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His thesis that recessive disorders are practically more im-portant than dominants in relation to changes in mutation-rate is paradoxical. It is likely that dominant disorders, bothindividually and in total, have a higher incidence than reces-sives in Anglo-Saxons, and probably elsewhere too, except inpopulations with the special situation of a higher frequency ofsickle-cell anæmia or thalassxmia. Some of the evidence is setout by one of us (C.O.C.) in the forthcoming issue of the Jour-nal of Medical Genetics to which we referred. This higher fre-quency of dominants is perhaps less familiar to those with onlypsediatric experience. Dominants tend to be less severe, of lateronset, and more variable in their manifestations than reces-sives. The common dominants are naturally those whose onsetis usually in adult life, after the patient may already have hadchildren. It does not follow that the social load they cause isless. Twelve years’ suffering from Huntington’s chorea is per-haps a greater load than two years’ suffering from Tay-Sachsdisease.

Certainly new monogenic disorders will be recognised in thefuture; but these are as, or more, likely to be dominant thanrecessive. The first convincing verification of the existence ofthe mutant gene for familial hypercholesterolaemia came fromits severe manifestation in the rare homozygote and not themilder manifestations in the relatively common heterozygote.

As regards mutation, it is the dominant (and to a lesserextent the X-linked) conditions whose frequency will immedi-ately, directly, and at present inevitably reflect an increase inthe mutation-rate. In the case of recessives the full effect of a

change in the mutation-rate would not be seen for more thana thousand years. Unless we revert to barbarism, any such in-crease in their frequency will be prevented. Genetic counsell-ing will also limit the effect on the frequency of commondominants by reducing the number of generations for whichthe mutants responsible persist.

In monitoring the genetic effects of radiation or other

mutagens in man it is the dominants and the chromosomal dis-orders which are the ones to watch.

Geneticists may derive some comfort from the fact that

simultaneously others will be as much, perhaps more, con-cerned about the possibility of radiation induced cancer. Theadmittedly rough estimate obtained from the forum of 140cases of genetically determined disease in all the descendantsof 1 million people of pre-reproductive age exposed to 1 radfrom X or Y rays may be compared with the current estimateof 100-200 cases of cancer per million people in all age-groupsalso exposed to 1 rad.3 4

M.R.C. Radiobiology Unit,Harwell, Didcot,Oxon. OX11 0RD

PATRICIA ASH

J. VENNARTM.R.C. Clinical Genetics Unit,Institute of Child Health,30 Guilford Street,London WC1N 1EH C. O. CARTER

TRANSPARENTZLISTE

SIR,-In Round the World (March 12, p. 500) you claimthat the West German pharmaceutical industry was able toobtain a court order prohibiting the sale of TransparentzTele-gramm, a drug register brought out by the publisher of Arznei-telegramm. This is not correct.The court order obtained by the Pharmaceutical Manufac-

turers’ Association of the Federal Republic of Germany (Bun-desverband der Pharmazeutischen Industrie) is solely directedat the use of the symbolic "red hand" for publicity distribu-tions 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 bio-logical effects of ionizing radiation. National Research Council, Washing-ton, D.C., 1972.

to prevent the abuse of a symbol which, for years, has beenused by our member firms as external identification for all

warnings distributed on drug risks. The Transparentzliste,contrary to your contention, is obtainable in bookshops. At nostage was its sale prohibited, not even as a temporary measure.Der Spiegel, which your commentary cited, has since with-

drawn its assertion (in its issue of March 28).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-pre-served heparin (March 26, p. 705) points out that most of theheparins in use in the U.K. contain phenol derivatives. Thesame preservative is used in some preparations of morphinesulphate injection B.P. The British National Formulary1976-78 only reveals sodium metabisulphite as an additive,but a commonly used preparation (Marcarthys Ltd.) contains02% w/v chlorocresol. If this preparation of morphine is usedfrom 15 mg ampoules for high-dosage morphine anesthesia forcardiac surgery toxic amounts of chlorocresol will be given ifthe dosage of morphine exceeds 1.5 mg/kg in a 70 kg patient.

It is regrettable that all additives are not clearly stated onlabels or even included in data sheets. Some narcotic analgesicsalso contain large amounts of additives. One preparation offentanyl (’Sublimaze’, Janssen Pharmaceutical Ltd.) containsmore preservatives than the active ingredient-viz., a 2 mlampoule contains fentanyl citrate 0.1 mg, methylparaben 1.0mg, and propylparaben 0.1 mg.

This information should be given on labels and in datasheets. Until this is done the reporting and recording ofadverse reactions to preservatives is going to be incomplete andinaccurate.

Department of Anæsthetics,Queen Elizabeth Hospital,Birmingham B15 2TH EDWARD MATHEWS

SEASONALITY AND MATERNAL AGE IN DOWNSYNDROME

SIR,—Dr Sever (April 2, p. 754) suggests that our hypoth-esis (March 5, p. 515) does not accommodate the inconstancyof seasonality in populations and that it does not explain themost important feature of the Down syndrome-namely, theincreasing risk with increasing maternal age. In listing reportson seasonality, Dr Sever overlooked two. Jongbloet1 foundbimodal seasonality in a group of 441 Down cases from theNetherlands, and there is an excellent review of seasonality inDown syndrome by Lilienfeld.2 Seasonality might be occurringonly in populations with a relatively high incidence of Downsyndrome, such as the one Harlap described in Israel.’ Inter-estingly, a similar situation seems to occur for seasonality inanother malformation-anencephaly and spina bifida. Sea-

sonality has been observed in Britain, which has a relativelyhigh incidence of this malformation,4 but it has not beenfound, for example, in the United States where the incidenceis lower. j Therefore, it seems possible that seasonality in somemalformations occurs primarily in populations where the inci-dence is high.

There are at least two possible explanations for the incon-stancy 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.

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of the two suggests that there is a basal level of Down syn-drome which is not seasonal, while the environmental factorswhich affect the endocrine system and provoke a high inci-dence of a malformation do have a seasonal distribution. If so,seasonality would occur only where the incidence is high. Thealternative is that the seasonally variable factor in the endo-crine system merely defines the incidence limit (or seasonalenvelope) of a defect in the population. For example, this

might result if the critical endocrine factor was actually pro-viding a protective effect. Then, probability would allowalmost any seasonal configuration to occur when the rate is

submaximal, and only when the incidence approaches themaximum will the precise seasonal distribution definitely beepidemiologically visible.Although we did not discuss a maternal age effect, our

hypothesis will accommodate this important feature. The en-docrine factor or factors responsible for seasonality in the tis-sue concentration of hormone receptors are not yet known, butseasonality in adrenal secretory activity may be one of thosefactors. Seasonal fluctuation in urinary 17-ketosteroids hasbeen reported. It follows a distinct bimodal pattern which isthe inverse of the seasonal variation in both the rate of Down

conceptions and the seasonal fluctuation in the mammarytumour concentration of oestrogen receptor. We believe thatthe adrenal hormones may play a protective role against Downsyndrome through modification of oestradiol-receptor concen-tration in the developing follicle. Adrenal secretions diminishwith age. Vermeulen’ has shown that adrenal production ofdehydroepiandrosterone, which is a precursor of the urinary17-ketosteroids, does change with age, being significantlylower in postmenopausal women. Therefore, the increasingrisk of the Down syndrome in the approach of menopause mayresult from progressive loss with age of a protection affordedby adrenal secretory activity. More direct evidence that theadrenal may be involved in this way is seen in Harlap’s datafrom Israel. She found distinct bimodal seasonality over eachof the seven years studied, except that the major spring peakfailed to occur nine months after the 1967 six-day war. Sincestress causes increased adrenal secretory activity, perhaps thedecrease in Down syndrome conceptions around the time ofthe war was caused by some protection afforded the mother byincreased adrenal secretions during the wartime stress on thepopulation.Cancer Control Bureau,New York State Department of Health,Albany, N.Y., U.S.A. DWIGHT T. JANERICHDepartment of Obstetrics and Gynecology,Albany Medical College HERBERT I. JACOBSON

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 themeiotic divisions which took place just before conception. Thishypothesis is to some extent in line with the seasonal-preovula-tory-overripeness-ovopathy hypothesis one of us proposed atthe 1973 Seattle symposium on Aging of Gametes.’ However,the Albany workers’ hypothesis differs in not explaining thewell-established two-peak total births curve with a major anda minor birth peak; the apparent splitting of the major andoften of the minor peak, leading to three or four peak featureof most birth curves of patients with developmental anomaliesand psychopathological disturbances with or without chromo-somal aberrations;1-3 and the concomitance of both curves.

6 Halberg, F, Engeli, M., Hamburger, C., Hillman, D. Acta endocr. 1965, 54,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, 111.3 Jongbloet, P. H., van Erkelens-Zwets, J. H. J., Holleman-van der Woude,

G. Reap, 1976, 2, 243.

Because of the concomitance of the total and "pathological"birth curves we believe that any attempt to explain the deviantbirth curves of patients should account both for the physiologi-cal biorhythm expressed by a two-peak total birth curve andfor the pathological biorhythm expressed by a four-peak curve.The seasonal-preovulatory-overripeness-ovopathy hypothesisseems to do this: it is founded on the universality of the two-peak total birth curve and on the existence of a seasonallydetermined alternation of ovulatory and anovulatory cycles innon-human primates (this pattern seems to be smoothed inman, but it is still present). This hypothesis states that at thetimes of the seasonal breakthrough from anovulatory to ovula-tory periods, and vice versa, preovulatory overripeness ovo-pathy will be more common, leading to a four-peak pathologi-cal birth curve explicitly concomitant with the two-peak totalbirth curve. We believe that most of the birth curves of pa-tients with chromosomal aberrations as well as those with

developmental defects and /or psychopathology fit this hypoth-esis.1 2

Preovulatory overripeness ovopathy as the underlying causeaccounts not only for the seasonality of birth of patients withchromosomal and non-chromosomal aberrations but also forthe higher frequency of abnormal conceptions in other motherswhose endocrine system is disturbed-i.e., where the anovula-tory cycles have to make the change over from anovulation toovulation or vice versa. For example, in very young girls andin women just before the menopause, in the first (or even thesecond) cycle after abortion, after childbirth or discontinua-tion of oral contraceptives, in subfertile, diabetic, or hypo-thyroid women, and in post-midcycle conceptions despiteapplication of calendar rhythm.2 4 5

Centre for Observation andTreatment of Mental Retardates,

Huize "Maria Roepaan",Ottersum, Netherlands P. H. JONGBLOETInstitute of Human Genetics,Free University,Amsterdam J. H. J. VAN ERKELENS-ZWETS

CORONARY-ARTERY DISEASE ANDAORTIC-ANEURYSM SURGERY

SIR,—Of 123 patients undergoing elective abdominal aorticaneurysmectomy at this hospital over the past eight years 7(5.7%) have died; this is in line with the experience of mostother units. All 7 deaths were ascribed to myocardial infarc-tion and all the patients who died were in the group of 59 whocame to surgery with known ischasmic heart-disease. The mor-

tality after elective aneurysm surgery in this group was thus12%. If the mortality from elective aneurysmectomy is to bereduced, patients at high risk of postoperative myocardial in-farction must be identified. Myocardial infarction after majorsurgery carries a mortality in excess of 50%. Because the prog-nosis of an abdominal aortic aneurysm greater than 6 cm indiameter is so much worse than that of coronary-artery diseasethese patients cannot be denied surgery. There may be a placefor regular stress E.c.G. testing and, in some patients, coronaryarteriography in the assessment of aneurysm patients forwhom surgery is being considered,’ the object being to identifyhigh-risk patients, such as those with three-vessel disease orhigh-grade lesions of the left coronary artery.l This is likely toidentify a group of patients with surgically correctable lesionsin the coronary circulation.McCollum et al.3 have reported that patients who have had

4. Jongbloet, P. H. Maandschr. Kindergeneesk. 1971, 39, 351.5. Jongbloet, P. H., van Erkelens-Zwets, J. H. J. Contribution to a Workshop

on Risks, Benefits and Controversies in Fertility Control, held in Arling-ton 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. Sur-

gery, 1977, 81, 302.