competent physician. At the same time, I see no reason why a bachelor of medicine who desires to write a comprehensive monograph on a subject in which he is interested, and having attained the appropriate standard, should not be recognised and duly rewarded by his own university for his efforts. a more
J. C. BARKER.
MONOAMINE-OXIDASE INHIBITORS, BROAD BEANS, AND HYPERTENSION SIR,-We wish to draw attention to the onset of hypertensive crises after eating broad beans (Viciafaba L.)
in patients receiving monoamine-oxidase (M.A.O.) inhibitors. The active substance appears to be the natural aminoacid-3,4-dihydroxyphenyl alanine (dopa). A hypertensive male, aged 65, treated with the M.A.O. inhibitor pargyline (M0911, ’Eutonyl’) 37’5 mg. daily, experienced severe headache and palpitations on two occasions after eating whole, cooked, broad beans. Controlled feeding tests on this patient showed a rise of blood-pressure from 165 mm.Hg to 262 mm.Hg systolic starting about twenty minutes after eating 260 g. of whole beans and accompanied by the same symptoms (fig. 1). Bean pods alone produced a similar effect, but the seeds had little or no pressor activity in this patient. Tender, young broad beans, thinly sliced like runner beans, are commonly eaten whole in this country. Two other patients on pargyline therapy were fed whole beans with similar results, but without notable symptoms: the second of these showed a 120 mm. Hg increase in systolic bloodpressure. In each, the pressor response could be promptly reversed by intravenous phentolamine (’ Rogitine ’) as shown also in fig. 1. The attacks were accompanied by bradycardia, and electrocardiograms in two patients revealed premature ventricular systoles and T-wave changes when the bloodpressure was at its height. An untreated healthy subject showed no change in bloodpressure after eating 375 g. of bean pods. Two normotensive volunteers, taking pargyline 50 mg. daily, showed characteristic pressor responses after 200-300 g. of pods, the increase in one over 70 mm.Hg systolic. The ethanol-soluble fraction of bean pod was demonstrated to have pressor activity when given intravenously to pargylinetreated rats. An inhibitor of dopa decarboxylase, L-a-methyl dopa, completely blocked this pressor response (fig. 2). The pressor effect of pure dopa was similarly blocked by decarboxylase inhibition, but that of dopamine was unaffected.
Fig. 2-Mean arterial blood-pressure of rat: with pargyline (10 mg, daily by injection for 3 days) and L-a-methyl dopa (100 mg. 4 hours before experiment); and with pargyline alone in similar doses,
Analysis of the active fraction onDowex 50 ’resin and by chromatography showed no significant amounts of any sympathomimetic amines, including tyramine; moreover, the amine-containing fraction from the Dowex column was inactive in the rat. Dopa was the predominant aminoacid found, and the only one present with pressor activity. paper
Previous reports have shown that dopa exerts pressor activity in patients on M.A.o.-inhibiting drugs,!and this activity has been presumed to depend on its conversion to dopamine by decarboxylation. The natural occurrence of dopa in significant quantities seems to be confined to the pods and seeds of some leguminous plants,3 but until this is certain caution is obviously called for. We have found pargyline effective in the treatment of selected hypertensive patients, and we believe that its use under supervision is still justified. But great care must be exercised in prescribing M.A.O. inhibitors until the associated dangers have been more fully assessed. It is noteworthy that in two out of three patients the rises in blood-pressure were unaccompanied by warning symptoms : the true incidence of such episodes may therefore be much higher than has been realised. A
detailed report of these
findings is in preparation.
Wellcome Medical Research Institute and Department of Biochemistry,
University of Otago,
Dunedin, New Zealand.
J. V. HODGE E. R. NYE G. W. EMERSON.
X-CHROMOSOME MOSAICISM WITH TRISOMY-21
SIR,-The report by Dr. van Wijck and his colleagues (Jan. 18) of a 3-month-old girl with trisomy-21 and XO/XX mosaicism prompts us to record another instance of X-chromosome mosaicism accompanying trisomy-21. We became aware of this chromosomal abnormality during cytogenetic studies in patients with Down’s syndrome at the Brandon Training School for the mentally retarded, Brandon, Vermont. The patient is a 12-year-old female, who was born after a normal full-term pregnancy and normal delivery; birth-weight was 3110 g. The mother and father were 26 years old at the time of the child’s birth; there is one normal 16-year-old sister, The mother has not had any known miscarriages. The child’s growth and development have been slow, but her general health has always been good. At present the patient has the characteristic appearance of a child with Down’s syndrome with brachycephaly, slanting eyes with epicanthal folds, and small hands and feet with stubby fingers and toes. She is 125 cm. tall and weishs 27 kg. Her mental age is 4-2 vears with an 1.0. of 4’ 1. and
intravenous Fig. 1-Blood-pressure changes response phentolamine (’Rogitine’) in hypertensive subject after ingestion of 260 g. whole cooked broad beans. to
McGeer, P. L., Boulding, J. E., Gibson, W. C., Foulkes, R. G. J. Amer. med. Ass. 1961, 177, 665. Schildkraut, J. J., Klerman, G. L., Friend, D. G., Greenblatt. M Ann. N.Y. Acad. Sci. 1963, 107, 1005. Sealock, R. R. Biochem. Prep. 1949, 1, 25.
(Stanford Binet). There is a large excess of soft tissue on both sides of the neck; the carrying angle of the elbows is normal. The external genitalia are hypoplastic, axillary and pubic hair are absent, and there is no palpable breast tissue. She has not menstruated. Blood-pressures in arms and legs are normal. In a buccal smear and a vaginal smear, 13% and 21% of cells respectively had a single sex-chromatin body; no double bodies were seen. Single drumsticks are present in 4% of granulocytes. On two separate occasions short-term cultures of peripheral blood were made and the following modal numbers were found (the number of metaphase-plates analysed is given in parentheses):
All karyotypes showed the presence of five chromosomes in the 21-22 group. There were sixteen chromosomes in the 6-12 group in the plates, with a modal number of 47. In the metaphases with forty-six chromosomes, only fifteen chromosomes in the 6-12 group were found; while those with forty-eight chromosomes had seventeen chromosomes in the 6-12 group. We have interpreted these findings as evidence of
trisomy-21 associated with XO/XX/XXX mosaicism. The absence of double Barr bodies in buccal and vaginal smears, despite the presence of XXX cells in the blood-cultures, may indicate further and more complicated mosaicism.
character disorders. The 5th patient, a previously been suffering from a manic state and was slightly senile with a possible hysteric aphonia, not having said a word for three years.
That mental disorder is more common among persons with chromatin-positive Klinefelter’s syndrome than in the general population is shown by the present study, giving a prevalence-rate for Klinefelter’s syndrome in a mentalhospital male population 5-6 times higher than the expected maximum rate of 1-96 per 1000, and in relation to non-schizophrenic patients a rate 10-11 times higher than the rate to be expected from the studies of newborn boys by Maclean et aLl A more detailed report about the present study will be published; and the investigation will be extended to an incidence study of all male patients admitted to the hospital during six months, and to a prevalence study of all male patients in nursing-homes and in family under the same State hosnital. Institute of Psychiatry, Århus State Hospital, Risskov, Denmark.
CHROMOSOMAL ABNORMALITY AND CHRONIC LYMPHOCYTIC LEUKEMIA
very interested to read Dr. Court
(May 2) because a recent investigation in woman, aged 55, supports Dr. Court Brown’s arguments. The mother of our patient died of " abdominal lymphomas "; and some years ago her sister, aged 32, died of chronic lymphoBrown’s letter
Additional studies of this child and her immediate relatives are in progress. One of us (D. H.) was supported by grant GM 10210 from the
United States Public Health Service. Departments of Pathology and Pediatrics, LJILJANA ZERGOLLERN Dartmouth Medical School, DICK HOEFNAGEL. Hanover, New Hampshire.
in this unit. A cousin is said to suffer from a " blood disorder with lymphomas ", too, but we have been unable to investigate him. The patient-also with untreated chronic lymphocytic leukoemia-shows no deviation of the G-group chromosomes in the preparations of short-term cultures from sternal marrow, and no Ch1 chromosome could be found.4 The modal number of chromosomes was 46, and detailed analyses revealed a normal female karyotype. Some mitotic figures showed the " faded " chromosomes described in leukaemia and other malignant diseases by other workers.5-’ Serum-protein levels were normal ; on immunoelectrophoresis no abnormal precipitation was found; and the leucocyte alkaline-phosphatase activity was
PREVALENCE OF KLINEFELTER’S SYNDROME IN PATIENTS WITH MENTAL DISORDERS
SIR,-The frequency of chromatin-positive cases of Klinefelter’s syndrome among newborn boys has been found to be 1-96 per 1000 by Maclean et aU; and Barr et al. and Maclean et al.3 have shown that the rate of Klinefelter’s syndrome among mentally defectives is around 10 per 1000. The present letter is a preliminary report of a sex-chromatin prevalence study of the male population in a Danish mental hospital. So far, buccal scrapings from all 450 male inpatients have been studied. Among these 450 cases, 5 were found to be chromatin-positive cases of Klinefelter’s syndrome, giving a rate of 1L1 1 per 1000. No cases of Klinefelter’s syndrome were found among the schizophrenic patients, who made up 44% of the 450 in the hospital-a finding that leaves a prevalence-rate for Klinefelter’s syndrome of 20-8 per 1000 for the nonschizophrenic patients, and a prevalence-rate of zero for the
schizophrenic patients. There are certain similarities in the personality and intelligence pattern of the 5 cases of Klinefelter’s syndrome-they are all immature and sensitive with little initiative, and I.Q. low in the normal range for 4 of the patients and below the normal range for 1 case with 48 chromosomes and sex chromosomes XXXY. This suggests that persons with the typical personality and intelligence pattern of Klinefelter’s syndrome are especially sensitive to all forms of stress and consequently might be expected to develop mainly affective mental disorders or to be classified as having character disorders. Of the 5 patients with Klinefelter’s syndrome found in this study, 2 had psychogenic paranoid psychoses; and 2, both of whom had depressive reactions and were unstable in their social function, were 1. Maclean, N., Harnden, D. G., Court Brown, W. M., Bond, J., Mantle, D. J. Lancet, Feb. 8, 1964, p, 286. 2. Barr, M. L., Shaver, E. L., Carr, D. H., Plunkett, E. R. J. ment. Defic. Res. 1960, 4, 89. 3. Maclean, N., Mitchell, J. M., Harnden, D. G., Williams, J., Jacobs, P. A., Buckton, K. A., Baikie, A. G., Court Brown, W. M., McBride, J. A., Strong, J. A., Close, H. G., Jones,
Lancet, 1962, ii, 293.
within normal limit-- ÄutoradioQ"ranhic studies Medical Policlinic,
University of Tübingen, Germany.
F. HENI H. SIEBNER.
SiR,ńIn discussing the finding by Gunz et al. 8 of an inherited chromosomal abnormality (Chl) in association with chronic lymphatic leukxmia, Dr. Court Brown concludes: " It seems reasonable to regard the reported association as fortuitous." To substantiate this conclusion, he has to demonstrate that the incidence of chronic lymphatic leukxmia (C.L.L.) in carriers of the Chl chromosome does not exceed chance expectations. He has so far failed to do this-which is scarcely surprising as the following argument will show. From mortality statistics9 for England and Wales (1955-57), can be calculated that the chance expectation of a person dying from C.L.L., for an average life span of 70 years, was about 7 x 10-1. (The exact value is sex-dependent, it has shown a clear cohort effect, and it varies from country to country.) If it is assumed that three cases of C.L.L. have been found in Chl carriers, it is necessary to show, for example, that about 3/7 x 10-4, or about 4000 other Chi carriers, have survived to 70 without developing C.L.L.; alternatively, a larger number of younger carriers would need to be examined. So far, it appears 4. Gunz, F. W., Fitzgerald, P. H., Adams, A. Brit. med. J. 1962, ii, 1097. it
Nowell, P. C., Hungerford, D. A. J. nat. Cancer Inst. 1961, 27, 1013. Sandberg, A. A., Ishihara, T., Crosswhite, L. H., Hauschka, T. S. Cancer Res. 1962, 22, 748. 7. Lewis, F. J. W., Poulding, R. H., Eastham, R. D. Lancet, 1963, il, 306. 8. Gunz, F. W., Fitzgerald, P. H., Adams, A. Brit. med. J. 1962, ii, 1097. 9. Court Brown, W. M., Doll, R. ibid. 1959, i, 1063.