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,

1006 a

coronary-artery

bypass graft withstand subsequent major

surgery well. The question now is-should aneurysm patients with high-risk coronary-artery lesions be excluded from surgery or offered coronary-artery bypass as a preliminary to

aneurysmectomy? Department of Surgery, Harvard Medical School, Peter Bent Brigham Hospital,

ANTHONY E. YOUNG NATHAN P. COUCH

Boston, Massachusetts, 02115, U.S.A.

ARRHYTHMIA PREVENTION IN EARLY MYOCARDIAL INFARCTION

SIR,—The suggestion by Dr Sheridan and his colleagues (April 16, p. 824) that their lignocaine regimen in early myocardial infarction could be combined with an oral antiarrhythmic drug to extend protection from the early hours to the first 2 days has serious objections. The plasma concentration versus time profiles of both mexiletine’ and disopyramide,2 which they mention, are such that to ensure that therapeutic concentrations would be reached before the effect of lignocaine had worn off, oral dosage would have to be given at the same time as the lignocaine injections. Because a narcotic analgesic and, possibly, a phenothiazine antiemetic may also recently have been given, there would be an increased risk of adverse drug effects and interactions in an already sick patient. A single drug for both immediate and extended prophylaxis would seem safer. Oral disopyramide is an effective prophylactic on a coronarycare unit,3 and the drug is now available in the U.K. as an ARRHYTHMIAS DETECTED IN THE

4h

AFTER

TREATMENT*

suitable for analysis over at least the first 4 h. Twenty-three patients had acute infarction, and three patients acute ischa:mia, confirmed, and fourteen of these had received diso-

pyramide. In the first 4 h serious arrhythmias were detected in nine patients in the placebo group compared with four in the disopyramide group, a significant difference (P