929
quarian interest? If we read Delacroix it is for his diary, and Whistler for his wit. Ruskin writes superbly about the role of iron in art and in nature ("we cannot even blush without its help") though we do not go to him for physiology, but perhaps he hardly counts as a painter anyway. So I am not suggesting that we should continue to read the ancients only because in their writings we can find the first statements of so many of the beliefs that we hold today, such as tha matter is atomic, that the brain is a great gland, and that the substance that activates the muscles travels down the nerves. I cannot deny, though, the sense of pleasurable superiority that hindsight bestows. Had Arthur Keith carefully considered Harvey’s beautiful description of the temporal sequence of the cardiac contraction, the motion appearing to begin from the auricles and to extend to the ventricles, and his almost poetic account of the dying heart (all other parts being at rest and dead, the right auricle still beats) he might have found the sinoauricular node earlier, by design, rather than later by accident.4 Or if someone had read Lower on the effects on the venous return in the pregnant woman of "the pressure of the uterine mass on the vena cava and both iliacs in the pelvis" more perceptively, the supine hypotension syndrome might have been described much earlier, and we would have been spared the nonsensical theories about the peculiar susceptibility to anaathetics during pregnancy that my generation was taught, and many deaths. Dormandy likens a great work of science to the food at a banquet. If I might take up his analogy I would suggest that the attitude he describes-that only the immediately assimilable is important, an attitude that concentrates on the essence and rejects the fibre-is responsible for the cerebral diverticulosis that afflicts so many today. Of course, as for the appreciation of art, some preparation and guidance is necessary, but in Garrison we have our Gombrich, in Cumston our Clark, and our Panofsky in Pagel. Finally, a good reason for reading the works of the great scientists is that they have said it all before, and so much better. I would recommend to your readers Stillman Drake’s most apposite, eloquent, and informative introduction to his translation of Galileo’s astronomical discoveries, and will end with the following quotation: "If modern physicists care nothing for the works of Galileo, that is of taste and not merely of progress. Modern poets still read Homer, and modern philosophers Plato, not only because those works are excellently written but because they throw light upon the origins of poetry and philosophy-matters of special interest to poets and philosophers, and not without a certain value and attraction to the rest of us. Similarly the works of Galileo are well written, and throw light upon the origins of modern science; hence, even if few physicists are interested in them today, it does not necessarily follow that no one else ought to be."5 a matter
Now read on. Enfield District
Hospital,
Enfield, Middx. EN2 8LJ
DAVID ZUCK
CLONIDINE IN OPIATE WITHDRAWAL
SiR,—We have given clonidine 5 p.g/kg to five male opiate addicts after withdrawal of 15-50 mg chronic methadone treatment. They had been addicted to opiates for 6-10 years and on methadone for 6-60 months. All gave informed consent to the study which required a 2-day phased withdrawal from methadone before admission to the research unit and at least 36 h without opiates. All had signs of opiate withdrawal, and urine specimens showing residual methadone only. A nurse recorded objective signs of opiate withdrawal every 30 min from 8 A.M. while the patients were at bed rest. At 11 A.M. and 1 P.M. the patients were given clonidine or placebo in matching capsules. Neither the patient nor his nurse or physician knew the order of administration.
Withdrawal symptoms after clonidine
(C) and placebo (P).
The severity of opiate withdrawal increased during the baseline period. After clonidine, withdrawal signs rapidly disappeared (see figure). All patients reported dramatic relief of distress. Placebo had no effect. Four patients were offered clonidine alone on discharge. All chose it rather than methadone. The first patient studied also chose outpatient clonidine, but was given 5 mg methadone as well having previously been on 25 mg methadone daily. All patients took 5 g/kg clonidine orally twice daily for a week. The only complaint was occasional sleep difficulty, and there were no signs of withdrawal. All of these patients had made previous unsuccessful attempts to withdraw from methadone. So far the four patients treated with clonidine alone for a week after hospital discharge are opiate-free and doing well. We tried clonidine because of the possibility of a noradrenergic mechanism being responsible for opiate withdrawal, as suggested by studies on a major brain noradrenergic nucleus, the locus coeruleus, in monkeys. The effects of electrical or pharmacological activation of this nucleusl-4 were strikingly similar to those noted after opiate withdrawal. Both morphine and clonidine blocked the effects of activation of the locus cceruleus1,4 in primates, correlating with the time course of decreased 1. Gold, M. S., Redmond, D. E., Jr. Neuroscience, 1977, 3, 250 (abstr). 2. Redmond, D. E., Jr., Huang, Y. H., Gold, M. S. ibid. 1977, 3, 258. 3. Redmond, D. E., Jr., Huang, Y. H., Snyder, D. R., Maas, J. W. Brain Res.
1976, 116, 502. 4. Keith, A. An Autobiography; p. 258. London, 1950. 5. Drake, S. Discoveries and Opinions of Galileo. New York,
1957.
4. Redmond, D. E., Jr. in Animal Models in Psychiatry and by I. Hanin and E. Usdin); p. 293. Oxford, 1977.
Neurology (edited
930 neuronal activity in the locus creruleus5-7 and decreased noradrenaline release.8.9 While clonidine and the opiates have similar effects on the locus coeruleus, clonidine appears to exert specific effects through non-opiate, alpha-2 adrenergic receptors. 6, These data suggested that the opiate-withdrawal syndrome is due to increased noradrenergic neuronal activity in areas such as the locus coeruleus which are regulated both by alpha-2 adrenergic and opiate receptors. Our preliminary results in man support a noradrenergic system mediation of opiate withdrawal and suggest that clonidine may be a more definitive treatment for opiate withdrawal than others now available. Department of Psychiatry and Connecticut Mental Health Center, Yale University School of Medicine, New Haven, Connecticut 06510, U.S.A.
MARK S. GOLD D. E. REDMOND, JR H. D. KLEBER
HLA AND CONGENITAL ADRENAL HYPERPLASIA
LINKAGE CONFIRMED
SiR,--Congenital adrenal hyperplasia (c.A.H.) is an autosomal recessive disease, associated in most cases with 21-hydroxylase deficiency. 1,2 Dupont et al. suggested that the locus responsible for 21-hydroxylase deficiency is in close linkage with the HLA system. We have typed six families with one or more children with C.A.H. and report data supporting this linkage (table). HLA typing
was done by the standard two-stage National Institutes of Health lymphocytotoxicity test. 118 different sera were used to detect HLA A, B, and C antigens with the exception of CW6. In all families in which the segregation of W4 and W6 could be determined these antigens behaved as expected. In all families the segregation of the HLA haplotypes was established. Seven children with C.A.H. confirmed biochemically to be due to 21-hydroxylase deficiency were studied. The salt-losing form of 21-hydroxylase deficiency was present in four families while the remaining families (A and E) had the non-salt-losing form.
5. Svensson, T. H., Bunney, B. S., Aghajaman, G. K. Brain Res. 1975, 92, 291. 6. Cedarbaum, J. M., Aghajanian, G. K. ibid. 1976, 112, 413. 7. Cedarbaum, J. M., Aghajanian, G. K. Eur. J. Pharmac. 1977, 44, 375. 8. Braestrup, C. J. Pharm. Pharmac. 1974, 26, 139. 9. Maas, J. W., Hattox, S. E., Landis, D. H., Roth, R. H. Brain Res. 1976, 118, 167. 1. Bongiovanni, A. M., Root, A. W. New Engl. J. Med. 1963, 268, 1283. 2. New, M. I., Levine, L. S. in Advances in Human Genetics (edited by K. Hirschhorn and H. Harris); p. 251. New York, 1973. 3. Dupont, B., Oberfield, S. E., Smithwick, E. M., Lee, T. D., Levine, L. S. Lancet, 1977, ii, 1309.
In family B both children had the HLA haplotype A3, BW47. The children seemed to be HLA homozygous although the parents were not first cousins and denied any known consanguinity. Family A was ascertained through child 5, a girl with C.A.H. The HLA typing of the family showed that her oldest brother was HLA identical. This 23-year-old man was further investigated and on both clinical and biochemical grounds was considered to be homozygous for 21-hydroxylase deficiency. Thus, the diagnosis was first suggested by HLA typing and then confirmed by clinical and biochemical studies (this case will be discussed in greater detail elsewhere). In a Pakistani family (F) the parents were first cousins and the only affected child was an HLA homozygote. In this family, child 4 carried a maternal HLA A/C,B recombinant haplotype while inheriting the same paternal haplotype as the affected sib. Thus, the two children (4 and 5) are HLA indentical at the A locus but different at the C, B loci showing that the gene for C.A.H. segregated with HLA-B rather than with HLA-A since child 4 "escaped" 21-hydroxylase deficiency. In three families (C, D, and E) with two children discordant for 21-hydroxylase deficiency the affected and unaffected children were not HLA
identical. In our families and those of Dupont et al. no recombination between the HLA-B locus and the gene for C.A.H. has been found in a total of 35 children (or a total of 40 meiotic divisions including the family F first cousins). However, two recombinants between HLA A and B have been found in the twelve families. No association between particular HLA antigens and 21-hydroxylase deficiency gene occurred. These findings have implications for both prenatal and postnatal diagnosis of 21-hydroxylase deficiency. Biochemical tests, though encouraging, have not yet provided unequivocal means of diagnosis in fetal life.’ If diagnosis proves possible by the HLA typing of amniotic cells taken in the second trimester, it will allow parents with a previous previously affected child the opportunity to consider selective abortion. The ethics of abortion of a fetus with a condition amenable to postnatal treatment and compatible with life must be carefully considered. Unequivocal diagnosis in early pregnancy would make the more positive goal of prenatal treatment to prevent clitoral enlargement more feasible. HLA types of amniotic cells in late pregnancy or of cord-blood lymphocytes would supplement biochemical studies and allow early diagnosis and prompt treatment. Finally, identification of heterozygotes can be made with greater certainty thus facilitating the study of the carrier
4.
New, M. I. in Congenital Adrenal Hyperplasia (edited by P. A. Lee, L. P. Plotnick, A. A. Kowarki, and C. J. Migeon); vol. i, p. 511. Baltimore, 1977.
HLA GENOTYPES IN SIX FAMILIES WITH C.A.H.
Affected child. t 2 1-hydroxylase deficiency homozygote, clinically normal (see text). t HLA recombinant: HLA-AI,-B5/Al, Bw35,Cw4. *
F
=
father; M = mother.
quarian interest? If we read Delacroix it is for his diary, and Whistler for his wit. Ruskin writes superbly about the role of iron in art and in nature ("we cannot even blush without its help") though we do not go to him for physiology, but perhaps he hardly counts as a painter anyway. So I am not suggesting that we should continue to read the ancients only because in their writings we can find the first statements of so many of the beliefs that we hold today, such as tha matter is atomic, that the brain is a great gland, and that the substance that activates the muscles travels down the nerves. I cannot deny, though, the sense of pleasurable superiority that hindsight bestows. Had Arthur Keith carefully considered Harvey’s beautiful description of the temporal sequence of the cardiac contraction, the motion appearing to begin from the auricles and to extend to the ventricles, and his almost poetic account of the dying heart (all other parts being at rest and dead, the right auricle still beats) he might have found the sinoauricular node earlier, by design, rather than later by accident.4 Or if someone had read Lower on the effects on the venous return in the pregnant woman of "the pressure of the uterine mass on the vena cava and both iliacs in the pelvis" more perceptively, the supine hypotension syndrome might have been described much earlier, and we would have been spared the nonsensical theories about the peculiar susceptibility to anaathetics during pregnancy that my generation was taught, and many deaths. Dormandy likens a great work of science to the food at a banquet. If I might take up his analogy I would suggest that the attitude he describes-that only the immediately assimilable is important, an attitude that concentrates on the essence and rejects the fibre-is responsible for the cerebral diverticulosis that afflicts so many today. Of course, as for the appreciation of art, some preparation and guidance is necessary, but in Garrison we have our Gombrich, in Cumston our Clark, and our Panofsky in Pagel. Finally, a good reason for reading the works of the great scientists is that they have said it all before, and so much better. I would recommend to your readers Stillman Drake’s most apposite, eloquent, and informative introduction to his translation of Galileo’s astronomical discoveries, and will end with the following quotation: "If modern physicists care nothing for the works of Galileo, that is of taste and not merely of progress. Modern poets still read Homer, and modern philosophers Plato, not only because those works are excellently written but because they throw light upon the origins of poetry and philosophy-matters of special interest to poets and philosophers, and not without a certain value and attraction to the rest of us. Similarly the works of Galileo are well written, and throw light upon the origins of modern science; hence, even if few physicists are interested in them today, it does not necessarily follow that no one else ought to be."5 a matter
Now read on. Enfield District
Hospital,
Enfield, Middx. EN2 8LJ
DAVID ZUCK
CLONIDINE IN OPIATE WITHDRAWAL
SiR,—We have given clonidine 5 p.g/kg to five male opiate addicts after withdrawal of 15-50 mg chronic methadone treatment. They had been addicted to opiates for 6-10 years and on methadone for 6-60 months. All gave informed consent to the study which required a 2-day phased withdrawal from methadone before admission to the research unit and at least 36 h without opiates. All had signs of opiate withdrawal, and urine specimens showing residual methadone only. A nurse recorded objective signs of opiate withdrawal every 30 min from 8 A.M. while the patients were at bed rest. At 11 A.M. and 1 P.M. the patients were given clonidine or placebo in matching capsules. Neither the patient nor his nurse or physician knew the order of administration.
Withdrawal symptoms after clonidine
(C) and placebo (P).
The severity of opiate withdrawal increased during the baseline period. After clonidine, withdrawal signs rapidly disappeared (see figure). All patients reported dramatic relief of distress. Placebo had no effect. Four patients were offered clonidine alone on discharge. All chose it rather than methadone. The first patient studied also chose outpatient clonidine, but was given 5 mg methadone as well having previously been on 25 mg methadone daily. All patients took 5 g/kg clonidine orally twice daily for a week. The only complaint was occasional sleep difficulty, and there were no signs of withdrawal. All of these patients had made previous unsuccessful attempts to withdraw from methadone. So far the four patients treated with clonidine alone for a week after hospital discharge are opiate-free and doing well. We tried clonidine because of the possibility of a noradrenergic mechanism being responsible for opiate withdrawal, as suggested by studies on a major brain noradrenergic nucleus, the locus coeruleus, in monkeys. The effects of electrical or pharmacological activation of this nucleusl-4 were strikingly similar to those noted after opiate withdrawal. Both morphine and clonidine blocked the effects of activation of the locus cceruleus1,4 in primates, correlating with the time course of decreased 1. Gold, M. S., Redmond, D. E., Jr. Neuroscience, 1977, 3, 250 (abstr). 2. Redmond, D. E., Jr., Huang, Y. H., Gold, M. S. ibid. 1977, 3, 258. 3. Redmond, D. E., Jr., Huang, Y. H., Snyder, D. R., Maas, J. W. Brain Res.
1976, 116, 502. 4. Keith, A. An Autobiography; p. 258. London, 1950. 5. Drake, S. Discoveries and Opinions of Galileo. New York,
1957.
4. Redmond, D. E., Jr. in Animal Models in Psychiatry and by I. Hanin and E. Usdin); p. 293. Oxford, 1977.
Neurology (edited
930 neuronal activity in the locus creruleus5-7 and decreased noradrenaline release.8.9 While clonidine and the opiates have similar effects on the locus coeruleus, clonidine appears to exert specific effects through non-opiate, alpha-2 adrenergic receptors. 6, These data suggested that the opiate-withdrawal syndrome is due to increased noradrenergic neuronal activity in areas such as the locus coeruleus which are regulated both by alpha-2 adrenergic and opiate receptors. Our preliminary results in man support a noradrenergic system mediation of opiate withdrawal and suggest that clonidine may be a more definitive treatment for opiate withdrawal than others now available. Department of Psychiatry and Connecticut Mental Health Center, Yale University School of Medicine, New Haven, Connecticut 06510, U.S.A.
MARK S. GOLD D. E. REDMOND, JR H. D. KLEBER
HLA AND CONGENITAL ADRENAL HYPERPLASIA
LINKAGE CONFIRMED
SiR,--Congenital adrenal hyperplasia (c.A.H.) is an autosomal recessive disease, associated in most cases with 21-hydroxylase deficiency. 1,2 Dupont et al. suggested that the locus responsible for 21-hydroxylase deficiency is in close linkage with the HLA system. We have typed six families with one or more children with C.A.H. and report data supporting this linkage (table). HLA typing
was done by the standard two-stage National Institutes of Health lymphocytotoxicity test. 118 different sera were used to detect HLA A, B, and C antigens with the exception of CW6. In all families in which the segregation of W4 and W6 could be determined these antigens behaved as expected. In all families the segregation of the HLA haplotypes was established. Seven children with C.A.H. confirmed biochemically to be due to 21-hydroxylase deficiency were studied. The salt-losing form of 21-hydroxylase deficiency was present in four families while the remaining families (A and E) had the non-salt-losing form.
5. Svensson, T. H., Bunney, B. S., Aghajaman, G. K. Brain Res. 1975, 92, 291. 6. Cedarbaum, J. M., Aghajanian, G. K. ibid. 1976, 112, 413. 7. Cedarbaum, J. M., Aghajanian, G. K. Eur. J. Pharmac. 1977, 44, 375. 8. Braestrup, C. J. Pharm. Pharmac. 1974, 26, 139. 9. Maas, J. W., Hattox, S. E., Landis, D. H., Roth, R. H. Brain Res. 1976, 118, 167. 1. Bongiovanni, A. M., Root, A. W. New Engl. J. Med. 1963, 268, 1283. 2. New, M. I., Levine, L. S. in Advances in Human Genetics (edited by K. Hirschhorn and H. Harris); p. 251. New York, 1973. 3. Dupont, B., Oberfield, S. E., Smithwick, E. M., Lee, T. D., Levine, L. S. Lancet, 1977, ii, 1309.
In family B both children had the HLA haplotype A3, BW47. The children seemed to be HLA homozygous although the parents were not first cousins and denied any known consanguinity. Family A was ascertained through child 5, a girl with C.A.H. The HLA typing of the family showed that her oldest brother was HLA identical. This 23-year-old man was further investigated and on both clinical and biochemical grounds was considered to be homozygous for 21-hydroxylase deficiency. Thus, the diagnosis was first suggested by HLA typing and then confirmed by clinical and biochemical studies (this case will be discussed in greater detail elsewhere). In a Pakistani family (F) the parents were first cousins and the only affected child was an HLA homozygote. In this family, child 4 carried a maternal HLA A/C,B recombinant haplotype while inheriting the same paternal haplotype as the affected sib. Thus, the two children (4 and 5) are HLA indentical at the A locus but different at the C, B loci showing that the gene for C.A.H. segregated with HLA-B rather than with HLA-A since child 4 "escaped" 21-hydroxylase deficiency. In three families (C, D, and E) with two children discordant for 21-hydroxylase deficiency the affected and unaffected children were not HLA
identical. In our families and those of Dupont et al. no recombination between the HLA-B locus and the gene for C.A.H. has been found in a total of 35 children (or a total of 40 meiotic divisions including the family F first cousins). However, two recombinants between HLA A and B have been found in the twelve families. No association between particular HLA antigens and 21-hydroxylase deficiency gene occurred. These findings have implications for both prenatal and postnatal diagnosis of 21-hydroxylase deficiency. Biochemical tests, though encouraging, have not yet provided unequivocal means of diagnosis in fetal life.’ If diagnosis proves possible by the HLA typing of amniotic cells taken in the second trimester, it will allow parents with a previous previously affected child the opportunity to consider selective abortion. The ethics of abortion of a fetus with a condition amenable to postnatal treatment and compatible with life must be carefully considered. Unequivocal diagnosis in early pregnancy would make the more positive goal of prenatal treatment to prevent clitoral enlargement more feasible. HLA types of amniotic cells in late pregnancy or of cord-blood lymphocytes would supplement biochemical studies and allow early diagnosis and prompt treatment. Finally, identification of heterozygotes can be made with greater certainty thus facilitating the study of the carrier
4.
New, M. I. in Congenital Adrenal Hyperplasia (edited by P. A. Lee, L. P. Plotnick, A. A. Kowarki, and C. J. Migeon); vol. i, p. 511. Baltimore, 1977.
HLA GENOTYPES IN SIX FAMILIES WITH C.A.H.
Affected child. t 2 1-hydroxylase deficiency homozygote, clinically normal (see text). t HLA recombinant: HLA-AI,-B5/Al, Bw35,Cw4. *
F
=
father; M = mother.
