1004 His thesis that recessive disorders are practically more important than dominants in relation to changes in mutationrate is paradoxical. It is likely that dominant disorders, both individually and in total, have a higher incidence than recessives in Anglo-Saxons, and probably elsewhere too, except in populations with the special situation of a higher frequency of sickle-cell anæmia or thalassxmia. Some of the evidence is set out by one of us (C.O.C.) in the forthcoming issue of the Journal of Medical Genetics to which we referred. This higher frequency of dominants is perhaps less familiar to those with only psediatric experience. Dominants tend to be less severe, of later onset, and more variable in their manifestations than recessives. The common dominants are naturally those whose onset is usually in adult life, after the patient may already have had children. It does not follow that the social load they cause is less. Twelve years’ suffering from Huntington’s chorea is perhaps a greater load than two years’ suffering from Tay-Sachs disease. Certainly new monogenic disorders will be recognised in the future; but these are as, or more, likely to be dominant than recessive. The first convincing verification of the existence of the mutant gene for familial hypercholesterolaemia came from its severe manifestation in the rare homozygote and not the milder manifestations in the relatively common heterozygote. As regards mutation, it is the dominant (and to a lesser extent the X-linked) conditions whose frequency will immediately, directly, and at present inevitably reflect an increase in the mutation-rate. In the case of recessives the full effect of a change in the mutation-rate would not be seen for more than a thousand years. Unless we revert to barbarism, any such increase in their frequency will be prevented. Genetic counselling will also limit the effect on the frequency of common dominants by reducing the number of generations for which the mutants responsible persist. In monitoring the genetic effects of radiation or other mutagens in man it is the dominants and the chromosomal disorders which are the ones to watch. Geneticists may derive some comfort from the fact that simultaneously others will be as much, perhaps more, concerned about the possibility of radiation induced cancer. The admittedly rough estimate obtained from the forum of 140 cases of genetically determined disease in all the descendants of 1 million people of pre-reproductive age exposed to 1 rad from X or Y rays may be compared with the current estimate of 100-200 cases of cancer per million people in all age-groups also exposed to 1 rad.3 4 M.R.C.

Radiobiology Unit,

Oxon. OX11 0RD

PATRICIA ASH J. VENNART

M.R.C. Clinical Genetics Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH

C. O. CARTER

Harwell, Didcot,

TRANSPARENTZLISTE

SIR,-In Round the World (March 12, p. 500) you claim that the West German pharmaceutical industry was able to obtain a court order prohibiting the sale of TransparentzTelegramm, a drug register brought out by the publisher of Arzneitelegramm. This is not correct. The court order obtained by the Pharmaceutical Manufacturers’ Association of the Federal Republic of Germany (Bundesverband der Pharmazeutischen Industrie) is solely directed at the use of the symbolic "red hand" for publicity distributions made by the publisher of Arzneitelegramm. The idea was 3. United Nations Scientific Committee on the Effects of Atomic Radiation. Ionizing Radiations Levels and Effects. United Nations, New York, 1972. 4. National Academy of Sciences. The effects in populations of exposure to low levels of ionizing radiation: a report of the advisory committee on the biological effects of ionizing radiation. National Research Council, Washington, D.C., 1972.

for years, has been external identification for all on drug risks. The Transparentzliste, to contrary your contention, is obtainable in bookshops. At no stage was its sale prohibited, not even as a temporary measure. Der Spiegel, which your commentary cited, has since withdrawn its assertion (in its issue of March 28).

to

prevent the abuse of

by our member warnings distributed used

a

symbol which,

firms

as

Press and Publicity, Bundesverband der Pharmazeutischen Industrie E.V., 6000 Frankfurt (Main), West Germany

H. J. CRAMER

PRESERVATIVES IN DRUGS

SIR The report of an adverse reaction to chlorocresol-preheparin (March 26, p. 705) points out that most of the heparins in use in the U.K. contain phenol derivatives. The same preservative is used in some preparations of morphine sulphate injection B.P. The British National Formulary served

1976-78 only reveals sodium metabisulphite as an additive, but a commonly used preparation (Marcarthys Ltd.) contains 02% w/v chlorocresol. If this preparation of morphine is used from 15 mg ampoules for high-dosage morphine anesthesia for cardiac surgery toxic amounts of chlorocresol will be given if the dosage of morphine exceeds 1.5 mg/kg in a 70 kg patient. It is regrettable that all additives are not clearly stated on labels or even included in data sheets. Some narcotic analgesics also contain large amounts of additives. One preparation of fentanyl (’Sublimaze’, Janssen Pharmaceutical Ltd.) contains more preservatives than the active ingredient-viz., a 2 ml ampoule contains fentanyl citrate 0.1 mg, methylparaben 1.0 mg, and propylparaben 0.1 mg. This information should be given on labels and in data sheets. Until this is done the reporting and recording of adverse reactions to preservatives is going to be incomplete and inaccurate. Department of Anæsthetics, Queen Elizabeth Hospital,

Birmingham

B15 2TH

EDWARD MATHEWS

SEASONALITY AND MATERNAL AGE IN DOWN SYNDROME

SIR,—Dr Sever (April 2, p. 754) suggests that our hypothesis (March 5, p. 515) does not accommodate the inconstancy of seasonality in populations and that it does not explain the most important feature of the Down syndrome-namely, the increasing risk with increasing maternal age. In listing reports on seasonality, Dr Sever overlooked two. Jongbloet1 found bimodal seasonality in a group of 441 Down cases from the Netherlands, and there is an excellent review of seasonality in Down syndrome by Lilienfeld.2 Seasonality might be occurring only in populations with a relatively high incidence of Down syndrome, such as the one Harlap described in Israel.’ Interestingly, a similar situation seems to occur for seasonality in another malformation-anencephaly and spina bifida. Seasonality has been observed in Britain, which has a relatively high incidence of this malformation,4but it has not been found, for example, in the United States where the incidence is lower. j Therefore, it seems possible that seasonality in some malformations occurs primarily in populations where the incidence is high. There are at least two possible explanations for the inconstancy of seasonality in different populations. The more simple 1 Jongbloet, P. H. in Aging Gametes: international symposium held in Seattle, p. 300. Basle, 1975. 2. Lilienteld, A. M. Epidemiology of Mongolism; p. 47. Baltimore, 1969. 3. Harlap, S. Am. J. Epidemiol. 1974, 99, 210. 4. McKeown, T., Record, R. G. Lancet, 1951, i, 192. 5. MacMahon, B., Pugh, T. F., Ingalls, T. H. Br. J. prev. soc. Med. 1953, 7, 211.

1005 of the two suggests that there is a basal level of Down syndrome which is not seasonal, while the environmental factors which affect the endocrine system and provoke a high incidence of a malformation do have a seasonal distribution. If so, seasonality would occur only where the incidence is high. The alternative is that the seasonally variable factor in the endocrine system merely defines the incidence limit (or seasonal envelope) of a defect in the population. For example, this might result if the critical endocrine factor was actually providing a protective effect. Then, probability would allow almost any seasonal configuration to occur when the rate is submaximal, and only when the incidence approaches the maximum will the precise seasonal distribution definitely be epidemiologically visible. Although we did not discuss a maternal age effect, our hypothesis will accommodate this important feature. The endocrine factor or factors responsible for seasonality in the tissue concentration of hormone receptors are not yet known, but seasonality in adrenal secretory activity may be one of those factors. Seasonal fluctuation in urinary 17-ketosteroids has been reported. It follows a distinct bimodal pattern which is the inverse of the seasonal variation in both the rate of Down conceptions and the seasonal fluctuation in the mammary tumour concentration of oestrogen receptor. We believe that the adrenal hormones may play a protective role against Down syndrome through modification of oestradiol-receptor concentration in the developing follicle. Adrenal secretions diminish with age. Vermeulen’ has shown that adrenal production of dehydroepiandrosterone, which is a precursor of the urinary 17-ketosteroids, does change with age, being significantly lower in postmenopausal women. Therefore, the increasing risk of the Down syndrome in the approach of menopause may result from progressive loss with age of a protection afforded by adrenal secretory activity. More direct evidence that the adrenal may be involved in this way is seen in Harlap’s data from Israel. She found distinct bimodal seasonality over each of the seven years studied, except that the major spring peak failed to occur nine months after the 1967 six-day war. Since stress causes increased adrenal secretory activity, perhaps the decrease in Down syndrome conceptions around the time of the war was caused by some protection afforded the mother by increased adrenal secretions during the wartime stress on the

Because of the concomitance of the total and "pathological" birth curves we believe that any attempt to explain the deviant birth curves of patients should account both for the physiological biorhythm expressed by a two-peak total birth curve and for the pathological biorhythm expressed by a four-peak curve. The seasonal-preovulatory-overripeness-ovopathy hypothesis seems to do this: it is founded on the universality of the twopeak total birth curve and on the existence of a seasonally determined alternation of ovulatory and anovulatory cycles in non-human primates (this pattern seems to be smoothed in man, but it is still present). This hypothesis states that at the times of the seasonal breakthrough from anovulatory to ovulatory periods, and vice versa, preovulatory overripeness ovopathy will be more common, leading to a four-peak pathological birth curve explicitly concomitant with the two-peak total birth curve. We believe that most of the birth curves of patients with chromosomal aberrations as well as those with defects and /or psychopathology fit this hypothdevelopmental esis.12 Preovulatory overripeness ovopathy as the underlying cause accounts not only for the seasonality of birth of patients with chromosomal and non-chromosomal aberrations but also for the higher frequency of abnormal conceptions in other mothers whose endocrine system is disturbed-i.e., where the anovulatory cycles have to make the change over from anovulation to ovulation or vice versa. For example, in very young girls and in women just before the menopause, in the first (or even the second) cycle after abortion, after childbirth or discontinuation of oral contraceptives, in subfertile, diabetic, or hypothyroid women, and in post-midcycle conceptions despite application of calendar rhythm.2 45 Centre for Observation and Treatment of Mental Retardates, Huize "Maria Roepaan",

Ottersum, Netherlands

P.

Institute of Human Free University, Amsterdam

J. H. J.

VAN

ERKELENS-ZWETS

CORONARY-ARTERY DISEASE AND AORTIC-ANEURYSM SURGERY

SIR,—Of 123 patients undergoing elective abdominal aortic

population.

at this hospital over the past eight years 7 have died; this is in line with the experience of most (5.7%) other units. All 7 deaths were ascribed to myocardial infarction and all the patients who died were in the group of 59 who came to surgery with known ischasmic heart-disease. The mortality after elective aneurysm surgery in this group was thus 12%. If the mortality from elective aneurysmectomy is to be reduced, patients at high risk of postoperative myocardial infarction must be identified. Myocardial infarction after major surgery carries a mortality in excess of 50%. Because the prognosis of an abdominal aortic aneurysm greater than 6 cm in diameter is so much worse than that of coronary-artery disease these patients cannot be denied surgery. There may be a place for regular stress E.c.G. testing and, in some patients, coronary arteriography in the assessment of aneurysm patients for whom surgery is being considered,’ the object being to identify high-risk patients, such as those with three-vessel disease or high-grade lesions of the left coronary artery.l This is likely to identify a group of patients with surgically correctable lesions in the coronary circulation. McCollum et al.3 have reported that patients who have had

aneurysmectomy

Cancer Control Bureau, New York State Department of Health, Albany, N.Y., U.S.A.

DWIGHT T.

JANERICH

Department of Obstetrics and Albany Medical College

HERBERT I.

JACOBSON

Gynecology,

H. JONGBLOET

Genetics,

SIR,—Dr Janerich and Professor Jacobson (March 5, p. 515) suggest that the cause of seasonality in Down syndrome, and the underlying cause of this congenital malformation, could be the status of the mother’s endocrine system during the meiotic divisions which took place just before conception. This hypothesis is to some extent in line with the seasonal-preovulatory-overripeness-ovopathy hypothesis one of us proposed at the 1973 Seattle symposium on Aging of Gametes.’ However, the Albany workers’ hypothesis differs in not explaining the well-established two-peak total births curve with a major and a minor birth peak; the apparent splitting of the major and often of the minor peak, leading to three or four peak feature of most birth curves of patients with developmental anomalies and psychopathological disturbances with or without chromosomal aberrations;1-3 and the concomitance of both curves.

P. H. Maandschr. Kindergeneesk. 1971, 39, 351. P. H., van Erkelens-Zwets, J. H. J. Contribution to a Workshop on Risks, Benefits and Controversies in Fertility Control, held in Arlington in 1977. (In the press.) 1. Tomatis, L. A., Fierens, E. E., Verbrugge, G. P. Surgery, 1972, 71, 429. 2. Bruschke, A. V. G., Proudfit, W. L., Sones, F. M., Jr. Circulation, 1973, 47, 1147. 3. McCollum, C. H., Garcia Rinaldi, R., Graham, J. M., DeBakey, M. E. Surgery, 1977, 81, 302.

4. 5.

6 Halberg, F, Engeli, M., Hamburger, C., Hillman,

D. Acta endocr. 1965,

suppl. 103, p. 5. 7. Vermeulen, A. J. clin. Endocr. Metab. 1976, 42, 247. 1. Jongbloet, P. H. in Aging Gametes; p. 300. Basle, 1975. 2 Jongbloet, P. H., Zwets, J. H. J. Int. J. Gynœc. Obstet. 1976, 14, 3 Jongbloet, P. H., van Erkelens-Zwets, J. H. J., Holleman-van G. Reap, 1976, 2, 243.

54,

111. der Woude,

Jongbloet,

Jongbloet,