ee anne pean case tneted ete ere jaa one enna wee WW NO HIN Hitt UEETTEETTEE Gere gE Digitized by the Internet Archive in 2010 with funding from University of Toronto http://www.archive.org/details/harveylectures11harv THE HARVEY SOCIETY THE HARVEY LECTURES Delivered under the auspices of THE HARVEY SOCIETY OF NEW YORK Previously Published FIRST SERIES. . . 1905-1906 SECOND SERIES . . 1906-1907 THIRD SERIES . . 1907-1908 FOURTH SERIES. . 1908-1909 FIFTH SERIES. . 1909-1910 SIXTH SERIES . . 1910-1911 SEVENTH SERIES . 1911-1912 EIGHTH SERIES. . 1912-1913 NINTH SERIES . . 1913-1914 TENTH SERIES . . 1914-1915 ELEVENTH SERIES 1915-1916 “ ; Ley aa 4 ry at ee Ue if [> Pe } N ; CopyRiGHT, 1917 By J. B. Lippincott ComPANy od I H33 Sey.|] PREFACE THE Harvey Society presents to the public in this volume the papers comprising the eleventh series of lectures. The list of contributors differs from those of previous years in that no foreign country is represented. Heretofore, it has been the custom of the Society to invite as lecturers men of science with- out regard to country or nationality. However, in planning the program for the past season it was not deemed expedient on account of the existing war, which has made international com- munication slow and difficult, to extend invitations to any one outside our own country. While this decision necessarily limited the number of those available as lecturers, the Society has reason to congratulate itself on the result; for this series of lectures, as judged by attendance and interest manifested, was probably the most successful in the Society’s history. We take this oppor- tunity to extend the thanks of the members of the Harvey Society to the speakers of the year whose splendid and generous service has made this success possible. Following the custom of former years of making acknowledg- ment to journals in which any of the lectures have already been published, we wish to express our indebtedness to the American Journal of Medical Sciences for the re-publication of the papers by Professor Longeope and Dr. Du Bois. Ropert A. LAMBERT, Secretary. November, 1916. i ie iF i ~ be AWM), f e ‘ ‘ . | i a, — * THE HARVEY SOCIETY A SOCIETY FOR THE DIFFUSION OF KNOWLEDGE OF THE MEDICAL SCIENCES CONSTITUTION be This Society shall be named the Harvey Society. it The object of this Society shall be the diffusion of scientific knowledge in selected chapters in anatomy, physiology, pathology, bacteriology, pharmacology, and physiological and pathological chemistry, through the medium of public lectures by men who are workers in the subjects presented. III. The members of the Society shall constitute three classes: Active, Associate, and Honorary members. Active members shall be laboratory workers in the medical or biological sciences, residing in the City of New York, who have personally con- tributed to the advancement of these sciences. Associate members shall be meritorious physicians who are in sympathy with the objects of the Society, residing in the City of New York. Members who leave New York to reside elsewhere may retain their membership. Honorary members shall be those who have delivered lectures before the Society and who are neither active nor associate members. Associate and honorary members shall not be eligible to office, nor shall they be entitled to a vote. Members shall be elected by ballot. They shall be nominated to the Executive Committee and the names of the nominees shall accompany the notice of the meeting at which the vote for their election will be taken. 7 CONSTITUTION ay. The management of the Society shall be vested in an execu- tive committee, to consist of a President, a Vice-President, a Secretary, a Treasurer, and three other members, these officers to be elected by ballot at each annual meeting of the Society to serve one year. ,' & The Annual meeting of the Society shall be held soon after the concluding lecture of the course given during the year, at a time and place to be determined by the Executive Committee. Special meetings may be held at such times and places as the Executive Committee may determine. At all the meetings ten members shall constitute a quorum. 7s: Changes in the Constitution may be made at any meeting of the Society by a majority vote of those present after previous notification of the members in writing. OFFICERS OF THE HARVEY SOCIETY OFFICERS Grorce B. WALLACE, President Rurus Coie, Vice-president Epwarp K. DunHAM, Treasurer Rospert A. LAMBERT, Secretary COUNCIL GRAHAM LUSK WarFIELD T. LONGCOPE Stantey R. BENEDICT Hans ZINSSER The Officers Ex-O ficio ACTIVE MEMBERS . JOHN S. ADRIANCE . F. M. ALLEN . Hugo AUCHINCLOSS . JOHN AUER . O. T. AvERY . GEORGE BAEHR . F. W. BAncrorr . S. R. Benepict Dr. Herman M. Bices . HarLow Brooks Dr. W. H. Brown . Lro BUERGER . R. Burton-Opitz . E. E. BuTrerFiELD . ALEXIS CARREL . R. L. Ceci. oP, F. Cuark . A. F. Coca Dr. A. E. CoHN . Rurus Coe . RoBert COOKE . H. D. Dakin . C. B. DAVENPORT Dr. A. R. DocuEz Dr. GEORGE DRAPER . E. F. Du Bors . KE. K. DuNHAmM . WALTER H. Eppy . W. J. EvLSER . Haven EMERSON Dr. . JAMES EWING . L. W. FAMULENER . J. S. Fercuson . C. W. Fietp . Morris 8. FINE . Smmon FLEXNER . Neuuis B. Foster . ALEXANDER FRASER . Francis R. FRASER . F. L. Gates . A. O. GETTLER . H. R. GEYELIN . W. J. GrEs . T. S. GrrHEeNns . FREDERICK GOODRIDGE . F. M. Hangs . T. W. Hastines . R. A. HatcHer . A: FS Hiss . J. G. HopKins . Paut E. Howe . JOHN HOWLAND . G. S. Huntineton . Hotmess C. Jackson . W. A. JAcoBs . H. H. JANEwAy . THEODORE C. JANEWAY . JAMES W. JOBLING . Don R. JosEPH Epuraim M. Ewine ACTIVE MEMBERS—Continued Dr. D. M. Kaptan Dr . L. S. KuEIner Dr. CHARLES KRUMWIEDE Dr. R. V. LaMar Dr. Ropert A. LAMBERT Dr. Freperic S. Lee Dr. E. S. L’ ESPERANCE Dr. P. A. LEVENE Dr. Isaac LEvIN Dr. E. Linsman Dr. Dr. Cc. C.. Lis WanrFIELD T. LONGCOPE Dr. GraHAmM LUSK . W. G. MacCattum Dr. W. J. MacNrau . F. H. McCruppen . FRANKLIN C. McLEAN . A. R. MANDEL . JOHN A. MANDEL . F. S. ManpLesaum . W. H. MAnwarinG, JR. Dr. S. J. MELTZER Dr. ApoLF MEYER . G. M. Meyer Dr. L. S. MILNE Dr. C. V. Morrinu Dr. H. O. MosentHAL Dr. J. R. Muruin . JAMES B. MurpHy . V. C. Myers . W. C. Nosie . Hipeyo Noeucui . CHARLES Norris . Horst OERTEL Dr. Peter K. Ouitsky . EuGene L. Opie . B. S. OppenHEIMER . REUBEN OTTENBERG . A. M. PApPENHEIMER . WimuuiAM H. Park . F. W. Preanopy . LOUISE PEARCE Dr. Dr. Dr. Dr. Dr. Dr. Dr. . C. G. Rosinson . Peyton Rous . H. von W. ScHULTE . Orro H. ScHULTZE . E. L. Scorr . H. D. SENIoR . E. G. STILLMAN . C. R. Srockarp . I, Strauss . Homer F. Swirt . DouGuaAs SYMMERS . Oscar TEAGUE . B. T. Terry . WiiuiAM C, THRO . FREDERICK TILNEY . J. C. TorREY . D. D. Van SiYKE . Kart M. Voce . AuGustus WADSWORTH . A. J. WAKEMAN . G. B. WALLACE . RicHarD WEIL . Wa. H. WELKER . J. CLARENCE WEST . J. S. WHEELWRIGHT . A. O. WHIPPLE . C. G. Wiccers . ANNA W. WILLIAMS . H. B. WriiuramMs . R. J. Winson . Witu1AM H. WoGiom . MartHa WOLLSTEIN . Francis C. Woop . JONATHAN WRIGHT . Hans ZINSSER Ricuarp M. Pearce F. H. Pike Harry Piorz FREDERICK PRIME T. M. PruppEN A. N. RicHarps A. I. RINGER ASSOCIATE MEMBERS . Rosert ABBE . C. F. Apams . LsAac ADLER . F. H. ALBEE . W. B. ANDERTON . Wu. ARMSTRONG . GorHAM Bacon . PEARCE BaILEY . T. B. BARRINGER . F. H. Barrett . Simon BarucH . W. A. BasTepo . JOSEPH A. BLAKE . GEORGE BLUMER . A. Bookman . Davip BovairbD, JR. . J. W. BRANNAN . J. BRETTAUER . GeorcE E. BREWER . NatHaAn FE. Britu . Wm. B. BrinsMaDE . EK. B. Bronson . S. A. Brown . J. G. M. BuLLOWwa . 8. R. Burnap . GLENTWoRTH R. BUTLER . C. N. B. Camac . Wn. F. CAMPBELL . R. J. CARLISLE . H. S. Carter . A. F. CHAcE , C. G. CoaKLEy . H. C. Cor . WARREN COLEMAN . W. B. Cottey . C. F. Coins . L. A. CoNNER . C. B. CouLTer . E. B. Cragin . Fuoyp M. CranDALu . G. W. Crary . Epwarp CUSSLER meet, Dawa . THomMAS DARLINGTON . WILLIAM DARRACH . D. Bryson DELAVAN . E. B. DENCH . W. K. DRAPER . ALEXANDER DUANE . THEODORE DUNHAM . Cary EGGLESTON . Max EINHORN . CHARLES A. ELSBERG . A. A, Epstein . Evan M. Evans . S. M. Evans . EK. D. FIsHer . Rou¥re FLoyp . JOHN A. ForDYCE . JOSEPH FRAENKEL . R. T. FRANK . F. G. FREEMAN . WoLFr FREUDENTHAL . L. F. FRISsELL . VirGIL P. GIBNEY . CHARLES L. Gipson . J. RIDDLE GOFFE . S. S. GoLDWATER . M. GooprinGe . N. W. Green . J. C. GREENWAY . M. S. Grecory . R. H. Hausey . GRAEME M. Hammonp . T. Stuart Harr . JOHN A. HartTweELu . R. S. Haynes . Henry Heiman . W. W. Herrick . August Hocu . A. W. Hottzis . H. A. HoucHton . Husert S. Howe - . Francis Huser . E. L. Hunt . Woops HutcHinson ASSOCIATE MEMBERS—Continued . LEOPOLD JACHES . ABRAHAM JACOBI . GEORGE W. JAcoBYy . RALPH JAcoBy . Watrer B. JAMES . S. E. JELLIFFE . FREDERICK KAMMERER . L. Kasr . JACOB KAUFMAN . F. L. Keays . Foster KENNEDY . C. G. Kerrey . P. D. Kerrison . E. L. Keyes, JR- . ELEANOR KitHamM . Orro KIIANI . R. A. KInseiua . ARNOLD Knapp . Linnagus E. La Ferra . A. R. Lams . ALEXANDER LAMBERT . S. W. LAMBERT . BoLestAw LAPOWSKI . Berton Latrin . B. J. Lee . J. S. LEoPoup . Ext Lone . Wm. C. Lusk . H. H. M. Lyi . D. H. McAupin . J. F. McKernon . Morris MANGES . George MANNHEIMER . WiLBur B. Marpie . H. H. Mason . FRANK S. MEARA . VictoR MELTZER . WALTER MENDELSON . ALFRED MEYER . Witty MEYER t. MicHarL MICHAILOVSKY . G. N. MILLER Dr. Dr. Dr. Dr. . L. K. NErr . M. Nicouu, Jr. . WATER L. NILES . VAN Horne Norrie . W. P. NorrHrup . N. R. Norton JaMeS A. MILLER A. V. Moscucow1rTz JoHN P. Munn ARCHIBALD Murray A. T. Oscoop . H. McM. Painter . ELEANOR Parry . STEWART PaTON . Henry S. Patrerson . CHARLES H. Peck . FREDERICK PETERSON . G. R. Pisex . Wiutu1AmM M. PoLkK . SIGISMUND POLLITZER . EUGENE H. Poou Dr. NATHANIEL B. Porrer Dr. Dr. . Francis M. RacKAMANN . JOHN H. RicHarDs . A. F. Riaes . ANDREW R. ROBINSON . JOHN RoGers, JR. . J. C. ROPER . JuLIus RupiscH Dr. Dr. Dr. Dr. Dr. Dr. Dr. Dr. Dr. Dr. Dr. 12 Wm. J. PULLEY EDWARD QUINTARD BERNARD SACHS E. F. SAmpson T. B. SATTERTHWAITE ReGiInaLtp H. Sayre Max G. ScHLAPP H. J. SCHWARTZ E. W. Scripture N. M. SHAFFER Wituiam H. SHELDON H. M. Siuver M. J. SIrTreNFIELD PrRor. PRoF. PROF. PrRoF. Pror. PRrRor. PRorF. PRor. PRorF. Pror. PROF. PROF. PROF. Pror. PRror. PROF. Pror. PROF. PRoF. Pror. PROF. ASSOCIATE MEMBERS—Continued . MARTIN DE Forest SMITH . KF. P. Soutzy . F. E. SonpERN . J. BENTLEY SQUIER . N. STADTMULLER . ANTONIO STELLA . ABRAM R. STERN . Georce D. Stewart . R. G. STILLMAN . L. A. STIMSON . Wa. S. STONE . A. McI. Strone . MILLS STURTEVANT . GrorceE M. Swirt . ParKrer Syms . A. S. Taynor . JOHN §. THACHER . A. M. THomas . W. Gruman THOMPSON Dr. Dr. Dr. . PHtnip VAN INGEN . J. D. VOORHEES . H. F. WALKER . JOHN B. WALKER . JOSEPHINE WALTER . JAMES S. WATERMAN . R. W. WEBSTER . JOHN E. WEEKS . Hersert B. WILCOX : . Linsty R. WILLIAMS . W. R. WILLIAMS . MarGaret B. WILSON . G. WooLsey . J. H. WYCKOFF . CHaRLES H. YouNG . JOHN VAN DoREN YOUNG Wma. Hanna THOMPSON S. W. THURBER Wm. B. TRIMBLE HONORARY MEMBERS J. G. ADAMI J. F. ANDERSON E. R. BaLpwIn LEWELLYS F. BARKER F. G. Benepict R. R. BENSLEY A. CALMETTE WaAtterR B. CANNON A. J. CARLSON W. E. CAstie CHARLES V. CHAPIN Hans CHIARI R. H. CuitrTeNDEN Henry A. CHRISTIAN Orro CoHNHEIM Epwarp G. CONKLIN W. T. CouncILMAN G. W. CrILE Harvey CUSHING ArtHur R. CusHNny Henry A. DONALDSON PROF. PROF. PROF. PROF. PROF. PROF. PROF. PROF. PROF. PROF. PRor. PROF. PROF. PROF. PROF. PROF. PROF. PROF. PROF. D. L. Epsauu JOSEPH ERLANGER WILLIAM FALTA Orro Fouin F. P. Gay J. S. HALDANE W. S. Haustep Ross G. HARRISON Sven G. HepiIn Lupwia HEKkTOoEN L. J. HENDERSON W. H. Howe G. CarL HuBER JOSEPH JASTROW H. S. JENNINGS K. O. JoRDAN K. P. Josuin FRANZ KNoop ALBRECHT KOSSEL Pror. J. B. LEATHES Pror. A. Macnus-LEevy 13 HONORARY MEMBERS—Continued Pror. Max RUBNER Pror. F. F. RussELL Pror. FLORENCE R. SABIN Pror. E. A. SCHAEFER Pror. ADOLPH SCHMIDT Pror. W. T. SEDGWICK Pror. THEOBALD SMITH Pror, Paut A. LEwIs Pror. THomAs Lewis Pror. JACQUES LOEB Pror. A. 8. LOEWENHART Pror. A. B. MacatLtum Pror. J. J. R. MacLeop Pror. E. V. McCoLtuM Pror. F. B. MAuLuory Pror. E. H. StTarLiInG Pror. L. B. MENDEL Pror. G. N. STEWART Pror. Hans MEYER Pror. C. W. STILES Pror. T. H. Morcan Pror. Ricuarp P. SrronG Pror. FRIEDRICH MULLEB Pror. A. E. TAayLor Pror. KARL vON NOORDEN Pror. W. S. THAYER Pror. Frep G. Novy Pror. Vicror C. VAUGHAN Pror. G. H. F. Nurrauu Pror. Max VERWORN Pror. Henry FarrFIELD OSBORN Pror. A. D. WALLER Pror. T. B. Ossporn Pror. J. CLARENCE WEBSTER Pror. G. H. ParKER Pror. Wu. H. WELCH Pror. W. T. Porter Pror. H. Giron WELLS Pror. J. J. Putnam Pror. E. B. WiLson Pror. T. W. RICHARDS Pror. R. T. WoopyattT Pror. M. J. RosENAU Pror. Sir ALMROTH WRIGHT “ DECEASED Dr. SAMUEL ALEXANDER Dr. Francis P. KINNICUTT Dr. L. Botton BAancs Dr. HERMANN KNAPP Dr. Cart BECK Dr. Gustav LANGMAN Dr. J. H. BoRDEN Dr. Eapert LE FEVRE Dr. T. G. Bropre Dr. CHaArLes H. Lewis Dr. F. Titp—ENn Brown Dr. S1IGMuUND LUSTGARTEN Dr. S. M. BricKNER Dr. CHARLES McBURNEY Dr. J. D. Bryant Dr. GeorGe MCNAUGHTON Dr. Jonn G. CurTIS Dr. CHarues 8. Minor Dr. Austin FLINT Dr. S. Wer MircHEeLL Dr. C. Z. GARSIDE Dr. C. C. Ransom Dr. Emit GRUENING Dr. Wa. K. Srarpson Dr. FRANK HARTLEY Dr. A. ALEXANDER SMITH Dr. CuristiAn A. HERTER Dr. RicHARD STEIN Dr. Puitre Hanson Hiss Dr. H. A. STEWART Dr. EvGeENE HoDENPYL Dr. WisNER R. TOWNSEND Dr. Jonn H. Huppieston Dr. R. Van SantvoorpD Dr. Epwarp G. JANEWAY Dr. H. F. L. Zrecen CONTENTS , PAGE Recent Studies on School Children, with Special Reference to Hookworm EBM SPM EEEION «| GS. A aerate Selah a Ae «Sed So mnaRI Be s/s 19 Pror. Cu. WARDELL Stites—U. 8S. Public Health Service On the Nervous Control of the Hunger Mechanism................... 37 Pror. A. J. CarLSon—University of Chicago. The Respiration Calorimeter in Clinical Medicine.................... 101 Dr. Evcent F. Du Bots—Russell Sage Institute ot Pathology. The Method of Growth of the Lymphatic System...................... 124 Pror. FLoRENCE R. Sasin—Johns Hopkins University. The Present Significance of the Amino-Acids in Physiology and Pathology 146 Dr. Donatp D. Van StyKeE—Rockefeller Institute. OO TUTRIBEL. . oo vagdlae amen peg 5 Ce a mre ARR Ea 2 09, 8 ka Ue a POR 174 Dr. Hipeyvo Nogucui—The Rockefeller Institute for Medical Research. The Susceptibility of Man to Foreign Proteins ....................--. 271 Pror. Warrietp T. Lonecorr, M.D.—Columbia University and the Medical Clinic of the Presbyterian Hospital, N. Y. Same eases of the Nephritis Problem:............0....0.5.2.00005. 303 Pror. Henry A. Curistian, M.D.—Harvard University. Studies on Intermediate Carbohydrate Metabolism................... 326 Dr. R. T. Woopyarr—Otho S. A. Sprague Memorial Institute Laboratory for Clinical Research. WmnerAcidan its Relations to Metabolism.........0.0......0.0ceceeae 346 Pror. Stantey R. Benepicr—Cornell University. Medical Education in the United States...............0 0.0. eee ec eee 366 Pror. WiitutraM H. Weica—Johns Hopkins University. ILLUSTRATIONS Formula of a decapitated amino-acid................. 0.000 cee eee eee 147 Coupling of the amino-acids, alanine and glycocoll, to form the di- PET CUAIV IG ELI COCOI. 6.55. 5.3 aye eG Bide oe io eh ea 148 Formula of an imaginary protein containing one molecule of each known (UTE CL RNG ag i Re Aer Lecce, A079 BL nu aan 149 The amino-acid content of the blood during fasting and protein digestion 158 The absorption and retention, by different tissues, of amino-acids injected 7 RIED TIS pena AN ote ae ere TEMES Reaver ibre Meet to 160 The blood urea during fasting and protein digestion.................. 161 Time curve of blood urea changes during protein digestion............. 162 Effect of adding lysine and tryptophane to diet deficient in these amino- DRUM I se Sopa ki ak 0 icin enepe ime ered so IN Cee EN SE 166 1 : 10,000 dilution of salvarsan in 5c. c. of medium.................. 219 1 : 10,000 dilution of neosalvarsan in 5 ec. c. of medium ................ 220 1 : 1,000 dilution of bichloride of mercury in 5c. c. of medium.......... 220 LIST OF PLATES Fig. 1.—A period of gastric hunger contractions of a human infant, nine hours aiter birbh, and before nursing..22).5..s.)0s'... 2.26 «+ 90 Fig. 2.--Showing inhibition of the contractions of the empty stomach and the parallel cessation of the hunger pangs...................... 90 Fig. 3.--The inhibitory effect of hydrochloric acid, water, and alcohol PMmbHe AUN Fer MOVEMENTS: 4)3 fied eae oe tod | citimioae Cries tele oie ele 90 Fig. 4.—- Record of contractions of the empty stomach, showing tempo- EINE TEENUUI Sct SUSE aS ote iat ee eR Oe Se Pe eh cael 90 Fig. 5.—Record of contractions of the empty stomach, showing acid ERED R LIN CIERRA U> (niles Se Tee ats a Gee apoR alee teins ache ote aes 90 Fig. 6.--Records from the empty stomach, showing alcohol inhibition... 90 Fig. 7.—Records of the gastric hunger contraction.................... 90 Fig. 8.—Diagram to represent the local and the long reflex mechanisms involved in inhibition of the gastric tonus and the hunger contrac- tions from stimulation of the gastric mucosa...................-- 90 Fig. 9.—Record of gastric hunger contractions, showing stimulation.... 90 Fig. 10.—Record of gastric hunger contractions, showing usual ending of RRPESE RTGS Tn TOTT OC paste ets esha bs ees irae Colts. Me A ede ate ecley uethey Beale tat 90 Fig. 11.—Record of gastric hunger contractions (man), showing inhibi- tion on strong constriction of abdominal belt.................. 90 Marais tor Continuous perfusion... .. 2.2... 0... c ere eee e eee e ees 330 u RECENT STUDIES ON SCHOOL CHILDREN, WITH SPECIAL REFERENCE TO HOOK- WORM DISEASE AND SANITATION * PROF. CH. WARDELL STILES U. S. Public Health Service ONSERVATION”’ and ‘‘efficiency’’ are two of the most popular catchwords of the day. To many persons, they seem to represent new lines of thought. When analyzed, how- ever, they are seen to represent in reality two of the most impor- tant elements contained in the old-fashioned word ‘‘economy.’’ This word economy is not a popular one, and if one takes it as a text he is not very likely to have an attentive audience, for the word immediately brings up thoughts of sacrifices, notwithstand- ing the fact that the first essential of economy is to prevent unnecessary ‘‘waste’’ rather than to do without something that is valuable, necessary, or desirable. The best and most practical definition or description of econ- omy I have ever heard is that it consists in spending the greatest amount of money that will give the greatest possible returns. _ This evening JI invite your attention to certain phases of economy as applied to the health and advancement of school children, but in order to avoid misunderstanding permit me to emphasize the point that my text involves not a restriction in expending money or care, but rather an increased expenditure of both in order to bring about the fundamental elements of economy, namely, prevention of waste and promotion of con- servation and efficiency. To the popular mind, it is the ‘‘epidemic’’ of unusual disease that is something to be dreaded, and the average person rarely * Delivered October 16, 1915. 19 20 HARVEY SOCIETY stops to think that the aggregate of little losses, here and there, may present a grand total which far exceeds that from some of the much dreaded epidemics. How few persons recall, for instance, that in this country the annual loss in human life from tuberculosis alone is greater than that we have suffered from yellow fever during more than a century. Yet the public excite- ment caused by one case of yellow fever is much greater than that caused by more than a hundred thousand cases of tuberculosis. In the case of yellow fever we have the sudden appearance of an unusual disease, while in the hundred thousand cases of tuber- culosis we have a daily drain, a daily waste, that results in a total of much greater sorrow and inefficiency. To take a more familiar illustration, compare in your mind the public comment produced in a school district by the appear- ance of an epidemic of measles, chicken-pox, or whooping-cough, with the apathy usually attending the presence of adenoids, enlarged and infected tonsils, poor eyesight, poor teeth, or a heavy endemic infection of hookworm disease. Without multiplying comparisons further, I would present as my thesis this evening the point that economy in public school administration (or, if you prefer, conservation and efficiency among our school children) calls for a greater expenditure of care and money in order to prevent the constant little daily drains on child-life that are due to such factors as adenoids, enlarged tonsils, defective eyesight, poor teeth, and to poor sani- tation at schools and at homes, insanitation that results in such common infections as dysentery, diarrhea, typhoid fever, nook- worm disease, and other excreta-borne maladies. One of the earliest recollections of my childhood is the expres- sion, “‘If you take care of your pennies, the dollars will take eare of themselves.’? The same general principle holds in publie health, namely, if we are careful about little things in econ- serving health and life, many of the larger problems will auto- matically take care of themselves. In recent years, I have been especially interested in certain phases of child-life. Some of my friends have accused me of being somewhat interested in hookworms, but as a matter of fact HOOKWORM DISEASE AND SANITATION 21 the hookworm, from my point of view, is and always has been only an incident, a stage-setting or base of supplies, so to speak, in attacking a much broader problem of child-life and efficiency, as influenced by sanitation. From the cold-blooded stand-point of zodlogy, the common hookworm of this country is a diccious nematode belonging to the superfamily Strongyloidea, family Strongylide, sub-family Uneinartine, genus Necator, species Necator americanus, with this, that, and the other technical details that are of considerable interest to a few specialists (possibly twenty in the entire world) in helminthology, and of little interest to the public in general. From a warm-blooded human stand-point, however, the hook- worm is a factor that makes for suffering, sickness, inefficiency, and retardation. What, for instance, can a teacher expect to accomplish with groups of children such as you see in the picture before you? It is this, not the zodlogical view-point, that espe- cially appeals to me. It is the hookworm child and its mother, rather than the hookworms that occupy my thoughts, and this only as representing an example of a large class of conditions that ean and should be changed for the better. While studying hookworm infection in school children, I have frequently been impressed by the fact that in general the sanitation of the home is a practical working index to the physical condition of rural children, and in order to reduce these results of general observation to concrete examples, and especially in order to see whether the differences apply also to urban children, I have recently studied the school children of a certain county, which we may call X, located in the sandy area of the South and in which the whites happen to outnumber the negroes. Because of the uncertainty as to exact age, a considerable number of negro pupils and not an inconsiderable number of the white students had to be eliminated from all summaries in which age-groups must be considered. This may appear strange to you, for one is accustomed to view a knowledge of one’s birthday and exact age as self-understood, and a lack of that knowledge as a lack of intellectual development. Has it, however, occurred to you that the custom of giving birthday parties and birthday 22 HARVEY SOCIETY presents is an important factor in impressing upon one’s memory his birthday and birthyear, and that as the average per capita wealth decreases so that there are many families that cannot afford birthday presents, a knowledge of one’s birthday is less essential to happiness and less likely, therefore, to obtain? One evening I had 14 girls, varying from about 7 to 15 years of age, in a railroad hospital car ; it was near Christmas time, and I asked the children about their dolls; 8 out of 14 of these girls stated that they had never owned a doll. Birthdays meant nothing to these children, and Christmas meant little more. Lack of knowledge regarding one’s age is in these cases not so much a question of lack of intellect or a retardation in mental age, but a question of the family pocket-book which happens to be so thin that even a doll cannot be purchased for a 7-year-old girl! So there is nothing strange in the fact that some of my groups are reduced in number of members by the circumstance, for instance, that not a few of my children or their parents had little reason to remember ages and birthdays. I know in fact cases where children could not attend school regularly simply because they did not have sufficient clothing to comply respectably with ordi- nary police regulations. My age-groups consist of quarter-year groups which are then summarized into total-year groups. For instance, all 10-year-old children fall into the groups 10 years flat, 10.25, 10.50, and 10.75 years old ; and they are summarized into a 10-year-old group. The children are also classified by sex, and further by sanitary groups, as follows: Group S ineludes the children from homes provided with sewer connection, but without privy; Group P includes the children known to be from homes provided with privies; and Group U includes children from homes of unknown sanitation. It is self-understood that with this extensive sub- division, some of the sex-quarter-year-sanitary groups contain very few individuals, but with this point in mind it is legitimate to inquire whether the total-year sanitary groups show any par- ticular tendencies in any direction. In general, do the children of Group 8 (with sewer sanitation) and those of Group P (with privy sanitation) show any differences, and if so what are these differences ? HOOKWORM DISEASE AND SANITATION 23 INTESTINAL PARASITES One of our tests was a microscopic examination to determine what intestinal parasites were present. The results, though not unforeseen, are instructive and to my mind important: There was a total of 3594 city pupils, of whom 2248 were white and 1346 negro; 32 per cent. of the whites and 38 per cent. of the negroes furnished specimens for microscopic examination ; thus in this test the negroes co-operated somewhat better than the whites; 49 per cent. of the negroes examined, and 37 per cent. of the whites examined showed infection with one kind or another of intestinal parasite. This difference is largely due to the fact that in general the negroes live under poorer sanitary conditions than do the whites, for 76 per cent. of the total negroes, as com- pared with 20 per cent. of the total whites, belong to Group P. In considering the sanitary groups, we find that in Group P 50 per cent. of the white children and 50 per cent. of the negro pupils show intestinal parasites, as compared with Group S in which 34 per cent. of the whites and 41 per cent. of the negroes show infection. It makes no difference whether we consider the totals, or the two races, or the two sexes, the general conclusion is the same, namely, that intestinal infections are more common in children who live at homes with poorer sanitation than among those who live at homes with better sanitation. Intestinal infections are more common among white boys than among white girls, but negro boys show approximately the iden- tical percentages of these parasites as do negro girls. If, how- ever, the figures are analyzed closely the conclusion seems justified that some of the infections take place away from the home, and this seems to hold especially for the white boys. Coprophagia.—The parasites in question naturally fall into two biological categories, namely, 6 species that may be contracted in one way and in one way only, by actually swallowing, doubt- less accidentally, minute amounts of human excrement, and two species not necessarily contracted by this unconscious coprophagia. For instance, if we find Endameba, Lamblia, Trichomonas, eel- worms (Ascaris), pinworms (Ozyuris), or whipworms (T7'r- churis), we have positive, absolute, undeniable proof that that 24 HARVEY SOCIETY person has actually swallowed germs that have come from the excreta of some other person, a proof that holds equally well when we find that a person is suffering from typhoid fever, Asiatic cholera, and certain forms of diarrhcea and dysentery. This proof is not present, however, in case we find tapeworms or hookworms. If now we analyze our statistics from this point of view, we have positive proof that 28 per cent. of the white children and 48 per cent. of the negro pupils had actually swallowed human excrement. ‘This means that it is merely a matter of chance that about one-fourth of the white children and about one-half of the negro children did not present typhoid, or a history of recent typhoid. Comparing the two races, it is seen that the negro pupil runs a greater chance of unconscious coprophagia than does the white, and comparing the two sexes of each race we find that the white boys run a greater chance of coprophagia than do the white girls (namely, 34 to 20), while in the negro the chances are more equal (namely, about 47 in the boys to 49 in the girls). Compar- ing next the sanitary groups, we find that children of Group P show a greater amount of coprophagia than do children of GroupS. Thus, in white girls the chances are 24 to 19, in white boys 40 to 33, in total whites 32 to 27, in negro girls 50 to 44, in negro boys 49 to 33, and in total negroes 49 to 41. These figures fully justify us in expecting that children of Group P will have a greater proportion of absenteeism due to such diseases as typhoid, diarrhcea, and dysentery, than will children of Group S, and that, consequently, children who live under poorer sanitation will show a greater retardatign in school advancement due directly to absenteeism caused by these diseases than will be found among children who live under better sanitation. Making a broad application of this conclusion, it seems evident that the home sanitation under which children live has a direct influence upon the administration of school funds. That is to say, the school authorities cannot possibly expect to have the same HOOKWORM DISEASE AND SANITATION 25 total or average educational returns per $1000 expended upon teaching 1000 children who live under poorer sanitary conditions that they can expect to have in the case of 1000 children who live under better sanitary conditions. To put it more bluntly, it costs more per capita to obtain a given amount of education among poorer children than it does among children from families in better financial circumstances, and the conclusion is therefore justified that an increase in the amount of sanitary supervision and improvement of the sanitation under which the poorer fami- lies live means an actual economy in the public school funds. To the professional sanitarian and to the professional edu- eator, this conclusion is, or should be, almost axiomatic. To the taxpayer, however, it is less evident. In the statistics presented on the subject of unconscious coprophagia we have, I believe, an argument which should appeal to parents in general, and which has already been an important factor among the citizens of the County of X in arousing their determination to improve sanitary conditions in general. Another conclusion follows from these studies, namely, that the influence of the sanitation at a given home is a matter which involves not only the members of that particular home but also the community in general, for our experiments clearly show that a given backyard has an influence which may radiate in all direc- tions of the compass, and which may, therefore, influence the neighbors, for we have actually demonstrated by experiment that some of the parasites in question can be carried by flies and that these flies may therefore spread the excrement at one home to the food of the neighbors. Turning next to the second category of parasites, namely, those not necessarily contracted by coprophagia, our examinations show that among the white children hookworm infection was about three times as common in children of Group P as in pupils of Group S. Since, now, hookworm infection has a direct effect in inhibiting both mental and physical development, we must naturally expect greater retardation from this cause among children of Group P than among children of Group S, 26 HARVEY SOCIETY SCHOOL-GRADE ADVANCEMENT Let us next examine the actual school-grade advancement of the white pupils. My statistics show this point for 2166 students, 1062 boys, 1104 girls. From the data at hand, it seems clear that the girls made 80 per cent., the boys 78 per cent. of the school grades to which they were theoretically entitled, as estimated on basis of their exact age. If we compare the sanitary groups, the point develops that the girls of Group S made 84 per cent. as compared with 72 per cent. attained by the girls of Group P, while the boys of Group S made 81 per cent. as compared with 68 per cent. attained by Group P. If we study the cases of infection with Endameba coli or with Lamblia, no evidence is obtained that these two parasites had any measurable effect in the retardation noted. Our data for Trichom- onas, pinworms, whipworms, and tapeworms are not sufficient to warrant deductions. But although the 83 hookworm infections were, in general, not severe, they show a total extra retardation of 17.56 grades or school years, as compared with their respective croups, thus giving an average of nearly 14 grade (0.23 grade) per child. When we consider the relatively light degree of infec- tion found, and when we compare these figures with our general experience in rural schools, I do not hesitate to interpret this retardation of 17.56 years as due in large degree to the hookworm infection. The 58 pupils infected with eelworms showed a total extra retardation of 3.45 years as compared with the average of their respective groups. This average extra retardation of 0.07 grade per pupil seems negligible when considered alone, but it represents one of the little drains that could easily be avoided. TOBACCO HABITS If we study the tobacco habits and consider only those eases for which these habits are admitted either by the children, or for them by their parents, the point develops that smoking was admitted by a greater percentage of children in Group S and HOOKWORM DISEASE AND SANITATION Q7 chewing was admitted by a greater percentage of children in Group P. This result is in harmony with my studies of rural school children in another county, where I found that smoking increased and chewing decreased coincident with the improved sanitary conditions found at the homes. HEIGHTS AND WEIGHTS For standing height, sitting height, and weight of the white pupils, data are present as follows: In general the sitting height is a little more than one-half of the standing height, but in girls from 13 to 17 years inclusive, it is considerably more than one-half of the standing height. The children show two rather striking interruptions in growth. At 11, there is a rather striking decrease of the increase in the standing height, sitting height, and weight of the boys, and a less marked decrease of the increase in the sitting height of the girls. At 14, there is a sudden and very pronounced decrease of the increase in the standing height, the sitting height, and the weight of the girls. In this connection it is rather suggestive that these girls average their first menstruation at 13.2 years of age. The change in growth of the boys is much less striking, but. they show a marked interruption in the increase in weight. In general, the growth of boys from 13 to 17 is far in excess of that of the girls, and this is especially marked at 17 years. Of the total-year periods (12 for boys, 12 for girls), Group 8 excelled in standing height in 17 periods, Group P in 7 periods; in sitting height, Group S excelled in 13 periods, Group P in 11 periods; in weight, Group S excelled in 15 periods, Group P in 9 periods. Thus, in the total of 72 units, Group S excelled in 45 units (62.5 per cent.) and Group P in 27 units (37.5 per cent.). No evidence was obtained that infection with Ascaris, Lam- blia, or Endameba was a measurable factor in retarding growth, but it may be noted that the infections with Ascaris were light. The data for whipworms are too limited for deduction. 28 HARVEY SOCIETY In children showing infection (light or rather light cases) with hookworms, the evidence is not striking but it summarizes as follows: Below average Above average Standing Height ........... 30 21 Sitting Height 27.2 wise se 35 25 WSLS ie were areca ra ate everee ear 26 22 91 68 Thus, in final score the hookworm cases were below average in 91 markings and above the average in 68 markings. The con- clusion appears, therefore, to be justified that even in the hight cases with which we were dealing, the infection had an appreciable effect on heights and weights. LUNG CAPACITY Our white boys from 6 to 13 years old inclusive showed an average from 100 to 200 ¢.c. greater lung capacity than the girls of the same age. From 14 to 17 years they had progressively from about 300 to about 1100 ¢.c. greater lung capacity than the corre- sponding girls. In the case of both the boys and the girls, the children from homes with better sanitation had a tendeney (15 to 9) to greater lung capacity than the children from homes with poorer sanitation (9 to 15). Our studies did not show that infee- tion with hookworms, Ascaris, Lamblia, or Endameba coli had any noticeable effect upon the spirometer tests. BLOOD EXAMINATIONS Data on complete blood examinations are present for 574 white pupils 295 boys, 279 girls. In total red blood-cells Group S excels in 15 total-year periods (6 for boys, 9 for girls) and Group P excels in 7 total-year periods (5 boys, 2 girls), while for 2 periods no comparison could be made. It is self-understood that some of the groups are reduced to a very small number of individuals, but if one objects strenuously to this point we may compare the average of grand totals for Group S with those for HOOKWORM DISEASE AND SANITATION 29 Group P. This comparison shows that the 234 boys of Group S average 4,633,000 as compared with an average of 4,591,000 for the 51 boys of Group P, while the 200 girls of Group S average 4,752,000 as compared with an average of 4,498,000 for the 74 girls of Group P. In hemoglobin, Group S excels in 13 total-year periods (7 for boys, 6 for girls) and Group P excels for 9 periods (4 for boys, 5 for girls). Taking the average for all children of these groups, the 234 boys of Group 8 averaged 86.7 per cent. as com- pared with an average of 84.4 per cent. for 51 boys of Group P, and 200 girls of Group S averaged 87.7 per cent. as compared with an average of 87.5 per cent. for girls of Group P. The leucocytes excelled in 13 total-year periods (7 for boys, 6 for girls) in Group P as compared with 9 total-year periods (4 for boys, 5 for girls) in Group P. For the 234 boys of Group 5S the leucocytes averaged 7860 as compared with an aver- age of 8687 for 51 boys of Group P, and for the 200 girls of Group S they averaged 7731 as compared with an average of 7771 for 74 girls of Group P. Asa high leucocyte count is indica- tive of infection of some kind, it is seen that the comparisons made on basis of total-year periods indicate a greater average of infections in Group P than in Group 8. MEMORY SPAN IN NUMBERS One of the various mental tests used was the common test for the memory span, a test that is so frequently utilized in psycho- logical and psychiatric studies. Data were obtained for 1581 urban white pupils, 748 boys, 833 girls, from 6 years flat to 17.75 years old, inclusive. Summarized, our results show that in the locality in question, children of 6 flat to 7.75 years inclusive can reasonably be expected to have a memory span of 5 numbers, children from 8 flat to 13.75 inclusive can be expected to have a memory span of 6 numbers, and children of 14 flat to 17.75 inclusive can be expected to have a memory span of 7 numbers. These figures are based upon the averages of the total-year groups. If the boys are compared with the girls, the conclusion seems justified that the differences are not of sufficient constancy to 30 HARVEY SOCIETY justify the conclusion that either sex excels. If the sanitary groups are compared the conclusion seems justified that the com- parison is more favorable to Group S in the proportion of 14 to 10 or 7 to 5, for 7 total-year male groups and 7 total-year female groups of Group S excelled as compared with 5 total-year male groups and 5 total-year female groups of Group P. A further analysis of the statistics shows that in the 55 infee- tions with Endamaba coli, in the 67 infections with Lamblia, and in the 38 infections with eelworms, we are not justified in con- cluding that these parasites resulted in an average decreased mem- ory span; our 52 cases of hookworm infection showed an average loss of 0.08 (boys 0.15 loss, girls 0.06 gain) when compared with the average of their respective groups. As already stated the infections were in general rather light. Knox Cube Test.—For another mental test, known as the Knox Cube Test, somewhat similar results were obtained. Our results show that the urban white children of 6 flat to 7.75 years, inclusive, in the region in question may be reasonably expected to reach C in this test; while children from 8 flat to 17.75 years inclusive may be reasonably expected to reach D. These figures are based upon the total-year averages. As a mat- ter of fact, however, 21 out of 61 children of the 6 total-year group attained E and 36 out of 49 of the 17 total-year group attained E. The oldest child to attain A was in the 14.75 year subgroup. Comparing the total-year sanitary groups, the final seore stands 1414 to 914 in favor of Group S; that is to say, among the boys, Group S excelled in 9 total-year periods as compared with Group P, which excelled in 3 total-vear periods, while among the girls Group S excelled in 5 periods, Group P 6 periods, and the two groups were equal in 1 period. SUMMARY The statistics thus far presented for the county of X seem to confirm the point that school children who live at homes with better sanitation are ahead of school children from homes with poorer sanitation, for the figures show that in general and on the average the comparison is more favorable to children of HOOKWORM DISEASE AND SANITATION 31 Group S than to those of Group P in the following 14 particulars: 1. Children of Group S show a lower percentage of intestinal parasites in general. 2. They show a lower index of infection with Lamblia, eel- worms, whipworms, and hookworms, all of which are more or less pathogenic. For the other parasites, except Hndameba coli which is not pathogenic, our cases are too few in number to warrant emphasis. 3. They show a lower index of coprophagia, therefore, 4. They are less liable to contract typhoid, diarrhceas, and dysenteries. 5. They show a better growth in standing height. 6. They show a better growth in sitting height. 7. They show a better growth in weight. 8. Their lung capacity is slightly better. 9. They average a higher red blood count. 10. They average a higher percentage of haemoglobin. 11. They average a lower leucocyte count, hence indications are that certain bacterial infections are less frequent or less severe. 12. They make a higher percentage of their theoretical school grades. 13. They average a higher mental span. 14. They make a higher average in the Knox Cube Test. Doubtless, the question has already arisen in your minds as to how much of the rather consistent differences noted between Group S and Group P is due to the sanitation of the home, and how much is simply coincident with the sanitation but due to other factors, such as heredity, food, economic status in general, educational status of the parents, and a dozen or more other factors that come up in your minds. The question is an emi- nently fair one, but the answer is difficult to express in percentages. In my answer to your query, I would make the following points in particular: First. The spread of all of the parasites mentioned is entirely due to lack of proper sanitation and to no other cause. If excreta 32 HARVEY SOCIETY were properly disposed of, both in the direct environment in which these children are living and in the more distant environ- ments that influence their lives, not one of the intestinal parasites would be present. Second. Under proper public health conditions, such infee- tions as typhoid, dysentery, and diarrhea would nearly or entirely disappear. Third. Several of the infections mentioned play réles which may be greater or less, often unmeasurable, according to cireum- stances, and if the sanitation is improved, the differences due to these infections would gradually disappear. Fourth. The insanitation, in being responsible for bacterial, protozoal, and verminous infections mentioned, forms a vicious circle with the general economic conditions, each contributing to the index of the other, and if the sanitation is improved, then the economie condition will improve to the extent that the lowered economie condition may be due to inefficiency, sickness, and death in the families, caused by disease that is spread by insanitation. Fifth. The increased economic status that ean be obtained by eliminating one fundamental cause (namely, insanitation) of its decrease will react with a good percentage of annual inter- est in enabling the family to combat other causes that decrease its economic status. Sizth. It would be fundamentally wrong to claim that the question of sanitation alone is the only factor involved, but it is undoubtedly one of the many factors that must be considered and it forms a general working index by which we may actually classify our school children into two groups (S and P) that actually show differences when the children are compared. Seventh. The insanitation under which many school children are to-day living, not only at their homes but, sad to relate, at the publie schools and churches they attend, is the cause of a daily drain upon them which can easily be eliminated, and the elimination of this insanitation is one factor in the economy we should have in mind, namely, the spending of a greater amount of money and eare for the sake of the conservation and efficiency | of ehild-life. HOOKWORM DISEASE AND SANITATION 33 MATHEMATICAL ESTIMATE OF DISEASE The question naturally arises whether it is possible to give an approximate or working estimate in terms of mathematics comparing diseased conditions of children, somewhat similar in nature to the statistical studies of psychologists in their experi- mental work. I know of no published attempt of this kind in reference to Southern conditions. The attempt to apply to the effects of disease the comparative mathematical methods used in certain collateral fields of work is indeed tempting, and not long ago the opportunity for such an attempt was presented in a study of hookworm children of the County of Z, conducted as a co-opera- tive undertaking between the Rockefeller Sanitary Commission and the U. S. Public Health Service. The details of the mental work will be published by the Rockefeller Foundation and of the medical work by the U. S. Public Health Service. In these studies, I had under observation about 175 white rural school children, taken at random, except for age, from several near-by rural schools, all located in the same county. In the final results, 115 children were available for comparison. First, the children were subjected to a thorough physical schedule study lasting three hours or more per child, including blood counts; then, some of the children were put under medical treatment; after the lapse of time averaging about three months they were re-examined on the same schedule plan; finally, they were divided into 5 groups, A to E; the composite characters of the groups were summarized, and the groups were compared. That the method has not exact mathematical exactness is self- understood, because not all physical characters have the same value. Nevertheless, the final results compare very favorably with general experience and seem to be justified. The least that ean be said of the results is that as a first attempt of this kind, as applied to hookworm disease, the figures are interesting. But since the same chances for error apply to all the children, I feel that the results are more than simply interesting. In fact, I feel that they are about as exact as it is possible, at present, to obtain, and that they must be taken seriously, at least until some- one develops a much better method. 3 34 HARVEY SOCIETY Group A contained 23 negative controls, namely, children who, upon microscopic examination in the first test, showed no hookworm infection ; Groups B—E showed this infection. Group B contained 12 positive controls, namely, children whom I did not treat for hookworm disease, while Groups C—E were treated. Group C contained 36 infected children from whom an average of 40 hookworms per child was collected, and at the third test they showed no evidence of hookworm infection; we may eall them the completely cured. Group D contained 32 infected children from whom an aver- age of 93 hookworms per child was collected, but at third test they still showed some evidence of infection; they were incom- pletely cured. Group E contained 12 infected children from whom an aver- age of 100 hookworms per child was collected, but they failed to furnish specimens at the third test, so it is impossible to state whether all their worms were expelled. Let us now conceive of these 5 groups of children as repre- senting 5 colleges that send representatives to an athletie track meet, and let us accept each of the 186 physical characters con- sidered as representing a separate entry in the contest; then let us apply the point system of athletics to our results, and dis- tribute $10 for each first place made by a group, $8 for each second place, $6 for each third place, $4 for each fourth place, and a consolation prize of $2 for each fifth place. Let us then summarize the prizes for each group and see where they stand. The chart shows that Group A, consisting of 23 non-infected children, easily won first place in the first test, namely, in the pre-treatment examination, by taking $1485 in prizes. Group B, consisting of 12 infected children, took third place by winning $1098 in prizes. Group C, consisting of 36 infected children, took second place by winning $1242. jroup D, consisting of 32 infected children, took fifth place by winning $823 in prizes. Group E, consisting of 12 infected children, took fourth place by winning $932 in prizes. HOOKWORM DISEASE AND SANITATION 35 These ratings represent the comparative physical efficiency of the 5 groups, as nearly as it was possible to express this in fieures, on basis of the first physical study of three hours or more to each child, and they represent the composite work of several examiners. Recall, now, that Groups C—E were treated and that an average of 40 hookworms was obtained from the children in Group C, 93 from those in Group D, and 100 from those in Group E. After a lapse of time another track-meet or examina- tion takes place and the same 186 entries or physical characters are considered. The summary shows that: Group C, which was second, now wins first place, with $1366 in prizes; after expelling their hookworms, these 36 children actually went ahead of the 23 children who in the first meet showed no hookworm infection. Group A, our 23 negative controls, which won first place in the first meet, dropped to second place in the last meet, but carried off $1290 worth of prizes. Group E, which had fourth place originally, won third place with $1093 worth of prizes, after expelling an average of 100 hookworms. Group D, the original tail-ender, rose to fourth place, with $984 worth of prizes, as a result of expelling an average of 93 hookworms. And Group B, our positive controls, 12 hookworm children who won second place in the first meet, but were not treated, dropped to fifth place in the last meet by taking only $847. These figures for the last meet represent to my mind approxi- mately the relative physical efficiency of the 5 groups of children in the post-treatment examination. If now we compare the relative improvement made between the first and last examination, it is seen that: Group D had the greatest outlook for improvement since it stood fifth in the first test ; actually it gained first place in improve- ment by taking $1329 worth of improvement prize money. Group E had the second best chance potentially, as it orig- inally stood fourth; it actually gained second place in the improve- ment by winning $1161 in improvement prize money. 36 HARVEY SOCIETY Group B had the third best chance, for it stood third in the first test; but the children were not treated and the Group made only fifth place, with $634 in improvement prize money. Group C had potentially fourth chance, but it made third place, with $1160 in improvement prize money. Group A had least chance for improvement, potentially, as it took first place in the first test, but it made fourth place in the improvement by gaining $816 in improvement prize money, due to the fact that the hookworm Group B continued to keep its infection. This presentation is, admittedly, a rather unusual method of presenting a medical subject, but I believe it is thoroughly justified. Taking the two presentations given to-night, one a comparison of school children who live under better sanitary conditions with school children who live under poorer sanitation, and following that with a study of one of the diseases which owes its spread to insanitation, I submit that I have demonstrated my thesis for the evening, namely, that one of the premises in the economy in administration of public school funds is the sanitation under which the school children live at home and at school. A corollary to this thesis is that an increase in expenditure of care and money in improving this sanitation will result in an actual economy in child-life in the terms of conservation and efficiency. ON THE NERVOUS CONTROL OF THE HUNGER MECHANISM * PROF. A. J. CARLSON University of Chicago OUTLINE PAGE PERT CUR CEN REM r t ictrstar a. red: ch chetaie cin eal cnontvoravnevareimaaiabera terefey wie taral fieteye os 39 I. CENTRAL CONTROL OF THE HUNGER MECHANISM................ 39 1. Effect of removal of cerebrum. 2. Gastric hunger mechanism during sleep. 3. Effect of cerebral states (emotional states, intellectual proc- esses). 4, Influence of lower brain centres (mid-brain, medulla) on the gastric hunger contractions, as determined by sec- tion of (a) splanchnic nerves, (b) vagi, (ec) splanchnic and vagi nerves. Il. REFLEX CONTROL OF THE HUNGER MECHANISM—INHIBITION FROM THE MOUTH IN MAN AND OTHER ANIMALS..............-- 50 1. The inhibition of the contractions of the empty stomach by stimulation of the gustatory end-organs in the mouth. 2. Inhibition of the tonus and the contractions of the empty stomach by chewing indifferent substances. 3. Inhibition of the tonus and contractions of the empty stomach by chewing palatable foods when hunger and appetite are present. 4, Factors involved in the inhibition of the contractions of the empty stomach by palatable foods in the mouth. 5. The inhibition of the tonus and the contractions of the empty stomach by swallowing movements. 6. The relation of the reflex inhibition of the tonus and the movements of the empty stomach from the mouth to the sensation of hunger. * Delivered November, 1915. 37 38 HARVEY SOCIETY PAGE III. THe INFLUENCE OF STIMULATION OF THE GASTRIC MUCOSA ON THE HUNGER CONTRACTIONS 2. 256s: bees cso ween 5 ble eee 57 Discussion of 1. Condition or stimulation of the gastric mucosa. 2. Condition of the blood. 3. Nervous impulses through the vagi. 4, Primary automatic action of the local neuromuscular mech- anism of the stomach. a. Results of experiments on man: 1. Action of water, acids, alkalies, local anws- thetics, alcoholic beverages, CO, and air. 2. Influence of inhibitions from the gastric mucosa on the fundamental rhythm of the gastric hunger contractions. b. Results of experiments on dogs: 1. Action of water, acids, alkalies and alcoholic beverages. 2. Action of carbon dioxide. 3. Effects of complete section of the splanchnic nerves, 4, Effects of section of vagi nerves and of the vagi and splanchnic nerves. c. Results of experiments on other species. IV. INHIBITORY REFLEXES FROM THE INTESTINAL MUCOSA TO THE Hurpry STOMACH (45%0 2 os clwvesia sim eres eieieleenee tS. c Dalai ete 79 V. INHIBITION OF HUNGER BY SMOKING AND BY PRESSURE ON THE ABDOMEN (CONSTRICTION OF THE BELT) .......20ches meee 82 VI. INFLUENCE OF PHYSICAL EXERCISE AND COLD ON THE HUNGER MECHANISM, © o'e.c0c5 so ajejoies bon in o. oleic nls whem oie rele 86 a. Results of experiments on dogs: 1. Running on treadmill. 2. Effects of 4-6 mile walk. 3. Etfect of intense stimulation of the cutaneous nerve- endings for the sensation of cold. b. Results of experiments on man: 1. Direct effect of muscular exercise. 2. After-elfects of muscular exercise. 3. Direct effect of stimulation of the cold nerve- endings of the skin. 4. After-effect of the stimulation of cold nerve-endings of the skin. VIT. Tue AFFERENT OR SENSORY PATIIS OF THE HUNGER COMPLEX AND THE QUESTION OF THE CEREBRAL ” HUNGER-CENTRE”......... 96 1. The role of the vagi. 2. The sensory nuclei of the vagi nerves in the medulla as the primary hunger-centre. 3. The role of the optic thalami and the mid-brain. 4. Cortical hunger-centres. NERVOUS CONTROL OF HUNGER MECHANISM 39 HE question of the nervous control of the gastric hunger mechanism embraces several important physiological prob- lems, none of which is as yet completely solved: First, on the motor side there is the possibility of actual initia- tion of the gastric hunger contractions through the motor fibres in the vagi nerves by impulses from cerebral as well as lower centres acting on the motor nuclei of the vagi in the medulla. Even if the contractions are not actually caused in this manner, it can be shown that they are in part dependent on a ‘‘ tonus ”’ influence exerted on the stomach by the vagi nerves. Hence the control of the vagi tonus becomes a question of paramount importance in the physiology and pathology of hunger. Second, on the afferent or sensory side we must determine central paths of the afferent gastric nerves in order to elucidate the genesis of the conscious hunger sensation, as well as the con- scious and sub-conscious reflexes evoked by these afferent impulses. This raises the question of the sensory hunger centre in the cerebrum. Third, we have also to deal with the very important reflex control of the gastric hunger mechanism as well as of the nervous foci in the medulla, mid-brain, and cerebrum concerned in the conduction of sensory and motor hunger impulses. And, last, we must consider the automatic or reflex elements in the gastric hunger mechanism itself, independent of all central nervous system control. An understanding of these several fac- tors is of particular importance for the interpretation and the control of the changes in hunger and appetite that we meet in disease. I. CENTRAL CONTROL OF THE HUNGER MECHANISM 1. Effect of Removal of the Cerebrum.—Removal of the cere- bral hemispheres in the guinea-pig leads to somewhat increased gastric tonus and hunger contractions (King). In the pigeon this operation does not change the hunger contractions of the empty crop, except that visual and auditory stimuli do not lead to inhibi- tion of these movements in the decerebrated bird (Rogers). In frogs removal of the cerebrum has no effect on hunger contractions 40 HARVEY SOCIETY of the stomach (Patterson). We may, therefore, conclude that in so far as the stomach hunger contractions are dependent upon tonus and motor nervous impulses via the vagi nerves, these impulses do not originate in the cerebral hemispheres. 2. The Gastric Hunger Mechanism during Sleep—In man (infants as well as adults) the gastric hunger contractions are at least as frequent and intense during sleep at night as during the waking state. In our five days’ starvation experiment con- tinuous records of the stomach were taken during sleep at night. These records show that the author’s stomach was in strong tonus and hunger contractions practically half of the time of sleeping. The hunger periods were less frequent during the day when the subject was about his work. Numerous experiments on dogs show the hunger contractions and the gastric tonus more vigorous and regular when the animal is sleeping than when he is awake and taking notice of things about him. The only apparent exception to this condition so far observed in any species is the rumen of the goat. A few obser- vations on one goat seemed to show that the hunger contractions of the rumen, or first stomach pouch, decreased in intensity when the animal was lying down sleeping. We are not satisfied that this is so until the same result is obtained on a number of ruminants. Possibly the gastric motor part of the vagi nervous apparatus in the ruminating animals is under a more direct control from the cerebrum than in other species. During sleep there is decreased activity of the central nervous system in general, decreased tonus of the skeletal muscies, de- creased tonus of the musculature of the blood-vessels, at least in certain parts of the vascular system, decreased tonus of the urinary bladder, ete. ; in short, a lowered activity of all the neuromuscular mechanisms so far investigated. One might have expected that in so far as the tonus of the empty stomach depends on a central influence by way of the vagi, the gastric tonus and hunger con- tractions should be diminished during sleep. But instead of being depressed in sleep the hunger contractions continue with the same vigor as during the waking state, and in many instances with increased vigor. The increase in the gastric hunger contrac- NERVOUS CONTROL OF HUNGER MECHANISM 41 tions during sleep may be due to the elimination of all inhibitory impulses by way of the splanchnic nerves. But the absence of depression certainly indicates that the vago-gastric tonus mechan- ism, at least in man and the dog, occupies a unique position in the organism, a degree of independence of afferent impulses (extero- ceptors) and central processes not known in the ease of any other neuromuscular apparatus. 3. The Effect of Cerebral States (Emotional States, Intellec- tual Processes).—In the dog the cerebral processes of joy, fear, anger, eagerness (for food), attention, etc., cause temporary inhi- bition of the gastric hunger contractions. This inhibition takes place by way of the splanchnic nerves, not by a depression of the vagus tonus. This, again, points to an unusual independence of the vago-gastric tonus apparatus. The sight or smell of food on the part of the starving dog does not initiate or augment the gastric hunger contractions. Luckhardt has recently shown that when the sleeping dog dreams the gastric hunger contractions are inhib- ited in the same way that cerebral and emotional processes tend to inhibition of the contraction when the animal is awake. In man, intellectual processes (attention, reading, figuring, arguing) have no distinct influence on the course of the hunger period. Actual anxiety causes temporary inhibition, probably through the splanchnies. We have not been in a position to make observations on the effects of actual anger, fear and joy, but there is no reason to believe that these processes act differently in man from that in the dog. In man we have paid particular attention to the effects of seeing and smelling palatable food, as it seemed a priori reasonable that the impulses generated by these stimuli might make more intimate connection with the vago-gastrie tonus apparatus. Cannon assumes a “‘ psychic gastric tonus ’’ analo- gous to the ‘‘ psychic secretion ’’ of gastric juice. Gliickmann states that the borborygmi are increased in rate and intensity on seeing and smelling palatable food. He ascribes this to increased gastric contraction. Extensive experiments on Mr. V. and on the author seem to show that is not the case. These stimuli neither initiate nor augment the gastric tonus and hunger contractions; so far as they influence them at all, it is in the direction of inhibi- 42 HARVEY SOCIETY tion. One of the tests on the author might be given. Before beginning the five days’ starvation period, our colleague, Dr. Luckhardt, was asked to bring in, unknown to the author, a tray of choice food in the midst of a hunger period. The arrangements being made, the matter was dismissed from the author’s thoughts. One o’clock of the morning of the fourth starvation day the subject was asleep and the record showed at this time a period of vigorous and regular hunger contractions. He was awakened to behold Dr. Luckhardt and an assistant enjoying a feast of porterhouse steak with onions, fried potatoes, and a tomato salad. The tray of edibles was placed not more than four inches from the subject’s face and the delicious odor of the food filled his nostrils. He felt the hunger pangs as unusually intense, and there was considerable salivation. However, the gastric hunger contractions were not increased either in rate or intensity. In a few minutes, on the contrary, the. hunger contractions became weaker and the intervals between them greater, and the period terminated by this gradual depression much sooner than it prob- ably would have done in the absence of the dinner scene. This was undoubtedly due to local acid inhibition from copious secre- tion of appetite gastric juice. When the hungry individual sees or smells good food the gastric hunger pangs are felt more intensely, although there is no change, or even when there is some decrease in the strength of the gastric hunger contractions. This is, therefore, a phenome- non of central reinforcement. Our data on normal men and dogs seem incapable of any other interpretation than that the vago-gastric tonus apparatus, so far as it concerns the empty stomach, oceupies a unique and physiologically isolated position, in the way of nervous control, while the inhibitory apparatus by way of the splanchnic nerves is readily influenced by central and reflex processes. We feel, how- ever, that these observations must be extended to other groups of vertebrates as well as to such pathological cases in mah in which there are indications of abnormalities of the vago-gastric tonus, before final explanations are attempted or speculation indulged in as to the usefulness of this physiological isolation. NERVOUS CONTROL OF HUNGER MECHANISM 43 This evidence for the physiological isolation of the hunger mechanism in the way of positive cerebral or central control is of interest in connection with the view that the cravings of hunger and appetite are subjective and largely a matter of habit, and that the periodicity or intensity of these cravings may be altered almost at the will of the individual. Chittenden states this view as follows: ‘‘ The so-called cravings of appetite are largely arti- ficial and mainly the result of habit. Any one with a little per- sistence can change his or her habits of life, change the whole order of cravings, thereby indicating that the latter are essentially artificial and have no necessary connection with the welfare or needs of the body. The man who for some reason deems it advisable to adopt two meals a day in place of three or four, at first experiences a certain amount of discomfort, but eventually the new habit becomes a part of the daily routine, and the man’s life moves forward as before, with perfect comfort and without a suggestion of craving or a pang of hunger.’’ Our studies of the hunger mechanism seem to show that the above view is essentially wrong. In the normal individual the gastric hunger periods begin as soon as the stomach is empty and continue (in the absence of inhibitory processes) as long as the stomach is empty, irrespective of the time of day or night, and without reference to the time the individual is accustomed to eat. In individuals accustomed to eat the usual three meals in the day time and to sleep during the night, the gastric hunger periods are more frequent and usually more vigorous during the night (that is, during sleep) than during the day, provided, of course, the stomach isempty. In the normal individual the empty stomach exhibits periodic hunger activity, and there is no evidence to show that this primary automatism of the empty stomach is in the least influenced by eating one or by eating five meals a day. The basis for the view that the time of appearance of the ‘‘ cravings of hunger ’’ can be changed at will is probably to be sought in the fact that the milder hunger contractions do not enter conscious- ness as pangs of hunger if the individual’s attention is directed into other channels. They are felt as hunger pangs if the indi- vidual’s attention is directed towards food and eating. The 44 HARVEY SOCIETY attention is thus directed, consciously or sub-consciously, about the time the individual is accustomed to eat. The periodicity of this subjective attention to the milder hunger cravings can prob- ably be altered by training. But this applies only to relatively mild pangs of hunger. The more severe ‘*‘ cravings of hunger ”’ caused by the gastric hunger tetanus rise above the threshold of consciousness, except in deep sleep or under conditions of a cerebral process involving intense interest. When an individual who is accustomed to eat three times a day turns to a régime of one meal a day, the quantity of food ingested in that one meal is much greater than that at any one of the three meals usually taken. The emptying of the stomach and the appearance of the pangs of hunger are correspondingly delayed. The view that prompt appearance and the persistence of the gastric hunger activity in the empty stomach have no relation to the actual need of the individual for food cannot be seriously maintained for the normal animal. 4. The Influence of the Lower Brain Centres (Mid-brain, Medulla) on the Gastric Hunger Contractions—The most direct and at the same time the least objectionable method of attack on this problem is the section of the extrinsic nerves to the stom- ach, although this operation abolishes not only all direct influences from the brain of a motor or inhibitory type, but also the central reflexes (motor or inhibitory) that may be ealled into action through the sensory nerves in the stomach. The splanehnie nerves were sectioned through a median incision. The vagi nerves were sectioned 2—3 em. above the diaphragm, thus leaving the fibres to the esophagus, the heart and the lungs intact. (a) Complete Section of the Splanchnic Nerves—Observations were made on five dogs with complete sections of the splanchnic nerve on both sides. The longest period of observation after the splanchnie section was two months. Observations were in some cases begun two hours after the operation. When the records of these five dogs are viewed as a whole, it is clear that the complete section of the splanchnic nerves in dogs increases the gastric tonus and augments the gastric hunger contractions. The hunger con- tractions become more rapid and continuous, that is, there is less NERVOUS CONTROL OF HUNGER MECHANISM $45 evidence of the periodic groups with intervening periods of rela- tive quiescence. It is not uncommon to observe contractions at the rate of about two per minute during an entire observation period of two to four hours. The section of the splanchnic nerves does not abolish the periodicity completely, however. It seems to be a question of relative degree of gastric tonus. If for any reason the tonus of the empty stomach is relatively low on any day, the hunger contractions are less frequent, and there is greater evidence of periods of relative quiescence. We desire to emphasize the fact that the above conclusion is based on the obser- vations as a whole. Even the dogs with the splanchnic nerves sectioned showed on some days no greater tonus of the empty stomach or greater rate and persistence of the gastric hunger contractions than does the dog with these nerves intact. And occasionally a dog with the splanchnic nerves intact exhibits as great a degree of gastric tonus and rate and persistence of the gastric hunger contractions as the maximum observed in dogs with the splanchnic nerves out. This is to be expected, as by section of these nerves one eliminates only one (and in the normal probably one of the least important) of the factors in the motor activity of the empty stomach. The conditions that affect the stomach through the blood and through the vagi are still subject to the same variations as in the animal with the splanchnic nerves intact. After complete section of the splanchnic nerves the psychic or reflex inhibition of the gastric hunger contractions is greatly diminished. The stimuli that cause anger, fear, pain, joy, or pleas- ure no longer lead to complete cessation of the hunger con- tractions. The maximum effect is a slight and transitory weakening of the contractions. It is, therefore, evident that the inhibitory fibres in the splanchnic nerves (and possibly also the secretory fibres of the adrenals) constitute the main efferent path in this type of inhibition. The slight degree of inhibition usually in evidence after section of the splanchnic nerves must be due to some central inhibition of the vagus tonus or to action of the few inhibitory fibres in the vagi. Particular attention was given to the effect of seeing and 46 HARVEY SOCIETY smelling food on the hunger contractions in these dogs with section of the splanchnic nerves, in order to determine whether these stimuli augment the tonus of the vagi and thus increase the hunger contractions. The results were negative. Even with the greater part of the extrinsic inhibitory fibres to the stomach elim- inated, the sight, smell, and taste of food not only fails to inhibit or augment the gastric hunger contractions, but so far as these stimuli affect the stomach at all it is in the direction of inhibition of the hunger movements. The apparent increase in the intensity of the hunger pangs in man on seeing or smelling palatable food must therefore be essentially a central phenomenon of facilitation or ‘‘Bahnung.”’ (b) The Section of the Vagi.—Section of both vagi in the chest was made in three dogs, and after this operation obser- vations on the gastric hunger contractions were continued for from two weeks to three months. Observations were made in some cases two hours after the vagi section. Section of the vagi leaves the empty stomach on the whole permanently hypotonic, that is, at least for a period of up to three months after the operation. The tonus of the empty stomach in these dogs varies somewhat from day to day, and occasionally the tonus may approach that of a dog with the vagi intact, but on the whole the tonus is per- manently much lower than normal. This is evident not only from the observations by means of the balloon in the gastric cavity, but also on direct inspection and by palpation (introdue- ing the finger through the fistula). The hunger contractions of the empty stomach in these dogs are changed mainly in rate and regularity. The duration of each individual contraction is about normal, or on the whole less than normal. The long-drawn-out contractions or tetanus are rarely seen. But the intervals between the contractions vary on the whole from two to five minutes or even up to eight minutes. The strength or rather the amplitude of the individual con- tractions may appear greater than normal, evidently because the contractions start rather suddenly and without any marked preliminary increase in tonus, and the maximal contractions are so complete that all the air is forced out of the balloon. These NERVOUS CONTROL OF HUNGER MECHANISM 47 contractions may continue of fairly uniform amplitude and rate for two to three hours, that is, during a whole observation period. The contractions vary in strength and rate from day to day, and on some days they may be completely absent during the entire observation period (two to four hours). The periodicity of the hunger rhythm is, on the whole, obseured, except on the days when the gastric tonus approached that in normal dogs. On such days the contractions appear at shorter intervals, and tend to fall into groups similar to those in normal dogs. Periods of gastric hunger contractions of normal rate and intensity have been observed as early as twelve hours after complete section of the vagi in the chest. The period of most powerful hunger contractions so far observed in any dog was recorded in one dog twenty-four hours after the vagi were sectioned. The dog had, during the four weeks preceding the vagi section, showed almost invariably the Type II rhythm. It was therefore a dog with unusually intense gastric motor activity. The complete section of the vagi causes on the whole less depres- sion in dogs that exhibit great hunger contractions while the vagi are intact. The variations in the rate and intensity of the gastric hunger contractions in different dogs are therefore primarily due to individual variations in the condition of the stomach rather than to variations in the central innervation or the central inhibition. In the dogs with vagi sectioned, but the splanchnic nerves intact, the ‘‘ psychic”’ or reflex inhibition of the gastric hunger contractions is still in evidence, but the inhibition appears not to be so marked as when the vagi are intact. Accurate comparisons are, however, difficult to make because of the lowered tonus, and the usual long intervals between the hunger contractions after section of the vagi. We expected an augmentation of the inhibition through the splanchnics after the vagi section. Instead of finding this to be the case there actually appeared a gradual diminution in the influence of the splanchnic nerves on the empty stomach in the dog observed for three months after section of the vagi. It was not due to the regeneration of the vagi fibres, and conse- quent restoration of the vagus tonus. If further work should 48 HARVEY SOCIETY establish this as a fact, we would have a significant instance of physiological readjustment,—either an actual diminution in the inhibitory impulses through the splanchnics in consequence of a dynamic readjustment in the central nervous system, or else an increased resistance, or ‘‘tolerance,’’ to the splanchnic impulses and to epinephrine on the part of gastric motor mechanism. (c) Section of Both Splanchnic and Both Vagi Nerves.—Com- plete section of the splanchnic and vagi nerves was made on four dogs, and observations made on the gastric hunger contractions for thirty to sixty days after the operation. The sections of the splanchnic nerves were made seven days after the section of the vagi. After this complete isolation of the dogs’ stomachs from the central nervous system, there is practically a permanent hypotonus of the stomach except under conditions of prolonged starvation. The gastric hunger contractions are much the same as when the vagi alone are severed. The contractions are usually of great amplitude, but the intervals between the contractions are frequently longer than in normal dogs. The grouping of the contractions in periods is usually in evidence. These contractions of the isolated and empty stomach are present ten to twenty hours after the vagi section, and there is some improve- ment in the rhythm or an approach towards the normal tonus and contraction rate during the thirty to sixty days of observation. On the whole the hunger contractions of the isolated stomach conform to Type I. The Type II is rare, except during prolonged starvation. Short periods (two to three minutes) of incomplete tetanus are frequently seen, especially during prolonged starva- tion, and during the first half of the hunger period. It is, there- fore, clear that all the essential characteristics of the hunger con- tractions of the empty stomach are determined by the local gastrie mechanisms rather than by the character of the central inner- vation or the central inhibition. Cannon has reported observations on the effects of vagi and splanchnic section on the gastric movements of digestion in eats. Section of the splanchnie nerves did not materially affect the movements of digestion: section of the vagi caused slowing and weakening of the peristalsis of digestion, but the normal rate of NERVOUS CONTROL OF HUNGER MECHANISM 49 peristalsis was practically restored in a few days. Combined vagi and splanchnic section left the digestive movements of the stomach practically normal, even shortly after the operation. It seems that section of the vagi or complete section of the vagi and the splanchnic nerves in dogs causes on the whole a greater change in the movements of the empty stomach than does the same lesion in cats in case of the movements of the filled stomach. This probably means that the tonus of the vagi plays a greater role in the movements of the empty than in the movements of the filled stomach. For it is not likely that there is such marked difference in the relative importance of the vagi in cats and dogs. The changes in the character of the gastric hunger contractions after isolation of the stomach from the central nervous system seem primarily due to the persistent hypotonus. This is indicated by the fact that on days when the stomach of a normal dog shows relatively slight tonus, the hunger contractions approach the type shown by the isolated stomach, and on days when the isolated stomach exhibits tonus approaching that in normal dogs the hunger contractions tend to assume the normal type. Occasion- ally records are obtained from the empty and isolated stomach that practically demonstrate the above point. During a period of relatively slow hunger rhythm the tonus for some unknown reason may increase markedly for periods of varying length and during these periods the hunger contractions are identical in rate and character with those of the intact stomach in normal (strong) tonus. In one of the dogs with the vagi and splanchnic nerves sectioned, six days’ fasting led to the appearance of periods of very great gastric tonus and during these periods (virtually periods of incomplete tetanus) the gastric contractions assumed the form of Type III. However, the details of the changes in the hunger rhythm after isolation of the stomach from the central nervous system ‘seem of minor importance in this connection. The essential point is that since the empty stomach, completely isolated from the central nervous system, does exhibit the typical hunger contrac- tions, the efferent function of the gastric nerves is that of modi- fying or regulating a primarily automatic mechanism in the 4 50 HARVEY SOCIETY stomach wall. In other words, the extrinsic nerves to the stomach play a role similar to that of the nerves to the heart in the regu- lation of the heart rhythm. Further analysis of the hunger mechanism must be directed primarily to the intrinsic neuro- muscular apparatus of the stomach, and secondarily to the factors that control the vagus tonus. Il, REFLEX CONTROL OF THE HUNGER MECHANISM The Inhibition from the Mouth in Man and Other Animals Our gastric fistula man, Mr. V., offers an exceptional oppor- tunity for studying the relations of certain conscious states, par- ticularly those associated with foods and with eating, on the activi- ties of the empty stomach. The esophagus is completely closed at the level of the upper end of the sternum, so that nothing ‘can enter the stomach from the mouth. The swallowing mechanisms are normal, and the man can swallow and hold in the esophageal pouch about 25 ¢.c. of material. The gustatory (and olfactory) sense is normal. The senses of thirst and hunger are normal. He masticates his food in the usual way, and the chewing proc- esses are accompanied by the normal conscious states. The masticated food is placed in a syringe and introduced into the stomach through the fistula, which does not involve any pain or discomfort, and the man is adjusted to this condition, as this has been his method of feeding for the last eighteen years. Because of the ample size of the gastric fistula the man may sit down at the dinner table, see, smell, taste and chew his food in the usual manner up to the point of introducing the food through the fistula, while tracings are being taken of a tonus and the movements of the stomach, and records made of the seeretion of the gastrie juice. We know, particularly through the researches of Pavlov on dogs, and from many observations on man, that when appetite is present the sight, smell, taste (especially taste) of palatable foods cause a reflex secretion of gastric juice, the so-ealled ** psychie secretion.’’ The efferent nerve fibres for this reflex reach the stomach through the vagi. The more recent work of Cannon and others has demonstrated that the tonus of the stomach museula- ture is also primarily dependent on efferent nervous impulses NERVOUS CONTROL OF HUNGER MECHANISM 51 through the vagi. A certain degree of tonus is a pre-requisite for the digestion peristalsis or contractions in the empty stomach. The suggestion is therefore obvious that the same stimuli which lead to psychic secretion of gastric juice may at the same time cause an augmentation of the tonus and the contractions of the stomach musculature. Cannon postulated such a ‘‘psychic tonus,’’ but no evidence for its extent has been recorded. It is a universal experience that the sight or smell (or even the mem- ory) of palatable foods seems to induce hunger and appetite, or intensify these sensations if they are already present. The sim- plest explanation of this fact would be that the smell or taste of palatable foods initiates or augments the stomach contractions, thus increasing the hunger sensation by increasing the intensity of the gastric stimulation. The facts, at least in man and dog, are the very opposite of those demanded by this hypothesis. There are two sources of error in experiments of this charac- ter. In the first place, the periods of contraction of the empty stomach vary in intensity and duration, and the intervening periods of relative quiescence vary in length. The periods of quiescence may be interrupted by occasional contractions. This being the case, the initiation of stomach contractions simul- taneously with tasting palatable food during quiescence of the stomach, for example, may be a mere coincidence. An augmen- tation of the contractions seemingly due to tasting food during a contraction period may simply be the usual increase in strength of the stomach contraction during such period. In the same way, if tasting food towards the end of a contraction period should be followed by cessation of the stomach contractions, this apparent inhibition may be a coincident, the cessation of the contractions being ‘‘spontaneous”’ and not casually connected with the tasting of food. These difficulties were realized before the work was undertaken, as it was preceded by an extended survey of the ** spontaneous ’’ stomach movements when not interfered with experimentally. Because of the variability of the ‘‘spontaneous”’ stomach activity, the individual tests must be repeated a great number of times, and little or no significance can be ascribed to exceptional results. 52 HARVEY SOCIETY A source of error more serious, because not so readily con- trolled, lies in certain subjective states of an inhibitory character. Pavlov found that while the sight and smell of palatable foods ordinarily caused ‘‘psychie’’ secretion of gastric juice in dogs when hungry, if the dogs knew from past experience that they were not to be permitted to eat the food, the same stimuli caused no secretion. We may have analogous conditions in regard to the stomach tonus and movements. It is possible that, no matter how great the hunger or appetite in man, the knowledge that the seeing, smelling or tasting food was part of an experiment might initiate cerebral processes of an inhibitory character. This source of error has been controlled in two ways: (1) In Mr. V. the masti- cation or tasting food was made part of his ordinary routine in preparing the food to be put into the stomach, and the man knew that as soon as the food was prepared it would be introduced into the stomach in the usual way. (2) Records were made of the presence or absence of the psychic secretion of gastric juice. If the tasting and chewing of food start a copious flow of gastric juice, we can infer that the tasting and chewing do not give rise to cerebral processes of an inhibitory character. 1. The Inhibition of the Contractions of the Empty Stomach by Stimulation of the Gustatory End-Organs in the Mouth.—The substances used for stimulation were sugar (solid and in solu- tion), quinine in weak solution, sodium chloride (solid and in solution), weak solutions of acetic and hydrochloric acids. Tests were made at all stages of activity of the empty stomach. The results were uniform and practically identical for the four kinds of stimuli employed. If the substances were used in sufficient concentrations to affect the stomach activity, the effects were inhibitions of the tonus and contractions. These inhibitory effects follow promptly on placing the substanees in the mouth, and disappear, on the whole, very soon after removing the substances from the mouth and rinsing the mouth with warm water. Quinine and the acid produced the longest inhibitory after-effects, proba- bly because of the diffieulty in completely removing these sub- stances by rinsing the mouth with water. This gustatory inhibition is, on the whole, proportional to NERVOUS CONTROL OF HUNGER MECHANISM 53 the strength of the stimuli (7.¢., the concentration of the sub- stance), and varies inversely with the degree of the stomach activity. Thus a weak solution of acetic acid that produced distinet inhibition during the first stage of a period of hunger contraction when the individual contractions are relatively weak may have little or no effect when placed in the mouth during the tetanus stage of the contractions. If the gustatory stimuli are weak and allowed to act in the mouth for five to fifteen minutes, the stomach ‘‘escapes’’ from the inhibition gradually. This is particularly true of sweet (sugar). Moderate strength of acids and quinine may hold the stomach in nearly complete inhibition up to fifteen minutes. The stimulating substances are, of course, gradually diluted by the secretion of saliva. Are these gustatory inhibitions primary and relatively simple reflexes independent of the states of consciousness, or are they of the type of conditional reflexes, and therefore due to cerebral states of unpleasant effective tone? This question must be an- swered by experiments on lower animals with less development of the cerebrum and especially on decerebrated mammals, and on so-called ‘‘acephalic’’ infants. 2. The Inhibition of the Tonus and the Contractions of the Empty Stomach by Chewing Indifferent Substances—We have been unable to obtain any definite evidence of inhibition of the stomach movements by the movements of mastication when the mouth is empty. But chewing what may be ealled indifferent substances, such as paraffin, gum, or straw, produces distinet inhi- bition. Most of the experiments were made by chewing paraffin. Most people can chew paraffin without any disagreeable or unpleasant sensation, or pleasant either, for that matter. Mr. V. said he ‘‘did not care for the paraffin,’’ naturally. But he has no dislike for it. The chewing of indifferent substances pro- duces, on the whole, less inhibition than do gustatory stimuli. The stomach ‘‘escapes’’ from the inhibition in a few minutes, even though the chewing is continued with uniform vigor. The chewing usually fails to produce any effects in the tetanus stage of the stomach activity. Inasmuch as the masticatory movements do not 54 HARVEY SOCIETY cause inhibition if the mouth is empty, we may conclude that inhibition produced by chewing indifferent substances is initiated by mechanical stimulation of afferent nerve-endings in the mouth, 3. Inhibition of the Tonus and the Contractions of the Empty Stomach by Chewing Palatable Foods When Hunger and Appetite are Present.—Tests were made with all food substances palatable to Mr. V. and during all stages of gastric tonus and contractions, which imply all degrees of hunger and appetite. But most of the experiments were made with meats in the form of stews, fricassees, or pot roasts, fried eggs, and crackers or bread soaked in milk, soups or meat gravy. The results are uniform without exception. Chewing or tasting palatable foods inhibits the tonus and the movements of the empty stomach. ‘The inhibition is in evidence within a few seconds after placing the food in the mouth, and may or may not continue for some time after removing the food from the mouth and rinsing the mouth with warm water. The inhibition is least in evidence during the hunger tetanus. In fact, we are uncertain whether the chewing of palatable foods is able to materially affect the stomach in hunger tetanus. It is difficult to determine whether cessation of the hunger tetanus that follows (usually not very promptly) on placing palatable food in the mouth is a ‘‘spontaneous’’ cessation, or due to inhibition from the mouth. The records show, however, that so far as the stimuli in the mouth affect the processes of the hunger tetanus, the influence is in the direction of inhibition. The inhibition of the motor activity of the stomach by chewing palatable foods does not appear to have any after-effects in the nature of increased tonus or contractions. Some of the tracings do suggest a motor after-effect, but we are inclined to interpret them in a different way. ‘These effects are obtained only when the tests are made during the relative quiescence of the stomach or at the beginning of a contraction period (‘‘thirty-seconds rhythm’’). Moreover, these results were not always secured even during these periods. It would, therefore, seem that these apparent augmen- tary after-effects represent the ‘‘spontaneous’’ initiation of a contraction period, or the gradual increase in the magnitude of the contractions characteristic of the periods of the thirty-seconds rhythm. NERVOUS CONTROL OF HUNGER MECHANISM. 55 4. The Factors Involved in the Inhibition of the Contractions of the Empiy Stomach by Palatable Foods in the Mouth.— Boldyreft has reported that the contractions of the empty stomach in the dog cease during the periods of ‘‘spontaneous’’ secretion of gastric juice. We know that tasting or chewing palatable foods leads to reflex or ‘‘psychic’’ secretion of gastric juice in mammals (including man). May not the inhibition described above be an indirect one due to the secretion of gastric juice, rather than a reflex inhibition of more direct character? This question has been investigated and settled. A rapid secretion of gastric juice is associated with cessation, partial or complete, of the stomach contractions in Mr. V. This is due, not to the processes of secre- tion, as such, but to acid stimulation of nerve-endings in the mucosa. When the chewing or tasting of palatable foods leads to copious secretion of gastric juice, this gastric juice is one factor in the accompanying inhibition of the stomach movements. We know, from Pavlov’s work on dogs, that the latent period of the ‘‘psychic’”’ secretion is about five minutes. The latent period of the ‘‘psychic’’ secretion in man is shorter (2-3 min.). The inhibition of the stomach tonus and movements follows within a few seconds after placing the food in the mouth. Hence it is not an acid inhibition from the stomach. The same thing can be shown by some instances when the tasting or chewing of the food produces only a scanty secretion of gastric juice. The inhi- bition appears in the normal way, and the contractions reappear on removing the food from the mouth despite the slow secretion of gastric juice. It seems that a certain quantity of gastric juice must accumu- late in the stomach or the free hydrochloric acid in the stomach must reach a certain concentration before the acid inhibition takes place. Thus, if the period of chewing or tasting the palatable food is short (four to six minutes), the stomach contractions may reappear at the end of the stimulation in the mouth, and shortly afterwards again be inhibited by the acid gastric juice. This inhibition continues during the phase of rapid ‘‘psychic”’ secre- tion. When the psychic secretion is more copious, the reflex inhibition from the mouth merges into the acid inhibition from the stomach, 56 HARVEY SOCIETY 5. The Inhibition of the Tonus and the Contractions of the Empty Stomach by Swallowing Movements.—It has been shown by Cannon and Lieb for the dog that the movements of swallowing lead to a temporary inhibition of the tonus of the stomach. This inhibition is designated the ‘‘ receptive relaxation’’ of the stomach. This inhibition is readily demonstrated in man. Mr. V. makes repeated swallowing movements with only enough saliva in the mouth to initiate the swallowing reflex, a prompt but transitory inhibition of gastric tonus and contractions is produced. The reader will recall that the swallowed saliva does not reach the stomach, but collects in the wsophagus pouch. Complete inhibi- tion of the stomach contractions was never secured through the swallowing act, and when the stomach is in the condition of hunger tetanus, or in very strong and rapid contractions border- ing on tetanus, the swallowing movements seem to have no effect on the stomach. The inhibition of the stomach tonus due to the act of swallowing is most readily demonstrated at the beginning of a period of hunger contractions. 6. The Relation of the Reflex Inhibition of the Tonus and the Movements of the Empty Stomach from the Mouth to the Sensa- tion of Hunger.—The stimulation of the gustatory end-organs in the mouth, the chewing of indifferent substances, and the tasting and chewing of palatable foods abolish the sensations of hunger to the same degree that these measures inhibit the stomach con- tractions. The inhibition of the stomach activity and the cessa- tion of the hunger pains run parallel. This conclusion is based on experiments on a number of men beside Mr. V. In the dog, food or other substances in the mouth cause inhibition of the hunger contractions of the stomach. But since these manipulations disturb the animal, and induce salivation, and in many cases swallowing movements, the precise mechanism of the inhibition must remain in doubt until it ean be investigated on dogs from which the cerebrum has been removed, since most of the dog’s cerebral processes (pleasant or unpleasant) induce the same inhibition. In the rabbit the sight, smell or taste of food, or the chewing (without swallowing) of such foods as cherries, carrots, apples, NERVOUS CONTROL OF HUNGER MECHANISM 57 earrot leaves moistened with sugar, acid or quinine do not inhibit the stomach contractions (Rogers). The same is also true for the guinea-pig (King). In the case of the single goat so far studied the chewing of ordinary food (hay, oats, carrots) appeared to increase rather than decrease the hunger contractions of the rumen. In the pigeons Rogers encountered the same difficulties that we met in the dogs. Any disturbance of the normal pigeon inhibits the hunger contractions of the empty crop. And since it is not possible to put food or other substances in the mouth of these birds without more or less disturbance by the handling, we cannot be sure that the resulting inhibition proceeds from stimulation of nerves inthe mouth. In the decerebrated bird visual and audi- tory stimuli do not inhibit the crop, but handling the bird, as in feeding or placing anything in the mouth, causes inhibition. If the disturbing factors other than the mouth stimulation could be eliminated it is likely that the mouth stimulation alone would cause little or no inhibition unless accompanied by swallowing. In the frog stimulation of the nerve-endings in the mouth by food substances, acids, or alkalies causes little or no inhibition of the empty stomach. This is true whether the frog is normal or decerebrated (Patterson). It is thus evident that the marked reflex inhibition of the gastric hunger contractions from mechanical and chemical stimuli acting in the mouth of man is much less in evidence, although not entirely absent, in the lower mammals, birds and frogs. This leads us to suspect that in man and the higher animals where the reflex is preponderant it involves conscious cerebral processes. The question could possibly be settled by experiments on infants and on persons in deep sleep. Ill. THE INFLUENCE OF STIMULATION OF THE GASTRIC MUCOSA ON THE HUNGER CONTRACTIONS The character of the periodic and continuous motor activity of the empty stomach in man and other animals has been described. It has also been shown that the contractions of the empty stomach 58 HARVEY SOCIETY give rise to the sensation of hunger or the ‘‘hunger pangs’’ by stimulation of afferent nerve-endings in the gastric mucosa. We have also seen that in man the hunger contractions of the stomach are inhibited, reflexly, by all stimuli acting on end-organs of taste and general sensations in the mouth cavity, so that in ease of chewing palatable foods when in hunger we have the so-called psychic secretion of gastric Juice preceded and paralleled by a psychic inhibition of gastric motility and tonus. It has also been shown that the hunger contractions persist in their essential char- acter after section of the nerves connecting the stomach with fhe central nervous system. If we are to attempt to determine more specifically the cause of the hunger contractions our attention must be directed to the stomach itself. The contractions of the empty stomach may be due to several conditions. 1. The Condition or the Stimulation of the Gastric Mucosa.— The absence of food means absence of mechanical stimuli and cessation or diminution of the secretion of gastric juice, and hence a diminished acidity. Carbon dioxide may be secreted into the empty stomach and may act as the primary stimulus. Carbon dioxide and other gases may enter the stomach from the intestines, and act as stimuli. Succus entericus, pancreatic juice, and bile may enter the stomach and act as the primary stimulus through alkalinity or by means of specifie substances such as the bile acids. The reader will recall that a number of workers maintain that bile facilitates the intestinal movements. 2. The Condition of the Blood, Such as the Relative Concen- tration of Nutrient Substances, Tissue Metabolites, and Hor- mones.—It is possible that the neuromuscular apparatus of the stomach is specially sensitized to slight variations in these sub- stances. While we recognize the condition of the blood as a pos- sible factor, it does not seem a probable one; in the first place, because the composition of the blood is on the whole more constant than the composition of the tissues, and because in young and vigorous individuals the hunger contractions of the stomach begin as soon as the stomach is empty, and while digestion and absorp- tion is still in progress in the intestines, so there ean be no lack of nutrient substances in the blood. In view of the relative con- a Se eee +e De ee? eS ee ee ee ee NERVOUS CONTROL OF HUNGER MECHANISM 59 stancy of the composition of the blood serum, as shown by all past work, the existence of a periodic fluctuation in the concen- tration of any one substance in the blood parallel of the periodicity of the hunger contractions seems improbable. 3. Nervous Impulses Through the Vagi.—lIt is well known that the tonus of the stomach depends, in part, on impulses from the vagi, and that the stimulation of the peripheral end of the vagi induces strong contractions on the stomach whether empty or filled with food. It is also known that the stomach is capable of carrying out the movements of digestion to a fair degree of efficiency after section of both the vagi and the splanchnic nerves. In other words, the neuromuscular apparatus of the stomach seems to be primarily automatic, as regards the genesis of the movements of the digestion. The experiment of sectioning the vagi does not prove this point, however. The experiment does prove the plasticity of the gastric motor mechanism. One would expect that the extrinsic gastric nerves bear the same relation to the movements of the filled and of the empty stomach. This phase of the problem cannot be studied in man. If it should develop that the periodic hunger contractions of the empty stomach are caused by periodic discharges through the vagi, the ultimate question of the cause of hunger would again become a problem of physiology of the central nervous system. 4. A Primary Automatic Action of the Local Neuromuscular Mechanism of the Stomach.—This can be established only by exclusion of the three other possibilities outlined above. Benedict and Emmes: Ibid., 1915, xx, 253. 73 Benedict: Ibid., 1915, xx, 263. * Means: Jour. Med. Research, 1915, xxxii, 121. * Palmer, Means, and Gamble: Jour. Biolog. Chem., 1914, xix, 239. * Means: Jour. Biol. Chem., 1915, xxi, 263. 71 Soderstrom, Meyer, and Du Bois: Arch. Int. Med., 1916, xvii, 872. * Rubner: Gesetze des Energieverbrauchs, 1902, Leipzig. * Lusk: Animal Calorimetry Papers. Paper XI, Jour. Biolog. Chem., 1915, xx, 555, and previous papers of series in same journal. *° Magnus-Levy and Falk: Arch. f. Anat. und Physiol., 1899, Suppl. 315. ** Howland: Ztschr. f. physiolog. Chem., 1911, lxxiv, 1. * Benedict and Talbot: Carnegie Inst., Washington, 1914, Pub. No. 201. 88 Benedict and Talbot: Am. Jour. Dis. Child., 1914, viii, 1. * Benedict and Talbot: Carnegie Inst., Washington, Pub. No. 201. % Murlin and Hoobler: Am. Jour. Dis. Child., 1915, ix, 81. * Bailey and Murlin: Am, Jour. Obstet. and Dis. of Women and Child., 1915, Ib.o.0 9 yl Ke * Du Bois: Archiv. Inter. Med., 1916, xvi, 887. Coleman and Du Bois: Arch. Int. Med., 1915, xv, 887. ® Miiller, Fr.: Deutsch. Arch. f. klin. Med., 1893, li, 335. “ Magnus-Levy: Berl. klin. Wehnschr., 1895, xxxii, 650. “ Magnus-Levy: Ztschr. f. klin. Med., 1897, xxxiii, 269. “ Magnus-Levy: Ztschr. f. klin. Med., 1904, lii, 201. “Stiive: Fest. Stiidt. Krankenh., Frankfurt a. M., 1896. “Hirschlaff: Ztschr. klin. Med., 1899, xxxvi, 200, —< THE RESPIRATION CALORIMETER 123 * Salomon: Berl. klin. Wehnschr., 1904, xxiv, 635. * Du Bois: Archiv. Inter. Med., 1916, xvi, 915. “ Pribram and Porges: Wien. klin. Webnschr., 1908, xxi, 1584. *Undeutsch: Experimentelle Gaswechseluntersuchungen bei Morbus Base- _ dowii, Inaug. Dissert., 1913, Leipzig. “Von Noorden: New Aspects of Diabetes, New York, E. B. Treat & Co., 1912, p. 20. ® Joslin: Arch. Int. Med., 1915, xvi, 693. * Allen and Du Bois: Archiv. Inter. Med., 1916, xvi, 1010. Reilly, Nolan, and Lusk: Am. Jour. Physiol., 1898, i, 395. * Mandel and Lusk: Deutsch. Arch. f. klin. Med., 1904, Ixxxi, 472. Lusk: Arch. Int. Med., 1909, iii, 1; also the Harvey Lectures, 1908-1909. ® Tusk: Arch. Int. Med., 1915, xv, 939. Allen, F. M.: Boston Med. and Surg. Jour., 1915, vol. i. * Pettenkofer and Voit: Ztschr. f. Biol., 1867, iii, 380. ® Nehring and Schmoll: Ztschr. f. klin. Med., 1897, xxxi, 59. *® Magnus-Levy: Ztschr. f. klin. Med., 1905, lvi, 83. ® Du Bois and Veeder: Arch. Int. Med., 1910, v, 37. * Rolly: Deutsch. Arch. f. klin. Med., 1912, ev, 494. *% Leimdoérfer: Biochem. Ztschr., 1912, xl, 326. * Lusk: Science, 1911, xxxiii, 433; also Jour. Biolog. Chem., Animal Calori- metry, 1915, xi, xx, 598. “Falta: Die Erkrankungen der Blutdriisen, Berlin, Springer, 1913, p. 440. ® Shaffer and Coleman: Arch. Int. Med., 1909, iv, 538. * Kraus: Ztschr. f. klin. Med., 1891, xviii, 160. * Svenson: Ibid., 1901, xliii, 86. ®Grafe: Deutsch. Arch. f. klin. Med., 1911, ci, 209. ® Rolly: Ibid., 1911, ciii, 93. ™ Kocher: Deutsch. Arch. f. klin. Med., 1914, xev, 82. ™ Magnus-Levy: Ztschr. f. klin. Med., 1906, lx, 179. @Kraus: Ztschr. f. klin. Med., 1893, xxii, 458. ® Bohland: Berl. klin. Wehnschr., 1893, xviii, 417. “Thiele and Nehring: Ztschr. f. klin. Med., 1896, xxx, 41. ® Grafe: Deutsch. Arch. f. klin. Med., 1911, cii, 406. * Meyer and Du Bois: Archiv. Inter. Med., 1916, xvi, 965. “ Peabody, Meyer and Du Bois: Archiv. Inter. Med., 1916, xvi, 980. * Grafe: Deutsch. med. Wehnschr., 1914, xl, 518. ® Du Bois: Jour. Am. Med. Assn., 1914, lxiii, 827. * Carpenter and Murlin: Arch. Int. Med., 1911, vii, 184. " Loewy: Arch. f. d. gesammte Physiol., 1890, xlvii, 601. ®Lindhard: Jour. Physiol., 1911, xlii, 337. * Edsall and Means: Arch. Int. Med., 1914, xiv, 897. “ Higgins and Means: Jour. Pharm. and Exp. Ther., 1915, vii, 1. ® Lusk: Animal Calorimetry, Papers 1 to 12, Jour. Biol. Chem., 1912-1915. THE METHOD OF GROWTH OF THE LYMPHATIC SYSTEM * ‘ PROF. FLORENCE R. SABIN Johns Hopkins University i" SELECTING a title connected with the general subject of the lymphatic system, I have chosen to emphasize the phase of the subject with which the anatomist of to-day is concerned. As a matter of fact, in studying the problem of growth he is seeking to understand the nature of the lymphatic capillary. This is no new problem, but rather has dominated the study of the lymphatic system for nearly three hundred years. The colorless fluid of the tissues was called lymph long before lymphatics were discovered. It was thus natural that when vessels were found containing this fluid they were called lymphatics. As soon as the lacteals and then the general lymphatics were discovered, the question arose in regard to the nature of these new vessels, what was their extent and how they ended in relation to the surround- ing tissues. At first the lymphatics were thought to begin in wide mouths in the walls of the various cavities of the body and then, as these openings proved difficult to find, attention became focused on the relation of the lymphatics to the tissues. The number of terms which have been used in seeking to analyze the relation of the lymphatics to the tissues, for example lymph- radicles, lymph-rootlets, lymph-spaces, parenchymal spaces, tissue- spaces, will serve to illustrate how persistent has been the quest of the anatomist to understand the lymphatic capillary. Stated in other terms, this is the time-honored question of open and closed lymphatics. In presenting to you the conception of lym- phatie capillaries as definite vessels completely lined by endothe- lium, and related to tissue-spaces just as blood-capillaries are, it will be necessary to emphasize first the importance of tissue- * Delivered December 18, 1915. 124 GROWTH OF THE LYMPHATIC SYSTEM 125 spaces. Indeed the general subject of tissue-spaces as important systems in the body, related to blood-eapillaries and to lymphatic capillaries in function, is, I believe, nowhere sufficiently empha- sized in the literature. It is well known that the plasma of the blood is constantly exuded from the blood-vessels into the tissue-spaces, so that all the cells of the supporting tissues, as well as the special cells of each organ, are bathed in fluid. Moreover, it is obvious that with all the varying activities of the cells of the body, the fluid becomes laden with different nutritive and with different stimula- tive substances and with different waste products, so that it varies widely in its composition. The subject of tissue-spaces—meaning not empty spaces but spaces which always contain fluid—is by no means simple. There are primarily the general, small spaces to which I have just referred, between all of the fibres and cells of the connective tissues and between the parenchyma of each organ and its supporting tissues: but there are also special systems of great spaces, which arise from the small spaces by a definite method, which have a definite structure and contain a fiuid which is different from the other fluids in the body, such, for example, as the subarachnoid spaces which surround the central nervous system. That the cerebrospinal fluid is secreted by a special organ and contains certain products of internal secretion is now known. The pia-arachnoid membrane has been shown by Weed? to have an extremely interesting structure and development. I will men- tion here only the very important arachnoidal villi, which are lace-like projections of the arachnoid into the dura. They lie along the dural veins and lead to the dural sinuses. These villi, which he has shown to be the organs of absorption for the cerebro- spinal fiuid, are covered with a layer of mesothelial cells, which become more abundant at the tips, forming cell nests. Other great systems of spaces are found in the internal ear and in the eye. The scala tympani and scala vestibuli of the cochlea have been called perilymphatic spaces, though they have no relation to the lymphatic system. These spaces of the ear have just been shown by Streeter? to have a most interesting 126 HARVEY SOCIETY development. The scala tympani and scala vestibuli are formed from spaces in the mesenchyme which at first become slightly larger than the usual spaces and then coalesce into still larger spaces. Moreover, this process is not indefinite but has two dis- tinct places of origin, one between the sacule and the oval window and the other between the cochlea and the round window. From these two areas the formation of the two great spaces of the cochlea proceeds in a definite and constant direction, so that a model of their form from one specimen is the same as that from any other specimen of the same stage. Moreover, when studied in sections this process appears to be a gradual dilatation of pre- existing tissue-spaces, with a disappearance of more and more of the original connective-tissue syncytium, rather than being caused by a differentiation of the mesenchyme cells forming the border of these spaces. As the cavity thus formed reaches its ultimate dimensions some of the remaining mesenchyme cells do differentiate to form a mesothelial lining. I emphasize this method of the formation of a cavity out of mesenchymal spaces for the reason that I believe it to be essentially different from the method of formation of blood-vessels. Again in the eye there are two cavities having an entirely dif- ferent development. Posterior to the lens is a space filled with fluid, which begins not by a hollowing out of tissue-spaces in mesenchyme, but as a definite differentiation of a primitive vit- reous body by the retina. In the formation of this body the mesenchyme is only secondarily concerned. On the other hand, the history of the aqueous chamber of the eye is analogous to that of the formation of the cerebrospinal system of tissue-spaces. Along the pathway of the blood-vessels of the central nervous system are special chains of tissue-spaces, lined by an indefinite mesothelium, but arranged in sufficiently definite lines to have received the name of perivascular lymphatic spaces. These spaces, however, have no relation to lymphatics and should be called peri- vascular tissue-spaces. Along the nerves also are chains of spaces which can be injected in the embryo, and which may be termed perineural spaces. Similar chains of connecting spaces have been injected by Lhamon‘ along the course of the Purkinje fibres of the GROWTH OF THE LYMPHATIC SYSTEM 127 heart. Beside these very interesting special systems of tissue- spaces there is a group of great spaces which is still better known —namely, the great serous cavities of the body. These cavities, which form as a dilatation of spaces in the mesenchyme, have also a definite embryological history, a definite cellular wall of meso- thelium, and a special very scanty content of fluid. In order to analyze the relation of the general tissue-spaces and of these special systems of large tissue-spaces which develop out of the general ones, it is necessary to submit them all to some type of experiment. Fluids containing a suspension of minute granules, or true solutions whose location can be detected subse- quently by the precipitation of granules injected into these various spaces, give widely and astonishingly different results. Weed has carried out a very interesting series of experiments of injections into the subdural and subarachnoid spaces. In these experiments he injected a solution of potassium ferrocyanide and iron ammonium citrate, at the same time withdrawing an equiva- lent amount of cerebrospinal fluid, to eliminate phenomena due to pressure. He found that when the granules of Prussian blue were precipitated by an acid fixing agent, they were in the meshes of the arachnoidal villi, within the cells of the nests of mesothelium at their tips and within the dural sinuses. On the other hand, when he produced a cerebral anemia by bleeding, the fluid was sucked into the special and very important tissue-spaces that sur- round the nerve-cells. These experiments demonstrate conclu- sively that the central nervous system has a special system of tissue-spaces beginning, one might say, with the spaces surround- ing every individual nerve-cell of the brain, extending into the subarachnoid area and draining not by lymphatics but by another special system of absorbents, namely, the arachnoidal villi, into the cerebral sinuses. Wegefarth* has shown that the anterior chamber of the eye has a similar system of absorbents, the pec- tinate villi. These lead to the canal of Schlemm, a vein analogous to the cerebral sinuses. When injections are made into the peritoneal cavity the results vary widely, according to the nature of the fiuid injected. Asa matter of fact our knowledge of this important subject is far 128 HARVEY SOCIETY from complete, but it has been shown that certain true solutions are absorbed by the blood-vessels. On the other hand, it is known that granules are in large part taken up by special, large, phago- cytic cells, some of which pass into the lymphatics of the dia- phragm. This gives a suggestion of a possible differentiation in absorption between blood-vessels and lymphatics. Indeed, a partial differentiation in function is a most familiar phenomenon : J refer to the villi of the intestine, where almost all of the fat passes into the central lacteal while the carbohydrates pass directly into the blood-stream. It is well known, on the other hand, that when a needle is introduced into certain areas under the skin or into specific layers of many of the organs and a fluid © containing granules is injected, the granules always appear in the lymphatic trunks which drain the area. What is the differ- ence between tissue-spaces which are drained by lymphatics and those which are not? What is the difference between areas in which injections always show lymphatics and those which never show lymphatics? What is the nature of the fluids which pass through the lymphatics and those which do not? In other words, exactly what happens at the point of the needle when an artificial cedema is produced? This I understand to be the meaning of the main problem connected with the lymphatic system—the solution of the enigma of the mechanism of absorption. The difficulty of the problem was well expressed by Bartels * as late as 1909, when he said that the relation of the lymphatic eapillary to the tissue-spaces was a philosophical rather than an anatomical problem. My understanding of the recent work on the lymphatic system is that it tends to take the system out of the realm of the mythical and to make it a definite anatomical entity. The investigations of the last fifteen years have demonstrated that the blood-vessels are the primary absorbents, and that subsequently partial systems of absorbents develop, such as the arachnoidal villi and the lymphaties which drain into the veins. I have been greatly interested in the attempts of the earliest anatomists to solve the problem of absorption. They brought to the subject of tissue-spaces and the fluid within them, a great freshness of interest and constantly sought to understand the GROWTH OF THE LYMPHATIC SYSTEM 129 meaning of their various observations. ‘They saw the arteries become smaller and smaller, they were familiar with lymphatic trunks and with some lymphatic capillaries. What then was more natural than to assume that when the arterioles became so small that the corpuscles could not enter, there were still smaller vessels which carried the plasma over into the lymphatics? These tiny hypothetical vessels were called ‘‘vasa serosa.’’ 9.0. ov b con hes eee be ae Zuelzer, 1912. | Smuenouurete *) . 6. 1.c'bb iD kis Mei ty Radel age eee Zuelzer, 1912. FS ABRUIST ou 5's o's ea Hot spring. 30-100u x0.5-0.754 Cantacuzene, 1910. * Zuelzer cultivated these varieties in a suitable medium and proved each of them to be different from the others; hence he made subspecies. Schaudinn considered them to represent male and female forms. t In the water of hot springs of Dax (52°-56° C.). CRISTISPIRE AND SAPROSPIRZ (LARGE SAPROPHYTIC AND COMMENSAL FORMS IN THE ALIMENTARY CANALS OF SHELLFISH) Cristispira balbianiif...... Ostrea angulata O. edulis..... 100-120 X3-5u.Certes, 1882. GU BRBGONUE ic. & sie xg tunt 5 Fresh water mussel, A. eygnea; also A. mutabilis .130u4*3-4u..... Keysselitz, 1906. C. spiculifera§............ (¢ 28-36 X0.7-1.14.Schellack, 1909. Cre Fa aes a5 Prima squamosa, Pe nobilis-:..4eee 10-60 X0.5-3y. .Gonder, 1908. G@smactrences 2. oes t Mactra sulecataria 45-70u X0.8-1.0uProwazek, 1910. Cp pechines 044 8i\2514 Pecten jacobeus..72u X1.5yu....Gross, 1910. CS) PLPITORALIONISS. 544 Suche cauieees aes 25u X0.5u....Gross, 1910. i ONERIEY in aioe cies Wenilld GAstA: ia: cc te eae ee Dobell, 1910. SHpIOMpire (COHGis . 4c 05.22. sis ce cde weit aces oe Gross, 1912. FF. MUI Ges ee As bk pee OF eects eC Reee ebes Eee Gross, 1912. * Gonder once described a blepharoplast near one blunt end; nucleus in single rod or irregular masses. Specimens with rod-formed nucleus may be male elements, since they are highly active, the others female or indifferent elements. A concentration of all the chromatin into one rounded mass was : sometimes observed. Encystment also occurs. Gonder no longer upholds his above-cited interpretations, explaining them on the ground of faulty y technical handling of the preparation. ' - t Once considered to be trypanosome or spirocheta. § Bosanquet doubts its being a separate species from C. anodonte. g 197 SPIROCHATES *peqyurod dieyg ‘de “4 ou ‘divys euo “4un[q pud su0 ‘de “4 ou ‘popunoyy ‘de 4 ou ‘poyulog ‘de "4 [euoIsvo00 = ‘papuno xy ‘de -4 ou ‘papunoy ‘de “4 ou ‘popunoy ‘de “4 ou ‘popunoyy ‘de “4 ou ‘papunoyy “WIRY “4 ‘pozurog ‘de ‘4 ou ‘popunoyy ‘de -4 ou ‘popunoy ‘de ‘4 ou ‘dieyg ‘de *4 ou ‘papunoyy spay F'0-2'0 i sl SI S'1-9'T Et 11-60 OT VAL eT PI-ELT oT S'I-0'T PI T I-80 OT 6'0-2'0 80 TI-20 60 G 1-60 OT G1-8'1 VI €T-0'T TT Sy) eae Sir SOUIOI}X edBIOAY qipeeg FI-GT 4uejsuo0o c&-0E G'6F-G' SP GE-62 0Z-G'8T Ly-GE TE-66 OF-9E G'9E-8Z - S'0S-6€ G'9F-SP G'CP-8E GP-GE SaUTII4X qi3ueT 484SHWO ON “YOVPEYyoY Jo vyjesnd *g YAM IO Japuoy jo TUUBUTPeY ByeyoordY YA [oyUepl oq AvUL syUIY} oY YOIYM YyZua] ul wZT-OT eyeyoosds v punoy yonbuvsog , &I 62 T€ LE ote T61 Lé POE GLE €€ OF 9°SP GTP 6€ ODBIIAY © 8 trie .0 ine 049 ‘sod y, “eUITT ‘our ‘eyuopouy Vaietre fe aw feline Ps eyjesnd ‘g oWehegatereetl eaewarielts wiqnp "°°" * eueyoorsed ‘O Scarartatnes Rls worjore “xUg AuOIXES “O Sia core eee eyay soduy,”*** °°: eyeurumoe “5 Sauclerereveh ove eyessnoap \L°° "°° °°" “sojedey "ZO ase yet uinsoyided *-° °°‘ asorpided parvo “a **-ouury Ty ‘oyepurerp wun] ‘O Cue) Ree ee. 6 .@) (8: 0, ene sT[Iqou il mete a OB UIETCL 6) Satter oyeqaeq “°° + -@eporpour “5 Sele aMeciewereire wyuopouy'*** "+: waozttnoids Te) *“STIqeynur eyuopouy’*** #jUOpoue *d > { BS101}STUIS ah Sere atdeo eBUIeyD *O saproyddéis vureydD ‘+++ gimp wayso ttt @.1}80 *O Shah silevahatots st[Npa warysQ’ °° °° °°" “MURIqIeq ‘9 (HOVTITRHOG) 198 HARVEY SOCIETY q SPIrRONEMA | S. obermeieri* ... Man, Europe.8—16y X0.25yColin, 1877 (“). | S. carteri........ Man, India. .8—16y X0.2yu.. Mackie, 1907 (7°). S. duttoni....... Man, West Africa. .16-30.. 9 (aa pee Novy and Knapp, 1906, Breinl, 1906. BU o 1 ae Man, East Africa......... Schellack, 1907 (7). S. berbera....... Man, Algiers........ 12... .Sergent, 1908. S. egyptica...... Man, Egypt ........ 13.5p. MONG on nites ats Man, North America.12y..Schellack, 1907 (*). S. ictero-hemor- rhagie..... Man, 4-9 X0.3,, exception- aby Boys: ss sce wee ae Inada, 1914-15 (*%). S. nodosum...... Man: it oe sec ane Hiibener and Reiter, 1916 (*). 5, gallinarum, 5. Bowl. 2275 cs 5.6. sede ee Marchoux and Salimbeni, 1903 ®), BU GUNA sis CHORES se eieso's den ks Wes Ot Sacharoff, 1890 (5). S: theileri...-... Cattle .20-30u X0.25-0.33y . Laveran, 1902. S, bovis cattnis.. atile soc tee ae Nuttall, 1910. SSel fk wea en Elorse:.£ eo. pe eee Novy and Knapp. S. equina........ Horse Biss ate Dee sale Theiler, 1906 (**). SA OVINGE: oc soe Sheep WOTJNIOS *gued Jed OT WOTNIORSIP :UOIyNjOs “yueo sod Of ‘peAdeseid-[jom SsulIOy ynq ‘1ouUUTyy ieodde Auvur! u01yez -TTIqouur 940;du100 :UOTyNTOS “yued Jed T sesueyo [Vo1so;oydiow ou 4nq ‘paztrqouran : WOTYNOS *9u90 rod T "iat va Yet Os Je hose “8§0078N anoy [ Ur u0ry -N[Ossip {Ulu QE UI qouTJsSIpUl Polepuer : WOTJNTOS "4us0 Jed OT SUIST -UBS10 BY} SOA[OSSTP :UOTyNTOs “yue0 sed Og ‘eules oY} INoY [ ‘SeAINO JoUTSTpUT ‘Us]JOMsS ‘IepnuUeIs ‘pouayroys ‘ATo}eIp “OUT PoeZzTIqourMy] :UoTyNyTOS “yuo sed T sep Aueul JOJ uorsod “Ip 9143.41} 04} 4SISoY (OO"8N ‘gueo aiod g'Q jo ‘0°O OT Ul ZO) uIsdérL, 210 HARVEY SOCIETY ture of 30° C. (summer) and 4° C. (winter), although no growth was obtainable with material exposed for 12 hours (Akatsu). Drying promptly kills them, that is, no growth can be obtained by transplanting the dried cultures into new media. The thermal death points for 7. pallidum as tested out with pure cultures are as follows: 5min. 10min. 15min. 30min. 60 min. BOON ats ais ou 2 + “> + | 1 ate, CS + -- + + fh Bo aha as Hea + os — = =e CORR ha ae be ke — -- — = a el Cages Bie BS — -- — = = The above data were obtained by Akatsu and closely agree with those obtained by Bronfenbrenner,’** who found that the several strains of 7. pallidum were destroyed at slightly lower temperatures. It must be stated that Bronfenbrenner used iso- lated organisms suspended in saline or ascitic fluid, while Akatsu subjected them to the action of heat in a thin culture tube. Microchemical Reaction.—As mentioned elsewhere, a number of substances have been found to exert a dissolving or disinte- erating action upon so-called ‘‘ spirochetes ’’ in general as well as upon certain protozoa. This phenomenon is claimed by certain authors to be decisive enough to place the spirochetes among protozoan organisms as the majority of bacteria (pneumococeus is an exception) remain unaffected, and some can multiply freely in a saponin solution which destroys spirochetes. While a too far-reaching generalization from these observations may be avoided, these reagents nevertheless furnish us with an excellent means of studying the microchemical structure of the organisms. The preceding table contains a summary of all available data which however are very fragmentary and incomplete. As will be noticed in the table, certain reagents demonstrate the existence of a resistant membrane in Cristispira, a trypsin resistant axial filament in Spirocheta, and a shadowy sheath ( ?) 5 ; : ; f | a ae SPIROCHATES 211 as well as an axial spiral filament in Spironema and Treponema. As in the case of Spirocheta no true dissolution of Spironema (both gallinarum and recurrentis) or Treponema was effected by the saponin, but after several hours’ contact they were shriv- elled and broken up into irregular pieces. Resistance to Disinfectant and Chemotherapeutic Agents.— Attempts to determine the resistance of various ‘‘spirochetes’’ are not lacking, but no satisfactory and accurate results were to be expected from the experiments in which their death point had to be determined through the intermediary of susceptible ani- mals. Since the successful cultivation of different ‘‘spirochetes”’ has been effected, it has become possible to determine the effect of different chemicals. The following table shows a summary of the results obtained in two independent series of experiments by the use of common disinfectants. RESISTANCE TO CHEMICALS At 87° OC. Lugol kills in 1:3 dil.; 1: 5-1: 10 in 15 min.; 1: 50 not in 1 hour. al \ killsin1:5000 dil.; 1:10,000 in 15 min; 1:50,000 in 30 min.; 1: 100,000 not in 1 hour. At Room Temperature. Phenol kills in 1: 200; 1: 1000 in 30 min.; 1: 5000 not in 1 hour. Lysol kills in 1: 1000; 1: 5000 not in 1 hour. Formalin kills in 1: 200; 1: 500 in 15 min.; 1: 1000 not in 1 hour. ou } kills in 1: 1000; 1: 5000 in 15 min. ; 1: 10,000 not permanganate : in 1 hour. Turning our attention to the chemotherapeutic agents it is searcely necessary to remark that, thanks to the pioneer work of Ehrlich and his collaborators, especially to his contribution to our chemical treatment of spironematoses and trypanosomiasis, 212 HARVEY SOCIETY a new field of scientific research has been inaugurated. Thus Morgenroth initiated a chemotherapy for bacterial diseases by discovering various quinin derivatives as a specific for pneumo- coccus. Flexner and Clark, the collaborators of Jacobs and Heidelberger,'** made an extensive series of experiments in order to discover an effective chemical compound to combat poliomye- litis, wherein they obtained some encouraging results. In their early work they had employed numerous new derivatives of urotropin (hexamethylenetetramine) as this substance was known to penetrate into the intrathecal space. The work has since been extended to include various bacterial infections as well] 7**, 17°, 126 127 as trypanosomiasis and spironematosis (Brown and Pearce) with the use of additional new arsenic and mercurial compounds. While I do not wish to assert that the therapeutic effect of a chemical compound has any direct relation to the latter’s disinfecting or sterilizing power against the causative agent im vitro, it was nevertheless thought of interest to find out how these new compounds, including various derivatives of uro- tropin, arsenic and mercury, would behave in relation to the various species of Spironema and Treponema in cultures. It is a well-known fact that atoxyl arsacetin or arsenophenol, or even salvarsan, attack the trypanosomes and spironemata only after being introduced into the body, where they undergo reduction and produce a highly parasitotropiec component. Yet, as will be shown in the following table, salvarsan is by no means inactive in vitro against T. pallidum. It is a fairly powerful treponemicide. Hence it is not without interest to study these compounds in vitro and then, when completed, compare the results with their therapeutic effects in vivo. The test tube determination of the germicidal property of these substances should form a part of our knowledge in perfecting chemotherapy. With the co-operation of Dr. Jacobs, who is in charge of the preparation of chemotherapeutic agents at the Rockefeller Insti- tute, the following compounds were tested on cultivated strains of T. pallidum in vitro with the results indicated in the tables. A fuller report will be made later by Dr. Akatsu. Table I gives a general survey of these compounds, while es ———E—— eo pe Ride SPIROCHATES 213 TaBLe I Concentration | Concentration No. Preparation quien.) |) loner tals T. pallidum T. pallidum 9 | p-Bromobenzylhex. chloride............. 1 : 1,000 1 : 2,500 16 | o—Xylylenedi—hex. chloride.............. 1 : 2,500 1 : 5,000 19 | 2—-Nitro-3,4—Dimethoxybenzylhex.chloride | 1 : 2,500 1 : 5,000 21 | 1-(w-chlorobenzyl) —2-oxy -3 -naphthoic methyl ester)-thex.................- 1 : 2,500 1 : 5,000 28 | 5-Chloromethylvanillin+hex.............| 1: 750 1 : 1,000 29 | 5-Chloromethylsalicylic acid-++hex........ 1 : 2,500 1 : 1,500 40 | p-iodobenzylbromide+hex.............. Wis50 1 : 1,000 46 | o-nitrobenzylchloride+hex.............. 250 1 : 500 47 | p-nitrobenzylhex. chloride............... 1: 750 1: 1,000 amievicchyihex. lodide. 3.5.00 sae. e cc ee 8 1: 100 1250 84 | Chloroacetamide+hex.................. 1 : 1,000 1 : 2,500 86 | Oxymethylchloroacetamide+hex......... 12.50, 1500 90a | Ethyl bromoacetate+hex............... 1 : 1,000 1 : 2,500 96 | Chloroacetylaniline+hex................ 1 : 1,000 1 : 2,500 97 | B-acetoxy—a—chloroacetylnaphthobenzyla- MINTO =} NEXM i o fe! siolacg idiola/evstae eae eis 1 : 1,000 1 : 2,500 102 | Chloroacetyl-a-naphthylamine+hex..... 1 : 500 Lao 107 | Chloroacetylbenzylamine+hex........... 1: 500 1: 750 109 | Chloroacetyl-8-naphthylamine+hex..... 1 : 1,000 1 :,2,500 111 | o—Methylchloroacetylbenzylamine+hex...| 1 : 2,500 1 : 5,000 112 | Chloroacetyl-p-aminobenzoic ethyl ester AICO e 1 eA Ae a Re RRA Ae URS boa 1 : 1,000 1 : 2,500 114 | Chloroacetylurea+hex.................. 1 : 1,000 1 : 2,500 121 | Phenoxyethylhex. bromide.............. 1 : 250 1: 500 122 | p-Bromochloroacetylaniline+hex........ 1 : 2,500 1 : 5,000 126 | Chloroacetylaminoazotoluene+hex....... 1 : 250 1 : 500 134 | Chloroacetyl—p-—anisidine+hex........... 1 : 2,500 1 : 5,000 138 | Chloroacetylphenylhydrazine+hex....... 750 1 : 1,000 142 | Chloroacetothylamide+hex..............| 1: 1,000 152,500 146 | Menthyl bromoacetate+hex............. Lisfo0 1 : 1,000 147 | Bromoethylphthalimide+hex............ 1 : 1,000 1 : 2,500 148 | p-nitrobenzoic bromoethyl ester+hex..... e250 1 : 500 150 | Bromoethyl benzoate+hex.............. 1: 500 1: 750 158 | 6-Iodopropionyl—o-anisidine+hex........ 1 : 1,000 1 : 5,000 -163 | p-ethoxyphenyl bromomethyl ketone +hex.| 1 : 500 1: 750 164 | Chloroacetyl-’-cumidine+hex......... .| 122,500 1 : 5,000 168 |p-Acetamino- w-bromoacetophenone+hex.| 1 : 750 1 : 1,000 214 HARVEY SOCIETY | Concentration Coacntae : sufficient which no No. Preparation to kill longer kills | T. pallidum T. pallidum 171 | m-Chloroacetylaminomethylbenzamide +- | Os RE PLP) Sie suplsere de ee eer 1 : 1,000 1 : 2,500 172 | m-Chloroacetyl-a, a,—phenylbenzylhydra- | ZING }SNOK4.0)< . Synetind eso eae eee hal 2,500 1 : 5,000 174 | Chloroacetyl-aminoethyl anisate+hex....| 1 : 500 1: 750 204 | 3-(w Bromoacetyl) quinaldine+hex......| 1 : 2,500 1 : 5,000 218 | Tribromo-—p-cresyl bromoethy] ether+hex.| 1 : 2,500 1 : 5,000 219 | Chloroacetyl-p-aminoleucomalachite green +hex*...... OF iekiiae ica tera ee eee | 1: 5,000 1 : 7,500 229 | Chloroacetyl-p —aminobenzeneazo-p’ —di- methylaniline-+hex.* ............... 1 : 500 4: 750 232 | p- Chloroacetylaminobenzeneazo — p’ — di-) ethylanilines-hex. 3050006) ee oats 1: 1,000 1 : 2,500 234 | a-naphthyl bromoethyl ether+hex...... | 1:500 1 : 750 239 | o-Acetaminophenyl bromoethylether+hex.| 1 : 1,000 1 : 2,500 242 | p-chloroacetylaminodiethylaniline+hex...| 1 : 1,000 1 : 2,500 244 | Hex.+chloroacetylaminoethyl p-nitroben- ZORLE HAO I oh Cee ae en eee 1 : 2,500 1 : 5,000 249 | Chloroacetyl-p-aminodipropylaniline + Bae see BAe eo ae eae eka epee 1 : 500 1: 750 252 | Chloroacetyl-p-—aminotetraethyl—p’, p’’,- diaminotriphenylmethane+hex....... 1 : 1,000 1 : 2,500 253 | Chloroacetyldiethylamine+hex........... 1 : 1,000 1 : 2,500 255 | p-Cyanobenzylhex. chloride............. 1 : 1,000 1.: 2,500 257 | Chloroacetyl-o-aminophenyl benzoate+ ex's. Seta G1. deat des ea ee 1 : 1,000 1 : 2,500 261 | Chloroacetyltriphenylmethylamine+hex..} 1 : 1,000 1 : 2,500 262 | Chloroacetylleucoauramine +hex. (* ?)....| 1 : 1,000 1 : 2,500 263 | Chloroacetylaminoethyl o—nitrobenzoate + BOX it oie eater ota ORR ate eee 1 : 1,000 1 : 2,500 267 | Chloroacetylaminoethyl 8-naphthoate + | (:) Ge PUNE PE EDR eS Re re Ui NN eae 1 : 2,500 1 : 5,000 271 | Chloroacetyl - N - phenylaminoethyl — p - nitrobenzoate +hex...............56: 1 : 1,000 1 : 2,500 272 | m-Acetamino—p-tolyl w-iodoethyl ketone eho i) by. Putas ceca See teat Oe ree 1 : 5,000 1 : 7,500 273 | Chloroacetylethylaminoethyl p-nitroben- BORO -HHOR: ¢.ho.c dorado teeatete ish ein sie ets 1 : 1,000 1 : 2,500 ce nnn eaEyEEyE EyUnEIISESSES SS SIEENSSSEESSEn? SPIROCHZETES 215 M7 Preparation a, $8-Diphenylchloroacetylamino-ethanol Chloroacetyl—-m—aminoacetophenone +hex. a—Phenyl —-a—oxy -8- chloroacetylamino- Bae yO 5-12 3/3 Svcs delete toe ae p-nitrobenzoylaminoisopropyl chloroace- fodopropanol--hex. :.. 0.052.664.5602 0 ss . 2-Chloroacetylamino-3-oxy-3-methylbu- BeeTIE AIG Ee A iote safe cise (chal tee apt ote es Chloroacetyl—o—methylphenoxyethylamine Chloroacetyl-6—amino-S-butanol+hex.... 8-Phenyl—s-oxy-S-chloroacetylaminopro- pane+hex.. Kor neh B-Naphthyl Bromine piles siege Bats AA 2-oxy-3, 5-dibromobenzyl bromide (+?) Chloroacetyl—-m-iodoaniline+hex......... Chloroacetyl—5—iodo-o-toluidine+hex.... (4-[p-oxybenzeneazo]—phenylmercuric ace- EELS) 5 AS hey CEN EE ae Roc > ed a [o-oxybenzylideneamino] phenylmercuric PeeE Cn EY.) A Nui) oot /2 s/ete nee se peas 1—Amino -2-[p-naphthaleneazophenylmer- curic acetate|—5-sulfonic acid......... Concentration | Concentration sufficient which no to kill longer kills. T. pallidum T. pallidum 1 : 250 1 : 500 1:1,000 | 1:2,500 1 : 1,000 1 : 2,500 1 : 500 1: 750 1 : 500 L750 1:2,500 | 1:5,000 1 : 1,000 1 : 2,500 1 : 250 1 : 500 1 : 1,000 1 : 2,500 1 : 1,000 1 : 2,500 1:1,000 | 1:2,500+ 1 :750 1 : 1,000 1 2750 1 : 1,000 1: 50,000 | 1: 75,000 1 : 50,000 1 : 75,000 1 : 25,000 1 : 50,000 Hex. co =Grind up in a mortar with a little water and add 5 NV until dissolved. t=Treat as above, using A NaOH instead of HCl. 9 HCl carefully Table IL puts down the strengths of various well-known disin- fectants and chemicals for the sake of comparison. gives the resistance of several culture strains of pallidum and other allied species to the action of two different new compounds. As briefly mentioned, the spironemicidal (or treponemicidal) Table III 216 HARVEY SOCIETY TaBLe II Concentration Concentration in Names of substances sufficient to kill | which T. pallidum T. pallidum survived MEM tas has's's Lie wie avis te ee Oe eee tere 1 : 2,500 1 : 5,000 Mrommarnayd 253 oie ve wwe eae ae ees Oe 1: 750 1 : 1,000 GV OUA YE Me Sites cstc, cielo Site Dele ane 1 : 5,000 1 : 7,500 IIR Se cla t eS is,d ck ee ae eee ee 1 : 100,000 1 : 500,000 RIRRUAIOATLE sc uyetcrc y= bieh ae olch ame ae 1 : 7,500 1 : 10,000 DIGURAIPARRER thie 2. Soc: hn elie eho ete 1 : 2,500 1 : 5,000 PATRIA or) GD. ce oe: sae WL Soe Ye eae 1:10 1:25 SOUMMMHOGIGE! ces .n ee eee eee 1:10 1°25 IB OLARSIUDINOGIGO. ©: 2 aoe ee eee 1:10 1:25 EPA BOON 2 ot ok bis pte aire oes ie i Neer es 1: 100 Todox Wenz Acids. es eee eee see 1 +500 1 : 1,000 EN MIMORLON hee ceo he eee 1 : 25,000 1 : 50,000 Neciry pesairol 8.8. sie Seo be ee 1 : 250 1 : 1,000 POONA CHGIAbE. ok oe eam ue oe ee 1 : 5,000 D5 Sodium glycocholate....................- 1 : 2,500 1 : 5,000 Odum pANTOCHolate..).425) eee ee 1: 2:500 1 : 5,000 § Sodium olemicum=:-ti.ccr eee eee eee 1 : 25,000 1 : 50,000 Baponin pent oe nee i, Bolted nse esr 1 : 75,000 1 : 100,000 ; CMMIESUCEINY th nel Sans de Ue eee Ce ae No action No action GUre Metts s. 6.50% Penns eco ee 1 : 1,000 1 : 5,000 SERVO TOTIN otis, Lies a ton re Nee: Woe 1 : 1,000 1 : 5,000 4 TaBie III Preparation M1 Preparation No. 253 4 Names of organisms : ‘ a | ex: 1 } 10,000 25,000 50,000 1,000 2,500 7 T. pallidum, heavy type. . _ + | = a T. pallidum, thin type... . - + — + } T. calligyrum............ se - + | - + 4 TP PGMOOBUM «5 coe ks ce bas ope - + _ + T. microdentium......... Ae - + - + y Seren gens. 6 ssc. ke ke aS - + | - + : SPIROCHATES Q17 power of salvarsan and neosalvarsan is alleged to increase con- siderably when introduced into the living body. In a series of experiments,'”? it was found that by allowing a sterile extract of freshly removed rabbit’s liver or defibrinated blood of the same animal to act upon neosalvarsan for three hours at 37° C. the germicidal power of this drug increased from 1: 1000 to 1: 2000 in the case of the liver extract, and from 1: 1000 to 1: 5000 in the ease of the blood. The addition of boiled extract had no such activating effect. Acquisition of Increased Resistance to Drugs.—It will be recalled here that the failure of chemotherapy of trypanosomiasis in man and animals is partly due to the production of so-called drug-fast strains of various trypanosomes after the latter have on several occasions been subjected to the action of certain arsenic compounds. ‘These organisms will be destroyed to a great extent by the first injection of the drugs, but if there remain a few which have resisted the first medication, they will multiply and the animal will once more be infested with the organisms. The offspring is more resistant to the action of the same drug than the preceding generation. A large dose of the medicament is necessary to destroy the organisms and to overcome this increased resistance. But as a matter of fact, the increased resistance of the organism to the drug is relatively much greater than that of the infected hosts, and the limit will soon be reached beyond which the quantity of the drug cannot be further increased without seriously affecting the infected man or animals. Experiments of this nature have been made with atoxyl, arsacetin, arsenophenylglycin, ete. To employ Ehrlich’s terms, the organotropie affinities of these drugs were so close to the parasitotropic, that it was impossible to employ a sufficient quan- tity to completely sterilize the infected body, since the adminis- tration of such a quantity would mean death or the serious impairment of some of the functions. Ehrlich’s conception of a specific chemotherapy was based upon the fact that different cell groups are provided with their characteristic receptor apparatus (chemoceptor), to which a given chemical molecule attaches by means of its side chains. Thus, for trypanosomes there are cer- tain receptors which will fit in with a certain atom complex of 218 HARVEY SOCIETY atoxyl, arsacetin, ete., while of the infected hosts the organs show much less affinity for them. In developing chemotherapy for syphilis, Ehrlich finally evolved a compound in which the spiro- nematropic atom complexes were far more in excess than the organotropic groups. This compound, as is universally known, is dioxydiamidoarsenobenzol, better known as salvarsan. Accord- ing to Hata '*§ the ratio of the dosis curativa and dosis tolerata of this compound is 1:3 for mice and rats infected with Spiro- nema recurrentis, and 1:58 for chickens with S. gallinarum, while in the case of experimental chancre in rabbits it is between 1/,—'/,). In these animals Ehrlich’s Therapie sterilisans magna was achieved, as also in eases of relapsing fevers in man. In human syphilis, however, in spite of the most powerful spirone- micidal action, his original aim to sterilize the syphilitic body with a single injection of a large dose was not uniformly attained. Yet there is no doubt that a prompt administration of salvar- san in sufficient dose during the early stage of infection sterilized the patients, as was evidenced by the increased instances of per- manent abortion of the infection and of reinfection after the salvarsan treatment. On the other hand, we are also confronted with repeated recidives in certain patients. We often hear of mereury resistant as well as salvarsan refractory eases. It has been known for some time that Spironema recurrentis as well as Spironema duttoni produces an arsenic-fast strain in mice or rats when the latter are treated with atoxyl, arsacetin, ete. In this respect these spironemata resemble trypanosomes. Marks 7° once considerably raised the resistance of a bacteria to arsenious acid by allowing it to accustom itself gradually to the action of this chemical in test tube cultures. It therefore seems not at all improbable that Spironema as well as Treponema become more resistant to the parasitotropic effect of arsenic compounds and possibly of mercurial salts, not only in vivo, but in vitro. Akatsu 7°? carried out a number of experiments in my laboratory in which he has apparently succeeded in raising to many times their original degree the resistance of the Treponema group to salvarsan, neosalvarsan, and bichloride of mereury. The experi- ments were carried out with cultures of these organisms, the eee ae a a SPIROCHETES | 219 general plan being to cultivate the organisms in media containing these substances in a concentration just short of that required — ‘to suppress the growth completely, and to make subcultures from it into new media containing somewhat greater quantities of the chemicals than the preceding series. In the present experiments fluid cultures consisting of ascitic fluid and a piece of fresh rabbit’s kidney covered with a layer of liquid paraffin were employed. Subcultures from one medicated culture to another were made at two weeks’ intervals, during which time the general condition of the cultures could be estimated. As mentioned above, subcultures are made from tubes still showing numerous actively motile organisms. It is difficult to carry on the culture if one attempts to make a subculture in which too much medica- ment is present to give a fairly good growth, since no growth will be obtained in a subculture which has been inoculated with a poor culture arrested in its development by an excess of the drugs. The results of our experiments may be summarized in the following. charts: 1: 10,000 dilution of Salvarsan in 5 c.c. of medium. | T. pallidum, strain a. AN pallidum, strain b. | T. microdentium. 4 9. refringens. L.D FOR PALLIDUM DEC.27 dJAN.9 220 HARVEY SOCIETY 1: 10,000 dilution of Neosalvarsan in 5 c.c. of medium. 3 T. pallidum, strair S. refringens. T. pallidum, b. T. microdentium, T. pallidum, c. NOV.12 NOV. 26 DEC.i1 DEC.27 > JAN.1 1: 1000 dilution of Bichloride of Mercury in 5 c.c. of medium. T. pallidum. S. refringens. T. microdentiu: SEPT4 SEPT2i OCT6 ocl.25 - NOVIL NOV24 DEC. = DEG.25 In order to suppress the growth of various treponemata which had not previously been in contact with these compounds, the fol- lowing doses were found necessary in a total volume of 5 e.e. of the culture medium. The solutions of salvarsan and neosalvarsan were 1:10,000 dilution in water, and bichloride of mereury in SPIROCHETES 221 1:1000 dilution. Salvarsan was neutralized with NaOH, as usual. Salvarsan Neosalvarsan HegCle Mermnrens 2.1... ee se 0.4 Ge. 0.6 ¢.e. 0.02 ¢.¢. Pallidum (two strains) .. 0.375 c¢.ce. 0.5 @.e. 0.02 c.e. Mierodentium ........... 0.2 «c.e. 0.3 ¢.¢. 0.02 ¢.c. It will be seen from the charts that the resistance of different species of Treponema and also of different strains of the same species (7. pallidum) seems to increase gradually until at the end of ten weeks (namely, five transfers) they were still able to erow very well in a medium which contained several (2-3.5) times the quantity of the arsenic compounds originally sufficient to restrain their growth completely. In case of bichloride of mercury the increased rate of tolerance was still more striking within a certain limit of concentration, but there was no further increase in resistance when the medium contained more than 0.5 ¢.e. of the 1: 1000 dilution of this salt. The tissues which usually remain fleshy pink in color for several days became quickly discolorized into a dirty greyish black when mixed with the above concentration of HgCl.,. The question of the duration of the acquired resistance to the drugs has not yet been studied a sufficiently long time to draw any conclusions, but the resistance has remained unmodified for at least three generations. It may be mentioned that Spironema recurrentis was carried through two generations in mice without undergoing any change in its acquired drug fastness. Transmission of Spironema and Treponema to Man and Animals.—Under natural conditions the transmission of a blood- inhabiting Spironema to man or animals is effected through the bite of an infected blood-sucking insect. The transmitter in each instance is highly, if not strictly, specific, although other blood- sucking insects may also be infected by sucking the blood of an animal which is suffering from an infection with any of the pathogenic blood spironemata. These unnaturally infected ticks, bedbugs, fleas or lice are not good transmitting agents as compared with the natural carrier of the infection. That the spironema 222 HARVEY SOCIETY in such non-specific insects can survive for some time can be shown when the disease is produced in a susceptible animal by inoculating it with the crushed material of the infected insects. It is possible, therefore, that an infection can be occasioned by smearing the excreta or crushed body contents of the infected insect over any defect of the epidermic layer of a susceptible subject. For example, in the case of Spironema recurrentis, both body-lice and bedbugs may be infected by sucking the blood of a patient suffering from the European relapsing fever, but the lice alone can transmit the disease to the next person they bite. Bedbugs are never known to spread the infection by their bites, although by crushing the infected bugs directly over a minute skin trauma (scratch, ete.), a person may become infected. A brief summary is given below of the natural intermediary hosts of different bearing spironemata, as well as certain experimental data bearing on the réle of other blood-sucking insects and on the susceptibility of various animals to each Spironema. Spironema recurrentis, the causative agent of the European relapsing fever, is naturally transmitted by Pediculus corporis. Pediculus caputi was found by Gonder to be ineapable of trans- mitting the disease, although its body may contain the organism. The common bedbug (Acanthia lectuaria) may likewise harbor the Spironema for as long as 50 days,!*®.**1, 1%? but, according to the experiments of various investigators, does not spread the in- fection. The rat-louse (Hematopinus spirulosus) ean earry the infection from rat to rat, while the monkey-louse does the same among monkeys. Breinl and Kinghorn," as well as Neumann,*** Manteufel,’*’ and Sergent and Foley,’** sueceeded in transmitting the infection to rats with ticks (Ornithodorus moubata). Sehu- berg and Kuhn report a successful transmission by Stomazys, the blood-sucking’ flies. The infection can be transmitted subeutaneously as well as per os in experimental animals. Infected organs fed to rats produce the infection in these animals, as shown by Uhlenhuth and Haendel*** and others.” Manteufel considers the uninjured skin permeable to S. recur- rentis, and Nattan-Larrier produced the infection per vaginam, 7 ? zg SPIROCHATES 223 per penis, ete., in rats, while Gozony successfully transmitted the disease also by means of subcutaneous, conjunctival, and intes- tinal application of the Spironema. Schellack,*** who obtained a positive result in one out of 28 experiments on rats, was able to demonstrate a microscopical defect of the skin at the point of entrance. The organism is experimentally transmissible to monkeys and from monkeys to rats, mice, guinea-pigs, and some- times rabbits. S. duttoni, the causative agent of the African tick fever, is normally carried by Ormthodorus moubata, as was recognized by Dutton and Todd,**® and Koch.'** The last-named investigator discovered the spironema in the ovaries four to five days after the tick had sucked the infected blood. Carter **® confirmed this finding, while Neumann *** found the organisms in freshly laid eggs. Hereditary infection for one or more generations was shown to occur by the study of Dutton and Todd, Wolbach,'** and others. The tick is infectious an hour after sucking and re- mains so as long as 90 days (Wittrock '**). This author always found the Spironema in the infective ticks. Ornithodorus sa- vignyt has been suspected of carrying the infection,*** and Brumpt once succeeded in infecting a monkey by this tick. Robledo holds Argas americanus responsible for the spreading of S. novyt (the American type of relapsing fever) in Colombia, but this theory calls for further investigation. According to Breinl and Kinghorn,‘ the rat’s foetus may be infected through the placenta when a mother rat is inoculated with S. duttoni. The organism is experimentally transmissible to rats, mice, monkeys, guinea- pigs, and rarely to rabbits. As has been briefly mentioned elsewhere, Leishman, Fantham, Hindle, and others assume a granular or coccoid phase in the life history of this and allied species and maintain that the spiro- nema gradually undergoes granulation when it reaches the tick’s body and multiplies in the Malpighian tubules and ovaries. The tick becomes infective after an incubation of 1-2 days at 37° C. Hindle 7® demonstrated the infectivity of the coxal fluid, in which he found numerous granules and some spironemata. This investigator thinks that the Spironema or infective granules in 224 HARVEY SOCIETY the coxal fluid enter the body of persons through the wound pro- duced by the bite of the tick. The infected eggs become infective after being incubated, as was demonstrated by Hindle by inject- ing the crushed material into the susceptible animals; Leish- man **°, 14° found numerous spiral rods in the infected tick eggs when the latter were incubated for a few days at 35° C. Schubert and Manteufel showed the infectivity of the ticks to be lost when they are kept at a temperature below 22° C., but Gonder failed to find any such difference. Marchoux and Convy, Gleitmann, Wolbach, Wittrock, Kleine and Eckard, and others, believe that wherever infectivity is present, there are always to be found some typical spironemata, either in the tick or in its eggs. Spironema berbera (the North African type) is carried by Pediculus corporis but not by Argas, the flea or bedbug *** **8 (Sergent, Gillot and Foley). S. carterz is also transmitted by body-lice. In this case Mackie **® found the organisms more numerous in the female lice than in the male; they are distributed in the mouth, stomach, and digestive tract. Mackie believes, how- ever, that Acanthia lectuaria sometimes carries the infection. Among the ticks which transmit spironema in cattle and sheep may be mentioned Boophilus decolaratus and Rhipicephalus evertst. The virus is carried by heredity. The causative agent of chicken fever, S. gallinarum, is carried by Argas persicus under natural conditions, while other species (Argas reflexus and Argas miniatus) can transmit the disease experimentally (Schellack).1°8 Ornithodorus moubata is doubtful, as Schel- lack 1** failed to produce the infection while Filleborn and Mayer *°° claim a success with this organism. Schellack was able to produce the infection in 3 out of the 15 experiments per- formed by him on chickens by the pereutaneous application of the infected blood. Feeding fowls with infected ticks may cause the infection. The organism is experimentally transmissible to ducks, geese, sparrows, canaries, and sometimes rabbits. S. icterohemorrhagia, the causative organism of Weil’s disease, has been shown by Inada and his associates to be but rarely conveyed by direct contact, but no natural intermediary hosts have been discovered. The organisms are abundantly pres- 7 "] SPIROCHATES 225 ent in the urine during the convalescent stage and they are fully virulent for guinea-pigs. According to the experiments of Inada and his associates, the Spironema as contained in the liver emul- sion is capable of penetrating an apparently uninjured skin of the guinea-pig a short time after contact (5 minutes is sufficient to cause infection).* Therefore it is altogether possible to infect a person through direct contact with some of the excreta of a patient. The infection can be induced in guinea-pigs by intro- ducing the infected material into the stomach after it has been previously neutralized with bicarbonate of soda. In regard to the Spironema found by Futaki and others at the site of or in glands adjacent to the rat-bite infection, we must assume that this represents the occurrence in rats of pathogenic Spironema which produces fever and other symptoms when transmitted to human subjects. Further investigation in this direction is most desirable. The organism is most easily experimentally trans- missible to guinea-pigs. Monkeys, rats, and mice are less susceptible. Prior to Futaki’s work there appeared a report by Kitagawa and Mukoyama, who also found a spironema in the inflamed tissue of the bitten finger of a woman. By transmitting the tissue into guinea-pigs and white rats, these authors claim to have repro- duced symptoms resembling the so-called rat-bite fever. In the smears of the kidney and liver taken from the dead animals, they found two types of spiral organisms, namely, in the guinea-pig tissues the refringens type and in the white rat the minute and short type. In examining the preparations kindly sent to me by the authors, I found their findings to be entirely correct, but the refringens type is more like 7’. macrodentium, and a large number of bacteria, such as fusiform bacilli and big rods, ete., were also present in the same preparations. As to the short type one can only say that its morphology is almost indistinguishable from that of S. muris or S.microgyratum. These organisms do not agree with the illustrations and description of the spironema reported some time later by Futaki and others. In the case of Kitagawa and * Of eight guinea-pigs experimented upon only one escaped the infection which developed in from ten to twelve days with typical symptoms. 15 226 HARVEY SOCIETY Mukoyama the local and general symptoms may have been due to a mixed infection by the oral flora of a rat. | Relapses of Infection.—The Spironema of relapsing and tick fevers also causes in man a well characterized type of fever accom- panied by two attacks interrupted by a period of apyrexia lasting several days. During the apyrexia the blood is free of the para- sites. But it is not at all rare for the recidive to be repeated more than once. While at the highest point of the fever the organisms are most abundant in the blood, they are also present in different organs. Dutton and Todd, Breinl, Leishman and Fantham believe that the spironemata are taken up by phagocytes within which they undergo transformation into the granular phase which in turn gives rise to the new generation of spironema. salfour considered the intraglobular forms of Spironema granu- losa penetrans (similar, probably identical, with S. gallinarum) as an asexual and the extracellular forms as a sexual phase. Fantham observed some extracellular granules which may start the relapse. Darling would hold the phagocytized spironemata within the endothelial cells of the liver responsible for the source of the recidive, as he found the organism to remain intact for some time during reconvalescence. Gabritschewsky sees in the surviving resistant specimens, which had been shielded from destruction in various organs, the progeny of the organisms pro- ducing the second attack. In the case of S. cartert, Mackie assumed the possible existence of an ultramicroseopie phase, as the serum taken from a patient at the apyrexic period is said to be infective in spite of the absence of any spiral forms. It may be remarked that to detect a sparse number of any Spironema under the microscope is one of the most difficult tasks, and one is very liable to overlook the organism. T. pallidum and T. pertenue are the only pathogenic varieties among the group. In the case of syphilis our knowledge is quite complete, so far as the mode of transmission is concerned. On the other hand, much still remains to be learned regarding the manner in which yaws is communicated from person to person. Probably, like syphilis, its infection is spread by direct contact with a patient or any object which, after having been in contact SPIROCHZTES 227 with a patient, harbors the live organisms; although the possibil- ity of transmission through flies, mosquitoes and ticks is not ex- eluded. Castellani and Chalmers *** quote an instance in which a fly which sucked on a yaws papule infected a monkey whose eye- brow was scarified. Modder *°? assumes transmission of yaws by ticks (Argas and Ixodes) in Ceylon. It is said that vaccination and wet nursing spread the infection. In order to facilitate their entrance into the human body both organisms need only a micro- scopical defect of the epidermis. After penetrating the skin or mucous membrane, 7’. pallidum elicits a local reaction characterized by the circumscribed round cell infiltration known as chancre (primary lesion), then several weeks later, at about the time when the chancre recedes, it pro- ceeds to enter the adjacent lymph-glands and general cutaneous and mucous membrane tissue, producing roseola, papules and flat econdyloma. At this period the organisms invade almost every tissue, producing the so-called secondary symptoms. Peri- ostitis, meningitis, iritis, laryngitis are very frequently observed. One of the most constant symptoms is the Wassermann reaction in the blood serum. After a period of several months longer, during which the secondary manifestations abate, another period known as the tertiary stage may supervene accompanied by still deeper tissue destruction caused in the organism than at any previous stages. It affects skin, bones, visceral organs, cardiovascular system and central nervous system. The disease may be progressive or marked with alternate activity and latency. Yet in the latent period repeated abortions may occur. From the time of infection until the central nervous system is affected (general paralysis, tabes), the average period of latency of the disease is from eight to twelve years. During the tertiary stage the lesions are often summatous and affect the connective tissue, muscles and blood- vessels, while in cases of general paralysis and tabes the parasites diffusely pervade the parenchyma.*®** 1°% 4°, 45° his form is a syphilitic parenchymatous encephalomyelitis. In acquired syphi- lis, T. pallidum has been demonstrated in every syphilitic con- dition. It was first demonstrated in the primary and secondary 228 HARVEY SOCIETY lesions by its discoverers, Schaudinn and Hoffmann; in liver gumma by Schaudinn; in aortitis by Wright and Richardson,** Schmorl,"** and Reuter ;*°* in arteriitis cerebralis by Bender ;*°° in heart muscles and pancreatitis by Warthin;** in adrenal glands by Hoffman,'*? Jacquet and Sezary ;** in nephritis by Hoff- mann ;'** in the cerebrospinal fluid by Hoffmann,'®* Nichols and Hough,*** and Suzary and Paillard;’** in the blood during the secondary stage by Uhlenhuth and Mulzer;'** in pareties by Graves,’*’ in interstitial keratitis by Igelsheim;*° in cerebral gumma by Dunlap;'! in the paretic brains by Noguchi and Moore,'** Marinesco, and Miner,'** Levaditi, Marie and Bankow- sky,'™* Mott, Rosanoff,’** Tomasezewski and Forster,*® Wile,**? and others; in spinal cord by Noguchi,'*® Versé,’™ ete. It should be mentioned that the first demonstration of T. pal- lidum in sections of tissue from acquired syphilis was accom- plished by Bertarelli and Volpino **° by means of their silver im- pregnation ; a method which has since been superseded by a sim- ilar procedure amended by Levaditi. In congenital syphilis the number of organisms present in the different organs and in different foetuses varies greatly. In some it may be extremely tedious to demonstrate the organisms, in others the whole foetus may be thickly interwoven with the inter- twining nets of treponemata. The favorite site of invasion is the liver and skin, although stomach, intestines, adrenals, kidney, spleen, heart muscles, pancreas, bone-marrow, lymph-glands, thy- mus, testes, ovaries, and brain have been shown to contain the parasites, even in large numbers in certain instances.*** The pla- centa and navel cord are also affected. For the first demonstra- tion of the organisms in congenital lues, we are indebted to Levaditi,'*? who introduced his well-known silver impregnation method for this study. According to personal experiences in connection with syphilitic infants who lived several days after birth, the number of pallida present was always very small and it sometimes required many hours’ search to find a single specimen. manner. This also points to the absence in such cases of any lasting immunity after the first infection has been eradi- cated. A thorough investigation is required in order to ascer- tain whether or not a certain degree of immunity develops in some of the cured cases, thereby affording protection. In some ways the question of immunity in syphilis is comparable to that in protozoan diseases, in which, though latent, no typical infection can be reinduced until the first attack is completely cured, and where no congenital immunity has yet been demonstrated. Let me now review the situation of the immunity question in experimental syphilis. Metschnikoff and Roux, Neisser and Bruck, and others found that monkeys which have once been infected with Treponema pallidum may prove refractory to subse- quent inoculation. Metschnikoff *°° thought he sueceeded in pro- tecting a monkey against the infection by inoculating it with an attenuated living virus which was no longer able itself to produce typical reactions. That the vaccination against syphilis was not equivalent to that against variola in its fundamental principle was later demonstrated by Neisser and others, who were able to show that the monkeys which had been ‘‘ vaccinated ’’ with an attenuated virus and which were rendered ‘‘immune’’ to the subsequent inoculation with a fully virulent material were harbor- ing the infection in various localities escaping the usual clinical EEE —————— EE cS & — SPIROCHATES 249 detections. Thus the emulsions, prepared from the bone marrow, spleen, etc., of the ‘‘ vaccinated ’’ animals were able to infect new susceptible animals. This phenomenon is similar to the state of anergy observed in syphilitic human subjects. Fontana,?°* Uhlen- huth and Weidanz,?** Bertarelli,?*’ Truffi 2* 7° and others pointed out that a rabbit which carries syphilitic keratitis in one eye is not refractory or immune to the infection in the other eye. A rabbit, one of whose testicles is infected with T. pallidum, offers no greater resistance in the other, which may be infected with the virus at any stage of orchitis preceding that on the opposite side. Tomasezewski 7°? thought that a skin infection produced in rab- bits in which scrotal lesions had been persisting for about two months was much milder than in normal animals. According to personal observations a rabbit in which a syphilitic orchitis, or keratitis, or scrotal chancre has been cured either spontaneously or through the administration of salvarsan, enjoys no perceptible immunity to syphilis. Truffi repeatedly inoculated rabbits with a fetal liver emulsion containing an abundance of T. pallidum, but found no immunity to develop. Uhlenhuth and Mulzer **® im- munized rabbits with the testicular pallidum emulsion without obtaining any decisive result, although in some cases they thought it exerted a beneficial influence upon the syphilitic process. In my personal experience it has been found that the susceptibility of the rabbit to syphilis is decidedly diminished in some animals by immunizing them with T. pallidum for several months. With a strain which gave 100 per cent. takes in normal rabbits’ testicles only about 60 per cent. positive results were obtained in the im- munized animals. This tends to show that the lower percentage of positive takes in the immunized rabbits may be due to the destrue- tive influence of the treatment upon the invading pallida. But it was also found that in the immunized rabbits in which the inocu- lation succeeded the symptoms were not any milder. In fact, not only were the local reactions just as marked as in the control ani- mals, but there was a tendency to the formation of generalized lesions. In two of the rabbits scrotal lesions developed after the intravenous inoculation of a virulent strain. It appears that an incomplete immunization exerts an adverse influence on the de- 250 HARVEY SOCIETY fensive factors of the rabbit. This phenomenon finds verification in the work of Grouven and Sowade *°* *°* who recommended for the animal a few preliminary intravenous inoculations of the pal- lidum in order to insure a generalized infection through a subse- quent intracardial introduction of the organisms in huge quantity. I also endeavored to ascertain whether a local administration of devitalized pallida (killed at 60° C.) on many successive occasions will not bring about a state of local immunity to Treponema pallidum, but my results were rather unsatisfactory, for the reason that the testicular parenchyma which was repeatedly inoculated with the pallidum emulsion underwent gradual atrophy and the resulting hard fibrous structure was no longer a suitable test-object for this fastidious parasite. Nevertheless I was able to produce small nodular lesions in two out of several rabbits so treated. Moreover, reinfection of the same tissues (cornea, testis, skin) after a spontaneous or chemotherapeutic healing has been found possible as long as the suitable structures of the tissues are preserved. Our knowledge pertaining to the immunity phenomena in vitro is of more recent date, for the test-tube experiments with T. pallidum were made possible since the discovery of the organ- ism and were particularly facilitated by the successful cultivation of the parasites on artificial media. Attempts to demonstrate the presence of a specific agglutinin for T. pallidum in the sera of human and experimental syphilis were made by Hoffmann and Prowazek,”?* Herxheimer and Loser,”°* Hoffmann?** Brénnum and Ellerman,?** Babes and Pinea,?*® Metschnikoff and Roux, Land- steiner and Mucha,?"° Zobolotny and Maslakowetz,*™* and others, with the pallida derived from the syphilitic tissues. Their experi- ments were indecisive, owing to the difficulty found in obtaining a pure material free from various tissue constituents. Uhlenhuth and Mulzer '*® found no agglutinins in the sera of the rabbit, goat and monkey after repeated intravenous injections of the rabbit’s testicular emulsion rich in the pallidum. In 1910-1911, soon after obtaining pure cultures of T. pallidum, we started the immunization of rabbits with different strains of the organ- ism. In the sera obtained from the immunized rabbits we were SPIROCHZTES 251 able to demonstrate the presence of the specific agglutinins and complement binding principles for the cultivated pallidum strains. We were unable to produce with the sera any unmistakable agglu- tination of the pallidum derived directly from the syphilitic or- chitis of the rabbit, but considered this to be due to the simultane- ous presence of tissue debris and other cellular elements which may have interfered with the agglutination phenomenon. These sera were not strictly specific, but contained a small quantity of agglutinins for other treponemata obtained in pure cultures. There were also a sufficient number of specific complement- binding bodies, but there was at the same time a more or less definite group reaction for other treponemata. The work was continued later (1915-1916) by Akatsu at my laboratory with similar results. He was able to obtain a serum which could agglu- tinate the pallida in a dilution of 1 : 50,000. In order to know whether syphilitic human sera have any definite agglutinating and complement-binding properties, a number of sera obtained from the various stages of syphilis were examined with pure cultures as well as with the tissue pallidum derived from rabbits’ testicles. All experiments were unsatisfactory owing to the difficulty experienced in reading the reaction in the case of agglutination and also owing to the high anti-complementary powers of the antigens and the feebleness of the reaction in the case of the complement fixation test, except in the case of the pure culture antigens which fixed complement with the immune rabbits’ as well as with some of the syphilitic human sera (chiefly late and tertiary cases). According to our experi- ments there is a certain degree of group reaction or the other treponemata (T. calligyrum, T. microdentium, Tl’. mucosum, and S. refringens). Kolmer 2”? first described the agglutination of a pure culture of Treponema pallidum by the sera of rabbits injected with a living and heat-killed culture furnished by our laboratory. His results show that normal rabbit sera do not agglutinate the culture palli- dum in dilutions as low as 1: 20, while the sera of immunized ani- mals produced agglutination in dilutions as high as 1: 1280. No definite agglutination was observed with human syphilitic sera in 252 HARVEY SOCIETY a dilution of 1:20 or higher. Nakano *** also reported the pres- ence of agglutinins in the sera of rabbits injected intravenously with a pure culture in dilutions from 1:10 to 1:70. Kissmeyer** immunized rabbits with a pure culture of T. pallidum and was able to obtain agglutinins in dilutions as high as 1: 200,000 to 1: 500,000 of the immune sera, while the sera from individuals with primary, secondary, tertiary and congenital syphilis con- tained agglutinins for the pallidum in dilutions of 1:100 and higher in a percentage of 40 to 60 out of 59 cases. Normal human sera may agglutinate the pallidum on dilutions as high as 1:50. Zinsser and Hopkins ** state that normal rabbit serum may agglutinate the pallidum in dilutions lower than 1: 10, but the sera of their immunized rabbits (intravenous injections of the pallidum cultures) agglutinated it in dilutions as high as 1:2000. They added that the normal as well as certain syphilitic human sera may agglutinate the culture pallidum in emulsions. Zinsser, Hopkins and McBurney **° failed to observe any aggluti- nation when the pallida from human lesions were mixed with the immune sera (rabbits and sheep) produced with the culture pallida. Zinsser and Hopkins demonstrated the treponemicidal bodies for T. pallidum (cultivated) in the immune serum pro- duced by them.**? In the sera of animals experimentally infected with syphilis the presence of specific complement-binding antibodies for T. pallidum has not been satisfactory proved. It is true that we were able to demonstrate the positive complement fixation in the sera of animals immunized with cultivated treponemata, but this does not hold good when dealing with the syphilitic animal sera and the virulent pallidum strains found in tissues. On the other hand, these syphilitic sera do bind complement when mixed with pure cultures, not only of T. pallidum, but also of various bacteria, such as colon bacilli (Zinsser and Hopkins). Undoubt- edly the phenomenon is non-specific but pathognomonic, as is the Wassermann reaction which is caused by certain lipoidal sub- stances. These cultures must serve as the containers of the similar lipoids. Indeed, Craig and Nichols *** long ago showed that the alcoholic extracts of the pure pallidum and pertenue cultures SPIROCHATES 253 produced almost equally strong complement fixation when mixed with the human syphilitic sera giving a positive Wassermann reaction with pure lipoidal antigens derived from other tissues. In a word, a syphilitic animal may give a positive complement fixation with various lipoids without at the same time containing any specific antibody for T. pallidum. In human syphilitic sera the same is also true, except in the sera of certain late and tertiary cases in which there may be a positive reaction due to the specific antigens and antibodies in the strict sense of Bordet- Gengou’s phenomenon.?”® The nature of the Wassermann reaction in the sera of human experimental syphilitic subjects is still unexplained, but one fact has been established viz., that it is due to a peculiar change of the sera not specific for syphilis; it occurs in yaws, leprosy, trypanosomiasis, malaria (febrile period), and sometimes in malignant tumors. The fact that so many lipoidal substances as well as certain salts (sodium taurocholate, sodium cholate, ete.,) derived from different sources can bring about a positive fixation precludes any strict specific antigen-antibody reaction. Accord- ing to personal observations, the lipotropic complement-fixation reaction is not present in immune rabbit sera which have been obtained by injecting the pallida repeatedly, and which contain a large number of specific complement fixation bodies from the pallidum strains employed for their production. Closely related to immunity is the question of allergy in syphilis. From the chronic nature of the disease many investi- gators considered the possibility of its occurence at one stage or another. Jadassohn, Meierowsky, Ciuffo, Fontana, Neisser, Bruck and others made numerous observations which rendered the presence of allergy still more probable. These investigators were handicapped by not having a pure culture of T. pallidum. Soon after the isolation of the pallidum strains Professor Welch sug- gested that I undertake a study of this subject in human syphilis with the pure material. In the meanwhile it was ascertained experimentally that the prolonged treatment of rabbits with intravenous injections of the pure pallidum culture as well as with the organisms obtained direct from the rabbit’s orchitis 254 HARVEY SOCIETY lead to the production of a state of hypersensitiveness of the skin to the inoculation of the extract of a pure, heat-killed pallidum culture.**° The reaction was found to be apparently specific for T. pallidum. There was no injurious effect following the injection into the rabbits of the heat-killed pallidum emulsion. The emulsion, since known as luetin, was employed as a means of diagnosing human syphilitic cases, with the result that the luetin reaction was found to be most frequently present in the latent tertiary and congenital syphilis cases where one would naturally expect most constantly to find the allergetie or hypersensitive state of the skin. As an auxiliary or supplementary factor in pro- ducing a positive luetin reaction I have already pointed out that the pathological state of the skin of chronic syphilitic patients designated by Neisser as ‘‘Umstimmung’’ a réle in nearly 10 per cent. of tertiary cases in which the skin reacted intensively to the inoculation of the control emulsion without the pallida. No efforts were made to explain this peculiarity of hypersensitive- ness of the skin of certain syphilitics. But a recent work of Camp ** points out that the administration for many days of potassium iodide to a non-syphilitie individual produces in the skin a hypersensitiveness to any trauma, including the inoculation of the leutin. Probably this finding may furnish the solution of the problem of Neisser’s ‘‘ Umstimmung,’’ or at least of one of the contributing factors. The clinical evidences thus far accumu- lated seem to show, however, that in a large number of cases the luetin reaction was positive in spite the fact that no iodide had been given during the period when the test was applied. Recently Akatsu **? at my laboratory carried out several series of experi- ments regarding the influence of potassium iodide upon the reac- tivity of the skin of rabbits to the intradermal inoculation of the luetin, control fluid and plain bouillon. The iodide was admin- istered intravenously for a period of from 7 to 9 days, given in increasing doses of 0.5 to 2 ¢.c. of a 10 per cent. aqueous solution. At the end of seven days or later the skin was tested for the luetin, control and plain bouillon. It was found that the skin of normal rabbits did not react to the injections after the iodide treatment. There was no change in its reaction to the trauma. The skin of ee ee ae ee SPIROCHZTES 255 the rabbits which had been previously rendered hypersensitive to the luetin by means of prolonged immunization with pure palli- dum cultures mostly remained the same, that is, it reacted to the luetin with the same intensity as it did before the administration of potassium iodide. Only in a few instances was the reaction somewhat intensified. There was no definite reaction to the control emulsion of plain bouillon. In some rabbits in which the testicular orchitis after several months had shrunk to a small fibrous nodule the luetin reaction was mildly positive, but the intensity of the re- action was but little influenced after the injection of potassium iodide, except in a few rabbits where the second tests came out more distinctly. The above findings show that the potassium iodide has no noticeable influence upon the reactivity of the skin of normal as well as of syphilitic rabbits. It would be interesting to study whether in other spironematoses (relapsing fever, tick fever, rat-bite disease, infectious jaundice) there appears any skin allergy comparable to that described for other bacterial infections (typhoid, gonorrheea, etc.). In cases of yaws the skin reacts to the intradermal inoculations of the luetin and of the frambesin with equal intensity and cannot be differentiated by this method (Baermann and Heinemann) °*** The last and probably the most important field is chemo- therapy. The inauguration of modern chemotherapy by Ehrlich is as interesting as it is romantic. It can be traced back to Schaudinn’s suggestive but unsupported theory that the spiro- chxtes represent a stage of the life-cycle of trypanosomes, or at least were closely related to the latter. The introduction of or- ganic compounds of arsenic into the treatment of trypanosomiasis was promising much when Schaudinn discovered T. pallidum which he regarded as a protozoa allied to the trypanosomes. Ehrlich took up experimental chemotherapy in connection not only with the latter, but also with the newly discovered spirilloses, as he called them, including syphilis and the fowl fever caused by 8. gallinarum. The achievements of Ehrlich and his collaborator Hata, in discovering salvarsan for the treatment of these two diseases, mark a new era in modern chemotherapy. To review this phase of the spirochete problem would be out of the scope of 256 HARVEY SOCIETY my present paper. Suffice it to say that to the great pioneers, Schaudinn and Ehrlich, Metschnikoff and Neisser, we owe an inestimable debt, not merely for their own researches, but also for rekindling in us the sublime stimuli which have already inspired so many investigators to discover new facts, and which will con- tinue to urge us still more to take up this task and to extend our knowledge regarding the classification, morphology, biology, pathogenesis, and experimental as well as clinical aspects of the micro-organisms known as spirochetes. LITERATURE 4 1Ehrenberg, Ch. Die Infusionstierchen als vollkommene Organismen. Leipzig, 1838. 2 Schaudinn, F. Generations—und Wirtswechsel bei Trypanosomen und Spirocheten. Arb. a. d. k. Gsndhtsamte, 1904, xx, 387. * Sergent, Ed., and Sergent, Et. Les hématozoaires d’oiseaux. Ann. de V’Inst. Pasteur, 1907, xxi, 251. *Mayer, M. Kin Halteridium und Leukocytozoon des Wildkauzes. Arch, f. Protistenk., 1911, xxi, 232. ; 5 Mathis, C., and Leger, N. 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Bakteriol., 1909, — Orig., xlix, 529. %™Sambon. Manson’s tropical diseases. Wood, N. Y., Ed. 4, 1907, 833. “Schilling. Die neueren Forschritte auf dem Gebeite der pathogenen Protozoen. Centralbl. f. Bakteriol., 1908, Abt. I. Ref. Beil., xlii, 80. ® Klebs, G. Flagellatenstudien. Ztschr. wissensch. Zool., 1892, lv, 265. Se SPIROCHATES 257 Gross, J. Cristispira nov. gen., ein Beitrag zur Spirochetenfrage. Mitt. a. d. zool. Station zu Neapel, 1910, xx, 1. “Perrin, A. Researches on the life history of Trypanosoma balbianii (Certes). Arch. f. Protistenk., 1906, vii, 131. 8 Novy, G., and Knapp, R. E. Studies in Spirillum Obermeieri and related organisms. Jour. Infect. Dis., 1906, iii, 291. ” Schellack, C. Studien zur Morphologie und Systematik der Spirocheten aus Muscheln. Arb. a. d. k. Gsndhtsamte., 1909, xxx, 379. * Gross, J. Ueber Systematik, Struktur und Fortpflanzung der Spirone- macea. Centralbl. f. Bakteriol. Abt. I, 1912, lxv, 83. Gross, J. Zur Nomenklatur der Spirocheta pallida Schaudinn und Hoffmann. Arch. f. Protistenk., 1911, xxiv, 109. * Zuelzer, M. Ueber Spirocheta plicatilis Ehrenberg und deren Verwandt- schaftsbeziehungen. Arch. f. Protistenk., 1911, xxiv, 1. ** Gonder, R. Die Stellung der Spirocheten unter den Protisten. Centralbl. f. Bakteriol., 1909, xlix, 190. * Dobell, C. C. On Cristispira veneris nov. spec. and the affinities and classification of spirochetes. Quart. Jour. Micr. Se., 1910-1911, lvi, 507. * Dobell, C. C. On the systematic position of the Spirochetes. Proc. Roy. Soc., 1912, Ixxxv, 186. 27 Dobell, C. C. Researches on the Spiroghetes and related organisms. Arch. f. Protistenk., 1912, xxvi, 117. * Hoelling, A. Spirillum giganteum und Spirocheta balbianii. Centralbl. f. Bakteriol., Orig., 1907, xliv, 665. * Hoelling, A. Vergleichende Untersuchungen tiber Spirocheten und Spi- rillen. Arch. f. Protistenk., 1911, xxiii, 101. *Fantham, H. B. Spirocheta balbianii (Certes) and Spirocheta anodonta (Keysselitz), their structure, movements and affinities. Quart. Jour. Mier. Se., 1908, lii, 1. *® Fantham, H. B. Some researches on the life-cycle of Spirochetes. Ann. trop. Med. and Parasit., 1911, v, 479. 1 Swellengrebel, N. H. Sur la cytologie comparée des spiroghétes et des spirilles. Ann. de l’Inst. Pasteur, 1907, xxi, 448, and Compt. rend. Soc. de biol., 1907, lxii, 213. * Bosanquet, W. C. Note on the structure and development of Spirocheta anodonte Keysselitz. Quart. Jour. Micr. Se., 1911, lvi, 387. * Bosanquet, W. C. Spirochetes. W. B. Saunders & Co., Philadelphia and London, 1911. * Doflein, F. Lehrbuch der Protozoenkunde, Jena, 1912. * Fantham, H. B., and Porter, A. The modes of division of Spirocheta re- currentis and Spirocheta duttoni as observed in the living organisms. Proc. Roy. Soc. Biol., 1909, lxxxi, 500. “Schaudinn, F. Zur Kenntnis der Spirocheta pallida und andere Spiro- cheten. Nachlass. Arb. a. d. k. Gsndhtsamte., 1907, xxvi, 11. 17 258 HARVEY SOCIETY *Borrel, A. Cils et division transversale chez le spirille de la poule. Compt. rend. Soe. de biol., 1906, Ix, 138. % Zettnow, E. Geisseln bei Hiihner—und Recurrensspirochiiten. Deutsch. med. Wehnschr., xxxii, 376. *® Hoffmann, E., and Prowazek. S. v.,—Balanitis, und Mundspirochiiten, Centralbl. f. Bakteriol., 1906, xli, 741. ” Prowazek, 8S. v. Vergleichende Spirochiitenuntersuchungen, Arb. a. d. k. Gsndhtsamte., 1907, xxxvi, 22. “ Landsteiner, K., and Mucha, V. Zur Technik der Spirochiitenunter- suchung. Wien klin. Wehnschr., 1906, xlv, 1349. “ Biitchli, O. Ueber den Bau der Bakterien und verwante Organismen. Leipzig, 1890. * Biitchli, O. Bemerkungen iiber Cyanophyceen und Bacteriaceen. Arch. f. Protistenk., 1912, i, 41. “Gross, J. Sporenbildung bei Cristispira. Arch. f. Protistenk., 1913, xxix, 279. *Gonder, R. Spironemacea (Spirochiiten). | Prowazek’s Handbuch der pathogenen Protozoen, 1914, 671. * Cantacuzéne. 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Spirocheta (treponema) pallida and syphilis. Journ, Exp. Med., 1907, ix, 464. Gonder, R. Studien iiber die Spirochiite aus dem Blute von Vesperugo Kuhlii. Arb. a. d. k. Gsndhtsamte., 1908, xxvii, 406. * Noguchi, H. A method for pure cultivation of pathogenic Treponema pallidum. Jour. Exper. Med., 1911, xiv, 99. *s Prowazek, 8. v. Morphologische und entwicklungsgeschichtliche Studien iiber Hiihnerspirochiiten. Arb. a. d. k. Gsndhtsamte., 1906, xxiii, 554. SPIROCHZETES 259 ° Prinkel, C. Geisselfiiden an den Spirillen des Rekurrens und Zecken- fiebers. Centralbl. f. Bakteriol., 1908, xlvii, 349, 471. ® Szécsi, St. Lucidol, ein neues Fixiermittel. Deutsch. med. Wehnschr., 1913, xxxiii, 1584. _ Galli-Valerio, B. Note de la Méthode de Casares-Gil pour la coloration . des cils des bactéries. Centralbl. f. Bakteriol., Abt. I, 1915, Ixxvi, 233. *% Nakano, H. Ueber die Reinziichtung der Spirocheta pallida. Deutsch med. Wehnschr., 1912, xxxix, 1332. % Krysztalowicz, F., and Siedlecki, M. 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Liverpool School of Tropical Medicine, Memoirs, xvii, 1905. 4 Koch, R. Vorlaiifige Mitteilungeniiber die Ergbnisse einer Forschungs- reise nach ost-Africa. Deutsch. med. Wehnschr., 1905, xxvi, 1865, and Uber afrikanischen Recurrens. Berl. klin. Wehnschr., 1906, xlvii, 185. 4 Carter, R. M. The presence of Spirocheta duttoni in the ova of Ornitho- dorus moubata. Ann. Trop. Med., 1907, i, 155. 11 Wolbach, S. B. On the filterability and biology of Spirocheta. Amer. Jour. Trop. Dis. and prev. Med., 1915, ii, 494. 12 Wittrock, O. Beitrag zur Biologie der Spirochete des Riickfallfiebers. Ztschr. f. Hyg. u. Infectionskrankh., 1913, Ixxiv, 55. 43 Wellman, F. C. Relapsing fever; its occurrence in the tropics and its relation to tick fever. Am. Med., 1905, x, 151. ™Breinl, A. On the Specific Nature of the Spirocheta of the African Tick-fever. Lancet, 1906, i, 1690. © Leishman, W. B. Preliminary note on experiments in connection with the transmission of tick fever. Jour. Roy. Army Med. Corps, 1909, ota 2S. “6 Leishman, W. B. Relapsing fevers. Internat. Congr. of Med., London, 1913, xxi, 282. “7 Sergent, E., Gillot, V., and Foley, H. Typhus Récurrent Algerien, Sa Transmission par les Poux. Compt. rend. Soc. de Biol., 1911, Ixx, 1039. 48 Sergent, E., and Foley, H. De la période de latence du Spirille chez le Pou infecté de fiévre recurrente. Compt. rend. Acad. Sc., 1914, clix, 119. 1 Mackie, F. P. A Preliminary Note on Bombay Spirilla Fever. Lancet, 1907, ii, 832, and Part Played by Pediculus Corporis in the Trans- mission of Relapsing Fever. Brit. Med. Jour., 1907, ii, 1706. 264 HARVEY SOCIETY Fiilleborn, F., and Mayer, M. Uebertragung der Spirocheta Obermeieri auf Miiuse. Med. Klin., 1907, iii, 487. 1 Castellani, A. Experimental Investigations on Frambesia tropica (yaws). Jour. Hyg., 1907, vii, 558. #2 Modder, E. E. Transmission of yaws by ticks. Jour. of Trop. Med., 1907, LON. *% Noguchi, H. Découverte du tréponéme pile dans les cerveaux des paralytiques généraux. Compt. rend. Soc. de biol., 1913, lxxiv, 349. *#* Nonne, M. Der heutige Standpunkt der Lues Paralysefrage. 1913, xlix, 38. | *° Mott, F. W. An address on the degeneration of the neurone in the light ~ of recent research, especially in relation to syphilis and general paralysis. Lancet, 1913, ii, 1367. * Mott, F. W. The Diagnosis and Treatment of Parenchymatous syphilis. Jour. of Ment. Sc., April, 1915, 175. ** Wright, J. H., and Richardson, O. Treponemata (Spirocheta) in syphili- tic aortitis. Publ. of the Mass. Gen. Hosp., 1908-09, ii, 395. *$Schmorl, G. Die Firbung der Spirochete pallida im Schnittpriiparat nach Giemsa. Deutsch. med. Wehnschr., 1907, xxxiii, 876. *” Reuter. Neue Befunde von Spirochete pallida (Schaudinn) in men- schlichen Kérper und ihre Bedeutung fiir die Atiolgie der Syphilis. Ztschr. f. Hyg., 1906, liv. *” Bender, K. Spirochiitenbefund bei tertiiirer syphilis. Deutsch. med. Wehnscehr., 1906, xxxii, 1318. * Warthin, A. S. The presence of active lesions and spirochetes in the tissues of clinically inactive or “ cured” syphilis. Jr. Assn. Am. Physi- cians, 1914, xxix, 416-429. * Hoffmann, E. Nachtrag zu der Arbeit von Schaudinn und Hoffmann iiber Spirocheta pallida bei Syphilis. Berl. klin. Wehnschr., 1905, xxiii, 726. *% Jacquet, L., and Sezary. Sur vénalité Syphilitique de Adulte. Presence de Tréponéme pale. Bull. de la Soc., med. des hopitaux, 1906, xxiii, 314. Des Formes atypiques et dégéneratives du Tréponéme pale, ibid., 1907, xxiv, 114. * Hoffmann, E. Ueber das Vorkommen von Spirocheten bei ulzerirten Karzinomen. Berl. klin. Wehnschr., 1905, xxviii, 811. 5 Hoffmann, E. Weitere Mitteilungen iiber das Vorkommen yon Sp. pallida bei Syphilis. Berl. klin. Wehnschr., 1905, xxxii, 1022. *® Nichols, H. J., and Hough, W. H. Demonstration of Sp. pallida in the © cerebrospinal fluid from a patient with nervous relapse following upon the use of salvarsan. Jour. Am. Med. Assn., 1913, Lx, 108. “ Sezary, A., and Paillard, H. Treponeme dans le liquide cephalorachidien au course de l’hemiplegie syphilitique. Compt. rend. Soe. de biol., 1910, xviii, 295. SPIROCHZTES 265 *8UJhlenhuth, P., and Mulzer, P. Beitriige zur experimentellen Patho- logie und Therapie der Syphilis mit besonderer Beriicksichtigung der Impf. Syphilis der Kanichen: Arb. a. d. k. Gsndhtsmte, 1913. xliv, 307. 19 Graves, W. W. Can rabbits be infected with syphilis directly from the bloods of general paretics? Jour. Am. Med. Assn., 1913, lxi, 1504. 1Toersheimer, J. Experimentelle Untersuchungen zur Syphilis des Auges. Miinch. med. Wehnschr., 1912, lix, II, 2089. ™ Dunlap, C. B. Personal communication. "3 Noguchi, H., and Moore, J. W. A demonstration of T. pallidum in the brain in cases of general paralysis. Jour. Exper. Med., 1913, xvii, 232. “8 Marinesco, G., and Minea. Relation entre les Treponema pallidum et les lésions de la paralysie générale. Compt. rend. Soc. de biol., 1913, Ixxv, 231. 14 Teyaditi, C., Marie, A., and Bankowsky. Le tréponéme dans le cer- veau des paralytiques généraux. Ann. de l’Inst. Pasteur, 1913, XXVii, 577. ™™ Rosanoff. Personal communication. “6 Tomasczewski, E., and Forster, E. Nachweis von lebenden Spirochiten im Gehirn von Paralytikern. Deutsch. med. Wehnschr., 1913, xxxix, 1237. ™7 Wile, U. J. Exper. syphilis in the rabbit produced by the brain substance of the living paretic. Jour. Exper. Med., 1916, xxiii, 199. “8 Noguchi, H. Hautallergie bei Syphilis. Miinch. med. Wéehnschr., 1911, lvii, 2372. 9 Versé, M. Ueber Vorkommen der Spirocheta pallida bei friih- und spiitsyphilitischen Erkrankungen des Centralnervensystems. Miinch. med. Wehnschr., 1913, Ix, 2446. ™ Bertarelli, E., and Volpino, G. Spirocheta pallida in den Schnitten primirer, sekundiirer und tertiiirer Syphilis. Centralbl. f. Bakteriol. 1906, xli, 74. ™ Ranke, O. Gehirnveriinderungen bei der angeborenen Syphilis. Ztschr. f. Erf. u. Beh. d. jungendl. Schwachsinns, 1908, ii, 32. ™ Levaditi, C. Le cil du Treponema pallidum. Compt. rend. Soc. de biol., 1911, lxxi, 156. * Metschnikoff, E., and Roux, E. Etudes expérimentales sur la Syphilis. Ann. de l’Inst. Pasteur, 1903, xvii, 809; 1904, xviii, 1 and 657; 1905, xix, 673; 1906, xx, 785. ™ Schultze, W. Impfung mit Luesmaterial an Kaninchenaugen. Klin. Monatsbl. f. Augenh., 1905, xliii, 253, and Impfungen mit Cytorhyctes luis an kaninchenaugen. Med. Klin., 1905, I, 466. ™ Bertarelli, E. Ueber die Transmission der Syphilis auf das Kaninchen. Centralbl. f. Bakteriol., I. 1906, xli, 321. 266 HARVEY SOCIETY *6 Parodi, U. Ueber die Uebertragung der Syphilis auf den Hoden des Kaninschens. Centralbl. f. Bakteriol., 1907, xliv, 428. *7 Neisser, A. Erforschung der Syphilis. Arb. a. d. k, Gsndhtsamte., 1911, XXXVii. #8 Hoffmann, E., Loehe, H., and Mulzer, P. Syphilitischer Initialaffekt der Bauchhaut an der Einstichstelle nach Impfung in die Hoden von Affen und Kaninchen. Deutsch. med. Wehnschr., 1908, xxvii, 1183. *° Uhlenhuth, P., and Mulzer, P. Ueber experimentelle Kaninchensyphilis mit besonderer Beriicksichtigung der Impfsyphilis des Hodens. Arb. a. d. k. Gsndhtsamte., 1909, xxxiii, 183. ™ Grouven, C. Ueber positive Syphilisimpfung am Kaninchenauge. Med. Klin., 1907, xxvi, 774. *!Grouven, C. Zur sekundiirsyphilis niederer Affen und des Kaninchens. Miinch. med. Wehnschr., 1911, xvii, 909. ™Grouven, C. Ueber bemerkenswerte Resultate der Syphilis Impfung beim Kaninchen. Med. Klin., 1908, iv, 267. * Nichols, H. J. Further Observations on certain features of experimental syphilis and yaws in rabbits. Journ. Exp. Med., 1911, xiv, 196. 4 Tomasezewski, E. Ueber eine einfache Methode bei Kaninchen Primiir- affekte zu erzeugen. Deutsch. med. Wehnschr., 1910, xxii, 1025. *° Tomasczewski, E. Ueber die Ergebnisse der Superinfektion bei der Syph- ilis der Kaninchen. Berl. klin. Wehnschr., 1910, xlvii, 1447. “ Tomasczewski, E. Ueber Kaninchen- und Meerschweinchensyphilis. — Dermat. Ztschr., 1911, xviii, 1. FI * Tomasczewski, E. Impfungen an Affen mit maligner Syphilis. Berl. klin. Wehnsehr., 1911, xx, 890. ** Brown, W. H., and Pearce, L. Personal communication. * Nichols, H. J. Observations on a Strain of Spirocheta pallida Isolated from the Nervous System. Jour. Exp. Med., 1914, xix, 362. > | 7 Reasoner, M. A. Early death from cerebral syphilis with successful rab- : bit inoculation. Jour. Am. Med. Assn., 1916, Ixvi, 1917. . « * Noguchi, H. Morphological and pathogenic variations in Treponema pal- lidum. Jour. Exper. Med., 1912, xv, 201. 2022 Tomasczewski, E., and Forster. Personal communication in 1913 after publishing their work referred to under 176. } 8 Wile, U. J. Cultural experiments with the Spirocheta pallida derived — from the paretiec brain. Jour. Am. Med. Assn., 1916, Ixvi, 646. 74 Neisser, A., Baermann, G., and Halberstiidter, L. Experimentelle ver suche iiber Framboesia tropica an Affen. Miinch. med. Wehnschr., — 1906, liii, 1337. i * Castellani, A. Experimental investigations on framboesia tropica ‘ (yaws). Jour. Hyg., 1907, vii, 558. * Nichols, H. J. Experimental yaws in the monkey and rabbit. Jour. Kxper. Med., 1910, xii, 616, a SPIROCHATES 267 2" Halberstiidter, L. Weitere Untersuchungen iiber Framboesia tropica an Affen. Arb. a. d. k. Gsndhtsamte., 1907, xxvi, 47. *S Todd. J. L., and Wolbach, 8. B. Concerning the filterability of Spirochxta duttoni. Jour. Med. Res., 1914, xxv, 27. Huebener and Reiter. Beitriige zur A‘tiologie der Weil’schen Krankheit. Deutsch. med. Webhnschr., 1915, xli, 1275. *® Klingmiiller and Baermann, “Ist das Syphilisvirus filtrierbar? ” Deutsch. med. Wehnschr., 1904, xxx, 766. *1 Casagrandi, O., and de Luca, R. Se nei filtrati di manifestazioni sifilitiche ottenuti attraverso candele Berkefeld, etc. Ann. d’igiene sperim., 1906, Xvi, 23. 2 Nakano, H. Ueber die Reinziichtung der Spirocheta pallida. Deutsch. med. Wehnschr., 1912, xxxix, 1333. 43 Wolbach, S. B., and Binger, C. A. L. The cultivation of a free living filterable Spirocheta (Spirocheta elusa, n. sp.). Jour. Med. Res., 1914, pomx.,| 9. *4 Wolbach, 8. B., and Binger, C. A. L. Notes on a filterable spirocheta from fresh water Spirocheta biflexa. Jour. Med. Res., 1914, xxv, 23. * Norris, C., Pappenheimer, A. M., and Flournoy, T. Spirochete from a case of relapsing fever. Jour. Inf. Dis., 1906, iii, 266. *6 Noguchi, H. The pure cultivation of Spirocheta duttoni, ete. Jour. Exper. Med., 1912, xvi, 109. *" Noguchi, H. Cultivation of spirocheta gallinarum. Jour. Exper. Med., 1912, xvi, 620. *8 Plotz, H. Personal communication. *” Hata, 8. A contribution to our knowledge of the cultivation of Spiro- echeta recurrens. Centralbl. f. Bakteriol., 1913, lxxii, 107. *Tunnicliff, R. The identity of fusiform bacilli and spirilla. Jour. Infect. Dis., 1906, iii, 148. *“ Ito, T., and Matsuzakitt, H. The pure cultivation of Spirocheta ictero- hemorrhagie. Jour. Exper. Med., 1916, xxiii, 557. io Volpino, G., and Fontana, A. Einige Voruntersuchungen iiber kiinstliche Kultivierung der Spirochete pallida. Centralbl. f. Bakteriol. Abt. 1., 1906, xlii, 666. * Lebailly, C. Multiplication in vitro du Treponema pallidum. Compt. rend. de l’Acad. de Sc., 1908, exlvi, 312. ** Levaditi, C., and McIntosh, J., Contribution 4 Vétude de la culture de Treponema pallidum. Ann. de l’Inst. Pasteur, 1907, xxi, 784. ™ Miihlens, P., and Loehe. Ueber Ziichtungsversuche der Spirocheta pal- lida. Centralbl. f. Bakteriol., Abt I, 1908, xlvii, 487. *6Schereschewsky, J. Ziichtung der Spirocheta pallida. Deutsch. med. Wehnscehr., 1909, xxxv, 835. *! Schereschewsky, J. Weitere Mitteilungen iiber die Ziichtung der Spiro- cheta pallida. Deutsch. med. Wehnschr., 1909, xxxv, 1260. 268 HARVEY SOCIETY 8 Miihlens, P. Ueber Ziichtungsversuche der Spirocheta pallida und Spiro- cheta refringens sowie Tierversuche. Klin. Jahrb., 1910, xxiii, 339. 2° Noguchi, H. Zur Ziichtung der Spirocheta pallida. Berl. klin. Wehn- schr., 1912, xlix, 1554. *0 Noguchi, H. Kulturelle und immunisatorische Differenzierung zwischen Spirocheta refringens und Spirocheta pallida. Ztschr. f. Immunitiitsf., 1912, xiv, 412. 21 Sowade, H. Eine Methode zur Reinziichtung de Syphilisspirochete. Deutsch. med. Wehnschr., 1912, xxxviii, 797. *2 Tomasczewsky, J. Ein Beitrag zur Ziichtung der Spirocheta pallida. Berl. klin. Wehnschr., 1912, xlix, 792. *8 Baeslack, F.W. On the cultivation of Treponema pallidum. Jour. Infect. Dis., 1913, xii, 155. 4 Zinsser, H., Hopkins, J. G., and Gilbert, R. Notes on the cultivation of Treponema pallidum. Jour, Exper. Med., 1915, xxi, 213. *° Hoffman, W. H. Reinziichtung der Spirocheta pallida. Ztscht. f. Hyg., 1911, lxviii, 2160. 26 Hoffmann. Uebertrag der Syphilis auf Kaninchen mittels reingeziichteter Spirochiiten vom Menschen. Deutsch. med. Wehnschr., 1911, xxxvii, 1456. 27 Schereschewsky, J. Vereinfachung des Verfahrens zur Ziichtung der Syphilis-Spirochiiten. Deutsch. med. Wehnschr., 1913, xxxix, 1408. 8 Bruckner, J., and Galasesco, P. Orchite syphilitique chez le lapin par cultures impures de spirochetes. Compt, rend. Soc. de Biol., 1910, Ixviii, 684. 2 Smith, Th. Das Gihrungskélbchen in der Bacteriologie. Centralbl. f. Bakt., 1890, vii, 502. “© Hoffmann, E. Spirocheta pallida. Handb. d. Geschlechtsk., Wien: Holder, 1912. 2 Noguchi, H. Gewinnung der Reinkulturen von pathogener Spirochete pallida und von Spirocheta pertenuis. Miinch. med. Wehnschr., 1911, Iviii, 1550. #2 Noguchi, H. Pure cultivation of Spirocheta refringens. Jour. Exper. Med., 1913, xv, 466. 23 Levaditi and Stanesco, V. Culture de deux spirochetes de l-homme. Compt. rend. Soc. de Biol., 1909, xvii, 188. 4 Miihlens, P., and Hartmann, M. Leber bacillus fusiformis and Spiro- cheta dentium. Ztschr. f. Hyg. u. Infectionskrankh., 1906, lv, 81. *6 Gabritschewsky, G. Les bases de la sérotherapie de la fiévre récurrente. Ann. de l’Inst. Pasteur, 1896, x, 629. 6 Tevaditi, C., and Manouélian. Recherches sur la spirillose provoquée par le spirille de la Tick Fever. Compt. rend. Soc. de Biol. 1906, lxi, 566. 27 Manteufel, Untersuchungen iiber spezifische Agglomeration und Komple- mentbindung bei Trypanosomen und Spirochiiten. Arb. a. d. k, Gsndht- SPIROCHATES 269 samte., 1908, xxviii, 172, and Experimentele Beitrige zur Kenntniss der Rekurrensspirocheten und ihrer Immunsera. Arb. a. d. k. Gsndht- samte., 1908, xxvii, 327. *8Kolle, W., and Schatiloff, P. Untersuchungen iiber Komplementbindung bei Recurrenserkrankungen des Menschen und experimenteller Recur- rens-Spirochiitese der Miuse und Ratten. Deutsch. med. Wehnschr., 1908, ii, 1176. © Korschun, S., and Leibfried. Ueber Komplementbindung bei Typhus recurrens. Deutsch. med. Wehnschr., 1909, ii, 1179. Finger, E. Studien iiber Immunitit und itiologische Therapie der Syphilis. Sitzungsber. d. k. Akad. d. Wissenschr. Math-naturw. KL, 1905, exiv, 3 Abt. 547, and Weitere Studien iiber Immunitit bei Syphilis und bei der Vakzination gegen Variola. Wien. klin. Wchnschr., 1906, xix, 620. *i Finger, E., and Landsteiner. Syphilis an Affen. Arch. f. Dermat., 1906, Ixxxi, 147. 2 Landsteiner, K., and Finger, E. Immunitit bei Syphilis. Centralbl. f. . Bakteriol., Abt. I, beil., 1906, xxxviii, 107. ~* Kraus, R. Sitzungsb. d.k. Akad. d. Wissenschr. Math-naturw. K1., 1905, ; exiv, 3 Abt. 547. * Spitzer, L. Altiologische Therapie der Syphilis. Wien. klin. Wchnschr., 1905, xviii, 1171. * John, F. Reinfectio syphilitica. Samml. klin. Vortriige, Leipzig, 1909, n. F., No. 525-832. _ *§ Metschnikoff, E., et Rouxe. Etudes expérimentales sur la syphilis. Ann. de l’Inst. Pasteur, 1903, xvii, 809; ibid., 1904, xviii, 1 and 657; ibid., 1905, xix, 673, xvii, 809. =" Fontana, A. Contributo allo studio della sifilide corneale del coniglio. \ Rev. d’Igiene, 1907, 646. 8 Uhlenhuth, P., and Weidanz, O. Priiventive Wirkung des Atoxyls im Vergleich mit Hg bei der experimentellen Kaninchensyphilis. Deutsch. med. Wehnschr., 1908, xxxiv, 862. * Bertarelli, E. Ueber die Immunisierung des Kaninchens gegen Horn- hautsyphilis. Centralbl. f. Bakteriol., Abt. I, 1908, xlvi, 51. ~* Truffi, M. Immunisierungsvérsuch gegen Syphilis beim Kaninchen. Centralbl. f. Bakteriol., Abt. I, 1910, liv, 145. *t'Truffi, M. Ueber die Empfiinglichkeit des Kaninchens gegeniiber syph- ilitischen Reinfektionen. Centralbl. f. Bakteriol., Abt. I, 1910, liv, 337. _* Tomasczewski, E. Ergebnis der Superinfektion bei der Syphilis bei Kanin- chen. Berl. klin. Wehnschr., 1910, xlvii, 1447. *Sowade, H. Syphilitische Allgemeinerkrankung beim Kaninchen durch intracardiale Kulturimpfung. Deutsch. med. Wchnschr., 1911, xv, 622. *4Souade, H. Ueber Spirocheta pallida Kulturimpfungen, nebst Bemer- kungen iiber die Wassermann Reaktion beim Kaninchen. Deutsch. med. Wehnschr., 1911, xlii, 1934. 270 HARVEY SOCIETY 5 Hoffmann, E., and Prowazek, 8. v. Cited by Neisser and Bruck in Beit- : riige zur Pathologie und Therapie der Syphilis, Berlin, 1911; Arb. a. d. cs v Gsndhtsamte., 1911, xxxvii, 205. a *6 Herxheimer, K., and Liéser. Ueber den bau dere Spirochete pallida. ; Miinch. med. Wehnschr., 1905, lii, 2212. 7 2" Hoffmann, E. Mitteilungen und Demonstrationen iiber experimentelle — Syphilis, Spirocheta pallida und andere Spirochetenarten. Dermat. — Ztschr., 1906, xiii, 561. *§ Brénnun, A., and Ellermann, V. Spirocheta pallida in den inneren Organen bei Syphilis hereditaria. Deutsch. med. Wehnschr., 1905, xxxi, — 1757. **Babes, V., and Panea, J. Ueber pathologische Veriinderungen und Spirochete pallida bei congenitaler Syphilis. Berl. klin. Wehnselhr., 1905, xlii, 865. *” Landsteiner, K., and Mucha, V. Beobachtungen iiber Spirochete pallida. Centralbl. f. Bakteriol., Ref. 1907, xxxix, 540. 1 Zabolotny, D., and Maslakowetz. Beobachtungen iiber Beweglichkeit und Agglutination der Spirochete pallida. Centralbl. f. Bakteriol., 1907, xliv, 532. 72 Kolmer, J. A. Concerning Agglutinins for Treponema pallidum. Jour. Exper. Med., 1913, xviii, 18. 23 Nakano, H. Ueber Immunisierungsversuche mit Spirocheten Reinkul- turen. Arch. Dermat. u. Syph., 1913, exvi, 265. 4 Kissmeyer, A. Agglutination der Spirocheta pallida. Deutsch. med. Wehnschr., 1915, xli, 306. *° Zinsser, H., and Hopkins, J. G. Antibody formation against Treponema pallidum-agglutination. Jour. Exper. Med., 1915, xxi, 576. 6 Zinsser, H., Hopkins, J. G., and McBurney, M. The difference in behavior ' in immune serum between cultivated non-virulent Treponema pallidum and virulent Treponemata from lesions. Jour. Exper. Med., 1916, Xxili, 341. *7 Zinsser, H., and Hopkins, J. G. Spirocheticidal antibodies against Trepo- nema pallidum. Jour. Exper. Med., 1916, xxiii, 323. *8 Craig, Chas. F., and Nichols, H. J. A study of complement fixation in syphilis with spirocheta culture antigens. Jour. Exper. Med., 1912, xvi, 336. *” Noguchi, H. Experimental research in syphilis with especial reference to Spirocheta pallida. Jour. Am. Med. Assn., 1912, Iviii, 1163. *” Noguchi, H. has shown that such a thing is possible if tuberculo-protein instead of Koch’s O. T. tubereulin is used as an antigen. Animals actively sensitized to tubereulo- protein may give a very faint skin reaction to O. T. tuberculin, though the infected animals, of course, react strongly. In fine, the skin reaction and the general reaction to O. T. tubereulin seem to depend upon the presence in the body of an active tuber- culous focus, and Bail,'!* in transplanting tuberculous tissue from a tuberculous to a normal animal, found that the reaction after the injection of tuberculin always takes place in the tuberculous tis- sue. Itis evident, therefore, that though the reaction in the tuber- culous patient or animal is the same whether tuberculo-protein or O. T. tuberculin is employed, the anaphylactic reactions differ greatly and cannot be obtained with the latter. To what extent the forms of allergy such as the diagnostic skin reaction in infectious processes are dependent upon protein sensitization, and ean thus be accredited to true anaphylaxis, is uncertain, but before sweeping conclusions can be made upon the identity of allergy and anaphylaxis much eareful experi- mental work is necessary. The analogy is very close, however, and since one of the strik- ing features in infectious processes is the response on the part of the body by exudation and proliferation of cells, namely an inflammation, it is important to determine whether similar proc- esses accompany or follow anaphylactic reaction to simple pro- teins. The characteristic result of acute shock in guinea-pigs is the appearance of hemorrhages. But the guinea-pig that has SUSCEPTIBILITY TO FOREIGN PROTEINS — 297 recovered from a single shock shows no permanent trace of these lesions. Repeated injections of serum made subcutaneously in rabbits, on the other hand, give rise to edema, hemorrhage and necrosis, as was pointed out by Arthus, and the lesion is charac- terized according to Schlecht and Schwenke **” by an exudation of mononuclear cells and eosinophilic leucocytes. Friedberger *** and Ishioka *!® showed, too, that horse serum sprayed into the trachea of sensitized guinea-pigs produced a cellular type of pneumonia, the exudate into the alveoli being rich in mononuclear cells and eosinophiles. We??° have found that repeated intra- venous injections of horse serum and egg-white in sensitized guinea-pigs, rabbits, dogs and cats, brought about focal necroses in the liver, kidney and heart muscle which was followed by an exudation of mononuclear cells. In over 80 per cent. of the ani- mals changes were found in the kidneys which were often so extensive that they led to an advanced form of nephritis. Though it would not be justifiable to apply the results of such experiments to disease in man, it is interesting to note that one of our patients who showed spontaneous sensitiveness to several proteins from plants and especially to phaseolin, and who had had several violent attacks of asthma, urticaria and diarrhea after eating beans, developed a pronounced and persistent albu- minuria and eylindruria following such an attack one year ago. Undoubtedly infection is the most important factor in the cause of nephritis in man, but such observations suggest that the progressive process in the kidney may depend upon an allergy or attend susceptibility of this tissue towards the bacterial protein. It is known that about 10 per cent. of patients with serum sickness have a mild degree of albuminuria and show both hyaline and granular casts in the urine, and it was, therefore, with much interest that Dr. Rackemann and I studied the functional activity of the kidney during the course of this disease. Most of the patients have developed their serum sickness after the use of large amounts of antipneumococcus serum, which Dr. Cole has kindly furnished us for the treatment of pneumonia caused by the pneumococcus type I. In this study attention has been paid especially to the excretion of phenolsulphonaphthalein, water and 298 HARVEY SOCIETY sodium chloride. The nitrogen metabolism is so much disturbed during and after an attack of pneumonia that little significance can be attached to the changes in the total non-protein nitrogen of the blood. The coéfficient of urea excretion, however, employed by Ambard, has been studied by the recent modification in technie described by McLean,'*! and we have not found that this is greatly modified during serum sickness. The excretion of chro- rides and water, on the other hand, is often profoundly affected. The changes that take place in the elimination of salt and water during convalescence from an attack of pneumonia, that has not had serum, are as follows: During the attack the excretion of water is low and the chlorides are eliminated in small amounts and low concentration. Shortly after the attack the retained chlorides are excreted in excess of the intake and in high concen- tration, but on a fixed water and salt intake soon come to a normal balance. We have not found that this course is materially interfered with by such febrile complications as empyema. In the serum sickness that may follow the use of antipneumococcus serum and in one case after the intraspinous injection of anti- pneumococcus serum, the ordinary course of the elimination of water and sodium chloride was greatly disturbed. With the onset of serum disease the excretion of water diminished rapidly and with it the elimination of sodium chloride. One important point, too, is that the patient is unable to concentrate the sodium chloride, which may fall below 0.2 per cent., a very low figure. The excretion of phthalein is in a few eases slightly affected as well and with the appearance of albumin and casts in the urine and the development of cedema, the patient presents a clinical picture very closely resembling a mild case of nephritis of the salt retention type. Sufficient studies have not been made to determine whether this salt retention is in the blood or tissues, but at all events, it is usually accompanied by edema. These alterations, so far as we have observed them, are purely transi- tory, and with the subsidence of the attack the patient and the renal function return to a normal state. Such studies are designed primarily to throw some light upon the possible importance of repeated anaphylactic shocks in the iD ge” Ln a i ITI SUSCEPTIBILITY TO FOREIGN PROTEINS ~— 299 spontaneously and highly sensitized individual, and it would be the greatest mistake and misfortune at the present time if they were allowed to have any bearing on the use of antitoxic and anti- bacterial sera. The concentrated diphtheria antitoxin, such as is employed now, rarely produces serum disease or sensitizes suffi- ciently highly to make a second dose, particularly if it is given subeutaneously, in the least dangerous, and it is only to the spontaneously sensitive who react to the first injection that harm is likely to come. To prevent accidents in such unexpected instances, especially if large quantities of serum are given intravenously, a prelimi- nary intracutaneous injection of 0.1 to 0.01 ¢.c. of serum should be made to determine whether or not the patient is spontaneously sensitive to the serum which is to be employed. Though it would be interesting to recount the methods which have been employed to desensitize both artificially and spon- taneously sensitized individuals, this important problem in thera- peutics must be left, since there is not time to do it justice, and in conclusion I shall point out the conditions which such methods must combat. The injection of foreign proteins in man brings about the same condition of hypersensitiveness towards subsequent injec- tions that it does in animals. Certain individuals may show spontaneous hypersuscepti- bility to one of several foreign proteins. These people differ from the artificially sensitized in that their susceptibility is very great, is shown towards several different proteins and has a tendency to occur in families. And finally, that this state is associated with and directly responsible for some well-defined pathological conditions. REFERENCES *Lublinski: Deut. med. Wehnschr., 1894, xx, 854. ? von Pirquet and Schick: Die Serumkrankheit, 1905. * For full bibliography, see: Doerr: Handb. d. path. Microérg. (Kolle and Wassermann), 1913, ii, 947. Richet: L’Anaphylaxie, 1912. von Pirquet: Arch. Inter. Med., 1911, vii, 259, 383, 300 | HARVEY SOCIETY Friedmann: Jahresb. ii Immunitiitsforsch, 1, Abt., 1910, vi, 31. Besredka: Ibid., 1912, viii, 90. Vaughan: Protein Split Products in Relation to Immunity and Dis- ease, 1913. Rosenau and Anderson: Arch. Inter. Med., 1909, ii, 579. Otto: Handb. d. path. Microorg. (Kolle and Wassermann), 1908, ii, 255. Auer: Forchheimer’s Therapeusis, 1914, v, 39. *Gay and Southard, Jour. Med. Research, 1907, xvi, 143. * Otto: Miinch. med. Wehnschr., 1907, liv, 1665. ° Friedmann: Ibid., p. 2414, * Besredka and Steinhardt: Ann. de ]’Inst. Pasteur: 1907, xxi, 117, 384. *Rosenau and Anderson: Bull. 29, M. S. Hyg. Lab., 1906, No. 29; 1907, No. 36. * Axenow: Jahrb. f. Kinderh., 1913, Ixxviii, 565. ” Weaver: Arch. Inter. Med., 1909, iii, 485. » Bokay: Deut. med. Wehnschr., 1911, xxxvii, 9. 44 Schulz: Berl. klin. Wehnschr., 1914, li, 349, 401. * Goodall: Jour. Hyg., 1907, vii, 607; Brit. Med. Jour., 1913, ii, 1359. 4 Park: Trans. Assn. Amer. Physicians, 1913, xxviii, 95. * Nemmser: Deut. med. Wehnschr., 1913, xxxix, 740. %* Cuno: Ibid., 1914, xl, 1017. 7 Koch: Berl. klin. Wehnschr., 1915, lii, 685. * Hutinel: Presse med., 1910, xviii, 497. ”Grysez and Dupuich: Bull. et mem. Soc. med. d. hop. de Paris, 1912, xxxiil, 374. * Archard and Flandin: Compt. rend. Soc. Biol., 1912, lxxiii, 419. * Auer: Forchheimer’s Therapeusis, 1914, v, 39. “Lucas and Gay: Jour. Med. Research, 1909, xx, 251. * Moss: Jour. Amer. Med. Assn., 1910, lv, 776. “Hamburger and Pollok: Wien. klin. Wehnschr., 1910, xxiii, 1161. *® Michaels: Arch. Mal. d. Enfants, 1913, xvi, 835. ** Cowie: Amer. Jour. Dis. Children, 1914, vii, 253. *7 Knox, Moss and Brown: Jour. Exper. Med., 19J0, xii, 562. * Hamburger and Moro: Wien. klin. Wehnschr., 1903, xvi, 445. * Doerr and Russ: Ztschr. f. Immunitiitsforsch, Orig., 1909, iii, 181. Doerr: Handb, d. path. Microorg. (Kolle and Wasserman), 1913, ii, 947. * Weil: Jour. Immuol., 1916, i, 1, 19, 35, 47. * Wells: Jour. Infec. Dis., 1915, xvi, 63. “2 Doerr: loc. cit. * Lewis: Jour. Infec. Dis., 1915, xvii, 241. * Burkhardt: Ztschr. f. Immunitiitsforsch. I Abt., Orig., 1910, viii, 87. * Weill, Halle and Lémaire: Compt. rend. Soe. Biol., 1908, Ixy, 141. * Anderson and Frost: U. 8S. Hyg. Lab. Bul., 1910, No. 64. . i ee ee SUSCEPTIBILITY TO FOREIGN PROTEINS 301 % Anderson and Frost: loc. cit. 38 Archard and Flandin: loc. cit. 3 Weil: Proc. Soc. Exper. Biol. and Med., 1914, xii, 37. * Yamanouchi: Compt. rend. Soc. Biol., 1910, Ixviii, 1000. *t Novotny and Schick: Ztschr. f. Immunitiitsforsch., Orig., 1909, ili, 671. “ Grysez and Bernhard: Comp. rend. Soe. Biol., 1912, Ixxiii, 387. *s Pearce and Kisenbrey: Trans. Cong. Amer, Phys. and Surg., 1910, viii, 402. “ Schulz: Jour. Pharmacol. and Exper. Therap., 1910, i, 549; U. S. Hyg. Lab. Bul., 1912, No. 80. * Dale: Jour. Pharmacol. and Exp. Therap., 1913, iv, 167. * Weil: Jour. Med. Research, 1914, xxx, 87, 299. 47 Zinsser: Arch. Inter. Med., 1915, xvi, 223. “Pfeiffer: Ztschr. f. Hyg., 1892, xi, 293. * Wolff: Centralbl. f. Bakt., Orig., 1904, xxxvii, 390, 566, 684. 5° de Waele: Bull. Acad. roy. de Med. de Belgique, Brux., 1909. 5 Bied] and Kraus: Wien. klin. Wehnschr., 1909, xxii, 363. Vaughan: Protein Split Products in Relation to Immunity and Disease, 1913. ** Friedberger: Ztschr. f. lmmunititsforsch., Orig., 1911, ix, 369. ** Weichardt and Schittenhelm: Ztschr. f. exper. Path. u. Therap., 1912, x, 412, 448; xi, 69. 5 Abderhalden: Ztschr. f. physiol. Chem., 1912, Ixxxii, 109. °° Cammerer and Pincussohn: Ztschr. f. physiol. Chem., 1909, lix, 293. 5’ Pfeiffer and Jarisch: Ztschr. f. Immunitiitsforsch., Orig., 1912-13, xvi, 38. 58 Zunz and Gyorgy: Ztschr. f. Immunitiitsforsch., Orig., 1915, xxiii, 402. % Jobling and Petersen: Jour. Exper. Med., 1915, xxii, 401. © Gottstein: Therap. Monatsh., 1896, x, 269. 61 Gillette: N. Y. State Med. Jour., 1909, ix, 373. * Blackley: Experimental Researches on the Cause and Nature of Hay Fever. London, 1873. ® Dunbar: Deut. med. Wehnschr., 1903, xxix, 149. 6 Weichardt: Centralbl. f. Bakt. Centralbl. f. Bakt., Ref., 1906, xxxviii, 493. ® Wolff-Eisner: Das Heufieber. Miinchen, 1906. *° Wolff-EKisner: Dermat. Centralbl., 1907, x, 164. * Auer and Lewis: Jour. Exp. Med., 1910, xii, 15. * Meltzer: Trans. Assn. Amer. Phys., 1910, xxv, 66. ® Schloss: Amer. Jour. Dis. Child., 1912, iii, 341. * Lesne and Richet: Arch. d. mal. d. enfants, 1913, xvi, 81. "Talbot: Boston Med. and Surg. Jour., 1914, clxxi, 708. ™ Kleinschmidt: Monatsh. f. Kinderh., Orig., 1913, xi, 644. *% Smith: Arch. Int. Med., 1909, iii, 350. %* Wechselmann: Deut. Med. Wehnschr., 1909, xxxv, 1389. ® Goldschmidt: Miinch. med. Wehnschr., 1910, lvii, 1991. % Stéiubli: Deut. Med. Wehnschr., 1912, xxxviii, 2452. 302 HARVEY SOCIETY ™ Kaufmann: Ibid., 1913, xxxix, 272. ™ Twaschenzoff: Miinch. med. Wcehnschr., 1912, lix, 806. ” Draper: Jour. Amer. Med. Assn., 1916, Ixvi, 400. Friedberger and Ito: Ztschr. f. Immunitiitsforsch., Orig., 1912, xii, 241. * Swift: Jour. Amer. Med. Assoc., 1912, lix, 1236. * Bruck: Berl. klin. Wehnschr., 1910, xlvii, 517, 1928. * Klaussner: Miinch. med. Wehnschr., 1910, lvii, 1451, 1983; 1911, lviii, 138. * Zieler: Miinch. med. Wehnschr., 1912, lix, 401, 1641. > Pohlmann: Ibid., 1914, lxi, 543. * Beclere, Chambon and Manard: Ann. d. l’Inst. Pasteur, 1896, x, 567. *? Clowes: Proc. Soc. Exp. Biol. and Med., 1913, x, 69. * Koessler: Forchheimer’s Therapeusis, 1914, v, 671. ®* Bruck: Arch. f. Dermat., 1909, xevi, 241. © Schloss: Amer. Jour. Dis. Children, 1912, iii, 341. ™ Cooke: The Laryngoscope, Feb., 1915. SOME PHASES OF THE NEPHRITIS PROBLEM* PROF. HENRY A. CHRISTIAN, M.D. Harvard University OME of my predecessors as lecturers before the Harvey Society have selected topics of which it was impossible to present a quite comprehensive review of contemporary knowl- edge within the limits of such a lecture; while others have had personal investigations to report of such completeness and impor- tance that their presentation fulfilled amply the requirements of the occasion. My subject and my own work fall within neither of these groups. From the vast literature on nephritis no reviewer could condense into the space of an hour any adequate presentation of the results of the many valuable investigations of the past, while my own studies have not a value deserving the occupancy of an hour of your time. I have chosen to speak of only certain phases of the nephritis problem illustrative of the present-day viewpoint of the subject and indicating the trend of recent investigation. In doing this I will speak relatively more of the work during the past eight years of myself and my associates in the laboratory of the Depart- ment of Medicine at Harvard and the Medical Clinic of the Peter Bent Brigham Hospital than of the work of others because I am more familiar with our own work, not because I have the opinion that it is of proportionately as great value as many of the splendid researches that have come in the last decade from other laboratories and clinics. From the time of Bright’s publication in 1827 with which began any real knowledge of nephritis down to the late nineties almost all investigations concerned themselves with renal struc- ture in nephritis or with statistical study of symptomatology. In these studies structure rather than function was predominately the point of interest. A conception of the relations of the dis- eased kidney to the patient’s symptoms was evolved in large part from an examination of kidneys from men dead of nephritis. 303 304 HARVEY SOCIETY Hypotheses as to the probable relations of these pathological changes to observed symptoms and to disturbances in urinary excretion were formed. Beginning in 1900 interest shifted toward animal experimen- tation. Renal function in nephritis, whether produced experi- mentally in animals or arising naturally in man, replaced renal structure as the problem of greatest interest. A considerable pro- portion, however, of this interest in renal function was founded on the hope of a more satisfactory correlation of renal function as observed during life with changes in renal structure as found after death; a hope as yet unrealized, in fact, almost given up as an unattainable goal. In 1907 I became interested in the problem of nephritis and since then have devoted such time as was available from medical teaching and the conduct of a hospital service to the study of some of these problems. In this study I have associated with me a number of men, R. M. Smith, Walker, O’Hare, Dawson, Fitz, Frothingham, Peabody, Smillie and Woods, whose independent work I will describe in connection with my own. We began with a few of the problems of experimental nephritis. Our first study, the work of R. M. Smith,’ was on the origin of urinary casts. ‘Two views prevailed; one that all casts originated from disintegrated tubular epithelium, the other that some of them at least were formed from albumen which escaped through the damaged glomeruli. Acute types of experimental nephritis furnished excellent material for the study of this prob- lem, inasmuch as the urine might be examined in relation to renal lesions of varying severity and age and at any period the kidney might be studied histologically. From our work it seemed very probable that all casts were composed of material primarily coming from the tubular epithelium and that granular casts were relatively young casts, hyaline casts older in the sense of requir- ing a longer time for their preparation. It did not seem very probable that albumen excreted from the glomerulus in solution would coagulate or precipitate in the tubule, though this mechan- ism might easily take place with fibrin casts if such really ever occurred in the urine. NEPHRITIS PROBLEM 305 The work of Schlayer and his co-workers at about this time had aroused much interest in the functional disturbances resulting from experimental acute renal lesions. They had differentiated the two main groups of disturbances, the tubular and the vascular, and had outlined the functional disturbances characteristic of each. In their work they had emphasized the frequent discrep- ancies between functional change and demonstrable anatomical lesion, especially in the group of vascular nephritides. O’Hare and myself undertook a careful study of the finer histology of some of these experimental lesions and were able to show that in the vascular group glomerular lesions were more common than Schlayer and his co-workers had found and that they occurred in a considerable variety of forms. One of these lesions consist- ing of the deposition of fine hyaline granules in the wall of the glomerular tuft was a type of glomerular degeneration pre- viously undescribed,” while others of them were similar to lesions sometimes or often found in human kidneys.* Still there remained a definite discrepancy between functional disturbance and ana- tomical change in the kidney, and our histological studies did not throw much light on the nephritis problem in man, whether looked at from a functional or from a structural viewpoint. Experimental acute lesions lend themselves well to study with functional tests. It was interesting to see the relation of the phenolsulphonephthalein test to the non-protein nitrogen or urea nitrogen of the blood; the phtalein output quickly drops, the blood nitrogen more slowly increases; the former expresses the immediate functional condition of the kidney ; the latter measures the result of the past and present hindrance to renal excretion.* In the same way the amylase in the urine was studied by Fitz ® in contrast to the urea nitrogen of the blood. Fitz found that amylase followed much the same curve of exeretion as did *phthalein but as a test for renal function was less delicate than the *phthalein test. As had been done by Schlayer, water, salt, lactose and potassium iodide excretion were studied. Using experimental lesions, since their severity can be controlled very accurately, a good understanding of several of these functional tests and their relative values was obtained by us and by others 20 306 HARVEY SOCIETY more quickly than would have been possible from the study of human acute nephritis where much time would have been lost in waiting for the necessary number of suitable cases to turn up, and so for experimental study we were in a better position to apply these tests to human cases. Equally well are the acute experimental lesions adapted to the study of the effect of diuretic drugs. O’Hare, Walker, Dawson and myself have investigated in this way theobromine sodium salicylate,® theocin, caffein, potassium acetate and water,’ and found that all tended to shorten rather than prolong the life of animals with severe acute uranium nitrate nephritis. Using *phthalein as a measure of renal function we were unable to dis- cover any definite constant improvement in renal excretion fol- lowing the use of theobromine sodium salicylate. Over short periods of time with animals anesthetized with urethane Fitz * found that with an acute renal lesion produced with uranium nitrate, theobromine sodium salicylate and theocin caused an increased output of water, sodium chloride and nitrogen and did not diminish ’phthalein excretion; while with a lesion produced with potassium bichromate there was no increased output of nitrogen and ’phthalein excretion was diminished when there was a mild renal lesion. When the lesion was severe the *phthalein usually indicated that the diuretic had made the function of the kidney worse.* These diuretic substances quickly lead to renal fatigue with decreased excretion. Our experiments as a whole indicate harm rather than benefit from giving diuretic drugs in acute nephritis. Very interesting observations were made on the relation of potassium excretion to renal lesions. In one of our patients with ehronie nephritis it was noticed that a substitution of potassium chloride for sodium chloride in a dietary test of renal function produced toxic symptoms. In animals with acute experimental renal lesions Smillie’® found that a stage was soon reached, measured by a non-proteid nitrogen value in the blood of 100 mg. per 100 ¢.c. of blood, in which the kidney was very slightly per- meable to potassium salts. Under these conditions potassium salts were markedly toxic, rapidly causing the death of the ani- mals, though an animal with a normal function could tolerate large 6 GN DANN NEPHRITIS PROBLEM 307 doses of potassium without any evidence of injury. The rapid excretion of potassium with an intact kidney prevented any evidence of toxicity ; delay excretion by a renal lesion and toxicity at once became evident. These studies indicate that large doses of potassium iodide, for example, might be definitely injurious in a patient with markedly impaired renal function. In man chronic rather than acute renal lesions are encountered most often, and the problems of chronic nephritis receive the greatest attention from pathologists and clinicians. Could one produce with regularity in animals various types of chronic renal lesions analogous to those found in man, many problems could be studied by methods not applicable to the human being. To pro- duce such a chronic nephritis experimentally many efforts have been made. Like other experimenters we have been able to pro- duce in animals, chiefly rabbits, lesions of a chronic nature with connective tissue overgrowth very similar to those found in the types of chronic nephritis seen in man. With repeated sublethal doses of uranium nitrate and of potassium bichromate, chronic experimental lesions were produced by Smith,! and similar, pos- sibly more constant, results were obtained by O’Hare ’? with a combination of a chemical substance (uranium nitrate) and bacteria (B. coli communis). These lesions were quite similar to those obtained by other observers using a variety of substances as causative agents, but all alike fail of the intent held by most workers; namely, to produce regularly chronic lesions capable of functional study with a view to throwing some light on the cause, the symptomatology and the treatment of chronic nephritis in man. The kidney of animals possesses a surprising power of regenerative repair which makes uncertain the production of chronic lesions. Moreover, however close the resemblance, it cannot be said that in animals a condition identical with chronic nephritis in man has been produced as yet by any experimenter. Finally the methods usually employed for the production in ani- mals of such chronic lesions are at best only remotely related to any possible causative factors of chronic nephritis in man. To help in any understanding of human chronic nephritis, chronic lesions must be produced in animals with great regularity 308 » HARVEY SOCIETY and they must cause in the animal changes of a nature similar to those observed in man, such as vascular hypertension, cardiac hypertrophy, dyspnea, cedema, uremia, ete., before such infor- mation can be gained about chronic nephritis from animal experi- mentation. Looked at in this way all work on experimental chronic nephritis falls short, though some of the phenomena mentioned above can be produced. However, it does not seem impossible that in some animal a true chronic renal lesion with the typical secondary conditions that go to make up the picture of chronic nephritis in man should be produced by experimental methods of investigation. Such an accomplishment would faeili- tate undoubtedly the unraveling of the nephritis problem in man, and its value would be so great that it is well worth while to continue to strive for its attainment. Though the experimental studies of Schlayer and his co- workers ** differentiated two very distinct types of renal lesion, the vascular and the tubular, and though with their methods of study each type was shown to cause very characteristic disturb- ances of renal function in animals, the value of these studies has been rather in re-arousing interest in the investigation of renal function in human nephritis than in furnishing us with the satisfactory functional classification of renal lesions in man. In each case of human nephritis both tubules and vascular apparatus usually are involved. The one structure or the other may be disturbed in greater amount, but it has not been possible, except in very few cases, to separate the patients with any sharpness into cases with tubular lesions and cases with vascular lesions in the sense of Schlayer and his co-workers. Two of the sub- stances which they used for functional testing in animals have hardly in the human being measured up to the usefulness which might have been anticipated from the results in animals or which was claimed at first from their use in man. Schlayer utilized the time required for the excretion of a given amount of potassium iodide as an index of tubular efficiency and the time and amount of lactose excretion to indicate the efficiency of the glomeruli. We, like other observers, have used. these substances in a very ‘NEPHRITIS PROBLEM 309 considerable number of patients, but gradually have discarded them as furnishing comparatively little useful information. Widal and his co-workers '* studied the renal excretion of sodium chloride and nitrogen and grouped their cases of chronic nephritis into those with deficient power to excrete sodium chlo- ride, which cases usually showed cedema as a chief symptom, and those unable to excrete nitrogen readily in which uremic manifes- tations generally were prominent. Our study of salt and nitrogen excretion except in an occasional case has not yielded any sharp differentiation of patients. There is an occasional patient with a marked inability to excrete sodium chloride who becomes cede- matous when sodium chloride intake exceeds sodium chloride output and whose kidney shows but little if any impairment of its function to rid the body of nitrogenous substances, but such cases often are not, strictly speaking, cases of nephritis, but rather patients with disturbed salt elimination and no more to be regarded as nephritis than would be cases of diabetes mellitus or diabetes insipidus. If the typical cases of chronic nephritis, whether cedema is a prominent feature or not, are investigated with respect to salt and nitrogen elimination, it has been our experience that in most patients both show delayed excretion ; in the earlier stages salt excretion rather than nitrogen excretion is disturbed, but as the disease progresses nitrogen excretion becomes increasingly delayed until in advanced cases both salt and nitrogen excretion are markedly and about equally dis- turbed.'° We have not encountered cases of the type described by Widal with normal salt excretion and delayed nitrogen excretion. In all of the earlier functional studies of patients with nephritis the desire to make an anatomical diagnosis has been prominent; sometimes it has been the acknowledged goal, at other times, though not so stated, it is evidently the aim of the investigator. Little by little it has become recognized that such an attainment has not been approached with any closeness and I think by most investigators it is now regarded as improbable that we will ever be able to correlate closely postmortem anatomi- cal appearances with the functional disturbances of the kidney 310 HARVEY SOCIETY during life, at least so long as present pathological technie and classification continue in use. Improved methods of studying renal lesions, of course, may change these conditions at any time. In a number of patients we have had the opportunity to carry out a group of functional renal studies and on the death of the patient have submitted the kidneys to pathological examination.*® In these patients there was no evident relation to be made out between anatomical changes in the kidney and antecedent fune- tional disturbances in any selective sense that would justify an anatomical classification. In our experience in a functional sense patients with nephritis do not separate themselves into distinctive groups; rather is it indicated that there is a progressive increase in functional disturbance with advance of the lesion, though there is an undoubted tendency for certain cases to show continuously a much more marked impairment of function as measured by one set of tests than by another, indicating that functional disturb- ances depend on selective excretory activity and that were not the various renal structures pretty generally involved in nephritis a more definite classification based on tests of renal function could be made. However, at the present time tests of renal function are of more value for indicating the presence of renal lesion, for measur- ing its extent and for indicating its management than as a means of classification of cases. For these purposes they add greatly to the value of our clinical study of patients with nephritis. Out of the very numerous methods of testing renal function certain ones have survived either by reason of ease of application or by reason of yield of information in proportion to the amount of labor they require. Some have been discarded because the same in- formation may be obtained from simpler procedures, or from ones requiring less complicated and expensive apparatus or occupying less time in their carrying out. Others have been given up because they caused more discomfort and inconvenience to the patient than some other one yielding the same information. Those that are still in use, though they yield much valuable infor- mation, are not thoroughly satisfactory and better ones probably NEPHRITIS PROBLEM 311 can be worked out with our increasing knowledge of renal func- tion under varying conditions in man and animals. The functional tests now most generally used are the ones that show the power of the kidney to excrete a dyestuff and those that measure the efficiency of the kidney in the excretion of water, salt and nitrogen. Of the former group the phenolsulpho- nephthalein test of Geraghty and Rowntree '* very largely has superseded all others as being the best of these tests owing to its simplicity and its accuracy. To determine the excretion of water, salt and nitrogen, several methods are employed. These substances are quantitated in the urine in relation to a fixed dietary intake ; or they are quantitated in the blood; or the relation between the amount in the blood and the urine is expressed in the form of a formula of excretion. The impetus more recently to the study of urinary water, salt and nitrogen in relation to dietary intake we owe to the German clinics, especially to von Monakow'*® and to Schlayer and Hedinger.’® Two general plans have been followed. By one of these the patient is on a fixed diet containing a known amount of fluid, salt and nitrogen. By quantitating these substances in each twenty-four-hour amount of urine the promptness and complete- ness of excretion of the added salt and nitrogen are determined. Delay in excretion or incomplete excretion is indicative of dis- turbed renal function. By another plan on one day the patient has a standard mixed diet containing definite amounts of salt, nitrogen, water and purin bases, in certain of the meals little, in others a considerable amount. The urine is collected in two-hour portions and the salt, nitrogen and specific gravity of each portion is determined. The eurves of excretion as plotted from the values so obtained in comparison with the excretion from normal kidneys indicate departure from normal renal function. The determination of these substances, salt and nitrogenous bodies, in the blood has been made by numerous observers in the past but the simplified methods of Folin *° and of van Slyke”? recently have stimulated and made possible many new and excellent investigations of this phase of the subject, 312 HARVEY SOCIETY To Ambard ** is due most credit for our present interest in the rate of excretion of nitrogen and salt as determined from formule which take into account the concentration of these substances in blood and urine, rate of urine flow and weight of the patient. Ambard and his co-workers have worked out many of the laws governing these excretions and have shown their constancy under normal conditions. McLean,** by a slight variation in the strue- ture of the formul# of Ambard, has expressed the excretion as a numerical index which has some advantage over Ambard’s way of expressing his results. Van Slyke’s urease method of deter- mining urea has rendered more accurate the determinations and this method has been used by McLean to give a greater constancy to his figures than would have obtained with the older methods of determining the urea. However, it is only fair to Ambard and his co-workers to say that the work of others has amplified rather than corrected the conclusions drawn by Ambard from the studies made by himself and his associates. The work of all of these observers is open to the criticism that each observer has used, as a rule, but a single method of studying renal function, usually the method devised by himself, and he has not compared often the results that might be obtained by applying to the same patients several methods of study. Fur- thermore, it is surprising how few of the eases studied by fune- tional methods have had checking up from postmortem anatomical study. We have already called attention to the unsatisfactoriness of the correlation between histological changes in the kidney and prior functional renal study. Still the autopsy checking up of results is very salutary and of course excludes certain errors such as the diagnosing of a simple chronic passive congestion as a chronic nephritis. It is to be remembered, however, that most of the fatal cases will have had functional study under the handicap of the seriousness of the patient’s condition hindering the earry- ing out of many functional studies and really represent the fune- tion of the late stages of a nephritis in relation to postmortem findings. As already stated, we have had a certain number of eases for functional study and later have had opportunity to examine their kidneys. However, in almost all of these the dietary Jap fa ala hale Ba Bi 4 a 4 Mule oe NEPHRITIS PROBLEM 313 tests were impossible of carrying out satisfactorily owing to the advanced stage of the disease, and so the studies of renal function were incomplete. It will be necessary to make studies of renal function at intervals during the course of nephritis and then on the death of the patient study the kidney histologically before a satisfactory verdict can be rendered on the relation between renal function and renal structure as shown by the pathological study of the terminal stage of the nephritis. We have been able to study a considerable number of non- fatal cases with a variety of methods of testing renal function, such as the phenolsulphonephthalein test, the added urea and salt dietary test, the test renal day, the determination of the indices of urea and salt excretion, ete.** Some of these tests can be carried out almost simultaneously; others of them require several days and only one at a time can be done. For these reasons there is the possibility for variations in the patient’s condition influencing renal function so that in comparing the results of different tests conditions are not always identical. Still in most cases there is a surprisingly close parallelism between the results obtained from different methods of testing renal func- tion. Almost always a low ’phthalein output is accompanied by an increase in urea or total non-protein nitrogen in the blood and the index of nitrogen excretion is proportionately lowered below the average normal figure. In these cases dietary tests of any sort show delayed excretion of nitrogen and salt with fixation of specific gravity and percentage concentration of nitro- gen and salt. Occasionally there are exceptions and one set of tests indicates less disturbance of renal function than another set. In some of these patients these variations are obviously due to extra-renal causes or changes in the patient’s condition during the course of the testing. There remain, however, a few cases where no explanation can be found for failure of the results of different tests to agree and for this reason alone, it is important not to confine one’s study of renal function to too few tests, however satisfactory the individual test would seem to be. Patients who show these marked disturbances of renal function as measured by several tests usually are quite evidently seriously 314 HARVEY SOCIETY ill patients when studied merely by the regular routine methods of history of symptoms and simple physical examination. They are undoubted cases of advanced chronic nephritis and there is no question as to diagnosis; renal tests are not needed to make the diagnosis and really do not help from that viewpoint. Neverthe- less, by using tests of renal function some cases are found which, while showing marked disturbance of renal function, have but few if any symptoms and appear to be but slightly sick individ- uals. Their poor renal function comes as a great surprise to the clinician in charge. Here the tests are of much use in making a prognosis and enable the physician to warn his patient of impend- ing catastrophe. Although he may be unable in any way to prevent this catastrophe, foreknowledge of it may be of incal- culable value to the patient and family. In our experience in such cases the progress of the disease has borne out the accuracy of the information from the tests of renal function provided they have not been made during a period of acute exacerbation of renal disturbance or when renal insufficiency is aggravated by an increased, though temporary, circulatory insufficiency. In eases in which there is any suspicion of these conditions the renal tests should be repeated after an interval. In our experience, however, acute exacerbations of renal disturbance and circulatory deficien- cies are evident in studying almost all of the cases and should not form any appreciable source of error in interpretation. Ob- viously tests of renal function like all clinical tests should not be exalted into a fetich; without an admixture of brains and common sense they can lead to absurd conclusions with the man who is willing to stake all on a single test. A recent excessive ingestion of proteid by a patient with a stricture of his urethra but otherwise healthy could easily simulate a marked renal insuffi- ciency by several tests and mislead that type of clinician who, with but a scant glance at his patient and no conception of the patient’s symptoms, rushes to his laboratory tests with the idea that scientific accuracy increases by the square of the distance from the bedside and by the cube of the time spent in earrying out a test out of touch with the sick man, This would seem so : 4 NEPHRITIS PROBLEM 315 evident a proposition as not to need repetition, and yet I regret to say that I have seen almost this identical mistake made. As I have pointed out earlier in this paper, tests of renal func- tion have a value for three purposes: for diagnosing the presence of renal lesion, for measuring its extent and for indicating its management. For diagnosing the presence of marked renal disturbances the tests as just pointed out are not of great value because the existence of marked nephritis is usually evident with- outthem. In the earlier stages of nephritis tests of renal function are of considerable value in diagnosis. It must be admitted that albumen and casts in the urine are among the most delicate indi- cators of disturbed renal function. When found the question arises, do they indicate a disturbed function of a type to be regarded as a nephritis that will progress? In these earlier cases phenolsulphonephthalein excretion is so nearly normal as to be of no diagnostic aid. Non-protein nitrogenous bodies in the blood are well within normal limits and their determination does not help. It is in these earlier cases that the dietary tests indicate distinct disturbance of the type found in definite chronic nephritis, though the disturbance is less evident than in a somewhat more advanced stage of the lesion. Delay in excretion of sodium chloride, a tendency to fixation of specific gravity, hypersensi- tivity with polyuria or rapid fatigue, all are suggestive of an actual nephritis in the patient with slight albuminuria or cylin- druria. We have found just these changes in cases in which phenolsulphonephthalein output was good and blood urea was normal, but in which symptomatology, slight cedema, moderate hypertension, etc., seemed to clearly indicate that they were cases of early chronic nephritis. Very likely without this collateral evidence a diagnosis of early chronic nephritis should be made on patients with slight albuminuria and these changes just enu- merated as indicated by dietary tests. These cases very fre- quently show, too, a lowered index of urea excretion and often a plus salt balance, and these methods are of equal value with the dietary tests. We should not be too dogmatic, however, with regard to the diagnosis of early stages of chronic nephritis by renal dietary 316 HARVEY SOCIETY tests or determinations of the indices of urea and salt excretion. Almost all of these studies have been made very recently and one is not justified in saying that a patient with these slight disturb- ances of renal function is in an early stage of nephritis until many such cases are tested and watched and retested over a period of five or ten years and found to develop with great regularity into typical cases of chronic nephritis, which means that they show themselves to have a progressing renal lesion ultimately fatal and showing at the postmortem examination an anatomically demonstrated chronic nephritis. We are in danger in present enthusiasm to overlook the fact that in the study of a chronie disease almost no method can have a proved value until much time has elapsed. Such a proved value certainly cannot be attached at present to these tests of renal function. What are the relative values of dietary tests such as the added salt and urea test and the dietary renal day as compared with the determination of the indices of urea and salt excretion? I do not believe that we are in a position to give an answer now. As I have already pointed out, in our patients all the tests agree surprisingly well, but we have not observed long enough the very early cases to be justified in holding any definite opinion as to relative value. The dietary tests are time consuming for both patient and laboratory worker, unless they can be simplified materially. Their inapplicability to ill patients unable to take the diets does not apply to early cases but other objections do. The determination of the indices of excretion is quicker for the patient at least and simpler in not requiring hospital observation and a weighed diet. It seems to me, however, that variations in the indices in relation to variations in water output are not sufficiently well understood to justify our feeling completely satisfied with them. Then the occasional abnormally high indices that we get have not received satisfactory interpretation; they, too, require the time element and repetitions from period to period to be understood. So I feel that both methods of testing renal functions should be persisted in for a much longer time before we are justified in giving up either one in favor of the other. What value have these tests in prognosis? It is in this con- A aha ee NEPHRITIS PROBLEM 317 nection that we get most help from tests of renal function. The tests aid very greatly in determining the severity of renal involve- ment and so aid in making a prognosis. The prognosis based on the tests, however, is one of degree of renal lesion rather than of duration of life. Duration of life depends on rate of progress of the lesion and the ability of the body to adapt itself to deficiencies in renal excretion, both difficult of foretelling. So until the tests indicate a very marked degree of renal insufficiency we can only surmise in a very loose way as to probable length of life. Repetitions of the tests at intervals give us some measure of rate of progress, but the course of development of the renal lesion in many cases undoubtedly is one of periods of exacerbation fol- lowed by periods of quiescence and little change. This decreases the accuracy of prognostic deductions from tests made at inter- vals. Still, tests of renal function do aid us materially in forming an opinion as to the probable period of activity of life of our patient and without them this becomes to a larger extent a matter of mere guess work. For some time we have been planning the therapeutic manage- ment of patients with nephritis on the basis of the evidence from our tests of renal insufficiency. There seems little doubt but that a more appropriate degree of limitation of activity can be made with a knowledge of the condition of renal function. Dietary regulations based on the ability of the kidney to excrete water, nitrogen and salt as compared with the normal would seem to have a rational basis. If it is evident that the kidney excretes any of these substances slowly, or if fatigue appears shortly after excretion begins, the deduction made is that an excess of any of these substances in the food intake will overwork the kidney and probably increase the renal damage; on the other hand, a decrease in the intake will allow of a rest of renal function with either a gradual increase in power to excrete or a less rapid progression in the renal lesion. This is the hypothesis on which we work in planning a diet based on the ability of the kidney to handle water, salt and nitrogen. Long experience has indicated that an empirical reduction in intake of salt and nitrogen does benefit the patient. There has been much discussion as to whether 318 HARVEY SOCIETY water should be increased or decreased. Limitation determined by renal function seems a more rational plan. Further trial and continued observation of patients alone can show how far this is true. If salt is excreted poorly and there is edema, reduction in salt intake usually decreases the cdema if it does not arise from circulatory deficiency, and this benefits the patient. When there is poor salt excretion but no tendency to edema, does a salt excess in the food really act as a renal irritant in any sense? Probably it does, but I do not think our work so far has answered that question definitely. In the same way, if nitrogen elimination is poor, a diet low in proteid leads to a decrease in blood urea and in total blood non-proteid and the index of urea excretion appears to improve, but we do not know how much this change really benefits the patient. We do not believe that these nitrogenous substances which we quantitate, urea, uric acid, amino-acids, ete., are injurious in themselves. We assume that when they are poorly excreted the actual toxic substances are retained in the body because in the uremic or toxie state when presumably they are being retained we usually obtain high values for non-proteid nitrogen in the blood and have a low index of excretion indicating defective excretion of nitrogenous substances. "We assume that the toxie substance is a nitrogenous body and so at the same time is poorly excreted. Very likely this is true, but as yet it is only an assumption and should be recognized as such. Decreasing food nitrogen, like decreasing food salt, very probably leads to renal rest and improvement in renal function and so to better excretion of toxie substances. Much eareful observation, how- ever, is needed as to the effect of dietary limitations on renal function before we can diet rationally our patients with nephritis. Just the same thing holds with regard to the desirable amount of liquids for a patient with nephritis. In the patient with redema, water reduction is indicated. Without edema we are far from sure how to proceed in the question of the amount of fluid to be given. Observation of the relation between the amount of fluid intake and urine output helps us, NEPHRITIS PROBLEM 319 but in some cases definite renal hypersensitivity is present and we do not know the relation that exists between fluid intake and hypersensitivity with regard to renal fatigue, renal irritation and progress in renal damage. Here again much more careful observation is needed. Our attitude towards dietary restrictions must be interwoven closely with that towards diuretic drugs. Water, salt and some of the nitrogenous constituents of food are diuretic in their action inasmuch as they increase urinary excretion. In considering dietary regulations we have emphasized the importance of con- sidering the element of renal fatigue and of renal irritation in determining the advisability of certain dietary limitations. These same factors must be considered in regard to diuretic drugs. The effect of digitalis in improving cardiac function is one of our most brilliant therapeutic effects, and yet we know that with too long- continued doses of digitalis damage to cardiac function quickly results. For digitalis we have quite good indications as to when it is doing damage. Do diuretic drugs have any analogous relations to renal function? May they do damage to renal funce- tion? Have we indications of an injurious effect from them ? I have already pointed out that in acute experimental renal lesions we do have considerable evidence that diuretic drugs are harmful and there is very little evidence of a beneficial action. For chronic lesions animal experimentation gives us no satisfac- tory material for testing and so we are compelled to base our opinions on observations of patients with chronic nephritis in whom complicating factors render judgment more likely to be fallacious. Diuretic drugs under certain conditions can increase the output of urine. If there is present a considerable degree of edema theocin and theobromine sodium salicylate will increase the amount of urine in certain patients. In our experience *° this has been mainly in patients with cardiac insufficiency rather than renal insufficiency. Without cardiac insufficiency and with renal insufficiency diuresis in our experience usually does not occur from diuretic drugs even when the cedema is marked. This suggests that if the renal damage is in itself sufficient to cause cedema, diuretics are unable to stimulate the kidney directly or 320 HARVEY SOCIETY indirectly to sufficient additional activity to increase the flow of urine. When a diuresis occurs what constituents are increased ? Of course the output of water is increased. Some recent obser- vations of ours show that with the increase in water there is a considerable increase in sodium chloride ouput, but relatively much less of an increased output of nitrogen. The removal of the excess of fluids from the patient’s tissues is certainly bene- ficial, but their removal may not improve renal function. In fact, our observations show that following an active diuresis there may be for a day or two a decrease in renal function as measured by the index of urea excretion. Such a decrease we have seen more often than an increase. Probably this is due to renal fatigue and not to renal damage. Even so, it indicates the possibility of harm from overyigorous diuresis. If in the presence of edema nitrogen output is only moderately increased by diuretics, this should arouse skepticism as to the value of diuretics in patients without cedema in whom their toxic condition indicates retention of toxic substances. What evidence have we that diuretics in any way increase the output of these hypothetical toxic substances possibly nitrogenous in nature? It seems to me that we have very little acceptable evidence for this. Although in cases with- out obvious cedema after the use of diuretics we do at times get a considerably increased elimination of fluid and salt, to a less degree of nitrogen, we do not know that this benefits the renal condition. The possibility of doing damage with diuretics always has to be kept in mind. Unlike digitalis we have very unsatisfactory signs of real damage from diuretics. If a diuresis does not occur it is probable that a continuation in the use of diuretic drugs will work an injury. If a diuresis does occur we are not sure that this is beneficial except in so far as the removal of fluid makes the patient more comfortable. Possibly our tests of renal function may prove very useful in determining benefit or harm from diuretics. At present the factors concerned in diuresis are far too little known and much study of the action of diuretics in chronic nephritis in man are needed before we are prepared to utilize them rationally in the treatment of nephritis. In such a study it would seem that very little help is NEPHRITIS PROBLEM 321 to be expected from experimental pharmacology. The work must be done on man. With our greatly improved methods of clinical observation and particularly with our methods of testing renal function our clinics probably can advance our knowledge of the action and use of diuretics. We must acknowledge frankly the present meagreness of our knowledge of diuretics and approach the problem with both enthusiasm and scientific skepticism. With this attitude I feel that the study of diuretics is an impor- tant problem for the clinician to work on. Moreover it gives promise of yielding important results. Certainly almost any definite knowledge of the laws or principles underlying the action of diuretics will be an addition welcome to all clinicians. So far I have confined my attention to renal structure and to renal function in relation to diet and diuretics. Other important problems in nephritis are concerned with certain results of the disturbed renal function. In this group come hypertension, uremia, albuminuric retinitis, edema, dyspnea, ete. Of them much study has been made and some of them have been discussed by previous Harvey lecturers and I can add relatively little to what they have said already to you. Graphic methods of studying the cardiovascular apparatus have emphasized the early occurrence of hypertension, cardiac hypertrophy and myocardial disturbance in many eases of nephritis, but they have not thrown much light on the relation between them and the renal lesion. In my own clinic where we have made much use of the electrocardiograph in the study of the cardiac condition of our cases, I have been struck with the great frequency of cardiac changes in cases of chronic nephritis and the very great importance of them as causes of the patients’ incapacity. Particularly interesting in this connection have been cases in which hypertension seemed undoubtedly the primary condition, myocardial disturbance secondary and renal insuffi- ciency a negligible feature in the case. Studying the cases we find very slight evidence of impaired renal function and in a few fatal cases the kidneys have been essentially normal as far as glomeruli and tubules were concerned. There was marked chronic passive congestion of the kidney, for these patients have 21 322 HARVEY SOCIETY died from cardiac insufficiency. Arterioles everywhere showed thickening and therein seemed to be the cause of the hypertension. It has seemed that in this type of case myocardial insufficiency was slower in appearance than in patients with renal insufficiency and hypertension. All clinicians are familiar with this type of patient, but it seems to me that they are probably more numerous than we have supposed, because without studying their renal function we have assumed them to have a more extensive renal lesion than they do and so classified them among our cases of chronic nephritis when really they did not belong there. Pos- sibly a more careful study of this group may throw some light on the mechanism of the hypertension in chronic nephritis. None of our studies have been concerned with the cause of uremia. Its importance is obvious, but none of our group of workers have possessed the chemical knowledge needed for such a study. The primary problem in uremia is to know the nature of the toxic substance that causes the uremic manifestations. Important studies have been made on the problem in other labora- tories, but not yet have they advanced to the point of giving us a means of recognizing toxic substances and studying their distribution and effects as a part of the problem of the clinical study of nephritis. In our cases Woods *® has made a careful study of the eye grounds to see if any relation between albuminuric retinitis and renal function could be found. It has been claimed by Widal and his co-workers ** that albuminurie retinitis was closely related to nitrogen retention. To see if this was true the total non- protein nitrogen of the blood was determined in a group of cases and the figures obtained tabulated along with the changes observed in the retina. Naturally since in cases of severe nephritis retinal changes are more common than in mild eases, our cases with high non-protein nitrogen figures showed retinal changes more often than those with low figures. However, there was no relation to be made out between the retinal disturbance and degree of nitrogen accumulation in the blood. To see whether there was any parallelism between the occurrence of retinitis and the amount of various forms of nitrogenous bodies in the blood, deter- NEPHRITIS PROBLEM 323 minations of urea, uric acid, creatin, creatinin, ammonia and amino-acid nitrogen were made, but no relationship could be found to exist. It was thought possible that some relation might exist between the amount of non-proteid nitrogen in the spinal fluid and retinal changes, so this was determined, as well as the urea content of the spinal fiuid, but here again no relationship was found. It was interesting to see how closely parallel to each other ran the urea values for blood and spinal fluid, there being very slight differences between the two, while for total non- protein nitrogen the amount in spinal fluid lagged very consider- ably behind that in the blood. Not enough spinal fluid was avail- able for determination of the other nitrogenous bodies which we quantitated in the blood. The dyspneea of nephritis is of much interest ; often it is a very distressing symptom in our patients. It presents itself in many forms. Very often it is paroxysmal with a proneness to nocturnal attacks. Periodicity commonly is a feature, often of the typical Cheyne-Stokes type. In other cases the dyspncea is present almost continuously. In a few cases it is of the low deep variety, the air hunger type such as we see in association with diabetic coma. In many patients the dyspnea in large part is associated with the cardiac insufficiency which is marked as a condition due to the hypertension and myocarditis secondary to the nephritis. In other cases the cardiac element is slight or absent. In our clinic Peabody ** has studied the relation of the dyspncea to aci- dosis, as this has been claimed by some to be the chief factor in the production of the non-cardiac dyspnea of chronic nephritis. Peabody found that in mild cases of nephritis there was no evi- dence of acidosis. More advanced cases show an acidosis in the sense that much larger amounts of alkali are required to render the urine alkaline in reaction than is normally the case. Such patients, however, show no decreased CO, tension in the alveolar air. It is only in the very advanced cases that acidosis becomes marked enough to cause a decreased CO, tension in the alveolar air. The evidence at hand favors acid retention in these cases of nephritis rather than an abnormal formation of acid. The usual type of dyspnea in nephritis is a periodic breathing of an ——— = 324 HARVEY SOCIETY irregular shallow type and this will persist after the giving of an alkali has rendered the urine alkaline and restored the CO, ten- sion to a higher value. In some cases the dyspnea is of the ‘air hunger’’ type and this may disappear after giving alkali. Acidosis does not seem to be a sole factor in any sense in the usual dyspnea of nephritics who have no cardiac insufficiency. It probably has some influence, but other factors undoubtedly are active. Very likely variations in the sensitivity of the respiratory centre play an important part. Ifthe respiratory centre is abnor- mally sensitive then very slight changes in the blood may be effective under these abnormal conditions and both changes in the respiratory centre and in the blood are concerned in the dyspnea of nephritis. What I have presented to you this evening is far from a com- plete account of the very interesting phases of the nephritis prob- lem. As I said in the beginning I have made it fragmentary by limiting my discussion to those phases on which I and my asso- ciates have worked. I have purposely refrained from presenting tables, figures or statistics, as such details are so difficult to keep in mind while listening to a paper. They may be found by those specially interested in the individual reports of our work which have been published in current medical journals since 1908 and for which references will be found in this address when printed. If I have succeeded in rekindling any interest in the fascinating problems of nephritis by presenting this account of our work, my purpose has been fully accomplished. REFERENCES Boston Med. and Surg. Jour., 1908, elviii, 696. * Christian: Boston Med. and Surg. Jour., 1908, elix, 8. 3 Christian and O’Hare, Jour, Med. Res., 1913, xxiii, 227. *Frothingham, Fitz, Folin and Denis, Arch. Int. Med., 1913, xii, 245. 5 Arch. of Int. Med., 1915, xv, 524. ° Christian and O’Hare, Arch. of Int. Med., 1913, xi, 517, and O’Hare, Arch. of Int. Med., 1915, xv, 1053. 7 Walker and Dawson, Arch. of Int. Med., 1913, xii, 171, ®’ Arch. of Int, Med., 1914, xiii, 945. ® Christian, Arch. of Int. Med., 1914, xiv, 827. 2” Arch. of Int. Med., 1915, xvi, 330. NEPHRITIS PROBLEM 325 4 Arch. of Int. Med., 1911, viii, 481. ® Arch. of Int. Med., 1913, xii, 49. 48 Schlayer and Hedlinger, Deutsch. Arch. f, klin. Med., 1907, xe, 1. * Mouvement Med., 1913, 1, 1. See paper of Frothingham and Smillie, Arch. of Int. Med., 1915, xv, 204, and Frothingham, Am. Jour. Med, Sc., 1915, exlix, 808. 1 Frothingham, Am. Jour. Med. Sci., 1916, cli, 72. “ Jour. Pharm, and Exp. Therap., 1910, 1, 579. 48 Deutsch, Arch. f. klin. Med., 1911, cii, 248. ® Deutsch. Arch, f. klin. Med., 1914, exiv, 120. *0 Folin and Denis, Jour Biol. Chem., 1912, xi, 493. Van Slyke and Cullen, Jour. Biol. Chem., 1914, xix, 211. # Physiologie Normale et Pathologiques des Reins, Paris, 1914. 3 Jour. Exp. Med., 1915, xxii, 212. *0’Hare, Arch. of Int. Med., 1916, xvii, 711. * Am. Jour. Med. Sci., 1915, ci, 635. 78 Arch. of Int. Med., 1915, xvi, 577. 77 Widal, Morax and Weill, Ann. d’ocul., 1910, exlili, 345. 2 Arch. of Int. Med., 1911, xiv, 236 and 1915, xvi, 955. STUDIES ON INTERMEDIATE CARBO- HYDRATE METABOLISM By DR. R. T. WOODYATT Otho S. A. Sprague Memorial Institute Laboratory for Clinical Research INTRODUCTION | 1842, F’. Bidder observed that the metabolism as a whole comprised two circuits, a greater circuitbeginning with the entrance of matter into the body from the outside world and ending with the return of this matter to the outside world; and a lesser laid between the ends of the greater, this lesser circuit beginning and ending within the organism proper. In 1847, Bidder and Schmidt, alluding to this distinction (in their mono- graph on The Digestive Juices and Metabolism) employ the term ‘‘Intermediarer Stoffwechsel’’ to designate the transfor- mations of matter within the organism proper. This, as Lusk has noted, would seem to have been the origin of the term. Since then it has been used by some in more restricted senses and applied particularly to the purely chemical processes which occur as intermediate steps in the synthesis, destruction or transfor- mations of proteins, fats and carbohydrates or other body sub- stances. According to this usage processes of absorption, secre- tion and circulation or transport generally would be omitted from the study of intermediate metabolism, but owing to the intimate connections which exist between the physical and the chemical phenomena, the older usage is here preferred. During the past few years the staff of the Sprague Institute Clinical Laboratory, including E. J. Witzemann, W. D. Sansum and Russell M. Wilder, have carried out detailed studies of certain phases of this general problem with particular reference to the intermediate metabolism of the sugars. The phases studied have been selected with reference to their bearing on certain general views. To facilitate the discussion of this work and in order that it may not appear disconnected, it will be necessary to develop briefly the point of view from which it was undertaken. 326 CARBOHYDRATE METABOLISM 327 It is assumed tacitly that the intermediate metabolism taken as a whole represents multiple separate chemical reactions, or groups of reactions, confined to certain places or media with provisions whereby certain material and energic reaction prod- ucts separate out of each and are carried among and into others, thereby bringing all of the separate chemical reactions into a sort of dynamic equilibrium. For purposes of study it is convenient to recognize two metabolic spheres: a sphere of chemical changes in which molecules are breaking down, rearranging, building up; and a physical sphere or sphere of transport, in which intact mole- cules, singly or in clusters, are in transit between the sites of chem- ical change. A third or energie sphere may, for the purposes of the moment, be omitted from discussion. The first two spheres imply matter existing in two corresponding states: that undergo- ing chemical changes consisting of smaller particles carrying an excess of positive or negative charges such as ions and 1on-like residues in general, that showing little chemical reactivity but greater physical motion—consisting in the larger and relatively non-dissociated or saturated molecules and of clusters of two or more such molecules, these clusters ranging in size through the gamut of dimensions which characterize colloid particles. Anatomie counterparts for these spheres are sought in funda- mental classes of media which constitute phases in the hetero- geneous or colloid structure of protoplasm and body fluids gener- ally, this being merely the application to the study of intermediate metabolism in higher animals of the precept of Bichat to ‘‘first isolate the fundamental tissues of which all organs are made up and study each, no matter where it is found, in order finally to understand the several organs in their special characteristics,”’ and in harmony with the viewpoint of the general physiologists made familiar through the work of such writers as Verworn, J. Loeb, Kiithne, Weinland, A. P. Matthews, M. H. Fischer, Lillie and others. A tendency in the special literature covering various aspects of the intermediate metabolism in higher animals is still to deal with special organs as things separate and distinct, and in accordance with this tendency the circulating media, especially the blood, might be considered as representative of the physical 328 HARVEY SOCIETY and the cells of the chemical sphere. The blood plasma is of course essentially a medium of transport in which chemical reac- tions are avowedly slow. The work of Michaelis and of McGuigan has shown specifically for glucose that this metabolite exists in the blood in a state of physical solution. The cells, on the other hand, are recognized as the chief sites of active chemical changes. But individual cells possess powers of absorption, secretion and chemical correlation, and even in the blood plasma some chemical changes occur—wherefore it is preferable to regard both plasma and cells as made up of the same fundamental types of media but in different proportions, like the fat and the watery phases in cream and skimmed milk respectively. If in the study of intermediate metabolism we deal with the fundamental media which constitute the phases of such systems, it is readily understandable how metabolites such as glucose, amino-acids, and others, existing within the body, may be dis- tributed between such phases in definite proportions, how in one type of medium they may exist in a state of simple physical solu- tion, and in another encounter conditions (enzymes, catalysts, or what not), which will favor a high degree of chemical] dissocia- tion. Illustration is afforded by the well-known behavior of a fatty acid such as butyric acid, which when added to an emulsion of benzene and water divides itself between the benzene and the water phases in accordance with laws which pertain to the par- tition of dissolved substances between two partly immiscible solvents. The butyric acid then exists in the benzene in simple physical solution as single molecules in dynamic equilibrium with clusters of two or more molecules—the twos predominating—while in the water the butyric acid exists as single molecules in dynamic equilibrium with hydrogen and butyrate ions. In the water the dissolved substance is sufficiently dissociated to enter into chemi- cal reactions characteristic of acids, such as the turning of ordinary indicators, the liberation of CO, from sodium ear- bonate, etc., but in the benzene such reactions occur if at all only toa very minute extent. The degree of dissociation of the butyric acid in the water phase may of course be greatly influenced by the simultaneous presence there of other substances. CARBOHYDRATE METABOLISM 329 The study of intermediate metabolism resolves itself therefore into a study (1) of the chemical reactions which occur among metabolites when mixed together in different proportions in homogeneous media which favor a high degree of dissociation and chemical reactivity; (2) of the physical or physico-chemical reactions which occur when they are mixed in physical solvents; and (3) of the modifications which occur when the physical and chemical solvents are in contact with one another as phases in an heterogeneous system. For the explanation of reactions of the first type, chemical dissociation and the laws of chemical equi- librium will be of the greatest service, for the second, the laws of molecules, and for the two taken together, the laws of equi- librium in heterogeneous systems. In the final analysis all phenomena of intermediate metabolism must represent the work- ing out of these underlying principles. METHODS The recognition of processes proceeding within the organism in accordance with laws of chemical equilibrium must necessarily depend on the successful application of the principles of quanti- tative chemistry to the study of various biological reactions now known in a purely qualitative sense. Indispensable to the move- ment in this direction is the development of refined methods of urine, blood and tissue analysis which has received such material advancement in this country through the efforts of Folin, Van Slyke, S. J. Benedict, Shaffer, MeCrudden and others. A fur- ther necessity consists in methods which will enable us not only to detect but to create at will within living cells different, defi- mitely related concentrations of selected substances and to main- tain these concentrations for periods of time sufficiently long to permit measurements of the rates at which different physio- logical processes proceed under these conditions. When dealing with simpler marine forms definite concentra- tions of selected substances may be created within the cells by adding known quantities to the sea water surrounding them, and to maintain these concentrations it is only necessary to make the volume of water sufficiently large in proportion to the mass 330 HARVEY SOCIETY of the cells employed. In the higher animals the sea water has its counterpart in the circulating media, and to produce a definite concentration of a given substance in the cells it may be made to assume a certain concentration in the blood. But since the ratio of the blood volume to the cell mass is small, in order to maintain a uniform blood concentration, the substance must be added continuously to the blood exactly as fast as it disappears from the blood into or through the cells. Methods of administra- tion in which the substance must be absorbed from the alimentary tract or a subcutaneous, intramuscular, intraperitoneal or other local injection site prior to entering the general circulation, are open to the objection that absorption rates vary with many factors which are not subject to experimental control and but sluggishly and within limits to those which are. An exception should be made of intrapulmonary administrations. Owing to the expanse of absorbing surface presented by the alveoli and the great perfec- tion which has been attained in the development of respiration methods, it is exactly in this field that the most striking progress has been made in the study of quantitative aspects of intermediate metabolism and it is to such methods that the pharmacology of the inhalation anesthetics owes its distinctive character. But only gaseous and volatile substances are susceptible of adminis- tration by inhalation. The majority must be administered in solution and the practical problem then resolves itself into one of ways and means for making direct intravenous injections at predetermined rates and of sustaining them uniformly for long periods of time. A number of writers have devised apparatus for this purpose, but with the exception of a motor-driven quantitative pump de- scribed by Friedenthal, and exhibited at the International Con- gress of Physiologists at Gréningen, in 1913, none would appear to have embodied the qualifications necessary for work of the type under consideration. Nor are we aware of the existence in the literature of descriptions of experiments which would indi- cate that intravenous injections have been carried out with any type of apparatus at exact rates for periods of time exceeding three or four hours. During the past two years machines have 4 y Pa ~~ Yr penegereees * 6 arent Apparatus for Continuous Perfusion. CARBOHYDRATE METABOLISM 331 been developed and used by the staff of our laboratory by means of which direct intravenous injections have been given to dogs and rabbits at predetermined uniform rates for periods of from 4 to 24 hours, and to men for as long as five hours. LHarler models have been demonstrated from time to time, the cut illus- trating a newer and more satisfactory instrument. It consists of a graduated glass barrel with a metal piston, the nozzle con- necting with a metal block in which is housed a metal valve con- structed on the principle of a two-way stop-cock. obtained the opposite result, but the general conclusion has been that caffeine ingestion in man does not lead to increased uric acid formation. In Table IV are recorded two experiments upon our Dal- matian to determine the effect of caffeine given subcutaneously. A daily dose of 100 milligrams of the drug is followed by a slight decrease in the uric acid output. Although the variation is not marked, we have obtained it in each of three similar experiments. With a larger dose (200 milligrams daily) of caffeine there is scarcely any perceptible effect upon the uric acid output, but there is a very notable retention of nitrogen during this period. 358 HARVEY SOCIETY In Table V is recorded an experiment to study the effect of caffeine ingestion upon the uric acid output in man. The micro- method of analysis was employed for the uric acid determination, a method which we have found to be highly accurate. The sub- ject was placed upon a purine-free diet, which was kept approxi- mately constant but which was not weighed. During the pre- liminary period five cups of a caffeine-free (Kaffee Hag) were ingested daily. During the caffeine period the diet was just the same, but to each of the five cups of coffee taken were added 200 milligrams of caffeine, making a total of 1 gram of caffeine per day. The uric acid figures of the urine showed a slight but definite and progressive increase during the caffeine period, which increase was still somewhat apparent for two days after the caffeine intake was stopped. This experiment was so carefully conducted and the results are so clearcut that I believe we are justified in concluding from it that caffeine may lead to increased uric acid formation in man, and furthermore, as evidenced in Tables III and IV, that it may lead to some nitrogen retention. Indeed, on the basis of our experiments, I am somewhat skeptical as to whether caffeine, even in small doses, is quite so innocuous a substance as we have assumed it to be. In Table No. VI experiments are reported showing the effect of the addition of nuclear material in the form of thymus gland to the diet of the Dalmatian. It will be noted that after the thymus ingestion the increase in the uric acid eliminated is not nearly so great as the increase of allantoin. Thus, on the purine- free diet the uric acid nitrogen is more than double that of the allantoin, while after the thymus ingestion the increase in uric acid nitrogen eliminated is only about one-half the increase to be found in the allantoin nitrogen. These results might be taken to indicate that exogenous nuclear material undergoes catabolism along different lines from that of the endogenous purine-contain- ing material. The question involved will require further work before any definite conclusion can be drawn. This is especially evident when we note (as shown in Table VI) that urie acid administered subcutaneously is followed by a marked inerease in the allantoin output, and this in spite of the fact that the uric URIC ACID 359 TaBLeE IV Total Uric acid Allantoin N N N Remarks grams grams grams 5.37 0.129 5.65 0.126 | 0.213 6.07 0.128 ; 5.52 0.125 100 mgm. caffeine. 5.41 0.113 0.192 100 mgm. caffeine. 5.23 0.116 100 mgm. caffeine. 5.13 0.115 5.20 0.128 5.34 0.127 5.31 0.128 4.82 0.136 sats 200 mgm. caffeine. 4.80 0.139 ane oe 200 mgm. caffeine. 4.60 0.127 ae oa 200 mgm. caffeine. 4.22 0.123 NEG cee 200 mgm. caffeine. 4.22 0.128 Seton 200 mgm. caffeine. 4.51 0.125 4.72 0.124 4.90 0.122 4.96 0.127 TaBLe V.—Sussect FE. O. Volume Total Creatinine | Uric acid c.c. N N N Remarks grams grams grams 1300 12.60 0.495 0.540 1290 13.12 0.486 0.522 1300 13.74 0.508 0.540 1240 10.76 0.504 0.558 | 1 gram caffeine. 1640 10.42 9.484 0.564 | 1 gram caffeine. 1210 8.03 0.519 0.642 | 1 gram caffeine. 1080 10.74 0.531 0.702 | 1 gram caffeine. 1200 9.05 0.543 0.636 1100 13.53 0.531 0.600 1400 12.51 0.502 0.546 360 acid is recovered quantitatively as such in the urine. HARVEY SOCIETY It seems probable that uric acid and allantoin are inter-related in metab- olism in other ways than have been heretofore assumed. We finally turn to what may be regarded as essentially the TABLE VI F Increase | Increase | U U Allan- | +merease | } Tete Jammoaia| acid | “doin | %¥H¢ | in allan aul aaeros grams grams grams pee poe 4.37 | 3.86 | 0.120 | 0.050 "Normal diet. 4.54 4.03 0.125 | 0.050 4.82 4.36 0.127 | 0.050 6.48 5.87 | 0.177 | 0.210 Same diet+100 grams 6.86 6.15 0.197 | 0.210 Jos 0.480 thymus daily =0.32 7.30 6.58 | 0.200 | 0.210 | grams purine N. 5.75 5.27 0.129 | 0.058 Normal diet. 5.54 5.08 0.132 | 0.058 5.27 | 4.84 | 0.137 | 0.058 | 5.18 4.50 | 0.290 | 0.115 Same diet +500 mgm. of 5.13 4.47 0.299 | 0.142 uric acid subcutaneously. 5.00 4.30 0.305 | 0.133 5.02 | 4.54 | 0.124 | 0.066 most modern field of uric acid research, the investigations of uric acid in blood. This field of work will be irrevocably associated with the name of Otto Folin. For many years Folin, more than any other man either here or abroad, has been a maker of high- grade tools for the biochemist. In methods of urie acid research he has recorded another notable achievement. Before the Folin method was available it was questionable whether uric acid existed at all in normal human blood. Quantities up to 300 eubie centimetres were necessary for even approximately accurate results with bloods known to contain an excess of urie acid. Now we are able to determine uric acid with accuracy in twenty or even in ten cubic centimetres of normal human blood. The method is equally applicable to the blood of other species, URIC ACID 361 The finding of uric acid in pathological human blood dates I} back to the work of Garrod in 1848. With a truly outrageously inadequate method of analysis this brilliant worker was able to obtain results of permanent value and to demonstrate for the first time that there is an accumulation of uric acid in the blood of gout and nephritis. But from the time of Garrod until the introduction of the Folin method almost no progress was made or even attempted in this field of work. The recent researches on uric acid in blood have yielded some results of interest in connection with lower animals as well as in man. In order to appreciate these results we must look backward for a moment. A hypothesis to explain gout, based upon the presence of two forms of uric acid in blood, was put forth a num- ber of years ago and the questions involved here have received a great deal of attention from the experimental side ever since. Pfeiffer *° thought that he had obtained proof of two forms of uri¢e acid in urine, but his work was shown to be erroneous. Kossel and Neumann, Goto,”’ and Minkowski called attention to the fact that uric acid seems to form a compound with thymic acid and Minkowski suggested that uric acid may circulate in the body in this form. There has been no experimental proof that this is the case. One interesting observation of Minkowski’s has been interpreted as showing that some purines, at least, are catab- olized in the body in combination and not as the free base. Minkowski found that when free adenine was given to dogs the gastro-intestinal tract showed marked inflammation and a erystal- line deposit of what he thought was adenine was to be found in the kidneys. These effects did not follow the ingestion of adenine in the form of nucleic acid. Subsequently, Nicolaier 7° showed that the deposits found in the kidneys after adenine ingestion consisted of di-oxy-adenine, thus showing that the organism may oxidize a purine before splitting off the NH, group. Such obser- vations as these, and especially the more recent work of Bloch,”® have tended to show that uric acid may exist in the organism in more than one form, but positive evidence has been lacking. Through use of the recent methods of blood analysis it has been shown beyond a doubt that in some mammals, at least, uric acid 362 HARVEY SOCIETY exists in the blood chiefly in combination. In fresh ox blood, for instance, using the Folin method of determination, we find about one-half of one milligram of uric acid in 100 grams of blood. If, however, the blood filtrate after removal of protein is boiled with hydrochloric acid and then the uric acid determined, it is found that the quantity present is more than ten times that orig- inally obtained. The same figure is ultimately reached if the whole blood is simply allowed to stand, thus indicating that an enzyme is present in blood which can split the uric acid combina- tion. The combined form of urie¢ acid is contained wholly in the corpuscles of the ox blood. In birds, in which urie acid is an end-product, the blood contains none of the combined urie acid ‘and that present is almost wholly in the serum. It is of interest to note that the blood of the ox, an animal which eliminates almost - no uric acid in the urine, contains actually about 50 per cent. more uric acid than does that of birds. In the ox blood it is combined and in the bird’s blood it is free. These results have been received with considerable skepticism in many quarters, but since the uric acid can be readily quantitatively isolated as such, the correctness of the work is not open to question.*® The results seem to show that it is probably form rather than quantity of uric acid in blood which is of importance. These findings have been extended to the blood of other species and the results have shown that, with the exception of man, all mammals probably have two forms of uric acid in the blood. In the case of human blood the data so far available are not conclusive. It is quite probable that here, too, uric acid exists in the blood in at least two forms, but they are quite unlike the forms present in ox blood. A new technic is being developed to study this question. The clinical findings in regard to urie acid in human blood are of considerable interest. The field of work here is new and we must be cautious in drawing conclusions. The recent re- searches of Folin and his pupils in Boston and of Myers and Fine at the Post-Graduate Medical School in New York have shown that normal human blood contains from one to three milligrams of uric acid in 100 grams of blood. In lead poisoning, in gout, and in nephritis, the uric acid content of the blood is usually URIC ACID 363 markedly increased, and the determination of uric acid in the blood of suspected gout is of unquestioned value. In connection with gout the recent researches have shown that the old idea that in this condition the blood becomes ‘‘saturated”’ with uric acid must be abandoned. The solubility of urie acid in blood serum has been shown to be much greater than the con- centration of uric acid occurring in the blood of gout. Further- more, in nephritis the uric acid content of the blood may be quite as high as in gout for long periods of time without any symptom of uric acid deposition occurring. We must therefore assume that in gout there is not only a kidney insufficiency in respect to uric acid elimination, but that there is also a direct vicarious excretion of uric acid from the blood stream into certain tissues where it finally reaches the saturation point and is deposited in the form of sodium acid.urate. The view of Min- kowski and others that the uric acid circulates in gout in some abormal form, finds some support in the results of studies upon the blood of lower mammals mentioned above. It is my opinion that this view will prove to be the correct one. In connection with the use of salicylates and of atophan in gout, it is of interest to note that Fine and others have shown that the administration of either of these drugs to gouty patients is followed by a prompt drop in the uric acid content of the blood. Frequently this drop may be so great that the uric acid practically wholly disappears from the blood for a time. With continued administration of either drug, however, the uric acid reaccumu- lates in the blood. Hence it is of no service to give salicylates or atophan continuously. Whether, by alternating these two drugs for a period of a week or two with each, the blood could be kept relatively free from uric acid continuously, has not yet been determined. Table VII, for which I am indebted to Professor Myers of the Post-Graduate Hospital, illustrates the findings of Myers and Fine in regard to the early accumulation of uric acid in the blood in nephritis. From this table we should infer that of all the common products of metabolism uric acid is the first to | accumulate in the blood when the kidney function is impaired. 364 HARVEY SOCIETY Whether uric acid in high concentration in the blood is per se toxic to the kidney is not yet known. The frequent development of nephritis in gout might be regarded as lending support to this TasLe VII Uric Acid, Urea N. and Creatinine of Blood in Gout and Early and Late Nephritis Uric Acid Diagnosis Creati- nine — lood Urea N Pressure Megms. to 100 c.c. Blood 8.4 72 6.8 9.5 8.0 5.0 Tek 6.6 6.3 8.7 7.0 6.3 6.3 8.0 4.9 8.3 5.3 Chronic Diffuse and 9.5 Chronic Interstitial Nephritis 25 ie 4 6.7 8.3 6.5 22.4 236 16.7 | 210 Typical Cases of Gout Typical Early Interstitial Nephritis 15.0 240 20.5 Typical Fatal Chronic Interstitial ypical Fata ronic Interstitia 143 263 pis 290 Nephritis 13.0 90 11.1 8.7 144 11.0 225 Myers and Fine: Arch. Int. Med., 1916. URIC ACID 365 view. Occasionally, apparently normal individuals are encoun- tered whose blood has a uric acid concentration of over 3 milli- grams per 100 grams of blood. If such individuals could be followed for some years we would probably obtain valuable data upon the possible etiological importance of uric acid in nephritis. REFERENCES. 1Scheele: Opuscular, 1776, ii, 73. ?Pearson: Phil. Trans. Royal Soc., London, 1798, 15. *Fourcroy: Ann. de Chemie, 1793, xvi, 113. *Wohler and Liebig: Liebig’s Ann., 1838, xxvi, 241. 5 Moritz: Deut. Archiv. fiir klin. Med., 1890, xlvi, 217. ®*Medicus: Liebig’s Ann., 1875, elxxv, 230. "Garrod: Brit. Med. Jour., 1883, i, 495. ® Hopkins: Phil. Trans. Royal Soc., London, 1895, 186, 661. ® Kossel: Ztschr. f. physiol. Chem., 1879, iii, 284. 2” Horbaczewski: Monatshefte fiir Chem., 1889, x, 624. * For a discussion of the chemical and biological aspects of the nucleic acids the reader is referred to the admirable monograph by Jones: Nucleic Acids, Their Chemical Properties and Physiological Behavior, Mono- graphs on Biochemistry, Longmans, Green & Co., 1914. * Minkowski: Arch. fiir Exp. Path. und Pharmak., 1886, xxi, 87. * Kowalewski and Salaskin: Ztschr. f. physiol. Chem., 1901, xxxiii, 210. * Burian and Schur: Pfliiger’s Archiv. f. d. ges. Physiol., 1900, lxxx, 241. * Mendel and Lyman: Jour. Biol. Chem., 1910, 11, viii, 115. 1° Givens and Hunter: Jour. Biol. Chem., 1915, xxiii, 299. “Taylor and Rose: Jour. Biol. Chem., 1913, xiv, 419. % Siven: Archiv. f. d. ges. Physiol., 1912, cxlvi, 499. * Raiziss, Dubin and Ringer: Jour. Biol. Chem., 1914, xix, 473. »» Hopkins and Hope: Jour. Physiol., 1898-9, xxiii, 271. #1 Smetanka: Pfliiger’s Archiv. f. d. ges. Physiol., 1911, exxxviii, 271, 275. 22Mendel and Stehl: Jour. Biol. Chem., 1915, xxii, 215. 2 Fine: Jour. Biol. Chem., 1915, xxiii, 471. 4 Burian and Schur: Pfliiger’s Archiv. f. d. ges. Physiol., 1900, Ixxv, 241. * Taylor: Amer. Jour. Med. Sci., 1889, cxviii, 141. * Pfeiffer: Verhandl. des VII. Kongr. f. inn. Med., Wiesbaden, 1886, 444. ™ Goto: Ztschr. f. physiol. Chem., 1900, xxx, 473. 2 Nicolaier: Ztschr. f. klin. Med., 1902, xlv, 359. 2 Bloch: Archiv. f. klin. Med., 1905, Ixxxiii, 499. % Benedict: Jour. Biol. Chem., 1915, xx, 633. MEDICAL EDUCATION IN THE UNITED STATES * PROF. WILLIAM H. WELCH Johns Hopkins University ASSURE you that it is a great delight to me to have this opportunity—and I seize everyone that presents itself—of returning to my old home. I treasure the associations of those © days when I was a part of the profession of New York, and it has been a delight to me to continue in contact with things medical and with my friends and colleagues of this city. I esteem it a high honor to be asked to give one of these lectures. I must pay tribute to the conception underlying the establishment of the Harvey Society. When one considers the purpose of these lec- tures, the opportunities which they offer, and the influence which they exert, it is an honor for anyone to be asked to be a Harvey Lecturer. The purpose of the lectures is to present the results of original research. I am rather glad that Dr. Wallace relieved me of the responsibility of having chosen the subject I am to speak on. It would not have been one of my own choice and I question whether it is altogether suitable for this course of lectures. Nevertheless, it is not altogether undesirable that a lecture on medical education should come under this foundation, because everything that con- cerns research and the conditions favorable for it are dependent upon education, and surely the roots of scientifie research lie in the educational system of the country. I think it is more clear than ever in these days, with the establishment of separate research institutions and the interests attaching to scientific investigation in general, that, after all, without a satisfactory foundation on the educational side, research cannot flourish. It is enough, I think, to point out that such an independent, fruitful research institution as the Rockefeller Institute doubt- less would not have justified its establishment twenty-five years *Delivered April 20, 1916 366 MEDICAL EDUCATION 367 ago. That is because improvements in medical education had to precede the foundation of such an institution, and I venture to say that themes which relate to all the conditions which affect the development of laboratories, all the material conditions so little understood in general which figure in the development of research, are not out of place in a course of lectures where the prime purpose is to present the results of research. I am somewhat at a loss how to treat the subject of Medical Education in the United States which has been suggested to me. It is obvious that it is impossible to cover the whole subject and I must ask your indulgence for selecting certain aspects of it, not altogether connected, but such as seem to me to be particularly of primary, or, at least, of special interest. Nothing is more remarkable in medical conditions in this country than the progress of the last half century in the develop- ment of medical education and of medical science, and especially during the latter half of that period. This progress came first in medical education, and as I have already indicated, I think it was a necessary condition for the subsequent development of investigation in medicine. The progress is remarkable when one contrasts it with conditions which had existed before; more remarkable when one contemplates how very far short we still fall of the ideal. We cannot contemplate with any great satis- faction the early history of medical education in America. Prob- ably medical education had nowhere, at any time, fallen to such a low estate as it did during a large part of the last century in our country. The early traditions, which came from Scotland, were sound. They recognized that a medical school should be a part of a university and they also recognized the essential relationship of such a school to a hospital. But with the rapid development of the country, and largely as a consequence of that rapid develop- ment, new ideas, essentially novel, unheard of before or since, developed as to the organization of our medical schools. I refer to the establishment of independent medical schools without con- nection with universities, without vital connection with hospitals, with the power to grant the doctor’s degree, and that degree carrying with it the license to practice. 368 HARVEY SOCIETY We are so familiar with the existing system in this country that we hardly realize that there has been a distinctive problem in America, the fundamental evil resulting, of course, from the divorce of the medical school from the university and from the hospital, in that each followed its own line of development, with little or no heed to the other. Our problems to-day are, to a very large extent, the result of that condition. They consist to a very large extent in an effort to establish a relationship which should have existed at the beginning between the medical school on the one hand and the university and the hospital on the other. And it is not a little remarkable that on the whole it is much easier to establish the desired relationship with the university than it is with the hospital. Now I do not wish to be too harsh in judgment of the old order of things in medical education in this country. The system was about as bad as it could be, but there were compensations, and these were undoubtedly due to the character and calibre of the teachers in many instances. Even the characteristic medical schools that are of historic interest in the frontier of America had a very remarkable class of teachers and professors—Nathan Smith, Daniel Drake, McDowell, Dudley. Mere mention of these names to one who knows about the history of medicine in this country is enough to indicate that any young man who came under the influence of such teachers as these must have derived great profit. In other words, the results were better than the system. I received my own education here in New York before any marked change or improvement had taken place in these con- ditions, but I entertain and cherish a great feeling of gratitude to many of my teachers. I received stimulus from men like Dalton and Delafield, and later from Dr. Jacobi, my Attending Physician at Bellevue Hospital, and the elder Janeway. Mere mention of these names rouses enthusiasm and interest. We received a stimulus and were brought into contact with high ideals of the profession, notwithstanding all the defects in the system of medical education. MEDICAL EDUCATION 369 Now a change has taken place, and, as I have indicated, a change so great as to mean a definite break from the old order, and it is worth while inquiring as to some of the factors which are concerned in this improvement. The enumeration of them will enable me to make a few comments of a somewhat general nature. There has been, for half a century or more, an awakening of professional opinion on the subject, which, however, has had very little effect on medical schools. If one were to enter into a historical review, it would be necessary to go back as far as 1859 when the Medical Department of Northwestern University established a graded course. Later on, at Harvard and at the University of Michigan, improvements came in as regards stand- ards, methods, and certain requirements for admission. But I trust that it will not be deemed immodest if I suggest some of the contributions which the establishment of the Johns Hopkins Medical School in 1893 made to medical education. It had no monopoly of contribution to progress in this direction, but there were certain conditions which enabled us to make rather distine- tive advances. In the first place, we were fortunately situated, as things were at that time, on the material side. There existed the Johns Hopkins Hospital and the University, and an endow- ment, which, although not large, was larger than any existing at that time for the promotion of medical education. There was the standard set by the University in the promotion of a higher university education, as distinguished from college education, so that we realized that we had an opportunity. We felt that it was not worth while to start a new medical school unless we made an addition to the methods of medical education. When the school was started it had certain preliminary requirements, which still exist, which were not altogether of our own free choice because they were a part of a condition of the endowment which enabled us to begin. I do not propose to dis- cuss in detail the subject of the preliminary education for the study of medicine, but I would point out that the particular requirement which was introduced at that time represented an effort to adjust medical education to the existing, rather anom- 24 370 HARVEY SOCIETY alous condition of general higher education in this country. We require, as you know, a liberal education as represented by a degree in arts and science. Recognizing that the college keeps the students longer than it should for entrance upon professional studies, we ask them to supply training in the sciences funda- mental in medicine, Chemistry, Physics, General Biology, with a reading knowledge of French or German. These subjects— Chemistry, Physics, Biology—in the curriculum of European uni- versities come under the medical studies, so that a comparison with these foreign medical schools represents at least a five-year period of study. We ask the college, then, to supply one at least, possibly two or three, subjects which abroad are included in the medical curriculum. We did not think at the time, nor do we think now, that it is a standard likely to be generally adopted in this country. We have never urged it. It has worked well with us and we are not inclined to make a change. It is an adjustment to existing conditions of higher education. All other efforts to adapt medi- cal education to secondary and collegiate education in America encounter many difficulties. A high school education is not suffi- cient, unless our high schools develop into something more com- parable to the German gymnasium, as there is some tendency to do in the West. But we must try to find a place to stop between the high school and graduation from college. The tendency, which, however, does not seem to be the solution, is to require two years of college work; to bisect transversely, if you will, the college course, and very often associated with that is the telescop- ing of the last two years of the college course into the professional school, so that two years of professional study are counted both for the Bachelor’s degree and for the Doctor’s—obviously a make- shift arrangement. The result of this development of the medical school and college or university apart forms a condition which would never have existed if it had not been for the marvelous development on each side. I do not feel, whatever you may mean by a liberal education, that it is highly desirable that it should be demanded by the medical school. Of course the demand that is really desirable, the sort of education which we all feel is so MEDICAL EDUCATION 371 lacking in most of our medical students, the power of observation, the right attitude toward the subjects he is studying, the capacity to interpret and all of that which is talked of so much now by Mr. Abraham Flexner, may be met by possible improvements in secondary education. Those of us who are interested in medical education must be very much alive to the possible improvements in secondary edu- cation. It is to be hoped that the time will come when the young man may complete his secondary education, have added to that the college education and be enabled to enter upon his medical studies when he is 19 or 20 years of age. This will be solved, I believe, rather by an improvement in secondary education than anything else. Such, in brief, were our requirements for admission, which still hold, to the medical school. I think we can also point to the organization of the laboratory, or so-called pre-medical subjects, on a more adequate scale than previously existed in this country as a contributing factor in the progress of medical edu- cation. The anatomical laboratory, of course, had existed for centuries, from the time of Vesalius, and by virtue of the fact that anatomy was the only subject with which the medical student gained any sort of direct, personal contact with his subject, it had great educational value. It still remains, of course, a funda- mental subject, but it has acquired undue prominence in the medical curriculum by virtue of the fact that it was the only subject which was pursued by laboratory methods until recent times. The physiological laboratory is traced, in this country, mainly to the work of Bowditch in Boston and Newell Martin at Johns Hopkins, but it cannot be said, I think, that physiology had taken the place which it should hold in medical education much before a quarter of a century ago. One of the great marks of progress in medical education is due to the recognition of the fundamental nature of physiological study for the training of the physician, so that the study of the activities of the normal body are, to say the least, just as important as a study of the structures of the normal body, and it is a rather distinctive con- tribution for American medical schools to have established good 372 HARVEY SOCIETY laboratory courses for medical students. I see in the audience Dr. Porter of the Harvard School who has had such an influence and done so much in advancing these courses. It is still difficult to arrange an entirely satisfactory routine course for under- graduate students in the physiological laboratory, but we do more in that direction than is done abroad. The other subjects which we were able to establish upon a fairly adequate basis were pathology, bacteriology, pharmacology and physiological chemistry, and perhaps in the first instance, because this great group of pre-clinical subjects, designated now as laboratory subjects or medical sciences (as if the clinical sub- jects were not a science), for the first time were adequately organized with laboratories, with a group of teachers as heads of laboratories, with their staff devoting their entire time to the work and with an emphasis upon the practical and laboratory training as compared with didactic lectures or demonstrations of the subjects. These first two years of the medical course were founded upon certain principles. In the selection of the teachers, they were ever the best to be found or available, but emphasis was made, in that selection, upon the productive capacity of the men. That qualification of the teacher, the productive capacity, is, in a med- ical school, the important thing and headships were given to men who had earned them by their contributions, and in general their published contributions to their subjects. This guided us at that time. As regards the clinical side, we at the beginning made slower progress. To Osler, especially, we owe the plan which was adopted. The main thing perhaps was the introduction of the English plan of teaching the fourth year students in the wards of the hospital by the system known as ‘“‘clinical clerks,’’ a marked advance, I believe, in clinical teaching. The change from the old order was not so striking on the clinical side as on the laboratory side. At once, you might say, the laboratory side of medical education passed from being the weakest, almost non- existent side, to the strongest side of the medical curriculum. The plan of the organization of the hospital which was estab- MEDICAL EDUCATION 378 lished at this time, in 1893, was, I think, a considerable improve- ment. It consisted mainly in the introduction of a higher pro- fessional staff over the internes, so-called house officers; that is, there were resident physicians, surgeons, gynecologists, obstet- ricians, over the interne. I have often wondered that this system has not been more widely adopted in this country. It offers a very great advantage. It affords opportunities for the prolonged advanced training of the young men and also the young women who are so fortunate to obtain these positions. The positions are for an indefinite period. The young men devote their entire time, of course, to hospital work and are expected to undertake some investigative work. If you recall the names of those who have held these positions as resident physicians and surgeons, I think you will feel that by the time they have left they have established their reputation, and that the value of that system of organization of the professional staff of the hospital is very clear. More recently we have come to hope that we shall be able to initiate a very great reform on the clinical side, in the placing of the clinical portion on the university basis by which the heads of the departments may give their entire time to the work. I shall touch on this point later. These various points, then, I think, mark and set an example for a very considerable improvement in the medical educational system. I do not desire to claim any monopoly on the part of Johns Hopkins University for these advances, because other uni- versities have contributed largely, such as the University of Michigan, but we happened to be first in the field in many of these directions, and I think the plan adopted by Johns Hopkins is one factor which has advanced medical education in this country. The State Licensing Boards have had great influence in exerting pressure on the inferior medical schools, crowding them to the wall and very often driving them out of existence. The principle, of course, is that the license to practice should go with the granting of the degree of Doctor of Medicine, especially when one considers the system and the conditions under which the degree is granted. The influence of these State Licensing Boards 374 HARVEY SOCIETY has thus been very good in bringing up the general average. They have been of no particular assistance and some time ago almost threatened to be a handicap to the better medical schools. Of course we all recognize what such examinations should be. The character of these examinations falls very far short of the ideal. especially in the lack—although there is an improvement with time—but in general, in the lack of a practical examination, so that it is not any real test of the power of the student to use the implements of his profession or of his real living knowledge of the subject. They will improve, doubtless, and it is to be expected that in time conditions will be such that those on the Examining Board will be also teachers in our schools. The Council on Medical Education of the American Medical Association and the Association of American Medical Colleges have done a great deal in improving conditions, especially in lead- ing professional opinion on the subject and inciting to a very considerable degree a moral pressure. There have been at times, I am frank to say, certain tendencies in the Council on Medical Education to make one pause. . I refer to the efforts to ‘‘ stand- ardize the curriculum.’’ I think it a very horrible thing to attempt to indicate the number of hours, for example, to be devoted to the study of a subject, and at one time our State Licensing Boards seemed inclined to introduce some such scheme. Of course we want as elastic a condition as possible. When one considers the importance of adjusting medical education to the changes and advancing conditions of medical knowledge, how absurd to attempt to specify the number of hours to be given to any subject, bacteriology for example. Only a few years ago the subjects of immunology and serology were not thought of as belonging in the medical curriculum, but to-day things have changed and they should be a very important part of the medical curriculum. We owe our great working policy in medical educa- tion to the conferences held annually in Chicago, attended by leading educators, not only in medicine but other subjects as well. Such conferences are very valuable and the publications very interesting and often important. Another great factor is Dr. Abraham Flexner’s report for MEDICAL EDUCATION 375 the Carnegie Foundation. I consider it to be one of the most remarkable and influential publications in educational literature. It has had not only a large influence upon the professional opinion, but especially a large influence on universities and upon public opinion. It is to be characterized as one of the important factors which illustrate this remarkable advance in medical education. But of course the progress of medicine lies back of it all. The face of medicine has changed greatly in the last thirty or forty years, although it is the same medicine in many ways. That medical education should continue without advance during all the great discoveries characteristic of this era, would hardly be conceivable. I have run briefly over the history of some of these factors, because I wish to make some comments of a more general charac- ter. I have already spoken of the development of the laboratory subjects. It is worth repeating, perhaps, that it was a conse- quence of the organization of the laboratories of anatomy, physi- ology, pharmacology, bacteriology, ete., and the selection of men devoting their entire time to the work, selected on the basis of scientific ability, that these great sciences have progressed to the point which they have in this country and of which we are so proud. To give an instance of the close relationship between the progress of medical sciences on the one hand, and of our educational system on the other, it was only two or three years after our medical school had opened that we started the Journal of Experimental Medicine. It was the pioneer journal devoted to the publication of papers of a more or less technical or monographic character in these sciences. I recall so well the doubt expressed as to whether there existed enough material of the sort which was desired to keep the journal alive. We never dreamed of limiting it to any one of these so-called laboratory subjects. We endeavored to select a title which excluded merely practical, clinical medicine, and was not restricted to any one line of research. I cite all this as an example of conditions which existed only a short time ago. It was within two or three years that Dr. Porter found the time had come to establish a Journal of Physiology, which was the first offshoot from the 376 HARVEY SOCIETY Journal of Experimental Medicine, and then came in rapid suc- cession, the Journal of Anatomy, Journal of Biological Chemis- try, Journal of Medical Research, Journal of Infectious Diseases, Journal of Pharmacology and Therapeutics, and still more recently the Journal of Bacteriology and the Journal of Im- munology. Is it not wonderful that in a comparatively short space of time these subjects should have developed to the height of which we are so proud? America to-day, as a contributor to the various sciences of medicine, stands in a position to medicine commensurate with the size and importance of the country. We lay, I believe, probably greater emphasis upon the teaching of undergraduate medical students in the laboratory than is done elsewhere; we devote more time to the teaching of undergraduate medical sub- jects by laboratory courses in certain subjects particularly— I have already cited them—than is done abroad. There are already developed certain distinctive characteristics of our American medical schools, and this is one of them. Of course it makes us inquire whether we are possibly giving undue prominence to some subjects, but I would be the last one to ad- mit that, although at the same time we should bear in mind certain things. We cannot teach in the laboratory more than a very small fraction of the contents of the subject; only a part of it, and that not necessarily the most significant and im- portant. In other words, is there not some risk of acquiring too restricted and limited a conception? Is there not some risk of a loss of perspective in the subject by exclusive emphasis upon teaching in the laboratory? I believe so firmly in the labora- tory method in imparting that kind of knowledge which is really vital, a knowledge that gives power, that I do not wish to be misunderstood and be thought to minimize its value, but I think we must supplement the laboratory teaching by efforts to secure these broader conceptions and this clearer perspective. I have never been willing to give up altogether the lecture. If one does not believe in lecturing, I think he had better not lecture. I think there is some value in a lecture, and I think proper emphasis in lectures and recitations will enable teachers to MEDICAL EDUCATION 377 stimulate the student and exert some pressure to make him read. The students do not read enough. As a rule they know only the subjects which are taught in the laboratory. I will not labor the point, but I would emphasize the fact that we should consider it very carefully. I turn now from the laboratory side of medical education to the clinical side. That, of course, is the central feature. The teaching of the clinical subjects should be carried out along the same general lines. At the start there were efforts in this direc- tion, especially in the use of students in the wards of the hospital, acting as clinical clerks and surgical dressers. I shall not attempt to discuss this system. The plan of organization of the professional staff shall always remain a controversy between the clinical and laboratory side. | When one considers what should be the functions of the head of a principal department of medicine, when one considers that he is responsible for the teaching, responsible for stimu- lating investigation and for having the right sort of men for the conduct of investigation in his field, responsible for the study and care of the patients in the hospital, and the whole organization of the department, it sems to me that it requires no argument that whoever assumes that responsible position as head of a clinical department should be prepared to devote his entire time to it. There is no time to engage in an outside practice. I know that it is urged that the clinical teacher who limits his experience to patients in the hospital is deprived of a very valuable experience to be derived from outside practice. It is a valuable experience undoubtedly. I think it would be more valuable if he had a rural practice. I doubt if anything in the ordinary conditions of a consulting practice in the city is as likely to develop resourcefulness in a physician as a rural practice. In a word, of course, the more varied the experience of the clinician is to be, the more must he be brought in con- tact with patients and unusual conditions, but there are limits to human endurance, time and energy, and the question is, what is the best use of his time? Can we doubt whether it can be successfully maintained that the expenditure of time in seeing 378 HARVEY SOCIETY patients in consulting practice is as valuable to him as the study of cases of diseases in the hospital under all of the opportuni- ties which exist there? The time has gone by when a man can do both competently and with justice to his position as the head of an important clinical department in the medical school. How this condition is to be brought about is, of course, very important. We endeavored at Johns Hopkins University to do this by making no compromises. Through a generous appro- priation from the General Education Board, we have been en- abled to place three of our main clinical departments, those of medicine, surgery and pediatrics, upon the so-called ‘‘ university basis, ’’ or, as more commonly called, the ‘‘ full-time ’’ system. I do not particularly like the name; for teachers under this system are the only ones who have any leisure time. Of course the heads of departments should not be pro- hibited under the new arrangement from seeing private patients, but they are paid such salaries through this endowment that there is no necessity for them to earn a livelihood through private patients. They can see them if they lke, but not hav- ing any financial difficulties, they will see only those that are of special interest to them. Now, our experience thus far shows that the amount of this private practice is kept within pretty narrow limits by the withdrawal of financial necessity. The patient, of course, pays a fee, but the fee goes to the fund for the promotion of the system. I do not see very well how one could justify the raising of a large sum for clinical heads on the university basis if they should supplement their income from private practice. This would be a great injustice to the labora- tory men. The salaries which they receive are much larger than those received by the laboratory men. I do not think outside salary limits desirable for university professors, at least I think university professors who are of the calibre of the men oceupy- ing these positions ought to receive similar salaries, but, as a matter of fact, I think you can justify a somewhat larger salary to the heads of clinical departments on the ground that they are serving the hospital as well as the university ; that they have very responsible duties in the care of the patients and that after MEDICAL EDUCATION 379 all a clinical department, with its staff and hospital branches of clinical and investigatory laboratories, is a larger undertaking than a single laboratory, so that one can defend the paying of larger salaries. But it is sufficient, I think, to say that the opportunity has been presented to us and we have been glad to initiate this system and to pay these salaries. How widely the system as we have adopted it should be generally applied, I am unable to say. It has no saving virtue in itself; it is the men who operate it who are fully responsible for its failure or success. To intro- duce it where conditions are not suitable, where the hospital does not afford the requisite patients and laboratory facilities, and the staff of full-time young men, would be useless. It is only where conditions are suitable that the system should be adopted, but when it is carried out in the uncompromising way that we have done, it undoubtedly marks, I think, one of the greatest improvements in medical education of recent times, and is bound to exert a very great influence on the character of organi- zation of the medical school. We have had it for two years and we like it. I think it has passed the experimental stage as far as we are concerned. I do not wish to say that we are satisfied with our conditions, but it gave us the opportunity to make a very great improvement and we were glad to seize that oppor- tunity. The plan does not necessarily do away with the services of part-time men in the school. Whatever faults there may be in this condition, the outside work is very valuable for a man and makes him a better teacher. He finds a place in the school, only he is no longer the head of the department. I take it that this marks a new career for young men. The very fact that what seems to so many a serious objection in a curriculum, the difficulty of filling positions with men who are qualified for this kind of work, is in itself something of a criticism of the existing system and I believe that one of the great dangers of the new order of things would be the opening up of a most attractive career leading to that of consulting physician. But I do not know what could be better than to enter into such an oppor- tunity as is now offered, devoting one’s time to the study of problems of disease as they are presented by the living tissue, to work in the laboratory and study at the bedside. 380 HARVEY SOCIETY As regards the establishment of the proper relations of the hospital to the medical school, there is much that can be said, but the time has gone by when it is necessary any longer to emphasize the great service which the hospital devoted to educa- tion and scientific work, as well as the humane care of the patients, does for the community. But it is necessary to dwell on the character of organization of the university clinic, as dis- tinguished from the general hospital. You know, those who are familiar with medical education abroad, especially in Germany, that part of it is the clinic, the rest a general hospital. In other words, the mere saying on the part of the trustees that you can use the hospital, is not enough. It is a very considerable under- taking to transform it in whole or in part into a general uni- versity clinic, meaning by that that there is one man in charge with a staff of men, assistants or associates, with a chemical and biological laboratory available for the study and investigation of problems of disease, and all the necessary arrangements for teaching and the treatment of patients grouped as a single depart- ment. That is, in a word, what I conceive to be the proper or- ganization of the true university clinic. I understand that efforts are being made here in New York to establish a clinic on that basis and everyone must realize how important it is to have the right conception of what a true university clinie should be. I have jotted down a great many things, but let me just give them in a word. Certain of these other topics are of especial interest to me. I would like to say something on the general subject of research and teaching and also on the relationship of the independent research institution to educational institu- tions in general. There is a little apprehension, particularly on the part of the university, that the independent research insti- tutions, like the Carnegie Institute of Washington and the Rocke- feller Institute, are getting too much attention; that they draw the able investigator from educational institutions; that they tend to create dissatisfaction. I think, on the other hand, that these research institutions have abundantly justified their ex- istence by their contributions to science. That is, indeed, quite MEDICAL EDUCATION 381 obvious. But I think as time goes on that they will supplement the educational institutions. Anything that increases the oppor- tunities and rewards for the scientific worker is undoubtedly of very great advantage. One reason why Germany has obtained such a high stage in scientific investigation has been because the eareer of the scientific man was made attractive. By rewards I do not mean so much the pecuniary ones as the satisfaction which comes from contributions, the esteem in which the worker is held by the community. I think the opportunity for these careers in this country are enormous and rendered more attractive by the establishment of these institutions. It is true, of course, that some of the very best trained men are withdrawn from the educa- tional field by their work in the research institutions, but it is of very great advantage to the teaching institution to know that such positions are available for students. It increases their value, I think, in that way very much. It acts as a stimulus on the educational institution to further research. As time goes on there will begin to return to the educational institutions men who have had this very superior training in research. I believe, on the whole, that over-multiplication would be unsatisfactory. The future relation between the independent research institu- tion and the educational institution—of course we are speaking of the medical school and medical research institution—the mutual relations, will be advantageous and each is going to be of great help in the end to the other. I must omit a great many topics, which I should like to have touched upon. I wanted to say something about the medical curriculum, optional courses, and many other things. I do not wish to leave the impression that there are no great deficiencies in our own medical school. I have enlarged upon the progress which has been made more in contrast with the past than from a feeling that we have begun to approach the goal. It would be interesting to point out and to dwell upon some of the deficiencies, but time allows an enumeration of just a few. We are lacking in the proper cultivation of legal medicine, a very important subject and one of importance to the clinician. 382 HARVEY SOCIETY Of course we all recognize that one of the great needs of medical education is the establishment of institutions of hygiene. I would like to have said a few words about the teaching of the history of medicine in our medical schools. It adds greatly to the at- tractiveness of medical study, and I believe also to the enjoyment of the physician later in his professional work, to find how knowl- edge came to be. I do not advocate systematic lectures on this subject. I do not know of anything that would be more definitely dull and uninteresting, but there are other ways of cultivating this subject. Are we training men to serve the community in the treat- ment of disease any better than they did in the old days? From the beginning the aim in medical training has been to enable the physician to prevent and cure disease and injury, to relieve suffering, and to preserve health. These aims are the same to-day as they were forty years ago. It is this consistency of purpose which gives the wonderful interest and continuity to the study of medicine. Notwithstanding all of the wanderings of the past, we are striving for the same aim as before. There have been opened out new fields, new vistas, new methods, so that what was suitable for a training to meet these great aims in the past is no longer the best available. The fundamental thing, the fundamental problem in medicine, is to train men to use the re- sources of the medical science and art most efficiently for the prevention and cure of disease, and I believe that while many of the commonest ailments of mankind are no better treated to-day than in former days, we are acquiring a new kind of knowledge of disease more important in its practical values. We feel that the existing knowledge and resources of the medical art are only imperfectly realized, and my belief is that the newer methods of medical education can be most useful in enabling the student to acquire a better scientific knowledge of the nature of disease and enabling him to apply this knowledge more successfully in the treatment and prevention of disease. . ' y4 ifs a tee: ‘ o a = a “ = * = ~~ . \ . i> A . 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