348
12. Desmonts G, Couvreur J. Congenital toxoplasmosis: a prospective study of 378 pregnancies. N Engl J Med 1974; 290: 1110-16. 13. Alford C, Stagno S, Reynolds D. Congenital toxoplasmosis: clinical laboratory and therapeutic considerations with special reference to subclinical disease. Bull NY Acad Med 1974; 50: 160-79. 14. Wilson CB, Remington JS, Stagno S, Reynolds DW. Development of adverse sequelae in children born with subclinical congenital toxoplasma infection. Pediatrics 19806; 66: 767-74. 15. Koppe JG, Loewer-Sieger DH, De Roever-Bonnet H. Results of 20-year follow-up of congenital toxoplasmosis. Lancet 1986; i: 254-56. 16. Hall SM. Congenital toxoplasmosis in England, Wales and Northern Ireland: some epidemiological problems. Br Med J 1983; 287: 453-55. 17. Hall SM, Glickman M. Report from the British Paediatric Surveillance Unit. Arch Dis Child 1989; 64: 439-46. 18. Hall SM, Glickman M. Report From the British Paediatric Surveillance Unit. Arch Dis Child 1990; 65: 807-09. 19. Payne RA, Joynson DHM, Balfour AH. Public health laboratory service enzyme linked immunosorbent assay for detecting toxoplasma specific IgM antibody. J Clin Pathol 1987; 40: 276-81. 20. Daffos F, Capella-Pavlovsky M, Forestier F. Fetal blood sampling during pregnancy with use of a needle guided by ultrasound: a study of 606 consecutive cases. Am J Obstet Gynecol 1985; 153: 655-60. 21. Marteau TM. Psychological cost of screening. Br Med J 1989; 299: 527. 22. Couvreur J, Desmonts G, Thulliez PH. Prophylaxis of congenital
toxoplasmosis. Effects of spiramycin J Antimicrob Chemother 1988; 22 (suppl B):
on
placental infection.
193-200.
THE SECRET OF SEX? Since the 1950s we have believed that maleness in man, and in other mammals, requires a Y chromosome.1-3 In the succeeding years that concept has remained basically secure but it has become clear that only a part of the Y chromosome has a sex-determining role. Detailed analyses of a series of "XX males" bearing a very small translocated Y segment and of "XY females" with tiny deletions of the Y have whittled the critical region down to a size that becomes manageable in molecular terms.4,5 Three years ago, the claim was made that a particular gene isolated from this region might be the sex-determining element.6 The product of that gene is a DNA binding protein, with a characteristic structure suggesting that its function is to regulate the expression of other genes, (a "transcription factor").7 Such a role would be consistent with the proposed modus operandi of the gene in sex determination-ie, by inducing differentiation of the "neutral" embryonic gonad to become a testis. All subsequent development of sexual characteristics depends on the influence of testicular hormones on the embryonic tissues.8,9 If the male inductive signal is not received, the gonad tends to become an ovary (although in the XO Turner’s syndrome female it degenerates into a nonfunctional streak) and other anatomical development is essentially female. The original candidate, termed ZFY, failed to gain endorsement as the sex-determining gene on several counts.10-12 First, it was disturbing to find very close homologues on the human X chromosome and on the autosomes of mice and marsupials, which suggested that the association with maleness might be insecure. Second, the equivalent genes (there are two) on the mouse Y chromosome are not expressed in the embryonic testis at the developmental stage or in the manner expected. Third, some mouse mutants that develop testes and become masculinised (although no germ cells are produced) lack the Zfy gene equivalents. Finally, XX males were identified without ZFY, but with other Y-derived DNA sequences. Now another contender has emerged.13,14 A fresh look at one of the most infomative "sex-reversed" individuals, a female with an X and a Y;22 translocation chromosome, showed that there were two separate regions deleted from the Y. Whereas ZFY maps to one of these, the other
(previously unsuspected) includes sequences that are present in all XX males." A single gene has been cloned from that very small region. Designated SR Y (sexdetermining region of the Y) it too encodes a DNA binding protein and has a counterpart (Sry) on the mouse Y chromosome, but it appears to be clearing the hurdles that brought down ZFY. SR Y is present in all XX males but far. The murine appropriate stage of embryonic and, whilst the range of tissues
absent from all XY females examined gene is
so
expressed gonadal development examined is still small, its expression may be testis specific. Close homologues are present in DNA from the males, but not the females, of a range of mammals from the rabbit to the tiger, while more distantly related genes include one that encodes the yeast mating type protein, Mc, a major component of what is probably an ancestral sexual at an
differentiation mechanism. Thus, SR Y has strong credentials as the elusive master sex-determining gene and perhaps one of its strongest selling points is that there is very little room in the still unexplored sex-determining region of the Y for another gene to be lurking. If one assumes that its status is consolidated in due course, what are the implications? It will be an advantage in some intersex states to be able to identify the genotypic sex of the infant, but this information will never be a panacea. Despite all that has gone before, sex and sexuality are emphatically not determined by a single gene. The XY individual with testicular feminisation syndrome has a full complement of Y DNA, including the testisdetermining region (since she has testes), but because of an inability of the tissues to recognise and respond to androgens, she is both female and feminine. Conversely, the XX individual with some forms of the adrenogenital syndrome or other androgen-producing conditions may be appreciably virilised at birth, in the absence of any Y DNA. XX males with a translocated SR Y gene and XY females without it tend to show various degrees of incomplete sexual development in addition to being infertile. That there is some correlation between the degree of masculinisation and the amount of Y DNA from the sex-determining region represented in the genome, raises the possibility that other Y chromosome genes in addition to SR Y may influence sex determination. 15 There is no suggestion that SR Y has any relevance to sexual orientation, nor that it could be manipulated in man to influence the sex of an unborn child. There may be a place for genetic engineering in farming-eg, a bull with a normal Y chromosome and an X bearing a translocated SR Y would produce only bull calves, (although half would be XX sterile males), which could be economically significant. For man, the new discovery is likely to increase our understanding of the control of tissue differentiation. In this instance we are dealing with an especially important aspect of organogenesis-that of the testis and all that follows from it. The latest findings do not, however, demystify sexthank goodness. WJ, Russell Lb. The Y chromosome as the bearer of male determining factors in the mouse. Proc Natl Acad Sci USA 1959; 45:
1. Welshons
560-66.
Jacobs PS, Strong JA. A case of human intersexuality having a possible XXY sex determining mechanism. Nature 1959 183: 302-03. 3. Ford CE, Jones KW, Polani PE, de Almeida JC, Briggs JH. A sex-chromosome anomaly in a case of gonadal dysgenesis (Turner’s syndrome). Lancet 1959; i: 711-13. 4. Page DC. Sex reversal: deletion mapping the male-determining function of the human Y chromosome. Cold Spring Harbour Group Quant Biol 2.
1986; 51: 229-35.
349
5. McLaren A. What makes a man a man? Nature 1990; 746: 216-17. 6. Editorial. The Y chromosome and sex determination. Lancet 1988; i: 973-74. 7. Page DC, Mosher R, Simpson EM, et al The sex-determining region of the human Y chromosome encodes a finger protein. Cell 1987; 51: 1091-104. 8. Jast A. Problems of fetal endocrinolgy: the gonadal and hypophyseal hormones Rec Progr Horm Res 1953, 8: 379-418. 9. McLaren A. Sex determination in mammals. Trends Genet 1988; 4: 153-57. 10. Palmer MS, Sinclair AH, Berta P, et al. Genetic incidence that ZFY is not the testis-determining factor. Nature 1989; 342: 937-39 11. Koopman P, Gubbay J, Collignon J, Lovell-Badge R. Zfy gene expression patterns are not compatible with a primary role in mouse sex determination. Nature 1989; 342: 940-42. 12. Palmer MS, Berta P, Sinclair AH, Pym B, Goodfellow PN. Comparison of human ZFY and ZFX transcripts. Proc Natl Acad Sci USA 1990; 87: 1681-85. 13 Sinclair AH, Berta P, Palmer MS, et al. A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature 1990; 346: 240-44. 14. Gubbay J, Collignon J, Koopman P, et al A gene mapping to the sex-determining region of the mouse Y chromosome is a member of a novel family of embryonically expressed genes. Nature 1990; 346: 245-50. 15. Page DC, Fisher MC, McGillivray B, Brown LG. Additional deletion in sex-determining region of human Y chromosome resolves paradox of X,t(Y;22) female. Nature 1990; 346: 279-81.
THE SCOTS AND THEIR HEARTS How can coronary heart disease (CHD) in Scotland be reduced? The Scots and their doctors, who live and work in a country with unenviable and largely unexplained high rates of CHD morbidity and mortality, would dearly like to know. The compilers of a report1 sponsored by the Scottish Home and Health Department claim to have some of the answers. "One of the exciting recommendations... (is) the establishment of a new body directly responsible for health promotion" they declare in the foreword, but this recommendation is really a recipe for further procrastination. Much of the report repeats what has been stated better elsewhere and some of it is at variance with more authoritative accounts. Was this because only 6 of the 17 members of the working group were doctors (1 of whom resigned), and only 2 are established CHD researchers? Little sense of urgency is imparted by the tedious reiteration of the relation between various risk factors and CHD. The underlying theme in the commentaries about single factor and multifactorial intervention trials is negative. Whilst it is entirely legitimate to point out the weaknesses of some of the studies considered, their positive findings receive only passing mention. Thus, the consistent finding from the major primary prevention cholesterollowering trials of a significant reduction in CHD incidence in hypercholesterolaemic men receives scant emphasis and equal importance is given to the lack of reduction of total mortality (although the power of the former finding is far greater). Were these important trials analysed seriously? No reference is made of the far fuller and more carefully presented reports of the European Atherosclerosis Society,2 the British Cardiac Society,3 the British Hyperlipidaemia Association,4and the US National Cholesterol Education Programs among others-astonishing in 1990. We do not know whether the working group was simply unaware of these authoritative statements or chose to dismiss them, but the fact is that the group’s recommendation about reduction of raised blood cholesterol is completely out of line with that of the other reports. Thus "persons with blood cholesterol levels between 52 and 10-0 mmol should initially receive
lifestyle counselling... ". Dunnigan6 from has already protested about this point. It is only Glasgow above a level of 10 mmol/1 that reference to a lipid clinic is firmly recommended, and it is stated that lipid-lowering drugs "should not normally be prescribed for persons with levels below 10 mmol." Uniquely, this Governmentsponsored Scottish report does not recommend concerted action at lower levels, even though it states that mean serum cholesterol is 6-4 mmol/1 for Scottish men and 6-6 mmol/1 for women and that a generally acceptable adult level is 5-2
nutritional and
mmol/1. The more usual cholesterol level chosen for reference to a lipid clinic and for probable drug treatment is in the region of 7 mmol/1; in the USA it is 6-2 mmol/1.’’ One can calculate that about 400 000 men in Scotland have serum cholesterol levels of more than 6-5 mmol/F and 120 000 have levels above 78 mmol/1. By contrast, there may be no more than 20 000 with levels above 10 mmol/l. Thus, about 380 000 hypercholesterolaemic Scotsmen, known to have an exponential increase in cholesterol-attributable CHD, are merely recommended to have "further counselling [regarding healthy eating]: refer to a lipid clinic if necessary". Astonishingly, also, no mention is made of any lipid other than cholesterol. High-density lipoprotein concentrations receive no consideration in relation to action on cholesterol levels, and triglycerides are completely ignored although triglyceride levels are known to be higher in Scots. No mention is made of the use of the powerful cholesterol-lowering reductase inhibitors. Action in women is not considered separately. The dietary recommendation is merely that which was put forward for the general population in the 1984 COMA report,8 but the COMA recommendations for individuals with high cholesterol levels have not even been identified or reaffirmed. A degree of conservatism is necessary and appropriate to balance some of the existing American evangelism for of management hypercholesterolaemia, but the recommendations of this report for the country with the second highest rate of CHD in the world are reactionary beyond belief. Doctors in Scotland would do well to ignore and reject the recommendations on management of raised blood cholesterol and act on those made by more experienced counsellors. It is especially depressing that very little consideration is given to causes of CHD other than the conventional risk factors or to the extent of unknown influences in Scotland. No recommendations are made for further research. Department and Scottish Health Service Advisory Council Prevention of Coronary Heart Disease in Scotland. Edinburgh: HM Stationery Office, 1990. 2. Study Group, European Atherosclerosis Society Strategies for the prevention of coronary heart disease: a policy statement of the European Atherosclerosis Society. Eur Heart J 1987; 8: 77-88. 3. British Cardiac Society Working Group on Coronary Prevention. Conclusions and recommendations. Br Heart J 1987; 57: 188-89. 4. Shepherd J, Betteridge DJ, Durrington P, et al. Strategies for reducing coronary heart disease and desirable limits for blood lipid concentrations: guidelines of the British Hyperlipidaemia Association. Br Med J 1987; 295: 1245-46. 5. National Cholesterol Education Program. Report of the Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults. Arch Intern Med 1988, 148: 36-69. 6. Dunnigan MG. Prevention of coronary heart disease in Scotland. Br Med J 1990; 300: 1583 7. Tunstall-Pedoc H, Smith WCS, Tavendale R. How-often-that-high graphs of serum cholesterol. Lancet 1989; i: 540-42. 8. Committee on Medical Aspects of Food Policy: Diet and cardiovascular Disease. DHSS 28. London: HM Stationery Office, 1984. 1. Scottish Home and Health
12. Desmonts G, Couvreur J. Congenital toxoplasmosis: a prospective study of 378 pregnancies. N Engl J Med 1974; 290: 1110-16. 13. Alford C, Stagno S, Reynolds D. Congenital toxoplasmosis: clinical laboratory and therapeutic considerations with special reference to subclinical disease. Bull NY Acad Med 1974; 50: 160-79. 14. Wilson CB, Remington JS, Stagno S, Reynolds DW. Development of adverse sequelae in children born with subclinical congenital toxoplasma infection. Pediatrics 19806; 66: 767-74. 15. Koppe JG, Loewer-Sieger DH, De Roever-Bonnet H. Results of 20-year follow-up of congenital toxoplasmosis. Lancet 1986; i: 254-56. 16. Hall SM. Congenital toxoplasmosis in England, Wales and Northern Ireland: some epidemiological problems. Br Med J 1983; 287: 453-55. 17. Hall SM, Glickman M. Report from the British Paediatric Surveillance Unit. Arch Dis Child 1989; 64: 439-46. 18. Hall SM, Glickman M. Report From the British Paediatric Surveillance Unit. Arch Dis Child 1990; 65: 807-09. 19. Payne RA, Joynson DHM, Balfour AH. Public health laboratory service enzyme linked immunosorbent assay for detecting toxoplasma specific IgM antibody. J Clin Pathol 1987; 40: 276-81. 20. Daffos F, Capella-Pavlovsky M, Forestier F. Fetal blood sampling during pregnancy with use of a needle guided by ultrasound: a study of 606 consecutive cases. Am J Obstet Gynecol 1985; 153: 655-60. 21. Marteau TM. Psychological cost of screening. Br Med J 1989; 299: 527. 22. Couvreur J, Desmonts G, Thulliez PH. Prophylaxis of congenital
toxoplasmosis. Effects of spiramycin J Antimicrob Chemother 1988; 22 (suppl B):
on
placental infection.
193-200.
THE SECRET OF SEX? Since the 1950s we have believed that maleness in man, and in other mammals, requires a Y chromosome.1-3 In the succeeding years that concept has remained basically secure but it has become clear that only a part of the Y chromosome has a sex-determining role. Detailed analyses of a series of "XX males" bearing a very small translocated Y segment and of "XY females" with tiny deletions of the Y have whittled the critical region down to a size that becomes manageable in molecular terms.4,5 Three years ago, the claim was made that a particular gene isolated from this region might be the sex-determining element.6 The product of that gene is a DNA binding protein, with a characteristic structure suggesting that its function is to regulate the expression of other genes, (a "transcription factor").7 Such a role would be consistent with the proposed modus operandi of the gene in sex determination-ie, by inducing differentiation of the "neutral" embryonic gonad to become a testis. All subsequent development of sexual characteristics depends on the influence of testicular hormones on the embryonic tissues.8,9 If the male inductive signal is not received, the gonad tends to become an ovary (although in the XO Turner’s syndrome female it degenerates into a nonfunctional streak) and other anatomical development is essentially female. The original candidate, termed ZFY, failed to gain endorsement as the sex-determining gene on several counts.10-12 First, it was disturbing to find very close homologues on the human X chromosome and on the autosomes of mice and marsupials, which suggested that the association with maleness might be insecure. Second, the equivalent genes (there are two) on the mouse Y chromosome are not expressed in the embryonic testis at the developmental stage or in the manner expected. Third, some mouse mutants that develop testes and become masculinised (although no germ cells are produced) lack the Zfy gene equivalents. Finally, XX males were identified without ZFY, but with other Y-derived DNA sequences. Now another contender has emerged.13,14 A fresh look at one of the most infomative "sex-reversed" individuals, a female with an X and a Y;22 translocation chromosome, showed that there were two separate regions deleted from the Y. Whereas ZFY maps to one of these, the other
(previously unsuspected) includes sequences that are present in all XX males." A single gene has been cloned from that very small region. Designated SR Y (sexdetermining region of the Y) it too encodes a DNA binding protein and has a counterpart (Sry) on the mouse Y chromosome, but it appears to be clearing the hurdles that brought down ZFY. SR Y is present in all XX males but far. The murine appropriate stage of embryonic and, whilst the range of tissues
absent from all XY females examined gene is
so
expressed gonadal development examined is still small, its expression may be testis specific. Close homologues are present in DNA from the males, but not the females, of a range of mammals from the rabbit to the tiger, while more distantly related genes include one that encodes the yeast mating type protein, Mc, a major component of what is probably an ancestral sexual at an
differentiation mechanism. Thus, SR Y has strong credentials as the elusive master sex-determining gene and perhaps one of its strongest selling points is that there is very little room in the still unexplored sex-determining region of the Y for another gene to be lurking. If one assumes that its status is consolidated in due course, what are the implications? It will be an advantage in some intersex states to be able to identify the genotypic sex of the infant, but this information will never be a panacea. Despite all that has gone before, sex and sexuality are emphatically not determined by a single gene. The XY individual with testicular feminisation syndrome has a full complement of Y DNA, including the testisdetermining region (since she has testes), but because of an inability of the tissues to recognise and respond to androgens, she is both female and feminine. Conversely, the XX individual with some forms of the adrenogenital syndrome or other androgen-producing conditions may be appreciably virilised at birth, in the absence of any Y DNA. XX males with a translocated SR Y gene and XY females without it tend to show various degrees of incomplete sexual development in addition to being infertile. That there is some correlation between the degree of masculinisation and the amount of Y DNA from the sex-determining region represented in the genome, raises the possibility that other Y chromosome genes in addition to SR Y may influence sex determination. 15 There is no suggestion that SR Y has any relevance to sexual orientation, nor that it could be manipulated in man to influence the sex of an unborn child. There may be a place for genetic engineering in farming-eg, a bull with a normal Y chromosome and an X bearing a translocated SR Y would produce only bull calves, (although half would be XX sterile males), which could be economically significant. For man, the new discovery is likely to increase our understanding of the control of tissue differentiation. In this instance we are dealing with an especially important aspect of organogenesis-that of the testis and all that follows from it. The latest findings do not, however, demystify sexthank goodness. WJ, Russell Lb. The Y chromosome as the bearer of male determining factors in the mouse. Proc Natl Acad Sci USA 1959; 45:
1. Welshons
560-66.
Jacobs PS, Strong JA. A case of human intersexuality having a possible XXY sex determining mechanism. Nature 1959 183: 302-03. 3. Ford CE, Jones KW, Polani PE, de Almeida JC, Briggs JH. A sex-chromosome anomaly in a case of gonadal dysgenesis (Turner’s syndrome). Lancet 1959; i: 711-13. 4. Page DC. Sex reversal: deletion mapping the male-determining function of the human Y chromosome. Cold Spring Harbour Group Quant Biol 2.
1986; 51: 229-35.
349
5. McLaren A. What makes a man a man? Nature 1990; 746: 216-17. 6. Editorial. The Y chromosome and sex determination. Lancet 1988; i: 973-74. 7. Page DC, Mosher R, Simpson EM, et al The sex-determining region of the human Y chromosome encodes a finger protein. Cell 1987; 51: 1091-104. 8. Jast A. Problems of fetal endocrinolgy: the gonadal and hypophyseal hormones Rec Progr Horm Res 1953, 8: 379-418. 9. McLaren A. Sex determination in mammals. Trends Genet 1988; 4: 153-57. 10. Palmer MS, Sinclair AH, Berta P, et al. Genetic incidence that ZFY is not the testis-determining factor. Nature 1989; 342: 937-39 11. Koopman P, Gubbay J, Collignon J, Lovell-Badge R. Zfy gene expression patterns are not compatible with a primary role in mouse sex determination. Nature 1989; 342: 940-42. 12. Palmer MS, Berta P, Sinclair AH, Pym B, Goodfellow PN. Comparison of human ZFY and ZFX transcripts. Proc Natl Acad Sci USA 1990; 87: 1681-85. 13 Sinclair AH, Berta P, Palmer MS, et al. A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature 1990; 346: 240-44. 14. Gubbay J, Collignon J, Koopman P, et al A gene mapping to the sex-determining region of the mouse Y chromosome is a member of a novel family of embryonically expressed genes. Nature 1990; 346: 245-50. 15. Page DC, Fisher MC, McGillivray B, Brown LG. Additional deletion in sex-determining region of human Y chromosome resolves paradox of X,t(Y;22) female. Nature 1990; 346: 279-81.
THE SCOTS AND THEIR HEARTS How can coronary heart disease (CHD) in Scotland be reduced? The Scots and their doctors, who live and work in a country with unenviable and largely unexplained high rates of CHD morbidity and mortality, would dearly like to know. The compilers of a report1 sponsored by the Scottish Home and Health Department claim to have some of the answers. "One of the exciting recommendations... (is) the establishment of a new body directly responsible for health promotion" they declare in the foreword, but this recommendation is really a recipe for further procrastination. Much of the report repeats what has been stated better elsewhere and some of it is at variance with more authoritative accounts. Was this because only 6 of the 17 members of the working group were doctors (1 of whom resigned), and only 2 are established CHD researchers? Little sense of urgency is imparted by the tedious reiteration of the relation between various risk factors and CHD. The underlying theme in the commentaries about single factor and multifactorial intervention trials is negative. Whilst it is entirely legitimate to point out the weaknesses of some of the studies considered, their positive findings receive only passing mention. Thus, the consistent finding from the major primary prevention cholesterollowering trials of a significant reduction in CHD incidence in hypercholesterolaemic men receives scant emphasis and equal importance is given to the lack of reduction of total mortality (although the power of the former finding is far greater). Were these important trials analysed seriously? No reference is made of the far fuller and more carefully presented reports of the European Atherosclerosis Society,2 the British Cardiac Society,3 the British Hyperlipidaemia Association,4and the US National Cholesterol Education Programs among others-astonishing in 1990. We do not know whether the working group was simply unaware of these authoritative statements or chose to dismiss them, but the fact is that the group’s recommendation about reduction of raised blood cholesterol is completely out of line with that of the other reports. Thus "persons with blood cholesterol levels between 52 and 10-0 mmol should initially receive
lifestyle counselling... ". Dunnigan6 from has already protested about this point. It is only Glasgow above a level of 10 mmol/1 that reference to a lipid clinic is firmly recommended, and it is stated that lipid-lowering drugs "should not normally be prescribed for persons with levels below 10 mmol." Uniquely, this Governmentsponsored Scottish report does not recommend concerted action at lower levels, even though it states that mean serum cholesterol is 6-4 mmol/1 for Scottish men and 6-6 mmol/1 for women and that a generally acceptable adult level is 5-2
nutritional and
mmol/1. The more usual cholesterol level chosen for reference to a lipid clinic and for probable drug treatment is in the region of 7 mmol/1; in the USA it is 6-2 mmol/1.’’ One can calculate that about 400 000 men in Scotland have serum cholesterol levels of more than 6-5 mmol/F and 120 000 have levels above 78 mmol/1. By contrast, there may be no more than 20 000 with levels above 10 mmol/l. Thus, about 380 000 hypercholesterolaemic Scotsmen, known to have an exponential increase in cholesterol-attributable CHD, are merely recommended to have "further counselling [regarding healthy eating]: refer to a lipid clinic if necessary". Astonishingly, also, no mention is made of any lipid other than cholesterol. High-density lipoprotein concentrations receive no consideration in relation to action on cholesterol levels, and triglycerides are completely ignored although triglyceride levels are known to be higher in Scots. No mention is made of the use of the powerful cholesterol-lowering reductase inhibitors. Action in women is not considered separately. The dietary recommendation is merely that which was put forward for the general population in the 1984 COMA report,8 but the COMA recommendations for individuals with high cholesterol levels have not even been identified or reaffirmed. A degree of conservatism is necessary and appropriate to balance some of the existing American evangelism for of management hypercholesterolaemia, but the recommendations of this report for the country with the second highest rate of CHD in the world are reactionary beyond belief. Doctors in Scotland would do well to ignore and reject the recommendations on management of raised blood cholesterol and act on those made by more experienced counsellors. It is especially depressing that very little consideration is given to causes of CHD other than the conventional risk factors or to the extent of unknown influences in Scotland. No recommendations are made for further research. Department and Scottish Health Service Advisory Council Prevention of Coronary Heart Disease in Scotland. Edinburgh: HM Stationery Office, 1990. 2. Study Group, European Atherosclerosis Society Strategies for the prevention of coronary heart disease: a policy statement of the European Atherosclerosis Society. Eur Heart J 1987; 8: 77-88. 3. British Cardiac Society Working Group on Coronary Prevention. Conclusions and recommendations. Br Heart J 1987; 57: 188-89. 4. Shepherd J, Betteridge DJ, Durrington P, et al. Strategies for reducing coronary heart disease and desirable limits for blood lipid concentrations: guidelines of the British Hyperlipidaemia Association. Br Med J 1987; 295: 1245-46. 5. National Cholesterol Education Program. Report of the Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults. Arch Intern Med 1988, 148: 36-69. 6. Dunnigan MG. Prevention of coronary heart disease in Scotland. Br Med J 1990; 300: 1583 7. Tunstall-Pedoc H, Smith WCS, Tavendale R. How-often-that-high graphs of serum cholesterol. Lancet 1989; i: 540-42. 8. Committee on Medical Aspects of Food Policy: Diet and cardiovascular Disease. DHSS 28. London: HM Stationery Office, 1984. 1. Scottish Home and Health
