The association of bowel disease with vitamin C deficiency

THE ASSOCIATION OF BOWEL DISEASE WITH VITAMIN C DEFICIENCY. BY L mUT.-COI,. F-`. P. MACKII;, o.n.> ♦., v.x:s., i.M.s., AND G. D. CHITRE, L.M. & S., B.M.S. (Being. Part III of the Sprite Investigation at the Haffkine Institute, Paret, Bombay.) [Received, for publication, February 27, 1928.1 Wr attempted ill a series of experiments detailed in a previous paper * to produce the clinical feature of spree in animals by infecting them with sprue feces or with monilia isolated therefrom. In some of these experiments we tried to induce susceptibility in monkeys by keeping them on a diet deficient in vitamin C. We were not successful in reproducing sprue in these animals, but we found that avitaminosis in itself produced* an increased susceptibility to disease of the intestinal tract. We used sixteen monkeys (Af. sinicits and rhesus) in two batches. The first batch included ten monkeys including four controls which latter were fed on a normal diet and which did not receive infected material. In this batch the six monkeys fed on a deficient diet which also received infective feeds ,of .sprue material, all developed an inflammatory or degenerative condition of the alimentary tract resembling dysentery, whilst the four control monkeys remained quite free from this disease. This batch of experiments suggested that the feeds of infective material from sprue cases were responsible for the bowel disease referred to. The second hatch of experiments was more exacting in that all the six monkeys were maintained on a deficient diet, but the three controls received no infective feeds. The six animals were housed on the same verandah but were separate from each other. All six animals developed the same clinical symptoms and showe(b the same post-mortem conditions, so it is fair to 'asstune that the causative or predisposing factor was the deficiency in vitamin C and not the infected feeds. *' Animal 1~xperiments and sprue' (this number), pp. 49-75. ( 77 ) subito e.V. licensed customer copy supplied for Helsinki University Main Library (SL103X00759E) 78 'Association of Bowel Disease tvith Vi•tantin C Deficiency. The dietary given to induce scurvy was that recommended by I,ieutenantColonel R, McCarrisou, r.M.s., and consisted of— Polished rice (boiled)  100 grins. Ground-nuts (parched)  ..  30 grins, Autoclaved milk  ..  ..  .. 200 c.cs, Butter  ..  ..  ..  10 gyms. Orange juice  ..  ..  ..  2 c.cs. The infective feeds of spree material were generally given when the animals began to lose weight and to exhibit symptoms of ill health. Where the scorbutic condition was advancing too rapidly, an attempt was made to check it by giving a small amount of orange juice or, to one or two cases, by •putting the anitllal back on a full normal diet. In two animals so treated the signs of dysentery receded and the animals quickly recovered (Monkeys 279 and 280), but in monkeys in which a more marked scorbutic condition was present the exhibition of vitamin C was too late to save them. The most marked result was a loss of weight. This was generally slight at first and was represented by a slow but steady decline in the LNtrlier weeks. When once the decline was established, there came a point when the weight came tumbling down especially with the onset of dysentery and the loss increased ill rapidity till the animal died. In some animals no definite signs of scurvy appeared or were found after death, but in others definite scorbutic signs appeared, such as puffiness and ecchymosis around the eyelids or other parts of the face. Small •hmnlorrhages or bruises under the skirl and sometimes haemorrhages into the muscles were found post-mortem, I,00sening of the teeth and bleeding from the guns were seen in the more severe cases. Apathy, wasting and `staring' of the coat were common signs, but diarrhoea was not a prominent feature datring life except in a few cases. The infected feeds were generally commenced when the animals' weight began to decline and consisted of saline suspensions of'the fresh faeces of human spree cases or of cultures of Monilia psilosis isolated therefrom or of both together. Post-1 , nortent appearances. On opening the abdomen, the intestine was generally seen to be injected and the large bowel was often thickened and congested, No obvious naked eye changes were seen in the viscera, but the heart was generally pale and flabby, On opening up the alimentary canal, small hTmorrhages or diffuse ecchymosis were sometimes present in the stomach. The small intestines were frequently congested, but rarely showed much change till the lower part of the ileum .was reached. At this level the mucous membrane was thickened and velvety,. whilst small superficial erosions were occasionally present, but ulceration was never seen above the level of the ileocwcal valve. The large intestine showed well-marked changes in every case, particularly in the c scum and . the descending -colon and sigtnoid. The changes varied from subito e.V. licensed customer copy supplied for Helsinki University Main Library (SL103X00759E) P. P. Mackie and G. A Chitre.  79 deep congestion with thickening of the mucous and submucous layers to ,frank ulceration and widespread superficial sloughing of the mucous membrane. Perforation of the caecunt and invasion of the adjoining surface of the liver was noted in one case, The condition in the severe cases resembled a toxic form of dysentery with ulcers, hemorrhages and surface sloughs. The impression one gained was that the inflanintatory changes were less obvious than those of degeneration and this was borne out by a study of the micro-histology. Micro-histology. The stomach and upper part of the small intestine rarely showed any change except for small hemorrhages which were part of the scorbutic state. The lower portion of the ileum was generally congested and the mucous membrane thickened. In places there was loss of staining power and cloudy swelling of the superficial layers suggesting an early stage of toxwmia. The large intestine in every instance showed these inflammatory and toxic changes more profoundly. Wide areas were almost deauded of the surface epithelium which lay in the lumen in a state of coagulative necrosis containing swarms of bacteria. Ulceration was seen in some specimens extending to the subniucosa or more rarely to' the muscular coat. In the more profound cases the whole of the gut wall was swollen and the muscle cells showed diffuse eosin staining with loss of nuclear definition as if the local toxins had affected these structures also. The parenchyma of the liver, kidney and mesenteric glands often showed well-marked toxic changes as evidenced by obliteration of cell outlines, diffuse staining and small celled infiltration. '.Clue blood of some of the animals was studied during life and revealed a progressive anaemia without signs of regeneration and with little change in the b6titi marrow after death, The intestinal unueosa was invaded by numerous bacteria chiefly cocci and Gram-negative colifornas which were mostly in the degenerated layers or in sloughs, but there was some evidence of deeper invasion O f bacteria into the living tissues. N101 - tilia were never seen to have invaded the living tissues, though they were often present in the faecal contents and in the sloughs. Bacteriological exantination of the diseased intestine. V,xamitiations of the dysentery-like faeces both before life and immediately after death were carried out in nearly every rase. mesh scrapings from the large intestine never showed amcubac or their cysts. flagellates and blastocysts and bodies resembling coccidia were found on occasions. Large undulating slowlymotile bacteria were seen on several occasions but were not grown in any of the media used. The faecal organisms were studied in most cases, but only on one occasion was a dysentery-like organism (of flexner Y type) isolated and a I eus-like bacillus also in one or two occasions. Non-hemolytic cocci were numerous in all cases, Afonilia of Psilosis type were sometimes isolated from the feces before the experiment was began and in most cases were recovered from the diarrhoeal or dysenteric stools, but there is no reason to associate them with the evolution of the bowel subito e.V, licensed customer copy supplied for Helsinki University Main Library (SL103X00759E) 80 Association of .Bower Disease with Vita-mint C Deficiency. disease, (Fuller details will be found in the report on each monkey in the attached protocols,) RJMARKS. On going through such literature as we have at our disposal, we find .that though a great deal of work has been done on experimental scurvy in animals (including monkeys), references to lesions of the intestinal tract are very infrequent and it is clear that the extensive dysentery-like condition present in our monkeys is somewhat exceptional, Thus Harden and Silva (1918-1919) describe in detail the symptomatology of experimental scurvy in monkeys but make no reference to any intestinal lesions. On the subject of vitamines and infection, hindlay (1922) had made a series of observations on guinea-pigs suffering from experimental scurvy. No mention is made of the condition of the alimentary tract. He confirms the question of lowered resistance to bacterial infection. The result of his experiment with four species of bacteria shows that guinea-pigs, fed on a diet deficient in vitamin C, succumb to a smaller infecting close of bacteria than animals fed on a complete diet and that the symptoms of toxemia are manifested more rapidly in scorbutic than in control pigs. He associates this fact with an altered condition of the bone marrow and concludes that guinea-pigs with chronic scurvy, though showing few clinical symptoms, are less resistant to bacterial infection. Several writers, Cohen and Mendel (1918), Jackson and Moody (1916), point out the lowered resistance to bacterial invasion which is seen in scorbutic animals, and this suggests that the dysentery-like condition found in our animals may have been clue to the invasion of faecal organists of exalted virulence rather than to specific organisms of human dysentery. The occasional absence of all clinical signs of dysentery daring life in spite of the ulcerated condition present in' the large intestine as revealed by necropsy is a remarkable clinical fact. It recalls an' incident which the senior writer witnessed in Mesopotamia during the late war. An officer had been invalided from the front after suffering considerable hardship, including poor feeding, and was admitted to the officers' hospital in Baghdad for some minor surgical condition. He was under the close observation of experienced surgeons and trained nurses for a week after admission but at no time presented any signs of intestinal disease and his motions were reported to be normal, He died soddenly of heart failure (in itself a suspicious sign of 'avitaminosis) and at the autopsy his large intestine was found to be in a condition resembling acute dysentery with extensive superficial ulceration and sloughing of the mucous membrane. Scurvy was at that time rife in the outposts of the war area and one is tempted to compare the condition in this patient with what one observed iui several of the monkeys in the present experiments. About the same time a terrific outbreak of dysentery occurred amongst a number of refugees who had recently' arrived in Baghdad in a condition of extreme malnutrition and poverty, being a survival of those who escaped'massacre at the han& of the Turks in the highlands of Persia. The appaling severity of the elSidem4o_ (resembling cholera - 'at its worst) and the profound intestinal changes subito e.V. licensed customer copy supplied for Helsinki University Main Library (SL103X00759E) F. P. Mackie toad C. A Chitre.  81 found at the post-mortem impressed one with tlic conviction that the condition of malnutrition was largely responsible for the virulence of the epidemic. The prevailing organism found was Shiga's bacillus, but the predisposing cause was the scorbutic or sub-scorbutic state which starvation had impressed on these unfortunate people. The writer who has laid most stress on the intestinal changes in avitaminosis is McCarrison (1918) and he also has called attention to the deficient resistance t0 bacterial invasion which is brought about by a vitamin-deficient diet. His principal researches in this connection are described in two papers (McCarrison, 1919 and 1920) and an abstract of these papers is given in Brit. llled. Jour., hebruary 21, 1920, p. 249. A study of these researches reveals results with which the observations in the present paper are in close accord. The symptoms and progress of the disease in monkeys as also the postmortem signs and the morbid histology are almost precisely those which we have described, the only difference being that in McCarrison's series the duodenum and tipper part of the small intestine were equally affected with the large intestine, whereas in our series the tipper part of the alimentary' canal was almost always free from disease. McCarrison appears to have satisfied himself of the existence of atneebic infection in some of his cases, whereas we were unable to find any such cause. He did not carry out bacteriological examinations of the intestinal contents so that the causation of the dysentery-like condition, if bacterial, was not demonstrated in his animals. CONCI,USIONS. 1. Monkeys which are fed on a dietary deficient in or lacking `vitamin C' become debilitated and anaemic, lose weight rapidly and generally suffer from a terminal dysentery which ends in death. Definite signs of scurvy appear in most of the animals. 2. This scorbutic condition can be checked by the administration of orange juice or by a return to a normal dietary provided it is not advanced. When once the scorbutic condition is well established, this treatment cannot be depended upon to save the animals' lives. 3. The post-tnortem signs are most marked in the large intestine which shows a succession of changes suggestive of local poisoning. These signs vary from local congestion and thickening of the mucous membrane to a condition indistinguishable from ulcerating and sloughing dysentery. 4. The morbid histology suggests degenerative changes due to the action of a toxin to which inflammatory changes are added secondarily. 5. Specific excitants of dysentery such as amoebae or dysentery bacilli are not found in the large majority of cases. 6. The commoner faecal flora are found in some cases to have invaded the living tissues of the bowel wall and this suggests that the toxic changes observed are the effect of suich bacteria acting on tissues devitalised by the ill-balanced dietary. 7. These changes appeared in the alimentary canal in all animals kept on a diet deficient in vitamin C whether given infective sprite material or not. subito e.V, licensed customer copy supplied for Helsinki University Main Library (SL103X00759E) 82 Association of Bowel Disease with Vitamin C Defacievey. , Monilia were not found to have invaded the diseased areas nor can the changes be attributed to their action. 8. A defective dietary by itself acts as a powerful predisposing cause of bowel derangements and acts probably by reducing the natural resistance of the intestinal epithelium to the invasion of bacteria or their toxins. REFERENCHS. ComN and M1 , '.ND8L (1918)  1;xperimcntal Scurvy in Guinea-pigs in Relation to the Diet. Jour, Biol, Cheat., Vol. XXX V, p. 425. HARDr,N and SIt,vA (1918-1919)  .. Experimental Scurvy in Monkeys. Jour, Moth, and fact., No. 3, p. 246. FINDLAY (1923)  ..  .. Jour. Path, and Fact., Vol. XXVI, No. 1. JACICsoN and MOODY (1916)  „ Bacteriological Studies on Experimental Scurvy in Guinea-pigs. Jour. Inf, Ibis., Vol. XIX, Sept,, P. 511, MCCARRISON (1918)  ..  .. The Pathogenesis of Deficiency Disease. Ind. Jour. hied. Iles., Vol. VI, Jan., p. 344. MCCARRISON (1919)  . ,  , . The Pathogenesis of Deficiency Disease: (1) The Effect of Autocalved Rice Dietaries on the Gastrointestinal Tract of Monkeys, It d. Jour. Med, Res., Vol. VII, No. 2, Oct., p. 283; (2) The General a ffects of Deficient Dictarics on Monkeys, Ibid., Vol. VIII, p. 308. subito e.V. licensed customer copy supplied for Helsinki University Main Library (SL103X00759E) F. P. Mackie and C. A Chi.tre.  83 PROTOCOLS. Protocol 1. Monkey 278. Put on deficiency diet oil 25th February 1927. Infected feeds, 29th March 1927, saline suspension of sprue faeces. 2nd April 1927, culture from spree faeces. 8th April 1927, saline suspension of sprue faeces. 19tH May 1927  „  91  of  11 11th June 1927  ,1 to  1/  1/ Clinical Course.—Gradual loss of weight from 1,600 to 1,300 grammes (vide Charts I and II). No subcutaneous haemorrhages or bleeding of gums, noted. Signs of dysentery set in on 20tH June 1927. Faeces were normal till this date, but subsequently they became loose and contained blood and mucus. Blood films examined during the course of the experiment showed no abnormality. Monilia of 1 M' type were found on two occasions in the faeces before the experiment was begun. M. psilosis found on several occasions after commencement of infected feeds and also after death. Bacteriology of faeces after the onset of dysentery— (1) Numerous strains of a Gram-positive cocetis giving the following reactions—acid in lactose, glucose, rnaitose, saccharose, galactose and milk. Mannite and dulcite nil. (2) None of these strains were hemolytic. (3) Strains giving the reaction of B. soli or B. anerrogenes. (4) Strains giving the reactions resembling B. paracolon. (5) A strain resembling B. f(ccalis'alcaligines. Post-vtortrin Signs.—Died 22nd June 1927. Stomach deeply injected and shows subinticous haemorrhages, Small intestine deeply injected, 111licous membrane velvety, no surface lesions. Large intestine acutely inflamed and shows the presence of small superficial ulcers and erosions. No naked eye changes in the other organs. P'emttr contains red marrow. No monilia found in heart's blood or viscera. mesh scrapings from the inflamed gut showed trichonlonads, yeasts and blastocysts btlt no atilwbae or cysts. N7i:cro-Histology.---Stomach normal. Small iutestitle showed some aggregation of small cells under mticosa and epithelitull was in a condition of cloudy swelling. barge intestine showed early coagulative neurosis of superficia' lavers of epithelium with dentidatloil and actual ulceration extending to submucotts layer in places. The nntscular coat was swollen and blurred as if toxic. Crowds of bacilli in necrosed areas. Signs mostly toxic and little evidence of inflanlnlation. Kidney epithelial" showed toxic changes. subito e.V. licensed customer copy supplied for Helsinki University Main Library (SL103X00759E) 84 Associatioa of Bowel Disease with Vitantbt C Deficiency. Monkey 279. Put on deficiency diet on 25th February 1927. Infected material given:- 29th March 1927, saline suspension of sprue faeces. 2nd April 1927, culture from spree faeces. 8th April 1927, saline suspension of spree faeces. 19th May 1927  „ 11th June 1927 Clinical Course.--INreight fell gradually from 2,000 to 1,850 grammes between commencement of experiment to middle of May. 'Thence dropped rapidly to 1,400 grammes about 20th June. Then began to rise and reached 1,850 in midSeptember. Showed signs of dysentery on 21st June 1927. Continued ill for ten days showing blood-stained. mucus and made gradual recovery after having been put back on full diet oii 26th June 1927. Blood examinations at the height of dysentery showed severe anaemia: R.B.C.  , .  , .  ..  1,375,000 W.R.C.  ..  ..  ..  12,500 Hb.  ..  ..  50 per cent. H.I.  ..  ..  ..  1.8 No nucleated reds. Bacteriology of Purees.---I+resh preparations showed trichomonads and their cysts, yeasts and their mycelia, a few bodies resembling coccidia. No amoebae. Bacterial flora appeared normal.' Previoas to commencement of experiment, monilia of psilosis type and of M type (cryptococcus) were found and subsequent to giving infected material AT. psilojis and cryptococci were again found. Bacteriology of fakes was not clone. Result.---The animal 'developed dysentery but recovered on being placed on a diet abundant in vitamin C. Monkey 280. Deficiency diet begun on 25th Vebruary 1927. Faecal examination previous to giving infected material; monilia of species undetermined found on one occasion. Infected feeds:- 29th March 1927, saline suspension sprue faeces. 2nd April 1927, culture from sprue fakes. 8th April 1927, saline suspension sprue faeces. 19th May 1927 „  to  to  „ 11th June 1927  „  to  10 Clinical Course.--Showed gradual decline in weight from 1,630 to 1,480 grammes and a sudden drop about the middle of May to 1,240 grammes. At the end of May, began to rise in weight and eventually approached 1,600 grammes. subito e.V. licensed customer copy supplied for Helsinki University Main Library (SL103X00759E) P. P. Mtckie and G. D. Chitre.  85 Diarrhoea commenced on 26th May 1927, which continued off and oil till the end of June. The faeces at their worst were thin and sanious-like meat juice. The monkey was put on ordinary diet on 26th May 1927, when the dysentery symptoms started; but the symptoms continued off and on for a month and then gradually cleared tip as the animal improved in weight and in general health. i;'xaminatioii of Stool.—On 20th June 1927. Some flagellates, trichomonas and cysts. Yeasts. Bodies resembling coccidia. No amoebae seen. Blastocysts present. The faeces were not examined bacteriologically,  Monilia of types m. psilosis, kruxei and ` M ' cryptococcus were isolated from stools during the course of the dysentery. Reutorks.--This animal began to show signs of dysentery and marked loss of weight two months after the first infected feed, It was then put back on full diet and the dysenteric signs gradually subsided and a month later the animal began to resume its normal health. ?lfonkcy 281. Put on deficiency diet on 25th February 1927. Faecal examination previous to infected feeds. ' M. psilosis and cryptococcus (M type) present. Infected feeds:- 29th March ,1927, saline suspension sprue faeces. 2nd April 1927, culture from sprue faeces. 8th April 1927, saline suspension sprue faces. 19th May 1927  „ 11th June 1927  „ Clinical Course. --The animal began to lose weight soon after the dietary was curtailed and dropped from 1,750 to 1,600 grammes by mid-May. After this dropped ra*idly till date of its death on June 23rd, when it weighed 1,000 grammes. Developed dysentery on 20th June 1927. Motions resembled liquid meat juice with blood-tinged mucus and the animal was very anaemic and the blood films showed anisocytosis, and poikilocytosis without nucleated red cells or other signs of regeneration. Examinatioii of Stool.---20th June 1927. Flagellates and cysts with yeasts and mycelia, a few coccidia-like bodies, No amoebae seen. Monilia of psilosis, kru.-ei and cryptococcus types were isolated from the faeces. Gram-positive cocci giving reactions similar to those described under Monkey 278 were numerous. Those of the coli group were abundant. Several strains of a Gram-negative, non-motile aerobic'bacillus of coliforitu type having the following sugar reactions—lactose and dulcite negative, acid only in glucose, saccharose, mannite and milk. (The reactions in maltose and galactose were inconclusive.) These strains were not agglutinated by any of the high tore dysentery sera. Post-mortent Appearances.--Died on 24th June 1927. There were abundant submucou-s haemorrhages near the pyloric end of the stomach. The small intestine was injected but showed tto breach of surface.  The .large intestine was subito e.V. licensed customer copy supplied for Helsinki University Main Library (SL103X00759E) 92 Association of Bowel Disease with Vitamin C Deficiency, PR OTOCOI, IT. Characters of different tykes of bacilli and cocci isolated from the contents of intestine of seven of the experimental n ► o ►► keys. ;Morphology. SUGAR FEMENTATIAN REACTIONS. REMARKS. C'3 ~ C3 ai .so b i 2 B. (coliform) B•  (  of  ) I,  T.aclnRe — nun A AG .. ACS fermenlers, — AG A A Flexner typo. 3 B. (  ) AG AG AG 4 B. (fnsiform sporing) A A 5 B. (short) -F A B. (coliform) 1. — La ctose A A fermenterR. A A A A A 7 B. (short, thin) A AG AG AG AG Act 8 B.  (  ► ,  to  ) A A A A A AG AG AC AG AG AC 10 B. (coliform) AG AG AG AG AG AC 11 B. (  ) AG AG AG AG AG A 12 B. + AG AG AO AG AG A 13 B. (medium thielcness) AG AG AG AG A -I14 B. (coliform) .  . . AG AG AG AG AG C 15 B, (  „ A lt3 17 .Co. (round) Co. (minute diplo) .(. 111, Cocci. A 18 Co. (diplo) A A C 19 Co. (large) + A A A A A 20 CO. (  to  ) + A A A 21 Co.  . . A A A A A 22 Co. (small, round) + A A A A A A 23 Co. (minute) A A A A A C 24 Co. (diplo) A A A 1 Note.--Group I. Contains lactose non•formenters. Group iI. Contains laotose fermonters mostly B. coli and its oongoners. Group III. Contains the various types of cocci present. subito e.V. licensed customer copy supplied for Helsinki University Main Library (SL103X00759E) Pr,n ri; XT. Vig. S.  Fig. G. subito e.V. licensed customer copy supplied for Helsinki University Main Library (SL103X00759E) l',Xl'I,ANATluN uV 1'1,.~~rn \I. 1  1,uw power nla;; Ili lication of ilrtllll of luunkey sbuwillg~ coag'lllatiun necrosis of sullerlicial nutcosa, and of large ,trots in the subnwcous layer. 2. Ctectuu of NOWN , 331 showing Immial destruction of unlcous layer and liirutic changes ill snbnlncous layer. 3. C'X( , tllll of 1\Wnkev 281 showing earlier dc";enerative, Changes in 11111CMts nuCnlbrane, d. Cxci nl of NIunkcy 331 shuAng clmngs similar to those in lJig, 2. 5. 1,ano intestine of Ah"d cy 327 showing coagulative necrosis of umcous Illellibranc, (i. Dnodcnunt of \lullkey 332 showing similar changes with early sloughing of mucous nlelllbrane ;old irritation and thickening of subtllucotts layer. subito e.V. licensed customer copy supplied for Helsinki University Main Library (SL103X00759E) 1?xIII,ANATION uW L't,~~'rt; A I I. I:ig, 1. Changes in duc,dcnttttt of 111o~nlwy 332 similar lu I,rcccdhi'g.  Figs. 2, 3 and 4. Cwcnnt c,f N1„nkcy 32.E  c,f c,nc of the nc,clttics del,ic ic-d  ill  Ow cc,lutlrcd I,lale.  I?xlcansivc rcOgilla(iun nccrc,siti of nittcolls nlclnl,r;utc gill ► Iil,rc ► sis ;Inc( sivall Celled hilillralic ► n of sttl,nittc•c,tls laycrs. All g - l;tnclttl;ir rind cl,i(hclial elenlenls arc dcslruvcd and rcl ► lac•cd I,y sltlru•n(c inflanun;Ilc ► ry Iissrlc' Low powcr scetic,n of liver showing; logic ('11m)l;cs in lc,wcr cells ;end (heir destrttc•Iiuli ill c•crlain are;Is. ~  ~~'~i  r  u  u  n` ,Saute as 1 I h . 5 Itndr'r hid her nu ► ~;nilir;Il ic,Il s Ic,wlu,~ tc,sic c han ; ,cs in liver Cells. Ip ig. 5. „ C. subito e.V. licensed customer copy supplied for Helsinki University Main Library (SL103X00759E) PI,A'jT XIT. 1 , 1 1g. S. Vii, (r. subito e.V. licensed customer copy supplied for Helsinki University Main Library (SL103X00759E) Fig. 2. Pf"vi'I; r`rITf. Fig, 5.  f.' ig. 4. subito e.V. licensed customer copy supplied for Helsinki University Main Library (SL103X00759E) I~if;. 1. $~  3 . INIT%NAITA or 11,ATH XIII, ;shows ex(ensive toxic ncerosis of the renal lobules. Show"; ch;u~gcs in I,icl>rrknhl's follicles of L•tr,;e intestine at the ecl1;e of a necro wd area. Sho\%"s the invasion of the Intros, at the margin of a necrotic area by inllannn.ctory cells.  I , he ;lan(liilar elements arc ahno;t completely Test royal. Shows the invasion of the dN lwr hgvr of the st"o"ws, in the MOM part of the intestine h~v nunx'rous bacteria. "I'lle invasion of a villas by slender Curved bacilli (ma,;niGcation about 1,tMO Similar bacilli (n agnilication abrntl: 3,(00) lyin,; in the : lbmucxous layer of lar,"e intestine. 'These bacilli during , life showed a ;flow serpighums motility and could not be recovt:recl by ctihurc. „ 5. 6 . subito e.V, licensed customer copy supplied for Helsinki University Main Library (SL103X00759E) E XPLAtvATlc,N O  1'c,a~ra; X1V'. Shows ll,c rccnm a,f c.Xperianentral hodwy 328, 'I'I,c anucons nwn,I,i;,nc is in(l.atruecl ruacl Ilacrc are ;a 1111in1wr of nccrulic uuclulcs c;appccl will, Sloughs I,rutruclii,ti from Il,c 5111'ftacc. subito e.V. licensed customer copy supplied for Helsinki University Main Library (SL103X00759E) Pi-vri; \ I V. subito e.V. licensed customer copy supplied for Helsinki University Main Library (SL103X00759E) % 1 s s 8 .d 1 3 W 1 , 4V 8 J HI 1 F1 J 1 3 M 5 3wwV)10" 1 1 W O 1 7 M x • nn 10 o O N ' E ..mow e. '17•.~~iljJ 'Y'IY 7~6i1 N +411.0. a1...-8 uup /-- r w to X W z N 0 qM.V U) r w Z 00 L ial w Z O CW L Df W d X W (GHT CH AR TS P. t1hickic, and ( ► . D. ("h4h e.  93 CIIART 1. Showing wrlghts of r.i. - po - harnta! mon/.rys. subito e.V. licensed customer copy supplied for Helsinki University Main Library (SL103X00759E)