Fig. l«r,.— Healing of blister caused by a burn (alcobo cat's paw, forty-eight hours after the production of a bliste. . (1, newly formed epithelium ; . upon which it rests — is not changed. After destruction of liver-tissue both liver-cells aud the epithelium of the bile-ducts (Fig. Kq.) prolif- REGENERATION OF EPITHELIUM. 287 erate, and the cell -division attendant upon an injury to the liver may extend to a relatively great distance from the wound. Experimental wounds of the liver heal through the formation of connective tissue, into which only offshoots of the bile-ducts penetrate, while a local reproduc- tion of liver-tissue does not take place. Likewise, in the kidneys, testi- cles, thyroid, and ovary the local production of glandular tissue in the connective-tissue scar is very slight or wholly wanting, and does not lead to the formation of functionating tissue. In the salivary and mu- cous glands, on the other hand, there occurs a branching of the gland- ducts, and a new -formation of glandular alveoli. When portions of the mucosa and submucosa of the intestine are lost as a result of ulcerative processes, there occurs during the process of healing a glandular rjroliferation, which, according to the nature of the defect, forms partly typical, partly atypical (Fig. 144, i) glands which grow into the submucosa. The new gland-formation takes its start from the old glands, whose epithelium pushes over the edge and base of the ulcer (Fig. 14 1, g, h) and also lines any depressions which may happen to be present (Jc). In a similar manner ulcerative defects of the stomach mucosa are again made good; and even extensive ulcers may become covered over with a gland-containing mucosa, although the glands do not for the most part show a typical devehyprnent — that is, are not trans- formed into characteristic gastric glands. The epithelial portions of the uterine mucosa which are in part lost, as a physiological process, during menstruation and parturition, and are afterward replaced, may be restored in a similar manner in the healing of pathological defects of the endometrium. The new-formation of epi- thelium takes its origin from the glandular remains. Compensatory hypertrophy of a kidney or liver, as the result of the loss of kidney- or liver-tissue, is brought about through the formation of new gland-cells, and the enlargement of existing renal tubules, or liver-rods respectively . After extirpation of one kidney the beginnings of compen- satory hypertrophy are recognizable even on the third day, by the ap- pearance of division figures in the epithelium of the urinary tubules; and there then follows a further proliferation, continuing for some time, of the epithelium of the uriniferous tubules and glomeruli as well as of the cells of the vessel-walls, as a result of which all the parts become enlarged. In the liver the lobules are enlarged, but no new-formation of these occurs. Literature. {New-formation of Epithelium and Gland- Tissue.) Adler: Helle (junge) Zellen in der Leber. B. v. Ziegler, xxxv. ,1902. Arnold: Epithelregeneration . Virch. Arch., 46 Bd., 1869. Ascoli: Formaz. della mucosa gastria. A. per le So. Med., xxv., 1901. Barbacci: Rigeneraz. flsiol. degli dementi epiteliali. Arch, per le Sc. Med., xiii., 1889. v. Bardeleben • Die Ileilung der Epidermis. Virch. Arch., 163 Bd., 1901. Bizzozero: Regen. d. Drusenzellen. Virch. Arch., 110 'Bd. ; Arch, per le Sc. Med., xi 1H87; Die sehlauehfOrmigen Drlisen d. Magendarmkanals. Arch. f. mikr. An'at., 32 Bd., 1893. Bockendahl : Regen. v. Flimmerepithel. Arch. f. mikr. Anat,, xxiv., 1885. Bossi Reprod. de la muqueuse de l'uterus. Arch. ital. de Biol., xxiv., 1895. Coen: Veriinderungen der Haut nach der Eimvirkung von Jodtinctur. Beitr. v. Zieg- ler ii. ; Znr Anatomie der Milchdruse. lb., ii., 1887. Coen e D'Ajutolo: Sulle alterazioni istologiche dei reni, dei muscoli, dello stomaco, degli intestini e del fegato nel avvelenamento cronico di piombo. Beitr. v. Ziegler, iii.T 1888. 2SS THE PROGRESSIVE CHANGES. Corn.il et Carnot : Regen. cicatricielle des conduits muqueux. Arch, de med. exp., x., 1898; Keg. des cavites muqueuses. lb., xi., 1899; Cicatrisat. des plaies du foie. Sern. rued., 1898. Fuckel: Regen. d. Submaxillar- u. Infraorbitaldriisen. Inaug. Diss., Freiburg, 1896. Flemrning: Regen. v. geschicht, Plattenepithel, Darmepithel u. Flimraerepithel des Eileiters, Follikelepithel des Ovarium. Arch. f. mikr. Anat., xviii., xxiii., xxiv., 1880-85. Golgi, C. : Neoformazione dell' epitelio dei canalicoli orinif eri. Arch, per le Sc. Med., vi., 1881; Arch. ital. de Biol., ii., 1882. Griffini: Gontribut. alia patol. del tessuto epitel. cilindr., Torino, 1884; Arch. ital. de Biol., v., 1882; Sulla riproduzione parziale del testicolo. Arch, per le Sc. Med., xi., 1887; Sulla riproduzione degliorgani gustatori. Rendicouti dell' Istituto Lorn- bardo, 1887. GrirE.mii. Vassale: Ueber d. Reproduction d. Magenschleimhaut. Beitr. v. Ziegler, iii., 1888. Hochhaus: Gewebsver&nderungen nach Kalteeinwirkung. Virch, Arch., 154 Bd., 1898. Jatta: Rigen. dell' epitelio del rene. Arch, per le Se. Med., xxi., 1897. Jung: Reg. d. Uterussekleimhaut nach Verletzung. Cbl. f. Gyn., 1897. Kahn: Etude sur la regeneration du foie, Paris, 1897. Karg: Studien liber transplantirte Haut. Arch. f. Anat. u. Phys., 1888. Mall: Healing of Intestinal Sutures. Johns Hopkins Hosp. Rep., i., 1887. Mayzel : Theiluug der Kerne in Epithelzellen. Cbl. f. d. med. Wiss. , 1875. v. Meister : Recreation des Leber*; ewebes. Beitr. v. Ziegler, xv., 1894. Morpurgo : Zellneubildung wfthrend , osteoblast with division-ngure; c, two cells shortly after division, showing thread-skein iu nucleus; d, blood-vessel with proliferating endothelium; c, endothelial cell with nuclear division-figure ; /, large lymphocytes; g, small lymphocytes. X 350. division-figures. Besides mitoses, direct division of the nuclei also takes place. Wheu only a few cells are destroyed in the event of an injury to the tissue newly formed cells replace those destroyed without the occurrence of any marked structural changes in the tissues. If, on the other hand, under pathological conditions, a considerable amount of new tissue is produced within a short time, the proliferating cells form an embryonic tissue consisting essentially of cells, blood-vessels, and a somewhat fibril- lated ground-substance (Fig. 168). The extent of such formation nat- urally varies greatly and is dependent partly upon the capacity of the tissue for proliferation, and partly upon the lesion leading to the prolif- eration. Proliferating cells are always larger than the cells of fully developed and resting connective tissue which are relatively poor in protoplasm. They contain large, bladder-like nuclei with nucleoli, and for the greater part only one or two nuclei (Figs. 168, 169), though multinuelear cells (Fig. 1 00, cj, the so-called giant-ceUs, also occur. In association with the 292 THE PROGRESSIVE CHANGES. enlarged tissue-cells there are always found after a more marked tissue lesion exudative cells arising from the blood-ves^ Is (Figs. 168, g, f, and 169, «, a , ) which take no part in the formation of the new tissue (see § 95). Since all these cells are the antecedents of the future tissue they are designated as formative cells, those giving rise to fibrous connective Kiu. lt>9.~ Isolated fells from a granulating woi leucocytes; ?>, different forms of mononuclear flbr nuclear formative colls; d, Ubroblasts in stage of ueetive tissue. X 5UU. Lymphocyte ; >, endosteum containing no fat; c, scattered osteoblasts ; ,/). The osteoblasts come to lie iu irregular spaces furnished with processes (Figs. 3 74, o; 175, 6), and are then usually known as bone-corpuscles. In extensive development of cellular embryonic tissue Fig. 174.— Formation of osteoid trabecule from the proliferating periosteum. Preparation from a fourteen-dav old fracture (Miiller's fluid, picric acid, hajmatoxylin, carmine), a, Flhres belonging to the outer periosteum ; li, embryonic tissue ; c, osteoid tissue ; (/.cartilage: c, uune-marrow. ;- "5. ;e into bone is limited to certain parts of the tissue, so that tissue trabecular (Fig. 174, c) are formed, which, the chang within the embryonic ,so long as they do not undergo full development into bone and do not NEW-FORMATION OF THE CONNECTIVE TISSUES. 295 become calcified, are called osteoid trabecule. The embryonic tissue (b) lying between becomes changed into marrow=tissue by the cells be- coming united to each other through processes, while between them there appears a fluid basement-substance, in which round-cells later appear embedded. If only a little bone-tissue is to be formed and deposited upon old bony trabecular, the osteoblasts (Fig. 175, c) arrange themselves upon the surface of the latter, and these later on produce bone (b) in the manner described above, which appears as a new bony lamella. Fibrillated connective tissue, bone, and cartilage are closely related to each oilier and one may, therefore, be fey-u. ffl*«i^®aiB& easily transformed into the other (see §88). 'f!^m'^' < &^^mm' Mucous tissue arises from embryonic t>(^ : , ■yp5;',' : tij S . - '^s-*: . -5|jq* tissue through the formation of a mucin - ^""/^: ^^^r*^ containing, homogeneous, gelatinous base- fc^° -3---— :— -~^--. — j : ^S | ment -substance between the cells which at "iE^BSSE "-"— l.^f-^ESjE-EEil' 1 ' least in part become united through proc- gpf^^p- ■- ^^p^^—TT^^i esses to form a network. ggs^g- ^-^-?-.-— -»^W- -^■sfe,-.^ Lymphadenoid tissue can develop fig. 175. -Formation of bone, through from embryonic tissue through the for- aeposits made by osteoblasts upon the sur- J . . ° „ face of old bone (Mttiier's fluid, picric acid, mat ion of a supporting reticulum lrom a hematoxylin, carmine), a, Old bone; (1, f f +h ncMa while. lt-Tn-nhnrJ-trt as crafhe-r newly formed bone ; c, osteoblasts. X2C0. part 01 tlie Cells, Willie lympUOCJ tes g.ltliei in the meshes of this network, the spaces of which contain lymph. In injured lymph-glands, the cells of the retic- ulum proliferate and form ordinary fibrous tissue ; a reticular develop- ment of this connective tissue into lymphadenoid connective tissue either does not take place at all or but to a very slight degree. Spleen-tissue is not formed anew after injury to this organ; the wound heals through ordinary cicatrization. Compensatory hypertrophy does not take place after the removal of large portions of the organ. Fat=tissue arises through the taking up of fat into the cells of em- bryonic tissue, mucous tissue or fibrous connective tissue, the cells be- coming changed into fat-cells through the confluence of the fat-droplets which they take up. The basement=substance of the tissues described above is a product of the protoplasm of the formative cells. Whether in its formation portions of the cell-protoplasm are changed directly into intercellular substance, or whether they secrete the latter, or separate it from the in- tercellular fluid, is often a difficult question to answer; but it is probable that only the first two methods of formation occur. Fibrillar connective tissue can develop from any of the connective tissues possess- ing the power of proliferation, but there must first be formed an intermediate stage of embryonic tissue. Bone arises chiefly from the periosteum, perichondrium, and endosteum, but may also develop from other connective-tissue substances, as, for example, from the intermuscular connective tissue and from the connective tissue of the blood-vessels. Cartilage arises chiefly from proliferating perichondrium, periosteum, endosteum, and cartilage itself; but may also be developed from other connective tissues, as, for example, in the connective tissue of the testicle and parotid. The cartilage-cells near a lesion may under certain circumstances proliferate and form a large-celled embryonic tissue, but this does not reach any great size. In the proliferation of cartilage-cells within cartilage the cell-multiplication and new-formation of cartilage occur in the same way as in the physiological proliferation of this tissue. Very often the newly formed cartilage is only a transitory tissue, and is soon transformed again into bone and mar- row-tissue, or into connective tissue. New lymphadenoid tissue may, under pathological conditions, arise either from lymphadenoid tissue or fat-tissue (Bayer) or from fibrillated connective tissue. It is formed from the latter most frequently in the connective tissue of the mucosa and sub- 296 THE PROGRESSIVE CHANGES. mucosa of the intestinal tract, as well as in the glandular organs; rarely in the inter- muscular connective tissue. New haemolymph-nodes are formed in adipose tissue after splenectomy (W arlhin) . Mucous tissue may develop from any proliferating connective-tissue substance, but rarely appears in large masses, and is usually a transitory form passing over either into fat or connective tissue. Fat-tissue develops particularly in those regions normally containing fat, but oc- curs also at times in other places, for example, in the reticular connective tissue of atrophic lymph-glands, in the perimysium internum of atrophic muscles, etc. The close relationship of the connective-tissue substances to each other enables the different forms to pass from one to another without the need of an intermediate stage of embryonic tissue produced by proliferation. Further details in regard to this point are contained in § 88. Literature. ( New-formatio7i of Connective-tissue and Elastic Fibres.) Bernheim: Entw. d. elast. Fasern in d. Lunge. Jahrb. d. Hamburger Krankenanst., vii., 1902. Borst: Heilungsvorgange nach Sehnenplastik. B. v. Ziegler, xxxiv.. 1903. Busse: Heilung asept. Wunden derHaut. Virch. Arch., 134Bd., 1893. Drnitrij eff: Verand. d. elastischen Gewebes b. Arteriosklerose. Beitr. v. Ziegler, xxii., 1897. Fischer: Exper. Unters. iib. d. Heilung von Schnittwimden d. Haut. Inaug.-Diss., Tubingen, 1888. Flemming: Histogenese d. Bindesubstanzen. Handb. d. Entwickehmgsl., hi., 1902. Gardner: Histogenese d. elastischen Gewebes. Biol. Cbl., xvii., 1897. Graser: Feinere Vorgange bei Verwachsung peritonealer Blatter. Zeit. f. Chir. , xxvii., 1S8S. Grohe: Bedeutung d. elast. Fasern. Munch, med. Woch., 1901. Hamilton: On the Presence of New Elastic Fibres in Tumors. Trans. Chicago Path. Soc, 1900. Hansen: Genese einiger Bindegewebegrundsubstanzen. Anat. Anz., xvi., 1899. Homen: Regeneration der fixen Hornhautzellen. Fortschr. d. Med., i., 1883. Jores: Neubildung elast. Fasern. Beitr. v. Ziegler, xxiv., 1898; xxvii., 1900. Kromayer: Regen. d. elast. Fasern in Hautnarben. Monatsh. f. Derm., xix., 1895. Levi: Einfl. v. Zug auf d. Bildung faser. Gew. A. f. Entwickelungsmech., xviii., 1904. Lwoff: Entwickelung d. Fibrillen des Bindegewebes. Wiener Sitzber., 98 Bd., 1889. Mall: Developm. of the Connective Tissues. J. of Anat., L, 1902. Maximow: Entztindl. Neubild. v. Bindegewebe. B. v. Ziegler, Suppl. v., 1902. Melnikow: Unters. lib. d. elastischen Gewebe. Beitr. v. Ziegler, xxvi., 1S99. Merkel: Histogenese d. Bindegewebes. Verh. d. anat. Gesellsch., v., 1S96. Minervini: Ausbildung der Narben. Virch. Arch., 175 Bd., 1904. Neumann: Entwickelung d. Bindegewebes in pleuritischen Schwarten. Arch. d. Heilk., 1809. NikiforofT: Bau u. Entwickelung des Granulationsgewebes. Beitr. v. Ziegler, viii 1890. Oliver: Elastic Tissue in Cirrhosis of the Liver. Trans. Chicago Path. Soc, 1902. Passarge u. Krosing: Regen. d. elast. Gew. d. Haut. Derm. Stud. v. Unna, xviii 1894. Pearce: The Increase of Elastic Tissue in the Lung in Chronic Congestion. Jour of Med. Res., 1901. Podwyssozki: Regeneration der Driisengewebe. Beitr. v. Ziegler, i., ii., 1886-87. Poljakoff: Anat. d. Bindegewebes. Arch. f. mikr. Anat., 45 Bd., 1895. Ranvier: Mecanisme de la cicatrisat. Lab. d'histol. du College de France, 1900. Schaffer: Grundsubstanz, Intercellularsubstanz. An. Anz., xix., 1901. Schiffmann: Histogenese d. elast. Fasern. C. f. a. P., xiv., 1903. Seggel: Heilung von Sehnenwunden. Beitr. v. Brims, 37 Bd., 1902. Spuler: Histogenese der Bindesubstanz. Anat. Hefte, xxi., Wiesbaden, 1896. Teuffel: Entw. elast, Fasern in d. Lunge. Arch. f. Anat., 1902. Yamagiva: Zellenstudien an sich regenerirendem Sehnengewebe. Virch. Arch., 135 Bd., 1894. Zachariades: Tissu conjonct, Lab. d'histol. du College de France, 1900. Ziegler: Untersuch. ubeir pathol. Bindegewebs- u. Gefassneubildung, Wurzburg, 1876, See also Inflammatory New-formations of Tissue. NEW-FORMATION OF ERYTHROCYTES. 297 (New-formation of Cartilage.) Bardeleben: Knorpel. Eulenburg's Realencyklop., 1S96. Ewetzky: Entziindungsversuche am Knorpel. Arb. a. d. pathol. Instit. in Zurich, in., Leipzig, 1875. Gies: Heilung v. Knorpelwunden. Deut. Zeitse.hr. f. Chir., xviii., 1882. Kassowitz: Die normale Ossification, etc., Wien, 1881. Lel'as: Reparat. du cartilage articulaire. A. de med. exp., 1902. Matsurka:^Regen. des Knorpelgewebes. Virch. Arch.. 175 Bd.. 1904. Peyrand: Etudes exper. sur la regen. des tissus cartilagineux et osseux, 1S69. Schaffer: Bau u. Entwickl. d. Knorpelgewebes. Z. f. wiss. Zool., 70 Bd., 1901. Schleicher: (Knorpelzelltheilung.) Arch. f. mikr. Anat., xvi. Schottelius: Die Kehlkopfknorpel, Wiesbaden, 1879. Sieveking-: Wachsthum u. Regen. d. Knorpels. Morph. Arbeiten v. Schwalbe, ii., 1891. Solg-er: Ueber Knorpehvachsthum. Fortschr. d. Med., vii., 1889. Spuler: Bau u. Entstehung d. elast.'Knorpels. Inaug.-Diss. , Erlangen, 1895 (Lit.). Srdinko: Histologic u. Histogenese d. Knorpel. An. Anz., xxii., 1903. (New -form at ion of Bone.) Barth: Knochenimplantation. Beitr. v. Ziegler, xvii., 1895. Bonome: Knochenregeneration. Virch. Arch., 100 Bd., 1885. Bruns: Die Lehre v. d. Knochenbrtichen. Deut. Chir., Lief. 27, Stuttgart, 1886. Kassowitz: Die normale Ossification, etc., Wien, 1881, 1882. Kolliker: Die normale Resorption des Knochengewebes, Leipzig, 1892; Gewebelehre, 1889. Krafft: Zur Histogenese des periostal. Callus. Beitr. v. Ziegler, i., 1S86. Sacerdotti: Heteroplast. Knochenneubildung. Virch. Arch., 168 Bd., 1902. Troja: Experiences sur la regeneration des os, Paris, 1890. Wolff: Enters, lib. d. Entwickelung d. Knochengewebes, Leipzig, 1874; Virch. Arch., 101 Bd., 1885. Ziegler: Proliferation, Metaplasie u. Resorption d. Knochengewebes. Virch. Arch., 73 Bd., 1878. See also Pathological Anatomy of the Bones. (Formation of Lymphadenoid Tissue and Spleen-tissue. ) Bayer: Regeneration u. Neubildung der Lymphdrusen. Prager Zeitschr. f. Heilk., vi., 1885; ITeber kranke Lymphdrusen. Langenbeck's Arch., 49 Bd., 1895. Ceresole: Regeneration de la rate. Beitr. v. Ziegler, xvii., 1895. Czermak: Entwickelung d. Lymphknotchen d. Darmwand. Arch. f. mikr. Anat., 42 Bd., 1893. Galland: The Development of Lymphatic Glands. Jour, of Path., ii., London, 1894. Hitter: Heilung nach Rese,kt. v. Lyniphdriisengewebe. Verh. d. D. path. Ges., vii., 1904. Laudenbach: Totale Milzregeneration. Virch. Arch., 141 Bd., 1895. RTbbert: Regeneration u. Entzundung der Lymphdrusen. Beitr. v. Ziegler, vi., 1889. Saxer: Entwickelung d. Lymphdrusen. Anat. Hefte, Wiesbaden, 1S96. Stohr: Die Entwickelung des adenoiden Gewebes. Anat. Anz., vi., 1891; Entwick- elung der Darmlymphknotchen. Arch. f. mikr. Anat., 41 Bd., 1898. Warthin: The Changes Produced in the Ha>molymph Nodes of the Sheep by Splenec- tomy. Jour, of lied. Res., 1902; The Relation of the Ha?molymph Nodes to Adi- pose Tissue. Trans. Phil. Path. Soc, 1903. Zehnder: Ueber regenerative Neubildung der Lymphdrusen. Virch. Arch., 120 Bd., 1890. S 84. The new-formation of the red blood-cells or erythrocytes oc curs through the mitotic division of nucleated young forms of red cells known as erythroblasts (Bizzozero, Neumann, Flemming). In the adult this new-formation is restricted to the bone-marrow, and this is true 298 THE PROGRESSIVE CHANGES. also df other mammals, birds, reptiles, and tailless amphibians, while in the tailed amphibians and in fishes the spleen also takes part in the proc- ess. In embryonic life the new-formation and increase of the red blood- cell takes place throughout the entire vascular system, but later it be- comes restricted to the spleen, liver, and bone-marrow, and finally to the last alone. The entrance of the red blood-cell into the circulation takes place after the loss of its nucleus. In the increased new-formation of red blood-cells following- a loss of blood, as well as in severe chronic amemias and leukaemia, nucleated red blood-cells may appear in the circulating blood outside of the bone- marrow. The fatty marrow may thereby take on again in part the character of the splenoid marrow, this change being accomplished by the dilatation and congestion of the blood-vessels with an increase in the colorless and red cells of the marrow, while the fat present in the sup- porting reticulum disappears. The new=formation of the colorless cells of the blood and lymph grouped together under the broad term leucocytes occurs essentially in the lymphoid tissue of the lymph-glands, mucous membranes, spleen, thymus, and bone-marrow; but leucocytes within the blood- and lymph-vessels and tissue-spaces outside of these organs may also divide, and well-defined foci of prolif- eration may thus be formed. The mono- nuclear cells, known as lymphocytes, develop chiefly in the first-named regions, and numerous karyomitoses (Fig. 176) are con- stantly found in the so-called germinal centres. The polymorphonuclear; or polynu- clear leucocytes and the eosinophile cells, on the other hand, are formed in the bone-mar- row. Whether the large cells with clear nuclei known as mononuclear leucocytes, and the transition forms with horseshoe-shaped nuclei developing from the latter, are also formed in the bone-marrow is doubtful. They can also be regarded as more fully- developed lymphocytes. A pathological increase of the colorless cells ( leucocythaemia) may take place through an increased emigration iif cells from the formative tissues without an actual increase in cell- production. A long-continued persistence of such an efflux presupposes an increased production also. A transitory leucoeytlueniia is designated leucocytosis, while a perma- nent one is called leukaemia. The former is characterized by an increase in the neutrophile polynuclear leucocytes, rarely by increase in the lymphocytes. Two forms of leukaemia are distinguished: a lymphcemia in which the lymphocytes are increased, and a myelwmia or myeloid leuJcmmia, characterized by the appearance in the blood of myelocytes, mono- nuclear cells with neutrophile granulation arising in the bone-marrow. (See Pathology of the Blood.) The polynuclear leucocytes escaping from the circulatory system show no progressive changes. The mononuclear cells of the blood may, on the contrary, appear in various forms known as epithelioid cells, plasma-cells ~ & M J?. Fig. 17G.--Seetion from the germi- nal centreof a mesenteric gland (after K lemming). <(, Large, /t, small lymphocytes; c, Karyomitoses; d, di- rect nuciear division or nuclear frag- mentation : e, cells containing near the nucleus "tangible bodies" and small yellowpignientgrauules, whose significance is unknown. ;■; 41)0. NEW-FORMATION OF BLOOD-CELLS. 299 Idasmatocyies, and mast-cells. With reference to their power to give rise to different forms of cells they may be designated as polyblasts (Maxi- niow). (See also chapter on the Inflammatory New-formation of Tissue. ) According to Neumann, the young forms of the red blood-cells multiply in the lymphoid marrow. Bizzozero and Denys hold that this new-formation takes place normally only within the marrow-vessels, and the new-formation of the red blood-cells is completed within the same. The change of the nucleated cells into non-nucleated ones is brought about, according to many writers, through a disappearance of the nucleus. According to Rindjieisch, Howell, Malassez, and Maximow, the nucleus is extruded. According to Maximow, there maybe distinguished in the protoplasm of erythroblasts possessing old pyknotic nuclei a granular area surrounding the. nucleus and a homo- geneous peripheral substance. After the extrusion of the nucleus the inner granular substance, which stains with neutral red and other dyes, is at first preserved, but vanishes with the ripening of the capsule. According to Bizzozero, the young forms of the red blood-cells are cells of an individ- ual type that are always haemoglobin-containing and have no colorless ancestors. Denys, Lbwit, Howell, and Pappenheim, on the contrary, hold that they arise from nucleated haemoglobin-free, colorless cells (basophile leucocytes, Pappenheim) believed by Denys to increase within the marrow-vessels; while Lbwit thinks that the colorless antecedents of the red cells, which divide by mitosis and which he calls erythroblasts, occur in the lymph-glands and spleen as well as in the marrow, and lie both within the vessels and in the meshes of the reticular tissue. Flemming, who agrees with Bizzozero concerning the haemoglobin-content of the nucleated young forms of red cells, is inclined to assume that the young forms present in later life are the direct descendants of the young forms of the embryonic period. Neumann holds that this hypothesis is not sufficient to explain all the phenomena of later life; as, for example, the replacement of the fatty marrow which contains no nucleated red cells by blood-forming lymphoid marrow, and the formation of red blood- cells in such newly-developed marrow. He finds himself forced to the conclusion that either a development of the nucleated red cells takes place from the leucocytes of the blood which after birth are carried to the marrow through the arteries, or that they arise from the tissue-elements of the bone-marrow. Petrone believes that the red blood-cells of the mammals are only apparently non- nucleated, and that it is possible by means of especial methods of fixation and staining to render the nucleus visible. This invisible nuclear substance is iron-containing and shows an affinity for acid stains, while the nucleus of the erythroblasts stains with basic dyes. Literature. (New-formation of Blood-cells. ) Arnold: Theilungsvorgange an Wanderzellen. Arch. f. niikr. Anat., 30 Bd., 1887; Knochenmarkzellen. Virch. Arch., 144 Bd., 1896. Askanazy; Extrauterine Blutbildung in d. Leber. Verh. d. D. path. Ges., vii., 1904. Bizzozero: Bau d. Knochenmarks bei Vogeln. Arch. f. mikr. Anat., 35 Bd., 1890; Arch. ital. de Biol., xiv., 1890. Blumenthal: Rech. sur la genese des cellules sanguines, Bruxelles, 1904. Dekhuysen: Mitosen in frei im Bindegewebe gelegenen Leukocyten. Anat. Anz., vi., 1891. Denys: La structure de la moelle des os. La Cellule, iv., 1S87; La genese du sang des oiseaux. lb., iv., 1888. Dominici: Origine des polynucleaires. Arch, de m6d. exp., 1902. Drews: Zellvermehrung in der Tonsilla palatina. Arch. f. mikr. Anal., 24 Bd., 1885. Eberth. Ueber die Vermehrung der roten Blutkorper. Fortschr. d. Med., hi., 1885. Ehrlich u. Tazarus: Die Aniimie, i.. Wien, 1898. Engel: Ein Leitfaden zur klin. Untersuchung d. Blutes, Berlin, 1902. Feuerstack: Entwickelung der r. Blutkorperchen. Zeitschr. f. wiss. Zool, xxxviii., 18S3 Flemming-- Zellvermehrung in Lvmphdrusen, Theilungsarten der Leukocyten. Arch. f. mikr. Anat., 24 Bd., 1885; Theilung u. Kernformen bei Leukocyten. lb., 37 Bd., 1891 Havem: Du sang et de ses alterations organiques, Pans, 1889. Heinz- Blutdegeneration u. Regeneration. Beitr. v. Ziegler. xxix., 1901 ; I ebergang kemhaltiger r. Blutkorp. in kernlose. V. A., 168 Bd., 1902. 300 THE PROGRESSIVE CHANGES. Israel u. Pappenheim: Entkemung d. Erythroblasten. Virch. Arch.. 143 Bd., 1S96. Jolly: Diff. types de glob, blanes. " Lab. d'hist. du Coll. de France. 1900. Levaditi: Contrib. a t'etude des Mastzellen, Paris, 1902. v. Limbeck: Klin. Pathologie des Blutes, Jena. 1S96. Lowit: Neubildung u. Zerfall weisser Blutkorperchen. Sitzber. d. K. Akad. d. Wiss. in Wien, 92 Bd., 1885; Anat. Anz.. i.. 1886; Neubildung u. Beschaffenheit d. weissen Blutkorperchen. Beitr. v. Ziegler, x., 1891; Die Anordnung \'on Leuko- blasten u. Erythroblasten in d. Blutzellen bildenden Organen. Anat. Anz., vi., 1891; Arch. f."mikr. Anat.. 38 Bd.. 1891. Malassez: Gaz. med. de Paris 1874 and 1S78; Arch, de phys., ix., 1882. Maurel: Rech. experimentales sur les leucocytes, Paris, 1891. Maximow : Struktur u. Entkemung d. r. Blutkorp. A. f. Anat., 1S99. Mbbius: Zellvermehrung in der Milz. Arch. f. mikr. Anat.. 24 Bd.. 188.5. Mondino: Sulla genesi degli elementi del sangue. Palermo, 18SS; A. ital. de Biol., xii., 1889. Mosso: Umwandlung d. roten Blutkorperchen in Leukocyten. Virch. Arch.. 109 Bd., 1S87. Miiller: Zur Frage der Blutbildung. Wien. Sitzber., 1889: Zur Leukumiefnige. Deut. Arch. f. klin. Med., 48 Bd., 1891; Mitose an eosinophilen Zellen. Arch. f. exp. Path., 29 Bd., 1891. Negri: Persistenz des Kernes v. Blutkorp. Anat. Anz., xvi.. 189!). Neumann: Bed. d. Knochenmarks ftir die Blutbildung. Centralbl. f. d. med. Wiss., 186S; Arch. d. Heilk., x., 1869; Entwickelung roter Blutkorperchen imneugebild. Knochenmark. V. A., 119 Bd., 1890; Blutbildung b. Froschen. lb., 143 Bd., 1S96. Oppel: Die Entstehung der rothen u. weissen Blutkorperchen. Cbl. f. allg. Path., 1892 (Lit.). Pappenheim: Entwickelung d. Erythroblasten. Virch. Arch., 14.5 Bd., 1896 (Lit.); Entstehung d. roten Blutzellen.' lb.. 1.31 Bd., 1898; Bez. d. farblosen Blutkor- perchen zu einander. Virch. Arch.. 160 Bd., 1900. Paulsen: Zellvermehrung in Lymphdriisen u. Tonsillen. Arch. f. mikr. Anat., 24 Bd., 1SS5. Petrone: Sur le sang. Resume des travaux publ. A. ital. de Biol., xxxvi.. 1901. Rindfleisch. : Knochenmark u. Blutbildung. Arch. f. mikr. Anat. xvii.. 1879. Roemer: Formativcr Reiz der Proteine Buchner's auf Leukocyten. Berl. klin. Woch., 1891. Sanfelice: Genese des corp. rouges dans la moelle des os. Arch. ital. de Biol., xiii., 1890. Saxer: Abstammung d. weissen u. rothen Blutkorper von primaren Wanderzellen. Cbl. f. allg. Pathol, vii.. 1896. Schedel: Zellvermehrung in der Thymus. Arch. f. mikr. Anat.. 24 Bd.. 1883. Schmidt: Ceber Blutzellenbildung in Leber u. M. B. v. Ziegler, xi.. 1S92. Spuler: Ueb. d. intracellulare Entstehung roter Blutkorper. A. f. mikr. An., 40 Bd., 1892. Timofejewsky : Regenerat. d. r. Blutkorperchen. Cbl. f. allg. Path., vi., 189.5. Trachetti: Glob, rossi ed emoglobina nelle anemie sperim. Arch, per le Sc. med. 1896. Zenoni: Entstehung versch. Leukocytenformen. Beitr. v. Ziegler, xvi., 1S94. § 85. The new=formation of transversely striated muscle=fibres takes its start from portions of old muscle-fibres; and although, after injury to a muscle, the intermuscular connective tissue may lie excited to active proliferation, there is formed in consequence only connective tissue, or probably also the sarcolemma of new fibres, but never new contractile substance. The first signs of a formative activity if the muscle-fibres after injury appear in the muscle-nuclei, in that these become elongated and then divide into a varying number of fragments. Even on the second day there may occur mitotic division (Fig. 177, a, l>) of the muscle nuclei. This form of division seems to lie the only way in which multiplication takes place, and under favorable conditions it occurs very actively after the second day. The behavior of the contractile substance of the muscle differs very markedly according to the nature and extent of the injury. In the case KEGEXERATION OF MUSCLE. 301 of traumatic, toxic, and anaemic injuries it suffers a fragmentation into larger and smaller portions, so that the muscle-cells come to lie in spaces of varying size between the detritus of the muscle-fibres. Crushing and tearing can bring about a wide separation of the parts of the contractile substance. The ends of the pieces of muscle-fibres, in such a case, may be couical, oblique, transverse, or torn in an irregular edge, but not infre- quently after a short time the ends become split into two or more pointed filaments (Fig. 177. a). The mitotic division of the muscle-nucleus takes place, not only in nuclei that rest upon living fibres (a), but also in the muscle-cells lying free iu the spaces between the separated muscle-fibres (/>) ; and in both places leads to the production of large multinuclear cells, which form multinuclear protoplasmic masses on the ends of the muscle-fibres (e, /) as well as on the body of the fibres (c). Into these masses the trans- Fig. 177.— Portions of muscle-fibres showing regenerative proliferation, from muscle-wounds of dif- ferent ages (Fleinming's, safranim. a. Pointed enfls of the split stump of a muscle-fibre, with nuclear divi- sion-tigures, three days after laceration of the muscle ; b, proliferated muscle-nuclei transformed into cells rich in protoplasm, one of which is in process of mitotic division ; c, piece of a muscle-fibre eight days after tying the muscle ; m tfte posterior columns of a case of , Mallory's method), a, Glia-cells with ongttudinal section; />, sclerotic tissue REGENERATION OF NERVES. 305 Schwann undergo mitotic division and form cells rich in protoplasm, which may take up into themselves the products of the destruction of the nerve-fibres. Of the proximal portion of the nerve the peripheral extremity alone degenerates, as far as the next Eanvier's node, or the next one beyond. The regeneration of the nerves begins a few days after the operation, in the proximal portion, about 0.4-2 cm. above the cut end. The first change consists in a swelling of individual axis-cylinders in the peripheral parts of the nerve- bundle of the proximal end, which is later followed by a splitting- off of two to five or more new axis-cylinders. The new axis-cylinders arising in this way from the old ones grow in a longitudinal directiou (Fig. 179, a, b) and form, within the sheath of Schwann, whole bundles (Figs. 179, c ; ISO, e) of newly formed nerve-fibres, which for the most part fill up the entire lumen of the old nerve-tubes, and indeed stretch it, and more rarely enclose remains of the old fibres (Fig. 180, /'). Single, fibres may even break through the old sheath of Schwann, and then either extend further in the endoneurium, or penetrate through the perineurium of the nerve-bundle into the epineurium. In this way there are formed on the lower end of the proximal portion of the nerve a large number of new nerve-fibres, which in the beginning consist only of the newly formed axis- cylinders, but immediately surround themselves with a medullary sheath, which by reason of its irregular de- velopment gives to the nerve-fibres a varicose appearance (Fig. 179, c). Later the fibres acquire a neurilemma- sheath — that is, a connective-tissue covering which is probably formed from the nerve-corpuscles concerned in the proliferation. "When a nerve is entirely severed and there is no possibility of a union with the distal portion — as, for ex- ample, occurs in all amputations of the extremities — there is formed in the re- gion of the cut end an embryonic tissue, springing from the connective tissue of the nerves, which later on becomes changed into connective tissue. In the beginning free from nerves this con- nective tissue becomes penetrated by young nerves growing out from the Fig. 170. —Old and newly formed nerve-flbres from an amputation- stump, in longitudinal section (Mul- ler's fluid, Weigert's stain), «, b, Old nerve-flbres, from which several young nerve-fibres have grown; c, neuri- lemma with young nerve-flbres. X 180. FIG. 180.— Cross-section of a nerve-bundle of the median nerve just above awotind divid- ing the nerve, made four months previously (Midler's fluid, carmine), a. Perineurium; 6, endoneurium; c, cross-section of a vessel; d, old unchanged nerve-fibre; e, bundle of newly formed nerve-flbres ; /, newly formed nerves, with remains of old flbres inside the same sheath. X 200. 20 306 THE PROGRESSIVE CHANGES. nerve-fibres of the nerve-stump, which, arranged in small bundles, or scattered, grow into the connective tissue and penetrate it in every direc- tion (Fig. 181). Not infrequently the growth of nerves is so extensive that nodular or clubbed swelling's (Fig. 181, b) arise on the ends of the nerves. Such a swelling is known as an amputation-neuroma. When a nerve after division is again united, or if the division of the nerve is only partial, the nerve-fibres growing out from the proximal end after penetrating the connective tissue formed in the site of the wound, may in part, or all, find their way into the per- ipheral portion of the nerve where, in the mean time, the nerve-fibres have been de- stroyed. In this way the distal end may again become neurotized — that is, supplied by new nerves. According to investiga- tions of Forssmann, the direction of the newly growing fibres is governed by chemotaetic influences arising from the disintegration-products of the old nerve- fibres. According to the investigations of Vanlair the growth of a regenerating nerve is about 0.2-1 mm, daily, accord- ing to the. character of the tissue. A portion of the new nerve-fibres may pen- etrate into the old, empty sheath of Schwann; others extend into the epineur- ium and perineurium, and in this situa- tion grow toward the periphery to the end-organ. Single fibres may pass by the end of the nerves, and grow toward the periphery, either along the old nerves or by an independent route. Many fibres, which leave the old route, are finally lost in the tissues. In the lower portion of the intermediate substance (Vanlair) the nerve-strands begin to collect into bundles again, and with the formation of a perineurium about the latter, the re- generated nerve takes on more and more the structure of a normal nerve. The above-described process of regen- eration requires for its accomplishment months, and sometimes is not complete after several Fm. 181.— .Amputation-neuroma of the sciatic nerve, in longitudinal section (am- putation of nerve nine years previously) (Muller's fluid), a, Nerve; &, neuruuia. X 3. weeks or even months. The question of the regeneration of the central nervous system is still under discussion. It is generally accepted, as having been established beyond all doubt, that in the cold-blooded animals, reptiles, and tailed amphibia, a regenerative new forma- gation of portions of the central nervous system can take place. In the case of warm- blooded animals, particularly in the mammals, the majority of experimental investi- gations have failed to demonstrate a regenerative new-formation of ganglion-cells TedescM, Vitzou and others, claim to have observed, after injuries of various kinds both a new-formation of neuroglia and of ganglion-cells and nerve-fibres; but the investigations carried out in my laboratory by Tschistowitsch seem to me to contradict REGENERATION OF NERVE-TISSUE. 307 these assertions. The results obtained by Grunert in experimental work with pigeons agree with the conclusions arrived at by Tschistowitsch. Monti and Fiesehi could demonstrate no evidences of regeneration in the ganglion- cells of the sympathetic after injuries. Torelli found only degenerative changes in the ganglion-cells of the intervertebral ganglion after injury of the same. The new=formation of peripheral nerve-fibres has been made very frequently the subject of experimental research, and different observers have come to very differ- ent conclusions (see Stroebe, I. c. ). The above-described mode of new-formation I regard as firmly established, in so far as its essentials are concerned, upon the ground of per- sonal investigations. I have been unable to confirm the views of Neumann, Dobbert, Daszkiemicz, Oattani, Weir Mitchell, (jluck, Beneke, ran. Biingner, Wieting, and others, who hold that the new fibres in the distal portion of the severed nerve rise autoehthon- ously from the nuclei of the sheath of Schwann, or from the old axis-cylinder, or from a protoplasmic mass formed by a chemical transformation of the medullary sheath and axis-cylinders (Neumann-Doljbert). The view held by Belhe, that the nerve-Cbres arise without participation of the ganglion-cells in the fused ectodermatic cells whose remains later represent the cells of Schwann, appears to me to have been shown by von Kolliker to be incorrect. Likewise, the attempt made by Neumann and Wieting (Marchand) to bring into accord the established fact of the outgrowth of the axis-cylinders of the proximal portion into the scar uniting the severed ends, with the theory of the origin of new nerve-fibres from the nuclei of the sheath of Schwann, or from the remains of old fibres, or from both, by the assumption that the axis-cylinders growing from the proximal end convey a stimulus from the nerve- centres to the distal portion and thereby make possible the development of new fibres, I regard as unsuc- cessful, and hold to the above-given view. lam further of the opinion that the medul- lary sheath is not formed by the cells of the sheath of Schwann, but represents a product of the axis-cylinders; but further investigations as to this point are needed. According to JSissl, Marinesco, and others (see Barbacci, I. c.) there occurs, after the severing of a nerve, first a degeneration in the corresponding ganglion-cells with disintegration of the Nissl's bodies, and this may lead to the destruction of individual cells. Later, progressive changes with new-formation of chromatin take place, and may lead to hypertrophy of the cells {Marinesco) ; these changes reach their maximum in about ninety days, after which time there is a return to the normal condition. The regenerative new=formation of the tissues of the eye has in recent years been repeatedly an object of research. According to Wolff, Midler, and Kocltn the lens of tritons may regenerate, after removal, by means of a proliferation of the epithelium of the inner layer of the iris. According to Rating, the same thing occurs in the trout. Oonin observed in rabbits, after the lens had been removed in such a manner that the capsule and some of the equatorial lenticular fibres and epithelium of the anterior wall were left behind, that there occurred a proliferation of this epithelium, leading to the union of the anterior and posterior walls through cells resembling connective-tissue cells. A new-formation of lenticular fibres from these cells does not take place. Remains of the lenticular fibres may form a rudimentary, useless lens, which in the case of young animals may become somewhat enlarged through the growth of the fibres. Randolph obtained somewhat better results in guinea-pigs. In the human eye similar formations are seen after removal of the lens, and are known under the name of " Krys- tallwulst" (Baas). According to Franke, Kriickmann, anil Stoewer, the sclera possesses but slight power of proliferation. Wounds of the same are healed chiefly through proliferation of the choroid and episcleral tissue. According to Baquis, there occurs, in the injured retina of the rabbit, division of both ganglion and neuroepithelial cells. According to Kriickmann, the pigment- epithelium is capable of extensive regeneration, but neuroepithelium, on the other hand, is not again formed. Literature. (Regeneration of the Elements of the Central Nervous System.) Bardeen: The Histogenesis of the Cerebrospinal Nerves. Am. J. of Anat., iv., 1903. Barfurth: Zur Regeneration der Gewebe. Arch. f. mikr. Anat., 37 Bd., 1891. Bethe: Allg. Anat. u. Phys. d. Nervensystems, Leipzig, 1903. Borst: Kegenerationsfahigkeifc des Gehirns. B. v. Ziegler, xxxvi., 1904. Caporaso: Rigeuerazione del midollo spiuale della coda dei Tritoni. Beitr. v. Ziegler, v., 1-89. Coen: Ueber rlie Heiltmg von Stiehwunden des Gehirns. Beilr. v. Ziegler, ii., 1889. Friedmann: Progressive Verauderungen an den Ganglienzellen bei Entzundtingen. 308 THE PROGRESSIVE CHANGES. Arch. f. Psych., xix., 1SS7; Zur Histologie der acuten Encephalitis. Neurol. Cbl., 1889. Grunert: Regenerationsfahigkeit d. Gehirns. Arb. a. d. path. Inst. Tubingen, ii., 1S99. Heg-ler: Regenerationsfahigkeit d. Gehirns. Arb. her. v. Baumgarten, iv., 1902. Held: Bau der Neuroglia, Leipzig, 1903. His: Histogenese u. Zusammenhang d. Nervenelemente. Verh. d. N. intern, med. Congr., ii., Berlin, 1891; Die Neuroblasten u. deren Entstehung im embryonalen Mark, Leipzig, 1889. Keresztszeg-hy u. Hanns: R.egenerationsersch. im Ruckenmark. Bcitr. v. Ziegler, xii., 1892. Masius et Vanlair: Regen. d. Riickenmarks bei Froschen. Mem. de l'Ac. de Bel- gi(|ue, T. 21, 1S70. Mondino: Sulla cariocinesi delle cellule nervose. Rend. It. Institute Lombardo, 188.5. Monti et Fieschi: Gue>ison des bless, des ganglions sympathiques. Arch. ital. de Biol., xxiii., 1895. Miiller, H. : Regen. d. Wirbelsaule u. d. Riickenmarks v. Eidechsen u. Fischen, Frank- furt. 1864. Sanarelli: Les proc. de reparat. dans le cerveau et dans le cervelet. Arch. ital. de Biol., xiii., 1S90. SchiefTerdecker : Ueb. Reg., Deg. u. Architektur d. Riickenmarks. Yirch. Arch., 67 Bd., 1876. Sg-obbo: Sulle rigen. del midollo spinale. La Psichiatria, viii., 1891. Strahuber: Deg. u. Reg. b. multipler Sklerose. B. v. Ziegler, xxxiii., 1903. Stroebe: Heilung v. RXickenmarkswunden. Bcitr. v. Ziegler, xv., 1894; Histol. d. de- gen, u. regen. Processe im centralen Nervensystem. Cbl. f. allg. Path., 1895 (Lit.). Tedeschi: Regen. d. Gewebe d. Centralnervensystems. Beitr. v. Ziegler, xxi.. 1897. Tirelli: Proc. repar. dans le ganglion intervertebral. Arch. ital. dc Biol., xxiii., 1895. Tschistowitsch: Heilung von Hirnverletzungen. B. v. Ziegler, xxiii., 1898. Vitzou: La neoform. des cell, nerveuses dans le cerv. du singe. Arch, de phvs., ix., 1897. (Regeneration of the Peripheral Nerves.) Barbacci: Die Nervenzellen (Verand. nachNervendurchschneid.). Cbl. f. a. Path., x., 1899 (Lit.). Bethe: Allg. Anat. u. Phys. des Nervensystems, Leipzig, 1903. Biedl: Verh. d. Nerven u. ihrer Centren n. Durchschneidung. Wien. klin. Woch., 1S97, v. Btingner: Regenerationsvorgange an Nerven nach Verletzungen. Beitr. v. Ziegler, x., 1891. Cattani: Sulla deg. e neoformaz. delle fibre nervose. Arch, per le Sc. Med., xi., 1SS7. Demoor: Contrib. a 1'etude de la fibre nerveuse, Bruxellcs, 1891. Forssmann: Ursache der ■ Wachsthumsrichtung d. periph. Nervenfasern. Beitr. v. Ziegler, xxiv., 1898; Ncurotropismus. lb., xxvii., 1900. Galeotti u. Levi; Neubildungen nerv. Elem. im regen. Muskelgewebe. Beitr. v. Ziegler, xvii., 1895 (Lit.). Gessler: Die motorischen Endplatten, Leipzig, 1885. His: Histogenese u. Zusammenhang d. Nervenelemente. X. intern, med. Congr., ii., Berlin, 1891. Huber: A Study of the Operative Treatment for Loss of Nerve Substance in Peripheral Nerves. Jour, of Morph., vol. xi., 1895. Kleist: Verand. der Spinalganglien nach Nervendurchschneidung. Virch. Arch., 173 Bd., 1903. v. Kblliker: Die Entwickelung der Nervenfasern. Anat. Anz., xxv., 1904. Kolster: Regen. durchschn. Nerven. Arch. f. mikr. Anat., 41 Bd., 1893; Histogenese und Regen. periph. Nervenfasern. Beitr. v. Ziegler, xxvi., 1899. Lemke : Regen. d. periph. Nerven. A. f. Psych., 38 Bd., 1904. Neumann: Degeneration u. Regeneration nach Nervendurchschneidung. Arch. d. Heilk., ix., 1868; Nervenquetschung u. Nervenregeneration. Arch. i. mikr. Anat., xviii., 1880; Axencylindertropfen. Virch. Arch., 158 Bd., 1898. Nissl: Verand. d. Ganglienz. d. Fac. n. Ausreiss. d. Nerven. A. Zeit. f. Psych., 48 Bd. v. Notthafft: Regenerationsprocesse am verletzt. periph. Nerven. Zeit. f . wiss Zool 55 Bd., 1S93. Peterson : Peripheral Nerve Transplantation. Amer. Jour, of Med. Sc. , 1 899. Ranvier: Lecons sur Phistologie du syst. nerveux, Paris, 1878. Santi Sirena: Pacerche sperim. snlla riproduz. d. nervi, Palermo, 1880. Stroebe: Degeneration u. Regeneration periph. Nerven. Beitr. v. Ziegler, xiii., 1803; Cbl. f. allg. Path., vi., 1895 (Zusfass. Ref. iib. Regen. d. Nerven u. d. Endap- p anile). Vanlair, Arch, de bio! de van Beneden et van Bambeke, 1882-85; Arch, de phys., x., TKANSPLANTATION AND IMPLANTATION. 309 1SS2; vi., 1S85; viii., 1886; Compt. rend, de 1'Acad. des sciences, 1885; Sur 1'in- nervat. indireote de la peau. lb., 1886; De l'organisat. des drains de caoutchouc, etc. Revue de Chir., 1886; La suture des nerfs, Bruxelles, 1889; La persistence de l'aptitude regeneratrice des nerfs. Bull, de l'Acad. Roy. de Belgique, 1888; Rech. ehronomrtriqu.es sur la regrti. des nerfs. Arch, de phys., vi., 1894. Wieting': Regen. periph. Nerven. Beitr. v. Ziegler, xxiii., 1898 Wolberg: Nervennaht. Deut. Zeitschr. f. Chir., xviii. and xix., 1883. (Regeneration of the Tissues of the Eye.) Baquis: Etude exper. sur les retinites. Beitr. v. Ziegler, vi., 1888. Barfurth: Reg. d. Auges u. d. Linse beim Huhnerembryo. Verh. d. anat. Ges. 1902. Coluzzi: Rigen. parziale dell' occhio nei tritoni. Mem. Ace, Bologna, i., 1891. Fischel: Regen. d. Linse. Anat. Anz., xiv., 1898. Gonin: Regen. du cristallin. Beitr. v. Ziegler, xix., 1896 (Lit.). Kochs: Regen. d. Organe bei Amphibien. Arch. f. mikr. Anat., 49 Bd., 1897. Kruckinann: Pigmentzellen dec Retina. Arch. f. Ophthalm., 48 Bd., 1899. ' Muller: Regen. der Linse bei Tritonen. Arch. f. mikr. Anat., 48 Bd., 1896. Randolph: The Regeneration of the Crystalline Lens. Johns Hopkins Hosp Ren ix.. 1900. Schimkowitsch: Linsenregen. bei Amphibien. Anat. Anz., xxi., 1902. Stoewer: Heilungsvorg. bei Wunden d. Auges. Arch. f. Ophthalm., 46 Bd. 1899. Wolff: Linsenregeneration bei Tritonen. Biol. Cbl.. xiv., 1896; An. Anz. xviii. 1900; Regen. d. Urodelenlinse. A. f. Entwickelungsmech., xii., 1901. III. The Results of Transplantation and Implantation of Tissues and Organs. § S7. The local regeneration of tissue is, as mentioned in the last part, very often but slight, so that losses of tissue may be followed by perma- nent defects, and in place of the original structures there may appear only a cicatricial tissue of a lesser value. Consequently, from practical reasons, many attempts have been made, through transplantation and implantation of tissue, to aid and to improve the healing-process; and such attempts have in part been successful. At the same time they have also thrown light upon the individual life of the tissues and upon the behavior of the organism toward implanted living tissue. The most successful results have been obtained in the transplantation of tissues which remain connected with their nutrient vessels, since the same, at the point of union between the transplanted portion and the under- lying tissues upon which it is placed, grow together with the latter in essentially the same manner as do the edges of the wound in the case of a cut. This method is utilized most frequently in the case of plastic oper- ations upon the surface of the body, but it finds application also in inter- nal surgery. For example, wounds of the bladder, intestine, ureters, tubes, etc., may be easily closed through implantation of the omentum; and the surface presenting upon the lumen of the organ concerned becomes very quickly covered over by the neighboring epithelium, which extends over it from the edges, or is also transplanted from the opposite epithelial surface (Cornil, Carnot) ; while the omentum itself grows to the adjacent wound-surfaces, and thus through changes in its structure completely closes up the defect. Very often such an implantation of the omentum occurs spontaneously, as, for example, in the case of traumatic or ulcerative perforations of the intestine, stomach, gall-bladder, etc., and even large openings may be closed in this manner. As experimental investigations have shown, portions of intestine provided with blood- vessels may be implanted into other portions of the intestines, into the bladder (Enderle), stomach (Eeerink), and can heal perfectly in these 310 THE PROGRESSIVE CHANGES. locations with preservation of their own epithelium. Likewise, portions of bone or cartilage connected with the periosteum or perichondrium respectively, and with nutrient vessels, may be implanted into neighbor- ing tissue. Transplantations of tissues completely freed from their basement- structures have also been successfully performed, sine*' cells loosened from their connection with the organism are able to preserve their vital- ity for a certain length of time. The cells of the epidermis are able to live for the longest time; when kept cool they may be preserved alive for several (two to nine) days (Wentscher claims to have been able to preserve epithelium alive for twenty two days). ( 'iliated epithelium may also be preserved alive for several days and still show movements of the cilia. Next to the surface-epithelium in this respect stand the connec- tive tissues, while other tissues quickly die, the cells of the brain and kidney most rapidly, dying within a few hours after an obstruction to the blood-supply. According to the investigations which have been made up to the present time the tissues of the skin, periosteum, inter- articular cartilages, muscle and cartilage easily preserve their vitality for two to three days. Morpurgo found cells of the periosteum to be capable of reproduction even after seven to eight days. The tissues of the vessels, tendons, and neurilemma appear to lie somewhat more re- sistant. Exact statements with regard to this point cannot be made at present, since, on the one hand, the expiration of life does not take place, suddenly, but gradually with the constant diminution of vital cells; and, on the other hand, the conditions under which the excised portions of tissue are preserved also influence the duration of life. Transplantations of slcin give the best results, and were first recom- mended by Eevei'din and Thiersch for the healing over of broad, open wounds and have since been extensively used for this purpose. The material used consists of pieces of skin which may be taken cither from the same individual or from another person. Ordinarily, strips of skin removed by means of a sharp knife are used, which include the tips of the papilla? and the upper layers of the coriuni. Epithelium in connec- tion with a thicker layer of the coriuni may also lie successfully trans- planted, and in the case of injuries, large portions of the skin which have been completely torn off may be again joined by healing to the deeper tissues on the very same spot from which they had been removed. The transplantation may be made either upon a, fresh wound-surface or upon one already showing proliferation. The strips of skin are held firmly in place by means of moist bands of gauze. The pieces of skin become fastened to the surface of the wound by means of coagulated blood or lymph. In successful cases a firm union with the underlying tissue, takes place within about eight days. The nourishment of the transplanted pieces (Fig. 182, d) is obtained first from the tissue-fluids which exude from the underlying tissues. Later, there begins in the latter a vascular connective-tissue proliferation (b, c), and the transplanted portion becomes penetrated from below by new blood-vessels (g) accompanied by fibroblasts, so that it finally be- comes interspersed with new blood-containing vessels and areas of granu- lation tissue. Under favorable conditions the old vessels may again become opened through the ingrow T th of now vessels. The behavior of the transplanted portion varies in individual cases, the number of cells living and proliferating changing with the condi- TRANSPLANTATION . ill tions. A part of the cells of the transplanted portion is always lost, and this is shown inacroscopically in part by the repeated desquamation of the superficial layers of the epithelium (/). Other cells, both epithelial and connective-tissue cells, proliferate and produce new tissue. The final outcome of a successful transplantation is the covering over of the area with transplanted epithelium and in part also by transplanted corium. Through the latter it is made possible that the cicatricial area comes to possess papillae. To what extent in a given case the superficial layers of the cutis arise from the skin-graft or to what extent from the tissue upon which it is planted, cannot be determined. If the papillary e£? ■:=>*- wmmsmmm *& .^ d ^fesVKte ^> Fig. 182.— skin-graft four and one-half days old (formalin, hematoxylin, picrofuchsin) . n, Deep layer of the corium; h, proliferating granulation-tissue; c, boundary of proliferating zone; *',< i"r'i' B£&* &;..<£■-. ■;^. Fig. 185. — Periosteal formation of cartilage in metastatic carcinoma, of a rib. (Haemt toxylin, picric acid, fuchsin.) a, Fibrillated connective tissue; b, connective tissue undergoin condensation; c, fully developed cartilage. < 300. Fig. ISO.— Healed tracheotomy wound in the cricoid cartilage, fifty-two days old. < Formalin hematoxylin, and eosin.) a, Old cartilage; b, h, connective tissue arising from the perichondrium' undergoing metaplasia into cartilage. X 60. METAPLASIA. 317 ordinary fibrillated connective tissue, particularly when its lice surface is covered, with connective tissue. The metaplastic processes thus described are connected with preced- W^^W^y^ .— e Fig. 187.— Metaplasia of cartilage into reticular tissue, in arthritis fungosa (alcohol, hematoxylin), a, Hyaline cartilage ; o, tissue consisting of branched cells ; c, cartilage-cells, set free by the liquefaction of the basement-substance of the cartilage, and becoming transformed into cells of mucous tissue. X 400. w!~*'m -f y EOT'- S^'WaSae^ ii^^/J ^ uii/iMiu .Xtfas^si . mMu... M/zMjt*- ^t/frJM C c $ € Fig. 188.— Metaplasia of cartilage into osteoid tissue, in a callus fourteen days old (Muller's fluid, picric acid, hsematoxylin, carmine), a. Hyaline cartilage; h, marrow-spaces; c, blood-vessel ; d, cellular, 6, flbrocellular marrow; f, osteoid tissue; j/, osteoblasts; 7i, cartilage-cells freed through the disappearance of the ground-substance ; t, proliferating cartilage-cells in opened capsule; k, proliferating cartilage-cells in closed capsule. X 200. ing proliferations and may be associated further with appearances of pro- liferation. But there occur metaplasias, such as are described above, which have no connection with any proliferative change, or are only as- 318 THE PROGRESSIVE CHANGES. sociated with it at a later period; thus myxomatous tissue may become changed into adipose tissue if the star-shaped tissue-cells become changed into round fat-cells through the taking up of fat, while the mucoid ground- substance disappears. Lymphadenoid tissue may, after the disappear- ance of the lymphoid elements, be changed into adipose tissue through the taking up of fat into the cells of the stroma. Through the disap- pearance of fat, adipose tissue may take on the appearance of mucoid tissue, and occasionally comes to contain mucin. In the change of connective tissue into myxomatous tissue the fibrilke vanish and there appears in their place a jelly-like mucus. If numerous lymphoid round cells collect in fibrillated connective tissue and there oc- curs at the same time a reticulation or a disappearance of the connective- tissue fibres, while the connective-tissue cells remain preserved and through the formation of processes unite themselves to form a reticular tissue, lymphadenoid tissue may be developed. Epithelial metaplasia occurs most frequently in chronic inflamed mucous membranes, for example, uterus, urethra (gonorrhoea), nose ( ozsena), and the trachea, cylindrical epithelium being transformed into pavement epithelium. This change occurs in the following manner: after repeated loss of the original epithelium the regenerating epithelium changes its character. In mucous membranes possessing stratified pavement -epithelium the upper cell layers may show cornification, not only in places which nor- mally rjossess pavement-epithelium, as, for example, the tongue and cheeks, but also in those possessing transitional epithelium (the urinary tract), or cylindrical epithelium (nose, ureters, and gall-bladder). In connection with this phenomenon should be mentioned the fact that epithelial tumors arising in mucous membranes possessing transitional or cylindrical epithelium may bear the character of squamous-celled epithelial tumors. Literature. (Metaplasia.) Dietz : Plattenepithelkrebs d. Gallenblase. V. A., 164 Bd., 1901. Finger: Die chronische Urethralblennorrhoe. Arch. f. Derm., Erganzungsheft, 1891. Hansemann : Studien lib. Specificitat, Altmismus u. Anaplasied. Zellen, Berlin, 1893. Hildebrandt : Ueber einen Katarrh d. weibl. Geschlechtsorgane. Samml. klm Vortr., No 32. Kartthack : Stud. Ub. d. Histologie d. Larynxsckleimkaut. Virch. Arch., 119 and 12C Bd., 1890. Kischensky : Plattenepithelkrebs der Nierenkelche. B. v. Ziegler, xxxi., 1901. Lubarsch: Die Metaplasiefrage. Arb. a. d. p. I. v. Lubarsch, Wiesb., 1901. Neelsen : Ilistol. Verand. i. d. chron. entzilndet. Urethra. Vierteljahrsschr. f Derm 1887. Ohloff: Epithelmetaplasie u. Krebsbildung in Gallenblase u. Trachea. Inaug -Diss Greifswald, 1891. Pollack: Beitr. z. Metaplasiefrage. A. a. d. p. I. v. Lubarsch, Wiesb., 1901. Sangalli : Die Metaplasie d. krankh. Gewebe. Int. Beitr., Festschr. f. Virehow ii Berlin, 1891. Schmiedeberg : Die chemische Zusammensetzung desKnorpels. Arch. f. exp Path 1891. Schuchardt : Ueberd. Wesen d. Ozaena. Samml. klin. Vortr., No. 340, Leipzig, 1891 Virehow Gesammelte Abbandl., Frankfurt, 1856, pp. 500, 509; Cellularpatho'l. iv Aufl., p. 70. Virch. Arcii., Sand 97 Bd. , Deut. med. Woch., 1884. Zeller : Plattenepithel im Uterus. Zeitsehr. f. Geburtsh., xi., 1885. CHAPTER VII. Inflammation. I. The Early Stages of Acute Inflammation. § 89. Under the designation inflammation are grouped those patho- logical phenomena which represent a combination of different patholog- ical processes, consisting on the one hand of tissue=degenerations and tissue=proliferations, and on the other of pathological exudations from the blood= vessels. Degenerations of tissue and pathological exudations init- iate the process ; with these tissue-proliferation is sooner or later associated, the latter leading in the further course of the process to a compensation for the disturbance — that is, to healing. The proliferation of tissue may, therefore, be regarded as regenerative, but such new-formation of tissue may be in excess of that which is useful to the body. The tissue-degen- erations and proliferative processes described in the previous chapters appear for the greater part as participating factors in inflammation ; the process acquiring its inflammatory character throughthe combination of tissue- degenerations and tissue-proliferations with pathological exudations. Deeper tissue-lesions — that is, injury of tissues containing blood-vessels — which in some way or other affect the vascular system, will, therefore, constantly bear at some time during their course the character of an inflamma- tion. The formation of scar tissue, the healing of transplanted tissues, as briefly described in the last chapter, always take place through processes essentially inflammatory in nature. Exudation in acute inflammation is constantly associated with a pronounced hypermmia, which appears even before the beginning of the exudation, and hence ushers in the latter. As a result of the combina- tion of hyperemia and exudation the inflamed tissue becomes reddened and swollen. When situated on the surface of the body, where a cooling of the tissues takes place, the increased flow of warm blood from the deeper tissues causes a local increase of temperature. If the tissue af- fected contains sensory nerves, the sensation of pain will be produced as the result of the changed conditions in the inflamed area. Redness, swelling, increased warmth, and painfulness of the in- flamed tissue are phenomena which even in ancient times were regarded by physicians as the signs of inflammation ; and rubor, tumor, calor, and dolor were designated by Celsus, at the beginning of our era, as the cardinal symptoms of inflammation. To these four was then added still a further symptom, functio lassa, altered function of the inflamed tissue. The causes of inflammation may lie either in mechanical, thermal, electrical, or chemical influences, as well as in the influence of parasites. The common characteristic of all these injurious agencies is the produc- tion, in the first place, of a local tissue-degeneration, which, when of a certain extent and intensity, is associated with disturbances of the circulation and of the vascular secretion. The causes of inflammation are not specific ; any 319 320 INFLAMMATION. injurious agent may excite inflammation if on the one hand its action is sufficiently intense to cause certain disturbances of circulation in asso- ciation with tissue-degenerations, but on the other hand not so intense as completely to destroy the tissue and stop the circulation. The great majority of the causes of inflammation reach the human organism from the outside, but excitants of inflammation may be formed also within the body. In the first place bacteria which have penetrated into the tissues very often form within their protoplasm or from sub- stances present in the body certain products which are capable of excit- ing inflammation. Moreover, substances that excite inflammation may arise within the organism without the aid of parasites; particularly as the result of the death of large masses of tissue from any cause, as, for example, as the result of anaemia, or when as the result of disturbances of metabolic processes (gout) products of metabolism are deposited in the tissues. The causes of inflammation may act upon the tissues either from the portions of the body accessible from without, or from the lymph and the blood; and we may, therefore, distinguish ectogenous, lymphogenous, and hematogenous inflammations. Through the spread of an inflam- mation to neighboring tissues there arises an inflammation by con= tinuity ; as the result of the transportation through the lymph or blood stream of an agent causing inflammation, there are produced metastatic inflammations. If injurious substances are discharged through the excretory organs, excretory inflammations may arise. When a local injury to tissues has reached such a degree as to pro- duce the exudation characteristic of an inflammation, there is usually found in the first place a congestive hyperemia, as a result of which the blood flows through the dilated blood-channels with increased veloc- ity. After a short time there is a lessening of the speed of the circula- tion which leads finally to an abnormal slowing of the bIood=current. The first disturbances of circulation, which find expression in the congestive hypersemia, may be due either to a stimulation or paralysis of the vasomotor system or to a direct action upon the vessel -walls, par- ticularly upon the arterial walls, leading to a dilatation of the lumen. Although these disturbances very frequently precede the inflammatory exudation, they do not form an essential characteristic of inflammation, and occur very often without being followed by an inflammatory exuda- tion. Further, they may be absent during the course of au inflammation. The circulatory disturbances characteristic of inflammation are shown only when the slowing of the bSood=current and the pathological exudation from the blood=vessels set in. The slowing of the blood- stream in the dilated channels and the pathological exudation are de- pendent upon a change in structure, an alteration of the vascular walls, through which there results a lasting dilatation of the vessel and an adhesion of the blood to the vessel-wall, causing an increase of friction- resistance and an increased permeability of the vessel-wall. In the capil- laries the persistent dilatation is in great part the result of relaxation of the connective tissue surrounding the capillaries, inasmuch as the thinness of the capillary walls makes this tissue bear the greater part of the blood-press- ure resting upon them. The tissue-lesion which leads to the phenomena of inflammatory dis- turbances of circulation and exudation usually affects all parts of the tissue, bat under certain conditions may be limited to the vessel-wall, particularly in the case of a hajmatogenous inflammation, in which the THE EARLY STAGES OF ACUTE INFLAMMATION. 321 iuj urious agent acts from the blood. However, the tissue in the region adjoining the capillary walls must soon become involved in association. The tissue-changes brought about .by the excitants of inflammation are sometimes only slight, and even on microscopical examination are either not recognizable at all or only with difficulty ; at other times they are more severe, so that they may be easily recognized even on macroscopic examination. The latter is particularly the case when some time has elapsed after the action of the injurious agent. During the further course of the inflammatory process there are often added to the lesions produced directly by the causes of inflammation other tissue-changes, which are brought about by the inflammatory disturbances of circulation and the collection of exudate in the tissues. If in any tissue the cause of inflammation has led to that alteration of the vessels which is the requisite antecedent of an inflammatory dis- turbance of the secretion of the vessels, i.e., the formation of an inflam- matory exudate, and if as a result of this there is already evident a slowing of the blood-stream, the capillary circulation becomes irregular, and there occurs here and there either stagnation or a permanent or transitory stasis. Since in this event the white blood-corpuscles often remain clinging to the vessel-walls while the red blood-cells are carried on, there arises in the capillaries a more or less marked increase of white blood=corpusc!es as compared to the red. In the veins, in which there can be distinguished in the normal circulation an axial red stream and a peripheral plasma-zone free from cells, a greater or less number of leucocytes pass over into the peripheral plasma=zone, when the slow- ing of the circulation has reached a certain degree. A still greater slow- ing of the, current leads to the passing over of blood-plates and red blood-cells into the peripheral plasma-zone, and finally the difference between the axial-stream and the peripheral zone maybe entirely lost. When leucocytes pass over into the peripheral zone they either roll along in the same or cling to the wall of the vein, either to roll on again after a time or to remain permanently attached. If this occurrence leads to a marked accumulation of leucocytes along the vein-walls, the condi- tion is known as the marginal disposition of the white corpuscles (Fig. 189, (1). Following the accumulation of the leucocytes in the capillaries and the marginal disposition in the veins there occurs later an emigration of the leucocytes (Fig. 189, d, e) from the vessels involved, and at the same time a, pouring-out of fluid from the vessels into the tissues. The emigration of the white corpuscles is an active process, which is accomplished through the aniceboid movement of the cells, and to a certain extent occurs under normal conditions. The cause of the marked emigration seen in inflammations is doubtless a change in the vessel - walls, which favors the clinging of the cells to the walls and their pas- sage through the latter. According to investigations by Arnold, Thoma, and others, the leucocytes pass out through the lines of cement-substance between the endothelial cells ; and in the alteration of the vessel-wall due to inflammation localized defects occur in the wall as the result of the widening of these lines. The emigration is accomplished by the leuco- cytes first sending a process through the vessel-wall, the remainder of the cell-body then flowing after the process, until finally the entire cell- body is outside of the vessel. Arrived here the leucocytes first remain lying in the immediate neighborhood of the point of diapedesis, but often wander farther, the direction of the wandering being determined 21 322 INFLAMMATION. partly by mechanical stimuli, partly by chemotaxis — that is, the repelling or attracting influences exerted, by chemical substances present in solu- tion in the tissue- juices. Possibly chemotactic influences sometimes exert an action even upon the leucocytes in the capillaries or those in the peripheral zone of the veins. The cells emigrating from the vessels are at first polynuclear leucocytes, but lymphocytes may very soon ac- company them. The polynuclear cells which occasionally alone pass out, and in great numbers, are after their emigration known as pus- cells. The pouring=out of the fluid exudate, whose composition always differs more or less from that of the normal tissue-lymph, and which is characterized by a relatively high albumin-content, is a process which is Fig. 189. —Inflamed human mesentery (osmic-aeid preparation), a. Normal trabecula; b, normal epithelium (endothelium); e, small artery ; (/, vein with leucocytes arranged peripherally; e, white blood- cells, which have emigrated or are emigrating; /, desquamating endothelium; f,, multinuclear cells • a extravasated red blood-cells. X 180. ' also to be referred to an alteration of the vessel-wall, in consequence of which the secretory function of the latter suffers a disturbance. It takes place at the same time with the emigration of the leucocytes, but may begin before this event, and may occur also in cases in which the emigra- tion of the leucocytes (for example, as a result of a paralysis of the same ) does not take place at till, or remains within very narrow limits. The composition of the exudate is dependent, in all cases, partly upon the es- pecial property of the affected vessels, which always varies according to the tissue-formation to which the vessels belong, and partly upon the degree of vascular alteration; and it may be assumed that the albumin- content is the higher the greater the damage to the vessel-walls. If the extravasated fluid contains fibrinogenie substances and fibrin-ferment coagulation — that is, a separation of fibrin — takes place. If the alteration of the vessels is of a very high degree, or if at- the same time there is a marked stasis, red blood-cells may also pass out of the vessels (Fig. 189, , goblet-cells ; c, cells showing marked mucous degeneration; c,, mucoid cells with mucoid nuclei ; d, desquamated mucoid cells ; e, desquamated ciliated cells ; / , layers of drops of mucus ; f,, layer consisting of thready mucus and pus-corpuscles; g, duct of mucous gland tilled with mucus and cells; ft, desquamated epithelium of the excretory duct ; i, intact epithelium of the duct; 7c, swollen hyaline basement-membrane : I, connective tissue of the mucosa, infiltrated with cells in part; m, dilated blood- vessels; n, mucous gland filled with mucus; u 2 , lobule of mucous gland without mucus; o, wandering cells iu epithelium ; p, cellular infiltration of the connective tissue of the mucous glands. X 110. the epithelium dissolve (Fig. 192, d, f, g, h), the lesions thus produced are called vesicles and blisters. When the exudate from serous surfaces collects in the body cavities, there are formed iu the latter inflammatory effusions, which not rarely reach a very large size, distend the affected cavity, and compress the organs contained within it. It is customary to express the occurrence of an inflammation of au organ by addiug the termination "itis" to the Greek name of the organ. Thus, for example, are formed the terms endocarditis, myocarditis, peri- carditis, pleuritis, peritonitis, encephalitis, pharyngitis, keratitis, orchi- tis, oophoritis, colpitis, metritis, hepatitis, uephritis, amygdalitis, glos- sitis, and gastritis. The ending "itis'Ms also sometimes affixed to the Latin names, as, for example, conjunctivitis, tonsillitis, and vaginitis. To denote an inflammation of the serous covering of an organ or of the 330 INFLAMMATION. tissues immediately about it the prefixes "peri" and "para " are placed before the Greek names with the termination "itis. " Thus, for example, are formed the words perimetritis, parametritis, periproctitis, perityph- litis, paranephritis, and perihepatitis. For certain forms of inflammation especial names are used, as, for example, inflammation of the lungs is called pneumonia, and inflamma- tion of the palate and tonsils, angina. Since Cohnheim taught that the migration of leucocytes en masse is an important feature of inflammation and serves as a source for the cells in the exudate, the ques- tion of the origin of the cells present in the exudate of acute inflammations has been many times the subject of discussion. While some have regarded all the cells in the exudate as extra vasated leucocytes, others have held that the leucocytes arising from the blood-stream form only an unessential element, and that the main part of the cells in the exudate have, arisen on the spot from the tissue "irritated" by the cause of the inflammation. SI richer held the opinion that the swelling and hardening of the tissues in inflamma- tion are not caused by the collection of exudate, but by the swelling of the cell-reticulum which was thought to traverse the tissues ; and that these changes represent a phenome- non of growth of the cells and their processes which is characterized by swelling. The cellular exudate — that is, pus — he accounts for partly through the segmentation and division of the cell-reticulum swollen by the inflammation, and partly through a trans- formation of connective-tissue fibrillar into pus-corpuscles. Heitzmann regarded the inflammatory tissue-changes asareversion of the tissue to the embryonal condition, and believed that the living material is not contained in the cells alone, but infiltrates the entire ground-substance, and increases, in the progress of an inflammation, with the liquefaction of the ground-substance. Connective-tissue cartilage and bone become resolved during inflammation into those elements from which they are formed — i.e.. into cells — which then immediately reproduce their kind. Grawitz believes that both the cellular infiltrate and pus are formed without any participation of the leucocytes worth mentioning. Everywhere in the tissue, according to his view, there lie concealed in great numbers cells, which he designates slumber-cells, and which are not affected by our nuclear stains and therefore not recognizable (according to him, only from five to ten per cent, of the tissue-cells are known to us); these cells awake in inflammation, and again come into sight — that is, increase in size, stain with nuclear stains, and there- fore again become recognizable. According to the results of an unprejudiced and careful examination of inflamed tissues, 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 correspond to the conditions as they actually exist. The cells which lie in recently inflamed tissue consist in part of leucocytes which have wandered from the vessels and in part of tissue-cells which are more or less degenerated, and are often separated from the under- lying tissues. Later, to these there are added newly formed cells which have arisen through the division of preexisting tissue-cells. Literature. (The Processes Occurring in the Tissues during Inflammation, and the Origin of the Cells in the Exudate. ) Baumgarten: Ilerkunft d. in Entzundiingshcrdcn auftret. lymphkorperart Elementc Cbl. f. allg. Path., i., 1890. Bottcher: Ent.stehung der Eiterkorperehen bei der traumatisehen Keratitis. Virch Arch., 58 Bd., 1873; Ueber die circumscripte Keratitis. lb., 62 Bit, 187,y Cattani: Ueber die Reaction der Gewebe auf specifische Reize. Beitr v Ziegler vii 1891. Coen: Veriinderungen der Haut nach Einwirkung von Jodtinetur. Beitr v Zicler ii., 1887. Eberth: Entziindung d. Ilornhaut. Enters, a. d. path. Inst, in Zurich, Leipzig, 1874 and 187. r ); Kern- u. Zelltheilung bei Entziindung. Intermit. Beitr Eestsehr f Virchow. ii., Berlin, 1891. Grawitz: DieEntwickelung der Eiterungslehre. Dent. med. Woch., 1889; Histolog Veriinderungen bei der eitrigen Entziindung. Virch. Arch., 118 Bd., 1889; Atlas VARIETIES OF INFLAMMATION. 331 der pathol. Gewebelehre, Berlin, 1893; Entziindung d. Hornhaut. Virch. Arch., 144 Bd., 1896. Griinwald : Zellen im Auswurf u. entziindl. Ausschwitzungen. Virch. Arch., 158 Bd., 1899. Key u. Wallis : Exp. Unters. ilb. d. Entziindung d. Hornhaut. Virch. Arch., 55 Bd., 1872. Krafft : Zur Histogenese des periostalen Callus. Beitr. v. Ziegler, i., 1886. Marchand : Untersuch. iiber die Einheilung von Fremdkorpern. Beit. v. Ziegler, iv., 1888. Neumann: Variabilitat der Leukocyten. Virch. Arch., 174 Bd., 1903. Nikiforoff: Bau u. Entwickelung des Granulationsgewebes. Beitr. v. Ziegler, viii. , 1890. Pappenheim : EinkSrnige Zellen in gonorrhoischen Sekret. V. A., 164 Bd., 1901. Podwyssozky : Regeneration der Drfisengewebe. Beitr. v. Ziegler, i., ii , 1884-8S. Roemer : Die chemische Reizbarkeit thierischer Zellen. Virch. Arch., 128 Bd., 1892. Strieker: Studien a. d. Institute f. exp. Pathologic, Wien, 1870; Verschied. Auf- satze in den Wiener med. Jahrb. a. d. J. 1871-83; Allgem. Patholo- gic, Wien, 1,877-83. Weigert : Die Virchow'sche Entziln- dungstheorie u. d. Eiterungslehre. Fortschr. d. Med., vii., 1889. Wlassow u. Sepp : Emigration der Lympljoevten. V. A., 176 Bd., 1904 (Lit.). Ziegler: Exp. Unters. ilber die Her- kimft der Tuberkelelem en to, Wilrzburg, 1875; Unters. liber patholog. Bindegewebs- u. Gefass- neubildung, Wlirzburg, 1876; Ueber die Betheiligung der Leu '•&V* • • '« V?V *" "•* , jiVv>' ,t ' / ''' { '^>*%"i kocyten an der Gewebsneubildung. Verb. d. X. internat. med. Congr., ii., Berlin, 1891; Ueber die Ur- sachen der pathol. Gewebsneubil- dung. Festschr. f. Virchow, ii.. Berlin, 1891; Historisches u. Krit- isches iiber die Lehre von der Entziindung. Beitr. v. Ziegler, xii., 1892. See also g§ 89, 91, and 92. § 91. Both the local tissue- degeneration and the exudation different % v'5- '•': ':•.■'■'< > i it is called a serous exudate. When contained within a tissue — for example, within the skin and subcutaneous tissue, or in the kings — there results an in- flammatory oedema. The es cape of the fluid on the free ciSnlu^^T^K^SS^nnreSn, ":'^ surface of a mucous or serous of pus-corpuscles and desquamated epithelium; ft,intact membrane gives the picture OI rtppnpst laver of epithelium; c, basement-membraue ; .' . -i i d hyperamic and infiltrated connective tissue of the a serous catarrh ; circumscribed mWsa; e, infiltrated submucosa with mucous glands, collections of fluid beneath the 332 INFLAMMATION. horny layer of the epidermis with the liquefaction of the soft layers of epithelium lead to the formation of vesicles and blisters with clear con- tents (Fig. 192, d,f). When the exudation of fluid on the surface of a mucous membrane is associated with a marked mucoid degeneration of the superficial epithe- lium (Fig. 194, b, c, cj, and of the" mucous glands (»), there arises a Fig. 396— Catarrhal secretion of different mucous membranes. A, Secretion from mucous membranes with columnar cells; li, from the mouth; C, from the bladder. 1, Round cells (pus-cells); 2, large round cells with bright nuclei, from the nose; 3, mucoid columnar cells from the nose; 4, spirillum from the nose ; 5, mucoid cells with cilia, from the nose ; 6, goblet-cells from the trachea; 7, round-cells with spherules of mucus from the nose; 8, epithelial cells containing pus-corpuscles, from the nose; 9, fatty cells from a chronic catarrh of the pharynx and larynx ; 10, ceils containing carbon pigment, from the sputum ; 11 and 12, squamous epithelium from the mouth; 13, mucoid pus-corpuscles; 14, micrococci; 15, bacteria; 10, leptuthrix buccaUs; 17, spirmtmte dentieola; 18, superficial, 19, middle layer of bladder epithelium; 20, pus-corpuscles ; 21, sehizomyoetes. X 400. ' mucous catarrh (d, f, /,, g). If a marked desquamation of the epithe- lium, with or without a mucoid change, occurs (Fig. 195, a), the condi- tion is termed a desquamative catarrh ; and such a process may occur not only on mucous membranes, but also in the respiratory parenchyma of the iungs, on serous surfaces (Fig. 189, /,/,), in the kidney-tubules, etc. If many pus-corpuscles are present, in the exudate it may be spoken of as a desquamative purulent (Fig. 195, a), or finally as a pure puru- lent catarrh, in which condition the exudate becomes white or yellow- ish-white, milky or creamy. The form and character of the cells of a catarrhal secretion vary with the location and the variety of catarrh (Fig. 196). Bacteria are often present in the cells of the exudate (Fig. 196, 4, H, 15, 16, 17, 21). If in a fluid exudate there occurs a deposition of fibrin or coagula- tion, there are formed fibrinous and serofibrinous exudates, which are often designated as croupous. These occur chiefly upon the surface of serous and mucous membranes, and in the lungs ; but masses of fibrin VARIETIES OF INFLAMMATION. 333 >£» (f;C'j eT^T, =1^ may be formed in tissues infiltrated with exudate, as well as in lymph- vessels. On the mucous membranes the fibrinous exudates form whitish patches and coherent membranes, which sometimes lie upon them only loosely, but at other times are firmly attached to the underlying surface. In the serous cavities the fibrinous coagula float in the form of flakes in the fluid portion of the exudate, or form a firmly attached deposit upon the surface of the membranes. Such deposits consist at times only of thin, attached films ,or granules which give to the wiped-off surface a cloudy, lustreless, rough, or granu- lar appearance; at other times of larger yellowish or yellowish-red, firm membranes, which often give to the surface a felted or villous appearance (cor villosum). In the lung, croupous inflammation leads to a filling of the alveoli with a coagulated mass, in consequence of which the lung acquires a firm con- sistence. On mucous surfaces the formation of croupous membranes takes place when the epithelium is already des- quamated and the connective tissue, at least in part, is exposed; but tis- sues covered with epithelium may also become the seat of fibrinous de- posits extending from denuded areas. The desquamation of the epithelium, in such a case, may follow gradually, or at other times more rapidly through the lifting up of whole layers of epithelium (Fig. 197, &), which are either well preserved or already degenerated or necro- tic, and infiltrated with exudate (Fig. 199, a). The exudation of fibrin may begin un- derneath the raised- up epithelium with the formation of fine needle-like forms re- sembling crystals (Fig. 197, <7), which are ar- ranged radially about a centre, in which at times there lies a small body, probably a product of the disintegration of a red corpuscle, or a blood-plate. Very soon there form thicker or thinner threads (Figs. Fig. 197.— Acute hemorrhagic fibrinous in- flammation of the trachea, caused by vapor of ammonia (Midler's fluid, hematoxylin, eosin). a. Superficial layer of the connective tissue of the mucosa, with greatly dilated blood-vessels and extravasated red blood-cells ; /», deep layer of epithelium raised up in toto ; c, desquamated epithelial cells; d, hemorrhagic fibrinous exu- date with radiating, crystal-like masses of fibrin, In part proceeding from small, colorless spher- ules. X 300. Fig. 198.— Croupous memhrane from the trachea, a. Section through membrane ; h, uppermost layer of the mucosa infiltrated with pus-corpuscles (-.' fc, Necrotic inflammations are most frequently seeu on the mucous mem- branes, and are here usually called diphtheritis, particularly those which are caused by infection. The necrosis may at first affect the epithelium, which iu consequence loses its nuclei (Fig. 210, b) and later acquires a lumpj 7 ap- pearance. If there are formed white, opaque patches upon the mucous membrane, as in the phar- ynx in diphtheria, the con dition may be epithelial or super fheriNs. Usually, the designation applied only croses in whic and infiltrated tissue unde r (Fig. 211, a), and becomes converted into a lumpy or granular mass without nu- clei, or into a more homo- geneous mass containing fibrin, in which the struct- ure of the tissue can no longer be recognized. Diphtheritic sloughing of the tissues of a mucous membrane is observed par- ticularly often in the intestine (Fig. 211), but occurs also in other mucous membranes, as in those of the vagina, the descending urinary passages, and the region of the throat, where the tonsils are especially frequently affect- ed, etc. The ne- crotic tissue forms white, or grayish - white, or, through the admixture of blood or bile or other impurities, dark green, yellow, brown, or other- wise colored sloughs, which are surrounded by red- dened and innamed tissue. If some time has already elapsed since it's formation, and if a liquefaction of the tissue at the bound- ary between t h e Fig. 211.— Bacillary diphtheritis ol the large intestine in dysentery (alcohol, gentian violet), a. Necrotic portion ol the glandular layer ol the mucosa, infiltrated with bacilli ; h, intact inflamed mucosa; c, muscularis mucosas; d, sub- mucosa ; e, colonies ol bacilli ; /, glands with living epithe- lium; fl, glands with necrotic epithelium and bacilli ; ?i, con- nective tissue infiltrated with cells ; i, blood-vessels. X KG. Fig. 212.- Section of the uvula in pharyngeal diphtheria with croupous deposits (alcohol, aniline brown), o, Normal epithelium; b, connective tissue of the mucous membrane ; c, reticulated fibrin ; d, connective tissue ol mucosa infiltrated with coagulated fibrin and round cells, and partly necrotic ; e, blood-vessels ; /, hemorrhage ; g, clumps ol micrococci. X 75. HEALING OF ACUTE INFLAMMATION. 345 living and dead tissues lias occurred, with a separation of the latter, the necrosed parts form loosely attached or wholly free deposits lying on the surface of the membrane, these consisting at times only of small Hakes, at other times of larger sloughs. Diphtheritis of mucous membranes may be associated with croupous de- posits (Fig. 212, c, d), so that the. tissue-necrosis (d) may be covered over with fibrin (c). Wound-granulations may also ne- crose in the same way as do inflamed mucous membranes; such a condi- tion may therefore be called wound- dvphtheritis. Acute tissue-necroses caused by infection occur in the case of the internal organs, chiefly in the lymph- glands (Fig. 213 J, spleen and bone- are characterized by the formation of opaque grayish- or dirty-gray sloughs. Not infrequently fibrinous exudations are seen within the necrotic tissue ( Figs. 212, (7 ,■ 21.3). In the necrosis caused by tuberculosis the destruction of the tissue occurs gradually, and bear's the character of a caseation. When an inflammatory focus contains bacteria which excite putrid decomposition of albuminoid bodies, the inflammation may take on the character of a putrid gangrene ; and the tissue may disintegrate into a dirty gray or black, tinder-like mass which gradually dissolves and gives off an extremely disagreeable odor. Gas-bubbles are also sometimes developed in the focus. (See § 92.) Fig. 213.— Diphtheritic necrosis within a swollen mesenteric lymph-gland, in typhoid fever (alcohol, florin-stain). Fibrin network- between the necrotic cells. X 300. marrow, and white, yellowish, Literature. (Necrotic Inflammation.) Cornil. Anat. pathol. des ulcerations intest. dans la dysenteric. Arch, do phys., v., 1883. Hoffmann: Unters. Liber, d. pathol. -anat. Verilnd. der Organe bei Abdominaltyphus, 1869. v. Kahlden: Die Aetiologie u. Genese der acuten Nephritis. Beitr. v. Ziegler, xi., 1892. Kaufmann ■. Die Sublimatvergiftung, Breslau, 1888. Virch. Arch., 117 Bd., 1889. Kelsch: Contrib. a 1 'anat. pathol. de la dysenteric Arch, de phys., v., 1873. Lesser: Die anat. Verand. d. Verdauungskanales durcli Aetzgifte. Virch. Arch., 83 Bd., 1881. Letulle et Vaquez: Empoisonnement par l'acide chlorhydrique. Arch, de phys., i., 1889 Marchand: Darmveranderungen bei Typhus abdominalis. Cbl. f. allg. Path., i., 1890. Matzenauer: Hospitalbrand. Arch. f. Derm., 55 Bd., 1901. Neuberg-er: Wirkung des Sublimats auf die Nieren. Beitr. v. Ziegler, vi., 1889. See also §§ 89-92 II. The Termination of Acute Inflammation in Mealing. § 94. Should there occur in any tissue whatsoever an acute inflamma- tion sooner or later there always arise processes which have in aim the 346 INFLAMMATION. removal of the changes established and a restoration of the degenerated tissue, and which may therefore be regarded as processes of repair. If the cause which excited the inflammation is no longer present, these processes consist essentially in the cessation of the pathological exudation and its replacement by the normal vascular secretion, the removal or absorp- tion of the exudate present and of the necrotic tissue, and the restoration of the destroyed tissue. If the exciting cause of the inflammation is still present in the tissue and active, it must be removed or rendered inert. The cessation of the alteration of the vessel=walls is brought about through the restoration of the normal blood-supply to the damaged blood- vessels, so that the nutrition of the vessels again becomes normal. If the alteration was slight, and if the exciting cause of the inflammation had acted only for a short time — if it is the case, for example, only of the brief action of a trauma, or high temperature, or chemical substance, that was quickly removed — the restoration of the vessels may take place in a, very short time, i. e. , in a ti me that may be measured in minutes and hours. When the exciting cause of the inflammation acts for some length of time — as, for example, in the case of bacteria which live and multiply in the tissues, or if changes are brought about through the inflammation itself, which act in such a. manner as to alter the vessels — if there has been, for example, a tissue-necrosis — the vessels are subjected for some time to a continued harmful action, which hinders the complete restora- tion of their functions. — \ - -%*',„•' ' Fig. 214. — Phagocytes from granulation tissue with included leucocytes and fragments of same (sub- limate, Biondi's stain j. a. Round, h, spindle, fibroblast with leucocytes ; c, d, e, fibroblasts containing re- mains of leucocytes. - 500. The absorption of the exudate occurs in many cases easily and quickly, in that it is taken up by the lymph-stream, eventually also by the blood. This takes placemost quickly in the case of serous exudates, yet in many places fibrinous exudates may also be quite rapidly removed, but this occurs only when the coagula soon liquefy. For example, the coagulated exudate in the lung may be liquefied and made capable of absorption through the action of a, proteolytic enzyme (Midler) that arises most probably from the leucocytes. The absorption of exudates is very often aided by phagocytes, that is, through the activity of amoeboid cells present in the inflamed area, in taking up corpuscular substances and destroying them. Thus, for example, large mononuclear cells (macro- phages) lying within the inflamed area, may lake up through ain), and in part possess long processes. Young forms without processes may resemble epithelial cells and are therefore classed with the so-called epithelioid cells. With the help of their processes they can push into the tissue spaces, but usually show no lively amoeboid movements. In the further development of the granulation tissue the fibroblasts form connective=tissue fibrillar, a portion of the protoplasm taking on ^KOtF mm m - - - ■■ be. ■: isse a - . hi , mmtimr^ Fig. 216.— Scar fifteen days old (Maximow, 1. c). a, Fibroblasts; ft, polymorphous lymphocytes (polyblasts); c, unchanged lymphocyte (polyblast). X 500. a fibrillar appearance, or first becoming more homogeneous and then producing fibrillae (Figs. 215, (7, e; 216, a; 217, a). The polynuclear leucocytes of the granulation tissue ( Fig. 215, a) arising from the blood are not capable of further development and either wander farther or finally die, particularly those which as pus-corpuscles collect on the surface of the tissue or in abscesses. If bacteria are pres- ent in the tissue (streptococci, staphylococci, gonococci, anthrax-bacilli, etc.) the leucocytes may act as phagocytes (microphages) and aid in the destruction of the bacteria. The lymphocytes and mononuclear leucocytes of the granulation- tissue are cells which for the chief part arise from the blood, although such cells may later be present in the tissue, and, increasing by division 3.52 INFLAMMATION. may be mingled with the cells of the exudate. Many of them die in the granulation tissue, as do the polynuclear leucocytes ; or, on the other hand, they may change into various cell-forms, and from this point of view they may be designated polyblasts. Enlargement of the cell-protoplasm and a certain enlargement and clearing of the nucleus give them the character of epithelioid cells ; yet usually they are of smaller size than fibroblasts and their nuclei stain Fig. 217. — Tissue from a scar sixty-five days old (Maximow, 1. c). a, Fibroblasts; 6, &,, spindle- formed lymphocytes (polyblasts), with elongated nuclei embedded in the tissue; c, plasma cell. .- 500. darker (iron-haematoxylin or methylene blue) than those of the fibro- 1 ilasts. By sending out plump pseudopodia they may take on the most varied forms { Fig. 216, b). On the surface of smooth foreign bodies they may also form an epithelial-like deposit or coveriug. In the development of fibrous cicatricial tissue they may be embedded as permanent elements of the same in the form of spindle cells which finally can be distinguished only with difficulty or not at all from the ordinary connective-tissue cells (Fig. 217, b, b t ). Occasionally they assume also a character corresponding to that of the so-called Idasmatocytes of Rainier (Fig. 218, b), that is, they form spindle or branched cells, coarsely granular, showing many vacuoles and often containing granules staining metachromatically (polychrome methylene blue). Further, they can assume the appearance of plasma-cells (Figs. 217, c, 218, c), that is, round oi- irregularly formed cells having an eccentric nucleus and a bright cen- tral and a dark granular peripheral plasma.. These plasma-cells later die or take on the appearance of the first-named forms. The derivatives of the lymphocytes, polyblasts, are those cells which diow the greatest activity in the granulation tissue as phagocytes, and GRANULATION TISSUE. 353 not only take up bacteria but also cells, red blood-cells and leucocytes (Fig. 214), and destroy them or carry them away. They have also an especial inclination to form multinucleated giant- Fig. 218. — Plasma cells and klasmatocytes within scar tissue, forty days old (Maximow, I. a), a, Fibroblasts; b, klasmatocytes; c, plasma cells; d, blood-vessel. X 500. cells, and, indeed, syncytial forms, that is, through the confluence of cells lying in close contact. This is most frequently observed when larger or smaller foreign bodies or necrotic portions of the tissue lie within the granulation tissue (Fig. 219, d), and they are therefore designated as foreign-body giant-celis. Soluble substances, for example, catgut sutures or necrotic muscle-substance, can be gradually dissolved by them. The presence of certain forms of bacteria (tubercle-bacilli and lepra- bacilli) can also lead to their formation. The blood-vessels of the granulation tissue arise through offshoots from the old vessels (see Fig. 166), which very early, even at that time in which the immigration of leucocytes takes place (Fig. 220, b, &,), show Fifj. 219.— Dog's hair encapsulated in the subcutaneous tissue (alcohol, Bismarck brown), fibrous tissue ; c, proliferating granulation tissue ; d\ giant-cells. X 66. a. Hair ; b, proliferative processes (a), and in the formation of granulation tissue take on a very lively proliferation. The .young granulation tissue, as a result, becomes permeated by a great number of blood-vessels, so that it acquires a red appearance. During the transformation of the granulation 23 354 INFLAMMATION. Fig. 220. —Cross-section of blood-vessel from the deep layers of the skin, forty hours after painting the skin of a rabbit with tincture of iodine (Flemming's solution, safranin). a. Endothelial cells with mi- toses; &, h u leucocytes. ■' 350. tissue into connective tissue or scar-tissue there occurs an obliteration of the vessels and the scar becomes pale. The structure of the granulation tissue, the origin and the fate of the cells contained in it, have been for decades the object of investigation and discussion, and even to-day not all of the questions can be regarded as solved. It has been demon- strated beyond doubt, however, that the builders of cicatricial tissue, the fibroblasts , are derivatives of the fixed connective-tissue cells ; further, it is certain that the polynuclear leuco- cytes arise from the blood and undergo no fur- ther development. The origin of the small mononuclear cells which resemble the lympho- cytes and the mononuclear leucocytes of the blood is still a matter of dispute, as is also the role which they play within the granulation- tissue. Even in the "year 1S76, on the ground of experimental investigations, I expressed the opinion that the}' were capable of a further development into epithelioid cells ami that at the time of their formation and transformation they exert phagocytosis and take up other cells and digest them and that they can become changed into permanent elements of cicatricial tissue. I have further demonstrated that under especial conditions they form syncytial giant- cells. Maximow, through investigations carried on in my laboratory in the years 1901- 1902, has confirmed the view that the mononuclear leucocytes and lymphocytes, after passing out from the blood-vessels, may undergo further development, and has demon- strated that within the cicatricial tissue they take on in part the appearance of klas- matocytes, plasma-cells , and mast-cells, also in part appearances similar to those of the ordinary fixed connective-tissue cells, so that finally differentiation of the two cell-forms is no longer possible. They also change in part to fixed connective-tissue cells, but do not produce, as 1 formerly assumed, the fibrillary ground-substance. With reference to the varied forms which these cells show, Maximow has designated them polyblasts. Much more appropriate would be the term polymorphocytes or poikilocytes, although the latter term is in common use for various forms of degenerating red blood-cells. The differentiation of the different cell-forms as given above, rests essentially upon differences in the structure of the protoplasm. Plasma cells ( Unna) or the " krumel- zellen" (von Marschalko) are mononuclear, round or oval, at times elongated cells that stain intensely with methylene blue and possess an eccentrically placed nucleus showing a chromatin network and five to eight chromatin granules. At the periphery of the cell the protoplasm is more densely clumped, so that there is formed a lighter area surrounding the nucleus. The klasmatocytes (Ranvier) are spindle-shaped, branched or stellate cells with blunt or swollen ends and a granular protoplasm that often contains little vacuoles. The mast-cells (Ehrlich) are round or flat or spindle-shaped cells, with numerous distinct coarse granules that, with the basic aniline stains, show an intense metachromatic reaction. Cells of the character of lymphocytes, leucocytes, plasma-cells, klasmatocytes, and mast-cells occur even in normal tissue and are regarded by some authors as especial forms of tissue cells and by others as cells arising from the blood. According to what we know of their occurrence the most correct view is probably that which regards them as different stages of development of a mesenchymal group of cells of an especial kind that are to be separated from the tissue-building fixed cells, and to this group there should be added also the polynuclear leucocytes anil the eosinophil cells. Certain stages of development are present in the blood, others are found in the tissue and, indeed, partly in especial tissue-formations (lymphadenoid tissue, bone-marrow), and partly in ordinary connective tissue. Under certain conditions (he individual forms may pass into one another, as, for example, lymphocytes may become transformed into plasma cells and klasmatocytes into mast cells. The mononuclear cells that collect so quickly in an inflammatory area arise, for the chief part, from the blood-vessels. When the given cell-group occurs at the place of inflammation (as, for example, perivascularly situated klasmatocytes or lymphocytes) they may increase by division and take part in the formation of the cellular collections. In scar tissue, for example, polyblasts of the appearance of klasmatocytes may change again into cells corresponding to amoeboid lymphocytes. INFLAMMATORY NEW-FORMATION OF TISSUE. 35.5 Literature. {Inflammatory New-formation of Tissue.) Arnold: Teilungsvorgange an den Wanderzellen. A. f. mikr. Anat., xxx., 1S87; Altes u. Neues tiber Wanderzellen. Virch. Arch., 132 Bd., 1893. Askanazy: Das basophile Protoplasma der Osteoblasten. C. f. a. P., xiii., 1902. Ba.llance: The Genesis of Scar Tissue. Verh. d. X. internal:, med. Kongr., ii., Berlin, 1891. Baquis: Et. expe>. sur les retinites. Beitr. v. Ziegler, iv., 1888. Bardenheuer: Die histologischen Vorgiinge bei der durch Terpentin hervorgerufenen Entzundung im Unterhautzellgewebe. Beitr. v. Ziegler, x., 1891. Beattie: The Cells of Inflamm. Exudations. J. of Path., viii., 1902. Borst: Chron. Entziind. u. pathol. Organisation. Ergeb. d. allg. Path., iv., 1900. v. Brann: Ueber die Entzundung seroser Haute. B. v. Ziegler, xxx., 1901. Bxisse: Heilung asept. Schnittwunden d. Haut. Virch. Arch., 131 Bd., 1893. Biittner: Verh. d. Peritonealepithels bei Entztindung. Beitr. v. Ziegler, xxv., 1899. Coen: Veranderung d. Haut unter d. Wirkung v. Jodtinktur. Beitr. v. Ziegler, ii., 1888. Cornil: Des hematomes. Arch, des sc. med., Paris, 1896; Adherences des membranes sereuses. Arch, de med. exp., 1897. Dominici: Polynucleaires et macrophages. A. de med. exp., 1901. Eberth: Kern- u. Zellteilung bei Entzundung. Festschr. f. Virch., ii., Berlin, 1891. Ehrlich, L.: Ursprung der Plasrnazellen. V. A., 175 Bd., 1904. Enderlen u. Justi: Unnasche Plasrnazellen. D. Z. f. Chir., 62 Bd., 1901. Fischer: Experim. Enters, lib. d. Heilung v. Schnittwunden d. Haut. I.-D., Tubin- gen, 1888. Foa: Sur la prod, des cell, dans l'inflamm. A. ital. de Biol., xxxviii., 1902. Grawitz: Wanderzellenbildung in der Hornhaut. V. A., 1.58 Bd., 1899. Hamilton: On Sponge Grafting. Edinb. Med. Journ., xxvii., 1881-82. Haug-: Ueber die Organisationsfahigkeit der Schalenhaut des Hiihr.ereies. Munchen, 1889. van Heukelom: Sarkome u. plastische Entztindung. Virch. Arch., 107 Bd., lOGV. Jolly: Sur les mouvements des lymphocytes. A. denied, exp., 1903. Justi: Die Unnaschen Plasrnazellen. V. A., 150 Bd., 1897. Karg-: Entztindung und Regeneration. Dtsch. Zeitschr. f. Chir., xxv., 1S87. Klemensiewicz: Eiterzellen. Mitt. d. Ver. d. Aerzte v. Steiermark, 1898. KrafFt: Zur H, corium ; c, fibrinous exudate, in part haemorrhagic ; d. newly formed epidermis, containing numerous division-figures, and with plugs of epithelium extending into the underlying exudate ; e, division-figures in epithelium at a distance from the cut ; /, proliferating embryonic tissue, developing from the connective-tissue spaces, and containing cells with nuclear division- figures, and in part also vessels with proliferating walls ; g, proliferating embryonic tissue with leucocytes • h, focus of leucocytes in deepest angle of wound ; i, fibroblasts lying within the exudate, one showing :i nuclear division-figure ; k, sebaceous-gland ; 1, sweat-gland, x 70. wound, the thickness of the exudate between the edges of the wound, and the intensity of the proliferation, the masses of embryonic tissue growing from the edges of the wound blend together, and there follows the forma- tion of young connective tissue, which joins the edges of the wound to- gether, and at the same time extends also into the old tissue, so that the boundary between the old and the new tissue becomes indistinct. While connective tissue is being formed in the deeper parts of the wound, the epithelial covering on the surface is also being regenerated (Fig. 222), and indeed in this manner, that the epithelium pushes over the wound-surface, and through a continuous cell-division (d, e) forms an epithelial covering consisting of many layers. The epithelium may HEALING BY FIRST INTENTION. 359 push across the wound-surface even before a new-formation of cells has taken place. The young connective tissue of the scar uniting the edges of the wound is distinguishable for a long time from the neighboring older tis- sue through its richness in cells (Fig. 223, d, /), as well as through the finer fibrillation of its ground-substance ; and in large incised wounds of the shin there may be found in it, here and there, after the lapse of " . a.: s~i- ;■..>'■-■■-- V UA,, ■";■ ■■■■■ l - ^Mc'^RJIr portion of a laparotomy cicatrix, sixteen days after the operation (Miiller's heson's). a. Epithelium ; o, coriutn; c, subcutaneous fat tissue; ci, scar in Fig. 223.— Cutaneous fluirl, hematoxylin. Van (j coriuin ; e, new epithelial covering ; /, scar in fat tissue weeks or even months, slight evidence of proliferation and inflammations. In general, however, transformation processes gradually occur in the blanching scar, so that its tissues come to approach more closely to the normal, and finally the place of the incision can no longer be easily rec- ognized. If the wound heals by the interposition of abundant embryonic tissue, there may occur a defect of the papillary bodies (Fig. 223, e), so that the scar remains smooth. § 97. "When there is found upon the surface of an inflamed serous membrane (Fig. 224, «) an adherent layer of fibrin (6), there usually develop quickly beneath it granulation=formations. The earliest begin- nings of these can be seen as soon as the fourth day after the formation of the fibrinous deposit, and they consist at first of the appearance of fibroblasts (/) and polyblasts in the deepest layers of the fibrinous mem- brane. These arise through the proliferation of the connective-tissue cells of the affected serous membrane, and wander to the surface, and into the fibrin. lu association with this phenomenon there follows very 360 INFLAMMATION. Fig. 224.— Fibrin deposit and beginning formation of granulation (issue in a fibrinous pericarditis live days old (Miller's fluid, hema- toxylin), a, Epieardium ; h, Minn-membrane ; c, dilated, congested vessels ; ri, round cells infiltrating the tissue ; e, lymph-vessel Mled with cells and clots ; f, fibroblasts within the deposit. X 150. soon a new-formation of blood-vessels, and in the course of days or of weeks there is developed upon the surface a vascular embryonic tissue or granulation tissue, which, when the overlying fibrin layer' is very com- pact, lifts this up in toto (Fig. 225, b, c) ; or penetrates into the interstices of the fi- brin-membrane (Figs. 224, /,• 226, b, d), and in the course of time replaces the fi- brin. Remains of the fibrin (Fig. 226, e) may, however, often persist for a long t i m e , w e e k s o r months, within the granulation tissue. In the formation of the granulation tissue and the development of scar-tissue the epithelium (endothe- lium) of the serous membranes takes no part, since it produces no fibro- blasts. On the other hand, the products of the inflammatory prolifera- tion become covered later with epithelium. The final result of the process is the formation of connective tissue, which leads either to a thickening of the serosa which had been covered with fibrin, or to an adhe- sion of the opposing surfaces of the serous membrane, so that the inflammation may be designated as adhesive. The result in individual cases depends partly upon the amount of the' fibrin deposit and partly upon the situation of the affect- ed organ, and its condition during the process of heal- ing. Small deposits of fibrin, limited to one sur- face of the serous mem- brane, lead only to thick- enings of the serosa, which, becoming pale with the obliteration of the ves- sels, are represented final- ly by white thickenings frequently designated as tendinous spots. The firm glueing together of two serous layers by an abundant deposit of fibrin leads also to a firm adhesion of the same through the abundant forma-' Fig. 235.— Development of granulation tissue in the pleura, in bronchopneumonia and pleuritis of fourteen days' duration (alco- hol, Van Gieson) . a, Hvpenemie, infiltrated pleura ; /*, very vas- cular granulation tissue; c, tlbrln; ri, pus-corpuscles, and gran- ules of precipitated albumin. V 1U0. ORGANIZATION OF EXUDATES. 361 a F]) or extends into the exudate lying in the alveoli, in the form of an embryonic tissue (d, e), which later comes to contain newly formed blood- vessels (//). riasses of coagula with= in blood=vessels, which are called thrombi, give rise, in case no infection occurs, to an inflammatory — that is, associated with cell-emigra- tion — proliferation of the vessel-wall, a proliferating vasculitis. This process cor- responds exactly to the in- flammatory proliferation of the serous membranes. It is entirely immaterial whether the thrombosis has been caused by a preceding inflammatory process or by any other conditions, inas- much as the presence of the mass of coagulum is suffi- cient to cause inflammation and tissue-proliferation. The first change intro- Fto. 227. — Intraseptal and intra-alveolar formation of con- nective tissue in the luntr (alcohol, hematoxylin), a. Thick- ened nbrocellular alveolar septum, in part infiltrated with round cells (M; c, fibrinocelluiar exudate in the alveoli; il, intra-alveolar formative cells ; e, strand of spindle-cell fibroblasts; (/, intra-alveolar uewlv formed blood-vessel. X 200. 362 INFLAMMATION. duced in the substi- tution of the throm- bus by connective tissue is here also the appearance of fibroblasts (Fig. 228, A), which arise from the vessel-wall, and later, with the aid of vessels growing in from the vessel-wall and its neighbor- hood, form an em- bryonic tissue, which ultimately changes into connective tis- sue. The complete substitution of an obturating throm- bus or e m b o Ins leads to the obliter- ation of the vessel- lumen by vascular- ized connective tissue (Fig. 229, (/) ; the substitution of a formation of fibrous mm Fig. 328.— Development of embryonic tissue in I artery of an old man, three weeks after ligation (a n. Media; b, elastic limiting membrane; c, intiin older inflammatory processes ; r/, coagulated blood thrombosed femoral ;ohol, baematoxylin ) . i, thickened through alar infiltration of the media, /, of the intima ; f/, round cells, partly in the thrombus, partly between it and the intima; /i, different forms of fibroblasts. ■ 300 parietal thrombus, on the other hand, results in the thickenings of the vessel-wall. As the result of an 6 t, ,1 C f 'M fesSis Wsg&pz i : 'i it H'tfl 1/ FIG. 239.— Periphery of a healing pulmonary infarct (Midler's fluid, hematoxylin, eosin). a Blood- extravasate changed into a yellowish granular mass; b, necrotic alveolar septa without nuclei • c newly formed connective tissue; d, vascular granulation tissue within the alveoli; t, fibroblasts within 'alveoli containing the residue of the hemorrhage ; /, artery : g, vascular connective tissue formed within the artery at the place of the embolus. X 40. ORGANIZATION OF NECROTIC TISSUE. .363 9 fppp — b ', fc«S& 'H;/'!' W: imperfect substitution and liquefaction of the part not substituted, there arise strands and threads of connective tissue, which cross the lumen of the vessel. The calcification of portions of thrombi not replaced by connective tissue leads to the formation of vessel-stones (arterio- or phleboliths). Necrotic tissue, which cannot lie secpiestrated and discharged exter- nally, is also replaced by a vascuiar connective tissue, which becomes converted into scar-tissue ; and this substitution takes place in the same manner as in the case of fibrinous exudates and thrombi. The requisite condition for this substitution is that the necrotic tissue shall contain no sub- stances (bacteria) which hinder tis- sue-proliferation or excite severe inflam- mation. In general ic. is immaterial how the necrosis has oc- curred, and whether the necrotic tissue is free from exudate or is infiltrated with exudate or blood. The first phenom- enon leading to healing is the asso- ciation with the in- flammatory exudate, in the neighborhood of the necrosis, of a tissue-proliferation, which p r o d u c e s granulation tis- sue, which grows toward the necrotic tissue (Fig. 229, d, e), dissolves it, and finally replaces it. If this process is not disturbed by any influence whatever, even very large tissue-necroses (for example, a hemorrhagic infarct of the lungs) may in the course of weeks and months be made to disappear and may be replaced by connective tissue. It may also happen, however, that certain tissues resist absorption, or that the development of granulation tissue stops so early that remains of the necrosed tissues persist and later become calcified. When, as the result of an inflammation or ischemia within an organ, only the more sensitive elements die— for example, epithelial or muscle cells while the connective tissue remains intact, the absorption of the necrotic portions takes place very quickly, and there is formed withiu a short time a, scar or ccdlus of connective tissue (Fig. 230, e), in which the specific tissue -elements are lacking. Pus is quickly absorbed from small abscesses, and the defect dosed by granulation and scar tissue. Large amounts of pus may be absorbed from the body-cavities and from the lungs. Fig. 230.— Fibroid area in heart-muscle. Section through a muscle-tra- hecula which has undergone fibroid change (Miiller's fluid, hematoxylin). a. Endocardium ; h. cross-section of normal muscle-cells ; c, hyperplastic connective tissue rich in cells ; d, atrophic, muscle-cells in hyperplastic connective tissue; c, dense connective tissue, poor in nuclei and contain- ing no muscle-cells; f, vein, in whose neighborhood muscle-cells are still preserved ; g, smail blood-vessels ; /i, small-celled Infiltration. X 40. 304 INFLAMMATION. Abscesses cause in their neighborhood a proliferation of granulation tissue which leads to the formation of an abscess-membrane. The abscess-cavity may become obliterated through the absorption of the pus aud the growing together of the granulation -membrane covering the walls of the cavity ; the abscess finally heals and leaves a scar. Incomplete absorption may lead to thickening of the pus and later a calcification of the residue. If the pus does not become inspissated, the abscess may persist and in the course of time may be increased in size by secretion from its walls. Empyemata may heal in a similar manner to abscesses through the absorption of pus. At the time of absorption the tissues enclosing the pus produce granulation- and scar-tissue, which may reach a consider- able size when the process of absorption takes a long time (Fig. 232). When incompletely absorbed, calcification of the thickened pus may oeeiir. Foreign bodies, so far as they are absorbable and exert no specific influence upon their surroundings, are likewise dissolved, and replaced by connective tissue in the same way as are tissue-necroses or fibrin masses. If they possess accessible interstices, these may be penetrated by granulation tissue. If (heir mass cannot be absorbed, they become encapsulated. Literature. (Mealing of Wounds anil Productive Inflammation.} Anschutz: Primarer Wundverschluss. Beitr. v. Brims, xxw, 1899. Bartb.: Knochenimplantation. B. v. Ziegler, xvii., 1895. Baumgarten: Die sog. Organisation des Thrombus, Leipzig, 1877; I lie Rolle der fixen Zellen in der Entzundung. Berl. klin. Woch., 1900. Beneke: Die Ursachen der Thrombusorganisation. Beitr. v. Ziegler, vii., 1S90. Borst: Chron. Entzijnd. u. pathol. Organisation. Ergeb. d. allg. Path., iv.. 1900. Biittner: Verb. d. Peritonealepithels bei Entzundung. Beilr. v. Ziegler, x.w , 1899. Cassaet: De l'absorption des corps solides. Arch, de med. exp., iv., 1892. Chlamsky: Methoden der Darmvereinigung. Beitr. v. Brims, xxv, 1899. Cornil et Carnot: Regen. cieatricielle des conduits et des cavitcs muqueuses. Arch. de med. exp., 1898 and 1900; Cicatrisation cles plaies du foie. Sem. med.. 189S. Councilman: Acute Interstitial Nephritis (Plasma-cells). Jour, of Exp. .Me, I , 1S98. Enderlen ii. Justi: Heilung v. Wunden d. Gallenblase. Z. f. Chir., lil Bd., 1901. Foa: Ueber Niereninfarkte. Beitr. v. Ziegler, v., 1889. Giovannini: Lesioni inflammatorie e neoplastiche del la pelle. Arch, per le Sc. Med., x., 1886. Graser: Die feineren Vorgange bei Verwachsung peritonealer Blatter. Deut. Zeii. f. Chir., xxvi., 1888; Zusammenheilung von serosen Hauten. Verh. d. Chir.-Congr., 1895. Hallwachs: Ueber Einheilen von organischem Material. Langenbeck's Arch. , 24 Bd. 1879. Hamilton: ( >n Sponge Grafting. Edinburgh Med. Jour., xxvii., 1881-82. Herbert: The Young Plasma-Cell in Chronic Inflammation. Jour, of Path., vii 1900. Hilclebrand: Implantation v. Haaren in Dermoidcysten. B. v. Ziegler, vi., 1890. Hinsberg: Betheil. d. Peritonealepithels bei Einheilung v. Fremdkorp. Virch. Arch 159 Bd., 1898. Jacobsthal: Histologic der Arteriennaht. Beitr. v. Bruns, xxvii., 1900. Kaneko: Kiinstliche Erzeugung von Margines falciformes u. Arcus tendinei. A. f. Entwiekelungsmech. , xviii.. 1904. Kiener et Duclert: Formation et guerison des absces. Arch, de med. exp., v., 1893 Kruekmann: Heilung v. Lederhautwunden. v. Graefe's Arch., 42 Bd., 1890.' Krister: Wunden. Eulenburg's Realencyklop., xxvi., 1901. CHRONIC INFLAMMATION. 365 Latis: Riassorbimento del catgut. La Riforma Med., 1891. Meyer: Fremdkdrperperitonitis. B. v. Ziegler. xiii., 1893. Mbnckeberg : Verh. d. Pleuroperitonealepithels bei Einheilung von Fremdkorpern. B. v. Ziegler, xxxiv., 1903. Muscatello: Condiz. necess. alia produz. di aderenze periton. Arch, per le Sc. Med., xx., 1896. Ocheton: Transplantation toter Knochenteile. Virch. Arch., 124 Bd.. 1891. Poggi: La cicatrisation immediate des blessures de l'estomac. Beitr. v. Ziegler, iv., Jena, 1888. Ranvier: Mecanisme hist, de la cicatrisation. Lab. d'hist. du College de France, 1900. Roloff: Rolle d. Pleuroperitonealepithels bei d. Entsteh. d. Bindegewebsadhasionen. Arb. a. d. Inst. v. Baumgarten, ii., 1897. Salzer: Ueber Einheilung von Fremdkorpern, Wien, 1890. Schottlander: Kern- u. Zelltheilung im Endothel d. entziind. Hornhaut. Arch. £. mikr. Anat., xxxi., 1888; Ueber EinstichstuberkuIo.se, Jena, 1897. ScrrujeninofF: Veranderungen d. Haut nach Aetzungen. Beitr. v. Ziegler, xxi., 1897. Sanftleben: Verschluss der Gefasse nach der Unterbindung. Virch. Arch., 77 Bd., 1879. Vermorel: Rech. sur 1'inflanim. pleurale, Paris, 1S98. Ziegler, E.: Entzilndung der serosen Haute. Beitr. v. Ziegler. xxi., 1897. See also §§ 94 and 95. IV. Chronic Inflammations. § 98. Inflammation various conditions may Fie. 231. —Necrosis of fifteen years' duration in the lower pan ot the diaphysis of the femur, a. Seques- trum ; 0, c, edges of the opening in the thickened bone (alcoholic preparation) . Reduced one-third. is, according to ils nature, an acute process, but cause the phenomena of tissue-degeneration and exudation to persist for a longer time, and the inflammation be- comes chronic. The causes of chronic in- flammations may be found, in the first place, in the fact that in the course of an acute inflam- mation there occur changes which prevent a rapid healing. In this sense, as may be deduced from the foregoing, act all large tis- sue defects and tissue necroses, as well as large masses of exu- date which are with difficulty absorl table. When necrotic masses of tissue are not com- pletely absorbable, as iu the case of large pieces of bone, they may indeed become sequestrat- ed, but persist as sequestra for years (Fig. 2.31, a), and keep up a constant inflammation. Fol- lowing the production of a large, superficial defect of the skin as a result of a burn, there devel- ops a granulation tissue, but months may pass before the wound surface is covered over with epithelium from the edges and the process thereby brought to a close. A further cause of chronic 36G INFLAMMATION. inflammation is found in con For example, the frequently repeated inhalation of dust may cause chronic inflamma- tion of the lungs; repeated rubbing of the skin may cause a chronic inflammation of the part affected ; patho- logical alterations of the stomach contents may cause chronic inflammation of the stomach. In the canals of the body in which concretions may form, the latter may give rise to lasting tissue- lesions. When there exist in a tis- sue unfavorable nutritive con- ditions — i.e., marked conges- tion — these may enable slight external influences, that under normal conditions either pro- duce no inflammation at all or one soon subsiding, to set up ulcerative processes show- ing no tendency to heal. In this manner, for example, chronic ulcers of the leg may arise. A very frequent cause of chronic inflammation is fur- nished by infections, particu- larly those caused by bacteria and moulds, which multiply in the body and thus constantly give rise to new inflammatory irritation. The inflammations which they cause are distin- guished from others chiefly by the fact that they lead to connective - tissue prolifera- tions (infectious granulation tumors), and that they usually show a progressive character, and form metastases through the lymph- and blood-vessels. Finally, chronic intoxica- tions form a last cause. These affect chiefly the kidneys and the liver, and may be at- tributed either to the con- tinued introduction into the organism through the gastro- intestinal tract, lungs, or skin stantly repeated injury by external influences. ,■-%> 1 , & f mm mm Fig. 233.— ( manges in the lent pleuritis lasting six Thickenerl lung tissue with fibres in the newly form< ened pleura; c newly ton >*. m pleura and lung after a puru- nonths (alcohol, orcein) a, gland-like alveoli, and elastic : connective tissue; b, tbick- ed connective tissue without i tissue covered with pus- e t the pleura: /, elastie fibres. CHRONIC INFLAMMATION. 367 Fig. 333.— Section of a stonecutter's lunsr with fibroid nod- ules (alcohol, picrocarmine). a. Group of fibroid nodules; h, normal lung tissue; c, thickened lung tissue still containing bronchi, vessels, and a few alveoli. X 9. of substances harmful to the organs directly concerned or to others; or injurious substances may be produced -within the body itself, through disturbances of the processes of metabolism, thus giving rise to a chronic autointoxication. The forms of chronic inflammation are determined partly by their fundamental causes, partly by the character of the affected tissue. Chronic inflammations characterized especially by hyperplastic formations of connective tissue are found especially in the ser- ous membranes, lungs, and eg skin, but may occur also in other tissues. h r o n i c pleuritis, caused by exu- dates which are with diffi- culty absorbable, or by chronic infections, lead to extensive near-like thickenings of the pleura (Fig. 232, o, c), the new-formation of tissue occurring in part upon the pleura (c) and in part with- in it (b). Moreover, indu- ration of the lung («.) may follow various infectious in- flammations, or may be caused by the continued in- halation of stone dust, in the latter case being character- ized by the formation of fibroid nodules (Fig. 233, «), in part also by diffuse induration (c). Continued irritation in the neighborhood of the orifices of the urogenital apparatus, as through the discharge of irritating secretions (chronic gonorrhoea), leads frequently to the formation of pointed condylomata (condylomata acuminata) — i.e., to a hyperplasia of the papillae and epithe- lium, in which the inflamed and infiltrated papillae grow out with their vessels (Fig. 234, a, b) and frequently di- vide into branches. Frequently repeated or continued slight inflamma- tions of the skin and sub- cutaneous tissue, due to me- chanical lesions, parasites, or any other continued irrita- tion, may also, if they reach a considerable extent, give rise to a diffuse hyperplasia of connective tissue, which is known as elephantiasis. Inflammatory prolifera- tions of the periosteum and bone-marrow, which give rise to pathological new-formations of hone or a hyperostosis (Fig. 235), may be caused both by non-specific irritations— for example, by inflammations which run their course in the neighbor- hood of chronic ulcers — as well as by specific infections — for example, syphilis or tuberculosis. Fig. 234. — Condyloma acuminatum (injected preparation). a. Enlarged branching papillas ; b, epidermis. X 20. 368 INFLAMMATION. Chronic catarrhs of the mucous membranes are sometimes caused by specific infection (gonorrhoea, tuberculosis), sometimes by non-specific injuries (concretions, pathological changes in the gastric or intestinal contents), and sometimes by continued disturbances of circulation (con- gestion). Chronic abscesses arise usually from acute abscesses, and have the same etiology as the latter; but may also develop more gradually and are then caused by special infections, most fre- quently tuberculosis and actinomycosis. They are usually limited externally by a connec- tive-tissue membrane covered with granula- tion tissue, and may increase in size partly through the secretion of pus from the ab- scess-wall, and partly through the destruction of the wall and the neighboring tissue. Pro- gressive enlargement toward the deep-lying parts leads to the formation of burrowing or congestive abscesses. Their increase in size is always to be ascribed to the persistence of the infection. Perforation into neighboring tissues leads accordingly, also, to new infect- ive inflammations. The tuberculous and actinomycotic forms of chronic abscesses are distinguished from other forms partly by the specific characteris- tics of the pus and partly by the peculiar structure of the abscess-membrane (see Tuber- culosis and Actinomycosis, Chapter X.). Chronic ulcers are caused chiefly by spe- cific infections (tuberculosis, syphilis, gland- ers), but non-specific injurious agents may lead to chronic ulcerative processes in tissues which are especially susceptible to such changes. Thus chronic congestion in the vessels of the leg may have such an effect that ulcers arising through any mechanical influence may be prevented from healing un- der the unusual conditions in which the leg finds itself. Likewise peculiar qualities of the stomach contents may hinder the healing of an ulcer of the stomach. If healing be- gins at one edge of an ulcec while the ulcera- tion advances at other parts, there arises the form of ulcer known as serpiginous. The ex- cessive development of granulation tissue in an ulcer leads to the production of an ulcus eleoatum Jiypertrophicum j a dense callous, lardaeeous thickening of the edge and base gives rise to the form known as ulcus callomm, or indolens or atonicum. Chronic proliferations of granulation tissue — i.e., granulations tohieh persist as such for a longer or shorter time without becoming changed into connective tissue — occur chiefly in various specific infections, the best known being tuberculosis, syphilis, lepras)/, glanders, rhinoscleroma, and actinomycosis. Since the granulations in these infections often form Periosteal hyperostosis of the tibia, at the base of a chronic ulcer of the leg. Reduced twe- lfths. VARIETIES OF CHRONIC INFLAMMATION. 301:1 fungoid proliferations and tumor-like formations, they are often also called fungous granulations or caro luxurians and infectious granula= tion tumors or granulomata. All these show certain peculiarities which enable us to recognize, from the structure, origin, and life-history Fig. 236. — Section through the mucosa of an atrophic lan?e intestine (alcohol, alum-carmine), a. Glan- dular layer decreased to one-half its normal height; b, muscularis mucosa; ; c, submucosal d, muscularis; e, total atrophy of the mucosa. X 31). of the granulation -formation, also its specific etiology (see Chapter X.). It should be noted, however, that the etiology of some of the granulo- mata developing in the skin is still unknown. Chronic inflammations in which atrophy of the specific tissue is Fig. 237. — Induration and atrophy of the renal tissue in chronic nephritis (alcohol, alum-carmine), a, Thickened and fibrous capsule of Bowman ; o, normal glomerular vessels; c, glomerulus whose vascular loops are in part impermeable and homogeneous, and the epithelium for the greater part lost; d, com- pletely obliterated glomerulus; c, homogeneous masses of coagulation, arising from exudate and desqua- mated epithelium, and studded with nuclei; f, desquamated glomerular epithelium; g, capsular epithe- lium; li, collapsed urinary tubule with atrophic, epithelium; i, collapsed tubule without epithelium; h, hyperplastic connective-tissue stroma; !, cellular foci; m, normal, somewhat dilated tubules; n, afferent vessel ; o, vein. X 25(1. associated with hyperplasia of the connective tissue, occur particularly in the mucous membrane of the gastro-intestinal tract, and in the kid- neys and liver. 24 370 INFLAMMATION. In the intestinal canal the cause may lie in specific (dysentery) as well as in non-specific irritations ; the latter being dependent upon some abnormal property of the contents of the canal. The epithelial elements may undergo necrosis in association with persistent desquamation, the connective tissue being unaffected ; or they may necrose and disintegrate at the same time with the connective tissue upon which they rest. The final result is a mucous membrane (Fig. 236) which either contains no glands (e) or only rudimentary ones (a). In the liver and kidneys the chronic inflammations which lead to atrophy and induration, and whose final results are known as cirrhosis of the liver and indurated contracted kidney, are hematogenous dis- eases, in so far as they do not depend upon disturbances in the efferent PIO. 238.— Connective-tissue hyperplasia ami proliferation of bile-ducts in chronic hepatitis (alcohol, hsematoxylin). a.ii^ Liver-lobules; o, hyperplastic periportal connective tissue; c, old bile-ducts: d, newly formed bile-ducts ; e , foci of small-celled infiltration. / 55. passages (obstruction, inflammation of pelvis of kidney, formation of concretions), and are caused partly by infect ions and partly by intoxica- tions. They may begin either as acute inflammations or more insidiously, and are characterized by atrophy and degeneration of the glandular tis- sue (Fig. 237, h, i), hyperplasia of the connective tissue (Fig. 237, a, 1c, and Fig. 238, 5), through cellular infiltration, formation of granulation tissue (Fig. 237, I, and Fig. 23S, e), through obliteration of old vessels (Fig. 237, c, d ), and through the formation of new vessels. In the liver there occurs also very frequently a formation of new bile-ducts' (Fig. 238, d), which, however, for the greater part do not functionate. CHAPTER VIII. Tumors. I. General Considerations. § 99. A neoplasm, or autonomous new-growth, atypical blastoma or tumor in the narrower sense, is a new-formation of tissue, apparently arising and growing independently, having an atypical structure, inserted uselessly into the organism, possessing no function of service to the body, and showing no typical termination to its growth. The atypical character of the structure of a tumor is shown in its external appearance as well as in its internal organization in that a true tumor departs more or less in struct- ure from that of a normal organ. When this departure is but slight, the structure of the tumor approaches closely to that of the tissue-hypertro- phies; and there occur cases in which the difference in structure is so little that it becomes very difficult to decide whether an excessive new- growth of tissue is to be classed as a tumor or a hypertrophy. Tumors may develop in any tissue of the body which is capable of growth, and arise through the proliferation of the tissue-cells, asso- ciated with a new-formation of blood-vessels. Xot infrequently there occurs also an emigration of leucocytes and. lymphocytes into the tumor, and exudative processes and inflammatory tissue-proliferations may take place in its neighborhood, but these phenomena form no essential part of the develojjment of the tumor. The processes of cell-division and new-formation of blood-vessels are the same as those described in §§ 80 and 82 — i.e. , the division of the cells takes place by karyomitosis, and the new vessels are formed from buds given off by the proliferating cells of the walls of old vessels. The mitoses are for the greater part typical (Fig. 239, b), but there are also found relatively often atypical forms, such as asymmetrical divisions, nuclear figures with abnormally large chromatin masses (so-called giant mitoses), pluripolar mitoses, and forms of nuclear fragmentation, and also direct segmentation. In their fully developed condition tumors are for the greater part well defined from the surrounding tissues, but in some cases they may pass into the neighboring tissue without any sharply defined border of transition. Further, an entire organ may become transformed into a tumor, or large portions of tissue not sharply outlined from their surroundings may take on the character of a tumor. Through the disintegration of tumor tissue there very fre- quently arise ulcers. The difference between the structure of a tumor and that of normal tissue is usually recognizable even macroscopically, but there are also tumors which so closely resemble the parent tissue from which they arise that the difference can be made out only through a more careful exami- nation. The circumscribed tumors are usually nodular (Figs. 240, d ,• L'42, d, e ; 243, a). The size of the single nodules varies, according to the kind of 371 m TUMORS. tumor and the stage of development at the time of examination, from the smallest visible miliary and submiliary nodules to masses weighing ten to twenty kilograms or more. When situated upon the surface of an organ nodular tumors not infrequently take on the form of a sponge (Fig- 240, d) or of a polyp, and are accordingly designated fungoid or polypoid tu- mors. "When a new-growth on the surface of a mucous membrane or the skin leads to an enlargement and branching of the papillae there present, or if new papidae are formed, there arise warty, verrucose, and papillary tumors or papillomata (Fig. '241). A further development of the papillary structure may lead to a dendritic branching and the formation of a cauli- flower mass. Tumors usually develop from small beginnings; only rarely do they arise from centres extending diffusely throughout an entire organ. Their w Fig. 239. — Tissue from a carcinoma of the breast, containing numerous division-figures in different phases of mitosis (Flerflming's solution, safranin). a, Stroma; /», epithelial plugs. 500. growth may be either rapid or slow, and with occasional periods of qui- escence. Their growth may be suspended for years, and then suddenly again they become active. The structure of the tumor is determined, by the parent tissue from which it takes its origin ; and although the true tumors always show a cer- tain atypical character, they yet retain certain characteristics of the parent tissue. According to their structure and genesis tumors may be divided into three groups: 1, connective -tissue tumors: 2, epithelial tumors; 3, teratoid tumors and cysts. It should be noted, however, that there are many forms of tumors which, according to Hie point of view, may be classed as be- longing to two, or even to all three groups. The connective-tissue tumors or the tumors arising from the sup- porting-tissue substances, and which are often called histoid tumors, con- sist of tissues which in their structure correspond in part to mature and in part to embryonal connective tissue of the mesoderm, and moreover take their origin from mesodermal connective tissues. Ordinarily there GENERAL CONSIDERATIONS REGARDING TUMORS. 373 are also included in this group those tumors arising from the specific elements of the nervous system, the glia-cells and ganglion - cells, and also the muscle-tumors, since these in their structure resemble the connective-tissue tumors much more than they do the epithelial. The differences in the types of the con- nective - tissue tumors are essentially depen- dent upon the charac- ter of the ground-sub- stance, and in part also upon tin- cells. When the tumors are very rich in cells and (he ground - substance but slight] y developed, they acquire a soft con- sistency and are classed with the sarcomata. Very soft forms are designated as medullary or fix ii g i medullares. Through the combina- 1 ion of differenl forms of connective tissue there arise mixed, con- nective-tissue tumors. The epithelial tu = mors are composed of cells derived from sur- face epithelium or from (/land '-cells, and also of vascular connective tissue — which forms a supporting framework in the spaces of which the cells arising from the proliferation of surface epithelium or gland-cells lie in definite groups. Inasmuch as this arrangement gives to the tumors a. structure suggesting that of a gland, they are often also called organoid tumors, in contradistinction to the histoid connective-tissue tumors. It should be noted, however, that there are also included in the connec- tive-tissue group of tumors certain varieties (endotheliomata) which have an organoid structure. The cells which give the epithe- lial tumors their especial character arise either from the ectoderm or en- toderm, and from the glands devel- oping from the same, or finally from the mesodermal epithelium of the pericardium, and of the pleural and peritoneal cavities, or of the glands arising from this layer (kidneys, sexual glands, adrenals). Tumors having the last-named origin often show more or less distinctly the especia from which they arise. Very soft cellular epithelial tumors are also designated medullary fig. ::w. wall of the tumor. Tw -Fungoid carcinoma of the endometrium of the posterior uterus, a, Body of the uterus; h, cervix ; c, vagina; '/, j-thirds natural size. Fig. 241.— Pa] try adenoma of rectum, ural size. character of the parent tissue 374 TUMORS. Combinations of epithelial proliferations with proliferations of the connective tissue, which exceed the ordinary amount of supporting tis- sue or bear a sarcomatous character, lead to the formation of epithelial mixed tumors. The teratoid tumors and cysts form a group which is especially characterized on the one hand by the fact that they contain the most varied kinds of tissue which may be derived from all three germ-layers {teratoid mixed tumors), and on the other hand by the presence of tissue formations in regions where they do not normally occur. Tumors, there- fore, which according to their structure may be placed in one of the other groups, may be considered as teratomata on account of their situation. Further, there are also included in the group of teratoid tumors certain formations which according to their structure, origin, and physiological relations ought not to be classed with the tumors. Tumors usually develop singly ; but it also happens that within a certain tissue system there may appear either coiucidently or in succes- sion a great number of tumors of the same kind, so that it must be assumed that the conditions requisite for the development of these tu- mors were present in different parts of the system affected. At times there develop in different organs of the same individual two entirely dif- ferent varieties of tumors, which stand in no relation to each other, and whose coincident appearance is purely accidental. The exact determination of what should he included under the term tumor is hardly possible ; and consequently the designation tumor is applied to many different formations which, according to their etiology, genesis, and life-characteristics, have not the same significance. The idea of tumor is, therefore, very differently conceived by different authors. I regard it as advisable, and also as based upon the life-characteris- tics of the tissue-formations which we are about to consider, to exclude in the first place from the class of tumors all hyperplastic proliferations, and further all retention-cysts which arise purely through the retention of secretions and show no independent new- formation of tissue. Further, according to my view, there should be separated from the true tumors all proliferations of tissue due to the presence of parasites or to infection, par- ticularly the infectious granulomata which occur in tuberculosis, syphilis, leprosy, etc. Should it be proved — which so far has not bceu done — that some of the new-growths now included with the true tumors are caused by infection, the}' should also be ex- cluded from the category of true tumors. The above classification of tumors is based essentially upon their histological character and histogenesis. They may of course be classified according to other points of view. Lubavsch has offered the following classification with reference to the growth and behavior of the tumor: (1) Tumors which differ from the parent tissue in the arrangement of their elements, hut for the chief part present no recognizable increase or at most only a transitory growth (various teratoid new-growths, misplaced tissue anlage, congenital niuvi, many adenomata, myomata, fibromata, lipomata, cliondro- mata, and osteomata); (2) tumors which show a certain autonomy and independence in their structure, but yet on the whole obey the normal laws of life in that they always respect the physiological tissue boundaries (myomata, adenomata, angiomata. lipomata) • (3) tumors which are wholly emancipated from the physiological laws of life anil rule in the tissues in total lawlessness of growth (carcinoma, sarcoma). The atypical structure of tumors is not given so much prominence by all au- thors as has been done above. This is particularly true with reference to those tumors which are similar in structure to the parent tissue from which they arise, and which are accordingly designated homoplastic tumors. It should be noted, however, that even in these tumors, in so far as they represent true neoplasms (chondroma, osteoma, fibroma etc. ), there occur in general, in the histological structure, coarser' organization and external form, pronounced departures from the normal. Tumor-like congenital tis- sue-hypertrophies (for example, many osteomata), as well as hyperplastic new-for- mations of tissue resulting from inflammatory processes, must be separated from the true tumors. Tumors are in no sense useful to the organism as many tissue-hypertrophies may be. Tumor-tissue does not possess the specific activity of that tissue' from which DEVELOPMENT OF TUMORS. 375 it springs, so that tumors can in no way be regarded as useful new-formations of tissue. It happens, indeed, that in certain tumors there occur processes of secretion which correspond to normal secretions— thus, epithelial tumors may produce mucous or horny or colloid material (thyroid tumors), or bile-pigment (liver-tumors), even in metastatic nodules — but from these facts we can conclude only that, in many tumors which do not differ too greatly in structure from the parent tissue, the cells may retain, to a certain degree, for a number of generations, the functional capacities of the parent tissue. There is, however, no basis for believing that new useful tissue is formed as in the case of hypertrophy from increased labor ; the products are for the chief part of no use to the body, and though perhaps in especial cases the iodine-containing colloid produced by malignant tumors of the thyroid may be made use of, such a function must surely be of much less value than that of the normal tissue. The tumors arising from the mesodermal epithelium of the serous membranes or of the glands arising from these are included in the group of epithelial tumors. This is justified by the fact that such tumors correspond in their structure and clinical be- havior to the epithelial tumors of the ecto- and entoderm. I have also considered the question whether it would not be advisable (as Hansemann has proposed) to class also among the epithelial tumors — i.e., the adenomata and carcinomata — those tumors which have a framework of connective tissue, the spaces of which are filled, in a manner sug- gesting epithelial tissues, with cell nests arising from the proliferating endothelium of the blood- and lymph-vessels. Aside from the similarity in the structure of these tumors with the ordinary adenomata and carcinomata, there may be taken in favor of this view the fact that from the anatomical side the endothelium of the blood- and lymph-vessels is often designated as mesodermal epithelium. AgaiDst such a grouping of the endo- thelial with the epithelial tumors may be urged the facts that, aside from the general acceptance of the term endothelioma, the behavior of the endothelium of the blood- and lymph-vessels under pathological conditions is very different from that of epithelium, and that in many tumors it is impossible to separate the products of the growth of the endothelium of the blood- and lymph-vessels from the products of proliferation of con- nective-tissue cells. Literature. (Development of Tumors.) Adami: (Classification of Tumors.) Jour, of Path, and Bact., 1902. Alberts: Das Carcinom, Jena, 1887. Albrecht: Physiolog. Funktionen in Geschwulsten. Munch, med. Woch., 1902. Aoyoma: Indirecte Kerntheilung in verschiedenen Neubildungen. Virch. Arch., 106 Bd., 1SS6. Arnold: Kerntheilungen in den Zellen der Geschwulste. Virch. Arch., 78 Bd.; Kern- theilung und vielkernige Zellen. lb., 98 Bd., 18S4. Bard: Anatomie pathol. generate des tunieurs. Arch, de phys., v., 188.5; Embryologie d. Geschwulste. C. f. a. P., xiv., 1903. Borst: Die Lehre v. d. Geschwulsten, Wiesbaden, 1902. Brault: Des tumeurs. Man. d'hist. path, de Cornil et Ranvier, i., 1901. Bucher: Multiple Carcinome. Beitr. v. Ziegler, xiv., 1893. Casper: Geschwulste bei Thieren. Ergebn. d. all. Path., hi., 1898, u. Wiesbaden, 1899. Cornil: Division indirecte des noyaux et des cell, dans les tumeurs. Arch, de phys., 1886. Hansemann: Asymmetrische Zelltheilung in Epithelkrebsen. Virch. Arch., 119 Bd., 1890; Pathologische Mitosen. lb., 123 Bd., 1891 ; Die Anaplasie der Geschwulst- zellen u. die asymmetrischen Mitosen. lb., 129 Bd., 1S92; Die mikrosk. Diagnose der Geschwulste, Berlin, 1902; Gleichzeit. Vork. verschiedenart. Geschwulste. Z. f. Krebsforsch., i., 1904. van Heukelom: Sarkome u. plastische Entziindung. Virch. Arch., 107 Bd., 1S87. Kaufmann: Multiplicitat d. prim. Carcinoms. Virch. Arch., 75 Bd., 1S78. Klebs: Allgem. pathol. Morphologie, Jena, 1889. Lannois et Courrnont: Deux cancers primit. du tube digestif. Rev. de med., 1894. Lubarsch: Hyperplasie u. Geschwulste. Ergebn. d. allg. path. Morph., Wiesbaden, 1895; Zur Lehre v. d. Geschwulsten, Wiesbaden, 1899; Geschwulste, Ergeb. d. a. P., vi., 1901 (Lit.). Marchand: Bezieh. d. path. Anat. z. Entwickelungsgesch. Verh. d. Deut. path. Ges., ii., Berlin, 1900; Gewebsw 7 ucherung u. Geschwulstbildung. D. med. Woch., 1902. Muller: Cellulare Vorgange in Geschwulsten. Virch. Arch., 130 Bd., 1892. Muller, J.: Ueber den feineren Ban und die Formen der krankh. Geschwulste, 1883. Paget: Lectures on Tumors, 1852. 376 TUMORS. Petrone: Breve guida alio studio dei tumori, Catania. 1S90. Ribbert: Geschwulstlehre, Bonn, 1904. Schimmelbusch: Multiples Auftreten prim. Carcinome. Langenbeek's Arch., 39 Bd., 1SS9. Schmidt: Secret ionsvorgange in Krebsen. Virch. Arch., 148 Bd.. 1897 (Lit.). Senii: Pathology and Surgical Treatment of Tumors, 1895. Strobe: Kerntheilung und Riesenzellenbildung in Geschwidsten. Beitr. v. Ziegler, vii., 1890; Cellulare Vorgange u. Erscheinungen in Geschwidsten. lb., xi., 1891; Neuere Arbeiten fiber Histogenese u. Aetiologie des Carcinoms. CM. f. allg. Path., ii., 1891. ' Thiersch.: Der Epithelkrebs der ausseren Haut, 18(35. Trambusti: Bau u. Theilung der Sarkomzellen. Beitr. v. Ziegler, xxii., 1897. Virchow: Die krankhaften Gesclrwulste, i.-iii., 1863-G7. Wells: Multiple Primary Tumors. Jour. Path, and Bact., 1900 (Lit.). White: The Definition, Terminology, and Classification of Tumors. Jour, of Path., vi., 1899; Pathogenesis of Tumors. J. of Path., vii.. 1901. Williams: The Principles of Cancer and Tumor Formation, London, 1S89. Wilms: Die Mischgesehwiilste, i.. ii., Leipzig, 1899, 1900. See also §§ 100 and 101. § 100. The etiology of tumors is by no means uniform, and very often cannot be determined with certainty. In the majority of cases, however, the conditions, at least, under which the new-growth appeared can be assigned and we may accordingly establish different groups of tumors. Infection is indeed very frequently advanced as a cause of tu- mors, but such etiology has not in any case been demonstrated beyond doubt. As the first group of tumors, according to etiology, may be taken those arising from especial congenital anlage, so that we may in a certain sense regard them as local malformations of tissue. They develop either in uterine life, and are present at birth, or later in extra-uterine life, dur- ing the period of growth or even later, in which case trauma not infre- quently gives the immediate occasion for the beginning of the develop- ment of the tumor from the preexisting anlage. To this group belong in the first place many osteomata, choudromata, angiomata, gliomata, fibromata (of the nerves and skin), sarcomata and adenomata. Further, many teratoid tumors and cysts are also to be included in this group, inasmuch as they represent in part either re- mains of foetal structures, transpositions or monogerminal inclusions of embryonic tissue, implantations of rudimentary portions of a twin em- bryo (bigerminal implantations), or probably also the results of disturb- ances of the earliest, stages of the development of the ovum. A second group develops after traumatic injuries of the tissues ; and. it has been reckoned that in about seven to fourteen per cent of cases a trau- matic origin can be assigned ; particularly in the case of sarcoma, carci- noma, and osteoma. The causes of the tumor-formation may be a single injury, a. stab, a blow, crushing, fracture, etc., as well as repeated me- chanical irritation, such as rubbing, scratching, etc. Ju a third group the development of the tumor follows inflammation, par- ticularly the formation of granulation tissue with subsequent cicatrization. The inflammation and ulceration may be caused by non-specific as well as by specific injurious agents. For example, cancer of the gall-bladder (Fig. 242, d, e) almost invariably develops only in gall-bladders which contain stones, and are consequently the seat of chronic inflammation. In the stomach, cancer may develop in the edge of an ulcer or in the result- ing scar- and also in a mucous membrane which lias suffered severe changes as the result of previous inflammation. In the external skin and also in the mucous membranes of the pharynx and larynx cancers occasionally ETIOLOGY OF TUMORS. 377 arise in the base of a tuberculous <>r syphilitic granuloma or in the scar of such a process. In a fourth group the development of the tumor* appears to owe its origin Fig. S4XJ. —Primary carcinoma of the gall-bladder enclosing an imparted gall-stone. Frontal section through the Rail-bladder and liver, a. Liver ; />, duodenum ; c, gall-stone ; the gall-bladder tumor. Natural size. to an unequal atrophy of the elements which make vp a tissue, so that certain hindrances to growth are removed or lessened. Not mechanical resistance alone, but influences dependent upon the chemical conditions of the tis- sue, should be considered in this connection. Here belong especially cer- tain epithelial proliferations (cancers) which develop in old age, or in organs which after a period of increased activity become atrophic. In this way, for example, the development of cancer of the skin may be explained on the ground that the connective tissue of the skin undergoes a certain retrogression leading to a relaxation of its structure, while the epithelium is still possessed of its full power of proliferation. At the same time the chemical composition of the connective tissue may be altered. It cannot lie doubted that the etiology of tumors is not always the same, as is shown by the variety of conditions under which they arise. It is difficult to say what is the nature of the influence which excites the cells to the production of an atypical tissue. We are at first inclined to think of the same causes which underlie hypertrophy and regeneration of tissue, also, on the one hand, of espe- cial congenital anlage or of stimuli which increase the formative activity of the cells, 378 TUMORS. and on the other hand, of a lessening or removal of hindrances to growth. But it still remains a problem why there should not be formed typical tissues which would so fit into the organization of the body that they would be of service to the latter. In the attempt to explain this phenomenon, which is at the same time associated with an in- crease in the vital and reproductive capacities of the cells, even under pathological con- ditions (metastasis of the cells through the blood- and lymph-vessels), many writers have sought and would recognize as the cause the presence of parasites (see Etiology of Carcinoma) ; but our present knowledge does not in any way justify us in attributing the development of true tumors, of autonomous new-growths, to the influence of para- sites. On the contrary, the development and life-history of tumors, and in particular the formation of metastases, which without doubt arise through the multiplication of living tumor-cells transported in the lymph- or blood-stream, speak against the hypoth- esis of the parasitic nature of tumors. Coltnht'im advanced the theory that all true tumors arose from especial tumor- anlage which had their origin in the persistence of foci of embryonal tissue. Neither the results of clinical observation nor of the anatomical investigation of the tissues speak in favor of such a theory. Bibbert is of the opinion that the cause of the pathological proliferation which leads to tumor-formation is to be found particularly in a separation of cells or cell-groups from their organic relations, such a separation occurring cither as the result of intra- uterine disturbances of development or later under the influence of external agencies. Nevertheless, such transplantations or separations of cell-groups take place very fre- quently in intra-uterine life, or after trauma, after ulceration, in scars and in infectious granulomata, without any subsequent development of a tumor. These transplanta- tions of tissue constitute only one of the predisposing causes of tumor-formation, but some other factor is necessary to excite the atypical progressive tissue-proliferation — i.e., the development of the tumor. The development of a tumor is, therefore, in no icise depen- dent upon a transplantation of tissue ; rather does the tumor-proliferation take its origin in cells winch are normally situated ; and this may be actually demonstrated, particularly in the case of epithelial tumors. Beard holds the view that tumors, in particular the carcinomata, arise from sexual cells which, during the development of the body, have been displaced between the so- matic cells and are there preserved. Our knowledge of the causes of tumor-development at the present time may be summed up as follows: Inherited and acquired conditions of certain cells and cell-groups, which assert themselves in a tendency to increased formative activity with the production of atypical tissue, lead to the formation of tumors. In many cases this proliferation is prepared for, favored, and excited by the transplantation of cells and cell-groups, but often also through changes in the neighborhood of the cells concerned. No general scheme applicable to the development of all tumors can be given. On the contrary, the conditions vary not only with the different forms of tumors, but also with the indi- vidual cases of the same tumor-type. Moreover, it should not be forgotten that the formations which we class as tumors do not all possess the same significance, and that many of the same ought more properly to be classed with other phenomena of growth (malformations). f Literature. (Etiology and Genesis of Tumors.) Adarni: On Growth and Overgrowth, etc. Med. Chron., 1900; Concerning the Causa- tion of Cancerous and Other New-Growths. Yale Med. Jour., 1901. Askanazy: Geschwlilste d. in d. Niere eingeschloss. Nebennierenkeime. Beitr. v. Ziegler, xiv., 1893. Beneke: Neuere Arbeitcn z. Lehre vom Carcinom. Schmidt's .lahrb., 234 Bd., 1892; Ganglioneurom. Beitr. v. Ziesrler, xxx., 1901. Bogehold: Entwickelung von malignen Tumoren aus Narben. Virch. Arch., 88 Bd., 1883. Boll: Pas Prineip das Waehsthums, Berlin, 1876. Bonnet: Zur Aetiologie der Embryome. Mon. f. Gebh., 1901. Borsch: Pathogenese d. malignen Geschwlilste. Virch. Arch., 162 Bd., 1900. Buxton: Enzymes in Tumors. Jour, of Med. Res., 1903. Cohnheirn: Vorlesungen liber allgemeine Pathologic, Berlin, 1882. Crone: Lupuscarcinom des Kehlkopfs. Arb. a. d. path. Inst. v. Baumgarten, ii., 1894. Ozerny: Warum diirfen wir die parasit. Theorie fur die bosart. Geschwillste nicht aufgeben? Beitr. v. Bruns, xxv., 1899. Foa Sui parassiti et sulla istologia patologica del cancro. Arch, per le Sc. Med., xvii.. 1893. ETIOLOGY AND GENESIS OF TUMORS. 379 Haberern: Daten zur Lehre von den Callusturnoren. Langenbeck's Aich., 43 Bd., 1893. Hansemann; Specificitat, Altruismus u. Anaplasie der Zellen, Berlin, 1893. Hauser: Das chron. Magengeschwiir, Leipzig, 1883; Das Cylinderepithelcarciuoni des Magens u. d. Danns, Jena, 1880; Histogenese d. Plattenepithelkrebses. Beitr. v. Ziegler, .xxii.. 1897; Primare z. Geschwulstbild. fiihr. Epithelerkrankung. lb., xxxii., 1902. Hegar: Zur Aetiologie bosart. Geschwillste. Beitr. z. Gebh., iii., 1900. Israel: Aetiologie u. Biologie d. Geschwillste. V. A., 173 Bd. 190.3. Kahane: Theorie des Carcinom. Cbl. f. allg. Path., vi., 1895. v. Karwowski: Leber Callusturnoren. Inaug -Diss., Freiburg, 1895. Kirmisson: Chirurgische Krankheiten angeborenon Lrsprungs, Stuttgart, 1899. Krister: Frag en d. path. Pflanzenanatomie (Gallenbildung). Biol. Cbl., xx., 1900. Liebe: Theer- und Paraffinkrebs. Schmidt's Jahrb., 236 Bd., 1893. Levin: Cell Proliferation under Pathological Conditions with Especial Reference to the Etiology of Tumors. Studies from Dept. of Path., Columbia University, 1901-02. LowenthaL Traumatiscbe Entstelmng v. Geschwillsten. Arch. f. klin. Chir.,49Bd., 1895. Marchand: Gewebswucherung u. Geschwulstbildung. D. med. Woch., 1903. Petersen u. Exner: Hefepilze u. Geschwulstbildung. Beitr. v. Bruns, xxv., 1899. Pianese: Beitr. z. Histologic . u. Aetiologie d. Carcinoms. Beitr. v. Ziegler, Suppl., 1890. v. Recklinghausen: Adenomyome u. Cystadenome d. Uterus, Berlin, 1896. Ribbert: Histogenese d. Carcinoms. Virch. Arch., 135 Bd., 1894; Die Entstehung d. Geschwillste. Deut. med. Woch., 1895; Das patholog. Wachsthum d. Gewebe, Berlin, 1896; Ueber Rlickbildung v. Zellen u. Geweben u. die Entstehung v. Geschwulsten, Stuttgart, 1897; Das Gefasssystem der Geschwillste. D. med. Woch , 1904. Saal: Z. Biologie d. Tumoren (Parasiten). D. med. Woch., 1904. Schuhardt: Entstehung der Carcinome aus chron. -entziindlichen Zustanden, Leipzig, 1885. Schulthess: Statistische Untersuch. lib. d. Aetiologie d. Carcinoms. Beitr. v. Bruns, iv., 1881. Siegert: Aetiologie des Gallenblasenkrebses. Virch. Arch., 132 Bd.. 1893. Stern: Maligne Tumoren im Kindesalter. Deut. med. Woch., 1892. Strobe: Neuere Arbeiten liber Histogenese u. Aetiologie des Carcinoms. Cbl. f. allg. Path., ii., 1891; Die parasitaren Protozoen in ihren Beziehungen zur menschl. Pathologic, insbes. zur Histogenese u. Aetiologie des Carcinoms (Ref.). lb., v., 1894; Entstehung d. Gliome. Beitr. v. Ziegler, xviii., 1895. TaufFer: Sarkome auf narbig lupijsem Boden. Virch. Arch., Suppl,, 151 Bd., 1898. Volkmann: Krebs d. Extremitaten. Samrnl. klin. Yortr., Nos. 334, 335, 1890. Weisflog-: Ueber Callusturnoren. Beitr. v. Bruns, x., 1893. Wilms: Die teratoiden Geschwillste d. Hodens. Beitr. v. Ziegler, xix., 1896. v. Winiwarter: Beitr. z. Statistik d. Carcinome, Stuttgart, 1878. Wieland: Primare multiple Knochensarkomc. Inaug. -Diss. , Basel, 1893. Wiirz: Traumat. Entstehung der Geschwillste. Beitr. v. Bruns, 26 Bd., 1900 (Lit.). Zahn: Zur Aetiologie der Epithelkrebse. Virch. Arch., 117 Bd., 1889. Zenker: Der Krebs d. Gallenblase. Deut. Arch. f. klin. Med., 44 Bd., 1889. Ziegler, P.: Bezieh. v. Traumeu zu malignen Geschwulsten. Munch, med. Woch., 1895. See also § 99. § 101. When once a tumor has arisen in any tissue and has reached a certain stage of development it may become quiescent in growth, and remain for a life-time without undergoing further change. This is true particularly of those tumors which according to their origin are re- garded as local tissue- malformations ; but tumors which develop first in later life may also come to a standstill after attaining a certain size. The growth of a tumor takes place independently, and in many cases continues even until death occurs. From the surrounding tissues the tumor acquires both its blood-ves- sels and thereby its food material, but may besides grow independently — i.e., through an increase of the cells which form the elements of the tumor. In many cases the tumor increases in size essentially through an 380 TUMORS. interstitial expansive growth, and the neighboring tissue is only crowded or pushed aside. In other cases the tumor tissue grows by infiltration and forces its way into the intercellular spaces of the neighboring tissue, so that new areas of tissue are thus brought under the influence ot the tumor. In this way the cells of the newly invaded tissue are often excited to proliferation," so that an enlargement of the tumor takes place through an oppositional growth, in which both the cells of the original tumor and of the surrounding tissue take part. The characteristic feature" of growth by infiltration consists in the involvement of the tissues of the organ which lie in the neighborhood of the primary tumor. Further, the tissue of neighboring organs (Fig. 242, e, f) Fig. 243,— Section through n primary eancer of the liver (a), with multiple metastases (h) within the liver itself. Three-sevenths natural size. may become involved by the tumor through its spread by contiguity. If tumor-cells gain entrance into the great body-cavities they may spread over the serous surfaces and lead to the development of tumors. If, in the process of infiltration, a tumor gains entrance into a lymph- or blood-vessel — an event which in particular is always likely to occur in the case of the tumors called carcinoma and sarcoma — and if living tumor- cells capable of proliferation are transported through the lymph- or blood- vessels, there often arise tumor=metastases — i.e., a development of daughter-tumors which are not directly connected with the primary tumor. The daughter-tumors may at first develop in the organ primarily affected (Fig. 243, b), but usually soon involve other organs as well ; in the case of rupture into the lymph-vessels the lymph-glands are first affected; in rupture into the blood-vessels, those organs to which the blood carries the living cells. The direction of the transportation is usually that of the lymph- aud blood-stream, but retrograde transportation not infre- quently occurs, particularly in the lymph-vessels, the lumina of which are easily obstructed by tumors. The development of daughter=tumors takes place in all cases from transported cells. In the event of metastasis by the lymph-vessels the affected I ympli- vessels (Fii;-. 244, a) are first filled with cells, which INFILTRATION AND METASTASIS. 381 develop from the transported tumor-cells. Later there follow a pro- liferation and new-formation of blood-vessels on the part of the neigh- boring tissue, and as a result of these processes there develop larger or FIG. 244.— Periglandular lymph-vessel (in the axillary region) filled with cancer-cells arising from a primary carcinoma of the mammary gland (Midler's fluid, hematoxylin), a, Cancer-cells; 6, wall of lymph-Vessel. X 300. smaller nodules. It also not infrequently happens that the lymph-vessels are more uniformly distended by the growth (Fig. 244, a), without any real formation of nodules, or at least only small swellings develop along the course of the lymph-vessels. In the event of metastasis into lymph-glands mm wHk Fir,. 245.— Metastatic development of cancer in the branches of the portal vein and liver-capillaries (Midler's fluid, ha?matoxylin, and eosin). ?55>J FIG. -48. — Hard fibroma from lobe of the ear (alco- hol, hsematoxylin). a. Longitudinal section ; b, trans- verse section of bundles of fibres. >; 400. («) Fibroma. § 102. A fibroma is a tumor composed of fibrous connective tissue. It occurs most frequently in the form of nodules, which are sharply circum- scribed from the surrounding tis- sues, and usually involve but a por- tion of the affected organ. Very rarely an entire organ (ovary) may become changed into a single tumor-mass. On a free epithe- lial surface and on mucous mem- branes a fibroma may appear in the form of a papilloma or a polyp. According to the character of the connective tissue of which it is composed, the consistency of a fibroma may vary greatly. Often it is hard and tough, creaking un- der the knife (desmoid), and show- ing on its cut surface a white, tendon-like, shining tissue; but in other cases the growth may be soft, flaccid, the cut surface being more uni- formly grayish - white and somewhat translu- cent. Instill other cases the individual strands of connective tissue are indeed white and shin- ing, but the tumor as a whole has a looser struc- ture and is correspond- ingly flaccid. Between the hard and soft growths there exist all possible transi- tion-forms, and even in one tumor different parts may possess dif- f e r e n t characteristics. Under the microscope the hard kinds appear to be composed chiefly of thick bundles of coarse fibres (Fig. 248, a, b), in which lie scattered a larger or smaller number of cells. In the softer forms the bundles of fibres are more delicate 25 Fig. 349.— Section of an oedematous fibroma of the uterus (osmic acid, glycerin), a. Closely lying Ubres; b, fibres pressed apart by fluid; c, spindle-shaped cells; d, swollen round cells; e, blood- vessel. X 200. 386 TUMORS. (Fig. 249, a). If as a result of venous congestion or other cause a clear fluid collects between the fibrillar there is formed an edematous fibroma, whose bundles of fibres (Fig. 240, b) are pressed apart by the fluid, the tissue becoming softer and more moist and translucent, and finally resembling the tissue of the umbilical cord. The soft forms of fibroma, which present a partly translucent, grayish- white cut surface, are usually very rich in cells; so that it is possible by teasing to isolate numerous slender spindle-shaped cells (nuclei with Fig. 250.— Fibroma pericanalicular mammae (Muller's fluid, alum carmine, eosin). a, Gland-tubules ; b, newly formed pericanalicular connective tissue rich in cells ; c. connective tissue poor in cells. -: 35. tails). The intercellular substance is correspondingly less in amount, the fibrilke more delicate and arranged in finer bundles. Sections through such fibromata, when stained, appear very rich in nuclei (Fig. 250, b). Fibromata develop from proliferating connective-tissue cells, and it is usually possible to find in the tumor certain areas which are richer in cells than the main mass of the tumor tissue, and in which the cells appear not only as small spindle cells, but also iu part as round cells, or as short, thick spindles, or even as stellate cells. The transformation of the newly formed cellular tissue into connective tissue takes place in the same way as that described under Hyperplasia of Connective Tissue. A new-formation of elastic fibres is usually wanting, but at times such a new-formation does occur, particularly in the neighborhood of the blood- vessels. Fibromata may appear in any part of the body which contains any form whatsoever of connective tissue. They occur most frequently, for example, in the nerves, skin, periosteum, fascia, mamma', and mucous membrane of the nose; more rarely in the ovary, intestinal tract, etc. In the mammary gland the development of the fibroma takes place par- ticularly around the canaliculi (Fig. 250, b), so that the latter come to be surrounded by connective tissue rich in cells. Fibromata do not form metastases, but often occur as multiple tumors, especially in the nerves and skin (see Neurofibroma, § 111 i. Moreover^ MYXOMA. 387 it is not uncommon to see within a tumor several centres of growth — that is, the mass of the tumor is made up of several nodules or bands held together by ordinary connective tissue (Pig. 250, b). Fibromata are malignant only through their size and position. Fibromata may undergo mucous or fatty degeneration or may soften and disintegrate, so that cavities may lie formed within them. They may also break through and give rise to ulcers. Their blood-supply varies greatly, at times being scanty, at other times abundant. Occasion- ally the blood-vessels are ectatic, so that the tissue is interspersed with wide channels and clefts, from which blood escapes when the tumor is examined in a fresh state. In other cases dilated lymph-channels are seen. Keloid is the designation applied to a hard, nodular, or flat and banded, or stellate growth of the skin, which in its fully developed state consists of dense fibrous tissue without elastic fibres. The direction of the fibres is often at right angles to the surface of the skin, or at least does not accord with that of the normal fibres. It usually develops after injuries or inflammations (cicatrix-keloid), but it may also appear without such association (spontaneous keloid). The cause of the keloid growth is not known ; the tendency to recurrence after removal, the multiple oc- currence, and the fact that many cases frequently occur iu the same family (Hutchinson) speak in favor of a special predisposition on the part of the skin. Literature. (Fibroma and Keloid.) Aschoff: Geschwiilste. Brgebn. d. allg. Path., v., 1900. Jacobson: Keloid. Arch. f. klin. Chir., xxx., 1884. Jores: Elastische Fasem in Bindegewebsgeschwtilsten. Beitr. v. Ziegler, xxvii., 1900, p. 389. Joseph: Ueber Keloide. Arch. f. Derm.. 49 Bd., 1899. Jurg-ens: Primare Herzgeschwiilste. Berl. klin. Woch., 1891. Lian.gb.ans : Keloid. Virch. Arch., 40 Bd., 1867. Lison: Sur la cheloide inguinale spontanee, Paris, 1887. Peterson: Ovarian Fibromata. American Gynaecology, 1902 (Lit.). v. Recklinghausen: Ueber die multiplen Fibrome der Haut, Berlin, 1882. Schiitz: Wahres Keloid combin. mit Narbenkeloid. Arch. f. Derm., 29 Bd.. 1894. Thorn: Spontanes Keloid. Arch. f. klin. Chir., 51 Bd., 1895. Unna: Die Histopathologic d. Hautkrankheiten, Berlin, 1894. "Wilms: Pathogenese des Keloids. Beitr. v. Bruns, 23 Bd., 1899. See also § 112. (6) Myxoma. § 103. A myxoma is a tumor which consists essentially of mucous tissue, and is made up of cells and a fluid or gelatinous intercellular sub- stance containing mucin. The cells of the tumor are for the greater part polymorphous, with processes of varying length (Fig. 251) which anas- tomose with one another (Fig. 252, a). The tissue is markedly trans- lucent, soft, and the blood-vessels are easily seen through it. From the cut surface gelatinous masses or a stringy fluid, which swell up in water, may be obtained. No tumor is ever wholly made up of myxomatous tissue ; the latter is usually combined with other forms of tissue, particularly with fibrous connective tissue, fat tissue, cartilage, and sarcomatous tissue. For this reason such tumors are properly designated fibromyxoma, lipomyxoma (Fig. 254), chondromyxoma (Fig. 257, c), and myxosarcoma (Fig. 252). : ;ss TUMORS. Mucous tissue may develop from fibrous connective tissue through the collection of a mucin-containing fluid between the fibrillar and the gradual disappearance of the latter. Adipose tissue may pass over into myxomatous tis- sue through the disappearance of fat from the fat-cells and the appearance of a mucin-contain- ing gelatinous substance be- tween the cells, during which process the fat-drops become broken up into swollen droplets (Fig. 254, b, c), while the cells themselves become smaller and star-shaped (rf). Cartilage may also become transformed into mucous tissue through a mucoid degeneration of the basement- substance and a change of form of the cells (Fig. 257, c, d). Myxosarcomata (Fig. 252) arise either through a local increased activity of cell -proliferation in myxomata or through a collec- tion of mucoid substance be- tween the sarcoma cells. Myxomata, myxofibromata, and myxolipomata develop most fre quently in the connective tissue of the periosteum, skin, heart, fascia, and sheaths of the muscles, as well as in the fat tissue of the subeuta Fie. 251. —Cells from a myxoma of the the femur (gold preparation). : periosteum of 400. 352.— Section of a myxosarcoma (Miiller's fluid, carmine, glycerin), n. Myxomatous tissues h strands of cells ; c, fibrous tissue. X 325. "" )u ' sln " ms neous and subserous tissues and of the endosteum. Myxochondromata occur particularly in the parotid, and constitute the most common form of tumor found there. LIPOMA. 389 These forms are all benign tumors, which rarely produce metastases. Myxosarcomata, on the other hand, have the characteristics of sarcomata and may form metastases. Literature. {Myxoma.) Berthenson: Myxome de l'oreillette gauche. Arch, de med. cxp., 1893. Hertz: Myxom im rechten Seitenventrikel. Virch, Arch., 49 Bd., 1870. Heyfelder: Zur Resection des Oberkiefers. Virch. Arch., 11 Bd., 1857. Jiirgens: Primarc Herzgeschwillste. Berl. klin. Woch., 1891. Koster: Myxom u. odemat. Bindegewebe. Sitzber. d. Niederrhein, 6es. f. Naturk., 1881. Miiller, J.: Myxom. Arch. f. Anat. u. Phys., 1836. Orth: Schleim u. Schleimgeschwillste. Ges. d. Wissenscli. zu Gottingen, 1895. Robin: Myxome du cceur. Arch, de med. exp., 1893. Rumler: Ueber Myxom. Inaug.-Diss., BoDn, 1881. Virchow: Myxom". Virch. Arch., 11 Bd. ; Geschwulste, i., 1863. Wagner: Collonema im Gehirn. Virch. Arch., 8 Bd., 1855. Weichselbaum : Myxom d. Oberscheukels m. secund. Knoten in d. Lunge. Virch. Archiv, 54 Bd., 1872. (c) Lipoma. §104. A lipoma is a tumor consisting of -adipose tissue (Fig. 253). These tumors are sometimes soft, ahnost fluctuating, sometimes firm, usually nodular and lobulated, and very often attain a very great size. In structure they are very similar to the subcutaneous adipose tissue — that is, they consist of fat-lobules held together by thick or narrow connective-tissue trabecular. Histologically, the tissue of a lipoma resembles the fat-lobules of the subcutaneous panniculus (Pig. 253), although the tendency to form typical grape-like clusters of fat-cells is wanting. If, as not infrequently happens, mucous tissue is also formed in connection with the fat tissue, or if the latter, fol- lowing a disappearance of its fat, becomes changed into myxo- matous tissue, the tumor is des- ignated a lipomyxoma (Fig. 254); if there is an abundance of fibrous tissue present, it is called a lipofibroma or fibroli= poma. Lipomata develop most com- monly from adipose tissue, but may arise also from connective tissue which normally contains no fat. Calcification, necrosis, gan- grene, and sloughing are of not infrequent occurrence in lipomata of large size. These tumors do not produce metastases, but are occasionally of multiple occurrence. A complete disappearance of a lipoma does not take place in the case of extreme general emaciation of the individual. Lipomata are sometimes observed even in new-born children — for Fig. 253.— Lipoma of shoulder region, with relatively small tat-cell3 (Jliiller's fluid, hieiuatoxylin). X 300. 390 TUMORS. example, as tumors developing in or over the cleft-formations of spina bifida— but they occur much more frequently in later years. The most common seats of these growths are the subcutaneous tissues of the back, Fig. 254.— Lipomyxoma of the bark (Miiller's fluid, Van Gieson's). o, Large fat-cells; 7), c, fat-cells in which the fat is broken up into little droplets ; (/, mucous tissue ; c, blood-vessel. X 300. buttocks, neck, axilla, abdomen, and thigh; but they are found also in the intermuscular connective tissue, subserous fat tissue, in the kidneys, intestine, mammary gland, under the aponeurosis of the forehead, in the meninges, skin, fingers, lymph-glands, joints, etc. They may occur as multiple growths, and in such cases may be symmetrically distributed. In man there may occur a. formation of fat tissue about the neck and throat, leading to nodular and lobnlated disfigurations of the skin of this region, and giving occasion for the designation fatty collar (Madelung). The development of fat in these cases takes place partly in the subcuta- neous tissue, partly in and under the fascia and between the muscles. An abnormal development of fat in an extremity may give rise to a condition of lipomatous elephantiasis. Should the process extend to the trunk and upper extremities, etc, conditions are established which re- semble very closely general obesity. Literature. (Lipoma.) 18117. Adami: Retroperitoneal Lipoma. Mont. Med. Jo Alveoli: La genesi del lipoma. Policlinlco, 1900. Askanazy: Entsteh. multipler Lipome in Lymphdriisen. Vircli 1899. Blaschko: Erbliche Lipombildung. "Viroh. Arch., 124 Bd., 1801. Brohl: Zur Actiologie u. Statistik der Lipome, Wiirzburg, 1886. Ehrmann: Multiple symmetrisehe Xanthelasmen u. Lipome. Beitr 1888. Goebel: Ueber multiple Lipome. Cbl. f. allg. Path., vi.. 1895 (Lit. — UebersV Grosch: Studien tiber das Lipom. Dtscli. Zeitschr. f. Chir., xxvi., 1887. Koettnitz: Symmetr. Auftreten der Lipome. Zeitschr. f. Chir., 38 Bd., 1894. Langer: Multiple eymmetrische Lipome. Arch. f. klin. Chir., 4(5 Bd., 1893. Archiv. 158 Bd., Bruns, iv., CHONDROMA. 391 Madelung: Ueber den Fetthals. Langenbeck's Arch., xxxvii., 1888. Mestre : Essui sur le lipome, Montpellier, 1862. Mtiller: Lipome d. Nieren. Virch. Arch., 145 Bd., 1896. Steinheil: Ueber Lipome der Hand u. Finger. Beitr. v. Bruns, vii., 1891. Virchow: Die Krankhaften Geschwiilste, i., 1863. Warthin: Fibrolipoma of the Kidney. Jour, of Path, and Bact., 1897. (d) Chondroma. § 105. A chondroma or enchondroma is a tumor consisting essen- tially of cartilage. The amount of connective tissue taking part in the structure of the tumor, in part covering its surface or accom- # - • % . panying the blood-vessels into t * " • * , * * _ <— ^Jr 7'iTriir ~ • *. fc « '■*#»• if^r" --' " '3^ ' : • ,*' *»•;"«» ' ••;'.': ffe : ?6» > ,»;.V'^ : fSfmBBBsm* * - - - - •*•••• Flo. 255. Fig. 256. FIG. 255.— Periosteal chondroma of a digital phalanx, seen In longitudinal section, a. Chondroma ; 6, phalanx. Natural size. Flo. 256.— Section from a chondroma of the ribs (hematoxylin, carmine), a. Cartilage rich in small cells ; b, cartilage rich In large cells. X 80. its interior, is so slight as to fall completely into the background when compared with the cartilage. Chondromata develop chiefly in those places where cartilage is found normally — that is, iu the osseous system or in the cartilages of the respiratory tract; but they also occur in tissues which normally possess no cartilage — for example, in the salivary glands, particularly in the parotid, and in the testicles, and more rarely in other organs. In the bones they develop from remains of cartilage which persist after ossi- fication, in the case of bones developing from cartilage ; but more often take their origin from the periosteum and endosteum (Fig. 255). They form tumors which vary greatly in size. The small ones are usu- ally spherical (Fig. 255) ; the larger ones nodular or lobulated. The individual nodules are of ten separated from one another by connective tis- sue. Not infrequently they are multiple, particularly in the skeleton, and here again of most frequent occurrence in the hands and feet and also in the testicles. The tissue of an enchondroma presents most often the characteristics of hyaline cartilage (Fig. 256), more rarely that of reticular or fibrous cartilage. At the periphery of the tumor the cartilage passes over into connective tissue, which forms a kind of perichondrium. The number, size, form, and grouping of the cartilage cells vary greatly in different cases and also in different parts of the same tumor. Many enchondromata are very cellular (Fig. 256), others poor in cells, many contain large cells, others small cells, or both large and small cells. 392 TUMORS. The cells are sometimes surrounded by the so-called capsule, at other times not; sometimes they lie in groups inside of the mother-capsule, at other times they are more regularly distributed. All the varieties of cartilage occurring normally in the organism are found in en- chondromata. Accord- ingly the cells vary in form, the majority show- ing the familiar spherical form, but spindle and stel- late cells are not rare, particularly in the neigh- borhood of the connective- tissue bands which divide the tumor into nodules or surround it as a whole. Cartilage, the perichon- drium, endosteum, perios- teum, and different forms of connective tissue may form the matrix of enchon- dromata. Those arising from cartilage or bone are known as ecchondroses. The tissue of enchondromata very frequently suffers retrogressive meta- morphoses. The ground-substance in large tumors shows a tendency to undergo in areas a mucoid degeneration and liquefaction. This may lead Fig. 257.— Chondromyxosarcomaparotidls (alcohol, carmine). «, Cartilage; b, sarcomatous tissue: c, myxomatous tissue; d, cartilage in process of liquefaction and being converted into sarcomatous and myxomatous tissue. X 80. PIG. 356.— Periosteal chondroma of the calcaneus, with areas of calcification (MiiUer's fluid, hematoxylin) a, Hyaline cartilage ; 6, c, calcified cartilage, x 235. CHONDROMA. 393 cither to the formation of mucous tissue (Fig. 257, c), thus giving rise to a eltondromyxoina ; or to a total liquefaction of the ground-substance with destruction of the cells, thus forming degeneration-cysts containing fluid. Fro. 259.— Osteochondroma of the humerus (alcohol, picric acid, hematoxylin, carmine). «, Hyaline car- tilage ; b. In me ; c, cartilage which is becoming converted into bone ; d, blood-vessel. X 250. Iii other cases the cartilage may become calcified (Fig. 25S, b, c), or true bone may be formed (Fig 259, e, b), so that the tumor must be termed an osteochondroma. Through a marked proliferation of the cartilage cells sarcomatous tissue may be developed, the tumor becom- ing changed to a chondrosarcoma (Fig. 257, b). The enchondromata are, on the whole, benign tumors, although metastases may occur following a rupture into a lymph- or blood-vessel. In the region of the spheno-occipital suture, in the median line of the clivus, there is not infrequently found a small tumor which has been designated ecchondrosls phy= salifera sphenooccipitalis (Vircliow). It either lies beneath the dura, or at its high- est point breaks through this membrane and penetrates into the arachnoid and pia. In its typical form the tumor consists of bladder-like cells, resembling plant-cells; and takes its origin partly from the bone-marrow, partly from the surface of the bone. Cartilage and bone tissue maybe associated with the peculiar tumor tissue, and for this reason Virctiow regarded the growth as a chondroma arising from remains of the sphenooccipital cartilage and characterized by a peculiar vacuolar degeneration of the cells. The peculiar character of the tissue, however, favors the view advanced by H. Mutter, and recently supported by Ribbert, that the growth is a product of a prolifera- tive activity of remains of the chorda (chordoma). It is probable that it is only a pe- culiar chondroma developing from the endosteum or periosteum. Literature. (Chondroma.) Beneke : Chondrom. Bibliothek d. med. Wiss. v. Drasche, Wien, 1900. v. Biesiadecki : Metastasenbildung. Sitzungsber. d. Wiener Akad., xvii. Birch-Hirschfeld : Zur Casuistik der Geschwulstembolie. Arch. d. Heilk., x., 1869. v. Dembowski: Chondro-Endotheliome. Zeitschr. f. Chir., 32 Bd., 1891. Ernst: Uncew. Verbreitung e. Knorpelgeschw. i. d. Blutbalm. Beitr. v. Ziegler, xxviii..l900. 394 TUMORS. Francois: Oontrib. a Vet. d. Venchondr. du bassin. These de Paris, 1876. Kast u. v. Recklinghausen : Ein Fall von Enchondrom mit ungewohnlichen Multi- plicationen (Combination mit Cavernom). Virch. Arch., 118 Bd., 1889. Klebs: Enchondrosis sphenooccipitalis amylacea. Virch. Arch., 31 Bd., 1864. Kiittner: Geschwttlste d. Submaxillaris. Beitr. v. Bruns, xvi., 1896 (Lit.). Lesser: Enchondroma osteoides mixtum der Lunge. Virch. Arch., 69 Bd., 1877. Nebelthau: Gallertgeschw. d. Clivus Blumenbachi. Inaug.-Diss., Marburg, 1897. Paget: Metastasenbildung. Med.-Chir. Transact., xxxviii., 1885. Ribbert: Ekchondrosis physalifera sphenooccipitalis. Cbl. f. allg. Path., v., 1894 (Lit.); Exper. Erzeugung einer Ekchondrosis physalifera. Verb., d. XIII. Congr. f. inn. Med., 1895. Schlapfer, E. : Das Rippenchondrom, Leipzig, 1881. Steudel: Multiple Ekchondrome. Beitr. v. Bruns, viii., 1891. Virchow: Die krankh. Geschwillste, i., Berlin, 1863; Monatsber, d. K. Akad. d. Wiss. zu Berlin, 1875 ; Deutsche Klin. , 1884. Volkmann: Endothelial Geschwillste. Zeitschr. f. Chir., 41 Bd., 1897 (Lit.). Wagner: Zur Casuistik des Enchondroms. Arch. d. Heilk., ii., 1861. Wartmann: Rech. sur Venchondrome, Paris, 1880 (Lit.). "Weber: Exostosen u. Enchondrosen, Bonn, 1856; Zur Geschichte d. Enchondroms, namentl. in Bez. auf heredit. Vorkommen u. secundare Verbreitung. Virch. Arch., 35 Bd., 1866. Zeroni: Entwiekelung d. Enchondroms d. Knochen. Arb. a. d. path. Inst, zu Got- tingen, 1893. (e) Osteoma. § 106. The term osteoma is applied to tumors which consist of osseous tissue. Such growths arise chiefly front the bones of the skeleton (Pigs. 2(50-263), but may develop elsewhere. The new-growths of bone arising in connection with the skeleton have been variously designated according to their location and relations. A small circumscribed new-growth of bone attached to old bone is called an osteophyte; when of a larger size and more tumor-like, -am exostosis. Circumscribed formations of bone inside of bones are known as enostoses. New-growths of bone not attached to old bone are classed as follows: movable periosteal exostoses, which have their seat in the periosteum but are separated from the bone ; parosteal osteomata, lying near the bone ; dis- connected osteomata, which are situated some distance from the bone, in the muscles and tendons ; and, finally, heteroplastic osteomata, which occur in other organs, as, for ex- ample, in the lungs, mu- cous membrane of the trachea, in the skin, arte- ries, mamma., etc. Excrescences on the teeth, consisting of ce- ment - substance, are known as dental osteo- mata; those consisting of dentine, as odontomata. According to their structure, osteomata may be divided into hard or eburneous osteomata (osteoma, durum or eburneum) (Figs, 260 and 262), and softer spongy forms (osteoma spongiosum or medullare) (Figs. 261 and Fig. ,'200.— Ivory-like exostosis of the parietal hone. Natural size. OSTEOMA. 395 263). The former consist of firm, compact tissue like that of the cortical portion of (he long bones, and possess very narrow nutrient canals (Pig. 262, a); the latter are made up of narrow, delicate bony trabecule and wide medullary spaces (Fig. 263), and resemble spongy bone in structure. The surface is sometimes regular and smooth, so that the whole tumor presents the form of a cone (Pig. 260), or of a sphere, or a pedunculated button; or it may be irregular', rough, and nodular, without definite resemblance to any given form (Fig. 261). The first variety occurs par- ticularly in the eburneous forms, which are found most frequently as exostoses upon the skull (Figs. 260 and 202); the latter in the spongy exostoses and the dis- connected and heteroplastic osteomata, such as are found, for example, in the falx of the dura mater (Fig. 263). Osteomata may occur as single or multiple tumors, the latter mode of occurrence being relatively common. The ivory- like exostoses of the cranium and the osteomata of the dura mater are very frequently of mltiple occurrence, and circumscribed bony growths often appear in great numbers on the bones of the extremities and trunk. In uch cases the epiphyseal ends of the bones id the points of insertion of tendons, or )th at the same time, are the favorite seats f development. It is probable that such rowths are to lie referred to an inherited redisposition of the part affected to over- owth, or to disturbances in the development f the skeleton. At times a hereditary fac- ir can be demonstrated. The bony plates and spicules, which in rare cases develop in the lung or in the mucous membrane of the air-passages, may also occur in large numbers. The development of the bone takes place partly through the formation of osteoblasts, as described in § S3, and partly through metaplasia of formed tissues (S 88). The matrix is formed chiefly from the connective tissue of the periosteum, as well as that of the tissue from which the osteoma arises; and also from that of the perichondrium and endosteum. If an exostosis develops in such a manner that cartilage is first formed from the prolif- erating periosteum or bone-marrow, and from this cartilage bone is later developed, it is called a cartilaginous exostosis (Fig. 261) ; when the exos- tosis is formed directly from the proliferating periosteum without an in- lermediate stage of cartilage, it is known as a connective-tissue exostosis (Pigs. 260, 262, and 263). The combination of connective tissue and bone in. a tumor, in such a manner that the connective tissue represents a chief constituent of the growth and does not simply represent the periosteum and bone-marrow Tic. 261.— Exostosis carl of tbe upper diapliysis of t Reduced about one-half. 390 TUMORS. of the bone, gives rise to an osteofibroma. This is a very commos tumor of the osseous system. The abundant production of bone in a Fig. 262.— Ivory-like osteoma t< the parietal bone, seen in frontal section, a, Osteoma; 5, skull-cap. Eight^ninths natural size. chondroma leads to the formation of an osteochondroma (Pigs. 259 and 264); these tumors are likewise usually found in the long bones. The FIG. 263.— Osteoma of the dura mater (alcohol, picric acid, hieiuatoxylm, carmine) . X 40, OSTEOMA. 307 new-growth may develop in the periosteum (Fig. 264, e) or in the endosteum («, b). An abundant formation of bony trabecule (/, h, Jc) in the cartilage (e, g, i) gives to the tissue a firm, hard consistence. Many of the new-growths of bone which come under observation are not tumors in the strict sense of the term, but are malformations of the skeleton or hyperplasias resulting from excessive growth or from inflam- matory processes. This is true particu- larly of many osteo- phytes and exostoses, and also in part of the parostoses and the disconnected osteo- mas (bone forma- tions in lymph-glands and lungs). The bony plates not in- frequently found in the falx of the dura, and which have a nor- mal bone -marrow (Pig. 263), are to be regarded as misplaced portions of the skele- ton. The formations of bone known as rider's bone and drill- bone, which are found in the adductors of the thigh and in the deltoid muscle, as the result of riding and the repeated shoul- dering of arms, are to be regarded as tu- mors, which develop from a congenital anlage, in that the connective tissue (if the muscle shows characteristics which ordinarily belong only to the periosteum and bone-marrow. The so-called myositis ossificans — a peculiar disease of the muscles, characterized by a progressive ossification of their con- nective tissue during childhood — is to be similarly interpreted. Fig. 264.— Osteochondroma of the humerus (alcohol, picric acid, he- matoxylin, carmine), a, Cortical portion of the humerus; b, medul- lary cavity ; c, periosteal deposit of bone ; d, normal Haversian canals ; e, dilated Haversian canals filled with cartilage, containing newly formed bone at /; g, cartilage with bone-trabecul£e ft, formed by the periosteum ; i, cartilage with newly formed bone-trabeculte, arising from the endosteum ; /,\ /, old bone trabecular ; m-, remains of marrow- iiwue. Pocket-lens magnjucation. Literature. ( Osteoma. ) Arnold, J.: Osteome der Stirnhohlen. Virch. Arch., 57 Bd., 1873 Arnsperg-er: Knochenbildung in der Lunge. Beitr. v. Ziegler, xxi., 1897. Benjamin- Kuochengesehwulst im Gehirn. Virch. Arch., 14 Bd., 1858. Chiari: Multiple Exostosen. Prag. med. Woch., 1892. Cohn; Diffuse Knochenbildung in der Lunge. Virch. Arch., 101 Bd., 1885. Cohnheim: Multiple Exostosen. Virch. Arch., 38 Bd., 1867. Dennig: Leber Knochenbildung in der Trachealschleimhaut. Beitr. v. Ziegler, iL, 1888. DeWitt: Myositis Ossificans. Amer. Jour, of Med. Sc, 1900 (Lit.). Ebstein: Osteom der 1. Kleinhirnhcmispbare. Virch. Arch., 49 Bd., 1870. Forster: Verastigte Knochenbildung in der Lunge. Virch. Arch., 18 Bd., 185S. Heuking-: Multiple Exostosen. Virch. Arch., 77 Bd., 1879. 39S TUMORS. Heymann: Hereditare multiple Exostosen. Virch. Arch., 104 Bd., 1886. Huber: Multiple Exostosen. Virch. Arch., 88 Bd., 1882. Lenhossek : Knorpeliihnliche u. wahre Knochenbildung im Penis, Vireh. Arch., 60 Bd., 1874. Meschede: Osteom des Grosshirns. Virch. Arch., 35 Bd., 1866. Mischnikoff: Knochenbildung in der Trachealschleimhaut. Inaug. -Diss. , Zurich, 1894. Neumann, E.: Osteom des Hodens. Arch. d. Heilk., 1875. v. Recklinghausen: Eiu Fall von multiplen Exostosen. Vireh. Arch., 05 Bd. , 1866. Reinecke: Erblichkeit multipler Wachsthumsexostosen. Beitr. v. Bruns, vii., 1891. Spengler: Ueber die Erblichkeit multipler Exostosen, Strassburg, 1887. Steudener: Osteome der Trachea. Virch. Arch., 42 Bd., 1868. Virchow: Die kranklmften Geschwlilste, ii., 1865. Weber, O.: Exostosen u. Enehondrome, Bonn, 1856. (/) ILvmangioma and Lymphangioma. § 107. tinder the terra angioma are grouped those tumor -like forma- tions in the structure of which blood-vessels or lymph-vessels constitute such an important part as-to determine the character of the tumor. Vascular tumors arising from blood-vessels are called hsemangiomata, or angiomata in the restricted sense of the term ; those arising from lymph-vessels are designated Iymphangiomata. Such tumors for the greater part represent formations which may be regarded as malforma- tions of a more or less extensive vascular area. Of the hsemangiomata there may be distinguished four chief varieties: hemangioma simplex, hemangioma eavernosum, hemangioma hypert roph ieinn , and angioma arteriole racemosum. A haemangioma simplex or teleangiectasia is a, tissue-formation in which, within a ground tissue of normal occurrence in the body, there is i?ig. 265.— Teleangiectasis of the pannieulus adiposus of the abdominal wall (formalin, hematoxylin eosin) a, Blood-vessels filled with blood ; h, adipose tissue. X 80. found an abnormal increase in the number or in the size of the capillaries and veins, whose structure in, part is essentially changed. Such formations occur most frequently in the skin and subcutaneous tissue. They are usually congenital, but increase in size after birth. They are designated vascular nasvi, and are often found in places HEMANGIOMA AND LYMPHANGIOMA. 399 where fetal clefts have closed (fissured angiomata). Of a tumor in the ordinary sense it is often scarcely possible to speak, since the skin may show no tumor -like elevation. On the other hand, there occur extensive Fig. 266.— Dilated capillaries of a telangiectatic tumor of the brain, isolated from a portion of tumor by means of shaking. X SOU. teleangiectases of the skin and subcutaneous tissue, presenting either as circumscribed growths or as flat, occasionally nodular thickenings of the skin, which may Avith propriety be termed tumors. The smooth timvus vasculosus, on the other hand, appears as an extensive superficial substitu- tion of the skin by another tissue. The color of the affected portion of the skin is either bright red (ncevus flammeus) or bluish-red {noevus mnosus). The line of demarcation between the normal and affected skin is usu- ally not a sharp one; around the edge and in the neighborhood of the chief area of dis- coloration there are often found little, cir- cumscribed red spots appearing as outrun- ners of the process. The red color is due to the dilated blood- vessels whicu are silu- ated either in the cer- ium or in the subcutaneous fat tissue (Fig. 2G5, a) ; and cases occur in which large areas of the subcutaneous adipose tissue present a red ap- pearance as a result of the pathological development of blood-vessels. Fig. 267. — Angioma cavernosum cutaneum congenitum (Miiller's fluid, hematoxylin), a, Epidermis; b, corium; c, cavernous blood- spaces. X 20. 400 TUMORS. More rarely than in the skin and subcutaneous tissues, there occur sim ilar angiomata in other places: in glands (mamma), bones, brain (Fig, 266), and spinal cord and their membranes. Not infrequently, on the other hand, there are found analogous vascular changes in tumors, as. for example, in gliomata or sarcomata. If the vessels, which are usually abnormally abundant, are isolated, it becomes evident that the capillaries, or also the small veins (angioma simplex venosum), are more or less dilated. These dilatations (Fig. 266) are either spindle-shaped or cylindrical, but may be saccular or spherical, and the different forms of dilatation may lie combined in the greatest variety of ways. The dilated blood-vessels are united with Fig. 2f>S.— A ;in). a, Livertissue; ?>, angi- each other by capillaries of normal size or of moderately increased cali- bre. The walls of the vessels are thin — that is, in comparison with nor- mal capillaries they are but slightly thickened. A haemangioma cavernosum or tumor cavernosus is a vascular tumor consisting essentially of a cavernous spongy tissue, whose structure suggests that of the corpus cavernosum or spongiosum of the penis (Figs. 267 and 268). Through the filling of the spaces with blood these tumors present a bluish-red or dark red lolor. The cavernous angioma, like ishe angioma simplex, occurs chiefly in the skin (Fig. 267, c) and subcu .meous tissues, where during the period of development it appears as a pathological formation of the vascular system. At times it forms only a small bluish-red spot (nawus vasculosvs vinosus) ; at other times, a smooth, elevated (Fig. 267), or slightly nodular bluish-red wart (ncevus vasculosus prominens, verruca vasculosaj; or, finally, a circumscribed bluish-red discoloration or thickening of the skin. In the event of an extensive development of cavernous tissue in Hie subcutaneous or intermuscular connective tissue, there may result HEMANGIOMA. 40 ] large tumors and elephantiasis-like disfigurations of portions of the body (elephantiasis hcemangiomatosa). Within the body the cavernous angioma is found most commonly in the liver (Fig. 268, a, b), but may develop also in other organs: Fig. 269.— Angioma simplex hypertrophieum (formalin, hematoxylin), a. Vessels containing blood; b, empty and collapsed thick-walled blood-vessels rich in nuclei. X 100. kidney, spleen, intestine, bladder, bones, muscles, uterus, brain, etc. In the liver it appears in the form of dark-red areas, varying in size from that of a pin-head to several centimetres in diameter. They take the place of the liver tissue, and are not elevated, or but slightly, above the liver surface. The width of the blood spaces and the thickness of the trabeculae vary greatly in different cases; the angioma may in portions or through- out be composed of fibrous tissue, in that more fibrous tissue was formed in the beginning, or fibrous prolifera- tions have taken place later as se- quela; to the thrombosis. The blood spaces are lined with endothelium ; at times smooth muscle-fibres may be demonstrated in their walls, and the interstitial tissue is often rich in elas- tic fibres (Briichanow). The tumor is usually sharply outlined from the neighboring structures by connective tissue. Usually no liver cells are found in the trabecular, but varieties do occur in which the latter in part enclose such, and in which, further, the blood spaces here and there pass over into the liver-capillaries, such a communication ordinarily not taking place. The cavernous angioma of the liver occurs in old individuals, and also in infants and children of different ages, and not infrecpiently is of mul- Fig. 270.— Angioma simplex hypertrophieum cutaneum et subcutaneiun (alcohol, carmine). In the middle of the section is the duct of a sweat-gland cut transversely. X 300. 402 TUMORS. tiple occurrence. It is probably caused by a local disturbance of de- velopment, which proceeds from the vessels of Glisson's capsule or from the intra-acinous capillaries; and is characterized by an abnormal de- velopment of the blood-vessels at the expense of the other tissues. The growth is slow and limited; ordinarily (he liver-cells in the immediate neighborhood show no signs of degeneration. 1 Hiring the period of rapid growth (Briichanow ), there may occasionally be demonstrated in children the presence at the periphery of the growth of a cellular granulation tis- sue, in which the blood-vessels consist of delicate endothelial tubes hav- ing a narrow lumen. The hemangioma hypertrophicum, in its most typical form ( hceman- gioma simplex hypertrophicum}, occurs most frequently in the skin and subcutaneous tissues, where it forms circumscribed nodules similar in part to the soft, smooth warts. The pathologically altered vessels may lie in the papillae and cerium as well as in the subcutaneous tissue, and either form narrow tubes tilled with blood (Figs. 269, a, and 270), the FIR. 271. — Antrioma cavernosum hypertrophicum (angloendothelioma) of the skull-cap (Muller's fluid, hematoxylin), a, Blood-vessel with flattened endothelium; 5, blood-vessel with cubical and cylindrical endothelium. X -50. walls of which are more or less thickened and abnormally cellular, or else solid cords of cells (Fig. 269, b), which are either collapsed, (hick- walled vessels, or possess no lumen whatever. In very rare cases it happens that in angiomata, which from the cali- bre of the vessels bear the character of cavernous angiomata, there occurs a hypertrophy of the vessel-walls; and this hypertrophy is due to the fact that the flat endothelial cells become changed into cubical and cylindrical cells (Fig. 271, /))• Such a tumor may be classed as an angioma cavernosum hypertrophicum, or as a- blood-vessel-endothelioma, or hcemangioitic endothelioma; the last term being in particular applicable when, as a result of the marked proliferation and multiplication of the endothelium, there are produced nests of large cells which till up the blood-vessels (compare Endothelioma, £§ 114 and 115). A cirsoid aneurism, or angioma arteriale racemosum, or angioma arteriale plexiforme (Fig. 272), is a condition in which the arteries of an entire vascular area are dilated, tortuous, and thickened, so that there is HEMANGIOMA. 403 formed a convolution of enlarged and thickened arteries. To the palpat- ing finger they feel like a bunch of earth-worms. Many of these angio- mata, which occur particularly upon the head, and which may cause Fig. 272.— Angioma arteriole plextforrae arteria? angularis et frontalis dext. et sin. erosion of the cranial bones, arise from congenital anlage; others appear to be acquired, and develop after a traumatism, but it is possible that- special conditions may have existed before the trauma. Literature. (ITiriniuii/ioina.) Appia: Des tumeurs sanguines erectiles, Paris, 1877. Beneke: Zur Genese der Leberangiome. Virch. Arch., 119 15(1., 1890. Briichanow: Hamangiom der Leber. Zeit. f. Heilk., xx., 1S99. Burckhard: Pathol. Anat. d. eavernosen Angioms der Leber. Inaug.-Diss., "Wiirz- burg, 1894. Dibbern: Leber iiussere Angiome (Zusammenstellung v. 95 Fallen), Kiel, 1869. Heine: Angioma art. racein. am Kopfe. Prag. Vierteljahrsschr., iii., iv., 1809. Hildebrandt: Leber multiple cavernOse Angiome. Lent. Zeitschr. f. Cbir., 30 Bd., 1889. Kretschmann : Ueber das Angioma arteriale racemosum, Halle, 1881. L/ang-hans: Beitriige z. Lelire von den Gefassgeschwulsten. Virch. Arch., 75 Bd., 1879. Markwald: Intravasculares Endotheliom d. Knochen. Virch. Arch., 141 Bd., 1895. 404 TUMORS. Mauclair et de Bovis: Los angiomes, Paris, 1896. Muscatello: Angiom der willkurl Muskeln. Virck. Arch., 135 Bd., 1894. Nauwerck: Hyperplastisches Capiliarangiom. Virch. Arch., Ill Bd., 1888. Pfeiffer; Ueber Teleangiektasie u. eavernose Blutgeschwulst, Tubingen, 1854. Reinbach: Zur Lehre v. d. Hamorrhoiden. Beitr. v. Bruns, xix., 1897. Ribbert: Wachsthum u. Genese der Angiome. Virch. Arch., 151 Bd., 1898. Schmieden: Genese d. Lebercavernoms. Virch. Arch., 161 Bd., 1900. Schneck: Ueber d. Wesen u. d. Entstehung des Angioma arteriale racemosum, Berlin, 1885. Scbrobe: Teleangiektasieen d. Leber. Virch. Arch., 151 Bd., 1898. Virchow: Die krankhatten Geschwl'ilste, iii. Wagner: Das arterielle Rankenangiom d. oberen Extremitaten. Beitr. v. Bruns, xi., 1894 (Lit,). "Weil: Beitrilge zur Kenntniss der Angioma, Prag, 1877. See also § 116, § 108. Angioma lymphaticum or lymphangioma is a tumor com- posed of a tissue the greater part of which is made up of dilated lymph- vessels. The following different forms may be distinguished: lymphan- gioma simplex or teleangiectasia lymphatica (Fig. 273); lymphangioma cavernosum (Fig. 274); lymphangioma cystoides ; and lymphangioma hyper- trophieum. The cavities of these tumors usually contain a clear, light- colored lymph, but more rarely it is milky and contains lymphocytes, mononuclear and polynuclear leucocytes, and usually also eosinophile cells. The walls consist of connective-tissue trabecuhe of varying thick- ness and containing more or less in voluntary muscle ; the spaces are liued with endothelium. In the lymphangioma simplex (Fig. 27:!) the lymph-vessels of a more or less extensive area are dilated and their walls for the greater part are thickened. In the cavernous lymphangiomata the number of Fig. 273.— Weeping subepithelial lymphangioma of the skin (alcohol, carmine), a, Corium ; b, epithelium c, ci, lyniph-spaces. X 14, lymph-vessels is still greater, their spaces are larger, and the intervening tissue is less abundant, so that, even to the naked eye, the tissue presents a spongy appearance, The cystoid lymphangiomata contain cysts vary- ing in size from that of a pea to a walnut. The tissue between the dilated lymph-vessels consists, according to the location of the tumor, either of connective tissue (Fig. 273), fat tissue (Fig. 274, c), muscle, or some other tissue. At times nodes of lymphadenoid tissue may be en- closed (e), and may present evidences of active proliferation. LYMPHANGIOMA. 405 Lymphangiomata are sometimes congenital ; at other times they make their first appearance at a later period of life. The congenital forms occur particularly as different varieties of ectasia of lymph -vessels, and are found chiefly in the tongue (macro- glossia), palatal arch, lips (macrocheilia), skin (ncevus lymphaticus), sub- cutaneous tissue, in the neck {hygroma colli congenitwm), vulva, etc. The lymphaugiomata of the skin spread over more or less extensive areas of the skin, aud form either smooth or irregular elevations of the same. If the blood-vessels are numerous the growth may have a red color. The rupture of dilated lymph-vessels lying immediately beneath the epithe- lium (Fig. 273, cl) may give rise to a moist condition of the surface and Fig. ?74.— Lymphangioma cavernosum subcutaneum (alcohol, alum-carmine), n. Ectatic lymph-vessels; />, connective tissue ; e, adipose tissue : d, large blood-vessels ; 6, cellular areas. >.'20O. eventually to a lymphorrhcea. The extension of the cavernous develop- ment of the lymph-vessels over large areas of the skin and subcutaneous tissue may give rise to elephantiasis-like disfigurations of the part affected. Not infrequently the intervening connective tissue also takes part in the hypertrophic growth, or there develops a fibrous elephantiasis in connec- tion with lymphangiectasia. In rare cases chyle-containing growths (chylangiomata) are found in the intestinal wall or mesentery. Cystic lymphangiomata are also found rarely in the peritoneum, as pedicled cysts. The pathological formations which may be classed as hypertrophic lymphangiomata represent peculiar changes of the skin, which are either congenital or develop in early youth. They are commonly known as pigmented moles, lentigines, freckles, and fleshy warts. The pigmented moles, or ncevi pigmentosa, or melanomata, form larger or smaller smooth areas which are not elevated above the general surface of the skiu (ncevus spilus), or prominent warty growths (ncevus prominens, ncevus verrucosus). When covered with hair, as is frequently the case, they are called hairy moles (ncevus pilosus) . In color they are usually light brown or dark brown, or even black (Fig, 275) ; and are usually 406 TUMORS. covered by epidermis of normal thick- ness, more rarely by hypertrophic epi- thelium. They are usually small, but may be as large as the palm of the hand, or under certain conditions may cover a large part of the body surface. Lentigines appear at any time after birth, and upon any part of the body surface ; and when once formed they re- main for life. They form sharply cir- cumscribed yellow to brownish - black spots closely resembling the little pig- mented nsevi ; and vary in size from that of a pinhead to that of a lentil. Freckles or ephelides are small, irregu- larly outlined, serrated, pale-brown spots, which are not elevated above the surface of the skin. They occur in young indi- viduals, particularly on the face, hands, and arms, rarely on other portions of the body ; and may either remain permanently or disappear after a longer or shorter time. The pigmentation is favored by exposure to sunlight. Fleshy moles (yerrucm carneie) are 11011- pigmented, circumscribed, smooth (Fig. 276) or slightly irregular, or more rough and papillary (Fig. 278) prominences of the skin, over which the epidermis is at times normal, at other times somewhat hypertrophic (Fig. 27S, a). In all of the pathological formations just described the connective-tissue frame work encloses collections of cells, either (Figs. 276, 277, 278, rf, */,), which lie partly in in the corium ; and are the more abundant the Fir;. 275. — Large hairy and pigmented nsevus of back, buttocks, and thighs, with scattered smaller pigmented spots over the remaining portions of the body. (After Roliring.) (Reduced from original.) Ill round or cord- like masses the papillae and partly more the growth pro- Fig. 276.— Lymphangioma hypertrophicum. Section through a small, soft, smooth wart (formalin hema- toxylin, eoain). X 40. LYMPHANGIOMA. 407 Fig. 277.— Lymphangioma hypertrophicum. Rounded summit of a large, soft, smooth wart (formalin, hematoxylin, eosin) . Sharply outlined cell-nest in corium. < 250. jects above the surface of the skin. In the pigmented forms the cells of the cell-nests may also contain the pigment (chiefly in the form of brown or yellow granules, but in part diffused throughout the substance M&/|sg, :« . Mastny: Maligne Myome des Uterus. Z. f. Heilk., 22 Bd., 1902. Neumann: Myoma striocellulare des Hoderis. Virch. Arch., 103 Bd., 1886; Multiple Dermatomyome. Arch. f. Derm,, 39 Bd., 1897. Orlandi: Rabdomioma del nervo ischiadico. Arch, per le Sc. Med., xix., 1895 (Lit.). Paviot et Berard: Cancer musculaire lisse (maligne Myome). Arch, de mcd. exp., 1897. Pernice: Myosarcoma striocellulare des Uterus. Virch. Arch., 113 Bd., 1888. Prudden: Rhabdomyom d. Parotis. Amer. Jour, of the Med. Sciences, April, 1883. v. Recklinghausen: Die Adenomyome u. Cystadenome des Uterus, Berlin, 1890. Ribbert: Myosarcoma striocellulare des Nierenbeckens. Virch. Arch., 106 Bd.; Zur Kenutn. der Rhabdomyome. lb., 130 Bd., 1892. Ricker: Aetiologie der Uterusgeschwiilste. Virch. Arch., 142 Bd., 1895. Seiffert: Multiple Rhabdomyome des llerzens. Beitr. v. Ziegler, xxvii., 1900. Smith: Fibromyomatous Tumors of the Vagina. Amer. Journ. of Obst., 1902. Steiner: Myome d. Magendarmkanales. Beitr. v. Brims, xxii., 1898 (Lit, ). Tusini: Rabdomioangioma del dorso. Arch, per le Sc. Med., xx., 1896. Virchow: Die krankhaften Geschwulste, iii., 1865. Williams: Histogenese d. Uterussarkome (Myoma sarcomatodes). Zeitschr. f. Heilk., xv., 1894. Wolfensberger : Rhabdomyom der Speiserohre. Beitr. v. Ziegler, xv., 1894. Zenker, K. : Rhabdomyosarkom der Orbita. Virch. Arch., 120 Bd., 1890. (h) Glioma and Neuroglioma Ganglionare. § 110. A glioma is a tumor which develops from the cells of the sup- porting tissue of the central nervous system (neuroglia), and in its fully developed condition consists essentially of these cells. In the brain the gliomata form tumors, which for the most part are not sharply defined from the normal brain-sub- stance, but pass into the latter by insensible gra- dations. At times they appear simply as local swellings of the brain, and only the difference in color and the disappear- ance of the normal tissue- contrasts between the dif- ferent elements of the brain, give evidence to the eye that a tumor is present. In the spinal cord they arise most fre- quenrly in the neighbor- hood of the central canal, and may extend over a large portion of the cord. Their appearance varies greatly; sometimes they are light-gray, somewhat translucent, and similar in color to that of the cortex, and. moderately firm in consistence ; at other times they are more grayish- white, denser, and firmer; and again they are not infrequently grayish - Fir;. 282.— Glioma cerebri. A, Cells isolated by teasing and stained with carmine. B, Section from same glioma after harden- ing in Mutter's fluid (Bismarck brown). X 3o0. 414 TUMORS. Fir;. : with a Million - Section ■vies i j ftboil.) erebrum, atoxylin, red or dark red in color and are then sharply circumscribed from the sur- rounding brain substance. In the last case they are traversed by numer- ous large vessels. Gliomata well supplied with blood often contain hemorrhagic areas. Fatty degeneration, softening, and destruction of the tissue are also of common occurrence. A section of a fully developed glioma shows under the microscope a network of extremely delicate glistening fibrilhe (Fig. 282, B), in which are imbedded numerous short oval nuclei. About the nuclei there is but a scanty amount of protoplasm, and this can be distinguished only with difficulty. When examined in the fresh state or after maceration in Midler's fluid it may be seen dis- tinctly that these nuclei belong to cells (astrocytes) which are charac- terized by a great number of fine processes extending in all directions, and often branching (Fig. 282, A). By proper staining-methods the con- nection between some of the fibres may be demonstrated also in sections (Fig. 283). The cells are very similar to nor- mal glia-cells (short-processed or long-processed); but are not in- frequently much larger, occasion- ally more plump, and some may possess two, three, or four nuclei. The development of gliomata takes place ordinarily from the stipporting cells of the white and gray subslance. A preponderance of cells with a slight development' of the cell-processes leads to the formation of medullary gliomata; while a more marked for- mation of processes and of the nbrillated ground-substance gives rise to hard forms. As the result of the proliferation of the perivascular connective tissue gliosarcomata may be formed. In gliomata developing in the neighborhood of the ependyma, the ependymal epithelium, consisting of cylindrical cells with a basal process, may also share in the proliferation, so that the surface of the tumor becomes covered with a layer of ependymal cells. Epithelial ingrowths resembling gland-ducts may be formed so that the tumor in part takes on the character of an epithelial adenoma ( nciiro-epithelioma adenomatosum glioniatostim) . A similar appearance may be produced when, as the result of disturbances of development, misplaced portions of the medullary canal lie within the glioma,. Proliferations arising from the epithelium of the plexus bear the character of epithelial growths. A neuroglioma ganglionare (Fig. 284) is a tumor of the central nervous .system, composed of hyperplastic glia-tissue, ganglion-cells, and nerve-fibres, and forms either poorly defined swellings of larger portions of the brain, or circumscribed, nodular enlargements of smaller portions. To the naked eye the structure of the brain may in general appear to be still preserved, though the difference between the cortical and medul- lary substance is less distinct than normal, and the tissue throughout is white of grayish-white, or spotted gray and white, and at the same time more or less hardened. The main portions of these masses consist of a more or less thick <>lia- GLIOMA. 415 tissue containing a certain number of nerve-fibres (d) and ganglion- cells (a, b, c), or cells resembling ganglion-cells, not only in the cortical tissue, but also in the white substance. Probably all of these formations are to lie regarded as the result of disturbances of the embryonal development of the brain — that is, as local malformations of the brain, which are characterized essentially by a, pathological development of neuroglia (gliomatosis) and by a development of part of the neuroblasts, probably also of the spongioblasts, into large ganglion-like cells (a) such as are not found normally in the brain. Fir.. 384.— Section from a nodular neuroglioma (fangllonare of tin- central convolution of tin- cerebrum (Miiller's fluid, Weigert's stain) . A, Portion of tissue rich in ganglion cells. B, Portion of tissue contain- ing nerve-fibres. C, jelly-like portion, a, Ganglion-cells arranged in groups; h, scattered ganglion-cells; e, ganglion-cells with two nuclei ; d, nerve-fibres with medullary sheath ; e, glia-cells ; /, blood-vessel. X 275. The term glioma is also applied to certain tumors of the retina occur- ring during childhood. These growths, a certain portion of which tire of congenital origin, are evidently to be referred to some disturbance in the development of the retina. They form cellular, soft, white or reddish tumors, the greater part of which consists of small, round or irregular cells poor in protoplasm, resembling the cells of the stratum gramilosum. In part they possess smaller or larger processes. These cells are found best preserved in the neighborhood of the blood-vessels, while in other portions of the tumor they often show retrograde changes. The tumor may also contain ganglion-cells, cylindrical cells, and peculiar rosette and ribbon-like cell-formations (Wintersteiner), these latter being re- garded as aggregations of rods and cones. Wintersteiner has, therefore, designated the tumor a neuroepithelioma. The glioma of the retina often shows areas of necrosis in its central portion. In its growth it may break into the retrobulbar space, or for- ward through the cornea and sclera; it recurs after operation, and gives rise to metastases. With reference to the origin of neuroglia and ganglion-cells from the ectoderm, various writers class the different forms of gliomala with the epithelial tumors. In so far as the ependymal proliferations resembling epitheliomata and adenomata (§§ 118, 119) are concerned, such a classification is justified. The ordinary gliomata, however, show a structure resembling that of the other connective-tissue tumors, so that it is more proper to class them with the latter. 416 TUMORS. Literature. (Glioma and Neuroglioma.) Baumann: Zur Kenntniss der Gliomeu. Neurogliome. Beitr. v. Ziegler, ii., 1SSS, p. 500. Bittorf: Him- u. Riickenmarksgeschwulste. Beitr. v. Ziegler, xxxv., 1904. Eisenlohr: Gliom der Netzhaut'. Virch. Arch., 123 Bd., 1891. Emanuel: Gliom. d. Pars oil. retinae. Virch. Arch., 161 Bd., 1900. Ernst: Missbildung d. Kleinhirns. Beitr. von Ziegler, xvii., 1S95. Gayet et Poncet: Gliome de la retine. Arch, de ph'ys., ii., 1875. Gerhardt: Gliome. Festschr. z. Sacularfeier der Universitat, Wiirzburg, 1882. Greeff: Ban d. Glioma retinae. Dent. med. Woch., 1896. Levy: Zentralkorperchen in Gliomen. Virch. Arch., 171 Bd., 1903. Linck: Ependymare Gliome. Beitr. v. Ziegler, xxxiii., 1903. Muthmann u. Sauerbeck: Gliageschw. d. 4. Ventrikels. B. v. Ziegler, xxxiv., 1903. Neumann: Gliom der Substantia perforata. Virch. Arch., 01 Bd., 1874. Pusey: The Genesis of Glioma Ret ina> in Neuroglia. Johns Hopkins Hosp. Bull., 1902. Reisinger: Ueber das Gliom des Rtickenmarks. Virch. Arch., 98 Bd., 1884. Rosenthal: Neuroepithelioma gliomatosum. Beitr. v. Ziegler, xxvii., 1900. Saxer: Gliome. Beitr. v. Ziegler, xxxii., 1902. Scaffldi: Histogenese des Netzhautglioms. V. A., 173 Bd., 1903. Simon: Spinnenzellen u. Pinselzellen im Gliom. Virch. Arch., 61 Bd., 1874. Steinhaus: Netzhautgliome. Cbl. f. allg. Path., xi., 1900. Stertz: Multiple Gliomatose des Gehirns. B. v. Ziegler, xxxvii., 1905. Stolpe: Eigenartiges Gliom. Festschr. d. Krankenh., Dresden, 1899. Strobe: Ban u. Entstehung der Gliome. Beitr. v. Ziegler, xix., 1896. Thomas and Hamilton: Neuroglioma of the Brain. Journ. of Exp. Med., ii., 1897. Virchow: Die krankhaften Geschwiilste, ii., 1S64. Wintersteiner : Neuroepithelioma (Glioma) retinae, Wien, 1896 (Lit.). (i) Amputation Neuroma, Neurofibroma, and the True Neuroma. § 111. The tumors designated neuromata occur most frequently on the euds of amputated nerves, where they form more or less prominent swellings, either circumscribed or blending into the surrounding tissue without any clearly defined demarcation. From the conditions of their origin they are known as amputation-neuromata (Fig. 285, b). Thedevel- opment of these neuromata is to be referred to the changes taking place after the nerves have been severed ; during the development of connective tissue in the stump the euds of the axis-cylinders of the proximal portion of the affected nerve divide and grow longitudinally, so that the scar- tissue comes to be penetrated by nerves which at first have no sheaths, but are soon surrounded by medullary sheaths. The mass of nerves penetrating into the granulation tissue may be large, so that the con- nective tissue after a certain length of time may contain a very rich supply of nerves, which, radiating from the end of the old nerve, extend into the connective tissue in all directions (Fig. 285, b). The process is, therefore, an example of a useless regenerative proliferation of a nerve- stump exceeding the physiological needs. As another form of so-called neuromata are classed those growths developing -spontaneously, without external cause, along the course of nerves; aud which consist essentially of an increase in the connective tissue of the nerve, usually of the outer, more rarely of the inner layer of the endoneurium. At the point of tumor-growth the nerve-bundles become surrounded by a more or less thick layer of connective tissue, which is usually loose, more rarely dense (Fig. 286, b, d), or the bundles maybe split apart into their individual fibres (c). Occasionally the perineurium takes part in the proliferation. In the case of large nerve-trunks the epineu rium may be affected in association with the endoneurium and permeu- NEtJROMA. 417 rium of the individual bundles, although the process is most frequently confined to the endoneurium. According to their structure these tumors are not true neuromata, but are neurofibromata or fibromata nervorum. They are usually of multiple occurrence, and may extend throughout the entire peripheral nervous system, but are more often limited to a definite area of nerve- distribution. Inveryrare cases they occur in the nerve-roots and spinal cord. The nodules are sometimes situated along the course of the nerve-trunks, sometimes on the finer branches, most frequently of the cutane- ous nerves; and in the skin form more or less numerous, larger or smaller, tumor- nodules, for the greater part of soft con- sistence, to which the designation multi= pie fibromata of the skin is usually applied. The smallest nodules can be seen only with the microscope ; the ma- jority vary in size 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 wholly lost sight of in the great mass of connective tissue. At- rophy of the fibres may be caused by the increasing connective tissue, the fibres finally vanishing completely. In addi- tion to the formation of circumscribed nodules there may occur also in the af- fected area a diffuse thickening of the nerves from hypertrophy of their connective tissue. Moreover, with this condition there may be associated a hypertrophic prolifera- tion of the connective tissue of the skin and subcutaneous tissue, leading to ele- phantiasis-like thickenings of the shin. A third form of false neuroma is the cirsoid neuroma (Brims) or plexiform neuroma (Yerneuil;, a tumor formation which is characterized by the develop- ment in the domain of one or more nerve- branches of a convolution of tendril-like, twisted or interwoven, thickened and nodular nerve-strands (Fig. 287). When examined in detail this formation is also found to depend essentially upon a fibro- matosis of the nerves (Fig. 286), the pro- liferation of the endoneurium resulting partly in a diffuse and partly in a nodular thickening of the nerves. In addition, it may be found in such formations that the nerves of the affected area are lengthened and thereby rendered tortuous, while at the same time the nerves are in- creased in number, so that the number of the nerves of the skin and subcutaneous tissues is greater than under normal conditions. The con- dition must, therefore, be regarded as one of true neuroma, a neuroma verum associated with & fibromatosis. The nerves are for the greater part medullated (neuroma myelinicum). It is very difficult to determine to 97 Fig. 285. — Amputation-neuroma, of t-be sciatic nerve (nine years after amputation of the nerve). Longitudinal section, a, Nerve ; b, neuroma. Drawn from a preparation which hart been hardened in Midler's fluid. X 3. 418 TUMORS. what extent non-medullated nerves are present in such formations, but nevertheless cases have been reported in which the nerve-fibres were for the greater part non-medullated (neuroma amyelinicum). Cirsoid neu- PiG. 2 Q fi.— Nerves from an elephantiasis-like cirsoid neuroma of the cheek and lower jaw (Flemming's solution, safranin). o, h. Nerves, the outer layers of whose endoneurium have undergone marked pro- liferation ; the nerve-fibres lie in the axial portion ; c, nerve with markedly proliferated endoneurium and separated nerve-fibres ; o\ thickened nerve with a small strand of nerve-fibres at the left end ; e, loose con- nective tissue, rich in nuclei and containing fat, lying between the nerves. X 7. romata occur on the head, trunk, and extremities, and give rise iisually to elephanti- asis-like disfigurations of the, affected areas. True neuromata consist- ing of nerve-fibres and ganglion- cells (neuroma, gangliocellulare verum) are rare tumors; but from the observations of Weichselbaum, Beneke, Busse, Knauss, Schmidt and others, the occurrence of such growths cannot be doubted. They form tumors varying in size from that of a millet-seed to that of an apple, and de- velop particularly in the sym- pathetic system. In a case described by Knauss there were present multiple, nod- ular neuromata of the skin containing nerve-cells, and it is probable that these growths had their origin in sympa- thetic nerves containing gan- FiG. 287.— Cirsoid neuroma of the sacral region (After a drawing by P. Bruns). The nodular, twisted and inter- woven nerves are in part free (a), and in part (b) covered by connective tissue. Natural size. NEUROMA AND NEUROFIBROMA. 410 glion-cells. These tumors consist of connective tissue, non-medullated and medullated nerve-fibres, and ganglion-cells which resemble those of the sympathetic ganglia. Both the neurofibroma and the t rue neuroma are, as regards their origin, to be referred to a congenital anlage. They form no metastases, but cases occur in which neurofibromata take on a sarcomatous character and thereby become malignant. Literature. (Neuroma anil Neurofibroma.) Aschoff: Gescliwiilste. Ergebn. d. allg. Path., v., 1900. Beneke: Ga-igliose Neurome. Cbl. f. allg. Path., ix., 189s u. B. v. Z., xxx., 1901. Borst: Neuroma ganglionare. Sitzber. d. phys.-med. Ges., Wlirzburg, 1897. Bruns, P.: Ueber das Bankenneurom. Virch. Arch., 50 Bd., 1870; Beitr. z. klin. Chir., viii., 1891; Arch. f. kliu. Ohir., 42 Bd., 1892. v. Bung-ner: Multiple Neurofibrome. Langenbeck's Arcli., 55 Bd., 1897. Busse: Neuroma gangliocellulare d. Synipathicus. Virch. Arch., 151 Bd., Suppl., 1898. Courvoisier: Die Neurome, Basel, 1886. Esinarch u. Kulenkamp : Die elephantiastischen Formen, Hamburg, 1885. Fabris: Ganglioneuromi del sist. simpat. A. per le Sc. med., xxvii., 1903. Glockner: Neuroma verum gangliosum. A. f. Gyn., 63 Bd., 1901. Goldman: Beitr. ■/.. Lehre von den Neuromen. Beitr. v. Brims, x., 1892. Haenel: Neuroganglioma myelinieum. Arch. f. Psych., 31 Bd., 1898. Herczel: Ueber Fibrome u. Sarkome der peripheren Nerven. Beitr. v. Ziegler, viii., 1890. Jordan: Elephantiasis congenita. Beitr. v. Ziegler, viii., 1890. Knauss: Echte multiple Neurome. Virch. Arch., 153 Bd., 1898. Krause: Ueber maligne Neurome, 1887. Lecroix et Bonnaud: Nevrome plexiforme amyelinique. Arch, de med. exp., ii., 1880. Petren: Multiple allgem. Neurome. Nordiskt Med. Ark., 1897. Preble and Hektoen: Multiple Fibromata of the Nerves, etc. Trs. Ass. (if Amcr. Phys., 1900 (Lit.). v. Recklinghausen: Ueber die multiple" Fibrome der Haut. Berlin, 1882. Schmidt: Ganglicnzcllcnhalt, wahres Neurom d. Synipathicus. Virch. Arch. 155 lid., 1899. Stienon: Etude sur la structure du nevrome, Bruxelles, 1883. Strube: Combinat. v. Neurofibrom rait Gliom. d. Ruckcnmarks. Virch. Arch., 151 Bd., Suppl., 1898. Thomson: On Neuroma and Neurofibromatosis, Edinburgh, 1900. Verneuil et Depaul: Bull, de la soc. anat. , Paris, 1857. Virchow: Die krankh. Geschwulste, iii. ; Das wahre Neurom. Virch Arch., 13 Bd., 1858. Westphalen . Multiple Fibrome der Haut. u. der Nerven mi! Uebergang in Sarkom, und Metastasenbildung. Virch. Arch., 110 Bd., 1887. Weichselbaum : Ganglioses Neurom der Nebenniere. Virch. Arch., 85 Bd., 1881. (7c) Sarcoma. § 112. A sarcoma is a connective-tissue tumor whose elements, either because of their number or often because of their size, predominate over the intercellular substance. Sarcomata are closely related to the undeveloped connective tissues, so that sarcomatous tissue may be compared with em- bryonal tissue. Sarcomata develop either in previously normal tissue belonging to the connective-tissue group — as, for example, in the skin, subcutaneous tissue, intermuscular connective tissue, periosteum, spinal cord, menin- ges, connective tissue of the glands, etc. — or in some preexisting con- nective-tissue tumor, as a fibroma, myoma, chondroma, hypertrophic 420 TUMORS. lymphangioma, etc. The transformation of the parent tissue into tumor tissue takes place through the growth and multiplication of the existing cells. The division of the cells takes place chiefly by mitosis, and mitoses are the more abundant the more rapid the growth of the tumor. In addition to typical mitoses there are frequently observed atypical forms, also nuclear fragmentation, and more rarely segmentation. In their fully developed state sarcomata form more or less sharply circumscribed growths. They may appear in any portion of the body where connective tissue is present ; but are found in certain tissues more frequently than in others. Thus, for example, they are found much oftener in the skin, fascia, intermuscular connective tissue, bone-mar- row, periosteum, brain, and ovaries, than in the liver, intestines, and 1 ungs. The development and form of the cells vary greatly in different sarcomata. The intercellular substance is sometimes very scanty, soft, and delicate; at other times more abundant and in character resembling the ground-substance of the mature normal connective-tissue substances. The amount of the intercellular substance has a marked influence upon the consistence and color of the tumor. The medullary forms are soft and very cellular, and poor in intercellular substance ; on section they present a marrow-like white or grayish- white surface. The hard, dense forms, on the other hand, are poor in cells and rich in fibrous inter- cellular substance; they pass by insensible gradations into fibromata. Transition-forms are known as fibrosarcomata. The cut surface of a sarcoma presents a nearly uniform appearance, in case retrograde changes or differences in the blood-content do not cause alterations of the same; it is usually uniformly smooth, in the medullary forms milk-white, in the firmer varieties clear grayish-white, somewhat translucent, or more of a clear grayish-red or grayish-brown color. The hard forms are glis- tening white or yellowish-white. The development of the blood-vessels varies greatly ; sometimes the vessels are, very numerous, large, and ectatic (telangiectatic sarcoma). Usually the vessels have walls easily distinguishable from the tumor tis- sue ; but the tumor-cells may also constitute the outer cells of the vessel- wall; and in such a case the cells of the vessel -walls also take part in the growth of the tumor. Retrograde changes — such as fatty degeneration, mucous degenera- tion, liquefaction, caseation, necrosis, htemorrhage, gangrene, \rlceration, etc. — are of frequent occurrence in sarcomata. The sarcomatous tumors may be divided into three classes. The first of these includes the simple sarcomata, or sarcomata in the narrower sense — that is, tumors of the type of embryonal connective tissue, showing a more or less uniform distribution of the cells without the formation of distinct groups of cells. The second class includes those sarcomata which show a special arrangement and grouping of the individual elements, so that tumor-formations arise which are very similar to the epithelial tumors. The third class is characterized by the appearance of secondary changes in the cells, in the intercellular substance, and inthe blood-vessels, these changes giving to the tumors concerned a characteristic appearance. The etiology of sarcomais not a simple one. It occurs more frequently in youth than in old age. Some sarcomata develop even in embryonic life, and the origin of such may be referred to some local malformation. Occasionally trauma appears to be an exciting cause. A parasitic origin has not been demonstrated (see Etiology of Carcinoma). Usually ouly one primary tumor is formed, but multiple primary sarcomata sometimes SARCOMA. 421 occur, particularly iu the skin and- bone-marrow. The softer tumors give rise to metastases. § 113. The simple sarcomata include both soft medullary forms and those of a firmer consistence, which pass by insensible degrees of transition into the fibrosarcomata and fibromata. According to the char- acter of the cells, several forms may be distinguished. The small round=celled sarcomata are very soft, quickly growing tumors, which develop particularly in the connective tissue of the motor afjparatus and supporting framework, and also in the skin, testicles, ovaries, and lymph-glands. On section they appear milky-white, and occasionally present caseous or softened areas. When scraped the cut surface yields a milky fluid. Their structure is very simple ; the tumors consist almost wholly of round cells and blood-vessels (Fig. 288, c). The cells are small and frail; they possess very little protoplasm, and have spherical or slightly oval, rather large, bladder-shaped nuclei (c), which appear to be more highly developed than the nuclei of lymphoid cells. Between the cells lies a very scanty amount of fibrogranular intercel- lular substance. The vessels traverse the masses of cells in the form of thin-walled canals. If such a tumor growing iu muscle be examined at its periphery it appears as an aggregation of round cells (Fig. 288, b, c) in the intermuscular connective tissue. Not mfrecpiently lymphoid cells lie near the tumor-cells, the nuclei of the former (d) staining more intensely than those of the tumor-cells. A second form of round-cell sarcoma is designated lymphosarcoma oi- sarcoma lymphadenoides ; it imitates to a certain extent the struc- FKi. 288. Fig. 289. Fig. 288.— Section through the edare of a sarcoma of the intermuscular connective tissue of the cervical muscles (alcohol, carmine), a, Transverse section of normal muscle ; 0,, transverse section of an atrophic muscle-fibre; b, round cells of the sarcoma, between the muscle-fibres; c, fully developed tnmor; d, lymphocytes. X 300. Fig. 289.— Section from a lymphosarcoma of the nasal mucous membrane (alcohol, carmine), n. Retic- ulum; h, cells of the reticulum; c, round cells; a (at the upper left), blood-vessel with proliferating cells. X 300. ture of a lymph-gland in that the stroma for the greater part of the round cells consists of a vascular reticulum (Fig. 2S9, a), which in part at least' is composed of branching and anastomosing cells (b), as may be demonstrated by shaking a small section of the tumor in a test-tube. According to the amount of reticulum which they possess, the lymphosarcomaia may be divided into the soft and hard forms. Iu the denser 422 TUMORS. varieties the reticular framework may take on more and more the appear- ance of ordinary fibrous connective tissue. Especial forms of round-celled sarcoma arising in the bone-marrow are known as myelomata. Lymphosarcomata arise most frequently in the lymph-glands and the adenoid tissue of the mucous membranes, in the spleen and medias \ Kr '■■ ~ ' -*"^5Sto. Atlf^^Sgl^^ ws # «?- „.--,'.- U'i ..■' ■■■,,■■ '.' : ■■ ■■"■,■ .1 ^ ( S||;^^ s '- J * ! «« : ^| 1 r- :i =s^ Fig. 290. Fig. 290. — Section from a fungoid large round-celled sarcoma of the skin of the leg (carmine preparation). ■ 400. Fig. 291.-— Section from a sarcoma of the mamma with cells of different shapes (alcohol. Bismarck- brown), a. Connective tissue ; h, sarcoma tissue ; c. small cells ; o 7 , cells with hypertrophic nuclei : e, mul- tinuclear cells. ■.300. tinum, but are found also in other places. The tumor-proliferation in- volves successively a more or less considerable portion of the lymph- adenoid tissues named. Large round=celled sarcomata, the cells of which are much larger than those of the forms just described, appear in the same places as do the small round-celled variety, aud closely resemble the latter. The cells possess an abundant protoplasm and large, bladder-like, oval nuclei (Fig. 290). Many of the cells have two nuclei, some more than two. Between the round cells there lies a reticulated intercellular substance (Fig. 290), as well as spindle-shaped and branched cells, which together form an alveolar network in whose meshes lie the large round epithelial-like cells. In other forms of large round-celled sarcomata the tumor-cells are very unequal in size (Fig. 291), and at the same time there are mingled with the round cells elongated or irregularly shaped cells, so that the tumor may be called also a sarcoma with polymorphous cells. The nuclei likewise vary greatly i n size (Fig. 291), and in individual cells (e) may be present in large numbers (multinuclear giant-cells). The large round-celled sarcomata and the polymorphous-celled vari- ety are on the whole less malignant than the small-celled, but they also give rise to metastases. Spindle=celled sarcomata belong to the most commonly occurring tumors. As a rule, they are much firmer than the round-celled forms, but soft medullary forms also occur. On section they present ordinarily a grayish-white or yellowish-white, rather translucent surface, which may be more or less reddened according to its vascularity. Medullary tumors whose cells have undergone fatty degeneration may possess a pure white color. In general, these sarcomata are more benign than the round-celled varieties, but their character in this respect varies accord- ing to their location and their richness in cells. SARCOMA. 423 According to the size of the cells there may be distinguished large spindled=celled and small spindle=celled sarcomata. Through the teas- ing of small pieces of the tumor the cells may in part be isolated, and in this way very long spindles may be obtained (Fig. 292). The cells lie side by side with their flat sides approximated, and are grouped in bun- dles, which, in sections, are cut partly longitudinally, partly transversely, and partly obliquely — evidence that they are interwoven in different directions. The arrangement of the spindles in bundles is often very striking; iu other cases it is wanting ; and the spindles for considerable distances run in the same direction. Sometimes the direction of the spindles is determined by the direction of the blood-vessels — that is, the individual bundles form sheaths about their respective blood-vessels. Between the spindles there is often but a very scanty intercellular substance, or it may not be possible to demonstrate in sections the pres- ence of such. Iu other cases it maybe more abundant, and show a fibril- lar character. The cells in such cases 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 cells seem to spring directly from the nucleus (nuclear fibres). Such varieties are dense and hard. They represent the connecting-link be- tween sarcomata and fibrotuata, and are designated f ibrosarcomata. Sarcomata with polymorphous Fig. 392. Fig. 293. Fig. 292.- Spindle-cells from a large spindle-celled sarcoma of the cheek (teased preparation). X 400. Fig. 293. —Cells from a myelogenous giant-celled sarcoma of the tibia. (Hiematoxylin.) X 400. cells are found also among the spindle-celled forms ; and contain spin- dle-shaped, pyramidal, prismatic, stellate, and very irregular cell-forms (Fig. 29.3). Both in polymorphous- and spindle-celled sarcomata there may be found more or less numerous giant cells (Figs. 291, 293, and 294), so that the designation giant-celled sarcoma may be applied to these tumors. They arise particularly from the bones, but they may occur also in other places. If a sarcoma develops in preexisting new growths there may be 252), The lymphosarcoma of the lymph-glands and lymphadenoid apparatus of the spleen and the mucous membrane of the gastrointestinal tract gives rise to a peculiar disease of these organs, which is characterized by a progressive increase of the lymphadenoid tissue, leading to the formation of extensive npdules. Under these circumstances the characteristic structure of the lymphadenoid apparatus is lost, and the newly-formed tissue shows a marked departure from the structure of typical lymphadenoid tissue — namely, a fibrous thickening of the reticulum or the formation of giant-cells. Since similar growths occur also in other organs, such as the liver, the disease cannot be looked upon as a pure hypertrophy ot lymphadenoid tissue, but as a tumor-formation with the production of lymphoid cells. It is also possible that it is an infectious dis- ease. Likewise the condition known as sarcomatosis cutis, which is characterized by the formation of numerous round-celled nodules in the skin, is to be classed with it. The myelomata of the bones, occurring as multiple nodules either concealed in the bones or projecting from their surface, demand especial consideration. According to recent investigations (Sternberg, Sibbert, Hoffmann) they are composed of cells corre- sponding either to the myelocytes, lymphocytes, erythroblasts, or plasma-cells. The common characteristic of the lymphosarcoma and myeloma is that, aside from the reticular framework, they consist essentially of derivatives of free mesenchymal cells, and are thereby differentiated from the ordinary sarcomata that arise through the pro- liferation of fixed tissue-cells. They form, therefore, an especial group "among the connective- tissue tumors, but the investigations so far carried out are not sufficient to fix their position more definitely. Literature. (Sarcoma.) Ackerman: Histogenese u. Histologic d. Barkome. Samml. kl. Vortr. No Leipzig, 1383. Beneke: Versprengung v. Nebennierenkeimen nebst Bcmerkungen etc Ziegler, ix., 1891. Birch.-Hirsch.feld: Sarkom. Eulenburg's Realencyklop., xxi., 1899. Bizzozero: Stroma di sarcomi. Arch, per le So. Med., ii., 1878. Borrmann: Sarkom. Ergebn. d. a. Path., vii., Wiesbaden, 1902 (Lit.). Daniels: Das Stroma d. Sarkome. Virch. Arch., 165 Bd., 1901. Dreschield: Beitrag zur Lchre vom Lymphosarkom. Deut. med. Woch., Mexner: Multiple Lymphosarcoma^. Johns Hopkins Hosp, Rep., iii Goldmann: Verbreitungswege bosartiger Geschwulste. Beitr. v. Brui Goppert: Lymphosarkomatose. Virch. Arch., 144 Bd., Suppl., 1896 (Lit.). van Heukeiom: Sarcome et inflammation, Rec. delrav. du Lab. Boerhaave Hoffmann: Ueber das Myelom. Beitr. v. Ziegler, xxxv., 1904. 233, 234, Beitr. v. 1891. 1893. , xviii. 1897. 1899. ORGANOID SARCOMA. 425 Joseph: Haulsarkomatose. Arcli. E. Derm., 40 Bel.. 1898. v. Kahlden: Das Sarkom des Uterus. Beitr. v. Ziegler, xiv., 189S. v. Karwowski: Ueber Callustumoren. Inaug.-Diss., Freiburg, 1890. Langhans: Das maligne Lympliosarkom. Vircli. Arch., 49 Bd., 1872. Lartigau: Primary Sarcoma of Thyroid. Anicr. ,Tourn. of Med. Sc, 1901 (Lit.). Linser: Sarkom der Haut mit Schrumpfung. Beitr. v. Bruns, 26 Bd., 1900. IiOwenthal: Traumat. Entstehung d. Geschwiilste. Langenbeck's Arch., 49 Bd., 1875. Manz: Riesenzellensarkorn d. Brustdruse. Beitr. v. Bruns, xiii., 1895. Neumann: Sarkome mit endothelialea Zellen. Arch. d. Heilk., xiii.. 1892. Paltauf: Lympliosarkom. Ergebn. d. allg. Path., iii., 1897. Pawlowski: Parasitare Emschliisse in sarkomatosem Gewebe. Virch. Arch., 133 Bd., 1893. Perl: Sarkom der Vena cava inferior. Virch. Arch., 53 Bd., 1871. Putiata-Kerschbaurner : Das Sarkom des Auges, Wiesbaden, 1900. Ribbert: Das Myelom. CM. f. a. Path., x v., 1904. Sanger: Sarcoma uteri deciduo-celhilare. Arch. f. Gyu., (34 Bd., 1898 (Lit.). Schmidt: Ueber das Angiosarkom der Mamma. Langenbeck's Arch., xxxvi., 1888. Sokolow: Ueber die Entwickelung des Sarkoins in den Muskeln. Vircli. Arch., 57 Bd , 1873. Spiegelberg: Mulfcipel auftretende Knochensarkomc. Inaug.-Diss., Freiburg, 1894. Sternberg: Myelom. Verb. d. D. path. Ges. , vi., Jena, 1904 Steudener: Beitrage zur Onkologie. Vircli. Arch.. 59 Bd., 1874. Tillmanns : Beitr. z. Lclire v. d. Sarkomen. Arch. d. Heilk., xiv., 1873. Trambusti: Ban u. Theiluug d. Sarkomzellen. Beitr. v. Ziegler, xxii., 1897. Virchow: Die krankhaften Geschwiilste, 2Bd.,.1864. Wieland: Primftr multiple Knochensarkome. Inaug.-Diss, Basel, 1893. Williams: Histologic u. Histogenese d. Uterussarkoms. Zeitschr. E. Heilk., iv., 1894 (Lit.). See also §g 114-1 16 § 114. Sarcomata which present an organoid structure appear in those forms known as alveolar and tubular sarcomata. These are con- nective-tissue tumors in which the cellular (dements, especially the larger cells, are arranged in groups, so that it is possible to distinguish a vas- cular connective-tissue .stroma and strands or nests of cells. According to their genesis, these growths may be divided into t w< > types : lymphangiosar- coma and hcemangiosarcoma. There are, however, also alveolar sarcomata which possess stroma and cell-nests, but which, in so far as their devel- opment is concerned, cannot be included with the above-named types. The lymphangiosarcomata are tumors which arise from a prolifera- tion of th' j endothelium of the lymph-vessels am] lymph- spaces. They may accordingly be designated as lymphangioendotheliomata or as endo- theliomata in the narrower .sense They may develop either in previously normal tissue, or in preexisting tumor-like formations, such as the hy- pertrophic lymphangioma in particular (pigmented moles and warts, see § 108), aud also frommyxochondromata. The first occur particularly in the meninges of the brain, and in the serous membranes of the great body-cavities; but may develop also in other organs; the second are found chiefly in the skin; while those arising from myxochondromata develop in the mixed tumors of the salivary glands, palate, and orbit. The endotlieliomata of the inner meninges of the brain ami spinal cord occur partly as nodular growths and partly as flattened proliferations; they develop through the transformation of the flattened endothelium, which covers the connective-tissue network of the subarachnoideal tissue and pia, into cubical or even cylindrical cells (Fig. 295, d, e). In con- sequence, the new-growth at first presents the appearance of gland-like formations ; in the event of a more active proliferation solid nests of cells aTe formed. Inasmuch as the pia is continued as a lymph-sheath around I he cerebral vessels, there are formed around the latter strands of large epithelial-like colls (Pig. 295,/, g, in. 420 TUMORS. The endothelioma of the dura mater arises through a proliferation of the endothelium of the lymph -vessels, and leads, through the filling up ot the latter wiih large cells, to the formation of anastomosing cords of cells (Pig. 296, c, d, e), which in some places may still contain a lumen. The endotheliomata of the pleura or of the peritoneum appear usually as flattened thickenings of the affected membrane, but scattered nodular elevations may occur throughout the areas of thickening. These growths FIG. 295.— Section through an endothelioma of the pia mater and cerebral cortex, diffusely spread over the surface of the brain and spinal cord (Miiller's fluid, hematoxylin), a, Superlleial pia; h, pia in a sulcus ; c, cortex ; if, c, endothelial proliferations in the pia sheaths of the cortical vessels ; /, , c), and gives rise to the formation of large cords of cells (c) or of smaller cell- nests. The proliferating cells are characterized by a great variation in the size, character, and form of the nucleus and cell-body. The endothelioma of the skin, which arises from the hypertrophic lym- phangioma (warts and pigmented moles), resembles these in its general structure, and possesses also cell-uests of varying size (Fig. 277)." Fur- ther, there also occur endotheliomata of the skin, which do not arise from warts, and may develop in great numbers (Spiegler, Mulert). The endothelial proliferations which arise in myxomata and myxochondro- ma form cords of cells of different shapes fFk b) ; but it should ENDOTHELIOMA. 427 be noted that in these cases similar proliferations may also arise from the blood-vessels (Fig. 302, c, d), s that it is often impossible to decide as to the nature of the cell-strands. The alveolar, tabular, or plexiform structure of the endothelioma is well marked only in the first stages of the tumor, and usually disappears tnem Fig. 296.— Endothelioma dura matris (Miiller's fluid, haematoxylln). a. Connective-tissue stroma; h- swall-celled focus; c, groups and strands of cells arising from the proliferation of lymph-vessel endothe- lium ; d, endothelial cell-strand with a lumen ; e, area of fatty degeneration in nest of endothelial cells; f, strand of cells, passing gradually, on the right, into the surrounding connective tissue. X ~5. in part with the advancing growth of the tumor. This is due, on the one hand, to the fact that the endothelial proliferation extends, without Fig. 2MT.— Endothelioma of the pleura (alcohol, haematoxylln). a, Proliferated and thickened pleural con- nective tissue : 6, cell-strands. X 100. sharp limits, into the neighboring connective tissue (Fig. 29t>, f) ; and, on the other hand, to the circumstance that the connective-tissue cells 4L'X TUMORS. take on a, proliferative activity similar to that of the endothelium, so that there is formed a diffuse, cellular new growth of the character of Fig. 298. — Endothelioma of the mammary gland Uik-ohul, hematoxylin, eosin). a, Cuniiec.tive tissue; b, enlarged cells in the connective-tissue spaces ; c, strands of cells ; <1, diffuse cell-proliferation. X 300. an ordinary sarcoma (Fig. 1I!)S, d). Accordingly, the endothelioniata cannot lie sharply distinguished from the sarcomata, and may become transformed into the latter. The similarity in structure between endothelioniata and carcinomata raises the question whether it would not be expedient to class the former as endothelial cuimm. The structure of these tumors would certainly justify such a classification., but I con- sider it better to avoid the use of this term. In the lirst place, the term endothelioma is in general use and is entirely appropriate, and the introduction of the term endothe- lial cancer would easily give rise to confusion ; by the term cancer in general is under- stood an epithelial tumor, and it does not seem expedient to introduce two types of cancer — an epithelial and an endothelial. I have classed as endothelioniata (hose tumors of the serous membranes which are characterized by the formation of cell cords in the lymph channels, on the assumption that these cords of cells arise from the endothelium of the lymph-vessels and lymph- spaces. I must admit, however, that f do not consider this assumption as absolutely proved, in spite of the concurring' definite statements of a number of authors (see Olockner). The possibility of their development from the epithelium of the serosa is not excluded (I'xinhi), and if such an origin could be proved, the question would arise whether it would not be better to class these tumors with the carcinomata. since the corresponding tumors of the kidneys and ovaries, whose gland-cells arise from Deri toneal epithelium, are classed with the epithelial tumors. According to investigations by M. B. Schmidt, the cellular elements of the sarco- mata of the dura mater, as well as of the psammomata (§ 110), that for the chief part are located in the neighborhood of the dural sinus, arise from enilnihelint cdU of the untchnoifl that under physiological conditions are pushed into the tissue of the dura in part by the ingrowing Pacchionian bodies, and in part as independent cell-plugs from the smooth surface of the arachnoid. Literature. (Endothelioma [LumphiDif/toxtircoiiKtl .) Adler: Primary Endothelioma of the Pleura. Barth: Lymphangioma rkom d. Mundbodens. Benda: Primitres Carcinom d. Pleura. Dent, Bdhme: Primares Sarko-carcinom der Pleura. Borrmann: Endotheliome. Ergebn. d. allg. Res., liiij] . er. xix., 1S96(LH.). Jour, of 3Iei Beitr. v. Zie med. Woch., lsii? Virch. Arch.,, si Bd.. INSO. Path., vii., Wiesbaden, I ill 13 (Lit.) ENDOTHELIOMA. 429 1902 (Lit.). Beitr. v. Ziegler, xiii.. Burkhard: Sarkoni u. Endotheliom. Beitr. v. Bruns, 36 Bd.. Driessen: Untersuch. ilber glykogenreiche Endotheliome. 1893. Eberth u. Spude: Familiare Endotheliome. Virch. Arch., 153 Bd., 1898. Ferrio e Orevere: Endot. della Pleura. A. per le Sc. Med., xxvi., 1902. Gallina: Endotheliome d. Lymphdrttsen u. Lymphbahnen. V. A., 172 Bd., 1903. Gebhardt. Endotheliom der Pleura. Inaug. -Diss., Freiburg, 1894. Glockner: Endothelkrebs d. serosen Haute. Zeitschr. f. Heilk., xviii., 1897 (Lit.); Riesenzellen u. endotheliale Geschwiilste. Beitr. v. Ziegler, xxvi., 1899. Kelly: The Histology and Histogenesis of Certain Tumors of the Parotid, with Par- ticular Reference to Those of Endothelial Origin. Phila. Month. Med. Journ., 1899. Kromayer: Endothelioma tuberosum colloides. Virch. Arch., 139 Bd., 1895. Krompecher: Endotheliom des Hodens. Virch. Arch., 151 Bd., Suppl., 1898. Kiittner: Geschwiilste der Submaxillaris. Beitr. v. Bruns, xvi., 1896 (Lit.). Lancereaux: Traite d'anatomie pathol., iii., Paris, 1889. Linser: Verkalkte Epitheliome und Endotheliome. Beitr, v. Bruns, xxvi., 1900. Marchand. Endotheliom d. Antrum Highmori mit hyal. Kugeln. Beitr. v. Ziegler, xiii., 1893. Mulert: Multiple Endotheliome der Kopfhaut. Langenbeck's Arch., 54 Bd., 1897. Neumann, E. : IJeber Sarkoine mit endothelialen Zellen. Arch. d. Heilk., xiii., 1872 v. Ohlen- Beitr. z. Kenntn. d. Parotisgeschwulste. Beitr. v. Ziegler, xiii., 1893. Perls: Beitr. z. Geschwulstlehre. Virch. Arch., 56 Bd., 1872. Perthes: Verkalkte Endotheliome. Beitr. v. Bruns, xii., 1894. Pollmann: Endotheliom d. Pleura u. d. Peritoneums. Beitr. v. Ziegler, xxvi., 1899. Bitter: Pettgehalt der Endotheliome d. Knochen. Zeitschr. f. Chir, 50 Bd., 1899. Bossier: Cancer primitif de la plevre. Beitr. v. Ziegler, xiii., 1893. Schmidt: Pachion. Granul. u. Sarkome d. Dura mater. V. A., 170 Bd. , 1902. Schulz, B. : Das Endothelcarcinom. Arch. d. Heilk., xvii., 1876. Tanaka: Endotheliome (bes. d. Haut). Deut. Zeitschr. f. Chir., 51 Bd., 1899. Teixeira: Zur Casuistik, des primaren Pleuraendothelioms. Inaug. -Diss., Preiburg t 1894. Volkmann: Endotheliale Geschwiilste. Deut. Zeitschr. f. Chir., 41 Bd., 1895 (Lit.). Waelsch: Aus weichen JSTaevi entsteh. bosart. Geschw. Arch. f. Derm., 49 Bd., 1899. Warthin: Endothelioma of the Lachrymal Gland. Arch, of Ophth., 1901. See also §§ 113 find 115. § 115. The haemangiosarcomata represent a group of organoid sar- comata, in which the walls of the blood-vessels and their surrounding v,* oqq ni^nrt ™«, perivascular cylinders of cells cut transversely and showing numerous mitoses : c, granular masses, with scattered cells, between the cell-cylinders. X 73. blood-vessels or those newly formed in haemangiomata, through a more active development and proliferation of the endothelium giving rise to b lit!*-''. ' "\Cr-T=5>-S- V imtJ^-:^'S^fS&- ?~ ■, ■ ■' , ■ i, FlG. 801.— Angiosarcoma of the testis (Mijller's flu'd. hsemntoxvlin, i closely purled cells; I), areas poor in cells; c, hyaline lumps; , dense sarcoma tiasue ; c, blood-vessel ; d, cell-strands arising [rom blood-vessels, and ill part containing a hyaline substance. X 80. (plexiform angiosarcoma). The tissue lying between the cell-strands is the remains of the original tissue (Fig. 301, 6), and may still contain characteristic tissue-formations, as, for example, glands (<■). Should a more active proliferation of the perivascular mantle of cells occur, and if these become confluent with each other (Fig. 301) the tumor passes over into an ordinary sarcoma. This change almost invariably occurs in the larger tumors of this kind. Hsemanglosarcomata occur in the most varied organs: testicles, kid- neys, salivary glands, bones, brain, mamma, thyroid, skin, carotid gland, coccygeal gland, ovaries, and liver. In the last-named organs they are rare. Both forms may so occur that the tumor throughout bears the char- 432 TUMORS. acter of a lnemangiosarcoma ; but it also happens that such proliferations of the vessels form only a single feature of other tumors (Figs. .302, c, d; 311, d); and though this feature indeed gives charac- ter to individual portions, it is, on 1 he whole, overshadowed by other features of the growth — as, for ex- ample, a fibro-cellular tissue, car- tilage (Fig. 302, «, b) or myxo- matous tissue (Fig. 311, a). Lymphangiosarcomaia and hsemangiosarcomata cannot al- ways be sharply differentiated from each other, and tumors occur to which both designations may be applied with propriety. The perivascular development of the endothelial proliferation with- in the brain in endothelioma of the pia (Fig. 295,./', g, h) would justify also the application of the term ha-mangiosarcoma. If in a lyniphangiosarcoma of the skin there is such a rapid de- velopment of the cell-nests that the space between the vessels becomes wholly filled with cells, so that the framework of the tumor conies to consist only of blood-vessels (Fig. 303), it becomes an open question as to whether the tumor should be called a lymphangioendothelioma or a haemangiosarcoma. For?t, in his work on tumors, has entirely separated the endotheliomata (lymphangio- and hemangioendothelioma) from the sarcomata, and has attempted to class them as an especial form of neoplasm. In so far as typical microscopical pictures are concerned, such a separation is indeed possible, but the endotheliomata in general do not show in all portions so typical a structure that they can be distinguished from ordinary sarco- mata. Further, it is by no means determined that endothelial cells of the lymph- spaces and vessels do not take part in the formation of sarcomata. It seems to me, therefore, better to consider the endotheliomata as an especial form of sarcoma in which the structure of the tumor still permits us to see that undoubted endothelial cells give rise to the cell-masses. Literature. ^ Hwmangiosarcoma [Endothelioma] . ) Fir;. 303.— Alveolar melanotic sarcoma of the skin (alcohol, hsematoxylin). a, Mononuclear, n,, multi- nuclear sarcoma cells of epithelial character; b, pig- ment-containing cells; c, stroma with blood-vessels and pigment. X 300. Beitr. v. Ziegler, viii., 1X90. Arch., 151 Bd., 1898; Wachsthum Arnold: Primare Angiosarkome der Leber. Borrrnann: Blutgefassendotheliom. Virch Gefassgeschwiilste. lb., 1.57 Bd., 1899. Colmers; Sarkom u. Endotheliom d. Penis. Beitr. v. Ziegler, xxxiv., 1902. Franke: Endothelioma intravasculare hyalogenes. V. A., 121 Bd., 1890. Frattin: Endoteliomi dei vasi sang. A. per le Sc. Med., xxv., 1901. de Haan: Angiosarkom d. Leber. Beitr. v. Ziegler, xxxii., 1903. Hansen; Hemangioendothelioma uteri. Virch. Arch., 171 Bd., 1903. Harris: Malignant Disease of the Pleura. Journ. of Path., ii., 1893. v. Heinleth,: Perithelioma gland, caroticae. Cbl. f. allg. Path., xi., 1900. Hildebrand: Tubulares Angiosarkom der Knochen. Deut. Zeitschr. f. Chir., 31 Bd., 1890; Nierentumoren. Arch. f. klin. Chir., 47 Bd., 1894. v. Hippel: Zur Casuist.ik der Angiosarkome. Beitr. v. Ziegler, xiv., 1893. v. Hleb-Koszanska: Peritheliom der Steissdruse. B. v. Ziegler, xxxv., 1904. Jarisch: Hautgeschwiilste (Hamangioendotheliom). Arch. f. Derm., 28 Bd.', 1894. Jolly: Angiome sarcomateux. Arch, de m£d. exp., vii., 1895. Kolaczek: Ueber das Angiosarkom. Deut. Zeitschr. f. Chir., ix. and xiii. Limachet: Blutgefassendotheliom. Virch. Arch., 151 Bd., Suppl., 189S. MELANOSARCOMA. 433 Low and Lund: Tubular Perivascular Sarcoma. Journ. of Med. Res., Marchand: Anat. d. Glandula carotica. Intern. Beitr., Festschr. f. 1891. Markwald: Multipl. intravaskulares Endotheliom d. Knochen Marx: Tumor der Leber. Beitr. v. Ziegler, xxxvi., 1904. Maurer: Beitr. z. Kenntniss des Angiosarkims. Virch. Arch., 77 Bd. 1902. Virchow. ii. V. A., 141 Bd., 1899. 1879. Beitr. v. Ziegler, xi. Paltauf : Geschwiilste der Glandula carotica (Angiosarkom). 1892. de Paoli: Primares Angiosarkom der Niere. Beitr. v. Ziegler, x., 1891. Rindfleisch u. Harras: Endotheliom d. Knochenmarks. V. A., 103 Bd., 1886. Ritter: Fetthaltiges Endotheliom der Knochen. Zeitschr. f. Chir., 50 Bd., 1899. Sailer: Primary Endothelioma of Left Sup. Pulm. Vein. Cont. from the William Pepper Labor., 1900. Schmidt: Ueber das Angiosarkom der Mamma. Arch. f. klin. Chir., 36 Bd., 1887. Waldeyer: Die Entwickelung der Carcinome. Virch. Arch., 55 Bd., 1872. Wolters: Haemangioendothelioma tuberos. multiplex cutis. Arch. f. Derm., 53 Bd. , 1900. See also §§ 114 and 116. § 116. Sarcomata which acquire a peculiar character through especial products of the cells or through changes in their ground- substance are to be found both among the simple and the organoid forms. The chief types belonging in this class are the melanosarcoma, chloroma, osteosarcoma, osteoid sarcoma, the petrifying sarcoma, psammoma, and the sarcomata containing hyaline formations. Melanosarcomata occur in tissues which contain pigmented connec- tive-tissue cells — chromatophores. They develop most frequently in the choroid of the eye and in the skin. In the latter case they arise chiefly from pigmented moles and lentigines. They belong to the malignant sarcomata, grow into the neighboring tissues, and give rise to metastases. The fully developed tumor is in whole or in part smoky gray to black or brownish-black, the color being due to the presence of round, angular, fusiform, and branched cells, which are filled with yellowish-brown pig- Fio. 304.— Melanotic sarcoma of the skin (alcohol, carmine, eoBln) . a. Sarcoma tissue rich In cells ; It, cell- nests; c, pigment-cells ; d, blood-vessels with hyaline walls. X 300. 28 484 TUMORS. ment i granules (Figs. 304, b, e ; 305, c), or are .stained a diffuse yellow. In the alveolar forms both the large cell-nests, as well as the smaller cells of the supporting framework, may contain pigment. It is often rfMr*?-~~ < --S~ r ~ K ^~. A i. Mfe ft. r"'«S "V..-/J '*&Wf 0»Ct Lf\j 3 VC>* 1 "' ^ s dA. Jf°*^»s ^«*^*3ffS?iS;- Fig. SOS.— Metastasis of a melanotic sarcoma of t lie skin i ntery of the small intestine tforma- i- Hi. o' ''eii ■*';'.}.'*» ■ .i--^ ■>'-.;':; .■ •*.. ..' • •";".- ■v'*«W" i -v'""cV-'*i*'' Fig. 306. — Endosteal osteosarcoma of the humerus. (Formalin, nitric acid hffiraatoxv'in and eosin.) a, Old bony trabecule of the spongiosa; 6, sarcomatous proliferation arisin" from lie' endosteum; c, c,, new-formed bone; «, blood-vessel, X SO. CHLOKOMA. 4,^5 especially abundant in the neighborhood of the blood-vessels (Pigs. 303, e ; 304, d) ; but this pigment is not hsemosiderin. The metastases are likewise more or less pigmented (Fig. 305) ; and the smallest ones may consist essentially of pigmented cells (e, d). Cases occur in which numerous organs, the skin, muscles, pia, serous mem- • > \ .;--:-*;■ ;y ' .V ^ ^ •» ' v t . • '•'-^'• r ;}' J '.'*':■.■■■■>'■ ■':'/'£:■';. * ~ ?.'■'■■ '■'•.-- .' ' ' . - \ JTV- - "•-=- _-'-* -.-'".' '-- . ■ •• -, I • * ^-.'•' • ; * . ■■- "- '. " •"• .'-vrrVfci"~- /'"-'/">" r -' ''■ '■ " ^- -.", - *-•' - 3* "[ ,• "- '*/■}&*.•:-"- ■' V--v'-**''.'' L .\i'%-*"-''-*"' i '-.'-^.'-'--. -«:-' .'-•-* .'-.-.'^ -* i ' V -' '-■/' *-**-.''":•.". " * "" " *v/r"/ '* : ' y jr.*.**. ~.- ' .'■';.'''" — ~_ *"*- "**"*- '1 " r 6 Fig. 307. — Sarcoma ossificans. (Formalin, nitric acid, hematoxylin, and picrof uchsin. ) a. Sarcoma tissue; b, new-formed bone; c, areas of transition. X 40. branes and adipose tissue (Pig. 305) are spotted black through the for- mation of innumerable metastases. Chloromata are tumors the cut surface of which presents a light- green color which on exposure to the air takes on a dirty appearance- Fid. 30b,— Osteoid sarcoma of tbeetbmoid bone (Muller s fluid, Hematoxylin, eosln). a. Sarcoma, tissue; b , osteoid tissue : r old bone-traberulse ; d. vascular fibrous tissue. X 45. 436 TUMORS. They develop most frequently from the periosteum of the cranium; and consist of tissue made up of round cells and a reticular stroma. & •■---■■ : ts>4 P ^M^> •,k |»^^ M '^ FiCr. 3(19. -Petrifying Iar^e-celled sarcoma of the tibia 'Midler's fluid, hematoxylin, eosin). a. Poly- morphous tumor-cells; b, alveolar stroma; c, trabecular of stroma containing small calcareous concre- tions ; d, petrifying trabecule of the stroma. X '330. They may, therefore, be classed with the lymphosareomata. They may be associated -with a lymphsemia. Eecent studies (Wartlrin, Klein and Steinhaus, etc. ) show that cldoromata are primary tumors of the bone- marrow, arising- from the parent-cells of the white-cells. Some consist chiefly of myelocytes, either neutrophile or eosinophile, while others are composed of cells resembling-lymphocytes. There is usually an associ- ated leukemic condition of the blood. According to Chiari and Gruber, the green color is due to the presence in the cells of small shining spherules which give the microchemieal reactions of fat. In harmony with this view is the fact that the color disappears in alcohol. On the other hand, von Reckling- hausen holds that the color is a property of the parenchyma and that no morphological elements are the carriers of the color. Osteosarcomas or ossifying sarcomata occur chiefly in con- nection with the skeleton and are characterized by the new-forma- tion of bone within sarcomatous tissue. The new bone arises at times from a thick homogeneous ground-substance (e, <\ ) formed between the tumor-cells (Fig. 306, b) which is either connected O,) with the old bony trabecule (a) or arises independently (c), or at other times from a coarsely fibrillated connective tissue (Fig. 307 c) : which gradually becomes condensed (h) and, taking up lime-salts, is transformed into bone. Osteoid sarcomata develop in the endosteum and periosteum, and ;©'o^>i - '■ <&^ - fe^r^* ~S^> dura Fig. 310.— Section from a psammoma ol the mater (alcohol, picric acid, hfematoxylin sin Hyaline nucleated spherule inclosing calcareous con- 'Z"' f i'l"V !\ ca i care ? us , <™cretion with byaline non- nucleated border. Inclosed In fibrous connective tis- sue; i\ calcareous concretion surrounded by hyaline connective tissue; d, spicule of lime in the connec- tive tissue; r. spicule with three concretions < 180 PSAMMOMA. 487 are characterized by a thickening of the ground-substance in certain areas, so that there are formed trabecule: of osteoid tissue (Fig. 308, b). Such tumors are closely related to the osteosareomata, but differ from them in the absence of deposits of lime-salts. Petrifying sarcomata likewise occur most frequently in connection with the skeleton, and are characterized by the development- between the tumor-cells of trabecular of a delicate ground-substance (Fig. 309, c), through the calcification id) of which the tumor tissue becomes hard- ened, although no typical bone is formed. Psammomata or sand tumors (acervulomataj are sarcomata or fibro- sarcomata of the dura, inner meninges, or pineal gland, which contain concretions of lime-salts in greater or less abundance. Some of these con- cretions are similar in structure to the normal brain-sand, the basis of their formation being concentric layers of cells which have undergone hyaline degeneration (Fig. 310, a, b, c). Occasionally the chalky spker- ,nles lie inside of individual cells and represent hyaline products of the cells which have later become calcified. Others are more of the nature of spicules (d), and arise through the deposit of lime-salts in connective tissue or blood-vessels which have undergone hyaline defeneration. Fig. 311.— Myxo-angiosarcoma of tlie parotid, with hyaline formations (Muller's fluid, hematoxylin, eosin). a. Myxomatous tissue ; b, cell-strands Inclosing hyaline spherules ; c, hyaline spherules in myxo- matous tissue ; m^-M mm MM :'■ '"8: ,:3 : "k *n : ?h V \\!'—c w m ■ ff si siitsiiStil ':l C« i !;s®<; Fig. 32(i. —Adenoma mammas alveolare (alcohol, alum-carmine) . a, Terminal alveoli; b, gland-ducts ; c, connective-tissue stroma, x 27. liver, contracted kidney, ovaries containing scar tissue), or from remains offokal structure*. The new-formation of glands is dependent upon a pro- 440 TUMORS. liferation of the surface -epithelium or of glandular epithelium, the steps or this process being similar to those occurring in the regeneration of normal gland-tissue. The beginning of the adenomatous proliferation may be recognized by changes in the form and staining of the cells. This is particularly easy in the case of the stomach and intestine in which adenomatous proliferations so often develop in connection with inflam- matory and ulcerative processes. The change of the gland-cells into high cylindrical cells staining intensely may occur at the same time or successively in a number of glands and is then followed by cell -prolifera- tion and new-formation of glands. The cause of the new-formation of gland-tissue within normal organs is wholly unknown. Glandular new-formations developing in tissues which have been altered by inflammation, and which lead to tumor-like growths, may in t li e beginning bear the charac- ter of a regener- ative or hyper- plastic new-for- mation, and for this reason the adenomata cannot he sharp!// differ- entiated from re- generative a n d hyperplastic pro- liferations. Tubular adenomata rep- resent the most common form of the adenomata. They occur par- ticularly in mu- cous membranes (Figs. 317; 318, /') provided with tubular glands (intestine, uterus) ; but are found also in such glands as the breast (Fig. 319), liver, ovary, and not infrequently in the kidneys. They are characterized by the formation of simple and branched gland-tu- bules (Figs. 317, a, ft.- 318, /; and 319, a, b) which are lined by simple col- umnar or cubical epithelium and form nodular tumors varying in size from that of a pea to that of an apple or a man's fist, or rarely even larger. The alveolar adenomata arise from glands (mamma, ovary, thyroid sebaceous glands) ; and are characterized by the formation of' numerous terminal berry-like alveoli (Fig. 320, a), as well as gland-ducts (/>). Papillary adenomata (Fig. 321, a) arise through the formation within the tubules of an adenoma, of little elevations of epithelium into each of which a connective-tissue papilla grows. The local epithelial prolifer- ation (e) and the formation of papilla? (d) may accompany the atypical gland-formation. The stroma of an adenoma is at times well developed, at other times but slightly, and consequently adenomata may be divided into hard (mammary gland) and soft varieties (kidney, liver, ovary, testicle). An especially marked development of the connective tissue leads to the for- Fig. 321. — Developing pupillary adenoma of the ki liEematoxylin, picrofuchsin early stages of development of t b. Fully develop le tumor. ' X 150. (Alcohol, d tumor-tissue; c, d, ADENOMA. 447 ination of fibro-adenomata or fibrous adenomata. Such forms occur most frequently in the mammary gland. If, as happens not infrequently in the mammary gland, the connec- tive-tissue proliferation in an adenoma is not of a diffuse character, but takes place particularly around the canaliculi (see Fig. 250), the tumor is ordinarily designated as a fibroma pericanaliculare. If, as the result of more marked local proliferative activity on the part of the connective tissue (Fig. 322, c, d, e), an ingrowth of rather broad and short papillae Fig. 322.— Fibroma intracanaliculare mamma? (flbro-adenoma papilliferum) (alcohol, alum-carmine). a, Dense, intercanalicular growth of fibrous tissue : n, pericanalicular tissue rich in cells ; c, ') into the gland-spaces takes place, the resulting tumor is known as a fibroma intracanaliculare. According to its genesis such a tumor may also be appropriately designated a fibro=adenoma papilliferum. Adenomata cannot be sharply differentiated from tumor-like glandular hypertro- phies on the one hand, and carcinomata on the oilier. For example, in the healing of intestinal ulcers the regenerative processes in the glands may be so active as to give rise to polypoid formations, which may either be called glandular hypertrophies of the raucous membrane, or adenomata, according to the individual standpoint. Likewise, different names may be applied to the glandular polypi which occur so frerpuently in the uterus. The carcinomatous nature of a new-growth resembling an adenoma (see § 121) is generally made evident by a more marked epithelial proliferation and by its infiltrative mode of growth. There are, however, adenomata, having a single layer of columnar cells, which grow by infiltration (particularly in the intestine), and thereby assume the character of malignant tumors. They should accordingly be classed with the careino- 448 TUMORS. mata, and must be designated as adenocarcinoma. On the other hand, there are also adenomata with marked atypical epithelial proliferation (mamma, endometrium), which — for a long time at least— do not show any malignant characteristics. Literature. (Adenoma.) 1895 (Lit.), iii., Stuttgart. 1886. id., xiii., Zii Bd., ijler, Barlow: Adenomata sebacea. Deut. Arch. f. klin. Med., 55 Bd. Beneke: Leberadenom. Beitr. v. Ziegler, ix., 1891. Billroth.: Tumoren der Brustdriisen. Handb. d. Frauenkrankh. Bock: Leber ein Adenom der Talgdriiseu, Berlin, 1890. Bonome: Contr. alio studio degli adenomi del fegato. Arch, per le So. Me 1889. Brinaud: Du polvadenome gastrique. Arch. gen. de med., 1885. Eberth: Das Adenom der Leber. Virch. Arch., 43 Bd., 1868. Hauser: Polyposis intestinalis adenomatosa. Deut. Arch. f. klin. Med., 1895; Primare z. Geschwulstbildung fiihrende Epithelerkrankung, B. v. xxxiii., 1903. Hoffmann: Adenom der Leber. Virch. Arch. , 39 Bd., 1S67. Kelsch et Kiener: Contrib. a 1 'hist, de l'adenome du foie. Arch, de phys., 187C. Lang-hans: Ein Driisenpolyp des Ileums. Virch. Arch., 3S Bd., 1867. Leser: Biitr. z. path. Au. d. Geschwiilste d. Brustdriisen. Beitr. v. Ziegler, ii.,lSSS. Lubarsch: Adenome. Ergebn. d. allg. Path., vii., 1902. Menetrier: Des polyadenomes gastriques. Arch, de phys. , i., 18SS. Nissen: Leberadenom bei Cirrhose. Inaug. -Diss., Freiburg, 1895. v. Noorden: Das verkalkte Epitheliom. Beitr. v. Bruns, 1888. V.Recklinghausen: Die Adenomyome u. Gystadenome d. Uterus u. d. Tube Berlin 1896. Ricker: Geschwiilste der Niere. Cbl. f. allg. Path., viii , 1S97. Rovighi: Adenoma racemoso del fegato. Arch, per le Sc. Med. , vii., 18,83. Simmonds: Die knot. Hyperplasie u. d. Adenom d. Leber. Arch, i klin Med 34 Bd., 1884. Steudener. Adenom der Brustdriisen. Virch. Arch., 42 Bd., 1868, Weichselbaurn u. Greenish: Adenom der Niere. Wiener med. Jahrb 1883 See also §§ 118 and 120. § 120. A cystadenoma or adenocystoma is an adenoma whose gland- spaces have undergone cystic dilatation through the accumulation of secretions. Such tumors are usually com- posed of numerous cysts, and are, therefore, designated as multilocular cystomata. Ac- cording to the character of the cyst-wall there may be distin- guished a smooth-wailed or simple cystoma (cystoma simplex), or a papiMferous cystoma (cystoma pap- illiferum). Small amounts of secretion are often seen in the ordinary adenomata (Fig. 317), and the spaces of both simple and pap- illary adenomata are often so wide (Figs. 319, a; 322) that they at once attract the eye on cross-section of the growth. In cystadenomata such cyst -forma- tion is the predominating feat- ure. The early stages of the cysts are represented by gland-tubules of vary- ing shape (Figs. 323 and 324, h), which lie in a more or less richly developed connective-tissue stroma. Through the accumulation of secre- JMMm 323.— Section of a cystadenoma ovarii papilliferum (Milller's fluid, hematoxylin) . X 40. CYSTADENOMA. 44!) lion these tubules become gradually dilated so that numerous small cysts arise (Pig. 325), or else both large and small cysts (Pigs. 326-330) are FIG. 324. — Adenocystoma of the bile-passages in the first stages of development (alcohol, hematoxylin). o, Liver tissue; ?>, adenoma tissue in the periportal connective tissue. X 9u. formed. Often the relationship is such that the tumor may consisl of a few large cysts (Pig. 32!)) in whose walls smaller cysts occur; or there Fig. 325. rc Y\«t.'\ FIG. 326. Fig. ;)2o.— Section of a portion of a multilocular adenocystoma of the ovary. Reduced about one-sixth, FIG. 326.— Section through an adenocystoma of the testis of a four-year-old hoy. Natural size 29 450 TUMOKS. ig. 327.— Multilocular adenocystoma of the liver, seen in section, a, Liver parenchyma ; /'. ms margin of the left lobe ; c, d, large cysts ; e, group of smaller cysts, separated rnnn earl iy connective tissue ; f, portal vein ; (/, hepatic artery. Two-thirds natural size. Fig. 327.— Multil brano— only I Fin. 328.— Cystoma "f the kidney, cut transversely. Eleven-fourteenths natural size. CYSTADENOMA. 451 may be found, by the side of large cysts (Fig. 327, c), portions of tissue, which contain only small cysts (e) or even appear solid — that is, consist- ing of a tissue the glands of which are not dilated. FIG. 329.— Adenocystoma ovarii partim simplex, partim papilliferum, a, Smooth-walled cysts; 7j, soft papillary growth covered with simple, mucus-forming cylindrical epithelium. (Metastatic nodules were present in the peritoneum.) Reduced one-third. All the different varieties of cystomata may develop in the ovaries (Figs. 325 and 329), testicles (Fig. 326), liver (Figs. 324 and 327 ). kidneys (Fig. 328), and the mammary glands. Fir,. 330.— Portion of a papillary adenocystoma of the ovary, seen in section. (Drawn from a specimen hardened In chromic acid.) Four-fifths natural size. 452 TUMORS. In the ovaries cystomata not infrequently develop coinoidently on both sides, and may be associated with dermoid formations. Adenocys- tomata of the testicles not infrequently inclose within their stroma foci of cartilage or other tissue, so that such growths should he classed with the teratoma ta (§ 128). The epithelial liniiif/ of cystomata is usually com posed of simple colum- nar cells, but may be a ciliated, cubical, or flattened epithelium. The cyst-contents usually consist of a clear, oil en distinctly ropy fluid, which contains a mucin-like substance (pseudomucin, see § 59). This substance is a product of the epithelial lining in which goblet-cells are often found (Fig. 331, c). Not infrequently the fluid also contains whit- ish flakes, the products of cells which have undergone fatty degeneration ; or it may be more or less cloudy or reddish or brownish from previously occurring haemorrhages. An abundant secretion in many cysts may lead to the formation of tumors of enormous size; in the ovary, for example, they may reach a weight of from ten to twelve kilograms or more. The papillary adenocystomata constitute a common variety of adeno- cystoma. They are characterized by the fact that sooner or later papil- lary excrescences develop in the glands which have undergone cystic degeneration. In the adenocystomata. of the ovary these excrescences are usually slender and delicate, forming villous-like outgrowths (Fig. 330) or cauli- •m %* iW^ r 'J^i\'Mtim«^i^ ■:'-" :-> : ' #^*Hl^$£ «1S^- IS '•?% »«l»t AE#M»S«l"Wt ^V^s-^SS^S. *%?><*■ -a ■/-■ Fig. LRU.— Cystoma papilliferum ovarii (Miillfir's fluid, bEematoxylin, eosin). a Stroma with n-iniilv b, gland-tubule with small papillae; e, high cylindrical epithelium; rf, mucus-conta'iniosr cell, withir :fh,' cyst-spaces. X 150. " luu flower elevations, which may fill up a larger or smaller part of the cysts. Minute papillary elevations, extending over an extensive area, of the inner surface of the cyst-wall, may give to the latter a velvety appear- PAPILLARY CYSTADENOMA. 453 ance similar to that of a mucous membrane. If the excrescences develop in cysts of small size, they may fill these, and the tissue may thereby take on the appearance of a dense, non-cystic, medullary tumor, though from the cut surface more or less mucus can usually be obtained. Larger papillte are always more or less branched (Fig. 331), and con- sist of a cellular stroma (a), whose surface is usually covered with tall is its I F&L. 1 »> ^L^SS^? ^m^m JUS MOT 'if;' 1 -ttf^'s-e ? e$a/ar lite- FIG. 333. — Papillary adenocystoma of the ovary with myxomatous degeneration of the connective tissue of the papilla? (MUller's fluid, hsematoxylin) . a, Fibrous stroma; o, papillse which have undergone myxomatous change; c, epithelium. X 80. columnar cells (c) of the character of goblet-cells. The contents of the cysts consist of ropy mucus (d) mingled with more or less numerous desquamated cells which have undergone mucous degeneration, or the remains of such cells. In rare cases the connective tissue of the papillse may undergo a mucous degeneration (Fig. 332, a, b), and may swell to a marked degree, and finally become changed into myxomatous spheres covered externally with epithelium. Adenocystomata of the liver, testicles, and kidneys usually form no papillae, or at most very small ones. In the papillary adenocystomata of the mammary gland the. excrescences are usually broad and plump (Fig. 333), as is the case with those of the papillary adenomata (Fig. '6'22). Accordingly, on the cross-section of such tumors the cyst-spaces are found to be filled with polypoid proliferations of various forms (Fig. 333), which are often flattened through mutual pressure, and give to the sur- face of such a cross-section a laminated appearance. Since in these tumors the connective-tissue elements predominate over the epithelial, these growths are often classed with the connective-tissue tumors, and designated, according to the character of the connective tis- sue, as eystofibroma, cystomyxoma, or cystosarcoma. When showing a structure of leaf-like layers they have received the name of sarcoma phyllodes. The papillary adenocystomata. show a certain malignancy, even when the papillae are covered with a simple epithelium (see cystocarcinoma). 454 TUMORS. This is shown in the first place, in the fact that the papillary prolifer- ations may break through the cyst-wall, in the case of such tumors of both the ovary and mammary gland, and in the latter situation they may Fig. 333.— Papillary eyst( or intracanalicular papillary fibroma of the breast, laid tudinal incision. One-half natural size. t'y a Iongi- also break through the skin. Papillary ovarian cystomata (Fig. 329, 6) may in this way give rise to metastases in the peritoneal cavity, and these in turn display i lie characteristics of papillary epitheliomata. The adenocystomata represent u variety of tumorwhich possesses no sharply defined limits; for example, papillary cystomata may arise from the development of papillary excrescences in dilatation-cysts which are formed from pre-existing glands (see ^ 118). Further, malformations of organs — for example, of the kidneys (Fig. 328) — may lead to the formation of multilocular cystomata, the cystic dilatation affecting not only the urinary tubules, but also Mutter's capsules. That teratomata may appear in the form of adenocystomata has already been mentioned in the text. Finally, a transition from cystadenoma to cystocarcinoma may also take place. Literature. ( Adenocystoma.) Bard el Lernoine: La maladie kyslique essent. des organes glandulaires. Arch. gen. de med., 1890. Baumgarten : Ovarialkystom niit Metastasen. Vireh. Arch., !I7 Bel., 1884. Billroth: Handb. d. Frauenkrankheiten, iii.. Stuttgart, 1886. Bottcher . Entwickelung multiloculiirer Eierstockseysten. Virch. Arch., V.) Bd., 1S70. Brissaud: Maladies kystiques de la mamelle. Arch, de phys., iii,. 1884. Brodowski: .Mil- Flimmcrepithel ausgekleidete Ovarialcysten. Virch. Arch., 67 Bd., 1876. CARCINOMA AND CYSTOCARCINOMA. 455 Burckhardt: Genese d. multilocul. Ovarialcystcn. Virch. Arch., 144 Bd., 1896. Coblenz: Kystome der Ovarien. Zeitschr. f. Gel), u. Gyn., vii., 1882; Genese u. Entwickehmg von Kystomen. Virch. Arch., 84 13d., 1881. Dmochowski it. Janowski: Totale cystische Entartung d. Leber. Beitr v Ziegler xvi., 1894 Flaischlen: Multiloculiire Flimmerepithelkystome der Ovarien. Zeitschr. f Gvn., vi., 1881. Goebel: Kiefertumoren v. Zahnsystem ausgehend. Chi. f. allg. Path., 1897 (Lit). Hess: Ueber eine subcutane Plimmercyste. Beitr. v. Ziegler, viii., 1890. v. Hippel: Multiples Oystenadenom der Gallengange. Virch. Arch., 123 Bd., 1891. Israel: Epithelioma follicular cutis. Fcstschr. d. Assist, f. Virchow, Berlin, 1891. v. Kahlden : Genese der multiloc. Cystenniere u. d. Cystenleber. Beitr. v. Ziegler, xiii., 1893; Congen. Adenom bcider Nieren. lb., xv., 1894; Entsteh. d. Ovarial- cystcn. lb. xxvii. 1900. Kocher: Die Krankheiten des Hodens, Stuttgart, 1882. Labbe et Coyna: Traite des turn, benignes du sein, 1876. Leser: Beitr. z. pathol. Anatomic d. Gesclnvulste d. Brustdrilsen. Beitr. v. Ziegler, ii,, 1888. Malassez: Maladies kystiques du testicule. Arch, dephys., 1875. Marchand: Beitr. z. Kenntniss der Ovarialtumoren, 1879. Michalowicz: Degenerescence kystique des reins et du foic, Paris, 1877. Monod et Terillon: Traite des maladies du testicule, Paris, 1889. Nag-el: Genese der epithelialen Eierstocksgeschwiilste. Arch. f. Gyn., 33 Bd., 1888. Nauwerck u. Hufschmid: LTeb. d. multilocul. Kystome d. Niere. " Beitr. v. Ziegler, xii., 1892. Olshausen: Die Krankheiten d. Ovarien. Handb. d. Frauenkranklieiten, ii., Stutt- gart, 1886. Pfannenstiel : Die Pseudomucine der cystischen Ovarialgeschwillste. Arch. f. Gyn., 38 Bd., 1890; Neubildungcn des Eierstocks. Handb. d. Gyniik. v. Veit, iii., 1898. Ruge: Papilliformcs Atlierom. Virch. Arch., 136 Bd., 1894. Sabourin: Degenerescence kystique du foie et des reins. Arch, ile phys., x., 1882. Sasse: Cystcn u. cystische Tumorcn der Mamma. Langenbeck's Arch.. 54 Bd., 1897. Schmidt: Cystosarkom der Mamma. Arch. f. Gyn., xxii., 1884. de Sinety et Malassez: Sur la structure, l'originc et le developpement des kystes de l'ovaire. Arch, de phys., 1878, 1879, 1880,1881. Stratz-. Die Geschwillste des Eierstocks, Berlin, 1894. Terburgb: Leber Leber- u. Nierencysten. Inaug.-Diss., Freiburg, Leiden, 1891. v. Velits: Genese der Flimmerepithel-Kystome des Eierstocks. Zeitschr. f. Geb., xvii., 1891. Zoppritz : MultiloeuHlre Kiemcngangscystcn. Beitr. v. Bruns, xii., 1894. See also ; 119. (c) Carcinoma and Oystocarcinoma. § 121. The carcinomata are malignant epithelial tumors characterized by infiltrative growth and the formation of metastases. They develop : (1) In the skin, mucous membranes and in glands, all of which ap- peared to be normal, before the development of the carcinoma. (2) In the skin, mucous membranes, and in glands, which have already suffered changes before the development of the carcinoma. (3) In already existing papillary epifheliomata, adenomata and ade- noeystomata. (4) From the remains of foetal epithelial structures, and from epithe- lial tissues which have been misplaced through disturbances of develop- ment, and have already developed into pathological formations. (5) From the epithelial tissues of the chorionic villi and placenta. The most essential, characteristic of the development of a carcinoma is that presented by atypical proliferations of epithelium which sooner or later penetrate into the tissue bordering upon the affected glands or surface=epithelium. This phenomenon is usually accompanied by a proliferation of connective tissue ; but this is not absolutely essential 45(5 TUMORS. to the development of a carcinoma. The tissue invaded by the epithelial proliferation — whether glandular tissue, muscle, bone, etc. — is sooner or later destroyed by the growth, although within the stroma of the car- cinoma there may occur a new-formation of other tissue than connective tissue, as, for example, bone. The cause of the atypical growth of epithelium is not known with certainty; it can only be said that certain conditions favor such growth. Thus, for example, old age predisposes to the development of carcinomata of the skin, inasmuch as in this period of life the connective tissue of the skin undergoes a certain amount of atrophy and becomes looser in structure^, while the epithelium, at least in part, continues to increase, and under certain conditions shows here and there distinct evidences of increased activity (formation of coarser hairs upon the nasal septum, lobes of the ears, and in the eyebrows). Likewise carcinomata. of the mucous membranes and the glands usually appear in the later years of life, although they may occur earlier in life, even in childhood. A further predisposition to the development of carcinoma is found in regenerative processes following the destruction of surface epithelium and glandular tissue. These occur most frequently in old inflammatory proc- esses that have led to tissue-destrnction and new-formations of tissue, particularly in the, mucous membrane of the intestinal tract, gall-bladder, and uterus, and also in glands and in the skin. In the stomach the round nicer {Ulcus ex digest/one) may form the starting-point of a cancer. In the first place the regenerative proliferation following the tissue-injury may form the basis for an atypical malignant proliferation. In addition an important role is played by the snaring-off and, misplacement of epithelial cells into the neighboring altered, connective tissue, a phenomenon of frequent occurrence in the healing of ulcers, the growth of epithelium over gran- ulation-tissue, and in tuberculosis, and other chronic infective granulo- mata, both in the mucous membranes and skin and also in glands. All these predisposing factors do not constitute the unique cause of the development of a carcinoma. They may exist for a long time with- out giving rise to a cancer. It appears that something else must be added to cause the unlimited atypical proliferation of epithelium, and what this something is is at present unknown. Whether this cause is to be found in a bioplastic stimulus comparable to that of fertilization oi- in chemical influences stimulating the cells to increased proliferation or in the removal of the influences that inhibit and regulate proliferation cannot be stated at the present time. In recent years the opinion has been many times advanced and main- tained that parasites cause carcinomatous and sarcomatous prolifer- ations. But the majority of the appearances which have been described as parasites (as protozoa, especially sporozoa, and as yeast-fungi) have not been parasites at all, but degenerated nuclei and nuclear division- figures, or leucocytes inclosed within tumor-cells, or degeneration-prod- ucts of such, or products of cell-protoplasm, particularly keratohyaliu and colloid, or epithelial hyalin and mucin. In the few cases in which true parasites were present in the tissues, this occurrence could very well have been a secondary infection, which in no way could be regarded as a cause of the development of the tumor. In not a single ease has it been proved beyond all doubt that parasites have been the cause of either carcinoma or sarcoma. Certain portions of the intestinal tract — the rectum, the flexures of the colon, the pylorus and cardia of the stomach, the oesophagus, CARCINOMA. 457 pharynx, tongue, and gums — are favorite seats for the development of cancer. Cancer may develop in any portion of the skin, but "it occurs more frequently on the lips and nose than on the remaining portions of the face, or on the extremities, and on these again more frequently than on the trunk. Of the sexual apparatus the parts most commonly affected are the mammary gland and cervical portion of the uterus ; less fre- quently, though relatively often, the ovary, testicles, body of the uterus, vulva, vagina, and penis. The liver, kidneys, bladder, trachea, bronchi, lungs and pancreas occupy a middle ground; while the larynx and gall-bladder are, on the other hand, more frequently affected. Cancer usually develops in the form of nodules, which are not sharply differentiated from the neighboring tissues; on the mucous membranes they are not infrequently elevated above the surface in the form of sponge -like, or pohjpoid, or papillary growths. From the point of origin they spread by an infiltrative growth of the epithelial proliferations, by which either the nodules increase in size or there are formed diffuse superficial thickenings, as in the case of the intestinal wall. The ovaries, testicles, uterus, kidneys, etc. , may be partly or wholly transformed into carcinomatous tissue. Often the boundaries of the organ originally affected are overstepped, and the epithelial infiltration extends into neighboring tissues and organs. Thus, for example, a carcinoma of the mamma may infiltrate the neighboring fat, skin, and muscle; one of the gums, the maxillary bone ; one of the uterus, the vagina, parametrium, bladder, and rectum ; a cancer of the gall-bladder may involve the liver ; one of the thyroid, the trachea; and one arising in the bronchi, the lungs, etc. The formation of metastases may take place either through the lymph- or blood-vessels, and is of very frequent occurrence by both routes. It leads to the development of secondary nodules in different organs ; but it may happen that large lymphatic areas — as, for example, the lymphatics of the lung — may be simply dilated by the new-growth, without the formation of circumscribed nodules. The transportation of cancer-cells to the bone-marrow may lead to a carcinomatous degener- ation of the marrow of an entire bone or of several associated bones. Moreover, it should be noted that probably not every transportation of cancer-cells is followed by the development of a cancer, but that many of the cells so transplanted die. The tissue of a carcinoma is sometimes white and soft like marrow, sometimes firm and dense ; but it is almost always possible to obtain from the cut surface more or less of a whitish, cloudy fluid called cancer juice or cancer milk. Very often the cut surface presents a tough, fibrous framework in the meshes of which the softer masses lie ; and from which the latter may be squeezed out by pressure either iu the form of fluid, or as plugs or as crumbling masses. The masses obtained from the cut surface through pressure and scrap- ing consist, for the chief part, of atypically proliferating epithelial cells, the so-called cancer=cells, which are found in a greed, variety of forms, and usually show degenerative changes, particularly fatty de- generation. A true secretion of these epithelial cells is usually not found; but cancers occur — particularly in the mucous membranes, ovaries, mammary glands, and thyroid — which produce mucin, pseudo- mucin, or colloid. The amount of secretion may at times be so abundant as to lead to the formation of cysts and thereby to cystocarcinoma. Retrograde changes occur very often in cancers at an early stage. 458 TUMORS. They are caused partly by the feeble vitality of the new growth, partly by circulatory disturbances, which may be due to the filling-up of capil- laries and veins by the ingrowing cancer-cells, and partly by external causes. These changes lead, in the first place, to a destruction of cancer- cells in certain portions of the tumor and the formation of central cavities due to the liquefaction of the dead portions, so that, after re- sorption of the dead material, the tissues often sink in, and in this way depressions are caused over the surface of the tumor-nodules. Such de- pressed areas are seen particularly upon primary cancer-nodules in the mammary gland- and on secondary nodules in the liver, lungs, and other internal organs, and are often spoken of as cancer-umMlications. The retrograde changes often lead to complete destruction of tumor- tissue, and thereby to the formation of ulcers. This occurs particularly in cancers of the mucous membranes, these growths at the patient's death usually revealing a more or less extensive ulceration; but such ulcerations also take place in carcinomata of the mammary glands and skin. In the latter situation the cancer may take on the appearance of a rodent ulcer. The edge of such ulcers is sometimes elevated and re- sembles a wall, or it may be studded with nodules; at other times it is more sharply defined and only slightly infiltrated. The base of the ulcer is sometimes fissured and ragged, and covered with necrotic tissue; at other times it is smooth. The view that the cause of carcinoma and sarcoma is to be found in parasites still finds adherents, although the investigations of recent years do not support it. Publications concerning cancer and sarcoma parasites have not been wanting (Sanfelice, Roncali, Aievoli, Maffuci, Secchi, Foa, Buffer, Plimmer, Gaylord, Wlaeff, Sjobring, Schiiller, von Leyden, Feinberg, Leopold, Podwyssotzki, and others'), but in the majority of cases proof has been wanting that the supposed parasites were really living organisms; or, when living organisms (yeasts, rhizopods) have been cultivated from tumors, there has been no positive proof that they stood in any causal relation to the given neoplasm. The experiments, in particular, of Sanfelice, Wlaeff, Leopold, and Sjobring are far from offering any convincing evidence. It is very striking and worthy of note that nearly every author has found a different parasite and has not recognized the parasitic forms described by the others. This speaks against the correct interpretation of the findings. Moreover, in the case of the majority of the formations described as parasites another interpretation is possible. Some of them are degenerating leucocytes or the remains of such enclosed in cancel- cells; others are vacuoles, hyaline or mucoid products of the cancer-cells, or degener- ating nuclei or cell-division figures, or fragments of these. Only rarely is it impossible to give a satisfactory interpretation of the findings, but this fact is not sufficient grounds for ascribing a parasitic nature to the formations. The attempt to compare the "bird's eyes" of von Leyden, or the Plimmer 's bodies, to which they correspond, with the parasite found in the root-tumors of cabbage, the Plasmodiophora brassicoe, and to regard these root-tumors as analogous to cancer, is, likewise, without justification, since the two diseases have scarcely anything in common. The plasmodiophora multiplies within the plant-cells and distends the latter. Only after the destruction of the affectei I cells does a regenerative proliferation occur in the neighboring cells. In cancer there is from the very beginning an unlimited and at, the same time an infiltrative growth of tissue- cells. The natural history and clinical behavior of cancer are not such as to make il probable that it is of parasitic nature. The formation of cancerous tumors as a result of disturbances of development speaks against this view. The metastases develop from transported tumor-cells, and cell-inclusions are not necessary to their formation. The transplantation of cancer and sarcoma into animals of the same species, and the implantation-cancers occasionally observed after operation, are the result wholly of the transplantation of living tumor-cells, and cannot be used as arguments in favor of the parasitic theory. If protozoa are the cause of cancer we must assume, according to our present knowledge of these parasites, that a given species can find a suitable sod only in a certain variety of epithelium. Cases of transmission of cancer from man to man occasionally cited as evidence can be utilized hypothetically in support of the CARCINOMA. 459 parasitic theory only when the cancer develops in the affected individual in the same mother-tissue. To increase our knowledge concerning the cause of cancer a committee was appointed to study the statistics, and through a collective investigation on October 15th, 1900, attempted to determine the number of living cancer-patients in Germany. In so far as the view of the parasitic nature of cancer is concerned this work was negative, since in only 3.6 per cent (of 12,179 cases) was an infection suspected. A hereditary trans- mission was thought possible in 17 per cent, but the number was reduced to 4.3 per cent when the possibility of such an inheritance was limited to those cases in which the same organ was affected. Since 1888 the number of cancer-cases is said to have in- creased about a third, but even this statistical evidence is without significance since it may be satisfactorily explained as the result of greater skill in diagnosis as well as the result of an increase in the average length of life. Moreover, it should be noted that even now many cases of cancer (cancer of stomach) are not diagnosed even up to death, and on the other hand cases are regarded as cancer when occurring in tissues in which carcinoma does not develop. (The statistics mentioned above contain 201 cases of primary carcinomata of the bones.) Literature. (Etiology of Carcinoma.) Alberts: Das Carcinom, Jena, 1887. Apolant ii. Emden: Natur der Zelleinschlusse in Carcinomen. Zeitschr. f. Hyg.,42 Bd.,1903. d'Arcy: Some Effect ; of Chronic Irritation upon Living Tissues. British Med. Journ., ii., 1893. Binaghi: Blastomyceten in Epitheliomen. Zeitschr. f. Hyg., xxiii., 1896 (Lit.). Borrel: Sur la signification des figures decrites comme coccidies. Arch, de med., ii., 1890. Bosc: Le cancer, mal. infect. a sporozoaire. Arch, de phys., x., 1898. Brosch: Genese der malignen Geschwulste. Virch. Arch., 102 Bd., 1900. Burchardt: Bin Coccidium im Schleimkrebs des Menschen. Virch. Arch., 131 Bd., 1893. Chaintre: De l'epithelioma des cicatrices. Lancet, ii., 18S9. Claessen: Ueber die in Carcinomzellen gefundenen Einschliisse. Beitr. v. Ziegler, xiv., 1893. Clarke: Observat. on the Histol. of Cancer. Cbl. f. Bakt., xvi., 1894. Debenedetti: Eziologia del cancro, Torino, 1887. Fabre-Dornerg-ue: Les cancers epitheliaux, Earis, 1898. Feinberg-: Die Gewebe des Menschen u. die Krebsgeschwulste, Berlin, 191 IM. Firket: De l'origine du cancer. Ann. de la Soc. beige d. microsc. xvi., 1891. Foa: Sui parassiti et sulla istologia patologica del cancro. Arch, per le Sc. Med., xvii.; Arch. ital. de Biol., xx., 1893. Foulerton: Pathogenic Action of Blastomycetes. Journ. of Pathol, and Bacterid., 1899. Gaylord: The Protozobn of Cancer. Amer. Journ. of Med. Sc., 1901. Greenough: Plimmer's Bodies in Carcinoma. Journ. Bost. Soc. Med. Sc, 1900; Cell Inclusions. Journ. of Med. Res., 1902. Hauser: Das chron. Magengeschwur, sein Vernarbungsprocess u. dessen Bezieh. zum Magencarcinom, Leipzig, 1SS3; Das Cylinderepithelcarcinom d. Magens u. d. Darms, Jena, 1890. Honda: Z. parasit. Aetiologie d. Carcinoms. V. A., 174 Bd., 1903. Israel: Das Problem d. Krebsatiologie. A. f. klin. Chir., 67 Bd., 1902. Karg-: Ueber das Carcinom. Deut. Zeitschr. f. Chir., 34 Bd., 1892. Klimenko: Fcinbergs Krebsparasiten. C. f. a. P., xiii., 1900. Lack: Experim. Production of Cancer. Journ. of Path., vi., 1899. Le Count. Analogies Between Plimmer's Bodies and Certain Structures found Nor- mally in the Cytoplasm. Journ. of Med. Res., 1902. Leopold: Aetiologie d. Carcinoms. Arch. f. Gvn., 61 Bd., 1900. v. Leyden: Aetiologie des Carcinoms. Z. f. klin. Med., 43 Bd., 1901 , u. 52 Bd.. 1904; Krebsparasiten. Z. f. Krebsforschung, i., 1904; Bericht fiber die ram Komitee fur Krebsforschung am 15 Okt. 1900 erhobene Sammelforschung, Jena, 1902. v. Leyden u. Schaudinn: Leydenia gemmipara. Sitzber. d. Akad. d. Wiss., Berlin, 1896. 460 TUMORS. Liebe: Ueber den Paraffinkrebs. Schmidt's Jahrb., 236 Bd., 1892. Lubarsch.: Patholog. Anatomie u. Krebsforschune, Wiesbaden, 1902. Nichols: First Annual Report on the Etiology of Cancer. Journ. Bost. Soc. Med. 8c, 1900; Second Report. Journ. of Med. Res., 1902. Ndsske: Die als Parasiten gedeuteten Zelleinschliisse. Deutsche Zeit. f. Chir., 64 Bd., 1902. Petersen u. Exner: Hefepilze u. Geschwulstbildung. Beitr. v. Bruns, xxv., 1899. Pfeiffer: Untersuchungen fiber den Krebs, Jena, 1893. Pianese: Beitr. z. Histologie u. Aetiologie d. Carcinoms, Jena, 1896. Plimmer: On the Etiology and Histology of Cancer. The Practitioner, 1899, 1900. Podwyssotzki: Parasitare Myxomycetengeschwiilste. Zeit. f. klin. Med., 47 Bd., 1902. Reichelmamn: Krebsstatistik v. path.-anat. Standpunkt aus. Berlin, klin. Woch., 1902. Roncali: Aetiologie dcs Krebses. Cbl. f. Bakt., xxi., 1897. Rosenthal: Mikroorganismen in Geschwulsten. Zeitschr. f. Hyg., v., 1889. Ruffer: Les parasites dcs tumeurs epitheliales. Trait6 de pathologic gen., i., Paris, 1896. Ruffer and Plimmer: Parasitic Protozoa in Cancerous Tumors. Journ. of Path., i., 1892; ii., 1SS3. Sanfelice: Wirkung d. Blastomyceten. Zeitschr. f. Hyg., xxi., 1895; xxii., 1896; xxix., 1898; xliv., 1903. Schuller: Zur Aetiologie d. Geschwulste. Cbl. f. Bakt., xxvii., 1900. Schulthess: .Statist. Unters. lib. d. Aetiologie d. Mammacarcinoms. Beitr. v. Bruns, iv., 1881. Schiitz: Protozoen- u. coccidienart. Mikroorganismen in Krebszellen. Munch, med. Woch., 1890. Schwarz: Ueber den Carcinomparasitismus, Wien, 1895. Sjbbring-: Mikroorganismen in Geschwiilsten. Cbl. f. Bakt., xxvii., 1900, u. Langen- becks A., 65 Bd., 1902. Spirlas: Yerdauungsvakuolen u. ihreBez. zu Foa-Plimmerschen Krebsparas. Munch. med. Woch., 1903. Steinhaus: Ueber Carcinomeinschliisse. Virch. Arch., 126, 127 Bd., 1891. Sternberg: Zelleinschliisse in Carcinomen. Beitr. v. Ziegler, xxv., 1899 (Lit.); Aetio- logie. Wien. med. Ztg., 1903. Steven and Brown: On the So-called Parasitic Protozoa, of Cancer. Journ. of Path., ii., 1893. Strobe: Histogenese u. Aetiologie des Carcinoms. Cbl. f. allg. Path., ii., 1S91 (Lit.); Die parasitaren Sporozoen in ihren Beziehungen zur menschl. Pathologie, insbes. zur Histogenese u. Aetiologie d. Carcinoms. lb., v., 1894 (Lit.). Vdlcker: Das Wesen der Schilllerschen Parasiten. D. med. Woch., 1901. Volkmann: Ueb. d. primaren Krebs d. Extremitaten. Samml. klin. Vortr., No. 334-335, 1900. Watzdorf: Verbreitung der Krebskrankheit im D. Reiche. D. med. Woch., 1902. Wlaeff: Role des Blastomycet.es dans l'organisme. Soc. An. Paris, 1900; Cbl f allg Path., 1900. Zenker: Der primare Krebs der Gallenblase u. seine Beziehung zu Gallensteinen u. Gallenblasennarben. Deut. Arch. f. klin. Med., 44 Bd., 1889. See also § 122. § 122. The development of carcinoma of the skin takes plaee most often from the surface epithelium, and is characterized essentially by the growth of the interpapillary portions of the same into the deeper por- tions of the skin, in the form of epithelial pings (Fig. 334, d) which fill up the connective-tissue spaces. The stratum corneum (c) may also undergo hypertrophy along with the cells of the rete Malpighi'i, and penetrate into the deeper tissues with the epithelial plugs (d). More- over, the horny cells which get into the deeper tissues may form epithelial pearls (e). Besides the surface-epithelium, the epithelium of the hair-follicles and sebaceous glands may also take part in the development of the cancer; and there occur carcinomata of the skin, which develop entirely from DEVELOPMENT OF CARCINOMA. 401 the sebaceous glands, and therefore should be classed with the gland- cancers. The connective tissue may remain entirely passive during the ingrowth of the epithelium, but is sooner or later excited to growth (Fig. 334, a), and the papillae often develop into long, branched" formations (/ ).' In Pig. 334.— Transverse section through a in a state of proliferation ; 6, epithelium ; e. corium ; e, epithelial plugs with horny pear cinoma of the lip (alcohol, hematoxylin, eosin). a, Corium, tokened horny layer; rt, epithelial plugs extending into the ■ut obliquely ; /, enlarged papillae. X 12. the proliferating connective tissue there are often found in association with the fibroblasts also leucocytes and lymphocytes, which may penetrate into the epithelium. They become especially numerous in the event of tissue-destruction, so that under such circumstances the proliferation of the connective tissue acquires wholly the character of an inflammatory granulation-tissue. The origin of the carcinomata arising from mucous membranes covered with squamous epithelium may be the same as that of a can- cer of the skin — that is, it is introduced by a proliferation of the surf 'ace epithelium (Fig. 335, a, c). If glands are present they may also take part in the development of the cancer. It is a remarkable fact that in the for- mation of such a tumor, glands with cylindrical epithelium may furnish epithelial products which correspond with those of the surface-epithe- lium. The epithelial proliferation may at first be intracanalicular and lead to a diffuse thickening and stratification of the epithelium (Fig. 335, f), or to the formation of excrescences (e). Later, the proliferating epithelium breaks into the connective tissue. The connective tissue behaves in the same manner as in the case of cancer of the skin. The cylindricaNcelled carcinomata of the mucous membranes arise in the case of the intestine from the tubular (/lands or from the crypts, the epithelium of which at first undergoes an active proliferation, and be- comes stratified, while the glands become dilated (Fig. 336, l>). Later, the glands become changed into branching, atypically formed structures (c), which possess an epithelium arranged in many layers, and which grow into the neighboring tissues. In the stomach the gastric glands change their character (Fig. 337, /■), and then through a continued growth infiltrate the submucosa (g), the muscularis (d), and the serosa (e). 4(12 TUMORS. The epithelium of the newly- formed glands stains more deeply with nuclear stains than does normal epithelium. The connective tissue, as in the case of cancer of the skin, sooner or later proliferates, and in connection with this proliferation there may occur also an emigration of leucocytes and lymphocytes. The development of cancer in glands — as, for example, in the mam- mary gland — likewise begins with an epithelial proliferation, as the result of which the glands (Fig. 338, a) become widened, altered in form (//), while their lining epithelium becomes stratified (b). With the breaking through of the epithelium into the neighboring connective-tissue spaces, the epithelial infiltration of that tissue is begun. According to the Structure of the gland in which the cancer arises, and according to the Fig. :535. — Beginning development of carcinoma In Hie vaginal portion of tho uterus (alcohol, Bismarck- brown), a, Epithelium; /i, connective tissue ; c, surface epithelium growing into the deeper 'tissues - ct dilated glands ; e, glandular epithelium growing out in form of plugs; f, cross-section of a gland 'the cylindrical epithelium of which has become converted into stratified epithelium. X +.">. variety of the cancer itself, there will lie produced varying microscopical pictures. The connective tissue of the gland through proliferation also takes part in the building-up of the tumor; but in the early stages of develop- ment such proliferation may be slight or entirely wanting. The development of a carcinoma in an adenoma or fibro -adenoma DEVELOPMENT OF CARCINOMA. 46i fFig. 339, a) is likewise initiated by a change in the character of the cells and by a more active proliferation of the epithelium, through which the simple epithelium becomes stratified (b, c). The later ingrowth of the Fin. 3311. — Developing adenocarcinoma of the large intestine (Miiller's fluid, ha?matnxylin, eosin). a. Mucosa with unchanged glands ; o, glands showing carcinomatous change ; c, carcinomatous areas in the submucosa. x 101 1. epithelium into the connective tissue, which often occurs at a very late stage, is a further sign of malignancy — that is, of the carcinomatous transformation of the new-growth. b c , w- a , Fig. 337. — Adenocarcinoma of stomach in process of development (formalin, alcohol, haematoxylin, eosin) . a. Mucosa ; o, muscularis mucosae ; c, submucosa ; d, muscularis ; e, serosa : f , y, adenocarcinoma. > 15. The development of carcinoma from papillary epitheliomata takes place in the same manner as from the normal skin and mucous mem- 464 TUMORS. branes; and is characterized especially by Hie infiltration of the epithe- lium into the basement-tissue upon which the epithelioma rests. Fig. 33R— Developing cystoearcinoma of mamma (alcohol, hematoxylin). Tumor of the size of a bean. a, Normal gland-tissue ; b, proliferating gland-tissue. • 100. Wmlk® 111 mi : >'"-- Fig. 339.— Tubular adenoma of mamma showing a beginning transition to carcinoma (formalin, hema- toxylin), ft, Branching gland-tubules with simple epithelium: the pericanalicular connective tissue is proliferating and very cellular; b, c, gland-tubules, the epithelium of which is partly simple, partly strati- fled. X 100. DEVELOPMENT OF CARCINOMA. 465 The development ot carcinoma from transplanted or misplaced epithelium or from remains of foetal structures proceeds in the same maimer as that of carciuomata arising in either surface or glandular epithelium. Carcinomatous proliferations of the cell-layer and the syncytium of the chorion, both of which arise from the fcetal ectoderm ( Bonnet), may occur either in the chorion of young ova or in the placenta of older embryos, and in atypical cases are characterized by a mixture of the two forms of cells (Fig. 340, a, b"). They grow into the neighboring uterine Fig. 340. — Intravascular epithelial pint? of a placental carcinoma. (Formalin, alcohol, hematoxylin, eosin.) a, Derivatives of tile cell-layer; b, syncytial cells; c, wall of blood-vessel; d, blood. X 40. tissue, particularly into the blood-vessels of the uterus (c), and may through the formation of thrombi lead to extensive destruction of the tissues of the uterus, and may give rise to metastases. Myxomatous degeneration of the chorion or placental villi (hydatid mole ) appears to favor the development of such carcinomatous growths. The development and growth of carcinoma have been in recent years the object of searching investigations. Besides Ribbert and Burst, "who have expressed their views in their works on tumors, Krompecher, Hauser, Petersen and Cahners, and Borrmann have published treatises of considerable size upon these questions. All of these writers agree that the.developing neoplasm, in so far as its epithelial elements are concerned, grows through its own resources and does not excite the neighboring tissue, that is, neighboring epithelium, to a cancerous proliferation. The neighboring tissue is in part compressed and in part infiltrated. On the other hand, differences of opinion exist concerning the beginning of the cancerous growth. According to Hauser, Krom- pecher, Petersen and Colmers, the development may be unicentric or multicentric, in the latter case starting in several places in the epithelium. Borrmann assumes a unicentric 30 4firj TUMORS. origin; in those cases in which the development apparently proceeds from several places he assumes that there is a coincidental development of several primary cancers. According to Hauser, Krompecher, and Petersen, with whom I agree, the develop- ment of carcinoma takes place from cells of the superficial epithelium, hair-follicles, glands, and gland-ducts. According to Borrmann, a developing carcinoma is a growing cell-complex, which existed as such before it began to grow; it is an isolated embryonal cell-complex. Squamous-celled cancers, although not "all of them, arise from extremely small cell-complexes that lie within the superficial epithelium, and probably become isolated during foetal life through a closure of a furrow or through some other anomaly of development. According to the first-named authors, the pathological new-formation has its origin from epithelium or at least takes its point of departure from it. According to Borrmann and Ribbert, the process begins with inflammatory changes in the connective tissue; in the skin these may be caused by a retention and infection of the secretion of the sebaceous glands causing an elevation and stretching of the epithelium. As the result of this stretching and the accompanying hyperemia, the included foetal cell-complex proliferates and grows into the deeper tissues. The independent proliferations of the foetal ectoderm arc at this time usually designated as chorioepithelioma (Marehand) in accordance with the view that they represent an epithelial proliferation. There is no reason for not classing them with the carcinomata, since they are characterized by an epithelial proliferation which in- filtrates the neighboring tissues. The metastasis through the blood-vessels which characterizes the chorionic carcinomata occurs also very frequently in other carcino- mata, for example, carcinomata of the stomach. Carcinomata arising in the skin or mucous membranes are often called cancroids, a term used to distinguish them from other carcinomata, the origin of which was formerly thought to be from connective tissue. To a certain extent the character of the parent tissue is preserved in cancer-cells, but a careful examination shows in all cases that there is a certain amount of change both in their morphological and in their physiological character (anaplasia) . This is shown in changes in the form and structure of the cells, their changed behavior toward stains, in an altered position and arrangement of the cells, and in their changed rela- tions toward the surrounding tissues. The traumatic displacement of surface-epithelium in wounds may lead to the formation of the so-called traumatic epithelial cysts — that is, cysts varying in size from that of a hemp-seed to that of a nut, which are lined with epithelium, and, in case they arise from the epidermis, contain a pultaceous mass of desquamated epithelium. They occur most frequently after puncture-wounds of the volar surface of the fingers and in the hollow of the hand. Literature. (Genesis of Carcinoma.) Bandler: Chorioepithelioma. Amer. Journ. of Obst., 1902. Bayha: Lupuscarcinom. Beitr. v. Brims, hi., 188S. Behla: Die Carcinomliteratur bis 1900, Berlin, 1901. Beneke: Neuere Arb. z. Lehre v. Carcinom (1886-89). Schmidt's Jahrb., 234, 1892. Bonnet: Syncytien u. Plasmodien der Placenta. Mon. f. Gebh., 1903. Borrmann: Das Wachstum u. d. Verbreitungweise des Magencarcinoms, Jena, 1901; Die Entstehung u. das Wachstum d. Hautcarcinoms. Z. f. Krebsf., ii., 1904. Borst: Die Lehre v. d. Geschwulsten, Wiesbaden, 1902. Bozzi: Zungenearcinom nach Psoriasis. Beitr. v. Bruns, xxii., 1899. v. Brunn: Prim. Krebs d. Extremitaten. B. v. Bruns, 37 Bd., 1903. Bucher: Beitr. z. Lehre v. Carcinom. Beitr. v. Ziegler, xiv., 1893. Cullen: Cancer of the Uterus, New York, 1900. Fabre-Domergue: Les cancers epitheliaux, Paris, 1898. Fiessinger: La pathogenic du cancer. Rev. de med., 1893. Hemming: Ueber Ban u. Entstehung der Driisen. Arch. f. Anat. u. Phys., 1888. Franke: Carcin. entart. Epidermoid des Daumens. Virch. Arch., 121 Bd., 1S90. Frankel: Vom Epithcl d. Chorionzotten ausgeh. Carcinom. Arch, f, Gyn., 48 Bd.; Blasenmolcn. lb., 49 Bd., 1895; Chorionepitheliom. Encyklop. Jahrb. v Eulen- burg, ix., 1900. v. Franque: Chorionepithelioma malignum. Z. f. Gebh., 49 Bd., 1903. Friedlander : Leber Epithelwuchcrung u. Krebs, 1877. VARIETIES OF CARCINOMA. 467 Gaylord: Malignant Growths of the Chorionic Epithelium. Amer. Journ. of Obst., 1898. Hansemann: Ueber asymmetrisehe Zelltheilung in Epithelkrebsen. Virch. Arch., 119 Bd., 1889; Die mikroskop. Diagnose bosartiger Geschwiilste, Berlin, 1902. Hauser: Das Cylinderepithelcarcinom des Mageris u. des Dickdarms, Jena, 1890; His- togenese d. Krebses. Virch. Arch., 138 Bd., 1894, 141 Bd.. 1895; Polyposis in- testinalis adenomatosa. Deut. Arch. f. klin. Med., 5- c Bd., 1895; Histogenese des Plattenepithelkrebses. Beitr. v. Ziegler, xxii., 1897; Neue Arb. uber d. Carcinom. Cbl. f. allg. Path., ix., 1898; Primare z. Geschwulstbildung fiihr. Epithelerkrankung, B. v. Ziegler, 33 Bd., 1903. Heidemann: Bedeut. d. kleinzelligen Infiltration in Carcinomen. Virch. Arch., 129 Bd., 1892. Israel: Ueber die ersten Anfiinge des Magenkrebses. Berl. klin. Woch., 1890. Jung-: Zur Lehre vom Carcinom. Langenbeck's Arch., 51 Bd., 1895. v. Kahlden: Destruirende Placentarpolypen. Cbl. f. allg. Path., ii., 1891. Karg-: Ueber das Carcinom. Zeitschr. f. Chir., 34 Bd., 1892. Krompeeher: Der Basalzellen-Krebs, Jena, 1903. Liuser: Epitheliom u. Carcinom in Dermoidcysten. B. v. Bruns, 31 Bd., 1901. Lubarsch: Primarer Krebs des Ileums (Carcin. cvlindromatosum). Virch. Arch., Ill Bd., 1888. Marchand: Deciduale Geschwiilste. JLmatssehr. f. Gebh., 1895. Mertens: Carcinom a. d. Boden e. Dermoids. B. v. Bruns, xxxi., 1901. Milner: Gibt es ein Impfcarcinom? A. f. klin. Chir., 74 Bd., 1904. Miinzer: Chorioepithelioma malignum. Cbl. f. allg. Path., xiii.. 1902 (Lit.). Noegg-erath : Beitr. ■/,. Structur u. Entwickehmg des Carcinoms, Wiesbaden, 1892. v. Notthafft: Entstehung d. Carcinome. Deut. Arch. f. klin. Med., 54 Bd.. 1895. Perez: Branchiogenes Carcinom. Beitr. v. Bruns, 23 Bd., 1899. Petersen: Beitr. z. Lehre v. Carcinom. B. v. Bruns, 32 Bd., 1902. Petersen u. Colmers: Magen- u. Darrncarcinome. B. v. Bruns, 43 Bd.. 1904. Polzl: Krebs einer Dermoidcyste. Cbl. f. allg. Path., xv, 1904. Ribbert: Das pathologische Wachstum, Bonn, 1896; Geschwulstlehre, Bonn, 1904. Risel: Ueber das maligne Chorionepitheliom, Leipzig, 1903 (Lit.). Schimmelbusch: Ueber multiples Auftreten primarer Carcinome. Langenbeck's Arch., 49 Bd. Schmidt, M. B. : Plexiformes Epitheliom der Haut mit hyaliner Degeneration. Beitr. v. Ziegler, viii., 1890. Schuchardt: Beitrage zur Entstehung der Carcinome, Leipzig, 1885. Schiitz: Mikroskopische Carcinombefunde, Frankfurt, 1890. Schwalbe: Carcinom in einer tuberkulosen Caverne. Virch. Arch., 149 Bd., 1897. Snow: A Treatise on Cancers and the Cancer Process, London, 1893. Sticker: Carcinomliteratur, Berlin, 1903. Strobe: Histogenese u. Aetiologie d. Carcinoms. Cbl. f. allg. Path., ii., 1891 (Lit.); Cellulare Vorgange in Geschwulsten. Beitr. v. Zirgler. xi., 1891. Tauffer: Carcinom. Degeneration von Dermoidcysten. Virch. Arch., 142 Bd., 1895. Teacher: On Chorioepithelioma. Journ. of Obstetr., ix., 1903. Thiersch: Der Epithelkrebs. namentl. der iiuss. Haut, 1865. Tillmanns: Aetiologie u. Histogenese d. Carcinoms. Langenbeck's Arch.. 1., 1895. Virchow: Zur Diagnose u. Prognose des Carcinoms. Virch. Arch.. Ill Bd., 1888. Waldeyer: Die Entwickehmg der Carcinome. Virch. Arch., 41 and 55 Bd.: Samml. klin. Vortr. v. Volkmann, No. 33. Williams: Chorioepithelioma. Amer. Journ. of Obst., 1898 (Lit.). Yamagiva: Carcin. Degen. von Dermoidcysten d. Ovariums. Virch. Arch., 147 Bd., 1897. Zahn: Beitr. z. Histogenese der Carcinome. Virch. Arch., 117 Bd., 1889. See also §§ 121 and 123. (Traumatic Epithelial Cysts.) Bohn: Trauinatische Epithelcysten. Virch. Arch., 144 Bd., 1897. Garre: Traumat. Epithelcysten. d. Finger. Beitr. v. Bruns, xi., 1894. Kaufmann: Enkatarrhaphie v. Epithet Virch. Arch., 97 Bd., 1884. Worz: Traumat. Epithelcysten. Beitr. v. Bruns, xviii., 1897 (Lit.). § 123. The structure of a carcinoma is determined by its origin. The manner in which the epithelium proliferates and the associated pro- 468 TUMORS. FIG 341.— Horny cancer of the tongue (Miiller's fluid, bsematoxylra, eosin) epithelial pearls ; /j, stroma. X 100. a, Epithelial plugs with liferation of the connective tissue make it possible to distinguish a con- nective=tissue stroma which contains the blood-vessels, and nests and strands of cells — the so-called cancer=plugs — which lie embedded in the stroma. If the cancer grows into a tissue having a special si ructure, the stroma may contain niuscle- tibres, bone trabecular, unchanged glandular tissue, etc. ; but these tissues usually die after a time. Iu general a carcinoma possesses an alveolar structure, at times suggesting an imperfectly developed acinous gland, at other times a tubular gland, so that it is possible to distinguish acinous and tubular types of carci- noma. When the cell- plugs are solid, with- out a lumen, the growth may be called a carcinoma solidum or merely carcinoma. The presence of a lumen in the cell-plugs gives to the growth an appearance resembling anatomically the adenomata, and warrants the designation carcinoma adenomatosum 01 adenocarcinoma. The type of carcinoma is to a certain degree dependent upon theparent- tissue in which it arises, and the cells may still show the characteristics Fig 342 —Carcinoma of the skin, with delicate cellular network and areas of hyaline connective tissue. (Alcohol. hematoxylin.) X SO. VARIETIES OF CARCINOMA. 469 of the parent epithelium. Squamous-celled carcinoma may be expected to occur wherever there is squamous-celled epithelium, and cylindrical- celled carcinomata in mucous membranes having cylindrical cells. Cornification takes place in carcinomata of the skin, mucoid degenera- tion in those of mucous membranes, while the formation of colloid occurs in those arising from the thyroid. Departures from this rule are, how- ever, common, in that the epithelial cells may remain at a less highly differentiated stage, so that the type of the cell-variety concerned may not be developed to its fullest; or it may happen that the cells lose their FIG. 343.- Adenocarcinoma recti tubulare (alcohol, alum-carmine), a. b. Epithelial gland-tubules ; c, C], stroma ; (2, collections of leucocytes in the gland-tubules. X 65. original character and take on others. For example, colloid-like sub- stances may be formed in cancers of the skin, mucus may be produced in mammary cancers, or horny squamous-celled carcinomata may develop in mucous membranes possessing cylindrical epithelium (gall-bladder) or in those having transitional epithelium (pelvis of kidney). (1) Squamous=celled cancers develop in the skin and in those mucous membranes covered with squamous cells. They occur, therefore, in the external skin, mouth cavity, pharynx, cesophagus, larynx, vaginal portion of the cervix, vagina, and external genitals. In rare cases they may develop in mucous membranes possessing cylindrical epithelium — for example, in the trachea and gall-bladder — or in the remains of foetal structures — for example, in the remains of the branchial clefts, and in dermoids. The flat- celled cancer is characterized chiefly by the formation of relatively large cell-nests (Figs. 341, «) of irregular shape; but they often form also small strands of cells. The epithelial cells which are collected in masses show clearly the character of stratified squamous epithelium with the formation of prickle-cells, but on account of their multiplication within the tissue-spaces are usually polymorphous, and no longer manifest their typical characteristics. Very often the formation of keratokyalm and cornification takes place within the large epithelial plugs which have penetrated into the deeper tissues. The cells which have undergone a horny change become arranged in concentric laminse 470 TUMORS. resembling those of an onion (Fig. 341, a). Such cell-nests are known as epithelial pearls or homy bodies, and give occasion for the designation of the tumor as a horny cancer. If, instead of cornirication, the central Fig. 344.— Adenocarcinoma fundi uteri r. isolated cancer- 150. ■f Wmlmm % WMU itt 4 ®?. Fro. 345.— Carcinoma simplex mammae (alcohol, haematoxylin). rr, Stroma; b, cancer-plugs; c, isolated cancer-cells ; d, blood-vessels; e, small-celled infiltration of the stroma, x 300, VARIETIES OF CARCINOMA. 471 portions of the cell-nests undergo necrosis and liquefaction, the carcinoma may take on an adenoma-like structure. Besides these typical flat-celled cancers there often occur in the skin and mucous membranes possessing squamous cells carcinomata having Fig. 346.— Acinous carcinoma of the mammary gland with large nests of cells (Muller's fluid, hematoxylin). X 100. epithelium persisting at a lower stage of development, so that the cell-strands remain slender and delicate, and consist of small epithelial cells of different forms (Fig. 342) that do not change into prickle-cells Fig. 347.— Tubular scirrhous cancer oi the mammary gland (Muller's fluid, hematoxylin), a. Area with well-developed elongated nests of cells ; b, portion of tumor in which the cell-nests have for the greater part disappeared. X 100. and horny cells. Krompecher designates such cancers as basal-celled carcinomata, since they develop from the layer of basal cells. The cell- cords of these carcinomata are usually solid, but through the production 472 TUMORS. of hyaline cell-products in the centre of the cell -masses they may take on an adenomatous appearance. (2) Cylindrical-celled carcinomata develop chiefly in those mucous membranes possessing cylindrical epithelium — intestines, stomach, respi- ratory tract, body of the uterus, and gall-bladder, but occur also in glands — ovary, mammary gland, liver, etc. — as well as iu the cerebral ventricles. Such tumors exhibit, at least in the early stages of develop- ment, the character of carcinoma adenomatosum or adenocarcinoma (Figs. 336, 337, 343), and also form epithelial structures which resemble glands and consist of variously formed gland tubules lined by a simple or stratified epithelium. A more active proliferation of the epithelial cells leads finally to the formation of compact cell-nests possessing no lumen (Fig. 344). The stroma of cylindrical-celled carcinomata is usually poorly de- veloped ; and the tumor consequently bears the character of a soft can- cer, a carcinoma medullare. Nevertheless the cancerous tissue ma3 r in some cases possess a firm consistence. (3) The carcinoma simplex or carcinoma in the narrower sense — that is, a cancer whose especial characteristics are derived from the form and position of the cancer-cells, in that these are arranged simply in irregu- lar, compact heaps (carcinoma solidum) — occurs most frequently in glands, but may develop also in the mucous membranes and skin. The cell-nests are in part very irregularly shaped (Fig. 345), in part round (Fig. 346), or in other cases elongated or fusiform (Fig. 347). These variations have given occasion to the employment of the terms carcino= Fig. 348.— Section through a segment of a carcinoma of the breast (alcohol, hematoxylin), it Nipple ■ b, tissue of gland; c, skin ; d, gland-ducts; e. carcinomatous masses occupying the place of the gland tissue ;/', carcinomatous infiltration of fat tissue; (/, portion of skin infiltrated with carcinoma; /t, nests of cancer-cells in the nipple ; i, normal gland-lobule ; Magnified by hand-lens. k, small-celled infiltration of the connective tissue. ma acinosum (Fig. 346) and carcinoma tubulare (Fig. 347) as distin- guishing types of corresponding character. It should be noted, however, VARIETIES OF CARCINOMA. 473 that these different types may be present in the same tumor (Fig. 348, e >f> ff)> since the character of the cell-nests depends partly upon their manner of growth and partly upon that of the connective-tissue stroma in which they develop. At the seat of origin of the tumor the cell-nests may have a variety of shapes (e) ; in adipose tissue they are rounded (/) ; in the unyielding connective tissue of the skin they are small and fusiform (g). An abundant development of cell-nests within a delicate connective- tissue stroma leads to the formation of a carcinoma medullare. A marked development of the connective-tissue stroma with the formation of relatively few cancer-cells gives rise to a hard tumor, which is called a carcinoma durum or a scirrhus (Fig. 347). FIG. 349.— Mucoid carcinoma of the mammary gland (Miiller's fluid, hematoxylin, eosin). a. Normal gland tissue : h, c, early stages of carcinomatous proliferation with beginning formation of mucus ; d, larger cell-nests with masses of mucus ; e, /, carcinoma tissue showing marked mucous degeneration. X 30. The hard variety of cancer owes its origin to the fact that the cell- nests are from the beginning relatively few and small, while the connec- tive-tissue stroma is abundant and hard. Such tumors are formed espe- cially when the epithelial proliferation infiltrates into hard connective tissue, as, for example, in the mammary gland and skin, but the same characteristics may be exhibited in the case of newly-formed connective tissue. In the course of time a cancer becomes harder by reason of the destruction of a large portion or of all of the nests of epithelial cells (Fig. 347, b), while the connective tissue increases in amount. An originally soft cancer may become hard through a more or less pronounced shrinkage of the cancerous tissue in association with the induration of 474 TUMORS. A mm ilflll||fl& Fig. 35(1.— Early stages of development of a mucoid carcinoma of stomach, arising in an atrophic mucosa (formalin, alcohol, hematoxylin, eosin). a, mucosa; /», muscularis mucosae; c, submucosa ; ft, musoularis; e, serosa; /, g. Mucoid cancer. X 9. the tissue. Carcinomata of the mammary gland, stomach, and intestine very often show such secondary hardening, and in cancer which has un- dergone snch a fibrous change the nests of cancer-cells may be en- tirely absent. (4) The chorion- carcinoma or malig- nant chorio-epithelU oma is distinguished from other carcinomata by the presence in the individual cell-masses of a mixture of vari- ous cell-forms (Fig. 340, a, b) belonging to the foetal ectoderm. Such a combination is not everywhere pres- ent, and does not occur especially where single cells or cell-groups penetrate into the blood- stream or are transported passively. The conditions favoring a de velopment within the blood-vessels are found when "fluid and%oagu- lated masses of blood lie between the tumor-cells (c). (5) Cancers characterized by peculiar secondary changes arise through the formation of especial products by the cancer cells, orthrough peculiar metamorphoses of the same, or more rarely through changes in the stroma. Mucoid or gelatinous cancer— carcinoma mucosum (G. gelatinosum ('. colloides) — is that form of carcinoma in which the epithelial cells pro- duce mucus (mucin or pseudomucin) or a more colloid-like gelatinous substance. Such production of mucus occurs particularly in cancers of Fir., dol.— Carcinoma mucosum mammae (alcohol, hematoxylin), (i. Stroma; h, cancer-plugs ; c, alveoli without cancer-cells; ft, cells containing spherules of mucus. X 21)0. VARIETIES OF CARCINOMA. 475 Fig. 353.— Carcinoma with hyaline drops within the cell-nests (Carcinoma eylindromatosum). a. Cell- nest without ; h, cell-nest with a few hyaline spher- ules; c, cells which have been reduced to strands ar- ranged in a network, as the result of the formation of numerous hyaline spherules. X 150. the intestine, stomach (Pig. 350), and mammary gland (Fig. 349); and may be manifest in the earliest stages of the development of the tnmor(Figs. 349, b, <■; 350,/,*/), so that the mucoid products of the cells collect first in the centre of the cell-nests after the manner of a gland-secretion. Later the border of cells surrounding the mucoid material is broken through, the cells pushed aside, separated from the underlying structures, and crowded toward the centre of the mucus-contain- ing alveolus (Fig. 349, d, r, f). Ultimately, the epithelial cells are wholly destroyed. In intestinal cancers the for- mation of mucin takes place in goblet-cells, which are similar to the goblet-cells occurring under normal conditions. In cancer of the breast the mucus appears in the form of droplets within the cancer-cells (Fig. 351, d), and becomes free either by escaping from the cell, or through the complete destruc- tion of the cell itself. Through the development of mucoid or colloid-like masses within the cancer-cell nests, the latter may become studded with hyaline drops, and thereby acquire a mesh-like appearance (Fig. 352). Such formations were formerly designated as cylindromata, and classified * with the corresponding sar- comata. Should it lie thought desirable to retain this no- menclature, such a tumor may be designated carcinoma eylin- dromatosum ; but it seems un- necessary to separate these growths from the mucoid and colloid carcinoniata. When the cancer-cells at- tain an extraordinarily large size, as occurs, for example, in fiat-celled cancel's or in cancers of the breast, the tu- mor may be termed a carcN noma gigantocellulare. If the, enlargement of the cells is not due to an increase in the amount of protoplasm, but to a swollen condition of the cells or to a collection of drops of fluid in the cells and their nuclei (Fig. 353), the cells are designated physalides (carcinoma physaliferum). Myxomatous degeneration of the connective-tissue stroma may occur in portions of a cancer, so that the cancer-cells become separated from each other by myxomatous tissue (Fig. 354, e). Such growths may be called earchtom a myxom atosum . Fig. £i3. — Enlarged hydropic cancer-cells, from a car- cinoma of the mamma (Midler's fluid, Bismarck-brown). a, Ordinary cancer-cells ; b, hydropic cells containing: drops of fluid; c, swollen nucleus; a cuwicij uucu nun (jauiiiorj pj< " • ' adenomatous proliferations; «, papilla of the mamma. Reduced 'about ^ one-third ysts ; c, cysts con- e, small, encysted possess a soft, medullary appearance, and when developed in great num- bers give to the entire tumor a marrow-like character. Both the cyst-wall and the papillary proliferations, which branch in the same manner as do those of the papillary cystadenomata, arc covered with a thick, stratified layer of epithelium (Fig. 357, h, c, d ; 35S, c). VARIETIES OF CARCINOMA. 479 The papillae are usually slender (Fig. 357, c, d), but through myxomatous degeneration of their connective tissue may attain a large size (Fig. 358, a.-S Fig. 357.— Cystocareinoma papilliferum ovarii (Mtiller's fluid, hematoxylin), a, Stroma ; h, epithelium ; c, (J, papillae. X 72. b). Through total myxomatous degeneration of the connective tissue of the papillae the latter may ultimately become converted into mucous cf/.s-te sur- rounded by epithelium. If at the same time the epithelial layers of FIG. 358.— Papillary cystocareinoma of the mamma with papilla' which have undergone myxomatous degeneration (Muller's fluid, hematoxylin, eosin). a. Dense connective tissue ; b, myxomatous papillae : c, proliferating epithelium, arranged in several layers. X 73. neighboring papillae become confluent, the epithelium finally comes to represent a stroma which incloses balls of mucus. 480 TUMORS. The metastases of cystocarcinomata may have the character of cauli- flower-like, papillary growths, and this is particularly the case when ovarian tumors of this nature spread throughout the peritoneal cavity. Other metastases show the characteristics of ordinary carcinornata. Literature. (Cystocarcinoma. ) Baumg-arten : Ovarialkystom mit Metastases Virch. Arch., 97 Bd., 1884. Billroth: Handb. d. Frauenkrankheiten, ii., Stuttgart, 1886, Leser: Zur pathol. Anat. d. Geschwtilste der Brustdriisen. Beitr. v. Ziegler, ii., 1888. Pfannenstiel : Papillare Geschwillste des Eierstocks. Arch. f. Gyn., 48 Bd., 1895. Sasse : Cystische Tumoren d. Mamma. Langenbeck's Arch., 54 Bd., 1897. Schmidt: Secretionsvorgange in Krebsen. Virch. Arch., 148 Bd., 1897 (Lit.). Stratz: Die Geschwillste des Eierstocks, Berlin, 1894. See also § 122. § 125. Growth by infiltration and the involvement of the surround- ing tissues takes place, during the early stages of development (Sec. 122), through the penetration of the epithelial elements alone into the neigh- boring tissue in the form of connected plugs or cords of cells. Not infrequently there appear in the tissue-spaces single epithelial cells that "■/•, w m,m ■'*■;'* ,£■ **. WW Fig. 359.— Colloid-containing cancer of thyroid infiltrating the thyroid cartilage (alcohol, hematoxylin eosin). a, Cartilage; b, cancer-tissue ; (\ colloid ; d, cancer-tissue growing into the cartilage. X 85. multiply and form strands or round masses of cells. In the growth of a tumor into neighboring organs, the connective-tissue stroma (Fig. 359, d) surrounding the cell-nests breaks into the neighboring tissue (a) and re- places it. Such a mode of infill ration occurs to the most marked degree in the case of carcinomatous infiltration of cartilage (a) and bones. The formation of metastases, which takes place more frequently in METASTASIS OF CARCINOMA. 481 the case of carcinoma than any other form of tumor, is the natural result of its infiltrative mode of growth. In the process of infiltration the cancer-cells break into the lymph-vessels (Fig. 244), and through these are carried to the lymph-glands. In both pi aces there results a multiplica- tion of the transported, cancer-cells (Figs. 244, a ; 360, d). In the lymph- glands the lymphadenoid tissue becomes replaced by cancer tissue ; the lymphocytes vanish, while the connective tissue of the lymph-gland serves as a framework for the cancer. The development of cancer in the lymph-channels is either limited to the filling and distention of the lymph-vessels by the cancer-cells (Fig. 244) or it may likewise lead to the formation in this situation of daugh- ter-nodules. The epithelial obstruction of the lymph-vessels is often very exten- sive; and through the blocking-up of individual lymph-channels or of the thoracic duct itself, a retrograde metastasis of cancer-ceils may be caused. For example, in the case of a cancer of the stomach the lymph-vessels of the mesentery and the thoracic duct, and those of the lungs, or even of the upper extremities, may become the seat of metastatic growths. Through the thoracic duct cancer-cells may be carried into the blood-stream. The epithelial proliferation breaks into blood-vessels not less frequently than into the lymphatics ; and the invasion of the veins by cancer-cells is to be regarded as a constant phenomenon. In consequence the vessel- lumen becomes filled with cancer-cells, and at a later stage the affected portion of the vessel becomes converted into cancer-tissue, the frame- work of which is formed through the proliferation of the constituents .of the more or less altered vessel -wall. Fig. 3fi0.— Section from an enlarged axillary gland, with beginning development of cancer (alcohol, hsematoxylin). a, Germ-centre of a lymph-node; h. lymph-sinuses ; c, artery; d, nests of cancer-cells. X 60. If cancer-cells pass from the thoracic duct or from a vein into the circulation there are formed hcematogenous metastases. In carcinoma of 31 482 TUMORS. the stomach and intestine cancer-cells are very often carried through the portal vein into the liver (Fig. 245, b, c). The thoracic duct and the systemic veins permit a transportation of cancer-cells to the lungs. Ac- cording to investigations byM. B. Schmidt, the lungs are very frequently the seat of metastases, but in many cases these do not develop into nod- ules visible macroscopically. Much more frequently only microscopic intraarterial groups of cancer-cells embedded in thrombi are found. A part of these metastases can through the proliferation of the tumor-cells develop into daughter-nodules, and the lungs may contain numbers of these. Very often, however, the transported cells fail to develop into cancer-nodules (Schmidt). The transported cells, that perhaps have re- : | ^ ' ' J ntn v 'Wfj ! Fig. 361.— Metastatic collection of young cancer-cells within a liver-capillary, arising from a primary adenocarcinoma of the stomach (alcohol, haematoxylint. X 300. Fir. 362— Metastatic development of cancer within the liver-capillaries, arising from a primary carci- noma of the pancreas (alcohol, carmine), lloth connective tissue and nests of carcinoma colls have de- veloped within the capillaries. ■ 250. cently proliferated, die, and there occurs only a proliferation of connec- 1 i vo tissue in the vessel -wall, leading to the organization of the thrombus. In other cases the cancer-cells increase within the vessel-lumen without forming large nodules. When cancer-cells enter the systemic circulation there occurs a distribution of the carcinoma to the various organs. It is not yet known to what extent the transported cells die. The favorite seats of secondary development of cancer are the bones, liver, and kidneys. Occasionally a development of carcinoma may take place in all the organs of the body, so that the resulting condition may be styled a general carcinomatosis. The secondary cancer -foci develop first intravascularly (Figs. 361, 362, and 363, c). In the beginning the neighboring tissues are but little changed (Fig. 363). Later there occur in part tissue-degenerations ( Fig. 363,/) and in part connective-tissue proliferations (Figs. 362, 364, c, d), and the newly formed connective tissue serves as the stroma for the de- veloping cancer-nodule. The amount of this connective tissue varies greatly, and is dependent in part upon the parent-tissue in which the tumor develops and in part upon the variety of cancer. The most 483 Fig. 363. — Carcinomatous metastases in the upper layer of the uterine mucosa, in universal carcinomatosis following carcinoma of the mamma. (Formalin, hematoxylin and eosinj a, Muscularis of the uterus; 6, normal mucosa; c, nests of cancer-cells in the vessels between the uterine glands; d, upper layer of the mucosa densely infiltrated with nests of cancer-cells; e, uterine epithelium; /, ulcerated a'rea. (Blood-clots containing cancer-cells were found in the uterus.) X 100. m VP$ Fig. 364.— Metastatic development of cancer in the diploe of the skull-cap in primary car- cinoma of the stomach. (Formalin, ha-matoxylin. eosin.) a. Marrow-tissue; 6, nest of cancer- cells: c, proliferated endosteum with nests of cancer-cells; d, fully developed area of carcinoma. X 40. 4S4 TUMORS. marked connective-tissue proliferation occurs in the cancer-inetastases in bones (Fig. 364), particularly when there is a diffuse growth of the carcinoma through the bone. With the destruction of the old bone the carcinoma may form in place of the bone-substance an abundant fibrous stroma in which osteoid tissue or new bone may be formed in large amounts. It would appear that many carcinomata must produce sub- stances that excite a marked proliferation of the periosteum and endos- teum. Similar marked proliferations may occasionally be observed when carcinomata spread over the serous membranes, particularly the periosteum. As has already been mentioned in § 101, carcinomata may be trans- planted to individuals of the same species, and after operations im- plantation-carcinomata may develop. Recurrences after the removal of the tumor by operation are very common in the case of cancers, and in advanced cases can scarcely be avoided. They arise usually from remains of the primary tumor or from metastases already present in the body either in the immediate neigh- borhood or in distant organs. In rare cases the conditions favoring the growth of the cancer may again arise in the neighborhood of the scar resulting from the operation, so that after several years a new cancer develops. Recurrences and metastases of the chorionic carcinomata grow extremely rapidly so that within a. few days tumors of considerable size may be formed. The dark-red color shows even to the naked eye that blood is largely concerned in their make-up, and the microscopical examination shows that the rapid increase in size is in a large measure due to the large hemorrhages caused by the development of the tumor. The epithelial masses may form a relatively small part of the entire bulk of the growth. Chorion carcinomata, that is, the epithelial cell-masses characteristic of these tumors, have been repeatedly observed ouside of the uterus, in various organs (Schmauch, Schmorl, Risel, Busse, Zagorjanski-Kissel), also in cardiac thrombi (Busse), without any tumor of the uterus having been demonstrable . This phenomenon may be explained by the fact that the epithelial cells of the normal chorion or of the hydatid mole, that is, of myxoma- tous chorionic villi, may be transported through the blood-stream and proliferate without the development of a tumor at the placental site. Literature. (Metastasis of Cancer.') Busse: Chorionepitheliome ausserhalb der Placentarstellen. V. A., 174 Bd., 1903. Cuneo: De 1'envahiss. du syst. lymph, dans le cancer de l'estomae, Paris, 1900. Dagonet: Transmissibilite du cancer. A. de med. exp., 1904. Ely; A Study of Metastat. Carcinoma of the Stomach. Am. Journ. of the Med. Sc , 1890. Gierke: Knochentumoren mit Schilddriisenbau. V. A.,170Bd., 1902. Goldrnann : Verbreitungswege bosartiger Geschwiilste. Beitr. v. Bruns, xviii., 1897. Gussenbauer: v. Langenbeck's Arch., 14 Bd., 1872. Hanau: Erfolgreiche Uebertragung von Carcinom. Fortschr. d. Med., vii., 1889. Jensen: Exper. Unters, liber Krebs bei Mausen (Uebertragung 19 Generationen hindurch). Cbl. f, Bakt., xxxiv., 1903, Orig. v. Kahlden: Carcmomrezidive. Arch. f. klin. Chir., 68 Bd., 1902. Krukenberg-: Metast. Carcinom d. Chorioidea. Mon. f. Augenheilk., Beilh., 1903. Milner: Impfcarcinome. A. f. klin, Chir., 74 Bd., 1904. Risel: Ueber das maligne Chorionepitheliom, Leipzig, 1903. Schmauch: Syncytioma vaginale, Z. f. Gebh., 49 Bd., 1903. Stiles: Dissem. of Cancer of the Breast. Brit. Med- Journ. , i., 1899. Wehr: Carcinomimpfungen von Hund zu Hund. Langenbeck's Arch., 39 Bd., 1889. Zehnder: Ueber Krebsentwickelung in Lymphdriisen. Virch. Arch., 119 Bd., 1890 See also § 101. TERATOID TUMORS AND CYSTS. 4S5 3. The Teratoid Tumors and Cysts. § 126. Under the head of teratoid tumors and cysts niay be grouped those tumor-like formations which are characterized by the fact that, the tissue-formations of which they are composed either do not occur nor- mally at the site in question (heterotopous growth'), or at least do not nor- mally appear there at the time at which they are found (heterochronous growth). Part of the teratoid tumors and cysts, which are classed as teratomata in the narrower sense, exhibit, moreover, the peculiarity that they are composed of a variety of tissues. The teratoid tumors and cysts may be conveniently divided, according to their structure and their origin, into three groups, as follows: (1) The simple teratoid tumors; (2) the simple teratoid cysts ; (3) the complex teratomata, which in part contain tissues derived from all the germ-layers. The heterotopous tissue=growths, which are classed with the teratoid tumors may occur iu the most various organs, but are more frequently found in certain regions than in others. Among the more common tumors of this class are the chondromata and choudromyxomata of the salivary glauds and the testicle, osteomata of the muscles, lipomata of the pia mater, adenosarcomata of the kidney containing striped muscle, and the adrenal tumors found in the kidney. Among those occurring more rarely are the chondromata and osteomata of the skin or of the mammary gland, rhabdomyomata of the testicle, etc. The occurrence of tissue-formations in regions in which such tissues are not normally present can be explained in part by the assumption that cells or groups of cells of a tissue have not undergone a normal differ- entiation into definite tissue-forms, but retain the capacity of forming different kinds of tissues. Nevertheless, in many cases the explanation is to be sought rather in a germinal aberration or a misplacement of tissue, iu that either in early embryouic life embryonal cells of one organ find their way into the anlage of another organ, or that, later, tis- sues in process of development or already formed are displaced from their normal position. The first process can be inferred only from the sub- sequent appearance of pathological tissue-formations ; the latter, on the other hand, may at times be recognized, later on, iu the anatomical re- lations. Thus, for example, iu the retrograde changes occurring in her- nias of the sacral portion of the spinal cord, adipose tissue and muscle-tis- sue may find their way into the spinal canal and the arachnoidal sac and grow around the nerves. Arnold observed transposition of fat-tissue, gland-tissue, cartilage, and neuroglia at the lower end of the trunk, in a case of myelocyst with complete absence of the lumbar, sacral, and coccygeal portions of the spinal column. He also found in a lipomatous teratoma of the frontal region that the intracranial portion of the tumor communicated with the extracranial through a defect in the cranium. The teratoid cysts may be divided into two great groups: the ecto- dermal on the one hand, and the entodermal and mesodermal epithelial cysts on the other. The ectodermal cysts vary in size from that of a pea to that of a man's fist. Their walls present ectodermal characteristics, either in that they consist only of a smooth connective-tissue membrane, covered with stratified squamous cells — the so-called epidermoids ; or the cyst walls may present all the characteristics of skin — that is, contain papillae, seba- ceous glands, hair follicles, hairs and sweat-glands, and often also subcu- taneous fat — the so-called dermoids or dermoid cysts or dermatocysts. 486 TUMORS. The cyst-contents consist either of desquamated horny cells alone, or of such cells, fat, and blond hair. Epidermoids and dermoids are found chiefly in the shin and subcuta- neous tissues, where they present themselves in the form of tumors contain- ing a pultaceous material, which resemble atheromata, i.e., tumors caused by the retention of secretion in the excretory ducts of the sebaceous glands and in the hair-follicles. They are also found at the sides of the neck and in the median line either above or below the hyoid bone ; further, in the thoracic cavity, particularly in the mediastinum, in the peri- toneal cavity (rarely), pelvic cellular tissue, coccygeal region, and in the raphe of the perineum. Finally, they also appear within the cranium, in the dura or in the hypophysis. Of frequent occurrence are the intracranial forma- tions which are known as cholesteatoma or as pearl tumors. These growths vary in size from that of a pea to that of an apple ; they form spherical or nodular tumors, having a white satiuy surface, and consist for the chief part of thin, non-nucleated, scale-like cells, arranged in closely crowded lamina*. They are invariably situated at some point on the pia (Bostrom), and at such places the vascular pia is covered with stratified squamous cells, which in the course of years produce the deli- cate epithelial scales of which the tumor is composed. The neighboring brain tissue and the arachnoid, which may in part extend over the growth, are not concerned in the formation of the horny scales. In rare cases cholesteatomata may contain sebaceous material and fine hairs in addition to the horny scales and cholesterin. In these cases there may be found seated here and there upon the pia dermal structures, i.e., true skin tissue containing sebaceous glands and hair-follicles, from which the sebaceous material and hairs found in the growth arise. The simple cholesteato- mata may therefore be designated as epidermoids (Bostrom), those containing hair as dermoids. Cholesteatomata occur at the base of the brain, in the neighborhood of the olfactory lobe, tuber cinereum, corpus callosum, choroid plexus, pons, medulla oblongata (very rarely in the spinal cord), and in the cerebellum. The dermoids and epidermoids under consideration probably owe their origin to a transplantation of epithelial germs to the sites in question. In the case of the epidermoids probably only embryonal epi- thelial cells are transplanted ; in dermoids embryonal dermal tissue is also transplanted. The intracranial cholesteatomata originate proba- bly in an early implantation of epidermal anlage in the pia. Mediasti- nal dermoids probably depend upon disturbances of development of the thymus, which arises from the ectoderm. The dermoids on the sides of the neck arise from remains of the branchial clefts, particularly of the second ; those hanging from the hyoid bone or lying beneath it are prob- ably to be regarded as the remains of the ductus thyreoglossus. Dermoids of the pelvic cellular tissue may be explained as arising from epithelial iushoots from the perineum. Simple entodermal and mesodermal epithelial cysts are character - ized by a lining of cylindrical cells, which are often ciliated. They occur most frequently in the broad ligament and tubes. They are found also in other portions of the peritoneal cavity, in the intestine, in the neigh- borhood of the trachea and bronchi, in the lungs, pleura, neck, tongue, vagina, glandular organs, etc. They form cysts varying in size from that of a pin-head to that of a man's head. The occurrence of these cysts may be explained in most cases by the TERATOID TUMORS AND CTSTS. 4S7 persistence of foetal glands or canals or by the separation through constriction of portions of entodermal or mesodermal epithelial tubes. In the neck remains of the internal branchial clefts, in the posterior portions of the tongue the remains of the ductus thyreoglossus or of epithelial buds and glands developing from the same, in the oesophagus and respiratory tract snared-off portions of the intestinal canal or of the air-passages, or remains of the communication between alimentary tract and air-passages, may form the foundation for the development of such cysts. In the broad ligament, uterus wall, and tubes the cysts arise from remains of the canals of the Wolffian duct and the duct of Gartner; in the tubes, cervix, portio vaginalis, vagina, and hymeu they Fig. 365.— Adenoma-like isolation in the subinucosa of a portion of the raucous membrane of the small intestine, giving rise to a ridge-like prominence of the mucosa 2 em. in length (alcohol, hematoxylin). From a child six weeks of age. a, b, c, Normal intestinal wall ; d, e, portions of mucosa included within the submueosa ; /, mucous tissue rich in cells. X 35. arise from the remains of the latter ; in the peritoneal cavity in part from snared-off portions of the intestine (evterocijsts), or in part from portions of the urachus (urachus-cysts). Within the glands — for example, the liver or the kidneys — portions of the gland-tubules may become con- stricted off during the period of development, and later develop into cysts (adenocysts). Cysts located in the central nervous system or its immediate neigh- borhood — for example, at the lower end of the trunk — may arise from the medullary canal (myelocysts), in the latter place also from remains of the hind-gut (enterocysts). The origin of the cysts lined with cylindrical epithelium can usually be determined only from their position and the character of their walls, but in the majority of cases the origin can usually be ascertained beyond doubt. The diagnosis can be made with the greatest certainty when the misplacement of the separated portion is slight (Fig. 3G5, d, e), and when the formation still shows clearly the character of the mother-tissue. 4S8 TUMORS. The significance of ectodermal, entodermal, and mesodermal cysts is dependent upon their position, size, and the secondary changes which occur in them. Their size varies from that of a pin-head to that of a man's head. Among the secondary changes — aside from inflammation — may be mentioned the development of adenomata and ca rcinomata. For example, remains of the Wolffian body which are present in the dorsal wall of the uterus near the angles of the tubes (von Eecklinghausen), or FIG. 360. -Adenoma-like remains of the Wolffian body, within the uterine musculature (formalin, alcohol, hematoxylin, eosin). a, Muscle tissue ; h, glandular tissue ; c, sections of vessels. X 100. in the broad ligament in the inguinal region (Aschoff, Pick) may give rise to adenomata, cystadenomata (Fig. 360, b), or adenomyomata. Der- moids may be the seat of development of a squamous- celled cancer (branchio- genicand subcutaneous carcinoma); while from separated portions of the intestinal mucous membrane (Fig. 305) it is probable that cylindrical- celled carcinomata may take their origin. Cysts, cystadenomata,, and car- cinomata may develop in the jaw from misplaced portions of the epithelial milage of the teeth. Literature. (Ectodermal, Entodermal, and Mesodermal Teratoid Cysts, and Solid Tercdomata.) Albrecht: Nebenmilzen. Beitr. v. Ziegler, xx., 1S96. Arnold: Hygroma colli congenitum. Virch. Arch., 33 Bd., 1865; Angeb. lipomatoser Teratom der Stirn. lb., 43 Bd., 1868; Congenitales zusammengesetztes Lipom der Zunge und des Pharynx mit Perforation in die Schadelhohle. lb., 50 Bd., 1870; Behaarte Polypen der Rachenmundhohle. lb., Ill Bd., 1888; Ein knorpeltialtiges angeborenes Fibroin des Scheitels mit Hypertrichosis. Beitr. v. Ziegler, viii., 1890; Myelocyste, Transposition von Gewebskeimen u. Sympodie. lb., xvi., 1894. Aschoff: Cysten, Ergebn. d. allg. Path., ii., 1897 (Lit.); Cystisches Adenofibrom d. Leistengegend. Monatsschr. f. Gebh., ix., 1899. TERATOID TUMORS AND CYSTS. 4S9 Askanazy: Die bosartigen Geschwiilste der in der Niere eingeschlossenen Neben- nierenkeime. Beitr. v. Ziegler, xiv., 1893. Beneke: Zur Lehre v. d. Versprengung von Nebennierenkeimen in den Nieren, nebst Benierkungen zur allg. Onkologie. Beitr. v. Ziegler, x., 1891. Bostrbm: Piale Epidermoide, Dermoide u. Lipome u. durale Dermoide. Cbl. f. allg. Path., 1897 (Lit.). Brans, P.: Branchiogene Carcinome. Mitthcil. a. d. chir. Klinik zu Tubingen, i., 1884. Buttersack: Congen. Knorpelreste am Halse. Virch. Arch., 106 Bd., 1886. Chiari: Genese d. Atheromcysten. Cbl. f. allg. Path., 1890; Zeitschr. f. Heilk., xii., 1891. Cullen: Adenomyoma of the Round Ligament. Johns Hopkins Hosp. Bull., 1892. Czyzewicz: Retrosakrales Dermoid. B. v. Bruns, 36 Bd., 1902 (Lit.). Dehler: Atheromcysten am Halse. Beitr. v. Bruns, xx., 1898. Deichert: Knorpel u. Knochen in d. Tonsiilen (Reste d. 2 Keimenbogensj. Virch. Arch., 141 Bd., 1895. Ddderlein: Embryon. Driisengeschwulst d. Nierengegend. Cbl. f. Krankh. d. Harn- org., 1894. Dossekker: L T rachuscysten. Beitr. v. Bruns, x., 1893. Eberth: Flimmerepithelcysten d. Leber u. d. Gehirns. Virch. Arch., 35 Bd., 1866. Frank: Cholesteatom d. weichen Hirnhaute. Inaug.-Diss., Marburg, 1897. Franke: Das Atherom. Arch. f. klin. Chir., 34 Bd., 1887; Virch. Arch., 121 Bd., 1890. Frobenius: Ueber einige angeb. Cystengeschwulste des Halses. Beitr. v. Ziegler, vi., 1889. Goebel: Vom Zahnsystem ausgehende Kiefertumoren. Cbl. f. allg. Path., 1897 (Lit.). Grawitz: Ueber die sog. Lipome der Nieren. Virch. Arch., 93 Bd., 1883. Gurlt: Die Cystengeschwulste des Halses, Berlin, 1855. Hektoen: Vitelline-Duct Remains at the Navel. Amer. Journ. of Obst., 1893. Helbing-: Rhabdomyom an Stelle d. 1. Lunge. Cbl. f. allg. Path., ix., 1898. Hess: Ueber eine subcutane Flimmercyste. Beitr. v. Ziegler, viii., 1890. Heusinger: Hals-Kiemenfisteln mit Knorpelresten. Virch. Arch., 29 Bd., 1864. Hildebrand: Unters. tiber Spina bifida (Gewebstranspositionen). Dent. Zeitschr. f. Chir., 36 Bd., 1893; Langenbeck's Arch., 46 Bd., 1893; Cysten u. Fisteln d. Halses. lb., 49 Bd., 1894; Spina bifida (Gliom in Hydrencephalocele). Deut. Zeitschr. f. Chir., 36 Bd., 1893. Hueter: Angeb. Darmgeschwulst. Beitr. v. Ziegler, xix., 1895. Joachimsthal : Spina bifida occulta mit Hypertrichosis. Virch. Arch., 131 Bd., 1893. Kelly: Hypernephromas of the Kidney. Phil. Med. Journ., 1898. Kuhne: Zur pathol. Histologic d. Cystenbildung. Virch. Arch., 158 Bd., 1900. Lannelongue et Achard: Traite des kystes congenita ux, Paris, 1886. Malassez: Sur le role des debris epitheliaux paradentaires. Arch, de phys., 1885. Mallory: Sacrococcygeal Dimples, Sinuses, and Cysts. Am. Journ. of the Med. Sc, 1892. Marchand: Rhabdomyom der Dammgegend. Virch. Arch., 100 Bd., 1S85. Mermet: Les kystes congen. du raphe genito-perineal. Rev. de chir., 1S95. Meyer: Ueber epitheliale Gebilde im Myometrium, Berlin, 1899; Subserose Epithel- knotchen an Tuben, Lig. latum, Hoden u. Nebenhoden. V. A., 171 Bd., 1903; Ektodermcysten am Lig. latum, am Samenstrang u. Nebenhoden. lb., 168 Bd., 1902; Adenom- u. Carcinombildung an der Ampulle d. Gartnerschen Ganges. lb., 174 Bd., 1903. Mintz: Nabeladenom. Deut. Zeitschr. f. Chir., 51 Bd., 1899. Neumann: Myoma striocellulare d. Hodens. Virch. Arch., 103 Bd.. 1886. Paltauf: Schilddrusentumoren im Kehlkopf, u. d. Luftrohre. Beitr. v. Ziegler, xi., 1891. Perez: Branchiogene Carcinome. Beitr. v. Bruns, 23 Bd., 1899. Permann: Cystoses Sacrococcygealteratom (grosse Mvelocyste). Arch. f. klin. Chir., 49 Bd., 1895. Pflam: Dermoidcysten des Mediastinums. Zeitschr. f. Heilk., xvii., 1896. Phble: Angeb. Cysten d. Genitoperinealraphe. Beitr. v. Bruns, xx., 1898. Pick: Adenomyome d. Leistengegend u. d. Scheidengewolbes. Arch. f. Gyn., 57 Bd., 1899. v. Recklinghausen: Untersuchungen uber Spina bifida. Virch. Arch., 105 Bd., 1886; Die Adenomyome u. Cystadenome d. Uterus, Berlin, 1896. Reinhold: Oelcyste auf d. Schlafenschuppe. Beitr. v. Bruns, viii., 1892. Richard: Geschwiilste der Kiemenspalten. Beitr. z. klin. Chir., v. Bruns, iii., 1888. Rug-e: Retroperitoneale Dermoidcyste. B. v. Ziegler, xxxiv., 1903. 400 TUMORS. Samter: Ein Beitrage z. Lehre v. d. Kiemengancsgesehwiilsten. Vireh. Arch., 112 Bd., 1SSS. Sanger: Dermoidcysten d. Beckenbindegewebes. Arch. f. Gyn., 37 Bd., 1895. Schirkele: Die Lehre von den mesonephrischen Geachwiilsten. Chi. f. allg. Path., xv., 1904 (Lit.). Schmidt: Leber die Flimmercysten d. Zungemvurzel, Jena, 1896. Schoeb.: Congen. zahnhaltige Cyste der Unterlippe. Inaug.-Diss., Basel, 1893. Schulz: Embryon. Arschnurungen v. Epidermis. Virch. Arch., 95 Bd., 1SS4. Volkmann : Branchiogene Carcinome. Cbl. f. Chir., xxii., 1885. Westenryk: Media stinalcysten. Prag. med. Woch., xxv., 1900. Wette: Fisteln u. Cysten d. Sacrococcygealgegend. Langenb. Arch., 47 Bd., 1894. Wyss: Zur Kenntniss heterologer Flimmercysten. Virch. Arch., 51 Bd., 1870. Zahn: Kiemengangscysten. Deut. Zeitschr. f. Chir., xxii., 18S5; Myxosarkom der Wange bei sechsnionatl. Lotus. Deut. Zeitschr. f. Chir., xxii., 1885; Congen. Knorpelreste am Halse. Virch. Arch., 115 Bd.; Llimmerepithelcysten des Oeso- phagus d. Leber u. d. Pleura. Virch. Arch., 143 Bd., 1896 (Lit.). Zdppritz: Multiloculare Kiemengangscysten. Beitr. v. Bruns, xii., 1894. See also § 128. § 127. Complex teratomata occur most frequently in Hie sexual glands, partly in the form of dermoid cysts and partly as solid tumors asso- ciated with multiple cyst-formation. The first occur particularly in the ovary, the latter in the testicles. The so-called dermoid cysts of the ovary form rather thick-walled cysts, varying in size from that of a pea to that of a. man's head, and are filled with a fatty material containing blond hair. At some point in the wall there will be found extending into the cyst-cavity a viWus-likr, nodular, flattened, or septum-like prominence, which is covered, with hairs and, Fig. 387.— Portion of the wall of a dermoid cyst of the ovary, a, Smooth wall ; h, prominence consist- inp of futand cutaneous tissues, c, swollen protuberance, bent down upon itself above and bearing hairs and teeth (), namely, hair- follicles with hairs, sebaceousg glands; subcutaneous fat is also usually present (/). layers are found other tissue-formations, such as cysts with ciliated columnar epithelium (d), bone iff), mds, and sweat- In the deeper and tubes lined cartilage, teeth (h), Fig. 368. — Section through a prominence in a multiloeular dermoid (alcohol, nitric acid, hematoxylin, eosin). «, c/, . a 3 . Epidermis; />, corium with sebaceous glands; c, sinus lined with squamous epithelium ; <(, sinus lined with cylindrical epithelium; e, tubular glands; /, tat-tissue ; y, bone ; /(, teeth; i, brain- tissue with corpora amylacea ; k, ovarian tissue. ;■: 5. muscle-tissue (also heart-muscle [Katsurada] ), brain-tissue («), nerves, groui>s of ganglion-cells, mucous glands, intestinal mucosa, and thyroid tissue, as well as pigmented formations resembling the rudimentary tis- sues of the eye. Kidney and liver tissues have not yet been found. The remaining portion of the cyst-wall of the dermoid is either covered with cylindrical epithelium or is bare; if hairs are present in this portion, they are the result of a secondary implantation, and may be surrounded by granulation -tissue, often also by giant-cells. If in association with the cysts containing fat and hairs there are also found cysts filled with a serous or mucoid fluid, the latter may be explained as arising through the cystic dilatation of spaces of the dermoid which are lined with cylin- drical cells. More frequently, however, they represent formations re- sulting from the cystic degeneration of neighboring ovarian follicles or of adenomatous new-growths. The ovary may be entirely destroyed by 492 TUMORS. the dermoid ; but remains of its tissue are often present (k). In very rare cases several dermoids may develop coincidently in one ovary ; a double-sided occurrence is seen iu about fifteen per cent, of all cases. Ovarian dermoids are observed most frequently in individuals of middle age, but occur also in children. The most characteristic feature of ovarian dermoids lies in the fact that they contain elements of all three germ-layers, and that a certain law in the arrangement of the different elements is observed. The deriva- tives of the ectoderm and mesoderm, in particular the skin and its ap- pendages, also bone and teeth, and often brain substance, are developed to the most marked extent; while entodermal formations, cylindrical- celled tubules, and mucous glands are ordinarily developed to a much less degree, and lie concealed in the deeper parts of the growth. The structure of the growth as a whole gives the impression of a rudimentary embryo with an unequal development of ecto- and entodermal tissue, and such tumors have therefore been appropriately designated as embryo- mata (Wilms). The solid teratomata of the ovary are much more rare than the der- moid cysts. They form tumors which are composed of a confused mix- ture of the most varied tissue-formations, viz., epidermis, epithelial pearls, hairs, sebaceous glands, sweat-glands, tubules, and cysts lined with ciliated epithelium, acinous glands, connective tissue rich in cells, adipose tissue, muscle, cartilage, and bone. In rare cases teeth, intes- tine, thyroid and brain tissue of a rudimentary character may be present. Since these formations also contain elements of all three germ-layers, and are distinguishable from the dermoids only through the lack of any regular order of arrangement of the different tissues, and through the more rudimentary development of the individual tissues, they may like- wise be classed with the embryomata. With reference to their lack of any structural organization approaching that of the human embryo, Wilms has designated these formations as embryoid tumors. Since the embryoma contains elements of all three germ-layers, in part in orderly arrangement, the genesis of such a tumor may be ex- plained by the assumption of a development from an ovum. Bonnet regards it as probable that either in the development of a fertilized ovum, in the early stages of division, a blastomere (or several) may be delayed in division and later give rise to an independent formation containing ele- ments of all germ-layers, or that (Marchand) a fertilized polar body (the fertilization of the polar body has been demonstrated in vertebrates) finds its way between the blastomeres of a developing ovum, and later develops within the embryo. The first assumption seems more probable, and the embryomata of the ovary may consequently be regarded as rudimentary unioval twin mat [formations (§ 128), which are to be placed iu the same category with the foetal inclusions of other organs. The fact that the ovaries (and testicles) form the favorite seats of such growths is probably dependent upon the fact that the urogenital aulage in its earliest sta°-*e forms relatively such a large part of the embryonal aulage (Bonnet), or that the blastomeres, from which the sexual glands later arise more easily than others take on an especial development, that may lead to the formation of a rudimentary twin. The teratomata of the testicle occur most frequently in forms which according to their structure are designated as adenocystoma, chondro- adenoma, chondrosarcoma, adenomyosarcoma, cystosarcoma, ci/stocarcinoma, etc. In some cases the formation of cysts with fluid contents forms TERATOID TUMORS AND CYSTS. 493 the most striking feature of the tumor (Fig. 326); in other cases cysts are found only in certain parts of the growth; and, finally, in still other cases the tumor may be solid throughout. These growths may reach the size of a child's head. They may be congenital, but de- velop more frequently in adult life, and then grow rapidly. The lining of the cysts is, as a rule, of entodermal character, but may vary in one and the same cyst (Fig. 369) . Simple cubical (Fig. 369, b) and cylindrical epithelium either with or without cilia, as well as strati- fied ciliated epithelium (d) and pigmented epithelium (e), may be found. Ectodermal tissue is present only in scanty amount, and is limited to pigmented epithelium or to scattered groups of cells showing cornifica- tion ; or it may be entirely absent, or, at all events, cannot be demon- 9 ^U/jut »*S ,'■<%'' ''•..'" .a*a»I* o a ;„( J a , <" aft U * „ •■5% >l"Q ' ','H'Tk » . ■ ■•*<■'>■■• $^&^ .!%,„* *■'.*, »- -, » ,*"'«>,, - B „ at J <** »-».e. ^I* : ■AX*. Fig 369 -Congenital adenocystoma (teratoma) of the testicle with pigmentation and formation of car- tilage (Mflller's fluid, hematoxylin) . o, Connective-tissue stroma ; ft, simple cubical epithelium ; c, strati- fied cylindrical epithelium; d, stratified ciliated cylindrical epithelium; «, pigmented epithelium lining gland-tubule ; /, pigmented connective-tissue cells ; g, cartilage in connective tissue ; ft, cartilage lying in a gland-tubule. (Section taken from tumor pictured in Fig. 320.) X 100. strated in the case of tumors of large size. Besides the cysts, mucous glands may also be found. Of the connective -tissue substances, fibrous tissue, myxomatous tis- sue, cartilage (Fig. 369, g, h), and occasionally also muscle (Fig. 370, a), fat tissue, and more rarely bone, are present. According to investigations by Schlagenhaufer, Wlassow, Eisel, and others, the teratomata of the testicle may also contain tissue-formations corresponding in their structure to the malignant chorio-epitheliomata, characterized in particular by syncytial formations. 494 TUMORS. Teratomata of the character of dermoids, containing, as in the case of the ovarian dermoids, such structures as skin, brain tissue, cranial and tracheal tissues, and more rarely teeth and structures resembling the eyes, are of rare occurrence in the testicles, but are found both in children and in adults. To what extent the different teratomata of the testicles are to be classed with the embryomata, or to what extent they can be explained Fig. 370.— Teratoma (adenomyosarcoma) of the testicle (formalin, haematoxylrn, eosin). a, Cellular tissue with bands of muscle ; h, gland-tubule. X 100. by the assumption of tissue-implanations at later stages of embryonal development, cannot at present be determined. When elements of all the germ-layers are present in the tumor, the assumption is justified that the growth belongs to the embryomata or embryoid tumors, and has arisen in the same manner as has been assumed in the case of the ovarian dermoids. The occurrence of syncytial formations speaks in favor of this assumption. The presence of single tissue-formations — as, for ex- ample, of cartilage or of muscle — in tumor-formations of a, more simple character, may be explained by the assumption that such tissues find their way into the anlage of the testicle during the period of embryonal development. The proliferations of chorio-epithelial charm-tor found within teratomata of the testicles are believed by Schlagenhaufer to depend upon the development of festal membranes, and he regards the myxomatous tissue present in such tumors as repre- senting the chorionic stroma. According; to Marrhand and Risel, they are to be regarded only as products of the festal ectoderm having the same histogenetic significance as the other ectodermal structures of the teratoma. It is yet to be determined to what extent corresponding ectodermal formations occur in teratomata of other organs. Pick found them in a teratoma of the ovary in a nine-year-old girl. Further, it is to be noted that syncytial formations occur in tumors (angiosarcoma, endothelioma) having nothing to do with foetal ectoderm. It cannot, therefore, be regarded as positively determined that the syncytial formations in teratomata of the testis actually corre- spond to a chorio-epithelioma. Wlassow believes that the chorio-epitheliomatous pro- liferations observed by him in tumorsof the testis, and designated by him as epithelioma TERATOID TUMORS AND CYSTS. 495 syncytiomatodes, are to be regarded as derivatives of incompletely developed epithelium of embryonal gland tubules. Literature. (Teratomata of the Sexual Glands.) Anspach: Teratoma strum, thyreoideale ovarii. Pathol. Soc. of Phil , vi., 1903. Arnsperg-er: Dermoidcyste des Ovariums. Virch. Arch.. 156 Bd., 1899. Bandler: Die Dermoidcysten des Ovariums, Berlin, 1900; Amer. Journ. of Obstet 1901. Baumg-arten: Dermoidcysten d. Ovariums m. augenahnlichen Bildungen. Virch Arch., 107 Bd., 1887. Bonnet: Giebt es bei Wirbelthieren Parthenogenesis? Ergebn. d. Anat.. ix.. Wies- baden. 1900; Aetiologie d. Embryonic Monatsschr. f. Gebh., 1900. Delbet: Pathogenic des tumeurs heterotopiques. L'Un. med.. 1895. v. Hansemann: Ohorionepitheliom. Z. f. Gebh., 51 Bd., 1904. Katsurada: Zur Lehre v. d. sog. Dermoidcysten d. Eicrstocks. Beitr. v. Ziegler, xxx., 1901. Kockel: Hodenteratom. Chir. Beitr. Festschr. f. B. Schmidt. Leipzig, 1896. Kolaczek: Dermoid d. Ovariums m. Bauchfellmetastaseii. Virch. Arch., 75 Bd 1879. Marchand: Teratom des Ovariums. Bresl. arztl. Zeit., 1881. Marx: Tumor (Hamangiosarkom ) der Leber. Beitr. v. Ziegler. xxx\'i., 1904. Neumann: Dermoid d. Ovariums m. centraler Nervensubstanz. Virch. Arch 104 Bd., 1886. Pick: Epithelioma chorioectodermale. Berl. klin. YVoch., 1904. Pilliet et Costes: Les epitheliomes du testicule. Rev. «le chir., 1895. Ribbert: Neuroepitheliale Bestandt- in Embryomen. Verh. d. I), oath. Ges., vi 1904. Risel: Ueber das maligne Ohorionepitheliom, Leipzig, 1903 (Lit.). Sabbe: Tumeurs dermoides de 1'ovaire. Ann. de la Soc. de med. d. Gand, 1898. Saxer: Teratom (geschwulstart. Wuch. embryon. nervos. Subst.). Beitr. v. Ziegler, xxxi., 1901. Scheiber: Solides Ovarialteratom. Virch. Arch., 133 Bd., 1S93. Schlagenhaufer : Ohorionepitheliom u. traubenmolenart. Wucherungen in Tera- tomen. Wien. klin. Woch., 1902, u. Verh, d. I), path. Ges., v., Berlin, 1903. Steinert: Embryoide Geschw. d. Keimdriisen. V. A., 174 Bd.. 1903. Tauffer: Carcinomatose Degen. v. Ovarialcysten. Virch. Arch.. 142 Bd., 1896. "Wilms: Dermoidcysten u. Teratome. Dent. Arch. f. klin. Med., 55 Bd., 1895 (Lit.); Die soliden Teratome d. Ovariums. Beitr. v. Ziegler, xix.; Die teratoiden Ge- schwiilste d. Hodens. lb., xix.. 1896 (Lit. - ); Embryomeu. embryoide Tumorend. Hodens. Deut. Zeit, f. Chir., 49 Bd., 1898; Multiple Embryome d. Ovariums. Monatsschr. f. Gebh., 1899. Wlassow: Pathogenese d. sog. Sarcome angioplastique. V. A., 169 Bd.. 1902. Yamag-iva: Dermoidcyste d. Ovariums m. krebsiger Degeneration Virch. Arch 147 Bd., 1897. See also §§ 126 and 128. §128, Teratoid cysts of a complicated structure and solid tera- tomata are found, outside of the sexual glands, in the same regions as the simple teratoid cysts, but show a particular predilection for the region of the coccyx. The complex character of the cysts is shown by the pres- ence in the cyst- wall of cartilage, bone, fat tissue, mucous glands, smooth and striped muscle fibres, nerve-tissue, and tissue of a sarcomatous or carcinomatous nature. Dermoid cysts may also contain teeth, and further also ciliated epithelial cysls. Tlie solid teratomata occur, in the first place, as hairy polypi (nose, throat, and mouth) — that is, as polypoid tu- mors covered with hairy skin, and consisting essentially of adipose tissue, which may also contain muscle fibres, cartilage, bones, teeth, ami cysts. Another group consists of those kidney -tumors which, iu addition to tubular glands, inclose sarcomatous tissue, cartilage, fibrous tissue, adipose tissue, and muscle tissue, in rare cases also ectodermal tissues. 496 TUMORS. In t lie vagina and cervix uteri of children there occur tumors, for the greater part of a racemose character, which, in addition to connective tissue, myxomatous tissue, round and spindle-celled tissue, also contain smooth and striped muscle-fibres, and in rare cases also cartilage. Fi- nally, there occur tumor-like growths of a very complicated structure in the cranium, thorax, abdomen, urinary bladder, necli, lower jaw, and espe- cially in the region of the coccyx. They contain the most varied forms of tissue: connective tissue, adipose tissue, cartilage, bone, gland tissue, muscle, nerve and brain substance, as well as ectodermal and entodermal cysts. They may further inclose rudimentary, or completely formed, or at least easily recognizable, portions of the body. Both the complex teratoid cysts and the solid teratomata are in many cases to be regarded as local disturbances of development char- acterized by a misplacement of tissue or a separation of tissues by constriction within a single individual {monogerminal tissue-implanta- tion, autochthonous teratoma). The hairy polypi of the throat, the cystic or solid teratomata at the base of the skull or in the hypophysis may be ex- plained by the assumption of a misplacement of ectodermal tissue. The presence of cartilage and mucous glands in teratoid cysts of the medias- tinum may be explained by the proximity of the trachea. The teratoid mixed tumors of the kidney may be explained by the assumption that in the kidney region, in addition to kidney-tubules and remains of the Wolffian body, products of the mesenchyma arising from the myotome may undergo proliferation. The occurrence of squamous-celled forma- tions in such tumors must depend upon the fact that ectodermal tissue has found its way into the kidney anlage. The presence of striped muscle-fibres of cartilage in tumors of the vagina and uterus is explaina- ble by X\i% assumption of an implantation of myotome or of anlage of the \ r ertebr;e (sclerotome); but many writers hold the opinion that, striped muscle may be formed from unstriped. Wilms believes that the Wolffian duct and its development give occasion to and are the cause of the im- plantations into the cervix and vagina. In the case of the teratomata of the coccygeal region the manifold character of these growths may be ex- plained by the fact that portions of the terminal vertebrae, of the pelvis, and of muscular tissue, as well as remains of the neuroenteric canal, the hind-gut, and the medullary canal, take part in the formation of the tumor. In the intracranial teratomata, as well as in the simple dermoids, tissue-implantations probably form the basis for the growth. Moreover, there exists indeed the possibility of another mode of origin for those growths— namely, the presence of a rudimentary twin, a bigeminal im- plantation. Such an assumption is well founded in all those cases in which the teratoma contains fully developed or rudimentary parts of the body, or tissue-formations which cannot be explained by the assumption of a misplacement of the tissue elements of a single foetus at the spot in question. Ekehorn regards the complex dermoids of the mediastinal, which contain skin, cartilage, bone, and the constituents of mucous mem- branes, as bigerminal implantations. Lexer emphasizes such a mode of origin for the teratoid mixed tumors of the abdominal cavity (see §§ 127, LSI, and 147). Literature. (The Complex Teratoid Oysts and Tumors.) Ahrens- Fotalinklusion im Mesocolon. Langenbecks Arch., 64 Bd., 1901. A.rno>d: Behaarte Polypen der Rachen-MundhOhle. Virch. Arch., Ill Bd., 1888, TERATOID TUMORS AND CYSTS. 497 Aschoff: Cysten. Ergebn. d. allg. Path., ii., 1897 (Lit.). Beck: Teratom d. Hypophysis cerebri. Zeitschr. f. Ileilk., 1883. Birch-Hirschfeld: Nierengeschwulste. Beitr. v. Ziegler, xxiv., 1898. Borst: Die angeb. Geschwiilste d. Sacralregion. Cbl. f. allg. Path., ix., 1898 (Lit.); Sakraltumor mit hirnart. Bau. Beitr. v. Ziegler, xxxi., 1902. Bostrom: Piale Epidermoide, Dermoide u. Liporneu. durale Dermoide. Cbl. f. allg. Path., 1897 (Lit.). Braun: Die Doppelbildungen u. die angeb. Geschwiilste d. Kreuzbeingegend, Leip- zig, 1862. Buzzi: Angeb. Geschwiilste der Sacrococeygealgegend. Virch. Arch., 109 Bd., 1887. Christian: Dermoid Cysts and Teratomata of the Ant. Mediast. Jour, of Med. Res., 1902. Dangschat: Dermoidcystem u. Teratome im Mediastinum anticum. B. v. Bruns, 3? Bd., 1903 (Lit.). Eberth : Intracranielles Teratom. Virch. Arch., 133 Bd., 1898. Ekehorn: Dermoidcysten des Mediastinums. Arch. f. klin. Chir., 56 Bd., 1898. Engelken: Embr. Drilsengeschwulst d. Nierengegend. Beitr. v. Ziegler, xxvi., 1899. Englander: Teratoma omenti majoris. Cbl. f. allg. Path., xiii., 1902. Frank: Tumor sacralis (Teratom in. Dermoid- u. Flimmercysten) Prag. med. Woch 1894. Furstenheim- Kiemengangauswucbse m. Knorpel-Gerust. Jahrb. f. Kinderheilk., 1895. Hennig: Congen. Sacraltumoren. Beitr. v. Ziegler, xxviii., 1900. Hertzog and Lewis: Embryonal Renal Adenosarcoma. Amer. Jouru. of Med. Sc. , 1900. Jastreboff: Angeb. Geschwiilste in der Gegend des Kreuzbeins. Virch. Arch., 99 Bd., 1885. Jores: Dermoidcyste mit Cystosarkom der Lunge. Virch. Arch., 133 Bd., 1893. Kirmisson: Chirurg. Krankheiten angeb. Ursprungs, Stuttgart, 1899. Kolaczek: Dermoid d. Ovariums mit Bauchfellmetastasen. Virch. Arch., 75 Bd., 1879. Koslowski: Hodensack-Teratom. Virch. Arch., 148 Bd., 1897. Lexer: Teratoide Geschwiilste d. Bauohhohle. Arch. f. klin. Chir., 61 Bd., 1900; Fotale Inclusionen in der Bauchhbhle. lb., 62 Bd., 1900. Linser: Sacralteratome. Beitr. v. Bruns, xxix., 1901. Lusena: Tumori misti della reg. sacro-coccigea. B. v. Ziegler, xxxii., 1902. Marchand: Sacraltumorem. Eulenburg'a Realeneyklop., xxv., 1899. Marwedel: Bin Fall von persistirendem Urmund (Retroanal entwickeltes Darmstlick mit sacralem After). Beitr. v. Bruns, xxix., 1901. Middeldorpf: Angeb. Geschwiilste in der Gegend des Kreuzbeins. Virch. Arch., 100 Bd., 1885. Montgomery: A Terat. of the Abdom. Cavitj'. Jour, of Exp. Med.,iii., 1898. Moussaud: Des inclusions foetales. These de Paris, 1861. Nasse: Genese der sacrococcygealcn Teratome. Laugenb. Arch., 45 Bd., 1893. Otto: TJeber einen congenit. behaartcn Racheupolypen. Virch. Arch., 115 Bd., 1889. Penzo: Teratoma sacrale. A. per le Sc. Med., xxvii., 1903. Pommer: Teratologische Mittheilungen. Cbl. f. allg. Path., i. , 1890. Ritschl: Angeb. Saoralgeschwulste. Beitr. v. Bruns, viii., 1892. Rolleston: Adeno-chondrosareoma of the Mediastinum. Jour, of Path., iv., 1896. Saxer: Teratom im III. Ventrikel. Beitr. v. Ziegler, xx., 1896 (Lit.); Dermoid d. Harnblase. lb., xxxi., 1902. Schmidt: Bezieh. d. Steissgeschwiilste zu d. Steissdriise. Virch. Arch., 102 Bd., 1888; Zwei Falle von Geschwiilsten in der Gegend des. Sehwanzbeines. Arb. a. d. chir. Universitatspoliklinik v. B. Schmidt, Leipzig, 1891. Siegehbeek van Heukelom. Turn. cong. du cou. Rev. de trav. du Lab., Boer- haave, 1899. Stolpe: Angeb. Geschw. d. Kxeuzsteissbeingegend Deut. Zeitschr. f. Chir., 50 Bd., 1899. Strassmann u. Strecker: Ein Teratom im rechten Seiten ventrikel. Virch. Arch., 108 Bd. Sutton: Dermoids or Tumors containing Skin, Hair, Teeth, etc., London, 1889. Virchow: Teratoma myomatodes mediastini. Virch. Arch., 53 Bd., 1871. Weigert: Teratom d. Zirbeldruse. Virch. Arch., 65 Bd., 1875. "Wilms: Dermoidcysten u. Teratome. Deut. Arch. f. klin. Med., 55 Bd., 1895 (Lit.): Die Mischgeschwiilsteder Niere, Leipzig, 1899; der Vagina u. der Cervix, Leipzig, 1900. See also §§ 126 and 147. 32 CHAPTER IX. Disturbances of Development and the Resulting Malformations. I. General Considerations Regarding Disturbances of Development and the Origin of flalformations. § 129. After the copulation of the sexual nuclei has taken place, the development of the embryo proceeds by a progressive division of nuclei and cells, associated with which there arise iu an orderly manner especial groupings of cell-complexes and differentiation of the same into especial tissues and organs. The multiplication of the cells, as well as the devel- opment of individual cell-groups into especial organs and parts of the body, depends upon intrinsic causes, and is controlled by the character- istics which the embryo has received through the transfer of the inherit- able paternal or maternal characteristics at the moment of the union of the sexual nuclei, which are to be regarded as the carriers of inheritable characteristics. It follows, therefore, that the characteristics of the species as well as the especial peculiarities of the given individual are in general already predetermined in the germ, and the development of the embryo proceeds essentially under the control of innate moulding forces. Nevertheless, this development is not accomplished without the influence of environment, in that the embryo of necessity receives its nourishment from the maternal organism, and at the same time is exposed to mechani- cal influences on the part of its membranes and of the uterus. These influences may therefore operate to modify the development of the foetus. In every species of animal, man included, both the bodily form and the configuration of the organs present & particular type, which experience has shown constantly to recur, and which is therefore looked upon as normal. If more or less marked departures from this type occur, which can be referred to a more or less marked abnormal course of the intra- uterine development, the condition is designated as a congenital mal- formation. When the departure from the normal structure is very marked, so that the affected individual is grossly malformed, it is spoken of as a monster. According to common usage, the term malformation is usually ap- plied only to anomalies in the form of the body as a whole, or to single parts of it which present to external inspection rather striking departures from the normal. It is nevertheless entirely correct to use this term for pathological conditions of intrauterine origin, which consist not so much in an abnormal change in form, but rather in an incomplete or faulty organization of the affected part or organ. A malformation affecting a single individual is known as a single malformation or single monster; one made up from two individuals is termed a double malformation or double monster. Malformations may owe their origin to either intrinsic or extrinsic causes. 498 CAUSES OF MALFORMATIONS. 499 As intrinsic causes may be considered all such as already exist in the germ, so that in the development of the embryo malformations may arise spontaneously without the aid of extrinsic influences. When such a malformation occurs for the first time in a family, it must be regarded as & primary germ-variation. This may be explained in one of two ways: either one or both of the sexual nuclei entering into union may have been abnormal, or both may have been normal, but from their union a variety has arisen which from one point of view is to be regarded as pathological (cf. § 17). It is also possible that disturbances in the proc- esses of fertilization can give rise to pathological variations. If a similar malfor- mation has already oc- curred in the parent, the case may be regarded as one of inheritance. If the malformation appearing is a peculiarity which was not present in the parents, but did show itself in more remote ancestors, while want- ing in the intermediate links, the phenomenon is designated as atavism. As primary germ- variations appear the same malformations which are also inherit- able — that is, only those malformations are in- heritable which origi- ally appeared as primary germ - variations. To such inheritable malfor- mations belong the in- crease in the number of the fingers and toes (polydactylism), malformations of the hands and feet, abnormal hairiness, harelip, and certain pathological conditions of the nervous system, as, for example, multiple fibromata, of the peripheral nerves. Under extrinsic causes of malformations are to be considered espe- cially concussion, pressure, disturbances in the supply of oxygen and nourish- ment, and infections. Concussions of the uterus may in all probability directly damage the embryo at a very early stage. At a later stage of development the harm- ful effects of trauma are probably more often to be sought in a tearing loose of the egg and in decidual haemorrhages, whereby the nourishment of the embryo is disturbed. It is evident that haemorrhages from other causes, also changes in and contaminations of the maternal blood, as in infections, and, further, pathological conditions of the uterus itself, Fig. 371.— Malformation of the head, due to adhesions of the mem- branes to the fronta] region (firm adherence of placenta to uterus). a, Membranous sac inclosing a vascular, spongy tissue containing numerous cysts ; 7:>, eye ; c, lip ; d, funnel-shaped depression lined with mucous membrane; e, left, e u right ala nasi: /, connective- tissue bands. Reduced one-fourth. 500 DISTURBANCES OF DEVELOPMENT. may have a harmful influence upon the developing egg ; yet all these conditions probably lead more often to the death of the foetus and the expulsion of the egg than to the development of a malformation. Infec- tious diseases of the mother may be transmitted to the foetus and give rise to their characteristic changes in the latter. An abnormal pressure from the uterus or its mem- branes may be exerted upon the embryo, especially when there is a deficient amount of amniotic fluid; and malforma- tions of the extremities (Fig. 374), iu particular, not infre- quently show evidences of press- ure having been exerted. Prom the anatomical findings in many malformations it ap- pears that pathological condi- tions of the amnion may exert a damaging influence upon the embryo and give rise to different forms of malformations. This may be brought about through abnormal adhesions be tween, the embryo and the amnion, as well as by pressure of the am- nion upon the embryonal anlage. Even at the birth of the child adhesions in the form of bands and threads (Figs. 371, /; 373) may not infrequently be dem- onstrated, and their connection with the malformed parts is such as to leave no doubt that they stand in a causal relation to the malformation. Such adhesions may give rise to severe malformations of the cerebral (Fig 371) or of the facial (Fig. 372) portions of the head. Not infrequently portions of the extremities are snared off by amniotic bands (Fig- 373), and may be completely amputated and then absorbed. To what extent these adhesions of the amnion with the foetus are to be referred to primary adherence and intergrowth, and to what extent to inflammatory processes of later occurrence, is yet a disputed question. Not infrequently the adhesions at birth are no longer visible and the affected part presents only a scar-like appearance (Fig. 372). According to Dareste and Geoff roy St.-Hilaire, an abnormal tightness of the amnion may easily exert a harmful influence upon the embryo. An abnormal closeness of the cephalic cap of the amnion may cause the malformations known asanencephalia, exencephalia, cyclopia, and cebo- cephalia or arrhincephalia (§ 134); while an abnormal tightness of the caudal cap may give rise to sirenomelia (§ 1.3S). Further, the cleft malformations of the anterior abdominal and thoracic walls (§ 136) are also associated with a faulty development of the amnion; still the latter condition is ofteu not so much the cause as it is a concomitant of the malformation, which may be the result of a variety of causes, and, in- deed, is often to be regarded as a spontaneous or primary malformation. Fig. 372.— Malformation of the face, caused by amni- otic adhesion and pressure. Asymmetry of the face, a. Malformed nose; }>, h u rudimentary lid-clefts; c, c,, clefts in the upper lip and alveolar process of the upper jaw; d, intermaxillary bone with prominent lip; e, oblique facial fissure closed by scar tissue so as to form a groove. CAUSES OF MALFORMATIONS. 501 The period at which the injurious influence is active varies greatly, and consequently so does the extent of the damage done by it. The earlier the damage occurs, the greater the extent of the injury. Mal- formations in the narrower sense of the term arise chiefly during the first three months, during the period when the body and its individual parts are developing their proper forms. Damage to the foetus at a later period occasions changes which are more closely allied to those acquired after birth. Some malformations are typical — that is, they always appear in the same form ; while others again are wholly atypical, so that the most astonishing anomalies of form may arise. The latter are for the greater part the result of extrinsic harmful influences operating secondarily, while the former may be regarded as owing their origin chiefly to in- trinsic causes, although external influences may also cause typical mal- formations. Qeoffroy St.-Ililavre ("Hist. gen. et partic. des anomalies de l'organization chez l'homme et les animaux," Paris, 1832-37) discards entirely the teaching of a primary abnormality of the germ (Hatter and Winslow), and attributes arrests of development purely to mechanical influences. Panum (" Untersuch. fiber die Entstehung der Miss- bildungen," Berlin, 1860) agrees with him on the whole, although he admits the possi- bility of a primary abnormality. He produced malformations in hens' eggs by means of temperature variations and by varnishing the shells. Dareste ("Recherches sur la Fig. 373. FIG. 374. Fig. 373. -Hand stunted by amniotic adhesions ; ring-nnger snared off ; middle and index Angers grown together and distorted. Reduced one-sixth. Fig. 374.— Hand stunted and deformed by pressure ; thumb absent ; hand flattened ; great bending and shortening of the forearm. Reduced one-fifth. production artificielle des monstruosites," Paris, 1877) made similar experiments and produced malformations due to arrested development by keeping the eggs in a vertical position, by varnishing the shells, by raising the temperature above 45° C., and also by irregular warming of the eggs. Very recently L. Oerlttch, Fol, Waryimky, Bidder, Eoux, and Schultze have in par- ticular carried on experiments in this line, and have attempted, with partial success, to 502 DISTURBANCES OF DEVELOPMENT. produce malformations in chicken-embryos through the localized 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. Boux, experimenting on frogs' eggs, found that, after destruction of one of the first segmentation-spheres, the other continued to develop and formed the half of an embryo, thus demonstrating that each of the first two segmentation-cells, corresponding in (heir position to the right and left body -halves, contains within itself the anlage material for the corresponding half of the body. But since the body -half which is wanting may later be replaced by subsequent development from the und'estroyed half, and a whole structure be produced, each half must also possess the power of producing also the other half. According to investigations by IlerUtzkn, Brieseh, Morgan, Wilson, and others, the first two or even the first four segmentation-cells in tritons, teleosts, ascidians, and echinoderms possess the power of forming an entire embryo. Sohultze experimented on the eggs of amphibia; these normally always assunie such a position that the darkly pigmented protoplasmic substance of lighter specific gravity lies above, the heavier clear protoplasm rich in yolk granules lies below. By placing the eggs in an abnormal position and preventing their return to the normal position malformations may lie produced, the degree of malformation standing in direct relation to the size of the angle formed by the line of gravity and the abnormally- placed axis of the egg. By turning the egg through an angle of 180° in the two-cell stage a double monster is regularly produced. The same turning in the eight-cell stage causes a complete cessation of development. These disturbances arise from dis- placements consequent upon the sinking of the heavier and a rising of the lighter con- stituents of the egg. According to investigations by 0. Ilertwig, the eggs of axolotl, when kept in a 0.7- per-cent. solution of sodium chloride, undergo a .pathological development, which is confined to the central nervous system in the region of the head and trunk. If frogs> eggs are left before fertilization for one to four days in the uterus of the dead female and are then fertilized, there are formed, besides normal embryos, -various malformations due to defective development, for example, spina bifida. Recent studies have shown that monsters and malformations may be produced by Roentgen irradiation of fertilized ova or (if either ova or spermatozoa before fertiliza- tion. Giliinin and Baetjer found that the eggs of amblystoma developed abnormally under Roentgen irradiation, the embryos showing no mouths. Chicks developed in exposed eggs presented malformations of the occipital region and extremities and in the distribution of the feathers. Bartleen found that in frogs injury to the spermatozoa by Roentgen rays caused the development of monsters from eggs fertilized by such damaged spermatozoa. Literature. (Malformations ami Their Origin.) Ahlfeld: Berichte und Arbeiten aus der geburtshillfl. Klinik zu Marburg, 1SS.5-S6; Die Missbildungen des Menschen, Leipzig, 1880, 1882. Ballantyne: The Diseases and Deformities of the Fcetus, i. and ii., Edinb., 1893, 1895. Barfurth.: Leber organ bildende Keimbezirke u. kilnstliche Missbildungen d. Amphi- bieneies. Anat. Hefte, Wiesbaden, 1893; Regeneration bei Embryonen. Handb. d. Entwickelungsl., iii., 1903. Braun, C. : None Beitr. z. Lehre v. d. amniotischenBandern, Wien, 1862. Charrin et Gley: L'influence teratogene des prod, microbiens. Areh.de phys., 1896. Dareste: Rech. sur la production artif. des monstruosites, ii. cd., Paris, 1891. Davaine: Monstre, Monstruosite. Dictionu. encyclop., abgedr. in L'ceuvre de Da- vaine, Paris, 1889. Delage: Structure du protoplnsma et les theories de l'heredite, Paris, 1895. Driesch: Entwickelungsmeehau. Studien. Zcitschr. f. wiss. Zool. , 53, 55 Bd 1891 1892; Anat. Anz., vii., 1892. Duval: Teratogenic. Path. gen. publ. p. Bouchard, i., Paris, 1S9.5. Endres: Entwickelungsmechanik. Eulenburg's Jahrb., vii., 1897. Endres u. Walter: Anstichversuche an Eiern von Rana. Arch. f. Entwickelungs- mech., ii., 1895. Fischel: Gegenwart. Stand der ex perimentellen Teratologie. Verb. d. I) path Ges v., 1902 (Lit,). Folet Warynsky: Rech. exp. sur la cause de quelques monstruosites. Recueil zool Suisse, i., 1883. Forster: Die Missbildungen des Menschen, Jena, 1865. Foster: Z. Kenntniss d. Ilcmmungsmissbilduug d. tint, Korperhalftc. I.-D Frei- burg, 1903. CLASSIFICATION OF MALFORMATIONS. 503 Gerlach. Production v. Zwergbildungen im 'Hilhnerei. Biol. Cbl., ii., 1883; Neue Mcthodcn auf dem Qebiete der experinientellen Embryologie. Ib.,vii., 1889; Anat. Anz., 1887. Giaccomim: Anomalies de developp. de l'embryon humain. Arch. ital. deBiol., ix., 1888; xviii. and xix., 1892; xx., 1893; xxiv., 1895; Influence de 1'air rarefie. lb., xxii., 1894. Guinard: Precis de teratologic, Paris, 1893. Gurlt: Literatur liber Missgeburten. Virch. Arch., 74 Bd., 1878. Hertwig: Missbildungen u. Mehrfachbildungen, welche durch Storung des ersten Entwickehingsprocesses hervorgerufen werden. Handb, d. Entwickelungslekre, I, Jena, 1903. Hirst and Piersol: Human Monstrosities, Philadelphia, 1891. His: Ueber mechanische Grundvorgange thierischer Formbildung. Arch. f. Anat., 1894. Israel; Angeb. Spalten d. Ohrliippchens, ein. Beitr. z. Vererbungslehre. Virch. Arch., 119 Bd., 1891. Kirmisson: Chir. Krankheiten angeb. Ursprungs, Stuttgart, 1899. Kollmann- Die Korperform menschl. normaler u. pathol. Embryonen. Arch. f. An., 1889. Kiistner: Ueber eine noch nicht bekannte Entwickelungsursaehe amputirender amuiotischer Faden. Zeitschr. f. Geb., xx., 1891; Die Pathologie des Fotus, Stuttgart, 1888. Lannalongue et Menard: Affections congenitales. I. Tete et cou, Paris, 1891. March.and: Missbildungen. Eulenburg's Realencyklop., xv., 1897 (Lit.). Mitrophanow : Teratogenet. Studien. Arch. f. Entwickelungsmech., i., 1895. Morian: Die schrage Gesichtsspalte. Arch. f. klin. Chir., 1887. Moser: Missbild. durch amniotische Bander. Prag. med. Woch., 1894. Otto: Monstrorum sexcentorum descriptio anatomica, 1844. Panurn: Zur Kenntniss d. physiol. Bedeutung d. angeb. Missbildungen. Virch Arch., 72 Bd., 1878. Piersol: Teratology. Ref. Handbook of Med. Sc, 2d ed., 1903. Richter: Ueber die experimentelle Darstellung der Spina bifida. Anat. Anz., iii., 1888. Eoux: Zur Entwickelungsmechanik des Embryo. Zeitschr. f. Biol., xxi., 1886; Iviinstliche Hervorbringung halber Embryonen durch Entfernung einer der beiden ersten Furchungskugeln, u. Wachsthumsentwickelung der fehlenden Korperhiilfte. Virch. Arch., 114 Bd., 1888; Die Entwickelungsmechanik der Organismen, Wien, 1890; Ueb. das entwickelungsmeckanische Vermogen jeder der beiden ersten Furchungszellen des Eies. Verb. d. Anat. Ges., vi., 1892; Ueber die Specification der Furchungszellen und fiber die bei der Postgeneration und Regeneration anzunehmenden Vorgiinge. Biol. Cbl., xiii., 1893; Die Methoden zur Erzeugung halber Froschembryonen. Anat. Anz., ix., 1894; Einleitung zum Archiv filr Entwickelunsgmechanik der Organismen. Arch. f. Entwickelungsmechanik, i., 1894. Schultze: Die Bedeutung der Schwerkraft filr die organische Gestaltung, sowie fiber die mit Hulfe der Schwerkraft mogliche kilnstliche Erzeugung von Doppelmiss- bildungen. Verh. d. Phys.-med. Ges., 28 Bd., 1894; Entwickelungsgeschichte, Leipzig, 1896. Taruffi: Storia della teratologia, i.-viii., Bologna, 1881-96; Sull' ordinamento della teratologia. R. Accad. delle Sc. dell' 1st. di Bologna. 1896, 1898. Virchow: Descendenz u. Pathologie. Virch. Arch., 103 Bd., 1886. Wiedersheim : Der Bau des Menschen, Freiburg, 1893. Ziegler: Kijnnen erworbene patholog. Eigenschaften vererbt werden u. wie entstehen erbliche Krankheiten u. Missbildungen. Beitr. z. pathol. Anat., i., 1886; Die neuesten Arb. fiber Vererbung u. Abstammungslehre, u. ihre Bedeutung fur die Pathologie. lb., iv., 1889. Ziegler, K.: Zur Postgenerationsfrage. T. D., Freiburg, 1901. For literature of Malformations, see Anat. Anz., i.-xxvii., 1886-1907; and Cbl. f . allg. Path., i-xviii., 1890-1907. 8 1.30. Single malformations may be conveniently divided into five groups, according to the kind of change which characterizes them. As arrests of development or monsters due to defective develop- ment (monstra per defectum) may be classed in the first place all those malformations in which the whole or a part of the body is abnormally •504 DISTURBANCES OF DEVELOPMENT. small and imperfectly developed (hypoplasia), and also those malforma- tions characterized by the complete absence or very great stunting (agenesia or aplasia) of individual organs or parts of the body. If, in the case of parts or organs of the body which are normally formed by the union of anlage which are originally separated, such union should fail to take place as the result of a primary or secondary disturbance of growth, the arrest of development may show itself in the form of clefts and reduplications. Thus, for example, imperfect develop- ment of the plates forming the anterior body- wall gives rise to clefts in the median line of the thorax and abdomen ; a failure of union of the maxillary processes of the first branchial arch with each other or with the nasal process of the frontal bone gives rise to clefts in the face. Defective union of the bilateral portions of the female genital tract results in a more or less extensive reduplication of the uterus or vagina. When the anlage of two organs lie near to each other, these may under certain conditions become united so as to produce a coalescence or adhesion between two organs or parts which should normally T be sepa- rated. For example, the kidneys at times may be more or less united, and the eyes may be more or less completely merged into a single organ. flalformations due to excessive growth (monstra per excessum) are characterized in part by abnormal size of individual parts, and in part by an increase in number of the same. For example, an extremity or a portion of one, as a finger, may reach an abnormal size (partial giant growth), or the whole body may be involved in the abnormal growth (general giant growth). An increase in number occurs particularly in the case of the mammary gland, spleen, adrenals, and fingers. Additional glandular organs are designated accessory or supernumerary organs. As malformations due to an abnormal disposition of organs (mon- stra per fabricam alienam) are designated by Foister certain anomalies of the internal organs of the thorax and abdomen, which are character- ized by an abnormal position of the organs, and in part also by changes in the relation of individual parts to each other. In this class belongs the condition known as situs transversus — that is, the transposition of the thoracic or abdominal organs, or of both. Further, various defects in the heart and great vessels may also be classed here, though it should be noted that these are more properly regarded as arrests of development. A fourth group of malformations includes those characterized by displacement of tissues and by the persistence of foetal formations, as already mentioned in gS 126 and 128. Finally, as a fifth group may be classed those malformations ex- hibiting a mixture of the sexual characteristics, known as true and false hermaphroditism. True hermaphrodites possess both male and female sexual glands; false hermaphrodites are unisexual, but the remainder of the sexual apparatus does not correspond to the sexual gland, or there is a simultaneous formation of organs belonging to both the male and female. A part of these malformations are arrests of development; others are to be regarded as cases in which from the original bisexual anlage the organs of both sexes have developed, whereas normally the anlage of one sex undergo a retrograde change instead of developing and persist only in a rudimentary form. § 131. Double monsters (monstra duplicia) are malformations con- sisting of two individuals; if both twins are developed (symmetrical twins) they are always of the same sex and are united to each other in the same portions of the body; the duplicated portions are usually equally developed (equal), but unequal. forms also occur in which one twin CLASSIFICATION OF MALFORMATIONS. 505 is stunted in its development. Asymmetrical forms also occur in which one twin remains wholly rudimentary and is dependent upon the other for its nutrition ( parasitic double monster). Often it is implanted in the other or included within it (see § 127). All double monsters arise from one egg and have a common chorion. In the formation of symmetrical double monsters two separate embryonal an- lage are probably formed from one germinal vesicle, and these in their growth blend with each other to a greater or less extent, but a duplica- tion or a splitting may also occur within a single anlage, and this process occurs particularly 'in the anterior reduplications which can also be pro- duced experimentally in animals. The genesis of the rudimentary asym- metrical twins occurs chiefly in the manner described in § 127 (Teratomata). The causes of a duplication of the, embryonal anlage in a single germinal vesicle are not known. According to Fol, double and multiple monsters arise through the abnormal impregnation of an ovum with two, three, or more spermatozoa; but other observa- tions (Born) indicate that ova fertilized by two or more spermatozoa do not develop. According to Marchand, the doubling of the anlage is to be referred to conditions exist- ing before the beginning of segmentation, either to conditions within the egg before fer- tilization, or to the fertilization itself. Wiedemann and Wetzel hold the opinion that the origin of double monsters dates from the moment of impregnation, and is due to the fertilization of ova containing two germinal vesicles by two spermatozoa. Qerlach produced double monsters (anterior duplication) from hens' eggs by varnish- ing these before incubating, leaving free only a Y-shaped spot in the region of the prim- itive streak. Inasmuch as he only rarely succeeded in obtaining such results, it is pos- sible that these malformations, which not infrequently occur in chickens, were acci- dental. Sehultze obtained double monsters by turning frogs' eggs during the two-cell stage through an angle of 180° (cf. § 129). Spemann was able to produce double- headed embryos of tritons hy constriction of the embryonal anlage before the closure of the medullary plate to form the medullary groove ; also by a median constric- tion in the two-celled- and blastula-stage. Born succeeded in uniting together portions of the larva? of amphibia, not only of the same kind, but also of different species, genera, and families (Eaua escnleuta with Bombinator igneus, and with Triton). The conditions were most favorable for union in the case of larva: of about 3 mm. length. Not only the external coverings of the body, but also the anlage of organs (liver, intestine, heart-tube), were blended into a united organ, the union being completed through specific tissue of the same kind. From all these experiments the conclusion may be drawn that double monsters may be produced from a normal egg through secondary influences, and that neighboring embryonal anlage may grow one into the other. On the other hand lies the possibility that especial conditions within the egg before fertilization may be the cause of the duplication. xVccording to Sehultze, this may possibly lie in the presence of two nuclei or of two spindles, or in an over-ripe condition of the egg with a tendency to fragmentation into two halves, which divide shortly before fertilization. Therefore a normally fertilized ovum in the two-cell stage may be brought through some influence (as in the experiment of Sehultze) to the formation of two individuals. Literature. (Double Monsters. ) Ahlfeld: Die Missbildungen des Menschen, Leipzig, 1880, 1882. Born: Furchungen des Eies bei Doppelbildungen. Breslauer arztliche Zeitschr., 1887; Leber Doppelbildungen beim Frosch. lb., 1882; Leber Verwachsungsversuche mit Amphibienlarven, Leipzig, 1897, ref, Deut, mcd. Woch., 1898, S. 126. Dareste: Product, des monstruosites. Compt. rend. Ac. des sc, 1861, 1863, 1864, 1805, 1866. Debierre: La theorie de la monstruosite double. Arch, de phys., ii., 1890. Debierre et Dutilleul: Monstres doubles du genre synote. Arch, de plus., ii., 1890. Fol: Hecherches sur la fecondation, etc., 1879. Fbrster: Die Missbildungen des Menschen, Jena, 1865. Geoffroy Saint-Hilaire : Hist. gen. et partic. des anomalies de l'organisat. chez l'homme et les animaux, Paris, 1832-37. Gerlach, L. : Leber die Entstehungsweise der vorderen Verdoppelung. Deut. Arch., 506 DISTURBANCES OF DEVELOPMENT. f. klin. Med., 42 Bd. ; Die Entstehungsweise der Doppelmissbildungen, Stuttgart, 1883. Gschier: Thoracopagus tetrabrachius aequalis. Prag. med. "Woch., 1892. Klaussner: Mehrfachbildungen bei Wirbelthieren, Miinehen, 1890. Kormann: Ueber lebende Doppelmissbildungen der Neuzeit. Schmidt's Jahrb., cxliii, 1869. Lochte: Ein Fall von Doppelmissbildungen. Beitr. v. Ziegler, xvi., 1894. Marchand: Missbildungen. Eulenburg's Realeneyklop., xv., 1897. Myschkin: Zwillingsschwangersckaft u. angeb. Missbildungen. Virch. Arch., 108 Bd,, 1887. Pamim: Untersuchungen fiber die Entstehung der Missbildungen, Berlin, I860; Zur Kenntniss d. phys. Bedeutung d. Missbildungen. Virch. Arch., 72 Bd., 1878. Rauber. Die Theorie der excessiven Monstra. Virch. Arch., 71, 73, 74 Bd., 1877-78. Schafer: Ueber einen Dicephalus. Beitr. v. Ziegler, xxvii., 1900. Schultze, 0.: Ueber die Bedeutung der Sehwerkraft, etc. Verb., der phys. -med. Gesellsch., 28 Bd., 1864; Arch. f. Entwickelungsmech., i., 1894; Entwickelung d. Doppelbildungen. Cbl. f. allg. Path., x., 1899. Sobotta: Neue Anschauungen tlber Entstehung von Doppelbildungen, Wlirzburg, 1901. Spermana: Exper. Erzeug. zweikopfiger Embryonen. Sitzber. d. phys. -med. Ges., 1900; Entwickelungsphysik. Stud, an Tritonen. A. f. Entwickelungsmech., xv., 1902 u. xvi , 1903, u. Zool. Jahrb. vii., 1904. Wetzel: Drei aboorm gebildete Eier. Anat. Auz., xviii., 1900. Wiedemann: Entstehung d. Doppelbildungen. Virch. Arch., 138 Bd. , 1894 (Lit.). See also § 1 29. II. The Different Forms of Malformations in Man. I. Arrests of Development in a Single Individual. (a) Arrest of the Development of the Entire Embryonal Anlage. § 132. An arrest in the development of the entire embryonal anlage manifests itself in two ways. If the disturbance is very marked, a fur= ther development of the embryo is impossible, and it either dies at once or becomes stunted, and after a certain time perishes. If the disturbance is less severe there develops a normally formed foetus, but it remains small and stunted — that is, a dwarf is formed (nanosomia or micro- somia). A dead foetus is in the majority of cases expelled together with its membranes (abortion). In other cases in which the embryo for some cause or other remains stationary in development, the egg may remain for weeks or even months in the uterus and increase in size, so that there arises a disproportion between the size of the embryo and of the egg. According to His, the first changes after death are shown in a marked swelling of the central nervous organs, leading to changes in the con- figuration of the head. Later there, occurs an infiltration of the tissues with wandering cells, the boundaries of the organs become indistinct, the entire embryo becomes cloudy and soft, the superficial structure indistinct, and the embryo finally becomes completely dissolved. Ac- cording to Berlet and Engel, the wandering cells infiltrating the tissue arise in the embryo itself, and indeed from its own blood. When a foetus well advanced in development dies and remains within the maternal organism there may result the formation of a lithopa;dion. This occurs most frequently in the abnormal situation of the ovum known as extrauterine pregnancy, in which the embryo lies in the peritoneal cavity, in a tube, or in an ovary. If the foetus dies at such an advanced stage of development that it cannot be absorbed, it may be carried within the maternal organism for years. Not infrequently its form is perfectly LITHOP.EDION. 507 preserved (Fig. 375), and the whole foetus becomes inclosed in a connec- tive-tissue membrane. In other cases the foetus, iu the course of time, becomes converted into a partially fluid mass, which contains the osseous remains, as well as fat, cholesterin, and pigment, and is surrounded by a fibrous capsule. Lime-salts are usually deposited both in the newly formed membranes as well as in the portions of the foetus remaining, and for this reason the foetus is known m a "stone-child" or "petrified child." Fig. 375. — Lithoptedion, entirely inclosed in connective-tissue membranes (removed from abdominal cavity by operation two years after beginning of pregnancy). Extrauterine pregnancy caused by embryo breaking through the uterine portion of a tube into the abdominal cavity. Reduced to one-third." According to the condition of the foetus there may be distinguished three chief forms of lithopaedion (Kuchennieister). In the first the mummified foetus may be easily shelled out from the calcified membranes (Utlioceli/phos'j. In the second form the foetus becomes adherent to the membranes at various points which become calcified, while the other portions become mummified (lithocelyphopcedion). In the third form the foetus is discharged, through the rupture of the membranes, into the peritoneal cavity, and later becomes encrusted with lime-salts (lithopwdion in the narrower sense). The long retention of a ripe or even older fatus within the uterus (missed labor) is rare, but may occur (1) iu an accessory horn of the uterus, (2) iu interstitial pregnancy, (3) after rupture of the uterus. 508 DISTURBANCES OF DEVELOPMENT. Literature. (Disturbances of Development of the Embryo. Lithopcedion. ) Bandl: Die Extrauterinschwangerschaf t. * Handb. d. Frauenkrankbeiten, ii., Stuttgart, 1886. Ebertb: Myxom des Chorion. Virch. Arch., 39 Bd„ 1867. Engel: Riickbildungsvorgange an abortiven Embryonen. Beitr. v. Zicgler, xxviii., 1900. Giaccoruini . Entwickelungsanomal. d. menschl. Embryo. Ergebn. d. Anat., iv., 1894, and loc. cit § 130. His: Pragen d. path. Embryologie. Internal. Beitr. Festschr. f. Virchow, i., 1891. Kleirrwacbter : Missed Labor. Eulenburg's Realencyklop., v., 1895 (Lit.). Kroemer: Zur Kenntn. der Lithopadien. Munch, med. Woch., 1900. Kiicbenmeister : Ueber Lithopftdion. Arch. f. Gyn., xviii,, 1881. Mall: Pathology of Early Human Embryos. Johns Hopkins Hosp. Rep , ix., 1900. Marcband: Bau der Blasenmole. Zeit. f. Gcbh., 38 Bd., 1895 (Lit.). Martin- Extrauterinschwangerschaf t. Eulenb. Realencyklop., 1895 (Lit.). Muller, H. : Ueber den Bau der Molen, Wurzburg, 1847. Vircbow: Die krankh. Gescbwiilste, i., 1863. Wallenstein : Beitr. z. patbol. Embryologie. Inaug.-Diss. , Freiburg, 1897. (b) Defective Closure of the Cerebrospinal Canal and the Accompanying Malformations of the Nervous System. § 133. Defective closure of the vertebral canal leads to the mal- formations known as rachischisis or spina bifida. If the defect in the vertebral column is open so that at the bottom of the cleft the bodies of the vertebrae covered by membrane are seen, the malformation is ordi- narily termed rachischisis. When, at the site of the defect, there is seen a protruding sac, the malformation is usually designated spina bifida, or more correctly spina bifida cystica ; though to this formation the names rachischisis cystica or hydrorachis cystica may also be applied. In rachischisis totalis (holorachischisis) (Fig. 376) the bodies of the vertebrae form a shallow groove opening posteriorly, and usually covered by a thin, transparent membrane ; in rare cases rudiments of the spinal cord are still present in the form of whitish bands and lines. In this manner there occurs a total or partial amyelia. The defect involves principally the motor tracts and centres, as well as the columns of Clarke and the lateral cerebellar tract, while the spinal ganglia are devel- oped (Manz, Leonowa, K. and CI. Petren), and may send sensory fibres into the membranous masses of the spinal groove. The delicate membrane which lines the furrow and covers the dura mater lying beneath it upon the bones is the ventral portion of the spinal pia mater. A part of the nerve-roots may have undergone devel- opment, arising either from rudiments of the spinal cord or from spinal ganglia. Partial rachischisis (merorachisehisis) involves usually the sacrolum- bar or the upper cervical region, while the intervening portions of the vertebral column are only rarely the seat of malformations. The dorsal surfaces, with the overlying dura and pia mater, of the bodies of the vertebra? whose arches remain rudimentary are covered for the greater part by a mass of velvety vascular tissue, which contains rudiments of the spinal cord (the area medullo-vasculosa, von Recklinghausen), though the amount of this tissue may be very small or may even be wholly want- ing. To the outside of this tissue layer, which is not everywhere equally abundant and which diminishes at the sides, there comes next a delicate, transparent, vascular membrane which represents the continuation of SPINA BIFIDA. 509 the pia mater covered with epithelium (zona epithelio- serosa) ; and next, outside of this, a zone of epidermoidal tissue somewhat thinner than normal skin, and often covered with many hairs (zona dermatica), sepa- rating the reddened central area from the normal skin. Fir.. 37t> — Craniorachischisis with total absence of the brain and spinal cord. The base skull is cov ered with ragged membranous masses, the open spinal furrow with a delicate membrane (pia mater). Kypholordotic curvature and shortening of the spinal column. Reduced one-sixth. Spina bifida cystica or rachicele (raehischisis cystica) occurs iu three chief forms: myelomeningocele, meningocele, and myelocystocele. Accord- ing to its site there may be further distinguished a cervical, dorsal, lum- bar, lumbosacral, and a sacral spina bifida. In general, a spina bifida is characterized by the development of a fluctuating tumor, which is in most cases visible externally (Fig. 377) on the posterior aspect of the Fig. 377.— Spina bifida sacralis. (After Froriep and Forster.) Girl of nineteen years, born with a tumor the size of a pigeon's egg over the upper sacral and lower lumbar regions, which enlarged from the sixth year on, while at the same time club-feet developed. spinal column (spina bifida posterior) ; but instances also occur in which the sac projects anteriorly from the spinal canal (spina bifida anterior), and others in which it is so small that it is covered with normal skin and is not visible externally (spina bifida occulta). Myelomeningocele appears most frequently as a spina bifida lumbo- 510 DISTURBANCES OF DEVELOPMENT. sacralis, and usually forms a tumor varying in size from that of a nut to that of an apple and increasing in size after birth, in the region of the lower lumbar and upper sacral vertebrae. It is covered either by smooth or scar dike skin, or may be devoid of skin on its summit and there cov- ered by a reddish, mucosadike tissue (area medullovasculosa). The portion uncovered by skin may be drawn in, like a scar. In rare cases there may be no external tumor (spina bifida occulta), the site of the cleft being indicated only by a more marked growth of hair or by a depression. On opening the sac, which is composed of the arachnoid (Fig. 378, e) and the pia (/, /,), while the dura (g) does not extend over the dorsal portion of the sac, it may be seen that the lower end of the spinal cord (bj is drawn outward, and that the cavity of the sac is crossed by nerve- roots (i, ij. Occasional nerve-roots (h) may also spring from the columns of the cord (6J in its course through the sac. According to these findings there is, therefore, an accumulation of fluid in the meninges, a hydromeningocele (hydrorachis externa circum- scripta), which is combined with a pro- lapse of the spinal cord, a myelocele. At the site of the protrusion the vertebral arches are defective, and this defect may reach as far as the hiatus sacralis. Smaller defects may involve only one or two vertebrae. Dorsal and cervical meningoceles are much more rare than the lumbosacral. The defect in the vertebral arch is usu- ally confined to one or two vertebrae. The spinal cord is here involved in the meningocele, in so far that portions of it are drawn outward in the form of a band or cone. Hydromeningocele spinalis arises from a hernial protrusion of spinal arach- noid due to a localized collection of fluid iu the subarachnoidal space. It may oc- cur in the first place at the upper end of the spinal column in the case of a cleft of the upper cervical vertebra?, at the same time with hernia of the brain in the oc- cipital region. More frequently, how- ever, it occurs in the sacral region, where the hernial protrusion takes place either through a defect in the vertebral arches and bodies or through the hiatus sacralis, or between vertebral arches or through intervertebral foramina. In the majority of cases the dura takes no part in the formation of the sac, but views differ upon this point, and by many writers (Hildebrand) a dural sac is described. Through a progressive accumulation of fluid the sac may attain a very large size. Small meningoceles may be concealed in the deep tissues. According to the direction of the hernial protrusion there may be distinguished a meningocele posterior and a meningocele anterior, the latter taking place through a defect in the bodies of the vertebras (rachischisis anterior). Fig. 378.— Myelomeningocele sacralis in sagittal section, a little Ui tbe left of the median line. (After von Recklinghausen.) o. skin; 6, B„ spinal cord; c, area me- dullovasculosa; d, cranial, d,, caudal polar groove ; e, arachnoid ; /, pia, some- what separated from the arachnoid; f u portion of pia mater turned over ; g, dura mater; h, recurrent roots of the fourth lumbar nerve ; i, radix anterior ; i,, radix posterior of the fifth lumbar nerve, run- ning free through the arachnoidal sac ; h, sacral nerve-roots between the arachnoid aud pia ; I, fllum terminale. myelocystocele or hydromyelocele (syringomyelocele) takes its ori gin RACHISCHISIS. 511 in a dilatation of the central canal of the spinal cord, as a result of which a larger or smaller portion of the cord with its connective-tissue envelopes becomes converted into a cystic tumor. The dura is usually wanting over that portion of the sac protruding from the vertebrae. According to von Eecklinghausen, the wall of these sacs is formed essentially of the inner spinal meninges, but is lined on the interior by a cylindrical epithelium, and has at some part of its inner surface an area medullovasculosa — usually on the ventral side, rarely on the dorsal. Corresponding to this condition the roots, in case they are still pre- served, spring mostly from the ventral, rarely from the dorsal outer wall of the sac. The cavity itself is crossed neither by bands nor by nerves. Myelocystoceles occur, in the majority of cases, iu lateral clefts of the vertebral column. They show a tendency to be combined with defects and asymmetries of the bodies of the vertebrae, and thereby often with shortenings of the trunk, which at times affect only the dorsal region, at other times also the lumbar region. Very frequently there exists at the same time an exstrophy of the abdomen, bladder, and intestine. Myelocystoceles are mostly covered only by the outer skin, but are sometimes concealed deep down in the soft parts. They may further be combined with a meningocele, so that a myelocystomeningocele arises. In cases of rachischisis there sometimes occurs a division of the spinal cord into two parts (diastematomyelia), most often in the case of a total rachischisis, in which indeed the rudiments of the spinal cord are usually only indicated. In partial rachischisis such division is more rare, but the separated strands of spinal cord are better developed, and the fibrous and bony coverings may, at the beginning or end of the cleft, send dividing septa between them. Cases have occurred in which each cord-half possessed an H -shaped area of gray matter. In the earliest embryonic period the medullary groove is formed by the develop- ment on both sides of the median line of wall-like elevations of the ectoderm which are designated as the medullary folds. Through the converging growth and union of the latter the medullary groove is closed and formed into the medullary canal. Thereupon the cell-masses (primitive vertebral plates) lying at the sides of the newly formed canal form an envelope about it, which gives rise in the first place to a membranous, non- articulated vertebral column. Iu this, at the beginning of the second month, there arise discrete cartilaginous areas from which, in the course of further development, the vertebral bodies and arches are formed, while between them the intervertebral discs and vertebral ligaments appear. The development of the cartilaginous vertebra is not completed until the fourth month, and up to this time the dorsal covering of the med- ullary tube consists of the united portions of the membranous vertebral column. The cartilaginous constituents of the vertebrsu are in the course of development replaced by bone. The origin of rachischisis is to be referred to agenesia and hypoplasia of the medullary folds, which should form the medullary groove of the vertebral arches. The agenesia of the spinal cord is also to be dated from the very earliest period. Whether it is a primary agenesia predetermined in the germ, or whether extrinsic in- jurious influences, perhaps toxic substances (Sertwig), pressure from without, or the inclosure of total membranes, may have secondarily checked development or have de- stroyed parts already formed, it is usually difficult to determine; but the symmetrical distribution of the arrested development speaks in favor of the former view. In cases of spina bifida with hernial protrusion, the local defects in the bony vertebral column and the defective development of the dura mater, which is usually wanting at the site of the protrusion, are to be regarded as the primary condition. The growth of the sac may be explained as due to congestive and inflammatory transudation, and the residue of inflammatory changes, such as thickenings and membranous adhesions, may often be demonstrated in the pia. Von Eecklinghausen refers the origin of myelocystocele and myelocystomeningo- cele to a deficient growth in the long axis of the vertebral column, characterized ana- tomically by shortness of the column, absence of vertebra? or parts of vertebrae, separation of wedge-shaped bony pieces from the bodies of the vertebra?, and by uni- lateral defects in the arches. The neural canal, then, in the course of normal develop- 512 DISTURBANCES OF DEVELOPMENT. ment, becomes too long for the vertebral canal, and in consequence becomes curled or kinked, and there is a tendency to a partial protrusion of the medullary tube at the point of sharpest bending. Marchand believes that this hypothesis is not applicable to all cases, and Arnold is also of the opinion that the causal relations between arrests ot development in the muscle-plates and vertebral anlage on the one hand, and those ot the medullary canal on the other, are not constant, but that a variety of harmful influ- ences may give rise to one or more of these anomalies. Lucksch emphasizes particu- lary the effects of pressure as the cause of myeloschisis, but without excluding other causes. According to 0. Ilertwig, the ordinary spina bifida is an arrest of development depending upon a partially prevented closure of the blastopore ("Urmundspalte ")• Literature. (Malformations of the Spinal Cord and Vertebral Column.) D'Ajutolo: Contrib. alio studio delle varieta numeriche delle vertebre, II., Morgagni, xxx., 1888. Albrecht, P.: Defect der drei letzten Sacral- u. sammtl. Steisswirbel. Cbl. f. Chir., 1885. Arnold: Myelocyste, Transposition von Gewebskeimen u. Sympodie. Beitr. v. Ziegler, xvi., 1894. Beneke: Diastematomyelie mit Spina bifida. Beitr. z. path. An., Festschr. f. Wagner, (Leipzig, 1887. Bohnstedt: Spina bifida occulta. Virch. Arch., 140 Bd., 1895. Borst: Geschwulste d. Sacralregion. Cbl. f. allg. Path., ix., 1898 (Lit.) Braune: Die Doppelbildungen u. d. angeb. Geschwulste. d. Kreuzbeingegend. , Leipzig, 1862. Brunner: Spina bifida occulta mit Hypertrichosis. Virch. Arch., 129 Bd., 1892. Curtius: Spina bifida. Langenbeck's Arch., 47 Bd., 1894. Denime: Bericht liber, d. Thiitigk. d. Kinderspitals, Bern, 1883; Wien. med. Blatter, 1884. Fischer u. Marchand: Ueber d. lumbodorsale Rachischisis mit Knickung d. Wirbel- saule nebst Mittheilung eines Falles v. Myelocystocele lumbosacralis. Beitr. v. Ziegler, v., 1889. Fbrster: Die Missbildungen des Menschen, 1865. Hertwig: Urmund u. Spina bifida. Arch. f. mikr. Anat., 39 Bd., 1892. Hildebrand: Spina bifida u. Hirnbriiche. Deut. Zeitschr. f. Chir., 36 Bd., 1893 (Lit.). Jacoby: Doppelbildung des embryonalen Rilckenmarks. Virch. Arch., 147 Bd., 1897. Joachirnsthal : Spina bifida mit localer Hypertrichosis. Virch. Arch., 131 Bd., 1893 (Lit. ). Koch, W. : Beitr. z. Lehre von der Spina bifida, Cassel, 1881. Kollmann: Spina bifida u. Canalis neurentericus. Verh. d. Anat. Ges. , 1893. Kroner u. Marchand: Meningocele sacralis anterior. Arch. f. Gyn., xvii., 1881. Lebedeff : Ueber die Entstehung der Anencephalie u. Spina bifida. Virch. Arch., 86 Bd., 1881. Leonowa: Anencephalie mit Amyelic. Neurol. Cbl., 1893. Ijucksch: Bxper. Erzeugung d. Rachischisis. Z. f. Heilk., 1904. Manz: Das Augehirnloser Missgeburten. Virch. Arch., 51 Bd. , 1870. Marchand: Spina bifida. Eulenburg's Realencyklopadie, xxii., 1899. Markoe and Schley: The Sacrococcygeal Dimples, Sinuses and Cysts. Am. Jour, of Med. Sc, 1902. Muscatello: Die Angeb. Spalten d. Sckadels u. d. Wirbelsaule. Langenb. Arch., 47 Bd., 1894. Neumann: Subkutane Myelomeningocele. Virch. Arch., 176 Bd., 1904. Petren K u. G. : Nervensystcm bei Anencephalie u. Amyelie. Virch. Arch. 151 Bd., 1898. Pick: Zur Agenesie des Rilckenmarks. Arch. f. Psych., viii., 1878. v. Recklinghausen: Untersuchungen fiber Spina bifida. Virch. Arch., 105 Bd., 1886. Rex: Eigenthumliche Umbildungen des normalen Wirbeltypus. Prag. Zeitschr. f. Heilk., vii., 1835. Ribbert: Spina bifida occulta. Virch. Arch., 132 Bd., 1893. de Ruyter: Schadel- u. Rtickgratsspalten. Langenbeck's Arch., 40 Bd., 1890. Saalfeld: Spina bifida occulta mit Hypertrichosis. Virch. Arch., 137 Bd., 1894. Sulzer: Spina bifida mit Verdoppelung des Rilckenmarks. Beitr. v. Ziegler, xii., 1893. Taruffi: Delia rachischisi, Bologna, 1890. Virchow: Virch. Arch., 27 Bd. ; Die krankh. Geschwulste, i., 1863. Wiedersheim : Der Bau des Menschen, Freiburg, i. B., 1902. MALFORMATIONS OF THE CRANIUM. 513 Wieting: Ueber Spina bifida u. Zweitheilung d. Rilckenm. 1899. Beitr Bruua § 134. Faulty development of the cranium and the associated dis- turbances of cerebral development lead to those malformations known as cranioschisis, acrania, hemicrania, mierocephalus, anencephalus, exenceph- alus, micrencephalus, and cephalocele. Acrania and hemicrania or cranioschisis are the results of an agene- sia or hypoplasia of the bony and membranous portions of the cranial 379.— Anencephalia et acrania. Reduced one-half. Fig. 380.— Cranioschisis with Exencephalla. vault, which arise either as primary disturbances of development or as the result of harmful extrinsic influences upon the cerebral anlage. In acrania both the bouy portion and the skin of the cranial vault (Figs. 379, 381) are wholly wanting, the surface of the base of the skull being covered only with a membranous vascular tissue. If the defect in the cranial vault is as- sociated with a similar defect in the vertebral arches, there is pro- duced the condition known as craniora- chischisis (Pig. 376), in which the spinal column is usu ally shortened and bent, the head iu conse- quence being drawn sharply backward and the face turned up- ward. Through a marked bulging of the eyes with deficient development of the forehead, these malformations may resemble frogs (frogfmtus). Fig. 381.— Partial agenesia of the bones of the cranium in anence- phaJia. a. Defect ; b, squamous portion of the occipital bone ; c, parietal bone ; d, frontal bone. Reduced one-flfth. 514 DISTURBANCES OF DEVELOPMENT. Ill hemicrania the flat bones of the cranial vault have undergone more or less extensive development (Fig. 381, b, c, d) and form a cranial cavity, which is small, in that the flat bones of the vault are elevated but a short distance above the base of the skull. If the bones of the cranium which have undergone an imperfect development yet unite with one another as under normal conditions, there is produced a simple microcephalus, which may be present at birth or develop later, as the result of imperfect development of the skull. Acraniaand hemicrania are often associated with total anencephalus, the base of the skull being covered only with a membranous, vascular, spongy mass, which is usually composed of vascular connective tissue containing scattered hemorrhages, and showing no trace of brain tissue or only undeveloped rudiments (area cerebrovasculosa) . In other cases the meninges contain, besides cystic cavities and gland- like remnants of the medullary plate, also more or less developed brain- Fig. 882— Hydrenceplialocele occipitalis. Fig. 383.— Encephalomeningocele nasofrontalis. substance, which usually protrudes through the defect in the cranial vault, giving rise to exencephalus (Pigs. 380, 371). The hernial masses are either inclosed only by a soft membrane corresponding to the inner meninges, or they may be covered also by external skin. With microcephalus there is also micrencephalus— that is, an abnor- mal smallness of the brain. The development of the brain is also usu- ally deficient, or certain portions may be lacking. If the cranium is in general closed, but presents partial defects, portions of the cranial contents may protrude externally in the form of a hernial sac. Such a condition is known as hernia cerebri or cephalo- cele (Figs. 382, 383). Defects of ossification, as well as a local weaken- ing of the membranous cranial envelope, are doubtless the primary cause, though adhesions of the meninges with the amnion may also be a cause (St. -Hilaire). The dura mater is wanting over the extracranial portion of the sac (Muscatello). The size of the protruding sac varies greatly ; it may be so small as to be found only after careful examination, or it may be so large as to approach the brain in volume. If only the arachnoid and pia protrude as the result of a collection of fluid in the subarachnoidal space, the hernia is designated a meningocele. If at the same time there is a pro- trusion of brain-substance, it is known as meningoencephalocele. A hernia of brain-substance and pia without a collection of fluid is an encephalocele ; if the protruding brain-substance contains a portion of a ventricle filled with fluid, it is designated a hydrencephalocele. Cerebral hernias occur chiefly in the occipital region (hernia occipi- talis), close above the foramen magnum (Fig. 382), and at the root of DEFECTS OF THE CRANIUM. 515 \ H'X. Fir,. 384 — Synophthalmos clopia. the nose (hernia syncipitalis). In the latter region it may at one time involve chiefly the frontal bone (hernia nasofrontalis, Fig. 383), at another time the ethmoid (hernia nasoethmoid- alis) or the lachrymal bone (hernia naso-orbit- alis). More rarely hernias occur on the sides of the skull (hernia lateralis) or at the base of the skull (hernia basalts). The latter may bulge toward the nasopharynx (hernia spheno- pharyngea ), or into the orbit ( hernia spheno-orbit- alis), or into the fossa sphenomaxillaris (hernia sphenomaxillaris). In the case of a central hernia the brain may be either normal or more or less mal- formed. As a result of a marked stunting of development, particularly in the region of the foremost of the three cerebral vesicles, the cere- brum may remain single, while at the same time a deficient separation of the ocular vesicles takes place (cycleneephalia or cycloccphalia of St.- Hilaire). In severe grades of this form of disturbance of development ouly one eye may be formed, lying in the middle of tin; forehead, or two eyes united together may be found in one orbital cavity (Fig. 384), so that the mal- formation may be designated cyclopia, or synophthalmia, and as arrhinencephalus (Kundrat '). The nose is also stunted (Fig. 3S4) and forms a proboscis-like cutaneous tag attached above the eye, and devoid of bony foundation (ethmocephalia). When the eyes are sepa- rate, yet abnormally close to- gether, the nose in general may be normal, though very small at the root (cebocepha- lia). In the more severe grades of these malformations the ethmoid bone and nasal sep- tum may be wanting, and the upper lip and palate may be cleft in the median line, on one or both sides (Kundrat). In the lighter grades the fore- head is merely reduced in size and sharply pointed like a wedge. In the severe forms of these malformations the cerebrum consists of a sac (Fig. 385,/, i), oc- cupying more or less of the cranial cavity and filled with a clear fluid; at those points where the sac does not touch the cranial wall the inter- no. 385.— Crania] cavity of a synophthalmia microstomus opened by a frontal section (seen from behind), a. Skin and subcutaneous tissue; }>, cranium; c, dura mater; d. tentorium; e, arachnoid; f, posterior surface of the cere- brum, consisting of a thin-walled sac covered by pia mater; g, swollen eds_ r e of cerebral sac; }i, subarachnoidal space behind the cerebral sac; /, cavity of the cerebral sac, com- municating with the subarachnoidal space through the en- larged transverse fissure ; k, section through the corpora quadrigemina ; U section through the cerebellum ; m, atlas. Seven-tenths natural size. 516 DISTURBANCES OF DEVELOPMENT. rening space is filled by fluid distending the subarachnoidal space (h). In the less marked forms only individual portions of the brain are undeveloped, those parts chiefly affected being the olfactory lobes and nerves, the corpus callosum, a part of the convolutions, etc. The optic thalami are often blended together. The chiasm and the optic tract may be absent or present. The corpora quadrigemina (A), pons, medulla oblongata, and cerebellum ( I) are usually unaffected. The spinal cord and brain arise from t he medullary canal. In that portion that is to become the brain, the neural canal changes very early into three vesicles. The most anterior of these, the forebrain, throws out from its lateral portions the primary optic vesicles, while the middle portion grows forward and upward and divides into the telencephalon or forebrain, and the diencephalon (tlialamencephalon) or tweenbrain. From the former are developed the cerebral hemispheres, corpora striata, corpus callosum, and the fornix. From the tweenbrain are formed the optic thalami and the floor of the third ventricle. The second vesicle or midbrain forms the corpora quadrigemina. while the third vesicle divides into the isthmus, meteneephalon, and myelencephalon, from which there are developed the pons, cerebellum, and medulla oblongata. The cerebral portion of the medullary canal becomes inclosed by the primitive vertebral plates of the head, which form the membranous primitive skull, the basal portions of which become cartilaginous in the second month of foetal life. In the third month the basal cartilage and the membranous vault begin to ossify. According to G. St.-Hilaire, Forster, and Panum, acrania and anencephalus are to be referred to an abnormal accumulation of fluid in the cerebral vesicles, a hydroceplialus, occurring before the fourth month. Dareste and Perls oppose this view, and point out that in acrania the base of the skull is usually bulged inward and not pressed outward. They therefore seek the cause of acrania in a pressure exerted upon the cranium from without (Perls), due to an abnormal tightness of the cephalic cap of the amnion, which retards the development of the cranium. Lebedeff seeks the cause of acrania in an abnormally sharp 1 lending of the body of the embryo, which lie thinks occurs when the cephalic end of the embryo grows abnormally in the longitudinal axis, or in ease the cephalic covering lags behind in its development. By the sharp bending the change of the medullary groove into the medullary canal is thought to be hindered, or the canal after its formation is destroyed. From this could be explained the later absence of the brain, as well as of the membranous and osseous cranial covering. The cystic formations in the membranes lying upon the base of the skull are, according to Lebedeff, formed from the folds of the medullary plate, which sink into the mesoderm and are then suared off. Hertwig thinks it possible that chemical substances circulating in the blood or secreted from the wall of the uterus may destroy the anlage of the brain. According to K. and A. Petren, the spinal ganglia in anencephalus are always nor- mally developed; on the other hand, the columns of Clarke, the lateral cerebellar tracts, and the bundles of Gowers are either wholly wanting or are imperfectly developed. Likewise the pyramidal tracts are wanting, while the anterior-horn ganglion-cells and the anterior roots are developed. K. and A. Petren, therefore, regard the malformation as a system defect iu which the neurones of the second order are not formed ; and they incline to the view that the malformatiou is to be referred to an abnormal anlage of the germ. Literature. (Defects of the Cranium, Cerebral Hernia.) Ackermann: Die Schadeldifformitat bei der Encephalocele congenita, Halle-a.-S., 1881. Arnold: Gehirn, Riickcnmark u. Schadel eines Ilemicephalus. Beitr. v. Ziegler, xi., 1892. Beneke: Zwei Falle von multiplen Ilirnhernien. Virch. Arch., 119 Bd., 1890. Berger: L'origine et le mode de developpement de certaines cncephaloceles. Rev de chir., 1890. Ernst: Bildungsfehler d. Centralnervensystems bei Encephalocele. Beitr. v. Ziegler, xxv., 1899. Forster: Missbildungen des Menschen, Jena, 1865. Fridolin: Leber defecte Schadel. Virch. Arch., 116 Bd., 1889, Jacoby: Partielle Aneneephalie bei einem Embryo. Virch. Arch.., 147 Bd., 1897. MALFORMATIONS OF FACE AND NECK. 517 Jonkovski: Hemikeplialie u. Prosoposchisis. Virch. Arch., 169 Bd., 1902. Kluge: Hydrenenkephalie. Z. f. Heilk., 1902. Kundrat: Die Arrliinencepbalie. Graz, 1882. Lebedeff: Entstehung d. Anencephalie u. Spina bifida. Virch. Arch., 86 Bd., 1881. Leonowa: Anencephalie. Arch. f. Anat., 1890. Manz: Das Auge hirnloser Missgeburten. Virch. Arch., 51 Bd., 1870. Muhr: Enceplialoceie anterior. Arch. f. Psych., viii., 1878. Muscatello: Dieangeb. Spalten desScbadels. Langenbeck's Arch., 47 Bd., 1894 (Lit.). Petren, K. u. G.: Nervensystem bei Anencephalie u. Amyelie. Virch. Arch., 151 Bd., 1898 (Lit.). de Ruyter: Schadel- und Riickgratsspalten. Langenbeck's Arch., 40 Bd., 1890. Schiirhoff. Anatomie d. Centraluervensystems bei Hemicephalen, Stuttgart, 1894. Siegenbeek van Heukelom: Encepbalocele. Arch. f. Entwickelungsmech., iv., 1896. Spring-: Monographic de la hernie du cerveau, Bruxelles, 1853. Ssamoylenko : Kephalocele nasofrontalis. Beitr v. Brians, 40 Bd., 1903. Sternberg- u. Latzko. Hemikephalus. Z f. Nervenkrankh., 24 Bd. , 1903. Talko. Leber angeborene Hirnhernien. Virch. Arch., 50 Bd., 1870. Virchow. Die krankh. Geschwulste, i.. 1863. (c) The Malformations of the Face and Neck. § 135. The development of the face not infrequently suffers disturb- ances leading to more or less marked facial malformations, which may appear alone or iu association with malformations of the cranium. If the frontal process and the maxillary processes of the first branchial arch remain in a rudimentary state or are destroyed to a marked extent by pathological processes, there persists at the site of the face an open sinus giving rise to the conditions known as aprosopia (absence of the face) and schistoprosopia (cleft face), which may also be associated with a defective development of the nose and eyes. More frequent than these large defects are smaller clefts involving the lips, alveolar process of the upper jaw, the upper jaw itself, and the hard and soft palates (Fig. 386), which are designated as cheilo=gna= thopalatoschisis or " wolf's jaw." This malformation gives rise to a communication between the mouth and the nasal cavity (Fig. 3S6). The hard palate is cleft in the part bordering upon the vomer ; the soft palate in the median line. In the alveolar process of the upper jaw the cleft runs between the canine tooth and the outer incisor or between the outer and inner incisors. The malformation may be bilateral or unilat- eral, and is sometimes primary and inheritable, at other times acquired secondarily, in part as the result of amniotic adhesions (Fig. 371). Not infrequently the cleft involves only special portions of the regions mentioned, as the upper lip (harelip, labium, leporhmm), or, what is rarer, only the hard or soft palate. The lightest grades of this form of cleft-malformation are represented by a notch or cicatricial line in the lips, or by a bifurcation of the uvula. Prosoposchisis or oblique facial cleft (Fig. 372) is the designation applied to a cleft running obliquely from the mouth to an orbit. It is usually associated with malformations of the brain. According to Morian, three forms may be distinguished. The first is a cleft beginning in the upper lip as a harelip, passing into the nasal cavity, thence around the ala nasi toward the orbit, and may extend even beyond the latter. The second form likewise begins in the region of a harelip, but extends outward from the nose toward the orbit. The third form 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- 518 DISTURBANCES OF DEVELOPMENT. nally to the canine tooth. A transverse cleft of the cheek also occurs, pass- ing from the corner of the mouth toward the temporal region. nedian facial clefts (nasal cleft) run in the median line involving the nose, upper jaw, and also the lower jaw, and may extend as far down as the sternum. The tongue may also be cleft. Further, the de- fect may extend even to the frontal bone and brain. All of the above-mentioned clefts may be confined to small portions of the regions mentioned, and moreover attain varying depths. If the development of the inferior maxillary process of the first branchial arch is retarded, the inferior maxilla also is imperfectly devel- oped or wholly wanting, and there arise those malformations known as brachygnathia or agnathia (Fig. .°,S7). The lower portion of the face -Double cheilo-gnatbopalatoschisis. ( Wolf's jaw. ) Fig. 387. — Agnatbia and synotia. (After Guardan.) appears as if cut away; the ears are sometimes brought so close to each other as to touch (synotia). Usually the superior maxillary processes are also imperfectly developed ; not infrequently the ear is malformed. Abnormal largeness of the mouth (rnacrostoinia), abnormal smallness (microstomia), closure (atresia oris), and duplication of the mouth (dis- tomia) are all rare. When the embryonic external branchial clefts or internal branchial pockets fail in part to close, there persist fistula; opening either exter- nally or internally, or closed cysts. The former condition is known as fistula colli congenita. The mouths of the external fistula? are usually found at the side of the neck, more rarely nearer to the median line or in the median line; those of the internal fistuke open into the pharynx, trachea, or larynx. Very often the remains of the branchial pockets form only diverticula of the last-named organs. The fistula? are for the chief part covered with mucous epithelium, sometimes ciliated, arising therefore from the visceral branchial pockets, according to von Kos- tanecki and von Mielecki usually from the second. In rare cases there is found a complete branchial fistula with both external and internal openings. MALFORMATIONS OF FACE AND NECK. 519 The branchial cysts arising from the branchial - pockets are some- times lined with mucous epithelium (ciliated epithelium) and contain fluid ; hence they are called hydrocele colli congenita. At other times they possess an epidermoidal covering and inclose epidermoidal cell-masses, and are therefore classed with the atheromata and dermoid cysts. Cysts of the neck lying in the median line and reaching to the hyoid bone may develop from remains of the ductus thyreoglossus. The face and neck are developed in part from a single anlage, and in part from paired anlage. The latter are represented in the branchial or visceral arches growing from the lateral portions of the base of the skull ventrally in the primitive throat-wall. The single anlage, designated the frontal process, is a prolongation downward of the base and vault of the cranium, and is, in fact, nothing more than the anterior end of the skull. Between the individual branchial arches there are at a certain period cleft- like depressions known as the branchial pockets. The frontal process and the first branchial arch form the boundaries of the great primitive mouth-opening, which has a diamond shape. In the course of development the first branchial arch sends out two processes, the shorter of which applies itself to the under surface of the anterior portion of the head and forms the upper jaw, while from the longer one the lower jaw is developed. The frontal process, which forms the anterior boundary, gives rise to a broad prolongation of the forehead, and then pushes on two lateral processes which are know r n as the lateral nasal processes. By further differentiation of the central portion of the frontal process proper, the septum narium is formed, which by means of two spurs, the inner nasal processes, produces the borders of the external nasal opening and the nasal furrow. The lateral nasal processes are the lateral portions of the skull, and later develop within themselves the ethmoid labyrinth, the cartilaginous roof, and the sides of the anterior portion of the nares. At a certain stage they form with the superior maxillary process a furrow running from the nasal furrow to the eye, the lachrymal fissure. In the beginning the mouth is simply a large sinus, but is soon separated into a lower and larger digestive and an upper and smaller respiratory portion. This separa- tion is brought about by the development, from the superior maxillary processes of the first branchial arch, of the palatal plates, which from the eighth week on blend into each other and at the same time unite with the lower border of the nasal septum. The union of the anterior portions of the palatal plates takes place earlier than that of the posterior portions. Through the union of the contiguous portions of the frontal and nasal processes w.jii the superior maxillary processes the cheek is formed and a continuous superior maxillary border, from which are developed later the lip and the alveolar process of the upper jaw and intermaxillary bones, while the external portion of the nose devel- ops from the frontal process. The intermaxillary bones are developed as independent bones, but unite very early with each other and with the upper jaw. Literature. (Wolf's Jaw; Harelip; Oblique Faded Clefts.) Albrecht. Arch. f. Chir., xxxi. ; Fortschr. d. Med., hi.. 1885; Biol. Cbl., v., 1886. Bartels: TJeber vernarbte Lippenspalten. Arch. f. Anat. u. Phys., 1872. Biondi: Lippenspalte und deren Complicationen. Virch. Arch., Ill Bd.. 1888. Forster: Die Missbildunger des Menschen, Jena, 1865. Haymann: Amniogene erWche Hasenscharten. I.-D. , Leipzig, 1903. Kindler: Linksseit. Nasenspalte verbunden mit Defect d. Stirnbeirs. Beitr v Ziefler vi., 1889. ° ' Kolliker, Th. : Ueber das Os intermaxillare u. d. Anatomie d. Hasenscharte u. d. Wolfsracliens, Halle, 1882; Die einfache Anlage des Zwischenkiefers. Anat Anz iii., 1890. v. Kostanecki: Missbildungen in der Kopf- u. Halsgegend. Virch. Arch. 113 Bd 1891. Kredel: Angeb. Nasenspalten. Deut. Zeitschr. f. Chir., 4 7 Bd., 1898 (Lit.). Lannelongue : Du developpement de l'mtermaxillaire externe et de son incisive; pathogenie des fissures osseuses de la face. Arch, de med. exp., ii., 1890. Lexer; Angeb. mediane Spaltung der Nase. Arch. f. klin. Chir., 62 Bd., 1900. 520 DISTURBANCES OF DEVELOPMENT. Madelung: Unterlippenfistel u. seitl. Nasenspafte. Langenbeck's Arch., 37 Bd., 1889. Marwedel; Mediane Spalte der oberen Gesichtshalfte. Virch. Arch., 163 Bd., 1901. Merkel : Gesichtsspalte, Topograph. Anatomie, ii. Heft, 1887. Morian: Die schrage Gesichtsspalte. Arch. f. Chir., xxxv., 1887. Mtiller: Die Hasenscharten d. Tlibinger chir. Klinik i. d. J., 1843-85, Tubingen, 1885. Nasse: Mediane Nasenspalte. Langenbeck's Arch., 49 Bd., 1895. Schmidt: Spaltbildung im Bereiche d. mittl. Stirnfortsatzes. Virch. Arch., 162 Bd., 1900. Stohr: Zur Zwischenkieferfrage. Arch. f. klin. Chir., xxxi., 1885. TarufB: Casi di rneso-rino-sehisi. Mem. deila R. Ace. delle Sc. dell' Istit. di Bologna, 1890. Warynski: Bee de lievre simple et complexe. Virch. Arch., 112 Bd., 1888. WtilfLer: Zur Casuistik der medianen Gesichtsspalte. Langenbeck's Arch., 40 Bo.., 1890. Wolff: Hasenscharte. Eulenburg's Realencyklop., 1896 (Lit.). (Branchial-cleft Fistula:- and Cysts.) Baumgarten u. Neumann: Fistula colli congenita. Arch. f. klin. Chir., xx., 1870. Bidder: Knorpelgeschwulst am Halse. Virch. Arch., 120 Bd., 1890. Franks: Blutcysten d. seitl. Halsgegend. Deut. Zeitschr. f. Chir., 28 Bd., 1888 (Lit.). Frobenius : Leber einige angeb. Cvstengeschwulste des liaises. Beitr. v. Ziegler, vi., 18S9. Hammar: Kongen. Ilalskicmentistel. Beitr. v. Ziegler, xxxvi., 1904. Heusinger: Virch. Arch., 29 and 33 Bd. ; Deut. Zeitschr. f. Tliiermed., ii., 1875. Kbnig". Fistula colli congenita. Langenbeck's Arch., 51 Bd., 1896. v. Kostanecki: Zur Kenntu. d. Pharvnxdivertikel des Menschen. Virch. Arch., 11/ Bd., 1889. ■?. Kostanecki u. v. Mielecki : Die angeb. Halskiemcnnsteln. Virch. Arch., 120 u. 121 Bd., 1890. Nieny: Halskiemenfisteln. Beitr. v. Bruns, 23 Bd., 1899. Richard: Geschwi'ilste der Kiemenspalten. Beitr. v. Bruns, iii., 1888 (Lit.). Sch.lan.g-e: Fistula colli congenita. Langenbeck's Arch., 46 Bd., 1893. Schmidt: Halskiemenfisteln beim Kalbe. Zeitschr. f. Tliiermed., i., 1897. Strubing: Zur Lehie v. d. congen. Hals-Luftrbhrentisteln. Deut. med. Woch., 1892. Virchow: Ilalskiemcnristel. Virch. Arch., 32 Bd. ; Tiefes auriculares Dermoid. lb., 35 Bd , 1866. Zahn Kiemengangsflsteln. Zeitschr. f. Chir., xxii., 1885. (d) Faulty Closure of the Abdominal and Thoracic Cavities, and the Accom- panying Malformations. § 136. Arrests of development in the formation of the ventral body=wall may take place at different points and exhibit different grades of severity. They occur most frequently in the region of the umbilicus, where the closure of the abdominal cavity takes place latest. In the case of imperfect development of the abdominal wall at this point, so that a more or less extensive area of the abdominal cavity is closed in only by the peritoneum and the sheath of the umbilical cord — that is, the amnion— which are pushed forward by the abdominal organs (Fig. 388), there is produced the condition known as omphalocele, or hernia funiculi umbilicalis, or umbilical hernia. The umbilical cord is at- tached either to the summit or at one side of the hernial sac, and is more or less shortened. If the anterior abdominal walls either wholly or in part fail to unite, there arise those conditions which are designated fissura abdominalis, or gastroschisis completa and thoracogastroschisis. These are char- acterized by the undeveloped abdominal coverings not having been sepa- rated from the amnion, but passing into it. The greater part of the abdominal organs lies in a sac formed by the amnion and peritoneum MALFORMATIONS OF THORAX AND ABDOMEN. 521 (eventration^). The peritoneum, however, may also be wanting, likewise the umbilical cord, and the umbilical vessels may pursue their course to the placenta independently. A cleft confined to the thorax is called thoracoschisis. Should the heart, covered only with pericardium or wholly free, protrude through an opening in the cardiac region, the condition is designated ectopia cordis. When the failure to close is confined to the region of the sternum, the condition is designated fissura sterni. This defect may involve either the whole or a part of the sternum, at times affecting the bones, at other times only the skin. The protrusion of the urinary bladder through a cleft in the abdomi- nal wall is known as ectopia vesicae urinaria?. Clefts of the abdominal wall are not infrequently associated with clefts of the parts lying behind the wall, not only in the case of large clefts (total), but also in the case of smaller ones (partial). When a cleft of the lower portion of the abdominal wall is associated with a cleft, of the urinary bladder, so that, the posterior wall of the latter pro- trudes through the abdominal fissure (Fig. 3S9, c), the condition is known as fissura, or exstrophia, or inversio vesica; urinaria;. Occasionally the pelvic girdle and the urethra are also cleft, the latter being represented by a groove open anteriorly (Fig. 389, e). The exstrophy is then said to be complicated by a. fissura genitalis and epis- padias. When an abdominal fissure or an abdominal and vesical fissure is combined with a fissure of the intestines, there is produced a fissura abdominalis intestinalis or vesicointestinalis. The intestinal fissure is sit- uated in the caecum or be- ginning of the colon, and the mucous membrane of the cleft intestine protrudes through the opening iu the same manner as the posterior wall of the bladder, so that the condition is called ex= strophia or inversio intes= tini. If the omphalomesenteric duct does not undergo its normal involution, there re- mains at the lower end of the small intestine an ap- pendix of intestine called Meckel's diverticulum, which arises perpendicularly from the outer margin of the intestine. It has usually the appearance of a glove-finger, and is either free at its end or attached to the umbilical ring, sometimes being dilated at its end. In the case of adhesion to the umbilical ring the intestinal mucosa may appear at the navel in the form of a tumor (ectopia intestini, umbilicalis. Reduced to one-third. 522 DISTURBANCES OF DEVELOPMENT. adenoma umbilicale). In very rare cases a cyst lined with mucous mem- brane may be formed in the abdominal wall (omphalomesenteric cyst). Congenital fistula of the urachus, that is, fistula lying within the um- bilicus and connecting with the bladder by a fistulous' tract, depend upon an incomplete obliteration of the urachus or of the stalk of the allantois. They may be associated either with an open or a closed urethra. Fig. 389. — Fissura abdominis et vesicae urinaria? in a ffirl eighteen clays old. fo, peritoneum : c, bladder; d, small bladder-cavity corresponding to tbe trigonum : /, labia minora. a, Border of the skin; e, trough-like urethra ; The development of the body-form from the flat embryonic anlage begins by a snaring-off of the individual germ-layers from the outer embryonal area, and their fold- ing to form two tubes, the body-wall and the alimentary canal. The infolding of these layers takes place at the cephalic and caudal ends, as well as at the lateral portions of the embryonal anlage, and as the summits of the folds gradu- ally grow together from all directions, those which form the body-wall produce a tube whose cavity finally communicates only at the parietal umbilicus, by means of a peduncle-like prolongation, with the cavity of the extra-embryonic portion of the blastoderm known at this time as the vitelline membrane. While the lateral and ven- tral walls of the embryo are being thus formed, within the body the intestinal furrow also closes to form a tube, which is in communication at only one point lying within the parietal umbilicus, known as the visceral umbilicus, with the cavity of the umbili- cal vesicle, by means of a channel known as the omphalomesenteric duct. Umbilical hernia and clefts of the upper portion of the abdominal wall are fre- quently combined with craniorachischisis, while exstrophy of the bladder and intestine is often associated with myelocystocele. According to von Recklinghausen, the two malformations are to be regarded as coordinated with eaeli other. Further, large ab- dominal clefts are often associated with lordotic and scoliotic curvatures of the spinal column. Literature. {Clefts of Thoracic and Abdominal Walls ; Meckel' s Diverticulum ; Ectopia Intestini.) Aschoff: Verbiiltniss d. Leber u. d. Zwerchfells z. Nabelschnurbruchen. Virch Arch., 144 Bd., 1896 (Lit.). Chaudelux: Observation pour servir a l'histoire de 1 exomphale. Arch. d. phys., viii., 1881 rzog: Die in: Urachi Klautsch; Bauchspalten. Cbl. allg. Path., vi., 189 , lO'Jl. Herzog: Die Ruekbildung des Nabcls u. der Nabelgefasse, Muncben, 1892. Jahn: Urachusfisteln. Beitr. v. Bruns, 26 Bd., 1900 (Lit.). MALFORMATIONS OF EXTERNAL GENITALIA. 523 Kiistner: Das Adenom uud die Granulationsgesehwulst am Nabel. Arci f. Gyn.. ix., 1877; Vircli. Arch., 69 Bd., 1877. Preisz; Ueb. d. sog. Nabeladenom. Jahrb. f. Kinderheilk., 33 Bd., 1891. v. Reckling-hauseii : Spina bifida. Virch. Arch., 105 Bd., 1886. Rischpler: Drei Fade von Eventration. Arch. f. Entwickelunsgmech. , vi., 1898 (Lit.). Sauer: Prolaps eines offenen Meckel'schen Divertikels. Deut. Zeitschr. f. Chir., 44 Bd., 1897. Schild: Congen. Ektopie der Harhblase. Arb. a. d. path. Institute in Mtlnchea, 1886. Siegenbeek van Heukelom: Die Grenese der Ektopia ventriculi am Nabel. Virch. Arch., Ill Bd., 1888. Tillmanns: Angeb. Prolaps der Magenschleimhaut durch den Nabelring und fiber sonstige Geschwillste und Fisteln des Nabels. Deut. Zeitschr. f. Chir., xviii., 1883. Vejas: Eine seltene Missbildung. Virch. Arch., 104 Bd., 1886. Zunrwinkel : Subcutane Dottergangscyste. Langenbeck's Arch. , 40 Bd., 1890. (e) Malformations of the External Genitalia, awl Anus, due to Arrested Development. § 137. Malformations of varying degree of the external genitals may be associated with malformations of the abdominal wall, bladder, and the internal genital organs, or may occur independently of these. Com= plete absence of the external genitalia occurs most frequently in con- nection with other malformations of this region, particularly in the case of sirenomelia, yet the region may in general present also a normal structure (Fig. 392). The internal genitals are usually also malformed. A stunted condition of the penis is not rare, the organ in conse- quence coming to resemble more or less the clitoris. This condition is usually associated with a hypospadias — that is, the urethra opens on the under side of the organ, either beneath the glans, the body or the root of the penis (Fig. 390), or finally even behind the scrotum (hypo- Fig. 390. — Hypospadias with stunting of the penis. Reduced one-fourth. Fig. 391. —Epispadias. (After Ahlfeld.) spadias perineoscrotalis). These malformations may exist in penises otherwise normally developed, and depend upon a partial failure of the sexual furrow to close. Epispadias (Fig. 391) is that condition in which the urethral opening is found upon the dorsum of the penis. It is more rare than hypo- spadias, and is dependent upon a defective or delayed closure of the pelvis, so that the cloaca, before the closure, becomes divided into an intestinal (anal) and a genital opening (Thiersch). Under certain con- 524 DISTURBANCES OF DEVELOPMENT. ditions the penis remains cleft throughout its entire length ; at the same time a fissure of the bladder and abdomen may be present rare. If the preputial opening be drawn back over the glans, Hypertrophy of the prepuce is not is narrowed so that the prepuce cannot the condition is designated a hypertro= phic phimosis. Total absence of the prepuce is rare ; an abnormal shortness is more frequent. Defective development of the scro- tum is usually associated with retention of the testicles in the abdominal cav- ity or in the inguinal canal, and leads to appearances whereby the external genital organs of the male come to re- semble those of the female, especially so when the penis is also stunted. In the female the clitoris as well as the labia majora and minora may show a stunted development. Epispadias and hypospadias occur also in the fe- male sex, the former coincidently with a fissure of the abdominal and bladder walls (Fig. 389). In hypospadias a portion of the posterior wall of the ure- thra is lacking, and the urethral open- ing may be found at a greater or less distance within the vagina. Absence of the urethra occurs in both sexes (Fig. 302). In girls the bladder may open directly into the vagina. Closure (atresia) of the urethra occurs likewise in both sexes, and re- sults either from a partial defect of the same or from obliteration of the orifice. An accumulation of urine in the bladder may lead to a marked dilatation of the same (Fig. 302). An abnomal narrowness of the urethra may exist in a portion of its course or throughout its entire length. Further, its lumen may be narrowed as the result of a hypertrophic development of the colliculus seminalis. In rare cases multiple orifices of the urethra have been observed. Further, in men there may be found in the glans penis a blind tube lying beside the urethra. Atresia ani simplex is a closure of the anus, the intestine being at the same time well developed. It may arise from a failure of the ecto- derm to fold in at the anal site, or a cloaca already existing and open- ing outward may again become closed through subsequent adhesions ( Frank). If the rectum does not end immediately above the anal mem- brane but higher up, there exists in addition to the atresia ani also an atresia recti, a malformation which may occur even when the anus is well developed. When, with absence of the anus, there is also an arrested development of the vaginal wall, which grows downward, between the sinus urogeni- talis and intestine, to unite with the perineum, there remains a cloaca Fig. 392.— Complete absence of the urethra and external genitals, with extreme, dis- tention of the body due to an enormous dil- atation ot the bladder. Compression and stunting of the lower extremities. (In the posterior wall of the bladder rudiments of a female genital apparatus in the form of portions of the tubes and ovaries were found.) MALFORMATIONS OF THE EXTREMITIES. 525 in which the sinus urogenitalis and the end of the bowel unite. In other cases there are found fistulous communications between the rectum and the bladder or urethra (in boys) on the one hand, or be- tween the rectum and the vagina or uterus on the other (atresia ani vesicalis, urethraMs, vaginalis, ■uterina). In rare cases the intestine, in the case of anal atresia, may open outward by means of external fistulae in the perineum, scrotum, or sacrum. Further, external fistulte below the anus may occur as remains of the post-anal gut. Literature. (Disturbances of Development of the External Genitalia and of the Anus.) Bertholdy: Fistula ani congenita. A. f. Klin. Chir.. 66 Bel. 1902. Bergh: Epispadie. Virch. Arch., 01 Bit. 1867. Dienst: Atresia ani congenita. Virch. Arch., 154 Bd., 1898 (Lit). Epping-er: Atresia ani. Prag. med. Woch., 1880. Frank: Die angeborene Verschliessung des Mastdarms, Wien, 1892. Ftirst: Weibliche Epispadie mit Nabel-Urachusfistel. Arch. f. Kinderheilk. , xiv., 1892. Gartner: Atresie des Darms. Jahrb. f. Kinderheilk., xx., 1883. Goldmarm: Hypospadie. Beitr. v. Bruns, xii., 1894 (Lit.). Keibel: Eutwickelung v. Harnblase, Harnrohre u. Damm. Verb. d. Anat. Ges., 1895. !Loewy: Gong. Dilatation d. Harnblase. Prag. med. Woch., 1893. Mayr: Kloakenbildung bei Hausthieren. Ergebn. d. allg. Path., iv., 1899. Rasch: Weibliche Epispadie u. Fissura vesicae. Beitr. v. Bruns, xviii., 1897. Reichel: Entstehung d. Missbild. v. Harnblase u. Harnrohre. Langenb. Arch., 46 Bd., 1893. Roth: Missbildungen im Bereiche des Ductus omphalomesentericus. Virch. Arch., 86 Bd., 1881. Scherer: Imperf oration des Anus. Arch. f. Kinderheilk., xiv., 1892. Schneider: Atresia ani uterina et vesicalis. Arb. her. v. Baumgarten, i., 1892. Schwyzer: Atresie der Harnrohre. Arch. f. Gyn., 43 Bd., 1892. Seidler: Anus vaginalis. Arb. a. d. pathol. Inst, zu Gottingen, Berlin, 1893. Stieda: Atresia ani congenita. A. f. Klin. Chir., 70 Bd., 1903. Thiersch: Entstehung u. Behandlung (1. Epispadie. Arch. d. Heilk., x., 1869. (f ) Malformations of the Extremities due to Arrested Development. 8 138. Defective development of the extremities is not rare, and is to be referred in part to a primary defect of the anlage of an extremity, in part to a disturbance in the later develojmient of the limbs or the bones, and in part to constrictions caused by strands of the foetal mem- branes or by loops of the umbilical cord. Further, such defective devel- opment of the extremities may also follow malformations of the central nervous system. According to the degree and the kind of malformation, the following different forms may be distinguished : (1) Amelus. The extremities are completely absent; in their place are found only warty or stump-like rudiments. The trunk is usually well formed (Fig. 393). (2) Peromelus. Stunting of all the extremities. (3) Phocomelus. The hands and feet are alone developed and are attached directly to the shoulder and pelvis respectively. (4) Microvielus (microbrachius, micropus). The extremities are devel- oped, but are abnormally small (Fig. 394). (5) Abraehius and Apus. Absence of upper extremities with well- developed lower ones, or vice versa. (6) Perobrachius and Peropus. Stunting of the upper or lower ex- tremities. (7) Monobrachius or Monopus. Absence of one of the upper or lower extremities. 526 DISTURBANCES OF DEVELOPMENT. (8) Sympus, Sirenomelia, Synvmelia. The lower extremities are fused together (Figs. 395, 396), and at the same time turned upon their axes so that their external aspects are in contact. The pelvis is usually Fig. MS.— Amelus. Fig. 394.— Micromelus witb cretin-like facies. Fig. 395.— Sympus apua. Fig. 396.— Sympus dipus. MALFORMATIONS OF THE EXTREMITIES. 527 defective, as are also the external genitalia, the bladder, urethra, and the anus. At the eud of the blended extremities feet may be entirely FIG. 307 Fig. 398. Fig. 399. Fig. 397. — Absence of femur and fibula. Diminution in the number of phalanges. One-half natural size. Fig. 398. — Perodactylism with syndactylism. Left band of a new-born child. Seven-eighths natural size. Fig. 399.— Skiagraph of same hand as in Fig. 398. Seven-eighths natural size. wanting (sympus apus) and only a few toes may be present (Fig. 395) ; in other cases (Fig. 396) one (sympus monopus) or both feet may be pres- ent (sijmpu.ii dipuH). Fig -too. Fig. 401. Fig. 400.— Malformation of the right hand, perochirus, with blending of the fingers. (After Otto.) a, Supernumerary thumb; ft, thumb proper; c, stunted index finger; d, middle finger; c, ring finger;/, little linger, Fig. 401. — Skeleton of the hand (perochirus) shown in Fig. 400. seen from the dorsal side. (After Otto.) a-f, as in Fig. 400; g, ulna ; h, radius ; i. os naviculare ; -. os lunatum ; S, os triangulare ; 4, os pislforme; 5a\ os multangulum majus supertluum ; 5b, os multanguluni ordinarium ; 0, os multaugulum minus ; 7, os capita-turn ; ,s, os hamatum. 52S DISTURBANCES OF DEVELOPMENT. (9) Absence of individual bones may occur in any part of the extremi- ties (Fig. 397). (10) Perodactylism — stunting of the fingers or toes — appears in a great variety of forms, but in general is seen as a defective development (braehyphalangism) or complete absence of individual phalanges (Figs. 397, 399, 401, c), or as membranous (Fig. 398) or bony (Figs. 399, 401, d, e) connections between the fingers (syndactylism). If only the outer fingers or toes are developed while the middle ones are lacking, there arise those formations (Figs. 400, 403) designated as cleft-hand and cleft-foot (Kiimmel). In more extensive malformations Fig. 402. Fig. 403. Fig. 402.— Peropus or cleft-foot. (After Otto.) Right foot, a, Great toe ; ft, little toe. Fig. 4i )3.~ Skeleton of the foot in Fig. 402, seen from the dorsal side, a. Great toe; h, little toe; c, rudiment of third toe ; o\ tihia ; e, fibula ; J, talus ; «, calcaneus ; S, os naviculare ; /,, 03 cuneiforme maius ; 5, os cuneiforme minus ; 6, os cuneiforme tertium ; 7, os cubiforme. of the fingers there occur in part also malformations and defects in the region of the tarsal and metatarsal bones (Fig. 403) or carpal and meta- carpal bones respectively. These malformations are designated respec- tively as peropus and perochirus. Absence of the hand or foot is known as achirus or apus. Literature. (Malformations of the Extremities. ) Abramow u. Rjeranow: Sirenenbildung. Vircb. Arch., 171 Bd., 1903. Adrian: Kongen. Humerus u. Femurdefekte. B. v. Brims, xxx. , 1901 (Lit.). Arnold: Myelocyste, Transposition v. Gewebskeimen u. Sympodie. Beitr v Ziegler xvi., 1894. ' s ' Basch: Ueb. d. sog. Flugbautbilduug in d. Kniekehle. Zeitschr. f. Heilk., xii., 1891. Borner: Anat. Enters, ernes Kindes mit Phokomelie. Inaug.-Diss., Marburg, 1887 Brunner: Genese, congen. Mangel u. rudim. Bildung d Patella Vircb. Arch i°4 Bd., 1891. ' " Burcknardt: Knochendefecte am Vorderarm u. Unterschenkel Jihrb f Einder heilk., 31 Bd., 1890. Dareste, C. : Mem. sur les anomalies des membres. Journ de l'anat et do la nhvs 1882. ' ' J "' Ehrlich: Congen. Defecte n. Hemmungsbildungen d. Extretnitateu. Vircb Arcb 100 Bd., 1885. ' "' ABNORMAL POSITION OF EXTREMITIES. 529 Fischer: Congen. Defectbildung an d. Unterextremitat einessiebenj. Knaben, Rostock, 1886. Fricke: Ueber congen. Defect der Fibula, Bonn, 1887. Gebhardt: Ein Beifcrag zur Anatomie der Sirenenbildungnen (contains anatomical study of Figs. 384 and 385). Arch. f. Anat. u. Pliys., 1888. Goldmann: Beitr. z. Lehre v. d. Missbild. d. Extremitaten. Beitr. v. Bruns, vii., 1891. Grisson: Defect d. Oberschenkeldiaphyse. Langenbeck's Arch, 49 Bd., 1894. Gruber: Defecte d. Hand. Arch. f. Anat., 1803; Defect des Radius. Vireh. Arch., 32, 40 Bd., 1861. Hlavaceck: Extremitatenmissbildungen. Deut. Zeitschr. f. Chir., 43 Bd., 1896. Joachimsthal : Defecte langer Rohrenknochen. Dent. med. Woch., 1895; Braehy- dactylie u. Hyperphalaugie. Virch. Arch., 151 Bd., 1898; Die angeb. Verbildung d. ob. Extremitaten, Hamburg, 1900. Klaussner: Die Missbildungen der menschl. Gliedmaassen, Wiesbaden, 1900. Kiimmel: Die Missbildungen d. Extremitaten, Kassel, 1895. Lotheissen : Mangel d. Oberschenkelknochen. Beitr. v. Bruns, xxiii., 1899. Mayer: Spalthand u. Spaltfuss. Beitr. v. Ziegler, xxiii., 1898. Melde: Defect der Tibia u. Polydaktylie. Inaug.-Diss., Marburg, 1892. Mies: Angeb. Mangel des V. Fingers u. Mittelhandknochens. Virch. Arch., 121 Bd., 1890. Otto: L. c, § 129. Paster. Missbildung der Hande und Fiisse. Virch. Arch., 104 Bd., 1886. Pauly: Mangel der Diaphyse u. der unteren Epiphyse d. Tibia. Langenb. Arch., xxiv., 1879. Pfitzner: Brachyphalangie. Verb. d. anat. Ges. , 1898. Poelchau: Ein Fall von Perodaktylie. Inaug.-Diss., Konigsberg, 1891. Rascb: Syndactylie und Polydactylie. Beitr. v. Bruns, xviii., 1897. Rennert: Beitr. zur Kenntniss v. d. Missbildungen der Extremitaten, Leipzig, 1882. Bug-e: Sirenenbildung. Virch. Arch., 129 Bd., 1892. Schafer: Congen. Defecte von Hiinden und Fiissen. Beitr. v. Bruns, vii., 1891. Steinhaus: Congenitaler Tibiadefect. Virch. Arch., 163 Bd., 1901. Steinthal: Ueber angeb. Mangel einzelner Zehen. Vireh. Arch., 109 Bd., 1887. Strieker: Ueber angeb. Defect des Radius. Virch. Arch., 31 Bd., 1864. Teacher and Coats: Siren-malformation. Journ. of Path., in., 1895. Tschudi: Vollst. Verwachsung aller 5 Finger. Zeitschr. f. Chir., 35 Bd., 1893. § ISO. Among the abnormal positions of the extremities congenital luxations (slipping of the articular heads from their sockets) are of es- pecial interest. They are most common at the hip-joint, more rare at the elbow-, shoulder- and knee-joints. According to von Ammon, Grawitz, Kronlein, and Holtzmann, the congenital luxations are in part due to local arrests of development, but may also be the result of mechanical in- fluences. In the case of the hip- joint the disturbance of development results in a small and imperfect acetabular socket, and the head of the femur is usually more or less imperfectly developed. The small acetab- ulum lies in the normal position, but the head of the femur is displaced, most often backward (luxatio iliaca). At birth the ligamentum teres is always intact, and the capsule of the joint covers both the head of the femur and the acetabulum. After much use of the leg the ligamentum teres becomes stretched and may tear, the capsule becomes dilated and bag-like, and at the point where it is pressed against the bone may be- come perforated. A new joint may then be formed through the prolif- eration of the surrounding tissues. Abnormal positions of the feet and hands are to be referred partly to disturbances of development and partly to mechanical influences exerted upon the extremities during their growth. The most important is congenital club-foot (pes equinovarus), which, according to Esch- richt, is to be referred to an arrest of development, by which the foot is left in the fcetal position, with accompauying abnormal development of the bones and their articular surfaces. The inner border of the foot is 34 530 DISTURBANCES OF DEVELOPMENT. sharply elevated, and the foot at the same time brought into plantar flexion. The collmn tali is elongated in an anterior and inferior direc- tion (Hiiter, Adams). If the children thus afflicted learn to walk, they tread upon the outer side of the foot, which thereby becomes flattened, while the foot becomes still more sharply turned inward. Congenital club-foot, though usually to be regarded as a primary dis- turbance of development of the affected joint, may also under certain conditions be caused by an abnormal pressure due to a relatively small uterus (Volkmann). tinder these conditions develop also those patho- logical positions of the foot known as pes calcaneus and pes valgus, which are characterized partly by strong dorsal flexion and partly by an outward twisting of the foot. Frequently the evidences of the press- ure to which the feet have been subjected are seen in an atrophic con- dition of the skin and portions of the bones. The position of the hand known as clubbed-hand or talipomanus is caused by a rudimentary development of the radius, and is usually asso- ciated with other malformations. Literature. (Changes of Position of the Extremities.) v. Amnion: Die congen chir. Krankh. d. Menschen, Berlin, 1S42. Bessel-Hagen: Pathologie u. Therapie des Klumpfusses, Heidelberg, 1889. Debersaques : Pathogenic du pied bot congen. Ann. de la Soc. de med. de Gand, 1891. Dollinger: Congenitale luxation. Langenbeck's Arch., xx., 1S77. Grawitz: Ursachen d. angeb. Huftgelenkverrenkungen. Virch. Arch., 74 Bd., 1878. Hirsch: Die Entstehung d. angeb. Hilftverrenkung. Virch. Arch., 148 Bd., 1897. Holl: Plattfuss. Langenbeck's Arch., xxv., 1880. Holtzmann: Die Entstehung d. congen. Luxationen. Virch. Arch., 140 Bd., 1895. Joachinisthal: Hilftverrenkung. Eulenburg's Jahrb., ii., 1902. Kirmisson: Chirurg. Krankheiten angeb. Ursprungs, Stuttgart, 1899. Kocher: Klumpfuss. Deut, Zeitschr. f. Chir., ix., 1870. Kronlein: Luxationen. Deut. Chir., 26 Lief., 18S2. Lorenz: Pathologie u. Therapie der angeb. Huftverrenkung, Wien, 1895. Messner: Knoehenverand. bei Pes calcaneus congen. Arch. f. klin. Chir., 42 Bd., 1892. Michaud: Pied bot congenital. Arch, de phys., hi., 1870. Miiller: Congen. Luxation im Knie. Arb. a. d. chir. Universitatspolikl. in Leipzig, 18SS. Pauly. Plattfuss. Langenbeck's Arch., xxiv., 1879. Sonnenburg: Klumpfuss. Realencyklop. d. med. Wissensch.. 1896 (Lit.). 2. Abnormal Position of the Internal Organs and of the Extremities. § 140. Of the abnormal positions of the internal organs, the most im- portant is the one known as situs inversus viscerum — i.e., a lateral transposition of the internal organs, so that the position of the thoracic and abdominal organs forms a mirror-image of the normal position. This condition has been observed both in double monsters and in single indi- viduals. It may be restricted to the heart alone, or to the abdominal organs, or more rarely to a part of the latter (situs irregularis), but the last is rare. In general, abnormal positions occur especially in the case of the abdominal organs. For example, the kidney is not infrequently MALFORMATIONS DUE TO EXCESSIVE GROWTH. 531 found in an abnormal position (dystopia rents'), usually abnormally low, so that it approaches the sacral promontory or lies in front of the same. The testis is not rarely retained within the abdominal cavity {ectopia in- terna, or abdominalis testis, or cryptorchismus), or within the inguinal canal (ectopia inguinalis), or at the external ring (ectopia pubica), or in the fold between the thigh and scrotum (ectopia cruroscrotalis), or in the peri- neal region (ectopia perinealis) , or in the fold of the groin (ectopia cru- ralis). Abnormal positions of the intestines, particularly of the colon, are not rare. (Situs Inversus.) Allmaras: Ein Fall v. Situs transversus partialis. I.-D., Freiburg, i. Br., 1904. Arneill: Transposition of the Viscera. Amer. Jour, of Med. Sc, 1902. Buhl: Transposition d. Eingeweide. Mitteil. a. d. path. Inst, zu Munchen, 1878. Geipel: Situs transverus. Festschr. z. 50-jahr. Bestehen des Krankenhauses, Dres- den, 1899. Kipper: Situs transversus. I.-D., Marburg, 1896. Koller: Situs viscerum inversus. Virch. Arch., 156 Bd., 1899. Kuchenmeister: Die angeb. vollst. Verlagerung d. Eingeweide d. Menschen, Leipzig, 1883. IiOchte: Zur. Kenntn. d. Situs transversus partialis. Beitr. v. Ziegler, xvi., 1894; Situs viscerum irregularis. lb., xxiv., 1898. Martinotti : Delia transposizione laterale dei visceri, Bologna, 1S88. "Wehn : Zur Frage d. Situs transversus. Virch. Arch., 98 Bd., 1884. 3. Malformations due to Excessive Growth or Multiplica- tions of Organs or Body-parts. § 141. The malformation known as general giant growth occurs as the result of an excessive growth of the entire body, either during intra- uterine life or later. During extra-uterine life such an abnormal growth may occur that the size of the affected individual may far exceed the maximum normal limits. Partial giant growth may also take place during infra-uterine life or after birth. The head and portions of the extremities are usually af- fected. A unilateral giant growth is usually restricted to the half of the face or to one extremity, but in very rare cases the hypertrophy may in- volve all the parts of one side : face, trunk, and extremities. In extra- uterine life trauma sometimes gives the impulse to a pathological excess of growth. Should the other tissues become so increased in any portion of the body, the extremities, the trunk, or face, that malformations resembling the skin of the pachyderms are produced, the abnormal growth is designated elephantiasis (see § 76, Pigs. 130, 131). The increase in mass may de- pend upon a new-formation of connective tissue or adipose tissue or of blood-vessels or of lymphatics. When the thickened regions are sharply circumscribed the formation is regarded as a tumor and, according to its structure, is classed with the angiomata, lymphangiomata, or fibromata (see sections treating of these tumors). Circumscribed hypertrophies of the bones occur in various portions of the skeleton, and are sometimes multiple. The bones of the skull as well as those of the face may be thus affected, and there occur cases in which the hypertrophy of the bone may be so extensive that one or 532 DISTURBANCES OF DEVELOPMENT, both of these regions may show marked disfiguration, and there are pro- duced conditions which are known under the general term of leontiasis ossea (Fig. 137). Circumscribed hypertrophies of the bones lead to the formation of osteomata or exostoses, which are often multiple. On the trunk and extremities local growths of bone may lead to the enlargement of single bones as well as to the formation of atypical excrescences known as osteomata and exostoses, which are not infrequently multiple. Literature. (Giantism.) Andersen: Riesenwuchs der Extremitaten. St. Thorn. Hosp. Rep., London, 1882. Arnheim: Congenitale halbseitige Hypertrophic. Virch. Arch., 156 Bd., 1898 (Lit.). Bessel-Hag-en . Part. Riesenwuchs u. multiple Exostosen. Langenbeck's Arch., 41 Bd., 1891. Buhl: Ein Riese mit Hyperostose. Mitth. a. d. path. lust. Miinchen, 1878. Busch : Riesenwuchs der Extremitaten. Arch, f . klin. Chir. , vii. , 1866. Curling: Riesenwuchs der Finger. Med. -Chir. Trans., xxviii., 1845. Ewald: Hypertrophic der Hand. Virch. Arch., 36 Bd., 1873. Fischer: Riesenwuchs der Extremitaten. Deut. Zeitschr. f. Chir., xii., 1880. Frankel: Makrosomia. Virch. Arch., 46 Bd., 1869. Friedberg: Riesenwuchs der Extremitaten. lb., 40 Bd., 1867. Friedrich; Halbseitige congenitale Kopfbypertrophie. Ba., 28 Bd., 1863. Gruber: Makrodaktylie. lb., 36 Bd., 1872. Hals: Makrodaktylie. D. Zeitschr. f. Chir., 37 Bd., 1S93. Little: Riesenwuchs der Extremitaten. Trans. Path. Soc. , 1866. Trelat et Monod: De l'hypertrophie unilaterale. Arch. gen. de med., 1869. Vierordt, H. : Anatom., physiol. u. physikal. Daten u. Tabellen, Jena, 1893. See also § 76. § 142. The occurrence of supernumerary organs, or of a multipli= cation of parts of the skeleton, and of the muscular system, is relatively frequent. Such phenomena are to be attributed in part to a cleavage or multiple appearance of the given anlage, and in part to a more marked development or persistence of organs which normally remain in a rudi- mentary state, or undergo retrogression during the period of growth. Further, certain of the conditions included under this head may be re- garded as reversions. 1. Duplications of the extremities. A duplication of an entire ex- tremity without the duplication of the pelvic or shoulder bones has not been observed in man. Duplication of the hands and feet is very rare (Fig. 404), but a number of cases are reported in the literature. The number of fingers may reach nine or ten. Much more frequent is a multiplication of the fingers (polydactyl- ism ) on a single hand (or foot respectively), in which condition the super- numerary fingers (or toes) are attached in part at the ulnar or radial side (or tibial and fibular sides respectively), or in part intercalated between the others (Figs. 401, a; 405). Often the fingers are duplicated only in part — that is, by the cleavage of the first or the first and second terminal joints (Figs. 406, 407). Those attached at the margin of the hand may be well developed (Fig. 405) or rudimentary. Occasionally they appear as small pedunculated fibrous tumors. In the fully developed super- numerary fingers or toes the phalanges (Fig. 405) may articulate with the metacarpal or metatarsal bones of a neighboring finger or toe, or with their own (supernumerary) carpal or tarsal bones (Fig. 401, 5a). Poly- dactylism in certain cases is inherited and is therefore dependent upon POLYDACTYLISM AND SYNDACTYLISM. 533 intrinsic causes. In individual cases polydactylism occurs as an in- heritable condition and is therefore dependent upon intrinsic causes. Fig. 404. Fig. 405. FIG. 404. —Polydactylism with forking of the hand. (After Lancereaux.) Fig. 405.— Polydactylism in a new-born child. Skeleton. Duplication of the phalanges of the fourth and fifth tinkers. Natural size. Fig. 406. Fig. 407. Fig. 406. -Polydactylism and syndactylism of the left hand. Reduced one-fifth. Fig. 407.— Polydactylism and syndactylism of the right foot. Reduced one-nfth. 534 DISTURBANCES OF DEVELOPMENT. 2. Supernumerary nipples and breasts ( hyperthelia, hyper= mastia) are not uncommon malformations in both sexes, and are prob- ably to be regarded as a reversion to polymastia racial ancestors. The supernumerary organs are usually situated on the thorax, along two lines converging from the axillary to the inguinal regions, but in rare cases they may be found elsewhere — in the axilla, on the shoulder, on the abdomen, back or thigh. They are usually small, but in the event of pregnancy may take on functional activity. The number of the nipples may reach as high as ten. 3. The formation in men of breasts resembling those of women ( gynecomastia ) is rarely seen in well-developed men with normal sex- ual apparatus (see Hermapkrodisin, § 143), but it not infrecpiently hap- pens that the male breast undergoes a moderate enlargement at the time of puberty. 4. Duplication of the penis is of very rare occurrence, and may be associated with the formation of two urethra; having independent open- ings into the bladder, and with two scrota, the two penises being typi- cally developed (Lange). 5. Supernumerary bones and muscles are of frequent occurrence. Supernumerary vertebrae may be found in any part of the spinal column ; and at its lower end may in rare cases cause a lengthening of the column, resulting in the formation of a tail. According to Virchow, three forms of tails may be distinguished: true tails containing bones ; false or im- perfect tails which represent an elongation of the vertebral column, but contain neither cartilage nor bones (so-called pig's-tail) ; and tail-like appendages of skin which consist of different forms of tissue, and in part are to be classed with the teratomata. The true tails are very rare ; ac- cording to Bartels, they are more often the result of a separation or elongation of the vertebrae than of an increase in their number. Reduplication of the phalanges of one fiuger is very rare. Supernumerary ribs in the neck or lumbar region, as well as a forking of the libs, are not rare. Supernumerary teeth also occur. 6. Duplication or cleavage of the anlage of the thoracic and abdom- inal organs occurs most frecprently in the case of the spleen, pancreas, adrenals, ureters, pelvis of the kidneys, and lungs, more rarely in case of the ovary, liver, kidney, testicle, and bladder. Literature. (Supernumerary Organs or Parts.) D'Adjutolo: Contrib. alio studio delle variety numericke delle vertebre. IlMorgagni xxx., 1888. Ballowitz: Weichteile bei Hyperdaktylie. Virch. Arch., 178 Bd.. 1904. Bartels: Schwanzbildung. Arch, f. Anthrop., 15 Bd., 1884. Boinet: Polydactylie et atavisme. Bev. domed., xviii. , 1898. Bonnet: Die Mammaorgane. Ergebn. d. Anat. , it, Wiesbaden, 1893. Buschan: Polymastie. Eulefiburg's Realeacyklop., xix., 1898 (Lit.). Ecker: Schwanzbildung. Arch. f. Anthrop., xi.; Arch. f. Anat., 1880. Freund: Schwanzbildung beim Menschen. Virch. Arch., 104 I'd., 1886. Gegenbaur: Exit. Bemerkungen uber Polydaktylie als Atavismus. Morpli. Jahrb 1880. Gerlach: Schwanzbildung. Morph. Jahrb., vi. Hagenbach: Angeb. Sacrococcygeal tumoren. A. f. klin. Chir., 66 Bd., 1902. Harrison: Tails in Man. Johns Hopkins Hosp Bull., xii., 1901. Hennigu. Rauber: Ein Fall von geschw&nztem Menschen. Virch. Arch., 105 Bd 1886. HERMAPHRODISM. 535 Joachimsthal : Hyperphalangie. Virch. Arch., 151 Bd. ; Die angeb. Verbild. d. ob. Extremitat, Hamburg, 1900. Jolly: Polydaktylie m. Missbild. d. Arms. Int. Beitr., Festschr f. Virch., i., Berlin, 1891. Klaussner: Ueber Missbildungen d. menschl. Gliedmaassen, Wiesbaden, 1900. Kohlbrug-g-e : Schwanzbildung u. Steissdrusc. Natuurk Tijdschr. voor Ned. Ind. , 1897. Kollmann: Handskelet u. Hyperdaktylie. Anat. Anz., iii., 1888. Kiittner: Verdoppelung des Penis. Beitr. v. Bruns, xv., 1896. Lang-e: Complete Verdoppelung des Penis. Beitr. v. Ziegler, xxiv., 1898 (Lit.). Laurent: Les bisexues, gynecomastes et hermaphrodites, Paris, 1891. Leichtenstern : Supernumeriire Briisle u. Brustwarzen. Virch. Arch., 73 Bd., 1878 (Lit.). Levin; Ueberzalil. kleine Finger. Virch. Arch., 142 Bd., 1895. Lissner: Schwanzbildung beim Menschen. Virch. Arch., 99 Bd., 1887. Neugebauer: Polymastie mit 10 Brustwarzen. Cbl. f. Gyn , 188G; 35 Falle v. Ver- dopp. d iiuss. Genitalien. Monatsschr. f. Gebh., vii., 1897. Otto: Monstrorum sexcentorum descriptio anatomica, 1844. Pfltzner: Doppelbildung d. 5 Zehe. Morph. Arb., 1895 ; Verdoppelung d. Zeigefingers. lb., vii., 1897; Missbild. d. Extremitatenskelets. lb., viii., 1898. Piatnisky: Bau des menschlichen Schwanzes. Inaug.-Diss., Petersburg; Anat. Anz., viii., 1893 Schmidt: Normale Hyperthelie menschl. Embryoncn. Anat. Anz., xi., 1890. Bell: llyperthelie, Hypermastie u. Gj r nakomastie. Ber. d. Naturf. Gcs., Freiburg, ix., 1894 (Lit.). Stieda: Gyniikomastie. Beitr. v. Bruns, xiv.,1895. Stahr: Congen. Tumor am kl. Finger. Virch. Arch., 151 Bd., Buppl , 1898. Virchow: Schwanzbildung. Deut. med. Woeh., 1884. Viorin: Polydaktylie bei Ungulaten. Z. f. Tiermed., vi., 1902. "Wiedersheim: Der Bau des Menschen, Freiburg i. B., 1902. Zander: 1st die Polydaktylie theromorphe Varietal Oder Missbildung? Virch. Arch., 125 Bd., 1891 4. True and False Hermaphkodism. § 143. The fact that the sexual organs, both the sexual glands and the external genitals, of both sexes, develop from originally similar anlage which contain the beginnings of all the sexual organs of both sexes, makes it apriori probable that malformations might result through unequal development of the anlage of the right and left sides, or through a simultaneous development of organs peculiar to both sexes, or finally through a lack of harmonious development of the external and internal genitals. Those malformations which are to be referred to some one of the factors named, and which are characterized by the fact that the sexual apparatus of a single individual contains parts belonging to both the male and female, are grouped under the designation hermaphrodismus. When both sexual glands (testis and ovary) are p resent the condition is called hermaphrodismus verus (hermaphrodismus glandularis, Siegenbeek van Heukelom). If the mixing of sexual characteristics consists merely of a combination of male and female genital passages with the external geni- talia of the opposite sex, the condition is known as pseudohermaphro- dismus. The true sex is determined by the nature of the sexual glands. The body build of hermaphrodites f recpiently shows a curious mixture of male and female characteristics. For example, the breasts, neck, and shoulders may correspond to the female type, while the development of the beard, face, larynx, and voice may correspond to the male type. In false hermaphrodites the body characteristics do not always correspond to the true nature of the sexual glands ; a male may resemble a female, and vice versa. 536 DISTURBANCES OF DEVELOPMENT. The following chief types of hermaphrodism maybe distinguished: 1. Hermaphrodismus verus or androgynes. — 1. Hermaphrodismus verus bi- lateralis, or double-sided hermaphrodism, is characterized by the presence on both sides of both ovary and testis, or the presence on both sides of an organ containing both ovarian and testicular tissue. Heppner asserts that in a nine-months-old child, having hermaphroditic external genitals, with vagina, uterus, and tubes, both ovary and testis were found in the broad ligament; epididymis and vas deferens were wanting. 2. H ermaphrodismus verus unilateralis, or one-sided hermaphrodism, is that con- dition in which upon one side there exists but one sexual gland, while on the other both testis and ovary are present. Salen has reported a case of a woman of forty-three years of age, who had menstruated since her seventeenth year, in whom there was found upon the right side (castration on account of uterine myoma) a hermaphroditic Fig. 408. —Hermaphrodismus verus lateralis. (After Obolonsky.) a. Urethra: b, prostate: c, colliculus seminalis; d, hymen ; c, cunalis uroRenitalls ; /, bladder: [/, vagina; ft, uterus; 7t,, left uterine horn ; (, left tube; ■(,, in'fundibulum of left tube: it, left ovary; ?, ligamentum ovarii: m, ligamentum teres sin- istrum; ro, right tube; o, right testicle ; p, epididymis ; q, right vas deferens; r, ligamentum teres dextrum. About one-half natural size. (Specimen in the collection of the Pathological Institute of the German Uni- versity in Prague.) gland, the nature of which was confirmed by accurate microscopical examination. The ovarian portion of the gland was typically developed; the epithelium of the seminifer- ous tubules of the testicular portion consisted of follicular cells and cells of Sertoli, but lacked spermatogonia and seminal cells. Blacker and Lawrence have also de- scribed a case of hermaphroditic gland occurring in a child still-born at eight and a half months. In the hernial sac of an individual twenty years old Garri demonstrated the presence of a tube and both sexual glands with parovarium and epididymis (the microscopical examination was made by Simon). 3. II 'ermaphrodismus verus lateralis is that condition in which there is an ovary on one side and a testis on the other. It has been many times observed in man (Rudolph , Stark, Berthold, Barkoio, H. Meyers, Klebs, Messner, Kellner, and others), though in the majority of cases no careful microscopical examination was made, and when carried out, ovarian tissue could not with certainty be demonstrated. Several years ago Obolonsky reported a case (a twelve-year-old-girl) from the collection of the German University in Prague, in which the histological examination showed on the right side a testicle (Fig. 408, o), and on the left side an ovary (k), but it is to be noted that ova were not seen in the latter. The right broad ligament contained a testis (o), an epi- didymis (/>), a vas deferens (q), a rudimentary tube (»), a round ligament (r); the left broad ligament, on the other hand, contained an ovary (/,:), with an ovarian ligament (0, and a well-developed tube (t). Moreover, a uterus (h), vagina (g), and also a prostate (6) were present. According to the reported observations, the" corresponding HEKMAFiiKODISM. 537' sexual passages may be present or in part wanting. The external genitals are mal- formed, and combine structures belonging to both sexes. II. Hermaphrodismus spurius, or pseudohermaphrodismus, is characterized by a bisexual development of the sexual passages and external sexual organs in associa- tion with a unisexual development of the essential sexual gland. The most pronounced cases occur in males, who, in addition to their proper sexual organs, possess a more or less well-developed vagina, uterus, and tubes. It is much more rare to find in females a development of a portion of the Wolffian duct. In male false hermaphrodites the external genitals are frequently malformed aud approach the. female type, while in female false hermaphrodites the external genitals resemble those of the male (Fig. 409). The resemblance of the male external genitals to those of the female is brought about by a stunting of the penis and a total or partial failure of the sexual furrow in the penis to close (hypospadias), so that the two halves of the scrotum are separated, leaving a depression beneath the root of the penis, which represents the remains of the sinus urogenitalis. The scrotal halves come, therefore, to resemble the labia majora, particularly in the case of non-descent of the testicles. The external genitals of the female approach in appearance those of the male through the development of the clitoris into a sort of penis (Fig. 409, a), while the vaginal opening is narrowed or closed through the union of the labia. The vagina and urethra have a com- mon opening, or open separately be- neath the penis-like clitoris. The atypical development of the external genitals may or may not be associated with malformations of the sexual passages, and is, therefore, not dependent upon malformations in other portions of the sexual apparatus. 1. Pseudohermaphrodismui masculi- nus occurs in three varieties: First, pseudohermaphrodismus mas- culinus interims, in which condition the external genitals are of the male type, and the prostate is developed, but. is usually pierced at the colliculus semin- alis by a canal opening into the urethra, the former being continued above into a rudimentary or more or less well-de- veloped vagina, often also into a more or less well-formed uterus, and even tubes. The male organs may be well developed or more or less malformed. Second , pseudohermaphrodismus mas- culinus eompletus, or externus et internus, in whichform the vagina, uterus, and tubes are present in a state of rudimentary or more or less complete development, while the external genitals resemble more or less com- pletely the female type. The penis presents the condition of hypospadias and resembles the clitoris; beneath it lies a furrow at whose posterior end there is usually an orifice leading into a short vestibule which divides at once into a urethra and a vagina. Some- times the vagina and vestibule are separate. In rare cases the external genitals appear normal, but the penis contains a double canal, the upper one representing the urethra, the other the sexual passage. In the case of a more marked development of the ducts of Muller the vasa deferentia are frequently defective, and the seminal vesicles are sometimes wanting. Third, pseudohermaphrodismus maseulinus externus, in which only the external genitals depart from the male type, and resemble more or less closely the female. As in these cases the bodily habitus often simulates that of the female, the true sex of the individual may easily be mistaken. 2. Pseudohermaphrodismus femininus also occurs in three similar varieties, but is much more rare. In pseudohermaphrodismus femininus internus rudiments of the Wolffian ducts, lying in the broad ligament or in the uterovaginal wall, and sometimes extending to the clitoris, are found in association with well-developed external genitals. Fig. 409.— External genitals of a female false her- maphrodite, with stenosis of the vaginal orince. a. Penis-like clitoris ; b, labia majora. Reduced one- ninth. 538 DISTURBANCES OF DEVELOPMENT. Pseud 'ohermaphrodismus femininus externus is characterized by external genitalia resembling those of the male (Fig. 409). Pseudohermaphrodismus femininus cxtemus et interims, in which the external genitals resemble those of the male and there is a persistence of parts of the W olffian duets, is very rare. Of the internal male genitalia, there was found in one case a pros- tate, and in another case a prostate pierced by the vagina, an ejaculatory duct, and a sac resembling a seminal vesicle, which opened into the vagina. The internal sexual organs develop from the same undifferentiated anlage in both males and females. These anlage consist of a sexual gland lying on the medial ante rior side of the Wolffian body, and a sexual passage known as the duct of Mitller. The latter develops beside the Wolffian duet, and, like it, empties into the lower end of the bladder or into the sinus urogenitalis. In the male the duct of Midler disappears, only slight traces in the form of the uterus masculinus or vesicula prostatica remaining; the primitive sexual gland unites with a small part of the Wolffian body, which becomes the head of the epididymis, another small portion forming the vasa aberrantia testis (organ of Giraldes), the re- mainder disappears, while the Wolffian duct becomes the vas deferens and vesicula seminalis. In the female the Wolffian body and its duct disappear, leaving only a trace in the form of the gland-tubules known as the parovarium, but remains of the duct are not infrequently found preserved in the uterine wall. From the duels of Midler, which in part coalesce at their lower ends, develop the vagina, uterus, and tubes. The extreme upper end of the duet of Mailer not infrequently persists in the form of a little pedicled sac attached to the abdominal end of the tube, the hydatid of Morgagni. The anlage of the sexual glands appear in the fifth week. In mammalia (probably also in man) they develop through a localized thickening of the peritoneal epithelium, which becomes the germinal epithelium ( Waldeyer), while at the same time the meso- derm also proliferates. Whether the seminal tubules arise from peritoneal epithelium (Bornhaupt Egli), or whether the}' are derived from an ingrowth of the Wolffian body into the testis-anlage ( Waldeyer), is still an undecided question (Kblliker). The ova arise from germinal epithelium. The environing cells of the Graafian follicle are regarded by Waldeyer as also derived from the germinal epithelium; while Kblliker believes that they probably arise from the Wolffian body. The significance of the pedunculated and non-pedunculated hydatids, found in vary- ing numbers near the globus major of the epididymis, is not yet determined (Kblliker). The non-pedunculated cyst known as the hydatid of Morgagni is regarded by Waldeyer as a remnant of the duct of Mutter. According to Hotli, it may also stand in a close relation to the Wolffian body, inasmuch as there is occasionally found a vas aberrans of the epididymis communicating with it. In the development of the vagina and uterus the duets of Mailer and the Wolffian ducts unite at their lower portion to form a rounded quadrangular cord, the genital cord. At the end of the second month the ducts of Midler blend to form a single canal, which then develops into the vagina and uterus. This union takes place first near the middle of the genital cord. The Wolffian ducts play no role, though remains of these are found at birth in the broad ligament (Kblliker) and in the wall of the uterus (Beigel). According to observations of Riedel, remains of the Wolffian duct are found in about a third of adult females, in the form of a tube lined by cylindrical epithelium surrounded by muscle, or as a muscle-bundle without epithelium, lying anteriorly and to the side of the uterus and vagina. The external genitals begin to develop, even before the cloaca has separated into the intestinal and genito-urinary orifices, by the formation, in the sixth week, of a me- dian genital tubercle in front of the cloaca, and further, of two lateral folds, the genital folds. Toward the end of the second month the tubercle becomes more prominent, and shows on its lower surface a furrow, the genital furrow. In the third month the cloaca becomes divided to form the anal and genito-urinary openings. In the male embryo the genital tubercle becomes the penis, the glans being recognizable as early as the third month. In the fourth month the furrow closes to form a tube; at the same time the two genital folds unite to form the scrotum. The prepuce is formed in the fourth month. The prostate arises in the third month as a thickening of the tissues at the junction of the urethra and the genital cord. The glands of the prostate develop in the fourth month from the epithelium of the canal and grow out into the surrounding connective tissue. In the female embryo the closure of the genital furrow and the genital folds does Dot take place, so that the sinus urogenitalis remains short. The genital eminence becomes the clitoris, the folds become the labia majora, and the edges of the genital furrow the labia minora. HERMAPHRODISM. 539 Literature. (Trite and False Mermaphrodism.) Abel: Pseudohermaphrodismus masculinus. Virch. Arch.. 126 Bd. 1891 Arnold, J. : Uterus masculinus. Virch. Arch., 47 Bd., 1869. Becker: Ueber Zwitterbildung. Wilrzburger Verb., 1896. Benda: Hermaphrodismus. Ergebn. d. allg. Path., ii., 1897. Blacker aud Lawrence: Case of True Unilateral Hermaphrodismus with Ovotestis in Man. Trans, of the Obstetr. Soc. of London, xxxviii. Briibl: Ueber Hermaphrodismus. Inaug. -Diss., Freiburg, 1894. Creccbio: Hermaphrodismus fern, extern, et intern. Wien. med. Presse, 1866. Debierre: L'hermaphrodisme, Paris, 1891. Garre: Echter Hermaphrodismus. D. med. Woch., 1903. Henrichsen: Pseudohermaphr. mascul. extern, completus. Virch. Arch., 94 Bd., 1883. Heppner: Hermaphrodismus verus. Du Bois-Reyrnond's Arch., 1870; ref. Cbl. f. d. med. Wiss., 1871. Keibel: Entwickelungsgesch. d. Urogenitalapparatus. Arch. f. Auat., 1896. Kellner: Ilermaphroditismus lateralis. D. med. Woch., 1902. Klebs: Haudb. d. pathol. Auat., i. Bd., 2 Abth., Berlin, 1876. Klorpsch: Hermaphrodismus verus beim Schweine. Anat. Anz., xii., 1896. Laurent: Les bisexues, gynecomastes et hermaphrodites, Paris, 1894. Lukscb: Hermaphrodismus spur. masc. int. Zeit. f. Heilk., xix., 1900. Marchand: Hermaphrodismus spurius masculinus? Virch. Arch., 92 Bd., 1883. Messner: Hermaphrodismus verus. Virch. Arch., 129 Bd., 1892. Nagel: Entwiekelungsfehler weibl. Genitalien. Handb. d. Gyn., i., 1897. Neugebauer: Beobacht. a. d. Gebiete des Scheinzwittertums. Leipzig, 1904 (Lit.). Nonne: Pseudohermaphrodismus mascul. Jahrb. d. Hamb. Krankenanst., ii., Leip- zig, 1893. Obolonsky: Zur pathol. Anat. d. Hermaphrodismus hominis. Zeitschr. f. Heilk., ix., 1888. Putz: Hermaphrodismus verus unilateralis b. Schweine. Deut. Zeitschr. f. Thiermed., xv., 1889. Raake: Hermaphrodismus spur. masc. int. Wilrzburger Verh. , 1896. (Lit). Salen: Hermaphrodismus verus unilateralis. Verh, d. Deut. path. Ges., ii., Berlin, 1900. Scbmorl: Ein Fall von Hermaphrodismus. Virch. Arch., 113 Bd., 1888. Siegenbeek van Heukelom: Tubuliirer und glandularer Hermaphrodismus. Beitr. v. Ziegler, xxiii., 1898. Simon: Hermaphrodismus verus, Virch. Arch., 172 Bd., 1903 (Lit.). Stroebe: Pseudohermaphrodismus masc. int. Beitr. v. Ziegler, xxii.. 1897. Taruffi: L'Ermafrodismu. Mem. della Ace. delle .Sc. dell' 1st. di Bologna, 1899 (Lit.); Hermaphrodismus u. Zeugungsfahigkeit. Berlin, 1902 (Lit.) Vircbow: Wilrzburger Verh. HI. Berl. klin. Woch., 1872; Ges. Abh., Frankfurt, 1856. Wermann: Pseudohermaphrodismus masculinus completus. Virch. Arch., 104 Bd , 1886. Winkler: Pseudohermaphrodismus masculinus interims. Inaug. Diss., Zurich, 1893. Zweifel: Krankh. d. iiuss. weibl. Genitalieu. Hanbd. d. Frauenkrankh., iii., Stutt- gart, 1886. 5. Double Monsters. («) Classification of Double Monsters. § 144. Twin=formations lying within a single chorion may be divided, into two large groups: twins completely separated from one another, aud twins united by some portion of their bodies. Of the twins completely separated from one another there may be distinguished two types; one in which both twins are fully developed, and one iu which one twin is stunted. Twins joined together by portions of their bodies niay likewise be also divided into two groups: twins showing uniform development and twins 640 DISTURBANCES OF DEVELOPMENT. showing an unequal development. To the latter belongs an especial group of greatly stunted parasitic forms that may be classed as teratomata. According to the situation of the duplicated portions of the body, there may be distinuished (Foerster) : 1. Monstra duplicia katadidyma or duplicitas anterior. 2. Monstra duplicia anadidyma or duplicitas posterior. 3. Monstra duplicia auakatadidyma or duplicitas parallela. In general, these may also be con- veniently divided into three classes (Tarum): 1. Twins united chiefly by the epigastrium and thorax. 2. Twins united chiefly by the heads. 3. Twins united chiefly by the pelves. FiU. -L0. Fl.i. 411. Fig. 410.— Acardius acephalus, showing a rudimentary development of the lower extremities (acardius amorphus). Fig. 411. — Acardius pseudoacormus. (After Barkow.) a, Head; fo, rudiment of the left upper ex- tremity; c. rudimentary intestine ; (/, artery ; e, vein. Ahlfeld divides the double monsters into two chief groups, those with complete and those with partial doubling of the axial structures. In very rare instances triple monsters occur. Literature. (Double Monsters.) Ahlfeld: Die Missbiklungen des Menschen, Leipzig, 1880, 1882. Foerster: Die Missbildungen des Menschen, Jena, 1865. Marchand: Missbildungen. Eulenburg's Realencyklopadie, xv., 1897. Taruffi: Still' ordinamento della teratologia. Mem. della R. Ace. delle Scienze dell' Istituto di Bologna, v., 1896; vii., 1898. See also § 131. (b) The Chief Forms of Double Monsters. § 145. Twins separated from each other and lying within a single chorion are designated homologous twins. They are always of the same DOUBLE MONSTERS. 541 sex, have usually a common placenta, and resemble each other very closely. If from any cause one of the twins should die after its body has been developed, it may be pressed flat by the continued growth of its fellow, giving rise to the condition known as foetus papyraceus. When twins possess a common placenta within which the blood- vessels have abundant anastomoses, the heart of the stronger foetus may control the circulation and thereby cause changes in the direction of the blood-stream in the weaker twin. As ? result of this the latter .suf- fers severe disturbances of development, and becomes changed into an acardius, a monster without a heart, either developing no heart at all or only a rudimentary one. In the majority of such cases the head also fails to develop (acardius acephalus) or remains rudimentary (acardius paraceph- alus), and likewise there is usually no development, or only a rudimen- tary one, of the upper extremities, thorax walls, lungs, and liver, while the abdomen, pelvis, and lower extremities are more or less perfectly formed (Fig. 410). According to the development of the extremities the following varieties may be distinguished: acardius paracepalus (or acephalus) sympus, monopus, dipus, monobrachius, dibrachius. In rarer cases there is no recognizable development of any part of the body, and there is formed an acardius amorphus, consisting of a shapeless mass covered with skin, usually without any indications of extremities, and possessing internally only rudiments of organs. Of very rare occurrence is the formation known as an acardius pseu- doacormus (Fig. 411) — that is, a monster in which the head (a) only is de- veloped, while the other parts of the body are represented only by small rudiments (b, c). Literature. (Acardius.) Barkow: Pseudoacormus, Breslau, 1854. Claudius: Die Entwickelung der herzlosen Missgeburten, Kiel, 1859. Dareste: Compt. rent, de l'Acad. des sciences, 18(35, 1873. Heller: Acardiacus amorphus. Virch. Arch., 129 Bd., 1890. Hirschbrucli : Das Problem der herzlosen Missgeburten. Inaug.-Diss., Berlin, 1895. Lowy: Acardiacus anceps. Prag. med. Wocli., 1892. Mulder: Ueber cine herzlose Missgeburt. Inaug.-Diss., Freiburg, 1891. Orth: Drei menschl. Missgeburten. Virch. Arch., 54 Bd., 1872. Panum: Zur Kenntn. d. phys. Bedeutung d. angeb. Missbildungen. Virch. Arch., 72 Bd., 1878. Perls- Lehrb. d. allgem. Pathologie, ii., Stuttgart, 1879, 1886. See also § 147. § 146. Twins equally developed and united to each other occur in the following principal types : 1. Duplicitas anterior (monstra duplicia hatadidyma). Anterior du- plication with union of posterior portions of the body. Pygopagus (Fig. 412). Union of the twins in the region of the coccyx or of the sacrum. According as the union is more or less exten- sive, the sacrum, coccyx, lower end of the medullary canal, anus, lower end of the bowel, and the sexual apparatus are either doubled or are in part single. Ischiopagus (Fig. 413). Union of the twins in the pelvis, which thereby forms a wide ring, the two sacra being placed opposite each other. The anus, lower end of the bowel, and the sexual organs may be single or double, and the number of the lower extremities two to four. 542 DISTURBANCES OF DEVELOPMENT. Dicephalus (Fig. 414) and diprosopus (Fig. 415). The duplication is limited to the upper part of the trunk and head, or only to the neck and head, or the head alone, or, finally, only to portions of the head. As the external blending increases in extent, there occurs also a blending FIG. 413. Fig. 412.— Pygopagus. (After Marchand.) A. B, The two twins; a, h, separated umbilical cords; c, blended umbilical cords ; d, common placenta. There is a single coccyx and sacrum (from the second vertebra downward), and the lower end of the medullary canal is single. The two intestinal canals ter- minate in one anal opening. Vestibule of vagina single, the remaining portions of the sexual organs double. Fig. 413.— Ischiopagus. (After Levy.) of the internal organs, the intestine, liver, lungs, heart, spinal cord, brain, etc. According to the number of the lower and upper extremi- ties there may be distinguished dicephalus tetrapus, dvpus, tetrabrachius, tribrachius dibrachius (Fig. 414). When the heads have blended there may be distinguished diprosopus tetrophthalmus, triophthalmus, diophthalmus, tetrotus, triotus, diotus, distomus, monostomus, tribrachius and dibrachius (Fig. 415). The mildest grades of duplicitas anterior are represented by the rare cases of duplication of the jaw, mouth, or nose. 2. Duplicitas posterior (monstra duplicia anadidi/ma). Union of the twins at the head and thence farther downward with duplication of the posterior parts of the body. Craniopagys (Fig. 416). Union of the twins in the cranial region. According to the site of union there may be distinguished craniopagus parietalis, frontalis, occipitalis. When the union is more extensive por- tions of the brain are also single. Cephalothoracopagus or syncephalus (Fig. 417). Blending of the DOUBLE MONSTERS. 543 twins in the region of the forehead and face, and in part also of the abdomen. In the region of the united heads there is an anterior and a posterior face (janus, janiceps). The two faces may be equally (janus symmetros) or unequally developed (janus asymmetros), one face being well developed, the other imperfectly. The internal organs present dif- ferent degrees of blending and union into single organs. Dipygus. The duplication is limited to the lower half of the body and the lower extremities, while the upper parts are either wholly single or only partly cleft. The duplication of the spinal cord may begin at different heights. According to the number of extremities different Fig. 414.— Dicephalus dibrachius dipus. FIG. 415.- -IMprosopus distomus tetropMhalmus dlo- tus dibrachius. forms may be distinguished. The mildest grades of duplication are con- fined to the lower end of the spinal column, the anus, and the external genitals. 3. Duplicitas parallela (monstra duplicia andkatadidynm) . Duplica- tion of the anterior and posterior ends of the body with parallel positions of the trunk. Thoracopagus (Pig. 418). Union of the twins by the thorax. Ac- cording to the site and extent of the union, as well as the number of ex- tremities present, there may be distinguished different forms, particularly the following: xiphopagus (union at the xiphoid process), stemopagus (union at the sternum), thoracopagus tetrabrachius, tribrachius, dibrachius, tetrapus, tripus, and dipus. When portions of the faces have blended 544 DISTURB AXCES OF DEVELOPMENT. there results a, prosopothoracopagus. Blending and union of the internal organs into single organs vary with the degree of external blending. The heart may be double or single, in the latter case malformed. Thoracopagus is relatively fre- quent. Rachipagus. Blending of the twins in the region of the spinal column is very rare. Literature. (Double Monsters.) Ahlfeld: Die Missbildungen cles Menschen, Leipzig, 1880. Barkow: Monstra animalium duplicia per anatomen in- dagata, Lipsias, 1828. Burckhard: Zwei Doppelmissbildvtngen. Zeit f. Gebb.., xl., 1898. FIG. 416. Fig. 417. Fig. 416.— Craniopagus parietalis. Fir,. 417.— Cephalotboracopagus or syncephalus, with Janus head. Both anteriorand posterior fares am malformed, and possess but one eye, while the nose Is represented by a proboscis-like organ situated, above Henneberg: Verhaltend. Pygopagen Rosa u. Josefa. Berl. klin. Woch., 1903 Kamann: Thoracopagus tetrabrachius. A. f. Gyn., 68 Bel., 1903. Lochte: Doppelmissbildungen. Beitr. v. Ziegler. xvi., 1894.' Marchand: Pygopagus. Beitr. v. Ziegler, xvii., 1895; Missbildungen Eulcnb Realencyklop., 1897. Martinotti e Sperino : Diprosopus tetrophthalmus. Internat. Monatsschr. f. An v 1888. DOUBLE MONSTERS. 545 Ruhe: Janiceps asymmetros. Inaug.-Diss., Marburg, 189,5. Schaefer: Ueber einen Dicephalus. Beitr. v. Ziegler, xxvii., 1900. Siegenbeek van Heukelom: Monstr. double. Rec. de trav. du Lab. Boerhaave, i., 1899. Taruffi: Syncephalus dileoanus (Verdopp v. Penis, Scrotum, Anus). Mem. R. Ace. Bologna, ix., 1889; Feto umano con due mandibole. lb., ii., 1895. Virchow: Pygopagus. Berl. klin. Woch., 1873. See also ^§ 131 and 147. § 147. Twins joined together but unequally developed may occur iu any of the double forms described iu § 146. If the development of one of the twins remains rudimentary and if its heart does not develop, its nourishment can come only through its well-developed fellow. The better developed of the two is then known as the autosite, the other as the parasite. If the parasite is of only very rudimentary development, it may be classed with the bigerminal teratomata (cf . §§ 127 and 128). Fig. 418.— Thoracopagus tribrachius tripus. The hand of tne third arm, common to ooth halves, possesses two dorsal surfaces, and the laterally distorted fingers possess nails on ooth sides. The common third foot has eight toes. At the posterior ends of the body there may occur a rudimentary double monstrosity in the form of an increase in the number of the extremities, a polymelos (Figs. 419, 420). In so far as the lower extremities are con- cerned such a malformation may be classed as an ischiopagus or a dipy- gus. The supernumerary extremities may be one or two in number, and more or less well developed. Further, there not infrequently occur coccygeal teratomata in which the presence of rudimentary extremities (Fig. 421, a, b, c) or of various body elements leaves no doubt that the tumor-like formation covered by the skin of the autosite is to be regarded 35 546 DISTURBANCES OF DEVELOPMENT. as a double monster, a rudimentary pygopagus, or else as dipygus parasiticus. Such a parasite is designated as an epipygus. Supernumerary extremities (Fig. 422) may also be found upon tne FIG. 419.— Polymelos. (After Lancereaux.) Fig. 420.— Polymelos. (After Liesching.) FIG. 421. FIG. 422. FIG. 421.— Bigerminal teratoma of the coccygeal region (pygopagus parasiticus), a, 6, c. Extremities lying In a sac formed by the skin of the autosite. Fig. 422.— Thoracopagus parasiticus (thoracomelus). Three legs spring from the pelvis ; one of them Las a double foot. Two upper extremities project from the anterior cnest-wall. DOUBLE MONSTERS. 547 trunk, or there may occur a headless trunk with extremities (Fig. 423), or a rudimentary thorax without extremities, or, finally, teratomata which may be interpreted as thoracopagus parasiticus (omphalopagus) and as dipygus para- siticus. The malformation is also often called epigastrius. The inclusion of such teratomata beneath the skin of the abdomen or thorax, or within the abdominal or thoracic cavities of the autosite, gives rise to the condition known as inclusio fcetalis subcutanea, or abdom- inalis, or mediastinalis. The abdominal inclusion is also designated engastrius. FIG. 423. FIG. 424. Fig. 423.— Thoracopagus parasiticus. (After Schenk von Grafenoerg.) Parasite attached to chest of autosite. Fig. 424.— Epignathus. (After Lancereaux.) In the region of the head rudimentary twin -formations appear most often in the mouth cavity, forming usually an amorphous mass, firmly attached to the base of the skull, and consisting of skin, connective tis- sue, cartilage, bone, brain-tissue, teeth, intestinal elements and muscle, and rarely developed extremities. Such malformations are included under the designation of epignathus (Fig. 424). On other parts of the head (prosopopagus parasiticus) rudimentary twin formations or bigerminal teratomata are very rare (cf. §§ 127, 128) ; but they occur also in the cranial cavity (encranius) and in the neck (hygroma colli). Literature. ( Unequal Double Monsters.) Bohrn: Sacralteratom. Berl. klin. Woch., 1872. Braune: Die Doppelbildungen u. angeb. Geschwiilste d. Kreuzbeingegend, Leipzig. 1862. Breslau u. Rindfleisch: Foetus in foetu. Viroh. Arch., 30 Bd., 1864. Calbet: Contrib. a l'et. des tumeurs congen. d'origtne parasitaire de la region sacro- coccygienne, Paris, 1893. Foederl: Dipygus parasiticus. Langenbeck's Arch., 58 Bd., 1899. 548 DISTURBANCES OF DEVELOPMENT. Freyer: Kreuzbeingeschwulst. Virol). Arch., 58 Bd., 1873. Gross: Les monstres doubles parasitaires, Nancy, 1877. Hennig: Congenitale echte Sacral tumoren. Beitr. v. Ziegler, xxviii., 1900. Israel: Ein Fall von Verdoppelung der 1. Unterkieferhalfte. Inaug.-Diss. Berlin, 1867. Moussaud: Des inclusions foetales. These de Paris, 1861. Otto: Zusammenstellung d. bestbeschrieb. Falle v. Epignathu's. Arch. f. Gyn., viii. Schwalbe: Der Epignathus. Beitr. v. Ziegler, xxxvi., 1904. Schwarz: Beitr. z. Geschichte d. Foetus in foetu, Marburg, 1860. Taruffi: Caso d'engastro amorfo extraperitoneale. Mem. R. Ace. Bologna, iii., 1893. Wright and Wy lie: Included Foetus. Brit. Med. Journ., ii., 1900. See also §§ 127, 128, 131, 144, and 146. CHAPTER X. The Pathogenic Fission-fungi and the Diseases Caused by Them. I. General Considerations Regarding the Schizomycetes or Fission- fungi. 1. G-eneeal Morphology and Biology of the Fission-fungi. § 148. The Schizomycetes or fission-fungi, often also designated collectively as bacteria, belong to the protophytes — that is, to the smallest simplest forms of plant-life. Many of them are so small that they stand upon the very border-line of invisibility even with the use of the highest- power objectives and eye-pieces. When occurring in animal tissues, it is often very difficult to distinguish them from the products of cell-dis- integration; and often this can be accomplished only through the em- ployment of specific reagents or staining-methods, and occasionally only through culture experiments. The Schizomycetes throughout are non-chlorophyllaeeous, unicellular or- ganisms, but as a result of their growth and multiplication they often form colonies made up of numerous cells. The form and character of the single cells, as well as their manner of growth, division, and multiplication, vary greatly, and at present these differences are used as a basis for the classification of bacteria. In the first class are placed the Cocci, often designated as Micrococci or as Sphcero- bdcteria (Cohn), that form of bacteria which constantly occurs in the form of spherical or oval cells. According to the grouping of the cells during their division, there may be distinguished six forms of cocci: double-cocci or Diplococci, chain-cocci or Streptococci, clustered cocci or Staph- ylococci, tablet-cocci or Merismopedia , packet-shaped cocci or Sarcince, and tube-cocci or Ascococci. The second class constitutes the Bacilli (rod-shaped bacteria) which formerly were divided by Cohn into Microbacteria and Desmobacteria, ac- cording to the length of the rods. These may also be designated as short rods and long rods. In association with the designation bacillus many authors use the term Clostridium, particularly for bacilli which during spore-formation assume spindle or club shapes. Long threads are often also called Leptothrix. To the third class belong the Spirilla (screw-shaped bacteria). Screw-shaped forms with short, wide turns are known as Spirilla, those with drawn-out turns as Vibrios, those with a long, closely wound screw as Spirochetes. According to their length the spirilla may also be divided into short screws and long screws. All of the bacteria thus far referred to occur either in one single form or in a very limited cycle of forms of growth, and they may therefore be grouped together as monomorphous or oligomorphous bacteria. Cohn, 549 550 THE PATHOGENIC FISSION-FUNGI. to •whom we are indebted for the fundamental investigations regard- ing bacteria, united under the term bacteria only the oligoniorphie forms. Many writers, however, classify also as bacteria those organisms which during their development pass through a whole series of forms : spherical cells, as well as rods and simple and branching threads. These may be collected into a second group— the polymorphous bacteria — to which belong in particular the fungi known as Streptothrix, Cla&othrix, Beg- g'mtoa, Grenothrix, and Actinomyces. Other authors (Lehmann, Neu- mann, Levy, Lubarsch) class these forms with the Hyphomycetes or regard them as transition forms between the latter and the Schizomycetes. Pe- truschki collects them under the family term of hair-fungus or Irichomy- cetes, and classes them with the Hyphomycetes. All of the Schizomycetes consist of a plasmatic cell-contents and a cell=membrane, both of which, according to Nencki, consist essentially of an albuminoid body, mycoprotein, which varies with the species. Many bacilli contain fat within their cell -bodies, at times so abundantly that it may be demonstrated by staining witli Sudan 111. Some of these bacteria (tubercle-bacillus, lepra-bacillus, and actinomyces) show the presence of fat both when growing in living tissues and when cultivated upon artificial media,; others (staphylococcus aureus, anthrax-bacillus, bacillus of glanders) show the presence of fat only when grown upon cer- tain media (Sata). In many forms of bacteria the membrane under cer- tain conditions may swell and appear as a hyaline capsule surrounding the bacterial cell. In all forms of bacteria, with the exception of the cocci, there have been observed swarming movements which are brought about by means of fine thread-like flagella attached singly at the ends or scattered over the entire bacterial cell. In addition there also occur slow oscillatory or gliding and creeping movements which are dependent upon the con- tractile and flexible qualities of the plasma. Both forms of motion occur only under certain conditions of nutrition and growth, and only in cer- tain species. Hultiplication of bacteria takes place through a transverse division of cells which have previously become elongated. In some forms divi- sion can also take place in two or even three dimensions. After division the cells separate immediately or remain for a time attached to each other. When the cells remain attached after dividing transversely, threads are formed (Streptococcus, Leptothrix) ; after dividing both trans- versely and longitudinally, flat, tablet=like colonies (Merismopedia) ; after dividing in all three dimensions, colonies resembling a solid body (Sarcina) are produced. Long threads may become segmented into shorter pieces. According to the investigations of Buehner, Longard, andBiedlin, the period of reproduction — that is, the time from one cell-division to the next — is, in the case of the cholera-spirillum under favorable conditions of nutrition, about fifteen to forty minutes. If resting bacterial cells, as the result of a constantly progressing re- production or through the accumulation of neighboring cells, heap them- selves anywhere in great masses, there are often formed jelly-like colo- nies, which are called zoogloea. The jelly-like substance is formed from the membranes of the bacteria and, according to Nencki, consists of mycoprotein. The jelly masses may assume the most varied form, and occasionally reach a large size, so that the clumps, or lobulated masses, or strands may attain a diameter of one to three or more centimetres. GENERAL MORPHOLOGY AND BIOLOGY. 551 Under certain conditions many of the bacteria form spores. These are cells which are distinguished by the fact that they remain alive under conditions in which the ordinary forms of vegetation die; and, when brought into fresh nutrient solutions, are able to produce a new gener- ation. Spo"e-fornut£ion is most frequently endogenous — that is, the spore arises inside the cells (particularly in bacilli), and is developed out of the cell -protoplasm, in which there appears a small granule which grows into an oblong or round, highly refractive, sharply-contoured body always remaining smaller than the mother-cell. After the death of the latter the spore is set free. Arthrogenous spore-formation, as observed in micrococci, is said to occur through the direct assumption of spore-quali- ties by individual members of a colony or of a series of generations, which at the same time remain externally unaltered or take on other morpho- logical peculiarities. In old cultures bacteria nearly always show degeneration=forms, which are swollen and distorted, and stain poorly and irregularly. As non-chlorophyllaceous plants, the schizomycetes are restricted in their nutrition entirely to ready-formed organic substances which are soluble in water, and which are also supplied to them in an abundance of water. In addition they need also various mineral substances, especially sulphur, phosphorus, potassium or rubidium, or caesium and calcium (or magnesium, barium, or strontium). Changes in the condi- tions of nutrition may modify the form and dimension of bacteria and also change their vital properties. Some of the fission-fungi are either chiefly or wholly restricted for their food-supply to dead organisms or to solutions of organic matter, and are, therefore, classed as saprophytes ; others are able to take their nutrition also from living animals or plants, and live as parasites. If bacteria get into water which contains no food-material, many of them die in time. The spores survive the longest. Free oxygen is necessary for the development of many bacteria; others can dispense with it as long as they are under favorable conditions of nutrition in other respects; others develop only in the absence of oxy- gen. The first are designated obligate aerobes, the second facultative anaerobes, the third obligate anaerobes. The pathogenic bacteria are, according to Liborius, facultative or o bl i gate anaerobes. Carbon dioxide has no influence upon the development of many bacteria, as, for example, upon the typhoid-bacillus and Friedlander's pneumobacillus. Upon others, on the contrary, it has an inhibitory action, as, for example, upon Bacillus indicus, Proteus vulgaris, Bacillus phosphorescens, the bacilli of anthrax and cholera, the pus-cocci, and others (C. Frankel). The bacilli of anthrax, Asiatic cholera, and of rabbit septicaemia die out in a few hours in artificial Seltzer water, but anthrax-spores remain alive in it indefinitely (Hochstetter). Intense light has an injurious or destructive influence upon the de- velopment of many forms of bacteria, and it is therefore possible to dis- infect by means of strong light water which is infected (Buchner). The virulence of the bacillus of anthrax may be lessened by exposure to sun- light (Arnold, Gaillard). When exposed to the direct rays of the sun anthrax bacilli die in twenty-four to thirty hours, the spores survive as long as six to eight weeks (Arloing, Duclaux). According to Geisler the green, violet, and ultra-violet rays are particularly active. Accord- ing to Eieder bacteria may be destroyed by the Roentgen -rays. 552 THE PATHOGENIC FISSION-FUNGI. The temperature of the surrounding medium actsiu general upon the bacteria in such a way that when it falls the life-processes of the organ- isms become weaker and slower, and finally cease entirely, whereas with an elevation of the temperature they rise to a certain maximum, and at a slight increase above this suddenly cease; still higher temperatures kill the fungi. The maximum of permissible temperature lies at a dif- ferent height for different fungi, and is in part dependent also upon the character of the nutrient substance. There are forms of bacteria which grow well at a temperature of 55° 0. or higher. A low temperature checks development in all varieties ; they fall into a state of immobility, but do not die even at great degrees of cold. The immobility due to cold occurs at different temperatures with different varieties. The most favorable temperature for development lies between 30° and 40° C. for the anthrax bacillus ; at temperatures above 44° and below 15° C. its development ceases. Many bacilli form spores only at high temperatures. Boiling water and steam at 100° C. kill all bacteria and bacterial spores if allowed to act for some time. In dry air bacteria and their spores withstand higher temperatures, so that a temperature of 140° C. for three hours is necessary to kill the latter. Many bacteria are killed at a temperature of 60° to 70° C, provided it is kept up for a very long time. Anthrax-spores die in boiling water in two hours, in confined steam in ten minutes. The action of steam at 105° C. for ten minutes kills all spores. Live steam kills all spores in ten to fifteen minutes, and pene- trates very well into the objects to be disinfected (Koch, Gaff ky, Loftier ). If fission-fungi find themselves in a suitable medium, their multiplica- tion can still be brought to a standstill, since the fluid may contain sub- stances which hinder the growth of the bacteria or even kill them. This effect is produced by many substances (sublimate, lysol, carbolic acid, iodine, formaldehyde, etc.) — even in comparatively great dilution. Other substances act injuriously upon the bacteria only when in stronger concentration. The point at which the multiplication is hindered is always reached at a much greater dilution than that at which the bacteria are killed. Spores are much more resistant than the vegetative forms. The growth and multiplication of bacteria also cease iu the case of insufficient amount of water. The fact that fruits preserved in sugar do not ferment and that salted and dried meats do not putrefy depends upou this fact. Pood-stuffs can also lie preserved through the removal of water and by the addition of substances which are dissolved in the tissue-fluids and in this way increase the proportion of the same in solid contents. The limit at which the fission-fungi and yeast-fungi cease to develop is reached at a much higher degree of humidity than for the moulds. If a nutrient fluid contains other lower fungi besides the bacteria there often takes place a competition between the different micro-or= ganisms ; and fission-fungi, yeasts, and moulds may crowd one another out. Likewise a reciprocal crowding between the bacteria themselves may occur. For example, cocci may be crowded out and destroyed by bacilli, or one form of bacillus by another. This would happen when either the composition or the temperature of the nutrient medium is more favorable to one form than to the other; or also when one form of bacteria produces "products which act injuriously upon the other, or when one form grows more rapidly than the other, and thereby deprives its competitor of the necessary food-supply. GENERAL MORPHOLOGY AND BIOLOGY. 553 According to investigations by Pasteur, Emmerich, Bouchard, Wood- head, Blagovestchensky, and others, the antagonism between many forms of bacteria is shown also in inoculation experiments on animals. By simultaneous inoculation with different bacteria the development of a pathogenic bacterium in the body of a susceptible animal may be hin- dered. For example, the development of anthrax bacilli may be hin- dered by simultaneous inoculation with erysipelas-cocci (Emmerich) or with the Bacillus pyocyaneus (Bouchard). The question as to whether the bacterial cell contains a nucleus has been a subject of much discussion. A. Fischer denies it, while Butschli, Schottelius, Ziemann, Zettnow, Nakanishi, and Feinberg are inclined to favor the affirmative view. According to Zett- now, the bacterial cell contains chromatin or nuclear substance mixed with the ento- plasm; while the covering of the cell, or ectoplasm, does not contain chromatin. Accord- ing to the investigations of Ziemann, Zettnow, and Feinberg, it is possible through stain- ing with a mixture of methylene-blue and eosin (Romanowski-sta,m) to demonstrate within the majority of bacteria a "nuclear substance" or "chromatin" (Ziemann, Zettnow) or a "nucleus" (Feinberg) — that is, there may be demonstrated within the bacteria structures of varying size which stain red like the nuclei of malarial plasmodia (Romanowski) or of other protozoa or of tissue-cells, while the cell-plasma takes a blue stain. According to Nakanishi, circumscribed nuclei are found in young forms. The Romanowski-st&m. is a mixture of methylene-blue and eosin, whereby a red dye contained in methylene-blue (Rosin, Berl. klin. Wochen., 1899; Nocht, Cbl.f. Bakt., 1899) is precipitated. Zettnow's formula is as follows: 50 c.c. of a one-per-cent solution of a Hochst methylene-blue is treated with 3-4 c.c. of a five-per-cent solution of soda. To 2 c.c. of this there is added drop by drop while shaking 1 c.c. of a one-per- cent solution of Hochst eosin BA. Stain five minutes on cover-glass and examine in water. According to Nageli, Zopf, and others, many fission-fungi possess a membrane of cellulose or of a carbohydrate closely related to cellulose. Certain bacteria (red sul- phur bacteria) combine within their cell-substance coloring-matter; others (Bacillus amylobacter, Spirillum amyloferum) give at certain stages of their development the starch reaction with iodin. Babes and Ernst, by means of especial staining methods with Lbffler's methylene- blue, hematoxylin, and Platncr's nuclear black, have demonstrated the presence of granules within different forms of bacteria, which according to their behavior probably stand in some relation to the processes of division and spore-formation. Ernst desig- nated the appearances seen by him as sporogenous granules, since he was able in certain bacteria to demonstrate their transition into spores; he is inclined to regard them as of the nature of cell-nuclei, a view which Biitschli also favors. Bunge regards the gran- ules described by Ernst as cell-granules which have nothing to do with spore-forma- tion, and describes other granules, which stain with Lbffler's methylene-blue, as the forerunners of spores. Marx and Woithe regard the Babes-Ernst granules as not being nuclei in the ordinary sense of the word, but as representing products of the maximal condensation of the euchromatic substance of the cells, which are a sign of the highest intensity of vitality on the part of the cell. Wagner, on the contrary, holds that cer- tain bodies, which he has observed in typhoid- and colon-bacilli, are nuclei. According to Nakanishi, the spores form (in anthrax- and hay-bacilli) by a concen- tration of the chromophile substance about the nucleus, while the remaining portion of the protoplasm becomes clear; a membrane is then formed about the chromatin body, it takes on a fat-like shine, and loses its power to take stains (methylene-blue BB). The bacteria are able to take the carbon necessary for their growth from most of the carbon compounds which are soluble in water. They can also derive their carbon from dilute solutions of substances which in greater concentration are injurious to them — as, for example, from benzoic acid, alcohol, salicylic acid, phenol, etc. Their nitrogen is derived from albuminous matter; further, from those compounds designated as amins (methyl-, ethyl-, propylamin), amido-acids (asparagin, leucin) and amides (oxamide, urea), as well as from the ammonia-salts and in part also from nitrates. The albuminates, previous to their assimilation, are changed into peptone by means of a ferment given off from the bacteria. Free nitrogen cannot be assimi- lated as such. Nitrogenous and non-nitrogenous compounds are not only assimilable as such, but also in combination. The fission-fungi are able to take nitrogen from ammonia and nitric acid only in the presence of organic carbon compounds. Sulphur, according to Nageli, is essential to the schizomycetes, and they take it from sulphates, sulphites, and hyposulphites. The other mineral substances men- tioned above are derived from various salts. If in the case of an abundance of nutrient 554 THE PATHOGENIC FISSION-FUNGI. material there is too little water present, all further growth ceases; yet many of the fission-fungi are able to dispense with water temporarily. Spores suffer little from drying. Many bacteria are very sensitive to acids, so that, even a slight degree of acidity hinders their growth (for example, anthrax bacilli and the Frankel-Weichselbaum pneumoeoccus). Others are able to grow with a moderate amount of acid in the nutrient fluid. As a general rule they are especially sensitive to mineral acids, but the presence of a large amount of citric," butyric, acetic and lactic acids hinders also their multiplication. In this connection belongs the fact that the products of decomposi- tion caused by the fermentative action of the fungi are at a certain degree of concentra- tion harmful to the development of the fungus," and finally stop its growth entirely. Thus, for example, in butyric-acid and lactic-acid fermentation the amount of butyric or lactic acid gradually formed finally checks the multiplication of the fungus. A similar result occurs in the bacterial putrefaction of albumin, since the products of the same, such as phenol, indol, skatol, phenylacetic acid, phenylproprionic acid, etc., hinder the further development of the bacteria. To alkalies the fission-fungi are less sensitive, and many can bear a rather high degree of alkalinity in the nutrient fluid, but there also exist forms which do not thrive in alkaline fluids (acetic-acid fungus). According to the investigations of Pfeffer and Ali-Cohen, many motile bacteria show chemotaclic properties — that is, they are attracted or repelled by certain chemical substances dissolved in water. Bacteria swimming about in fluids collect, therefore, at places wdiere there are chemical substances which attract; for example, typhoid- bacilli and cholera-spirilla are attracted by potato-juice (Ali-Cohen). Potassium salts, peptone, and dextrin likewise attract, but the individual forms of bacteria be- have very differently toward these substances (Pfeffer). Free acids, alkalies, and alcohol have a repelling action. Literature. (Bacteria.) 1. Text-books unci Monographs de Bary: Vergl. Morphol. u. Biol. d. Pilze, Mycetozoen u. Bakterien, Leipzig, 1886; Vorles. liber Bakterien (bearb. v. Migula). Leipzig, 1900. Baumgarten: Lehrb. d. pathol. Mykologie, Braunschweig, 1886-89. Bouchard: Les microbes pathogeues, Paris, 1892. Cornil et Babes : Les bacteries, Paris, 1890. Duclaux. Traile de microbiologic, i. and ii., Paris, 1897-99. Eisenberg: Bakteriolog. Diagnostik, Leipzig, 1893. Fischer, A.: Vorlesungcn Liber Bakterien, Jena, 1903. Fraenkel, C. : Grundriss d. Bakterienkunde, Berlin, 1899. Fraenkel u. PfeifFer: Mikrophotograpliischer Atlas tier Bakterienkunde, Berlin, 1894. Fltigge : Die Mikroorganismen, Leipzig, 1896. Gamaleia: Les poisons bacteriens, Paris, 1892. Giinther: Einfuhrung in d. Studium der Bakteriologie, Leipzig, 1902. Hauser: Leber Faulnissbakterien, Leipzig, 1885. Hueppe- Naturwissenschaftl. Einfuhrung in d. Studium d. Bakteriologie, Wiesbaden 1896. Kitt: Bakterienkuude, Wicn, 1899. Kolle a. Wassermann: llandbuch der pathogen. Mikroorganismen, Jena, 1902- 1904. Eehmann u. Neumann: Atlas u. Grundriss d. Bakteriologie, Miinclien, 1904. Loffler: Voiles, lib. d. gesehichtl. Entwickelung der Lehre von d. Bakterien, Leipzig 1887. Migula: System der Bakterien, i. and ii., Jena, 1897-99. Naegeli- Die nied. Pilze, MUnchen, 1877; Unters. lib. niedere Pilze, Mimchen, 1882. del Rio, Luis: Elementos de micro biologia, Madrid, 1899. Park Bacteriology in Medicine and Surgery, 1899. Prazmowski: Untersuch. iiber die Eutwickelungsgesch. einig. Bakterien, Leipzig 1880. Koux: Les microbes pathogeues. Pathologic generale publ. par Bouchard, ii , Paris 1H96. Woodhead: Bacteria and their Products, Loudon, 1891. Zopf: Die Spaltpilze, Breslau, 1885. Zurn: Die Schmarotzer auf uud mdein Korper der Haussaugethiere, Weimar, 1882-89. GENERAL MORPHOLOGY AND BIOLOGY. 555 2. Journals and Tear-books. v. Baumgarten : Jahresber. ilber die Fortschritte in d. Lehre von den pathogenen Mikroorganismen, umfassend Bakterien, Pilze und Protozofin, since 1886. Duclaux: Ann. de l'lnst. Pasteur, Paris, since 1887. Koch: Jahresber. iiber die Fortschritte in d. Lehre von d. Gahrungsorganismen, since 1891. Koch u. Fliigge : Zeitschr. f . Hygiene, Leipzig, since 1886. Uhlworm: Cbl. f. Bakteriol. u. Parasitenkunde, Jena, since 1887. Ziegler u. Kahlden: Cbl. f. allg. Path, und path. Anatomie, since 1890. 3. Articles in Journals. Ali-Cohen Die Chemotaxis als Hiilfsmittel bakt. Forschung. Cbl. f. Bakt., viii., 1890. Arloing: Influence de la lumiere blanche et de ses rayons constituants sur le devel- oppement et les proprietes du bacillus anthracis. Arch, de phys., 1886. Babes. Isolirt farbb. Antheile v. Bakterien. Zeitschr. f. Hyg., v., 1888; Corpuscules chromatiques des bacteries. Ann. de l'lnst. de path, de Bucarest, i., 1890; Meta- chromat. KSrperchen, Sporen, Verzweigung, Kapsel- u. Kolbenbildung pathog. Bakterien. Zeitschr. f. Hyg,. xx., 1895. Behring: Desinfection, Desinfectionsmittel u. Desinfectionsmethode. Zeitschr. f. Hyg., ix., 1890. Blag-ovestchensky Sur l'antagonisme entre les bacilles du charbon et ceux de pus bleu. Ann. de l'lnst. Pasteur, iv., 1890. Boer : Ueber die Leistungsfahigkeit mehrerer chem. Desinfectionsmittel. Zeitschr. f. Hyg., ix., 1890. Boti.ch.ard. ■ Action des produits secretes par les microbes pathogenes, Paris, 1900 . Buchner: In Nageli, Untersuch. iiber niedere Pilze, 1892; Einfluss des Lichtesauf Bakterien. Cbl. f. Bakt., xi. and xii., 1892; xv., 1894; Ursache d. Sporenbildung. Bakt. Cbl., viii., 1890. Biitsehli : Ueb. d. Bau d. Bakterien u. verwandter Organismen, Heidelberg, 1890. Bunge: Sporenbildung bei Bakterien. Fortschr. d. Med., xiii., 1895. Cheyne-Kammerer : Die antiseptische Chirurgie, Leipzig, 1883. v. Christmas-Dirchinck-Holmfeld : Das Terpentine^ als Antisepticum. Fortschr. d. Med., v., 1887. Dietlocher: Morphologie u. Biologie d. Bakterien. C. f. allg. Phys., in., 1903 (Lit.). Duclaux: Action de la lumiere sur les microbes. Ann. de l'lnst. Pasteur, iv., 1890. v. Duugeru: Hemmung d. Milzbrandinfeetion durch Friedland. Bakt. Zeitschr. f. Hyg., xviii., 1894. Eidam : In Cohn. Beitr. z. Biol, der Pflanzen, i. and ii. Emmerich u. di Mattei : Vernichtung der Milzbrandbacillen im Organismus durch Erysipelkokken. Fortschr. d. Med., v., 1887; Arch. f. Hyg., vi. ; Heilung des Milzbrandes durch Erysipelserum. Munch, med. Woch. , 1894. Ernst: Ueber den Bacillus xerosis und seine Sporenbildung. Zeitschr. f. Hyg., iv., 1888; Ueber Kern- und Sporenbildung in Bakterien. lb., v., 1889. Feinberg: Ueber den Bau d. Bakterien. Anat. Anz., xvii. ; Cbl. f. Bakt., xxvii., 1900. Frankel, C. : Die Einwirkung d. Kohlensaure auf d. Mikroorganismen. Zeitschr. f. Hyg., v., 1888. Erankel u. Pfeiffer: Mikrophotogr. Atlas d. Bakterienkunde, ii. Aufl., Berlin, 1894. de Freudenreich : De l'antagonisme des bacteries. Ann. de l'lnst. Pasteur, ii., 1888. Gartner: Desinfection. Handb. d. spec. Therapie, i., Jena, 1894. Gaillard: De l'influence de la lumiere sur les microorganismes, Lyon, 1888. Garre : Antagonisten unter den Bakterien. Correspbl. f . Schweizer Aerzte, 1887. Geisler: Wirkung des Lichtes auf Bakterien. Cbl. f. Bakt., xi., 1892. Geppert: Ueber Desinfection. Zeitschr. f. Hyg., ix. ; Deut. med. Woch., 1891. Gerlach: Ueber Lysol. Zeitschr. f. Hyg., x., 1891. Globig: Ueber Bakterienwachsthum bei 50-70°. Zeitschr. f. Hyg., iii., 1888. Gotschlich: Morphol. u. Biol. d. Bakt. Handb. d. path. Mikroorg., i., Jena, 1903. Hochstetter : Mikroorganismen im kunstl. Selterswasser. Arb. a. d. K. G.-A., ii., 1887. Hoppe-Seyler: Ueber den Einfluss des Sauerstoffs auf Gahrungen, Strassburg, 1881. Ivanow: Eiweissstoffe d. Bakterien. Beitr. v. Hofmeister, i., 1902. Kitasato : Ueber das Verhalten d. Cholerabakterien zu anderen pathogenen u. nicht pathogenen Mikroorganismen in kunstlichen Nahrsubstanzen. Zeitschr. f. Hyg., vi., 1889. Klein, L.: Botan. Bakterienstudien. Cbl. f. Bakt., vi., 1889; vii.. 1890. 556 THE PATHOGENIC FISSION-FUNGI. Koch: Mittheil, a. d. Kais. Gesundheitsamte Berlin, 1881. Koch, Wolff htigel, Gaffky, u. Lbffler: Desinfection mit heissen Wasserdampf. Mittheil. a. d. Kais. Gesundheitsamte, Berlin, 1881. Kronig u. Paul : Chemische Grundlage d. Giftwirkung u. Desinfection. Zeitschr. f. Hyg., xxv., 1897 (Lit). Lachowicz u. v. Nencki: Anaerobiose. Pflilger's Arch., xxxiii., 1884. Iiewek: Wachsthumseinfluss nicht pathogener Spaltpilze auf pathogene. Beitr. v. Ziegler, vi., 1889. IiOffler: Die Beizung u. Farbung d. Geisseln. Cbl. f. Bakt., vi., 1889; vii., 1890. Iibwit: Zur Morphologie d. Bakterien. Cbl. f. Bakt., xix., 1896. Liideritz: Zur Kenntniss der anafiroben Bakterien. Zeitschr. f. Hyg., v., 1888. Marx u. "Woithe: Morphol. Unters. z. Biologie d. Bakterien. Cbl. f. Bakt., xxviii., 1900. Metschnikoff: Note sur le pleomorphisme des bacteries. Ann. de l'lnst. Past., iii., 1889. Nakanishi: Neue Farbungsmethode v. Leukocyten u. Bakteriensporen. Munch. med. Woch., 1900; Bau der Bakterien. Cbl. f. Bakt., xxx., 1903. Nencki: Journ. f. prakt. Chem., N. F., xix., xx. ; Beitr. z. Biol. d. Spaltpilze, 1880; Ber. d. Chem. Ges., xvii., 1884; Arch. f. d. ges. Physiol., xxxiii.; Arch. f. exp. Path., xx., xxi., 1886. Noetzel: Nachweis d. Kapseln d. Mikroorganismen . Fortschr. d. Med., xiv., 1896. Petruschki: Trichomyceten. Handb. d. pathog. Mikroorg., iii., Jena, 1903 (Lit.). Pfeffer. Ueber chemotaktische Bewegungen d. Bakterien. Untersuch. a. d. Botan. Institute zu Tubingen, 1886-88. Eamn: Der gegenwartige Stand unserer Kenntnisse iiber den Einfluss des Lichtes auf Bakterien und auf den thierischen Organismus. Zeitschr. f . Hyg., 1889. Rieder; Wirkung d. R&ntgenstrahlen auf Bakterien. Miinch. med. Woch., 1898. Romanowski : Zur Frage der Parasitologic u. Therapie d. Malaria, 1891. de Rossi: Metodo sempl. per colorare le cilie dei batteri. A. per le Sc. Med., xxiv., 1900. Roux: De Taction de la lumiere et de l'air. Ann. de l'lnst. Past., i., 1887. Salkowski: Antiseptische Wirkung d., Chloroformwassers. Deut. med. Woch., 1888. Sames: Bei h5heren Temperaturen wachsende Bakterien. Zeitschr. f. Hyg., xxxiii., 1900 (Lit.). Sata : Fettbildung durch verschiedene Bakterien. Cbl. f . allg. Path. , 1900. Schottelius: Kernartige Kiirper im Innem von Spaltpilzen. Cbl. f. Bakt., iv., 1888; Desinficirende Wirkung einiger Theerproducte. Miinch. med. Woch., 1890. Sirotinin: Entwickelungshemmende Stoffwechselproducte d. Bakterien. Zeitschr. f. Hyg., iv., 1888. Sjobring: Ueber Kerne u. Theilungen b. d. Bakterien. Cbl. f. Bakt., xi., 1892. Soyka u. Bandler: Die Entwickelurig von pathogenen Spaltpilzen unter wechselseiti- gem Einfluss ihrer Zersetzungsproducte. Fortschr. d. Med,, vi., 1888. Teuscher: Beitr. z. Desinfection mit Wasserdampf. Zeitschr. f. Hyg., ix., 1890. Wagner: Coli- u. Typhusbacillen sind einkernige Zellen. Cbl. f. Bakt., xxiii., 1898. Wernich: Desinfection. Eulenburg's Realencyklop., 1894 (Lit.). Wesbrook: Effects of Sunlight on Tetanus Cultures. Journ. of Path., iii., 1894. Zettnow: Romanowski's Farbung bei Bakterien. Zeitschr. f. Hyg., 30 Bd., 1899; Deut. med. Woch., 1900. Ziemann: Ueber Malaria u. andere Blutparasiten, 1898. § 149. The growth and multiplication of the fission-fungi give rise always to chemical transformations of the nutrient material, which are brought about in part through the influence of ferments pro- duced by the bacteria, and in part directly through the metabolic processes occurring within the cells themselves. Among the ferments or enzymes are to be mentioned first the prote- olytic or albumin- dissolving enzymes (bacteriotrypsins) which bring about a solution of the albuminous bodies and cause, the disintegration of the peptone-molecule. Further, bacteria give rise to diastatic ferments which convert starch into sugar, also to inverting ferments which transform cane- sugar (disacchafid) into grape-sugar (monosaccharid). The chemical results of bacterial metabolism, which are brought about by the vital activities of the fission-fungi aided by the enzymes GENERAL MORPHOLOGY AND BIOLOGY. 557 produced by them, consist in the first place of a decomposition of com- plex organic compounds. By many authors all these processes are desig- nated as fermentations, while others (Lehmann) speak of fermentation only when a fission-fungus breaks down a given food-material with espe- cial ease, thereby giving rise to one or more especial products in marked quantity, in association with or in place of its other metabolic products. Other authors still narrow the term fermentation to the decomposition of carbohydrates. In the decompositions caused by the fission°fungi very different products are formed, which vary according to the composition of the nutrient material and the character of the fission-fungus. For the pro- duction of fermentation a proper fermentable material is necessary. Many fungi are able to cause fermentation in the presence as well as in the absence of oxygen, while to some of them a lack of oxygen is neces- sary. Among the products of bacteria of especial importance to the physi- cian are those which have a poisonous action and cause tissue=changes, to which belong particularly those substances which are described as ptomains, toxins, and endotoxins. The ptomains are basic, crystallizable, nitrogenous products of the bacterial decomposition of albumin; they are also known as putrefactive alkaloids or cadaveric alkaloids. They show in part poisonous properties. The best known are sepsin, putrescin (diniethylethylendiamm), cadaver - in (pentamethylendiamin), collidin (pyridine derivative), peptotoxin, neuridin, neurin, cholin, gadinin, and substances resembling muscarin. The true toxins are specific bacterial poisons produced by pathogenic bacteria and are secreted by the latter, giving rise to the severe symp- toms produced in diphtheria, tetanus, and sausage poisoning. The en- dotoxins are substances clinging to the bacterial cells that also have a poisonous action. In the bacterial cell there occur also the bacterial proteins which give rise to local tissue-necrosis and inflammation. The significance of these substances in the infectious diseases has already been mentioned in § 11. Among other decompositions produced by bacteria the following are worthy of note: the formation of lactic acid, formic acid, acetic acid, propionic acid, butyric acid, often also the formation of alcohol and carbonic acid from sugar; the formation of acids (acetic, butyric, propionic, valerianic, succinic, formic, and carbonic) from alcohol and organic acids; the formation of indol, skatol, phenol, cresol, pyrocatechin, hydrochinon, hydroparacumaric acid, and paroxyphenylacetic acid (von Nencki, Salkowski, Brieger), and finally hydrogen sulphide, ammonia, carbonic acid, and water from albumin; the formation of ammonium carbonate from urea; the trans- formation of nitrous and nitric acids into free nitrogen; the reduction of nitrates to nitrites and to ammonia, etc. Finally, there are also bacteria living in the soil — the nitro-bacteria — which are able to form nitrous and nitric acids from ammonia (Wino- gradsky). Along with the nitrification of nitrogen there occurs simultaneously a decom- position of earthy alkali carbonates, as shown by the fact that the nitrobacteria are able in the presence of organic carbon compounds to derive from the carbonates the carbon necessary to the building-up of the cells. There takes place, therefore, through the vital activity of these organisms, a synthesis of organic material out of inorganic substances. Under the influence of the fission-fungi there are formed bitter, sharp, nauseating substances (bitter milk). Further, bacteria occasionally produce pigments of a red, yellow, green, blue, or violet color. For example, Bacillus prodigiosus produces a blood-red coating upon bread (bleeding bread); bandages and pus take on a bluish- green color as the result of the presence of the Bacillus pyocyaneus. In many cultures there is also formed a fluorescent colorine-matter. 558 THE PATHOGENIC FISSION-FUNGI. The phosphorescence not infrequently seen upon decomposing sea-fish depends also upon bacterial products of decomposition, as has been shown by Pfluger, and appears when there is an active multiplication of the bacteria. Literature. (Chemical Changes Produced by Schizomycetes.) Baumana u. v. Udranszky: Vorkommen von Diaminen (Ptomainen) bei Cystinurie. Zeitsclir. f. phys. Chem., xiii., 1889. Bocklisch.. Faulnissbasen aus Fischen. Ber. d. Deut. chem. Ges., xviii., 1885. Brieger: Ueber Ptomaine, Berlin, 1885, 1886; Berl. klin. Woch., 1886; Zusammenset- zung des Mytilotoxins, nebst einerUebersicht der bisher in ihren Haupteigenschaf- ten bekannten Ptomaine und Toxine. Virch. Arch., 115 Bd., 1889; Bakteriengifte. Zeitsclir. f. Hyg., xix., 1895. Buchner; Active'lbsliche Zellproductce. Mllnch. mud. Woch., 1897. Cahen: Ueb. d. Reductionsvermogen d. Bakterien. Zeitsclir. f. Hyg., ii., 1887. Duclaux: Fennents et maladies, Paris, 1892. Eijkman: Enzyme der Bakterien. Cbl. f. Bakt., xxix.. 1901. van Ermengem: Anafirob. Bacillus u. seine Bez. z. Botulismus. Zeitsclir. f. Hyg., 26 Bd., 1897. Fermi: Die Leim und Fibrin lbsenden u. die diastatischen Ferniente der Mikroorgan- ismen. Cbl. f. Bakt., vii., 1890. Forster: Ueb. einige Eigenschaften leuchtender Bakterien. Cbl f. Bakt., ii., 1887. Gamale'ia: Les poisons bacteriens, Paris, 1892. Gautier: Sur les alealoi'des derives de la destruction bacterienne ou physiologique des tissus animaux, ptomaines, et leucomaTnes. Paris, 18S6. Husemann: Ptomaine. Arch. d. Pharmacie, 1880-83. Ingenkamp: Unsere Kenntnisse v. Fiiulniss u. Gahrmig. Zeitsclir. f. klin. Med., x., 1885. Krannlials: Ueb. Kephir u. ilb. den Kephirpilz. Deut. Arch. f. klin. Med., xxxv., 18S4. Lassar: DieMikrokokken der Phosphoreseenz. Prli'iger's Arch., xxi., 18S0. Liideritz: Zur Kenntn. d. anaGroben Bakt. Zeitsclir. f. Hyg., v., 1888. Ludwig: Die bish. Unters. tiber pathogcne Bakterien. Cbl. f. Bakt., ii., 1887. v. Nencki: Zersetzung d. Gelatine u. d. Eiweisses bei d. Fiiulniss mit Pankreas, Bern, 1874; verscliied. Arb. im Journ. f. prakt. Chem.. im. .Tourn. f. phys. Chem. u. in d. Ber. d. Deutsch. chem. Ges. a. d. J. 1876-81; Die Anaerobien u. d. Gahrungen. Arch. f. exp. Path., xxi,, 1886. Oppenheimer : Toxine u. Antitoxine.. Jena, 1904. Pfluger: Pflilger's Arch., 1875; Phophorescenz der lebendigen Organismen. Arch. f. d. ges. Phys., x., 1875; Phosphoreseenz verwesender Organismen. lb., xi., 1875. Podwyssozki: Kephir. Petersburg, 1894. Salkowski: Zahlr. Arb. i. d. Ber. d. Deut. chem. Ges.; Zeitsclir. f. phys. Chem. aus den letzten Jahrzehnten. Vaughan and Novy : Cellular Toxins, 1902. Winogradsky : Rech. sur les organismes de la nitrification. Ann. de l'lnst. Pasteur, 1890, 1891. Wortmann: Ueb. d. diastatisehe Ferment d. Bakt. Zeitsclir. f. phys. Chem., vi. ; Pflanzl. Verdauungsprocesse. Biol. Cbl., iii. ; Organismen d. Nitrification u. ihre physiol. Bedeutung, Landwirthsch. Jalirb.. xx., 1891; ref. Bakt. Cbl, x., 1891. See also § 11. 2. General Considerations Concerning the Pathogenic Schizo- mycetes and their behavior in the human organism. § 150. As has already been explained in § 11, there are among the schizomycetes numerous species which are capable of causing disease- processes in the human organism, and are therefore called pathogenic schizomycetes. The first condition of such action is evidently that the bacteria concerned must possess properties enabling them to multiply in the tissues of the living human body. They must therefore find iii the tissues the suitable nutrient material, and in the body-temperature the PATHOGENESIS. 559 warmth necessary to their growth. The tissues, moreover, must not contain substances which are a hindrance to their growth (cf. § 31). If pathogenic fission-fungi succeed in growing in the tissues of the body, if infection takes place (cf. § 11), their action is in general char- acterized by the production, at the point of multiplication, of tissue-degener- ations, necrosis, inflammation, and new-growths of tissue, while at the same time the toxins produced by them cause manifestations of poisoning. In individual cases the pathological processes vary greatly, in that the distribution of the bacteria in the organism, and their local action, as well as the production of the poisons, differ greatly with the different forms of bacteria. With many the local action upon the tissue is the most prominent characteristic, with others the general intoxication. Many bacteria confine themselves to the region in which they have gained entrance ; others advance uninterruptedly upon the surrounding tissues ; others still are carried by the blood and lymph streams and lead to the formation of metastatic foci, and, finally, others increase within the blood. If a spread of the bacteria takes place through the blood, the bacte- ria may pass from the mother to the fasttis during pregnancy, since the placenta forms no certain filter against pathogenic bacteria. This has been demonstrated, for example, in the case of anthrax-bacilli, bacilli of symptomatic anthrax, glanders-bacilli, spirilla of relapsing fever, typhoid-bacilli, the pneumococcus, and the tubercle bacillus. According to observations of Malvoz, Birch-Hirschfeld, and Latis, changes in the placenta, such as haemorrhages, loss of epithelium, and alterations of the vessel-walls, favor the passage of bacteria. Moreover, bacteria — as, for example, anthrax-bacilli — can grow through the tissue -spaces. In gen- eral the passage of bacteria from the mother to the foetus presupposes 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 passage of the bacteria into the foetus. The bacteria which succeed in multiplying within the human organ- ism die out again in many cases within a short time ; and the disease pro- duced by them may proceed to recovery (cf. § 31). Nevertheless, it not infrequently happens that they are preserved for a long time within the body, and either excite a continuous disease process, or at times remain in a con- dition of inactivity, so that no pathological processes are recognizable until after a longer or shorter period of latency, an active reproduction again takes place and manifestations of disease show themselves anew. Not infrequently a secondary infection associates itself with an infec- tion already existing. The relation between the two infections is either that the second infection follows the first accidentally, or that through the first infection the soil is prepared for the second (cf. § 11). Finally, there not infrequently occur double infections, in that two or more forms of bacteria develop coincidently in the tissues, and pro- duce their characteristic injurious influence upon the latter. Bach pathogenic fission-fungus has a specific action upon the tissues of the human organism ; but, nevertheless, different species may exert a simi- lar action. For example, there are various bacteria capable of producing suppuration. Only in a certain proportion of cases do the pathological tissue-changes show such specific characteristics that from these the spe- cies of the pathogenic fission-fungus can be recognized with certainty. Further, it has been demonstrated that pathogenic properties of bacteria are by no means constant ; that, on the contrary, their viru- 560 THE PATHOGENIC FISSION-FUNGI. lence varies, so that bacteria, which cause severe— that is, fatal — infec- tions may become changed (weakened) through external influences, so that they either wholly lose their power of causing disease-processes in the organism, or at least cause only mild forms of disease. This pecu- liarity is not alone of theoretical interest, but is also of great practical importance. It explains to a certain extent, on the one hand, why a certain infection does not always run the same coarse, and, moreover, why along with severe attacks light ones also occur. On the other hand, it affords us the possibility of obtaining material for inoculation from attenuated cultures of bacteria, by means of which mild grades of infec- tion or intoxication can be produced, which are able to protect the organ- ism from severe infections or to bring about the cure of an infection already acquired (cf. g 32). Weakening of the pathogenic properties of a fission=fungus can be brought about through the suitable action upon cultures of the same, by high temperatures, oxygen, light, or chemical antiseptic substances, as well as by the cultivation of the fungus in the body of a less susceptible animal. In some forms it is only necessary to cultivate the bacteria in question for sometime upon artificial media (diploeoceus of pneumonia), or to expose the culture to the air for some time (bacillus of chicken- cholera), in order to bring about an attenuation. If it is desired to pre- serve the virulence of the pneumococcus for some time, it is necessary, from time to time, to pass the bacteria cultivated upon artificial media through rabbits, which are very susceptible. The glanders-bacilli, tu- bercle-bacilli, and the cholera-spirilla lose virulence when cultivated uninterruptedly upon artificial media for some time. The streptococcus of erysipelas (Emmerich) becomes so attenuated through continued cul- tivation in bouillon or nutrient jelly that it is no longer capable of kill- ing even mice. As to the nature of the attenuation of virulence of bacteria by the methods mentioned above, it is possible to give only hypotheses. If the bacteria cultivated for a long time upon artificial media change in viru- lence, this may perhaps be explained in part by assuming that in a series of generations the less virulent varieties, which surely often arise, grad- ually gain the upper hand. For the attenuation of virulence by heat, chemical agents, etc., such an explanation is not adequate. In this case there is very probably a general weakening or degeneration of the proto- plasm, and in harmony with this theory is the fact that such bacteria show a diminution in energy of growth. If the presence of bacteria be suspected in an}' tissue-fluid or in the tissue-paren- chyma, their demonstration may first be attempted by means of a microscopical investigation. Occasionally this is successful by the mere examination of a drop of the suspected fluid or of a smear-preparation of the tissue-juice diluted with salt-solu- tion or distilled water. In other cases it is necessary to employ staining methods, in which case cover-glass smears of the fluid are made and allowed to dry. The smeared cover-glass is then fixed by passing through the flame, and after cooling is stained. For this purpose methylene-blue is preferably employed, in a preparation of a one- per-cent. methylene-blue solution in a l-to-10,000 solution of caustic potash. Water solutions of fuchsin and methyl-violet are also frequently used. For many bacteria there are employed especial staining methods, in which ordinarily the preparations arc heavily overstained with a solution of gentian-violet or fuchsin in" aniline water, or with a water solution of methyl-violet, the excess of stain then being removed by means of weak acids or by iodine and alcohol (Gram's method). In this way it is often brought about that the bacteria alone remain stained, often certain forms of bacteria only. When it is desired to demonstrate the presence of bacteria in tissues, small portions of the tissue are hardened in formalin or in absolute alcohol, and are then cut into the thinnest possible sections, which are stained by appropriate methods. Here again the PATHOGENESIS. 561 methods most frequent]}' employed are those mentioned above: gentian-violet, methyl- violet, and fuchsin. Good objectives are necessary for the microscopic examination; if possible, oil-immersion lenses and illumination "with substage condenser should be employed. If through any method the presence of bacteria in the tissue has been demon- strated, the attempt is next made to cultivate them. For this purpose the methods developed by Koch are usually employed. These, in principle, consist in obtaining first a fluid containing the bacteria, by means of scraping the tissue or by rubbing up pieces of tissue in sterilized salt-solution. This fluid is then evenly distributed in a solution of gelatin or agar which has been liquefied by warming; and the mixture is then poured upon horizontal glass plates, solidifying as it cools. The individual bac- teria, or spores, thus separated from each other develop in thr firm nutrient medium. By a proper application of this method there are obtained in the layer of gelatin various colonies (Fig. 425), which differ in appearance so that they may often be differ- entiated from each other by the naked eye alone. When sufficiently separated from one another, the individual colonies may be taken up by means of a fine platinum needle, and transferred cither to a boiled potato, or to a sterile gelatin plate, or streaked upon the surface of the solidified nutrient fluid in a test-tube. Very often the infected needle is stuck into the solidified transparent, medium contained in a test-tube. If the culture on the gelatin plate is pure, and if the entire procedure is carried out with the necessary care and the avoidance of contamination, pure cultures may be ob- tained by this method. In stab-cultures, as well as in smear-cultures on potatoes or any other nutrient medium, special peculiarities often show themselves which make it pos- i±^^»L*J*^^ ^^^^^^•^^■- ^ .--~.-~ ^ .^r-^r- -.- . Fig. 425.— Gelatin plate containing pellicle-like, sinuate colonies of small bacilli, and small, spherical, white colonies of cocci. Culture made from the exudate of a purulent peritonitis. Reduced one-third. sible for the experienced observer to recognize the form of bacteria. At times, how- ever, it is necessary to make a thorough microscopic examination of the colonies. It is evident that all the above manipulations must be carried out with care, and that absolute cleanliness of the instruments used — glass-plates and test-tubes — as well as perfect sterilization of the nutrient medium are necessary. The proper methods of sterilization in which a long-continued heating or an exposure to high temperatures plays an important role, are best learned in properly equipped laboratories. The neces- sary guidance is furnished in the various books on bacteriological methods of examina- tion, which have recently appeared. An infusion of meat containing peptone and gelatin is commonly employed for making plates. It consists of a watery infusion of chopped meat, to which a definite amount of peptone and salt is added. This is further neutralized with carbonate of soda, and enough gelatin is added to give a solid consistence at ordinary temperatures. For streak- and stab-cultures this same gelatin is sometimes used; at other times a jelly made of a mixture of a watery extract of meat, peptone, and agar-agar; or again blood-serum which has been coagulated by warming. For stab-cultures the jelly is allowed to solidify within the test-tube in a perpen- dicular position; for streak-cultures the test-tube is kept in an oblique position until the jelly is set. Sterilized bouillon is often used for cultures. The inoculated nutrient media are kept either at room-temperature or at higher temperatures in an incubating oven 36 562 THE PATHOGENIC FISSION-FUNGI. (30°-40° C). The proper nutrient medium to be used in individual eases must be deter- mined by experiment. Experience has shown that the individual bacteria behave very differently in this respect, some growing best upon one, others upon another medium. To the nutrient medium there are often added with advantage such substances as sugar, glycerin, urine, brain-substance, etc. It is self-evident that the processes briefly described above may be modified accord- ing to the necessities of the case. For example, in those cases in which it is necessary to grow the bacteria at high temperatures, the use of gelatin should be avoided and agar-agar plates should be made instead. Occasionally membranes or exudates from mucous surfaces (diphtheria) or small bits of excised tissue are placed directly into the culture-medium. When it is desired to examine the cultures directly under the micro scope, cultures may be made upon glass-slides. In the case of many bacteria, as cholera-spirilla, the use of hanging-drop cultures is advised. In this method a drop of sterilized bouillon hangs down from the under surface of a cover-glass, and is inocu- lated from a previously cultivated pure culture of the fungus. The cover-glass is then placed over the excavation in a hollow ground-glass slide. Evaporation is prevented by the exclusion of the outer air from the cavity in the slide, by a rim of oil or vaseline placed beneath the edge of the cover-glass. By this method the multiplication of bac- teria can be observed for a long time. When bacteria are sought in water, a definite amount of the suspected water is dis- tributed in gelatin, and plate-cultures are made. Earth is rubbed up with sterilized salt-solution; air is made to pass in definite amount through a sterilized salt-solution; and the salt-solutions thus infected are then mixed with gelatin, and from this gelatin plates are made. The culture of bacteria- on and in different media, accompanied by the microscopic examination of the different stages of development, serves for « more exact characteriza- tion, and thereby for the differentiation of the species of the bacteria in question. After its properties have been thoroughly studied in this way, the influence of the bacterium upon the animal organism is tested. As experimental animals, rabbits, dogs, guinea- pigs, rats, mice, and small birds are most frequently employed. The bacteria to be tested are introduced, sometimes under the skin, sometimes directly into the blood- current, sometimes by inoculation into the internal organs, sometimes by inhalation into the lungs, or sometimes by administration with the food into the intestinal canal. Bacteria can be regarded as pathogenic for a given animal when they multiply within the tissues and excite disease processes. If relatively large amounts are inoculated, the animal experimented upon may die under certain conditions, even if the bacteria do not increase at all in its body, since the poisonous substances formed in the culture and introduced by inoculation often suffice to kill the animal. Experience has taught that only some of the bacterial infectious which occur in man, when inoculated into animals, run the same course as iu man, and, indeed, only those which also occur otherwise in animals. In other cases the pathogenic fission - fungi occurring in man or in certain animals are, it is true, pathogenic for the experi- mental animal, but the pathological process shows another localization and another course. In a third case the experimental animals are in part or wholly immune. Inversely, fission fungi that are often extremely pathogenic for the experimental animals are harmless for other animals or for man. Literature. {Methods of Bacteriological Investigation. ) Abel: Taschenbuch f. bakteriologische Praktikanten, Wiirzburg, 190-1 Fischer-. Vorlesungen fiber Bakterien, Jena, 1903. Fliig-g-e: Die Mikroorganismen, Leipzig, 1890. Fraenkel, C: Grund iss der Bakterienkunde, Berlin 1895 Friedberger^Die Methoden der Bakteriol. Handb. v. Kolle u. Wassermann, L, Gierke: Teclmik der patholog.-anatom. Untersuchungen, Jena 1904 Gunther: Einfiihrung in das Studium der Bakteriologie, Leipzig 1902 Hueppe: Die Methoden der Bakterienforschung, Wiesbaden 1891 Matzuschita; Bakteriologische Diagnostik, Jena, 1902. Mig-ula: Bakteriologisch.es Praktikum, Karlsruhe, 1892. Novy: Laboratory Work in Bakteriolosy, 1899 Numerous articles on the investigation of bacteria are found in the Centralblatt f Bakteriologie Of the many text-books m English dealing with bacteriology may be mentioned those by Grookshank, Sternberg, Abbott, Park, McFariand Muir THE COCCI. 563 II. The Different Forms of Bacteria and the Infectious Diseases Caused by Them. I. The Cocci, ob Sphjerobacteria, and the Morbid Peocesses Caused by Them. (a) General Considerations Regarding the Cocci. §151. The cocci or coccaceae (Zopf) are bacteria that occur exclu- sively in the form of round or oval or lanceolate cells. In their multi- plication by division they often form peculiar aggregations of cells. which are commonly designated by special names according to the char- acter of the different forms appearing. Since certain forms of cocci are especially likely to develop in definitely shaped aggregations, advantage has been taken of this fact, to classify them in different species. It should be noted, however, that a given species does not always appear in the same form, but may vary according to the nutrient conditions. Many of the cocci multiply by division in one plane only — at right angles to the length of the elongated spherical cell. If the spheres re- sulting from division remain together for some time in the form of double spheres, and if this form appears with especial frequency in the case of any one species, it is desig- nated as a diplococcus *-' X 'n "a* ■ * A". O ±- Fig. J2S. FIG. 426. FIG. 427 FIG. 42». Fig. 42R. — Streptococcus from a purulent peritonea] exudate of a case of puerperal peritonitis, a. Single cocci ; h, diplococci ; c, streptococci or torula-cnains. X 500. Fig. diy ~ —Colonies of micrococci in blood-capillaries of the liver, causing metastatic abscess-formation. From a case of pyaemia. Necrosis of liver-cells. X 400. Fig. 428.— Cocci grouped in tetrads (merismopedia), from a softening infarct of tue lung. X 500. Fig. 429.— Sarcina ventriculi. X 400. (Fig. 426, b). If, from a further continued division of the cells in one plane, rows of cocci (torula chains) result, these are known as strepto- cocci (Fig. 426, c ), and this term is used also as the name for a group. If the division of the cells takes place irregularly, and the cells remain together in small collections or heaps, the bacteria are usually desig- nated as micrococci (Zopf) (Fig. 427). By Ogston and Rosenbach the name staphylococcus or grape-coccus has been used to indicate some of these forms. Larger collections of cells, which are held together by a gelatinous substance derived from the cell-membranes, have been designated as zobglcea masses. If the masses of cocci are united into larger collections by means of a gelatinous envelope, they are spoken of as ascococcl or tube-cocci. To those cocci which remain united for a long time in a four-celled tablet (Fig. 428), the name of merismopedia, tetracoccus or tablet-coccus ■^64 THE PATHOGENIC FISSION-FUNGI. was applied by Zopf. Others class such bacteria with the micrococci. The cocci that go by the name sarcinae are characterized by division in three directions of space, so that compound cubical packets of spherical cells are formed from tetrads (Fig. 429). The cocci not infrequently show a tremulous molecular motion in fluids; swarming movements have not been observed with certainty. .Spore-formation has not been demonstrated in the majority of forms. According to Cieukowski, Van Tiegkem, and Zopf, the Coccus (leuconos- toc) mcsenterioides, that produces a frog-spawn-like culture on sugar or parsnips, forms arthrogenic spores, in that some particular cell in a torula chain becomes larger and glisteuiug. According to Prazmowsky the Micrococcus urew also forms spores. The saprophytic cocci grow upon very different nutrient substrata and cause by their growth in suitable media various processes of de- composition. Many also form pigments. Micrococcus urece causes a fer- mentation in urine by means of which ammonium carbonate is formed from the urea. Micrococcus viscosus is the cause of the slimy fermenta- tion of wine. The cause of the phosphorescence of decomposing meat was found by Prliiger to be a micrococcus that forms slimy coatings on the surface of the meal . Of the pigment-producers the best known are Micrococcus lutcus, Mi- crococcus aurantiacus, Sarcina lutea, Micrococcus cyaneus and Micrococcus violaceus, which, when grown upon boiled eggs or potatoes, produce yel- low, blue, and violet pigment respectively. Saprophytic cocci are found in the mouth cavity and intestine, as well as on the surface of the skin, and occasionally also in the lungs. Micrococcus heematodes (Babes) is said to be the cause of red sweat, and forms red zoogloea masses. Sarcina ventriculi (Fig. 429) occurs not infrequently in the stomach of man and animals, especially when abnormal fermentations are going on. According to Falkenheim the stomach sarcines can be cultivated upon gelatin, and form in this medium round, yellow colonies, which contain colorless monococci, diplococci, and tetrads, but never cubical packets. They form these, however, in neutralized hay-infusion, aud their growth causes a souring of the infusion. The membrane of the sarcinas is said to consist of cellulose. Microcococcus tetragenus (merismopedia) is not infrequently found in human sputum, and in the mouth and throat; it may be present further in the wall of tuberculous cavities, or in hemorrhagic or gan- grenous foci of the lungs. It forms tetrads (Fig. 42S) whose cells are held together by a gelatinous membrane. On gelatin-plates it forms round or oval, lemon-yellow colonies. It is pathogenic for white mice and guinea-pigs, to a less extent for rabbits, and, when injected subcuta- neously, excites purulent inflammations, in the mouse often also a sep- ticaemia. Intratracheal injections may give rise to inflammations of the respiratory passages and the lungs. The pathogenic cocci cause acute inflammations which usually heal after the death of the bacteria; but it not infrequently happens that cocci may remain in the body for a long time and give rise to chronic processes. THE PATHOGENIC COCCI. 565 Literature. (The Cocci.) Babes: Rother Schweiss. Biol. Cbl., ii., 1882. Bancel et Hasson : Sur la phosphorescence de la viande de homard. Compt. rend., t. 88, 1879. Bienstock: Bakterien d. Darmes. Fortsclir. d. Med., i. ; Zeitschr. f. klin. Med., vii., 1884. Bosc et Galavielle: Sur le micrococ. tetragenus. Arch, de med. exp., 1899. Brieger: Bakterien des Darmes. Berl. klin. Woch., 1884. Chauffard et Raymond: Septicemic tetragenique. Arch, denied, ex p., 189(5. Cohn: Beitrage z. Biologie d. Ptlanzen, i.-iv. Eberth: Blauer Eiter. Virch. Arch., 73 Bd., 1878. Escherich: Bakterien d, Darmes. Fortschr. d. Med., iii., 1885; Munch, med. Woch., 1886. Ealkenheim: Ueber Sarcine. Arch. I. exp. Path., xix., 1885. Gessard: De la pyocyanine et de son microbe. These de Paris, 1882. Lticke: Blauer Eiter. Arch. f. klin. Chir., 1892. Ludwig: Micrococus Pfltigeri (Phosphoreseenz), Hedwigia, 1884. Miller: Die Mikroorganismen der Mundhohle, Leipzig, 1892. Prazmowsky: Ueber Sporenbildung bei den Bakterien. Biol. Cbl., viii., L888. Prove: Micrococcus ochroleucus. Beitr. z. Biol. d. Pflanzen v. Cohn, iv., 1887. Schrdter: Pigmentbildende Bakterien. Beitr. z. Biol. d. Pflanzen, v., Cohn, i. Stubenrath : Das Genus sareina, Milnchen, 1897. Vignal: Rech. s. 1. microorganismes de la bouche. Arch. de. phys. , viii., 1886; Rech. s. 1. microorg. des matieres fecales. lb., x.. 1887. See also § 148. (b) The Pathogenic Cocci. § 152. The Streptococcus pyogenes ( Rosenbaeh ) is a coccus which, in multiplying, forms double spheres and chains of spheres (Fig. 426) of different lengths, containing from four to twelve or more cells. This chain-formation comes to an especially full development when the strep- tococcus is growing in fluids — in nutrient bouillon or fluid exudates — but is also usually seen when it is growing within the tissues. The cocci stain well by Gram's method, are facultative anaerobes, grow best at 37° C, and form small whitish colonies on gelatin and agar. Streptococcus pyogenes causes in man inflammations, which usually, though not always, assume a purulent character. Occasionally it is found also upon normal mucous membranes, for example, in the upper air-pas- sages, or in the vagina and cervix uteri; it may therefore be assumed in such cases that its virulence is very slight, or that the mucous membranes offer a successful resistance to its entrance into their tissues. An infection with streptococci may occur either in healthy indi- viduals, or in those who have received some injury, or finally as an ac- companiment and sequela of other infections, particularly of scarlet fever, smallpox, diphtheria, and pulmonary tuberculosis. If the streptococcus multiplies upon the surface of mucous membranes — for example, of the respiratory tract (Fig. 430) — it excites an inflam- mation, which may bear the character of a desquamative or purulent catarrh (e), or of a croupous exudation (d). If it penetrates into the connective tissues of the submucosa, it causes most frequently inflammations which are phlegmonous in character — i.e., a more or less quickly spreading, sero- purulent, or purulent, or fibrinopurulent, or serofibrinous inflamma- tion, which may at certain points lead to suppuration and abscess-for- 566 THE PATHOGENIC FISSION-FUNGI. ination. In the exudate the cocci may be found in part free (Fig. 431, c), or in part inclosed within cells (6). C « Fig. 430.— Streptococcus tracheitis in scarlet fever (alcohol, carmine, methyl-violet, iodine), a, Con- nective tissue; ft, desquamated epithelium ; r, inemhrane composed of cells and streptococci; d, fibrin- toreads. X o00. The multiplication of streptoeoeei in the stratum- yermitiuthmm- of the skin leads to the necrosis of epithelium and the formation of purulent resides or blebs. "& r: ft.'* Fig. 4:!1— Streptococcus pyogenes from a phlegmon- ous focus of the stomach (alcohol, carmine, methyl- violet, iodine) . a, Leucocytes ; ft, leucocytes containing streptococci ; c, free streptococci. X 500. less severe serous and cellular in- If the streptococcus spreads in the eorium, into which it penetrates especially in the case of small wounds of the skin, it utilizes the lymph-spaces and lymph-vessels (Figs. 432, a; 433, h, i; 434, c) as pathways and as places for the development of colonies, causing' a more or less severe inflammation, which is characterized macroscopically by an advancing redness and swell- ing of the skin known as ery- sipelas. To the external appear- ances there corresponds a more or filtration (Figs. 432, rl, e, /',• 433, vi; 436, c), and often also a tibrino- cellular exudation (Fig. 433, vij. The infection of the lymph-vessels in erysipelas involves at- tunes chiefly the superficial layers of the cutis (Fig. 433), at other times the deeper layers (Fig. 434, c). In the latter case, the erysipelatous process be- comes phlegmonous in character, so that between the two processes a sharp border-line cannot be drawn. At the same time with the infection of the Fig. taa.StreptticoecuxeriisiyelaU* Ui) inside a lymph- vessel (ft), in part composed of thickly crowded spheres, in part of torula-chains (alcohol, gentian-violet); c, neighbor- hood of the lympb-vessel. with pale, non-staining nuclei ; d, vein; c, perivenous cellular infiltration of tissue; /, accumu- lation of cells in the lymph-vessel. Section of rabbit's ear two days after inoculation with erysipelas-cocci. V. 225. STREPTOCOCCI. 507 deeper layers streptococci may spread on the surface of the epithelium —that is, beneath the horny layer (Fig. 434, g), and cause a loosen- ing of the epithelial cells and a desquamation of the horny layer (/). / f Fig. 433 —Section of the skin in erysipelas bullosum (alcohol, alum-carmine), a, Epidermis; o, coriuin ; c, vesicle ; d, covering of vesicle ; e, epithelial cells containing vacuoles ; /. swollen cells with swollen nuclei: (/, f/,, cavity caused by the liquefaction of epithelial cells, and containing fragments of epithelium and pus-corpuscles ; k, lymph-vessel, partly filled with streptococci ; i. lymph-vessel filled full of streptococci; 7c, colony of streptococci in the tissue; 7, h , necrotic tissue; »*, cellular, m,, Dbrinocollular infiltration ; n, flhrinn'rellulnr exudate in the vesicle. X HO. •>■ /»* 4 FIG. 434.— Erysipelas of the head in a child of one month of age (bacterial staining, carmine), a. Cutis with nair-follicles ; o, subcutis ; c, lymph-vessel with streptococci and inflamed surrounding area; d, rete Malplghli : c, /, horny layer ; g, streptococci lying upon the rete Malpighii. X 45. 568 THE PATHOGENIC FISSION-FUNGI. In cases of severe infection with very virulent streptococci the pro- cess may go on to liquefaction of the epithelium (Pig. 433, e, f, g, g.). and to the formation of vesicles (c, erysipelas bullosum), or to ne- ■v v ■ FlG - ^•r? e , 8 i'? nins streptococcus phlegmon on the trunk, after phlegmon of the arm (formalin car- mine, methyl-violet), a, b. Skin ; c, streptococci in the subcutaneous connective tissue ; rf be^innine col lection of leucocytes. X IB. fuming loi crosis and gangrene of the corium (I, l v erysipelas gangrenosum), or to suppuration of the tissue. In the subcutaneous tissue the spread and multiplication of the cocci (Fig. 435, c) lead to a progressive seropurulent (d) and fibrinopurulent inflammation, often with subsequent tissue-suppuration. Such forms of infection are known as phlegmons. If the muscles become involved in a phlegmonous. process, the streptococci increase and spread (Fig. 436, «) chiefly m the connective tissue of the perimysium internum, but may penetrate also into the sarcolemma-tubes Here also the consequences of the infection are more or less severe inflam mations leading to suppuration. Bronchogenous infection of the lungs causes purulent, or croupous or hemorrhagic exudations into the pulmonary alveoli Should bone become involved from the skin or from a mucous mem- brane—as, for ej ample, from the middle ear— the cocci may increase in very large numbers in the marrow tissue (Fig. 437, a, b), and here eiZ rise in the first place to tissue-necrosis, and later to a purulent inflam matron of the neighboring tissues. STREPTOCOCCI. 569 Fig. 436. — Streptococcus phlegmon in muscle. (Alcohol, Weigert'a stiiin.) n, Ma itreptoeocci; b, leucocyte infiltration; c, transverse section of muscle-fibres. X 100. FIG. 437.— Streptococcus infection of the petrous portion of the temporal bone, from a child of eight months of age (fonnalin, nitric-acid decalcification, carmine, methyl-violet), a. Medullary spaces com- pletely filled with streptococci ; h, beginning invasion by streptococci ; c, bone marrow ; d, trabecules of bone. X 300. 570 THE PATHOGENIC FISSION-FUNGI., A streptococcus infection may terminate, either sooner or later, in that the opposing forces of the organism restrict the further spread of the bacteria, and destroy them. Not infrequently, however, the infec- tion progresses up to the time of death. If the streptococci break into the lymph- and blood-vessels, metas- tases are often formed, and distant organs are in this way involved. Infection of the lungs leads easily to infection of the pleura. Infection of the female genital tract, which easily takes place during delivery and the puerperium, leads very often to a spread of the infection to the peri- toneum by means of the lymphatics. Infection of the serous membranes leads usually to a seropurulent, or fibrinopurulent exudation, the strepto- cocci developing luxuriantly in the free exudate, and forming long- chains. In infection of the blood, the streptococci do not increase in the circulating blood, but at the points where they come to rest; in the small capillaries of the lungs, heart, liver, kidneys, spleen, bone-marrow, joints, etc , or even on the valves of the heart. At the point of increase there is likewise produced an inflammation, which in general bears the same character as the primary inflammation, but is not infrequently less severe and more circumscribed. Hwmatogenous streptococcus-infection of the lung leads to the iormation of inflammatory foci (Fig. 438, a), which for the greater part show a Fig. 438.— Metastatic nsematogenous streptococcus pneumonia, after ano-inn - --"'.- -„~:..§ '■'■-■"**- -r-"-''-^-':' Fig. 440.-r-Erythema multiforme, due to streptococcus infection, arising in the middle ear (Fig. 437), from a child eight months old. Section through a red spot in the skin of the back of the foot (alcohol, methyl-violet, carmine), a, Corium; b, subcutaneous tissue ; c, capillaries filled with streptococci. X 46. 572 THE PATHOGENIC FISSION-FUNGI. If the cocci pass to a blood-vessel of the skin or subcutaneous tissue, they may increase in the same to such an extent that they form perfect casts of the capillaries (Fig. 440, c). As the result of the surrounding hypersemia there are produced in the skin red spots and swellings, and eventually purulent foci. In the kidneys, in whose vessels there often occurs an extraordinary multiplication of streptococci (Fig. 441, a, b), 7 ^ v ' ? - ' >;itf $ # '^< : ~ "& '•■•"• * "-4™ If .*#< ■^.•*.i k \-- P .. Fig. 441..— Extreme streptococcus infection of the kidney (grayish areas), arising after streptococcus angina (alcohol, Weigert's stain), a, Cocci in the intertubular, b, in the glomerular capillaries ; c, urinary tubules ; d, fibrin in the urinary tubules. X 280. there arise in the first place grayish- yellow circumscribed areas of dis- coloration, which are dependent upon the collection of bacteria, the local anaemia, tissue- necrosis, and often a beginning serofibrinous exudation (d). Later, yellow discolorations and softening of tissue appear, corre- sponding to suppuration. Similar changes may be demonstrated also in other organs. The danger of , fatty marrow; c, purulent area; <1 , cocci. V ion. (he metastasis to the internal organs, whereby inflammations of the lymph- vessels (lymphangoitis) and of the blood-vessels (phlebitis, arteritis) make their appearance. Cryptogenic infections are, however, of not infre- quent occurrence, so that the first recognizable localization of the infec- tion appears in the endocardium, myocardium, or bone-marrow. The spread of staphylococci through the blood-stream leads to multiple locali- zation with abscess formation, and this condition is designated pyasmia, as in the case of the similar condition caused by the streptococcus. The complication of a staphylococcus infection with severe symptoms of intoxication is also known as septicaemia ; and the combination of a staphylococci! s-pysemia with septicaemia is also known assepticopyasmia (cf. S 11). The Staphylococcus pyogenes aureus is also pathogenic for animals: horse, dog, cattle, goat, sheep, rabbit, guinea-pig, and mouse, particularly for STAPHYLOCOCC US. 58 ] the first-named, less so for the last. In these animals it causes suppu- ration. The staphylococcus loses its virulence easily in cultures. The inoculation of cultures of high virulence into susceptible animals causes a gelatinous cedema. Closely related to the Staphylococcus pyogenes aureus are the Staphy- lococcus pyogenes albus (Eosenbach) and the Staphylococcus pyogenes citreus ( Passet) ; these forms probably represent modified varieties of the aureus. The albus forms whitish, the citreus lemon-yellow colonies. These bacteria occur in the same regions and produce the same effects as the aureus, but are more rare than the last named. The Staphylococcus, pyogenes aureus usually occurs alone in the pus- foci, but not infrequently there may be associated with it other pus- cocci or even bacilli, as, for example, the Bacterium coli commune, or the typhoid-bacillus. The staphylococcus forms a hemolysin and a leukocidin (Van der Velde, Neisser, and Wechsberg) which destroys the leucocytes of rabbits, and also poisons which have a degenerative action upon the tissues. The bodies of dead staphylococci cause in- flammation when injected into the tissues. Staphylolysin and hemolysin and leukoci- din form in the organism anti staphylolysin and antileukocidin and therefore belong to the toxins. A serum produced by pathogenic staphylococci will agglutinate both the homol- ogous strain as well as the majority of other pathogenic strains (Kloppstock and Bochen- lirimer). Literature. {Staphylococcus Pyogenes Aureus. ) Babes: Bakt. Unters. lib. septische Processe im Kindesalter, Leipzig, 1889. Bockhart: Aetiol. d. Impetigo, d. Furunkels u. d. Sykosis. Monatsh. f. pr. Dermat., 1887. Bonome: Staphylocoques pyogenes. Arch. ital. de Biol., viii., 1887. de Christmas: Rech. exper. sur la suppuration. Ann. de l'lnst. Pasteur, ii., 1888. Dennig: Ueber septische Erkrankungen, Leipzig, 1891. Escherich: Staphylokokken in Hautabsccssen v. Sauglingen. Munch, med. Woch. 1886. (Jarre: Zur Aetiologie der acuten eiterigen Entziindung. Fortschr. d. Med., hi.. 188.J. Hessler: Die otogene Pyamie, Jena, 1896. Hohnfeldt: Histogenese d. durch Staphylococcus hervorger. Abscesse. Beitr. v. Zieg- ler, iii., 1888. Janowski: Die Ursachen der Eiterung. Beitr. v. Ziegler, xv., 1894 (Lit.). Jurgensen : Kryptogenetische Septikopyamie. Lehrb. d. spec. Path., Leipzig, 1894. v. Kahlden: Sepsis. Eulenburg's Realencyklop., 1899. Kloppstock u. Bockenheimer: Agglutination der Staphylokokken. A. f. klin. Chir., 72 Bd., 1904. Koch: Die Wundinfectionskrankheiten, Leipzig, 1878. Kocher: Osteomyelitis, Periostitis. Strumitis. Langenheck's Arch., xxiii., 1879. Kraske: Aetiologie d. acuten Osteomyelitis. Verh. d. XV. Chir.-Congr., Berlin, 1886 Krause: Mikrokokken der infectiosen Osteomyelitis. Fortschr. d. Mod., ii., 1884. Lenharte: Die septischen Erkrankungen, Wien, 1964. Liibbert: Der Staphylococcus pyogenes aureus, Wurzbuig, 1886. Neisser u. Lipstein: Die Staphvlokokken. Handb. d. path. Mikroorg., iii., Jena. 1903 (Lit.). Neumann: Micrococcus pyog. tenuis u. Pneumoniecoccus. Cbl. f. Bakt., vii., 1890. Ogston: Micrococcus Poisoning. Journ. of Anat. and Phys., xvi.. xvii., 1882. Oppenheimer: Staphylolysin u. Leukocidin. Handb. d. path. Mikroorg., iii., 190.1. Petruschky: Infection mit pyogenen Kokken. Zeit. f. Hyg., xvii., 1894. Ribbert: Experiment. Myo- u. Endocarditis. Fortschr. d. Med., iv., 1886; Veiiauf der durch Staphylococcus in d. Haut v. Kaninchen hervoreerufenen Entzundjn- ijen. Deut. med. Woch., 1889; Die patholog. Anat. u. die Heilung der durch d. Staphylococcus pyog. aureus hervorger. Veranderungen, Bonn, 1891. THE PATHOGENIC FISSION-FUNGI. Rodet et Courmont Subst. toxiques elab. par le staphvloc. pyog. Rev. cle xiii., 1S93. Rosenbach: Mikroorganismen d. Wundinfectionskrankh., Wiesbaden, 1884. Sahli: Aetiol. d. Gelenkrheumatismus (Staph, citreus). Corr. f. Schweiz. Ai 1892. Scholtz: Paras. Natur d. Ekzems. Deut. med. Woch., 1900. Singer: Aetiologie u. klin. d. acnten Gelenkrheumatismus, Wien, 1897. Steinhaus: Aetiologie d. Eiterung. Zeit. f. Hyg., v., 18SS. Struck u. Becker: Mikrok. d. infectiosen Osteomyelitis. Deut. med. Woch., Ullmann: Fundorte d. Staphylokokken. Zeitschr. f. Hyg., iv., 1888. Wyssokowitsch u. Orth: Beitr. z. I.ehre a-, d. Endocarditis. Virch. Arch , 103 lSSfi. 18S3 H.I. §155. The Micrococcus Gonorrhoea; or Qonococcus (Pig. 447) is a coccus first described by Neisser in the year 1879. It is constantly pres- ent in tlic discharges of the purulent catarrh, known as gonorrhoea, of the male and female urethra, and female genital canal (especially of the cervix), as well as in the secretions of gonorrhoea! ophthalmia. It is regarded as the cause of gonorrhoea as well as of the blennorrhea of the eye. Besides the specific cocci, other cocci may also be present in the gonorrhoeal secretions, some of them closely resembling the gonococcus ; the pus-cocci may also be present. The gonococcus may be cultivated upon coagulated human blood -serum, blood-serum gelatin, on human blood-ser- um-agar, on urine-agar; and forms on the surface of the nutrient medium a thin grayish-yellow layer having a smooth sur- face. It dies out easily, and grows only at higher temperatures. Wassermann recommends as culture-medium Vlti. 447.— Gunocorci in (he urethral se- cretion from ;i fresh case uf gonorrhoea (inethylene-blue, eosin). a, Mucus with single cocci and diplOCOCCi ; h, pus-cells with, c, pus-cells without diplococei. "00. Via. UK -Urethritis porn trrljtiif n. Gross-see lion M-;, uj^li itit ini thrown i p.to folds (Muller's flu id, ha •luatDxylln, i ,, \i 'final ci i li ii 'I'liini'inic \ rllirli infiltrate d, proliferating ninne L'tiVH I issue Of (In- lnut'o's'i [/, ! mill rate llll('('(i\ 1 ■ tissue ; /j, f, nilhi (tesquani iited cpithPliitl cells ;n Id |M,S- I'lirpusclps, If if i. ff epitl GONococcr.s. 583 swines'-serum-nutrose-agar; Wertheim, 2 to ■'! parts of a meat bouillon peptone-agar with 1 part of serum. The cell of the gonocoecus contains a poison (Wassermaun) which, when injected into the tissues, excites inflammation. Animals are immune against inoculations with the gonocoecus. Efforts made to inoculate human beings with artificially cultivated gonococci have beeu successful in producing a purulent catarrh of the inoculated mucous membrane. In the purulent secretion of the mucous membrane infected with gon- orrhoea the coccus usually forms clumps, and for the greater part appears in the form of diplococci, the opposing surfaces of which are flattened (Fig. 447); but occurs also in part free (a), and in part inclosed within cells (b). It stains easily with aniline dyes, but is decolorized by Gram's method. The gonocoecus penetrates into the epithelial layer of the affected mucous membrane, and lies partly between and partly in the epithelial cells, and in leucocytes. Only the uppermost layers of the connective tissue are infiltrated. The infiltration is most marked in the case of cylindrical epithelium, while in the regions covered by squamous epithe- lium (fossa navieularis, vagina) the cocci lie more superficially. They cause inflammations which bear the character of purulent catarrhs, and are associated with a cellular infiltration of the tissue of the mucosa (Fig. 44S, b, c, -1.2 (i broad, and possesses -1-8 peripherally arranged liagella. It stains according to Gram. In the ordinary nutritive media it grows best under anaerobic conditions at a temperature of 18 -L.'r>° ( !., and forms endogenous spores. Acids easily inhibit its growth. When growing in the foods mentioned above, it produces a true toxin which is very poisonous for experimental animals, and causes the forma- tion of an antitoxin. The poison is rendered inactive by heating to 80° ( ; ., but is not changed by the digestive juices. The consumption of food in which the bacillus has already formed its toxins leads, therefore, to intoxication. On the other hand, the bacillus does not develop in the human organism, its growth being hindered by the high body tempera- ture. The bacillus should be classed then as a toxicogenie saprophyte. The disease known asbotulismus or allantiasis or ichthyoismus comes on about twenty-four to thirty-six hours after the taking of the food, and is characterized essentially by nervous disturbances of central origin, secretory disturbances, motor paralysis (paralysis of accommodation, mydriasis, ptosis, and double vision), dryness and redness of the mucous membrane of mouth and pharynx, aphonia, dysphagia, etc. Constipa- tion and retention of urine frequently take place, or there may be diar- rhoea and vomiting. Death often results after a short time through bulbar paralysis. As Proteus vulgaris, Hauser has described a bacillus (Bacteri/um vul- gore of Lehmann) which is very frequently' present in decomposing ani- mal substances and in human cadavers, and in gangrenous ulcers, and causes putrid decomposition. It forms rods of varying length, and pro- duces substances poisonous for animals. According to observations by numerous authors, it is not infrequently found in human tissues, chiefly in association with other bacteria, streptococci, pneumococci, diphtheria- bacilli; and by its presence aggravates the course of the infection and causes putrid decomposU ion of the pus and the necrotic tissue. In rare cases it may alone, without the association of other bacteria, cause inflam- mations, particularly 7 of the urinary bladder (cystitis). Several cases of heemorrhagic enteritis have also been described, in which a form of protens was regarded as the causal agent. Further, protens has also been found in inflammations of the female genital tract, serous membranes, and liver 588 THE PATHOGENIC FISSION-FUNGI. (infectious icterus), and has been considered to be the cause of the given inflammation. Proteus must therefore be classed with the parasitic or pathogenic bacteria. Its pathogenic activity rests chiefly upon the forma- tion of poisonous substances. (Literature given by Meyerhof, 1. c. ). The pathogenic bacilli and polymorphous bacteria cause partly acute and partly chronic affections, the former terminating either in death or in healing after the destruction of the bacteria. It also hap- pens in the acute diseases that the bacteria may remain in the body for along time. The chronic affections are characterized by the persistence and multiplication of the bacteria within the body, so that the disease assumes a progressive character, and sometimes slowly, sometimes rapidly, new regions are in turn invaded by the bacteria and suffer pathological changes. Bacillus subtilis is a fission-fungus whose spores are widely distributed in the ground, hay (hay-bacillus), and in the air. When cultivated upon potato or upon the dung of herbivorous animals, it forms whitish-yellow colonies; upon liquids it forms thin and thick pellicles. It requires oxygen for its development. The fully developed rods (Fig. 449, a) are 6 p long. The snake-like motions occurring at times are produced by means of numerous lateral and terminal flagella. Through the growth of the rods undivided threads are formed which after division form chains of rods. The separate cells may develop in their interior glistening, sharply contoured spores (d, e), which lie either in the middle or nearer to one end of the cell. Later the cells in which the spores have been formed die. During germina- tion the spores become pale (Fig. 449/, '" 5 ), lose their glistening appearance and their sharp contour. A shadow then appears at each pole, while the spore begins a tremu- lous motion. After a time the contents of the spore project from the membrane of the spore in the form of a germinal utricle, which later becomes elongated, divides, and produces sw 7 arming rods. The Bacillus butyricus (Bacillus amylobacter of Van Tieghem, Vibrion butyriquc of Pasteur, Clostridium butyricum of Prazmowski) consists of rods of 3 to 10/i in length, and also forms threads and chains of rods. During spore-formation the cells become spindle-, club-, or tadpole-shaped (Fig. 450, d), and then produce one to two glistening spores. In germination, after the absorption of the spore-membrane a germinal utricle appears at one of the two poles (Fig. 450, e 1 - 7 ); this becomes elon- gated, and produces new rods by segmentation. The Bacillus butyricus does not need oxygen for its development; it produces butyric-acid fermentation with evolution of carbonic acid, in solutions of starch, dextrin, sugar or glycerin. In media containing starch, glycerin, or cellulose the bacilli are colored blue with iodine. Bacillus prodigiosus grows upon potatoes and bread, as well as upon agar- agar, and upon nutrient gelatin, liquefying the latter. It forms a red coloring matter which is soluble in alcohol. The pigment is formed only in the presence of oxygen; in the growth in milk the coloring-matter is contained in the fat-droplets. The bacilli themselves are always colorless. Bacillus fluorescens liquefaciens forms whitish cultures in gelatin, in the neighborhood of which the gelatin is liquefied, while in the remote surrounding portions it gradually takes on a greenish-yellow fluorescence. Bacillus cyaiiogenes (Neelsen, Hueppe), when cultivated in sterilized milk causes a slate-gray color that changes through the addition of acid to an intense blue! In unsterilized milk, in which lactic-acid bacteria develop at the same time a 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 (Fliiqge). Bacillus acidi lactic! ferments milk-sugar into lactic acid and coagulates casein In gelatin it produces white cultures. Bacillus caucasicus (Dispora caucasica) forms one of the constituents of the fungus-conglomerate known as kephir-ferment, which is used by the inhabitants of the Caucasus in the preparation, from cow's milk, of the alcoholic drink called kephir The kephir-ferment consists of small granules containing yeast-cells and bacilli The latter at times show movements, and form a round spore at the end of each rod \- the result of their growth in milk the milk-sugar is probably converted into glucose! while the yeast-cells produce alcoholic fermentation. ANTHRAX. 589 Bacillus pyocyaneus occurs occasionally in bandages upon suppurating wounds and causes a greenish-blue discoloration of the same. The coloring-matter called pyocyanin is soluble in chloroform and crystallizes from the solution in long blue needles. In addition it forms also a coloring matter soluble in water which produces a greenish fluorescence of the nutrient gelatin. (See § 163.) Literature. (Saprophytic [in Part Pathogenic] Bacilli.) Babes: Rech. sur les bacilles du pus vert. Ann. de l'Inst. de path, de Boucarest, i.. 1890. Banti: Sopra quatri nuove specie di Protei o Bacilli capsulati, Firenze, 1S8S. Bordoni-XTffreduzzi: Proteus hominis capsulatus. Zeitschr. f. Hyg., hi., 188.S. Bunge: Geisseltragende Bakterien. Fortschr. d. Med., xii., 1894; Sporenbildung. lb., xiii., 1895. Carbone: Ueber die von Proteus vulgaris erzeugten Gifte. Cbl. f. Bakt., viii., 1890. van Ermengem: Bacillus botulinus. Z. f. Hyg., 26 Bd., 1897, u. Handb. d. path. Mikroorg., ii., Jena, 1903 (Lit.). Ernst: Bacillus des blauen Eiters. Zeitschr. f. Hyg., ii., 1887. Foa et Bonome: Maladies causees par Proteus. Arch. ital. de Biol., vii., 18S7. Frankel: Ueber Gasphlegmone, Leipzig, 189.3. Frick: Griines Sputum u. griinen Farbstoff produc. Bacillen. Virch. Arch., 110 Bd., 1889. Gessard: Rech. sur le microbe pyocyanique. Ann. de l'Inst. Pasteur, 1890. Goebel: Bacillus d. Schaumorgane. Cbl. f. allg. Path., vi., 1895. Grethe: Keimung d. Bakteriensporen. Fortschr. d. Med., xv., 1897. Hauser: Ueb. Faulnissbakterien u. deren Beziehung z. Septikiimie, Leipzig, 1885. Heim: Versuclie uber blauc Milch. Arb. a. d. K. Gesundheitsamte, v., 1890. Jaeger: Die Aetiologie des infectiosen fieberhaften Ikterus. Zeitschr. f. Hyt;., xii., 1892. Jakowsky: Bakterien des blauen Eiters (B. pyocyaneus). Zeitschr. f. Hyg., xv., 1893. Krause: Zur Kenntn. d. Bac. pyocyaneus. Cbl. f. Bakt., xxvii., 1900. Lartigau: Bacillus pyocyaneus as a Pathological Factor. Phil. Med. Jour., 1898. Ledderhose : Ueber den blauen Eiter. Deut. Zeitschr. f. Chir., xxviii., 1888. Levy: Die Aktinomycesgruppe. Cbl. f. Bakt., xxvi., 1899 (Lit.). Meyerbof: Biologische u. thierpathogene Eigenschaft des Bacillus proteus (Hauser), mit einer Zusammenfassung d. wiehtigsten Literatur uber Proteus. Cbl. f. Bakt., xxiv., 1898. Prazmowski: Unters. uber d. Entwickelungsgeschichte einiger Bakterien, Leipzig, 1880. Perkins: Report of Nine Cases of Infection with Bacillus Pyocyaneus. Jour, of Med. Research, 1901. Schimmelbusch: Griiner Eiter u. d. Bac. pyocyaneus. Samml. klin. Vortr., No. 62, 1893. (b) The Pathogenic Bacilli and Polymorphous Bacteria, § 158. The Bacillus anthracis (Bacteridie du charbon) is the cause of anthrax, a disease occurring chiefly in cattle and sheep, and occasionally transmitted to man. It is a fission-fungus which, when inoculated into a susceptible animal, may increase within the tissues as well as in the blood. The anthrax-bacilli (Fig. 451) are 3 to 10 /< long and 1 to 1.5//. broad. In the blood of animals affected with anthrax they occur either singly or in thread-like jointed bands of two to ten rods, whose ends are for the greater part sharply cut across (Figs. 151, 152) more rarely slightly concave or even slightly convex (Johne). According to Pianese, Sera- fini, Giinther, and Johne they possess a gelatinous capsule which is besl brought out by the staining of dried preparations with methylene- blue. They can be cultivated upon blood-serum-gelatin, in bouillon, upon ; : % *v; • v "^ N-*— - ^l 1 _- Vv x ^. .'■■■• ' - N>^. '- ■ , ^V- V ^— — --- W \ :v, : %.. " V - S r> *V N ■ < ■ - \\\ V - — - \ *- V / v \ \ >1. seel hm from a liver \v h ise ca pilla rles numerous anthrax-bacilli and scatti ■red es lalonhol, o-enti an- violet, i'PSUVi n). 5VH) THE PATHOGENIC FISSION-FUNGI. slices of potatoes and turnips, in infusions of pens and niashed grain of various kinds, etc., in ibe presence of oxygen ( according to Kletl also in an atmosphere of nitrogen) ; and grow most rapidly at a temperature of from 30° to 40° C. At temperatures below 15° and above 43° C. development is impossible. Under suitable conditions of growth the rods increase in length, and may within a few hours form non-encapsulated threads of considerable length. These consist of short seg- ments wliose outlines may lie made visible by treatment with iodine or by stains (Fig. 451!). Ten hours later the clear contents of the threads become granular, and at regular intervals there become ap- parent dull-shining bodies, which alter a few hours enlarge into strongly refractive spores (Fig. 452). Later the threads disinte- grate and (lie spores become free. If the bacilli or the spores gain entrance into the blood, they in- crease and form rods as described i.fi.451. section from a liver whose capillaries above, which stain with different ontaln numerous anthrax-bacilli and scattered aniline dves, and also by Gram's .3ucopvfes laloohol, gentian-violet, vesuvm). • • ann. method. Sections of hardened I issue, show that they are present, in huge, numbers in the capillaries (Fig. 451), particularly in the spleen, liver, lungs, and kidneys. The neighboring parenchyma for the greater part appears unchanged; still the local proliferation of the ba- cilli can also cause tissue-degeneration, necrosis, and hemorrhagic in- flammation. If an infection of the blood takes place during preg- nancy the infection may pass over to the Actus. Anthrax-bacilli or (heir spores may gain entrance into the skin of man through small a wounds, an event which, is particularly likely to ^^ ^^OtJ^^caa happen in the case of individuals who butcher, "b j ^^ or shear, or prepare the skins of animals affected f| , ' ., with anthrax; or occasionally the infection may tv ^^P 001 lie transmitted by means of the sting of a fl'v > which has taken up blood from an animal iii- / fecfed with anthrax, 'there develops al the place of infection a. somewhat elevated pustule f, g . 452. -spore- containing ( Pig. 153) from l> nun. to several Centimetres in antb.rax-hae.ill1 and tree spores". diameter, having an arched or flattened surface cniuTOoilhe'SSiTrown"!! and of a, red or at tunes a more yellowish color. lui^XtSn^TmX Phis is often after a time covered with vesicles rtene-wue. < soo. or after the loss of the epithelium becomes moist, so that through the drying of the oozing, often bloody exudate a scab is formed (Fig. 453, w m% ** t Fig-. 454.— Portion of the anthrax pustule from the arm (Fig. 453), containing bacilli, >' 350, .592 THE PATHOGENIC FISSION-FUNGI. larger, with a grayish-yellow or greenish-yellow, discolored slough in the centre. In other cases the crests of the folds of the mucosa are swollen and h hemorrhagic, and show evidences of sloughing in the most prominent parts. The mucosa and submucosa are infiltrated with blood in the region of the foci ; the surrounding tissues are cedematous aud hypersemic. Bacilli are found in the tissues both in and about the foci, particularly in the blood- and lymph -vessels, and they may also be demonstrated in the neighboring lymph-glands. Primary lung infection may also occur in man as the result of the inhalation of anthrax-spores, proving fatal in from two to seven days. Individuals who have to handle the hair of animals that have died of anthrax are especially exposed to infection ; and the disease known as rag- sorter's disease, which occurs in men and women employed in the sorting of rags in paper-factories, is in a part of the cases nothing more than an anthrax infection. The spores taken into the lungs in the respired air develop in the bronchi (rarely in nose [Bosel] ) and alveoli, in the lymph- spaces of the lungs and pleura and in the bronchial glands, and penetrate also into the vessels. Their growth causes inflammatory hemorrhagic processes in the lungs, as well as serous hemorrhagic exudations into the pleural cavity and the mediastinal tissue, and swellings of the lymph- glands. It may also lead to the production of necrotic foci in the lungs and in the bronchial and tracheal mucosa. Mice, rabbits, sheep, horses, and sparrows are very susceptible to an- thrax ; white rats, dogs, and Algerian sheep are less susceptible or im- mune. Cattle are easily infected through the taking in of the spores from the alimentary canal, but are less susceptible to inoculation. Forma- tion of spores does not take place in the tissues and in the blood. According to Brefeld, Prazmowski , Klein, and others, the spore consists of a protoplasmic centre, which is enclosed by a double membrane, the exosporium and the endosporium. During germination the former is ruptured, the latter becomes the membrane of the embryo. The liberated embryo multiplies by division. Swarming movements are not seen throughout the entire period of development; the bacilli are always motionless. The bacilli of anthrax are easily killed by high temperatures, drying, and through the decomposition of the nutrient fluid. The spores, on the other hand, are very re- sistant, and are therefore usually the medium of the spread of the disease. The colonies upon gelatin show a wavy, irregularly shaped margin, and consist of many interlacing strands of threads, which later grow out of the culture in all direc- tions. The gelatin is liquefied immediately about the culture. On potato the bacil- lus forms grayish-white, slightly granular colonies having a sharply outlined border. On blood-scrum it forms a white coating. Stab-cultures in gelatin are white and during the process of growth they radiate at right angles from the line of inoculation out into the gelatin, particularly near the surface. After liquefaction of the gelatin they sink to the bottom. A marked attenuation of anthrax-bacilli may be produced by keeping the bacilli for ten minutes at a temperature of 55° C. (Toussaint) or for fifteen minutes at 52° C or for twenty minutes at 50° G. (Chauveau), or further through the influence of oxygen under high pressure (Chauveau). The bacilli attenuated by exposure for a short time to high temperatures quickly regain their virulence; those attenuated at lower tern peratures remain weakened for many generations. The addition of carbolic acid to the nutrient fluid in a proportion of 1 : 600 permits the further development of anthrax-bacilli, but destroys their virulence within twenty- nine days (Chainberland, Roux). Likewise, an attenuation may be produced by the addition of potassium bichromate (1 : 2,000-1 : 5,000). The addition of carbolic acid up to 1 : 800 hinders at the same time the formation of spores. Through cultivation of the bacilli at 42-4:3" O. (Toussaint, Pasteur, Koch) their virulence may be so weakened that they no longer kill first sheep, then rabbits and guinea-pigs, and finally mice. If the temperature is kept in the neighborhood of 43° C this result may be obtained in six days; at 42° O. it may require about thirty days to ANTHRAX. 593 decrease the virulence to this extent (Koch). By first inoculating with bacilli which kill mice but are harmless for guinea-pigs, and afterward inoculating with bacilli which kill guinea-pigs but not strong rabbits, an immunity against anthrax may be obtained in sheep and cattle but not in the case of mice, guinea-pigs, and rabbits. Such protec- tive inoculations are, however, not of practical value, since, in order to protect against natural infection with spores from the intestinal canal, such virulent inoculation-mate- rial must be used that a large per cent, of sheep (ten to fifteen per cent.) die from the inoculations. Further, the protection afforded by the inoculations is of very short duration, and the inoculation must be repeated within a year's time. According to observations by Ronx and ' hamberland anthrax bacilli which are cultivated in bouillon to which a small amount of potassium bichromate (1 : 2,000) or carbolic acid (1 to 2 : 1,000) has been added, permanently lose their power of spore-forma- tion while retaining their virulence. According to Koch, anthrax -bacilli may be cultivated in the presence of abundance of water upon potatoes and in an alkaline or neutral hay-infusion, cold infusions of pea- straw, on mashed barley and mashed wheat, in the juice of turnips, on maize, legumi- nous seeds, and numerous dead plants. Consequently they are able to grow and develop outside of the animal body — for example, in marshy regions and on river-banks (B. Koch). The entrance into the animal body is to be regarded as an accidental excur- sion of ectogenic bacilli. According to Boyka the development of spores takes place very quickly in a moist medium containing the necessary nutrient material at tempera- tures above 15° C. According to KM the dung of cattle forms a nutrient substratum for the bacilli. True toxins or endotoxins have not yet been demonstrated in the case of anthrax bacilli. Literature. (Bacillus Anthrads. ) Bail: Natiirl. u. kunstl. Milzbraiidimmunitat. Cbl. f. Bakt. Orig., xxxiii., 1903. Behring: Beitrage zur Aetiologie des Milzbrandes. Zeitschr. f. Hyg., vi., vii., 1889. v. Behring- u. Mach: Bez. der Bacillen zu endothel. Zellen. D. med. Woch., 1904. Bleuler: Hautmilzbrand: Correspbl. f. Schweizer Aerzte, 18S4. Blumer: Anthrax Septicaemia. Bull, of Johns Hopkins Hosp., vi., 1895. Brauell: Unters. betreffend den Milzbrand. Virch. Arch., 11 Bd., 1857. Buisson: Charbon intestinal chez 1'homme. Arch, de med. exp., i., 1889. Conradi: Toxinbildung bei Milzbrandbakterien. Z. f. Hyg., 37 Bd., 1899. Czaplewski: Unters. iib. d. Immunitat d. Tauben gegen Milzbrand. Zeit. f. Hyg.. xii., 1893. Davaine: Compt. rend, de lAcad. des sciences, 1863, 1864, 1865, 1868, 1870, 1873. Republished in L'ceuvre de C. J. Davaine, Faris, 1889. Dittrich: Prim. Milzbrandinfection des Magendarmkanales. Wien. klin. Woch., 1891. Eppinger: Die Hadernkrankheit, Jena, 1894. Frank: Milzbrandimpfung. Zeitschr. f. Thiermed., vii., Suppl., 1884. Hoffa: Die Natur des Milzbrandgiftes, Wiesbaden, 1886; Zur Lehre d. Sepsis u. d. Milzbrandes. Langenbeck's Arch., 39 Bd., 1889. Jacobi: Vier Falle v. Milzbrand beim Menschen. Zeitschr. f. klin. Med., 17 Bd., 1890. Johne: Morphologie der Milzbrandbacillen. Deut. Zeitschr. f. Thiermed., xix., 1893. Klett: Sporenbildung d. Milzbrandb. bei Anaerobiose. Zeit. f. Hyg., 35 Bd., 1900. Koch, B.: Beitr. z. Biol. d. Pfl. v. F. Cohn, 2 Bd., p. 272. Mittheil. a, d. K. Gesund- heitsamte, Berlin, 1881, 1884; Ueber die Milzbrandimpfung, 1882. Koch, W.: Milzbrand und Rauschbrand. Deut. Chir., 9 Lief., 1886. Krumbholz: Darmmilzbraud. Beitr. v. Ziegler, xvi., 1894. KurlofF: Im Laboratorium acquirirte Milzbrandinfection. Deut. Arch. f. kl. Med., xliv., 1889. Lewin: Milzbrand beim Menschen. Cbl. f. Bakt., xvi., 1894. Lodge: La maladie des trieurs de laine. Arch, de med. exp., 1890. Lubarsch: Milzbrand. Ergebn. d. allg. Path., v., 1900. Melnikow: Kunstliche Immunitat d. Kaninchcn geg. Milzbrand. Zeit. f. Hyg., xxv., 1897. Miiller: Der Milzbrand der Ratten. Fortschr. d. Med., 1893: Aeusserer Milzbrand des Menschen. Deut. med. Woch., 1894 (Lit.). Oppenheimer : Toxine u. Antitoxine. Jena, 1904, p. 154. Palm: Histologic des ausseren Milzbrandcarbunkels. Beitr. v. Ziegler, ii., 1888. Paltauf: Aetiologie d. Hadernkrankheit. Wien. klin. Woch., 1888. Parmier: La toxine eharbonneu.se. Ann. de l'lnst. Pasteur, 1895. 38 594 THE PATHOGENIC FISSION-FUNGI. Pasteur: La vaccination charbonneusc, Paris, 1SS3. Pawlowsky: Verhalten d. Milzbrandbacillen im Organismus. Vircli. Arch., 10S Bd., 1S87. Physalix: Nouv. rech. sur la maladie charbonneusc. Arch, de med. exp., iii., 1891. Pianese: La capsula del B. anthracis. Giorn. dell' Assoc, di Nat., 1891. Pollender: Casper's Vierteljahrsschr. f. ger. u. off. Med., S Bd., 185.5. Preisz: Studien iiber den Milzbrandbacillus. Cbl. f. Bakt. Orig., xxxv., 1904. Reinbach: Zur Aetiologie d. Lungengangran. Cbl. f. allg. Path., v., 1894. Roloff: Der Milzbrand, Berlin, 1883. Koux; Bacteridie charbonneuse asporogene. Ann. de l'Inst. 1'astcur, iv., 1888, Sobernheim: Milzbrand. Handb. d. path. Mikroorg., ii., 1903. Straus: Cas de charbon mortel. Arch, de phys., i., 1SS3; Contrib. a l'anat. pathol. de la pustule maligne. Ann. de l'Inst. Pasteur, i., 1887. Toepper: Die neueren Erfahrungen tib. d. Aetiol. des Milzbrandes, Jena, 1883. Toussaint: Rech. cxperimentales sur la maladie charbonneuse, Paris, 1889. Wagner: Le charbon des poules. Ann. de l'Inst. Pasteur, iv., 1890. Werig-o: Developp. du charbon chez le lapin. Ann. de l'Inst. Pasteur, 1894. Zorkendorfer: Darmmilzbrand. Prag. med. Woch., 1894. § 159. The Bacillus typhi abdominalis (Fig. 455), or the Bacterium typhi, is a fission fungus which occurs chiefly in the form of plump rods 2 to 3 y- long, having rounded ends, and in cultures growing also in pseudo- threads. It is regarded as the cause of typhoid fever. When examined * > 458) giving rise to a spherical swelling at the end of the rod (knobbed bacilli). In cultures it may form long pseudothreads. The cultures give off an offensive odor ; gelatin is slowly liquefied. The bacilli stain by Gram's method. They are motile except during the time of spore- BACILLUS TETANI. 603 formation, and possess peritrichous flagella. Pure cultures inoculated into horses, asses, guinea-pigs, mice, rats, and rabbits cause tetanus, but in the case of rabbits larger amounts must be injected. The tetanic con- tractures begin in the neighborhood of the point of inoculation. Suppura- tion does not occur at the point of inoculation. The bacilli cannot be demonstrated after the death of the animal, and are never found in the tissues except at the seat of inocula- tion. The specific action of the tetanus-bacillus is to be re- ferred to the production of a true toxin (tetanus toxin) which through its haptophore group is bound to the cells of the nervous system, and thereby after a certain period of incubation excites tetanic convulsions. An FIG 458._ Teta - antitoxin is produced in the body of man and experi- nus-baciiiiwitJiter- , . . r . , , ., . •> , -. . L mmal spores. X mental animals and by it animals may be made immune 1,000. against tetanus (see § 32). The infection — intoxication — of man takes place usually through the medium of small wounds ; idiopathic or rheumatic tetanus, which does not start from demonstrable wounds, may arise through infection from the mouth-cavity and the respiratory tract (Carbone, Perrero, Thalmann). A preexisting catarrh favors the infection (Thalmann). When taken into the alimentary tract the poison becomes inactive as the result of changes produced by the digestive juices (see § '29). The tetanus-bacillus is not found isolated either in the earth or in infected wounds; and inoculations, therefore, consist of a mixture of bacteria. Attempts to isolate the bacillus by means of cultures were therefore unsuccessful with the majority of investigators. In the year 1889 Kitasato, in Koch's laboratory, succeeded in iso- lating the tetanus-bacillus by heating for a half-hour to one hour, on the water-bath, at 80° C. mixed cultures that had been kept for several days in the incubator, and then plating the cultures in an atmosphere of hydrogen. Through the heating the bacteria growing at the same time with the tetanus-bacilli were killed, while the tet- anus-bacilli survived. Tetanus toxin (Kitasato) is destroyed by heating (65° C. and over) for a few minutes and by direct sunlight (fifteen to eighteen hours), and loses also its virulence in a few weeks under the influence of diffuse daylight. Literature. ( Bacillus Tetani.) Achard: Lesions des nerfs dans le tetanos. Arch, de med. exp., iv., 1892. Babes: Rech. sur le tetanus. Ann. d. PInst. de path, de Boucarest, iv., 1893. v. Behring-: Antitoxische Tetanustherapie. D. med. Woch., 1903. Beumer: Zur Aetiologie des Trismus sive Tetanus neonatorum. Zeitsch. f. Hyg., iii., 1887. Blumenthal: Tetanusgift. Zeitschr. f. klin. Med., 32 Bd., 1897. Brieg-er u. Boer: Toxine d. Diphtheric u. d. Tetanus. Deut. med. Woch., 1896. Carbone e Perrero: Aetiol. d. rheumat. Tetanus. Cbl. f. Bakt., xviii., 1896. Danysz: Toxine tetanique et subst. nerveux. Ann. de l'Inst. Pasteur, 1S99. Engelmann: Serumtherapie des Tetanus. Munch, med. Woch., 18S7 (Lit.). Fermi u. Pernossi: Ueb. das Tetanusgift. Zeitschr. f. Hyg., xvi., 1894. Kitasato: Der Tetanuserreger. Verh. d. XVIII. Congr. d. Deut. Ges. f. Chir., 1889; Deut. med. Woch., 1889; Tetanusbacillus. Zeitschr. f. Hyg., vii., 1889; Tetanus- gift. lb., x., 1891. Kitt: Ueber Tetanusimpfungen bei Hausthieren. Cbl. f. Bakt., vii., 1890. Kohler: Stand d. Serumtherapie d. Tetanus. Munch, med. Woch., 1898. v. Ling-elsheim : Tetanus. Handb. d. p. Mikroorg. ii., Jena, 1903 (Lit.). Marie: La toxine tetanique. Ann. de PInst. Pasteur, 1897. Moschcowitz: Tetanus, a Study, etc. (Lit.). Studies from Dept. of Path, of Colum- bia University, 1899-1901. 604 THE PATHOGENIC FISSION-FUNGI. Oppenheimer : Toxine and Antitoxine, Jena, 1904, S, 92. Rosenbach: Zur Aet.iol. cl. Wundstarrkrampfs. Langenbeck's Arch., xxxiv., 1886. Boux et Vaillard: Contr. a l'et. chi tetanos. Ann. de l'lnst. Pasteur, 1893. Thalmann: Aetiologie d. Tetanus. Zeitsehr. f. Hyg., 33 Bd., 1900 (Lit.). Tizzoni: Sieroterapia nel Tetano. Mem. della R. Ace. dell' 1st. di Bologna, 1901), 1901. Tizzoui u. Cattani: Tetanusgift. Cbl. f. Bakt., viii., 1890; Arch. f. exper. Pathol., 27 Bd., 1890; Widerstandsfahigkeit der Tetanusbacillen. Arch. f. exper. Path., 28 Bd., 1S90; Ueber die Arts einem Thiere die Immunitat gegen Tetanns zu i'lbertragen. Cbl. f. Bakt., ix.; Eigenschaften des Tetanus-Antitoxins. lb., ix., x., 1891. Tizzoni, Cattani u. Baquis: Bakteriol. Unters. lib. d. Tetanus. Beitr. v. Ziegler, vii., 1890. Vaillard: Immunite contre le tetanos. Ann. de l'lnst. Pasteur, v., 1891. Wellner: Tetanus. Ergebn. d. allg. Path., iii., 1897. Wiedenmann : Beitrag zur Aetiologie des Wundstarrkrampfs. Zeitsehr. f. Hyg., v., 1889. § 165. The Bacillus cedematis maligtii ( Vibrion septiqueof Pasteur) is an anaerobic bacillus first carefully studied by R. Koch. It is in-esentin various putrefying substances, and its spores are almost never absent from earth fertilized by decomposing fluids or liquid .manure . The bacilli are 3-3.5 /^long, and 1-1.1 abroad; they often form long pseudothreads. They resemble the anthrax-bacilli, though somewhat more sleuder, are rounded at the ends, and not sharply cut across. In spore-formation a swelling of the rod takes place, as in the case of the Bacillus butyricus, so that spindle- and tadpole-shaped forms arise. 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 gelatiu as well as in agar and coagulated blood- serum, but must be introduced deeply into the medium and protected from the air. Nutrient gelatin to which one to two per cent, of grape- sugar has been added is an especially favorable medium (Fliigge). Nutrient gelatin and blood-serum are liquefied, the latter with evolution of gas, The bacillus can be easily obtained by sewing up garden-earth under the skin of a guinea-pig, care being taken to prevent the access of air to Hie point of inoculation. The ensuing multiplication of the bacteria ex- cites a progressive cedematous swelling of the subcutaueous tissue. At a later stage the bacilli spread over the serous membranes, and involve the spleen and other organs. Mice, guinea-pigs, horses, donkeys, sheep, swine, cattle, and pigeons are susceptible to the bacilli ; rabbits and fowls are less susceptible, while rats, dogs, and cats are still less so. According to observations by Brieger, Ehrlich, Chauveau, Arloing, and others, the bacilli of malignant oedema may also occasionally develop in the human body, particularly when the tissues are poorly nourished and the bacilli through any accident— puncture of a hypodermic syringe —get into the deeper tissues. They excite gangrem >us ] irocesses associated with hemorrhagic oedema and gas-production. As the Bacillus phlegmones emphysematosa; R, Fraenkel in 1892 described an anaerobic bacillus staining with Gram's which iu many cases is to be regarded as the cause of phlegmonous inflammation asso- ciated with gas-formation. According to Fraenkel the bacillus is non- motile and only exceptionally forms spores. In cultures it forms gas. It occurs in the external world (by Fraenkel it was demonstrated upon a splinter of wood with which a man dying of gas-phlegmon had been BACILLUS PHLEGMONES EMPHYSEMATOSA. 605 wounded); and when injected subcutaneously into guinea-pigs or spar- rows produces a progressive gangrenous process with disintegration of the subcutaneous tissues and muscle, as well as free collections of fluid and gas. Intravenous injection into rabbits and guinea-pigs is followed by the formation of gas in the internal organs. Gas-phlegmon in man occurs most frequently after severe injuries, for example, compound and complicated fractures, but may also proceed from small wounds. The bacillus is found at times in company with other bacteria, pus-cocci, colon-bacilli ; at other times alone and may be present in foci in great numbers. In pure infections there occurs a pro- duction of gas associated with liquefaction of the tissue, particularly of the muscles and of the reticular connective tissue. It is probable that this bacillus is identical with one described by Ernst, Welch, and Nuttall (by the latter as Bacillus aerogenes capsu- latus) as the cause of "foamy liver" (" Schaumleber") (Ernst) — that is, with a bacillus which is regarded as the cause of gas -formation in the human liver (Ernst). The condition of "foamy organs" (Schaumorgane) probably arises (Praenkel) from the fact that the bacillus in question Stains an entrance before death into the tissues, into the liver in particu- lar. Fraenkel has obtained his gas-bacillus in pure cultures from foamy < irgans. Besides Fraenkel's gas-bacillus other bacteria can cause changes cor- responding to those of gas-phlegmon and foamy organs, especially as the Jesuit of a localization in an already infected inflamed tissue (lactic-acid- baeilli, proteus vulgaris, and colon-bacilli). Literature. ( Bacillus (Edcmatis Maligni. Bacillus Phlegmones Emphysematosa:.) Bachmann: Bacillus des malignen Oedems. Cbl. f. Bakt., Orig., xxxvii., 1904. Brieger u. Ehrlich: Malignes Oedem bei Typhus abdom. Berl. klin. Woch., 1882. Comevin: Gangrene foudroyante et son inoculation preventive. Rev. denied., viii., 1888. Davids: Malignes Oedem. Ergebn. d. a. P. vi., 1901 (Lit.). Dansauer: Gasgangran (Bact. coli). Munch, med. Woch., 1903. Ernst: Gasbildende Anaeroben u. ihre Bez. z. Schaumleber. Virch. Arch., 133 Bd., 1893. Frankel: Ueber die Gasphlegmone, Hamburg, 1893. Gasphlegmone und Schaum- organe. Z. f. Hyg., 40 Bd., 1902; Gasphlegmone, Gascysten, Schaumorgane. Ergebn. d. allg. Path., viii., 1, 1904 (Lit.). Ghon u. Sachs: Aetiologie des Gasbrandes. Cbl. f . Bakt., Orig., xxxiv.. 1903, u. xxxv., 1904. Harris, Welch: Morbid Conditions caused by Bacillus Aerogenes Capsulatus. Bull. of Johns Hopkins Hosp., 1900. Hesse, W. u. B.: Ztichtung der Oedembacillen. Deut. med. Woch., 1885. Hibler: Durch anaerobe Spaltpilze bedingte Infectionserscheinungen. Cbl. f. Bakt., xxv., 1899. Hitschmann u. Lindenthal: Schaumorg. u. Sehleimhautemphysem. K. Akad., ex., Wien, 1901. Howard: A Contribution to the Knowledge of Bacillus Aerogenes Capsulatus. Welch Festschrift, 1900; The Origin of Gas and Gas Cysts in the Central Nervous Sys- tem. Jour, of Med. Res., 1901. Jensen: Malignes Oedem. Handb. d. path. Mikroorg., ii., Jena, 1903 (Lit.). Kamen: Aetiologie d. Gasphlegmone. Cbl. f. B., Orig., xxxv., 1904. Koch, R.: Zur Aetiologie d. Milzbrandes. Mittheil. a. d. K. Gesundheitsamte, i., 1881. Norris: Infection with Bacillus Aerogenes Capsulatus. Amer. Jour, of Med. Sciences, 1899. Pasteur: Vibrion scptique. Bull, de LAcad. de med., 1877, 1881. Bonoa: Nosokomialgangran. A. f. Derm., 71 Bd., 1904. GOG THE PATHOGENIC FISSION-FUNGI. Sandler: Gasphlegmone mid Schaumorgane. Cbl. f. a. Path., xiii., 1902. Stolz: Gasphlegmone. Beitr. v. Bruns, 33 Bd., 1902 (Lit.). Welch and Nuttall: Johns Hopkins Hospital Bull., 1892. Westenhoeffer: Schaumorgane und Gangrene foudroyante. V. A., 16S Bd., 1902. I." § 160. The Bacillus pneumoniae (Friedlander) is a plump, non-motile bacillus without flagella, about 0.5-1.25 /i broad and 0.6-0.0 p. long. It forms no spores (Fig. 459). It belongs to the group known as capsulated bacilli characterized by the formation of a well-defined mucous capsule. It is easily stained with aniline dyes, but is decolorized by Gram's. It grows easily on the usual nutrient media., under both aerobic and anaerobic conditions, and does not liquefy ....--., gelatin. Stab cultures iu nutrient gelatin show the form of the so-called nail-culture (Fig. 400), in that the bacteria growing over the stab-canal form a white mass of bacilli similar to a nail-head. White mice and guinea-pigs are especially suscep- tible to the bacillus. The first named die within six- teen to forty-eight hours after subcutaneous inocu- lation. The point of inoculation and the regional lymph-glands are inflamed and contain encapsulated bacilli, and the latter are found also in the blood. Rabbits are almost immune to inoculation. Friedlander and Frobenius, who first described the bacillus (1882), believed that it was the most frequent cause of croupous pneumonia, a view that may be explained by its confusion with the, at that time unknown, DiploGOCCUSpneumonicc. It is now recognized that it is but relatively rarely the cause of this disease (according to Welch - selbaum, in about six per cent of cases, according to Honl, in eight to ten pel' cent); but it may cause focal pneumonia, pleuritis, pericarditis, pharyn- gitis, rhinitis, otitis media, and meningitis. In severe infections it can also pass into the blood and set up metastases. In the inflammatory exudates the ba- cilli are found in the form of rods and short oval cells surrounded by capsules, often forming chains (Fig 450). Capsule-bacilli similar to the pneumonia-bacillus-are often found in the chronic inflammation of the nasal mucosa known as ozcena, which is characterized by a foul-smelling secretion and the formation of scabs; and they have been demonstrated also in rhinoscleroma (see below), and it has been assumed that they stand in causal relation to these diseases, but this remains to be determine Fig. 45!).— Bacillus pneu- moniae (Friedlander). a. Oval cells and rows of cells with gelatinous capsule; h, rod with gelatinous capsule. •: Kim. ■V sHra ¥.. M Fig. 460.— Nail-shaped stab-culture of the Friedlander pneumonia- bacillus in gelatin. According to Frieke the bacterium of Friedlander is the chief representative of a jroup of bacteria which are classed together under the name Baeillus mucosus enpsu- specics. The fission-fungus described as the lalus, and represent varieties of a single BACILLUS OP INFLUENZA. 007 ozusna-bacillus is identical with the pneumonia-bacillus, probably also the bacillus from the milk-faeces of nurslings described as the Bacterium lactis aerogenes (EschericK). It is possible that a greater etiological significance may be attached to it in so far as the origin of many diarrhoeas is concerned. Literature. (Bacillus Pn&umonke. ) Abel: Die Kapselbacillen. Handb. d. path. Mikroorg. iii., Jena, 1904 (Lit.). Emmerich: Pneumoniekokken in der Zwischendeekfullung. Fortschr. d. Med., ii., 1884. Frankel: Pneumoniekokken. Zeitschr. f. klin. Med., x., xi .; Deut. med. Woch.. . 1S8tJ - Fricke: Ueb. d. sog. Bacillus mucosus capsulatus. Zeit. f. Hyg., xxiii., 1896 (Lit.). Friedlander: Pneumoniekokken. Virch. Arch., 87 Bd., 1882- Fortschr d Med. L, 1883. Grimbert: Pneumobaeille de Friedlander. Ann. de l'lnst. Pasteur, 1896. Sachs: Durch Pneumoniebacillen verursachte Erkrankungen (Prostatitis, Endocar- ditis, Meningitis, Nephritis). Z. f. Heilk., xxiii., 1902. v. Stiihlern: Bedeutung des Bae. pneumonia;. C. f. Bakt. Orig., xxxvi., 1904. Weichselbaum: L. c, § 1.53; Von einer Otitis media suppurativa ausgfchende, durch den Bacillus pneumonia- bedingte Allgemeininfection. Monatsschr. f Ohrenheilk 1888. Wilde: Leber d. Bacillus Friedlander. Cbl. i. Bakt., xx„ 1896. § 107. As the influenza=bacillus (Fig. 401) there was described by K. Pfeiffer, in the year 1892, a bacillus whose occurrence in influenza has been many times confirmed ; it is uow regarded as the cause of influ- enza. In individuals suffering from influenza it is found in the catarrh- ally affected respiratory passages, occasionally also in the lungs ; and the small bronchi may contain enormous numbers of the bacilli in pure cul- ture. It is assumed that their multiplication in the respiratory tract gives rise to the inflammation, and that the bacilli produce poisons, which, when absorbed, cause the symptoms characteristic of influenza. The bacilli may also pass into the blood and become spread throughout the body. The inflammatory changes of internal organs occurring during influenza are to be referred in part to the influenza-bacillus, in part to the poisons produced by them, and in part to secondary infections. The influenza-bacilli are very small, thin rods with rounded ends (Pig. 461), which lie separate or joined together in twos. They stain with the ordinary aniline dyes, but not by Grain's method. They may be cultivated at the body-temperature upon blood-agar or upon agar that has been smeared with human or pigeon blood or to which milk has been added. They form upon this medium small, drop-like colonies as clear as water. According to Ghon and v. Preiss, the nutrient medium must contain al- bumin. Spore-formation has not been observed. Tu apes a catarrhal inflammation of the respira- tory tract may be produced by intratracheal in- jections of pure, cultures. Babbits may be poi- soned through, the incorporation into their fig- *«l.— influenza-bacmi ,. .. i, j - kokicen. Zeitschr. f. Hyg., 29 Bd., 1898. Hill: Branching in Bacteria with Special Reference to Bacillus Diphtheria 1 . Jour, of Med. Res., 1902. Katz: Diphtherische Lahmungen. Arch. f. Kinderheilk., 1897. Klein: Beitnige zur Aetiologie der Diphtherie. Cbl. f. Bakt., vii., 1890. Kober: Diphtheriebacillen auf d. Mundsehleimhaut gesunder Menschen. Zeitsch. f. Hyg., 31 Bd., 1899. Kosse'l: Zur Kenntniss d. Diphtheriegiftes. Cbl. f. Bakt., xix., 1896. Kutscher: Nachweis d. Diphtheriebac. in d. Lunge. Zeitschr. f. Hyg., xviii., 1894. Lewandowsky : Die Pseudodiphtheriebacillen. Cbl. f. Bakt. Orig., xxxvi., 1904. Iibffler: Entstehung der Diphtherie. Deut. med. Woch., 1890; Bedeutung der Mikro- organismen fiirdie Entstehung der Diphtherie. Mittheil. a. d. Kais. Gesundheits- amte, ii., Berlin, 1884, u. D. med. Woch., 1890. Madsen: Zur Biologie d. Diphtheriebacillen. Zeitschr. f. Hyg.,xxvi., 1897. Millard et Regaud: Myocardite diphtherique. Ann. de l'Inst. Pasteur, 1897 (Lit.). Morgenroth: Bindung v. Diphtherietoxin u. Antitoxin. Z. f. Hyg., 48 Bd., 1904. MouraviefF: Infl. de la toxine diphth. sur le syst. nerveux. Arch, de med. exp., 1897. Oertel: Die Pathogenese der epidem. Diphtherie, Leipzig, 1887; Das diphtherische Gift. Deut. med. Woch., 1890; Toxine und Antitoxine, Jena, 1904. Peters: Diphtheria u. Pseudodiphtheria Bacilli. Journ. of Path., iv., 1896. Proschaska: Pseudodiphtheriabacillen d. Rachens. Zeitschr. f. Hyg., xxiv., 1897. Prudden: Studies on the Etiology of Diphtheria. Med. Rec, New York, 1891. Roux et Martin: Seroth£rapie de la diphtherie. Ann. de l'Inst. Pasteur, viii., 1894. Roux et Yersin: Diphtherie. Ann. de l'Inst. Past., ii., 1888; iv., 1890. Schottelius: Waehsthum d. Diphtheriebac. in d. Milch. Cbl. f. Bakt., xx., 1896. Schlesinger : Diphtherie d. Conjunctiva. Munch, med. Woch., l:><, 612 THE PATHOGENIC FISSION-FUNGI. Slawyk u. Manicatide: Variabilitiit J. Diphfeheriebacillen. Zeit. f. Hyg., 29 Bd., 1898. Spronck: Pathogene Bedeutung d. Diphtheriebacillus. Cbl. f. allg. Path., i., 1890; Invasion des Diphtheriebacillus in d. Unterhaut d. Menschen. lb., hi., 1892. "Welch: The Histological Changes in Exp.. Diphtheria. Bull, of the Johns Hopk. Hosp.. ii., 1891. Welch and Abbot: The Etiology of Diphtheria. Bull, of the Johns Hopk. Hosp.,ii., 1891. Williams: Persistence of Varieties of B. Diphtheria' and of Diphtheria-like Bacilli. Jour, of Med. Res., 1902. See also § 32. §169. The bacillus of bubonic plague (Bacillus pestis) was dis- covered in 1894 by Kitasato and Yersin, of the Japanese and French com- mission, while investigating- an epidemic whichhad broken out iullong- Xong. The pest -bacillus is a small rod with rounded ends (resembling the bacillus of chicken-cholera). It stains easily with aniline dyes, es- pecially well will), methyleue-blue, and in part shows an exquisite polar staining (Fig. 4(33). It is decolorized by Gram's method. It is found in all cases of plague, in especial abundance in the swollen lymph-glands, but also in the spleen and blood. It may be cultivated upon the various media, and forms bluish-gray colonies, which contain rods of various lengths. It multiplies abundantly in bouillon containing sugar, and forms toxins. Independent movements have not been observed. Spores are not formed. The bacilli are easily killed by warming, but are able to withstand drying well. The bubonic plague, which destroyed great numbers of the inhabitants of Europe, at the close of the seventeenth and beginning of the eigh- teenth centuries ("Black Death"), has since 1720 almost disappeared from Europe and has shown itself only here and therein Eastern Europe. In different countries of Asia (Yunnan in China, Arabia, Mesopotamia ), and in the interior of Africa. (Koch) the disease seems to be endemic, and spreads from time to time in the same manner as cholera. Man is infected usually through the skin, more rarely from the mu- cous membrane of the month, nose, throat, and conjunctiva, still more rarely from the deeper parts of the respiratory tract, although cases of primary pest-bronchitis and pest-pneumonia occur. Small wounds usu- ally form the avenue of entrance in the skin, but it appears (Albrecht and Ghon) that a violent rubbing of an area of the skin with infected fingers or clothing may be sufficient to bring about an infection. The bacilli are taken up by Hie lymph-vessels and taken to the regional lymph-glands, where they cause a very marked swelling of the infected gland or group of glands — the primary bubo. Through the in- fection of lymph-glands situated farther alone; the lymph-system Ihere arise yri- \* , , wary buboes oj the second class, and by »j , «SS» /. - ' metastasis through the blood-si ream * "•• -. - % " "'/ •'• secondary buboes are formed. The plagut — i thus characterized in the first place by r» -**♦ *• «sr (I IS an acute polyadenitis. Since the poisons which are in association with Hie bodies '* *"*" •.£ **-s» \ * ,, of the pest-bacilli exert a degenerative ? ; ** .. ~~'t~ '*'' \\, and necrotic effect upon the vessel-walls, &'*, „« «£» ( *., numerous hwmorrhages are also caused, »* •* . — — * . J» and these are absent only in rare eases. ** v * N V? si. To these changes there are also added FIG - v >\ -Plague baciiu duchsin). x sso. circumscribed foci in the spleen, liver, kidneys, lungs, skin, etc. With 1 he exception, therefore, of those cases BACILLI'S PESTLS. 613 in which the pest -infection s confined to the primary bubo, the disease is to be regarded as a general infection ( Albrecht and Ghon ) , which arises from the taking-up ox bacteria from a primary focus of infection, and runs its course with the clinical picture of a polyadenitis and a severe hcemorrhagie septiccem ia. The individual foci are characterized by tissue-necroses of the nature of coagulation-necrosis (Albrecht and Ghon), as well as by severe exuda- tions, inflammation, and hemorrhage, and are caused by the presence of extraordinarily large numbers of bacilli. The lymph-glands of the pri- mary bubo show either wholly or for the chief part the appearance of hemorrhagic infarction, and are swollen and of a medullary consistence. After the course of a few days they also show yellow necrotic areas which later undergo liquefaction. When the disease has lasted longer than six- days, the liquefaction of the lymph-glands may take on the character of a suppuration. The tissues in the neighborhood of the lymph-gland are always more or less oedematously swollen, infiltrated with blood ; and haemorrhages are also found iu the walls of the neighboring large veins. The secondary inflammations of the lymph-glands and of the lymph- adenoid tissue of the mouth and throat do not usually cause such a marked degree of swelling as do the primary ; they resemble the medul- lary swelling occurring in typhoid fever. The surrounding tissues are also less changed, but if the process be prolonged the picture comes to resemble that of the primary buboes. The spleen of plague-patients is somewhat swollen, dark red, finely granular, shagreened (Albrecht and Ghon), and often contains small necrotic foci, which arecaused by the development of the bacilli in great numbers. In the glandular organs and in the skin, there occur, besides haemor- rhages, also necrotic areas and exudative inflammations, all due to the presence of bacilli. In the lungs there may occur, iu addition to the primary pest-brouchopneumonia, secondary metastatic focal inflamma- tions and aspiratioji-bronchopneumonias. The majority of individuals infected with pest die within the first eight days, but others may live several weeks ami then die of maras- mus. Not infrequently secondary infections, particularly of streptococci and diplococci, are associated with the pest-infection. They arise chiefly in the tonsils and follicular glands of the tongue following the changes caused by the pest-bacilli (Albrecht and Ghon ). Among animals, rats, mice, apes, and cats are especially susceptible to pest; and in these, particularly in rats, spontaneous infections occur, so that they may aid in the spread of epidemics. Swine and dogs are less susceptible, birds still less so. The changes in infected animals agree in general with those observed in man. The infection may remain local or become general. After the lymphadenitis and the multiple haemorrhages there arise also miliary, tubercle-like foci in the spleen, liver, and lungs. The course is usually acute, rarely chronic. In the latter case the larger necrotic foci may be encapsulated by connective tissue. The animals are easily infected from the skin, as well as from the mucous membranes of the intestinal and respiratory tracts; and such infection may take place from an uninjured mucous membrane. The inoculation of one mouse confined in a cage with other mice may give rise to a cage-epidemic ( Schottelius). 614 THE PATHOGENIC FISSION-FUNGI. Attempts to immunize animals and man against pent by means of dead and attenuated pest-bacilli have been many times carried out, especially by Yersin, Haffkin, and bus- tig ; and have been successful in so far that rodents, horses, and apes have been ren- dered immune against inoculations otherwise fatal. According to the reports of such attempts in man, a smaller per cent, of inoculated individuals acquire the disease than of those not inoculated ; but doubt is thrown upon the results of these inoculations by other authors (Bitter). Further, attempts at immunization and healing ham been made in man, with the. serum of animals which hare been rendered immune, particularly of horses (Yersin, Lustig); and different authors ascribe to such serum a favorable influ- ence. Slicker differentiates the following forms of pest according to the first localization of the bacilli: (1) Bubonic plague (the most common form); (2) the cutaneous form (formation of vesicles and ulcers or furuncle-like inflammations); (3) the pulmonary form ; (4) the intestinal form. Through the investigations of Ducrey, Krefting, and Petersen (cf. Petersen, " Ulcus Molle," Arch. j. Derm., xxix., 1894; xxx., 1895, and Babes, " Handbuch d. pathog. Mi- kroorg.," iii., 1903) it is probable that the ulcus molle or soft chancre is caused by a bacillus. Tomasczewski (" DerErreger des Ulcus," Z.j. Hyg., 42 Bd., 1903) has demon- strated through self -inoculation that a typical ulcus molle can be produced with cultures grown upon blood-agar or blood. The bacillus is non-motile, does not stain with Gram's, and often forms chains. (See also "Observations on the Distribution and Culture of the Chancroid Bacillus," by Davis, Jour, of Med. Res., 1902). Some years ago Sanarelli ("Sur la fievre jaune," Ann. de VInst. Pasteur, 1897; Cent. f. Bald., xii.) described as the cause of yellow fever a bacillus whose proper- ties he sought to determine by means of culture-experiments and animal-inoculations. He is still of the opinion that his Bacillus icteroides is the cause of yellow fever ("Zur Lehre vom gelben Fieber," Cbl. f. Bakl., xxvii., 1900), and reports favorably of the protective and curative effects (" Expe>. sur l'emploi du serum curatif et preventif de la fievre jaune," Ann. de VInst. Paxteur, 1898) of his serum obtained from vac- cinated animals (dogs, horses, cattle). Freire ("Man. sur la baeteriologie, pathog^nie et traitement de la fievre jaune," Rio de Janeiro, 1898, Cbl. j. Bakt., xxvi.) on the other hand opposes energetically the correctness of Sanarelli's views, and maintains that the cause of yellow fever is a coccus earlier described by him, which he calls the Micrococcus xanthogenicus. Bandi ("Aetiologie und Pathogenese des gelben Fiebers," Z. ). Hyg., 46 Bd., 1904) favors the pathogenic significance of the Sanarelli bacillus. It is very probable that neither Sanarelli's bacillus nor the coccus described by Freire has any etiological relationship to yellow fever. It is much more likely that the cause will be found among the protozoa, since the pathogenesis corresponds more to that of malaria and infection with trypanosomes. (See these.) Other writers (Novy) sug- gest that the etiological agent of yellow fever may be found to belong to the spirilla. Literature. (Plague. ) Abel: Gesohieh.tlich.es uber die Rattenpest. Zeitschr. f. Hyg., 36 Bd., 1901. Albrecht u. Ghon: Ucber die Beulenpest in Bombay im j. 1897, Wien, 1898, 1900. Aoyania: Die Pestepidemie im Jahre 1894 in Hong-Kong, Tokio, 1S95. Babes: Durch Pestbacillcn verursachte Veranderungen. Virch. Arch., 150 Bd., 1897. Bitter: Schutzimpfungen gegen Pest. Zeitschr. f. Hyg., 30 Bd., 1899'. Dewel: Empfanglichkeit d. Frosche f. Beulenpest. Cbl. f. Bakt., xxii., 1S97. Bieudonne: Pest. Handb. d. path. Mikroorg., ii., Jena, 1903 (Lit.). Dtirck: Beitr. z. path. Anat. d. Pest. B. v. Ziegler, Suppl. vi., 1904. Flexner: The Pathology of Bubonic Plague. Univ. of Penn. Med Bull 1901 Gaffky, Pfeiffer, Sticker u. Dieudonne: Pest. Arb. a. d. K. Gcsundheitsamte xvi., 1899. Herzog: The Plague. Rep. of Gov. Laboratories, Manila, 1904, 1905. Kitasato: Preliminary Note of the Bacillus of Bubonic Plague, Hong-Kong, 1894 Koch: Verbreitung d. Beulenpest. Deut. med. Woch., 1898. ' -. - Kolle: Bakteriologie der Beulenpest. Deut. med. Woch., 1897. Lustig: Gewebsveranderungcn bei Beulenpest. Cbl. f. allg. Path., viii., 1897- Siero- terapia e vaccinazioni preventive contro la peste bubonica, 1897' Markl: Pesttoxine. Cbl. f. Bakt., xxiv., 1898. Metschnikoff: La peste bubonique. Ann. de l'lust Pasteur 1897 Miiller u. Poch.: Die Pest, Wien, 1900. Netter: Le microbe de la peste. Arch, de med. exp., 1900 (Lit.). BACILLI'S TUBERCULOSIS. 615 Nuttall u. KoUe: Die Insekten bei der Pest, CM. f. Bakt. xxii., 1897. Sata: Aetinlogie u. Anat. d. Pest, Arch. f. Hyg., 37, 89 Bd., 1900, 1901. Seheube: Pest. Eulenb. Realencyklop., 1897; Die Krankheiten d. warmen Lander, Jena, 1903. Schottelius: Die Bubonenpest in Bombay. Hygien. Rundschau, 1901. Simond: La propagation de la peste. Aim. de l'lnst. Pasteur, 1898. Wyssokowitz et Zabolotny : Rech. sur la pestc. Ann. de l'lnst. Pasteur, 1897. Yamagiva: Die Bubonenpest, Vireh. Arch., 149 Bd., Suppl., 1897. Yersin: Sur la peste bubonique. Ann. de l'lnst. Pasteur, 1894, 1897. Zettnow: Bacillus der Bubonenpest, Zeitschr. f. Hyg., xxi., 1890. § 170. The Bacillus tuberculosis is Hie cause of the infectious disease occurring so frequently in man and the domestic animals which is known ordinarily as tuberculosis, but is also sometimes called pearl disease (PerlmcM) in animals. The tubercle -bacillus was discovered and thoroughly studied by Koch in 1.882. It is a slender rod (Fig. 464), of 1.5-4 p. in length, and is usually slightly curved. It may be stained by aniline-dyes (fuchsin, gentian-violet) to an aqueous solution of which an alkali, or carbolic acid, or aniline oil is added. The bacilli when once stained retain the stain, even when the preparation is decolorized in dilute sulphuric acid, or nitric acid, or hydrochloric acid and alcohol. The stained bacilli not infrequently show in their interior clear, shin- ing, unstained areas, or are composed of little stained spherules. Koch formerly regarded these clear spots as spores, and this view was generally accepted for a long time. Nevertheless, a germination of these struc- tures could not be demonstrated, and at the present time they are no longer regarded as spores. Consequently, the tubercle-bacilli form no special resistant forms, but on the other hand the bacilli are more resist- ant against external influences, for example, against drying, than are many other bacteria, The tubercle-bacilli may lie cultivated at the body temperature and in the presence of oxygen upon coagulated blood-serum, blood-serum - gelatin, nutrient agar, and in bouillon. They increase, however, very slowly, so that only on the seventh to tenth day or even later, do the cul- tures become visible in the form of dull-white flakes resembling little scales. Larger cultures form, on the surface of coagulated blood-serum, whitish, irregularly shaped, lustreless deposits. According to Nocard, Roux, and Bisehoff the growth of the bacilli is greatly aided by the addition of glycerin (four to eight per cent). In cultures the tubercle-bacilli also form threads, which in part show branching. At temperatures below 28° C. and above 42° O. the growth of the bacilli ceases. Sunlight kills the bacilli in a short time (Koch). If the bacilli from pure cultures are ) i ■ inoculated into experimental animals, tuberculosis is produced in these; and the infection is transmitted as well by . , , . • , ., Fik. +(>■!.— Tubercle-bacilli. Sputum from inoculation under the Skill, Ol' into tne a nmn suffering with pulmonary tubercu- na,.itn,,nol nain'+tr nv flip -i it tpvior elm 1 1 1 - losis - Smear-preparation on cover-glass, peritoneal cavity, Ol ine anterior tnam stalne d with nicbsln ami methylene-blue. ber of the eye, as also by inhalation of x 4110. an atomized suspension of the culture, by feeding, and by injection of bacilli into the veins. In experimental feeding success is often attained only after long administration of the 616 THE PATHOGENIC FISSION-FUNGI. bacilli, since not every bacillus gaining entrance into the intestinal tract leads to infection. It is also true that bacilli lodging upon the mucous membrane of the respiratory tract do not always succeed in grow- ing in the tissue. Guinea-pigs, rabbits, cats, and gray field mice are especially susceptible; dogs, rats, and white mice less so. Infection of man and' of animals occurs from the taking up of tubercle-bacilli from the lungs, respiratory passages, and the intestinal tract, or from wounds and tissue - ulcerations. In the alimentary tract the lymphadenoid ap- paratus, tonsils, and the intestinal lymph - fol- licles form the most fre- quent avenue of en- trance. Xurslings are particularly susceptible to intestinal infection. Further, a direct trans- mission of the bacilli from the mother to the foetus in utero may occur, but this is rare. A mul- tiplication of the bacilli, that is, the production of tuberculosis, occurs usually at the points of entrance of the bacilli, but may also occur only after the transportation of the bacilli through the blood or lymph, so that hfematogenous or lymphogenous disease of the internal organs, for example, of the lymph- glands, bones, brain, and tubes, may occur as the primary localization. The bacilli are spread throughout the external world chiefly by the Fig. 465.— Tubercle from a fungous granulation of hone (51 tiller's fluid, Rismarck brown), a, Giant-cell ; 6, epithelioid cells; c, lymphoid cells. X 400. Fig. 466.-Giant-cell containing- bacilli, and showing necrotic centre, from a tubercle Stained with gentian-violet and vesuvin, mountedin Canada balsam. X :«0. sputa, under certain conditions also by the faeces and urine, further from tuberculous ulcers, or from tuberculous organs which are taken from living or dead persons. Since the bacilli are rather resistant, they may be preserved outside of the animal body for a long time under certain conditions, and may become mixed with the respired air, as well as Math BACILLUS TUBERCULOSIS. 61/ the food and drink. The milk of tuberculous cows contains the bacilli especially when the udder is diseased ; but the bacilli may also pass into Fig. 407.— Tuberculosis of the pleura (alcohol, Van Uieson's). n, Thickened and proliferating pleura; 6, tubercle with giant-cells ; c, deposit of fibrin. X 21X1. the milk when no disease of the udder can be demonstrated (Hirschberg, Ernst, Leuch). 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 V*f, ' i ,:: : ^::: : ,i^z-- ■ • ■-'■^•'. .-y V.*»;- :?. J- ■ >-0 '- /•: *r- v ■ aa\ •• '- J -^ *, a" -iA$t ^AA A lA^-AA- :. "«f"j£-»> . 'v-i J Trt, V- . fit*, i ~..-< !.„5— '" V I Kft T&rt v •~h:..r': ''^V^ Fig. 170.— Section of miliary tubercle of the omentum (alcohol, luematoxvlin eosin) containing remainsof fat-cells ; o, Bbroeellular periphery ; c, giant-eel Is ;\l fal tubercle at the height of its development shows usually three types of cells — large epithelioid cells, with clear nuclei (Fig. 465, />), multi-nuclear giant-cells (a), and lymphocytes (>■). The first 1 wo forms are found particu- TUBERCULOSIS. 619 larly in the central part of the tubercle, the latter at the periphery. The number of the individual cell-forms varies, and under certain conditions the lymphocytes may be so numerous as greatly to overshadow the larger Fig. 471.— Fibrocaseoua tubercle "f the lung (alcohol, Van Gieson's). a. Caseous centre; h, thick, homogeneous connective tissue poor in nuclei ; c, connective tissue rich in cells; il, lung tissue. ■ 8(1. cell-forms. On the oilier hand, at other times the epithelioid cells with lightly staining nuclei may predominate. These cells are in part changed Fig. 472.— Fibrous tubercle in the thickened synovial membrane of the knee-joint (alcohol, hematoxylin, picric acid, fuchsin). a. Connective tissue; b, c, d, fibrous tubercle. X 75. lymphocytes arising from the blood (polyblasts) ; in part fibroblasts arising through the proliferation of connective-tissue cells in loco. The giant-cells belong usually to the syncytial type and arise through 020 THE PATHOGENIC FISSION-FUNGI. the confluence of cells, but it is also possible that they arise through the multiplication of the nucleus in a single cell. The nuclei lie usually in the peripheral portion of the protoplasmic mass (Figs. 465, a, and 466) ; sometimes collected at one pole, sometimes at both poles ; sometimes ar- ranged in a wreath or in a crescent. They often contain numerous bacilli (Figs. 466 and 469, e). The non-nucleated portion of the protoplasm may often be recognized to be changed, degenerated, or necrotic because of its reaction toward stains (Fig. 466). Through the proliferation of the cells the remaining connective-tissue stroma of the original tissue is pushed farther and farther apart, so that the individual cells come finally to be separated from one another only by scanty fibres, whose general arrangement is in the form of a net- work, which is consequently called the reticulum of the tubercle. New vessels are not formed within the tubercle; and the old vessels are closed through the proliferation of the vessel- walls. Usually the nexvformu- tion of connective tissue stops with the production of fibroblasts. The neighborhood of the tubercle proper may show no essential change, but usually presents the appearance of an inflammation, particu- larly a small-celled tissue infiltration or proliferation (Fig. 467, a). A serous exudation is also usually associated with the cellular emi- gration, and fibrin may be formed both within the tubercle itself (Fig. 468, «) and in Us neighborhood (Fig. 467, c). At the height of its development the tubercle forms a small, gray, translucent cellular nodule, which may reach the size of a millet-seed, and encloses in its tissue tubercle-bacilli in larger or smaller numbers. When it has reached a certain size retrogressive changes usually appear in its centre, the tubercle in consequence becoming cloudy, opaque, and of a white or grayish-white or yellowish- white color — these changes being desig- nated as caseation. The caseation of the tubercle is dependent on the one hand upon a necrobiosis of the cells, and on the other upon the deposit of coagulated sub- stances in the spaces between the cells. The cell-necrosis is characterized by a loss of the nuclei and a transformation of the cells into lumpy masses which later disintegrate and become granular (Fig. 469, a, a). The deposit between the cells consists either of a network of fibrin (Fig. 468, a) or of a granular or hyaline reticulated fibrinoid substance resem- bling fibrin but which does not take the Weigert's fibrin stain and is stained yellow by Van Gieson's. In the further course of the process of caseation the fibrin and fibrinoid substance disintegrate into a granular mass which fuses with the cell-detritus, so that the central part of the tubercle consists of a lumpy granular mass (Figs. 469, a 471, a) which takes a weak diffuse stain with nuclear stains. The caseation affects at first the central portion of the tubercle, and is usually confined to this, while connective tissue is formed at the' per- iphery, so that the tubercle conies to consist of a caseous centre (Fig. 470, a) and a fibrocellular periphery (b) which usually contains giant-cells. Under certain conditions the caseatioii may involve the entire tubercle. If the caseation does not affect the periphery, the fibrocellular tissue of the peripheral zone, sooner or later, becomes transformed into a pure fibrous tissue, so that a fibrocaseous tubercle (Fig. 471, a, b) is formed the connective tissue of which is coarsely fibrillar or hyaline and poor in cells (b), and iu the course of time usually becomes sharply defined from the caseous centre (a), so that the latter appears to be encapsulated by connective tissue. If the tuberculosis runs a favorable course the cen- TUBERCULOSIS. 621 tre instead of caseating may undergo a connective-tissue metamorphosis (Fig. 472, b, c, d), so that the tubercle becomes changed into a fibrous nodule. The infectious nature of the disease known as tuberculosis had already beeu deter- mined by the experimental transmission of tuberculosis to animals (Yillemin, Lebert, Wyss, Vohnheim, Klebs, Langhans, and others), before the discovery of the tubercle- bacillus. Nevertheless, it was a long time before the view that tuberculosis was an infectious disease received general acceptance, and opposition to this view has even to- day not wholly disappeared (Middendorp). The peculiar behavior of the tubercle-bacillus toward stains — that is, its property of retaining the stain after treatment of the preparation with acids and alcohol, the so- called acid- and alcohol-resistance — makes it possible to demonstrate with relative ease the presence of tubercle-bacilli in the sputum or in the tissues, and to differentiate it from other bacteria. It should be noted, however, that other bacteria show these prop- erties; the bacillus of leprosy, the smegma-bacillus (a bacillus very frequently found on the corona glandis, between the scrotum and thigh and in the folds between the labia majora and minora), further two dilferent bacilli found in butter (one described by L. Bab- inowitsch and Petri, the other by Korn), and finally also different bacilli cultivated by Mueller from grasses (timothy-grass) and from cow-dung. All these acid-resisting bacilli may under certain conditions lead to errors of diagnosis; for example, the smegma- bacillus in the examination of urine, the butter-bacilli in the examination of butter, the latter particularly, since the bacillus described by Rabinowitsch, when injected into the peritoneal cavity of guinea-pigs, causes a disease of the abdomen similar to true inocu- lation-tuberculosis, while the bacillus described by Horn causes a pseudotuberculosis in white mice (these animals showing but slight susceptibility to true tuberculosis). Acid-fast bacilli, which probably represent a variety of the Rabinowitsch butter bacil- lus, have been found in gangrenous foci in the lung (Rabinowitsch) as well as in the sputum of cases of pulmonary gangrene (Folli, Mayer, Ophiils, Birt and Leishmcm). Moeller has found acid-fast bacilli in nasal and pharyngeal mucus. Since the tubercle-bacillus in cultures forms simple and branching threads (Klein, Fischel, Coppen-Jones, Nocard, Maffucci, and others) and bud- and club-like swellings, many authors are inclined to group it with the thread-fungi. Lehmann and Neumann designate it as Mycobacterium tuberculosis, Coppen-Jones as Tuberculomyces . Since the tubercle-bacillus in caseous pulmonary foci (Coppen-Jones), and after direct injection into the parenchyma of the brain, kidneys, mammary glands, and testi- cles, as well as after the intra-arterial injection of large numbers of bacilli (Babes, Leva- diti, Schulze, Lubarsch, Friedrich, and Nbsske) forms, in addition to the ordinary colonies of bacilli, fungus-masses also resembling those of actinomyces, on the outer surface of which ray-like clubs radiate into the surrounding tissue, Lubarsch and others, in the assumption that the fungus-masses consist of branching threads, have classed the tubercle-bacillus with the actinomyces or ray-fungi. Lubarsch regards the ray- fungi as a sub-class of the Streptothrices, an intermediate group lying between the Schizomycetes and the Hyphomycetes, and characterized by the formation of clubs; and to this class he assigns also the butter- and dung-fungi mentioned above. Accord- ing to Friedrich and Nbsske the fungus-masses regarded as resembling those of actino- myces consist only of rods. According to the investigations of Hammerschlag, Ruppel, Sata, and others, the tubercle-bacilli contain an abundance of fat, which under proper conditions may be demonstrated by staining with sudan (Sata). According to Hammerschlag the tubercle- bacilli contain twenty-seven per cent of substances soluble in alcohol and ether (fats, lecithin, poisonous substances), while other bacteria contain only 1.7-10 per cent of the same. The remaining substance insoluble in alcohol contains albumin and cellu- lose. Apparently the acid resistance of the bacilli is dependent upon the rich fat content, young bacilli winch lack the fat covering are not acid-fast (Marmorek), According to the investigations of Prudden, Hodenpyl, Kostenitsch, Vissmann, Ma- sur, Rocket, and others, dead tubercle-bacilli, when introduced into the tissues of an animal by inoculation, or injection into the blood-stream, or through introduction into the respiratory passages, excite, at the point of deposit, inflammation and tissue- proliferation similar to that caused by living bacilli, and in the case of a large inocu- lation may lead also to suppuration. These changes differ, however, from those pro- duced by living bacilli, in that the bacilli are destroyed after a few weeks and the nodules of granulation tissue heal through a transformation into fibrous tissue; and further, by the fact that the severity of the local tissue-proliferation is dependent wholly upon the amount of dead bacilli introduced, and that there is no spread of the process throughout the body. The dead bacilli must therefore contain substances (proteins) which cause inflammation and later also tissue-proliferation. (122 THE PATHOGENIC FISSION-FUNGI. In addition to the local effects, the substance contained in the cell-bodies of the bacilli may also cause emaciation of the animal. The active substance of the bodies of the bacilli — tuberculin — was first produced by Koch (1S90) from six- to eight-weeks-old cultures in a weak alkaline veal-infusion, to which one per cent of peptone and four to five per cent of glycerin were added, by evaporation upon a water-bath to one-tenth of the original volume and filtering through a filter of earthenware and silicious marl. Later (1897) he dried highly virulent cult- ures of tubercle-bacilli in a vacuum-exsiccator, then triturated the dry substance, mixed it with distilled water and centrifugated it. The active principle u contained in the muddy precipitate thus obtained, which is again dried and triturated and dis- solved in water to which twenty per cent of glycerin is added for the purpose of pres- ervation. This tuberculin (designated by Koch as T. R.) is said to contain lOmgm. of solid substance in 1 c.c. (prepared by Meister, Lucius, and Briinning). Whether the tubercle-bacilli produce a true toxin is a question that has not yet been decided, but this is probably not the case; and in favor of this is the fact that localized tuberculosis clinically shows no symptoms of intoxication. The tuberculins obtained by various methods contain a mixture of different substances which, like the substances derived from other bacteria, excite inflammation. Perhaps they contain also specific albumin bodies which, in the organism, cause the production of specific. bactericidal protective forces, either through the formation of bacteriolysins or of agglu- linins and ■precipitins that act upon the bacteria. (Sec § 33.) Through the investigations of Arloing and Courmont we know that an emulsion of cultures of tubercle-bacilli grown upon potatoes is agglutinated by the serum of tuberculous men and animals. Through an especial method Koch has prepared a fluid containing bacilli in which a clouding and a flocculent precipitate is produced by an agglutinating serum. The serum of healthy animals (rabbits, dogs, cow, and donkey) shows no agglutinating action when the test fluid is added to the serum in the proportion of 1:25; yet there are exceptions to this and horse serum usually shows an agglutinative power. According to Koch and Romberg the serum of children possesses no agglutinative power. After the fourteenth year it is very frequently present, probably as the result of latent tuberculosis. Through the treatment of an animal with dead or living cultures of tubercle-bacilli it is possible to produce a serum capable of agglutination (Koch) or to increase that already present, particularly easily in goats and donkeys. Animals possessing the power of agglutination show a more or less high degree of immunity against an artificial infection with tubercle-bacilli, and the agglutinative power may therefore be regarded as an indication of the existence of protective sub- stances. In men suffering from tuberculosis the power to agglutinate is not usually shown in dilutions of 1 : 25. In advanced tuberculosis the agglutination power is usually wan-ring, since in the course of a malignant tuberculosis the protective substances are either not formed at all or at least only in small amounts. A mixture of pulver- ized tubercle-bacilli in 100 parts of water plus 100 parts of glycerin when injected in increasing doses (0.S per cent salt solution, the first dose contains 0.0025 mg. of the cell substance of the bacilli) has, in the hands of Koch, increased the agglutination power of numerous consumptives (from 1 : 25 to 1: 100 and 1: 300), so that it may be assumed that it is also possible to produce in consumptives a certain amount of protec- tive substance. As to the value of the old and new tuberculin of Koch various writers differ. Its worth as a diagnostic aid is not questioned, particularly that of the old tuberculin, since small doses excite fever in tuberculous animals but not in healthy ones, yet there are exceptions also to this. The old tuberculin finds a use in the recognition and removal of tuberculous domestic animals. As a curative method (it is usee! in small doses in tuberculosis) it is praised by some, but at present its use is not very extensive. During the last year much clinical interest has been excited over the diagnostic use of tuberculin in the cutaneous reaction ("Pirqvct's reaction ") and the conjunctival reaction (" Calmelte's reaction"). Von Bchring has succeeded in rendering cattle immune against virulent bovine tubercle-bacilli. He uses first cultures of human tubercle-bacilli which are less viru- lent for cattle, and begins with an intravenous injection of ] mgm. of a serum-cult- ure of a definite strength of infection. In younger animals the immunization can be much more easily produced than in older ones. Von Behring regards it as pos- sible to feed nurslings with a milk of cows made immune against tuberculosis and thus to convey to them antibodies which may serve to protect them from infection TUBERCULOSIS. 623 Literature. (Tubercle -bacilli and Formation of Tubercles.) de Aquilar: Fibrinbildung in Producten der Tuberkulose. Arb. v. Baumgarten, ii., 1897. Arloing- et Courmont: De l'agglutination du bacille de Koch. Z. f. Tub., i., 1900, u. D. med. Woch., 1900. Arnold: Anatomie d. miliaren Tuberkels. Vircli. Arch., 82 Bd., 1880. Auclair: Les poisons du bac. tuberculeux. Arch, de med. exp., 1899. Babes u. Proca: Wirkung der Tuberkelbacillen. Zeitschrift f. Hygiene, xxiii., 1896. Barbacci: Istol. del tubercolo. Atti della R. Ace, xiii., Siena, 1902. Baumgarten: Tuberkelbakterien. Cbl. f. d. med. Wiss., 1882, 1883; Tuberkel u. Tuberkulose. Zeitschr. f. klin. Med., xi., 188"); Verhaltniss von Perlsucht und Tuberkulose. Berl. klin. Woch., 1901; Wirksamkeit d. Tuberkelbacillen. lb., 1901. v. Bearing-: Phthisiogenese u. Tuberkulosebekampfung. D. med. Woch., 1904, u. S.-A., Berlin, 1904. v. Behring, Romer, Ruppel: Tuberkulose, Marburg, 1902. Buhl: Lungenerrtztindung, Tuberkulose u. Schwindsucht, Munchen, 1872. Carriere: Alterat. du foie et des reins prod. p. 1. toxines tub. Rev. de med. exp., 1897. Cohnheini u. Frankel: Qebertragbarkeit d. Tuberkulose. Vircli. Arch., 4.~> Bd., 1869. Cornet: Die Tuberkulose, Wien, 1899, u. Handbuch d. pathogenen Mikroorg., ii., 1903. Courmont: L'agglutin. du bacille de Koch. A. de med. exp., xi.. 1900. Dobroklonski: Developpement de la tuberculose experim. Arch, de med. exp., ii., 1890. Diirck u. Oberndorfer : Tuberkulose. Ergebn. d. a. I'., vi., 1901. Ernst: How Far may a Cow be Tuberculous before her Milk becomes Dangerous as an Article of Rood? Anier. Journ. of .Med. Sc. 1889. Falk: Exudative Vorgange bei der Tuberkelbildung. Virchow's Arehiv, 139 Bd., 1395. Ferran: Neue Entdeckungen beziiglich d. Bac. d. Tuberkulose. Wien. klin. Woch., 1898. Fischel: Ueber die Morphol. u. Biol. d. Tuberkulose-Erregers. Fortschr., x., 1892, Wien, 1893. Fischer: Uebertrag. d. Tub. durch die Nahrung. Arch. f. exp. Path., xx., 18S6; Eintrittspforten. Munch, med. Woch., 1904. Fliig-g-e: Die Verbreitung der Phthise. Zeitschr. f. Hyg., 30 Bd., 1899; Ubiquitiii der Tuberkelbac. u. Disposition zur Phthise. D. med. Woch.. 1904. Fraenkel: Smegmabacillen. Cbl. f. Bakt., xxiv., 1901. Friedrich u. Nosske: Localisirung der Tuberkelbacillen. Beitr. v. Ziegler, xxvi., 1899. Hammerschlag': Bakteriolog.-chem. Inters, liber Tuberkelbacillen. Cbl. f. klin. Med., 1891. Herxheimer: Wirkungsweise der Tuberkelbacillen. Beitrage v. Ziegler. xxxiii., 1903. Hirschherg-er: Jnfeetiositat d. Milch tuberkuloser Kiihe. Dent. Arch. f. klin. Med., 44 Bd., 1889. Jani: Tuberkelbacillen in gesunden Geweben bei Lungensehwindsucht. Virch. Arch., 103 Bd.. 1886. Jones: Morphologic u. systematische Stellung d. Tuberkelpilzes. Cbl. f. Bakt., xvii., 1S95. Karlinski: Uebertragbarkeit d. menschl. Tuberkulose. Zeitst.hrift f. liermed., viii., 1904. Kastner: Beitr. z. lnfectiositat des Fleisches tuberkul. Hinder. Munch, med. Woch., 1889. Klebs: Impfversuche. Virch. Arch., 44, 49 Bd.; Arch. f. exp. Path., i., x.. xvii.; Prag. med. Woch., 1877. Koch: Die Aetiologie der Tuberkulose. Berl. klin. Woch., 1882. No. 16; 1883, No. 10. Verh. d. Congresses f. inn. Med., Wiesbaden, 1882; Mittheil. a. d. Kais. 4 THE PATHOGENIC FISSION-FUNGI. Gesundheitsamte, ii., Berlin, 1884; Mittheil. iib. cin Heilmittel geg. d. Tuberku- lose. Deut. med. Woch., 1890; Mittheil. iiber das Tuberkulin. lb., 1891; Neue Tuberkulinpraparate. lb., 1897; Ueber die Agglutination der Tuberkelbacillen. D. med. Woch., 1901. Kockel: Histogenese des Miliartuberkels. Virch. Arch., 143 Bd., 1896 (Lit.). Korn: Saurefeste Bakterien. Cbl. f. Bakt., xxv, 1899; xxvii. 1900; Bacillenbefunde in der Marktbutter. Arch. f. Hvg., 66 Bd., 1899. Kostenitsch: De revolution de la tubereulose par les bacilles morts. Arch, de me'd. exp., v., 1893. Kostenitsch et Wolkow: Rech. sur le developp. du tubercle. Arch, de med. exp., iv., 1892. Koster: Ueber fungose Gelenkentziindung. Virch. Arch., 48 Bd., 1869. Langhans: Die Uebertragung der Tuberkulose auf Kaninchen, 1S68; Riesenzellen mit wandstandigen Kernen in Tuberkeln. Virch. Arch., 42 Bd., 1868. Lebert u. Wyss: Uebertragung der Tuberkulose. Virchow's Arcliiv, 40 Bd., 1S67. Levene: Biochemical Studies on the Bacillus Tuberculosis. Jour, of Med. Research, 1901. Lubarsch: Zur Kenntn. d. Strahlenpilze. Zeitschr. f. Hyg., xxxi., 1899; Infektions- modus. Fortschr. d. Med., 1904. MafFucci: Prod, tossici del Bac. tubercularc. Policlinico, ii., Roma, 1895; Die Hiih- nertuberkulo.se. Zeitschr. f. Hyg., xi., 1S92. Masur u. Kockel: Wirkung todter Tuberkelbacillen. Beitrage v. Ziegler, xvi., 1S94. Menzi: Zuchtung u. Biol. d. Tuberkelbacillen. Z. f. Hyg., 39 Bd., 1902. Metschnikoff: Die phagocytare Rolle der Tuberkelriesenzellen. Virch. Arch., 113 Bd., 1888. Middendorp: La cause de la tubereulose, Groningen, 1897; u. Congr. intemat. cle med., Paris, 1901. ^ Milchner: Uebertragung d. Tub. durch Milch u. Milchproduete. Zeitschr. f. Tub., i., 1900. Miller: Histogenese d. Tuberkels in d. Leber. B. v. Ziegler, xxxi., 1902, u. .1. of Path., x., 1904. Morel et Dalons: Histogenese du tubercul. Arch, de med. exp., 1903. Nocard et Roux: Bacille de la tubereulose. Annales de l'Institut Pasteur, xi., 1897. Orth: Exp. Unters. iiber Fiitterungstuberkulose. Virch. Arch., 76 Bd., 1876; Wir- kung der Tuberkelbacillen. Verh. d. D. path. Ges., iv., 1902; Entsteh. d. Tub., Berlin, klin. Woch., 1904. Pappenheirn: Histogenese des Tuberkels. Virch. Arch., 169 Bd., 1902. Fawlowsky . Culture des bac. de la tub. sur la pomme de terrc. Ami.de l'lnst. Pas- teur, ii., 1888; Entwickelungsgeschichte der Gelenktuberkulose. Cbl. f. Bakt., vii., 1890. Pertik: Pathologic d. Tuberkulose. Ergebn. d. a. Pathol., viii., Wiesbaden, 1904 (Lit.). Predohl: Die Gesclhchte der Tuberkulose, Hamburg, 1888. Prudden: A Study of Experimental Pneumonitis in the Rabbit Induced by the In- fection of Dead Tubercle Bacilli. New York Med. Journ., 1891. Prudden and Hodenpyl: Action of Dead Bacteria in Living Body. New York Med Jour., 1891. Piitz: Die Beziehungen d. Tuberkulose d. Menschen zur Tuberkulose d Thiere Stuttg., 1883. Rabinowitsch : Zur Frage des Vorkommens von Tuberkelbac. in der Marktbutter. Zeitschr. f. Hyg., xxvi., 1897; Deut. med. Woch., 1899; Saurefeste Bacillen bei Lungengangran. lb., 1900; Uebertragung d. Tuberkulose durch Milch lb , 1900. Rabinowitsch. u. Kempner: Infectiositatd. Milch tuberk. Ktthe. Zeitschr f Hy« xxxi., 1899. Raymond et Arthaud: Rech. exper. sur l'etiologie de la tub Arch gen de me'd 1883. Ruppel: Chemie d. Tuberkelbacillen. Zeitschrift fiir physikalisohe Chemie xxvi 1898. "' Sata: Fettbildung durch verschiedene Bakterien. Cbl. f. allgemeine Patholotrie 1900. h ' Schieck: Experiment. Tuberkulose der Kaninchencornea. Beitr v Ziegler xx 1896. & ' TUBERCULOSIS. 625 Schmaus u. Albrecht: Die kasige Nekrose tuberkul. Gewebes. Virch. Arch., 144 r>d., Suppl., 1896. Sibeley: The Nature of the Giant-cells of Tubercle. Journal of Anatomy, xxiv., 1890. Sternberg: Wirkung toter Tuberkelbacillen. Centralblatt f, allgemeine Pathologie, xiii., 1902. Stock: Exper. hamatog. Tuberkulose des Auges. Monatschr. f. Augenheilk., Beil., 1903. Straus: La tuberculose et son bacille, Paris, 189.5; Tuberculose par ingestion. Ann. de m6d. exp., viii., 1896. Straus et Gamalei'a: Contrib. a \'6t. du poison tuberculeux. Arch, de m£d. exp., hi., 1891. Stroebe: Die Wirkung des neuen Tuberkulins T. R., Jena, 1898. Stschastny: Formation des cellules geantes, etc. Ann. de l'lnst. Pasteur, 188S; Virch. Arch., 115 Bd. Tappeiner: Inhalationstuberkulose. Virch. Arch., 74, 82 Bd. Tripier: Ueber den Bau der Miliartuberkel. Obi. f. allg. Path., i., 1890. Veraguth: Exp. Unters. uber. Inhalationstuberkulose. Arch. f. experim. Path., xvii., 1883. Villemin: Gaz. hebdom., 1865, No. 50; Compt. rend., lxi., 1866; Etudes sur la tuber- culose, Paris, 1886; Etudes exper. sur la tuberculose, Paris, 1887-98. Vissmann: Wirkung todter Tuberkelbacillen. Virch. Arch., 129 Bd., 1892. Walther: Ueber das Vork. v. Tuberkelbacillen im gesunden Genitalapparat bei Lun- genschwindsucht. Beitr. v. Ziegler, xvi., 1894. Watanabe: Wirkung in die Trachea, eingef. Bacillen. Beitrage v. Ziegler, xxxi., 1902. Wechsberg: Primare Wirkung der Tuberkelbacillen. Beitrage v. Ziegler, xxix., 1901. Weichselbaum : Bacillen im Blute bei allgemeiner Miliartuberkulose. Deut. med. Woch., 1884; Zusammenfass. Bericht ilb. d. Aetiologie der Tuberkulose. Cbl. f. Bact., iii., 1888. "Welcker: Phagocytare Rolle d. Riesenzellen. Beitr. v. Ziegler, xviii., 1895. Wesener: Beitr. z. Lehre v. d. Futterungstuberkulo.se, Freiburg, 1884. Wolff- Eisner: Die Ophthalmo- und Kutandiagnose der Tuberculose. Beitr. d. Klinik d. Tuberkulose, 9 Bd., 1908. Yersin: Etude sur le developpement du tubercle exper. Ann. de l'lnst. Pasteur, ii., 1888. Ziegler: Ueber die Herkunft der Tuberkelelemente, Wurzburg, 1875; Ueber patholog. Bindegewebs- u. Gefassneubildung, Wurzburg, 1S76; Tuberkulose. Eulenburg's Realencyklop., xxiv., 1900 (Lit.), u. Eulenb. Jahrb., ii., 1904. See also § 171. § 171. Tuberculosis is at the beginning a local disease, which occurs most frequently in the lungs, intestinal tract, and skin; that is, in places accessible from without. Cases of cryptogenic infection are by no means rare; in these the first demonstrable disease-changes appear in tissues concealed in the deeper portions of the body -parenchyma — as, for exam- ple, in the lymph-glands, adrenals, bones, joints, brain, tubes— and it is to be assumed that under certain conditions the bacilli enter the body without causing lasting changes at the point of entrance, so that they develop first in some distant organ to which they are carried by the blood or lymph, and through multiplication give rise to tissue- degeneration, to emigration of white blood-cells, and to proliferation of tissue. The local disease usually begins with the formation of miliary tu- bercles — that is, cellular nodules of the kind described above — which arise in the tissue either singly or (in case of multiple infection) in great numbers simultaneously, or one after another (secondary dissemination of the multiplying bacteria). The tissue in the neighborhood of the individual tubercles, as well as that between the tubercles, shows some 40 626 THE PATHOGENIC FISSION-FUNGI. times a more, sometimes a less pronounced appearance of inflammatory exudation and proliferation of an especially cellular' type ; and through these processes there are frequently formed large granulation=areas in the infected connective tissue. In the ease of a surface colonization of the bacilli, as is possible in the alveoli of the lung and in the smallest bronchioles, an exudative catarrhal inflammation may be the first sign of the infection, while proliferative processes in the connective-tissue stroma and in the pulmonary vessels appear only at a later period. In the mucous membranes and in the skin (Fig. 473) large areas of the mucosa and submucosa, or eorinni respectively, may through the mm Fig. 473.— Lupus of tlie skin with atypical growth of epithelium, from the region of the knee (alcohol, hematoxylin, fuchsia, picric acid), a, Corium converted into granulation tissue in which there are scat- tered tubercles ; h, epidermis ; c, epithelial plugs growing into the deeper tissues ; 0, tubercle. X 50, formation of such granulations undergo a nodular or a diffuse, flattened thickening. In the serous membranes there may develop large, flattened nodules in whose neighborhood the serosa is thickened and covered with a fibrinous exudate. In the synovial membrane of the joints and bursas there often arise soft, spongy proliferations, the so-called fungous granu- lations (Fig. 474) ; in the periosteum and bone-marrow round, grayish- red, or gray granulation-areas of varying size appear. All these areas have one feature in common — namely, in their neighborhood are found inflammatory infiltrations and proliferations of tissue, which bear the character of a granulation tissue (Fig. 47:!, a : 474, b) inclosing charac- teristic lion- vascular, cellular nodules — tubercles ( Figs. 47.'], d; 474, r) — which often contain giant-cells. In grayish-red tissues rich in blood the tubercles may often be recognized by the naked eye as gray, or, when undergoing caseation, as white or yellowish-white nodules. The area of tuberculous granulation tissue when once formed becomes larger in its further course of development by an oppositional growth, TUBERCULOSIS. 627 Fig. 474.— Tuberculous granulation tissue from the synovial membrane of "the knee-joint (Miiller's tluid, Bismarck brown), a. Connective tissue; />, granulation tissue ; c, tubercle. X 80. dense fibrous tissue (Fig. rangement (ft), and in part is more hyaline and homogeneous in char- acter. In the lungs such connective-tissue nodules contain more or less car- bon-pigment (Fig. 477). A second form of ter- mination is a combina= tion of caseation and fibrous induration com prising dense fibrous tis- sue (Fig. 478, b, d) and caseous foci (ft) of vary- ing size. The third termination consists essentially in caseation, the tubercu- w hereby the same processes, as just described, consummate themselves at the periphery. There may arise in this way, either within an in- fected organ, or upon the surface of such, nodules of large size, soli= tary tubercles (Fig. 475, c) as, for example, in the pia, brain, and upon the dura mater, which not infrequently resemble true tumors. Further, the tissue trans- formed by the tuberculous process or the newly formed tissue respec- tively, may suffer various fates; and there may be distinguished three chief forms of termination, which may, however, be combined in various ways. In a first group of cases the production of connective tissue forms the most striking feature, and there results a connective- tissue induration of the diseased tissue (Fig. 47(1) with the develop- ment of a dense, fibrous connective tissue («). If the process does not come to a standstill, there may be found in association with the fibrous tissue new proliferations of granulation tissue (b), and often also a larger or smaller number of typi- cal tubercles (c). If the process comes to a complete standstill and to a cure of the infection, the en- tire area may come to consist of a ft, b) which in part shows a nodular ar- 6 FIG. 475.— Large solitary tubercle of the pia mater of the cerebel- lum in vertical section, a. Cerebellum; b, dura mater adherent to the tubercle ; c, laminated tubercle ; il, gray peripheral zone adherent to the dura mater and beset with yellowish-white, nod- ular deposits. Natural size. (328 THE PATHOGENIC FISSION-FUNGI. lous granulation tissue dying and producing no connective tissue at all, or only in such a slight amount that it is completely overshadowed by the caseous masses (Fig. 479, c). Both the fibroeaseous and the purely caseous areas may become I ft 111 ■. u : *" -L '"■ ^ ■-. .... . ,. ll^iA Fig. 476.— Tuberculous induration of the lung (alcohol, hematoxylin, and eosin) . a, Dense, fibrous tissue ; b, cellular granulation tissue; c, giant-cells. X 40. mm j&^^v^' ■-■■■■ ,/4«x^ f .' ' ■ •" fa I 3-i 5 ;:.'|'f' C&W Fid. 177.— Tuberculous induration of the lung (alcohol, hacmatoxvlln, eosin). a Homogeneous fibroin nodules poor in cells and in part pigmented ; b, diffuse induration of the lung. X 24. TUBERCULOSIS. 629 healed, through their encapsulation from the .surrounding tissues by connec- tive tissue (Figs. 478, o; 479, c, e). Such a healing can be regarded as complete only when in the connective-tissue capsule (Pig. 479, c, e) and S? a Hi ; : M ellliii mz&%m Fig. 478. —Encapsulated area of caseation of the lung with induration and eruption of tubercles in the neighborhood (formalin, alcohol, hematoxylin, eosin). a. Caseous area ; ?>, fibrous capsule ; c, tubercle ; (/, indurated lung tissue ; e, area of granulation tissue. X 40. Fig. 479. —Encapsulated area of tuberculous caseation in the lung, a, Normal lung tissue ; h, pleura; c, area of caseation ; d, remains of elastic fibres in the area of caseation ; e, small encapsulated caseous nodules ; /", thickened pleura. X 16. 630 THE PATHOGENIC FISSION-FUNGI. its neighborhood (a) neither fresh granulation-tissue areas nor tubercles are still present. Occasionally calcification of the encapsulated caseous mass may occur as a further sign of the termination of the process. The caseous masses of tuberculous foci are sometimes firm, some- times soft, and in the latter case very often suffer a disintegration and liquefaction leading to the formation of milk-white, crumbling, and pul- taceous or even thin fluid masses, so that the tuberculous area comes to present the picture of an abscess surrounded by a wall (designated as cold abscess). Eupture and emptying of the same externally leads to the Fig. 480. — Tuberculous cavern in the tibia (alcohol, picric acid, naematoxylm, carmine). Transverse section, a. Periosteum ; 7», rarefied cortex : c, periosteal deposit of bone ; o\ fibrous tissue on the Inner surface of the cortex; r, granulation tissue containing tubercles;/, sequestrum with bony trabeculse, infiltrated with granulation fissoe; (/, union of the granulation tissue with the sequestrum ; h, cavity that had been filled with pus and caseous masses. X <1%. formation of cavities or caverns and fistulous passages accessible from without, and, when there is a wide ojiening, to ulcers. Disintegration and cavity -formation occur particularly in 'the lung, and may there lead to the formation of cavities as large as a man's fist or larger. They also occur not infrequently in caseating lymph-glands, and in caseous foci in the kidneys, brain, muscles, skin, and bones (Fig. 480). The cavities (70 contain in the beginning the liquefied tuberculous tissue, in which not infrequently remains of the original tissue may be recognized in the form of sequestra (/). After the evacuation of the contents the wall may furnish material sufficient to fill the cavity again either through the secretion of pus or through the breaking-off of necro- tic tissue. Haemorrhages not infrequently arise through the erosion of blood-vessels. The mills of the caverns and abscesses are usually lined by caseating granulation tissue containing tubercles (Fig. 480, e) ; the surrounding tissue becomes indurated in part, and in part the seat, of caseating foci. TUBERCULOSIS. 631 Ulcers occur most frequently in the mucous membranes (Fig. 481 A) and in the skin, since the softening caseous masses in these regions most 7. Via. 48L— Tuberculous ul Bismarck brown), a, Mu /, solitary follicle ; the pe- (ioO THE PATHOGENIC FISSION-FUNGI. riphery by the vacuoles containing the bacilli. Later they are destroyed, so that the entire cell becomes changed into a vacuole containing bacilli ( Fig'. 4'.)'.)). The cells in which the bacilli lie are in part the original cells of the tissue, and in part newly formed cells. * fe • ■S-f ■ :,/ ■ ",'•£' Fie.. 4.98.— Tissue from a leprous nodule (alcohol, fuchsia, methylene-blue). a, Fibrocellular tissue ; ft, round-cells ; c, medium-sized cells ; rf, very large cells filled with bacilli ; e, free bacilli. X 200. Fkj. 4'.!!).- Giant-cells, with vacuoles containing bacilli, from leprous proliferations of the nasal mucosa (alcohol, Gabbet's stain). ■ 400. The bacilli arc surrounded by a slimy envelope (Neisser), and react to stains in much the same manner as do tubercle-bacilli. The same staining methods may therefore be used for the former as for the latter. The stained bacilli often show clear spots or appear as if made up of stained granules. 1 4k, ■ ■ ■m. -1 *£■> ': '■ ■' ••• y / i . • v ■ :il. r. CV ■;'•■, W:-^ : '' A '■■tr '!•■;'■■■' •'- CSTf, , Fig. o(ki. -Section through a leprous nodule of the skin (alcohol, Gabbet's method), a, Epidermis- It conum; c, hair-follicle; . 90. b, c, (Fig. 504), which lie partly inside the canaliculi (b, c) and partly around them (d). The injection of the pus of glanders into the peritoneal cav- ity of male guinea-pigs causes the testicles to swell rapidly (Straus). After subcutaneous inoculations ulcers develop at the seat of inocula- tion, followed by swelling of the neighboring lymph-glands. Later, nod- ules may develop in the internal organs, and ulcers may be formed in the nose. Typical glanders may be produced in horses and asses. Cattle, white mice, and house-mice are immune. The usual atrium of infection in horses is the mucous membrane of the nose ; following this is the involvement of the submaxillary glands, and further a metastasis in various organs. In the nasal mucosa there 656 THE PATHOGENIC FISSION-FUNGI. arise as the result of the infection either diffuse cellular infiltrations of the mucosa or subepithelial nodules of the size of a millet-seed or a pea. In chronic farcy of the skin larger nodules are developed which join to- gether in rows, forming worm-like cords. The nodules of the mucous membrane break down easily. The cells of which they are composed bear for the greater part the character of pus- corpuscles. Through the disintegration, softening, and suppuration of the nodules ulcers with yellowish infiltrated bases are formed. These en- large through a progressive, nodular or more diffuse infiltration and subsequent disintegration of the edges of the ulcer, as well as through the confluence of neighboring ulcers. Horses dying of glanders often present in the mucosa of the nasal septum very extensive irregularly shaped, sinuate ulcers, with eroded edges and floors covered with gray and yel- lowish material. In addition to these there are numerous small, lenticu- lar ulcerations and gray or yellowish nodular foci which are on the point of breaking down. The whole process is closely related to purulent in- flammation. The healing of the ulcer is characterized by the formation of radiating scars. The cervical lymph-glands are constantly swollen and inflamed. Of the internal organs the lungs especially are involved. They contain either nodules having a caseated and disintegrated centre and a grayish cellular periphery, or foci of lobular pneumonia, which present either a clear gray or a more hemorrhagic appearance, or through fatty and cheesy metamorphosis become opaque and yellowish- white. Occasionally the mucosa of the alimentary tract contains nodules of varying size, in part clear gray and consisting of cellular tissue, in part opaque yellow- ish-white, undergoing caseation or approaching suppuration. The spleen, liver, kidneys, and bone-marrow may also contain nodules. In farcy, which runs a more chronic course than glanders, there are formed in the skin and muscles nodules consisting of a small-celled tissue which later undergoes retrogressive metamorphoses, caseates and disin- tegrates. In man an infection with glanders takes place usually through small wounds of the skin, but may also occur primarily in the mucous membranes adjacent to the skin. In the skin and subcutaneous tissue it gives rise to roseolar spots, hEemorrhages, and papular, nodular, and pus- tular exanthemata, carbuncular and phlegmonous inflammations which may result in suppuration, and to purulent inflammations of the lymph- vessels and lymph-glands. In the mucosa of the respiratory tract catarrhs are produced and suppurating nodules and nodes are formed, leaving ulcers behind. In the internal organs metastatic small-celled nodules are formed, showing a tendency to suppuration ; also extensive abscesses and purulent infiltrations, especially in the muscles. In chronic farcy which may last for years, large nodules are occasionally formed in the skin and muscles which through disintegration give rise to ulcers which heal with difficulty. For the diagnosis of the condition the bac- teriological examination and inoculation experiments are necessary. According to the investigations of Kalning, Preusse, and others, an active poison, mullein, may be extracted from cultures of glanders bacilli, which, when injected in small doses into horses sick of glanders, causes afebrile rise of temperature, and may be used as a diagnostic aid. RHINOSCLEROMA. 657 Literature. (Glanders and the Glanders-bacillus.) Babes: Observations sur la morve. Arch, de med. exp., iii., 1891. Ann. de l'lnst. de path, de Boucarest, ii., 1893, vi., 1898; Bekampfung d. Rotzes. Z. f. Hyg., 39 Bd., 1902. v. Baracz: Chron. Rotz beim Menschen. Virch. Arch., 159 Bd., 1900. Bass: Die Rotzkrankheit der Pferde. Deut. Zeitsehr. f. Thiermed., xix., 1893 (Lit.). Baumgarten: Zur Frage der Sporenbildung bei Rotzbacillen. Cbl. f. Bakt., iii., 1888. Bardoni-TJfrreduzzi : Ueber die Kultur der Rotzbacillen. Zeitsehr. f. Hyg., iii., 1888. Buschke: Chron. Kotz d. Haut d. Menschen. Arch. f. Derm.. 30 Bd., 1896. Cadeac et Malet: Et. exper. de la transmission de la morve. Rev. de med., vii.. 1887. Coleman anil Ewing: Septicemic Glanders in the Human Subject. Jour, of Med. Res., 1903. Duval: Morve humaine. Arch, dc med. exp., 1890. Eber: Ueber Rotzlymphc (Mallein). Cbl. f. Bakt., xi., 1892. Enrich: Rotz beim Menschen. Beitr. v. Bruns, xvii., 1896. Finger: Zur Frage der Immunitat u. der Phagocytose beim Ruiz. P.eitr. v. Zicgler, vi., 1889. Foth: Das Mallein. Fortschr. d. Med., xiii., 1895. Frothingham: The Diagnosis of Glanders by the Straus Method. Jour, of Med. Res., 1901. Galli-Valerio: La morphologie du B. mallei. Cbl. f. Bakt., xxviii.. 1900. Jakowski: Chron. Rotz beim Menschen. Zeitsehr. f. klin. Med., xvii., 1891. Johne: Mallein-Rotzimpfungen bei Pferden. Deut. Zeitsehr. f. Thiermed., xix., 1893. v. Kahlden: Rotz. Eulcnburg's Realencyklop., xx., 1899 (Lit.). Kernig: Ein Fall v. chronischem Rotz beim Pferde. Zeitsehr. f. klin. Med., xiii., 1887. Kitt: Impfrotz bei Waldmausen. Cbl. f. Bakt., ii., 1887. Kiittner: Rotz beim Menschen. Mich. Arch., 39 Bd., 1867. Leclainche et Montane: Anat. Path, de la morve pulmonairc. Arch, de l'lnst. P., vu., 1893. Loffler: Die Aetiologie der Rotzkrankheit. Arb. a. d. Ivais. Gesundheitsamte, i., 1886. MacCallum: Ilamatogener Lungenrotz. B. v. Ziegler, xxxi., 1903. Marx: Morphologie d. Rotzbacillus. Cbl. f. Bakt., xxv„ 1899. Mayer: Rotzbacillus u. Rotzknotchen. Cbl. f. Bakt., xxvii., 1900. Pflug: Zur pathol. Zootomic d. Lungenrotzes, Leipzig, 1877. Bemy: Morve chronique de l'homme. Arch, de med. exp., ix., 1M)7. Straus: Essais de vaccination contre la morve. Arch, de med. exp., i., 1889. Tedeschi: Rotzmeningitis. Virch. Arch., 130 Bd., 1892; Wirkungd. Einimpfung d Rotzes in die Nervencentra. Beitr. v. Ziegler, xiii., 189.'.. WladimirofF: Rotz. Ilandb. d. pathog. Mikroorg., ii., Jena, 1903 (Lit.). Zieler: Chron. Rotz beim .Menschen. Z. f. Hyg., 45 Bd., 1903. § 175. As the Bacillus of rhinoscleroma, Friseh, Pellizari, Chiari, Cornil, Alvarez, Kobner, Paltauf, von Eiselsberg, Dittrich, and others have described a bacillus with rounded ends, which is constantly present in the diseased condition known as rhinoscleroma or scleroma respira- torium (Bornhaupt, Yvolkowitseh), and is therefore regarded as the cause of the same. It stains best with methyl-violet, the sections being left in the stain for twenty-four to forty-eight hours. After staining, the sec- tions are treated with iodine water, or left in absolute alcohol for one to three days. The bacilli, for the greater part, possess a hyaline capsule and ai-fi closelv related to the pneumonia-bacillus (§ 10(i). Rhinoscleroma occurs chiefly in eastern Austria and southwestern Russia ; isolated cases have been observed also in Silesia, Italy, Egypt, Belgium, Sweden, Switzerland, and Central America. It is a chronic disease progressing for years, beginning in the nose (Wolkowitsch), more rarely in the pharynx, larynx, or palate, and extending thence to neigh- boring parts — the external nose, lips, lachrymal duct, trachea, etc. In 12 658 THE PATHOGENIC FISSION-FUNGI. the nose the disease is characterized by a thickening of the nasal wall which is sometimes diffuse, sometimes elevated or nodular. The exter- nal skin takes ou a red or brownish-red color, becomes stiff and fissured aud covered with scales. In the throat and respiratory tract dense, car- tilage-like infiltrations are sometimes present, at other times a contract- ing cicatricial tissue is formed. The infiltrations may appear in the form of nodes and nodules or as elevations and flattened areas of thickening, or they may be spread out more diffusely. By the transfor- mation of the infiltration into scar tissue marked deformities of the Flu. ".115. Fig. ".or.. Fig. 505.— Section of rhinoscleromatous tissue, with numerous degenerated and vacuolated cells contain- ing bacilli (osmic acid, ba?matoxylin I . Preparation by Stepanow. x 340. Fig. 506.— Cells in condition of hyaline degeneration, and hyaline spherules, from rhinoscleromatous tissue of the vocal cord and of the nose. Preparation by Stepanow. a, t>, c, d. Hyaline-degenerated cells containing .small bacilli; c, hyaline cells with encapsulated bacilli; /", ./, cells with hyaline spherules; /(, free hyaline spherules, o, /*, c, i/, stained with Loffler's solution ; e, with baematoxylin ; /, (/, /;, with fueh- siu. X 425. affected organs may be produced. Deep destruction of the tissues is absent; superficial ulcerations may, however, occur. On section the infil- trated tissue appears yellowish, spotted, but not infrequently shows a gray or grayish-red color. The tissue of the affected areas consists partly of granulation 1 issue, partly of fibrons connective tissue. If the former extends to the epithelial covering there appear in part proliferations, in part degenerative processes in the epithelial cells, the latter being char- acterized by the. formation of vacuoles and by an infiltration of the part with round cells. According to Stepanow the vacuoles may contain bacilli. The granulation tissue itself shows in many places no especial pecu- liarities; rather does it present the same conditions present in other inflammatory infiltrations and proliferations of connective tissue. In other places, on the contrary, there may be found a larger or smaller number of large connective-tissue cells containing one vacuole or show- ing a total vacuolar degeneration or a reticulated structure, in the meshes iif which bacilli may be demonstrated i Pig. 505), some of the latter pos- sessing capsules. Besides the cells showing vacuolar degeneration there also occur cells 1. 1' various shapes which have undergone hyaline change (Fig. 506, a, b, r, d, e). These also contain bacilli with and without capsules, and also coccus-like forms. Through the loss of their nuclei these cells may be- come converted into non-nucleated homogeneous lumps (d). Finally, there also occur cells which enclose hyaline spherules (/', g), and free spherules are also found lying in the tissues (/i). In places not yet af- RHINOSCLEROMA. 659 fected by cicatricial retrogression the hyaline formations may be present in large numbers. According to Paltauf, von Eiselsberg, Dittrich, Wolkoiritsch, and others, the bacilli of rhinoscleroma may be cultivated upon blood-serum, gelatin, agar-agar, and pota- toes, and also form capsules in the cultures. When grown in bouillon they show on the contrary no capsules (Dittrich). Stab-cultures in gelatin resemble closely the nail- cultures of the Friedlander pneumonia-bacillus, but are of a translucent grayish-white and not dead white. The bacilli stain more easily than the pneumonia bacilli, and also stain by Gram's method. Stepanow observed, in inoculations into the eyes of guinea- pigs, progressive inflammations and proliferating granulations containing the bacilli and hyaline degenerated cells. Literature. (L'liinoxeleroma.) Alvarez: Recherches sur l'anatomie pathol. du rhinoselerome. Arch, cle phys., vii. 1886. Babes: Rhinosklerom. Handb. d. path. Mikroorg., hi., Jena, 1903 (Lit.). Bender: Das Rhinosklerom. Cbl. f. Bakt., i., 1887. Chiari: Stenose des Kehlkopfes u. des Larynx bei Rhinosklerom. Wien. med. Jahrb., 1882. Cornil et Alvarez: Mem. p. serv. a l'hist. du rhinoselerome. Areh. de phys., vi., 1885. Dittrich: Ueber das Rhinosklerom. Zeitschr. f. Heilk., viii., 1887; Zur Aetiologie des Rhinoskleroms. Cbl. f. Bakt., v., 1889; Zeitschr. f. Heilk., viii. Frisch: Zur Aetiolologie des Rhinoskleroms. Wien. med. Woch., 1882. Jafnnger: Das Sklerom d. Schleimhaut d. Nase, etc., Wien, 1892. Konstantinowitsch: Entstehung der hyalinen Korperchen. Virch. Arch., 167 Bd., 1902. v. Marschalk6: Histologie des Rhinoskleroms. Arch. f. Dermatol., 53, 51 Bd., 1900. Mibelli: Beitrag zur Histologie des Rhinoskleroms. Monatsh. f. prakt. Derm., viii., 1889. Mikulicz: Ueber das Rhinosklerom. Langenbeck's Arch., 20 Bd., 1876. Nikiforoff: Ueber das Rhinosklerom. Arch. f. exp. Bath., xxiv., 1888. Paltauf: Aetiologie des Skleroms. Wien. med. Woch., 1891, 1892. Paltauf u. v. Eiselsberg: Zur Aetiologie des Rhinoskleroms. Fortschritte d. Med., 1886. Pawlowsky : Ueb. d. Aetiologie des Rhinoskleroms. Cbl. f. allg. Path., i., p. 601. Pellizari: il Rhinoskleroma, Firenze, 1883. Bona: Rhinosklerom. Areh. f. Derm.. 49 Bd., 1899, u. 58 Bd., 1901. Stepanow: Ueber die Impfungen des Rhinoskleroms. Cbl. f. Bakt., v., 1889; Zur Aetiologie des Skleroms. Monatsschr. f. Ohrenheilk., 1893. Wolkowitsch: Das Rhinosklerom. Langenbeck's Arch., 38 Bd., 1889. Zag-ari: Ricerche etiol. sul Rinoscleroma. Giorn. internaz. d. Sc. Med., 1889. § 176. The Actinomyces or ray=fungus is a polymorphous fission- fungus which appears in different forms of growth in the human and animal organism as well as in cultures. It is the cause of actinomycosis, a disease occurring in man as well as in cattle, swine, and horses, more rarely in sheep, dogs, and cats, and characterized by a progressive inflam- mation that produces in part granulation tissue and connective tissue, and in part pas. The botanical position of the fungus is still unsettled. By many it is classed with the thread-fungi, others group it with the poly morphoiis bacteria. Bostrom places it in the group cladothrix; Kruse, in the group streptothrix. (360 THE PATHOGENIC FISSION-FUNGI. According to the investigations of Bostrom actinornyees differs from the bacilli in the fact that in cultures upon beefs-blood serum or agar it forms branching threads. The threads of the cultures are partly straight, partly wavy, at times also twisted spirally. They break up by transverse division Fig. 507. — Actinomyces hominis. Teased preparation. X 700. Fie;. 508.— Actinomycosis of the tongue (alcohol, alum carmine.) a, Actinomyces druse; ?>, c, cellular m idules ; d, transverse section of muscle ; e, /, connective tissue with blood-vessels. X 1"". into short rods and coccus-like forms, which under suitable conditions again grow into threads. Within the human and animal organism the fungus appears in masses in the form of little granules scarcely recognizable by the naked eye, or a m ^^iw:wi e'« ; « ^ in spherules up to 2 mm. in diameter. These are sometimes colorless and transparent, at other times white and opaque, sometimes yellow or brown, or green and yellowish-green. Many of the smaller ones consist ACTINOMYCOSIS. 'il'l only of a t'eltwork of fine, partly branched threads, some of which are straight, or wavy, or twisted. The majority of the grannies contain, moreover, peculiar club-shaped structures (Fig. 507), which form the ends of the threads, and if present iu large numbers, as is the case par- ticularly in the larger granules, have a radial arrangement (Figs. SOS, a : • r >09, a), and so give to the colony of the fungus a ray-like appearance. Occasionally hand or fan-like forms develop on the ends of the threads. According to Bostrom, all these peculiar structures are due to a swelling 'v* -M'lr /--■ •'.-...= ■•,"■. 7s ! , - I ■ 7 ^«V 7 mm, mspm .'j7s.?>7-"7. .^►/JVHiVi^ -K^ > Hi . .■•■'■£■:*■ &M l :°>i^:% 77, T<*\ I $5& "7':* 77; . ^7-r : 777'7'. : V r'i • *'. ; : .'''v7-; : "'5* < ^: M 7«Vv -r^ , , < i/^=r *. 7 ■';7' ■ ■•iw^- '■.&£ jfe V . ,-r, . v . ■ ' 7 '7 ^V ,; ' 7 .^' : -0i c j>\ . 7 ^.-;^7 -;^; ;{:';;^,r7 v 7^ ^ 1 >■"-"" •'■' ''•■•■••••■•■•■ "-^fe--;' '.'Ny/ Fig. 510.— Actinomycosis of the lung (alcohol, carmine, (iram's). a, Fungus druse; o, small-celled nodule; c, fibrous tissue; , d). The fungus-granules may increase within the nodule and lead to its enlargement; and it very often happens that cellular nodules the size of a pea and larger contain a laro-e number of fungus-foci, which are usually situated in the periphery of the same. At the same time new fungus-foci, and consequently new cellular foci, may appear in the neighborhood. The further spread of the infection takes place by means of small rods and threads, which are broken off from the larger masses, and may be seen in the tissues partly free and partly enclosed in cells. Larger nodules often undergo in time a purulent liquefaction of their central portions, leading to the formation of small abscesses, which may become confluent to form larger pus-cavities or sinuses. In the neighborhood of the puru- lent areas (Fig. 510) there develops early an active proliferation of tissue, which leads to the formation of vessels (It) and young granulation tissue, which later becomes transformed into cicatricial connective tissue (c, (j, h). If the connective-tissue proliferation attains very considerable proportions, it leads to "an induration (Fig. 510), often also to an enlarge- ment of the tissue. The connective-tissue proliferation may finally extend into the small-celled areas, and replace the latter, the fungi probably being destroyed in this way. A predominance of tissue-necrosis and of suppuration over tissue-pro- duction gives rise to more or less extensive sinuous cavities and branch- ing fistulous tracts communicating with one another. The walls of these consist of granulation-tissue and hyperplastic connective tissue, and here and there contain fungus-foci. The masses of fungi may in part become calcified. In cattle the disease affects chiefly the lower jaw, but may involve also the upper jaw (Fig. 511, a), the tongue, throat, larynx, oesophagus, stomach, intestinal wall, skin, lungs, and subcutaneous and intermuscular tissues; in sivine it is found in the udder and different bones of the skeleton, while in horses it occurs chiefly in the vas deferens following castration. In cattle it leads to the formation of more or less extensive fibrous tumors containing purulent foci, and was formerly given various FlG. 51].— Frontal section through the nose and upper jaw of a steer affected with a tumor-like actinomycosis. 0, Nodules consisting of connective tissue, bone, and small pus foci. One-fourth nat- ural size. ACTINOMYCOSIS. 663 names, such as osteosarcoma, bone-cancer, bone-tuberculosis, lumpy jaw, wooden tongue, tuberculosis of the tongue, lymphoma, fibroma, worm- nodules, etc. In man the infection, so far as is known, takes place through the mouth, fauces, oesophagus, stomach, intestine, and lung, or through some external injury. In the first-named region an infection of actinomyces may take its start from carious teeth (cavities or fistula 1 ), or from any injury to the soft parts of the jaw or cheek. Thence it spreads over the neighborhood and may finally involve the -face and the hairy portions of the head, as well as the throat, neck, back, and breast. With the advent of the process there arise swellings which later soften and give fluctuation. When the latter is the case, pus is formed which is at times thin and watery, at other times more viscid, and con- tains the characteristic granules. If these abscesses break externally there may be formed fistulous tracts, which may either close again, or continue to secrete pus. Besides these purulent foci, which sometimes are small, at other times extensive, there is constantly formed more or less granulation tissue, which at times may be very abundant. As a result of fatty degeneration and disintegration of its elements the granulation tissue often becomes partially whitish or yellowish or reddish-white in color, and permeates the diseased tissue in an irregular manner. In other places it comes to a development of connective tissue, particularly in those places where the process is not spreading. Through this development of connective tissue a local healing result- ing in cicatricial indurations may take place, but in other parts the process usually makes further progress and may under certain circumstances lead to very extensive destruction. If the disease encroaches upon the bones of the spinal column or of the thorax these may be gradually destroyed from the surface, and become rough, eroded, and carious. Tu rare cases the jaw-bone may be attacked from within through an alveolar process, and so undergo destruction. From the base of the skull the process may extend into the interior of the skull arid lead to actinomycotic meningitis and encephalitis. In primary infection of the respiratory apparatus the process takes the form of a bronchopneumonia characterized by the formation of nod- ular foci (Fig. 510, b) the central portions of which at an early stage assume a yellowish -white color. Through the disintegration of the in- flammatory foci cavities may be formed which contain fluid, pus-corpus- cles, fatty detritus, spherules of fatty granules, disintegrated red cells, and masses of actinomyces. The tissue lying between the mycotic foci suffers a more or less extensive, often very marked, inflammatory thicken- ing aud induration (Fig. 510, e), and through a new -formation of cou- uective tissue may be transformed into a callous, slate-gray or gray and white mass, devoid of air, and later undergoing cicatricial contraction. In this manuer a large portion of the lung may become converted into a mass of connective tissue. From the lung the process sooner or later extends to the visceral pleura, and from this to the costal pleura or to the pericardium, giving rise in these places to inflammatory exudations and proliferations of tis- sue, which may lead to adhesions between the opposite layers of the pleura or pericardium. From the costal pleura the cellular infiltration as well as the pus formation and the fatty degeneration and disintegra- 664 THE PATHOGENIC FISSION-FUNGI. tion of the granulation tissue may extend between the ribs to the out- side, and spread in the contiguous soft parts, in the connective tissue and muscles, and may finally break through in places. From the lungs a rupture may sometimes take place into the mediastinum or pericardial sac, and finally into the heart. Under certain conditions a rupture may occur through the diaphragm into the abdominal cavity, or the process may extend from the posterior mediastinum into the retro- peritoneal connective tissue. The secondary areas of destruction lying outside of the lung often reach an extremely large size, while in the lung the primary process advances but little and undergoes cicatrization. At one time the puru- lent softening predominates, at another time the formation of granulation tissue and the induration. Primary actinomycosis of the intestinal tract begius with the forma- tion of plaque-shaped whitish patches of the fungus ( Chiari) or of nodu- lar mucosal and submucosal foci (Zemann), which contain the specific fungus, and lead to ulceration through the occurrence of disintegration. From the intestine the process spreads over the peritoneum and the retro- peritoneal connective tissue, as well as to the organs adjacent to the pri- mary focus — for example, the liver; and may finally break through the abdominal wall. Metastasis may be associated with the local progression of the disease, but is rather rare. It usually results from a direct rupture into a blood- vessel. The metastases arising from a primary focus in the intestine are found especially in the liver; those arising from a primary focus in the lungs are found in the skin, muscles, bones, brain, intestine, and kidneys. The metastatic nodules behave like the primary foci. In rare cases there occur also primary foci of actinomycosis in the internal organs — for ex- ample, in the brain and liver. The portal of entrance in these cases may not be demonstrable. Johne, Ponfick, Bostrom, Wolff, and Israel have attempted inocula- tion experiments upon animals, and according to their reports have obtained positive results in part (Johne, Ponfick, Wolff, and Israel). Wolff and Israel, by the inoculation of rabbits and guinea-pigs, obtained in almost all cases a characteristic disease with the formation of inflam- matory foci containing the fungus-masses. They were also able again to cultivate upon agar-agar the fungus contained within these foci. Levy, as well as Krusc, assumes that there are two forms of actinomyces, an aerobic cultivated by Bostrom, and an anaerobic cultivated by Wolff, Israel, Asehoff, and himself, the two forms being closely related. Mertens announces that he has succeeded in changingthe Wolff-Israel form into the Bostrom. Levy regards the actinomyces as well as the fine-threaded fungus known as streptothrix as belonging to a group, the Hyphomy- cetes, characterized by the formation of branching, probably unicellular mycelia and which multiplies through an acrogenic snaring-off of conidia-chains or through fragments of threads resembling bacilli. Since the ray-fungi do not correspond to any one^of the known hyphomycetes-groups, he places them in a, separate group, the Actiriomycetes. In this group he also places the tubercle-bacillus, the lepra-bacillus, the diphtheria- bacillus, and the bacillus of glanders. Lubarsch regards the streptothrices, with which he classes the ray-fungi (to which the tubercle-bacillus also belongs), as a transition form between the bacilli and the moulds. Berestnew also distinguishes different forms of actinomyces (cultivated by him from straw, hay, etc.), and, in addition to actinomycosis, recognizes a condition of pseudo- aclinomycosis, which runs a similar course to that of the former, but is caused by fungi which do not belong to the ray-fungi. AVowse and Gilbert likewise regard the etiological iactor of an actinomycosis as being of varied nature and not representing a definite entity Schiirmoyer emphasizes the variability of actinomyces according to the conditions of growth. Wright believes that human and bovine actinomycosis are identical and TRICHOMYCETES. 665 further holds that there is but one species of microorganism (Actinomyces bovis) con- cerned in the production of typical actinomycosis. The lesions produced by other forms of branching organisms he would class under the head of nocardiosis, reserving the term actinomycosis for those conditions in which characteristic " drusen " are formed. According to Dunker (Zeitschr. f. Mikroskopie und Fleischschou, iii., 1884) and Hert- ivig (Arch. f. viissensch. u. prakt. Thierheilk., xii., 1886) there occurs in hogs a ray-fungus which is always situated in the muscles, particularly in the diaphragm, abdominal and intercostal muscles, and causes a degeneration of the muscle-fibres in its neighborhood and proliferation of the intermuscular connective tissue. The fungus-masses form radially arranged clubs. They readily undergo calcification and then form wliite points in the flesh. Pelru-schky unites Actinomyces, Streptothrix, Cladothrix, and Leptothrix into one family, which he calls the Hair fungi or Trichomycetes. These he classes also with the hyphomyeetes, of which he distinguishes two great classes, the mould fungi and the hair fungi. Actinomyces is characterized by radiating forms; streptothrix by true branching, late fragmentation of the wavy threads and the formation of conidia; cladothrix by false branching of the threads (a lateral direction of the membrane with a continuation of the longitudinal growth in the other direction) and rapid fragmentation of the threads; while leptothrix is characterized by stiff threads without branching. There occur numerous observations in which organisms apart from the aetinomyces described above and belonging to the trichomycetes, particularly to the streptothrices, gave rise to local tissue-changes, particularly purulent and granulating inflammations, and in part also to tubercle-like changes, but in many cases the authors have not agreed as to what species the fungus concerned belonged. As early as 1855 fungus masses were observed by von Graefe in the inflamed lach- rymal duct. These were at first regarded as favus, but later Cohn (1874) regarded them as streptothrix and gave them the name of Streptothrix foersteri. Likewise Axenfeld, who has many times cultivated the fungus, regarded it as a variety of streptothrix. Under the term Cladothrix asteroides Eppinger has described a polymorphous fission fungus or hair fungus found in the pus of an old cerebral abscess causing death through meningitis. Since in the affected individual changes similar to tuberculosis were foimd in the lungs and bronchial glands and since inoculation of guinea-pigs and rabbits gave rise to a disease resembling tuberculosis, he has designated the disease produced by the fungus as Pseudotuberculosis cladothrichica. MacCallum regards Eppinger's fungus which he obtained from a purulent peritoneal exudate as belonging to the Actinomyces group and calls it Actinomyces asteroides. Schahad regards a fungus characterized by branching threads which he found in a subpectoral abscess, and according to its behavior in cultures apparently identical with the Eppinger fungus, as belonging to the aetino- myces group, and designates it an atypical aetinomyces which differs from the typical form in that it produces no chilis and is acid-fast. In animals it causes a pseudotuber- culosis. Buchholtz found a variety of streptothrix in a pneumonic lung containing large cavities of disintegration, with ragged walls. Longer found a streptothrix pathogenic for guinea-pigs in the sputum of a thirteen-year-old boy, which probably arose from an (esophageal diverticulum. According to investigations by Kanthack, Boyce, and Vincent it is very probable that the disease occurring in India known as Madura-foot or Mycetoma, characterized by gradual swellings in the extremity, with nodular deposits becoming changed into abscesses and fistulous tracts through suppuration, and on pressure discharging purulent gray, or brown to black, fish-roe or trufflelike granules is caused by a polymorphous fungus related to Actinomyces and designated by Vincent as Streptothrix madurce. Kan- thack regards the fungus which is enclosed in the granules as identical with the Actino- myces, but the investigations of Vincent and Boyce do not agree with this assumption. According to Boyce, the Streptothrix madurce occurs in two varieties, one white or yellow, with fine dichotomous branching threads and one black, with branched pigmented threads. Unna and Delbanco also distinguish different fungi which they class with the Actinomyces. According to Oppenheimer mycetoma is a granuloma with abscess for- mation caused by two kinds of fungi; the yellow form is an aetinomyces, while the fungus of the black form cannot at the present time be exactly classified, but probably belongs to the oi'dia or moulds. The parasite of the madura disease has been known since the year 1874 (Carter, Lewis, and Cunningham), and was formerly called Chionyphe Carteri. 666 THE PATHOGENIC FISSION-FUNGI. Literature. (Actinomycosis. ) Abee: Drei Falle von Aktinomykose. Beitr. v. Ziegler, xxii., 1897. Behla: Systemat. Stellung d. Aktinomyces. Cbl. f. Bakt., xxiii., 1S9S. Berestnew: Ueber Pseudoaktinomykose. Zeitschr. f. Hyg., xxix., 1899. Bollinger: Eine neue Pilzkrankheit beim Rinde. Cbl. f. d. med. Wiss., 1877; Deut Zeitschr. f. Thiermed., iii., 1877; Munch, med. Woch., 1887. Bostrom: Unters. ilber die Aktinomykose des Menschen. Beitr. v. Ziegler. ix., 1890. Chiari: Darmaktinomykosc. Prag. med. Woch., 1884. Gilbert: Aktinomyces thermophilus u. Aktinomyceten. Z. f. Hyg., 47 Bd., 1904. Grill: Aktinomykose d. Magens u. d. Darms. Beitr. v. Bruns, xiii., 1895. Hesse: Ueber Aktinomykose. Deut. Zeitschr. f. Chir., 34 Bd., 1892. Hoche: Histogenese du nodule aetinomycosique. Arch, de med. cxp., 1899. Howard: Actinomycosis of Central Nervous System (Lit.). Jour. ofMed. Res., 1903. Hummel: Entstehung d. Aktinomv kosedurch Fremdkorper. Beitr. v. Bruns, xiii., 1895. Illich: Beitr. z. Klinik d. Aktinomykose, Wien, 1892. Johne: Deut. Zeitschr. f. Thiermed'.. vii., 1881; Cbl. f. d. med. Wiss.. 1882: Aktino- mykose im Samenstrang kastrirter Pferde. Fortschr. d. Med., iii., 188,3. Israel, J.: Mykose des Menschen. Virch. Arch., 74, 78 Bd.. and Cbl. f. d. med. Wiss., 188.3; Klin. Beitr. z. Kenntniss d. Aktinomykose des Menschen, Berlin. 1885. Israel, O.: Kultivirbarkeit d. Aktinomyces. Yircli. Arch., 95 Bd.; Cbl. f. d. med. Wiss., 1880. Krause: Zur Kenntn. d. Aktinomyces. Cbl. f. Bakt., xxvi., 1899. Kruse: Systematik d. Streptotricheen in Flugge. Die Mikroorganismen, ii., 1890. Lebert: Anat. path. I c, Atlas t. 1.. pi. II., Fig. 10. Levy: Ueber die Aktinomycesgruppen. Cbl. f. Bakt., xxvi., 1X99 (Lit.). Iaeblein: Aktinomykose d. Haut. Beitr. v. Bruns, 27 Bd., 1901). Liebmann: L'Attinomyce dell' uomo. Arch, per le Sc. Med., xiv., 1890. Martin: Actinomycosis of the Brain. Journ. of Path., iii., 1894. Mertens: Aktinomycesforschung. Cbl. f. Bakt., xxix., 1901 , u. Z. I'. Hyg., 42 Bd., 1903. Moosbrugg-er: Ueb. die Aktinomykose des Menschen. Beitr. v. Bruns, ii., Tubingen, 1886. van Niessen: Aktinomyces-Reinkultur. Virch. Arch., 150 Bd., 1897. Partsch: Die Aktinomykose des Menschen. Samml. klin. Vortr., No. 306-7, 1888. Perroncito: Inoculation d'actinomyces. Arch. ital. de Biol.. \ ii., 18811. Ponflek: Bresl. arztl. Zeitschr., 1879, 9 Mai; Berl. klin. Woch.. 1879, p. :;47; Die Akti- nomykose des Menschen, Berlin, 1882. Schleg-el: Aktinomykose. Ergebn. d. allg. Path., v., Wiesbaden. 1900, u. Ilandb. d. path. Mikroorg." ii., 1903. Schurmayer: Ueber Aktinomyces. Cbl. f. Bakt., xxvii.. 1900. Tusini: Aktinomykose des Pusses. A. f. klin. Chir., 02 Bd.. 1900. Virchow: Trichinosis u. Aktinomykosis bei Schweinen. Virch. Arch., 95 Bd., 1884. Wolff u. Israel, J. : Reinkultur des A. u. Uebertrag. auf Thiere. Virch \rch 126 Bd., 1891. Wright: Madura Foot. Jour, of Exp. Med.. 1898; Actinomycosis, lief. Ilandb. of Med. Sc, 2d ed., 1900. Biology of the Microorganism of Actinomycosis Jour of Med. Res.. 1905. For literature on Streptothrix, Cladothrix, and Leptothrix see facing page. j< 177. In addition to those already described there is a large number of bacilli pathogenic for animals which may also cause infection in man. The most important animal diseases caused by bacilli are sympto- matic anthrax, swine-erysipelas, swine-plague, swine-pest, cattle-plague, and chicken-cholera. The bacillus of blackleg or symptomatic anthrax (Baderie du charbon sympto matique, Clostridium sarcophysematos buvis) is a rod with rounded ends about 3-5 a long and 0.5-0.0 //. broad, and sometimes possessing independent motion. According to the investigations of Bollinger, Feser, Arloing, Cornevin, Thomas, and others, it is constantly found in blackleg. Blackleg occurs particularly in young cattle and in lambs, and is usually fatal within two days. It is characterized anatomically by a tumor-like swelling of the skin Literature. (Streptothrix, Cladothrix, and Leptothrix.} Axenfeld: Pilzkonkremente in Tranenrohrchen. Handb. d. path. Mikroorg.. iii., Jena, 1903. Babes: Madurafuss. Handb. d. path. Mikroorg., iii., Jena, 190.3. Boyce: Plurality of Fungi in Madura Disease. Hyg. Runds., 1S94. Buchholz: Men schen pathogene Streptothrix. Z. f. Hyg., 24 Bd., 1897. Carter: Mycetoma or the Fungus Disease of India, London, 1874. Eppinger: Pathogene Cladothrix. Beitr. v. Ziegler, ix., 1891. Foulerton and Jones: Pathogen. Act. of the Genus Streptothrix. Trans, of the Path. Soc. of London, liii.,' 1901. G-ozzolino: Ein neues Fadenbakterium. Z. f. Hyg., 33 Bd., 1900. Kanthack: Madura Disease and Actinomyces. J. of Path., 1892. Langer: Streptotriohosis oesophagi. Z. f. Hyg., 47 Bd., 1904. Lewis and Cunning-ham: The Fungus Disease of India, Calcutta, 1875. MacCallum: On the Life-history of Actinomyces Asteroides. C. f. Bakt., Orig., xxxi., 1902. Oppenheim: Madurafuss. A. f. Derm.. 71 Bd., 1904 (Lit.). Petruschky: Die pathogenen Triohomyceten. Handb. d. path., Mikroorg., iii., Jena, 1903 (Lit.). Sabrazes el Riviere: Les parasites du genus streptothrix. Sem. Med., 1895. Schabad: Actinomyces atypica pseudotuberculoza. Z. f. Hyg., 47 Bd., 1904. Trolldenier: Beim Hunde gefund. pathogene Streptothrix. Z. d. Tiermed., vii., . 1903. TJnna u. Delbanco: Anatomie des indischen Madurafusses. M. f. prakt. Derm., 1901. Vincent: Et. sur le parasite tin pied de Madura. Ann. de l'Inst. Pasteur, 1894. 668 THE PATHOGENIC FISSION-FUNGI. and kidneys, where they also lie in the blood-vessels. The majority are free; some are enclosed in leucocytes. They are stained by Gram's method. Literature. Hess- Der Stabchenrothlauf u. die Schweineseuche. Thiermed. Vortr., i., 1888. Kitt: Der Stabchenrothlauf der Schweine und dessen Schutzimpfung. Jahresb. d. Thierarzneisch., Munchen, 1885-S6, Leipzig, 1887; Streptothrixform d. Bacillus. Cbl. f. Bakt., xxii., 1897. Loffler: Schweinerothlauf. Arb. a. d. K. Ges.-Amtc, i., 1885. Lorenz: Schutzimpfung gegen Schweinerothlauf. Cbl. f. Bakt., xv.. 1894. Lydtin und Schottelius: Der Rothlauf der Schweine, Wiesbaden, 1885. Preisz: Rothlauf d. Schweine. Handb. d. path. Mikroorg., iii., 1903. Schiitz: Rothlauf d. Schweine. Arb. a. d. K. Ges.-Amte, i., 18S5. The Bacillus suisepticus, the cause of German swine plague or swine septicaemia (swine plague [Salmon]) is a bacillus discovered by Loffler in 1886. It is about 1.2-1.4 ft long and 0.4-0.6 /( broad. It is a facultative aerobe, grows easily upon the ordinary culture media, and when stained usually shows a polar staining while the middle portion remains clear. In natural infection the hogs may die within twenty-four hours from septicaemia and bacteriaemia. The bacilli may be found in all the organs. If the skin is the avenue of entrance there occurs at this point a subcutaneous inflammatory oedema. Mere frequent is the form known as pectoral swine plague, which occurs both in an acute and a chronic form. In the former there occur multiple croupous-haemorrhagic broncho- pneumonias that become gangrenous, and may be associated with a pleuritis, pericar- ditis, and peritonitis. In the chronic form, which is the most, common in Germany, pulmonary hepatizations, with or without necrosis, are formed. In the majority of cases it is a bronchogenic pulmonary disease, but the infection may take place through wounds or the intestine and secondarily reach the lung. Hogs, mice, rabbits, and guinea-pigs are susceptible to inoculations; pigeons, chickens, and calves less so, and dogs and horses still less. The bacillus produces a local inflammation. If it passes from the lymphatics into the blood there occurs a marked increase of the bacilli, par- ticularly in the lung and liver (Joest: " Schweineseuche und Schweinepest." "Handb. d. path. Mikroorg.," iii., 1903). The Bacillus of Swine Pest or the American Swine Plague (hog cholera [Salmon], swine plague [Billings], sviine fever [Brown]), the Bacillus suipestifer (Bacillus cholera; suis [Smith]), forms rods with rounded ends about 1.2-1.8 /i long and 0.6 p. broad. It does not stain by Gram's method. When stained with basic aniline dyes it shows in part a polar or peripheral stain. It may easily be cultivated on the ordinary media, is a facultative aerobe, moves by means of numerous flagclla, and produces no spores. The plague is endemic in North America, and has been introduced thence into Europe. It occurs in two chief forms. The septic mnic-haimorrkagic form is characterized by haemorrhages in various organs, particularly the lymph-glands, serous membranes, intestine, and kidneys. In the intestinal form, which is more frequent, inflammatory changes are found in the intestinal tract, particularly in the colon, bearing in part the character of catarrhal or in part croupous, haemorrhagic, and diphtheritic inflammations. The infection takes place chiefly through the intestinal tract, where the most severe changes are found. Through the transportation of the bacilli through the lymph and blood changes in other organs are produced and a septicaemia or bacteriaemia. Mice, rabbits, guinea-pigs, and white doves are susceptible to inoculation; horses, sheep, and cattle are not killed by inoculation; local inflammations alone are produced. Swine pest and swine plague may occur in the same individual as a mixed infection, and may infect whole herds. Such epidemics are characterized by great virulence. Literature. Salmon and Smith.: Investigations of Infectious Animal Diseases. Ann. Rep. of the Bureau of Anim. Industry, vi. and vii., Washington, 1889 and 1890; and Hog Cholera, Washington, 1889. Joest: Schweineseuche und Schweinepest. Handb. d. path. Mikroorg., iii., Jena, 1903. Preisz: Schweinepest und Schweineseptikamie. Z. f. Tiermed., h., Jena, 1898'. Karlinski: Schweinepest und Schweineseuche. Z. f. Hyg., 28 Bd., 1898. The Bacillus of House Typhoid is a bacillus observed by Lf filer in an epidemic of mice kept in the laboratory. House mice and field mice are very susceptible to it. INFECTIOUS DISEASES OF ANIMALS. 669 It may be used as a means of extermination of field mice. (Loffler: " Epidemieen unter den im hyg. Institut. zu Greifswald gehaltenen Mausen und iiber die Bekamp- fung der Feldmauseplage," Cbl. f. Bakt., xi. u. xii., 1892.) The bacillus of chicken-cholera, or avian typhoid, or bird septicemia, a disease occurring epidemically among chickens, is a small bacillus from 1-1.2 a long, often somewhat constricted in its middle. It was first studied by Perroncito, then by Tous- saint, Pasteur, Rivolta, Marchiafava, Celli, and Kilt. It does not stain by Gram's method. The disease is characterized clinically by great exhaustion and stupor, occasionally also by diarrhceal intestinal discharges; anatomically by swellings of the liver and spleen, haemorrhages and inflammations of the intestine, and also frequently by pleuritis and pericarditis. The bacilli are found in the blood and therefore also in the capillaries of the differ- ent tissues. They may be cultivated upon nutrient gelatin, blood-serum, and neutral- ized bouillon, as well as upon potatoes. They form white colonies. Feeding or inocu- lation of the bacilli causes in chickens a typical chicken-cholera; pigeons, sparrows, pheasants, rabbits, and mice are also susceptible to the bacilli. In sheep, horses, and guinea-pigs they produce abscesses at the point of inoculation. Literature. Gamaleia: Aetiologie der Ilulmercholera. Cbl. f. Bakt., iv., 1888. Kitt: Geniigelcholera. Cbl. f. Bakt., i., 1887; Deut. Zeitschr. f. Thiermed., xiii., 1888. Pasteur: Compt. rend., xc, 1880. Wertheim: Cholera gallinarum. A. f. exp. Path., 26 Bd., 1889. Ziirn: Die Krankheiten des Hausgefliigels, Weimar, 1882. The Bacillus diphtheriae columbarum is a small, slender bacillus, which was isolated by Loffler (" Mittheil. a. d. k. Ges.-Amte," ii.) from the exudate of a pigeon dying of diphtheria, and is regarded (Babes and Puscarin, " Unters. iiber die Diphtheric der Tauben," Zeitschr. f. Hyg., viii., 1890) as the probable cause of pigeon-diphtheria, a disease resembling human diphtheria. Loffler was able to reproduce the disease in pigeons, but not in chickens, by means of inoculation of pure cultures of the bacilli. Mice died in about five days after inoculation, and the bacilli were found in the blood- vessels of all the organs. Streit (" Unters. iiber Gefiugel-Dipht.herie," Z. f. Hyg.. 40 Bd., 1904) found a bacillus in chicken diphtheria which he was able to cultivate and inoculate successfully in pigeons. As the Necrosis Bacillus (Bacillus necrophorus, Fliigge; Bacillus necroseos, Salomonsen; Streptothrix necrophora, Kitt, Streptothrix caniculw, Schmorl) there has I been described an anaerobic bacterium (Jensen : " Nekrose Bacillus." " Handb.d.pathog. Mikroorg.," ii., Jena, 1903) which forms rods and unbranched threads, does not stain according to Gram's method, and produces gas in cultures. It has been observed in all the domestic animals, including the chicken. It causes inflammations in the hoof of the horse, cattle, and reindeer, and on the tail, foot, and udder of swine and cows, and is the cause of the so-called calves' diphtheria (Loffler), rabbit diphtheria, and, perhaps, also in part of avian diphtheria. In hogs also it causes necrotic inflammation of the mouth and nose. It has been found also in inflammations of the colon in horses, and in the vagina and in the uterus of cows, and in the inflamed umbilical cord of calves. It can also produce metastases in the internal organs. It occurs in the regions named above, and also in other parts of the body, partly as a primary infection, and partly secondary to some other infection. Besides the above, there are many other bacilli which have been described as the cause of disease in animals. Thus, for example, according to Hoflich (" Die Pye- lonephritis bacillosa des Rindes," Monatsh.f. prakt. Thierheilk., ref. Centralb.f. Bakt., x.) and Enderlen (" Primare infectiose Pyelonephritis beim Rinde," Deutsch. Zeitschr. f. Thiermed., xvii., 1891, ref. Cent. f. Bakt., x.), the frequently occurring pyelonephritis of cattle is caused by a bacillus. Likewise, according to Nocard (" Note sur la maladie des bceufs de la Guadeloupe connue sous le nom de Farcin," Ann. de I'In. Past., ii., 1888) the worm disease of the ox, which was formerly of frequent occurrence in France; and according to Oreste and Armanni (" Studii e ricerche intorno al barbone dei bufali," ref. Cent. f. Bakt., ii., 1SS7) and von Ratz (" Die Barbonekrankheit," Deutsch. Zeitschr. f. Thiermed., xxii., 1896), the plague occurring among the Italian buffalo known as barbone dei bufali is due to a bacillus (by Voges regarded as the bacillus of hajmorrhagic septiccemia). In the dysentery of calves different bacilli, including the bacterium coli, have been described as the cause (Joest- " Untersuchungen uber Kalberruhr," Z. f. Tiermed.,\\\., Jena, 1903; Jensen: "Haudb. d. path. Mikroorg.," iii., Jena, 1903). According to 670 THE PATHOGENIC FISSION-FUNGI. Nocard and lioux (" Le microbe de la peripneunionie, " Ann, de I'lust. Pasteur, 1898), the lung -plague of cattle is characterized by a very small, lively motile bacillus whose form is determined with difficulty. According to Bang (" Aetiologie des seuchenhaften Ver- werfens," Zeitschr. f. Tiermed., i., 1887) and Preisz ("Bacillus des seuchenhaften Verwerfens," C. f. B., Orig., xxxiii., 1903) bacilli cause the epidemic abortion of cattle. Lundgren (" Die Renntierpest," Zeitschr. f. Tiermed., ii., 1898)and Bergman (" Renn- tierpest und Renntierpestbacillen," ft., v., 1901) on the ground of their investigations regard certain bacilli as causing reindeer plague. The contagium of reindeer pest is yet unknown (Kolle: " Rinderpest," Ergebn.d.allg. Path., vi., Wiesbaden, 1901). Likewise the cause of the hoof-and-mouth disease is still unknown (Loffler: " Bericht iiber d. Un- tersuch. d. ii. preuss. Kommission," D. med. Woch., 1903). It passes through all filters. 3. The Spirilla and the Diseases Caused by Them. («) General Remarks upon the Spirilla. % 178. The Spirilla, or Spirillaceae, or Spirobacteria are divided into two genera, one of them called Spirillum, the other Spirochete. Many writers recognize still another genus, Vibrio. The genus Spirillum is characterized by the formation of short, stiff, shallow spirals, which in part possess flagella and show an active swarm- ing movement. The wavy rods are also called vibriones by many writers. The genus Spirochaste is characterized by long, flexible, closely turned spirals. The Spirockcete plicatilis forms long, very fine, closely wound threads, from 100-225 /x long; it is of frequent occurrence in swamp-water and in gutters, and makes very rapid movements. Spirochaete buccalis sive denticola is 10-20 ,<» long, pointed at both ends, and is not infrequently observed in the secretions of the mouth and nose (cf. Fig. 19° and 30° C. ; at between 16° and 8° C. they are still capa- ^ r <. t ble of a feeble development. -> f J * ' y In fluid media in the presence of oxygen they "j|> _,. "» > show lively movements that may be easily observed in ^ < _^ ^^h the hanging drop. The movements are produced by *" v ~" N means of a terminal flageUum. fig. 513.— choiera- When gaining entrance to the intestinal tract of ture. Vw&r-ciassprep- man the spirilla, in so far as they are not destroyed n ™]j°" sta '^' 1 wi " by the action of the gastric juice or their growth otherwise prevented, develop both in the small and large intestines, and their multiplication is followed by a marked transudation from the intestinal mucosa, so that the intestine becomes tilled with a fluid re- sembling meal-soup or rice-water, in which flakes of desquamated epi- thelium which has undergone mucoid degeneration float about. The spirilla are always present in great numbers in the intestinal con- tents, and are found in the lumina of the intestinal glands, whence they may penetrate between and beneath the epithelial cells. In recent cases the spirilla, may usually be demonstrated in cover- glass preparations stained with methylene-blue or fuchsin. Fresh dejecta, as well as soiled linen, are suitable for the examination, since, according to observations made by Koch, the spirilla may multiply actively for some time upon moist linen and moist earth. In old eases the demonstration of the spirilla is more difficult, but nevertheless succeeds in all eases, and is attainable most surely by means of plate-cultures. The presence of cholera- spirilla in the intestine excites an inflammation, which in the beginning finds expression in redness, swelling, marked transudation, mucoid degeneration of the epithelium, and desquamation ; later, by haemorrhages, formation of sloughs, and ulceration. It is char- acterized constantly by a more or less marked cellular infiltration of the 672 THE PARASITIC FISSION-FUNGI. tissues. The solitary follicles and Peyer's patches are swollen even in fresh cases. Death 'may take place after a few hours or after one to three days. If the disease lasts a longer time, the intestinal contents become more consistent and the intestinal mucosa shows ulcerative changes. According to our present knowledge, the spirilla produce poisonous substances which cause local damage to the mucosa of the intestinal canal, and when absorbed give rise to symptoms of intoxication and cause paralysis of the vessels. Small foci of degeneration are often pres- ent in the liver and kidneys, within which the gland-cells show cloudy, fatty, or hyaline degeneration, or are necrotic. Moreover, the kidneys may frequently show cloudiness caused by a toxic degeneration of the epithelium ; occasionally also a swelling of the cortex. Ecchymoses in the epicardium are of frequent occurrence, and iu the later stages patches of necrosis may also occur in the mucous membrane of the vagina. The long-continued presence of spirilla iu the intestine may give rise to ulcer- ation. Finally, the spirilla may be crowded out by the putrefactive bac- teria present in the intestine, and ultimately die out. Through the absorption of the products of decomposition a new intoxication may arise, which is not dependent upon the original spirilla. According to Koch, Mcati, and Eietsch, cholera-spirilla may also be found in the vomitus. Mcati, Eietsch, Tizzoni, andCattani found them also in the ductus choledochus and in the gall-bladder. According to the statements of these authors the spirilla usually do not enter the blood, but in cases of severe infection they may be spread throughout the body. Koch demonstrated the presence of spirilla in a tank in India which furnished the inhabitants of the regi6n with their entire supply of water for drinking and other purposes, at a time when a part of the inhabi- tants were sick and dying of cholera. Since then, they have often been demonstrated in water-supplies during cholera epidemics. Asiatic cholera is endemic iu Lower Bengal and never entirely disap- pears there. Thence it spreads at times throughout India, and is carried by transportation over a larger or smaller part of the world. Since the spirilla are easily killed outside of the body the transportation must be effected mainly by individuals suffering from the disease. The infection probably occurs exclusively through the alimentary tract, as the re- sult of the introduction of infected beverages, food, or some other sub- stance into the mouth ; but without doubt not every introduction of cholera-spirilla into the intestinal canal is followed by infection. Moreover, it not infrequently happens that the spirilla increase in the intestine, but excite only slight changes, so that the infected individual suffers no marked symptoms, and the diagnosis can only be made through the demonstration of spirilla iu the stools. If the cholera-spirilla get into the water-supply and there increase, cholera may develop in the given region with very great rapidity. If on the contrary, the infection takes place by direct or indirect contagion from man to man, the spread is slow, in that the disease is confined to those who come into contact with the sick, or with articles contaminated by the latter. The incubation period is from one to two days. In the intestines of convalescents the spirilla, according to investiga- tions of Kolle, may live, for a long time and multiply without giving ii Se to any symptoms betraying their presence. Kolle was able to demon- CHOLERA. 073 strate them in a number of cases after five to eighteen days, and in indi- vidual cases as long as twenty to forty-eight days. One attack of cholera makes the individual immune for a certain time. The immunity depends upon the presence of bactericidal anti- bodies. Through these bodies the organism may be protected from cholera ; but in those who have already contracted the disease the protec- tive influence is of no avail (cf. § 32). On gelatin-plates cultures of cholera-spirilla form round, flat, yellowish discs which liquefy the gelatin Only slowly. At a low magnification the cultures are ir- regular in outline, and of a granular or furrowed and rough surface, appearing as if strewn with small particles of glass (Koch). Through the liquefaction of the gelatin in its immediate neighborhood there is formed a funnel-shaped cavity, to the bottom of which the colony sinks. Stab-cultures in gelatin form on the second day a whitish cord corresponding to the line of the stab (Fig. 514), in the immediate neighborhood of which the gelatin is liquefied. The canal thus formed widens out above into a funnel part which is filled in its lower portion with liquefied gelatin and .-*. _ -» in its upper with air. The widening of the funnel of the canal of k inoculation takes place very slowly, so that its edge reaches the -i^ r . wall of the tube only after five to six days. ;uM& On potatoes at from 30°-35° C. the spirilla form light-brown |W cultures, on agar-agar grayish-yellow slimy cultures. They grow ^Sv also in bouillon, blood-serum, and milk. They do not increase in pure water (Bolton), but do so in water contaminated with substances furnishing nutrient material. The cholera-spirilla are aerobic, but they are also able to grow under anaerobic conditions. According to investigations by Hueppe, cultivation with a deficient supply of oxygen increases the virulence of the culture; but the resisting power against injurious agents — for example, against acids — is on the other hand lowered; with free access of oxygen the reverse takes place. Pfeiffer, how- ever, found that young cultures grown in the presence of oxygen also contained poison. The spirilla present in fresh dejections (Hueppe) are easily killed, and have but little infecting power; whereas the growth of the spirilla outside of the body increases their resistance (for example, against the gastric juice) and makes them at the same time more capable of causing infection in new individuals. They are easily destroyed by desiccation in free air (Guyon) and by high temperatures, and by boiling for a short time. They are easily supplanted by saprophytic bacteria when the nutrient material and the temperature are not suitable. In the contents of privy-vaults they soon die out (Koch). They are very easily killed by acids, mercuric chloride, and carbolic acid. According to observations by Koch, they may live in well water for thirty days, in sewage for seven days, and on damp linen for three -■ to four days. Nicati and Reitsch found them alive after eighty-one ' ' days in water taken from the harbor of Marseilles. In cultures they sometimes form short rods, more or less curved (Fig. 513) and often joined in pairs; at other times they form long spirals. With these there also occur straight rods, and oc- casionally the majority form rods which show the curve only im- perfectly or not at all. At a certain degree of exhaustion of the food-material there frequently appear involution forms, in which the rods are some- times shrunken, sometimes swollen, thus creating a great variety of forms. A globular swelling, as well as the formation of spots which do not take the stain in stained preparations, occurs as the result of degeneration, and have often been erroneously interpreted as phenomena of fructification. Spore formation has not been de- monstrated. The addition of hydrochloric or sulphuric acid to cultures of cholera-spirilla in peptone-containing media (peptone- meat-infusion or an alkaline, one-per-cent solution of peptone containing one per cent of salt) causes the culture to assume a rose-red or Burgundy-red color, due to the 43 v; : !#pl ■'::: FlG.514.-Stab-cul- turp, in KHatin, of cholera-spirilla. 1'.i. — Section through a thrush-covered oesophagus uf a small child (alcohol, carmine, Gram's). a, Connective tissue ; b, normal epithelium ; c, swollen and desquamated epithelium intlltrated with fun- gus-threads ; d., 1891. Pusch: Fa lenpilze bei Thierkrankheiten. Ergebn. d. allg. Path., iv., 1899. Benon: Rech. clin. ct exp. sur la pseudotuberculose aspergillaire, Paris, 1893; Etude sur l'asoergillose chez les animaux et chez 1'homme, Paris, 1897 (Lit.). Ribbert: Der Untergang pathogener Schimmelpilze im Korper, Bonn, 1887; TJebcr wieierholte Infection mit pathogenen Schimmelpilzen. Deut. med. Woch., 1888. Roeckl: Ueber Pneumonomykosen. Deut. Zeitschr. f. Thiermed. x. 1884. Rothwell: Experiment d Aspergillus. Jour, of Path., vii., 1900. Saxer: Pneu nonomykosis aspergillina, Jena, 1900. Schenck: Subcutaneous Abscess Caused by a Fvingus. J. Hopkins Hosp. Bull., 1898. Schutz Da? Eindringen von Pilzsporen in d. Athmungswege u. die dad. bedingten Erkrankungen d. Lunge, Pilz d. Huhngrindes. Mittheil. a. d.K Ges-Amte Ber- lin, 1884. Siebenmann: Die FadenoiLe Aspergillus flavus, ni":er u. fumigatus, Eurotium renens u. Aspe'g : llus glaucus, Wiesbaden, 1883; Die Schimmelmykosen d. Ohres Wies- baden, 1889. FAVTJS. 686 (Thrush.) Bohn: Soor. Gerhardt's Handb. d. Kinderkrankh., iv. Cad: Oidien u. Oidiomykose. Zeitschr. f. Hyg., 34 Bd., 1900 (Lit.). Fischer u. Brebeck: Zur Morph. u. Syst. d. Kahmpilze. Monilia Candida u. d Soorerreger, Jena, 1894. Gra-witz: Parasit des Soors. Virch. Arch., 103 Bd., 1S86. Heller: Zur Lehre v. Soor. Deut. Arch. f. klin. Med., .5.5 Bd., 1895. Heubner: Soor-Allgemeininfektion. D. mcd. Woch., 1903. v. Hibler: Pyamie mit Soorinfektion. Cbl. f. B., Orig., xxxvi., 1904. Kehrer: Der Soorpilz, Heidelberg, 1883. JLinossier et Koux: Champignon du muguet. Arch, de med. exp., 1890. Plaut: Syst. Stellung d. Soorpilzes, Leipzig, 1S85; Neue Unters. z. syst. Stellung d. Soorpilzes, Leipzig, 18S7; Hyphenpilze. Handb. d. path. Mikroorg., i., 1903. Bees: Soorpilz. Sitzungsber. d. phys.-med. Soz. zu Erlangen, 1877, 1878. Schmidt, M. B.: Die Localisation d. Soorpilzes in den Luftwegen u. sein Eindringen in das Bindegewebe der Oesophagusschleimhaut. Beit. v. Ziegler, viii., 1890. Schmorl: Ein Fall von Soormetastase in der Niere. Cbl. f. Bakt., vii., 1890. Soltmann: Soor. Eulenburg's Realencyklop., xxii., 1S99. Steiner: Zur Pathogenese d. Soorpilzes. Cbl. f. Bakt., xxi., 1897. Teissier: Champignon du muguet. Arch, de med. exp., ix., 1897. Zenker: Hirnabscess. Jahresber. d. Ges. f. Natur- u. Heilk. in Dresden, 1S61-62. §182. Thread=fungi are to be .regarded as the exciting cause of disease in certain affections of the skin, as favus, herpes tonsurans, pityriasis versicolor, erythrasma. In all of these diseases the epithelial parts of the skin contain colonies of hyphse and conidia, and there re- mains no doubt that their presence causes in part tissue-degenerations, and in part proliferations and inflammations. The fungus of favus (Fig. 517) is usually called Achorion Schonleini (discovered by Schonlein in 1839). Favus (tinea favosa, scald-head) affects particularly the hairy portions of the head, more rarely other regions, as, for example, the substance of the nails. It is characterized by the formation of discs (favus scutula), varying in size from that of a lentil to that of a five-cent piece, of a sul- phur-yellow color, and indented or pierced by a hair. In au abortive course it may merely form scales similar to those of herpes. According to Kaposi, the favus scutulum originates as a small, punc- tiform, yellow focus lying under the epidermis and penetrated by a hair. This grows in a few weeks to the size of a lentil and then forms a sul- phur-yellow, indented disc showing through the upper layers of the skin. The scutulum consists of hyphas and conidia spores, and lies in a cup-shaped depression of the skin, beneath the horny layer which is drawn away above it. If the mass be removed during life, the cavity shows a red moist surface. The favus itself forms a white, crumbling mass which is easily disintegrated in water. If the scutula are not removed, they join together to form larger masses. When the epidermis is descpiamated the favus-mass becomes exposed and dries up into a yellowish-white, mortar-like material. The hairs appear lustreless, as if covered with dust, and are easily pulled out, since the mycelia and conidia of the fungus penetrate into the hair- shaft and hair-bulb, as well as into the sheath of the hair-root. Through the growth of the fungus-masses the hairs may not only be shed, but the papillae may become atrophic. At the same time there is produced in the neighborhood of the hair-follicle a more or less intense inflammation which may take on an eczematous character. The development of achorion in the nails (onychomycosis favosa) gives rise to sulphur-yellow deposits or uniform thickenings of the parenchyma of the nails with simultaneous loosening and cheesy disintegration of the same. Trichophyton tonsurans, the funeusof herpes tonsurans ("barber's 686 THE PATHOGENIC YEASTS AND MOULDS. itch," "ringworm"), consists of long narrow threads, branching but little, and with few conidia. It forms no scutulous masses, but penetrates easily into the hair-shaft, and makes the hairs brittle. It shows certain differ- ences of growth, according to whether the herpes develops upon hairy surfaces or upon areas devoid of hairs. Herpes or Trichophytosis tonsurans capillitii forms bare discs varying in size from that of a five-cent piece to that of a dollar. These spots in which the hairs are broken off short look like places in which the hair has been badly shaven. The surface is smooth or covered with scales, and somewhat reddened at the border of the disc. If the fungus-threads penetrate into the hair-follicles, pustules and scabs are formed. Such discs may appear in many places, and may constantly increase in size until healing tin ally takes place. On places devoid of hairs the herpes forms vesicles (Herpes tonsurans vesiculosus), and red scaly spots, discs, and circles (Herpes tonsurans squa- mosus). At times red spots appear in numerous places; these quickly spread, and as rapidly heal. The fungus is found between the upper- most layers of the epidermis, just beneath the stratum corneum (Kaposi). If trichophyton develops in the nail, the nail becomes cloudy, scales off, and is easily broken — a condition designated as onychomycosis tricho- phytina. Sycosis parasitaria arises through the fact that the development of the fungus is accompanied by a severe inflammation of the hairy parts of the skin, leading to infiltration and suppuration — that is, to the forma- tion of pustules, abscesses, and papillary proliferations. According to Kaposi and others eczema marginatum is also caused by the trichophy- ton tonsurans. The condition occurs in those regions where two surfaces of skin come into contact with each other and are macerated by sweat ; and is characterized by the formation of vesicles, pustules, and scabs, which are situated in the periphery of a pigmented surface. Microsporon furfur, the fungus of pityriasis or mycosis versicolor or dermatomycosis furfuracea, occurs likewise in the form of hyphte and conidia, which are somewhat smaller than those of other skin-fungi. The pathological changes produced by this fungus are characterized by the formation of pale yellow or yellowish-brown to dark-brown and brownish-red spots, varying in size from that of a lentil to that of the baud, sometimes smooth and shining, at other times dull and exfoliating, and of irregular shape. They may be spread uniformly over large areas of skin; and are found chiefly upon the trunk, neck, and flexor surfaces of the extremities, but never upon the hands, feet, or face. Microsporon minutissium is the name given to a thread-fungus, which is found in the skin affection known as erythrasma (von Baren- sprung). The disease is characterized by the formation, on the inner side of the thigh, of brown or reddish-brown patches, which are only slightly scaly, and may be as large as the palm of the hand. The fungus is found in the epidermis, and is smaller than that of pityriasis. The thread-fungi occurring in the diseased areas of the skin may be cultivated upon proper media (agar-agar, agar-gylcerin, gelatin, pota- toes, blood-serum, etc.), and on such the conidia develop into single and branching threads, which become jointed (Fig. 522, a), and form chains of short cells (b). Club-like formations which frequently ap- pear upon the ends of the threads in cultures, are regarded by Quincke and Blsenberg as imperfect sporangia. The botanical posi- tion of these fungi is not yet determined ; and nothing is known with TRICHOPHYTON. 687 certainty concerning their distribution outside of the human and animal body. According to Quincke, three forms of fungi occur in favus-masses, two of these being varieties of one species of fungus. Elsenberg found only two, which he regards as being varieties of the same species. Pick, Plaut, and Biro believe firmly in the etiological unity of favus. Sabouraud advances the view that the fungi causing trichophytosis represent very different species, all of which belong to the genus Botrytis. Krosing distinguishes three groups of trichophyton-fungi according to the different appearances of the cultures on potato, and emphasizes, moreover, the differences in their organs of generation and fructification. Rosenbach, who has studied the moulds occurring in deep suppurating inflammations of the skin, differentiates several trichophyton-fungi as the cause of these affections. According to Spietschka, the Micro- sporon furfur may be cultivated from the scales of the skin, and in cultures can be very well differentiated from the other pathogenic thread-fungi. Through the inoculation of the fungus a typical mycosis may be produced in man. From the great number of recent investigations by various writers it is impossible to deduce anything definite concerning the number of kinds of favus- and trichophyton-fungi. It is, however, evident from these investigations that the nature of the nutrient medium is of great influence on the character of the growth (Sabouraud, Waelsck), and tho difference in findings is to be referred in a great measure to differences in the nutrient media on which the moulds were grown. Inoculations with fungi grown in cultures, into the skin of human beings, rabbits, mice, etc., which were made by Grawitz, Boer, Munnich, and others, gave partly negative, partly positive results. Ac- cording to Plaut, the inoculations never give positive results when spore-formation has already taken place in the cultures. Von Hebra has described (Wiener med. Blatter, 1881: " Die krankh. Yerand. d. Haut," Braunschweig, 1881) as dermatomycosis diffusa flexorum a peculiar itching der- matosis, which occurs on the elbow and bend of the knee and is thought to be caused by fungi, which are like those of pityriasis versicolor. According to the investigations by Wehmer, the cause of the skin eruption known as tokelan which occurs in various South Sea Islands (Fiji, Samoa, and Solomon) and which is characterized by the formation of scaly rings, is an Aspergillus. Favus and herpes tonsurans occur also in domestic animals, as well as in mice and rats (cf. Friedebergcr and Friihner, " Lehr. d. spec. Pathologie der Hausthiere "). Waelsch inoculated human individuals with favus fungi, which he had cultivated from mice affected with favus, and obtained typical favus scutularis. Intravenous injections of favus-fungi into rabbits (Bukovsky) produced in the lungs of these animals a form of pseudotuberculosis; and cellular nodules are found in which fungus threads have developed in a manner suggesting the lesions of actinomy- cosis. After a time the fungi die. In invertebrate animals there not infrequently occur diseases produced by my- celium-fungi. Thus Botrytis Bassiani causes the so-called muscardine in silkworms; Cordyceps militaris destroys the injurious pine-spider Gastropachia pini; Tarichium megaspermum, a black-colored fungus, kills the destructive earth-caterpillar Agrotis segetum. Fungi belonging to the genus Empusa attack especially the caterpillars of the cabbage-butterfly (Empusa radicans), and the house-fly (Empusa muscw), their mycelia growing all through the caterpillar and finally killing it. Achyla prolifera, according to Harz (Jahresber. d. Munchener Thierarzneischule, 1882-83), grows through the mus- culature of crayfish, and is the cause of the crayfish-pest. Fig. 522.— Culture of Trichophyton tonsurans, a. Branching threads with long joints which have deli- cate walls; h, threads with thick-walled, short seg- ments, some of tbem being spherical. X 270. 688 THE PATHOGENIC YEASTS AND MOULDS. Literature. {The Fungi of the Dermatomycoses.) Adamson: Parasites of Ringworm. Jour, of Dermatol., vii., 1S95. Biro: Unters. iiber d. Favuspilz. Arch. f. Derm., 1893. Boer: Biologie des Favus. Vierteljahrsschr. f. Derm. u. Syph., xiv., 1887. Bonome: Tricofitiasi dermica a forma pemfigoide et polineurite tricofitica inmdividuo affetto da tabe dorsale. Arch, per Ie Sc. Med., xvi., 1892. Bukowsky: Eigenschaften d. Achorion Schonleini. Arch. f. Derm., 51 Bd., 1900. Campana: Trichophytiasis dermica. Arch. f. Derm. u. Syph., 1889. v. During: Dermatomykosen. Eulenburg's Jahr., 1896 (Lit.). Elsenberg: Ueber den Favuspilz bei Favus herpeticus. Arch. f. Derm., 1889, 1890. Fabry: Ueber Favus. Arch. f. Derm., 1890; Onychomykosis favosa. Arch. f. Derm., 1890. Fox and Blaxall: Plurality of Ringworm Fungi. Trans, of the Path. Soc. of London, xlviii., 1897. Grawitz: Soor, Favus u. Herpes tonsurans. Virch. Arch., 108 Bd., 1886. _ Krai: Polymorphismus pathogener Hyphomyceten. Arch. f. Derm., xxvii., 1894. Krbsing-: Trichophytonpilze. Arch. f. Derm., 35 Bd., 1896. Matzenauer : Bakteriologie d. Pityriasis versicolor. A. f. Derm., 56 Bd., 1901. Mazza: Trichophytonkulturen. Arch. f. Derm., xxiii., 1891. Muller: Favus u. Herpes tons. Correspbl. f. Schweizer Aerzte, 1S97. Neebe u. Unna: Die bisher bekannten neuen Favusarten. Cbl. f. Bakt., xiii., 1893. Pick: Favus. Zeitschr. f. Heilk., xii., 1891; Stand d. Dermatomykosenlehre. Arch. f. Derm., xxix. Cbl. f. Bakt., xvii., 1895; Favusfrage. Arch. f. Derm., xxxi., 1896. Pick u. Krai: Unters. iiber den Favus. Arch. f. Derm., 1891, Erganzungsheft. Plato u. Guth: Waclistum v. Triehophytonpilzen. Z. f. Hyg., 38 Bd., 1901. Plaut: Beitrag zur Favusfrage. Cbl. f. Bakt., xi., 1892; Ziichtung d. Trichophyton. lb., xxxi., Orig., 1902. Quincke: Ueber Favuspilze. Arch. f. exper. Path., xxii., 1SS6; Monatsh. f. prakt. Derm., vi., 1SS7, vhi., 1889; Arch. f. Derm., 31 Bd., 1895. Roberts. The Physiology of the Trichophyton. Jour, of Path., iii., 1895. Kosenbach: Ueber die tieferen eiternden Schimmelerkrankungen d. Haut, Wiesbaden, 1894. Sabouraud. Trichophytie. Ann. de Derm., 1892; Trichophyties a dermite profonde. Ann. de l'lnst. Pasteur, vii., 1893; Mycose innominee de l'homme. lb., vhi., 1894. Spiegler. Ekzema marginatum. Arch. f. Derm., 38 Bd., 1897. Spietschka: Microsporon furfur. Arch. f. Derm., 37 Bd., 1896. Unna: Drei Favusarten. Fortschr. d. Med., x., 1892. Waelsch: Anatomie dcs Favus. Arch. f. Derm., 31 Bd., 1895; Anatomie d. Tricho- phytosis, lb., 35 Bd., 1896; Mannigfaltigkeit d. Wachsthums d. pathog. Schim- melpilze. lb., 37 Bd., 1896; Anatomie d. Pityriasis versicolor. lb., 38 Bd., 1897; Favus bei Thieren u. dessert Bezieh. z. Favus d. Menschen. Prag. med. Woch., 1 898. Wehmer. Der Aspergillus der Tokelau. Cbl. f. Bakt., Orig., xxxv., 1904. CHAPTER XII. The Animal Parasites and the Diseases Produced by Them. I. Protozoa. Fig. 523. — Amwba coll nritis. Uoos.) a, Free motile amoeba* cystec! amcebas. X 590. (Alte Z>, en § 183. Of the Protozoa occurring as parasites in man, only a small number was known up to a few years ago ; and even the known forms possessed but slight significance, since there could be ascribed to them no marked influence upon the tissues. Through the investigations of the last few years, however, different forms have been recognized as the cause of morbid proc- esses; and it is quite possible that there are still other protozoa capable of exciting pathological changes in the human body. The forms already recognized are repre- sentatives of all four classes of protozoa. Of the Rhizopoda there occur in the in- testine three amoebae, known as the Amoeba coli vulgaris, the Amoeba coli mitts, and the Amoeba dysenteric?. The Amoeba dysenteric is certainly distinguishable from the other two, while the Amoeba coli vulgaris and the Amoeba coli mitis resemble each other very closely, and may possibly be identical. The Amoeba coli vulgaris is a harmless intestinal parasite which is not infrequently present in the intestine (Eoos, Kruse, Pasquale). The Amoeba coli mitis was observed by Eoos and Quincke in cases of chronic enteritis in patients who had always lived in North Germany. The Amoeba coli mitis consists, according to Eoos, of a protoplasmic cell-body, from 28-30 . mfi m^mhm ^ M Fig 530 -Portion of tissue and isolated cells from a splenic follicle with partial necrosis, in relapsing fever '(After f+ikiforoff. ) (Potassium bichromate and sublimate, inethylene-blue.) a, Free spirilla; h, lymphocytes with spirilla; c, non-nucleated lymphocytes; t/, large, e. small mononuclear pulp-cells; t, phagocytes enclosing leucocytes and red blood-cells and their remains; y, free red blood-eel, s. X about b(Ki. 694 THE ANIMAL PARASITES. numerous spirilla are found, especially in regions which are not wholly necrosed but contain degenerated and necrotic cells, in part free (a), and in part enclosed in leucocytes (b), partly well-preserved, and partly be- ginning to show disintegration. According to Karlinski and Schaudinn, the infection is probably transmitted by bed-bugs. Spirochetes have been observed also in birds, owls (Schaudinn), geese (Sacharoff, Gabritschewsky), and fowls (Marchaux, Salimbeni, Levaditi), and may cause epidemics in which great numbers of animals perish. The life-history of the Spirochetes classed with the bacteria was not known until recently. Through the investigations of Laveran and Schaudinn it was for the first time determined that in their life-cycle there occurs an alternation of generation and of host. Schaudinn carried out his studies on the spirochetes found in the small owl (Athene noctua), which he named Spirocha?ta ziemanni (called by Larcran the II wmamwba ziemanni). As a result of his investigations he believed that he had demonstrated the transmission of this spirochete from the owl into the mosquito, Culex pipiens, in the intestine of which it passed certain stages of development, as described in the following paragraphs. Within the owl there develop male and female individuals, the microgametocytes and the macrogametes. Copulation takes place in the intestine of the mosquito. From the fertilized macrogamete there develops an ookinete which produces in the intestine of the mosquito an enormous number of trypanosome-like offspring. These become transformed into true spirochsetes, spread throughout the body of the mosquito, increase by longitudinal division, and wander into the oesophagus, whence, in the act of biting, they again pass into the blood of the owl. After an asexual period of multiplication in the form of spirochetes they again form gametes or sexual individuals in the blood of the owl. As the result of their distribution throughout the body of the mosquito the spirochetes may pass into the ovaries of the latter and thereby be transmitted to the next generation. The fertilization in the intestine of the mosquito follows a ripening of the macro- gametes (female cells) and the formation of microgametes (spermatozoa) from the microgametocytes. The ookinete resulting from the fertilization of a macrogamete is a worm-like body rolled up into a complicated skein. Through the grouping of the protoplasmic masses around the individual nuclei there are formed small trypanosome- like individuals having a characteristic flagellum-apparatus. Further, there may be developed both male and female individuals. The female forms are larger than the indifferent forms, their plasma is dark, the nucleus and blepharoplast relatively small, and the margin of the undulating membrane is not continued to form a fiagellum. The males are very small and scarcely recognizable. Through continued division the indifferent spirochetes in the intestine of the mosquito also become very small, so that single individuals can barely be made out. Within the blood of the owl the spirochetes become parasites of the hemoglobin- containing erythroblasts, in that they attach themselves to these by their posterior extremities. This is seen particularly in the bone-marrow and also in the spleen. After a certain time they form in the blood macrogametes and microgametes, which, on gaining entrance into the mosquito, again form new generations in the manner described. The macrogametes can also produce new generations in the blood without fertilization (par- thenogenesis) and thereby cause relapses. The above-given life-cycle of the spirochetes according to Schaudinn falls to the ground in the light of Novy's studies. The latter has shown that the Spirochete ziemanni is not a spirochete, but a trypanosome, and has no connection with the intracellular parasites of the owl's blood. Further, Novy regards Sp. obcrmeieri as belonging to the bacteria, basing his view upon his inability to demonstrate in the organism°a nucleus, blepharoplast, undulating membrane, or fiagellum of the protozoan type. On the other hand the spirilla of relapsing fever possess whips having all the characteristics of those of bacteria, divide transversely, multiply rapidly, resist changes in osmotic tension, .show a greater resistance to heat than do the trypanosomes, excite the production of imimine and germicidal bodies, and do not exhibit the aerotropism shown by trypan- osomes. In relapsing fever we have most probably to deal with a group of closely related organ- isms {Novy), which, while they may in one sense lie regarded as distinct species are derived from one stem. Five distinct strains of spirilla causing relapsing fever have been discovered: Spir. obermcirri. Spir. noryi. Spir. koclii. Spir. duttoni, and/SmV carteri These differ from each other in (lie duration and severity of the initial attack, the fre- FLAGELLATA. 695 quency and intensity of relapses, and in the mortality following an injection of a uniform dose of 0.25 c.c. of spirillar blood. The relapse is probably due to the survival of a few- individuals that are more or less immune, so that a serum-fast strain develops. This in turn calls out a new antibody. If this is less active or more unstable, or more readily eliminated, the relapses will continue. If Schaudinn's views on the protozoan nature of the organism found in syphilis (Spir. pallida, Treponema pallidum) are correct, that organism should then be classed here with the protozoa. At the present time this question cannot be regarded as settled, but it is most probable that the organism is of bacterial nature and should be classed, along with the spirocha?tes of relapsing fever, with the spiral forms of bacteria (spirilla). (See Syphilis.) Literature. (Bpirochcetes. ) Cantacuzina: Spirilloses des oies. Ann. de ITnst. Pasteur, 1899. Gabritschewsky: Zur Pathol, d. Spirochaeteninfection. Cbl. f. Bakt., xxvi., 1899, u. xxvii., 1900. Heydenreich: Der Parasit des Riickfalltyphus, Berlin, 1877. Honl: Febris recurrens. Ergebn. d. allg. Path., iii., 1897. Karlinski: Aetiol. des Gefliigeltyphus. Cbl. f. Bakt., Orig., xxxi., 1902. Iievaditi: Spirillose des poules. Ann. de l'Inst. Pasteur, 1904. IiUbimoff: Patholog.-anat. Veranderungen bei Typhus biliosus. Virch. Arch., 98 Bd., 1884. Marchoux et Salimbeni: Spirillose des poules. Ann. de l'Inst. Pasteur, 1903. MetschnikofF: Ueb. den Phagocytenkampf bei Rtickfalltyphus. Virch. Arch., 109 Bd., 1887. Nikiforoff; Zur path. Anat. u. Histol. d. Milz bei Recurrens. Beitr. v. Ziegler, xii., 1892. Novy: Studies on Spirillum Obermeieri and Related Organisms. Jour, of Infect. Dis., 1906. Obermeier: Cbl. f. d. med. Wiss., 1873; Berl. klin. Woch., 1873, No. 33. Ponfick: Anat. Studien ilber den Typhus recurrens. Virch. Arch., 60 Bd., 1874. Puschkareff: Zur pathol. Anatomie der Febris recurrens. Virch. Arch., 118 Bd., 1888. Sehaudinn: Generations- u. Wirtswechsel bei Trypanosomen u. Spirochaten, Berlin, 1904. Sudakewitscb: Reel), sur la fievre recurrente. Ann. de l'Inst. Pasteur, v., 1891. Wladimiroff: Riickfallneber. Handb. d. pathog. Mikroorg., iii., Jena, 1903 (Lit.). § 186. The genus Trypanosoma forms a second class of blood-para- sites belonging to the Flagellata, found, in man, mammals, and birds, and also in cold-blooded animals. Most authors place all the parasites of this class in the genus trypanosoma and distinguish different species. Doflein divides them according to the character of the flagella into three sub-genera: Trypanosoma, Trypanomonas, and Herpetosoma. Von Wasie- lewski classes only the blood-parasites of the frogs and fish with the try- panosomes, aud would apply the name Herpetomonas, given by Kent, to the trypanosomes found in mammals. Trypanosoma lewisi, Kent (Herpetomonas, Trypanomonas, Trichomo- nas, Hwmatomonas) is a very common parasite of rats. It is 8-30 //. long and 3-8 ft broad (Fig. 531), consists of a nucleated granular entoplasm and a delicate hyaline ectoplasm or periplastem, the latter forming an undulating membrane (Fig. 532, c) and a flagelluni ( A, Fully developed parasite with nucleus (a), rod-shaped oody (/>). undulating mem- brane (c), and flagellum (d) ; B, parasite with two nuclei and one rod-shaped body ; C, parasite with one nucleus and two rod-shaped bodies ; D. division into two parasites; E, parasite with four nuclei and four tlacella; F, daughter-individuals still united into a colony. X 1,500. a division of the nucleus by them designated as the chromatin framework, while new nucleoli are snared off from the chromatin mass. According to von Wasielewski the chief nucleus (B) sometimes first divides, at another time the rod-shaped root of the flagellum or the blepharoplast (C) ; and the cells sometimes divide with two nuclei (D), and sometimes TRYPANOSOMES. 697 after the formation of several nuclei and flagellum-roots (E, F), so that the resulting- dividing flagellates remain for some time united into colo- nies. The natural infection of rats occurs probably through the medium of fleas and lice. Trypanosoma brucei, Plimmer and Bradford, is very similar to Tr. lewisi, only the body is somewhat broader and the posterior end somewhat blunter. It is the cause of Nagana or the tsetse=fly disease of cattle, horses, antelopes, buffalo, donkeys, dogs, sheep, and goats occurring in Southern and Southeastern Africa, which is transmitted through the tsetse-fly (Glossinu morsitans). The number of parasites in the blood may be very great ; the infected animals suffer from fever and become anaemic ; • edema develops in different parts of their bodies; further, there is also a conjunctivitis and the spleen is greatly swollen. The period of incu- bation is not more than nine days. The infected animals die after one and one-half to eight months. It is also probable that the disease known as Surra,.occurring endemi- cally in horses, mules, camels, buffalo, cattle, and elephants in Dutch India, Indochina, and the Philippines, and which is transmitted by gad- flies, is due to this trypanosome. It is likewise regarded as the cause of the trypanosome disease of horses and donkeys known as the coitus-dis- ease or dourine occurring in Algiers, Southern France, Sumatra, Novarra, and the Pyrenees, and which is spread by coitus, and is inoculable into rabbits, rats, and dogs. Many authors regard the parasites found in these diseases as representing different species, giving to the first the name of Trypanosoma evansi and to the latter that of Tr. equiperdum. A variety of trypanosome found in Central South America and which causes the disease of horses known as mal de eaderas is designated Tr. equinum. It is assumed that Stomoxys calcitrans acts as the agent of transmission of the parasite. A variety of trypanosonie known as Tr. theileri is found in cattle in South Africa and is inoculable only into this animal. The occurrence of trypanosomes in man was first observed by Kep- veu (1898). The investigations of recent years (Dutton, Todd, Boyce, Boss, Sherrington, Bruce, Castellani, Manson, Daniels, Laveran, etc.) have shown that trypanosome diseases occur also in man. The sleeping- sickness of the negro is now known to be due to a trypanosome infection. Castellani found the parasite in the cerebrospinal fluid of cases of sleep- ing-sickness, and his findings have since been confirmed by different observers. The disease occurs throughout tropical West Africa, and in recent years has spread throughout Central and Eastern Africa. Negroes are chiefly affected, but cases have also been observed in Europeans. The infection is transmitted by a biting-fly ( Glossina palpalis). The para- sites develop first in the blood, and during this period symptoms may be entirely wanting, or there may be attacks of fever. When the parasites gain access to the cerebrospinal fluid and there increase, cerebral symp- toms, particularly coma, are produced as the result of a meningitis. The disease runs a chronic course and is invariably fatal. Trypanosomes are found also in the disease known as Gamba-fever which occurs in Senegambia and the Congo, both in the natives and Europeans. According to Laveran, it is due to the same species of try- panosomes observed by Castellani in Uganda. Further, trypanosomes are believed to be the cause of the chronic disease known as tropical splenomegaly, which occurs in India, China, Arabia, Egypt, and Tunis, and is characterized bv intermittent or remittent attacks of fever associ- 698 THE ANIMAL PARASITES. ated with a marked swelling of the spleen, leading after many months' duration to a progressive anaemia and cachexia having a fatal termina- tion, and therefore distinguished from the ordinary malarial fevers by the designation of cachectic fever. It is very probable that the disease known as K&la-azdr (black fever), which is' widely distributed through the valley of Assam watered by the Brahmaputra, and is often character- ized by dark discoloration of the skin, is related lo tropical splenomegaly. The life-history of the trypanosomes is similar to that of the spirochaetes. According to investigations by Schaudinn the Halteridia (Hosmoproteus noctuce of Celli and San Felice) of the little owl are the sexual stages of a trypanosome which multiplies in the common mosquito, Culex pipiens, so that after a complicated wandering through the body of the mosquito, through its bite again reaches the blood of the owl, in which after a period of asexual increase it changes into the familiar male and female Halteridia. The parasite must, therefore, be called the Trypanosoma noctuoe. (Whether other members of the genus Halteridium or Hcemoproteus are to be classed with the trypano- somes remains to be settled.) According to Novy (Jour, of Infect. Dis., 1905) the observations of Schaudinn are open to an entirely different interpretation. He believes that the Trypanosoma noctuce and the Spirochceta ziemanni of Schaudinn probably represent, trypanosomes that have multiplied in the mosquito and are not to be con- sidered as stages in the life-history of cytozoa. According to Novy's investigations trypanosome infection of birds is very widespread. With the trypanosomes there may be associated intracellular parasites, but no constancy can be shown to exist between a given trypanosome and a given cytozoon. The life-cycle of the trypanosomes and halteridia according to Schaudinn, as given in the following paragraphs, cannot, there- fore, be accepted without question in the light of Novy's work. If the male and female halteridia-stages enter with the blood of the owl into the intestine of the mosquito, the first forms the microgametocytes and microgametes, each of which penetrates into one of the pigment-containing macrogametes. As the result of this fertilization the latter become changed into ookinetes. Through a complicated metamorphosis proceeding from the nucleus the ookinete can become transformed into an indifferent trypanosome. The karysome passing out from the nucleus, and which has the significance of a nucleus, moves to the right lateral border of the ookinete and forms there the blepharoplast of the trypanosome, that is, the structure which forms the undulating membrane and the flagella. The trypanosome thus formed can increase by longitudinal division. The ookinetes can also form female trypanosomes which are plumper and show a more marked granulation than the non-sexual forms. The female trypanosomes repre- sent permanent forms, and can produce new generations in the mosquito through par- thenogenesis. Finally, the ookinete can also be transformed into a male trypanosome which is smaller and clearer than the female. Through heterotopous mitosis there may be formed in both the female and male trypanosome a small nucleus near the large one, and this may increase until as many as eight are formed. While in the female these are destroyed and only the chief nucleus is preserved, each of the eight nuclei develops in the male into a blepharoplast from which a minute male trypanosome arises. The development of the microgametes in the blood of the owl takes place in the same manner as the formation of the male trypanosomes in the intestine of the mosquito, and they have the same structure as the latter. The indifferent trypanosomes passing from the mosquito into the blood of the owl are usually very small. They fasten them- selves by their flagellated anterior end to the red blood-corpuscles; the flagellum ap- paratus then degenerates and the parasite takes on the appearance of a sickle-shaped, bean- or worm-shaped halteridium. When it has about doubled its size, it leaves its host and again develops a flagcllum-apparatus, becoming changed again into a. trypano- some. This is repeated several times until a certain size is attained; there then follows a multiplication through longitudinal division, the products of the division again seeking red blood-cells. The fully formed female trypanosomes, the macrogametes in the owl's blood, are shaped like little worms; they penetrate the red blood : cells and deprive them of their ha-moglobin. They represent permanent forms and after a long interval can produce new generations by means of parthenogenesis. The male microgametocytes arise in the blood from indifferent forms and produce eight microgametes as in the intestine of the. mosquito. The ripening of the macrogametes and their fertilization by microgametes take place in the intestinal tract of the mosquito. It has not been positively decided at the present whet her human trypanosomiasis is due to more than one variety of trypanosome. The different clinical course of the TRYPANOSOMES. 699 affections makes this probable. In the forms known as tropical splenomegaly or cachectic fever and kdla-azdr there are found (Leishman, Marchand) in the spleen, liver, bone- marrow, lymph-nodes, and also in intestinal ulcers great numbers of small bodies, partly free and partly intracellular, consisting of an intensely staining ring-shaped chromatin body surrounded by a circular or oval, clear area staining lightly with eosin. Besides the chromatin-body there is often found also {Marchand, Ledingham) a small, intensely staining round or elongated granule, which is often connected with the chromatin-ring by a delicate stalk. These bodies (" Leishman-Donovan bodies ") were first found by Leishman and Donovan in smears made from the spleen, and were later studied by Marchand, Ledingham, Manson and Low, Bentley, Rogers, and others, and were given different interpretations, the general opinion being that they represented degeneration forms of trypanosomes. Rogers has succeeded in growing them outside of the body and in demonstrating their transformation into elongated flagellated organisms resem- bling trypanosomes. On account of the absence of an undulating membrane Rogers believes the organism to be a herpetomonas. Ross regards it as a new genus and has tailed it Leishmani donovani. Nothing is yet absolutely determined concerning the transmission of this fatal infection. Rogers believes that it is transmitted by bed-bugs or mosquitoes. Very recently Nicotic (Arch, de I' Inst. Pasteur, Tunis, 1908) has suc- ceeded in cultivating the Leishman-Donovan bodies from cases of infantile splenomegaly in Tunis. He regards the protozoon obtained as a new species, Leishmania infantum. The protozoa found in a case of tropical sore by Wright (Jour, of Med. Res., 1903) and called by him lielcosoma tropicum, are regarded as Leishman-Donovan bodies, and designated by Nicotic as Leishmania wrighti. They are to be regarded as the infective agent of "Delhi boil." According to the majority of writers trypanosome or Gambia?! fever is but the early stage of sleeping-sickness, both conditions being due to infection with the same parasite, the Trypanosoma gambiense. The first stage is of a variable duration, lasting from three months to three years or longer. During this stage there is a polyadenitis and the t rypanosomes may be demonstrated in the blood and lymph-nodes. As a diagnostic method the examination of a drop of fluid removed from an enlarged cervical gland by means of a hypodermic needle is advised, since the parasites can be found in this way immediately if they are present in the body. According to the views of many authors it is probable that yellow fever is a protozoan disease, although the parasite has not yet been demonstrated. Schaudinn showed that trypanosomes in certain stages formed such small individuals that they could not be recognized singly under the microscope. He would seek, therefore, the yellow-fever parasite among the flagellates. Yellow fever is endemic in the Antilles, Southern States of North America, Brazil, east coast of South America, and in many parts of West Africa. As the result: of the work of a LTnited States Commission consist- ing of Reed, Carroll, Agramonte, and Lazear, it was determined in 1900 that yellow fever is transmitted only through the bite of a mosquito (Stegomyia fasciata) . Subcutaneous inoculation of the blood-serum of a case of yellow-fever into a non-immune during the first three days of the disease will transmit the infection. The mosquito, therefore, to become infected must suck the blood of a patient during this time. The bite of the mosquito does not become dangerous until twelve days after taking up infected blood, so that it is apparent that the parasite must undergo a further development within t he body of the mosquito. The latter is able to infect after this period as long as it lives. Novy believes that the cause of yellow fever will be found to be a spirillum. The first successful cultivation of a pathogenic protozoon and the demonstration of its relation to the disease by the injection of pure cultures were attained by Novy and McNeal in the case of Trypanosoma lewisi and later of Tr. brucei. Literature. (Trypanosomes. ) Baker: Trypanosoma in Man. Brit. Med. Journ., i., 1903. Bradford and Plimmer: The Trypanosoma Brucei. Quart. Jour, of Micr. Sc, xlv., 1901. Bruce: Rep. on the Tsetse Fly Disease. Ubombo, 1895 and 1890; Trypanosomiasis. Brit. Med. Journ., ii., 1904. Bruce, Nabano, and Greig: The Etiol. of Sleeping Sickness. Brit. Med. Journ., ii., 1903. BylofF: Rattentrypanosomen. Sitzungsbericht d. Kaiserl. Akademie in Wien, cxiii., 1904. 700 THE ANIMAL PARASITES. Carini: Die pathogenen Trypanosomen. Korrbl. Sehweizer Aerzte, 1904. Castellani: Aetiologie der Schlafkrankheit. Centralblatt fur Bakteriol., Orig., xxxv., 1903. Danielewsky: Z. Parasitologic desBlutes. Biol. CM., v., 1SS6; La parasitologic du sang. Charkoff, 1889. Doflein: Die Protozoen als Parasiten und Krankheitserreger, Jena, 1901 (Lit.). Doflein and v. Prowazek: Die pathogenen Protozoen. Handb. d. pathog. Mikroorg., i., 1903 (Lit.). Donovan: The Etiology of One of the Heterogeneous Fevers of India. Brit. Med. Journ., ii., 1903. Dutton: Trypanosoma Occurr. in (he Blood of Man. Thompson- Yates Lab. Rep., iv., 1902. Dutton and Todd: Rep. to the Trypanosomiasis Exped. to Senegambia. Thompson- Yates Lab. Pep., v., 1903. Elmassian et Mogune: Sur le mal de Caderas. Annales de ITnstitut Pasteur, 1903. Gunther: Trypanosomen bei Menschen. Munch, med. Wocli., 1904. Kasewurm u. Steinbruck: Tier. Paras, bei Haustieren. Ergebn. d. allgem. P., viii., 1904. Koch: Flagellaten im Blute v. Haustieren. Mitteil. a. d. K. Ges.-A., Berlin. 1881; Reiseberichte iiber Rinderpest, Bubonenpest, Tsetse- oder Surrakrankheit, Texas- fieber, tropische Malaria, Schwarzwasserfieber, Berlin. 1S9S: Trvpanosomcn- krankheit. D. med. W'oeh., 1904. Lang-: Protozoen, Jena, 1901. Laveran: Des trypanosomes parasites du sang. A. de med. exp., iv., 1892; Trypano- somiase humaine. Compt. rend, de l'Ac. d. Sc, cxxxviii., 1904. Laveran et Mesnil : Maladie de la mouche tsetse. Ann. de l'lnst. Pasteur. 191)1'; Trypanosomes et Trypanosomiases. Paris, 1904. Leishman: On the Possibility of the Occurrence of Trypanosomiases in India. Brit, Med. Journ., i., 1903, p. 12.52; Discussion on the Leishman-Donovan Body. lb., ii., 1904, p. 042. Lignieres: Mal de Caderas. Ref. C. f. Bakt., xxxiv., 1904. MacNeal: The Life-history of Tr. Lewisi and Tr. Brucei. Journ. of Infectious I lis., 1904. Manson and Daniels: A Case of Trypanosomiasis. British Medical Journal, i., 1903. Marchand u. Ledingham: Leber Infekfion mil Leishmanschen Korperchen. X. f. Hyg., 47 Bd., 1904 (Lit.). Marchoux: La fievre jaune. Ann. de l'lnst. Pasteur, 1903. Nepveu: Trypanosome dans le sang de l'homme. Compt. rend. Soc.de Biol., Paris, 1898. Novy: The Trypanosomes of Tsetse Flies. Journ. of Infect. Dis., 1900. Novy and MacNeal: Cultivat. of Trypanosoma Brucei. Journ. of Infect. Dis., i., Chicago, 1902. u. Biol. Oil., xxiv., 1904; On the Trypanosomes of Birds. Journ. of Infect. Dis., 1905. Novy, MacNeal, and Torrey: The Trypanosomes of Mosquitoes. Journ. of Infect Dis., 1907. Plitnmer u. Bradford: Morphologic des Tsetseparasiten. CM. f. Bakteriol xxvi 1899. Rabinowitsch u. Kempner, Rattentrypanosomen. Z. f. Hyg., 30 Bd., 1S99 (Lit.); Trypanosomen in der Menschen- u. Tierpathologie. C. f. B., Orig , xxxiv 1904 (Lit.). Rattig: Leber Parasiten des Froschblutes. I.-D., Berlin. 1875. Rieck: Sporozoen als Kranksheitserreger bei Tieren. Deutsche Z. f Tiermed xiv 1889. Rouget: Trypanosomes des mammiferes. Ann. de l'lnst. Pasteur, 1S90. Ruge: Leber das deutsche Proteosoma. (bei Sperlingen). C. f Bakteriol xxix 1901. Salmon and Stiles: Rep. on Surra: XVIII. Ann. Rep. of the Bureau of Animal In- dustry, Washington, 1902. Schaudinn: Generations- u. Wirtswechsel bei Trypanosomen u. Spirochaten. Arb. a. d. K. Gesundheitsamte, xx., 1904. Schilling: Surrakrankheit der Pferde u. Rinder in Togo. C f Bakteriol xxxi Orkr 1902. ■' '' -'' Voges: Mal de Caderas. Z. f. Hyg., 39 Bd., 1902. Wasielewski u. Senn: Flagellaten des Pattenblutes. Zeitschr. f Hygiene 33 Bd 1900. ■' COCCIDIA.. 701 Wittich: Spirillen im Blute von Haustieren. Centralbl. f. i lie med. Wissenschaft., 1891. § 187. Of the Sporozoa occurring as parasites in man and in the mammals, the coccidia are to be mentioned first. In their young state they exist as non-encapsulated inhabitants of epithelial cells, particularly in those of the intestinal canal and its adnexa, the liver especially, and f. m ^-- ~ Z- 2 i ~'-^^' £* ~ Fig. 533.— Section through the wall of a dilated bile-duct, tilled with coccidia and lined with papillary proliferations. From a rabbit's liver that was studded with coccidia nodules (Midler's fluid, hematoxylin, eosin). a, Connective tissue; &, branching papillary proliferations covered with epithelium ; c, coccidia. X 23. from matui'i more rarely in those of the organs of excretion. Some of the mature forms surround themselves with a capsule and become changed into round or oval permanent cysts or oocysts (Schaudinn), which leave their resting-place and usually also their host, and under certain conditions form sickle-shaped sporozoites through the repeated division of their cell body (sporogony). Through the taking- up of sporozoite-contaiiiing oocysts into a new host there is produced an infection of the latter, in that the sporozoites are set free and seek out epithelial cells for their further development. Besides this form of multiplication there occurs within the infected organ also a reproduction by schizogony — that is, there are developed but nou-encysted individuals, by means of segmentation, a, large number of new sickle-shaped individ- uals, the so-called merozoites, which seek out epithelial cells, and develop further in the same. Coccidium oviforme (Fig. 534) is a para- site of the intestine and biliary passages, occurring especially in rabbits. Kiinstler and Pitres found similar coccidia in man in a pleuritic exudate. Podwyssozki claims to have observed them in the human liver. In the liver of rabbits the invasion of coccidia leads to the formation of white nodules which may reach the size of a hazel nut, and are designated as coccidia-nodules. These nodules contain a soft, white, or yel- lowish-white mass, and consist essentially of Fig. 534.— Coccidia from the biliary duct ot the rabbit's liver (Fig. 533), showing different stages of develop- ment (Miiller's Quid, haematoxylin). a, h, Small, coarsely granular young forms; c, o\ large forms with darkly staining peripheral granules; c,f. g, h, oval, encapsulated forms, the pro- toplasm of which— partly coarsely granular and partly fine— Alls up only a portion of the capsule. X 400. 702 THE ANIMAL PARASITES. dilated bile-passages, the inner surface of which is more or less richly furnished with papillary growths (Fig. 533), and whose lumen contains great numbers of coccidia. The coccidia occur in the bile-passages partly in the form of non-encap- sulated protoplasmic structures, and partly in the form of encapsulated bodies. The smallest coccidia, which are regarded as the younger forms, exhibit a coarsely granular protoplasmic structure (Fig. 084, a, 6), within which a nucleus (a) may occasionally be demonstrated. The larger forms exhibit on their outer surfaces regularly arranged granules ( c , d) , which stain intensely with hematoxylin. The encapsulated forms occur as oval, doubly contoured, clear bodies (e, f, g, h) within which lies a variously shaped mass exhibiting also various forms of granulation, but never entirely filling up the space within the capsule. To the coccidia belong probably also those parasites which occur in the epidermis of man and form there peculiar growths known as epithe- lioma contagiosum (Fig. 535). In its fully developed condition the growth consists of a small nodule, about the size of a pea or larger, which is elevated above the surface of the skin, shows a small groove in its centre, and possesses a waxy lustre. On section there may be seen a lobulated epithelial growth (Fig. 535, d), with a central cavity opening externally (g), thus forming a growth resembling a gland ; and it has been many times mistaken for a hyper- trophic sebaceous gland. It therefore represents an independent new- formation of epithelium due to a parasite. The parasites develop inside of the epithelial cells of the lobulated growth (e), but are pressed by the a '■•..., ■■■■■■■■:/,. Fig. 5:15.— Epithelioma contagiosum. Section through greatest diameter (Muller's tlm'd, hematoxylin). a, F^pidermis ; b, connective tissue; c, sebaceous gland; d, gland-like epithelial proliferations; e, para- sites ; /, horny cells mingled with parasites ; ;/, duct Ulled with horny epithelium and parasites. X 13. growth of the adjacent epithelium toward the central cavity of the new- formation (/), and lie there in a meshwork of desquamated and horny epithelial cells. The earliest stages of development of the parasites occur in the epi- thelial cells as small protoplasmic bodies (Fig. 53C, a, b), which can be distinguished from the cell -protoplasm only with difficulty; occasionally they contain in their interior small, distinct granules, and are therefore more evident. Later they increase in size, and finally fill up completely the epithelial cell (c, d, e), pressing the nucleus to one side. At the same time the granules within the cell (c) increase, and grow to larger bodies, so that the parasite finally becomes divided into a greater or less number of well-defined structures (, c, enlarged Plasmodia with pseudopudia ; d, Plasmodia before spornlation, the red blood-cell decolorized ; e, sporulation ; f, free parasite with flagellum (microgametocyte). division each Plasmodium splits up into from fifteen to twenty new cells (e), while the parasite of quartan fever forms only from six to twelve. According to Celli and Marchiafava, sporulation not infrequently occurs prematurely, from five to ten spores arising within a red cor- puscle. The parasite of tropical or pernicious malaria, the Plasmo- dium prcecox, differs from the hsemosporidia of the vernal fevers, particularly in the fact that it is much smaller (Fig. 541, a, b, c, d) and executes lively movements within the red cells. It completes its life- cycle in twenty-four to forty- eight hours. Through the for- mation of a central vacuole it often appears in the form of a ring. During the stage of mul- tiplication the parasite collects in the internal organs, so that the divi- sion-figures (d) must be sought in the spleen, liver, bone-marrow, and brain (where they are present in great numbers). Some of the infected red cells become crenated and prickly, and of a brassy color (Marchiafava, Celli); they die prematurely, and blood-cells which contain no parasites are also destroyed. The attacks of fever can in the case of autumnal tertian fever become so pro- longed that they pass into one another, and the condi- tion thereby assumes the character of a sub -continuous or continuous fever. According to Marchiafava and Celli, there also occurs a quotidian parasite very similar to the latter, but pro- ducing no pigment at all. Nuclear bodies may be de- monstrated, during certain stages of development, in the protoplasm of all the endo- globular forms of malarial htematozoa. According to Ziemann, in sporulation there first occurs a division of the chromatin into small clumps, and then later the division of the cell-body, so that every clump of chromatin is surrounded by a zone of protoplasm. Besides the forms of development already described which lead to an intracellular increase of the plasmodia through schizogony, there occur particularly extraglobular, in part also endoglobular, round and oval, sickle- or crescent-shaped structures (Figs. 539, i; 541, c, J"), as well as round bodies with flagella (Figs. 540, /; 541, g), which also contain a nucleus and pigment. The crescent forms occur particularly in the per- nicious fever (Fig. 541 , e, f). Celli regards them as a diagnostic feature of this form of fever; and Ziemann also holds that typical crescents are not formed in the other varieties of malaria. Fio. 541 . — Plasmodium ■prcefinx of tropical malaria, showing different stages of development. (AfterUolgi and Sanfelic.e.) a, First stages of development; h, Plasmodia with pseuriopodfa ; c, round Plasmodium with pigment, be- fore segmentation : U, sporulation; e, intraglobular sexual individual ; /', [/, free sexual cells. "]() THE ANIMAL PARASITES. The last-named forms Laveran had already described as structures belonging to the cycle of development of the Plasmodia, while Golgi, Oanalis, Celli, Marchiafava, Bignami, Bastianelli, Ziemann, and others regarded them as sterile vegetation-forms that die without further de- velopment. First through the investigations of Manson, Bignami, Boss, and MacOallum, to which were later added those of Grassi, Bastianelli, Bignami, Celli, Laveran, Koch, Schaudinn, and others, it was shown that the crescents, the oval bodies, the spherical bodies, or spheres, as well as the flagellated bodies known as polymitm, are intended for the reproduction of the parasites by copulation. The flagella-producing hyaline spheres aris- ing from the crescents arc male sexual individuals or mierogametocytes, and the flagella developing from them, in whose formation the chro- FIG. ■ niflration. FIG, i mosquito. 43.— OOkini (After Gr; Fir,. 543. s clavigcr. (After Meigen, toe. (it.) of human pernicious malaria (.Plasmodium prcecox) in the intestinal wall ot a matin of the cell takes an essential part (iSacharoff), have the signifi- cance of seminal cells, spermatozoa, or microgametes ; while the non-flag- ellated spheres arising from the granular crescents have the significance of female sexual cells or macrogametes. The crescents leading to the for- mation of the sexual cells appear only after the infection has lasted for several days. In the chronic cachexia following malaria the forms lead- ing to schizogony are absent, and the crescents alone are present. The copulation of the malarial parasites of man takes place normally in the stomach of the mosquito, in different species of Anopheles (Fig. 542), which take up the malarial parasites during the sucking of blood from malarial patients. The copula, arising from the union of the. macrogamete and micro- gamete is designated ookinete (Schaudinn), a long, motile structure (described earlier as vermiculus by Danielewsky) which penetrates into the stomach-wall of the mosquito (Fig. 543), where through the forma- tion of a capsule it becomes the oocyst. The latter then enlarges, and forms numerous daughter-nuclei, and then sporoblasts, -which break up into the sporozoites (Fig. 544) and the residual body. According to Grassi, as many as 10,000 sporozoites may be formed in one oocyst. The sporozoites, which are formed in enormous numbers, pass into the body-cavity after the rupture of the oocyst, and collect principally in the salivary glands, and through the bite of the infected mosquito are again transmitted to man, in whose blood they multiply within the red blood-cells through schizogony. MALARIA. 711 The pathogenic significance of the malarial Plasmodia rests in the first place upou the destruction of red blood-cells. In the pernicious form this may be so extensive that hemoglobinuria may take place. The melanotic pigment formed in the parasite is a product of the vital ac- tivity of the parasites. In addition, as the result of the destruction of haemoglobin, there occur deposits of haemosiderin in the bone-marrow, spleen, liver, and occasionally also in the kidneys. In the case of a marked destruction of the red blood-cells there may occur an excretion of dark red urine, a hemoglobinuria (blaclc-water fever). The massing of the parasites of pernicious malaria in the cerebral capillaries may cause circulatory disturbances with the occurrence of numerous hemorrhages, and consequent severe cerebral symptoms (perniciosa comatosa, soporosa, apoplectica, meningitica). As the result of the retention of pigment-containing malarial parasites and the deposit of the products of blood-destruction, there occurs a marked swelling of the spleen associ- ated with hyperemia, followed in part by tissue-degenerations and in part by tissue-proliferations. After a long duration of the process the spleen may become markedly en- larged, pigmented, and greatly changed in structure. Likewise, in the liver there may be found in part degenera- tions and pigmentations, and in part also indurative proliferations. Certain varieties of the Plasmodium correspond to the individual types of fever, as given above, but it must be noted that the fever-forms known as quotidian, subcontinuous, and continu- ous ("comitata"), may also arise through the presence in the blood of different generations of the plasmodia of tertian or quartan fevers, so that daily a portion of the parasites comes to sporu- lation. In this way there arise quotidian forms of fever, which must be regarded as a double tertian infection or as a triple quartan. According to the investigations by Schaudinn, the relapses that occur sometimes weeks and months after the original attack may be explained by the fact that the macrogametes, which are longer-lived, revert to schizonts by throwing off a portion of their nucleus and protoplasm. According to Plehn, basophile granules are found in the red blood-cells as long as the infection persists. They vanish when the infection finally comes to an end. The malaria occurring in northern countries ecu responds in general to the vernal forms of Italy, while the estivo-autumnal form is found in the tropics. Hsemosporidla — that is, sporozoa which live at the cost of the red blood-cells, and thereby produce diseases which are to be classed with malaria — occur very frequently in animals. Those of birds are best known (Danilewsky, MacC'attum, Ross, Grassi, Dionisi, Celli, and Schaudinn) and the life-cycles of the hscniosporidia of the pigeon, owl, and skylark have been determined. Labbe distinguishes two genera in birds, Hal- leridium and Proteosoma (Hmmoproteus of Kruse); as to the number of undifferentiated species, nothing can be said at the present time. Celli obtained from the birds men- Fig. fill Ml cyst i>r I'lit 712 THE ANIMAL PARASITES. tioned three well-defined species. Schaudinn assigns the parasites of birds designated as proteosoma to the genus Plasmodium. Of the Mammalia, cattle in particular suffer in different countries (Southern States of North America, Italy, South Africa, Roumania) from a malaria characterized by high fever and hemoglobinuria. In the malaria of cattle known as Texas-fever, Smith and Kilbourne found in tne red blood-cells a small, often pear-shaped, and paired parasite (Piroplasma bigeminum) , whose pathogenic significance they determined through the in- oculation of healthy cattle with blood containing the parasites. Babes found the same parasite in the epidemic haemoglobinuriaof cattle prevalent in Roumania. The first- named observers showed further that tlie natural infection takes place through parasitic ticks (Boiipkilus bon's) living upon the cattle, the infection being transmitted, not by the same tick which takes up the infected blood, but only through the generation descend- ing from the same. This mode of infection was confirmed by Koch in the hsemoglobin- uria of catt le occurring in German East Africa and by Grassi in that occurring in cattle in Italy. The mode of development of the piroplasma in the body of the tick is still unknown; and it therefore cannot be decided whether the parasite should be classed with the known malaria, parasites. Against a near relationship with the latter speaks the fact (Lake) that it increases within the red blood-cells by a repeated simple d'vision. According to Kolle, there occurs in South Africa, besides Texas-fever, another malarial disease of cattle (Fcbris malariaformis) , which is caused by an endoglobular parasite. Theiler also distinguishes two form.; of piroplasmosis of cattle in South Africa. The piroplasma occurring in dogs and in horses he regards as an especial form distinct from Piroplasma bigeminum. According to observations by Nocard and Almy and Molar a piroplasmosis associated with hemoglobinuria is not uncommon in dogs in France. According to Galli, Valeria, and Plana, it occurs also in Italy. According to Bonome and Celli, hemosporidiaalso cause malaria in sheep and lamb.., according to Koch and Kossel also in apes, and according to Dionisi in bats; but the life-history of all these parasites is unknown. Danilewsky and Celli have described hamiosporidia in the frog, and the latter ob- server determined also the development of the parasite in the blood. Whether the malarial parasites of man can be transmitted to animals, or whether the malaria of animals can lead to an infection of man through the medium of mos- quitos, is not decided with certainty, but appears improbable. The Plasmodia of the bat most closely resemble those of man, yet attempts at inoculation made by Dionisi gave no positive results. It may therefore be assumed that malaria would die out in a given region, either when all susceptible anopheles were killed, or all infected human individuals healed or protected from mosquito bites. The malarial plasmodia are stained best by the Romanowski stain, which differen- tiates the nucleus. The view that mosquitos were concerned in the distribution of malaria is very old. and has obtained in Italy since Roman times. Kuch found it held as a popular belief also among negroes. In recent times Manson (1896) and Bignami (1896) were the first to turn their attention to the problem and to give hypotheses concerning the role played by mosquitos in the spread of malaria. Bignami carried out experiments along this line, but came to no positive result. Ross was the first (1897-98) to determine the cycle of development of the malarial Plasmodium of birds (usually known as proteosoma). According to his investigations, the parasites taken up with the blood of the infected bird into the intestinal canal of mosquitos penetrate into the intestinal wall and there change into cysts in which innumerable rod-shaped germs develop. Becoming free, these germs giiin entrance into the salivary glands of the mosquitos, and thence into the organism of the bird during the act of blood-sucking. Ross found the parasites in the blood of the infected bird in from live to nine days after the infection. About the same time, Grassi found through painstaking observatiot s that the dis- tribution of malaria in man corresponded to the distribution of Anopheles claviger (Fabririns) (Fig. 542), and tint to that of the common mosquito (Culcx pipiem). Basing his experiments upon this observation, Bignami succeeded in producing malaria in healthy men by means of the bite of anopheles. Later Grassi, in cooperation with Bastianelli and Bignami, succeeded in determining the life-cycle of the malarial par- asite It was then shown that, several species of anopheles native in Italy (Anopheles claviger [ Fabrieius] or Anopheles maculipennis [Me/gen], Anopheles sitperpictvs, pseudo- picttis, bif ureal ns) spread the malaria occurring in man, while Ctilex pipiens is the host of the parasites of bird-malaria The cycle of development of the malaria Plasmodium is as follows Within the blood (of man as well as of birds) the multiplication takes place first by schizogony. The young form of the plasmodia, represented by a small, unpigmentcd body, grows within the red cells (Fig 545, 1) into a larger body (2), in whose central portion pigment- BLEMOSPORIDIA. 713 granules collect. This cell-body known as schizont shows in preparation for schizogony an increase of nuclei (3), and then divides into a number (varying with the species) of spores or merozoites (4) with the abandonment of a pigmented residual body. The mero- zoites then seek a red blood -cell (1), and the cycle is again begun. In sporogony the merozoites develop into sexual individuals, macrogametes (5) and microgametocytes (5a). When taken up into the stomach by blood-sucking mos- quitos, the sexual individuals become ripe for fertilization, the macrogamete by throwing off the karyosome (6), the microgametocyte through the formation of micro- gametes (6a). Copulation then follows (7). From the copula arises the motile ookinete (S), which in the wall of the mosquito's intestine becomes the oocyst, in which through the division of the nucleus the sporoblasts (9) are formed, which in turn break up into a large number of sporozoites (lu), which (11), becoming free, collect chiefly in the sali- vary glands, and are thence transferred by the bite of the mosquito to a new host, in whose blood they increase through schizogony (1-4)- According to the inves- tigations of Schaudinn, the macrogametes and the micro- gametocytes of Plasmodium vivax may be distinguished from each other in the earli- est stages of development within the red blood-cell, and also from the schizonts, at first through the peculiar structure of the nucleus and later through that of the protoplasm. In a new in- fection of tertian malaria the differentiation of the gametes began after the third attack. The growth takes place es- sentially slower than in the case of' the schizonts. 1 he pigment production is more abundant, while the nucleus is larger and less dense. r lhe larva; of anopheles live chieJy in slowly flowing water. 1 he eggs of Anoph- eles claviger re uire about thirty days at 20-25' C. for the development of the in- sects, and these in turn lay eggs when twenty days old. The pup e are resistant to drying, to cold, and to con- tamination of the water. _ _ The mos mitos fly during the evening and night, but do not rise very high above the level of the earth, and do not go very far away from the place of development. Ac- cording to Grassi, Bignami, and Bastianelli, the testivo-autumnal parasites will not develop in anopheles at a temperature of 14-15° C, and grow only slowly at 2CP-29" C." at 30° C. they complete their entire development up to the formation of sporo- zoites in about seven days. , . , rm ^ , , The literature concerning malarial parasites is extremely rich. Ine results ot the latest investigations are given in the publications of Grassi, Schaudinn, M annaberg , Nutlall, Celti, Marchiafava, Bignami, and Lithe. Fig. 5t5.— Cyrl dinn and Lube of development of Prntensoma. (After Schau- 1. Sporozoite (or merozotte) within a red blood- corpuscle; ~, schizont; 3, schizont with numerous nuclei; A, schiz- ogony, formation of merozoites; 5, macrogamete (female cell) arising from a merozoite ; 6', fully developed macrogamete after ex- trusion of the karyosome ; 5a, microgametocyte (male cell) arising from a merozoite; 6a, microgametocyte surrounded by loosened microgametes (spermatozoa) ; 7, fertilization of the macrogamete; •S', ookinete ; 9, oocysts with sporoblasts ; 10, oocysts with sporozoites ; 1 1, free sporozoite. Literature. (ScemGsporidia.') Babes- Paras, d. Hamoglobinurie der Rinder u. der Carceag d. Schafes. V. A., 115 Bd., 1S89 u. Cbl. f. Bakt., Orig., xxxiii., 1903. Barnacci Aetiologie d. Malarii. Cbl. f. allg. Path., hi., 1892 (Lit.); ISeue Arb. ub. Malaria Ibid., x., 1899 (Lit.). Barker: Fatal Cases of Malaria. Johns Hopkins Hosp. Rep 1S95 Biffnami: Anatom. patolog. delle perniciose. Atti della R. Accad. Med. di Roma A. xvi vol v Roma, 1890, ref. Cbl. f. allg. Path., n.; Chron. Malaria. lb., v., 1894; Tropenfiebe'r. Cbl. f. Bakt., xxiv., 1898. 714 THE ANIMAL PARASITES. Bonome: Parasitare Ietcrohaniatozoen d. Schafe (AmiJbo-Sporidien). Vircli. Arch., 189 Bd., 1895. Cattaneo e Mondi: Alteraz. malariche dei corp. rossi del sangue. Arch. p. le Sc. Med., xii., 1888. Celli: Le Malaria, Home, 1899; Die Malaria, Berlin, 1900 (Lit.). Celli e Marchiafava : Die Veranderung tier rothen Blutkorperehen bei Malaria- kranken. Fortschr. d. Med., i., 1883, iii., 1885, ix., 1891; Arch. p. le Sc. Med., ix., 1SS5, xi., 18S6, xii., 18S8, xiv., 1890; Ueber die Parasiten der rothen Blut- korperchen. Internat. Beitr., Festschr. f. Virchow, iii., Berlin, 1891. Celli u. Santori: Die Rindermalaria in d. Campagna. Obi. f. Bakt., xxi., 1897. Councilman: Unters. iiber Laveran's Organismus d. Malaria. Fortschr. d. Med., vi., 1888; Further Observations on the Blood in Cases of Malarial Fever. Med. News, i., 1889. Crookshank: Flagellated Protozoa in the Blood of Diseased and Apparently Healthy Animals. Journ. of the Boy. Microsc. Soc, Ser. ii., vol. iv., 1886. Danilewski: Zur Parasitologic des Blutes. Biolog. Cbl., v., 1885-86, Arch, slaves de biol., 1886; Cbl. f. d. med. Wiss., 1886; Nouvelles rech. sur les parasites du sang des oiseaux, Charkow, 1889, ref. Biol. Cbl., x.; sur les parasites de Pinfection malarique aigue et chronique chez les oiseaux et chez l'homme. Ann. de 1'Inst. Pasteur, iv., 1890; Ueber Polymitus malaria;. Cbl. f. Bakt., ix., 1891; Contr. a l'et. de la microbiose malarique. Ann. de 1'Inst. Pasteur, v., 1891. Dionisi: Les paras, endcglobulaires des chauves-souris. Arch. ital. de Biol., xxx., 1S99. Doflein: Die Protozoen als Parasiten, Jena, 1901. Ewing: Pathological Anatomy of Malarial Fever. Journ. of Fxp. Med., vol. vi., 1902; Malarial Parasitology. Journ. of Exp. Med., vol. v. Fajardo: Hamatozoarie der Beri-Beri. Cbl. f. Bakt., xxiv., 1S9S; xxvii., 1900. Galli-Valerio: Die Piroplasmose des Hundes. Cbl. f. Bakt., Ref., xxxiv., 1904. Glog'ner: Malariaerreger im Malaischen Archipel. Virch. Arch., 158 Bd., 1899. Golgi: Sull' infezione malarica. Arch. p. le Sc. Med., x., 1886, xiii., 1SS9; Gaz. degli Ospitali, 1886; Fortschr. d. Med., iv., 1886, vii., 1889; Arch. ital. de biol., ix.; II fagocitismo nell' infezione malarica. Rif. Med., iv., 1888; Ueber den angebl. Bacillus malarije v. Klebs, Tommasi-Crudeli, und Schiavuzzi. Beitr. v. Ziegler, iv., 1889; Intermittirende Fieberformen der Malaria mit langen Intervallen. lb., vii., 1890; Sur le cycle evolutif des parasites malariques dans la fievre tierce. Arch. ital. de Biol., xiv., 1890; Demonstration der Entwickelung der Malariaparasiten durch Photographieen. Zeitschr. f. Hyg., x., 1891; Ueber die im Sommer und im Herbst in Rom auftretenden Malariafieber. Cbl. f. Bakt., xv., 1894. Grassi: Intorno a alcuni protisti endoparassitici, Milano, 1882; Rapports entre la malaria et cert, insects particuliers. Arch. ital. de Biol., xxx., xxxii., 1899; Die Malaria, Jena, 1901. Grassi et Dionisi: Le cicle evolutif des hemosporidies. Arch. ital. de Biol., xxxi., 1899. Grassi u. Feletti: Ueber die Parasiten der Malaria. Cbl. f. Bakt., vii., 1890; Arch. ital. de Biol., xiii.; Malariaparasiten in den Vogeln. Cbl. f. Bakt., ix., 1891. Koch: (Flagellaten im Blute von Hamstern.) Mittheil. a. d. Kais. O.-A., Berlin, 1881; Die Entwickelung der Malariaparasiten. Zeitschr. f. Hyg., 32 Bd., 1899; Be- kampfung der Malaria. lb., 43 Bd., 1903. Kolle: Parasit im Blute von Rindern in Siid-Africa. Zeitschr. f. Hyg., 27 Bd., 1898. Kossel: Malariaahnlicher Blutparasit beim Affen. Zeitschr. f. Hyg~, 32 Bd., 1899; Ilamoglobinuric der Rinder. Handb. d. path. Mikroorg., i., Jena, 1903 (Lit.). Kruse: Ueber Blutparasiten (im Froschblut). Virch. Arch., 120 Bd., 1890. v. Kubassow: Die Pilze des Paludismus. Berlin, 1898. Labbe: Parasites du sang des vertebres. Arch, de Zool., 1894, ref. Cbl. f. Bakt., xvi. 1894; Sporozoa. Das Thierreich herausg. v. d. zool. Ges., 5 Lief., Berlin, 1899. Laveran: Nature parasitaire des accidents de I'impaludisme, Paris, 1881; Traite des hevres palustres, 1884; Les hematozoaires du paludisme. Ann. de 1'Inst. Pasteur, i., 1887; Arch, de med. exp., i., 1889; ii., 1890; Du paludisme et de son hema- tozoaire, Paris, 1891; Traite du paludisme, Paris, 1897. Laveran et Blancliard: Les hematozoaires de l'homme et des animaux, Paris, 1895. Luhe: Ergebirisse d. neueren Sporozoenforschung. C. f. B., xxvii., xviii., 1900 (Lit.).' Lutz: Waldmoskitos und Waldmalaria. C. f. B., Orig., xxxiii., 1903. MacCallum: Hemafozoan Infections of Binls. Journ. of Exper. Med., iii. 1898 Mannaberg-: Die Malariaerkrankungen, Wien, 1898 (Lit.); Die Malaria'krankheiten Wien, 1S99 (Lit.); Malaria. Ergebn. d. allg. Path., v., Wiesbaden, 1900 (Lit ) Manson: The Mosquito and Malaria. Brit. Med. Journ., ii., 1898. Marchiafavae Big'nami: Sulle febbri malariche. Boll', della R. Accad. di Roma xviii., 1892; Malaria. Twentieth Century Practice, New York, 1900; La Infezione malarica, Milano, 1902. Marchoux: Le paludisme du Senegal. Ann. de 1'Inst. Pasteur, 1S97. INFUSORIA. 715 Martini: Malariaknuikheiten. Eulenburg's Jahrb., ii., 1904. di Mattei: Infez. malarica sperimentale. Arch, per le Sc. Med., xix., 1895. Maurer: Die Malaria pernieiosa. C. f. Bakt., Orig., xxxii., 1902. Neumann: Das melanamische Pigment. Vireh. Arch., 116 Bd., 1S89. Nocard et Motas: Piroplasmo.se canine. Ann. de l'lnst. Pasteur, 1902. Nuttall: Die Rolle d. Mosquitos bei Verbr. d. Mai. CM. f. Bakt., xxv., xxvi., 1899; xxvii., 1900 (Lit.). Opie: On the ffcemocytozoa of Birds. Journ. of Exper. Med., iii., 1898. Plehn: Beitr. z. Kenntniss d. tropischen Malaria in Kamerun, Berlin. 189G; Weiteres iiber Malaria, Jena, 1901; Schwarzvrasserfieber. V. A., 174 Bd., 1903: Infek- tionskrankh. bei Negern. lb.; Anteil Koclvs an d. Malariaforschung. D. med. Woch., 1903. Ross: Mosquitos and Malaria, Brit. Med. J., i., 1899: Ann. de l'lnst. Pasteur, 1899. Rug-e: Malariaparasiten. Handb. d. path. Mikroorg., i., Jena, 1903. Sakharoff: Le parasite des fievres paludeeimes irregulieres. Ann. de l'lnst. Pasteur, v.. 1891. Sambon: Life History of Anopheles. Brit. Med. Journ., i., 1901. Schaudinn: Der Generationswechsel d. Coccidien u. Hamosporidien. Zool. Cbl., vi., 1899; Plasmodium vivax, d. Erreg. d. Tertianfiebers. Arb. a. d. k. Gesundheits- amte, xix., 1902. van der Scheer: Tropische Malaria. Yirch. Arch., 139 Bd., 1895. Scheube: Schwarzwasserfieber. Eulenb. Jahrb., viii., 1898; Die Krankheiten d. warmen Lander, Jena, 1903 (Lit,); Texasfieber. Eulenb. Realencyklop., xxiv., 1909 (Lit.). Sch.neidem.uhl: Die Protozoen als Krankheitserreger, Leipzig, 1898. Schwalbe: Beitr. z. Malariafrage, i., ii.. Berlin, 1900. Smith: Die Aetiologie der Texasfieberseiiche des Rindes. Cbl. f. Bakt., xiii., 1893; N. Y. Med. Journ., 1899. Stein: Structur des Paras, der Malaria tertiana. Virch. Arch., 159 Bd., 1900. Thayer and Hewetson: Malarial Fevers of Baltimore. Johns Hopkins Press, 1895. Theiler: Piroplasmosen in Siidafrika. Fortsehr. d. Veter.-Hyg., i., ref. C. f. B., xxxiv., 1904. Wilde: Ergebnisse der Malariaforschung. Munch, med. Woch., 1901. Ziemann: Blutparasiten bei heimischer u. tropischer Malaria. Cbl. f. Bakt., xx., 1896; Leber Malaria und andere Blutparasiten, Jena, 1898. § 189. Of the ciliates or infusoria occurring within the human organ- ism' the best known and most important is the Balantidium or Para- mascium coli, a unicellular animal 60-70 ,«. long, covered withshort uni- form cilia. At its anterior end it lias a short peristoma (Fig;. 540, a) which opens into a short gullet. The body is marked with parallel stripes and encloses a bean-shaped chief nucleus (b) and an accessory nucleus and two vacuoles. Multiplication takes place by division into two new individuals. It develops a permanent form in the shape of a spherical cyst with a firm membrane. Balantidium coli occurs very often in Hie colon of swine without causing apparent changes. In cases of chronic diarrhoea in man it has been found in the de- jections and in the colon, and probably stands in causal relation to the intestinal catarrh. According to investigations by Solowjew, Askanazy, Klimenko, and others the balantidia may penetrate into the mu- cosa and submucosa of the intestine and cause there ulcers. They may also wander into the blood-vessels. Other species of ciliates have been observed in the intestine of man, Balantidium minutum (Schaudinn, 1899) and Nykto- thcrus faba (Schaudinn). In the paunch and reticulum of rumi- nants, in which the cellulose digestion is carried on, and m the blind intestine of horses, infusoria are universally present and occur in enormous numbers, for example, Isotricha prostoma. Entodtmum caudatum, Ophryoscolcx caudatus, and others. Fig. Wk -Balantid- ium (paramcecium) coli, with two contrac- tile vacuoles. (Alter Claus.) a, Mouth ; h, nucleus; c, included starch grains ; d, for- eign body in the act of being extruded. High magnification. 716 THE ANIMAL PARASITES. ( Oiliates. ) Askanazy Pathog. Bedeutung d. Balantidium coli. Verh. d. D. path. Ges., v., 1003. Cohuheim: Infusorien im Magen und Darm. D. med. Woch., 1903. Doflein: Die Protozoen als Parasiten und Krankheitserreger, Jena, 1901. Eberlein: Infusorien im Wiederkiiuermagen (kommen normal vor). Cbl. f. Bakt., xx., 1S96. Grassi: Protistes endoparasites. Arch. ital. de Biol., ii. u. hi., 1SS2-S3. Grimm: Leberabscess und Lungenabscess mil Infusorien. Langenbecks A.,48Bd., 1S94. Hensen: Infusorien im Magen bei Carcin. ventriculi. D. A. f. klin. Med., 59 Bd., 1898. Jakoby u. Schaudinn: Neue Infusorien im Darm. Cbl. f. Bakt,, xx?., 1S99. Janowski: Balantidium eoli im Stuhl. lb., 32 Bd., 1897 (Lit.). Klimenko: Z. Pathologie d. Balantidium coli. Beitr. v. Ziegler, xxxm., 1903. Lang 1 : Protozoa, Jena, 1901. Malmsten: Ueber Balantidium coli. Vireh. Arch., 12 Bd., 1857. Molter: Zur Kenntnis des Balantidium coli. I.-D., Kiel, 1891. Solowjew: Balantidium coli als Erreger chron. Durchfalle. Cbl. f. Bakt., xxrx., 1901 (Lit,). Stieda: Ueber Balantidium. Vireh. Arch., 55 Bd., 1S96. Strong: The Clinical and Pathological Significance of Balantidium Coli, Manila, 1904. Strong and Musgrave: Infect, with Balantidium. Bull, of Johns Hopkins Hosp., xli., 1901. II. Vermes (Worms). A. Platyhelminthes (Feat- Worms.) 1. Trematoda, Sucking Worms. § 190. The Trematodes or sucking -worms are flat-worms of tongue or leaf shape. They possess a clinging apparatus in the form of ventral sucking-cups of varying number, and are sometimes furnished with hooks or clasp-like horny projections. The intestinal canal is without an anus, and is usually forked. The development takes place either by the direct growth to maturity of the embryos (miracidium) hatching from the eggs, or by the method of alternate generation through the formation of germs within the host. The miracidium, or ciliated embryo, penetrates into a snail or mussel, and there grows into a germ-sac (sporoeyst), within which there later develops, either directly or after the formation of an inter- mediate generation of germ-sacs (red he), a swarming generation of cer- carice, which are provided with rudder-like tails. These lose their tails and penetrate into a new host (mollusks, arthropods, fish, amphibia), become encapsulated, and attain sexual maturity as soon as they reach the final host. The germ-sacs which produce eercarire are designated primary. germ-sacs ("Ammen") ; if they first form redite and then cer- caria?, they are called secondary germ-sacs (" Grossammen"). Distoma hepaticmn, or liver-fluke, is a leaf -shaped sucking-worm about 28 mm. long and 12 mm. broad (Fig. 547). The cephalic end projects like a beak, and bears a small sucking-cup, in which the mouth is placed. Close behind this, on the ventral surface, is a second suckino-- cup, and between the two lies the sexual orifice. The uterus consists of a convoluted, globular sac behind the posterior sucking-cup. On each side of the hinder part of the body lie the yolk- sacs, and between the same are found the testicular canals, which branch many times. The forked intestinal tract (not visible in Fig. 517) is repeatedly branched. The eggs (Fig. 548) are oval, 0.13 mm. long and 0.08 mm. broad. In water there develops an embryo, the miracidium (Fig. 519, A), with TREMATODA. 717 cellular germ-balls (a) ; with the aid of its ciliated covering the embryo swims about, and seeks out a new host from the family of mollusks {Bimnceus mlnutus). On penetration into the snail the cutaneous layer is thrown off, and the miracidium, which possesses an intestine, an excre- tion-organ and a brain-ganglion, becomes changed into a sporocyst (B), in which the intestine and nervous system atrophy, while the cellular germ-balls develop further (B, a) and form a second generation of germ- sacs, the redice (B, b). The rediae (C), which possess an intestine {(', a), produce then within the same host the ce rear ice (B) from cells which are loosened from their germ- matrix (C, b); these abandon the host and with the aid of a rudder-like tail swim about in the water. With the loss of their tails they become encysted upon almost any foreign body, and then reach their final host (usually through the food), in which they attain sex- ual maturity. The sexually mature animal inhabits the biliary passages ; more rarely it is found in the intestine or inferior vena cava. The liver-fluke is rare in man, but common in cattle and sheep. The results of its invasion, especially when it is present in great numbers, are obstruction and ulcerative strictures of the bile-passages, formation of biliary concretions, inflammation of the tis- Fig. Mr .—Distoma hepaticum with male and female sexual apparatus. (After Leuckart.) X 3.2. Fir,. 548.— Eggs of Distouia hepatlcum. (After Leuckart.) X 300. sues in the neighborhood of the bile-ducts, and hyperplasia of the peri- portal connective tissue of the liver with atrophy of the glandular tissue. The same changes are found in cattle. In sheep, following a marked in- vasion of the liver, there may develop a general cachexia. Distoma lanceolatum is only 8-9 mm. long and 2-2.5 mm. broad, is lancet-shafted, and the cephalic portion is not especially marked off from the body (Fig. 550). The skin of the body is smooth. Two irregularly lobed testicles (h) lie close behind the ventral sucking-cuf), in front of the ovary (o) and the uterus («), the coils of which shine through the transparent^: ly The anterior coils are black with the ripe eggs, the others are rusty red. The yellowish-white yolk-sacs (d) lie in the middle of the lateral margin. The oval eggs are 0.04 mm. long, and while still in the uterus contain an embryo which escapes only after several weeks following the casting- i >ff of the eggs. Its metamorphoses are unknown. Distoma lanceolatum likewise inhabits the bile-passages, but is very 718 THE ANIMAL PARASITES. rare in man. It is of more frequent occurrence in sheep and cattle. When present only in small numbers, it causes no marked changes; but the presence of large numbers may excite inflammation and proliferation of the periportal connective, tissue. Fig. 549.— Development of the liver-fluke. (After Leuckart.i .1, Miraeidium with genn-balls (a) : B, sporocyst with germ-balls (a) and redice ih) ; C, redia, with intestine («) and germ-balls (t>) ; D, eercaria with mouth (a), abdominal sucking-cup (o), intestine tc), and glands UO. -worm occurring in 3.5-4 mm. broad. Distoma spathulatum (Fig. 551) is a sue! man in Japan and China. It is 10-14 mm. long and The eggs are 0.027-0.03 mm. long and 0.015-0.018 mm. broad. The parasite inhabits usually the bile passages and the gall-bladder, but may also gain access to the pancreatic duct (Katsurada), and pass out into the intestine. When occurring in great numbers (Katsurada counted 4,361 in one case) it causes an obstruction to the outflow of the, bile, and often excites a more or less severe inflammation and proliferation of connective tissue. The parasite is found also in cats and dogs (Katsurada). Distoma Westermanni (Kerbert), or Distoma pulmonale (Baelz) also occurs in Japan, China, and Oorea. The worm is 7.5-10 mm. long, 5-7.5 mm. broad, egg-shaped, with slightly flattened ventral surface. The oval eggs are 0.09 mm. long and 0.050 mm. broad. The internal organization (Fig. X>-2) resembles that of the other trematodes. It occurs in man as well as in cats and dogs (Katsu- rada). It is found most frequently in the lungs, but occurs also in other organs : the pleura, brain, liver, intestinal wall, peritoneum, orbital cavity, eyelid, scrotum, etc In each case it occupies small cavities surrounded by newly formed con- nective, tissue, and occurs occasionally in pairs. In the lung it may be found also in the bronchi, the walls of which show inflammatory changes (Katsu- rada). Tts presence in the lung may give rise to hfemoptoe" and cause death. The number of luna;- a .. . !*">0.— DLitnma lan- ccolatum. (After Hertwig.) .s'. Anterior sucking-cup, and entrance into the forked intestine; s", posterior sucking-cup; h, testicles with vasa deferentia; c, cirrus ; li, uterus ; o, ovary ; /, duct of Laurer and shell- gland ; rder < >f the segment. Before this is reached it widens into the seminal vesicle, and behind this into the fructifying can- al and the so-called "globular body." The germ-preparing organs, which must be sought in the immature segments, consist of a double ovary (fc) and a single albumin-gland (I) ; these are sac-like or tubular organs lying in the posterior portion of the segment and communicating with the globular body. The latter is joined to the anteriorly located uterus (n), which at the time of sexual maturity forms a straight canal. When the eggs enter the uterus from the globular body, in which they pass their first stage of development, the above-mentioned lateral branches sprout out and become filled with eggs. During this process the remaining sex- ual organs disappear. The cortical layer of the proglottides is essentially muscular iu nature, but in addition contains a larger or smaller number of so-called calcareous bodies, which are not entirely wanting in the middle layer as well. The musculature consists of smooth fibres, which form special groups iu the suckers of the head. The surface of the tapeworm is covered with a clear cuticle, which forms the hooks Fig. 558. — Segment of Tccnia solium with fully developed sexual apparatus. (After Sommer.) A, Surface view of segment; B, border of next anterior segment; C, that of next posterior segment, ; a, longitudinal excretory trunk; d,, transverse anastomosis; b, longitudinal plasma-vessel; c, testicular vesicles; d, seminal ducts; e, vas deferens; /, cirrus-bag witli cirrus ; g, porus genitalis ; It, border papilla ; i, vagina; k, ovarium ; 7, albumin-gland; in, shell-gland, and oviduct in front of same ; u, uterus. on the heads. The eggs in the skinned, pale and globular cells. In change into thick, more ovary are thin- yellow, nearly the uterus they yellow balls having a or less opaque shell, FIG. 559. Fig. 560. Fig. 559.- covered with closely set spicules (Pig. 559, a). The latter is often surrounded by a second layer, an albuminous envelope (&) limited by a membrane ; and in it there are embedded granules (primitive vitelline membrane). The diam- eter of the eggs, not including the vitelline membrane, is about 0.03 mm. The thick-shelled spheres are not undeveloped eggs, but contain an embryo with six booklets. An intra-uterine development of the em- bryo therefore takes place, the ripe segments are pregnant animals. -Eggs of Taenia solium, h. With primt tive vitelline membrane ; a, without primitive vitel- line membrane. (After Leuckart.) X 300. Fig. 560.— Cvsticercus cellulosre, with fully devel- oped head in situ. (After Leuckart.) X 4. 724 THE ANIMAL PARASITES. The further development of the embryos enclosed in the brownish shells takes place ordinarily in a new host. Should they gain access to the stomach of a liog. tbe egg-shell is dissolved, and the embryos, thus set free, penetrate into the stomach or intestinal wall. Thence they pass either by the blood-stream or by an active migration through the tissues into this or that organ. Having reached a resting-place, the embryos un- dergo various metamorphoses and become changed inside of two or three months into a cyst filled with serum (Fig. 560), the inner wall of which shoots forth into a bud from which there de- velops a new tapeworm head, a scolex, as well as a sac enclosing the same, a receptaculum scolicis. The cyst containing a tape- worm head is known as a " measle " or cysticercus cell= ulosae. The seoliees, when fully developed, possess a circle of booklets, suckers, a water-vas- cular system and numerous cal- careous bodies in their body- parenchyma. If they gain access to the human stomach, the cyst is dissolved, and there develops, through the formation of seg- ments from the scolex (Am/me), a new chain of proglottides, a new Taenia solium. Fig. 561,-Cysticerci of tin- Taenia solium, in the epi- The Twnia solium inhabits the cardium and myocardium ot a hoc small intestine of man, and is ac- quired by the eating of uncooked pork, since the "measles" belonging to this parasite occur almost solely in the hog and in man. By means of its sucking-cups and its circlet of hooks it clings firmly to the mucosa of the intestine; the remaining portions float freely in the intestine. Usually but a single parasite is present in the intestine, although the presence of several at the same time is not rare. Occasionally as many as thirty or forty have been ob- served in one individual. They excite irritation of the intestinal mu- cosa, colic, and rellex disturbances of the central nervous system. The "measles" occur in the tissues of the hog, sometimes singly, sometimes in great numbers (Fig. 561); and individual organs, as, for example, a muscle or the heart, may be thickly studded with them. In man, cysticerei occur in the most varied tissues — the muscles, brain, eyes, skin, etc. In the meninges and in the brain the measle may ap- pear in the form of mulberry or grape-like collection of cysts, known as cysticercus racemosus (Zenker). The cysts are for the greater part sterile, though some of them may contain a scolex. The importance of the measle depends upon its location, but is in gen- CESTODA. rib eral slight. Its presence in the brain often causes severe disturbances, but in other cases all signs of disease may be lacking. Locally it ex- cites a slight inflammation, which leads to a thickening of the connective tissue in its immediate neighborhood. The cyst may retain its vitality for years. After the death of the scolex the cyst contracts and there is deposited within it a chalky mass. The booklets are preserved in this mass for a very long time. Infection with the "measles " follows the in- troduction of eggs or proglottides into the stomach of man. Taenia mediocanellata or saginata sur- passes the Twnia solium not only in length, as it measures 4-7 metres and more, but also in its breadth and thickness, as well as in the size of the proglottides (Fig. 562). The head is devoid of rostelbun and circle of booklets (Fig. 563), has a flat crown and four large, powerful suckers, which are usu- ally surrounded by a black border of pig- ment. The eggs resemble those of Taenia solium. The, fully developed pregnant uterus (Fig. 564) has a large number of lateral branches which run close to each other, and instead of branching dendritically divide dichotom- ously. The sexual opening lies backof the middle of the lateral border. The segments discharged spontaneously are for the greater part empty of eggs. Fig. 562.— Portions of a Tcenia saginata. (After Leuckart.) Natural size. Fig. »;3.— Head of Taenia saginata, retracted. Black pigmentation in and between the suckers. Unstained glycerin preparation. X 30. Fig. 5114.— Segment of Twnia saginata. (After Leuckart.; y.%. The "measles" are found usually in the muscles and the heart, more rarely in the other organs of cattle (Cysticercus bovis). They are somewhat smaller than the measles found in pork. 726 THE ANIMAL PARASITES. The development follows a course similar to that of Tcenia solium. Malformations of this tapeworm are of very frequent occurrence. The parasite is acquired by man through the eating of raw beef. It has not been definitely settled whether the "measles" of this worm occur in man, but some authors (Arndt, Heller) believe that such an occur- rence does take place. By means of its powerful suckers the parasite is able to cling very firmly to the intestinal wall. Stieda has observed a case in which a taenia 15 cm. long had penetrated through the wall of the duodenum into the pancreas, and had caused tissue-necrosis and haemorrhage in its neighborhood. Taenia cucumerina or elliptica is 15-20 cm. long, and possesses a head with ros- tellum and circle of hooklets. It is of very frequent occurrence in dogs and cats, hut is rare in man. Its cysticercoid inhabits the louse and flea of the dog, more rarely the flea of human beings (Grassi). Taenia nana, a small tapeworm of from 8 to 15 mm. in length, has a head with four suckers and a circle of hooklets. It has been observed chiefly in Egypt and in Italy. B. Grassi was able to obtain several thousands of specimens from two Sicilians who had suffered from severe nervous disturbances. According to his investigations, the taenia passes its entire development, from the embrj'o on, within the same host. Yisconti (Rendiconti R. Istituto Lombardo, xviii., 1886) found, at the autopsy of a young man from northern Italy, great numbers of Tmnia nana in the lower portion of the ileum. In Germany it has been observed in only a few cases (Mertens, Leiclitcnstern, Boder). Taenia diminuta (Bud.) or flavopuneta (Weinland), minima (Grassi) is a tapeworm, 20-60 mm. long, and has a head without hooklets. It is of common occurrence in rats and mice, and has also been observed in a few cases in man. According to Grassi and Bovetti, the measles live in a small butterfly, as well as in beetles. Ton Linstow has recently described as Taenia africana a large tapeworm with scolex devoid of hooklets, which he observed among the negroes of German East Africa. Besides those which also occur in man, taeniae are of frequent occurrence in the domestic animals, both in the carnivora and in birds, as well as in the herbivora. ; Tmnia marginata of the dog is a tapeworm, 1-5 m. long, provided with a double circle of hooklets. Its cysticercus forms cysts (cyslicercus tenuicollis) of varying size in and under the serous membranes of sheep, cattle, goats, and hogs. Tmnia serrata is a tamia found in the dog. It is 50-100 cm. long, and possesses a circle of hooklets. The cysficerei (cysticercus pisiformis) are found in rabbits and hares. Tmnia cmnurus is a tapeworm of the dog, 40-100 cm. long, and is provided with hooklets. It passes its cystic stage most frequently in sheep, where it seeks the central nervous system and forms cysts varying in size from that of a millet seed to that of a hen's egg, which contain great numbers of scolices. Its presence in the brain (cwnurus cereiralis) gives rise to the so-called "staggers " of sheep. Tmnia plicata (10-25 cm. long), Tmnia inamillana (1-3 cm. long), and Tmnia perfo- liatit (3-5 cm. long) occur in horses. Tmnia expansa (4-5 m. long) and Tmnia denticu- lata (25-80 em. long) are the common tapeworms of cattle. Further, still other forms of taeniae occur more rarely as parasites in sheep and cattle. Literature. (Tmnia as Intestinal Parasites.) Blanchard: Cestodes monstrueux, Paris, 1894, ref. Cbl. f. Bakt.. xvii. 1895. Bloehmann: Plasmatische Liingsgefiisse bei Taenia sag. u. Taenia sol ' Cbl.' f Bakt xii., 1892. '' Braun: Die tierisehen Parasiten des Menschen, Wfirzburg, 1903. Erlang-er: Per Geschleehtsapparat v. Taenia cchinoeoecus. Zeitschr. f. wiss Zool . 50 Bd„ 1890. Grassi: Die Taenia nana. Cbl. f. Bakt., i. u. ii., 1887; Bandwunnentwickelung. lb., in., 1888; Entwickelungscyklus von Taenia cucumerina. lb., iv., 1888. Grassi, B., u. Rovelli, G.: Embryolog. Porschungen an Cestoden. Cbl f Bakt v 1889. " * Guillebeau: Helminthologische Beitritge. Virch. Arch., 119 Bd 1890. Huber; Bibliographic d. klin. Helminthologie, 1-4 Ilel'tc, Munohen, 1891-92. ECHINOCO-CCUS. 727 Kahane; Anatomic von Taenia perfoliate. Zeitschr. f. wiss. Zool., xxxiv. Kitt: Lehrb. d. pathol.-anat. Diagnostik, ii., Stuttgart, 1895. Leichtenstern : Taenia nana u. flavopunctata beim Menschen. Deut. med. Wocli., 1892. v. Ijinstow: Taenia nana u. niurina. Jen. Zeitschr. f. Naturwiss., 1896. Irutz: Beobacht. ub. Taenia nana u. flavopunctata. Cbl. f. Bakt., xvi., 1894. Mingazziui: Sur le mode d'adhesion des cestoides a la paroi iutestinale. Arch. ital. do biol., xxxii., 1899. Niemie: Ueb. d. Nervensystem d. Gestodcn. Arb. a. d. Zool. Inst. d. Univ. Wien, xii., 1886. Nuttall: The Poisons Given Off by Parasitic Worms in Man and Animals. Amer. Nat, 1899. Peiper: Thier. Parasiten d. Menschen. Ergebn. d. allg. Path., hi., 1897 (Lit,), u. vii., 902 (Lit.). Roder: Taenia nana in Deutschland. Milnch. med. Woch., 1899. Sommer: Ueber Bau u. Entwickelung der Geschlechtsorgane v. Taenia mediocanellata u. Taenia solium, Leipzig, 1874. Stieda: Durchbohrung d. Duodenums u. d. Pankreas durch. e. Taniae. Cbl. f. Bakt., xxviii. 1900. Stiles: The Type Species of the Cestode Genus Hymenolepis. Bull. U. S. Ilyg. Lab., No. 18, May, 1903. Stiles and Hassall : A Revision of the Adult Cestodes of Cattle, Sheep, and Allied Ani- mals, Washington, 1884; Tapeworms of Poultry, Washington, 1896. The Inspec- tion of Meats for Animal Parasites, U. S. Dept. Agr. Bulk, 19, 1898. Ward: A New Human Tapeworm (Tw)iia zonfusa). West. Med. Rev., 1896; Zool. Anz., 1897; Cestoda. Ref. Hdb. of Med. Sc, 2d ed., vol. ii. Weinland: Human Cestodes, Cambridge, 1858. Zschokke: Studien fiber den anatom. u. histol. Bau der Cestode. Cbl. f. Bakt., i., 1887; Reek, sur la structure des Cestodes, Bale, 1889. (Gysticercus in Man.) Askanazy : Cysticerkenbildung an der llirnbasis. Beitr. v. Ziegler, vii., 1890. Bitot et Sabrazes: Etude sur les cysticerqu.es en grappe r but little albumen, but on the other hand does contain sodium chloride, calcium oxalate, triple phosphates, uric acid, sugar (in the liver), and often also cholesterin. The brood- capsules are always situated on the inner surface, in case they are not mechanically dislodged ; and are visible through the transparent parenchyma as small white points. Occasionally the cyst remains sterile. In many cases daughter=cysts (Fig. 567, e) are formed. Their de- velopment proceeds in the depth of the cuticle independently of the real parenchymatous layer. Between two lamellae of the cuticle there arises Fig. 5B5. — Fii'H-prown Taenia echino- coccus. (Af- ter Leuckart.) X 12. Fifi. 566.— Wall of an echinococcus-cyst containing brood-capsules and sconces (alcohol, carmine) a Glutinous membrane; h, parenchymatous layer with vesicular cells; i', brood-capsules: it, <-. f a h scolices in different stasis of development. X 100. a collection of granules, which surround themselves with a cuticle, and thereby become the centre of a new set of layers. As the number of layers increases, the cavity grows larger and the contents become clear. ECHINOCOCC IS. 729 If the daughter-cysts grow they bulge out the wall of the mother-cyst like a hernial sac, until it finally gives way and liberates its contents. If they now pass outward by the side of the parent-cyst, they obtain from Fig. ;j67. — Echinococcus hyda&idoms. a, Surface of liver; h, indurated connective tissue; c, daughter-cysts within a parent-cyst, which has been opened by an incision ; if, adhesions. Three-fifths natural size. the parenchyma in which they lie an external, capsule of connective tis- sue, and then produce brood capsules in the same manner as the primary cysts arising from the six-hooked embryos. An echinococcus with an exogenous proliferation is called echinococcus granulosus (scolecipariens Kuehenmeister), or sometimes also echinococ= cus veterinorum from the fact that it is of frequent occurrence among the domestic animals. A second compound form of the echinococcus is the echinococcus hydatidosus. It is characterized by the presence of inner daughter-cysts (Fig. 567, c). According to statements made by Xaunyn, and also con- firmed by Leuckart, the scolices and brood-capsules undergo a cystic metamorphosis, and so become changed into daughter-cysts which occa- sionally produce grand-daughter cysts. Through the formation of numer- ous daughter-cysts the chief cyst may attain a very large size. The infection of man follows the ingestion of the eggs of the taenia which occurs in dogs. The cysts are most often found in the liver, but the echinococcus occasionally occurs in the most diverse organs — for example, in the lungs, spleen, kidneys, intestine, in a bone or in the heart. With the exception of the disturbance of the tissues from press- ure and of the local inflammation which it causes fthe latter leading to the formation of a connective-tissue capsule in many organs') the cyst often 730 THE ANIMAL PARASITES. produces no harmful effects upon the affected individual. It often dies on attaining a certain size (that of a walnut to that of an apple), the thud is absorbed, the cyst contracts, and there remains within it a fatty, cheesy detritus, which often calcifies to a mortardike mass. The hook- lets are preserved for a very long time. In other cases the echinococcus becomes larger, particularly when endogenous or exogenous daughter- cysts develop. It may become dan- gerous through its size alone. Severe inflammations are occasionally produced, particularly after trauma or after rupture of the cyst into one of the body-cavities. Eupture into a blood-vessel may also occur and lead to the metastasis of cysts and an embolic blocking of vessels. In more favorable cases rupture may take place externally or into the intestines. The spontaneous spread of brood-capsules and scolices in the same FIG. ;>68. — Transverse section of an Echinocncmis multilaciUarix. a, Alveolar echinococcus tissue; h, liver tissue ; c, cavity produced by softening ; (/, fresh nodules. Natural size. host, as well as the experimental transplantation of the same into another host (Alexinsky, Devi'-) may lead to the formation of new cysts. The form of the parasite known as echinococcus alveolaris or multilocularis presents itself as a hard tumor, situated usually in the liver, rarely in other organs (brain, spleen, adrenal), and possesses an alveolar structure (Fig. 568), in that a firm, dense connective-tissue mass encloses numerous cavities. Its contents are translucent and gelatinous, or consist of fluid and a gelatinous substance. The cavities are in part spherical and in part irregular in shape. Usually, through the soft- ening and disintegration of the parenchyma, ulcerative, cavities (c) are formed. In other places the tissue is fibrocaseous, necrotic or calcified, or is impregnated with bile. At times the caseation of the proliferating tis- sue is the most prominent feature of the process; at other times the alve- olar structure. When the development of the colonies has progressed further, there appear in the tissue gray and yellowish nodules (, ji), is much thicker, in the fe- male (11) cylindrical, and in the male (A) rolled up and provided with a spiculum (S-;. Fig. 586.— Encapsulated muscle trichinae. (After Leuckart.) < CO. side of the sarcolemma and penetrates even within the sarcolemma tube, the muscle- nuclei being destroyed. Fat-cells may appear later in the con- nective tissue of the capsule, the development of the latter being especially marked at the poles. The intestinal trichinae have a limited life of from five to eight weeks. The muscle-trichinae, on the other hand, may live for a very long, possi- bly an unlimited time — that is, until the death of the affected individ- ual ; or at any rate for years, although, accord- ing to Ehrhardt, a few may die before the en- capsulation. After some time there frequently occurs a deposition of lime-salts in the capsule, especially at the poles, causing it to appear glistening-white by re- flected light, and cloudy and dark by transmitted light. In rare cases the trichina} after dying also become calcified. Trichime have been observed, besides in man, also in the hog, cat, dog, rat, mouse, marmot, polecat, fox, marten, badger, hedgehog, and raccoon. Through the feeding of trichinous meat muscle-trichina? may also be developed in rabbits, guinea-pigs, sheep, dogs, etc. Man becomes infected through the eating of uncooked pork. The invasion of the tri- chiuae j)roduces various phenomena in man. The introduction of trichin- ous meat into the intestine is followed by the symptoms of an intestinal catarrh. With the invasion of the muscles there are produced pain, swelling, oedema, paralysis, and not infrequently fever. In the blood there occurs a marked increase of the eosinophile cells (Opie, Schleip). The symptoms are most severe in the fourth and fifth weeks. Death not infrequently results. The intensity and severity of the symptoms depend in general upon the number of the worms wandering into the muscles. The trichinae are found most abundantly in the diaphragm, tongue, in- tercostal muscles, the muscles of the neck and larynx, the lumbar muscles, and are scattered most sparsely in the distant muscles of the extremities. They are usually most numerous about the insertions of the tendons. .According to Frothingham (Jour, of Med. Res., 1906). the trichina embryos are found in the sinuses of the mesenteric lymph-nodes and in the liver sinusoids, showing that they enter the lymph-stream and are distributed by the circulating blood. Trichina embryos are found in the areas of haemorrhage occurring in the lungs. Local destruc- tion of tissue may take place in the liver, pancreas, brain, and heart as a result of the parasite leaving the blood-vessel. The capsule of the encysted trichinae is formed of connective tissue which surrounds the whole of the invaded fibre. Literature. ( Trichina. Spiralis ; Trichinosis. ) Askanazy: Zur Lehre von der Trichinose. Cbl. f. Bakt., xv., 1S94; Virch. Arch., 141 Bd., 1895. Cerfontaine : Contr. a let. de la trichinose. Arch.de bioh, xni., 1893; Cbl. f. Bakt., xxi., 1897. Chatin: La trichine et la trichinose, Paris, 1SS3. 740 THE ANIMAL PARASITES. Ehrhardt: Muskelveranderungen bei Trichinose. Beitr. v. Ziegler, xx., 1890. Graham: Naturgesch. d. Trichina spir. Arch. f. mikr. Anat., 1., 1897. Hertwig: Entwiekelung d. Trichinenkapsel. Munch, med. Woch., 1890. Johne: Der Trichinenschauer, Berlin, 1904. Langerhans: Ueber regressive Veriind. d. Trichinen u. ihrer Kapseln. Virch. Arch., 130 Bd., 1892. Lewin: Zur Diagnostik u. path. Anat. d. Trichinose. Deut. Arch. f. klin. Med., 49 Bd., 1892. Opie: Relation of Cells with Eosinophile Granulation to Infection with Trich. spir. Am. J. of the Med. Sc., 1904. Ossipow: Veriind. im Spatstadium d. Muskeltrichinose. B. v. Z., xxxiv., 1903. Riess: Triehinenkrankheit. Eulenburg's Realencyklop., xxiv., 1900. Schleip: Homberger Trichinosisepidemie (Eosinophilic). D. A. f. klin. Med., SOBd., 1904. Soudake'witsch: Modific. des fibres muscul. par la trichinose. Ann. de l'lnst. Pasteur, vi., 1892. Stiles: Trichinosis in Germany. Bull. 30, I*. S. Bureau of Animal Indus., 1901. Volkmann: Trichinose. Beitr. v. Ziegler, xii.. 1894. Williams: The Frequency of Trichinosis in the United States. Jour, of Med. Res., 1901. Zenker; Virch. Arch., IS Bd.; Deut. Arch. f. klin. Med., viii. § 202. Filaria or Dracunculus medinensis, the Guinea-worm (Fig. 587), is a thin, thread-like female worm from 00 to 100 cm. in length. The males (observed by Charles) which were attached to female filariae, were only 4 cm. long. The an- terior extremity is rounded off, while the posterior tapers into a pointed tail which is curved toward the belly. The. external cover- ing consists of a firm cuticle, which at the cephalic end is thickened in the form of a shield. The intestinal canal is narrow and has no anus. The uterus, filled with young, takes up nearly the whole of the body- cavity. The embryos, which are set free by the bursting of the mother- worm, have a firm cuticle and an awl-shaped tail. As in- termediate host, the embryos seek out small crustacere, in which they are probably taken into the stomach of man with the drinking-water. In Africa and Asia the worm is of fre- quent occurrence. It develops in the skin to sexual maturity and causes abscesses of the af- fected region. It is usually found on the lower extremities, especially in the region of the heels. Filaria sanguinis hominis is the name given to the larvce (Pig. 588) of a worm, which occur in • the blood and lymph of man, Fir,. riW. — raaria-slve Dracuiuulim medincnsi* (After Leuckart.) Natural size. Fir. 58R.— Embryo of Filaria Bancrnfti, known as Filaria eanauinis Jiomi/nis. (After Lewis.) X 400. FILAKIA. 747 and are about 0.35 mm. in length. The sexually mature worm is fili- form, the male about 8 cm. long and the female 15 cm. It is called Filaria Bancrofti after its discoverer. The worm inhabits the lymph- vessels, particularly those of the scrotum and lower extremities, and may l>e present in large numbers. It causes lymph-stasis and inflammations which lead to swellings of the lymph-glands and to elephantiasis-like thicken- ing of the tissue, associated with oedCma and lymphangiectasis. Purulent inflammations, lymph-abscesses, buboes, chylous hydrocele, and chylous ascites may appear in consequence of its presence. From the lymphatics of the limbs and scrotum the eggs and embryos (0.35 mm. long) (Fig. 588) pass into parts of the lymphatic system aud into the blood, giving rise to hematuria, chyluria, and chylous diarrhoea. According to Manson and Scheube the filaiiie are present in the blood taken from the skin only during the night; von Linstow explains this phenomenon as due to the fact that during sleep the peripheral vessels become dilated, and so permit the entrance of the filaria?, while the cap- illaries, being narrower during the day, do not permit such entrance. The hematuria is the result of the collection of embryos in the blood- vessels of the urinary tract. The chyluria and the chylous diarrhoea, on the olher hand, are due to the obstruction by the parasites of the thoracic duct, thus causing a lymph-stasis which extends to the lymphatics of the bladder and intestine and there occasions the escape of lymph. Accord- ing to Scheube the rupture of the lymphatics is also attended by a rupt- ure of blood-vessels, so that blood becomes mixed with the lymph. The embryos may pass out from the urinary apparatus through the urine. The distribution of the embryos is, according to Manson, accomplished by means of mosquitos, which take up the parasite during the act of blood- sucking. In the mosquitos they pass through a second stage of develop- ment and are then (James) after two or three weeks ready for the infec- tion of a new host. Manson formerly held the opinion that they entered the water, and in a free condition Mere taken up in the water into the intestinal tract. The investigations of James, Low, Grassi, aud NYte, who followed their development and migration in the body of mosquitos, make it seem probable that they are transmitted to a new host through the bite of the mosquito. The Filaria sanguinis occurs, so far as is known, only in the tropics (Brazil, Egypt, Algiers, Madagascar, Zanzibar, Soudan, South China, Calcutta, Bahia, Guadeloupe). Of the Acanthocephala, nematode-like worms having no intestine, and possessing at the anterior end a retractile proboscis set with booklets, the most important is the Echinorhyrwus gigas. The male is 10-15 cm. long, and the female 30-50. It occurs chiefly in the intestine of the pig, and penetrates into the intestinal wall. According to Lindemann, it occurs in Southern Russia also in man. The rose chafer and the May beetle serve as intermediate hosts. The Filaria bancrofti is found in the West Indies and occasionally in the Southern .States. More rarely cases are found farther north. Mackenzie estimated the number of filana-embryos present in the total oulk of the blood of a case of hffimatochyluria closely studied by him at from thirty-six to forty millions The patient died from empyema; during the disease the filaria; died. In the domestic animals numerous filaria-species occurand inhabit different parts of the body. Filaria papillosa is a common parasite of the horse, donkey, and cattle; it lives in the serous cavities and reaches a length of from 5-18 cm. Filaria hmmalica, a worm 13-13 cm. long, inhabits the right heart and the pulmonary artery of the dog, and in this situation gives off its embryos to the blood-stream. It occurs particularly 748 THE ANIMAL PARASITES. in America, China, and India. Filaria hcemorrhagica or multipapillosa causes a nodular cutaneous affection in the horse and donkey. Literature. (Filaria. ) Barth: De la filaire du sang et ses rapports avec l'elephantiasis des Arabes et quelques autres maladies des pays chauds. Ann. de derm, et syph., 1881. Blanchard. Filaria loa. Arch, de parasitol, ii., 1899. Charles: History of the Male of Filaria Medinensis. Scient. Mem. Med. Office Army of India, vii., Calcutta, 1892. Firket: De la filarose du sang. Accad. R. de med. de Belg., Bruxelles, 1895. Goetze: Die Chylurie, Jena, 1887. Grassi: Filaria inermis, ein Parasit des Menschen, des Pferdes u. des Esels. _ Cbl. f. Bakt., i., 1887; Entwickelungscyclus von 5 Parasiten des Hundes (Taenia cucu- merina, Ascaris marginata, Spiroptera sanguinolenta, Filaria immitis Leidy und Ha?matozoon Lewis). Ibid., iv., 1888; Hserriatozoon Lewis (Filaria des Hundes). lb., vii., 1890. Grassi u. Noe. Uebertrag. d. Blutfilaria (lurch Stechmiieken. Cbl. f. Bakt., xxviii., 1990. Havelburg: Leber Filaria Sanguinis und Chylurie. Virch. Arch., 89 Bd., 1882. Huber: Bibliographie d. klin. Hefminthologie, Suppl., Jena, 1898. James: On the Metamorphosis of Filaria sanguinis in Mosquitoes. Brit. Med. Journ., ii.. 1900. Kasewurrn u. Steinbriick: Nematoden bei Haustieren. Ergebn. d. a. P., viii., 1904 (Lit.). Laveran et Blanchard: Les vers du sang, Paris, 1895. Lewis: Geschlechtsreife Form der Filaria sanguinis. Cbl. f. d. med. Wiss., 1877. v. Linstow: Leber Filaria Bancroft! Cobbold. Cbl. f. Bakt., xii., 1892. Lothrop and Pratt: Two Cases of Filariasis. Amer. Journ. of Med. So., cxx., 1900 (Lit.). Low: Filaria nocturna in culex. Brit. Med. Journ., i., 1900. Mackenzie, St.: Transactions of the Pathological Society of London, 1892. Manson: The Filaria Sanguinis, London, 1883; The Filaria Sanguinis Hominis Major and Minor, Two New Species of Haematozoa. Lancet, 1891; rcf., Cbl. f. allg. Path., ii., 1891. Murata: ZurKenntniss der Chylurie. Mittheil. d. med. Fac. der TJniversitat, Tokio, 1888. Peiper: Tierische Parasiten. Ergebn. d. a. P., vii., 1902. Rieck: Filaria immitis u. ihre Embryonen im Blute v. Hunden. Deut. Zeitschr. f. Thiermed., xiv., 1889. Scheube: Die Krankheiten der warmen Lander, Jena, 1903. Sonsino: The Life-history of Filaria Bancrofti. Brit. Med. Journ., i., 1900. III. Arthropoda. 1. Arachnida. § 203. The parasites included among 1 the Arachnida are chiefly epizoa, which either temporarily or permanently inhabit the skin. Only one species — Pentastoma — occurs in the larval form within the tissues. The most common parasites of this group belong to the Mites (Aearina). The pentastoma belongs to the family of tongue-worms (Pentastomidce or Idnguatulidce) . (1) Acarus scabiei or Sarcoptes hominis, the itch=mite, is a para- sitic mite the size of a pinhead with a turtle-shaped body, provided on the ventral surface both anteriorly and posteriorly with two pairs of legs, each of which is furnished with bristles (Fig. 589). The anterior pairs of legs extend out into pedicled clinging-discs. The same arrangement is found in the posterior two pairs in the male, while in the female both of the posterior pairs end in long bristles. Several bristles are also found PARASITIC AKTHROI'ODA. 749 along (he border of the posterior portion of the body, while the back is studded with tooth-like knobs. The head is round and likewise set with bristles. The female is nearly double the size of the male. Fig. 589. — Female itch-mite, ventral surface. X 40. The mite lives in the epidermis (Fig. 5!t0, a, d) in which it forms burrows, some of which are 10 cm. long. In the burrows the female (d) lays the eggs, which develop in situ into the young itch-mites (e), which penetrate still deeper into the epi- dermis, and after repeated sheddings of their skins grow into sexually mature animals. The skin responds to the irritation produced by the Fig 590 —Scabies (alcohol, carmine), fi, Horav layer of the epidermis, perforated by numerous bur- rows of' the itch-mite- b, mucous layer, and papillary body, the latter greatly enlarged and infiltrated with cells; c, cutis infiltrated with cells; 3, section through a fully developed itch-mite; e, eggs and embryos of' different sizes ; /, fasces. X 20. 750 THE ANIMAL PARASITES. presence of the mites by an increased production of epithelial cells (a ) and inflammation (c). The latter is still further increased through the scratching of the spots which itch in consequence of the invasion. 2. Leptus autumnalis, the harvest-mite (Fig. 591) is the red-colored larva of a variety of TromMdidce, which lives upon grasses and bushes and upon grain, and when occasion offers alights upon the skin of man, where it penetrates the epithelium and causes itching and inflammation. 3. Demodex or Acarus folliculorum hominis (Fig. 502) occurs either ■singly or in numbers in the hair-follicles of the face, as well as in the ducts of the sebaceous and Meibomian glands. Hausche found the de- modex on the eyelashes in seventy-nine per cent., and Joers in sixty-four per cent, of the cases examined. Children under one year of age were free. The female is 0.4 mm. long, the male 0.3 mm. The eggs are de- posited upon the shaft of the hair or upon any other portion of tissue, and develop after two sheddings into sexually mature animals which are found in the entrances to the hair-follicles and sebaceous glands, with their heads directed inward. The assumption that the demodex causes inflammation (acne, blepharitis acarica) is not supported (Joers, Hausche), since in spite of its presence in the great majority of cases signs of inflammation are wanting. It has on its anterior ventral surface (Fig. 592) four pairs of short thick feet. The head possesses a snout and two feelers. 4. Ixodes ricinus, Ihe wood-jack or wood-tick (Fig. ">:>;;), is a. fait*y large yellowish-brown member of the Arachnida belonging to the ticks. MRS! *'*:' /f ^w; Pig. 591. Fig. TTTn " r "r i n'n n 'Trp rv FiG. 594. Fig. 591.— Leptus autumnalis. (Alter Kucheumeister and Zum.) Fig. 592.— Acarus folliculorum hominis. (After Perls.) X 300. Fig. 593— Ixodes ricinus, sucked half rail of blood. X ~>. Fig. 594.— Cephalic end of Pentastoma denticulatum. (After Perls.) parasitic abthbopoda. 751 It has a black head provided with a sucking apparatus, aud a very dis tensible leathery body. It is of common occurrence upon grass aud bushes, and sometimes alights upon man or beast. By means of its sucking apparatus it draws blood from the skin and swells up to a very remarkable extent. 5. Pentastoma denticulatum is the larva of Pentastoma taenoides, a lancet-shaped animal belonging to the tongue-worms or Pentastomidcc. It inhabits the nasal, frontal, and maxillary cavities of various animals, especially of the dog, very rarely of man (Laudon) and occasions inflani- mations. The female of the mature animal is 50-80 mm. long, and an- teriorly from 8-10 mm. broad; the male is 16-22 mm. long, and anteriorly from 3-4 mm. broad. The body consists of eighty-seven to ninety seg- ments, the most anterior of which bear lateral segment-appendages, the pairs of limbs. The eggs, which are produced in very great numbers, are oval. The larva is 4-5 mm. long, 1.5 mm. broad, plump, flattened, and inhabits chiefly the liver, lung, or spleen, or more rarely the other organs of man and the herbivora. It occurs in the form of a small nodule encap- sulated in connective tissue. The body consists of about fifty ring-shaped segments which are provided at the borders with spines (Fig. 594), and the cephalic end is provided with four hook-shaped feet. The eggs are taken in from the external world through the intestinal tract. The para- sites set free in the intestine wander by means of a boring apparatus through the mesentery into the mesenteric lymph-glands, or penetrate directly into the blood-vessels, and are carried by the blood-stream to the liver or even to the lungs, where after shedding they develop into the encysted larvae. The larvae may in their wanderings gain access to the nasal cavity of their host, and develop into mature animals, al- though the further development usually takes place only after their re- ception into a new host. According to the published reports of TanaJca a small red mite occurs in great numbers in different parts of Japan during midsummer, and clinging firmly to the skin of man causes the so-called Kedani-disease, which is characterized by inflammation of the skin and lymph-glands, with high fever, and often ends fatally. It is probable that these symptoms are due to secondary infections (proteus and streptococci) in the bites of the mite. Argas reflexus, a tick, causes by its bite not only local inflammation, but also nausea, diarrhoea, cardiac palpitation, asthma, etc., through a poison derived from its salivary glands. It is found also in pigeons. In the domestic animals living mites occur very frequently as parasites of the skin, and represent different species of various families [Sarcoptidcs, Dermatocoptes, Dermatopliages, and Acarides). Sarcoptes hominis, the burrow-mite or itch-mite of man. is found also in horses and Neapolitan sheep. In addition still other different species of sarcoptes may be distin- guished as parasites of the domestic animals — for example, Sarcoptes squamiferus in dogs, hogs, sheep and goats, and Sarcoptes minor in cats and rabbits. Dermatophagus, the devouring-mite (Fig. 595), with a broad head, occurs in different animals, and different species may be accordingly distinguished. It lives upon the cells of the epidermis and causes a desquamation of the skin. Dermatocoptes, the sucking-mite (Fig. 59b), with long narrow head, takes blood and lymph from the skin and causes inflammation. Dermatocoptes communis occurs in horses, cattle, and sheep. Dermatocoptes cuniculi is a parasite of the rabbit's ear, and causes the ear-scab which usually appears on the inner side of the auricle. Symbiotes equi of Gerlach is a mite which occurs chiefly upon the feet of the heavy English and Scotch horses, and causes a moist dermatitis, often incorrectly called midanders. Dermanyssiis avium is a long, red, blood-sucking mite, about 1 mm. long, and is often found upon birds. Dermatoryctes mutans causes the font-itch of chickens whereby the skin acquiresa mortar-like scabby covering. 752 THE ANIMAL PARASITES. Acarus folliculorum o; Demodex folliculorum, the mite of the hair-follicles, occurs most frequently in the dog or cat, more rarely in the hog, cattle, and the goat. In the dog it causes the formation of scales, falling out of the hair, and a pustular eruption. Demodex phylloides causes in swine nodular inflammations and ulcers particularly on the snout, neck, breast and flanks, and the inner surface of the thighs. The purulent foci contain great numbers of the mites. The mite may develop also on cattle. Firj. 595. — Male of Dermatophagus communis seen from the ventral side. (After Piitz.) X 50. Fir,. 596.— Male of Dcrmatocoptes communis, seen from the ventral side. (After Piitz.) X 50. Various species of Ixodes of the tick family occur on dogs, cattle, and sheep; Argas reflexus occurs on pigeons; and other forms of ticks occur on the domestic animals. Leptus autumnalis occurs also on dogs and chickens. Pentastomata occur also in cattle, sheep, and goats, and in certain regions are very common in the first-named. 2. Insecta. § 204. The parasites belonging to the class of Insecta are for the greater part epizoa. In part they are but transient inhabitants of the skin, deriving from it their nourishment ; in part they are permanent inhabi- tants and utilize the skin structures for the deposit of their eggs. Of the numerous species belonging to this class the following may be mentioned: (1) Pediculus capitis, the head louse (Fig. 597), inhabits the hairy portions of the head, and derives its nourishment (i.e., blood) from the skin, by means of its feeding apparatus. Its eggs (nits) are barrel-shaped and white, and are attached to the hairs by means of a chitinous shell. The embryo hatches in about eight days. In consequence of the scratch- ing induced by the itching there often arise inflammations of the skin, in particular eczemas, which are often relatively severe. (2) Pediculus pubis (Phthirius ingidnalis), the felt or crab-louse (Pig. 598), inhabits the hairy parts of the trunk and extremities. Its habits of life are the same as those of Pediculus capitis. (3) Pediculus vestimentorum, the clothing or body-louse (Fig. 599), lives in the wearing apparel, and lays its eggs in the same. It gets upon man to obtain its nourishment. PARASITIC AKTIIROPODA. 753 (4 ) Cimex lectularius, the bedbug, dwells in beds, floors, closets, etc. During the night it gets upon man to suck blood. It causes wheals in the skin. (5) Pulex irritans, Ihe common flea, also draws blood from the skin. At the point where it has sucked there is found a little punctate haemor- FIG.597. Fig. 598. Fl(i. 599. Flu. 597. —Femaleof Pcdiculus capitis, seen from the ventral surface. (KiichenmeisterandZurn.) /. 13. Fig. 598.— Male of Pcdiculus pubis, seen from the ventral surface. (Kuchenmeister andZurn.) X 13. Fig. ;>99.- Female of Pedicuhts vcstimentnrum, seen from the ventral surface. (Kuchenmeister and Ziirn.: • 9. rhage. Occasionally it causes whe;ils and swellings. It lays its eggs in the cracks of floors, in sawdust, etc. (6) Pulex penetrans (Sarcopsylla penetrans), the mud flea, occurs in South Africa in the sand. The female lays her eggs in the skin, thereby causing an intense inflammation. (7) riosquitos provided with stinging and sucking apparatus (Culici- dee and Tijmlidce), horse-flies (Tabanidce), and flies (Stomossyidce) draw blood frequently from the .skin of man. Various flies (CEstridce, biting Fig. 600. Fig. 601. Fig. 600.— Larva of Anthomia canicularis. (After Braun.) About ti. Fig. 601.— Larva of Musca vomiloria. (After Bniun.) About X 6. Fig. 602. — Larva of Lucilia macellaria. (After Uraun.) About x 0. Fig. 603. — Larva of Dcrmatobia ajuniventris. (After Blatichard.I ibout X 6. 48 '54 THE ANIMAL PARASITES. bot-flies, Muscidw or blow-flies) occasionally lay their eggs in the skin, m ulcers or wounds, or in the accessible body-cavities, in consequence of which the maggots developing cause local destruction of tissue and in- flammation {myiasis). Under certain conditions their larva (for example, that of Anthomia canieularis, Fig. 600) may get into the intestinal tract with the food and there undergo further development (myiasis intcstinaUs). This is especially likely to occur when abnormal conditions which inter- fere with digestion are present in the stomach and intestine. The eggs of the Muscidce (in Europe usually of SarcophUa wohlfarti and Musca vomitoria [Fig. 601], in America of Compsomyia or Lucilia maceUaria [Fig. 602], and Musca anthropophaga), when laid upon the mucous membranes or in wounds, hatch after a few hours, and cause destruction of the neigh- boring soft parts through their efforts to obtain nourishment. In the auditory canal, nose, and antrum of Highmore the bones may be laid bare (myiasis mucosa). In the course of about a week the larvre leave the ulcers and pass into the pupa stage in the earth. The CEstriclas (in Europe, Hypoderma bonis and Hypoderma (liana ; in America, Dermatobia cyaniventris [Fig. 603] or Cuterebra noxialis) lay their eggs upon wounds or in the intact skin. Thelarvse, hatching very soon, penetrate into the cutis by means of their hooklets, and after several sheddings grow in from one to six months into larger larva? about 2 cm. long. Tliey cause, particularly in their later stages, painful swellings of tlie neighboring tissue (myiasis cestrosa). GOi.—GastrophU'us cqu Male; ). ' (After Bnnicr > arva. Parasites belonging to the Muscidce and CEstridce play a more important role in the case of the domestic animals than in man; and the larva? of the species of CEstrus in particular occur as parasites in animals. For example, the larva? of Gastrophilus equi (Fig. 604), Gast. pecorum and (last. hosmorrhoidalis inhabit the stomach and adjacent portions of the intestinal tract of the horse, where they complete their development up to the pupa-stage, when they leave the animal. OEstrus ovis lays its larva 1 in the nasal cavities of sheep, whence they may wan- der, under certain conditions, into the frontal, nasal, and maxillary cavities, or even into the cranial cavity, and excite inflammation. Hypoderma or CEstrus bovis, the biting fly, or bot-fly, lays its eggs upon the skin of cattle. The larva bores into the skin and enters the spinal canal of cattle, completing here its development up to the pupa-stage, at which time it leaves (he animal. Accord- ing to Schneidemiihl, the larvre do not always enter through the skin, but are more often taken in with the food, whereupon they penetrate through the wall of the (vsophagus toward the skin and spinal canal. The latter follows from the fact that they are found in the wall of the oesophagus from October to January, and under the skin, on the other hand, from January to April. In the skin they cause the so-called " fly-boils." SarcophUa wohlfarti (Sarcoplwga magnified) lays its larva? upon the' skin of horses, sheep, cattle, dogs, and geese. Lucilia macellaria lays its eggs between the hind legs of lambs suffering with diarrhoea. The larvae seek the thick-wooled portions of the root of the tail and the lumbar region and bore into the skin. PARASITIC AHACHNIDA. 755 Literature. (Parasitic Arachnida and Insecta.") D'Ajutolo: Dell' argus reflexus parasita dell' uomo. Mem. della R. Accad. di Bolog- na, viii., 1899. Brauer: Monographie der Oestriden, Wien, 1863. Csokor: Ueber Pentastomen u. Pentastoma denticulatum aus d. Leber des Pferdes. Zeitschr. f. Veterinark., i., 1887; Cbl. f. Bakt,, i., 1887. Dubreuilh: Les dipteres cuticoles chez l'homme (Lit.). Arch, de men. exp., 1894; Dermatozoaires, Paris, 1900. Gartner: Ueber die sog. Fliegenlarvenkrankheit, Wien. klin. Woch., 1902. Gmeiner: Ohrraude des Kaninchens. D. tierarztl. Wochenschr., 1903. Hausche: Demodex folliculorum im Augenlide. Munch, med. Woch., 1900. Hoffmann: Fliegenlarven im menschl. Magen. Miinch. med. Woch., 1888. Huber: Bibliographie d. klin. Entomologie, i.-iv., Jena, 1898-1900, u. i., Jena. 1903. Joers: Acarus folliculorum u. s. Bez. z. Lidrandentziindung. Dent. med. Woch., 1899. Joseph: Ueber d. Fliegen als Schadlinge u. Parasiten d. Menschen. Deut. Modicinal- Zeit., 1887; Ueber Myiasis externa dermatosa. Monatsh. f. prakt. Derm., ]x,s7. Kitt: Lehrbuch d. path.-anat. Diagnostik, i., Stuttgart, 1900. Kraus: Farbetechnik z. Nachweis des Acarus folliculorum. A. f. Derm., 58 Bd , 1901. Kulag-in^Naturgeschichte des Pentastomum denticulatum. Cbl. f. Bakt., xxiv., 1898. Lallier: Etude sur la myase du tube digestif, Paris, 1897 (Lit.). Lampa: Fliegenmaden im Darm des Menschen. Cbl. f. Bakt., iv., 1888. Leuckart: Bau u. EntTvickelungsgeschichte des Pentastoma, Leipzig, 1880. JLublinski: Fliegenlarven im menschl. Magen. Deut. med. Woch., 1885. Majocchi: Demodex follic. nelle ghiand. Meibom. Arch. p. le Sc. Med., 1899. Nuttall: Insects, Arachnids and Myriapods as Carriers of Disease. Johns Hopkins Hosp. Pep., 1899. Osborne: Insects Affecting Domestic Animals. U. S. Dept. of Agric. Bull., 1S9C. Peiper: Fliegenlarven als gelegentl. Parasiten d. Menschen, Berlin, 1900; Arthro- poden. Ergebn. d. allg. Path., vii., Wiesbaden, 1902 (Lit.). Rahlmann: Blepharitis acarica. Deut. med. Woch., 1892; Monatsbl. f. Augenheilk 1X99. "' Salmon and Stiles: Sheep Scab, Washington, 1898. v. Samson-Himmelstierna: Ein Ilautmaulwurf. Arch. f. Derm., 41 Bd., 1897. Sandahl: Ueb. d. Vorkommen v. Insecten im menschl. Organismus. Cbl f Bakt v., 1889. Scheube: Die Krankheiten d. warmen Lander (Sandfloh, Fliegenlarven), Jena, 1903. Schlesinger u. Weichselbaum: Myiasis intestinalis. Wien. kl. Woch., 1902. Schneidemuhl: Entwickelungsgeseh. d. Bremsenlarven. Cbl. f. Bakt., xxii., 1897. Schoyen: Ueber das Vorkommen von Insecten am menschl. Korper. Biol. Cbl iv 1885. Scischka: Anatomic der Scabies. Arch. f. Derm., 53 Bd., 1900. Shipley: Revision of the Linguatulidse. Arch, of Parasit., 1898. Sommer: Pentastomum denticulatum. Eulenburg's Piealencyklop., xviii., 1^98 (Lit.). Tanaka: Aetiologie u. Pathogenese d. Kedani-Krankheit. Cbl. f. Bakt., xxvi., 1899. Ward: Arachnida. Ref. Handb. of Med. Sc, 2d ed., vol. i. Wilms: Myiasis dermatosa oestrosa. Deut. med. Woch., 1897. (Animal Parasites.) Blanchard: Parasites animaux. Traite de path. publ. par Bouchard, ii., 1890. Braun: Die thierischen Parasiten des Menschen, Wurzburg, 1903. Davaine: Traite des entozoaires, Paris, 1877. Huber: Bibliographie der klin. Helminthologie, Miinchen, 1891-98; Bibliographie der klin. Entomologie, i.-iv., Jena, 1,898-1900. Johne. Der Trichinenschauer, Berlin, 1904. Kiichenmeister u. Ziirn: Die Parasiten des Menschens, Leipzig, 1882. Leuckart: Die menschl. Parasiten, Leipzig, 1863-76; 2te AufL, 1879-1901. Moniez: Trait6 de parasitologie, Paris, 1896. Neumann: Traite des maladies parasitaires des animaux domestiques, Paris, 1888. Parona: L'Elmintologia Italiana, Genova, 1894 (Lit. bis z. J. 1890). 75b THE ANIMAL PARASITES. Perroncito: I parassiti dell' uomo e degli animali utili, Milano, 1882. Stiles: Bull. Hyg. Lab., U. S. Pub. Health and Mar. Serv. Ward: Articles on Parasites, Arachnida, Nematoda, etc., in B.ef. Handb. of Med. Sc, 2d ed. Ziirn: Die Krankheiten d. Hausgefliigels, Weimar, 1882; Die Schmarotzer auf und in dem Korper unserer Haussaugethiere, i., Weimar, 1883-S9. GENERAL INDEX. Abdominal cavity, faulty closure of, 520 Abortion, 506 Abrachius, 52.5 Abrin, poisoning by, 26 Abscess, 340, 364, 5S0 burrowing, 368 chronic, 368 cold, 630 congestion, 368 Abscess-membrane, 364 Acanthocephala, 747 Acardius acephalus, 541 amorphus, 541. pseudoacormus, 541 Acarina, 748 Acarus folliculorum hominis, 750 scabiei, 748 Acervuloma, 437 Accrvulus cerebri, 229 Aceto-acetic acid, 77, 70, 80 Acetone, 77, 79, 80 Achirus. 528 Achorion schonleini, 685 Achromatopsia, 52 Achyla prolifera, 687 Acids, corrosive, 22 acid-intoxication, 79 Acme of a fever, 92 Acne, 580, 750 Aconitine, poisoning by, 29 Acrania, 513 Acromegaly, 85, 270 Actinomyces or ray-fungus, 550, 659 Actinomycosis, 659 Acuminate condyloma, 367, 442 Addiment, 119 Addison's disease, 87 pigmentation of skin in, 239 Adenocarcinoma, 448, 468 development of, 462 Adenocystoma, 448, 452 papillary, 452, 453 Adeno-cysts, 487 Adenofibroma, 447 Adenoma, 440 alveolar, 446 carcinoma tosum, 468 conversion of, into a carcinoma, 462 papillary, 446 tubular, 446 umbilical, 522 Adenomata and carcinomata. difficulty of distinguishing between, 447 Adenomyoma, 482 Adenomyosarcoma, 492 Adenosareoma, 477 Adipose tissue, atrophy of, 193 development of, 295, 296 pathology of, 193 Adipositas, 49, 194 Adrenalin, 87 iEgagropils, 233 iEquatorial plate, 280 Aerobes, 557 Age, predisposition in old, 47 Agenesia, 180 partial, of the cranium, 513 Agglutination, 120, 121 Agglutination of colon bacillus, 599 of typhoid bacillus, 109, 597 Agglutinins, 109, 119, 120, 121 Aggressins, 39 Agnathia, 518 Agrotis segetum, 687 Air, entrance of, into the right heart, 70 embolism, 70 Albinism, 257 Albuminoid bodies, protective, 105 Alcohol, poisoning by, 28 Alexins, 104 protective, 105, 106. 1 I '.I Algor mortis, 169 Alkaloids, toxic cadaveric, 33. 38, 557 vegetable, 19 Alveolar sarcoma, 425 Amboceptor, 119 Amelus, 525 Amides, 553 Amido-acids, 553 Amins, 553 Amitotic nuclear division, 283 Amme, 716 Amnion, pathological conditions of, 500 Amniotic adhesions a cause of malforma- tions of the embryo, 50 Amceba coli felis, 690 coli mitis, 689 coli vulgaris, 689 dysenteriae, 689 Amphibolous stage of fever, 92 Amphimixis, 59 Amputation neuroma, 301, 416 Amyelia, total or partial, 508 Amyloid concretions, 220 degeneration, 214 local infiltration of, 220 Anabiosis, 1 , 9, 10 AniT'inia. 127, 133 "58 GENERAL INDEX. Amenvia, chronic, 127 collateral. 134 due to hookworm, 738 due to tapeworm, 734 general, 127 localized, 129, 133 Anaerobes, .551 Anaplasia, 466 Anaphylaxis. 122 Anasarca, 151 Anatomy, general pathological, 2 Anchylostoma duodenale, 43, 737 americana. 737 Androgynes, 536 Aneneephalia, .514 Anencephalus, total, .514 Aneurism, cirsoid, 402 Angioma, 39S arteriale plexiforme, 402 arteriale racemosum, 402 cavernosum, 400 fissural, 390 hypertrophicum, 402 lymphaticum, 404 plexiforme arteriale, 402 simplex, 398 venosum (varicosum), 411 Angiomyoma, 410 Angiosarcoma, 42*. > Anguillula intestinulis, 741 stercoralis, 742 Anhydriemia, 127 Aniline, poisoning by, 26 Animal diseases caused by cocci, .584 parasites, 42, 689 Anopheles, 44, 710, 712, Antagonism, bacterial, 552 Anthomia canicularis, 754 Anthrax-bacilli, 589 attenuation of, .592 Anthrax, protective inoculations against. .592 symptomatic, 666 Antibacterial substances, 103, 109, 118 Antibodies, 33, 104, 10.5 Antimony, poisoning by, 23 Antitoxins, 33, 104, 108, 109, 112, 1 18, 119 of diphtheria, 1 17 production of, 122 Anus, condyloma latum of the, 643 Aplasia, 167 Aprosopia, ,517 Apus, .52.5, .528 Apyrexia, 92 Arachnida, 46, 48, 743 Area eerebrovasculosa, .514 medullovaseuiosa, ,508 Argas reflexus. 751 Argyria, 2.56 Arrhinencephalus, ,5 1 .5 Arsenicismus, pigmentation in, 246 Arseniuretted hydrogen, poisoning by, 26 Arterioliths, 146 Arteriosclerosis. 222 Ail cry, obliteration of, 14!) terminal, 163 Arthritis urica, 231 Arthropoda, 748 parasitic, 43, 46 Ascaris lumbricoides, 73.5 megak ephala, 736 mystax, 736 suilla, 736 vituli, 736 Ascites, 153 chylous, 166 Ascococci, .549, 563 Asiatic cholera, 671 Aspergillus flavescens or flavus, 41, 682 fumigatus, 41, 682 nidulans, 682 niger, or nigricans, 683 Aspergillus-mycoses, 682 Asphyxia, 5 local, 172 Astrocyte, 304, 411 Atavism, 55, 499 Atheroma, 442, .519 Atmospheric pressure, effect of an in- crease of, 14 effects of sudden lowering of, 13 Atresia am, 524 ani vesicalis. 52.5 ani urethralis, 525 ani uterina, 52.5 ani vaginalis, 525 oris, 518 recti, 524 urethra?, 524 Atrophy, 184, 369 active, 187 brown, 185 degenerative, 186 disuse, 7, 189 excentric, 185 impaired nutrition, 188 neuropathic, 189 passive, 187 pigment, 185 pressure, 1SS senile, 188 simple, 186 Atropine, poisoning by, 28 Attenuation of bacterial virulence, 112 Attraction-spheres, 281 Auditory apparatus, pathological condi- tions of, .52 Auditory meatus, cholesteatomata in, 443 mould-fungi in, 671) Autochthonous pigment, 233 teratomata, 496 thrombi. 14.5 Auto-intoxications, 7.5, 77 enterogenous, 76, 77 histogenous, 76 Autolysin, 110 Autolysis, 177, 191, 202 Autolytie ferments, 177 Autosite, .54.5 Awl-tail, 736 Axis-cylinder, sprouting of, 304 Bacillace/E, 586 Bacilli, 549, 580 GENERAL INDEX. 759 Bacilli, acid-fast, 621 eapsulated, 606 pathogenic, 588, 589 polymorphous, 5SS, 580 saprophytic, 587 Bacillus acidi lactici, 588 aerogenes capsulatus, 605 amylobacter, 588 anthracis, 589 botulinus, 587 butter, 621, 629 butyricus, 588 caucasicus, 58S choleric suis, 668 coli communis, 598 comma, 671. cyanogenes, 588 diphtheria, 608 dysenteric, 601 enteritidis, 600 Huorescens liquefaciens, 588 icteroides, 614 indicus, 551 influenza', 607 lepra", 649 mallei, 654 mucosus capsulatus, 606 necrophorous. 669 necroseos, 669 necrosis, 669 icdematis maligni, 604 paratyphosus, 600 pertussis, 608 pestis, 612 phlegmones emphysematosa?, 604 phosphorescens, 551 pneumonia' of Friedlander, 606 prodigiosus, 588 proteus vulgaris, 587 pyocyaneus, 589, 601 smegma, 621 subtilis, 588 sui pestifer, 668 i sui septicus, 668 tetani, 602 typhi abdominalis, 594 Bacillus of anthrax. 589 of blackleg, 666 of bradsot, 667 of bubonic plague, 612 of chancroid, 614 of chicken-cholera, 669 of contagious pleuropneumonia, 670 of diphtheria of calves, 669 of diphtheria of chickens, 669 of diphtheria of pigeons, 669 of glanders and farcy, 654 of hemorrhagic septicaemia, 668 of influenza, 607 of leprosy, 649 of malignant oedema, 604 of mouse typhoid, 66S of ozsena, 606 ol paratyphoid, 597 of pseudodiphtheria, 610 of pyelonephritis of cattle, 669 of reindeer plague, 670 Bacillus of rhinocsleroma, 657 of swine-erysipelas. 667 of swine-plague, 668 of swine-septicaemia, 668 of symptomatic anthrax, 666 of tetanus, 602 of tuberculosis, 615 of typhoid fever, 594 of yellow fever, 614 of whooping-cough, 608 Bacteria, 32, 549 acid-resisting, 621 action of, 559 aerobic, 551 anaerobic, 551 association of, 559 attenuation of, 560 avenues of entrance of, 34 cultivation of, 561 degeneration, forms of, 551 distribution of, 34 ectogenic, 34 endogenic, 34 enzymes, 33, 556 ferments, 33, 556 intoxication due to, 35 local effects of, 35. 562 metastasis of. 36, 559 movements of, 550 multiplication, 550 non-pathogenic, 33 oligomorphous, 54!) parasitic, 551 pathogenic, 30, 33, 34, 558 phosphorescence of, 558 polymorphous, 550, 588 products of, 33, 39, 556, 557 protection against, 100 red sulphur, 553 saprophytic, 551, 564, 598 spores of, 551 , 553 structure of, 550 that cause suppuration, 341, 570 toxins of, 35 transmission to foetus of. 550 Bacteriacea?, 586 Bacteriaemia, 36, 37 Bactericidal antibodies, 105, 100 immune-bodies, 100 sera, 122 Bacteriotrypsins, 556 Bacteriolysins, 1 19 Bacterium, 586 coli commune, 598 lactis aerogenes, 607 of hemorrhagic septicaemia, 66S typhi, 594 vulgare, 587 Balantidium coli, 715 minutum, 715 Barber's itch, 685 Barbone dei bufali, 669 Barlow's or Moeller's disease, 160 Basedow's disease, 85 Bedbug, or cimex lectularius, 753 Bedsore, 179 Beggiatoa, 550 GENERAL INDEX. Benign tumors, 383 Beri-beri, 19 Bezoar stones, 233, 237 Bigerminal tissue- implantation, 496 Bile-pigment, 251 Bilbarzia luematobia, 719 Bilirubin, 251 Biophores, 60 Birds, malaria of, 711 tuberculosis of, 637 Biting-mite, 751 Black death, 612 Black gangrene, 178 Blackleg, 666 Bladder, urinary, papillary epithelioma of, 141 Blast oma, 371 Blastomycoses, 41, 677, 681 Blastomycetic dermatitis, 41, 6S2 Blastomycosis, 41, 682 Blebs, hemorrhagic, 159 Blennorrhcea, 340 of the eye, 582 Blister, 329, 332 Blood, antibacterial properties of, 103 coagulation of, 135 extravasations of, 158, 243 increase in mass, 127 parasites of, 693, 695, 707 protective powers of, 103, 109, 1 19 Blood-cells, red, new formation of, 297 white, new formation of, 298 Blood-corpuscle cells, 243 Blood-corpuscles, red and colorless, 298 Blood-current, slowing of, 138, 139, 320 Blood-hyalin, 225 Blood-plates, 140, 141 escape of, from the blood-vessels. 323 thrombus of, 140 Blood-poisons, 25 Blood-pressure, 124 increased arterial, 128 increased pulmonary, 129 lowered arterial, 128 lowered pulmonary, 129 Blood-serum, bactericidal action, 103 immunizing power, 112 Blood-vessels, alterations of walls of, 320, 346 hyaline degeneration of the walls of, 222 new formation of, 288 Body-louse, 752 Bone, in dermoid cysts, (111 necrosis of, 365 pathological new formation of, 367 reproduction of, 293 Bone-marrow, reproduction of, 295,299 Bones, supernumerary, 534 Bone-tissue, new formation of, 293 Bothriocephalus cordatus, 734 Mis, 734 latus, 43, 732 latus Liguloides, 734 latus Mansoni, 734 Botryococcus ascoformans, 5S5 Bot ryomyces, 585 Botryomycosis, 585 Botrytis bassiani, 687 Botulismus, 19, 587 Brachygnathia, 51S Brachyphalangism, 528 Bradsot, 667 Brain, concussion of, 10 development of, 516 telangiectatic tumor of. 399 Brain-hernias, 514 Brain-sand, 22S Brain-substance in dermoid cysts, 491 Branchial cysts, 519 fistula-, 518 Breast, see also Mammary gland adenoma of, 445, 416 Breasts, supernumerary, 534 well-developed, in men, 534 Bronchial calculi, 234 Bronchitis, purulent, 339 Bronchopneumonia, 339 Brood-capsules, 727 Buboes in plague, 612 Bubonic plague, 612 protection against, 1 15 Budding-fungi, 40, 677 Budding of cells, 288 Burns. 8 Butter-bacilli, 621 Cachexia, 5, 168 suprarenal, 87 thyreoprival, 82 tumor, 384 Cadaveric alkaloids, 19 petechia; or lividitv, 132, 169 Cadaverin, 33, 557 Calcaneus, chondroma of, 392 Calcification, 147. 226 Calcium, role in coagulation, 138, 112 Calculi, biliary, 234 bronchial, 234 dental, 233 intestinal, 233, 237 prostatic, 234 salivary, 233 urinary, 235, 237 Callus, 269', 362 Calmette's theory of anthracosis, 6:17 tuberculin reaction, 622 Calvariuni, atrophy of the. 187 Cancer, see also under Carcinoma, 155 cells. 157 cells, hydropic. 192, I7"> cylindrical-celled, 472 458 endothelial , 428 etiology of flat-cel'led, , 456, 169 horny, 470 medullary, milk, 157 472 plugs, 468 umbilieatic in, 45 Cancroids, 466 Cantharidin, 22 Carbon-dioxide , infh opment of bacteria, 55! ipon devel- GENERAL INDEX. n;i Carbon-monoxide-gas poisoning, 4, 25 ( 'arbon-bisulphide poisoning, 26 < 'arcinoma, 455, 46S acinosum, 472 adenomatosum, 468, 472 basal-celled, 471 branchiogenic, 48S calcification in, 476 chorionic, 474, 484 colloides, 474 cylindrical-celled, 472 cylindromatosum, 475 development of, 455, 460, 465 in adenoma, 462 in glands, 462 in mucous membranes, 461 in papillary epithelioma, 463 in skin, 460 different forms of, 467 durum, 473 etiology of, 456, 45S formation of metastases in, 4X0 gelatinosum, 474 giganto-ccllulare, 475 Sealing of, 477 hyaline degeneration in, 475, 476 implantation of. 484 infiltration of, 457. 480 medullare, 472 metastasis of, 457, 480 mucosum, 474 myxomatosum. 475 papilliferum, 478 parasites a possible cause of, 456, 45S, 705 petrifying, 476 physaliferum, 475 placental, 465 recurrence, 484 retrograde changes in, 157 scirrhosum, 473 simplex, 472 solidum, 468 squamous-celled, 469 structure of, 467 subcutaneous, 488 I ransplantation of, 484 tubular, 472 Carcinomata, 455 complete petrification of, 476 Cardiac muscle, new development of, 302 Caro luxurians, 369 Cartilage, hyaline, reproduction of, 293 in dermoid cysts, 482 metaplasia of, 315 pigmentation of, 241 transformation of, into reticular tis- sue, 315 Caseation, 175, 345 in tubercles, 620 Castration, effects of, 88 Catarrh, 329 chronic, 36S desquamative, 332 mucous, 332 purulent, 332, 340 serous, 331 Cattle, actinomycosis of, 659 tuberculosis of, 637 Cattle-pest, 1 14, 585 Cattle-plague, 115, 584 Caustics or corrosive agents, 22 Cavernous tumor. 400 Cavity-formation in tuberculosis, 630 Cebocephalia, 515 Cell-division, 280 Cell-protoplasm, division of, 282 Cells, hyaline products of, 225 Central corpuscles, 280 group, 118 nervous system, regeneration of, 303, 306 Centrosomes, 280 Cephalocele, 514 Cephalothoracopagus, 542 Cercariae, 716, 717 Cercomonas intestinalis, 692 Cerebrospinal canal, deficient closure of, 513 meningitis, epidemic, 577 Cerebrum, glioma of, 413 malformations of, 514 Cestoda, 721, 712 Chain-cocci, 550, 563, 565 Chancre, hard, 642 soft, 614 Cheese-poisoning, 19 Cheesy degeneration, 175 Cheilo-gnatho-palatoschisis, 5 1 7 Chemicals, as producers of suppuration, 342 Chemotaxis, 348, 554 and chemotropismus, negative and positive, 102, 34S Chemotropismus, 348 Chicken-cholera, 669 immunization against, 113 Chilblains, 9 Children, predisposition of, 47 Chills, 91, 93 Chionyphe Carteri, 665 Chloasma uterinum, 238 Chloral hydrate, poisoning by, 28 Chloroform, poisoning by, 28 Chloroma, 435 Chlorosis, Egyptian, 738 Cholaemia, 76 Cholera, Asiatic, 671 protective inoculations against, 114, 674 Cholera-red , 6 i 4 Choleratoxopeptone, 674 Cholesteatomata, 442, 486 Cholesteriu, 203 Cholesterin-calculus, 234 Cholin, 38, 557 Chondroadenoma, 492 Chondroblasts, 292, 293 Chondroitin-sulphuric acid, 216 Chondroma, 391 Chondromyxoma, 387, 393 Chi mdromyxosarooma, 392 Chondrosarcoma, 393, 192 Chordoma, 393 7(3 GENERAL INDEX. Chorio-epitbelioma, 4(3(i, 471, 494 Chorionic villi, carcinomatous transforma- tion of, 465 ( 'hromaffinic cells, 88 Chromatin, 280 Chromatophores, 239, 4.33 Chromosomes, 280 ( 'hylangioma, 405 Chylopericardium, 166 Chyluria, 166 Cicatricial tissue, 274, 347. 354 Cicutoxin, poisoning by, 2.8 Ciliates, 715 Cimex lectularius, 753 Cinnabar, in a tattooed skin, 255 Circulation, collateral, development of, 133, 134 of the blood and of (lie lymph, dis- turbances in, 124 Cirrhosis of the liver, 370 Cirrus, 72.3 Cirrus-sac of Botbriocephalus latus, 732 of taenia solium, 723 Cirsoid aneurism, 40.3 neuroma, 418 Cladothrix, 550 asteroides, 6(55 Clavus, 269 Clay eaters, 739 Cleft-foot, 528 Cleft-hand, 528 Cleft of the abdominal wall, 521 Clefts, 504 of the face, median, 518 of the face, oblique, 517 of the thorax, 521 Climate, influence of. upon man, 32 Clitoris, malformations of, 524, 537 Cloaca, formation of. 521 Clostridium, 519, 586 butyricum, 588 Clothing-louse, 752 Clots, post-mortem, 135 lardaceous, 135 Cloudy swelling, 190 Clubbed-hand, 530 Club-foot, congenital, 529 Clustered cocci, 549 Coagula. substitution of, 361 Coagulation, 135, 136, 141, 322 Coagulation-necrosis, 1 74 Coagulins, 1 19 Cocaine, poisoning by, 28 Cocci or coccaceae, 549. 563 pathogenic, 564, 565 saprophytic, 564 Coccidia, 42, 701 reproduction of, 70 1 Coccidioidal granuloma, 41 Coecidium fuscum, 705 oviforme, 101 schubergi, 704 Coccus mesenterioides, 504 Coccygeal region, bigerminal teratoma of 546 Ccenurus cerebralis, 720 Coitus disease, 697 Colchicine, poisoning by. 20 Cold, effects of, 9 abscesses, 630 ("olds, 9 Collateral circulation, development of, 133, 134 Colles' law. 62 Collidin, 38, 557 Colliquation-necrosis, 1 70 Colloid, 209 cancer, 474 different uses of the term, 211 production of, by epithelial cells, 210 Color-blindness, 52 Colorless blood-corpuscles, emigration of, 321 increase of, relatively to the red, 321 marginal disposition of, 321 Coma diabeticum, 79 Commotio cerebri, 16 Compensatory hypertrophy, 8, 127, 268 of the heart-muscle, 127, 268 Complement, 1 19 Compsomyia, 754 Conceptional infections, 61 of syphilis, 62. 648 of tuberculosis, 636 Concretions, 226 amyloid, 220 calcareous, 228, 237 free, in the body, 233 uric acid, 235, 237 Concussions, effects of, 10 Condyloma acuminatum, 367, 442 latum, 643 Congenital predisposition, 46 Congestion, 130 t longest ive-abseess, 368 Conglutination. 140 Cuiiidia-bearers, 678. 680 Conidia-spores, 67S Coniine, poisoning by, 2!) Connective tissue, hyaline degeneration of, 222 ■ transformation of, into bone, 315 Connective-tissue structures, regeneration of, 291 Constitutio epidemica, 33 lymphatica, 89 pestilens, 33 Constitutional diseases, 49, 81 Contagion, definition of, 30 Contagium animatum, 32 Continuous fever, 92 Convalescence, 92 • Copraemia, 76 Copula, 710 Cor villosum, 333 Cordyceps militaris, 0S7 Corn, 213, 269 Cornification of epithelium, 212, 143, 705 Cornu cutaneum. 204. Ill Cornutin, 23 Corpora amylacea, 220 Corpulence, 40 GENERAL INDEX. 763 Corpus Iuteum, function of, SO Corrosive agents, 22 Corynebacterium, 610 Cotton-mill anaemia, 739 Cowpox, 111, 705, 707 (bws, tuberculous, milk from, 60S Crab-louse, 7.52 Craniopagus, 542 frontalis, 542 occipitalis, 542 parietalis, 542 Crahiorachiscbisis, 513 ( 'ranioschisis, 513 Cranium, faulty development of, 513 partial agenesia of, 513 ( 'rayfish pest, 6S7 Crenothnx, 550 ( 'retinism, S3 operative, 83 Crisis, in fevers, 92 < Irossed embolism, 65 Croupous exudate, 332 membrane, forma! ion of, on mucous surfaces, 333 pneumonia, 335, 577 ( 'ruor, 135 Cryptogenic infections, 41, 573, 580 ( 'ryptorehismus, 531 Culex pipiens, 69S, 712 Culicidae, 753 Culture, methods of bacterial, 561 Curarine, poisoning by. 29 Cutaneous horn, 204, 411 Cuterebra noxialis, 754 Cyanosis, 125, 132 Cyclencephalia or cyclocephalia, 515 Cyclopia, 515 Cylindrical-celled cancer, 172 < 'ylindiomata, 438 Cystadenoma, 4 IS multilocular, 148 papillary, 448 Cyst-formation. 258 Cysticercus bovis, 725 cellulosa 1 , 724 pisiformis, 720 racemosus, 724 tenuicollis, 720 Cystin, 77 Cystin-calculi, 237 ( 'ystocarcinomata, 47S papilliferum, 478 Cyst of echinococcus, 728 Cystofibroma, 453 Cystomata, 448 multilocular. 4 IS papillary, 448 simplex, 448 Cystomyxoma, 453 Cystosarcoma, 453, 402 Cysts, branchial, 486, 570 degeneration, 260 dermoid, 485, 400 ectodermal, 485 entodermal, 486 mesodermal, 480 retention, 258 Cysts, simple teratoid, 485 traumatic epithelial, 466 Cyst- worm. 727 Cytase, 104, 119 Cytolysins, 120 Cytotoxin, 120 Daltonism, 52 Darier's disease, 705 Darwin, 50 Daughter-cysts of echinococcus, 728 Daughter-stars, 281 Daughter-tumors, 380 Deaf-mutism, 52, 53 Death, 1, 168 apparent, 1, 170 spots, 132, 109 Decomposition, 169, 557 Decubital necrosis, 1 73 Decubitus, 173, 178 Deer-disease, 670 Defect, 209 Defervescence, period of. in fevers, 92 Degeneration, amyloid. 211 colloid. 209 fatty, 103, 198 granular, 190 glycogenic, 205 hyaline, 209, 222 hydropic, 102 lardaceous, 214 mucoid. 207 parenchymatous, 100 waxy, 175 Degenerations, 167, 180 Deiter's cells, 304 Demodex, 750, 752 Dcrmanyssus avium, 751 Dermatobia cyaniventris, 75:'.. 754 Dermatocoptes, 751 communis, 751 cuniculi, 751 Dermatocysts, 485 Dermatomycosis diffusa flexorum, 686, 687 furfuracea, 686 Dermatophagus, 751 Dei'inatoryctcs mutans. 751 Dermoid cysts, 486, 400 Dermoids, '486, 494 Desmobacteria, 549 Desmoid tumor, 385 Destructive placental polyps, 466 Determinants or determining pieces, 60 Deuterotoxin, 610 Development, disturbances of, 108 Diabetes mellitus, 70 Diabrosis, 159 Diapedesis, 160, 322, 324 Diastatic ferments, 556 Diastematomyelia, 511 Diathesis, hemorrhagic, 100 Dicephalus and diprosopus, 542 Digestive juices, action upon toxins, 98 Digitalin and digitalein. poisoning by, 29 Dimethvlamin, 38 Diphtheria, 608 bacillus of. 60S 7(14 GENERAL INDEX. Diphtheria, blood- serum treatment of, 112, 114, 115 cohimbarum, 669 of calves, 669 of chickens, 669 of pigeons, 669 toxin, 610 Diphtheritic inflammations, 344 Diphtheritis, 344 Diplococci, 549, 563, 575 Diplococcus intracellularis meningitidis, 577, 5S5 laneeolatus, 575 pneumonia' (Fraenkel. Weichsel- baum), 575 rheumaticus, 574 Diprosopus, 542 Dipygus, 543 parasiticus, 547 Disease, extrinsic causes of, 4 generalization of, 63 intrinsic causes of, 53 invasion, 42 latency of, 1 sequelae of, 72 spread of, 63 the symptoms of, 1 trophoneurotic, 74 Diseases, cause, origin, and course of, 1 congenital, 44, 53, 61 constitutional, 49 general, 75 inheritable, 44, 48, 53, 58 intrinsic, 48 local, 2 Displacement of tissue as a cause of tumor- formation, 376, 485 Dispora caucascia, 588 Distoma felineum, 719 haematobium, 719 hepatieum, 716 lanceolatum, 717 pulmonale, 718 sibiricum, 719 spat hi datum, 718 westermanni, 718 Diatom ia, 5 IS Disuse atrophy, 189 Diverticulum, Meckel's. 521 Dochmms duodenalis, 737 stenocephalus, 7411 trigonocephaly, 7-1(1 Double monsters. 539 symmetrical, 541 unequal, 541, 5-15 Dourine, 697 Uracunculus medinensis, 74(1 Drill-bone, 397 Dropsy, 151 Druse, 660 Ductus thoracicus, obstruction of, 166 occlusion, 154 rupture of, 166 Ductus omphalomesaniirus. 522 lliyreoglossus, 480 Dung-fungi, 021 Duplications, 532 Duplicitas anterior, 541 parallela, 543 posterior, 542 Dura mater, endothelioma of, 427 osteoma of, 396 psammoma of, 437 Dust-diseases, 16, 367 Dust-particles, entrance of, into (lie body, 65, 256 metastasis of, 65 protection against, 98 Dwarfs, 49, 181 formation of, 181 Dyschromatopsia, 52 Dyscrasia, 168 Dysentery, bacillary, 601 due to amceb.T, 690 of calves, 669 Dystopia renis, 531 Ear-scab, 751 Eburneous osteoma, 394 Ecchondrosis, 392 physalifera sphenooccipital!-, 303 Ecchymoses, 15S Echinococcus alveolaris, 730 granulosus, 729 bydatidosus, 729 multilocularis, 730 scolecipariens, 729 veterinorum, 729 Eehinococcus-cyst, 43, 728 Echinorhyncus gigas, 747 Eclampsia, 77 Ectodermal cysts, 485 Ectogenic bacteria, 34 Ectopia cordis, 521 cruralis, 531 cruroscrotalis, 531 inguinalis, 53 interna, 531 intestini, 521 pubica, 531 testis, 531 vesicae urinaria', 521 Eczema, 5S0 marginatum. 686 Effusions, chylous, 100 inflammatory, 329 purulent, 340 Egyptian chlorosis, 738 Ehrlich's side-chain theory, I l.s Elastic fibres, development of, 292 Electric discharges, powerful effeel of 157 Elephantiasis, 203, 269, 307, 531. 747 Graecorum, '119 hremangiomatosa, 263, 401 lipomatosa, 263 lymphangieel atica, 203 neuromatosa, 263, 417 Embolism, 64, (55, 68, 140 air, 70 crossed, 65 fat, 67 paradoxical, 65 retrogni< le, 05 GENERAL INDEX. ((15 Embolus, riding, 68 septic, 148 straddling, 68 Embryoid tumors, 492 Embryoma, 492 Embryonal tissue, transplantation of, 31 1 Embryonic tissue, 291 development of, in a thrombosed ar- tery, 362 Emigration of white cells. 321 Emphysema of the skin, 70 Emphysematous gangrene, 17S, 604 Empusa, varieties of, 687 Empyema, 340, 364 Encephalocelc, 514 Encephalomcningocele nasofrontalis, 514 Enchondroma, 391 Encranius, 547 End-artery, 132, 163 Endocarditis, 571 Endochondritis syphilitica, 648 Endothelial cancer, 428 Endothelioma, 425 hiemangiotic, 482 lymphangiotie, 425 Endothelium, proliferation of, 288 Endotoxins, 33, 39, 557 Engastrius, 547 Enostoses, 394 Enterocysts, 487 Enterogenous intoxication, 7(1 Enteroliths, 233 Entodermal epithelial cysts, 476 Entodium ca.udn.tum, 715 Entogenic parasites, 31 Entozoa, 42 Enzymes, 39, 98, 556 Eosinophil cells, 225, 744, 745 Ephelides, 406 Epidemic, definition of, 31 Epidermoids, 443, 485 Epigastrius, 547 Epignathus, 547 Epipygus, 546 Epispadias, 521, 524 Epistaxis, 156 Epithelial cysts, ectodermal, entodermal, and mesodermal, 478 after transplantation, 312 dermoid, 478, 490 epidermoid, 478 traumatic, 466 Epithelial pearls, 213, 442, 470 Epithelioid cells, 301, 351, 609, 618 Epithelioma, 440 adenomatosum benignum, 440 contagiosum, 702 papillary, 440, 442 syncytiomatodes, 495 Epithelium, atypical growth of, in carci- noma, 455 hyperplasia of, 286 metaplasia of, 318 misplaced, development of a cancer from, 465 pathological eornifieation of, 212, 443 protective powers of, 97, 100 Epithelium, regeneration and hyperpli of, 286 transplantation of, 310, 480 Epizoa, 42, 752 Ergotism, 23 Erysipelas, 567 Erythema multiforme, 571 Erythrasma, 41, 686 Erythroblasts, 297 Erythrocytes, regeneration of, 297 Erj^throcytolysis, 136 Erythrocytorrhexis, 136 Erythroeytoschisis, 136 Ether, poisoning by, 28 Ethmocephalia, 515 Ethmoid bone, osteoid sarcoma of, 43.: Ethylendiamin, 38 Etiology, 1 Eumycetes, 40 Eurotium, 680, 683 malignum, 680 Eustrongylus gigas, 740 Eventration, 521 Exeneephalus, 514 Exhaustion due to excessive functic activity of an organ, (i Exostosis, 265, 394^ 532 cartilaginous 395 connective-tissue, 395 Exstrophia intestini, 521 vesica? urinaria;, 521 Extravasate, 158 Extravasations of blood, 158, 242 Extremities, defective development 525 duplication of, 532 Exudate, cellular, 326 lal croupous fibi'inopurulent. 341 fibrinous, 332 hemorrhagic, 337 purulent, 340 serofibrinous, 332 seropurulent, 341 serous. 331 Exudates, absorption of, 346, 361 Exudation, 320 Eye, regeneration processes in, 307 Face, malformations of, 517 Facial hemiatrophy, 189 Facies leontina in leprosy, 651 Facultative anaerobes, 551 Fallopian tube, dropsy of the, 260 Farcy, 654 Fastigium, 92 Fat-embolism, 67 Fat-granule cells, 197 Fatigue, 7 Fats, the, 197, 203 Fat-synthesis, 197 Fat-tissue, atrophy of, 193 new formation, 295 Fat -transportation, 201 Fatty degeneration, 198 deposit, 193 Favus, 41, 685 766 GENERAL JXDEX. Febris continua, 92, 709 intermittens, 92 malariaformis, 712 imartana, 707 quotidiana, 707 recurrens, 92 remit ten?, 92 subcontimia, 92 tertiana, 707 Feet, abnormal positions of, 525, 529 Felt-louse, 752 Femur, absence of, 527 Fermentation, 556, 557 Ferments, diastatic and inverting, 556 glycolytic, 81 Fever, 90 bactericidal action of, 110 black, 698 blackwater, 711 cachectic, 698 continuous, 92, 709 etiology, 93 intermittent, 92 malarial, the cause of, 707 nature of, 95 relapsing, 94, 693 remittent, 92 scarlet, 705 stages, 91 subcontinuous, 92, 709 typhus, 705 yellow, cause of, 614, 699 Pibrillated connective tissue, development of, 291 Fibrin, 136 Fibrin-ferment, 137, 1 12 membrane, 140 Fibrinogenic substance, 13S, 142 Fibrinopurulent exudates. 341 Fibrinous deposits, 332 exudates, 332 Fibroadenoma, 447 conversion of, into a carcinoma, 464 intracanalicular, 447 papilliferum, 447 pericanalicular, 386, 4 17 Fibroblasts, 292, 351 Fibroepithelioma, papillary, 442 Fibrolipoma, 389 Fibroma, 385 intraeanaliculare, 447 multiple, 387, 416 oedematous, 386 papillare, 442 pericanaliculare, 386, 447 Fibromatosis of the nerves, 417 Fibromyoma, 41 1 Fibromyxoma, 387 Fibrosarcoma, 423 Filaria bancrofti, 166, 269, 747 haematica, 747 hemorrhagica, 74S nicdinensis, 746 multipapillosa, 74S papillosa., 747 sanguinis hominis, 166, 746 Fingers, dwarfing of, 528 Fingers, malformations of, 528 multiplication, 532 l ? inkler-Prior spirilla, 674 Finsen light-treatment, 10 First intention, repair by, 357 Fish-poisoning, 19 I r ission-fungi, 549 methods of examining. 560 pathogenic, 558 Fissura abdominalis, 520 abdominalis intestinalis, 52 I genitalis, 521 sterni, 521 vesica? urinaria-, 521 vesico-iiitestinalis, 521 Fistula colli congenita, 518 Fistulous tracts, 340 Flagella, 550 Flagellates, 691, 693 Flat foot, 530 Flea, or pulex irritans, 753 Flemming's genii-centres. 298 Fleshy moles, 406 wart, 406 Flies, biting (CEstrida j ), 753 blow (Muscidacl, 754 hot (CEstridse), 753 common (StomoxyidaO, 753 stinging (Museida?), 753 Foamy liver, 605 organs, 605 Fcetal glands, persistence of. 487 glands, remains, developmenl of a cancer from, 465 Fcetus papyraeeus, 541 syphilitic infection of, by either I lie sperm or (lie ovum, 648 Food, effects of lack of, 5 Foot-and-mouth disease, 111. 5S5, 070 Foot, cleft, 528 Foods, poisoning by spoiled ,10 Foot-itch of chickens, 751 Foreign body in inflammation. 36 I in cyst, 260, 353 in giant-cell, 353 Formative cells, 292 stimuli, 277 Fowls, typhoid of, 669 Fragmentation , 283 Freckles, 239, 406 Freezing, effects of, 9 gangrene due to, 179 Friedlander's pneumobacillus, 606 FYok fcetus, 513 Fuehsinophile bodies. 224 Fungous granulations, 369 Fungus medullaris, 373 Furuncle, 580 Gadinin, 38, 557 Gall-ducts, adenocystoma of, 449 Gall-stones. 2.34 Gamba fever, 697 Ganglion-cells, new-formation of, 303 Gangrene, 178 black, 178 dry, 178 GENERAL INDEX. 761 Gangrene, emphysematous, 174, 008 due to freezing, 179 due to heat, 179 infectious, 179 marasmic, 179 moist, 178 neuropathic, 179 pressure, 179 putrid, 178, 345 senile, 179 symmetrical, 179 toxic, 179 white, 178 Gangrenous inflammation, 345 Gas, irrespirable, 23 Gas-phlegmon, 004 Gastropachia pini, 687 Gastrophilus equi, 754 hsemorrhoidalis, 754 pecorum, 754 Gasi roschisis, 520 Genitals, external, development of, 538 malformations of, 523 Germ-centres of Hemming, 298 Germ-sac, primary, 710 secondary, 710 Germ-variation, primary, 58, 499 Germinal anlage, misplaced, 485 Germinal transmission of disease, 61 Giant-cell sarcoma, 423 Giant-cells, 283, 353 embolism of, 09 foreign body, 353 in tubercles, G1S multinuclear, 283, 353 p las mo dial, 283 syncytial, 281 Giant growth, general, 49, 202, 531 growth, partial, 202, 531 Giants, 49, 255 Giraldes, organ of, 538 Gland-activity, cessation of, 79 Glanders, 654 Glia-cells, new-formation of, 304 Glioma, 413 Gliomatosis, 415 Gliosircorna, 414 Globulicidal antibodies, 105 serum, 120 Glossina morsitans, 697 palpalis, 697 Glycogen, 204 Glycosuria, 79 Gnats (Culicidae and Tipulid*), 753 Goblet-cells, 207, 453 Goitre, 84 exophthalmic, 85 Gonococcus, 582 Gonorrhoea, cause of, 582 Gout, 49, 77, 231 Gouty deposits, 77, 232 Granula, 241 Granular degeneration, 190 Granulation tissue, 347, 353, 3.>4 formation of, 354, 359, 303 i Iranulations, chronic, 368 fungus, 369 Granulation tumors, infectious, 368 Granules, hyaline, 224, 225 Granuloma, coccidioidal, 082 Granulomata, 369 Grape-mole, 465 Grass-bacilli, 621 Gravel, 235 Graves' disease, 85 Greenish coloration in decomposing ca- davers, 170 Grossammen, 710 Ground itch, 738 Growth, causes of, 277 Guinea-worm, 740 Gummata, 045 Gynecomastia, 534 il.EMANGIO-ENDOTHKLIOMA, 402, 429 Hemangioma, 398 cavernosum, 410 hypertrophicum, 412 plexiforme, 402 simplex, 398 Hemangiosarcomata, 431 Hemangiotic endothelioma, 102, 432 Hematemesis, 158 Hematidrosis, 158 Hematocele, 158 Hematochyluria, 747 Hematoidin, 243 Hematoma, 158 Hematometra, 158 Hematomonas, 695 Hematuria, 158 Hemochromatosis, 242, 247 Hemofuscin, 238, 240 Hemoglobin, 243 Hemoglobina>mia, 240 Hemoglobinuria, 240 Hemolysin, 25, 120 Hemolytic poisons, 25, 20 sera, 105 Hemopericardium, 158 Hemophilia, 00, 150 acquired, 160 congenital, 50, 160 of cattle, 712 Hemoproteus noctue, 098 Hemoptoe or hemoptysis, 1:38 Hemorrhage, 158, 230 diabrosin, 159 diapedesin, 159 rhexin, 159 Hemorrhagic enteritis, 587 septicaemia, 668 Hemosiderin, 244 Hemosiderosis, 247 Hemosporidia, 707, 711 Hemothorax, 158 Hair-fungi; 550, 665 Hairs in dermoid cysts, 486, 496 Hairy polypi, 495 tongue, 213 Halteridium, 698 Hand, cleft, 528 clubbed, 530 malformations of, 525 70S GENERAL INDEX. Hands, abnormal positions of, 529 Hanging-drop cultures. 562 Haptins, 39, 120 Harelip, 517 Harvest-mite, 752 Hay-fever, 40 Head, malformations of, 513 Head-louse, 752 Healing by first intention, 357 by second intention, 357 powers of the human body, 1(18 serum, 113 Heart, action of, 124 disturbed action of, 125 fibroid area in, 363 increased action of. 127 valvular lesions, 12li Heart-muscle, compensatory hypertrophy of, 127, 267 hypertrophy of, 127 pigment of, 246 rigor mortis of, 170 tiger, 201 Heart poisons, 28 Heart-polypi, 145 Heat-exhaustion, S Heat-stroke, S Hclcosoma tropicuni. 699 Helleborin, poisoning by, 20 Helvellic acid, poisoning by, 26 Hemiatrophy, congenital, 189 facial, 189 infantile, 180 Hemicrania, 514 Hepatitis, chronic, 370 Hereditary pieces or determinates, 60 Hereditary transmission, atavistic, 55 collateral, 55 direct, 54 pseudo-form of, 61 Heredity, degenerative. 54 identical, 54 theories concerning, 55, 56 transformational, 54 Hermaphrodism, false, 535 true, 535 Hernia basalis, 515 cerebri, 514 funiculi umbilicalis, 520 lateralis, 515 nasoethmoidal, 5 1 5 nasofrontal, 515 nasoorbitalis, 515 occipitalis, 514 sphenoorbitalis, 5 1 5 sphenomaxillary. 5 1 5 sphenopharyngpa , 515 syncipitalis, 515 umbilical, 520 Herpes tonsurans, 41, 0S5 Herpetomonas lewisi, 605 Herpetosoma, 695 Heterakis, 736 Heterotopous tissue-growths, 485 Hexamitus duodenalis, 692 Histoid tumors, 372 Hog-cholera, 60S Holorauhischlsis, 508 Holoschisis, 280 Homo delinquens, 50, 55 sapiens, 5! Hook-worm, 737 Horn, cutaneous, 264, 441 Hornv warts, 264. 441 Horse-flies (Tabanidae), 753 Humerus, osteochondroma of, 397 Hunterian induration, 642 Hyalin, connective-tissue, 222 ' epithelial, 209 exudative, 225 Hyaline cartilage, reproduction of, 293 Hyaline degeneration, 222 of connective tissue, 222 of connective tissue of heart, 223 of connective tissue of vessel-wall, 223 Hyaline exudations, 225 products of connective-tissue cells, 224 thrombi, 225 tissue-necrosis, 225 Hydatid mole, 465 Hydatids, 727 Hydrencephalocele, 514 Hydrocele colli congenita, 519 Hydrocyanic-acid poisoning, 25 Hydrogen-sulphide poisoning, 25, 26, 76 Hydromeningocele, 510 Hydromyelocele, 510 Hydropic degeneration. 192 Hydrops, 151 adiposus, 156 chyliformis, 156 chylosus, 156 Hydrorachis, 508 Hydrothorax chylosus, 1 66 Hygroma colli congenitum, 405 Hyoscyamine, poisoning by, 28 Hypera?mia, active, 130, 131 local, 130, 131 passive, 131 venous, general, 125, 131 Hyperkeratosis, 213 Hypermastia, 534 Hyperonychia, 264 Hyperostosis, 367 Hyperparathyreosis, 85 Hyperplasia, 262, 285, 367, 369 Hyperpyrexia, 91 Hypersusceptibility, 122 Hyperthelia, 534 Hyperthyreosis, 85 Hypertrichosis, 264 Hypertrophy, 262 compensatory, 127, 268 due to lessened tise, 268 due to non-resolution, 268 due to over-work, 7, 267 due to removal of pressure, 269 inflammatory, 269 of a muscle or gland, 7, 447 of the tissues and organs, 262, 26J>, 267 Hypluc, 40, 678 GENERAL INDEX. 7(39 Hyphomycetes, 550, 677 Hypochondria, 18 Hypoderma bovis, 754 • liana, 754 Hypophysis, 85 Hypoplasia, 180 Hyposarca, 151 Hypospadias, 523 Hypostasis, 133 post-mortem, 132, 169 Hypostatic congestion, 133 Hysteria, 18 Ichthyosis, 263 congenita, 263, 264 lrystrix, 261 Ichthyotic warts, 264, 440, 441 lchthyotoxin, 20 Icterus, 251 neonatorum, 251 Idiosyncrasy, 46 Immune-body, 119 Immune-sera, 119 Immunity, 44, 45, 99 acquiring of, 111, 118 active, 113 against poisons, 99, 118 Ehrlich's theory of, 1 18 Immunization, active and passive, 113 Implantation, 309, 312, 486, 496 bigerminal, 496 monogerminal, 496 Inactivity, effects of, 7 Inclusio fetalis, 547 Indolent ulcers, 368 Induration, Hunterian, 642 Infarct, anaemic, 163 embolic, 164 hemorrhagic, 158, 163 healing of, 164, 362 Infection, 30, 39, 559 by means of animal parasites, 42 cryptogenic, 37, 573, 580 double, 38, 559 hematogenous, 36, 37 insects as conveyers of, 43 intra-uterine, 37, 559 lymphogenous, 36, 37 metastatic, 36, 37 mixed, 38 origin of disease through, 30 protection against, 100, 111 secondary, 38, 559. 635 spread of, by mosquitos, 44 spread of, from mother to 1 61, 559 Infectious diseases, 30 healing of, 108 inheritance of, 37, 61 local, 35 Infectious foci, metastatic, 36 Infiltration, 326 growth of tumors by, 380 purulent, 340 serous, 331 small-celled. 339 Infiltrations of the tissues, 161 , 326 49 712 cetu: Infiltrative mode of growth of earcino- mata, 480 Inflammation, 319 catarrhal, 331, 340 chronic, 365 clinical significance of the term, 323 croupous, 333 different forms of, 331 diphtheritic, 344 excretory, 320 fibrinous, 332 interstitial, 328 metastatic, 320 necrotic, 343 parenchymatous, 329 purulent, 340 superficial, 329 suppurative, 340 termination of, 345, 347 Influenza-bacillus, 607 Infusoria, 715 Inheritance of pathological peculiarities, 48 Initial sclerosis, 642 Injection of sterilized cultures, 112 Innervation, disturbances of. 16. 17, 77, 129 Inoculation, 111 Inoculation of attenuated specific disease- germs, 111 Insanity, inherited, 50, 54 Insecta, 752 Insects, 43, 752 Insolation, 8 Insusceptibility to poisons, 40 Intermediate body, 119 Intermittent fever, 92 Internal secretion, 79 secretion, disturbances of, 75. 79 Interstitial inflammation, 328 Intestinal intoxications, 35 mucous membrane, adenoma-like pro- jection of, 487 Intestine, abnormal positions of. 521), 530 tubular adenoma of, 444 Intoxication, bacterial, 35 Intoxication, origin of diseases through, 18, 75 Invasion-disease, 45 Inversio intestini, 521 vesica? urinaria?, 521 Iodothyrin, 84 Iron, assimilation of, 249 content of foods, 6 deposit, 256 insufficiency of, 6 reaction, 244 Iron-free pigments, 243, 249 Irradiation, 10, 14 Ischemia, localized, 133 Iscliiopagus, 541 Isolysin, 120 Isotricha prostoma, 715 Isthmus, the, of aorta, 127 Itch-mite, 748 Ixodes ricinus, 750 GENERAL IXDEX. Janice ps, 543 Janus-head, 543 J airings of the uterus as a cause of mal- formations of the embryo, 499 Jaundice, 2.51 Jaw, actinomycosis of upper, 662 giant-cell sarcoma of, 424 lower, absence of, 518 Kakerlaken, 257 Kakke, 19 Kala-azar, 698 Karyokinesis, 280 Karyolysis, 171 Karyomitosis, 280 Karyorrhexis, 171 Kedani disease, 751 Keloid, 387 Kephir, 588 Kephir- ferment, 588 Keratin, 212 Keratohyalin, 212 Keratosis follicularis, 705 Kidney, amyloid degeneration of, 218 arteriosclerotic atrophy of the, 1X8 cloudy swelling of, 191 compensatory hypertrophy of, 287 contracted, 370 cystoma of, 450 deposits of fibrin in the, 33 : senile atrophy of, INN streptococcus infection of, 572 Kinetoses, 18 Klasmatocytes, 299 Kribbelkrankheit, 23 Krumelzellen, 354 Krystallwulst, 307 Labia majoha and minora, defective de- velopment of, 524 Labium leporinum, 517 Lumblia intestinalis, 692 Lardaceous degeneration, 214 spleen, 214 Larynx, papillary epithelioma of, 441 syphilitic ulceration of the, 647 Latency of disease, 1 Lead, deposit of, 256 Lead-poisoning, 23 Leiomyoma, 409 Leishmani donovani, 699 infantum, 699 wrighti, 699 Lens, regeneration of, 307 bentigines, 236, 409 beontiasis ossea, 265, 532 leprosa, 651 Lepra (or leprosy), 649 anaesthetica, 653 maculosa, 753 mutilans, 653 nervorum, 652 nodosa, 652 tuberosa sive tuberculosa, 652 ulcerosa, 652 Leprosy, 649 white, of the Jews, 258 Leptothrix, 540 Leptus autumnalis. 750, 752 Leucocytes, 106. 110, 298, 321, 339, 350, 351 emigration of, 321, 324 marginal disposition of. 321 new-formation of, 298 varieties of, 298 Leucocythsemia, 298 Leucocytosis, 298 Leucoderma, 258 Leuconostoe mesenterioides, 564 Leucopathia acquisita, 257 congenita, 257 Leucotrichia, 257 Leukamiia, 298, 682 Leydenia gemmipara, 690 Lice, 752 Life-trophoblasts or biophores, 60 Light, effects of, 10, 14 influence of, upon development of bacteria, 551 ultraviolet, 10 violet, 10 Lightning figures. 15 Lightning-stroke, 14 Lime-salts, deposit, of, 226 Linguatulidae, 748 Lip, carcinoma of, 461 - malformations of, 51 7 Lipochrome, 238, 240 Lipofibroma, 389 Lipoma, 389 Lipomatosis, 49, 194 Lipomyxoma, 389 Liquefaction-necrosis, I 76 Lithocelyphopa'dion, 507 Lithocelyphos, 507 Lithopredion, 506 Liver, abscess of, 690 amyloid degeneration of. 215. 217 angioma cavernosum of, 399 chronic inflammation of, 370 cirrhosis of. 370 coccidia disease of, 701 corset, 1S9 cystoma of, 449 foamy, 605 gumma of, 646 hypertrophy of, 287 multilocular adenocystoma of, 450 Liver-fluke, 716 Livores, 132, 169 Lucilia macellaria, 753, 754 Lungs, actinomycosis of the, 661 fibrinous exudates in the, 337 induration of, 367 mould-fungi in the, 679 red hepatization of the, 337 syphilitic disease of the, 64,s tuberculosis of the, 61 7, 619 62S 6_'o 631,632 Lupus of the skin, 626 Luxations, congenital, 529 Lymph, antibacterial properties of, 102 formation of, 15! hindrance to flow of, 1 .', I GENERAL INDEX. Lymphaclenoid tissue, reproduction of, 295 Lymphsemia, 298, 436 Lymphangioendothelioma, 425 Lymphangioma, 404 cavernosum, 404 cystoides, 404 hypertrophicum, 405 simplex, 404 Lymphangiosarcoma, 425 Lymphangoitis, 37 Lymphatic constitution, 89 Lymph-fistula, 166 Lymph-glands, action of, as fillers, 102 Lymphocytes, 322, 350, 351 Lymphorrhagia, 165 Lymphosarcoma, 421, 436 Lymph- vessels, new-formation, 290 Lysis, in fever, 92 Lysogenous substance of Frankel, 100 Macrocheilia, 405 Macrogamete, 704, 710 Macroglossia, 405 Macrostomia, 518 Madura disease or Madura foot, 665 Maidismus, 41 Malanders, 751 Malaria, 707 forms of, 708 in animals, 7 1 1 pigment in, 249 Plasmodia of, 708 the cause of, 708 Malformations, 498 congenital, 498 etiology, 499 varieties, 503 Maliasmus, 654 Malignant oedema, 604 tumors, 384 Mallein, 656 Malleus, 654 Mai perforant, 1 79 Mammary gland, adenoma of, 445 carcinoma of, 470, 471, 472 endothelioma of, 426 intracanalicular fibroma of, 447 mucous carcinoma of, 473, 474 papillary cystocarcinoma of, 464 papillary cystoma of, 454 tubular adenoma of, 464 Marasmic thrombi, 145 Marasmus, 8, 165 Margarin crystals, 203 Marginal disposition of leucocytes. 321 Mast-cells, 225, 354 Mastigophora, 691 Mastoid antrum, cholesteatomata in, 443 Measles of taenia", 721, 724 of trichina, 745 Meat-poisoning, 19, 35, 587, 600 Meckel's diverticulum, 521 Mediastinal dermoids, 486 Medullary cancer, 472 Megastoma entericum, 692 intestinale, 692 Mekena neonatorum, 160 Melanin, 238, 240 Melanornata, 405 Melanosarcomata, 433 Melanosis of internal organs, 241 Melasma suprarenale, 87 Membrane, pyogenetie, 364 Meningitis, epidemic cerebrospinal, 577 Meningocele, 509, 514 Meningococcus, 577 Meningo-encephalitis syphilitica, 644 Meningo-encephalocele, 514 Menorrhagia, 158 Merismopedia, 549, 550, 563 Merorachischisis, 508 Merozoites, 701, 704 Mesodermal epithelial cysts, 486 Metabolism, bacterial, 556 Metaglobulin, 142 Metakinesis, 281, 282 Metamorphosis, viscous, 140 Metaplasia, epithelial, 318, 583 of the tissues, 314 Metastasis, 64 direct, 65 formation of, in carcinomata, J57 hasmatogenous, 64 in tuberculosis, 632 lymphogenous, 64 of dust, 65 of parasites, 69 of parenchymatous cells, 07 of pigment, 69, 70, 242, 245 of placental cells, 67 of soluble substances, 6!) paradoxical, 65 retrograde, 65 Metastatic daughter-tumors, on, 380 infectious foci, 69 inflammations, 64 Methsemoglobin, 246 the formation of, 26 Methsemoglobinuria, 246 Methyl guanidin, 33 Metrorrhagia, 158 Miasm, definition of, 30 Miasmatic-contagious disease, definition of, 30 Miasms and contagions, boundary-line be- tween, 31 Micrencephalon, 50, 182 Micrencephaly, 182, 514 Microbacteria, 549 Microbrachius, 525 Microcephalus, 182, 514 Micrococci, 549, 563 Micrococcus ascoformans, 585 aurantiacus, 564 botryogenes, 585 cyaneus, 564 gonorrhoea?, 582 ha?matodes, 564 in meningitis, 577 in mycofibroma, 585 in mycosis of parrots, 585 in pseudotuberculosis of guinea-pigs, 585 luteus, 564 GENERAL INDEX. Micrococcus of foot-and-mouth disease, .585 of hemoglobinuria of cattle, 585 of lung-disease of horses, 585 of strangles, 585 pathogenic, 564, 565 pyogenes, 578, 584 tetragenus, 564 tetragenus of udder-disease, 585 ureas, 564 violaceus, 564 viscosus, 564 xantogenicus, 614 Microgamete, 705, 710 Microgametocyte, 704, 710 Microgyria, 182 Micromelus, 525 Micromyelia, 50 Microproteins, 34 Micropus, 525 Microsomia, 506 Microsporon furfur, 686 minutissimum, 6S6 Microtomia, 518 . Mieseher ; sacs of, 703 Miliary tubercles, 618, 625, 633 tuberculosis, hsematogenous, 633 Milk from tuberculous cows, 638 Mineral poisons, 111 Miracidium, 716 Missed labor, 507 Mites, 748, 751 Mitosis, 280 Mole, 405 fleshy, 406 hairy, 405 hydatid, 465 pigmented, 239, 405 Moller's or Barlow's disease, 160 Molluscum bodies, 703 Monilia Candida, 681 Monobrachius, 525 Monocercomonas hominis, 692 Monogerminal tissue-implantation, 496 Monomorphous bacteria, 538 Monopus, 525 Monsters, 498 double, 504, 539 single, 506 triple, 540 Morbus Addisonii, 87. 23) maculosus Werlhofii, 160 Morgagni, hydatid of, 538 Morphine, poisoning by, 28 Morphcea nigra et alba, 653 Mosquitos, agency of, in spreading certain diseases, 44, 712, 753 Mother-star, 280, 282 Mould-fungi, 40, 678 Moulds, 677, 685 Mouth, development of, 519 malformations of, 518 Mucins, the, 208 Mucor eorymbifer, 680, 682 pusillus, 682 ramosus, 682 rhizopodiformis, 682 Mucous degeneration, 207 membranes, carcinoma of, 461 membranes, papillary epitheliomata of, 441 tissue, reproduction of, 295 Midler's duct, 538 Multiple fibromata of the skin, 53, 417 Mummification, 178 Musca anthropophaga, 754 vomitoria, 754 Muscardine in silkworms, 687 Muscarin, poisoning by, 29 Muscida?, 754 Muscle, atrophy of, 187 heart, hypertrophy of, 267 heart, new-formation of, 302 in dermoid cysts, 491 non-striated, hypertrophy of, 302 non-striated, new-formation of, 302 striated, hypertrophy of, 302 striated, new-formation of, 300 waxy degeneration of, 175 Muscle-trichina, 744 Muscles, cadaveric stiffening of, 169 supernumerary, 534 Muscular system, pathological changes in the, 50 Mussel poisoning, 20 Mycelium, 678 Mycetoma, 665 Mycobacterium tuberculosis, 621 Mycoderma albicans, 681 Mycodermoid, 585 Mycofibroma, 585 Mycoprotein, 550 Mycosis of alimentary tract, 679 of respiratory tract, 679, 680 of skin, 685 versicolor, 686 Mycosozin, 104 Myelasmia, 298 Myelocele, 510 Myelocystocele, 509 Myelocystomeningocele, 5 1 Myelocysts, 487 Myeloma, 422 Myelomeningocele, 509 Myiasis, 754 Myofibroma, 411 Myoma, 409 lcevocellulare, 409 striocellulare, 411 Myosarcoma, 412 Myositis ossificans, 50, 397 Myxoangiosarcoma, 437 Myxoedema, 83 Myxofibroma, 387 Myxolipoma, 387 Myxoma, 387 Myxosarcoma, 387, 424 Nffivus flammetjs, 399 lymphaticus, 405 pigmentosus, 405 pilosus, 405 prominens, 400, 405 spilus, 405 GENERAL INDEX. Naevus vasculosus, 399, 400 verrucosus, 400, 405 vinosus, 399 Nagana, 697 Nanosomia, 506 Nasal mucous membrane, lymphosarco- ma of, 421 Navel stone, 234 Necator americanus, 738 Neck, malformations of, 517 Necrobiosis, 172, 175 Necrosis, 170 anaemic, 1 72 cheesy, 175 coagulation, 174 colliquation, 176 decubital, 173, 179 direct, 172 indirect, 172 liquefaction, 176 marasmic, 173 mummifying, 178 neuropathic, 173, 179 sequelae of, 173 senile, 179 thermal, 171, 179 Negri bodies, 705 Nemathelminthes, 734 Nematoda, 42, 734 Nematodium ovis pulmonalis, 740 Neoplasm, 371 Nerve- and heart-poisons, 27 Nerve elements, new-formation of, 303 Nerve-fibres, peripheral, new formation of, 304, 307 peripheral, pathological changes in, 51 Nerves, fibromata of, 417 fibromatosis of, 51, 417 leprosy of, 652 regeneration of, 305 Nervous system, central, pathological changes in the, 50 Neurasthenia, 18 Neuridin, 33, 38, 557 Neurin, 33, 38, 557 Neuroepithelioma, 415 Neurofibroma, 417 Neuroglia, hypertrophic growth of, 304 regenerative growth of, 304 Neuroglioma ganglionare, 414 Neuroma, 416 amputation, 306, 416 amyelinicum, 418 cirsoid, 417 ganglion cellulare verum, 418 myelinicum, 417 plexiforme, 417 verum, 418 Neuropathic atrophy, 189 gangrene, 179 necrosis, 173 Neuroses, traumatic, 17 Neurotization, 306 Nicotine, poisoning by, 29 Nitrate-of-silver poisoning, 23 Nitrobacteria, 557 Nitrogenous nourishment, importance of, 5 Nitrous oxide, poisoning by, 28 Nodes, gouty, 232 Normal serum, 115 Nuclear contents, 280 framework, 278, 280 Nuclear division, asymmetrical, 282 atypical, 282 direct, 276, 280 indirect, 283 pluripolar, 282 segments, 280 spindle, 281 Nucleinic acid, 105 Nucleus, composition of the, 2S0 Nutrition, retrograde disturbances of, 167 Nyktotherus faba, 715 Obesity, 49, 194 diabetogenous, 80 Obligate anaerobes, 551 Obturating thrombus, 145 Ochronosis of cartilage, 241 Odontoma, 394 (Edema and dropsy, 151 cachectic, 155 collateral, 155 due to arterial congestion, 154 due to obstruction of thoracic duct, 154 ex vacuo, 156 hydremic, 155 inflammatory, 155, 331 malignant, 604 purulent, 341 stagnation, 154 varieties of, 154 (Esophagus, growth of thrush upon the, 679 (Estridaj, 753 CEstrus bovis, 754 ovis, 754 O'idium albicans, 681 coccidioides, 682 Oidiomycosis, 41, 682 Olein, 203 Oligomorphous bacteria, 549 Omentum, tuberculosis of, 618 Omphalocele, 520 Omphalomesenteric cyst, 522 duct, 521 Omphalopagus, 547 Oneosphsera, 733 Onychogryphosis, 264 Onychomycosis favosa, 685 trichophytina, 686 Oocyst, 701, 704, 710 Ookinete, 710 Oophorin, 89 Ophryoscolex caudatus, 715 Opium and morphine, poisoning by, 28 Opsonic index, 106 Opsonins, 105 Organization of thrombi, 148 Organs, weight of, 266 volume of, 266 Ossification, 229 GENERAL INDEX. Osteoarthropathie hypertrophiante, 270 Osteoblasts, 292 Osteochondroma, 393, 396 ( (steofibroma, 396 Osteoid sarcoma, 436 of ethmoid, 43.3 trabecular 437 Osteoma, 394 dental, 394 disconnected, 394 durum seu eburneum, 394 heteroplastic, 394 medullars, 394 parosteal, 394 spongiosum, 394 Osteomyelitis, 569 Osteophyte, 394 Osteoporosis, 185. Osteosarcoma, 436 Ovary, adenocystoma of, 451 cystoma of, 451 dermoid cysts of, 490 multilocular adenocystoma of, 449 papillary cystadenoma of, 451, 453 papillary cystocarcinoma of, 479 papillary epithelioma, 440, 442 teratomata of, 492 transplantation of, 312 Over-exertion, 7 Over-heating, 8 Overwork, hypertrophy from, 7, 260 Oxidation, intra-organic, 93, 95 Oxygen, effects of a diminution in the supply of, 4 influence of, upon development of bacteria, 551 Oxyuris vermicularis, 736 Pachyakeia, 270 Packet-shaped cocci, 549, 563 Paget's disease, 705 Palate, malformations of, 517 Palmitin, 203 Pancreas, cyst of the, 259 diabetes after extirpation of, 80 Papillary adenomata, 446 conversion of, into a carcinoma, 464 * cystomata, 448 epitheliomata, 440 Papilloma, 3S5 Paracholia, 252 nervous, 252 Paradoxical embolism, 65 Parakeratosis, 208 Paralysins, 109 Paramecium coli, 715 Paramucin, 208 Parapedesis, 252 Parasite (in the case of twins), 545 Parasites, 30, 31 animal, 689 ectogenous, 31 endogenous, 31 formation of cysts by, 260 metastasis of, 69 Parasitic diseases, 30 infection, 30, 31 Parasitic arthropods, 43 protozoa, 42 worms, 42 Parasitism, origin of disease through, 30, 33 Paratyphoid bacteria, 591 fever, 597, 600 Parenchymatous cells, embolism of, (58 degeneration, 190 inflammation, 329 Parietal thrombus, 145 Parosteal osteomata, 394 Parotid gland, angiosarcoma of, 431 chondrofibroma of, 431 chondromyxosarcoma of, 392 myxoangiosarcoma of, 437 Parrots, mycosis of, 585 Pathogenesis, 1 Pathology and pathological anatomy, the, 1 chemical, 2 clinical, 2 general, definition of, 2 physiological, 1 problems of, 1 Pearl disease, 615, 637 tumors, 442 Pearls, epithelial, 213, 442, 470 Pediculus capitis, 752 pubis, 752 vestimentorum, 752 Pellagra, 19, 41 Penicillium glaucum, 41 Penis, duplication of, 534 stunting of, 523 Pentastoma, 43, 748 denticulatum, 751 taenioides, 751 Peptotoxin, 557 Peribronchitis, 339 Peripheral nerves, pathological changes in, 51 Perithecia, 683 Perithelioma, 431 Peritoneum, cystic lymphangioma of, 405 Peritriehous flagella, 603 Perlsucht, 615, 637 Pernicious malaria, 709 Perniones, 9 Perobrachius, 525 Perochirus, 528 Perodactylism, 528 Peromelus, 525 Peropus, 525, 528 Perturbatio critica, 92 Pes calcaneus, 530 equinovarus, 529 valgus, 530 Pest, 612 bacillus, 012 Pestilence, definition of, 32 Petechia:, 158 Petrifaction, 226, 507 in carcinomata, 476 Petrifying sarcoma, 437 Phagocytes, 98, 101, 346, 352 Phagocytosis, 97, 101, 346, 347 GENERAL INDEX. 775 Phallin, poisoning by, 26 Phimosis, hypertrophic, 524 I'hleboliths, 147, 234 Phlegmon, 341 wooden, 573 Phloridzin diabetes, 81 Phocomelus, 525 Phosphorescent phenomena, 55S Phosphorus poisoning, 23 Phthirius inguinalis, 752 Physalides, 475 Physiology, pathological, 1 Pia mater, cholesteatomata of the, 443 Picric acid, poisoning by, 26 Pigeon-diphtheria, 669 Pigment, autochthonous, 238 extrinsic, 255 haematogenous, 242 metastasis of, 69 pathological absence of, 257 pathological formation of, 238 Pigment-atrophy, 185 Pigment-carrying cells, 244, 245 Pigmented mole, 239, 405 warts, 239, 405 Pin worm, 736 Piroplasma bigeminum, 712 Pirquet's reaction, 622 Pithead tapeworm, 732 Pityriasis, 686 versicolor, 41 , 686 Placental cells, embolism of, 67 infections, intra-uterine, 61, 552 transmission of disease, 61 villi, carcinomatous transformation, 465 Plague, bubonic, 612 Plasma-cells, 298, 354 Plasmodiophora brassier, 458 Plasmodium immaculatum, 70S malariae, 707 pracox, 708,709 vivax, 708, 709 Plasmolysis, 136, 171 Plasmorrhexis, 136, 171 Plasmoschisis, 136, 171 Plate-cultures, 561 Platyhelminthes, 716 Pleroeercoid, 733 Plethora, 127 Pleura, endothelioma of, 427 Pleuritis, fibrinous. 335 Pleuropneumonia, contagious, of cattle, 585, 670 immunization against, 113 Plexiform neuroma, 417 Plimmer's bodies, 45S Plugs, epithelial, in cancer of the skin, 460 Pluripolar division, 2S2 Pneumococcus, 575 Pneumonia, croupous, 337, 575, 606 infectious, of cattle, 685 of horses, 585 Pneumotoxin, 577 Pointed condylomata, 307, 442 Poisoning, definition of, 19 Poisons, animal, 22 Poisons, bacterial, 33, 39 caustic, 22 classification of, 22 different sources of, 19 excretion of, 98 neutralization of, 98 protection against, 98 vegetable, 22 volatile, 23 Poison-theory of immunity, 112 Polar field, 280 corpuscles, 90, 278 Poliosis, 257 Pollen-diseases, 46 Polyblasts, 299, 352 Polydactylism, 532 Polymastia, 534 Polymelos, 545 Polymitus, 710 Polymorphism of cancer-cells. 457 Polymorphous bacteria, 550, 588 Polypi, hairy, 495 valvular, 145 Polythelia, 534 Polyuria, 53, 79, 80 Porokeratosis, 213 Post-mortem hypostasis, 131, 169 Potassium-chlorate poisoning, 25, 26 Potassium-cyanide poisoning, 25 Precipitin-reaetion, 121 Precipitins, 109, 120 Predisposition, acquired, 44 congenital, 44 due to age, 47 due to race, 48 due to sex, 48 local, 45 natural, 47 special, 46 temporary, 45 Prepuce, absence of, 524 hypertrophy of, 524 shortness of, 524 Pressure atrophy, 188 continuous, effects of, 16, 188 Proglottides, 721 Proliferation, causes of, 277 inflammatory, 350 phenomena ot, 323, 347 Prosoposchisis, 517 Prosopothoracopagus, 544 Prostatic calculi, 211 concretions, 21 1 Protective mechanisms, natural, 97 Proteins, bacterial, 33, 39, 557 Proteosoma, 712 Proteus vulgaris. 587 Prothrombin, 137, 142 Protophyte, 549 Protoplasm, 282 Prototoxin, 610 Protozoa, parasitic, 42, 44, 689 Psammomata, 437 Pseudalius capillaris, 639 ovis pulmonalis, 740 Pseudorliphtheria bacilli, 610 Pseudohermaphrodismus, 535 77(1 GENERAL INDEX. Pseudomelanosis, 245 Pseudomucin, 208 Pseudotuberculosis, 638 aspergillina, 638, 683 eladotrichica, 638, 665 due to animal parasites, 638 due to bacteria, 638 due to foreign bodies, 638 due to hyphomycetes, 638, 687 vcrmian, 639 Psorospermose folliculaire vegetante, 705 Psychoneurosis, 17 Ptomai'ns, 19, 38, 557 toxic, 38, 557 Puberty, precocious, 266 Pulegon, poisoning by, 23 Pulex irritans, 753 penetrans, or sand flea, 753 Pulmonary circulation, increase of resist- ance in, 129 Pulse, acceleration of, 127 venous, 126 Puriform softening, 147 Purpura, 159 hemorrhagica, 160 rheumatica, 160 simplex, 160 Pus, 339, 363 inspissated, calcification of, 364 Pus-cocci, 579 Pus-corpuscles, 339 Pustule, -340 Putrefaction, 33, 38, 557 alkaloids, 33, 38, 557 zymoids, 38 Putrescin, 33, 38, 557 Putrid gangrene, ] 78 Pyscmia, 37, 572, 580 Pyelonephritis of cattle, 669 Pygopagus, 541 Pyknosis, 171 Pyocyanin, 602 Pyosepthsemia, 572 Pyosepticsemia, 37, 572, 580 Quinine, poisoning by, 29 Rabies, cause, 705 protective inoculations against, 114 Race, predisposition of, 48 Rachicele, 509 Rachipagus, .544 Raehischisis, partial, 508 total, 508 Radioactivity, effects of, 1 1 Radium, 12 Rag-sorters' disease, 592 Rainey's bodies, 703 Ray-figures, 281 Ray-fungus, 659 Rays, Eecquerel, 11 red and yellow, sensitization to, 11 ultraviolet, 10 violet, 10 Receptaculum scolicis, 724 Receptors, 1 1 8 Rectum, cancer of. 469 Recurrent fever, 92, 675, 693 Redise, or secondary germ-sacs, 711), 717 Reduplications, 532, 534 Refrigeration, 9 Regeneration, 272, 285 causes, 273 of degenerated tissue, 347 partial, 274 Regenerative capacity of tissues, 276 Relapsing fever, 92, 675, 693 Remittent fever, 92 Repair by first and by second intention. 357 Respiratory apparatus, aspergillus my- coses of, 682 Restitutio ad integrum, 274 Retention cyst, 258 Retina, glioma of, 415 Retrograde changes, 167 Reversion, 532 Rhabditis stereoralis, 742 Rhabdomyoma, 411 Rhabdomyosarcoma, 412 Rhexis, 159 Rhinoscleroma, 606, 6.57 Rhizopoda, 689 Ribs, supernumerary, 55, 534 Rice-water intestinal discharges in cholera, 671 Ricin, 26 immunity to, 115 poisoning by, 26 Rider's bone, 397 Rigor mortis, 169 Rinderpest, immunization, 114 Ringworm, 686 Roseola syphilitica, 643 Round-cell sarcoma, 421. 41' 4 Roundworms, 734 Rudimentary twin, 492, 545 Russel's bodies, 224 Sacoharomyces ellipsoideus, 678 lithogenes, 682 neoformans, 682 Saccharomycetes, 678, 682 disease-producing, 678 Sacs of Miescher, 703 Sago-spleen, 214 Salts, caustic, 22 Sand flea, or pulex penetrans, 7.33 tumors, 437 Santonin, poisoning by, 29 Saprophytes, 35, 587 Saprophytic bacilli, 587 cocci, 564 Sarcina lutea, 564 ventriculi, 564 Sarcinaj, 549, 550, 564 Sarcocarcinoma, 477 Sarcocysts, 704 Sarcoma, 419 adeno-, 476 angio-, 429 alveolar, 425, 427 cysto-, 492 etiology of, 420 GENERAL INDEX. Sarcoma, fibro-, 420, 423 giant-cell, 423 haemangio-, 425, 429 large round-celled, 422 [ymphadenoides, 421 lymphangio-, 425 lympho-, 421 medullary, 420 melano-, 433 myo-, 424 myxo-, 424 organoid, 425 osteo-, 416 osteoid, 436 petrifying, 437 phyllodes, 453 plexiforme, 427, 431 polymorphous-celled, 418, 422, 423 rhabdomyo-, 412 simple, 421 small round-celled, 421 spindle-celled, 423 telangiectatic, 420 tubular, 427 Sa^eomatosis cutis, 424 Sarcophaga magnifica, 754 Sarcophilia wohlfarti, 754 Sarcoplasm, 302 Sarcopsylla penetrans, 753 Sarcoptes hominis, 748 minor, 751 squamiferus, 751 Sarcosporidia, 703 Sausage-poisoning, 19, 35, 587, 600 Scabies, 749 Scald-head, 685 Scall, 685 Scarlet fever, 705 Scar-tissue, 274, 357, 363 Schistoprosopia, 517 Schizogony, 701, 713 Schizomycetes, 549 Schizont, 704, 713 Seirrhus, 473 Sclera, regeneration of, 307 Scleroma respiratorium, 657 Sclerosis, 222 initial, 642 of nerve-tissue, 304 Scolex, 721 Scrofula, 636 Scrotum, malformations of, 524 Scurvy, 160 Scutula of favus, 685 Sea-sickness, 18 Sebaceous glands in dermoid cysts, 490 Secale cornutum, 23 Second intention, repair by, 3.52 Secondary infection, 38, 539, 635 Secretion, internal, 79 Segmentation, direct, 280 indirect, 280 Segmented skein, 281 Semilunar ganglia, pathological changes in, 87 Sepsin, 38, 557 Sepsis, 37 Septicaemia, 37, 572, 580 ha:morrhagic, 668 Septicopyemia, 37, 572, 580 Sequestration of necrosed tissue, 173.347, 365 Serpiginous ulcers, 368 Serum, healing, 112 protective, 112 Sex, predisposition of, 48 Sexual glands, teratoid tumors of. 90 removal of, 88 Sexual organs, internal, development of, 538 Shock, erethistic and torpid, 17 Shotty eruption, 705 Side-chains, 1 18 Sideroferous cells, 245 Siderosis, hematogenous, 247 Silver, deposit of, 23, 69, 249 Simple softening, 147 Sirenomelia, 517 Situs inversus, 530 Skein-like structure of the nucleus, 280 Skeleton, pathological changes in the, 50 Skin, absence of pigment of, 257 cancer of, 460 emphysema of, 70 healing of wounds of, 357 leprous nodule of the, 650 lupus of the, 626 melanotic alveolar sarcoma of, 433 multiple fibromata of the, 53 papillary epithelioma of, 441 pathological alterations of, 52 pigmentation of, 87, 238 Skin-transplantation, 3 1 Skull-cap, angioma cavernosum of, 402 Sleeping sickness, 697 Smallpox, pustule, 339 parasites of, 705, 707 Smear cultures, 561 Smegma bacillus, 621 Snake venom, 20, 23 immunization, 115 Soft chancre, (514 Special sense, organs of, new-formation of the tissues of, 307 Specificity of the tissues, 273 Spermin, 89 Spermolysin, 120 Sphacelinic acid, 23 Sphacelus, 179 Spha?robacteria, 549 Spheres, fatty granule, 197 Spider cells, 304 Spina bifida, 508 anterior, 509 cystica, 509 lumbosacralis, 510 occulta, 509 posterior, 509 Spinal column, pressure atrophy of the, 189 cord, development of, 511 Spindle-celled sarcoma, 423 Spindle, nuclear, 281, 282 GENERAL INDEX. Spirilla, or spirillacese, or spirobacteria, 549, 670 Spirillum amyloferum, 553 cholera 1 asiatieae, 071 deneke, 074 of Finkler and Prior, 674 rubrum, 670 rugula, 610 serpens, 670 sputigenum, 677) tenue, 670 tyrogenum, 675 undula, 670 volutans, 670 Spirobacteria, 670 Spirochete, 549, 670, 694 buccalis, 670 carteri, 694 denticola, 670 duttoni, 694 gallinarum, 693 kochi, 694 novi, 694 obermeieri, 69)5 pallida, 641 plicatilis, 670 varieties of, 670 ziemanni, 694 Spironema pallidum, 641 Spleen, amyloid degeneration of, 214 changes in, in relapsing fever. 693 tissue, reproduction of, 295 Splenomegaly, infantile, 699 tropical, 697 Sporangia, 680, Spore-formation, 551, 586 Spores, 34, 551, 703 Sporoblasts, 701, 710, 713 Sporocyst, 701, 704, 710 Sporogenous granules, 553 Sporogony, 701, 704 Sporozoa, 42, 701 Sporozoites, 701, 704, 705, 710, 713 Stab-cultures, 561 Stadium amphiboles, 92 decrement i, 92 increment i, 91 Staggers, cause of the, 720 Staphylococci, 549, 563, 57S Staphylococcus pyogenes allms, 5X1 pyogenes aureus, 578 pyogenes citreus, 581 Stars, 281 Starvation, 5 Stasis of the blood, 150 Stearin, 203 Stegomyia fasciata, 44, 699 Sterilized cultures, injection of, 112 Sternopagus, 513 Stigmatization, 101 Stomach, carcinoma of, 474 Stomoxyids, 753 Stomoxys calcitrans, 697 Stones (concretions), 233 Stone-cutter's lung, 367 Straddling emboli, 68 Strangles of horses, 5S5 Streptococci. 550. 563, 565 Streptococcus articulorum, 573 brevis, 573 erysipelatis, 573 lanceolatus, 575 longus, 573 meningitidis, 577 mucosus, 573 puerperalis, 573 pyogenes, 565 scarlatinosa, 573 Streptothrix madurae, 665 Strongylides, 737 Strongylus armatus. 740 bronchialis, 740 capillaris, 740 commutatus, 740 duodenalis, 737 filaria, 740 longevaginatus, 710 micrurus, 740 paradoxus, 740 pusillus, 740 rufescens, 740 syngamus, 740 tetracanthus, 740 trachealis, 740 Strychnine, poisoning by, 29 Substance, nbrinogenie. 137 lysogenic, 109 zymoplastic, 138 Sucking-mite, 751 Sucking-worms, 710 Suffocation, 4 Suffusion. 158 Suggillations, 158 Sulphur-met haemoglobin, 20 Sunstroke, 8 Supernumerary organs, '•>■'>, 532 Suppuration, causes of, 341 Suprarenal cachexia, 87 capsules, altered function of, 87 Suprarenin, 87 Surra, 697 Susceptibility to infections at different ages, 47 Sweat-glands in dermoid cysts, 490 Swine-erysipelas, 007 immunization, 113 Swine-plague, 668 S wi n e-septi csemia , 66S Sycosis parasitaria, 676 Symbiotes equi of Gerlach, 751 Symmetrical gangrene, 179 Symmyelia, 520 Symptomatic anthrax, 666 protective inoculations against, I 13. Sympus, 526 Syncephalus, 542 Syncope, 17 Syncytiolysin, 78 Syncytiotoxin, 78 Syncytium, 465 Syndactylism, 528 Syngamus branchialis, 740 trachealis, 740 Synophthalmia, 515 GENERAL INDEX. r?9 Synotia, 518 Syphilides, 643 Syphilis, 641 hereditary, 646 transmission to foetus, 62, 648 Syringomyelia, 50 Syringomyelocele, 510 TaBANIDjE, 753 Tablet-formed cocci, 540, 550, 563 Tactile irritability, 102 Taenia africana, 726 ccenurus, 726 cucumerina, 7l'0 echinococcus, 727 denticulata, 726 diminuta, 726 elliptiea, 726 expansa, 726 flavapuncta, 726 mamillana, 726 marginata, 726 mediocanellata, 725 minima, 726 nana, 726 perfoliata, 726 plicata, 726 saginata, 725 serrata, 726 solium, 722 Tail, formation of a, in the human being, 534 Talipomanus, 530 Tapeworms, see also under Tiutiin, 72 1 Tariehium megaspermum, 687 Tartar of the teeth, 233 Tattooing of the skin, 255 Teeth in dermoid cysts, 490 supernumerary, 534 Telangiectasia, 398 lymphatica, 404 Temperature, influence of, upon develop- ment of bacteria, 552 Temperatures, high, of the body, 8 low, of the body, 9 Tendinous spot, 360 Teratoid cysts, 485, 495 tumors, 485 Teratoma, autochthonous, 496 bigerminal, 496, 545 coccygeal, 495, 496, 545 complex, 490, 495 heterochronous and heterotopons, 485 monogerminal, 496 of sexual glands, 490 sacral, 485 solid, 492 Terminal artery, 163 Testicle, adenocystoma of, 492 adenomyosarcoma of, 495 angiosarcoma of, 430 congenital adenocystoma <>f. 49:; dermoid cysts of, 491 ectopia of, 531 retention of, in the abdominal cavity, 531 teratomata of, 492 Tetanotoxin, 603 Tetanus, 602 antitoxin, 112, 115, 603 Tetanus-bacillus, 602 Tetany, thyroprival, 82 Tetracoccus, 563 Texas fever, 712 Thallophytes, 677 Thoracic cavity, faulty closure of. 521 Thoracic duct, rupture of, 166 Thoracogastroschisis, 520 Thoracopagus, 543 parasiticus, 547 Thoracoschisis, 521 Threadworms, 736 Thrombin, 137, 142 Thrombo-arteritis purulenta. 148 Thrombogen, 138 Thrombokinase, 138 Thrombo-phlebitis purulenta, 148 Thrombosis, 136, 138, 144 scqueUe of, 146 Thrombus, 144 agglutination, 141 autochthonous, 145 formation of, 139 globular, 145 induced, 145 laminated, 139 mixed, 139 obturating, 145 parietal, 145 red, 138 valvular, 145 white, 139 Thrush, 41, 679 Thymus, disease of, 89 Thyreoprival cachexia, 82 tetany, 82 Thyroid, angiosarcoma of, 430 extirpation of, 82 Thyroiodine, 84 Tibia, tuberculous disease of, 630 Ticks, 750 Tinea favosa, 685 Tipulidae, 753 Tissue-implantation, bigerminal, 496 monogerminal, 496 Tissue-lesion. 320, 325 Tissues, restitution of the, 272 Toes, stunting of, 528 Tokelau, 687 Toluylendiamin, poisoning by, 26 Tongue, actinomycosis of the. 660 Tongue-worms, 748, 751 Tophi, gouty, 232 Torula-chains, 5133 Toxalbumins, 18, 33, 39 Toxenzymes, It) Toxic substances, 19, 36 Toximcmia, 35 Toxins, 33 bacterial, 34 intracellular, 33 Toxoids, 39, 98 Toxons, 39, 599 Toxoses, 98 780 GENERAL INDEX. Transmissible pathological conditions and tendencies, 55 Transplantation, 309 Transportation, retrograde, 6.5 Trauma, effects of, 16 Traumatic epithelial cysts, 466 neuroses, 17 Trematoda, 42, 716 Treponema pallidum, 641, 695 Trichina spiralis, 743 Trichocephalus dispar, 743 Tricholysin, 120 Trichomonas hominis, 689 intestinalis, 44, 692 vaginalis, 692 Trichomyeetes, 550, 665 Trichophyton tonsurans, 685 Trichophytosis, 687 Trichothecium roseum, 680 Trichuris trichuria, 743 Tritotoxin, 610 Trombidida?, 750 Trophoblasts, 60 Trophoneurotic diseases of the tissue's, 74 Tropical sore, 699 Trypanomonas, 695 Trypanosoma bruci, 44, 697 equiperdum, 697 equinum, 697 evansi, 44, 697 gambiense, 44, 699 lewisi, 695 nocture, 698 theileri, 697 Trypanosomiasis, 698 Tsetse disease, 677 Tube-cocci, 549, 563 Tubercle, 617 solitary, 627 Tubercles, miliary, 625 Tuberculin, 114, 622 Tuberculomyces, 621 Tuberculosis, 615 avian, 637 bacillus, 615 bovine, 637 hematogenous miliary, 633 infection with, 616 Tumors, 371 adenocarcinoma, 461 adenocystoma, 448 adenoma, 444 adenosarcoma, 476 angiosarcoma, 425 benign and malignant, 383 cachexia, accompanying, 384 carcinoma, 455 cavernous, 400 chloromata, 435 chondromata, 391 chordoma, 393 classification of, 374 congenital, 52 connective-tissue, 372 cure of, 383 cylindroma, 438 cystic, 448 Tumors, cystocarcinoma, 478 definition of, 371 dermoid cysts, 4S5 desmoid, 385 different varieties, 372, 385 enchondroma, 391 endothelioma, 425 epithelial, 37.3, 375, 440 etiology, 376 fibroma, 385 fibromyoma, 411 fibrosarcoma, 423 glioma, 4 1 3 growth of, 379 by expansion, 380 by infiltration, 380 luemangiomata. 398 histoid, 372 homoplastic, 374 keloid, 387 leiomyoma, 409 lipoma, 389 lyniphangiomata, 398 malignant, 384 mclanosarcomata, 433 metastasis, 380, 384 myofibroma, 411 myoma, 409 myxochondroma, 393 myxofibroma, 387 myxolipoma, 387, 389 mjrxoma, 387 myxosarcoma, 387. 424 neuroepithelioma, 4 15 neurofibroma, 417 neuroglioma ganglionare. 414 neuroma, 4J6 organoid, 420 osteochondroma, 393, 396 osteofibroma, 396 osteoid sarcoma, 436 osteoma, 394 papilloma, 385,440 psammoma, 437 recurrence of, 383, 484 retrogressive changes in, 3S2 rhabdomyoma, 411 sarcocarcinoma, 477 sarcoma, 419 secretion in, 375 structure of, 372, 374 _ teratoid, 374, 485 Twin-formations, rudimentary, 496 Twins, 539 homologous, 540 Tympanic cavity, cholesteatomata in, 442 Typhoid-carriers, 596 Typhoid fever, bacillus of, 594 protective inoculations against, 1 1 I of fouls, 669 of mice, 668 Typhus recurrens, 693 Udder-inflammations, 585, 669 Ulcer, 340 chronic, 368 indolent, 368 GKNEKAli INDEX. rsi Ulcer, serpiginous, 368 Ulceration, carcinomatous, 458 tuberculous, 63(1 Ulcus atonicum, 368 callosum, 368 elevatum hypertrophieurn, 368 indolens, 368 molle, 614 Umbilical hernia, 520 Uncinaria americana, 737 duodenalis, 737 Urachus-cysts, 487 Uraemia, 76 Urates, deposit of, in gout, 77, 232 Urethra, abnormal narrowness of, 524 absence of, 524 atresia of, 524 Urethritis, gonorrhoea], 582 Uric-acid deposits, 231, 235, 237 infarct, 235 Urinary calculi, 235, 237 Urobilin, 243 Urobilinuria, 243 Uterus, adenocarcinoma of, 470 beginning carcinoma of cervix, 462 myoma of, 409 Uvula, bifurcation of, 517 Vaccination, 1 1 1 Vaccines, ] 15 Vaccinia, 705 Vacuoles, 151, 171. 102, 327 Valves, lesions of, 1 26 Valvular thrombus, 145 Variation, 58 Variola, 705 Vascular nsevi, 399 system, pathological changes in the, ' 50 walls, pathological alterations of, 320 Vasculitis, proliferating, 361 Vasomotor nerves, irritation or paralysis of, 129 Vein-stones, 234 Venous pulsation, 126 pulse, 126 Veratrine, poisoning by, 29 Vermes, 716 Verruca carnea, 406 senilis, 441 vasculosa, 400 Vertebra?, supernumerary, 534 Vertebral canal, deficient closure of, 508 Vesicles, 329, 332 Vibrio cholerae, 671 of Metschnikoff, 675 rugula, 670 serpens, 670 Vibrion butyrique, 588 septique of Pasteur, 604 Viscera, abnormal positions of, 530 duplications of, 532 Viscous metamorphosis, 140 Visual apparatus, pathological conditions of, 52 Vitelline duct, cyst of, 522 Vitiligo, 257 Volatile poisons, 23 Wandering cells, 321 Warts, fleshy, 405 ichthyotic, 264, 441 senile, 441 venereal, 269, 367 Water, effects of lack of, 5, (3 Weights of different organs, 266 Weismann, 60 Whip-worm, 743 White gangrene, 178 Whooping-cough, bacillus of, 60 Widal-Gruber reaction, 109, 596 Wolffian body, 496, 538 Wolffian duct, 53S Wolf's jaws, 517 Wood-jack or wood-tick, 750 Worm-disease of the ox, 669 Worms, 42, 716 parasitic, 42, 716 Wound-diphtheritis, 344 Wound-granulations, 347 Wound-infection, 45 Wounds, effects of, Hi healing r , 356 Xanthin calculi, 237 Xiphopagus, 543 Yeast-fltngi, 677 Yellow-fever, 614, 699 Zona dermatica, 509 epithelo-serosa, 509 Zooglcea, 550 Zymase, 39 Zymoid, putrefactive, 38 Zymoplastic substance, 138, 142