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HYPOTHYROIDISM AND HEART-DISEASE
720
non-disjunction5 and in another report there is a very strong
presumption that an XYY male illegitimate XYY child.6
is the father of
an
Melnyk et al.l have suggested that the presence of a single Y chromosome in the spermatocytes of XYY males a unique mechanism which may be the consequence of eliminates the second Y chromosome prior to spermatocyte formation ". The facts, however, can be accounted for "
without postulating a special mechanism if it is assumed: (1) that the loss of a Y chromosome from a primitive germ-cell or spermatogonium of a 47,XYY male is a random event occurring at a rate not necessarily greater than that of the single Y chromosome in the corresponding cells of a normal 46,XY male; (2) that the 46,XY germcell has a strong proliferative advantage over the 47,XYY germ-cell; and (3) that 47,XYY spermatocytes, if formed, do not develop as far as diakinesis. It is conventional to suppose that random loss of chromosomes by anaphase lagging or non-disjunction occurs at a low but undefined rate in all dividing cell populations. Evidence favouring the second assumption is provided by three XX/XY mouse chimaeras produced experimentally by embryo fusion7 and by one natural XO/XYY mosaic mouse.8The spermatogonia of these animals were wholly XY and wholly XYY respectively, suggesting competitive elimination of one component from the germ-cell population, or alternatively, the total incapacity of XX and XO cells to form spermatogonia in this species. These observations may be thought insufficient to exclude an explanation based on chance segregation of cells early in embryonic life, although the probability that the Y-containing component should be the one segregated into the germ-line by chance in all four animals is only 1 in 16. However, independent evidence that germ-cells in a mixed population of different genotypes may proliferate at different rates is provided by other experimental mouse chimaeras with components distinguished by autosomal genetic markers.9 The third assumption may eventually be shown not to be true of all XYY males. The first two assumptions lead to the expectation that the primitive germ-cells or spermatogonia (or both) in human XYY males will give rise to clones of XY cells and that the size of these clones will depend on the distribution of Y-chromosome losses in relation to the magnitude of the germ-cell population at the time of each loss. Since the stem-cells among the type-A spermatogonia are presumed to be attached to the basal membrane of the tubule, and may therefore have limited opportunity to move laterally, each clone could occupy a discrete tubule segment. Evidence of clonal structure might be obtained from careful squash preparations from short segments of tubule. A further consideration is that if accidental loss of Y chromosomes from remaining XYY spermatogonia and differential proliferation of the resulting XY cells should continue throughout reproductive life it might lead to a progressive change in the character of the sperm population. There is good reason to believe that the recently discovered fluorescent body present in some interphase nuclei and sperm heads of normal 46,XY males indicates the presence of a Y chromosome.lO,l1 Two such bodies have been seen in nuclei from an XYY male, so examination of sperm from XYY males of different ages for the presence of these structures could be most informative. 5.
Tzoneva-Maneva, M. T , Bosdjieva, E., Petrov, B. Lancet, 1966, i, 1000.
Sundequist, U , Hellstrom, E. ibid. 1969, ii, 1967. Mystkowska, E. T., Tarkowski, A. K. J. Embryol. exp. Morph. 1968, 20, 33. 8. Evans, E. P., Ford, C. E., Searle, A. G. Cytogenetics, 1969, 8, 87. 9. Mintz, B. J. Amm. Sci. 1968, 27, suppl. 8, p. 51. 10. Pearson, P. L., Bobrow, M., Voga, V. G. Nature, Lond. (in the press). 11. Pearson, P. L., Bobrow, M. Unpublished. 6. 7.
as yet no evidence that a human Y chromosomes can enter meiosis, murine XYY spermatogonia can give rise to spermatocytes that at least reach first metaphase and may produce sperm. However, only very few sperm were found in the two XYY male mice known to us 12,13 and none at all in the XO/XYY male.8 Testis size was well below the normal lower limit, and the two animals that had been mated failed to give litters.8,u Evidently the presence of a second Y chromosome influences germ-cell behaviour in both man and mouse, though seemingly in different ways and at different times.
Although there is germ-cell with two
Much of this work formed part of a research programme financed by the research committee of the Sheffield Regional Hospital Board, using equipment provided by the Mental Health Research Fund. We are grateful to Miss A. Barron, B.Sc., for her assistance in the early karyotyping of the patient, and to Miss S. A. Harcourt for the tissue-cultures. Medical Research Council
Radiobiology Unit, Harwell. Berks.
United Sheffield Hospitals Centre for Human Genetics, Sheffield 10. Balderton Hospital,
Newark,
Notts.
E. P. EVANS C. E. FORD R. S. K. CHAGANTI.
C. E. BLANK. H. HUNTER.
FIRST PRINCIPLES IN PSYCHIATRIC EDUCATION Todd discussed curricula and Commission SiR,—The the of but it missed chance of considering periods study, adequately those fundamental aspects of medical practice and education to which Dr. Woodmansey refers (March 21, The relations between doctor and patient are p. 610). strongly influenced by the relationship between the medical student and his teacher. And so is the student’s learning. Dr. M. L. Johnson Abercrombie, in her book The Anatomy of Judgment, showed that eight weekly group tutorials enabled the student to acquire more useful attitudes to his teacher and his peers and led to improved powers of observation and judgment. Dr. Woodmansey’s article might well have been called a first necessity in medical education. Guy’s Hospital, RONALD MAC KEITH. London S.E.1.
UNIVERSITY UPHEAVAL SIR,-I perfectly agree with your Round the World correspondent (Jan. 10, p. 79), as do most of the chairmen of German universities, that the German universities are approaching a very severe crisis, mainly the universities of Berlin, Hamburg, and Frankfurt. Universitats-Kinderklinik, Wurzburg, Germany.
West
J. STRODER.
HYPOTHYROIDISM AND HEART-DISEASE
SIR,-The letter from Dr. P. B. S. Fowler in your issue of March 21 (p. 619) draws attention to an interesting phenomenon. However, the difficulty he mentions of the risk of aggravating angina by giving L-thyroxine is one that can be circumvented. The sympathetic effect of thyroxine on the heart can be suppressed by the use of the -adrenergic drug propranolol. By increasing the dose of thyroxine and propranolol in stepwise manner, it is, in my experience, always possible to giveadose of the former large enough to overcome both the metabolic defect and the hypercholesterolsmia. RAYMOND GREENE. 12. 13.
Cattanach, B. M., Pollard, C. E. Cytogenetics, 1968, 8, 80. Evans, E. P., Ford, C. E., Searle, A. G. Unpublished.
non-disjunction5 and in another report there is a very strong
presumption that an XYY male illegitimate XYY child.6
is the father of
an
Melnyk et al.l have suggested that the presence of a single Y chromosome in the spermatocytes of XYY males a unique mechanism which may be the consequence of eliminates the second Y chromosome prior to spermatocyte formation ". The facts, however, can be accounted for "
without postulating a special mechanism if it is assumed: (1) that the loss of a Y chromosome from a primitive germ-cell or spermatogonium of a 47,XYY male is a random event occurring at a rate not necessarily greater than that of the single Y chromosome in the corresponding cells of a normal 46,XY male; (2) that the 46,XY germcell has a strong proliferative advantage over the 47,XYY germ-cell; and (3) that 47,XYY spermatocytes, if formed, do not develop as far as diakinesis. It is conventional to suppose that random loss of chromosomes by anaphase lagging or non-disjunction occurs at a low but undefined rate in all dividing cell populations. Evidence favouring the second assumption is provided by three XX/XY mouse chimaeras produced experimentally by embryo fusion7 and by one natural XO/XYY mosaic mouse.8The spermatogonia of these animals were wholly XY and wholly XYY respectively, suggesting competitive elimination of one component from the germ-cell population, or alternatively, the total incapacity of XX and XO cells to form spermatogonia in this species. These observations may be thought insufficient to exclude an explanation based on chance segregation of cells early in embryonic life, although the probability that the Y-containing component should be the one segregated into the germ-line by chance in all four animals is only 1 in 16. However, independent evidence that germ-cells in a mixed population of different genotypes may proliferate at different rates is provided by other experimental mouse chimaeras with components distinguished by autosomal genetic markers.9 The third assumption may eventually be shown not to be true of all XYY males. The first two assumptions lead to the expectation that the primitive germ-cells or spermatogonia (or both) in human XYY males will give rise to clones of XY cells and that the size of these clones will depend on the distribution of Y-chromosome losses in relation to the magnitude of the germ-cell population at the time of each loss. Since the stem-cells among the type-A spermatogonia are presumed to be attached to the basal membrane of the tubule, and may therefore have limited opportunity to move laterally, each clone could occupy a discrete tubule segment. Evidence of clonal structure might be obtained from careful squash preparations from short segments of tubule. A further consideration is that if accidental loss of Y chromosomes from remaining XYY spermatogonia and differential proliferation of the resulting XY cells should continue throughout reproductive life it might lead to a progressive change in the character of the sperm population. There is good reason to believe that the recently discovered fluorescent body present in some interphase nuclei and sperm heads of normal 46,XY males indicates the presence of a Y chromosome.lO,l1 Two such bodies have been seen in nuclei from an XYY male, so examination of sperm from XYY males of different ages for the presence of these structures could be most informative. 5.
Tzoneva-Maneva, M. T , Bosdjieva, E., Petrov, B. Lancet, 1966, i, 1000.
Sundequist, U , Hellstrom, E. ibid. 1969, ii, 1967. Mystkowska, E. T., Tarkowski, A. K. J. Embryol. exp. Morph. 1968, 20, 33. 8. Evans, E. P., Ford, C. E., Searle, A. G. Cytogenetics, 1969, 8, 87. 9. Mintz, B. J. Amm. Sci. 1968, 27, suppl. 8, p. 51. 10. Pearson, P. L., Bobrow, M., Voga, V. G. Nature, Lond. (in the press). 11. Pearson, P. L., Bobrow, M. Unpublished. 6. 7.
as yet no evidence that a human Y chromosomes can enter meiosis, murine XYY spermatogonia can give rise to spermatocytes that at least reach first metaphase and may produce sperm. However, only very few sperm were found in the two XYY male mice known to us 12,13 and none at all in the XO/XYY male.8 Testis size was well below the normal lower limit, and the two animals that had been mated failed to give litters.8,u Evidently the presence of a second Y chromosome influences germ-cell behaviour in both man and mouse, though seemingly in different ways and at different times.
Although there is germ-cell with two
Much of this work formed part of a research programme financed by the research committee of the Sheffield Regional Hospital Board, using equipment provided by the Mental Health Research Fund. We are grateful to Miss A. Barron, B.Sc., for her assistance in the early karyotyping of the patient, and to Miss S. A. Harcourt for the tissue-cultures. Medical Research Council
Radiobiology Unit, Harwell. Berks.
United Sheffield Hospitals Centre for Human Genetics, Sheffield 10. Balderton Hospital,
Newark,
Notts.
E. P. EVANS C. E. FORD R. S. K. CHAGANTI.
C. E. BLANK. H. HUNTER.
FIRST PRINCIPLES IN PSYCHIATRIC EDUCATION Todd discussed curricula and Commission SiR,—The the of but it missed chance of considering periods study, adequately those fundamental aspects of medical practice and education to which Dr. Woodmansey refers (March 21, The relations between doctor and patient are p. 610). strongly influenced by the relationship between the medical student and his teacher. And so is the student’s learning. Dr. M. L. Johnson Abercrombie, in her book The Anatomy of Judgment, showed that eight weekly group tutorials enabled the student to acquire more useful attitudes to his teacher and his peers and led to improved powers of observation and judgment. Dr. Woodmansey’s article might well have been called a first necessity in medical education. Guy’s Hospital, RONALD MAC KEITH. London S.E.1.
UNIVERSITY UPHEAVAL SIR,-I perfectly agree with your Round the World correspondent (Jan. 10, p. 79), as do most of the chairmen of German universities, that the German universities are approaching a very severe crisis, mainly the universities of Berlin, Hamburg, and Frankfurt. Universitats-Kinderklinik, Wurzburg, Germany.
West
J. STRODER.
HYPOTHYROIDISM AND HEART-DISEASE
SIR,-The letter from Dr. P. B. S. Fowler in your issue of March 21 (p. 619) draws attention to an interesting phenomenon. However, the difficulty he mentions of the risk of aggravating angina by giving L-thyroxine is one that can be circumvented. The sympathetic effect of thyroxine on the heart can be suppressed by the use of the -adrenergic drug propranolol. By increasing the dose of thyroxine and propranolol in stepwise manner, it is, in my experience, always possible to giveadose of the former large enough to overcome both the metabolic defect and the hypercholesterolsmia. RAYMOND GREENE. 12. 13.
Cattanach, B. M., Pollard, C. E. Cytogenetics, 1968, 8, 80. Evans, E. P., Ford, C. E., Searle, A. G. Unpublished.