Effect of Five Salicylate-Containing Compounds Upon The

Gut, 1968, 9, 475-479 Gut: first published as 10.1136/gut.9.4.475 on 1 August 1968. Downloaded from

Effect of five salicylate-containing compounds upon loss of 5`chromium-labelled erythrocytes from the gastrointestinal tract of normal man

WARREN L. BEEKEN From the Department ofMedicine, University of Vermont College ofMedicine, Burlington, Vermont, and Hitchcock Clinic and Dartmouth Medical School, Hanover, New Hampshire, U.S.A.

The adverse effects of salicylates upon the gastro- Matsumoto, and Lichter, 1961; Pierson, Holt, intestinal tract of both man and experimental Watson, and Keating, 1961; Scott, Porter, Lewis, animals have been documented in numerous reports. and Dixon, 1961; Izak, Galewsky-Stein, Menczel, and These studies indicate that salicylate ingestion Groen, 1962;Wood, Harvey-Smith, and Dixon, 1962; frequently causes various upper gastrointestinal Leonards, 1963) assay of faecal blood loss during the symptoms (Caravati and Cosgrove, 1946; Freemont- consumption of these compounds. Most quantitative Smith, 1955; Muir and Cossar, 1955; Waterson, evaluations have been performed in groups consisting 1955; Lange, 1957b; Batterman, 1958; Muir and largely of patients with various disease states and Cossar, 1959), gross changes in the gastric mucosa there have been few systematic quantitative com- consisting of oedema, erythema, ulceration, and parisons of gastrointestinal blood loss induced in bleeding (Dodd, Minot, and Arena, 1937; Barbour normal subjects by common proprietary salicylates and Dickerson, 1938; Douthwaite and Lintott, available in the U.S.A. Watson and Pierson (1960) 1938; Hurst and Lintott, 1939; Stutzman, Orth, and compared faecal blood loss induced by regular Mellish, 1941; Seeberg, Hansen and Whitney, 1951; aspirin, enteric-coated aspirin, calcium aspirin Muir and Cossar, 1955; Jones, 1956; Lange, 1957b; complex, and choline salicylates in normal volunteers http://gut.bmj.com/ Muir and Cossar, 1961; Weiss, Pitman, andGraham, and report this in abstract form, but later communi- 1961; Roth, Valdes-Dapena, Pieses, and Buchman, cations from these authors (Pierson et al, 1961) do 1963; Vickers and Stanley, 1963; Fishler, 1964), and not clearly separate results in normal volunteers microscopical abnormalities of congestion and loss from patients in hospital. Scott and his colleagues of superficial epithelium (Roth and Valdes-Dapena, (1961) evaluated different salicylate preparations in 1963; Hurley and Crandall, 1964). Biochemical a large group of subjects, most of whom had studies (Croft, 1963; Menguy and Masters, 1964, rheumatoid arthritis or other diseases. Grossman, on October 2, 2021 by guest. Protected copyright. 1965) indicate that marked alterations in gastric Matsumoto, and Lichter (1961) also evaluated mucus are caused by salicylates, and bleeding of the various salicylate compounds, but again their studies gastric mucosa resulting from these drugs has been were carried out largely in a hospital population experimentally related to events resulting from an rather than in normal subjects. This study was increase in the permeability of the epithelial mem- undertaken to assess in a controlled fashion the brane (Davenport, 1964, 1965, 1966, and 1967). effect of five popular salicylate compounds upon the Retrospective clinical studies suggest that salicylate magnitude of erythrocyte and equivalent whole ingestionprecipitatesgastrointestinalbleeding(Brown blood losses from the gastrointestinal tract of normal and Mitchell, 1956; Kelly, 1956; Allibone and Flint, adults. 1958; Alvarez and Summerskill, 1958; Muir and Cossar, 1959; Levrat and Lambert, 1960), and METHODS receive support from qualitative (Lange, 1957a; Stubbe, 1958; Porter, Lewis, and Dixon, 1959; SALICYLATES TESTED The composition of the five Stubbe, 1962; Stubbe, Pietersen, and Van Heulen, salicylates evaluated and their doses were: 1962; Bannerman, Beveridge, and Witts, 1964; 1 Acetylsalicylic acid 0.325 g.... 2 tabs T.I.D. Lane, Holmes and Moyer, 1964) and quantitative 2 Acetylsalicylic acid 0-325 g (Matsumoto and Grossman, 1959; Cameron, 1960; Aluminium glycinate 0.049 g 2 tabs T.I.D. Holt, 1960; Watson and Pierson, 1960; Grossman, Magnesium carbonate 0 098 gJ 475 Gut: first published as 10.1136/gut.9.4.475 on 1 August 1968. Downloaded from 476 Warren L. Beeken

3 Acetylsalicylic acid 0-211 g) Acetophenetidin 0-195 g 2 tabs Q.I.D. Caffeine 0 015 gJ DECAY CURVE CR51-ERYTHROCYTES

4 Acetylsalicylic acid 0-146 g) _ Acetophenetidin 0 146 g 2 tabs Q.I.D.

Salicylamide 0.130 gr 0 Caffeine 0.065 g 0 , S Acetylsalicylic acid 0.520 g Acetophenetidin 0.325 g Caffeine alkaloid 0 033 g I powder T.I.D. a STOOL I I STOOL Citric acid 0.033 g 0 A-_ COLLECTION - COLLECTION - Potassium chloride 0-260 gJ

Acetophenetidin was not present in some of the tablets of e A compound 3, but these were distributed so that all subjects in this group received equal proportions of each type. The t_~~~~~~~~~~~~~~~~~~~~~~~~ drugs were taken randomly throughout the day in no SALICYLATE INGESTION a a a a 1% ib k. --_ specific relationship to meals. Placebo in the appropriate z 5 4 5 6 7 8 9 10 11 12 13 14 15 form of tablets or powder were taken on the same schedule DAYS as the salicylates. Ten subjects were studied with each FIG. 1. Design of 51Cr-erythrocyte study during placebo drug. and salicylate ingestion. SUBJECTS STUDIED Normal volunteers were selected ,, ,_ ,,_s,, activity monitoring. Blood and stool radioactivity was from groups of students, hospital personnel, and measured in a scintillation well counter. physicians. Ages ranged from 22 to 63 years, with a 51Cr-erythrocyte and equivalent whole blood losses a mean age of 30 years. None had history of anaemia, were calculated from stool and whole blood radioactivity gastrointestinal disease or bleeding, and each had a according to the following equations: normal baseline microhaematocrit and submitted faecal specimens for determination of occult blood by the Erythrocytes (ml) lost/day = radioactivity in stool/day benzidene dihydrochloride method. One woman was x haematocrit included in group 1 and 4, and two were in group 5. mean radioactivity/ml whole blood were not menstruation. A Females studied during written Whole blood (ml) lost/day = protocol was distributed to each subject before the study radioactivity in stool/day to minimize errors in procedure. mean radioactivity/ml whole blood http://gut.bmj.com/ ERYTHROCYTE AND EQUIVALENT WHOLE BLOOD LOSS Means, standard deviations, and significance of differences 51Cr-erythrocyte clearance studies were conducted as of means at 95 % confidence levels were calculated on a previously described (Beeken, 1967). Red cells were label- General Electric model 235 digital computer. led with 51Cr by the method of Ebaugh, Clemens, Rodnan, and Petersen (1958). Twelve to thirteen ml of the subject's blood was added to 2-5 ml of acid-citrate- RESULTS dextrose solution (Squibb) and mixed, and 50-100 ,c of Na2 51CrO, was added, the solution incubated at 51Cr-erythrocyte and equivalent whole blood losses on October 2, 2021 by guest. Protected copyright. room temperature for one hour and injected intra- are presented in Table I as mean values for each venously. The sequence of the study is illustrated in group during the periods of ingesting placebo and Figure 1. After administration of the labelled erythrocytes salicylates. Mean drug loss-placebo loss (D/P) ratios three or more days elapsed to permit urinary clearance of are also indicated. Note that erythrocyte and equi- free and the a circulating isotope subjects began seven-day valent whole blood losses were significantly greater course of the appropriate form of placebo. Complete four-day stool collections were made during the last during salicylate ingestion than during placebo four days of the placebo period and blood samples were periods in each of the five groups. Forty-eight of 50 drawn for microhaematocrit determinations and radio- subjects showed increased losses during drug activity monitoring at the beginning and end of the stool administration. Furthermore, mean losses during collection. The seven-day course of salicylate ingestion drug ingestion were all in excess of 2.5 times mean was then started, and after three days a second four-day losses during placebo periods; the mean D/P ratios stool collection was begun. Blood was again drawn for are conservative in that they do not include D/P determinations at the radioactivity and microhaematocrit of infinity occurring in subjects having no detectable beginning and end of this collection period. stool radioactivity in the placebo period. The Complete four-day stool specimens were collected in paint tins containing alcohol and fitted to portable greatest erythrocyte loss during salicylate ingestion commode chairs to aid collection. The specimens were was 3-80 ml per day, equivalent of 8-48 ml of whole diluted with tap water to facilitate pipetting, homogenized, blood. One subject in group 1 had erythrocyte and and weighed aliquots were then removed for radio- equivalent whole blood losses of 3.56 and 7-92 ml, Effect offive salicylate-containing compounds upon loss of51chromium-labelled erythrocytes 477 Gut: first published as 10.1136/gut.9.4.475 on 1 August 1968. Downloaded from TABLE I GROUP MEANS FOR 5'CHROMIUM ERYTHROCYTE STUDY Erythrocyte Loss (mi/day) Equivalent Whole Blood Loss (ml/day) Group Placebo Drug Drug Placebo Drug Drug Placebo Placebo 11,2 M 0 33 1-03 3-96 074 2-36 403 SD 0-18 051 3-02 0-38 1-23 325 21 M 0-69 1-97 4.03 155 452 4-15 SD 047 1-03 3 07 1-06 2-33 3-12 31 2 M 0.52 1-27 3.95 1-04 2-98 440 SD 045 0 58 2-48 1-00 1-37 2-20 41 M 0.43 0-86 2-92 1-04 209 2-89 SD 0-28 0.44 2-40 0-66 1-06 2-77 51 M 0.07 0-61 12-39 0-17 1-47 10-97 SD 0-08 0-28 11-75 0-20 0-63 12-72 'Difference of drug means significantly higher than placebo means (P = 0.05). 'Corrected for one bleeding subject during placebo period. respectively, and one in group 3 lost 2.51 ml of during salicylate ingestion to range from 2-3 to erythrocytes, equivalent to 5.97 ml of blood during over 5 ml per day, results again consistent with our the placebo period. These values were greater than values. two standard deviations from the means of their The mechanism of injury due to salicylates groups and hence the data from these subjects are responsible for the increased bleeding is not yet fully not included in the tabulation. Microhaematocrit understood. Decreases in carbohydrate moieties values and stool occult blood tests were normal in (Menguy and Masters, 1964, 1965) of gastric mucus both of these men. Four subjects ingested drugs other resulting in a less effective protective barrier probably than the prescribed compounds at some time during play an important role. In addition, increases in the study. These included primiquine, propoxyphene DNA concentrations in gastric aspirates after salicy- (Darvon), and empirin in various dosages. The results lates is thought to reflect more rapid mucosal for these subjects did not differ from the remainder exfoliation induced by these drugs (Croft, 1963). of their respective groups and omitting their data Recent investigations by Davenport (1964, 1965, didnotreducethesignificance of the mean differences. 1966, and 1967) and others (Johnson and Overholt,

Another subject omitted salicylate for several days 1967) indicate that ingesting salicylates initiates the http://gut.bmj.com/ without altering significantly the group mean value. following sequence. Increased permeability of the Two subjects had positive baseline tests for faecal epithelial membrane permits the influx of luminal occult blood, and quantitative blood loss in each hydrogen ion; an increased intracellular hydrogen during the placebo period was normal. There was ion concentration triggers histamine release, as no apparent decrease in mean serial haematocrit evidenced by the increased content in gastric venous determinations during the study. blood; and capillary vasodilatation and rupture

with subsequent bleeding occur. The back diffusion on October 2, 2021 by guest. Protected copyright. DISCUSSION of hydrogen ion also provides an explanation for the conflicting data regarding the influences ofsalicylates The use of 51Cr-erythrocyte to quantify gastro- upon gastric acid secretion. intestinal blood loss is a well-established technique. Should blood losses of the magnitude induced by It has been shown that the gut is impervious to salicylates in this study be perpetuated in menstruat- circulating hexavalent 51Cr not bound to erythrocytes ing females with marginal iron reserves, iron- (Owen, Bollman, and Grindlay, 1954), and when deficiency anaemia would probably result. However, 51Cr-erythrocytes enter the lumen the isotope is normal males and non-menstruating females with excreted quantitatively in the faeces (Owen et al, adequate iron stores could be expected to compensate 1954; Roche, Perez-Gimenez, Layrisse, and di Prisco, adequately for losses of this order. It is noteworthy 1957; Ebaugh et al, 1958, Leonards, 1963). Reported that salicylates increased blood loss in 48 of the 50 values (Ebaugh et al, 1958; Ebaugh and Beeken, normal subjects, thus suggesting that it is not 1959; Cameron, 1960; Holt, 1960; Watson and necessary to implicate any predisposing gastro- Pierson, 1960; Grossman et al, 1961; Pierson et al, intestinal lesion in this degree of bleeding. The 1961; Leonards, 1963) of faecal blood loss in normal documented increase in faecal blood loss is clearly subjects agree quite well with the losses during the abnormal and represents further evidence that placebo period in this study. Other investigators salicylates exert an untoward effect upon the gastro- have found whole blood losses in varied populations intestinal tract of normal man. 478 Warren L. Beeken Gut: first published as 10.1136/gut.9.4.475 on 1 August 1968. Downloaded from

SUMMARY Ebaugh, F. G., Jr, and Beeken, W. L. (1959). Quantitative measurement of gastrointestinal blood loss. II. Determination of 24- hour fecal blood loss by a chemical photospectrometric Gastrointestinal losses of 51Cr-erythrocytes and technique. J. Lab. clin. Med., 53, 777-788. whole blood were quantitated in separate studies of Clemens, T., Jr, Rodnan, G., and Petersen, R. E. (1958). Quantitative measurement of gastrointestinal blood loss. I. The five groups of 10 normal subjects during the ingestion use of radioactive Cr"l in patients with gastrointestinal hemor- of placebo preparations and five commonly used rhage. Amer. J. Med., 25, 169-181. salicylate compounds. Group mean losses were Fishler, J. J. (1964). Effects of aspirin, acetaminophen, and salicylamide on gastric mucosa of dogs. Amer. J. dig. Dis., 9, 465-470. significantly greater during the ingestion of each Freemont-Smith, P. (1955). Bufferin in the management of rheumatoid salicylate than during placebo control periods. arthritis. J. Amer. med. Ass., 158, 386-388. Grossman, M. I., Matsumoto, K. K., and Lichter, R. J. (1961). Fecal Mean erythrocyte losses increased by factors ranging blood loss produced by oral and intravenous administration from 2.92 to 12-39 during drug ingestion and of various salicylates. Gastroenterology, 40, 383-388. Holt, P. R. (1960). Measurement of gastrointestinal blood loss in equivalent whole blood losses increased from 2.89 subjects taking aspirin. J. Lab. clin. Med., 56, 717-726. to 10.97 times during the same period. It is concluded Hurley, J. W., and Crandall, L. A., Jr (1964). The effect of salicylates that salicylates produce abnormalities in normal upon the stomachs of dogs. Gastroenterology, 46, 36-43. Hurst, A., and Lintott, G. A. M. (1939). Aspirin as a cause of hsemate- man resulting in increased gastrointestinal erythro- mesis: a clinical and gastroscopic study. Guy's Hosp. Rep., 89, cyte and equivalent whole blood losses. Menstruating 173-176. Izak, G., Galewsky-Stein, K., Menczel, J., and Groen, J. J. (1962). females with marginal iron stores may be expected Influence of salicylate administration on iron metabolism. to develop iron-deficiency anaemia if losses of this Blood, 19, 601-611. Johnson, L. R., and Overholt, B. F. (1967). Release of histamine into magnitude are continued, but otherwise such losses gastric venous blood following injury by acetic or salicylic acid. could be compensated for by other normal subjects. Gastroenterology, 52, 505-509. Jones, F. A. (1956). Haematemesis and melena. Ibid., 30, 166-190. I acknowledge the invaluable technical Kelly, J. J., Jr (1956). Salicylate ingestion: a frequent cause of gratefully gastric hemorrhage. Amer. J. med. Sci., 232, 119-128. assistance of Misses Martha Benson and Dorothy Sears Lane, A. Z., Holmes, E. L., and Moyer, C. E. (1964). Gastrointestinal and the continued encouragement of Doctor Franklin bleeding in normal subjects: a comparison of aspirin and G. Ebaugh Jr. The Computation Centres of Dartmouth mefenamic acid. J. New Drugs, 4, 333-336. Lange, H. F. (1957a). Salicylates and gastric hemorrhage. I. Occult College and the University of Vermont aided with the bleeding. Gastroenterology, 33, 770-777. necessary statistical analyses. (1957b). Salicylates and gastric hemorrhage. It. Manifest bleeding. Ibid., 33, 778-788. REFERENCES Leonards, J. R. (1963). Aspirin and gastrointestinal blood loss. Ibid., 44, 617-619. Allibone, A., and Flint, F. J. (1958). Gastrointestinal haemorrhage and Levrat, M., and Lambert, R. (1960), Aspirin, gastrointestinal bleeding, salicylates. Lancet, 2, 1121. and peptic ulcer. Amer. J. dig. Dis., 5, 623-631.

Alvarez, A. S., and Summerskill, W. H. J. (1958). Gastrointestinal Matsumoto, K. K., and Grossman, M. I. (1959). Quantitative measure- http://gut.bmj.com/ haemorrhage and salicylates. Ibid., 2, 920-925. ment of gastrointestinal blood loss during ingestion of aspirin. Bannerman, R. M., Beveridge, B. R., and Witts, L. J. (1964). Anaemia Proc. Soc. exp. Biol. (N.Y.), 102, 517-519. associated with unexplained occult blood loss. Brit. med. J., 1, Menguy, R. B., and Masters, Y. F. (1964). Mechanisms of gastric 1417-1419. injury by aspirin. Surg. Forum, 15, 315-317. Barbour, H. G., and Dickerson, V. C. (1938). Gastric ulceration - (1965). Effects of aspirin on gastric mucous secretion. produced in rats by oral and subcutaneous aspirin. Arch. int. Surg. Gynec. Obstet., 120, 92-98. Pharmacodyn., 58, 78-87. Muir, A., and Cossar, I. A. (1955). Aspirin and ulcer. Brit. med. J., 2, Batterman, R. C. (1958). Comparison of buffered and unbuffered 7-12. acetylsalicylic acid. New Engl. J. Med., 258, 213-219. (1959). Aspirin and gastric hemorrhage. Lancet, 1, W. L. Clearance of circulating radiochromated 539-541. Beeken, (1967). on October 2, 2021 by guest. Protected copyright. albumin and erythrocytes by the gastrointestinal tract of (1961). Aspirin and gastric bleeding: further studies of normal subjects. Gastroenterology, 52, 35-41. calcium aspirin. Amer. J. dig. Dis., 6, 1115-1125. Brown, R. K., and Mitchell, N. (1956). The influence of some of the Owen, C. A., Bollman, J. L., and Grindlay, J. H. (1954). Radio- salicyl compounds (and alcoholic beverages) on the natural chromium-labelled erythrocytes for the detection of gastro- history of peptic ulcer. Ibid., 31, 198-203. intestinal hemorrhage. J. Lab. clin. Med., 44, 238-245. Cameron, A. D. (1960). Gastrointestinal blood loss measured by Pierson, R. N., Jr, Holt, P. R., Watson, R. M., and Keating, R. P. radioactive chromium. Gut, 1, 177-182. (1961). Aspirin and gastrointestinal bleeding. Amer. J. Med., Caravati, C. M., and Cosgrove, E. F. (1964). Salicylate toxicity: the 31, 259-265. probable mechanism of its action. Ann. intern. Med., 24, 638- Porter, I. H., Lewis, M., and Dixon, A. St. J. (1959). Salicylate therapy 642. and faecal blood loss. Ann. rheum. Dis., 18, 62-63. Croft, D. M. (1963). Aspirin and the exfoliation of gastric epithelial cells. Cytological and biochemical observations. Brit. med. J., Roche, M., Perez-Gimenez, M. E., Layrisse, M., and di Prisco, E. 2, 897-901. (1957). Study of urinary and fecal excretion of radioactive Davenport, H. W. (1964). Gastric mucosal injury by fatty and acetyl- chromium Cr51 in man. Its use in the measurement of intestinal salicylic acids. Gastroenterology, 46, 245-253. blood loss associated with hookworm infection. J. clin. Invest., (1965). Damage to the gastric mucosa: effects of salicylates and 36, 1183-1192. stimulation. Ibid., 49, 189-196. Roth, J. L. A., and Valdes-Dapena, A. (1963). Topical action of (1966). Fluid produced by the gastric mucosa during damage by salicylates on the buccal mucosa in man and on the stomach in acetic and salicylic acids. Ibid., 50, 487-499. the cat. In Salicylates, edited by A. St. J. Dixon, M. J. H. Smith, (1967). Salicylate damage to the gastric mucosal barrier. New B. K. Martin and P. H. N. Wood. Pp. 224-225. Little, Brown, Engi. J. Med., 276, 1307-1312. Boston, Mass. Dodd, K., Minot, A. S., and Arena, J. M. (1937). Salicylate poisoning: , , Pieses, P., and Buchman, E. (1963). Tropical action of an explanation of the more serious manifestations. Amer. J. salicylates in gastrointestinal erosion and hemorrhage. Gastro- Dis. Child., 53, 1435-1446. enterology, 44, 146-158. Douthwaite, A. H., and Lintott, G. A. M. (1938). Gastroscopic Scott, J. T., Porter, I. H., Lewis, S. M., and Dixon, A. St. J. (1961). observation of the effect of aspirin and certain other substances Studies of gastrointestinal bleeding caused by corticosteroids, on the stomach. Lancet, 2, 1222-1225. salicylates, and other analgesics. Quart. J. Med., 30, 167-188. Effect offive salicylate-containing compounds upon loss of51chromium-labelled erythrocytes 479 Gut: first published as 10.1136/gut.9.4.475 on 1 August 1968. Downloaded from

Seeberg, V. P., Hansen, D., and Whitney, B. (1951). Absorption and of calcium acetylsalicylate (as calsamate) to acetylsalicylic acid. distribution of salicylamide. J. Pharmacol. exp. Ther., 101, J. Pharmacol. exp. Ther., 73, 420-430. 275-282. Vickers, F. N., and Stanley, M. M. (1963). Aspirin gastritis: gastro- Stubbe, L. T. F. L. (1958). Occult blood in faeces after administration duodenoscopic observations. Gastroenterology, 44, 419-423. of aspirin. Brit. med. J., 2, 1062-1066. Watson, R. M., and Pierson, R. N. (1960). Cr5l assay of gastrointestinal (1962). The noxious effect of acetylsalicylic acid preparations on blood loss in subjects taking salicylates. Fed. Proc., 19, 191. the gastrointestinal tract. In Drug Induced Diseases, edited by Waterson, A. P. (1955). Aspirin and gastric haemorrhage. Brit. med. L. Meyler and H. M. Peck. Pp. 145-155. C. C. Thomas, J., 2, 1531-1533. Springfield, Illinois. Weiss, A., Pitman, E. R., and Graham, E. C. (1961). Aspirin and Pietersen, J. H., and Van Heulen, C. (1962). Aspirin preparations gastric bleeding. Amer. J. Med., 31, 266-278. and their noxious effect on the gastro-intestinal tract. Brit. med. Wood, P. H. N., Harvey-Smith, E. A., and Dixon, A. St. J. (1962). J., 1, 675-680. Salicylates and gastro-intestinal bleeding. Acetylsalicylic acid Stutzman, J. W., Orth, 0. S., and Mellish, C. H. (1941). A comparison and aspirin derivatives. Brit. med. J., 1, 669-675.

The June 1968 Issue THE JUNE 1968 ISSUE CONTAINS THE FOLLOWING PAPERS

Signposts Influence of the ABO blood groups and secretor status on bleeding and on perforation of duodenal ulcer D. A. P. Liver transplantation R. Y. CALNE EVANS, L. HORWICH, R. B. MCCONNELL, and M. F. BULLEN Antibodies and immunoglobulins in liver disease Absorption of iron instilled into the stomach, duodenum, GEOFFREY WALKER and DEBORAH DONIACH and jejunum J. RHODES, D. BETON, and D. A. BROWN Effect of corticosteroid therapy on bromosulphthalein excretion in active chronic hepatitis G. C. COOK, MARTA Idiopathic muscular strictures of the sigmoid colon C. CASSANO and A. TORSOLI VELASCO, and SHEILA SHERLOCK Havens' haemagglutination test in infective hepatitis Effect of hypophysectomy on the gastric mucosa of the B. ARORA and A. E. READ rat GERARD P. CREAN http://gut.bmj.com/ Ergot poisoning in acute hepatic necrosis M. J. WHELTON, A comparison between the effects of hypophysectomy and A. ALLAWAY, ANNE STEWART, and L. KREEL adrenalectomy on the gastric mucosa of the rat GERARD P. CREAN Epidemiological study of cholelithiasis among railroad workers in India with special reference to causation Psychogenic vomiting OSCAR W. HILL S. L. MALHOTRA Familial amyloidosis with gastrointestinal neuropathy A fresh approach to the pathogenesis of pancreatitis JOSE G. MONTEIRO on October 2, 2021 by guest. Protected copyright. A. D. MCCUTCHEON The extent of sigmoidoscopy shown on radiographs with Chronic pancreatitis and choledochoduodenal anasto- special reference to the rectosigmoid junction M. R. mosis M. KECLiK, P. FRIC, V. SMAT, and v. FRIEDBERGER MADIGAN and J. M. HALLS Value of exfoliative cytology in pancreatic carcinoma British Society of Gastroenterology HOWARD GOLDSTEIN and LUTZ E. VENTZKE with the technical assistance of CARL WERNETT Notes and activities

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