688 VARICOSE VEINS IN DEVELOPING COUNTRIES
SIR,—Iagree with Mr Hobbs (July 31, p. 259) that straining stool for a short while once a day, or lacking bran, perhaps only twice a week, is not very likely to play any major part in bringing about the valvular incompetence which is such a regular feature of varicose venous insufficiency. My support for Mr Hobbs’ hypothesis of some change in the supporting tissues derives from the observation throughout my surgical career of the almost consistent relationship of pes planus, often with valgus heels and acrocyanosis, with varicose veins in women. In men it does not seem to be so. If fibre lack can be thought to cause flat feet then I for one will be made happy, because, like most working surgeons, I believe we do good when we encourage patients to adopt the bran regimen, and any such collateral benefits as freedom from flat feet and varicose veins would be wonderful to achieve. at
4 Upper Harley Street, London NW1 4PN
ised and given as the average for all three dose levels. As the table shows, at 250 times the human dose (10 mg/kg) of cyproterone acetate-i.e., the dose most comparable to the highest dose of progestagens used in the C.S.M. study-no tumours occurred, and then appeared only after 1250 (50 mg/kg, and 6250 (250 mg/kg) times the human contraceptive dose. These data suggest that the increase in liver adenomas in the rat after high doses of progestagens is related to the dose level used rather than the chemical nature of the compound and that in this respect cyproterone acetate is not unique among progestagens. Department of Experimental Toxicology, Schering AG.,
J. SCHUPPLER
D-1000 Berlin 65
P. GÜNZEL
H. H. G. EASTCOTT
DIAGNOSIS OF PYOGENIC MENINGITIS
SIR,-Dr Mandal (July 17, p. 147) asks for evidence of the CYPROTERONE ACETATE a paper by Neuyou say that whereas there is no evidence that cyproterone acetate causes liver damage in man, rats injected with large doses of the drug developed hepatomas. We think this statement may give the impression that cyproterone acetate is unique in this way. We should therefore like to record the results of our evaluation of material published by the Committee on Safety of Medicines3 and our own toxicology studies in the rat. In the C.S.M. study rats were given the progestagen component of various oral contraceptives over a period of 2 yr at doses equivalent to 2-5, 30-150, and 200-400 times the human dose. In our studies 10, 50, and 250 mg/kg/day of cyproterone
SIR,—In your editorial,’ in whicn you cite
mann
and
Graf,2
given for 78 wk—equivalent to 250, 1250, and 6250 times the human oral-contraceptive dose (0-04 mg/kg) or 5, 25, and 125 times the human dose used in treatment of hypersexual states (2 mg/kg) without taking into account the fact that the compound accumulates at these dose levels in the rat. In all the studies the progestagens were mixed into the feed. The incidence of benign hepatomas is shown in the table. Unfortunately, in the C.S.M. report3 the incidence is summar-
acetate were
1. Lancet, 1976, i, 1003. 2. Neumann, F., Gräf, K. J. J. int. med. Res. 1975, 3, suppl. 4, p. 1. 3. Carcinogenicity Tests of Oral Contraceptives. Report by the Committee Safety of Medicines. H.M. Stationery Office, 1972.
superiority of countercurrent immunoelectrophoresis (c.t.E.) bacteriological culture in establishing a bacteriological diagnosis in patients with partially treated pyogenic meningitis. We have evidence to suggest that this is so.’ 10 of 129 patients with group-A meningococcal meningitis admitted to our hospital had an adequately documented history of chemotherapy before admission (long-acting sulphonamides in 5 and intramuscular penicillin in 5). Antigen was detected in the cerebrospinal fluid (c.s.F.) of 6 of these patients by C.I.E. but culture was positive in only 1. The effects of hospital treatment with full doses of penicillin (500 000 I.U./kg/24 h) or chloramphenicol (100 mg/kg/24 h) on bacteriological findings in the c.s.F. were studied in 21 patients whose c.s.F. was initially positive for group-A meningococci by culture and by C.I.E. 24 h after the start of treatment antigen was detected in the c.s.F. of 13 patients whilst culture was negative in all. 48 h after the start of treatment antigen was detected in 4 of 14 samples, but only 1 positive culture was obtained. Antigen persists in the c.s.F. of patients with pneumococcal meningitis for even longer.2 Antigen was found in the c.s.F. of 8 of 10 patients 3 days after the start of treatment with large doses of penicillin and in 4 of 8 patients 6 days after the start
over
on
Culture was not carried out on all these serial in but samples pneumococcal meningitis we have rarely found viable bacteria after 3 days of treatment. Our experience thus suggests that c.i.E. is more sensitive than culture in making a diagnosis in patients with partially
of
treatment.
1. Whittle, H. C., and others Am. J. Med. 1975, 58, 823. 2. Tugwell, P., Greenwood, B. M., Warrell, D. A. Q. Jl
Med. (in the press).
INCIDENCE OF BENIGN HEPATOMA IN PROGESTAGEN-TREATED RAT
*C.S.M.
studv.3
tested. In the C.S.M. study contraceptive dose.
N.T.not
ethynodiol diacetate, norgestrel, and lyncestrenol showed no increase of benign hepatomas up to 200-400 times the hum3n
689 treated meningococcal or pneumococcal meningitis. It is, howessential that high titre precipitating antisera are used in the c.).E. test if the small amounts of antigen present in the c,s.F. of these patients are to be detected. ever,
Facultyof Medicine, Ahmadu Bello University, Zaria, Nigeria
B. M. GREENWOOD H. C. WHITTLE
PARAQUAT POISONING RISK S)R,—I was interested in Dr Barraclough’s letter about paraquat toxicity,’ but I think it is better to argue on the basis of permanent risk rather in terms of numbers of deaths. Poisoning by paraquat is not common, few people being exposed to it. Farmers do not necessarily handle pesticides themselves, and paraquat is not used by all spraymen. However, if we consider the small number of people exposed to paraquat and the real number of poisoning cases, the accident risk might be very
high. Clinique Toxicologique, Hôpital Fernand Widal, 75010 Pans, France
S. DALLY
ABNORMAL POLYGRAPHIC FINDINGS IN NEAR-MISS SUDDEN INFANT DEATH
SIR,-The description, by Dr Guilleminault and his colleagues,’ of autonomic dysfunction in cases of near-miss sudden infant death prompts me to record my observations of the sudden unexpected death of a 5-month-old girl in my consulting-rooms in January, 1974. The baby had been brought to me because of problems with weaning. The apparently well baby was seen being bottle-fed, when pallor suddenly developed, and prescience of impending disaster led to hurried examination. The body-temperature was 38’C, the respiration became increasingly irregular without initial apnoea or observed respiratory obstruction, the pupils dilated unequally, the abdomen became distended, and bradycardia preceded worsening collapse. There had been no sleep disturbance, and previous development had been normal. Intensive resuscitation failed, and within 5 min of the first signs of distress the heart stopped beating. Post-mortem studies, including full microbiological investigation, were negative; there was no histological evidence for metabolic disease, although such may have been undetected. The parents had been more annoyed by what they interpreted as the child’s stubbornness on the previous day than worried by the possibility of acute disease. The infant’s problem might not have attracted attention but for the family historv, which included the stillbirth of the first full-term pregnancv and the death of the second child with proven respiratory-distress syndrome after elective term caesarean section-a relatively uncommon situation and, for the mother, a source of continuing anxiety (rightly in the event) with caring for this latest baby. Certainly, in the case described there was evidence of Autonomic-nervous-system dysfunction. The family history rams questions of high-risk association of sudden-infant-death - ndrome with a family history of unusual neonatal respira:m disorders. Perhaps others may be able to report similar :’.?cnences.
Royal Children’sHospital, Flemin
gton Road,
le 3052,
Parkvil
Australia
1 Barraclough, B 2 Guille
JOHN MCNAMARA
M. Lancet, 1976, i, 1353. minault, C , Anagno, R , Souquet, M , Dement, W. C Lancet, 1976,
i, 1326.
GLUTEN AND SCHIZOPHRENIA SIR,-We would like to comment on your editorial’ which discussed our work.2 Our report did briefly address the issue of whether wheatgluten effects could have been due to interference with the absorption or pharmacological activity of the concurrently given neuroleptics. Three observations spoke against this possibility-the adverse gluten effect predominated in the patients with less favourable response to neuroleptic treatment; the undesirable pharmacological effects of medication were as prevalent in the gluten-challenge period as in the gluten-free periods; and the gluten-sensitive psychiatric characteristics of the patients with coeliac disease tend to resemble those in schizophrenia and no neuroleptics are involved here. Wheat-gluten effects contrast with the effects of anticholinergic agents which we have also found, using a similar research design, to be countertherapeutic in schizophrenics.34 The therapeutic reversal with anticholinergics was predominantly seen in the more treatment-responsive patients,S suggesting that anticholinergics directly antagonised neuroleptic actions, whereas wheat-gluten effects probably appeared by accentuation of the components of schizophrenia not controlled by the medication. Consider the opposite issue-i.e., the attenuation of possible pathogenic effects of wheat gluten by the neuroleptics. Since wheat gluten is an abundant constituent of the diet the patients ordinarily eat, the neuroleptics must be effective in the presence of wheat gluten. At the same time, the need for continuous long-term medication to maintain symptomatic improvement in schizophrenia and the high probability of exacerbation after medication is withdrawn, would suggest that neuroleptics may be acting to block, if only partially, the pathogenic manifestations of a factor or factors that continue to act. This means that in our experiment, any pathogenic effects of wheat gluten may have been less evident than if the wheat gluten had been given to unmedicated recovered schi-
zophrenics. Your reference to the work of Curry et al.6 was not pertinent to the question of gluten effects in our study. Their work suggested that the chlorpromazine levels in plasma were sometimes lower when medication was given on a full stomach (with breakfast) than when given on an empty stomach. In our study, the relationship of medication intake to meals as well as to the "special drinks" was the same in the wheat-gluten challenge period as in the control periods, in which soy flour was substituted for wheat gluten in the drinks. Estimation of plasma levels of the medication, which you recommend, may not resolve the issue. There may be considerable intra-patient variations in plasma levels,6 and concentrations of chlorpromazine have been found to decrease merely as a function of time without a concomitant deterioration in the clinical state.’ The addition of barbiturates may further lower the plasma level of chlorpromazine without change in the clinical state.7 We believe, therefore, that for a more definitive answer, the next step should be to test the effect of wheat gluten in unmedicated recovered schizophrenics. You confuse the purely speculative issue of mechanism(s) of pathogenesis with the empirical finding that wheat gluten9 seems to worsen the schizophrenic process. Neither Dohan’s8 work nor ours was a test of any allergic mechanisms or immunological abnormalities in schizophrenia. Mechanisms that do not involve these processes (e.g., the absorption of some psy1. Lancet, 1976, 1, 844. 2. Singh, M. M., Kay, S. R. Science, 1976, 191, 401. 3. Singh, M. M., Smith, J. M. J. nerv. ment. Dis. 1973, 157, 50. 4. Singh, M. M., Kay, S. R. ibid. 1975, 160, 258. 5. Singh, M. M., Kay, S. R. unpublished. 6. Curry, S. H., Davis, J. M., Janowsky, D. S., Marshall, J. H. L. Archs. gen. Psychiat. 1970, 22, 209. 7. Loga, S., Curry, S., Lader, M. Br. J. clin. Pharm. 1975, 2, 197. 8. Dohan, F. C., Grasberger, J. C., Lowell, F. M., Johnston Jr., H. T., Arbegast, A. Br. J. Psychiat. 1969, 115, 595. 9. Dohan, F. C. Am. J. Psychiat. 1973, 130, 1400.
SIR,—Iagree with Mr Hobbs (July 31, p. 259) that straining stool for a short while once a day, or lacking bran, perhaps only twice a week, is not very likely to play any major part in bringing about the valvular incompetence which is such a regular feature of varicose venous insufficiency. My support for Mr Hobbs’ hypothesis of some change in the supporting tissues derives from the observation throughout my surgical career of the almost consistent relationship of pes planus, often with valgus heels and acrocyanosis, with varicose veins in women. In men it does not seem to be so. If fibre lack can be thought to cause flat feet then I for one will be made happy, because, like most working surgeons, I believe we do good when we encourage patients to adopt the bran regimen, and any such collateral benefits as freedom from flat feet and varicose veins would be wonderful to achieve. at
4 Upper Harley Street, London NW1 4PN
ised and given as the average for all three dose levels. As the table shows, at 250 times the human dose (10 mg/kg) of cyproterone acetate-i.e., the dose most comparable to the highest dose of progestagens used in the C.S.M. study-no tumours occurred, and then appeared only after 1250 (50 mg/kg, and 6250 (250 mg/kg) times the human contraceptive dose. These data suggest that the increase in liver adenomas in the rat after high doses of progestagens is related to the dose level used rather than the chemical nature of the compound and that in this respect cyproterone acetate is not unique among progestagens. Department of Experimental Toxicology, Schering AG.,
J. SCHUPPLER
D-1000 Berlin 65
P. GÜNZEL
H. H. G. EASTCOTT
DIAGNOSIS OF PYOGENIC MENINGITIS
SIR,-Dr Mandal (July 17, p. 147) asks for evidence of the CYPROTERONE ACETATE a paper by Neuyou say that whereas there is no evidence that cyproterone acetate causes liver damage in man, rats injected with large doses of the drug developed hepatomas. We think this statement may give the impression that cyproterone acetate is unique in this way. We should therefore like to record the results of our evaluation of material published by the Committee on Safety of Medicines3 and our own toxicology studies in the rat. In the C.S.M. study rats were given the progestagen component of various oral contraceptives over a period of 2 yr at doses equivalent to 2-5, 30-150, and 200-400 times the human dose. In our studies 10, 50, and 250 mg/kg/day of cyproterone
SIR,—In your editorial,’ in whicn you cite
mann
and
Graf,2
given for 78 wk—equivalent to 250, 1250, and 6250 times the human oral-contraceptive dose (0-04 mg/kg) or 5, 25, and 125 times the human dose used in treatment of hypersexual states (2 mg/kg) without taking into account the fact that the compound accumulates at these dose levels in the rat. In all the studies the progestagens were mixed into the feed. The incidence of benign hepatomas is shown in the table. Unfortunately, in the C.S.M. report3 the incidence is summar-
acetate were
1. Lancet, 1976, i, 1003. 2. Neumann, F., Gräf, K. J. J. int. med. Res. 1975, 3, suppl. 4, p. 1. 3. Carcinogenicity Tests of Oral Contraceptives. Report by the Committee Safety of Medicines. H.M. Stationery Office, 1972.
superiority of countercurrent immunoelectrophoresis (c.t.E.) bacteriological culture in establishing a bacteriological diagnosis in patients with partially treated pyogenic meningitis. We have evidence to suggest that this is so.’ 10 of 129 patients with group-A meningococcal meningitis admitted to our hospital had an adequately documented history of chemotherapy before admission (long-acting sulphonamides in 5 and intramuscular penicillin in 5). Antigen was detected in the cerebrospinal fluid (c.s.F.) of 6 of these patients by C.I.E. but culture was positive in only 1. The effects of hospital treatment with full doses of penicillin (500 000 I.U./kg/24 h) or chloramphenicol (100 mg/kg/24 h) on bacteriological findings in the c.s.F. were studied in 21 patients whose c.s.F. was initially positive for group-A meningococci by culture and by C.I.E. 24 h after the start of treatment antigen was detected in the c.s.F. of 13 patients whilst culture was negative in all. 48 h after the start of treatment antigen was detected in 4 of 14 samples, but only 1 positive culture was obtained. Antigen persists in the c.s.F. of patients with pneumococcal meningitis for even longer.2 Antigen was found in the c.s.F. of 8 of 10 patients 3 days after the start of treatment with large doses of penicillin and in 4 of 8 patients 6 days after the start
over
on
Culture was not carried out on all these serial in but samples pneumococcal meningitis we have rarely found viable bacteria after 3 days of treatment. Our experience thus suggests that c.i.E. is more sensitive than culture in making a diagnosis in patients with partially
of
treatment.
1. Whittle, H. C., and others Am. J. Med. 1975, 58, 823. 2. Tugwell, P., Greenwood, B. M., Warrell, D. A. Q. Jl
Med. (in the press).
INCIDENCE OF BENIGN HEPATOMA IN PROGESTAGEN-TREATED RAT
*C.S.M.
studv.3
tested. In the C.S.M. study contraceptive dose.
N.T.not
ethynodiol diacetate, norgestrel, and lyncestrenol showed no increase of benign hepatomas up to 200-400 times the hum3n
689 treated meningococcal or pneumococcal meningitis. It is, howessential that high titre precipitating antisera are used in the c.).E. test if the small amounts of antigen present in the c,s.F. of these patients are to be detected. ever,
Facultyof Medicine, Ahmadu Bello University, Zaria, Nigeria
B. M. GREENWOOD H. C. WHITTLE
PARAQUAT POISONING RISK S)R,—I was interested in Dr Barraclough’s letter about paraquat toxicity,’ but I think it is better to argue on the basis of permanent risk rather in terms of numbers of deaths. Poisoning by paraquat is not common, few people being exposed to it. Farmers do not necessarily handle pesticides themselves, and paraquat is not used by all spraymen. However, if we consider the small number of people exposed to paraquat and the real number of poisoning cases, the accident risk might be very
high. Clinique Toxicologique, Hôpital Fernand Widal, 75010 Pans, France
S. DALLY
ABNORMAL POLYGRAPHIC FINDINGS IN NEAR-MISS SUDDEN INFANT DEATH
SIR,-The description, by Dr Guilleminault and his colleagues,’ of autonomic dysfunction in cases of near-miss sudden infant death prompts me to record my observations of the sudden unexpected death of a 5-month-old girl in my consulting-rooms in January, 1974. The baby had been brought to me because of problems with weaning. The apparently well baby was seen being bottle-fed, when pallor suddenly developed, and prescience of impending disaster led to hurried examination. The body-temperature was 38’C, the respiration became increasingly irregular without initial apnoea or observed respiratory obstruction, the pupils dilated unequally, the abdomen became distended, and bradycardia preceded worsening collapse. There had been no sleep disturbance, and previous development had been normal. Intensive resuscitation failed, and within 5 min of the first signs of distress the heart stopped beating. Post-mortem studies, including full microbiological investigation, were negative; there was no histological evidence for metabolic disease, although such may have been undetected. The parents had been more annoyed by what they interpreted as the child’s stubbornness on the previous day than worried by the possibility of acute disease. The infant’s problem might not have attracted attention but for the family historv, which included the stillbirth of the first full-term pregnancv and the death of the second child with proven respiratory-distress syndrome after elective term caesarean section-a relatively uncommon situation and, for the mother, a source of continuing anxiety (rightly in the event) with caring for this latest baby. Certainly, in the case described there was evidence of Autonomic-nervous-system dysfunction. The family history rams questions of high-risk association of sudden-infant-death - ndrome with a family history of unusual neonatal respira:m disorders. Perhaps others may be able to report similar :’.?cnences.
Royal Children’sHospital, Flemin
gton Road,
le 3052,
Parkvil
Australia
1 Barraclough, B 2 Guille
JOHN MCNAMARA
M. Lancet, 1976, i, 1353. minault, C , Anagno, R , Souquet, M , Dement, W. C Lancet, 1976,
i, 1326.
GLUTEN AND SCHIZOPHRENIA SIR,-We would like to comment on your editorial’ which discussed our work.2 Our report did briefly address the issue of whether wheatgluten effects could have been due to interference with the absorption or pharmacological activity of the concurrently given neuroleptics. Three observations spoke against this possibility-the adverse gluten effect predominated in the patients with less favourable response to neuroleptic treatment; the undesirable pharmacological effects of medication were as prevalent in the gluten-challenge period as in the gluten-free periods; and the gluten-sensitive psychiatric characteristics of the patients with coeliac disease tend to resemble those in schizophrenia and no neuroleptics are involved here. Wheat-gluten effects contrast with the effects of anticholinergic agents which we have also found, using a similar research design, to be countertherapeutic in schizophrenics.34 The therapeutic reversal with anticholinergics was predominantly seen in the more treatment-responsive patients,S suggesting that anticholinergics directly antagonised neuroleptic actions, whereas wheat-gluten effects probably appeared by accentuation of the components of schizophrenia not controlled by the medication. Consider the opposite issue-i.e., the attenuation of possible pathogenic effects of wheat gluten by the neuroleptics. Since wheat gluten is an abundant constituent of the diet the patients ordinarily eat, the neuroleptics must be effective in the presence of wheat gluten. At the same time, the need for continuous long-term medication to maintain symptomatic improvement in schizophrenia and the high probability of exacerbation after medication is withdrawn, would suggest that neuroleptics may be acting to block, if only partially, the pathogenic manifestations of a factor or factors that continue to act. This means that in our experiment, any pathogenic effects of wheat gluten may have been less evident than if the wheat gluten had been given to unmedicated recovered schi-
zophrenics. Your reference to the work of Curry et al.6 was not pertinent to the question of gluten effects in our study. Their work suggested that the chlorpromazine levels in plasma were sometimes lower when medication was given on a full stomach (with breakfast) than when given on an empty stomach. In our study, the relationship of medication intake to meals as well as to the "special drinks" was the same in the wheat-gluten challenge period as in the control periods, in which soy flour was substituted for wheat gluten in the drinks. Estimation of plasma levels of the medication, which you recommend, may not resolve the issue. There may be considerable intra-patient variations in plasma levels,6 and concentrations of chlorpromazine have been found to decrease merely as a function of time without a concomitant deterioration in the clinical state.’ The addition of barbiturates may further lower the plasma level of chlorpromazine without change in the clinical state.7 We believe, therefore, that for a more definitive answer, the next step should be to test the effect of wheat gluten in unmedicated recovered schizophrenics. You confuse the purely speculative issue of mechanism(s) of pathogenesis with the empirical finding that wheat gluten9 seems to worsen the schizophrenic process. Neither Dohan’s8 work nor ours was a test of any allergic mechanisms or immunological abnormalities in schizophrenia. Mechanisms that do not involve these processes (e.g., the absorption of some psy1. Lancet, 1976, 1, 844. 2. Singh, M. M., Kay, S. R. Science, 1976, 191, 401. 3. Singh, M. M., Smith, J. M. J. nerv. ment. Dis. 1973, 157, 50. 4. Singh, M. M., Kay, S. R. ibid. 1975, 160, 258. 5. Singh, M. M., Kay, S. R. unpublished. 6. Curry, S. H., Davis, J. M., Janowsky, D. S., Marshall, J. H. L. Archs. gen. Psychiat. 1970, 22, 209. 7. Loga, S., Curry, S., Lader, M. Br. J. clin. Pharm. 1975, 2, 197. 8. Dohan, F. C., Grasberger, J. C., Lowell, F. M., Johnston Jr., H. T., Arbegast, A. Br. J. Psychiat. 1969, 115, 595. 9. Dohan, F. C. Am. J. Psychiat. 1973, 130, 1400.
