483

(1-8%) gave birth to a malformed baby, which again is not significantly different from the expected frequency. The rate of congenital heart defects observed in the group of mothers who received progestagen/oestrogen compound (4’29/ICOO) is not significantly different from the rate in controls (4-07/1000). Skeletal anomalies were not significant, the rates being 4.29/1000 in the treated group and 5.29/1000 in the control group. The VACTERL syndrome3 was not encountered in the survey. The number of microcephalics seemed high in infants born to mothers exposed to progestagen/ restrogen, the rates being 3-4/1000 (4/1165) and 0-6/1000 (6/9822) in the non-exposed group. The difference is significant at 1% (Fisher’s exact test). In a study on 88 cases of transposition of the great vessels and 176 controls (88 with ventric-4 ular septal defect and 88 with normal hearts), Mulvihill et a1. reported that in the transposition group who had first-trimester exposure to sex hormone, 2 infants had microcephaly, and among the control group, with 6 cases having a history of first trimester exposure, 1 infant had microcephaly as well. The incidence was greater than expected; the possibility of the rubella syndrome was not mentioned. The figures for the global rate of malformed infants are drawn from substantial series, but the numbers of individual malformations are small. The significance of microcephaly in the exposed group is not easy to interpret. Our data show no definitive evidence for the teratogenicity of hormonal pregnancy tests, and our impression is that any risk of malformation is small. Nevertheless, it would be better to discontinue the use of pregnancy testing with hormonal agents. vates, 15

INSERM

Groupe de Recherches Epidémiologiques sur la Mère et l’Enfant, 78110 lé Vesinet, France

J. GOUJARD C. RUMEAU-ROUQUETTE

tion (triglycerides); Holczinger’s reaction (free fatty acids); Baker’s reaction (phospholipids); periodic-acid/Schiff, ot-amylase, and Dische’s reaction (gangliosides). Five sections of tissue were extracted with 10 ml of chloroform/methanol (1/1, v/v). The solution, was evaporated to dryness, and the lipids were redissolved in 2/1 chloroform/methanol then chromatographed on silica-gel thin-layer plates in the solvent system

chloroform/methanoV2.5 mol/1 ammonia (60/40/9, v/v/v). Normal liver and brain, brain of GM1 gangliosidosis, and redblood cell gangliosides were used as controls. To locate lipid bands, the plate was exposed to iodine vapour instead of resorcinol because this method is more sensitive, although less specific in such minute quantities. The cytoplasmic glycogen was increased in the two livers and some nuclei were glycogenated. Glucose-6-phosphatase

activity (G.-6-p.ase) was decreased; 3-phosphoglyceraldehyde dehydrogenase (3-P.G.D.H.) and lactic dehydrogenase (L.D.H .) increased. p-glucuronidase was greatly decreased. Triglycerides were increased with macrovesicles as usual in steatosis but many nuclei showed an invagination of the cytoplasm with a lipid blot. Free fatty acids were increased in the perilobular area where acidophilic necrosis was present. Phospholipids were also increased in the two livers. In one case, we found histochemically an overload of gangliosides. It was confirmed by thin-layer chromatography: a spot was seen at the level of diswere

ialogangliosides. Decrease of G.-6-p.ase (with steatosis) suggests a minor form of type-r glycogen-storage disease. Increased 3-P.G.D.H. and L.D.H. may also, by the way of gluconeogenesis, explain this storage. Fatty-acid deposits may be involved in acidophilic necrosis. This strange abnormality in ganglioside storage and the role of pexid need further investigation. A. LAGERON R. POUPON Laboratoire de Biochimie, P. P. DE SAINT-MAUR C.H.U. Saint-Antoine, V. G. LÉVY Paris XII, France ,

LIVER GANGLIOSIDE STORAGE AFTER PERHEXILINE MALEATE

SIR,-Liver damage has been observed in some instances during perhexiline maleate (’Pexid’) therapy. In previously described neurological complications, electron microscopy of nerve tissue has shown polymorphous lamellated inclusions. We have examined liver tissue after pexid treatment. A 72-year-old man had been treated for coronary disease for 2 years with pexid 400 mg/day. A transient rash occurred after 2 months’ therapy. One year later, he complained of tingling, sensory changes in all four limbs and weight loss. The liver was enlarged, bromsulphalein clearance was impaired, and transaminases were increased without hyperbilirubinaemia. Blood-urea-nitrogen (60 mg/dl) and serum-creatinine (1-55 mg/dl) were also increased, and proteinuria was present (3 g/day). Pexid treatment was stopped. The second patient, a 63-year-old man, was admitted for polyneuropathy after 6 months of pexid treatment (150 mg/day). The liver was enlarged with impaired brornsulphalein clearance, increased transaminases, 5’-nucleotidase, y-glutamyl transpeptidase, and lactate dehydrogenase levels. Needle biopsies were performed m both patients with ultrastructural study 10 the second one. In the first case the portal tracts showed mild inflammation. The liver and Kupffer cells were pale and swollen with vcluminous foamy cytoplasm and bizarre nuclei. The general consistent with a storage disease. A repeat appearance biopsy showed the same featares 6 months after treatment had been stopped. In the second case we only found a mild steatosis with the general appearance of non-specific hepatitis. (A few hver cells contained small hyalin inclusions that might be considered as Mallory bodies.) Ultrastructural study showed numerous lamellar bodies in liver cells (suggestive of lipidosis somewhat similar to Niemann-Pick cells). The following histochemical techniques were used: periodicaad/Schin’ and amylase-a (glycogen); oil-red and Adams reacwas

3 4

Nora, A H., Nora, J. J. Archs envir. Hlth, 1975, 30, 17. Mulvihill, J. J., Mulvihill, C. G., Neill, C A. Lancet, 1974, i, 1168.

DRUG INTERFERENCE WITH LABORATORY INVESTIGATIONS

SIR The 1972 review of the effects of drugs

on

laboratory

by Young al.’contained 9000 entries. Three years later there were about 16 000 entries.2 Here are two examples of the tests

et

problem. Case1 A 50-year-old male asthmatic patient was admitted in cardiac failure and treated with digoxin. On admission his serumpotassium was 3.7mmol/1 (normal range 3-6-5-0). 3 days later he had an acute attack of asthma which was treated with intravenous salbutamol. A blood-sample taken after the attack showed hypokalxmia (2-8mmol/1) which the physicians interpreted as a laboratory error, a view apparently confirmed by repeat values of 3.6 and 3.8mmol/1. Indeed, the laboratory would have agreed with this view until Leitch et a1. demonstrated that intravenous salbutamol caused an acute hypokalaemic response. Case 2 A general practitioner telephoned to discuss a serum-urate of 0.58 mmol/1 (normal range 0.20-0.45) in a 63-year-old man with joint pains. It emerged that the patient was on mefruside, a drug known to increase the serum-urate by an average of 0-05 rnmol/1 on standard doses though values as high as 0.78 mmol/1 have been described.4 When mefruside was discontinued the serum-urate fell to normal (0-33 Young, D. S., Thomas, D. W , Friedman, R. B., Pestaner, L. C. Clin. Chem. 1972, 18, 1041. 2. Young, D S , Pestaner, L. C., Gibberman, V. ibid. 1975, 21, 1D. 3. Leitch, A. G., Clancy, L. J., Costello, J. F., Flenley, D. C Br. med J. 1976, 1.

i, 365 4. Wilson, C.

B., Kirkendall, W. M. J Pharmacol exp.

Ther. 1970,

171, 288.

484 ARSENIC IN OPIUM

SiR,—Ihave seen the typical clinical picture of arsenical neuropathy in patients consuming opium. They denied the intake of arsenic through any other source and lived in areas where the water was not contaminated by arsenic. 1These patients had been consuming 10-20 g of opium per day for the previous twenty years. To understand the significance of opium in the production of this clinical picture the arsenic conARSENIC CONTENT OF OPIUM

Report form giving quantitative data on drugs plus pathological information.

mmol/1). Thus the hyperuricaemia could be attributed

to

mefruside, and inappropriate treatment was avoided. These two cases show how drugs may result in misinterpretation of laboratory investigations by causing true changes in the blood concentration of the substances being studied. Drugs can also cause a spurious change in concentration by interfering with the chemical analysis. For example, paracetamol (acetaminophen) causes a spurious increase in serum-urate as measured by the Technicon SMA 12/60 method.-’ This is important because many patients with joint pains are likely to be taking paracetamol when investigated for gout. To assess the significance of drug interference with one common laboratory investigation (serum-urate, for which Young et awl.2 list nearly 300 entries), I drew up a short-list of the more important examples given in Hansten’s book .6 Serum-urate was measured with a Technicon ’AutoAnalyzer’ method N-13b (reduction of a phosphotungstate complex in the presence of sodium cyanide and urea). All clinicians who use our laboratory were shown specimens of four styles of report form and asked to comment on their suitability with special reference to avoiding misinterpretation of the serum-urate result. Clinicians were asked to vote for the style preferred, and both general practitioners (51%) and hospital doctors (40%) preferred the report form which showed both pathological and drug information and was the most complex (see figure). The least popular of the four styles was the simple, normal-range type in common use. A version of this form without the pathological information has now been introduced as routine. The new report form reminds clinicians of the drugs influencing interpretation of the laboratory investigation each time they see a serum-urate result, and an additional advantage is in the education of medical students and the training of junior laboratory staff. Clearly it would be difficult, though not impossible, to present such detailed information with a report form for a multichannel analysis. The extent of this problem is difficult to assess, but before informative reporting was introduced, I found that of a batch of 15 serum-urate analyses, 10 were for patients receiving drugs which influence interpretation (paracetamol, frusemide, bendrofluazide, methyldopa). Bold has suggestedthat the problem could be solved by computerised recording of all drugs administered to each patient so that the laboratory and clinician would be automatically alerted to a misleading result. Since computer facilities are scarce, the simple expedient of informative reporting using rubber stamps or some similar device might be more applicable. I thank Dr R. B. Payne for his initial scepticism and for his structive criticism, and Dr V. Standing for his advice. Department of Chemical Pathology, St. James’s University Hospital, Leeds LS9 7TF

con-

J. G. SALWAY

5. Wilding, P., Heath, D. A. Ann. clin. Biochem. 1975, 12, 142. 6. Hansten, P. D. Drug Interactions; p. 379. Philadelphia, 1973. 7. Bold, A. M. Lancet, 1976, i, 951.

tent

of

opium consumed by these patients was estimated.3 obtained from patients and from an illegal source had

Opium a very high arsenic content (table). One patient consuming opium containing 70 ug of arsenic/100 g had neuropathy and high concentrations of arsenic in urine (149 v. normal 40 p.g!day), nails (500 v. 50 (ig/100 g), and hair (107 v. 50 g/100 g). The precise source of arsenic in opium could not be traced. It is, however, quite commonly used in India as an aphrodisiac and for treatment of illnesses of diverse nature. Postgraduate Institute of Medical Education and Research,

Chandigarh-160011, India

D. V. DATTA

CATARACTS IN AVIATION ENVIRONMENTS

SIR,-Fifty years ago Duke-Elder demonstrated that cumulative radiant energy exposure, including long-term irradiation by sunlight, was the primary or sensitising aetiological factor for most cataracts ordinarily acquired during life.4 He presented data indicating that rays originating anywhere throughout the spectrum, from the longest rays generated by electrical oscillations to the shortest wavelengths of ionising radiation, could initiate cataract formation. Here our attention will be limited to the wavelengths occupying the middle region of the non-ionising spectrum (i.e., hertzian radiation) including microwaves and radiowaves. High levels of stray non-ionising radiation ("electronic smog") are now recognised as important air pollutants. 5 Millions of people in the general population are exposed daily (e.g., from telecommunication networks) to intensities far exceeding background levels.6 Cataracts apart, repeated microwave radiation exposure has been incriminated7 as an xtiological or contributory factor in neurophysiological, hormonal, haematopoietic, immunological and cardiovascular dysfunction, teratogenesis, and mutagenesis. However, doctors are not yet aware of these findings and their significance. Perhaps some insight may be gained by discussing a special population group at risk (operational aviation workers) and an objective sign (capsular cataract) which we believe to be correlative. Capsular cataract, originating in the membrane surrounding the lens, is unusual; cataract is usually found within the lens substance. That hertzian radiation may produce capsular cataract was first reported in 1964 in three young microwave workersB and confirmed in a young radar technician,9 and it 1 Datta, D. V. Luncet, 1976, i, 433. 2. Datta, D. V., Kaul, M. K J. Ass. Physns. India. 1976, 24, 599. 3. Kingsley, G. R., Schaffert, R. R. Anal. Chem. 1951, 23, 914. 4. Duke-Elder, S. Lancet, 1926, i, 1188. 5. Bowers, R., Frey, J. Sci. Am. 1972, 226, 13. 6. Tunney, J. V. Radiation Control for Health and Safety: Hearings before the Committee on Commerce, U.S. Senate. 1973. Serial no. 93-24. 7. Czerski, P. (editor). Biologic Effects and Health Hazards of Microwave Radiation. Warsaw, 1974. 8. Zaret, M M. U.S. Air Force Technical Documentary Report no. RADC-TDR-64-273, 1964. Griffiss Air Force base, New York. 9. Bouchat, J., Marsol, C. Arch. Ophthal. (Paris). 1967, 27, 593.