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have autoimmune thyroid disease than a comparablerandom population. This relationship is even morestriking when serological evidence is considered.Thus, antibodies to gastric parietal cells can bedetected in 30% of patients with autoimmune

thyroid disease; and, conversely, 50% of pernicious-anaemia patients have thyroid autoantibodies. Like-

wise, in Addison’s disease, the adrenal autoantibodiesare associated with an abnormally high frequency ofother organ-specific antibodies.

In this context, the findings of LANDING et al.1,MooRE and NEILSON,2 and UNGAR et al.,3 and thepaper by Dr. IRVINE and his colleagues at the front ofthis week’s issue, describing thyroid and gastricantibodies in a large series of diabetic patients with-out clinical thyroid disease or pernicious anaemia,raise the question of a possible role for auto-

immunity in the pathogenesis of certain forms ofdiabetes. Autoantibodies were commoner in the

insulin-dependent (juvenile-onset) type than inthe late-onset group of diabetics; and there wasa preponderance of females-a characteristic of

primary autoimmune disorders. Intrinsic-factorantibodies were more evident in the older patients:results were positive in 3-5% of this age-group,compared with 0-3% in controls. These patients allhad evidence of achlorhydria, and most had latentpernicious anaemia.The significant increase in antibodies in the

insulin-dependent form of the disease and theobservation that the duration of diabetes had noinfluence on the frequency of autoantibodies suggestthat the autoimmune manifestations are not secondaryto the diabetes. Hereditary factors are thought to beimportant in the development of autoimmunedisease 4 and of juvenile-onset diabetes. An asso-ciation between the two may well be the result ofa common genetic mechanism; and the most obvioushypothesis would be that diabetes is more likely toarise when there is a predisposition to autoimmunity.Present evidence for autoimmune processes directlyinvolving the pancreas is suggestive but not yetconvincing. GEPTS 11 described lymphocytic in-filtrations around the &bgr;-cells of the islets of Langer-hans in 68% of juvenile-onset diabetics. Somesuccess has been reported in the production ofinflammatory lesions in the {3-cells by experimentalimmunisation of rabbits and of cows 8 by insulin1. Landing, B. H., Pettit, M. D., Wiens, R. L., Knowles, H., Guest,

G.M. J. clin. Endocr. Metab. 1963, 23, 119.2. Moore, J. M., Neilson, J. McE. Lancet, 1963, ii, 645.3. Ungar, B., Stocks, A. E., Martin, F. I. R., Whittingham, S.,

Mackay, I. R. ibid. 1968, ii, 415.4. Roitt, I. M., Doniach, D. in Textbook of Immunopathology

(edited by P. A. Miescher and H. J. Muller-Eberhard); p. 517.New York, 1969.

5. Simpson, N. E. Diabetes, 1964, 13, 462.6. Gepts, W. ibid. 1965, 14, 619.7. Lee, J. C., Grodsky, G. M., Caplan, J., Craw, L. Am. J. Path.

1969, 57, 597.8. LeCompte, P. M., Steinke, J., Soeldner, J. S., Renold, A. E.

Diabetes, 1966, 15, 586.

preparations in complete Freund’s adjuvant; andthese changes were linked to a diminished content ofinsulin in the affected glands. It has also beenclaimed that serum from a proportion of untreateddiabetic patients can fix complement in the presenceof insulin 9,10 and that it can react with the (3-cells inimmunofluorescence tests." More intensive effortsare needed to establish directly whether autoimmuneresponses to pancreatic constituents take place indiabetes, particularly in the insulin-dependent formof the disease. It is to be hoped that these experi-ments will include some of the more recently avail-able in-vitro tests for cell-mediated hypersensitivity.Whatever the final outcome of such investigations, animmediate practical point should be considered. AsDr. IRVINE and his colleagues point out, an incidenceof 5% of latent pernicious anaemia in middle-aged toelderly female diabetics is a strong argument forscreening all these patients for intrinsic-factor anti-bodies and low serum-vitamin-B12 levels.

Congenital MalformationsTHE epidemiological picture of congenital mal-

formations has been under re-examination lately.STOCKS 12 used data derived from the registration ofcauses of stillbirths and of postnatal deaths to com-pare incidence in the regions of England and Wales.ELWOOD 13 studied the incidence of anencephalus withparticular attention to the secular and seasonal varia-tions in Belfast between 1950 and 1966. AndWEHRUNG and HEY, 14 using data from the UnitedStates national cleft lip and palate intelligence service,looked at the seasonal incidence of congenital mal-formations reported on certificates of live births in 29States and 2 cities between the years 1962 and 1965.How far advanced, therefore, is understanding of theaetiology of malformations and hence the ability toprevent them?STOCKS found that the female/male ratio for

deaths from birth up to one year of age due to mal-formations of the central nervous system (anen-cephaly, spina bifida, and hydrocephalus) varies froma high of 1-67 for Northern Ireland to lows of between0-90 and 0.99 for Israel, Greece, France, Sweden, andNorway. If stillbirths are included (and this is pos-sible only for the data from England and Wales), thenthe female/male ratio increases from 1-47 to 1-83. Themost remarkable feature is that the female excess

among liveborn infants with these neural-tube ano-malies is so much greater in the British Isles and theNetherlands than in Scandinavian countries. Within

9. Pav, J., Zezkova, Z., Skrha, F. Lancet, 1963, ii, 221.10. Chetty, M. P., Watson, K. C. ibid. 1965, i, 67.11. Mancini, A. M., Zampa, G. A., Vecchi, A., Gostanzi, G. ibid. p.

1189.12. Stocks, P. Br. J. prev. soc. Med. 1970, 24, 67.13. Elwood, J. H. ibid. p. 78.14. Wehrung, D. A., Hay, S. ibid. p. 24.

195

Britain, the female/male ratio varies from a high of2.12 in the Sheffield, Oxford, and Welsh regions to alow of 1-41 in Wessex. This group of defects has a

strong north-west to south-east downward trend in

mortality for each sex. In contrast to this, the varia-tion in the group of all other congenital malformationsis such that it could be explained by chance. Im-

pressed by the similarity to the distribution of mor-tality from cardiovascular disease, STOCKS was able todemonstrate that for women aged 25-54 death-ratesfrom cardiovascular causes had a closely similar

regional trend to those for neural-tube malformations,with correlation coefficients exceeding 0-8. Nephritis,stomach cancer, and bronchitis had a similar patternand correlations over 0-6. None of these causes ofdeath had any association with other kinds of mal-

formation ; and rates for all other diseases of womenshow no correlation with any form of malformation.STOCKS concluded that there must be some, factor,genetic or environmental, which simultaneouslyaffects the incidence of congenital malformations ofthe central nervous system and the mortality ofwomen from certain diseases. One suggestion is thatwater may be important.15ELWOOD 13 noted that the incidence of anencephalus

averages 3-95 per 1000 total births in Belfast, varyingfrom a low of 3-18 in 1953 to a high of 5-23 in 1961.Comparing his findings with other data, he showedthat both Scotland and South Wales have experiencedthe same small increase compared with Birmingham,where the mean incidence is significantly lower thanin Belfast and the overall trend is to decline. BothScotland and Belfast had peaks in 1960-61. A sig-nificant seasonal variation in the monthly numbers ofanencephalic births appeared in Belfast in 1956-66,with a winter excess and a peak in October. By con-trast, in the U.S.A., WEHRUNG and HEY 14 did notuncover any seasonal variations in malformations ofthe central nervous system, although, as they mention,the omission of fatal deaths from their inquiry limitsthe usefulness of these findings. But there were signi-ficant seasonal trends for cleft lip, with or withoutcleft palate, hypospadias, and positional foot defects.All three of these defects had periods of maximumincidence in the early part of the year, suggesting thatone or more teratogenic factors may be operating onsummer conceptions. Their analysis by region sug-gests that any such factors may be more potent incertain climates.

Three main points emerge, therefore, from thesefindings: the female excess of central-nervous-systemmalformations, with both intranational and inter-national variations of the sex ratio; varying seasonalpatterns of incidence; and close association in Britainbetween neural-tube anomalies and death-rates forcardiovascular disease in women aged 25-54. Thedemonstration of a female excess of malformations of

15. Crawford, M. D., Gardner, M. J., Morris, J. N. Lancet, 1968, i, 827.

the central nervous system is not new. REcORD andMCKEOWN 16 discussed it in 1949 and postulated that,in the absence of any other explanation, more malesmust be aborted in the period before the birth is noti-fiable. There is some evidence to support this. Bynuclear sexing of aborted specimens, PARKES 17 put theratio of males to females at conception at 120-150:100.SERR and ISMAJOVICH 18 gave estimates as high as166:100 in all abortions and 136:100 in spontaneousabortions. RHODES 19 found that, in accidental htmor-rhage, the male/female ratio was as high as 206:100for a small series in south-east London. Thus, inlooking at sex ratios, seasonal variations, and regionaldifferences, it must be remembered that they may notbe simply the results of conception and disturbedembryonic development: other factors affecting themaintenance of pregnancy may be playing a part.For the commoner malformations, which are general-ly held to be of mixed genetic and environmentalorigin, differences in distribution may in part reflectfactors operating towards abortion at any time duringthe gestation.

KEEP ON TAKING THE TABLETS...

WHY do patients fail to take their drugs ? How candefaulting be detected? And how can it be reduced?Some patients abandon their treatment quickly forsimple reasons: the tablets are too big to swallow, themedicine has a bad taste, or they may just forget. Butan important factor may be the meaning which thepatient attaches to the drug. After all, the doctoris not just giving a medication; he is giving instructionsabout a way of life. The patient may regard theprescription of a drug as a promise of continuedcontact and consideration, or as the very reverse-afinal and complete rejection of him as a person. Thedoctor’s attitude can determine whether the patienttakes his drugs conscientiously, irregularly, or never (itis a fair certainty that the patient will claim to becollaborating). Probably the most valuable way of re-minding the patient to take his drugs is the pill diary-but not many patients can be persuaded to keep one.

Since patients usually express a pr.eference for, anddefault less from, drugs on which their progress is

objectively better, it could be argued that there is littleneed for a check on whether the patients took thetreatment. Equally, though, there is the possibilitythat preferential defaulting may make a superiordrug appear inferior; so in a clinical trial it is clearlyimportant to know whether patients are opting out.

Porter 20 points out that very few clinical trialistsmention whether or not the patients took the pre-scribed drug or whether any attempt was made to findout. He lists three ways of checking: testing the urine,interrogation (direct or indirect,

" do you need more

16. Record, R. G., McKeown, T. Br. J. soc. Med. 1949, 3, 183.17. Parkes, A. S. in Man and His Future (edited by G. E. W. Wolsten-

holme); p. 49. London, 1963.18. Serr, D. M., Ismajovich, B. Am. J. Obstet. Gynec. 1963, 87, 63.19. Rhodes, P. Lancet, 1965, ii, 718.20. Porter, A. M. W. ibid. 1969, ii, 598.