- Email: [email protected]
Natural history of prostate cancer
699
THE LANCET
and 336 IU/L; pancreatic type 67% and 62%, respectively). Only 2 of the 36 patients who were not given ephedrine developed hyperamylasaemia. Salivary-type amylase was dominant in 1 of these (454 IU/L, salivary type 83%) while the pancreatic type was dominant in the other (311 IU/L, pancreatic type 82%). 28 patients had been intubated for general anaesthesia; of these, 13 received ephedrine. 8 developed postoperative hyperamylasaemia, 7 of whom had received ephedrine. The degree of hypotension before the administration of ephedrine did not differ between the two ephedrine-treated subgroups (the 33 patients with postoperative hyperamylasaemia and the 58 with normal serum amylase). However, the dose of ephedrine used in the 33 (18-5 [12-0], 4-52 mg) was higher than that in the 58 (13-1 [9.3], 4-40 mg). &bgr;-sympathomimetics induce hypertrophy of the salivary gland6 and stimulate amylase secretion.7 We believe that most of the observed cases of postoperative hyperamylasaemia resulted from stimulation of &bgr;-adrenoceptors of the salivary glands by ephedrine. Differences in the frequency of postoperative hyperamylasaemia in previous reportsl-4 may have been due to differences in the use of ephedrine or other sympathomimetics during surgery.
Department of Obstetrics and Jichi Medical School, Tochigi, 329-04 Japan
Gynaecology,
HISANORI MINAKAMI TOSHIMITSU KOIKE MASAMI SUGIMURA TAKASHI WATANABE TARO TAMADA
1. Perrman RG, Hoerr SO. Observations on postoperative pancreatitis and postoperative
elevation of the serum amylase. Am J Surg 1954; 88: 417-20. 2. Harada K, Kitamura M, Ikenaga T. Isoenzyme study on postoperative transient hyperamylasemia. Am J Gastroenterol 1974; 61: 212-16. 3. Morrissey R, Berk JE, Fridhandler L, et al. The nature and significance of hyperamylasemia following operation. Ann Surg 1974; 180: 67-71. 4. Fröhlich EP, Herz C, van der Merwe FJ, et al. Serum amylase levels after obstetric and gynecologic operations. Surg Gynecol Obstet 1990; 170: 292-94. 5. Minakami H, Takahashi T, Izumi A, et al. Enlargement of salivary gland after ritodrine treatment in pregnant women. BMJ, 1992; 304: 1668. 6. Selye H, Veilleux R, Cantin M. Excessive stimulation of salivary gland growth by isoproterenol. Science 1961; 133: 44-45. 7. McPherson MA, Dormer RL, Bradbury NA, et al. Defective &bgr;-adrenergic secretory responses in submandibular acinar cells from cystic fibrosis patients. Lancet 1986; ii: 1007-08.
Underuse of antenatal corticosteroids and future litigation SIR,-Dr Khanna and Dr Richmond (Jan 16, p 174) provide further evidence that some obstetricians are not making sufficient use of corticosteroids to prevent neonatal morbidity and to reduce the costs of neonatal care. Their findings are consistent with the evidence of underuse in the mothers of babies who participated in the OSIRIS trial (Dec 5, p 1363), on which you commented
editorially. A mother who gave birth to her first child at 31 weeks’ wrote to after reading about Khanna and Richmond’s findings in The Independent.1 After the birth she learned that if she had been given corticosteroids her child would have been substantially less likely to have suffered in the way that he did. At 16 weeks’ gestation in her second pregnancy she was assured that steroids would be prescribed if it seemed likely that she was going to give birth prematurely again. This assurance had greatly alleviated her anxieties and she did indeed receive steroids as promised when she began labour at 31 weeks. In fact, her contractions ceased and she went on to have a normal delivery at
me
term.
As far as I am aware, this woman’s first child has no long-term sequelae from his potentially preventable neonatal morbidity. It is certain, however, that other preterm babies whose mothers could have received prophylactic steroids have died and that others are suffering long-term consequences of neonatal morbidity. It seems probable that the parents of some of these children will come to realise that they were not offered a form of care that might have prevented their child’s suffering. In view of trends in litigation, it would be surprising if none of them considered suing for
negligence. Liggins and Howie2 first showed that antenatal corticosteroids were effective in reducing serious neonatal morbidity and mortality
than twenty years ago. Their findings were strengthened by the results of at least 13 subsequent randomised trials. The strength of the evidence was made clear in a systematic review published by Crowley in 1989,3 and in an article4 and commentaryS published in January, 1990, in the journal of the Royal College of Obstetricians and Gynaecologists. It was not until three years later, however, that the College eventually encouraged all obstetric units to "consider the use of such therapy when delivery is likely before 34 weeks" 6 The substantial delay between the availability of strong scientific evidence and the College’s recommendation raises at least two questions. First, at which point during the past twenty years will it be judged to have been negligent not to have administered steroids when there were no clear contraindications? Second, is it possible that the target of litigants will not be individual obstetricians, but the body responsible for educating them?
more
The Cochrane Centre, Summertown Pavilion, Middle Way, Oxford OX2 7LG, UK
IAIN CHALMERS
1. Hunt L. Pregnancy drug ’held back’. The Independent 1992; 30 Sept: 7. 2. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of respiratory distress syndrome in premature infants. Pediatrics 1972; 50: 515-25. 3. Crowley P. Promoting pulmonary maturity. In: Chalmers I, Enkin M, Keirse MJNC, eds. Effective care in pregnancy and childbirth. Oxford: Oxford University Press, 1989: 746-64. 4. Crowley P, Chalmers I, Keirse MJNC. The effects of corticosteroid administration before preterm delivery: an overview of the evidence from controlled trials. Br J Obstet Gynaecol 1992; 97: 11-25. 5. Liggins GC. Obstetric and paediatric collaboration to reduce morbidity after preterm birth. Br J Obstet Gynaecol 1992; 97: 1-10. 6. Simmons SC. President’s letter to fellows and members. London: Royal College of Obstetricians and Gynaecologists, December, 1992 4-5.
Natural history of prostate cancer SIR,-As Mr Carr points out in your Jan 9 commentary, there is little doubt that there is conflicting evidence about the natural history of prostate cancer. However, until more is known about the natural history of this unpredictable disease the suggested management of expectant treatment or radical therapy for those with a reasonable life expectancy should be severely criticised. The expectant approach (which is justified by an apparent low prostate-cancer-specific mortality) is disadvantaged partly because this outcome is subject to well known vagaries but also because the fact of death seems to be at least as important. For example, if a treatment reduced death from metastases but gave a corresponding increase in the number of dying from coronary thrombosis without affecting the overall survival, it could scarcely be counted a success. The alternative of treating localised disease on the sole basis of life expectancy will result in overtreatment of naturally indolent disease with needless morbidity and mortality and consumption of scarce resources.1 However, although there is no satisfactory prognostic marker,2 there is evidence that assessment of oncoprotein and proliferation markers might both predict survival and assist in selecting those patients who should have radical treatment.3,4 Therefore, any trials of radical treatment in early prostate cancer not only should involve randomisation according to accepted clinicopathological tenets but also should consider the tumour indices that are more directly related to oncogenesis. Nuffield Department of Pathology, John Radcliffe Hospital, Oxford OX3 9DU, UK
Departments of Urology and Pathology, Addenbrookes Hospital, Cambridge Department of Public Health, University of Sheffield Medical School, Sheffield
STEPHEN B. Fox
RAJ A. PERSAD NICHOLAS COLEMAN PAUL B. SILCOCKS
Epstem JI, et al. Prediction of prognosis in untreated stage A2 prostanc carcinoma. Cancer 1992 69: 511-19. 2. Fox SB, Persad RA, Royds JA, Kore RN, Silcocks PB, Collins CC. p53 and c-myc expression in stage Al prostatic adenocarcinoma: prognostic determinants? y Urol 1. Mohler JC, Partin AW,
(m press). 3. Miller J, Horsfall
DJ, Marshall VR, Rao DM, Leong ASY. The prognostic value of deoxyribonucleic acid flow cytometric analysis in stage D2 prostatic carcinoma. J Urol 1991; 145: 1192-96. 4. Nemoto R, Kawamura H, Miyakawa I, et al. Immunohistochemical detection of proliferating cell nuclear antigen (PCNA)cyclin in human prostate adenocarcinoma. J Urol 1993; 149: 165-69.
700
THE LANCET
A frisky genotype for
primary hypertension?
SIR,-Dr Old’s commentary (Jan 23, p 214) on heterozygote advantage reminds me of a simple experiment I have vainly advocated at meetings for the past twenty years. It seems unlikely that the probably diverse genotypes that raise arterial pressure are all reproductively neutral. Although most but all their effect on survival operates after middle age, this is still within male reproductive age, and survival of wiser or more energetic old men and women may also assist group survival. Before contraception modified natural history, such evidence as we had on association of arterial pressure with fertility suggested that this relation was negative,l implying that there must be other countervailing advantages at least for survival of groups, if they include at least a proportion with hypertensive genotypes. Although people in the lowest centiles of arterial pressure distribution are at lower risk of premature death, they apparently feel less frisky than people in higher centiles of the distribution,2,3 and may thus contribute less to group survival. One reason could be that they actually are less frisky; that genotypes determining higher pressures may confer some kinds of greater competence to heterozygotes, sufficient to outweigh the survival disadvantages of homozygotes, for the group if not for individuals. We already know that this is not merely a matter of aggressive competitiveness; type A personality is not significantly associated with arterial pressure.4 This hypothesis can be readily tested. Tracking for high arterial pressure seems to be well established by age 18-20. University medical centres serving undergraduates have a rapid throughput of large numbers routinely subjected both to intake physical measurements and to output measures of achievement in all dimensions, including sporting and cultural activities. All we need is to bring these two sets of data together, and to see whether higher arterial pressure is associated with greater achievement in some or all of these dimensions. Any enterprising university medical centre should be able to set such a study up and get an answer within 5 years. Of course, such investigation would not be straightforward. The entry measurements would have to be raised to research quality, and include related variables such as arm circumference as well as height, weight, and girth. Exit measurements would need to include term examinations so that dropouts would not be missed. Neel’s thrifty genotype hypothesiss is an imaginative explanation for high prevalence of non-insulin dependent diabetes. Why not a frisky genotype for primary hypertension? not
Gelli
Deg,
Penmaen, Swansea SA3 2HH, UK 1. 2.
JULIAN TUDOR HART
Hart JT. Hypertension. London: Churchill Livingstone, 1980: 67-68. Pilgrim JA, Stansfeld S, Marmot M. Low blood pressure, low mood? BMJ 1992; 304: 75-78.
Wessely S, Nickson J, Cox B. Symptoms of low blood pressure: a population study. BMJ 1990; 301: 362-65. 4. Shekelle RB, Schoenberger JA, Stamler J. Correlates of the JAS type A behaviour pattern score. J Chron Dis 1976; 29: 381-94. 5. Neel JV. Diabetes mellitus: a thrifty genotype rendered detrimental by "progress"? Am J Hum Genet 1962; 14: 353-62.
3.
SIR,-Dr Old’s commentary on heterozygote advantage leads to about how this theory could apply to psychiatric illness. The Epidemiological Catchment Area Studyi indicated that about comment
in five Americans has some form of mental illness at some time in his or her life, predominantly as anxiety and depressive-related syndromes. Although the genetics of psychiatric conditions seem complex, one must account for the relative frequency of these conditions even acknowledging the importance of psychosocial stressors as inducing factors, since psychophysiological diathesis must still be accounted for. Several workers have noted the potential connection between creativity and madness, and the studies by Jamison and colleagues2,3 on psychiatric histories of artists and other creative people have suggested that there is sometimes a positive aspect of being "too moody" (poets, in particular, showed the highest rate of admission for psychiatric illness and participation in psychotropic medication trials). Andreasen4,s further extended this notion by studying the one
psychiatric histories of attendees at the Iowa writer’s workshop and their relatives, where she showed a significantly higher incidence of individuals with affective disorder, as well as more self-starting, creative, artistic, and scientifically innovative people than in controls. It is noteworthy that 5 of the 7 Americans to win the Nobel prize for literature were or are alcoholics (Eugene O’Neill, William Faulkner, John Steinbeck, Earnest Hemingway, F. Scott that alcoholism is thought to be dependently associated with affective disorder as part of so-called depression spectrum disease.6 One explanation for these observations would be a model with multiple genetic loci with excessive loading (approaching homozygosity), leading to an overly brief, intensely felt, creative life, or such severe illness that creativity is crushed by symptoms, but milder degrees (approaching heterozygosity) leading to a longer, creative life filled with elan and joie de vivre. Such people are likely to be attractive and interesting, to have strong feelings (including sexual), and to therefore be more likely to reproduce. This argument probably applies even in arranged marriages and rigid social relationships, because the whole family takes part in the process of mate selection, and that choice is usually based on achievement, wealth, leadership, or other forms of social value. Such a model would also explain the low prevalence (about 1% in the world population) of schizophrenia, a disorder mainly associated with social withdrawal and diminished, rather than intensified, interaction with others.
Fitzgerald) and
Child, Adolescent, and Adult Psychiatry, 7500 E Hellman Avenue, Rosemead, California 91770, USA
STEPHEN G. HAYES
1.
Regier DA, Boyd JH, Burke JD, et al. One month prevalence of mental disorders in the US, based on five epidemiologic catchment area sites. Arch Gen Psychiatry 1988;
2.
Jamison KR, Gerner RH, Hammen C, Padesky C. Clouds and silver linings: positive experiences associated with primary affective disorders. Am J Psychiatry 1950; 137:
45: 977-86.
198-202.
Jamison KR. Mood disorders and patterns of creativity in British writers and artists. Psychiatry 1989; 52: 125-34. 4. Andreasen NC. Creativity and mental illness. Prevalence rates in writers and their first-degree relatives. Am J Psychiatry 1987; 144: 1288-92. 5. Andreasen NC, Glick ID. Bipolar affective disorder and creativity: implications and clinical management. Psychiatry 1988; 29: 207-17. 3.
6. Pitts FN, Winokur G. Affective disorder, VII: alcoholism and affective disorder. J Psychiatr Res 1966; 4: 37-50.
SIR,-Dr Old in your commentary states that "the best example of heterozygote advantage remains sickle cell
understood
haemoglobin". This view was promulgated when little was known about the natural history of the disorder. Heterozygote advantage is a mechanism by which a deleterious or even fatal gene is maintained at low frequency in a population because it confers a selective advantage on the heterozygous individual. It can never maintain a gene at the levels seen in some sickle populations-ie, in excess of 30%. The work of the Medical Research Council abnornnal haemoglobin unit in Jamaica has shown that most homozygotes for the sickle gene do not sickle, develop normally, and live to old age. Although substantial morbidity and mortality can be ascribed to the gene, the reason why the gene is maintained at high frequency is the presence of a large number of healthy homozygotes, and not the
postulated heterozygote advantage. Haematology Department, Central Laboratory, Saint Mary’s Hospital, Portsmouth P03 6AG, UK
Prevention of
P. J. GREEN
postsplenectomy sepsis
SIR,-We agree with Dr Waghorn (Jan 23, p 248) that patient compliance with life-long penicillin prophylaxis after splenectomy is unlikely. We take a pragmatic approach, recommending a minimum of 2 years of penicillin or amoxycillin prophylaxis, with the caveat that at the first signs of infection the patient is advised to consult their general practitioner for broad-spectrum antibiotic treatment. A &bgr;-lactamase-stable antibiotic such as amoxycillin/clavulanate is necessary to be certain of activity against &bgr;-lactamase-producing Haemophilus influenzae isolates.
THE LANCET
and 336 IU/L; pancreatic type 67% and 62%, respectively). Only 2 of the 36 patients who were not given ephedrine developed hyperamylasaemia. Salivary-type amylase was dominant in 1 of these (454 IU/L, salivary type 83%) while the pancreatic type was dominant in the other (311 IU/L, pancreatic type 82%). 28 patients had been intubated for general anaesthesia; of these, 13 received ephedrine. 8 developed postoperative hyperamylasaemia, 7 of whom had received ephedrine. The degree of hypotension before the administration of ephedrine did not differ between the two ephedrine-treated subgroups (the 33 patients with postoperative hyperamylasaemia and the 58 with normal serum amylase). However, the dose of ephedrine used in the 33 (18-5 [12-0], 4-52 mg) was higher than that in the 58 (13-1 [9.3], 4-40 mg). &bgr;-sympathomimetics induce hypertrophy of the salivary gland6 and stimulate amylase secretion.7 We believe that most of the observed cases of postoperative hyperamylasaemia resulted from stimulation of &bgr;-adrenoceptors of the salivary glands by ephedrine. Differences in the frequency of postoperative hyperamylasaemia in previous reportsl-4 may have been due to differences in the use of ephedrine or other sympathomimetics during surgery.
Department of Obstetrics and Jichi Medical School, Tochigi, 329-04 Japan
Gynaecology,
HISANORI MINAKAMI TOSHIMITSU KOIKE MASAMI SUGIMURA TAKASHI WATANABE TARO TAMADA
1. Perrman RG, Hoerr SO. Observations on postoperative pancreatitis and postoperative
elevation of the serum amylase. Am J Surg 1954; 88: 417-20. 2. Harada K, Kitamura M, Ikenaga T. Isoenzyme study on postoperative transient hyperamylasemia. Am J Gastroenterol 1974; 61: 212-16. 3. Morrissey R, Berk JE, Fridhandler L, et al. The nature and significance of hyperamylasemia following operation. Ann Surg 1974; 180: 67-71. 4. Fröhlich EP, Herz C, van der Merwe FJ, et al. Serum amylase levels after obstetric and gynecologic operations. Surg Gynecol Obstet 1990; 170: 292-94. 5. Minakami H, Takahashi T, Izumi A, et al. Enlargement of salivary gland after ritodrine treatment in pregnant women. BMJ, 1992; 304: 1668. 6. Selye H, Veilleux R, Cantin M. Excessive stimulation of salivary gland growth by isoproterenol. Science 1961; 133: 44-45. 7. McPherson MA, Dormer RL, Bradbury NA, et al. Defective &bgr;-adrenergic secretory responses in submandibular acinar cells from cystic fibrosis patients. Lancet 1986; ii: 1007-08.
Underuse of antenatal corticosteroids and future litigation SIR,-Dr Khanna and Dr Richmond (Jan 16, p 174) provide further evidence that some obstetricians are not making sufficient use of corticosteroids to prevent neonatal morbidity and to reduce the costs of neonatal care. Their findings are consistent with the evidence of underuse in the mothers of babies who participated in the OSIRIS trial (Dec 5, p 1363), on which you commented
editorially. A mother who gave birth to her first child at 31 weeks’ wrote to after reading about Khanna and Richmond’s findings in The Independent.1 After the birth she learned that if she had been given corticosteroids her child would have been substantially less likely to have suffered in the way that he did. At 16 weeks’ gestation in her second pregnancy she was assured that steroids would be prescribed if it seemed likely that she was going to give birth prematurely again. This assurance had greatly alleviated her anxieties and she did indeed receive steroids as promised when she began labour at 31 weeks. In fact, her contractions ceased and she went on to have a normal delivery at
me
term.
As far as I am aware, this woman’s first child has no long-term sequelae from his potentially preventable neonatal morbidity. It is certain, however, that other preterm babies whose mothers could have received prophylactic steroids have died and that others are suffering long-term consequences of neonatal morbidity. It seems probable that the parents of some of these children will come to realise that they were not offered a form of care that might have prevented their child’s suffering. In view of trends in litigation, it would be surprising if none of them considered suing for
negligence. Liggins and Howie2 first showed that antenatal corticosteroids were effective in reducing serious neonatal morbidity and mortality
than twenty years ago. Their findings were strengthened by the results of at least 13 subsequent randomised trials. The strength of the evidence was made clear in a systematic review published by Crowley in 1989,3 and in an article4 and commentaryS published in January, 1990, in the journal of the Royal College of Obstetricians and Gynaecologists. It was not until three years later, however, that the College eventually encouraged all obstetric units to "consider the use of such therapy when delivery is likely before 34 weeks" 6 The substantial delay between the availability of strong scientific evidence and the College’s recommendation raises at least two questions. First, at which point during the past twenty years will it be judged to have been negligent not to have administered steroids when there were no clear contraindications? Second, is it possible that the target of litigants will not be individual obstetricians, but the body responsible for educating them?
more
The Cochrane Centre, Summertown Pavilion, Middle Way, Oxford OX2 7LG, UK
IAIN CHALMERS
1. Hunt L. Pregnancy drug ’held back’. The Independent 1992; 30 Sept: 7. 2. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of respiratory distress syndrome in premature infants. Pediatrics 1972; 50: 515-25. 3. Crowley P. Promoting pulmonary maturity. In: Chalmers I, Enkin M, Keirse MJNC, eds. Effective care in pregnancy and childbirth. Oxford: Oxford University Press, 1989: 746-64. 4. Crowley P, Chalmers I, Keirse MJNC. The effects of corticosteroid administration before preterm delivery: an overview of the evidence from controlled trials. Br J Obstet Gynaecol 1992; 97: 11-25. 5. Liggins GC. Obstetric and paediatric collaboration to reduce morbidity after preterm birth. Br J Obstet Gynaecol 1992; 97: 1-10. 6. Simmons SC. President’s letter to fellows and members. London: Royal College of Obstetricians and Gynaecologists, December, 1992 4-5.
Natural history of prostate cancer SIR,-As Mr Carr points out in your Jan 9 commentary, there is little doubt that there is conflicting evidence about the natural history of prostate cancer. However, until more is known about the natural history of this unpredictable disease the suggested management of expectant treatment or radical therapy for those with a reasonable life expectancy should be severely criticised. The expectant approach (which is justified by an apparent low prostate-cancer-specific mortality) is disadvantaged partly because this outcome is subject to well known vagaries but also because the fact of death seems to be at least as important. For example, if a treatment reduced death from metastases but gave a corresponding increase in the number of dying from coronary thrombosis without affecting the overall survival, it could scarcely be counted a success. The alternative of treating localised disease on the sole basis of life expectancy will result in overtreatment of naturally indolent disease with needless morbidity and mortality and consumption of scarce resources.1 However, although there is no satisfactory prognostic marker,2 there is evidence that assessment of oncoprotein and proliferation markers might both predict survival and assist in selecting those patients who should have radical treatment.3,4 Therefore, any trials of radical treatment in early prostate cancer not only should involve randomisation according to accepted clinicopathological tenets but also should consider the tumour indices that are more directly related to oncogenesis. Nuffield Department of Pathology, John Radcliffe Hospital, Oxford OX3 9DU, UK
Departments of Urology and Pathology, Addenbrookes Hospital, Cambridge Department of Public Health, University of Sheffield Medical School, Sheffield
STEPHEN B. Fox
RAJ A. PERSAD NICHOLAS COLEMAN PAUL B. SILCOCKS
Epstem JI, et al. Prediction of prognosis in untreated stage A2 prostanc carcinoma. Cancer 1992 69: 511-19. 2. Fox SB, Persad RA, Royds JA, Kore RN, Silcocks PB, Collins CC. p53 and c-myc expression in stage Al prostatic adenocarcinoma: prognostic determinants? y Urol 1. Mohler JC, Partin AW,
(m press). 3. Miller J, Horsfall
DJ, Marshall VR, Rao DM, Leong ASY. The prognostic value of deoxyribonucleic acid flow cytometric analysis in stage D2 prostatic carcinoma. J Urol 1991; 145: 1192-96. 4. Nemoto R, Kawamura H, Miyakawa I, et al. Immunohistochemical detection of proliferating cell nuclear antigen (PCNA)cyclin in human prostate adenocarcinoma. J Urol 1993; 149: 165-69.
700
THE LANCET
A frisky genotype for
primary hypertension?
SIR,-Dr Old’s commentary (Jan 23, p 214) on heterozygote advantage reminds me of a simple experiment I have vainly advocated at meetings for the past twenty years. It seems unlikely that the probably diverse genotypes that raise arterial pressure are all reproductively neutral. Although most but all their effect on survival operates after middle age, this is still within male reproductive age, and survival of wiser or more energetic old men and women may also assist group survival. Before contraception modified natural history, such evidence as we had on association of arterial pressure with fertility suggested that this relation was negative,l implying that there must be other countervailing advantages at least for survival of groups, if they include at least a proportion with hypertensive genotypes. Although people in the lowest centiles of arterial pressure distribution are at lower risk of premature death, they apparently feel less frisky than people in higher centiles of the distribution,2,3 and may thus contribute less to group survival. One reason could be that they actually are less frisky; that genotypes determining higher pressures may confer some kinds of greater competence to heterozygotes, sufficient to outweigh the survival disadvantages of homozygotes, for the group if not for individuals. We already know that this is not merely a matter of aggressive competitiveness; type A personality is not significantly associated with arterial pressure.4 This hypothesis can be readily tested. Tracking for high arterial pressure seems to be well established by age 18-20. University medical centres serving undergraduates have a rapid throughput of large numbers routinely subjected both to intake physical measurements and to output measures of achievement in all dimensions, including sporting and cultural activities. All we need is to bring these two sets of data together, and to see whether higher arterial pressure is associated with greater achievement in some or all of these dimensions. Any enterprising university medical centre should be able to set such a study up and get an answer within 5 years. Of course, such investigation would not be straightforward. The entry measurements would have to be raised to research quality, and include related variables such as arm circumference as well as height, weight, and girth. Exit measurements would need to include term examinations so that dropouts would not be missed. Neel’s thrifty genotype hypothesiss is an imaginative explanation for high prevalence of non-insulin dependent diabetes. Why not a frisky genotype for primary hypertension? not
Gelli
Deg,
Penmaen, Swansea SA3 2HH, UK 1. 2.
JULIAN TUDOR HART
Hart JT. Hypertension. London: Churchill Livingstone, 1980: 67-68. Pilgrim JA, Stansfeld S, Marmot M. Low blood pressure, low mood? BMJ 1992; 304: 75-78.
Wessely S, Nickson J, Cox B. Symptoms of low blood pressure: a population study. BMJ 1990; 301: 362-65. 4. Shekelle RB, Schoenberger JA, Stamler J. Correlates of the JAS type A behaviour pattern score. J Chron Dis 1976; 29: 381-94. 5. Neel JV. Diabetes mellitus: a thrifty genotype rendered detrimental by "progress"? Am J Hum Genet 1962; 14: 353-62.
3.
SIR,-Dr Old’s commentary on heterozygote advantage leads to about how this theory could apply to psychiatric illness. The Epidemiological Catchment Area Studyi indicated that about comment
in five Americans has some form of mental illness at some time in his or her life, predominantly as anxiety and depressive-related syndromes. Although the genetics of psychiatric conditions seem complex, one must account for the relative frequency of these conditions even acknowledging the importance of psychosocial stressors as inducing factors, since psychophysiological diathesis must still be accounted for. Several workers have noted the potential connection between creativity and madness, and the studies by Jamison and colleagues2,3 on psychiatric histories of artists and other creative people have suggested that there is sometimes a positive aspect of being "too moody" (poets, in particular, showed the highest rate of admission for psychiatric illness and participation in psychotropic medication trials). Andreasen4,s further extended this notion by studying the one
psychiatric histories of attendees at the Iowa writer’s workshop and their relatives, where she showed a significantly higher incidence of individuals with affective disorder, as well as more self-starting, creative, artistic, and scientifically innovative people than in controls. It is noteworthy that 5 of the 7 Americans to win the Nobel prize for literature were or are alcoholics (Eugene O’Neill, William Faulkner, John Steinbeck, Earnest Hemingway, F. Scott that alcoholism is thought to be dependently associated with affective disorder as part of so-called depression spectrum disease.6 One explanation for these observations would be a model with multiple genetic loci with excessive loading (approaching homozygosity), leading to an overly brief, intensely felt, creative life, or such severe illness that creativity is crushed by symptoms, but milder degrees (approaching heterozygosity) leading to a longer, creative life filled with elan and joie de vivre. Such people are likely to be attractive and interesting, to have strong feelings (including sexual), and to therefore be more likely to reproduce. This argument probably applies even in arranged marriages and rigid social relationships, because the whole family takes part in the process of mate selection, and that choice is usually based on achievement, wealth, leadership, or other forms of social value. Such a model would also explain the low prevalence (about 1% in the world population) of schizophrenia, a disorder mainly associated with social withdrawal and diminished, rather than intensified, interaction with others.
Fitzgerald) and
Child, Adolescent, and Adult Psychiatry, 7500 E Hellman Avenue, Rosemead, California 91770, USA
STEPHEN G. HAYES
1.
Regier DA, Boyd JH, Burke JD, et al. One month prevalence of mental disorders in the US, based on five epidemiologic catchment area sites. Arch Gen Psychiatry 1988;
2.
Jamison KR, Gerner RH, Hammen C, Padesky C. Clouds and silver linings: positive experiences associated with primary affective disorders. Am J Psychiatry 1950; 137:
45: 977-86.
198-202.
Jamison KR. Mood disorders and patterns of creativity in British writers and artists. Psychiatry 1989; 52: 125-34. 4. Andreasen NC. Creativity and mental illness. Prevalence rates in writers and their first-degree relatives. Am J Psychiatry 1987; 144: 1288-92. 5. Andreasen NC, Glick ID. Bipolar affective disorder and creativity: implications and clinical management. Psychiatry 1988; 29: 207-17. 3.
6. Pitts FN, Winokur G. Affective disorder, VII: alcoholism and affective disorder. J Psychiatr Res 1966; 4: 37-50.
SIR,-Dr Old in your commentary states that "the best example of heterozygote advantage remains sickle cell
understood
haemoglobin". This view was promulgated when little was known about the natural history of the disorder. Heterozygote advantage is a mechanism by which a deleterious or even fatal gene is maintained at low frequency in a population because it confers a selective advantage on the heterozygous individual. It can never maintain a gene at the levels seen in some sickle populations-ie, in excess of 30%. The work of the Medical Research Council abnornnal haemoglobin unit in Jamaica has shown that most homozygotes for the sickle gene do not sickle, develop normally, and live to old age. Although substantial morbidity and mortality can be ascribed to the gene, the reason why the gene is maintained at high frequency is the presence of a large number of healthy homozygotes, and not the
postulated heterozygote advantage. Haematology Department, Central Laboratory, Saint Mary’s Hospital, Portsmouth P03 6AG, UK
Prevention of
P. J. GREEN
postsplenectomy sepsis
SIR,-We agree with Dr Waghorn (Jan 23, p 248) that patient compliance with life-long penicillin prophylaxis after splenectomy is unlikely. We take a pragmatic approach, recommending a minimum of 2 years of penicillin or amoxycillin prophylaxis, with the caveat that at the first signs of infection the patient is advised to consult their general practitioner for broad-spectrum antibiotic treatment. A &bgr;-lactamase-stable antibiotic such as amoxycillin/clavulanate is necessary to be certain of activity against &bgr;-lactamase-producing Haemophilus influenzae isolates.