1074

developed arrhythmias with fluorocarbon-ll.16 It is

noteworthy that one dog seemed to be much moresensitive to this effect than the others. These in-

vestigations disclosed a range of concentrations thatprovoke arrhythmias in the normal hearts of animalssuch as monkeys and dogs with or without adrenalinechallenge. As with most other aspects of toxicology,the effect must depend both upon individual sus-ceptibility and on the concentration to which thesensitive tissue is exposed.17 Application of thesedata to man has involved measurement of concentra-tions in alveolar gas and in arterial blood after use ofasthma inhalers, and calculations of myocardialconcentrations which occur during normal or exces-sive use of aerosol preparations.

Deliberate inhalation of very high concentrationsof fluorocarbons is undoubtedly dangerous. Thusthe glue-sniffers described by BASS almost certainlydied of a ventricular arrhythmia. However, there is

. a great difference between breathing an undilutedmixture from a plastic bag and breathing the contentsof a room in which an aerosol canister has been dis-

charged. Even if the whole of a domestic aerosolcanister was discharged into a small unventilatedroom, the average concentration in the air would beless than that needed to sensitise the dog heart in thepresence of large challenge doses of adrenaline,although the local concentration for short periodsmight be much higher. The concentrations measurednear the cryostats used by the American pathologyresidents were low (0-33%). The greatest hazardseems likely to arise when patients deliberately inhalefluorocarbons and sympathomimetic substances, as

they do in the treatment of asthma. Fluorocarbonconcentrations up to 5 tg. per ml. are found in arterialblood after one or two puffs from an inhaler .18 Theconcentrations required to sensitise conscious, dogschallenged with adrenaline were higher (20-35 p.g.per m1.).14,19 Furthermore, adrenaline seems muchmore apt to produce arrhythmias than other broncho-dilator drugs like isoprenaline. Calculation of theconcentration in myocardium after use of an aerosolinhaler twice within a minute gave a maximum

figure of 6-8 g. per g. compared with an estimated35-40 pug. per g. required to sensitise the dog heart.However, under conditions of grossly excessive use,such as firing an aerosol canister on every breath forone or two minutes, the concentrations in the humanmyocardium could approach, or even exceed, thosethat sensitise the dog heart. The provisional con-clusion from such calculations is that pressurisedaerosol cans are safe if used in the recommendedmanner. It is reassuring that the asthma-deaths

16. Mullin, L. S., Azar, A., Reinhardt, C. F., Smith, P. E., Fabryka,E. F. Am. ind. Hyg. Ass. J. 1972, 33, 390.

17. Williams, F. M., Draffan, G. H., Dollery, C. T., Clark, J. C.,Palmer, A. J., Vernon, P. Thorax, 1974, 29, 99.

18. Dollery, C. T., Williams, F. M., Draffan, G. H., Wise, G., Sahyoun,H., Paterson, J. W., Walker, S. R. Clin. Pharm. Ther. 1974, 15, 59.

19. Azar, A., Trochimowicz, H. J., Terrill, J. B., Mullin, L. S. Am.ind. Hyg. Ass. J. 1973, 34, 102.

rate in the U.K. has declined since 1967 almost backto the pre-1960 figure 20 although use of asthmainhalers has continued albeit with many warningsabout overdose. However, because of the difficultyof making extrapolations from animals to man andbecause of the individual variability that has beennoted in animals,21 research to discover safer methodsof dispensing inhaled drugs and other substancesshould go on.

Why Does Peptic Ulcer Happen?GASTRIC and duodenal ulcers are common diseases

which vary strikingly in frequency, yet little isknown of the causes. Since the mid-nineteenth

century, gastric ulcer (then a disease of young women)has been replaced by duodenal ulcer as the commonervariety, and both are increasingly becoming diseasesof the elderly. The tide of duodenal ulcer probablyreached its peak some ten years ago,22 and it nowseems to have become less frequent both in theUnited Kingdom and in the U.S.A.23,24 Gastric ulcerhas declined even more sharply-at least if hospital-admission rates can be accepted as criteria, in theabsence of satisfactory estimates of true populationfrequency. 25 Associated with these changes in ulcerfrequency and in age patterns there has been a

tendency for duodenal ulcer to join gastric ulcer as adisease of the socially underprivileged. Mortalitytables can be a poor guide to disease frequency,but the evidence that fifty years ago duodenal-ulcermortality was greater in those of social classes I and IIthan in poorer people is difficult to explain exceptby postulating that the disease was commoner (ormore prone to complications) in the well-off.26 Thistrend has now been reversed, and duodenal ulcerseems well established as a disease of poorer people,from the evidence of both mortality and morbiditystatistics.27,28

Patterns of this sort are not seen everywhere;thus, gastric ulcer seems to be relatively infrequent inpeople living in India and Africa. By contrast,duodenal ulcer is common in those areas, and theclinical characteristics may be unusual, stenosingulcer presenting a special problem. 29-32 The greatvariations in ulcer frequency between one tropicalarea and another need much better definition. In

20. Standing Medical Advisory Committee for the Central Health Ser-vices Council, Secretary of State for Social Services, and theSecretary of State for Wales. Deaths from Asthma. Department ofHealth and Social Security, 1973.

21. Roslaw, M., Belej, A., Smith, D. G., Aviado, D. M. Toxicology,1974, 2, 381.

22. Susser, M. J. chron. Dis. 1967, 20, 435.23. Meade, T. W., Arie, T. H. D., Brewis, M. Br. med. J. 1968, iii, 70124. Mendeloff, A. I. Gastroenterology, 1974, 67, 1020.25. Brown, R. C., Langman, M. J. S. Gut, 1974, 15, 335.26. Morris, J. N., Titmuss, R. M. Lancet, 1944, ii, 841.27. Litton, A., Murdoch, W. E. Gut, 1963, 4, 360.28. Registrar General’s decennial supplement on occupational mortality

for 1961. H.M. Stationery Office, 1971.29. Tovey, F. I. Trop. geogr. Med. 1972, 24, 107.30. Malhotra, S. L. Gut, 1964, 5, 412.31. Madanagopalan, N., Subramaniam, R., Krishnan, M. N. ibid.

1968, 9, 69.32. Konstam, P. G. Lancet, 1954, ii, 1039.

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Australia gastric ulcer seems to be unusually frequentas a disease of young to middle-aged women,33and here compound-analgesic intake is probablyan important provocative factor. 34, 35 However, thetrue role of aspirin, separated from the other com-ponents of compound tablets (especially phenacetinand caffeine), remains unclear. On the one hand,retrospective evidence suggests that aspirin-inducedulcer is an identifiable problem in North America 36and that such ulcers, unlike ordinary ulcer, mayarise in a relatively normal stomach. 37 On the otherhand, epidemiological evidence obtained in theBoston collaborative drug study in the U.S.A.

suggests that chronic aspirin ingestion accounts forvery few of the observed cases of gastric ulcer. 36

Epidemiological definition of risk factors for ulcerremains appallingly poor; apart from evidence that

smoking and perhaps aspirin consumption accountfor some ulcers (probably very few of the total),little is known. Examination of the health records of

university students at Harvard and Pennsylvaniasuggested that ulcer development was less frequent inthose who took more milk in their student days, thatalcohol consumption was not related to any later

risk, but that consumption of coffee and soft drinks(other than milk) was positively associated with ulcerdevelopment. 38 Finally, to compound confusion,the analysis suggested, as has been found elsewhere,an inverse association between blood-pressure andulcer.39 Clearly, more information is needed aboutrisk factors and some should be obtainable by ridingpiggyback on the many prospective investigationsbeing undertaken in cardiovascular disease.

If the cause of ulcer remains poorly understood,the logical basis of treatment totally escapes us. Anti-cholinergic agents impressively decrease food-stimu-lated acid output by the stomach,4O but there is noreal reason to believe that they alter the symptomsor prognosis of duodenal ulcer. In contrast, various

agents which do not alter gastric secretory potentialwill accelerate gastric-ulcer healing, and these form apresumptive group of mucosal strengthening agents.The best known of these, carbenoxolone sodium,induces glycoprotein synthesis by the gastricmucosa, 41 has some antipeptic activity,42 seems

to alter cell proliferation kinetics,41 and its actionin some way depends on an aldosterone-likemechanism .43 None of this information, how-33. Billington, B. P. Gut, 1965, 6, 121.34. Gillies, M. A., Skyring, A. Med. J. Aust. 1969, ii, 280.35. Duggan, J. M. Gut, 1972, 13, 631.36. Levy, M. New Engl. J. Med. 1974, 290, 1158.37. MacDonald, W. C. Gastroenterology, 1973, 65, 381.38. Paffenbarger, R. S., Wing, A. L., Hyde, R. T. Am. J. Epidem. 1974,

100, 307. 39. Medalie, J. H., Neufeld, H. N., Goldbourt, U., Kahn, H. A., Riss,

E., Oron, D. Lancet, 1970, ii, 1225.40. Richardson, C. T., Bailey, B. A., Walsh, J. H., Fordtran, J. S.

J. clin. Invest. 1975, 55, 35.41. Johnston, B., Lindup, W. E., Shillingford, J. S., Smith, M., Parke,

D. V. in Fourth Symposium on Carbenoxolone (edited by F.AVERY JONES and D. V. PARKE). London: Butterworths. 1975.

£7.50.42. Roberts, N. B., Taylor, W. H. Clin. Sci. mol. Med. 1973, 45, 213.43. Doll, R., Langman, M. J. S., Shawdon, H. H. Gut, 1968, 9, 42.

ever, gives us any real insight into the ulcer-

forming process. Biliary-reflux-induced mucosal

damage (perhaps predisposing to acid back-diffusion)has been a strong runner in the gastric-ulcer induc-tion stakes and carbenoxolone also reduces acidback-diffusion into the mucosa.44,45 Furthermore,another drug, metoclopramide, which alters antral

motility patterns, may have some healing action ingastric ulcer. 46 However, though patients with gastriculcer often have bile in their stomachs, there is noevidence that, in man, bile reflux produces ulcer;cholestyramine, a bile-acid-binding resin, does notseem to promote ulcer healing,47 and pyloric-sphincter dysfunction seems to continue unalteredeven if the gastric ulcer is induced to heal. -18 Finally,though gastritis can be induced by biliary reflux, 49atrophic gastritis seems to predispose to gastriccancer rather than to gastric ulcer. 50 Returning toduodenal ulcer, the picture seems, if anything, moreconfused, and the variety of possible mechanismsseems almost endless. Abnormalities includedisturbed emptying patterns, defective acid secretoryinhibition, and reduced duodenal neutralisation, as

well as gastric-acid hypersecretion.51 Potent treat-ments exist for high blood-pressure which tell usnothing about the disease, which is still largely notunderstood. The advent of potent antisecretoryagents in the histamine H2 antagonists and substitutedprostaglandins may well bring us to an analogoussituation in ulcer disease.

GENE FREQUENCIES AND HISTORY

DIFFERENCES in gene frequencies in populations ofsimilar ancestry may be explained by historical events,while similarities in gene frequencies in apparentlydifferent present-day populations may reveal a commonancestry despite lack of historical evidence. Thusgeneticists and historians may help each other.Different frequencies of recessive genes in subpopu-lations with the same ancestry may be due to randomgenetic drift, to emigration and founder effect, to

variation in the degree of inbreeding, to the introduc-tion of new genes by mutation or immigration, or toselection operating in some areas and not in others.For example, different patterns of migration explainwhy the Ashkenazi Jews have a high frequency of somediseases (familial dysautonomia, pentosuria, Tay-Sachsdisease, Gaucher disease, and torsion dystonia) whichare never or only rarely seen in Sephardi Jews; whilefamilial mediterranean fever is common in the Sephar-

44. Thompson, M. R., Elder, J. B., Rhodes, C. R., Gillespie, I. E.in Fourth Symposium on Carbenoxolone. London, 1975.

45. Calcraft, B. J., Rhodes, J., Cross, S., Hole, D., Aubrey, A. Am. J.dig. Dis. 1974, 19, 243.

46. Hoskins, E. O. L. Postgrad. med. J. 1973, 48, 95.47. Black, R. B., Rhodes, J., Davies, G. T., Gravelle, H., Sweetnam, P.

Gastroenterology, 1971, 61, 821.48. Fisher, R. S., Cohen, S. New Engl. J. Med. 1973, 288, 273.49. Lawson, H. H. Lancet, 1964, i, 469.50. Siurala, M., Lehtola, J., Ihamaki, T. Scand. J. Gastroent. 1974, 9,

441. 51. Wormsley, K. G. Gut, 1974, 15, 59.