- Email: [email protected]
LOW-DOSE RADIATION
161
experiments in rats have demonstrated that the interferoninducing agents Bordetella pertussis vaccine and the synthetic polynucleotide poly-rI.rC cause a fourfold increase in phenytoin half-life and a decrease in phenytoin hydroxylation by cytochrome P-450 dependent mixed-function oxidase in the liver.4 Since the half-life of theophylline is at least partially dependent on oxidation by cytochrome P-4505 the observations of Chang et al. are consistent with what we have observed in animals. Therefore our hypothesis that agents (infectious or otherwise) which can induce the formation of interferon also decrease the oxidation of drugs in the liver appears to hold good for man. This raises the interesting possibility that in man
many other agents which induce the formation of inter-
feron, including certain viruses, bacteria, and vaccines, will alter drug biotransformation and elimination. Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada B3H
4H7.
KENNETH W. RENTON
UPTAKE OF 14C-DOPAMINE IN PLATELETS OF HUNTINGTON’S CHOREA PATIENTS AND SYMPTOM-FREE OFFSPRING
SIR,-Altered metabolism of brain dopamine may be one of the factors explaining the pathophysiology of choreic movements.’,2 A reduced dopamine concentration has been demonstrated in the caudate nucleus of Huntington’s chorea patients.3,4 Taking blood platelets as a readily accessible model of brain synaptosomal function, Aminoff et al. found that platelet-rich plasma from patients with Huntington’s chorea took up significantly more dopamine than did control plasma. Since there is no satisfactory test to determine whether any of the offspring of an affected patient have inherited the disease before it becomes clinically apparent, Aminoff et al. suggested that their observations might be of value as a predictive test in individuals at risk of Huntington’s chorea. We have studied the uptake of dopamine in platelets of patients with Huntington’s chorea and their symptom-free offspring in an attempt to evaluate this problem.
LOW-DOSE RADIATION
SIR,-Dr Mole6 has wisely drawn attention
to the fact that of "bone-marrow" cancers (myeloma and myeloid leukxmia) among Hanford employees in the analysis carried out by Stewart and her coworkers,7 this excess was more than compensated by a large deficit in deaths ascribed to other neoplasms of the reticuloendothelial system. An additional reason for being cautious in interpreting this initial analysis of the Hanford data is that, although Stewart et al. classified "observed" deaths by the 8th revision of the International Classification of Diseases (I.C.D.), they classified "expected" deaths according to the 7th revision. This had the effect of greatly increasing the apparent excess of deaths due to myeloid leukaemia, since under the rules of the 7th revision any form of acute leukxmia (many of which are of the myeloid type) was ascribed to "other" leukaemia (I.C.D. 204.3). On recalculation using ,the 7th revision for observed as well as expected,8 and adjusting for the age distribution of the Hanford deaths (which Mancuso et al. had failed to do) the excess of 3 ’2myeloid leuksemia cited by Mole is reduced to 1.4.9 Doubtless much remains to be learned from the experience of the Hanford employees and of similar groups handling radioactive materials, but in the present highly emotional climate the data will need to be analysed with unusual care and detachment if wise conclusions are to be reached.
although
there
was
an
apparent
excess
of Preventive Medicine and Biostatistics,
Department
Faculty of Medicine, University of Toronto, Toronto, Canada M5S 1A8.
TERENCE W. ANDERSON
MALLORY-WEISS SYNDROME
SIR,-Your editorial’° emphasises the role of fibreoptic in the diagnosis of the Mallory-Weiss syndrome. I think that it should also be mentioned that this condition may in fact be produced by endoscopy. One of the most spectacular tears I have seen I produced myself in a patient who retched violently during the procedure. He made an uneventful recovery on conservative management, and did not require bloodtransfusion.
endoscopy
Derbyshire Royal Infirmary, Derby DE1 2QY
G. K. T. HOLMES
Renton, K. W. Proc. Can. Fed. biol. Soc. 1978, 21, 159. Aranda, J. V., Sitar, D. S., Parsons, W. D., Loughan, P. M., Neims, New Engl. J. Med. 1976, 295, 413. 6. Mole, R H. Lancet, 1978, i, 1155. 7. Mancuso, I F., Stewart, A , Kneale, G. Hlth Phys. 1977, 33, 369.
4. 5.
8. Stewart, A. Personal communication. 9. Anderson, T. W Hlth Phys. in the press) 10. Lancet, 1978, i, 1294.
A. H.
UPTAKE OF
CHOREA
14C-DOPAMINE PATIENTS,
IN PLATELETS OF
THEIR
OFFSPRING,
HUNTINGTON’S
AND CONTROLS
Figures in parentheses represent number of individuals studied.
Venous blood was collected in the fasting state between 8 and 9 A.M. in plastic syringes, and platelet-rich plasma was prepared.b Within 2 h of blood-sampling platelet uptake of l4C-dopamine (Amersham-Searle) was determined.7 After 10 min of preincubation, 14C-dopamine was added to platelet-rich plasma and incubated for 30 min at 37°C. Platelets were isolated by centrifugation and the radioactivity determined by liquid scintillation spectrometry. Platelets were counted in platelet-rich plasma microscopically (Neubauer Hemocytometers). Dopamine uptake was expressed in nmol 14C-dopamine per 10" platelets. The final concentrations of 14C-dopamine used were 1, 10, and 100 mol/1. The control group matched the patients as well as the symptom-free offspring for age within a decade. We included in our results individuals of either sex because no sex difference in platelet dopamine uptake had been found in a large number of normal subjects studied previously. None of the patients had received drugs known to influence dopamine metabolism. Informed consent was obtained in all cases. Statistical analysis was by Student’s t test. The results are given in the table. No difference in dopamine uptake was seen between the Huntington’s chorea patients and controls. Nor did the values of the offspring differ from those of normal or choreic patients. Thus we could not confirm the findings of Aminoff et al. The normal dopamine uptake found in the offspring makes it unKlawans, H. L. Eur. Neurol. 1970, 4, 148. Bonilla, E. Psych. Forum, 1976, 6, 45. Barbeau, A. ibid. 1973, 4, 8. Bernheimer, H., Birkmayer, W., Hornykiewicz, O, Jellinger, K., Seitelberger, F. J. neurol. Sci. 1973, 20, 415. 5. Aminoff, M. J., Trenchard, A., Turner, P., Wood, W. G., Hills, M. Lancet, 1974, ii, 1115. 6. Boullin, D. J., O’Brien, R. A. Br. J. Pharmac. 1971, 42, 114. 7. Barbeau, A., Campanella, G., Butterworth, R. F., Yamada, K. Neurology, 1975, 25, 1.
1. 2. 3. 4.
experiments in rats have demonstrated that the interferoninducing agents Bordetella pertussis vaccine and the synthetic polynucleotide poly-rI.rC cause a fourfold increase in phenytoin half-life and a decrease in phenytoin hydroxylation by cytochrome P-450 dependent mixed-function oxidase in the liver.4 Since the half-life of theophylline is at least partially dependent on oxidation by cytochrome P-4505 the observations of Chang et al. are consistent with what we have observed in animals. Therefore our hypothesis that agents (infectious or otherwise) which can induce the formation of interferon also decrease the oxidation of drugs in the liver appears to hold good for man. This raises the interesting possibility that in man
many other agents which induce the formation of inter-
feron, including certain viruses, bacteria, and vaccines, will alter drug biotransformation and elimination. Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada B3H
4H7.
KENNETH W. RENTON
UPTAKE OF 14C-DOPAMINE IN PLATELETS OF HUNTINGTON’S CHOREA PATIENTS AND SYMPTOM-FREE OFFSPRING
SIR,-Altered metabolism of brain dopamine may be one of the factors explaining the pathophysiology of choreic movements.’,2 A reduced dopamine concentration has been demonstrated in the caudate nucleus of Huntington’s chorea patients.3,4 Taking blood platelets as a readily accessible model of brain synaptosomal function, Aminoff et al. found that platelet-rich plasma from patients with Huntington’s chorea took up significantly more dopamine than did control plasma. Since there is no satisfactory test to determine whether any of the offspring of an affected patient have inherited the disease before it becomes clinically apparent, Aminoff et al. suggested that their observations might be of value as a predictive test in individuals at risk of Huntington’s chorea. We have studied the uptake of dopamine in platelets of patients with Huntington’s chorea and their symptom-free offspring in an attempt to evaluate this problem.
LOW-DOSE RADIATION
SIR,-Dr Mole6 has wisely drawn attention
to the fact that of "bone-marrow" cancers (myeloma and myeloid leukxmia) among Hanford employees in the analysis carried out by Stewart and her coworkers,7 this excess was more than compensated by a large deficit in deaths ascribed to other neoplasms of the reticuloendothelial system. An additional reason for being cautious in interpreting this initial analysis of the Hanford data is that, although Stewart et al. classified "observed" deaths by the 8th revision of the International Classification of Diseases (I.C.D.), they classified "expected" deaths according to the 7th revision. This had the effect of greatly increasing the apparent excess of deaths due to myeloid leukaemia, since under the rules of the 7th revision any form of acute leukxmia (many of which are of the myeloid type) was ascribed to "other" leukaemia (I.C.D. 204.3). On recalculation using ,the 7th revision for observed as well as expected,8 and adjusting for the age distribution of the Hanford deaths (which Mancuso et al. had failed to do) the excess of 3 ’2myeloid leuksemia cited by Mole is reduced to 1.4.9 Doubtless much remains to be learned from the experience of the Hanford employees and of similar groups handling radioactive materials, but in the present highly emotional climate the data will need to be analysed with unusual care and detachment if wise conclusions are to be reached.
although
there
was
an
apparent
excess
of Preventive Medicine and Biostatistics,
Department
Faculty of Medicine, University of Toronto, Toronto, Canada M5S 1A8.
TERENCE W. ANDERSON
MALLORY-WEISS SYNDROME
SIR,-Your editorial’° emphasises the role of fibreoptic in the diagnosis of the Mallory-Weiss syndrome. I think that it should also be mentioned that this condition may in fact be produced by endoscopy. One of the most spectacular tears I have seen I produced myself in a patient who retched violently during the procedure. He made an uneventful recovery on conservative management, and did not require bloodtransfusion.
endoscopy
Derbyshire Royal Infirmary, Derby DE1 2QY
G. K. T. HOLMES
Renton, K. W. Proc. Can. Fed. biol. Soc. 1978, 21, 159. Aranda, J. V., Sitar, D. S., Parsons, W. D., Loughan, P. M., Neims, New Engl. J. Med. 1976, 295, 413. 6. Mole, R H. Lancet, 1978, i, 1155. 7. Mancuso, I F., Stewart, A , Kneale, G. Hlth Phys. 1977, 33, 369.
4. 5.
8. Stewart, A. Personal communication. 9. Anderson, T. W Hlth Phys. in the press) 10. Lancet, 1978, i, 1294.
A. H.
UPTAKE OF
CHOREA
14C-DOPAMINE PATIENTS,
IN PLATELETS OF
THEIR
OFFSPRING,
HUNTINGTON’S
AND CONTROLS
Figures in parentheses represent number of individuals studied.
Venous blood was collected in the fasting state between 8 and 9 A.M. in plastic syringes, and platelet-rich plasma was prepared.b Within 2 h of blood-sampling platelet uptake of l4C-dopamine (Amersham-Searle) was determined.7 After 10 min of preincubation, 14C-dopamine was added to platelet-rich plasma and incubated for 30 min at 37°C. Platelets were isolated by centrifugation and the radioactivity determined by liquid scintillation spectrometry. Platelets were counted in platelet-rich plasma microscopically (Neubauer Hemocytometers). Dopamine uptake was expressed in nmol 14C-dopamine per 10" platelets. The final concentrations of 14C-dopamine used were 1, 10, and 100 mol/1. The control group matched the patients as well as the symptom-free offspring for age within a decade. We included in our results individuals of either sex because no sex difference in platelet dopamine uptake had been found in a large number of normal subjects studied previously. None of the patients had received drugs known to influence dopamine metabolism. Informed consent was obtained in all cases. Statistical analysis was by Student’s t test. The results are given in the table. No difference in dopamine uptake was seen between the Huntington’s chorea patients and controls. Nor did the values of the offspring differ from those of normal or choreic patients. Thus we could not confirm the findings of Aminoff et al. The normal dopamine uptake found in the offspring makes it unKlawans, H. L. Eur. Neurol. 1970, 4, 148. Bonilla, E. Psych. Forum, 1976, 6, 45. Barbeau, A. ibid. 1973, 4, 8. Bernheimer, H., Birkmayer, W., Hornykiewicz, O, Jellinger, K., Seitelberger, F. J. neurol. Sci. 1973, 20, 415. 5. Aminoff, M. J., Trenchard, A., Turner, P., Wood, W. G., Hills, M. Lancet, 1974, ii, 1115. 6. Boullin, D. J., O’Brien, R. A. Br. J. Pharmac. 1971, 42, 114. 7. Barbeau, A., Campanella, G., Butterworth, R. F., Yamada, K. Neurology, 1975, 25, 1.
1. 2. 3. 4.