- Email: [email protected]
DISULFIRAM, CARBON DISULPHIDE, AND ATHEROSCLEROSIS
284
Although the villi resemble the type of surface projections now regarded as characteristic of lymphoid cells, the origin of this cell is unknown. The inconsistencies in observations of different groups of workers who have examined cells in this disorder may be accounted for by differences in sampling (e.g., where gradient procedures are used), and the preparation techniques themselves.5 They could also result from the fact that hairy-cell leukxmia may be a broadly based syndrome involving differing cell types. Hæmatology, Medical and Biological Sciences Building, University of Southampton, STUART ROATH Bassett Crescent East, DIANE G. NEWELL. Southampton SO9 3TU.
STUDENTS AS PATIENTS
SIR,-I do not believe that it is justifiable to carry out procedures with a definite morbidity (such as intravenous transfusion) on medical students in order to show them the patient’s viewpoint and get them more involved with ward work (Dec. 14, p. 1433). I think that such procedures introduce an emotional element (particularly if a reaction to treatment occurs) and will distort future judgment. A psychiatrist colleague in Britain spends quite a time with student groups discussing the problems they experience in coming in contact with disease and death for the first time. This strikes me as a much more fruitful approach. 18
Merlyn Road, Dublin 4.
CHARLES DUPONT.
MALNUTRITION AND SCHOOL PROGRESS SIR,-Dr Richardson (Dec. 7, p. 1391) seriously mis" quotes me as attaching principal blame to malnutrition " for inferior performance in intelligence tests, citing one of my articles. I repeatedly, and apparently in vain, try to express the view that early malnutrition contributes significantly to the multifactoral algebraic sum of environmental factors which influence a child’s capacity for achievement. To attach principal blame to any single one of these factors is to underestimate the complexity of their interdependence, which will probably always defy quantitative
analysis. In summarising conclusions from her own as yet unpublished study, she may be- in danger of confusing continuing intellectual progress in previously malnourished children with " catch-up ", an expression which means quite literally what it says. It will be better if we stick to the accepted definition of the term. The only way to distinguish true " catch-up " from merely continuing development at a lower-than-normal level is to demonstrate some substantial convergence of the developmental curves; and an important part of this demonstration will be to show that the " normal controls " really are progressing normally, and not contributing to the convergence by any retardation of their own. Since the " controls " will usually be drawn from the same chronically subnourished or otherwise disadvantaged society, this will indeed be difficult to establish; even if one day someone devises " measure of achievement ", " learning intellect ". In a difficult subject we such ability ", should all avoid prefacing our conclusions with the word
an
acceptable or
"
no reasonable observer has denied, perhaps those theoretical nutritionists who used to regard them as brain-damaged in the older, pathological sense of mentally retarded. Even these can nearly always be brought substantially nearer their own limited potential, a phenomenon still widely and expensively confused with
children, something except
"
catch-up "
so far, she has not shown much more than a continuing capacity for development in previously malnourished
told
5. Newell, D. G., Roath, S. Unpublished. 6. Dobbing, J. Pediatrics, Springfield, 1974,
53,
2.
even " cure ".
JOHN DOBBING.
DISULFIRAM, CARBON DISULPHIDE, AND ATHEROSCLEROSIS SIR,-Disulfiram (’ Antabuse ’) administration has been associated with behavioural symptoms, including depression, lethargy, loss of libido, irritability, and psychosis; neurological findings, such as meningeal signs, unilateral weakness, hyperreflexia, Babinski responses, peripheral
neuropathy, ataxia, motor incoordination, encephalopathy, and paralysis; biochemical effects involving inhibition of brain dopamine P-hydroxylase, alterations in coumarin metabolism, and disturbances of other enzyme systems; and demyelinating lesions of the brain, spinal cord, and peripheral nerves.1-5 Disulfiram is metabolised to carbon disulphide (CS2) in man, and the behavioural, neurological, biochemical, and histopathological effects of disulfiram and CS are very similar. 6-8 When the two compounds are compared for equivalent CSg exposures (CS2 inhaled from the air or generated by disulfiram metabolism) the resemblance is even more striking.7 If disulfiram toxicity is a result of CSz poisoning, then patients on maintenance disulfiram could experience other effects of prolonged CS2 exposure.9 The most important of
,
these may be an increased incidence of atherosclerotic cardiovascular disease. The minimum daily dose of disulfiram which will elicit the alcohol-antabuse reaction is 125 mg. Exposure to 30 mg. per c.m. CSj! for an 8-hour day results in absorption of approxibe mately 30 mg. per day, the same amount which should produced from 125 mg. of disulfiram.7,10 Vertin 11 has studied a group of viscose rayon workers exposed to this . CS2 concentration. They experienced a much higher rate of cardiovascular disease (11% v. 3%) than controls during a 5-year observation period. The complete syndrome of CS2 atherosclerosis involves renal, cerebral, and myocardial sclerosis, with more than twice as many deaths from coronary-artery disease in workers chronically exposed to higher CSz levels.9 Thus, the risk of atherosclerotic disease should increase with prolonged disulfiram use. Recent evidence suggests that severe alcoholism has a hereditary component, and some alcoholics respond well to disulfiram. 12, 13 These and other alcoholic subgroups may Liddon, S. C., Satran, R. Am. J. Psych. 1967, 123, 1284. Goldstein, M. Pharm. Rev. 1966, 18, 77. Richert, D., Vanderlinde, R., Westerfeld, W. J. biol. Chem. 1950, 186, 261. 4. Cahill, C. A. New Engl. J. Med. 1972, 287, 935. 5. Child, G., Crump, M. Acta pharm. tox. 1952, 8, 305. 6. Merlevede, E., Casier, H. Archs int. Pharmacodyn. Thér. 1961, 132, 1. 2. 3.
427. 7.
"
clearly... ". I may be over-reacting to Dr Richardson’s brief preview of her forthcoming paper, but, from what we have been
or
Department of Child Health, University of Manchester, Medical School, Oxford Road, Manchester M13 9PT.
8. 9. 10. 11. 12.
13.
Rainey, J. M., Jr., Neal, R. A., Vogelfanger, R. William C. Menninger Award Address, Central Neuropsychiatric Association Annual Meeting, Ann Arbor, Michigan, U.S.A., Oct. 19, 1974. Kane, F. J. Am. J. Psych. 1970, 127, 690. Davidson, M., Feinleib, M. Am. Heart J. 1972, 83, 100. Jakubowski, M., Piotrowski, J. Toxicology of Carbon Disulphide (edited by H. Brieger and J. Teisinger); p. 70. Amsterdam, 1967. Vertin, P. ibid. p. 94. Goodwin, D. W., Schulsinger, F., Møller, N., Hermansen, L., et al. Archs gen. Psychiat. 1974, 31, 164. Gerrein, J. R., Rosenber, C. M., Manohar, V. ibid. 1973, 28, 798.
285
require chronic pharmacotherapy as part of their treatment, intensifying the need for investigation of this possible side-effect. Department of Psychiatry, School of Medicine, Wayne State University, and Lafayette Clinic, Detroit, Michigan 48207, U.S.A. Center in Environmental Toxicology, Department of Biochemistry, School of Medicine, Vanderbilt University, Nashville, Tennessee 37235, U.S.A.
SERUM-COPPER IN SICKLE-CELL ANÆMIA SIR,—Increased serum-copper concentrations have been reported in various haematological disorders, such as
thalassasmia, aplastic anaemia, pernicious anaemia,l.2 and in the lymphoreticular disorders. There are no previous of serum-copper in sickle-cell et al.,4 using the rubeanic acid staining technique, demonstrated excessive amounts of copper granules in erythrocytes containing S haemoglobin. Copper-staining granules were absent in normal (AA) erythrocytes. The importance of the increased copper content in sickled erythrocytes is unknown. We have measured serum-copper by atomic absorption spectrophotometry in a total of 217 subjects as previously described.5 72 of them had sickle-cell anxmia (SS), 46 were cases of sickle-cell haemoglobin C disease (SC), 32 had the sickle-cell trait (AS), and the remaining 67 were
reports of
JOHN M. RAINEY, JR.
R. A. NEAL.
A NEW SPECIES OF MICROFILARIA ? eastern zone of the Indian subcontinent is endemic area of filariasis, which is particularly common in West Bengal, Orissa, and Assam. In West Bengal, the common infecting species of microfilaria is Wuchereria bancrofti. Similar species of microfilaria has been detected in the district of Bankura, in the western mountainous region of West Bengal. Besides W. bancrofti a new species of microfilaria has often been seen in the peripheral blood of patients in this district. The microfilaria is a sheathed one and commonly found in the blood during daytime. Although the size, shape, and arrangement of the somatic
SiR,—The
an
SERUM-COPPER LEVELS IN
nuclei of this newly isolated species are similar to those of W. bancrofti, the cuticular structure is striated transversely from the head to tail. These striations are seen clearly under phase-contrast microscope and distinctly noticed after Giemsa or Leishman stain (see accompanying figure). Further serological study will help to confirm this newly isolated species of microfilaria. The clinical signs and symptoms produced by infection with this particular species of microfilaria are similar to those of classical W. bancrofti infection-fever, lymphangitis, and lymphadenitis. The disease responds to treatment with diethylcarbamazine.
INDIVIDUALS
S. K. BISWAS S. C. SAHA M. CHOUDHURY.
0.001 and f p < 0-025 when these groups normal individuals.
are
compared with
normal controls (AA). The haemoglobin types had preelectrophoresis on viously been established by low-voltage filter paper as previously described.6 The average serum-copper level in patients with SS was significantly increased in comparison with the control group (AA) (p < 0-001) (see accompanying table). Similarly, the serum-copper in patients with SC was significantly increased in comparison with normal controls (AA) (p < 0-025). The serum-copper levels in normal controls (AA) were identical with the levels in individuals carrying AS. Serum-copper in SS was significantly higher than in SC (P< 0-025). A reduction in plasma-zinc in sickle-cell ansemia has been reported 7,and copper and zinc, together with calcium,9 sodium, and potassium 10 may be involved in the maintenance of the structural integrity of the redblood-cell membrane. In the development of irreversible sickling there is a net gain in red-blood-cell calcium9 and sodium 10 and a net reduction in potassium.1O The changes’ in the serum levels of these metals could therefore provide an index of the amount of irreversible sickling that has taken place. 1. 2. 3.
4. 5. 6. 7. 8.
Department of Pathology and Bacteriology, B.S. Medical College, Bankura, West Bengal, India.
SS, SC, AND AS PATIENTS AND IN NORMAL
.
p<
Newly isolated microfilaria showing transverse striations (Leishman x 400).
measurements
anasmia, although Schaeffer
9. 10.
Cartwright, G. E., Hugnley, C. M., Ashenbrucker, H., Fay, J., Wintrobe, M. M. Blood, 1948, 3, 501. Prasad, A. S., Diwany, M., Gabr, M., Sandstead, H. H., Mohktar, N., Hefny, A. E. Ann. intern. Med. 1965, 62, 87. Hrgovcic, M., Tessmer, C. F., Minckler, T. M., Mosier, B., Taylor, G. Cancer, 1968, 21, 743. Schaeffer, K., Lofton, J. A., Powell, S. C., Osborne, H. H., Foster, L. H. Proc. Soc. exp. Biol. Med. 1968, 128, 734. Olatunbosun, D. A., Adeniyi, F. A., Adadevoh, B. K. J. Obstet. Gynœc. Br. Commonw. 1973, 80, 937. Isaacs, W. A. D.M. thesis, University of Oxford, 1971. Serjeant, G. R., Galloway, R. E., Gueri, M. C. Lancet, 1970, ii, 891. Karayalcin, G., Rosner, F., Kim, K. Y., Chandra, P. ibid. 1974, i, 217. Eaton, J. W., Skelton, T. D., Swofford, H. S., Koplin, C. E., Jacobs, H. S. Nature, 1973, 246, 105. Hellerstein, S., Bunthrarungroj, T. J. Lab. clin. Med. 1974, 83, 611.
Although the villi resemble the type of surface projections now regarded as characteristic of lymphoid cells, the origin of this cell is unknown. The inconsistencies in observations of different groups of workers who have examined cells in this disorder may be accounted for by differences in sampling (e.g., where gradient procedures are used), and the preparation techniques themselves.5 They could also result from the fact that hairy-cell leukxmia may be a broadly based syndrome involving differing cell types. Hæmatology, Medical and Biological Sciences Building, University of Southampton, STUART ROATH Bassett Crescent East, DIANE G. NEWELL. Southampton SO9 3TU.
STUDENTS AS PATIENTS
SIR,-I do not believe that it is justifiable to carry out procedures with a definite morbidity (such as intravenous transfusion) on medical students in order to show them the patient’s viewpoint and get them more involved with ward work (Dec. 14, p. 1433). I think that such procedures introduce an emotional element (particularly if a reaction to treatment occurs) and will distort future judgment. A psychiatrist colleague in Britain spends quite a time with student groups discussing the problems they experience in coming in contact with disease and death for the first time. This strikes me as a much more fruitful approach. 18
Merlyn Road, Dublin 4.
CHARLES DUPONT.
MALNUTRITION AND SCHOOL PROGRESS SIR,-Dr Richardson (Dec. 7, p. 1391) seriously mis" quotes me as attaching principal blame to malnutrition " for inferior performance in intelligence tests, citing one of my articles. I repeatedly, and apparently in vain, try to express the view that early malnutrition contributes significantly to the multifactoral algebraic sum of environmental factors which influence a child’s capacity for achievement. To attach principal blame to any single one of these factors is to underestimate the complexity of their interdependence, which will probably always defy quantitative
analysis. In summarising conclusions from her own as yet unpublished study, she may be- in danger of confusing continuing intellectual progress in previously malnourished children with " catch-up ", an expression which means quite literally what it says. It will be better if we stick to the accepted definition of the term. The only way to distinguish true " catch-up " from merely continuing development at a lower-than-normal level is to demonstrate some substantial convergence of the developmental curves; and an important part of this demonstration will be to show that the " normal controls " really are progressing normally, and not contributing to the convergence by any retardation of their own. Since the " controls " will usually be drawn from the same chronically subnourished or otherwise disadvantaged society, this will indeed be difficult to establish; even if one day someone devises " measure of achievement ", " learning intellect ". In a difficult subject we such ability ", should all avoid prefacing our conclusions with the word
an
acceptable or
"
no reasonable observer has denied, perhaps those theoretical nutritionists who used to regard them as brain-damaged in the older, pathological sense of mentally retarded. Even these can nearly always be brought substantially nearer their own limited potential, a phenomenon still widely and expensively confused with
children, something except
"
catch-up "
so far, she has not shown much more than a continuing capacity for development in previously malnourished
told
5. Newell, D. G., Roath, S. Unpublished. 6. Dobbing, J. Pediatrics, Springfield, 1974,
53,
2.
even " cure ".
JOHN DOBBING.
DISULFIRAM, CARBON DISULPHIDE, AND ATHEROSCLEROSIS SIR,-Disulfiram (’ Antabuse ’) administration has been associated with behavioural symptoms, including depression, lethargy, loss of libido, irritability, and psychosis; neurological findings, such as meningeal signs, unilateral weakness, hyperreflexia, Babinski responses, peripheral
neuropathy, ataxia, motor incoordination, encephalopathy, and paralysis; biochemical effects involving inhibition of brain dopamine P-hydroxylase, alterations in coumarin metabolism, and disturbances of other enzyme systems; and demyelinating lesions of the brain, spinal cord, and peripheral nerves.1-5 Disulfiram is metabolised to carbon disulphide (CS2) in man, and the behavioural, neurological, biochemical, and histopathological effects of disulfiram and CS are very similar. 6-8 When the two compounds are compared for equivalent CSg exposures (CS2 inhaled from the air or generated by disulfiram metabolism) the resemblance is even more striking.7 If disulfiram toxicity is a result of CSz poisoning, then patients on maintenance disulfiram could experience other effects of prolonged CS2 exposure.9 The most important of
,
these may be an increased incidence of atherosclerotic cardiovascular disease. The minimum daily dose of disulfiram which will elicit the alcohol-antabuse reaction is 125 mg. Exposure to 30 mg. per c.m. CSj! for an 8-hour day results in absorption of approxibe mately 30 mg. per day, the same amount which should produced from 125 mg. of disulfiram.7,10 Vertin 11 has studied a group of viscose rayon workers exposed to this . CS2 concentration. They experienced a much higher rate of cardiovascular disease (11% v. 3%) than controls during a 5-year observation period. The complete syndrome of CS2 atherosclerosis involves renal, cerebral, and myocardial sclerosis, with more than twice as many deaths from coronary-artery disease in workers chronically exposed to higher CSz levels.9 Thus, the risk of atherosclerotic disease should increase with prolonged disulfiram use. Recent evidence suggests that severe alcoholism has a hereditary component, and some alcoholics respond well to disulfiram. 12, 13 These and other alcoholic subgroups may Liddon, S. C., Satran, R. Am. J. Psych. 1967, 123, 1284. Goldstein, M. Pharm. Rev. 1966, 18, 77. Richert, D., Vanderlinde, R., Westerfeld, W. J. biol. Chem. 1950, 186, 261. 4. Cahill, C. A. New Engl. J. Med. 1972, 287, 935. 5. Child, G., Crump, M. Acta pharm. tox. 1952, 8, 305. 6. Merlevede, E., Casier, H. Archs int. Pharmacodyn. Thér. 1961, 132, 1. 2. 3.
427. 7.
"
clearly... ". I may be over-reacting to Dr Richardson’s brief preview of her forthcoming paper, but, from what we have been
or
Department of Child Health, University of Manchester, Medical School, Oxford Road, Manchester M13 9PT.
8. 9. 10. 11. 12.
13.
Rainey, J. M., Jr., Neal, R. A., Vogelfanger, R. William C. Menninger Award Address, Central Neuropsychiatric Association Annual Meeting, Ann Arbor, Michigan, U.S.A., Oct. 19, 1974. Kane, F. J. Am. J. Psych. 1970, 127, 690. Davidson, M., Feinleib, M. Am. Heart J. 1972, 83, 100. Jakubowski, M., Piotrowski, J. Toxicology of Carbon Disulphide (edited by H. Brieger and J. Teisinger); p. 70. Amsterdam, 1967. Vertin, P. ibid. p. 94. Goodwin, D. W., Schulsinger, F., Møller, N., Hermansen, L., et al. Archs gen. Psychiat. 1974, 31, 164. Gerrein, J. R., Rosenber, C. M., Manohar, V. ibid. 1973, 28, 798.
285
require chronic pharmacotherapy as part of their treatment, intensifying the need for investigation of this possible side-effect. Department of Psychiatry, School of Medicine, Wayne State University, and Lafayette Clinic, Detroit, Michigan 48207, U.S.A. Center in Environmental Toxicology, Department of Biochemistry, School of Medicine, Vanderbilt University, Nashville, Tennessee 37235, U.S.A.
SERUM-COPPER IN SICKLE-CELL ANÆMIA SIR,—Increased serum-copper concentrations have been reported in various haematological disorders, such as
thalassasmia, aplastic anaemia, pernicious anaemia,l.2 and in the lymphoreticular disorders. There are no previous of serum-copper in sickle-cell et al.,4 using the rubeanic acid staining technique, demonstrated excessive amounts of copper granules in erythrocytes containing S haemoglobin. Copper-staining granules were absent in normal (AA) erythrocytes. The importance of the increased copper content in sickled erythrocytes is unknown. We have measured serum-copper by atomic absorption spectrophotometry in a total of 217 subjects as previously described.5 72 of them had sickle-cell anxmia (SS), 46 were cases of sickle-cell haemoglobin C disease (SC), 32 had the sickle-cell trait (AS), and the remaining 67 were
reports of
JOHN M. RAINEY, JR.
R. A. NEAL.
A NEW SPECIES OF MICROFILARIA ? eastern zone of the Indian subcontinent is endemic area of filariasis, which is particularly common in West Bengal, Orissa, and Assam. In West Bengal, the common infecting species of microfilaria is Wuchereria bancrofti. Similar species of microfilaria has been detected in the district of Bankura, in the western mountainous region of West Bengal. Besides W. bancrofti a new species of microfilaria has often been seen in the peripheral blood of patients in this district. The microfilaria is a sheathed one and commonly found in the blood during daytime. Although the size, shape, and arrangement of the somatic
SiR,—The
an
SERUM-COPPER LEVELS IN
nuclei of this newly isolated species are similar to those of W. bancrofti, the cuticular structure is striated transversely from the head to tail. These striations are seen clearly under phase-contrast microscope and distinctly noticed after Giemsa or Leishman stain (see accompanying figure). Further serological study will help to confirm this newly isolated species of microfilaria. The clinical signs and symptoms produced by infection with this particular species of microfilaria are similar to those of classical W. bancrofti infection-fever, lymphangitis, and lymphadenitis. The disease responds to treatment with diethylcarbamazine.
INDIVIDUALS
S. K. BISWAS S. C. SAHA M. CHOUDHURY.
0.001 and f p < 0-025 when these groups normal individuals.
are
compared with
normal controls (AA). The haemoglobin types had preelectrophoresis on viously been established by low-voltage filter paper as previously described.6 The average serum-copper level in patients with SS was significantly increased in comparison with the control group (AA) (p < 0-001) (see accompanying table). Similarly, the serum-copper in patients with SC was significantly increased in comparison with normal controls (AA) (p < 0-025). The serum-copper levels in normal controls (AA) were identical with the levels in individuals carrying AS. Serum-copper in SS was significantly higher than in SC (P< 0-025). A reduction in plasma-zinc in sickle-cell ansemia has been reported 7,and copper and zinc, together with calcium,9 sodium, and potassium 10 may be involved in the maintenance of the structural integrity of the redblood-cell membrane. In the development of irreversible sickling there is a net gain in red-blood-cell calcium9 and sodium 10 and a net reduction in potassium.1O The changes’ in the serum levels of these metals could therefore provide an index of the amount of irreversible sickling that has taken place. 1. 2. 3.
4. 5. 6. 7. 8.
Department of Pathology and Bacteriology, B.S. Medical College, Bankura, West Bengal, India.
SS, SC, AND AS PATIENTS AND IN NORMAL
.
p<
Newly isolated microfilaria showing transverse striations (Leishman x 400).
measurements
anasmia, although Schaeffer
9. 10.
Cartwright, G. E., Hugnley, C. M., Ashenbrucker, H., Fay, J., Wintrobe, M. M. Blood, 1948, 3, 501. Prasad, A. S., Diwany, M., Gabr, M., Sandstead, H. H., Mohktar, N., Hefny, A. E. Ann. intern. Med. 1965, 62, 87. Hrgovcic, M., Tessmer, C. F., Minckler, T. M., Mosier, B., Taylor, G. Cancer, 1968, 21, 743. Schaeffer, K., Lofton, J. A., Powell, S. C., Osborne, H. H., Foster, L. H. Proc. Soc. exp. Biol. Med. 1968, 128, 734. Olatunbosun, D. A., Adeniyi, F. A., Adadevoh, B. K. J. Obstet. Gynœc. Br. Commonw. 1973, 80, 937. Isaacs, W. A. D.M. thesis, University of Oxford, 1971. Serjeant, G. R., Galloway, R. E., Gueri, M. C. Lancet, 1970, ii, 891. Karayalcin, G., Rosner, F., Kim, K. Y., Chandra, P. ibid. 1974, i, 217. Eaton, J. W., Skelton, T. D., Swofford, H. S., Koplin, C. E., Jacobs, H. S. Nature, 1973, 246, 105. Hellerstein, S., Bunthrarungroj, T. J. Lab. clin. Med. 1974, 83, 611.