Studies in Scurvy. Part IV: Scurvy and tuberculosis

STI]DIES II\ SOI]RYY BY J. ÂXEL HÕJEB X'omer ¡'i¡st ¡.ssistant at the Chil¡hen's Clinic of the Karolinska Institutef, gtockholm. (Chiet: Professo¡ I. Jundeu.) Thi.s worlc l¿as been, carried, out by øid, of gra,nts fronx the l{aroli,nslea Institattet ancl the Stced,ish Soci,ety for Medôcal, Research. UPPSALA 1924 ÀLMQVIST & \ryIKSEL],S BOKTRYCI(ERI-Ä.-B ACTA P.ry,DIATRICA REDÂCTORES: lN DANfA: C. E. BLOCH, xöreNnevN, S. MONRAD, rösnxul.v¡{. IN X'ENNIA: ELIS LöVEGREN, nor,- sINGFoRS, ARVP YLPPö, HELSINGFoRS. IN TIOLLANDIÄ: E. GORTER, LEIDEN, J.ITAVERSCITMIDT, IrrREcHr, CORNELIA DE LANGE, alrsronoau. IN NORVEGIA: TH, F.RöLICH, KRISTIANIA, AXEL JOHANNESSEN, xnrsrrlxr,l, CARL LOOFT, BERcEN. IN SUECIA: I. JUNDELL, srocrnor,nr,.{.. LICHTENSTEIN, srocxHow,WILH.'WERNSTEDT, srocKHoLM. EDrroR: I. JUNDELL, srocKHoLM Yol. III. Supplementum 17:Y. 1924 Almqoist û Witcselts Bolctrgclcer¿-Aktiebolag UPPSAI.A 1924 To Ørofn""or" -Qtn/ 9{o/"t ',/ TÁeodor Tral¡oÁ This worlt is reryectfully insuibed,.bg T.HE AUTHOR CONTENTS Preface Ïntroductory l'Iethods of experimental sc.rvy, from Holst to the lâtesô investigators Part I. Enanzinal,ion of the antiscorbttt'ic aaltte of som,e Desetuble ltroclucts. Survey of experiments Summary; discussion; concltrsions Part If. Hísto -p atho lo gi,c al s tt c d,i, es. Preliminary notes. Introclucúory The macroscopic changes Technique Nomenclatu¡e Classification of scurvy in different st¿ùges Grouping of the material within these stâges Chapter f. The bone formation in scurvy. ?èeth The endosmal ossification The enchontlral ossification. Cartilage * Four cases of infantile scurvy . t Summary ancl conclusions of Chapter I. Chapter II. Museìes. 'Ihe skeleton musculature Hearü Ohapter III. Liver Chapter IV. Spleen . . .. . Chapter V. Kiclney Chapter VI. Atlrenal Chapter VII. Salivary glancls . Chapter VIII. Lung Chapter IX. Blood ancl vessels. Hemorrhages in scurvy Chapüer X. Connective tissue . 8 I 2g 30 31 QO 0Õ so 38 48 50 60 64 18 22 68 79 QÐ 91 96 100 104 107 109 L74 Pørt III. Discussion of some scurug problems. Chapter I. Scurvy and infection Chapter II. Disposition Chapter III. Latent scurvy Chapter IY. The ca'lcium metabolism in scurvy Chapter Y. Scurvy ancl rickets Chapter VI. fnanition anil scurvy Chapter VII. ,t mocliûecl methotl for experimental rating of the antiscorbutic value of a protlucú Chapter VIII. Pathogenesis of scurvy. Relation of scurvy to other 11ó 1.22 r23 726 128 729 130 cleficiency tliseases Summarg a,nd, conclusi,ons of Parts fI and III Part IV. Scuruy and, tuberculos'is. Chapter I. Historical Chapter II. Experimental study on guinea-pig. Technique ancl survey of experiments fnfluence of scurvy on úuberculosis . fnfluence of tube¡culosis on scurvy . . . Chapter III. Experimental stutly on man. Survey of experiment Criticism ancl conclusion , . . Swm,marg and, concltcs'ions of Part IV . Part V. Re)cortls oÍ cases. Cases belonging to Part I . u), ,, Ð ,t oIY, , II ,),),,,IV,,ilI Literature cited: List of authors 94 nicrophotogrâms. 33 curves in the text. 6 colured plates. . t32 139 I40 t64 169 170 748 \64 L62 172 200 206 234 , 265 . 276 Preface. The work which is here presented was begun in July, 7922. rt would have been impracticable to fulfir it without the possibilities of technical aid offered by clinical laborato. ries. To Professors F. Hnrvscn¡w and G. Ificceulsr, who have allowed me to avail myself of these possibilities and, to whom I am also indebterl for much helpful advice, f beg to express my gratitude. My thanks are also due to professors I. ]u¡vopr,r and U. QurNsnr,, to Assistant professor Dr. C. Kr,rrve, Doctors R. Nonocnnr, G^. Vnsrnr:cr, II. D¡.v¡on, A. WlssÉN, S. Srvn, A. IMllr,cnnrv, Å. Årnnr,urvr, the Dental Surgeon Dr. G. \{.usrrrv, and others, for various reasons, some of which I have mentioned more particurarry in my book. speciar thanks are due to Doctor F. \4f^nr,annrv and Fil. Doctor L. G. Ro¡rnr,r, who have kinclly reacl the proofs. My late father, the historian Nrrs J. Ilö.rrn, who during all his life, beside his practical activity as a teacher, d.evoted himself to scientific work for science's sake, has been my model. My wife, Src¡rp Ilörnn, has been my helper. f have allowed myself as a respectful token of ad.mira_ tion to inscribe my work to professors Äxnr, rror,sr ancilrn¡ooon x'nör,rcn in christiania, the first investigators in the fieltt of experimental scuryy, whose work still remains unrivallecl. Even though the exaggeration is evicrent in x'unk's utterance (7922): usince the experiments of Ifoht and FröIich, no real progress has been macle (in.experimental seurvy), in spite of the numerous publications that have appearedr, yet his worcts show how high Holst and. Frölich's works rank among all the rest. Hagalund' sweden' T'ebruary 1924' J. Aret Höjer. 140 J..\XE], HOJI'Iì generall)' been misinterpretecl, are tlescribed for teeth, end.osrnal ancl enchondlral bone formation. For the connective tissue a general atrophy is desclibecl, lvhich especially overtakes the collagen fibrils. This change is also provedl in the vascular rvalls. In rnuscles, lymphoid tissue, liver, salivary glancl, adrenal and. kidney an atrophy combined" with necrosis has been found. Also in these regions the tissues seern more seyerely struck, the more the sc.urvy is cleveloperl. ft is established that sorne of the most active and most differentiated of the cells in the body are caught earliest antl most severely by the scorbutic atrophy. The changes which have been clescribed rnay be traced at a very early sta,ge of the latent period. The irnportance of subjecting this latent stage to a close study is strongly emphasized. Through these investigations the pathological picture of scurvy has thus been amplified, ancl the principal features of the disease have been analysed a,nd. found to be uniforrnly explainable. PART IV S t:tct'uy cLlld, txultel' czclosi's, CHAPTER I. Historical rev¡ew. An irnportance of the diet to the.progress of tuberculosis has been assumed alreacly by LrNnÉ. He rvrites in 1766: ,Ingesta nimis nutrantia --- noì1ne hinc saepissime oritur Phtisis 'iuvenurn?o On the contrary, subsequent investigators have as a rule regardecl the general malnutrition a,s acting upon the progress of tuberculosis, though the problern up till the present time has evoked a comparatively small interest. Conwnr ancl Kossnr, lvrite in 1913: ,Es ist rvohl clenkbar, class ein abgelrapselter Herd durch Untererniì,hrunE allsgelaugt und die Bacillen mobilisiert werden>. The authors are eviclently thinking of the theory of ,,clemineralisationr. LöwnNsrnrrs, rvho in the tt ô e STUDIES IN SCLIR,YY I4t same textbook (Kor,r,n-IMlssunlrEwx) rvrites the chapter on ,Tuberkuloseimmunität,,, is briefer still. In the first volume of Bn¿unn-Sc¡rnöonn-Bluun¡r¡'nln's'Handbuch der Tuberkulose,,, 1915, HaNs Mucn writes a hundred. pages about >Die Immunitä,tr, without mentioning the influence of the foocl' Fnrnpnrcn M¿.psnn writes in the same volume about 'Disposition und individ.uelle Prophylaxe'. He mentions the malnutrition only in passing a,nd" ends with some rules for the prophylaxis, which a,pply to the cornmunity antl to the individual' The public measures inclutle neutralizing of expectoration' hygien of the infants' miik, settling of the housing problem, sa,natorium treatment for the severest cases, compulsary notification for the arranging of home clisinfection and hospital nursing. The indiviclual prophylactic measures are summarizecl thus: >1. Belehrung cler Einzelnen äber Infektionsgefahr' 2. Erziehung zur Reinlichkeit. 3. Abhältung cler minder 'Wiclerstanclsfâhigen von besonclers gefährcleten Berufen' 4. Kräftigung aller clurch Hygiene cler Schule, Erziehung zum vernänftigen Sport tr' s. w.)) What the a,uthor wishes to set forth rvith regard' to the choice of suita,ble fooct will thus lie containecl in the )u' s' w') - No more does Pnrr,rp (1922), apart from the zomothelapv' mention anything about the relation of different articles of food to tuberculosis. Most of the systematic experiments on the sub'iect tha't have been unclertal<en are clevotecl to this so-called zomotherapy. It originates in experiments by HÉnrcounr and R'rcnnt (1900). These investigators founcl in the case of clogs inocuIated with tuberculosis that a good effect was worked through iniecting iuice from ::aw meat. The zomotherapy consists in feecling through the mouth with larger or smaller quantities of "iuice pressed frotn raw meat. It has been praised by many (RlrsonurnR, Josras, Josr¿'s ancl R,oux, Pnrr,rr), by others not (Srnrxrrz ancl IMnrcnnr). It does not seem to have been macle much use of. Without entering into the cluestion it 142 ,I..-\XEI, IIOJIìR ma,y only be pointecl out, that all those who aclvocate it, ind'rcate that the meat juice is effective only when raw. In this connection I may remark that B¡nr,ow recoülmenclecl rarv rneat juice a,s a good antiscorbutic in infantile scurvy. Ifere I rvould like to mention in a few worcls an experiment rvhich was made by me in the children's hospital 'Samaritenrl during the winter of 191-6-1917. Twenty children of clifferent ages rvith d.ifferent kinds of tuberculosis, most of them with tuberculosis of the bronchial glands, were given a daily ðose of 50-100. ccm. of ran' blood serum each. The lilood. rvas gathered uncler certain precautions at the claill; slaughtering of cattle in the slauqhter-house of Stockhohn and wa,s placed in the freezing-room. The serum rvas taken up by pipet the following day and given to the children in cocoa. It rvas taken reaclily. The experiment rvent on for four rnonths. The effect on the children's state of health seemed striking. Their appetite, colour ancl tonus improveil' and the tuberculous process rvent rapid.ly towarcls healing, as far as coulcl be iudged clinically and. by Roentgen rays' However, only a, small nurnber of the children remainecl in the hospital cluring the whole periocl of the experiment, and there was not a sufficient number of control patients, wherefore the experiment can not be saicl to have been conclusive. Other experiments are few. In 1907, R. Wnrennr macle experiments with different feed.ing of pigs infected' with tuberculosis. These experíments are saicl to have shown that the anirnals fed on a d.iet rich in fat (whole milk ancl oil of sesame) resisted the tuberculosis better than those fecl chiefly on carbohyd.rates (butterrnilk and bran, potatoes)' First of all the general condition rvas better, antl then there rvas also a certain difference in the extent of the process. But the diets used differ aiso in other respects than fat ancl ca bohydrates. The fat-rich diet must especially have helcl rnore A-vitamin. The experiments of T¡rorr¡s in 1913 only comprised 6 animals ancl gave ambiguous results. K¡'ncz¡c states I Chief: Dr. Il. ì{onocREN, to l'hom lny thanks ¿lre tlue f<¡r his kintl nssiitance in the experirlent. STUDII]S IN SCURVY 149 Half the number of experimental animals were infected on March 2glln,'J.923, with the same dosage of tubercle bacilli, 0.oooo¡ gram. The bacilli were obtained in a homogeneous emulsion from the Public Meclical Institute. They were of its stock No. 80, human type, inðicatecl of low virulence, anól came from a culture a fortnight olcl. The injection was ma'de intramuscula,rly into the aclductors on the inner posterior sitle of the right thigh. During the first twenty-four hours after the injection the animals were somewhat dishevellecl ancl felt hot. After another twenty-four hours, they coulcl not be distinguished from the controls as far as appearance and iiveliness went. Gnûr*nn ancl lf¡.¡rnunenn indica,te a sornewhat lower dosage of tubercle bacilli (O.ooooos gram) as a suitable dosage of infection in experimental studies on guinea-pigs, and Jonsr and Euno¡'¡' have usecl a still smaller dosage (0'ooooor gram).l fn order to determine a suitable dosage of stocl< No. 80, I rnacle a preliminary experiment, seven animals (No. 13-19) having been injectecl with doses on a sinlçing scale from 0.002õ to 0.oooooos gram. According to the outcome of this experiment the dosage was frxecl to 0.ooooo gram. The animals were cliviilecl into groups, with 8 (7) animals in each, the groups receiving clifferent dietary from the d'a5' of iniection. In each group half the number were tubercularly infected. Yet the animals on complete dietary of cereal, bran, 60 ccm. of unboilecl milk ancl fresh swedes' were 16 in number, of which 8 were tubercularly infected. 8 of the animals had scorbutic diet (see p. 12). The remaining 65 had the same scorbutogenetic basal diet anct besicles different closes of preservecl orange 'iuice. This latter I hatl preparecl irnmediately before the experiment by pressing the 'iuice of fresh juicy oranEes, pouring it into smaller bottles .of 200 grams, which were warmed, stopperecl ancl boiletl during 30 minutes immersecl in water. The dosage of the juice and the grouping of the animals a e shos'n in cletail by Table 6. Since the experirnent indicatecl that the minimum protective dose 1 I'L Slntu usetì. a larger dose (0,oooo grarn)' 1.50 J. AXEL HöJER Tøble 6. Division of guinea-pigs within different groups. Dietary per daY antl animaL Fraction of mNumbers of aø¿'- Numbers of ar¿¿'- pr. cl. of not infecled' mals dnfectcd tuberculosi,s wihh tuberct+losi,s scorbutic Complete mixecl clietarY More than 1.0 97. 98. 99. 100 104. 105.106. 107, 101. 102. 103. 183 108.109.110.111 Scurvy tlietary: $¿. Sc * 0.3 ccm. pres. olânge juice Sc.*0.6 " > ) , *1.0 , > , + 1.5 , , > D +2.0 " Ð " , +2.1o D Ð , +3.5 , ) , +5.0 , , Ð 112. 113. 1,1,4. L116.117.118.119 120. t2r. 122. t2 0 0.1 0.2 0.9 0.5 0.? 0.8 More than 1.0 Moret'han 1.0 I28.L29.130.131 13ó.136.137.138 t43. L44. t46. 146 Líl. 7rò2. t63. 164 169. 160. 161. 162 1,24. 12ó. 126. I27 132. I33. I34 139.140. t4l.t42 L47.148.149. 160 155. 156. L67. t68 163. 164. 165.166 77 7. r72. t73. t7 4 180. 181. 182 167. 168. 169. 1 r75. tl6. t17 . 17 179 (*. p". d.) of this 'iuice was larger llnan2.s ccm. ancl smaller than 3.õ ccm., it has been approximatêly fixed at 3 ccm', and the quantity of antiscorbutic given to each group has been calculated accordingly as fraction of the minimum protectiYe close. The inaccuracy involved in this estimating of the m' pr' cI' may be put to -l0.¡ ccm' : 'J-7 Vo. This relative figure is also applicable to the fractions of the m. pr. d. IMith the unceïtainty which is still inciclent to the upper limit of the range of scurvy (see p. 126) ihe most important thing, however, is not the absolute figure, but the relative value of the closes in the clifferent groups. The tubercular animals that cliecl during the course of the experiment or weïe chloroformect at the conclusion after ninety odcl d.ays, in all 42, were exarninecl macroantl microscopically. For cletermining the degree of scurvy, teeth ancl ribs were STUDIES IN SCURVY 151 Table 7. Survey of experiments. Á.bbreviations and. terms the same as in the table on p' 18 Series Remarks xxrv xxv XXVI 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 t1,2 113 tL4 116 116 t1.7 118 119 260 460 646 660 445 Ðlô 6t5 665 560 ó70 2t0 490 640 550 430 236 260 4l 260 360 Ðo1 390 280 270 280 230 2t0 52 96 96 96 96 96 96 93 93 93 2S 93 93 93 70 28 165 150 246 230 160 130 200 L60 300 200 180 290 260 260 290 o o o À o O 1õ 26 42 32 Ø I o o Ø cè a n<; O a) (*xx*) 19 {"Tl " brolchopnenmonia Killert Killett /Drowned in the milk \ basin 0 0 0 0 0 0 0 * * 0 0 0 0 * ,< * {. 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 n 0 0 0 xxvII t20 L2l 722 t23 390 390 410 390 445 645 496 410 370 otu 390 360 **** **t< 1 29 18 o0 36 24 Scurvy _O HF o Ë4 .5b ts] þ o p É z Weight in grâms Diet l-Ð2 Se¡ies XXVIII XXIX xxx J. ÅXI'L HOJER 724 l2'o 726 1.27 728 729 130 131 r32 t0Ð 734 1,3ó 136 137 138 139 110 1.47 143 r44 r45 146 747 r48 1,4C 1ó0 460 42"o 42í, 410 406 390 370 370 4'o0 440 4t0 415 425 385 210 460 395 360 340 39ó 370 270 430 380 425 39ó 35? 270 ófÐ 310 4t0 40'Ð 270 310 315 28 270 310 290290 270 330 350 - 360 3?026628'o 480 ** {< õ8 43 L7 15 22 29 2L 43 86 6 83 64 Ðt 40 tt 48 ó2 76 ã9 92 18 92 Ðt) ÔÐ 28 oÐ 22 90 6 19 92 f^ (n Ileurarks Diett of pneumonia at. . Dierl of pneumonia ae. Colitis ac. Gastrocluodenit. ac. /Died of DneumoDia + nec \ rosis ac. pancreat. Abscessus lienis rupturatus et hepâtis Diecl of ruptura lienis Dieil of septicemia Killecl Killetl I{illect Killed I)iecI o f pleu ropn eumoni ¡ t I]lcus cluocleni Killecl ø N + O (n : A Õ o + I a 0 0 0 0 0 0 0 0 {. 0 0 0 0 0 0 0 0 i( r42 3203ó0276 24ó 'o40 230 395 2Só 340 380 266 ó00 2ó0 420 280280 435 Ê + I a2 F --.: ,ti a) o-l â> o o6 Fl initi¿l \Yeight in g¡aìììs final o zDiet xxxr 151 t62 153 t64 165 1ó6 Series I xxxl XXXII \XXNI 3'o6 345 3ó0 32ó óoÐ 270 410 4t0 29',Ð 266 210 2lD ó80 520 520 280 326 410 2L0 757 158 159 160 161 L62 163 r64 165 166 L67 168 169 170 171 772 173 L74 Ots.: q)o2. + I rn + a) 4 ! + I (D :o : ts.i -o ro èD bD, E _T6 3ô 32í, 290 ÐÐÐ 36ó 325 350 280 220 47 í, 440 470 445 340 430 230 74-o 240 275 620 440 310 4'o0 380 XXIVx t7-a 776 177 178 179 180 181 182 1õ0 Ii,6 180 2i,0 240 290 200 265 330 380 2'J6 300 260 280 340 183 184 185 186 187 188 189 515270 1ó0 200 160 280 340 Compl€te dietary Corn \x_\v clietary Killecl S'TUDIES IIi SCURYY final initial Weight in grâms o.< o c aA a p E zDiet 22 40 29 92 92 Ôt 11 44 90 89 77 /i) 28 93 93 38 93 03 93 93 93 24 89 42 rã3 Rerna¡lis of gastroenterocolitis ùc. Iiilled Diecl of appencli<:itis lc. ' Killetl ) Diecl of pneumonia nc. Ruptura lienis Pneumorritl, peritonit. ¿tc. Bronchopneumouia Itillecl , , pneurttonia ll,c, Died of ) ) KiIIed )) lKilted. Had for some tinc \ beriberi-like symltorììs 96 I 74 11 11 1 vress oÍ twbercu' losis, 154 J. AXEL HOJER principally examinecl. For the study of the tuberculosis, the attention was chiefly clirected to the local focus in the thigh musculature, regional lymph-glands, spleen and liver' The other organs 'were examinecl microscopically as far as the macroscopical examination gave reason for supposing changes within thern. Lungs and tymph-glands other t'han the regional ones have thus been examinetl in most cases. six local foci in tlre thigh musculature (No. 119, 72Ú, 126, 127, 155, 171) are not noted in the recorcls of the macroscopic examination. One of these (Case 1?1)' was founcl in series of sections at microscopical examination, wherea,s in three (Cases lI9, 127 ancl 1ó5), pictures were hacl from the immed"iate vicinity of the necrosis. Microscopic pictures are lacking from the primary focus in Cases 106, 148. tr'or the regional lymph-glancls microscopical examination is lacking in 6 cases, No' 107, 1"16, 134, 139, L55, 166; for the spleen in one case' No' 157' The reason for this incompleteness of the microscopical examination, which, however, is of no very great importance to the stud.y, the material being so large' wa,s a misunclerstanding between the author ancl the technical aicl. The number of the examinecl sections also for this latter part of the examination stiil is greater than 1,500. They have been stainecl in three ways, all with hematoxylin-eosin, the majority also with Hansen's connective-tissue stain, antl with Ziehl's carbol-fuchsin on tubercle bacilli. For specific cases other special staining methocls, mentionecl on p. 32, have been used. lnfluence of sculvy on tuberculos¡s' The weight charts are founcl on pp. 207--233' They show that in general the curves of the tubercular animals follow those of tt e control animals, the lifetime seeming in most cases to be determinecl by the antiscorbutic d.ose. series 32 is an exception (ctaily d.ose 0.e m. Pr. d.)r p' 226, in which series three of tU" controls were alive at the conclusion of the experiment, but none of the tubercular animals. one of these cliecl of general tuberculosis on the 90th day after the injection. STUDIES IN SCURVY 155 Out of the 1ó tuberculized animals that had an antiscorbutic dose large enough to protect them from aII scorbutic pathological changes (Series 2b, 33 ancl 34), 9 animals, or 60 %, were alive at the conclusion of the experiment after 93 clays. Out of 16 animals not infected , 12, or 7-c %, were alive. The death rate for the tubercular animals was thus a little higher. Two of these clead animals haC. general tuberculosis (No. 174 ùfter 42 clays, No. 111 after ?0 clay.s). In one case (No. 1.?3, 89 clays) the cause of death was rupture of the spleen, which was changed tubercularþ. The progress of the tuberculosis was fairly uniform. Thus, 24 of. llne 25 animals that livetl more than 40 tlays showed tuberculous changes, besicles locally in the muscle, in the regional glands, spleen and liver, also in one or more other organs. One animal on complete dietary, No. 1"71, showecl no clinical symptoms of tuberculosis, ancl no m&croscopic changes when killecl after three months. In series of sections from the thigh musculature the miliary primary focus was found.' fibrously healecl; no tubercle bacilli were demonstrable. Among the animals that diecl during the first 40 clays of the experiment, the extent of the tuberculosis was more heterogerieous, as is seen from Table 8. Tøl¡le I The ertent of tubera.r,losis i.n ani'mals, deatl øfter a ilffirent nuntbet' of tlags si,nce begi.nni,ng of erperi.ment, høuing had' d'ffirent doses of ant'i,' scotbtetíc, cottnlecl i,n ccm. of preserued orange'juice, and, i'n fracti,ons of m'. pr. d. The nu,n¡,bcrs are those of the ønintrtls 'in the Recorcls. Á.bbreviations lo: tubercu,losis founcl in the place of injection in the thigh musculature ancl in regional lymph-glands; li: besicles in the primary focus also ir¡ the spleen; h: besitles in the primary focus also in the liver; u : tbc found also in other places than the primar¡' focns, liver and spleen. 20 -30 30-40 10-20 Fraction of n'r. pr. d. antiscorbutic Dietary 1ö6 So - scorì¡utic diet . , + 0.3 cctn ¡rres. or'. j , +1.ó ) ) r +, , + 2.'o " +3.5 , +5 )) Ð Courplete ilietarY .J. ,\XI'I, HÖJER 0 0.1 0.ó 0.7 0.8 ) 1.0 )1.0 ) 1.0 116 u 127 Ii 15ó o 163 u Days 119 u 724 tt 150 u 1ó7 lo 117 li h 118 "- t47 tt 172 u 180 li Il 107 o It is seen from the Records that the nurnber of microscopically examined orgarls is not the same for the different animals, anal also that this can not explain the differences noted. That the clifferent progress can no more be. explained a,s owing to the different degree of scurvy, is also immecliately eviclent from the table. Yet it is remarkable that the tuberculosis in the animals with pure scurvy clietary showecl a larger extent than in many of the rest, and also that among these four animals suffering from scorbut gravior there was one' No' 118, where alreacly after 36 days caseous glancls were founal in the hilus of liver ancl lung, a change not seen in any of the other ten animals. A similar difierence in the extent of tuberculosis in guineapigs is founcl by Gerhartz, who no lnore than the present writer considered. that it could be explainecl by the clifferent age or sex of the animals. In my experiments the C-vitamin has been variect without conclusive efiect. Possibly a mole a[istinct result would have been gained if a smaller close of tubercle bacilli had been iniectecl. The supply of A-vitamin has been practically constant. Among the factors that may have variecl in my experiments, I mention: 1) the hereditary contlitions of the animals; 2) the dietary of the mother during pregnancy ancl suckling; SÎUDIES IN SCURYY li,7 3) other conditions during the flrst weeks; 4) the place of the injection of tubercle bacilli (more or Iess superficially; into or between muscular bundles; rvith or without opening bloocl or tymph vessels); ó) the pressure at the injection; 6) intercurrent acute infections, not always easy to diagnose. The changes found in the 15 animals that had a, complete dose of antiscorbutic agree with those clescribecl by earlier writers. The primary focus in the musculature was bounclecl bv a rind, of connective tissue more than a millimeter thick. It was also penetrated by connective tissue. This connective tissue was seen also at the microscopical examination to penetrate with its extraordina,rily strong collagen fibrils the necrotic primary focus in the musculature (Plate III) as well as other tuberculous foci (Plate Y). Near the primary focus there were seen muscle fibres, parts of which were necrotized and to a large extent calcified. There was also an increase of fibroblasts. Also in the primary focus itself as well as in the regional lymph-gland.s and often in the spleen, extensive calcificationg a,re seen. This fincling is clifferent to that of Röunn who in his large material only saw two guinea-pigs rvith calcification of tuberculous foci. The extensive calcifrcation may perhaps be placed in connection with the small virulence in our stock of bacilli. fn Case I04, typicai Langhans' giant cells rvere seen in the primary rnuscle focus, the protoplasm of which was for the greater part calcified. About the genesis of these cells there has been disputes. The aboveurentioned observation I interpret as favouring the conception that these giant cells are results of a beginning d.egeneration (Bluuclnrnw a. o.). The pictures do not give the impression of a calcium lump absorbed. by the giant cell from the outside, but of a diffuse calcification of the protoplasm of the celI. In spleen and. Iiver there was typical tuberculous granula,- tion tissue, but of different character; nec oses, as has alread¡ earlier been clescribecl by others, dominating in the spleen (ihara,cter of thc tuberatÌott"s clnnges. 158 J. AXEL HöJER picture, antl a cirrhosis in the liver picture. fn the spleen the tubercle bacilli were rnore nuûìerous than in the liver, but also in each liver rvith an incipient cirrhosis bacilli were found, with some few exceptions, alrea,dy in the first or seconcl preparation. At such a change in the liver which may justly be called a cirrhosis tuberculosa, there are seen regenerative stranils of young liver columns, fibroblasts rvith cells of different types, epithelioid cells and giant cells, part irregular, part of Langhans' type. It has earlier been described in guinea-pigs by Sronnr, ancl afterward.s by Gouconot, Kltwc and LrcnrnrqsrErN. It is of the greatest interest to note this constant reaction of the guinea-pig liver to slight tubercular infection, especially in view of the elucidation it may give to certain liver cirrhoses in chilclren with stight tubercular infection (olcler writers, reported by Höìer). It was a striking circumstance that in the tuberculous foci, besicles typical Langhans' giantcells, there rvere also often found atypical such cells, ancl among them many that were more like the type d.escribed by Srnnwssnc. Since in rny material tubercle bacilli of a not very virulent stock were injected, possibly (LrcnrnNsrrnr) pictures like those in lymphogranulomatosis SrnnNsnne-Ptr,t¡u¡' might be expecteel. A great number of the lymph-glands were uniformly swellecl without macroscopically visible foci, but at the microscopical examination epithelioicl cells and tubercle bacilli were founcl in thern. Neither the macroscopic nor the microscopic picture otherwise resernbled that shownin Sternberg's lymphogranulomatosis. In the granulation tissue no eosinophile cells or )mast-cells) were founõl, nor were any plasm-cells found by staining according to Pappenheim. Àt the macroscopical examination of the tubercular animals that had severe scurvy, an essential d.ifference from the picture iust clescribe¿l was at once conspicuous. The tuberculous foci in muscle, lyrnph-glantl or spleen were not seen to be surrounded. or penetratecl by any connective tissue (Plates IY and. VI). The necrotic parts passed without such ilemarcation into nontubercular tissue. Besides this lack of reactive tissue, where such rnight be expected, there were found, together with the parç I STUDIES IN SCURVY 16ó ficing assistance in the whole of the experinent I owe hirn my best thanks. The dietary of the Sana'torium is as follows: At 7.ao a. rn. gruel and breacl , 10 > breakfast , 12 noon milk >> , 4.s0 > coffee with rrsks or white bread , 7 ) supper. The ?0 patients of the Sanatorium (of which half the number have been selected for the experiment; the children are in a special department) consume on an average 2 litres of milk a da,y each. No fixed schedule of foocl is followecl, but careful annotations are macle daily of what is served, and from these annotations I have made the following extracts. Of food that might be considerecl to contain antiscorbutic, there has been provided during the time March lst-May 31st 1923 (92 days): Potatoes lor no meal 5 clays, for one meal Ó2 days, for tt,uo meals 35 clays, in the last-mentioned case, often for one of the meals first boilecl a,nd then also fried.. Beet-root 1? times, alrvays together rvith potatoes. Beef-tea with vegetables 6 times. Mashed roots 4 times, swedes 1 time, always together rvith potatoes. Cabbage-soup 2 times, vegetable soup 2 times. Chive 3 times. Pears 1 time. Among courses which for one reason or another may be consitlered rather unimportant as far as the supplying of antiscorbutic is concernecl, may be mentioned recl whortleberry ja* (with Yorkshire pudding) 31 times, rhubarb moulcl 9 times, apple tart (driecl apples) etc. 10 times, other frrrit moulds 9 times, fruit-syrup sauce 3 times. 166 J. AxEL HoJER For every brea,kfa,st and supper are served vegetable margarine, harcl rye-bread and. cheese' rather rich, a,s much as is wishecl. Meat in solne form is given once or twice claily.l Tlæ døetøry møy be characteriøed, øs lienteous, a,nd comryIete 'in eaer"y resytect erceltt u'ith, resa,rd, to antiscorbwtic. As providing this substance there are first of all to be mentionecl milk and potatoes. During this time of the year (in 1923, the cows rrere not turnecl out to grass till after the conclusion of my experiments, in June) the milk is very deficient in antiscorbutic. To arrive at a clefinite estimation of the quantity of antiscorbutic supplied in 2 litres of milk, is not practicable. Pota,toes also are a weak antiscorbutic and' do not have any Tøble 70 1 + + + + n + n + + n I n + I n a b c d e f 1 Or. 2 3 Or. 4 õ Or. 6 7 Or. 8 9 Or. 10 11 Or, I2 13 Or. 14 III* III III* III III III II-III* I-II III* r-il III III* III III oÐ 3õ 2l 20 48 44 34 28 27 20 89 93 24 60 93 93 93 91 +? 93 93 Ð1 93 1 Meat rnost often given as mince-meat, frrst friecl and then boilecl. 4 2 Progress 66 Progress orânge comparecl to control Age, yeârs Duration of experiment,days Stage of tuberculosis Couple Number 46 2ù Ag", yeârs I)uration of experiment,clays Stage of t'uberculosis 6 Progress CoupIe 1 Number STUDIES IN SCURVY 167 7 rogress o comparecl to cont¡ol h15 Or. 16 L7 Or. 18 19 Or. 20 21 Or. 24 25 Or. 26 27 Ot. 28 29 'Or, 30 31 Or. 33 Or. 34 35 Or. 36 37 Or. 38 39 Or. 40 41 Or. 42 43 Or. 44 93 93 93 93 93 67 93 93 93 93 lt 93 93 93 93 93 93 93 93 93 93 93 92 93 93 to 93 _1 ôô 93 III* III III ilI ilI ilI II* I-II I I_II* I I II* I_II III* III III III III* IIII I* I I I T I 43 ôÐ 25 2t 32 63 20 16 18 24 t2 16 24 28 25 26 27 16 7 25 10 11 I 11 4 ó 4 + ll -t- + n n n n n? L n L n. + n + + a n + l1 n I + + + + + +? + + + + + I k 22 23 Or m .n o p q r s wI+ T2 4I 1 Discharged shortly after the beginning of tbe experinent. 168 J. AXEL HöJER consideïa,ble importa,nce as such till consumed in rather large quantities. In a,ny case the dietary is poor in fresh vegetables, roots ancl fruit. The dietary of the chilclren comprises an egg a clay, ancl 3 dessert-spoonfuls of cod-Iiver oil. The patients a,re not weighecl nakecl, and therefore the weight figures are liable to be somewhat uncertain. From time to time a,ll the patients are examined with Roentgen rays; radiograms are also taken in most cases. When the Roentgen examination or the racliogram ilo not add essentially to the information gainecl by the clinical examination, they are not quotecl. The principles of the treatment have been the hygienic rneasures usual in Sweclen. For special details, see the Recorcls. All the children were treated with quartz lamp. The dura,tion of the experiment has not been extendecl beyond three months, as the patients do not as a rule remain in the Sanatorium above that period. The experiments are summarized in Table f0 (p. 16ti). The figures in the first row corresponõl to those in the Iìecords. AII odcl numbers, which furthermore are accompa,nied by rO".,,, refer to patients who have been given a,n oïange. The even numbers a,re the patients, examinecl for the sake of control, who instead of the orange hacl a, pastry. The patient who in each couple must be rega,rded. as decid.edly the graver case of the trvo at the beginnine of the experiment is indicated by an asterisk in the fifth row, where the stage of the disease is recorded. As the pa,tients were chosen, the graver and the lighter case was every alterna,te time ta,ken as control patient within each cot'Lple. The progress is indicatecl, in the sixth ror{, by n, * a,nd. , accorcling to its being corresponding to what hatl been expectecl, better or worse than was expected. In the seventh row, the progress of the orange ca,se a,s cornpareil to that of the control patient is indicated. The sign means that both cases have shorvn a corresponding progress; *, that the orange case .lìas progressed. mole favour- STLIDIES IN SCUß\¡Y 169 ably, and. -, that it has progressed. less favourably than the control ca,se. From the sixth row is seen that out of 21 control cases 11 have progressed according to expectation, rvhile 2 have progressed. better and 8 worse. It must be borne in mind. that the seasorì in question, March-Ma¡', is the time of the year which is the most trying to tuberculosis patients. The death rate for tuberculosis is then at its highest. The rather bad. results among the control. patients are therefore not surprising and the fayourable progress in those who have had the orange is the rnore noteworthy. Among 22 such patients. the progress has been as expected in 6 cases, while 1,6 have d.eveloped more favourabiy than might have been expected.. In the seventh rorv which inclicates how within each couple the d.isease has progressed in the orange case, in comparison with the progress of the control case, we find tha,t the oranq'e case hacl a better course in 17 instances, similar in 3, and worse in 1 instance. Criticism. Gonclusion. Several objections might be ra,ised, against this experiment, such as its dealing with too smalL a number of patients and, too short a time. The first objection is irrelevant, as this has been only a primary experiment which must be r:epeatecl, ancl I hope w.ill be repea,ted in d.ifferent places antl rvith a, la,rger ma,terial. It will then be expeclient to extencl the experiment over a longer periocl, that is to sa,y, begin earlier in the year. The time of conclusion is fixecl for experiments of this kind, viz. the beginning of the early summer. A question rvhich carries more weight is whether the experiments have been conducted .with sufÊcient obiectiveness. In the first place it may be brought into question whether the patients have not been sub'iected. to a suggestive infl.uence of the orange d"iet, an influence which might have improved the appetite and. inclirectly the process. Although counter-actinE rneasures have been acloptecl, this possibility can not be entirely preclud.ed. In the seconól place there is the question a,bout the obiective- I7O J. ÅxDr, HöJDR ness of the investigator. I have thought the best safe-guard in this respect rvould be to entrust the actual examination and the .iudgment of the patients to an experienced specialist, and to iet my own opiniorL caïry weight in opposition to his, only when in so doing I have causecl the orange cases to have a less favourabÌe or the control cases a more fa,vourable verdict. Ànother objection is that the clietary in the sanatorium already without the ora,nge would" contain a protective close of antíscorbutic. This obiection woulcl have been more significant if the experiment hacl not given a clear eviclence' Conçlusiotz. The experiment seems to indicate that the addition of an orange to the da,iiy fare has favourably influencecl the progress of tuberculosis with a, number of patients iu the Väsby Sanatorium d.uring March-May 1923. The results encourage continued" investigation on a, larger scale in orcler to gain confrrmation of the theory that a suffrcient amount of antiscorbutic substance in the food strengthens the resistance aga.inst tuberculosis. Surnnocct"y und, concl,xcs'iolLs of Pc('r't IV. A tuberculosis may in different ways act on the onset or the progress of scurvy. The appetite may climinish so that a sufficient d.ose of antiscorbutic is not consumed. The conditions of the intestine ma,y become changed so that the consumecl close of antiscorbutic is prevented from having a'n effect. A scorbutic a,trophy of the vascular wall may give clinical symptoms (hemorrhages) in the neighbourhood" of tubercuLous foci. In a still higher degree a scurvY âppears to a'ct upon the progr:ess of a tuberculosis. The clinical observations, which are recorded" in the literature give good grounóls for supposing such an a,ction though they have not so far been cluly considered. These observations lend countenance to the notion that the resistance of the bod.y to tuberculosis is lessened cluring the course of scurvy. The experiments on man which S'IUDIER 1ì{ SCURYY 771 I have unclertalren point in the same clirection. Experiments on a larger sca,le are d.esirable especially in regions where, like in the Northern provinces of Sweden, the fresh vegetables are as rare as the tuberculosis is frequent. My experiments on guinea-pigs indicate that a scorbutic olganism has no power of reacting a,gainst a tuberculous focus with a connective-tissue formation of normal strength. The smaller the antiscorbutic d.ose in the foocl is, the less extensive and the more inferior in qua,lity (fibrosity) the nerv connective tissue becomes. This diminished faculty of healing tuberculous foci through connective tissue is apparent already early in the latent stagê, a fact which is of special interest. This cleficient reaction of the connective tissue to a tuberculous irritation agrees perfectly with what has been said in the preceding part of this worl< with regarcl to the scorbutic atrophy. I am far from wishing to attribute to this deficient developurent of fibrous tissue alone, or even principa1ly, the influence of scurvy on the progress of tuberculosis. It is probable that the scorbutic atrophy of other cells in the bod.y, which are important to the resistance, also is of account. As the benignity of a tuberculous process is often measured accord.ing to its more or less pronounced fibrosity, the change in this quality through scurvy, already in the latent stage, is yet worth observing. From a therapeutic point of view it may be sa,id that my investigations suggest the importance of supplying a sufficient fully protective antiscorbutic dose to persons, in whom the healing of a tubercular process is aimed at. This holcls true also, and. perhaps particuì.a,rly, with regarcl to early forms, for instance tuberculosis of the bronchial Eland.s in children. Since the standa,rd. of the fully protective dose of antiscorbutic for clifferent ages has not yet been establishecl, it may in d,ubious cases be recommended rather to give a little too much than too little of suitable antiscorbutic articles of foocl. STUDIES IN SCURVY 26ó Literature cited. -A.nopnn¡r,nnN, E., ancl Wonrr¡nrMER, E.: Weitere Beitrãge zur Kenntniss von organischen Nahrungsmitteln mit speziffscher Wirkulg. Pflügers Archiv f. Physiol., 191, 1921, p. 258. Anøls, H.: Über clie Rolle cler Infekte beim Skorbut der Kinder und" Säugtinge. Med. Klin. No. 43, 1919, p. 1084. Ao,tlls, J., and H.tttltltoN, *d.: .A visit to Germany. Brit. Journ. Childr. Dis.' July-Sept., 1919, p. I27. AnoEnsoN, E. V., DutcHttn, R. Å., Ecrlns, C. H., and Wtleun, J. 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S.rnrNrrz, F., ancl Wnlçnnr: Über Demineralisation 'ncl Fleischtherapie bei Tuberkulose' Jhrb' f. Khk., 61, 1905' Srrll,, G. F.; Brit. Med. Journ., July 31, 1920, p. 156' sronr,tzNnn, w.: Zur ctiätetischen Behantllung cler Tuberkulose. B. ki. W., 1920, P. 981' Tnoues, E.: Biochem. 2., 57, 1913, p. 456' THOll^s, E.: Über die Beziehung chronischer Unterernährung z.r Infektion. Z. IKin., 11, 1914, P' 317. Torr,nn, W.: Der Scorbut im Kindesalter. Z' f' Kh', Bd" 18, Orig., 1918, P.63. Tovnnul,-G.: Caries clentis. Norsk tancllaegefol' ticì', Dec' 1923' Journ. ,{.m. Dent. Ass., No. 3, 1923, p' 207' Toznø, F. M.: The effect on the guinea-pig of cleprivation-of vitamin Ä. Journ. Path. and tsact., Bc[' 24, I92L, p' 306' IJnepn: Mecl. Klin., Bd. 18, 1922, p. 851. VocT : Säuglingsscorbut. Jhrb. f. Kh. 91, 1920, p' 278' W.o,r,l,cnnn, A.: Acta Pædiatrica. Vol. II, 1923, pp' 376' --: wahi cler versuchstiere fär experimentelleTuberkulosestuclien. Braners Bei1or. z. Klinik tl' Tuberk., Bù. 47, 1921, s' 42'o' --' Z\r Symptomatologie unct Pathogenese iter oectema scorbuticum invisibile' Z. 1. Klnk., 1922, p. 35' 'WDIL, E., ancl MoumQUAND, G': Journ. physiol' path', 17, 1918' p. 849. Wr*Nfn.r, A.: Ilber phtisische Infectionen. Hclb. cl. ârztl. Erfahr. im Weltkriege., Bd. 8. wInr,enp: Bruning & Schwalbe, Hdb. cl. allg' Path' cl' Kinclesalters. 2: 1, 1913, P. 281' wIDNennçnR: Möller-Barlowsche Erkrankung. Klin. wochellscht., I, No. 4, L922, P. 119. Zrt,yt, S. S.: Influence of deficient nutrition on the prociuction of agglutinin etc. Biochem. Jl. 13, 1919, p' 172' --: Influence of aëration etc. Lancet 1921, I, p' 478' --: Conclitions of inactivation etc. Biochem. JI' 16, 1922, p' 42' SîUDIES IN SCU1ìVY Zu,vl^, S. S., ancl Wor,LS, F. M.: Changes in the teeth etc. Roy. Soc. London. B. 90, p. b0ó. List of authors. '¿to Proc. The olcl liúerature, not mentioned here, may be founcl in the books of W. Kocn (tSSg) arrcl Ao. Mpypn (tOOt). A. Abderhalden 83, 1:14, 158, 265. Abels 118, 719, 265. Àdams 145, 265. Àndersson 12, 266. Aron 32, 725,266. Aschoff 67, 63, 64, 66, 66, 67, 58, 59, 66, 87, 70, 77, 76, 77,79, go, 92, 93, 01, 92, 96, 100, 110, 111, 113, 176, 732, 144,266. B. Ilaginsky 49, 26'0. tsardin 265. Rahr<lt 6í,,727,265. Barlorv 49, 69, 111, 779, 112, 26-Ð. Barnes 25, 265. Rartenstein 138, 26õ. Baumann 83,265. Baumgarten 1õ7. Betlson 108, 109, ll0, 265. Bergheim 13, 268. Bettoy 747, 272. Beitzke 744, 265. Berg 132, 265. Bezssonoff 14, 265. Bierich 100, 109, 116, 123, !'36,747, 266. Bolle 138, 266. Branclt 108, 266. Broderich 132. c. Campbell 11, 130, 270, 274. Carr 1.2, 270. Carrell 115, 266. Chick 9, 17, 13, 17 , 25, I23, 124, 739, 266. Cohen 9, 76,129,266. Cole 15, 271. Cordier 125, 266. Cornet 140, 266. Cowarcl 27. Cramer 92, 136,266, D. Dahle 12, 266. Dalyell I24,739, 286. Darling 737, 266. Davey 26, 266, DeIf 12, I3,27,33,36, 66, 266. I)rummoncl 9, 266, Dutcher 72,25, 265, 266. E. llckles 12, 26-Ð, 266. Edelstein 66, I27, 26í, Ellis 12, 267, 268. Emhoff 75I, 270. Engstrand 15, 271. Epstein 700, 124, 267. Erclheim 7Ð, 267. F. Faber 13, 267. Finrllay 80, 101, 109, 112, 713,267. Finkelstein 24, 25, 26, 777 , I22, I24, 267. Fortenato 121. Fraenkel 48, 49, 50,55,66,60,65, 109, 111, 712, 126, 729, 730, 267. Frank, H., 124, 267. !-rank, M., 60, I27, 267. Freise 267. Freudenberg 734, 267. Frölich 9, I0, 12, I3, 76, 25, 29, 67, 69, 64, 69, 77, 76, 778, I17, I29, 131, 138, 267, 269. Ftrnk 9, 27, 99, 267. Ftrst 22, 267. G. Geoghegan 746,267. Gerhartz I43, 748, 756, 267 Gerstenberger 127, 267. Givens 13, 267. Gocllevski 33, 268. 276 .I. AXI.]I, H('.TFJR Gougerot 158. Graham 17, 39, 46, 49, 129, 273. Grüner 16L, 268. György 134,778,268. H. }Iall 25, 266. Hamburger 151, 268. Hamilton 745, 265. Happ 147, 268. H¿lrden 268. Hart, C., 9, 30, 48, 49, 60, 53, 57 , 68, 69, 76, 78, 79, 80, 93, 100, 109, 110, 111, i24, 136, r47, 266, 268. Hart, E., 3, 72, 25, 268. Hausmann 83, 109, 268. Hawl< 13, 268, l{ayern 65, 76,79, 82, 96, 268. Héricourt 741, 268. Hersharv 25, 266. Herxheimer 77, 268. Herzog 64, 7I, l0S, 726, 268. Hess 9, 11, 13, 16, 77,18, 26,26, 29, 30, 33, 39, 64, 64, 6ó,68, 70, gg, 91, 92, 96,109, 109, 110, 116, 120, L22, r24,1,26, 126,729,732, r33, 136, 137, 146, 163, 268. Heubner 724, 269. Hirschsprung 91. Iloffman 729, 269. Holmgren 77,269. Holsú 9, 10, 12, I3, 14, 16, 25, 26, 29, 30, ó7, 59, 64, 6Ð, 71, 76, 176, r77, 129, 131, 138, 269. Horne 13, 265. Hopkins 9,72,73, 269. Holvartl 83, 128, 265, 269. Horve 17, 36, 40, 46, 49, 726. Hume 9, 77, I3, 26, t23, 266. Iläggquisô 47. Höjer 158, 160, 269. t. Ide 113, 269. Ingier 53, 56, ó7,70,100, 110, 111, II2, 1,47,269. Ingvaltìsen 128,269. Irvabuchi 54, 65, 67, 83, 101, 103, 109, 110, 128,737,269, 270. J. Jackson 39, 69, 112, II7,270. .Tacobsthal 51, ó3, 69, 100, 111, 270 Jansen 137, 270. Joest 1õ1, 270. Joseph 159, 273. Josias 141, 270. K. I(aiserling 145. I{arczag I42, 270. I(assor"itz 147. I{iefer 143, 2?0. l{irch 108. I(Iing 1ó8, 270. l(Iocnrann 96,127, 728; 271. Koclr, \Y., 6-L, 53, 64, 55, 56, 57, ó8, 59, 66, 6?, 70,77,76,77, 79, 80, 82, 83, 9I, 92, 96,100, 110, 111, I12, L16, 732, 744, 265, 270. l{och, W., 33, 79, 82, 709, 7L7, I72, 779, 124, 270. l{ohlbrägge 270. I{orenchevsky 12, 270. Kossel 140, 266. I{ossler 12-Ð, 270. t-. La }Ier 11, 130, 270, 273. Lanilau 70I,270. Langstein 270. Lasègue 65, 270. Legroux 69,270. Leichtentritt 116, 119, 121, 270. Leitner 709, 270. Lesage 33, 270. Lessing 9, 30, 38, 48, 49, 50, ó3,57, 58, 69, 76, 79, 79, 80,83, 100, 109, 110, 111, 724, 736,147, 268. Leven 69, 79, 82, 271. Lichtenstein L58, 160, 271. v. Linné 82, 136, 740, 277. Loeb 136. Loervy 138,271. Looser ?0, l7'1., 772, 179, 271. Lopez Loma 1L, I3,277. Luba,rsch 733, 137, 271. Lukin 82, 91. Lust 96, I27. I28,27I. Lön'enstein 740, 277. M. I{ac Callum 8, 66, 271. Martinotti 703, 271". Martius t4L, 277. Masslow 74, 27I. l\{cOarrison 89, 100, 101, 104, 110, 725, 733, 737 , 271. i\lcClerrclorr 7ú, 17, 39, 16, 49, 27 7, 27 3 lfcCluggage I3, 267, 268. McCollnnr 1"I, 33, 723, 271. lfead 12, 266. n'Iectes 17, 39, 46, 49, 725, 278. ùIeclin 12, 67, 63, 27I. Nlelka 113, 273. Mellanby Il3, 132. Menclel 9, 16, 99, 12C, 266, 272. ÙIengering 136. lVleyer, Ad., 7C, 27I, 274. Nleyer, L. F., 124, 272. lficlrel 13, L1,128,129, 180, 147,162, 272. Midcllekauff 76, 27I. Monrail 12. n[ontagnani 100, 101, 27:]. Moore 39, 69,772, I77, 270. NIorel 128, 272. Ìfottranr 92, 738, 266. Monricluancl 1.3, 14, 128, l2g, IJ}, 147, 162, 272,274. Iluch 141, 2?2. Ilrirphy 77, 39, 46, 19, I2g, 278. N. l{aegeli I09, 141, 272. Nanrbn 60, 79, 80, 82,97,278. Nassau 779, 272. Nauwerk 10, 100, 273. Nehring 744,273. Nobel 137, I38, 740,272. Noeggerath 137. 0. Or)st"l 732, 272.. Osborne 99, 272. P. Paclua 99. Parsons 23, 89, 272. Peiper 13, I01, 273. Pìrilip 141, 273. v. Pirquet 138, 13C, 273. Pitz L7, 123, 128,277,27à. Prym 737, 273. 0. Qnensel 6I, 62, 63, 730, 2î8. R. ßaebiger 76, 273, Raissonnier 741, 273. U. Uurber 24, 108, 109, 7I0, 274 Unger 13, 2ó,268,269. Urizio 82. STUDJÐS IN SCUR\¡Y 277 Ilandoin 17, 73, 271. Iìeinert 01. Iìenon 27;1. ! Iìheinclorf 108, 113, 278. Ilichet 141, 268. l(obb 17, 31, 46, 49, 728, 27:1. Iìondoni 100, 101, 273. Iìosenberg 109, 110, 116, 186, 146, 763,273. lìosenbuncl 74, 273. Iloux 141, 270. Iìünrer' 159, 273. s. Salle 109, 110, 116, 736,146,16ts,2?8. Sato 69, 79, 82, 97, 273. Saxl 113, 273. Sclrnrorl 49, 50, 66, 777, 772, I47, 27 B. Schoedél 10, 49, 5I, 52, 55, rÒ6, bZ, 63, 69, 100, ltl, I24, I30, 747, 273. Sclrntz 32, 80, 107, 108, 278. Selter 744, 274. Shaefer 72,266. Sher¡rran 11, 13, 16, 17, 130, ItsL,271. Sinrnroncls 17, 271. Singer 119, 272. Skelton 9, 266. Snith 16, 747, 149, 268, 274. Sonnenburg 56. Steinitz I37, 147, 271. Stéenbocli 72, 27, 266, 268. Sternberg 168. sLilt 27,274. Stoeltzner 743, 274. Stoerk 1õ8. Snpplee 25,269. Srvitle¡ski 771, 712. T. 'Iailor 132. 'Ihévenon, L, 728, 272. l'homas I42, 274. 'Iobler 24, 108, 100, 274 Tovernd ¿0, ió,-id,' +q-àr, ro+, roo, 107, 109, 726, 274, 'Iozet 72,13, 33, 36, 66, 266,.274. 278 v. Variot 82. Virchow 136. Yogt L16,274. W. 'Wagner 82, 147, 288. 'Wailgren 116, 137, 148, L60, 274. Wassermann 108. 'Weigert !4L, L42, 144;274. 'Weil 274. J. AXEI, göJER 'Weinert L44, 214, 'Wells 39, 46, 46, L47,274. Wertheimer 83, L84, 266. 'VÍieland L4, L22, 274. 'Wienberger 68, 274, Wilbut L2, 2;ß6. Zielaskowsky Zilva L2, 73 274, 216. z. 116, 119, tzt,270, , 89, 46, 46,12L, 268,