CONGENITAL MALFORMATIONS AND MATERNAL DIABETES

644

(mg. per 100 ml.) ON DIFFERENT REGIMENS (Figures in parentheses denote numbers of observations.)

MEAN SERUM-CALCIUM

though-thanks to the antibiotic-examination of the culture yields a false-negative result. In this way evidence of persisting bacterial infection is obtained soon, and the efficacy of any given antibiotic can be judged. 3. Antibiotic elimination of

disappearance viscosity.

alteration in the manufacturers’ claims as late as September, 1963.) The results so far are given in the accompanying table. Taken together, they suggest that the average D.H.T. equivalent of one capsule of A.T.10 is nearer 0.1 mg. than 0.125 mg. and may vary from patient to patient, as would be expected with two different substances. The results in two of Dent and Friedman’s patients are consistent with a similar equivalence for the liquid preparation of 0-2 mg. of D.H.T. per ml. of A.T.10. If these figures are correct, then patients stabilised on the old A.T.10 whose treatment is changed to the new preparation according to the manufacturers’ recommendations will have their dose effectively increased by 20%. It is impossible to forecast what proportion of them will be exposed to the dangerous effects of hypercalcarmia ’ as a consequence.

I suggest

that, until much

more

knowledge has

accu-

any doctor who proposes to change his patient’s treatment in this way should disregard the manufacturers’

mulated,

recommendations, based

as they are on a mistaken inferfrom irrelevant animal experiments, and use instead a dose equivalence of 1 ml. of A.T.10 to 0-2 mg. of D.H.T. as a guide. The combined data of Dent and Friedman and myself supporting this suggestion are admittedly very scanty, but they are at present the only available relevant data on which to base such a decision. Very close observation with repeated measurement of serum-calcium will be needed until stabilisation on the new preparation has been demonstrated. ence

Medical Professorial Unit, Brisbane Hospital, Brisbane, Australia.

A. M. PARFITT.

MUCOPROTEINS AND SPUTUM VISCOSITY SIR,-Typically present in the sputum of asthmatics, the mucins are complex bodies consisting of proteins and

carbohydrates. They are designated as either mucoproteins or mucopolysaccharides, according to whichever part outweighs the other. Staining of these more or less negatively charged elements with basic dye will result in metachromasia. A further system of fibres are the desoxyribonucleinic acids (D.N.A.) found in purulent sputum only, where they significantly increase viscosity. They stem from the nuclei of disintegrating inflammatory cells. Since electron-microscopy is not suitable for routine clinical examinations, and contrast-phase microscopy as well as the examination of dehydrated fibres in polarised light is unsatisfactory, we have been looking for a simple analytical method. After fixing smears with ether-alcohol, we fluorochromate D.N.A.-fibre specimens at pH2 with acridineorange ; ultraviolet light will then produce a yellowishgreen fluorescence typical of D.N.A. Large-scale routine work with this method has shown the following: 1. D.N.A. fibres disappear from purulent sputum after 2 or 3 days of efficacious antibiotic therapy. There seems no point, therefore, in continuing desoxyribonuclease inhalations for more than a few days when an antibiotic is being given simultaneously. 2. If the pathogens causing bronchitis do not react to the antibiotic chosen, D.N.A. fibres in the sputum will persist, even 4.

Parfitt,

A. M.

Med. J. Aust. 1964, ii,

127.

of

D.N.A.

an

fibres, has

infection, no

as

bearing

well on

as the sputum

We have found at the very height of infection (probably owing to the action of bacterial ectoenzymes) that the acid mucopolysaccharides abundantly present in asthmatics are so disintegrated as to be scarcely in a position to have a bearing on sputum viscosity. But this changes radically when the infection is eliminated; for then we very soon observe acid mucopolysaccharide fibres in abundance, the difference being that, this time, these fibres remain intact. They may be dissolved, however, by a mucolytic agent, such as NA-274 (’Bisolvon’, Boehringer). Sputum viscosity falls to less than 20% of

days.

the initial values after treatment for an average of 9 In any event, the fragments of the mucopolysaccharides will generally be taken up in leucocytes by phagocytosis. Heiligenschwendi, Berne, Switzerland.

rj r<,— H. BURGI. BÜRGI.

CONGENITAL MALFORMATIONS AND MATERNAL DIABETES SIR,-From a massive 27-year investigation in Copenhagen, Pedersen and his colleagues1 concluded that infants born to women with diabetes were three times more likely to be malformed than the infants of women who were not diabetic. They felt that the magnitude of this danger justified the induction of abortion in some cases. Yet many workers have failed to substantiate this increase in malformations. A small study of this subject, made in the Birmingham Maternity Hospital during 1960-61, adds some support to this scepticism. The results are summarised in the accompanying table. Nearly all the liveborn infants (96%) were examined by the same person, and 98% of the infants who died in the perinatal period were submitted to necropsy (Dr. H. G.

Kohler). Among

the 4754 liveborn infants, 69 were born to women with frank diabetes; 4 of these infants (with an average birthweight of 21/21b.) were stillborn; 65 were born alive, but 8 died within three days of birth. Only 1 baby had a congenital malformation (microcephaly and encephalocele; stillborn). These findings are at variance with those of Pedersen and his colleagues, who found not only an increased number of malINFLUENCE OF MATERNAL DIABETES ON PERINATAL MORTALITY AND ON INCIDENCE OF CONGENITAL MALFORMATIONS

* If 2 missed abortions

are

excluded, the corrected figure is 14’5°o.

formations in the infants of diabetic women but-equally important-also a smaller number of malformations in the infants of non-diabetic mothers. Among perinatal deaths they found that 19-5% of the infants of diabetic mothers had congenital malformations as against 6-6% of those born to nondiabetic women (see their table n). By English standards it is the second, not the first, of these figures that would be considered abnormal; for, as Butler and Bonhamhave shown, the average rate for congenital malformations among perinatal deaths in this country is 20%. 1. 2.

Pedersen, L. M., Tygstrup, I., Pedersen, J. Lancet, 1964, i, 1124. Butler, N. R., Bonham, D. G. Perinatal Mortality. Edinburgh, 1963.

645

pitfalls both in the collection of accurate statistics on congenital malformations and in the comparison of one study with another are well known. They may be responsible for the differences of opinion that have beset this subject. Alternatively, the frequency of malformations may, in fact, be raised in some series and not in others. This might be explained by differences in the pattern of the diabetes and its complications, or, likelier perhaps, by differences in the antenatal management of the disease; in this context, the drugs used to control the diabetes and the onset of hypoglycaemia or ketosis in early pregnancy may be important. The

numerous

PETER M. DUNN.

Bristol.

ELECTROCARDIOGRAPHIC CHANGES ASSOCIATED WITH A CEREBROVASCULAR ACCIDENT SIR,- The diagnosis in the case reported by Dr. Harrison and Dr. Gibb (Aug. 29) is open to strong

challenge in the absence of confirmatory investigations. I suggest that it is just as likely that the patient had an embolism of the middle cerebral artery, via a patent foramen ovale and consequent on a late puerperal thrombophlebitis of the leg. Furthermore, the E.C.G. changes show extreme clockwise rotation of the heart, and this together with the ST changes and T inversions would be consistent with, although not characteristic of, pulmonary embolism, perhaps of the shower type. Again, the neurological syndrome, which largely resolved, and the E.C.G. changes, which also resolved, could both have been due to a viral illness.

In the absence of either cerebral angiograms or virusantibody investigations on serum, the diagnosis of cerebral venous thrombosis seems to be only tentative. Gateside Hospital, Greenock.

J. H. MITCHELL.

ACUTE RENAL CHANGES AFTER ORAL CHOLECYSTOGRAPHY SIR,-Dr. Doherty (Sept. 5) comments on the paper by Dr. Borges and his colleagues (Aug. 15) in which they draw attention to renal failure after giving the cholecystographic agentOrabilix ’ (buniodyl). Dr. Doherty states that this medium has been given " in this country to over

52,000 patients without

a

single fatality

or

serious reaction

being reported ". Even if it were true, it would be irrelevant to say that no such reactions have been reported here. They are so well known in the U.S.A. that it would be unlikely for us to be immune and, as I reported a month ago,’ we are not. That they are well known is evident from a glance at the American literature. I would draw Dr. Doherty’s attention particularly to the papers by Setter et al. and Wennberg et awl. A leading article in the issue of the Journal of the American Medical Association that carries Wennberg’s paper, noting that 12 fatal cases of renal toxicity following orabilix administration had been described (1 after a 4-5 g. dose), stated that orabilix " should not be a drug of choice ". If, as Dr. Borges, says, this cholecystographic agent has been withdrawn from the United States and Canadian markets (before it was granted an approved name in this country *) this action may have been taken because it was considered onerous to saddle the radiologist with the responsibility of determining renal and hepatic function before cholecystography. Since Setter et al. conclude that underlying liver disease, jaundice, and renal failure are not prerequisites, how would Dr. Doherty define " renal failure " ? Rennie, I. D. B. Brit. J. Radiol. 1964, 37, 628. Setter, J. G., Maher, J. F., Schreiner, G. E. J. Amer. med. Ass. 1963, 184, 102. 3. Wennberg, J. E., Okun, R., Hinman, E. J., Northcutt, R. C., Griep, R. J., Walker, W. G. ibid. 1963, 186, 461. 4. Lancet, 1964, i, 569. 1. 2.

It is more likely that orabilix was felt to be unsafe even in a normal dose, with apparently normal kidneys. Wennberg3 showed that there was a significant depression of endogenous creatinine clearance when orabilix was given in a single 4-5 g. dose in 4 out of 7 patients. 1 patient was transiently oliguric. He mentions that his patients did not demonstrate " previous significant renal or hepatocellular disease ". to

Wennberg felt that orabilix was too toxic in a 4-5 g. dose justify its use as a diagnostic agent. I agree with him.

Department of Medicine, Guy’s Hospital,

I. D. B. RENNIE.

London, S.E.1.

SWIMMING-BATH GRANULOMA

SIR,-I was interested in the this subject in The Lancet.566

two

communications

on

Here in Florida the isolation of acid-fast bacilli which are both guineapig-negative and nicotinic-acid-negative (unlike Mycobacterium tuberculosis) is far from uncommon, and we already have a register of well over 3000 persons from whom these unclassified mycobacteria have been isolated. The photochromogens and non-photochromogens (according to Runyon’s classification) are found particularly in association with pulmonary disease, but other groups have been found associated with suppurating lymph-glands and cutaneous abrasions. The majority of these individuals have negative P.P.D. (standard) reactions. Skin lesions due to Myco. balnei were discussed in Leprosy Briefs (American Leprosy Foundation) in August, 1952, and August, 1960, which described cases apparently identical with those reported in the two communications in your columns. Bureau of Preventable Diseases, Florida State Board of Health, Jacksonville, Florida, U.S.A

S. HOWARD FERGUSON.

DISACCHARIDE INTOLERANCE AND MUCOVISCIDOSIS SIR,-Dr. Trefor Jones (July 18) postulates that in a case of mucoviscidosis chronic diarrhoea caused transient disaccharide intolerance and later (Aug. 29) drew attention to the work of Sunshine and Kretchmerwhich also suggested that chronic diarrhoea caused transient disaccharide intolerance. Disaccharidases have been shown to be present in smallintestinal mucosal cells.8 The view that damage to smallintestinal mucosa can cause diarrhcea as well as disaccharidase deficiency seems reasonable. The disaccharide intolerance resulting from disaccharidase deficiency, can exacerbate the diarrhoea. Jeejeebhoy et a1.9 described malabsorption of lactose and acquired lactase deficiency in 30 adult cases of tropical malabsorption syndrome with diarrhoea and a lesion in the proximal small intestine-as indicated by malabsorption of folic acid and

to the small-intestinal diarrhcea as well as disaccharide intolerance, owing to deficiency of disaccharidases which are present in small-intestinal mucosal cells. The infants with gastroenteritis, reported by Sunshine and Kretchmer7and Dr. Trefor Jones (Aug. 29), presumably had a small-intestinal lesion which caused diarrhoea and disaccharide intolerance, but it still remains unexplained how pancreatic diarrhoea in the patient reported by Dr. Trefor Jones (July 18) could cause disaccharide intolerance, unless it could be attributed to disaccharidase deficiency-congenital 10 or acquired 9-due to an associated lesion of small intestine. In short, damage to the mucous membrane of the small

xylose. Thus, damage

mucosa can cause

intestine

diarrhoea as well as disaccharidase deficiency and result in disaccharide intolerance, but diarrhoea does not cause disaccharide intolerance. Is it can

cause

5. Morgan, J. K., Blowers, R. Lancet, 1964, i, 1034. 6. Welch, R. G., Inman, P., Cooke, R. T. ibid. July 4, 1964, p. 42. 7. Sunshine, P., Kretchmer, N. Clin. Pediat. 1963, 2, 17a. 8. Dahlqvist, A., Hammond, J. B., Crane, R. K., Dunphy, J. V., Littman, A. Gastroenterology, 1963, 45, 488. 9. Jeejeebhoy, K. N., Desai, H. G., Verghese, R. Lancet (in the press. 10. Holzel, A., Schwartz, V., Sutcliffe, K W. ibid. 1959, ii, 1126.