Studies in Scurvy. Part III: Discussion of some scurvy problems

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. STUDIES IN SCURVY 115 the formation of elongated fibrils has failecl. Before the formation of collagen is completely arrested-, there is thus a stage when it is very unevenly distributecl and irregularly arrangec[. It is related by several early authors that old bone fractures at the onset of scurvy have become softenecl. The cleficient callus-formation at fractures in scorbutically changed bones is also a common observation in the stucly of experimental scuryy. AIso for the explanation of these circumstances, the pronounced atrophy of the collagen connective tissue in scurvy is of interest. Even if, as C¡.nnp¡,r, has pointed out in experiments (1921), the cicatrization of lvounds apparenUy is initiated not by an internal but b,v an external factor, the answer of the organism to the irritation is decid.ecl by internal factors. That a supply of fuII antiscorbutic close is necessary to an answer of normal intensity, m&I be conclud.ed. from this investigation. A generai insufficiency in the coilagen formation is not, as far as I know, earlier d.escribed. PART III CHAPTER I Scurvy and infection. t. Complicating acute ¡nfect¡ons ¡n my animals. Of my 189 animals about a third (60) have sufferetl from complicating acute infection. In the ma'iority of cases it has been an acute infection of the upper respiratory canal. Pneumonia has been found in 13 animals, enterocoiitis in 5, septicopyemia in 8, peritonitis in L, necrosis of pancreas in 1. No wid.e-spread epiclemic has occurred. As remarkable may be mentionecl the appearance of pneumonia in 4 of the B animals in Series 34. In Series 29 two animals showed. abscesses in the spleen, I16 .I. ,\XEI, HöJDR ft rnay be mentioned that I ha,ve not in any case founcl âr1y coccicliosis. The liver was examinecl in nearly all cases. II. Influence of acute infection 0n scurvy, Since the hypothesis of scurv.y as being an infectious disease has rnore and. more had to yield. to the vitamin hypothesis, attempts have been macìe to represent the infection as a necessary factor for bringing about manifest syrnptoms in an olganism changed through lack of antiscorbutic. The reasons for these attempts are the same circumstances that causecl the supposition of an altogether infectious etiology: 1) the ,enclemic, occurrence in certain cases, 2) the. presence of a.cute infections in connection with the onset of the d.isease, and 3) the socalled scurvy fevel. With regard to these circurnstances the following observations may be made. Àc1 1). The endemic occurrence in persons with identical or similar clieta,r¡' is more satisfactorily explained by the vitarnin hypothesis. Ad 2). That certain acute infections may have an influence on the arising ancl coulse of scurvy, is certain. Ascno¡'¡' al.cl Kocn state that every powerful infection in a patient rvith olcl scuryy calls forth new hemolrhages. S¡.r,r,n and Ros¡x¡nnc mention that clysentery, typhoid. and malaria a,ggravate the scury)r. Yet they have only a small number of such cases at their disposal. Bronrcn saw in his large material a predisposing influence only of abdominal typhoid and. clysentery, but not of tuberculosis, lues, polyarthritis acLtta, or malaria. This a,ction of diarrhea diseases has alread.y in 1907 been observecl by Hor,sr ancl Fnör,rcu. ,Diarrhea creates very often a predisposition to scurvy,,. Several auth.ors coulcl verify this cluring the last war, and II¡ss clwells in 1920 specially on this fact. Concerning infants the same thing has been observecl by, a,mong others, Yocr ancl IM¡r,r,çnpx. LnrcutpNrnrrr ancl Zrnr,¡.sKowsrr write in 1922, that ,chronische Darmerkrankungen - gleichgùltig ob infectiöser, alirnentärer, konstitutioneller Grund.lage - clern Scorbut STUDIES IN SCURVY rt7 clie Wege ebnen und infolged"essen geradezu als 'Barlo.w-trop' aufzufassen sindr. It is near at hand to connect this circurnstance with an action in the intestina,I canal on the antiscorbutic from abnormal prod.ucts (oxidizing?). Concerning other infections there are no certain observations in a positive d.irection record.ed in the literature. Two of my guinea-pigs, ì{o. 50 ancl 55, see charts Fig. 10b ancl 106, pp. 186, 188, are examples of how scurvy seems to proceed in the rnanner cletermined, by the foocl, inclependently of an intercurrent acute infection. Such an infection seerns in these cases to haye caused. a clecrease in weight, which gives to the curves of these animals a course different from those of the other animals in the same series. The d.ecrease yields place to an increase, however, ancl it is then found that the curves go rising towarcls those of the other animals, ancl bend. clownt'ardls with these, as the animals also proceed to cleath at the same time as their fellows. The influence of certain acute infections on the onset ancl progress of scurvy can thus be limited, partly to diseases that bring about intestinal clisturbances, in which a clirect action on the antiscorbutic before its resorption rvill easily be conclucled, partly to causing hemorrhages in certain cases of alread.y scorbutic patients. It cloes not seern surprising, with the already describecl weakness in the vascular rvalls, rnole particularly explained, by me, that a hyperemia and thereby raised clemands shoulcl call forth a, hemorrhage. This may a,lso be cause¿l by other incidental circumstances, for instance trauma, or set in without any clemonstrable cause. Ad 3). The scurvy fever has always at closer analysis showed itself explainable either as a, resorption fever in connection rvith a hemorrhage (Frwror,srrrrv), or as a consequence of a complicating infection, whereas the scurv¡' as such proceeds rvithout fever, which has also been stated experirnentally (Jlcrson and Moonn). In the case of my guinea-pigs I have not taken the temperature, and I have as a rule rnade no cultures of bacteria,. Clinically, at the ltost-ntortem and the subsequent histological 1.24 .I. ,TXEI, HöJER long bones for instance become mole and more brittle. The rnoment when a latent stage passes into a manifest is for each case deterrnined by the relation between the a,trophy of the tissue ancl the clernancls made on it. A violent blow may, for instance, by causing a fracture reveal a scuryy which without this accident rnight still have been latent for a long time. It is the same rvith a hemorrhage causecl by an infectious hyperemia. From this it is obvious that the line of demarcation between la,tent and. manifest scurvy is rnovable. Most autho::s also suppose the presence of an intermediar;' stage betrveen the latent and the clistinctly manifest stage. Fn¡nNnnr, states that ,bei einem nicht geringen Prozentsatz cler Fälle welche unter ilem Diagnose Darmkataruh mit Anaemie, Päclatrophie u. dgl. mehr segeln, sich mancher Fall von Barlowscher Krankheit verbirgt>. II¡:unnnn expresses himself to the sarne purport. ErsrurN, Ifpss ancl also Fn¡.r*r state that the growing in height is already during this period arrestecl in children. Anon clenies the presence of such an initial stage, but in this he stands al.one against Kocu, Scnonnrr,, II¿nr ancl Lnssrwc, Ftlrnr,- srErN, L. F. Mrvnn, Cnrcrc and D¡r,vnr,r,, the above-mentionecl authors and all other investigators of ma,rk who have written on the subject. If thus the supposition of a clinical stage, during which the diagnosis of scurvy often can be made only for the therapeutic effect of antiscorbutics, seems to be well foundecl, my research has afforded. the possibility of understanding this better. Not only in the teeth and the bone-system, but also in muscles, liver, spleen, kiclney, salivary glancl, adrena,l, and" probably in other organs, a,Iready in the latent stage more or less severe changes appear, which together constitute the scorbutic atrophy of the organism. This atrophy is progressive ancl gives rnanifest symptoms after a length of time that varies for the different cases. The cluration of the latent period thus bears a ::elation first to the antiscorbutic dose given and then also to outward circurnsta,nces. fn guinea-pigs the latent periocì. is, approximately, with no antiscorbutic 1 week, rvith 0.t of the minimum S'TUDIES IN SCUIì\¡]: I2ó protective d-ose rnore tlnan 2 weeks, with 0.2 m. pr. cl. more than 3 weeks, with 0.g m. llr. d. about 10 weeks, &. s. o. When the closage of antiscorbutic approaches the completely protective close, marlied. clinical symptoms never a,ppear, only inclistinct signs of general ill-health. Ind.eecl, I think it ver¡' probable that theré is a stage of scurvy, ¡n'hen not even patho-anatomically any pathognomonic changes a,re demonstrable in the teeth, but rvhen nevertheless the promptness with which the vital functions of the bod.y ta,ke place is lowerecl, a scorbut initialis or functional scurvy. Znva argues in the same direction. Hnss writes: ,There is no doubt a consid.erable nurnber of infants, who quite unknown to any one pass through the state of latent scurv)'. If this la,rge group of cases rvele inclucled in the incidence of infantile scuryy, rve should" not look upon it as a d.isorder, rvhich occurs rarely during the first six months ef life., Elowever, it is probably the same also with other ages in districts, whele during certain periods there is oniy a limitecl suppl¡' of food.stuffs, valuable from the antiscorbutic point of view. In such places scuryy may therefore have a room in the d.iscussion concernins the pathogenesis of disea,ses of the clifferent organs. Among subjects alread.y dealt rvith I refer to the question about the relation of scurvy to the infections, p. 120, heart rveakness, p. 81, renal calculi, p. 98, Iiver changes, p. 89. Kossr,-on ha,s 1n 1922 communicated a, case where a patient, treated. for a d.igestive disorder with so-called" ,Ienient, clietar;', himself out of nervousness limitecl it still more, rvhereupon ¿ì, manifest scurvy set in. Such cases are probably not unfrequent. The question is whether in this case & latent scuryy, causecl b"v the physician, was not alreacly present.l Norv, earlier authors2, as rvell as the present rvriter, have in scorbutic guinea-pigs statecl the presence of ulcers in the ventricle or the d-uodenum. These ulcers are in the cluod.enum placed, above the papilla Yateri 1 Iu the case of Conotnn, reported the sarne year, medictrl advice regnrcìing tlietary hnd caused n¿cutifest scurvy. ? l'he criticisnì olì p. 101, applies to }Ic0a:rrisou's stnteruents in this matter. t26 J. ÄXEI, HöJER a,nd a strong congestive hyperemia is comrnon in this place. One might think of the influence of the a,citl gastric juice on an atrophic intestinal epithelium, perhaps with a complicating infection. Ilnnzoc presupposes a hemorrhage to be the cause. In any case it is highl¡' important that so-called, ulcus-dietary, as well as otheplenient, dietaries, should contain a sufficient dose of antiscorbutic, which surely is often not the case. It is of the greatest importance to fincl a test, by rvhich the presence of latent scuryy can be established. Among those inclicated for the diagnosis of scurvy bv other authors, Roentgen examination of the epiphyses of the long bones, accorcling to FnlnNrnl, or of the heart, according to Ifnss, may be taken into consicleration, but these examinations ma,y even in the manifest sta,ge give uncertain results. It seems to me as if the changes in the teeth with atrophy of the processes of the oclontoblasts in the dentin, or the precipitate calcium excretion through the urine in the latent stage might be used for creating a methocl of cliagnosine latent scurvy. Experirnents in this direction are in progress. CIIAPTER IY. The calcium metabolism in scurvy. Ifuss summarizes the few ancl partially conflicting examlnations of the metabolism in scurvy thus: >The only point in rvhich they ag'ree, is that d.uring the manifest stage the calcium balance is ¡iositive.> Ilowe antl Tovnnuo look upon scurvy as a disturbance in the calcium metabolism. Howe rvrites in 1921 : >fn calcium disturbances of this kind, two, things are to be considered: first, a sufficient supply of calcium and, second, the necessary elements for inducing the fixa,tion of the calcium. The fixation seems to be governed bv the vitamine content of the d-iet.' Thus, Ilowe and. Toverud have a conception of scurvy' which conesponcls to that generally prevailing in regardto rickets. My histological examinations give no reason to suppose that the calciurn rnetabolism is prirnarily disanangecl in scur:vy. SÎUDIES IN SCURVY 127 On the other hancl conclusions rnay be drawn frorn the pictures which are highly interesting for explaining the seconclary changes which the calcium excretion unclergoes in scurvy. In early stages of scurvy a bone is formecl which is calcified, but quantitatively as well as qualitatively inferior. The resorption of the old bone seems to proceecl normally. The new bone is of srnall scale a,nd cannot absorb the quantity of calcium rnacle free from the old bone. There ensues in the bocly a surplus of calcium, and. a precipitate excretion takes place, to which the pictures I have found in the kidney in cases of scorbut latens and. scorbut mitior bear witness. Afterwards, in the progress of the scuryy a circumstance arises which acts in the opposite direction. Different parenchymatous organs get more and more atrophic ancl necrotize partially. Dying tissue generally has greater affinity to calcium and thus we see in scorbutic guinea-pigs calcifrcations appea,r to a large extent in clifferent organs, principally muscles and liver. This may explain the calcium balance being positive cluring this stage. fn healing, again a strong excretion sets in, which has been notecl by several investigators. This interpretation of the calcium metabolism in scurvy as depenclent on different factors has alread.y been sketchecl in its outlines by Gnnsrnrvnnnçnn. It well ¿ùgrees with the results gained by Lusr ancl Kr,ocul.ltl, B.lunor ancl Ennr,srnrN, M¡nrl Fn¡.rsr (1920). B¡.nnnr ancl EprlsrnrN founcl consiclerably diminishecl calcium and. phosphorus contents in bones ancl muscles of a scorbutic infa,nt. The elements in cluestion were diminished in about the same percentage as the total ash. This discovery is not unexpectecl where a porotic bone is concerned. Bahrdt and Edelstein are of opinion that it is absolutely contrary to the result of Lust ancl Klocmann who founcl a positive calcium balance in florid scurvy, but a negative balance during the healing stage. These apparently opposite results ale explicable if we bear in mind that Bahrdt and Edelstein's children had manifest scurvl' since at least six weeks back, those of Lust ancl Klocmann since at least four months. 128 .f. ÀxEr, r{o,IElì How¿np ancl INcv¡LDsEN found calcium to be reta,inecl cluring manifest scurv)', but the less, the more the clisease proceeded. It is open to d.oubt, holvever, whether conclensed milk as only diet calls forth simple scurYv in monkey. It is proba,ble that in this food also other necessary substances beside the antiscorbutic are lacking. Monur, etc. examined the ash and calcium contents in the bones of ten scorbutic guinea-pigs, without further indicating which bones, ancl stated values fully comparable to those of the control animals. As the calcium contents of the bone ø ptríori may be supposed to be diminished in the osteoporotic diaphysis but increasecl in the epiphysis ivith its shapeless masses of calcium columns, it is necessary to state clearly from rvhere the examined piece of bone is takeu. Prcz' experiments, like others where no importance has been attached to the quantity of fresh milk consurnetl, can not be taken into consicleration. RoBB etc. have in 1921 publishecl experiments aimed" to elucidate the calcium metabolism in scorbutic guinea-pigs. The arrang'ement of the experirnent with use of calcium-free diet etc. is so unsuitable for the purpose, the juclgment of the experimental figures so uncritical, that no notice can be taken of the conclusions.l CIIAPTER V. Scurvy and rickets. The clifferences recold-ecl by previous investigators between the bone pictures in scurvy and in rickets have been established by rny investigations. Only i¡r one respect, the initial hyperemia, I have found these changes agreeing. Moreover, in scurvr this hyperemia soon gives place in the metaphyses of the long bones to a tissue containing very few vessels, the frame-work marrow. The most pronounce¿l clifference between 1 fw¡.nucur found in 1922 no noteworthy changes from the normal of tl"re calcium contents of bones, muscles, liver, spleen, in guinea-pigs rvith scorbnt mitior rn¡nifestus, 36-46 cìays. STUDIES IIi SCT'R\¡Y r29 scurvy ancl rickets in the bone-system is their relation to the calcification. In rickets, an osteoicl substance is formed, which is not calcified. In scurvy, a bone is formecl to a limitecl extent, which is rapiclly calcified. The histological picture gives the differential diagnosis as well as the Roentgen picture (Fnlnlvnnr,, HorruExr,r). Already macroscopically. the easily breaking, brittle anct light scorbutic bone differs frorn the -flexible, heavy rachitic bone. A real rlifficulty in distinguishing them only occurs when it is a question of healing rickets. Clinically, a scorbutic and. a rachitic ros&ry may be impossible to clistinguish from each other. Other findinqs rvili then ha,ve to decide the cliagnosis. Through the clescription, quoted. on p. 203, of the bone changes in a chilcl with coincitlent scurvy ancl rickets, euensel has shown holr the shares of both cliseases in the bone picture may be distinguished, a problem which Schoectel has designated as d.ifficult, if not impossible, to solve. CHAPTER VI. Scurvy and inanition. The question horv far the scorbutic changes ancl symptoms might be consequences of inanition has been examined b;. sevelal investigators from lfor,sr and Fnör,rcrr to Connrt ancl M¡rvopr,. All of them arriye at a conclusion agreeing with that of the two last-named authors, that >the inanition is a result of the scorbutic symptoms rather than a forerunner of themr. The latest to write on this matter are Mounrquauo anil M¡cnnr,: ,Le scorbut et f inanition sont d.eux faits absolurnent distincts. Nous estimons que I'apparition des symptômes cle scorbut n'a aucun rappor-t précis ayec f inanition et que cette d,ernière ne constitue pour eux qu'un épiphénomène généralement tardif.> On the whole the study of my 4 anirnals, rvhich have been put on relative general inanition but have receiyed a sufficient protective dose of antiscorbutic, has given a concordant result. The animals died after one to two weeks 9-2412õ. Acta pæd,ì,atrica. Vol. III. Supplenentum. a,nd shov¡ed at the death no tra,ce of the changes of teeth or bones rnhich have been rlescribecl as scorbutic. In the skeleton muscles, heart, liver, spleen, kitlneys, salivary glands, adrenals' of the inanition animals there are light atrophic changes resembling those describecl in scurvY. It can not be excludeil that the inanition has contributed to these changes in certain among the scorbutic animals. In others among these, where there has been no clecrease of weight, this is probably excluclecl' The possible inanition which may have been prevailing during the last clays is not sufficient alone to explain these changes in the parenchymatous organs of the scorbutic animals' The difference in degree between the changes in the inanition aninals and those with scurvy is too great for that' In the chapter on Pathogenesis I have set forth that I look upon the atrophic changes in animals upon clifferent deficiency diets a,s similar but not iclentical. 130 ,r. Åxnr, sö¡Pn CHA.PTER VII. A modified method for experimenta¡ rat¡ng of the antiscorbutic value. The method for testing the antiscorbutic value of a substance which has up till now been most frequently employed is to determine the minimum protective dose on guinea-pigs' The experimental periotl has generally been fixecl at 90 days, >after which time it is unlikely that cleath from scurvy will occur) (Snnnu.ln etc.). MounrQUA.ND and Mrcnpr' claim, however, that the animals shoulcl live 150 days and' more, as they have seen a latent scuïvy become manifest as late as that with a constant antiscorbutic dose. Neither the French, nor the American authors say anything about a rnieroscopical examination of the experimental animal' SnnnueN, Ll Msn ancl C¡Mrsrr'r' point out that if in a certain quantitv of a juice, that has been tested with regard' to its antiscorbutic value, there is not enough for'complete pro- STUDIDS IN SCURVY 13 t. tection, it is still possible to ìudge the relative quantity of antiscorbutic administered through comparing the rn'eight curves, survival periods, severity of the symptoms, and. autopsy findings for the animals exaurinecl with a stand.a,rd scale. ,Thus, one is not confined entirely to a comparison of the so-callecl rninimum protective doses, since the quantitative rating of the clegree of protection afford.ed permits comparisons to be rnade upon animals receiving less than the amount required for complete protection.> For this a reliable scale of cornparison is required. Sherman etc. communicate orle. My experiments give another, somewhat different. The origin of the difference is that Sherman etc. do not seem to und.ertake a rnicroscopic examination in this connection, and thus their minirnum protective dose means a dose which protects from changes enough ruarked to be obseryed ma,croscopically at the plst-mlrtenx examination. As I have provedl, a close trvice as large as this is necessarJ¡ to prevent anatomical changes in the teeth. fn my opinion it is to be preferred, by ,protective dose, to rnean a fully prolective dose, ancl in order to establish this amount a histological examination of the teeth is necessary. Of course, the method. employed by Sherman etc. is also practicable although somewhat uncertain, if only in every case it is indicated how the experiment has been mad.e. The early, markecl ancl pathognomonic changes in the teeth of guinea-pigs, which we have described, permit a moclification of the indicated methods. Àfter some animals (weight not much above 300 grams) have received a certain c¡rantity of the substance, the antiscorbutic value of which is to be tested, during 2 weeks, they are killecl. The lorver iaw is decalcified anil a cross section of the incisol root is examinecl in the manner described in the chapter on ,Teeth, p. 40. A completely protective close gives a picture like that in Fig. 30. Smaller closes rnay to a certain extent be rated. by a methocl analogous to that of Sherman etc., describecl above, whereby Fig. 22-29 m¿ùy serr¡e as scale of comparison. Ba meatzs of th'is m,ethod, the øntiscorbutic ualue of ø product can, be testecl 'in tltree rueelcs 'insteacl of three ntonths. t'ò2 J. AXEI, HOJEIì CHAPTER, VIII. Pathogenesis of scurvy. Relation of scurvy to other deficiency diseases. ,Vie'wing the situation broadly, it must be acknowledgecl that, except for the realization that scurvy is clue to a new foocl factor, a vitamin' our funclamental understancling of its pathogenesis has advanced but littlen (IInss 1920). AscnoFr' and. Kocn presume >eine kolloid-chemische Umstimmung cles Blutes oder der Gefässwände>. with >eine fehlende ocler schlechte Bild.ung von Kittsubstanzen, durch cleren Mangel clie Osteoblasten zur untätigkeit bestimrnt werclen und keinen anreiz zur Neubildung erha'Iten'. From different quarters (Mnr'r'lxrv, BRopnnrcn, TlYlon, quoterl after Onsi.N) the supposition has been brought forth, in accorclance with McCarrison's investigation, that the antiscorbutic substance would exercise its influence through the organs of internal secretion' The universal opinion is expressed by Bnnc 1922 thus: >fMie man die Haupterscheinungen, clie wir als teilweise Decomposition bezeichnen könnten, einheitlich aus einem Gesichtspunkte aus erklären soll, bleibt vorläufig ganz rä,tselhaft>. Two pathogenetic problems have up till now been placed" in the foreground for the stuclv of scurvy. The first is this: In which ways does the antiscorbutic influence the osteoblasts ancl vascular walls, directly or by the means of other organs (glancls, enclothelial celts)? The second' problem is: How cloes the antiscorbutic exercise its effect, by itself entering the products formed or by renclering certain reactions possible without itself being destroYed? The present investigation wiclens the first question' It has been established that the antiscorbutic is necessary to continued activity and. life of various more highly differentiated cells in vivid activity, oclontoblasts, osteoblasts, chondroblasts, fibroblasts, lymphoblasts, the muscle cells, ancl the parenchymatous . cells of the liver, salivar.y gland, aclrenal and kidne¡'. I STUDIES IN SCURVY 133 All these cells seem, in the absence or d.eficiency of antiscorbutic, to be subiect to a,trophy ancl yielcl a product which is quantitatively as well as qualitatively inferior. The sma,ller this insufficient close of antiscorbutic, the less cleveloped the appeara,nce of these cells and of their products (proved with regardto odontoblasts, osteoblasts and fibroblasts; to be presumed in the rest). If antiscorbutic is altogether lacking in the foocl, these cells go on iiving for a certain time and yield. cluring this time proclucts, which tleteriorate day by day till the activity is completely arrestecl ancl the death of the cell ensues. Hnss says in his chapter on symptomatology: >Scurvy reduces the nutritional state of probably all the cells ancl tissues of the body.u Even if this is presumable, I would like, in accordance with my investigations, for the time being to formulate this sentence thus: Scurvy retluces the nutritional state and. the active function of probably all the most active, rnost rapiclly growing ancl highest differentiated cells of the bocly. This reduction begins with the absence of antiscorbutic in the food. It becomes manifest aL a rale that varies for the clifferent cells and tissues: first in oclontoblasts, then in osteoblasts, muscle cells, Iymphoicl tissue, fibroblasts, ancl salivary glands, then in the liver, adrenal, chondroblasts, ancl last in the epithelium of the kidney. The order in rvhich the changes set in and continue in odontoblasts, osteoblasts ancl chond.roblasts seems to argue for the notion that phylogenetically olcler and' histo-functionall¡' less differentiated' cells are later and more lightly struck by the d.eficiency of antiscorbutic. The conforrnity which from a purely histological point of view is founcl with regarcl to the cell changes (cJ.,for instance, hyperemia, the initial disarrangement with disintegration of the gradually lowering cell layer as to odontoblasts and" chondroblasts) seems to indicate that antiscorbutic has a similar effect on clifferent cells. It seems to me most probable that this effect is exercisetl directly on the cells by the antiscorbutic rvhich has passed into the bloocl. In any case, after m¡. investigation the statement of Lunlnscn stili holcls true: uEine 140 J. ¡\XEL HOJEIì generally been misinterpreted, are described for teeth, en¿losrnal an¿l enchondral bone forrnation. For the connective tissue a general a,trophy is described, which especia,lly overtakes the collagen flbrils. This change is aLso proved in the va,scula,r rvalls. In muscles) Iymphoid. tissue, liver, salivary gland, aclrenal and. kiclney an atrophy combined with necrosis has been founcl. À1so in these regions the tissues seem rnore seYerely struclr, the more the scurvy is develope,-Ì. It is established that some of the most active and. most differentiated of the cells in the bocty are caught earliest ancl most severely by the scorbutic atrophy. The changes which have been clescribecl rnay be tracecl at a very early stage of the latent periocl. The irnportance of subiecting this latent stage to a cLose studv is strongly emphasizecl. Through these investigations the pathological picture of scurvy has thus been amplified, and. the principal features of the disease have been analysetl ancl founcl to be uniformly explainable PART IV Saut uy ccrld tzel)er"culosi's. CHAPTER I. Historical review. An importance of the diet to the progress of tuberculosis has been assume¿l alreacly by LrNnú. He rvrites in 1766: ,Ingesta nimis nutrantia - nonne hinc saepissime oritur Phtisis juvenurn?, On the contrary, subsequent investigators have as a rule regardecl the general rnalnutrition a,s acting upon the progress of tuberculosis, though the problem up tili the present time has evoked. a comparatively smail interest. Conwnr and Kossnr, write in 1913: >Es ist wohl clenkbar, dass ein abgekapselter Hercl clurch Unterernährung ausgelaugt uncl tlie Bacillen mobilisiert werden,r. The authors are evi¿lently thinking of the theory of >>clemineralisationr. Löw¡Nsrnrrs, rvho in the 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. 'W.: The influence of heal, ancl oxiclation upon the nutritive ancl antiscorbritic properties of cow's milk. Science, N. S., Vol. 53, No. 1375, p. 446. --: The nutritive ancl antiscorbotic properties of milk. Journ. Biol. Chem. 45, 1920. AuoN, H.: Ansatzförclerncle Wirkung volt Extral<tstoffen. Mon. Kh., Bd.. 22, t92t-t922. -A.scltonn, L., and Kocn, W.: Skorbut. Jena 1919. 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