1146 of antisera to p.s.A.P. to-localise this enzyme in the prostate and to demonstrate the prostatic histogenesis of metastases, as described by Dr Nadji and colleagues (March 24, p. 671), may also prove most useful where histological and/or clinical staging of the primary tumour remains questionable.lo Such antisera may also help in the identification of cultured prostatic epithelial cells which have undergone in-vitro transformations. In earlier studies,s,6 specifically absorbed rabbit antisera to saline extracts of normal, benign, and malignant human prostatic tissues were demonstrated by precipitation and passive haemagglutination to possess antibodies to P.s.A.P. Immunofluorescent (I.F.) studies with these antisera have permitted identification of P.S.A.P. in prostatic epithelial cells" and of epithelial cells present in smears prepared from bone-marrow aspirates of patients with metastatic prostatic cancer (our unpublished observations). These observations accord with those of Pontes and co-workers,’z,13 who also used I.F., and of Ji5bsis
’al. 14 and, presumably, Nadji et al., who used immunoperoxistaining with rabbit antisera to P.A.P. isolated from sperm-free ejaculate (Nadji et al. did not specify their source OfP.A.P.). Utilisation of specific antisera to identify P.S.A.P. as a biological marker for the prostatic histogenesis of metastases may prove most useful. Together with endeavours toward measure-
et
dase
’
skin cancer following photochemotherapy for psoriasis.’ So many centres took part that the data from each are unlikely to be miscible, it lacks proper controls, and its subgroups are hopelessly mixed. Significant changes were mostly found in those who already had skin cancer or who had been treated with ionising irradiation. We know that 8-methoxypsoralen and UVA can be made to play nasty tricks in the laboratory, but so can the tar preparations which we quite rightly continue to use for psoriasis. Most things produce laboratory cancer if applied with sufficient determination: the question is whether they do so in real life. The excuse which I have already heard for this N.E.].M. paper is that it will at least stop people and make them think-untrue, alas, since those who are stopped by it are the least likely to indulge in that activity. Photochemotherapy is the most exciting, acceptable, and cost-effective treatment for psoriasis we now have2 but before its use can be extended we must collect real evidence about its risks. We would be making a good start by rejecting the recent I paper of Stern et al. Department of Dermatology, University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne NE 1 4LP
SAM SHUSTER
ment of serum levels of P.S.A. p.7-9 and tumour-associated immunityls as screening tests for prostatic cancer, these approaches hold promise for earlier clinical detection and iden-
tification of metastases. Division of Immunology, Cook County Hospital, and Hektoen Institute for Medical Research, Chicago, Illinois 60612, U.S.A.
POST-TRANSFUSION HEPATITIS AFTER PROTHROMBIN COMPLEX CONCENTRATES RICHARD
J. ABLIN
SIR,-The report by Dr Wyke and colleagues (March 10, p.
520), showing a high incidence of fatal and non-fatal posthepatitis after administration of prothrombin complex concentrates (P.c.c.) to liver-disease patients, is worrying to those who use P.c.c. for liver biopsy in patients with severe coagulation defects. Although our experience3 is not so dramatic as that of Wyke et al. (only 1 case of post-transfusion hepatitis out of 32 treated patients) the danger emphasised by these investigators must be seriously considered. On the other hand, the clinician is often confronted with patients in whom biopsy is essential for diagnosis but in whom coagulation abnormalities make the procedure hazardous. Swedish experience over a period of 10 years offers a reason-
transfusion PHOTOCHEMOTHERAPY FOR PSORIASIS
SiR,-We welcome your advice (May 12, p. 1011) that photochemotherapy for psoriasis "should be restricted to a few centres possessing the facilities for scrupulous long-term follow-up of treated patients." But the need for great caution has been urged repeatedly by the Department of Health and Social Security (and by the Food and Drug administration in the U.S.A.). A product licence number has been withheld and official warnings issued. Nevertheless the number of clinics introducing the therapy has continued to rise rapidly, so that it is widely diffused throughout the Health Service. This is very worrying, and the widespread use of a loophole in the system of safeguards calls into question the framework for the protection of patients. Whatever the outcome of studies directed towards establishing the efficacy and safety of photochemotherapy for psoriasis, the present circumstances are wholly unsatisfactory and demand immediate action.
able solution to this dilemma. In Sweden, commercially available P.c.c. is prepared from a small pool of donors originating from Scandinavian countries characterised by a low incidence of post-transfusion hepatitis. Long-term follow-up of treated patients has shown that strict adherence to the small-pool concept has resulted in a very low incidence of post-transfusion hepatitis,2 suggesting the usefulness of this approach in the prevention of the infection. Dr H. Kjellman tells me that further follow-up strengthens the results published in 1976.4 Commercial and non-commercial manufacturers of P.c.c. should be encouraged to make available, as part of their production, special preparations made from small pools of donors with low risk of transmitting hepatitis. These fractions might be electively used in liver disease, mild haemophilia B, and in patients who, having received a small number of transfusions are not immunised against the agents of post-transfusion hepatitis and are at higher risk. 1,6 After multiple transfusions, such risk is likely to decrease5·6and patients could be switched to treatment with concentrations made from larger donor pools. This policy should also be applied to similar groups of patients with hxmophilia A and von Willebrand’s disease. Since the
-
R. G. Psoriasis Association, 7 Milton Street, Northampton NN2 7JG
JOBLING, Chairman
R. B.
COLES,
Vice-chairman
SIR,-Photochemotherapy of psoriasis with 8-methoxypsoralen and ultraviolet (UVA) radiation was introduced with a blast of inexcusable toxicological optimism: it should not now be ousted by an equally absurd epidemiological pessimism. Your editorial of May 12 (p. 1011) discussed a study of Ablin, R. J. in Urologic Pathology: the prostate (edited by M. Tannenbaum), p. 33. Philadelphia, 1977. 11. Ablin, R. J. in Protides of the Biological Fluids; colloquium 27 (edited by H. Peeters). Oxford (in the press). 12. Pontes, J. E., Choe, B., Rose, N. R., Pierce, J. M. J. Urol. 1977, 117, 459. 13. Pontes, J. E., Choe, B., Rose, N. R., Pierce, J. M., Jr. ibid. 1978, 119,
10.
772.
Jöbsis, A. C., Dr Vries, G. P., Anholt, R. R. H., Sanders, G. T. B. Cancer, 1978, 41, 1788. 15. Ablin, R. J., Bhatti, R. A., Guinan, P. D. in Immunodiagnosis and Immunotherapy of Malignant Tumors: relevance to surgery (edited by H.-D. Flad and others); p. 65. Heidelberg, 1979. 14.
1. Stern, R. S., Thibodeau, L. A., Kleinerman, A. B., Parrish, J. A, Fitz patrick, R. B. New Engl. J. Med. 1979, 300, 809. 2. Rogers, S., Marks, J., Shuster, S., Vella Briffa, D., Wann, A., Greaves, M Lancet, 1979, i, 455. 3. Mannucci, P. M., Franchi, F., Dioguardi, N. Lancet, 1976, ii, 542. 4. Iwarson, S., Kjellman, H., Teger-Nilsson, A. C. Vox Sang. 1976, 31, 136 5. Kasper, C. K., Kipnis, S. A. J. Am. med. Ass. 1972, 221, 510. 6. Lewis, J. H., Maxwell, N. G., Brandon, J. M. Transfusion, 1974, 14, 203
1147 cost to the community of these special fractions is outweighed by benefits, national health authorities should accept this addi-
tional financial burden. Angelo Bianchi Bonomi Hæmophiha and Thrombosis Centre, University of Milan, 20122 Milano, Italy
P. M. MANNUCCI
ORGANIC ACIDS AND REYE’S SYNDROME
SIR,-We were interested in the letter by Dr Leonard and his colleagues (March 24, p. 680) about a patient with p-hydroxyp-methylglutaricaciduria who presented with the symptoms of Reye’s syndrome. We have lately investigated a patient who had hyperammonasmia, caused by a deficiency of liver carbamyl-phosphate synthetase. The child presented in the early stages of her illness with increased 3-hydroxy--methylglutaric acid in her urine. For reasons described below we doubt that the increased excretion of this compound was direct cause of the hyperanirnonxmia. The patient was admitted to hospital at 3 weeks of age with metabolic acidosis. Blood aminoacid analysis showed a high plasma-glutamine (1-35 .mol/ml, upper limit of normal approximately 0.8) and a high plasma-lysine (0.41 jjunol/ml, upper limit of normal approximately 0.25). Blood ammonia was 350 .mol/1 (normal up to 35). The blood-urea-nitrogen was less than 1 mg/dl. A protein-restricted diet (between 0.5and 1-00 g protein/kg/day) was started. The plasma-lysine immediately fell to normal, but the increased glutamine and ammonia values continued. A urine sample, collected after the low-protein diet had been started, showed, in descending order of
succinate, a-ketoglutarate, p-hydroxyphenylp-hydroxyphenyllactic acid, &bgr;-hydroxy-&bgr;-methyl-
amounts seen,
acetic acid,
glutaric acid, and p-methylglutaric acid. At this time the child’s
and branched-chain aminoacid values low a pattern consistent with mild starvation.’ Later, the concentration of protein in the diet was raised cautiously to about 2 g/kg/day, and the urinary organic acids were again examined. No p-hydroxy-p-methylglutaric acid was seen after several days of this level of protein intake. The original paper of Faull et al .2 was checked and, although their patient had presented with what appeared to be the symptoms of Reye’s syndrome, the patient did not have hyperammonaemia. Indeed, more recent reports3-6 of children with this defect have stressed hypoglycsemia and have not mentioned any hyperammonamia in patients with &bgr;-hydroxy-&bgr;-methylglutaricaciduria. A needle liver biopsy was done and carbamyl phosphate synthetase, ornithine transcarbamylase, and succinate dehydrogenase (as a crude measure of mitochondrial integrity) were analysed. Carbamyl phosphate synthetase activity was not detectable but activities of the other two enzymes were normal. The child is now being treated with a low protein diet, supplemented by the addition of 10 g/day of the ketoacid analogues of the essential aminoacids (Dr M. Batshaw and Dr M. Walzer, Johns Hopkins University, Baltimore). On this regimen, the child is thriving. Glutamine levels are normal and the blood ammonia is slightly raised. In our patient, although we observed excretion of p-hydroxy&bgr;-methylglutaric acid-and in this sense our patient was similar to that of Leonard et al.-the organic acid excretion did not compare at all with the pattern in other patients reported with this particular organic acid disorder. However, the presence of this acid was puzzling and we did suspect, at one time, that we
plasma-glycme was high were
1. Applegarth, D. A., Poor, S. Clinica chim. Acta, 1975, 63, 49. 2. Faull, K., Bolton, P., Halpern, B., Hammond, J., Danks, D. M., Hahnel, R., Wilkinson, S. P., Wysocki, S. J., Masters, P. L. New Engl. J. Med. 1976,
dealing with a patient with p-hydroxy-p-methylglutaricaciduria. At the time we discovered this metabolite in the urine, the child was on a low protein diet and the plasma-leucine was low. We were inclined to suspect that the excretion of this acid might have been due to the increased metabolism of leucine in muscle of a starving patient, although the precise mechanism by which this might have occurred was not pursued. If our experience is typical, however, it would seem prudent for anyone following the advice of Leonard et al.-namely, to look for organicacideemia in patients with Reye’s syndrome-to assess organic-acid excretion more than once and under differing conditions of protein intake. It is possible that other patients with hyperammonaemia, caused by a deficiency of a specific enzyme of the urea cycle, could present transiently with a finding of increased excretion of &bgr;-hydroxy-&bgr;-methylglutaric acid. were
Biochemical Diseases Children’s Hospital,
Laboratory,
Vancouver, British Columbia, Canada McGill University/M.R.C. Biochemical Mass Spectrometry Unit,
Montreal, Quebec
D. A. APPLEGARTH P. M. MACLEOD J. R. TOONE L. T. KIRBY J. R. MACLEAN O. A. MAMER
J. A. MONTGOMERY
&bgr;-HYDROXY-&bgr;-METHYLGLUTARICACIDURIA, REYE’S
SYNDROME, AND ECHOVIRUS SiR,-Further to our letter of March 24 (p. 680)
11
in which described a child with &bgr;-hydroxy-&bgr;-methylglutaricaciduria, we would like to add that Echovirus 11 was isolated from the c.s.F. collected on the day of admission as well as nose and throat swabs and from the tracheal aspirate. The C.S.F. was acellular. The first child described with p-hydroxy-p-methylglutaricaciduria2 presented with a similar illness and apparently made a satisfactory recovery, whereas our patient had severe multifocal brain damage. Unfortunately it is not possible to determine the exact cause of this; Echovirus 11 usually causes aseptic meningitis and rarely severe encephalitis. We propose that a combination of factors, including the organicacidaEmia and the viral infection of the nervous system, was responsible. Thus in patients with Reye’s syndrome, even with an acellular c.s.F., virus isolation should be attempted as well as screening for organicacidxmia. This is of particular importance in patients with Reye’s syndrome presenting with atypical features. J. V. LEONARD J. W. T. SEAKINS Institute of Child Health N. K. GRIFFIN and Hospital for Sick Children, London WC1 W. C. MARSHALL we
DIAZEPAM AND EXPERIMENTAL TUMOUR GROWTH
SIR,-Dr Horrobin and colleagues’ (May 5, p. 978) report that
diazepam at 1 mg/kg intraperitoneally (i.p.) but not at 5 mg/kg i.p. increases the growth of two experimental tumours in rats2 has created considerable concern in Italy. The significance of these findings to the use of diazepam in man is not known, but we can report that not all benzodiazepines increase the growth of transplantable tumours. Our experiments were in CD-COBS male rats (Charles River, Italy) transplanted subcutaneously with 100 mg fragof Walker carcinosarcoma 256, one of the tumours used Horrobin et al. Oxazepam was given by gastric tube start-
ments
by
294,1013. 3. 4.
Schutgens, R. B. H., Heymans, H., Ketel, A., Veder, H. A., Duran, M., Ketting, D., Wadman, S. K. J. Pediat. 1979, 94, 89.
Duran, M., Ketting, D., Wadman, S. K., Jakobs, S., Schutgens, Veder, H. A. Clinica chim. Acta, 1978, 90, 187. 5. Faull, K., and others ibid. 1976, 73, 553. 6. Wysocki, S. J., Hahnel, R. ibid. 1978, 86, 101.
R. B.
1.
Faull, K., Bolton, P., Halpern, B., Hammond, J., Danks, D. M., Hahnel, R., Wilkinson, S. P., Wysoki, S. J., Masters, P. K. New Engl. J. Med. 1976,
2.
Karmali, R. A., Horrobin, D. F., Ghayur, T., Manku, M. S., Cunnane, S. C., Morgan, R. O., Ally, A. I., Karmazyn, M., Oka, M. Cancer Lett.
294, 1013.
H.,
1978, 5, 205.
’al. 14 and, presumably, Nadji et al., who used immunoperoxistaining with rabbit antisera to P.A.P. isolated from sperm-free ejaculate (Nadji et al. did not specify their source OfP.A.P.). Utilisation of specific antisera to identify P.S.A.P. as a biological marker for the prostatic histogenesis of metastases may prove most useful. Together with endeavours toward measure-
et
dase
’
skin cancer following photochemotherapy for psoriasis.’ So many centres took part that the data from each are unlikely to be miscible, it lacks proper controls, and its subgroups are hopelessly mixed. Significant changes were mostly found in those who already had skin cancer or who had been treated with ionising irradiation. We know that 8-methoxypsoralen and UVA can be made to play nasty tricks in the laboratory, but so can the tar preparations which we quite rightly continue to use for psoriasis. Most things produce laboratory cancer if applied with sufficient determination: the question is whether they do so in real life. The excuse which I have already heard for this N.E.].M. paper is that it will at least stop people and make them think-untrue, alas, since those who are stopped by it are the least likely to indulge in that activity. Photochemotherapy is the most exciting, acceptable, and cost-effective treatment for psoriasis we now have2 but before its use can be extended we must collect real evidence about its risks. We would be making a good start by rejecting the recent I paper of Stern et al. Department of Dermatology, University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne NE 1 4LP
SAM SHUSTER
ment of serum levels of P.S.A. p.7-9 and tumour-associated immunityls as screening tests for prostatic cancer, these approaches hold promise for earlier clinical detection and iden-
tification of metastases. Division of Immunology, Cook County Hospital, and Hektoen Institute for Medical Research, Chicago, Illinois 60612, U.S.A.
POST-TRANSFUSION HEPATITIS AFTER PROTHROMBIN COMPLEX CONCENTRATES RICHARD
J. ABLIN
SIR,-The report by Dr Wyke and colleagues (March 10, p.
520), showing a high incidence of fatal and non-fatal posthepatitis after administration of prothrombin complex concentrates (P.c.c.) to liver-disease patients, is worrying to those who use P.c.c. for liver biopsy in patients with severe coagulation defects. Although our experience3 is not so dramatic as that of Wyke et al. (only 1 case of post-transfusion hepatitis out of 32 treated patients) the danger emphasised by these investigators must be seriously considered. On the other hand, the clinician is often confronted with patients in whom biopsy is essential for diagnosis but in whom coagulation abnormalities make the procedure hazardous. Swedish experience over a period of 10 years offers a reason-
transfusion PHOTOCHEMOTHERAPY FOR PSORIASIS
SiR,-We welcome your advice (May 12, p. 1011) that photochemotherapy for psoriasis "should be restricted to a few centres possessing the facilities for scrupulous long-term follow-up of treated patients." But the need for great caution has been urged repeatedly by the Department of Health and Social Security (and by the Food and Drug administration in the U.S.A.). A product licence number has been withheld and official warnings issued. Nevertheless the number of clinics introducing the therapy has continued to rise rapidly, so that it is widely diffused throughout the Health Service. This is very worrying, and the widespread use of a loophole in the system of safeguards calls into question the framework for the protection of patients. Whatever the outcome of studies directed towards establishing the efficacy and safety of photochemotherapy for psoriasis, the present circumstances are wholly unsatisfactory and demand immediate action.
able solution to this dilemma. In Sweden, commercially available P.c.c. is prepared from a small pool of donors originating from Scandinavian countries characterised by a low incidence of post-transfusion hepatitis. Long-term follow-up of treated patients has shown that strict adherence to the small-pool concept has resulted in a very low incidence of post-transfusion hepatitis,2 suggesting the usefulness of this approach in the prevention of the infection. Dr H. Kjellman tells me that further follow-up strengthens the results published in 1976.4 Commercial and non-commercial manufacturers of P.c.c. should be encouraged to make available, as part of their production, special preparations made from small pools of donors with low risk of transmitting hepatitis. These fractions might be electively used in liver disease, mild haemophilia B, and in patients who, having received a small number of transfusions are not immunised against the agents of post-transfusion hepatitis and are at higher risk. 1,6 After multiple transfusions, such risk is likely to decrease5·6and patients could be switched to treatment with concentrations made from larger donor pools. This policy should also be applied to similar groups of patients with hxmophilia A and von Willebrand’s disease. Since the
-
R. G. Psoriasis Association, 7 Milton Street, Northampton NN2 7JG
JOBLING, Chairman
R. B.
COLES,
Vice-chairman
SIR,-Photochemotherapy of psoriasis with 8-methoxypsoralen and ultraviolet (UVA) radiation was introduced with a blast of inexcusable toxicological optimism: it should not now be ousted by an equally absurd epidemiological pessimism. Your editorial of May 12 (p. 1011) discussed a study of Ablin, R. J. in Urologic Pathology: the prostate (edited by M. Tannenbaum), p. 33. Philadelphia, 1977. 11. Ablin, R. J. in Protides of the Biological Fluids; colloquium 27 (edited by H. Peeters). Oxford (in the press). 12. Pontes, J. E., Choe, B., Rose, N. R., Pierce, J. M. J. Urol. 1977, 117, 459. 13. Pontes, J. E., Choe, B., Rose, N. R., Pierce, J. M., Jr. ibid. 1978, 119,
10.
772.
Jöbsis, A. C., Dr Vries, G. P., Anholt, R. R. H., Sanders, G. T. B. Cancer, 1978, 41, 1788. 15. Ablin, R. J., Bhatti, R. A., Guinan, P. D. in Immunodiagnosis and Immunotherapy of Malignant Tumors: relevance to surgery (edited by H.-D. Flad and others); p. 65. Heidelberg, 1979. 14.
1. Stern, R. S., Thibodeau, L. A., Kleinerman, A. B., Parrish, J. A, Fitz patrick, R. B. New Engl. J. Med. 1979, 300, 809. 2. Rogers, S., Marks, J., Shuster, S., Vella Briffa, D., Wann, A., Greaves, M Lancet, 1979, i, 455. 3. Mannucci, P. M., Franchi, F., Dioguardi, N. Lancet, 1976, ii, 542. 4. Iwarson, S., Kjellman, H., Teger-Nilsson, A. C. Vox Sang. 1976, 31, 136 5. Kasper, C. K., Kipnis, S. A. J. Am. med. Ass. 1972, 221, 510. 6. Lewis, J. H., Maxwell, N. G., Brandon, J. M. Transfusion, 1974, 14, 203
1147 cost to the community of these special fractions is outweighed by benefits, national health authorities should accept this addi-
tional financial burden. Angelo Bianchi Bonomi Hæmophiha and Thrombosis Centre, University of Milan, 20122 Milano, Italy
P. M. MANNUCCI
ORGANIC ACIDS AND REYE’S SYNDROME
SIR,-We were interested in the letter by Dr Leonard and his colleagues (March 24, p. 680) about a patient with p-hydroxyp-methylglutaricaciduria who presented with the symptoms of Reye’s syndrome. We have lately investigated a patient who had hyperammonasmia, caused by a deficiency of liver carbamyl-phosphate synthetase. The child presented in the early stages of her illness with increased 3-hydroxy--methylglutaric acid in her urine. For reasons described below we doubt that the increased excretion of this compound was direct cause of the hyperanirnonxmia. The patient was admitted to hospital at 3 weeks of age with metabolic acidosis. Blood aminoacid analysis showed a high plasma-glutamine (1-35 .mol/ml, upper limit of normal approximately 0.8) and a high plasma-lysine (0.41 jjunol/ml, upper limit of normal approximately 0.25). Blood ammonia was 350 .mol/1 (normal up to 35). The blood-urea-nitrogen was less than 1 mg/dl. A protein-restricted diet (between 0.5and 1-00 g protein/kg/day) was started. The plasma-lysine immediately fell to normal, but the increased glutamine and ammonia values continued. A urine sample, collected after the low-protein diet had been started, showed, in descending order of
succinate, a-ketoglutarate, p-hydroxyphenylp-hydroxyphenyllactic acid, &bgr;-hydroxy-&bgr;-methyl-
amounts seen,
acetic acid,
glutaric acid, and p-methylglutaric acid. At this time the child’s
and branched-chain aminoacid values low a pattern consistent with mild starvation.’ Later, the concentration of protein in the diet was raised cautiously to about 2 g/kg/day, and the urinary organic acids were again examined. No p-hydroxy-p-methylglutaric acid was seen after several days of this level of protein intake. The original paper of Faull et al .2 was checked and, although their patient had presented with what appeared to be the symptoms of Reye’s syndrome, the patient did not have hyperammonaemia. Indeed, more recent reports3-6 of children with this defect have stressed hypoglycsemia and have not mentioned any hyperammonamia in patients with &bgr;-hydroxy-&bgr;-methylglutaricaciduria. A needle liver biopsy was done and carbamyl phosphate synthetase, ornithine transcarbamylase, and succinate dehydrogenase (as a crude measure of mitochondrial integrity) were analysed. Carbamyl phosphate synthetase activity was not detectable but activities of the other two enzymes were normal. The child is now being treated with a low protein diet, supplemented by the addition of 10 g/day of the ketoacid analogues of the essential aminoacids (Dr M. Batshaw and Dr M. Walzer, Johns Hopkins University, Baltimore). On this regimen, the child is thriving. Glutamine levels are normal and the blood ammonia is slightly raised. In our patient, although we observed excretion of p-hydroxy&bgr;-methylglutaric acid-and in this sense our patient was similar to that of Leonard et al.-the organic acid excretion did not compare at all with the pattern in other patients reported with this particular organic acid disorder. However, the presence of this acid was puzzling and we did suspect, at one time, that we
plasma-glycme was high were
1. Applegarth, D. A., Poor, S. Clinica chim. Acta, 1975, 63, 49. 2. Faull, K., Bolton, P., Halpern, B., Hammond, J., Danks, D. M., Hahnel, R., Wilkinson, S. P., Wysocki, S. J., Masters, P. L. New Engl. J. Med. 1976,
dealing with a patient with p-hydroxy-p-methylglutaricaciduria. At the time we discovered this metabolite in the urine, the child was on a low protein diet and the plasma-leucine was low. We were inclined to suspect that the excretion of this acid might have been due to the increased metabolism of leucine in muscle of a starving patient, although the precise mechanism by which this might have occurred was not pursued. If our experience is typical, however, it would seem prudent for anyone following the advice of Leonard et al.-namely, to look for organicacideemia in patients with Reye’s syndrome-to assess organic-acid excretion more than once and under differing conditions of protein intake. It is possible that other patients with hyperammonaemia, caused by a deficiency of a specific enzyme of the urea cycle, could present transiently with a finding of increased excretion of &bgr;-hydroxy-&bgr;-methylglutaric acid. were
Biochemical Diseases Children’s Hospital,
Laboratory,
Vancouver, British Columbia, Canada McGill University/M.R.C. Biochemical Mass Spectrometry Unit,
Montreal, Quebec
D. A. APPLEGARTH P. M. MACLEOD J. R. TOONE L. T. KIRBY J. R. MACLEAN O. A. MAMER
J. A. MONTGOMERY
&bgr;-HYDROXY-&bgr;-METHYLGLUTARICACIDURIA, REYE’S
SYNDROME, AND ECHOVIRUS SiR,-Further to our letter of March 24 (p. 680)
11
in which described a child with &bgr;-hydroxy-&bgr;-methylglutaricaciduria, we would like to add that Echovirus 11 was isolated from the c.s.F. collected on the day of admission as well as nose and throat swabs and from the tracheal aspirate. The C.S.F. was acellular. The first child described with p-hydroxy-p-methylglutaricaciduria2 presented with a similar illness and apparently made a satisfactory recovery, whereas our patient had severe multifocal brain damage. Unfortunately it is not possible to determine the exact cause of this; Echovirus 11 usually causes aseptic meningitis and rarely severe encephalitis. We propose that a combination of factors, including the organicacidaEmia and the viral infection of the nervous system, was responsible. Thus in patients with Reye’s syndrome, even with an acellular c.s.F., virus isolation should be attempted as well as screening for organicacidxmia. This is of particular importance in patients with Reye’s syndrome presenting with atypical features. J. V. LEONARD J. W. T. SEAKINS Institute of Child Health N. K. GRIFFIN and Hospital for Sick Children, London WC1 W. C. MARSHALL we
DIAZEPAM AND EXPERIMENTAL TUMOUR GROWTH
SIR,-Dr Horrobin and colleagues’ (May 5, p. 978) report that
diazepam at 1 mg/kg intraperitoneally (i.p.) but not at 5 mg/kg i.p. increases the growth of two experimental tumours in rats2 has created considerable concern in Italy. The significance of these findings to the use of diazepam in man is not known, but we can report that not all benzodiazepines increase the growth of transplantable tumours. Our experiments were in CD-COBS male rats (Charles River, Italy) transplanted subcutaneously with 100 mg fragof Walker carcinosarcoma 256, one of the tumours used Horrobin et al. Oxazepam was given by gastric tube start-
ments
by
294,1013. 3. 4.
Schutgens, R. B. H., Heymans, H., Ketel, A., Veder, H. A., Duran, M., Ketting, D., Wadman, S. K. J. Pediat. 1979, 94, 89.
Duran, M., Ketting, D., Wadman, S. K., Jakobs, S., Schutgens, Veder, H. A. Clinica chim. Acta, 1978, 90, 187. 5. Faull, K., and others ibid. 1976, 73, 553. 6. Wysocki, S. J., Hahnel, R. ibid. 1978, 86, 101.
R. B.
1.
Faull, K., Bolton, P., Halpern, B., Hammond, J., Danks, D. M., Hahnel, R., Wilkinson, S. P., Wysoki, S. J., Masters, P. K. New Engl. J. Med. 1976,
2.
Karmali, R. A., Horrobin, D. F., Ghayur, T., Manku, M. S., Cunnane, S. C., Morgan, R. O., Ally, A. I., Karmazyn, M., Oka, M. Cancer Lett.
294, 1013.
H.,
1978, 5, 205.
