- Email: [email protected]
STRUCTURAL AND CONTROL GENE DEFECTS IN HEREDITARY DISEASES IN MAN
1066
interesting prediction which emerges from this hypothesis is that more affected males than females would be expected. A reliable estimate of the sex ratio in Down’s syndrome is not easy to obtain, but there is apparently sound evidence that boys do in fact exceed girls in a ratio An
FINDINGS IN TWO CARRIERS OF SEX-LINKED DUCHENNE MUSCULAR DYSTROPHY
of at least 4 to 3.2
sample investigated in the present study is relatively Those with access to larger samples may be encouraged to pursue the investigation further. The small.
This work was supported by N.I.H. grants MH-07820-01 (A. R. Kaplan and R. Fischer, principal investigators) and GRS-05563 (to the Cleveland Psychiatric Institute). The generous cooperation of Dr. Steven Zsako, of the Euclid Clinic Foundation, is gratefully acknowledged.
Department of Medical Genetics, Cleveland Psychiatric Institute, Cleveland, Ohio 44109, U.S.A.
EDWARD V. GLANVILLE.
MANIFESTATIONS IN CARRIERS OF X-LINKED MUSCULAR DYSTROPHY
Duchenne muscular dystrophy has been described in a female who was shown to have an XO sex-chromosome constitution.3 We recently reported two carriers of X-linked Duchenne muscular dystrophy who had definite muscle weakness,4 and it was suggested that the muscle weakness in these carriers might be the result of XO/XX mosaicism.5 Chromosome studies performed on peripheral leucocytes and skin fibroblasts in these two women showed a modal number of 46 with XX sex-chromosome constitution. The percentage of sex-chromatin-positive cells in the buccal smears and percentage of drumsticks in polymorph leucocytes were both consistent with an XX sex-chromosome constitution. These findings do not completely exclude the possibility of XO/XX mosaicism in these two manifesting heterozygotes, but they make it unlikely. A more reasonable explanation, for manifestations in female carriers of such X-linked disorders as Duchenne muscular dystrophy is the Lyon hypothesis concerning gene action in the X chromosome.4
SIR,- Typical
Thirteen female carriers of benign X-linked muscular have been examined but no clinical evidence of any muscle disease was found. However in twenty-four carriers of Duchenne muscular dystrophy, the calves were enlarged not only in the two carriers with muscle weakness but also in a third carrier with no clinical evidence of any muscle weakness. Enlarged calves in this third carrier may represent true hypertrophy or may be a minor manifestation of muscle disease. The latter possibility seems likely since her serum-creatinekinase level was higher than in any of the other carriers, except one with muscle weakness. The finding of muscle weakness in two out of twenty-four carriers of Duchenne muscular dystrophy was probably fortuitous, but there have been several reports of clinical manifestations in carriers of X-linked muscular dystrophy, 6-14 and muscle weakness may be commoner than is generally recognised. In the absence of a family history of Duchenne muscular dystrophy, such a manifesting heterozygote might be classified as either an apparent case of the autosomal recessive
dystrophy
2. Hug, E. Ann. Pœdiat. 1951, 177, 31. 3. Walton, J. N. Acta. genet. 1957, 7, 318. 4. Emery, A. E. H. Lancet, 1963, i, 1126. 5. Watkins, G. ibid. 1963, ii, 92. 6. Chung, C. S., Morton, N. E., Peters, H. A. Amer.J. hum. Genet. 1960, 12, 52. 7. Dubowitz, V. Proc. R. Soc. Med. 1963, 56, 810. 8. Fraser, F. C. Amer. J. Med. 1963, 34, 585. 9. Garcia del Rio, C., Alaba, J. Clin. y Lab. 1960, 69, 424. 10. Kryschowa, N., Abowjan, W. Z. ges. Neurol. Psychiat. 1934, 150, 421. 11. Levison, H. Acta psychiat. Kbh. 1951, suppl. 76. 12. Murphy, E. G. Symposium on Muscle Structure and Function, Edmonton, Alberta, 1964. 13. Sidler, A. Arch. Klaus-Stift Vererb Forsch. 1944, 19, 213. 14. Walton, J. N. Brit. med. J. 1964, i, 1344.
dystrophy resembling the Duchenne type if severely affected, or as an apparent case of limb-girdle muscular dystrophy if less severely affected. The distinction between a manifesting heterozygote of X-linked muscular dystrophy and a case of limb-girdle muscular dystrophy is important in genetic counselling. Limb-girdle muscular dystrophy is usually due to a rare autosomal recessive gene; hence unless an affected woman marries a heterozygous male (an unlikely event) the chances of her having an affected child are small. If she is a manifesting heterozygote of X-linked muscular dystrophy form of muscular
however, the chances
are that on average half her sons will be affected and half her daughters will be carriers. In any event, the prognosis for affected offspring in the two cases would be very different.
Unfortunately there is as yet no chemical or other test which will distinguish between a manifesting heterozygote of X-linked muscular dystrophy and a case of limb-girdle muscular dystrophy. This work was supported by grant GM-10, 189 of the U.S. Public Health Service and by a grant from the Muscular Dystrophy ’
Association of America. Division of Medical Genetics, Department of Medicine, Royal Infirmary, Manchester. Division of Medical Genetics, Johns Hopkins University, School of Medicine, Baltimore, Maryland.
ALAN E. H. EMERY
CATHERINE S. N. LEE.
STRUCTURAL AND CONTROL GENE DEFECTS IN HEREDITARY DISEASES IN MAN
SIR,-Since the pioneer work ofacob and Monod1 the control of enzyme formation in bacteria, it has become quite fashionable to interpret hereditary human diseases in terms of regulator or operator (" control ") gene mutations. Quite often, elaborate schemes are advanced in an attempt to explain otherwise uninterpretable observations. Although control genes and control-gene mutations may exist in man, this has not yet been proved, and the extent of their possible resemblance to the bacterial systems is unknown. Moreover, some qualifications should be considered in applying the concept of control-gene mutation to human disease: on
1. In mammalian systems induction is considerably slower than in bacteria, and the messenger R.N.A. seems to be longerlived. Mammalian induction, when hormonally stimulated, is generally much less specific than the substrate induction in bacteria.2 Again, whereas true metabolite repression does seem to exist in mammalian cells,8 true substrate induction has not been unequivocally demonstrated. There are situations (e.g., induction of tryptophan pyrollase by tryptophan or of thymidylate kinase by thymidine) in which the apparent substrate induction represents substrate protection of the enzyme against degradation, or activation of inactive precursors, rather than an’ increase in enzyme synthesis.2 45 2. In many human inborn errors of metabolism, the genedosage effect in heterozygous carriers may be regarded as Jacob, F., Monod, J. J. mol. Biol. 1961, 3, 318. Schimke, R. T., Sweeney, E. W., Berlin, C. M. Biochem. biophys. Res. Commun. 1964, 15, 214. 3. Schimke, R. T. J. biol. Chem. 1964, 239, 136. 4. Hiatt, H. H., Bojarski, T. B. Cold Spr. Harb. Symp. quant. Biol. 1961, 26, 367. 5. Rosen, F., Milholland, R. J. J. biol. Chem. 1963, 238, 3730. 1. 2.
1067 evidence against the existence of effective genetic control systems for the particular enzymes concerned. In these conditions (including methaemoglobinaemia due to diaphorase deficiency, galactossmia, acatalasia, haemolytic anaemia due to pyruvate-kinase deficiency, and glycogen-storage disease due to deficiency of debranching enzyme), enzyme activities or (in
protein levels in the erythrocytes, leucocytes, heterozyotes are about half those of the cells of healthy persons. 6-12 Therefore, for this group of intracellular enzymes, the enzyme levels found in healthy persons do not seem to be maintained by control systems concerned with the regulation of either the amount of enzyme activity or the a
few instances) fibroblasts of
or
amount of enzyme
protein.
For extracellular proteins, the situation is more complex. The synthesis of some proteins-for example, albumin-seems to be well regulated 13 (probably by means of serum osmotic whereas that of others, particularly the clotting pressure),14 factors 15-20 and pseudocholinesterase,21 may not be. In the latter instances, the heterozygotes for protein deficiencies often have significantly diminished levels of the circulating proteins 17 as estimated in terms of activity or, as in afibrinogenaemia and pseudocholinesterase deficiency,21 immunochemically. 3. A structural gene mutation can result in the synthesis of " a defective " protein in normal or reduced amounts, and the defect may be either in the enzymic or the structural properties of the protein. In addition, such a mutation can cause the synthesis of a non-recognisable protein or can completely prevent synthesis of the protein-both situations producing the same phenotypic result. If the concept evolved to explain " polarity mutations " 22 is correct, a structural gene mutation can also alter the rate of protein synthesis. Therefore, before an explanation entailing a structural gene mutation can be discarded in favour of one entailing mutation of a control gene, the protein must be shown to be unaltered in sequence, or, preferably, the mutation must be localised to a site outside the structural gene locus by genetic mapping (a procedure which, unfortunately, is not yet possible in man). 4. Increases in enzyme activity can be explained by structural gene mutations of several types: (a) the mutant enzyme has a higher specific activity; (b) the mutant enzyme is not effectively inhibited by its normal inhibitors; (c) the enzyme is less vulnerable to degradation, or (d) the enzyme is synthesised at a greater than normal rate. To determine the cause of an increase in activity it is necessary, therefore, to determine whether there is an actual increase in the quantity of enzyme present, whether there is an increase in the rate of its synthesis, and whether the enzyme is normal in structure.
hereditary diseases in man, hypotheses based structural gene mutations will adequately explain the known facts. In view of our lack of knowledge about human control-gene systems, the possibilities of structural gene mutations (as well as of other more complex genetic accidents) should not be summarily dismissed without experimental evidence to the contrary. In many
on
National Institute of Arthritis and Metabolic Diseases, Bethesda, Maryland 20014, U.S.A.
CHARLES
J. EPSTEIN.
Scott, E. M. J. clin. Invest. 1960, 39, 1176. Schwartz, V., Wells, A. R., Holzel, A., Komrower, G. M. Ann. hum. Genet. 1962, 25, 179. 8. Ogata, M., Takahara, S. Proc. Jap. Acad. 1963, 39, 783. 9. Krooth, R. S., Howell, R. R., Hamilton, H. B. J. exp. Med. 1962 115, 6. 7.
313.
10. 11. 12. 13. 14.
Oski, F. A., Diamond, L. K. New Engl. J. Med. 1963, 269, 763. Williams, H. E., Kendig, E. M., Field, J. B.J. clin. Invest. 1963, 42, 656 Aebi, H. Abstr. Int. Congr. Biochem. 1964, 3, 225. Bennhold, H. Verh. dtsch. Ges. inn. Med. 1956, 62, 657. Rothschild, M. A., Oratz, M., Wimer, E., Schreiber, S. S.J. clin. Invest. 1961, 40, 545. 15. Voss, D., Waaler, B. Thrombos. Diathes. hœmorrh. Stuttgart, 1959,3,375. 16. Graham, J. B., Barrow, E. M., Houghie, C.J. clin. Invest. 1957, 36, 497. 17. Gross, R., Schwick, A., Lang, N., Nies, D., Rahn, B., Becker, M., Hengstmann, H. Klin. Wschr. 1963, 41, 695. 18. Didisheim, P., Vanderwoort, R. L. E. Blood, 1962, 20, 150. 19. Bradlow, B. S. Afr. J. med. Sci. 1962, 27, 51. 20. Lewis, J. H., Didisheim, P., Ferguson, J. H., Li, C. C. Amer. J. hum.
Genet. 1963, 15, 53. 21. Hodgkin, W. E., Giblett, E. R., Levine, H., Motulsky, A. G. Program of American Society of Human Genetics, New York, July
19-21, 1963, p. 15.
22. Ames,
B., Hartman, P. Cold Spr.
Harb.
Symp. quant. Biol. 1963, 28,
349.
TREATMENT OF CHRONIC TENSION HEADACHE SIR,-The status of amitriptyline and other drugs for treatment of tension headache is not established with any precision in the paper by Dr. Lance and Dr. Curran.1 The only interesting, statistically significant difference was obtained by combining patients on amitriptyline and imipramine into one group, to be compared with another group made up of patients on ’Librium ’ (chlordiazepoxide) or ’Bellergal ’. The pairing of the latter two has resulted in a meaningless significant difference. The facts of the study are that amitriptyline is not significantly better than imipramine, bellergal, or librium, and that neither bellergal nor librium is significantly better than placebo (2 x 2 x2 test). Furthermore the claimed significance for the difference between the placebo and the combined bellergal and librium groups must rest on an error of calculation. As X2 (2 x 2) for this difference equals 0’87 (p > 0.7), it is unlikely that some more refined procedure from the authors’ stated statistical guide could have shown a significant result. Finally, the statement that diazepam was effective is not supported by the tabular data (X2=0.8 for its comparison with ’
placebo; p=0-3). I suggest that the relative effectiveness of the drugs still remains to be decided. Despite the authors’ rejection of the hypothesis that depressive illness was a factor in their results, one would expect study of the psychopathology of patients presenting with chronic headache of long duration to produce interesting results. It is suggested, for instance, by Nodine and Moyer2 that an analgesic, sedative, and tranquilliser combination is the best symptomatic treatment, but that preventive treatment is best accomplished
by psychotherapy. Mental Health Research Institute, Royal Park, Victoria, Australia.
NORMAN F. HOLT.
PSYCHIATRIC UNITS IN GENERAL HOSPITALS
SIR,-Iam grateful to Dr. Leyberg for emphasising (Oct. 10) the need for psychiatric units to work closely with the local authority as this was given insufficient emphasis in my article (Sept. 26). I was grateful, too, for his stressing the desirability of the unit being fully integrated into the work of the general hospital, as this was challenged by Dr. Cohen and Dr. Haldane (Oct. 24). Re-reading their articleII found that the sort of autonomy they were seeking was apparently far greater than that which they called for in their letter; originally Dr. Haldane4 asked for an initial period not only of medical but of administrative and nursing autonomy. I was glad to read that their views have been modified so much; even so, I suggest that a casualty officer who is adequately briefed by, and in close touch with, his psychiatric colleagues should be competent enough to decide, on most occasions, which patients are suitable for admission to the psychiatric unit. Integration does not mean dictation of therapy by a specialist in physical medicine, and I cannot understand why Dr. Cohen and Dr. Haldane have chosen to make this particular interpretation. Dr. Cohen and Dr. Haldane have, I think, misread the paragraph on medical staffing, as the comment on what might seem over-generous staffing did not apply to consultants only. The proposal of four and a half doctors for a sixty-bed unit is the same number that Dr. Cohen and Dr. Haldane have for a fifty-four bed unit. Regrettably there will be a discrepancy for 5 many years between what is desirable and what is available.5 On reflection, I do agree that the number of consultant sessions suggested for such a unit is too small, and makes no allowance for leave, and it would be desirable for a sixty-bed unit to be shared by two half-time consultants. ’
1. 2.
Lance, J. W., Curran, D. A. Lancet, 1964, i, 1236. Psychosomatic Medicine (edited by J. H. Nodine and J. p. 881. Philadelphia, 1962. Cohen, W. A., Haldane, F. P. Lancet, 1962, i, 1113. Haldane, F P ibid. p. 1350.
3. 4. 5. ibid.
Aug. 15, 1964, p. 352.
H.
Moyer);
interesting prediction which emerges from this hypothesis is that more affected males than females would be expected. A reliable estimate of the sex ratio in Down’s syndrome is not easy to obtain, but there is apparently sound evidence that boys do in fact exceed girls in a ratio An
FINDINGS IN TWO CARRIERS OF SEX-LINKED DUCHENNE MUSCULAR DYSTROPHY
of at least 4 to 3.2
sample investigated in the present study is relatively Those with access to larger samples may be encouraged to pursue the investigation further. The small.
This work was supported by N.I.H. grants MH-07820-01 (A. R. Kaplan and R. Fischer, principal investigators) and GRS-05563 (to the Cleveland Psychiatric Institute). The generous cooperation of Dr. Steven Zsako, of the Euclid Clinic Foundation, is gratefully acknowledged.
Department of Medical Genetics, Cleveland Psychiatric Institute, Cleveland, Ohio 44109, U.S.A.
EDWARD V. GLANVILLE.
MANIFESTATIONS IN CARRIERS OF X-LINKED MUSCULAR DYSTROPHY
Duchenne muscular dystrophy has been described in a female who was shown to have an XO sex-chromosome constitution.3 We recently reported two carriers of X-linked Duchenne muscular dystrophy who had definite muscle weakness,4 and it was suggested that the muscle weakness in these carriers might be the result of XO/XX mosaicism.5 Chromosome studies performed on peripheral leucocytes and skin fibroblasts in these two women showed a modal number of 46 with XX sex-chromosome constitution. The percentage of sex-chromatin-positive cells in the buccal smears and percentage of drumsticks in polymorph leucocytes were both consistent with an XX sex-chromosome constitution. These findings do not completely exclude the possibility of XO/XX mosaicism in these two manifesting heterozygotes, but they make it unlikely. A more reasonable explanation, for manifestations in female carriers of such X-linked disorders as Duchenne muscular dystrophy is the Lyon hypothesis concerning gene action in the X chromosome.4
SIR,- Typical
Thirteen female carriers of benign X-linked muscular have been examined but no clinical evidence of any muscle disease was found. However in twenty-four carriers of Duchenne muscular dystrophy, the calves were enlarged not only in the two carriers with muscle weakness but also in a third carrier with no clinical evidence of any muscle weakness. Enlarged calves in this third carrier may represent true hypertrophy or may be a minor manifestation of muscle disease. The latter possibility seems likely since her serum-creatinekinase level was higher than in any of the other carriers, except one with muscle weakness. The finding of muscle weakness in two out of twenty-four carriers of Duchenne muscular dystrophy was probably fortuitous, but there have been several reports of clinical manifestations in carriers of X-linked muscular dystrophy, 6-14 and muscle weakness may be commoner than is generally recognised. In the absence of a family history of Duchenne muscular dystrophy, such a manifesting heterozygote might be classified as either an apparent case of the autosomal recessive
dystrophy
2. Hug, E. Ann. Pœdiat. 1951, 177, 31. 3. Walton, J. N. Acta. genet. 1957, 7, 318. 4. Emery, A. E. H. Lancet, 1963, i, 1126. 5. Watkins, G. ibid. 1963, ii, 92. 6. Chung, C. S., Morton, N. E., Peters, H. A. Amer.J. hum. Genet. 1960, 12, 52. 7. Dubowitz, V. Proc. R. Soc. Med. 1963, 56, 810. 8. Fraser, F. C. Amer. J. Med. 1963, 34, 585. 9. Garcia del Rio, C., Alaba, J. Clin. y Lab. 1960, 69, 424. 10. Kryschowa, N., Abowjan, W. Z. ges. Neurol. Psychiat. 1934, 150, 421. 11. Levison, H. Acta psychiat. Kbh. 1951, suppl. 76. 12. Murphy, E. G. Symposium on Muscle Structure and Function, Edmonton, Alberta, 1964. 13. Sidler, A. Arch. Klaus-Stift Vererb Forsch. 1944, 19, 213. 14. Walton, J. N. Brit. med. J. 1964, i, 1344.
dystrophy resembling the Duchenne type if severely affected, or as an apparent case of limb-girdle muscular dystrophy if less severely affected. The distinction between a manifesting heterozygote of X-linked muscular dystrophy and a case of limb-girdle muscular dystrophy is important in genetic counselling. Limb-girdle muscular dystrophy is usually due to a rare autosomal recessive gene; hence unless an affected woman marries a heterozygous male (an unlikely event) the chances of her having an affected child are small. If she is a manifesting heterozygote of X-linked muscular dystrophy form of muscular
however, the chances
are that on average half her sons will be affected and half her daughters will be carriers. In any event, the prognosis for affected offspring in the two cases would be very different.
Unfortunately there is as yet no chemical or other test which will distinguish between a manifesting heterozygote of X-linked muscular dystrophy and a case of limb-girdle muscular dystrophy. This work was supported by grant GM-10, 189 of the U.S. Public Health Service and by a grant from the Muscular Dystrophy ’
Association of America. Division of Medical Genetics, Department of Medicine, Royal Infirmary, Manchester. Division of Medical Genetics, Johns Hopkins University, School of Medicine, Baltimore, Maryland.
ALAN E. H. EMERY
CATHERINE S. N. LEE.
STRUCTURAL AND CONTROL GENE DEFECTS IN HEREDITARY DISEASES IN MAN
SIR,-Since the pioneer work ofacob and Monod1 the control of enzyme formation in bacteria, it has become quite fashionable to interpret hereditary human diseases in terms of regulator or operator (" control ") gene mutations. Quite often, elaborate schemes are advanced in an attempt to explain otherwise uninterpretable observations. Although control genes and control-gene mutations may exist in man, this has not yet been proved, and the extent of their possible resemblance to the bacterial systems is unknown. Moreover, some qualifications should be considered in applying the concept of control-gene mutation to human disease: on
1. In mammalian systems induction is considerably slower than in bacteria, and the messenger R.N.A. seems to be longerlived. Mammalian induction, when hormonally stimulated, is generally much less specific than the substrate induction in bacteria.2 Again, whereas true metabolite repression does seem to exist in mammalian cells,8 true substrate induction has not been unequivocally demonstrated. There are situations (e.g., induction of tryptophan pyrollase by tryptophan or of thymidylate kinase by thymidine) in which the apparent substrate induction represents substrate protection of the enzyme against degradation, or activation of inactive precursors, rather than an’ increase in enzyme synthesis.2 45 2. In many human inborn errors of metabolism, the genedosage effect in heterozygous carriers may be regarded as Jacob, F., Monod, J. J. mol. Biol. 1961, 3, 318. Schimke, R. T., Sweeney, E. W., Berlin, C. M. Biochem. biophys. Res. Commun. 1964, 15, 214. 3. Schimke, R. T. J. biol. Chem. 1964, 239, 136. 4. Hiatt, H. H., Bojarski, T. B. Cold Spr. Harb. Symp. quant. Biol. 1961, 26, 367. 5. Rosen, F., Milholland, R. J. J. biol. Chem. 1963, 238, 3730. 1. 2.
1067 evidence against the existence of effective genetic control systems for the particular enzymes concerned. In these conditions (including methaemoglobinaemia due to diaphorase deficiency, galactossmia, acatalasia, haemolytic anaemia due to pyruvate-kinase deficiency, and glycogen-storage disease due to deficiency of debranching enzyme), enzyme activities or (in
protein levels in the erythrocytes, leucocytes, heterozyotes are about half those of the cells of healthy persons. 6-12 Therefore, for this group of intracellular enzymes, the enzyme levels found in healthy persons do not seem to be maintained by control systems concerned with the regulation of either the amount of enzyme activity or the a
few instances) fibroblasts of
or
amount of enzyme
protein.
For extracellular proteins, the situation is more complex. The synthesis of some proteins-for example, albumin-seems to be well regulated 13 (probably by means of serum osmotic whereas that of others, particularly the clotting pressure),14 factors 15-20 and pseudocholinesterase,21 may not be. In the latter instances, the heterozygotes for protein deficiencies often have significantly diminished levels of the circulating proteins 17 as estimated in terms of activity or, as in afibrinogenaemia and pseudocholinesterase deficiency,21 immunochemically. 3. A structural gene mutation can result in the synthesis of " a defective " protein in normal or reduced amounts, and the defect may be either in the enzymic or the structural properties of the protein. In addition, such a mutation can cause the synthesis of a non-recognisable protein or can completely prevent synthesis of the protein-both situations producing the same phenotypic result. If the concept evolved to explain " polarity mutations " 22 is correct, a structural gene mutation can also alter the rate of protein synthesis. Therefore, before an explanation entailing a structural gene mutation can be discarded in favour of one entailing mutation of a control gene, the protein must be shown to be unaltered in sequence, or, preferably, the mutation must be localised to a site outside the structural gene locus by genetic mapping (a procedure which, unfortunately, is not yet possible in man). 4. Increases in enzyme activity can be explained by structural gene mutations of several types: (a) the mutant enzyme has a higher specific activity; (b) the mutant enzyme is not effectively inhibited by its normal inhibitors; (c) the enzyme is less vulnerable to degradation, or (d) the enzyme is synthesised at a greater than normal rate. To determine the cause of an increase in activity it is necessary, therefore, to determine whether there is an actual increase in the quantity of enzyme present, whether there is an increase in the rate of its synthesis, and whether the enzyme is normal in structure.
hereditary diseases in man, hypotheses based structural gene mutations will adequately explain the known facts. In view of our lack of knowledge about human control-gene systems, the possibilities of structural gene mutations (as well as of other more complex genetic accidents) should not be summarily dismissed without experimental evidence to the contrary. In many
on
National Institute of Arthritis and Metabolic Diseases, Bethesda, Maryland 20014, U.S.A.
CHARLES
J. EPSTEIN.
Scott, E. M. J. clin. Invest. 1960, 39, 1176. Schwartz, V., Wells, A. R., Holzel, A., Komrower, G. M. Ann. hum. Genet. 1962, 25, 179. 8. Ogata, M., Takahara, S. Proc. Jap. Acad. 1963, 39, 783. 9. Krooth, R. S., Howell, R. R., Hamilton, H. B. J. exp. Med. 1962 115, 6. 7.
313.
10. 11. 12. 13. 14.
Oski, F. A., Diamond, L. K. New Engl. J. Med. 1963, 269, 763. Williams, H. E., Kendig, E. M., Field, J. B.J. clin. Invest. 1963, 42, 656 Aebi, H. Abstr. Int. Congr. Biochem. 1964, 3, 225. Bennhold, H. Verh. dtsch. Ges. inn. Med. 1956, 62, 657. Rothschild, M. A., Oratz, M., Wimer, E., Schreiber, S. S.J. clin. Invest. 1961, 40, 545. 15. Voss, D., Waaler, B. Thrombos. Diathes. hœmorrh. Stuttgart, 1959,3,375. 16. Graham, J. B., Barrow, E. M., Houghie, C.J. clin. Invest. 1957, 36, 497. 17. Gross, R., Schwick, A., Lang, N., Nies, D., Rahn, B., Becker, M., Hengstmann, H. Klin. Wschr. 1963, 41, 695. 18. Didisheim, P., Vanderwoort, R. L. E. Blood, 1962, 20, 150. 19. Bradlow, B. S. Afr. J. med. Sci. 1962, 27, 51. 20. Lewis, J. H., Didisheim, P., Ferguson, J. H., Li, C. C. Amer. J. hum.
Genet. 1963, 15, 53. 21. Hodgkin, W. E., Giblett, E. R., Levine, H., Motulsky, A. G. Program of American Society of Human Genetics, New York, July
19-21, 1963, p. 15.
22. Ames,
B., Hartman, P. Cold Spr.
Harb.
Symp. quant. Biol. 1963, 28,
349.
TREATMENT OF CHRONIC TENSION HEADACHE SIR,-The status of amitriptyline and other drugs for treatment of tension headache is not established with any precision in the paper by Dr. Lance and Dr. Curran.1 The only interesting, statistically significant difference was obtained by combining patients on amitriptyline and imipramine into one group, to be compared with another group made up of patients on ’Librium ’ (chlordiazepoxide) or ’Bellergal ’. The pairing of the latter two has resulted in a meaningless significant difference. The facts of the study are that amitriptyline is not significantly better than imipramine, bellergal, or librium, and that neither bellergal nor librium is significantly better than placebo (2 x 2 x2 test). Furthermore the claimed significance for the difference between the placebo and the combined bellergal and librium groups must rest on an error of calculation. As X2 (2 x 2) for this difference equals 0’87 (p > 0.7), it is unlikely that some more refined procedure from the authors’ stated statistical guide could have shown a significant result. Finally, the statement that diazepam was effective is not supported by the tabular data (X2=0.8 for its comparison with ’
placebo; p=0-3). I suggest that the relative effectiveness of the drugs still remains to be decided. Despite the authors’ rejection of the hypothesis that depressive illness was a factor in their results, one would expect study of the psychopathology of patients presenting with chronic headache of long duration to produce interesting results. It is suggested, for instance, by Nodine and Moyer2 that an analgesic, sedative, and tranquilliser combination is the best symptomatic treatment, but that preventive treatment is best accomplished
by psychotherapy. Mental Health Research Institute, Royal Park, Victoria, Australia.
NORMAN F. HOLT.
PSYCHIATRIC UNITS IN GENERAL HOSPITALS
SIR,-Iam grateful to Dr. Leyberg for emphasising (Oct. 10) the need for psychiatric units to work closely with the local authority as this was given insufficient emphasis in my article (Sept. 26). I was grateful, too, for his stressing the desirability of the unit being fully integrated into the work of the general hospital, as this was challenged by Dr. Cohen and Dr. Haldane (Oct. 24). Re-reading their articleII found that the sort of autonomy they were seeking was apparently far greater than that which they called for in their letter; originally Dr. Haldane4 asked for an initial period not only of medical but of administrative and nursing autonomy. I was glad to read that their views have been modified so much; even so, I suggest that a casualty officer who is adequately briefed by, and in close touch with, his psychiatric colleagues should be competent enough to decide, on most occasions, which patients are suitable for admission to the psychiatric unit. Integration does not mean dictation of therapy by a specialist in physical medicine, and I cannot understand why Dr. Cohen and Dr. Haldane have chosen to make this particular interpretation. Dr. Cohen and Dr. Haldane have, I think, misread the paragraph on medical staffing, as the comment on what might seem over-generous staffing did not apply to consultants only. The proposal of four and a half doctors for a sixty-bed unit is the same number that Dr. Cohen and Dr. Haldane have for a fifty-four bed unit. Regrettably there will be a discrepancy for 5 many years between what is desirable and what is available.5 On reflection, I do agree that the number of consultant sessions suggested for such a unit is too small, and makes no allowance for leave, and it would be desirable for a sixty-bed unit to be shared by two half-time consultants. ’
1. 2.
Lance, J. W., Curran, D. A. Lancet, 1964, i, 1236. Psychosomatic Medicine (edited by J. H. Nodine and J. p. 881. Philadelphia, 1962. Cohen, W. A., Haldane, F. P. Lancet, 1962, i, 1113. Haldane, F P ibid. p. 1350.
3. 4. 5. ibid.
Aug. 15, 1964, p. 352.
H.
Moyer);