35 DETECTION OF VIRUS-LIKE AGENT IN CSF IN RELATION TO
have demonstrated competitive substrates for LPL. 12 As the competition was associated with no decrease in the apparent Km values but with decreased catalytic rate constants, the competition could be overcome by higher enzyme concentrations. This in turn will result in lower plasma concentrations of remnant particles. The atherogenicity of remnants is well recog-
VLDL, and the corresponding that the
remnants
NEUROLEPTIC MEDICATION
remnants are
nised." The "atherogenicity" of low HDL does not apply to typeI hyperlipoproteinarmia or to Tangier disease. 14,11 In type i the massive hypertriglyceridaemia due to the absence of LPL does risk factor. These findings suggest that once the catabolism of VLDL due to the hydrolytic action of LPL has started it has to be rapidly completed if increased plasma concentrations of athernot seem to be a
ogenic remnants are to be avoided. High levels of HDLz could be expected to result from high LPL-activity. The other product from the degradation of VLDL is LDL. The rate of removal of LDL is independent of the degradation of triglyceriderich lipoproteins.’6 High concentrations of LDL have been shown to be a risk factor independent of the apparent protective effect ofHDL. 3-5 The above mechanisms have important clinical implications. In general, the measurement of HDL-chol is indeed relevant in the determination of the risk for atherosclerosis. However, there is no evidence of the beneficial effect of high plasma concentrations of HDL caused by increased splanchnic secretion of HDL. Increased cardiovascular mortality has been found associated with oestrogen therapy, despite the reported increase in HDL." Increasing plasma-HDL by medication should be indicated only when the observed low level can be shown to be due to low LPL activity, and the mechanism(s) by which the HDL concentration is to be increased should primarily be aimed at enhancement of the activity of LPL. Only physical activity,’ moderate alcohol consumption,18 and certain hypolipidxmic drugs’ seem to fulfil these criteria. .
Department of Medical Chemistry, University of Helsinki, SF-00170 Helsinki 17, Finland
like agent in CSF and history of neuroleptic medication before admission (table). The patients with neurological conditions in whom viruslike agents were detected were not receiving immunosuppressive treatment, and we have now tested CSF from thirteen patients receiving cytotoxic and other therapy for leukaemia and the results have all been negative. For these reasons we think it unlikely that the association we have reported between the presence of the agent (or agents) and schizophrenia and certain neurological diseases is secondary to the immunosuppressive, or other, effects of neuroleptic drugs. Nevertheless we accept (and emphasised in our papers) that a causal relationship between the virus-like agent(s) and the disease processes in question has yet to be demonstrated. T. J. GROW D. A. J. TYRRELL I. N. FERRIER Divisions of Psychiatry and Communicable Diseases, Clinical Research Centre, Harrow, Middlesex HA1 3UJ
E.C. JOHNSTONE J. F. MACMILLAN D. G. C. OWENS R. P. PARRY
PAAVO K. J. KINNUNEN FETAL-ALCOHOL SYNDROME IN CHILD WHOSE PARENTS HAD STOPPED DRINKING
VIRUS-LIKE PARTICLES IN CSF IN SCHIZOPHRENIA
SIR,-We have reported (April 21, pp. 839, 842) a virus-like agent in the cerebrospinal fluid (CSF) of some patients with schizophrenia and certain neurological conditions (including Huntington’s chorea and multiple sclerosis). Dr Dwyer (June 2, p. 1184) wonders if this association could be due to treatment with neuroleptic drugs. We think this unlikely since many CSF specimens from schizophrenic patients were taken before neuroleptic medication for this episode of illness was started, and there was no relation between detection of a virus12. Higgins
JM, Fielding CJ. Lipoprotein lipase: mechanism of formation oftriglyceride-rich remnant particles from very low density lipoproteins and chylomicrons. Biochemistry 1975; 14: 2288-2292. 13. Zilversmit DB. A proposal linking atherogenesis to the interaction of endothehal lipoprotein lipase with triglyceride-rich lipoproteins. Circulation Res 1973; 33: 633-638. DS, Goldstein JL, Brown MS. The familial hyperlipoproteinStanbury JB, Wyngaarden JB, Fredrickson DS, eds. Metabolic basis of inherited disease. New York: McGraw-Hill, 1978, 604-655. 15. Assmann, G. The metabolic role of high density lipoproteins: perspectives from Tangier disease. In: Gotto AM, Miller NE, Oliver MF, eds. High density lipoproteins and atherosclerosis. Amsterdam: Elsevier, 1978, 14. Fredrickson emias. In:
77-89. 16. Brown MS, Goldstein JL. Expression of the familial hypercholesterolemia gene in heterozygotes: mechanism for a dominant disorder in man. Science 1974; 185: 61-63. 17. Wallentin L, Varenhorst E. Changes of plasma lipid metabolism in males during estrogen treatment for prostatic carcinoma. Clin Endocr Metab
1978; 47: 596-599. P, Berg B, Hägerstrand I, Nilsson-Ehle P, Tornqvist H, Wiebe T.
18. Belfrage
Alterations of lipid metabolism in healthy volunteers ethanol intake. Eur J Clin Invest 1977; 7: 127-131.
during long-term
SiR,—The child described by Dr Scheiner and colleagues p. 1077) tallies with the dysmorphic condition seen children of alcoholic mothers, and we feel that the last sentence of their letter-in which Scheiner et al. state that they could not rule out the possibility that the mother had drunk while pregnant--contains the more likely explanation. Had the parents really given up drinking 1-Lyears before conception, the only explanation would be a mutagenic effect on the germ cells. The only observation of dominant lethal mutation induced by alcohol in male micel could not be reproduced by us and has been contradicted by others.2,3 Little is known about mutagenic effects on the ovum hidden in the graafian follicle and hardly anything has been published on the action of alcohol or its first metabolite, acetaldehyde. We have found that not even 1 ml/dl of alcohol (twice the human lethal dose) damages cultured human lymphocytes or fibroblasts or exerts a mutagenic effect;5 nor were these cells injured by acetaldehyde at concentrations below 40 mol/1 (more than the peak concentration
(May 19,
in
some
1. Badr
FM, Badr RS. Induction of dominant lethal mutation in male mice by
ethyl alcohol. Nature 1975; 253: 134-137. 2. Chauhan PS, Aravindakshan R, Sundaram K. Failure of ethyl alcohol to induce dominant lethal mutations in Wistar rats or to synergize the effect of ethylmethanesulfonate and X-rays in mice. Abstr 2nd Int Conf Envir Mutagens 1977:90. 3. McGragor DB, Wickramaratne A deS. Does ethanol cause chromosomal aberrations? Abstr 2nd Int Conf Envir Mutagens 1977:89. 4. Véghelyi PV, Osztovics M. The alcohol syndromes: the intrarecombigenic effect of acetaldehyde. Experientia 1978;34:195. 5. Véghelyi PV, Osztovics M, Karods G, et al. The fetal alcohol syndrome: symptoms and pathogenesis. Acta Paediat Acad Sci Hung 1978;19: 171-189.
have demonstrated competitive substrates for LPL. 12 As the competition was associated with no decrease in the apparent Km values but with decreased catalytic rate constants, the competition could be overcome by higher enzyme concentrations. This in turn will result in lower plasma concentrations of remnant particles. The atherogenicity of remnants is well recog-
VLDL, and the corresponding that the
remnants
NEUROLEPTIC MEDICATION
remnants are
nised." The "atherogenicity" of low HDL does not apply to typeI hyperlipoproteinarmia or to Tangier disease. 14,11 In type i the massive hypertriglyceridaemia due to the absence of LPL does risk factor. These findings suggest that once the catabolism of VLDL due to the hydrolytic action of LPL has started it has to be rapidly completed if increased plasma concentrations of athernot seem to be a
ogenic remnants are to be avoided. High levels of HDLz could be expected to result from high LPL-activity. The other product from the degradation of VLDL is LDL. The rate of removal of LDL is independent of the degradation of triglyceriderich lipoproteins.’6 High concentrations of LDL have been shown to be a risk factor independent of the apparent protective effect ofHDL. 3-5 The above mechanisms have important clinical implications. In general, the measurement of HDL-chol is indeed relevant in the determination of the risk for atherosclerosis. However, there is no evidence of the beneficial effect of high plasma concentrations of HDL caused by increased splanchnic secretion of HDL. Increased cardiovascular mortality has been found associated with oestrogen therapy, despite the reported increase in HDL." Increasing plasma-HDL by medication should be indicated only when the observed low level can be shown to be due to low LPL activity, and the mechanism(s) by which the HDL concentration is to be increased should primarily be aimed at enhancement of the activity of LPL. Only physical activity,’ moderate alcohol consumption,18 and certain hypolipidxmic drugs’ seem to fulfil these criteria. .
Department of Medical Chemistry, University of Helsinki, SF-00170 Helsinki 17, Finland
like agent in CSF and history of neuroleptic medication before admission (table). The patients with neurological conditions in whom viruslike agents were detected were not receiving immunosuppressive treatment, and we have now tested CSF from thirteen patients receiving cytotoxic and other therapy for leukaemia and the results have all been negative. For these reasons we think it unlikely that the association we have reported between the presence of the agent (or agents) and schizophrenia and certain neurological diseases is secondary to the immunosuppressive, or other, effects of neuroleptic drugs. Nevertheless we accept (and emphasised in our papers) that a causal relationship between the virus-like agent(s) and the disease processes in question has yet to be demonstrated. T. J. GROW D. A. J. TYRRELL I. N. FERRIER Divisions of Psychiatry and Communicable Diseases, Clinical Research Centre, Harrow, Middlesex HA1 3UJ
E.C. JOHNSTONE J. F. MACMILLAN D. G. C. OWENS R. P. PARRY
PAAVO K. J. KINNUNEN FETAL-ALCOHOL SYNDROME IN CHILD WHOSE PARENTS HAD STOPPED DRINKING
VIRUS-LIKE PARTICLES IN CSF IN SCHIZOPHRENIA
SIR,-We have reported (April 21, pp. 839, 842) a virus-like agent in the cerebrospinal fluid (CSF) of some patients with schizophrenia and certain neurological conditions (including Huntington’s chorea and multiple sclerosis). Dr Dwyer (June 2, p. 1184) wonders if this association could be due to treatment with neuroleptic drugs. We think this unlikely since many CSF specimens from schizophrenic patients were taken before neuroleptic medication for this episode of illness was started, and there was no relation between detection of a virus12. Higgins
JM, Fielding CJ. Lipoprotein lipase: mechanism of formation oftriglyceride-rich remnant particles from very low density lipoproteins and chylomicrons. Biochemistry 1975; 14: 2288-2292. 13. Zilversmit DB. A proposal linking atherogenesis to the interaction of endothehal lipoprotein lipase with triglyceride-rich lipoproteins. Circulation Res 1973; 33: 633-638. DS, Goldstein JL, Brown MS. The familial hyperlipoproteinStanbury JB, Wyngaarden JB, Fredrickson DS, eds. Metabolic basis of inherited disease. New York: McGraw-Hill, 1978, 604-655. 15. Assmann, G. The metabolic role of high density lipoproteins: perspectives from Tangier disease. In: Gotto AM, Miller NE, Oliver MF, eds. High density lipoproteins and atherosclerosis. Amsterdam: Elsevier, 1978, 14. Fredrickson emias. In:
77-89. 16. Brown MS, Goldstein JL. Expression of the familial hypercholesterolemia gene in heterozygotes: mechanism for a dominant disorder in man. Science 1974; 185: 61-63. 17. Wallentin L, Varenhorst E. Changes of plasma lipid metabolism in males during estrogen treatment for prostatic carcinoma. Clin Endocr Metab
1978; 47: 596-599. P, Berg B, Hägerstrand I, Nilsson-Ehle P, Tornqvist H, Wiebe T.
18. Belfrage
Alterations of lipid metabolism in healthy volunteers ethanol intake. Eur J Clin Invest 1977; 7: 127-131.
during long-term
SiR,—The child described by Dr Scheiner and colleagues p. 1077) tallies with the dysmorphic condition seen children of alcoholic mothers, and we feel that the last sentence of their letter-in which Scheiner et al. state that they could not rule out the possibility that the mother had drunk while pregnant--contains the more likely explanation. Had the parents really given up drinking 1-Lyears before conception, the only explanation would be a mutagenic effect on the germ cells. The only observation of dominant lethal mutation induced by alcohol in male micel could not be reproduced by us and has been contradicted by others.2,3 Little is known about mutagenic effects on the ovum hidden in the graafian follicle and hardly anything has been published on the action of alcohol or its first metabolite, acetaldehyde. We have found that not even 1 ml/dl of alcohol (twice the human lethal dose) damages cultured human lymphocytes or fibroblasts or exerts a mutagenic effect;5 nor were these cells injured by acetaldehyde at concentrations below 40 mol/1 (more than the peak concentration
(May 19,
in
some
1. Badr
FM, Badr RS. Induction of dominant lethal mutation in male mice by
ethyl alcohol. Nature 1975; 253: 134-137. 2. Chauhan PS, Aravindakshan R, Sundaram K. Failure of ethyl alcohol to induce dominant lethal mutations in Wistar rats or to synergize the effect of ethylmethanesulfonate and X-rays in mice. Abstr 2nd Int Conf Envir Mutagens 1977:90. 3. McGragor DB, Wickramaratne A deS. Does ethanol cause chromosomal aberrations? Abstr 2nd Int Conf Envir Mutagens 1977:89. 4. Véghelyi PV, Osztovics M. The alcohol syndromes: the intrarecombigenic effect of acetaldehyde. Experientia 1978;34:195. 5. Véghelyi PV, Osztovics M, Karods G, et al. The fetal alcohol syndrome: symptoms and pathogenesis. Acta Paediat Acad Sci Hung 1978;19: 171-189.
