- Email: [email protected]
THE LOMAX AFFAIR
264
of the two pigments is expressed, whereas in anomalous trichromacy two pigments are expressed but the anomalous pigment is displaced to a spectral location closer to that of its normal partner. Trichromacy is still achieved, but the ability to distinguish colours is slightly abnormal. Both opsin genes coding for the red and green sensitive pigments are composed of six coding regions or exons. Since exons 1 and 6 of the two genes are identical, the spectral differences between the two pigments must be a one
consequence of aminoacid substitutions in one or more of exons 2, 3, 4, and 5. Neitz and colleaguesz have lately determined the sequence of these exons in a male protanope -a subject who is red-green colour blind because he has only a single pigment sensitive to that region of the spectrum. The pigment is spectrally indistinguishable from the normal green-sensitive pigment. However, the gene encoding the pigment is a hybrid: exons 2 and 3 are derived from a normal red gene whereas exons 4 and 5 are derived from a normal green gene. Thus the spectral difference between the red and green sensitive pigments must be governed by aminoacid sequences encoded in exons 4 and 5. The number of non-homologous aminoacid substitutions that may be involved in the spectral difference between the two pigments is limited to two in exon 4 and three in exon 5. This finding has implications for the number of possible anomalous pigments that can be expressed from hybrid genes. That the hybrid genes present in all protoanomalous individuals examined at the molecular level have exon 5 derived from a green gene, while all deuteranomalous individuals have exon 5 derived from a red gene, strongly suggests that one or more of the aminoacid substitutions in this exon are responsible for the large spectral shift that distinguishes the red and green sensitive pigments. The smaller spectral shifts that differentiate the pigments in anomalous trichromats would depend on one or both substitutions in exon 4; since the nucleotides responsible for these two substitutions are only seven base-pairs apart, the production of a hybrid gene with an exchange site between them would be expected to be rare and has yet to be characterised. A much rarer form of X-linked colour vision deficiency, found in only about 0-01 % of the human population, is blue cone monochromacy. Subjects lack both of the longwavelength cone pigments and are completely colour blind. Their photopic vision is subserved by short-wavelength cones and consequently they have other visual deficiencies: their acuity is poor and they may have a pendular nystagmus. Nathans et all carried out a molecular study of 14 individuals from twelve families with this disorder. In all cases, alterations were observed in the gene clusters for the red and green sensitive pigments and these fell into two categories. Most had deletions of genomic DNA adjacent to the red and green gene cluster and, although the extent of the deletions varied between individuals, the researchers defined a small 579 base-pair regulatory region that is essential for the activity of both genes. This region is 4 kilobases upstream of the red gene and a massive 43 kilobases upstream of the green gene. The remaining individuals did not have the deletion; these subjects appear to have only a single gene from the red-green cluster which has undergone a further point mutation that renders it or its protein product non-functional. The molecular basis of these two forms of colour deficiency has now been established. Perhaps some of the more interesting outstanding questions relate to anomalous
trichromacy. How many "anomalous" pigments are there, what are their spectral locations, and what is the molecular genetic explanation? 1. Nathans J, Thomas D, Hogness DS. Molecular genetics of human color vision: the genes encoding blue, green and red pigments. Science 1986; 232: 193-203. 2. Neitz J, Neitz M, Jacobs GH. Analysis of fusion gene and encoded photopigment of colour-blind humans. Nature 1989; 342: 679-82. 3. Nathans J, Davenport CM, Maumenee IH. Molecular genetics of human blue cone monochromacy. Science 1989; 245: 831-38.
THE LOMAX AFFAIR In the mental health services, allegations of neglect and cruelty are hard to prove, and equally hard to dismiss. From
the Select Committee of the House of Commons, which investigated cases of alleged malpractice in private madhouses in 1763, through to the hospital inquiries of the 1970s-Whittingham, Normansfield, and many otherscommittees and commissions in the UK have sifted the evidence, and tried to get at the truth. Did these things really happen, or are the allegations unfounded? Are the staff covering up real abuse, or are they responsible people doing their best in a difficult job? Where there is a conflict of evidence, who is to be believed? How credible is this witness? Dr Montagu Lomax, whose story is told by Dr T-W. Harding in the latest issue of the British Journal of Psychiatry,l was not rated a very credible witness by his medical colleagues. His book, The Experiences of an Asylum Doctor,2 was described as "sensational" in his obituary in The Lancet;3the obituarist made it clear that Lomax was not qualified in asylum work: he was a temporary assistant medical officer in his early fifties, who had held only short-term and junior asylum appointments. When the Ministry of Health set up a committee of inquiry to investigate his allegations, he refused to give evidence, and most of his charges were dismissed. The Lancet was the only medical journal to grant Lomax an obituary of any kind. He had attracted the opprobrium of his professional colleagues, and drawn infuriated rebuttals in the journal of Mental Science. Yet asylums were badly run-down at the end of the 1914-18 war. Dr Lomax’s account of drab institutional life, of patients poorly dressed and poorly fed, of mechanical restraint and solitary confinement, of large doses of croton oil and occasional acts of brutality sounds likely enough in the circumstances. Why was his criticism so vehemently suppressed? Perhaps the real issue was whether an under-staffed and under-fmanced service could best be improved by professional solidarity or by going public-Lomax went public, and was discredited for it. Dr Harding has two substantial new pieces of evidence on the Lomax case. One is a long confidential minute written for the Minister of Health by Mr Percy Barter, a senior civil servant who supported Dr Lomax’s view and used The Experiences of an Asylum Doctor to bring about change. Lomax had asked for a Royal Commission. In 1924, the MacMillan Commission was appointed, and Barter was its secretary. Lomax willingly gave evidence this time. He was treated with respect, and the Commission made farreaching recommendations that led to the Mental Treatment Act of 1930. The confidential minute effectively ties Lomax’s account of asylum conditions to the subsequent reform of the mental health services. Dr
265
Harding’s other major piece of evidence consists of extracts from Lomax’s case-notes, which give a convincing picture of
a
humane and conscientious doctor with
a
respect for
patients’ rights. Is there any point in reviving the Lomax affair now, when the mental hospitals are emptying, and the new white-paper on community care promises a better service? One answer to this question is that injustice is always wrong, and it is better to put it right nearly seventy years later than to let it persist. Another is that mentally ill people can be neglected and ill-treated outside hospital4 as well as inside, and the mechanisms for monitoring their care in the community are much less effective than those that now operate in the hospital setting. Unless there is a very rapid growth of trained staff for community care, Britain may need another Montagu Lomax in the 1990s, with a wider remit. a reappraisal of Montagu Lomax’s contribution to mental health reform. Br J Psychiatry 1990; 156: 180-87. 2. Lomax M. The experiences of an asylum doctor. London: Allen and Unwin, 1921. 3. Obituary. Lancet 1933; i: 668. 4. Editorial. Dying with their rights on. Lancet 1989; ii: 1492.
1.
Harding T-W. Not worth powder and shot:
VOMITING AND CHEMOTHERAPY
vomiting are troublesome side-effects of cytotoxic drugs, especially cisplatin. In the early 1980s, Gralla1 reported the antiemetic efficacy of intermittent high-dose intravenous metoclopramide, and such regimens were believed to be an important therapeutic advance. It subsequently became clear that this was not a universally effective treatment, even when steady-state plasma concentrations were achieved by intravenous infusion. 2,3 Nausea and
Over the past ten years, research has followed various directions. Increasing the doses of other antiemetic drugs did not appear to have any advantage over high-dose metoclopramide; experimental evidence of a wide range of receptor systems in the area of the vomiting centres lent support to the hypothesis that simultaneous blockade of different systems with combinations of antiemetics might be beneficial; and since high-dose metoclopramide is associated with adverse effects, of which extrapyramidal reactions are the most prominent, attempts were made to reduce the frequency of these reactions by use of prophylactic therapy. Finally, recognition that metoclopramide at high doses exerted its effects via 5HT-receptor antagonism led to the development of new agents with this specific property, several of which are undergoing clinical trials.5 The emetic potential of the chemotherapy will influence the choice of antiemetic regimen, and some patients are more susceptible to emesis than others. These factors need to be considered when results of clinical trials are compared.6 Moreover, the extrapyramidal effects of metoclopramide appear to be age, and possibly sex, dependent.7 It is therefore not surprising that oncologists have investigated potential drug combinations that might be more efficacious, more acceptable for the patient, and easier to use
than infusion
Dexamethasone
regimens. was
potential in the late
early
first shown
1970s and
to
have antiemetic followed in the
lorazepam
1980s.° Dose-ranging studies with dexamethasone suggest that no benefit is achieved by increasing the dose above 8 mg intravenously." No such dose-ranging studies
have been done with lorazepam. The amnesia associated with 10razepamlO is a considerable advantage, but adverse effects such as sedation and dysphoria, especially in elderly patients, are dose-limiting. In highly emetic cytotoxic
(those containing cisplatin), significant improvement in efficacy is achieved by adding 10razepam12 or dexamethasone13 to high-dose metoclopramide. O’Brien and colleagues14 have lately investigated the effect of the combination of lorazepam and dexamethasone with or without high-dose metoclopramide. The combination of all three drugs was more effective in the management of cisplatin-induced vomiting (45% no vomiting, and 67% major control [two episodes or less of vomiting]) than were dexamethasone and lorazepam alone (11% no vomiting, 25 % major control). In this study, with a median patient age of 55 years, the frequency of extrapyramidal reactions was 11-5% with metoclopramide. Thus the combination of dexamethasone and lorazepam may be an alternative antiemetic regimen for patients receiving less emetogenic chemotherapy. In the USA a combination of metoclopramide, dexamethasone, and diphenhydramine intravenously has been investigated. is The frequency of dystonic extrapyramidal reactions, which are especially common in children and adults under 30 years, seems to be reduced by diphenhydramine. Lorazepam does not seem to share this benefit, but it probably produces better overall patient acceptability ratings than does diphenhydramine.11 Nausea and vomiting in patients who have left hospital 14 cannot be readily controlled by an intravenous regimen; the best therapy in such patients has not been established. Vomiting should be prevented whenever possible to reduce the risk of anticipatory emesis with future courses of chemotherapy. For cisplatin and other highly emetic chemotherapeutic regimens, the choice should be metoclopramide in combination with dexamethasone with either lorazepam or diphenhydramine. For less emetogenic regimens, the combination of dexamethasone and lorazepam may be effective and would avoid the risk of extrapyramidal side-effects seen with dopamine antagonists. Although most oncologists continue to use highdose metoclopramide intravenously, similar blood concentrations can be obtained with high doses orally.l’ However, a suitable oral preparation has not been developed. Perhaps the new 5HT3 receptor antagonists will enable patients to receive effective oral treatment while they are undergoing cancer chemotherapy. These agents, which should not cause the extrapyramidal effects associated with metoclopramide, have yet to be proved against the best of the existing antiemetic regimens. regimens
RJ, Itri LM, Pisko SE, et al. Anti-emetic efficacy of high-dose metoclopramide: randomised trial with placebo and prochlorperazine in patients with chemotherapy-induced nausea and vomiting. N Engl J
1. Gralla
Med 1981; 305: 905-09. 2.
Taylor WB, Procter SJ, Bateman DN. Pharmacokinetics and efficacy of high-dose metoclopramide given by continuous infusion for the control of cytotoxic drug-induced vomiting. Br J Clin Pharmacol 1984; 18:
3.
Warringon PS, Allan SG, Cornbleet MA, Macpherson JS, Smyth JF, Leonard RCF. Optimising antiemesis in cancer chemotherapy: efficacy of continuous versus intermittent infusion of high dose metoclopramide in emesis induced by cisplatin. Br Med J 1986; 293:
679-84.
1334-37. 4. Peroutka SJ, Snyder SH. Antiemetics: neurotransmitter receptor binding predicts therapeutic actions. Lancet 1982; i: 658-59. 5. Merrifield KR, Chaffee BJ. Recent advances in the treatment of nausea and vomiting caused by antineoplastic agents. Clin Pharmacy 1989; 8: 187-99.
of the two pigments is expressed, whereas in anomalous trichromacy two pigments are expressed but the anomalous pigment is displaced to a spectral location closer to that of its normal partner. Trichromacy is still achieved, but the ability to distinguish colours is slightly abnormal. Both opsin genes coding for the red and green sensitive pigments are composed of six coding regions or exons. Since exons 1 and 6 of the two genes are identical, the spectral differences between the two pigments must be a one
consequence of aminoacid substitutions in one or more of exons 2, 3, 4, and 5. Neitz and colleaguesz have lately determined the sequence of these exons in a male protanope -a subject who is red-green colour blind because he has only a single pigment sensitive to that region of the spectrum. The pigment is spectrally indistinguishable from the normal green-sensitive pigment. However, the gene encoding the pigment is a hybrid: exons 2 and 3 are derived from a normal red gene whereas exons 4 and 5 are derived from a normal green gene. Thus the spectral difference between the red and green sensitive pigments must be governed by aminoacid sequences encoded in exons 4 and 5. The number of non-homologous aminoacid substitutions that may be involved in the spectral difference between the two pigments is limited to two in exon 4 and three in exon 5. This finding has implications for the number of possible anomalous pigments that can be expressed from hybrid genes. That the hybrid genes present in all protoanomalous individuals examined at the molecular level have exon 5 derived from a green gene, while all deuteranomalous individuals have exon 5 derived from a red gene, strongly suggests that one or more of the aminoacid substitutions in this exon are responsible for the large spectral shift that distinguishes the red and green sensitive pigments. The smaller spectral shifts that differentiate the pigments in anomalous trichromats would depend on one or both substitutions in exon 4; since the nucleotides responsible for these two substitutions are only seven base-pairs apart, the production of a hybrid gene with an exchange site between them would be expected to be rare and has yet to be characterised. A much rarer form of X-linked colour vision deficiency, found in only about 0-01 % of the human population, is blue cone monochromacy. Subjects lack both of the longwavelength cone pigments and are completely colour blind. Their photopic vision is subserved by short-wavelength cones and consequently they have other visual deficiencies: their acuity is poor and they may have a pendular nystagmus. Nathans et all carried out a molecular study of 14 individuals from twelve families with this disorder. In all cases, alterations were observed in the gene clusters for the red and green sensitive pigments and these fell into two categories. Most had deletions of genomic DNA adjacent to the red and green gene cluster and, although the extent of the deletions varied between individuals, the researchers defined a small 579 base-pair regulatory region that is essential for the activity of both genes. This region is 4 kilobases upstream of the red gene and a massive 43 kilobases upstream of the green gene. The remaining individuals did not have the deletion; these subjects appear to have only a single gene from the red-green cluster which has undergone a further point mutation that renders it or its protein product non-functional. The molecular basis of these two forms of colour deficiency has now been established. Perhaps some of the more interesting outstanding questions relate to anomalous
trichromacy. How many "anomalous" pigments are there, what are their spectral locations, and what is the molecular genetic explanation? 1. Nathans J, Thomas D, Hogness DS. Molecular genetics of human color vision: the genes encoding blue, green and red pigments. Science 1986; 232: 193-203. 2. Neitz J, Neitz M, Jacobs GH. Analysis of fusion gene and encoded photopigment of colour-blind humans. Nature 1989; 342: 679-82. 3. Nathans J, Davenport CM, Maumenee IH. Molecular genetics of human blue cone monochromacy. Science 1989; 245: 831-38.
THE LOMAX AFFAIR In the mental health services, allegations of neglect and cruelty are hard to prove, and equally hard to dismiss. From
the Select Committee of the House of Commons, which investigated cases of alleged malpractice in private madhouses in 1763, through to the hospital inquiries of the 1970s-Whittingham, Normansfield, and many otherscommittees and commissions in the UK have sifted the evidence, and tried to get at the truth. Did these things really happen, or are the allegations unfounded? Are the staff covering up real abuse, or are they responsible people doing their best in a difficult job? Where there is a conflict of evidence, who is to be believed? How credible is this witness? Dr Montagu Lomax, whose story is told by Dr T-W. Harding in the latest issue of the British Journal of Psychiatry,l was not rated a very credible witness by his medical colleagues. His book, The Experiences of an Asylum Doctor,2 was described as "sensational" in his obituary in The Lancet;3the obituarist made it clear that Lomax was not qualified in asylum work: he was a temporary assistant medical officer in his early fifties, who had held only short-term and junior asylum appointments. When the Ministry of Health set up a committee of inquiry to investigate his allegations, he refused to give evidence, and most of his charges were dismissed. The Lancet was the only medical journal to grant Lomax an obituary of any kind. He had attracted the opprobrium of his professional colleagues, and drawn infuriated rebuttals in the journal of Mental Science. Yet asylums were badly run-down at the end of the 1914-18 war. Dr Lomax’s account of drab institutional life, of patients poorly dressed and poorly fed, of mechanical restraint and solitary confinement, of large doses of croton oil and occasional acts of brutality sounds likely enough in the circumstances. Why was his criticism so vehemently suppressed? Perhaps the real issue was whether an under-staffed and under-fmanced service could best be improved by professional solidarity or by going public-Lomax went public, and was discredited for it. Dr Harding has two substantial new pieces of evidence on the Lomax case. One is a long confidential minute written for the Minister of Health by Mr Percy Barter, a senior civil servant who supported Dr Lomax’s view and used The Experiences of an Asylum Doctor to bring about change. Lomax had asked for a Royal Commission. In 1924, the MacMillan Commission was appointed, and Barter was its secretary. Lomax willingly gave evidence this time. He was treated with respect, and the Commission made farreaching recommendations that led to the Mental Treatment Act of 1930. The confidential minute effectively ties Lomax’s account of asylum conditions to the subsequent reform of the mental health services. Dr
265
Harding’s other major piece of evidence consists of extracts from Lomax’s case-notes, which give a convincing picture of
a
humane and conscientious doctor with
a
respect for
patients’ rights. Is there any point in reviving the Lomax affair now, when the mental hospitals are emptying, and the new white-paper on community care promises a better service? One answer to this question is that injustice is always wrong, and it is better to put it right nearly seventy years later than to let it persist. Another is that mentally ill people can be neglected and ill-treated outside hospital4 as well as inside, and the mechanisms for monitoring their care in the community are much less effective than those that now operate in the hospital setting. Unless there is a very rapid growth of trained staff for community care, Britain may need another Montagu Lomax in the 1990s, with a wider remit. a reappraisal of Montagu Lomax’s contribution to mental health reform. Br J Psychiatry 1990; 156: 180-87. 2. Lomax M. The experiences of an asylum doctor. London: Allen and Unwin, 1921. 3. Obituary. Lancet 1933; i: 668. 4. Editorial. Dying with their rights on. Lancet 1989; ii: 1492.
1.
Harding T-W. Not worth powder and shot:
VOMITING AND CHEMOTHERAPY
vomiting are troublesome side-effects of cytotoxic drugs, especially cisplatin. In the early 1980s, Gralla1 reported the antiemetic efficacy of intermittent high-dose intravenous metoclopramide, and such regimens were believed to be an important therapeutic advance. It subsequently became clear that this was not a universally effective treatment, even when steady-state plasma concentrations were achieved by intravenous infusion. 2,3 Nausea and
Over the past ten years, research has followed various directions. Increasing the doses of other antiemetic drugs did not appear to have any advantage over high-dose metoclopramide; experimental evidence of a wide range of receptor systems in the area of the vomiting centres lent support to the hypothesis that simultaneous blockade of different systems with combinations of antiemetics might be beneficial; and since high-dose metoclopramide is associated with adverse effects, of which extrapyramidal reactions are the most prominent, attempts were made to reduce the frequency of these reactions by use of prophylactic therapy. Finally, recognition that metoclopramide at high doses exerted its effects via 5HT-receptor antagonism led to the development of new agents with this specific property, several of which are undergoing clinical trials.5 The emetic potential of the chemotherapy will influence the choice of antiemetic regimen, and some patients are more susceptible to emesis than others. These factors need to be considered when results of clinical trials are compared.6 Moreover, the extrapyramidal effects of metoclopramide appear to be age, and possibly sex, dependent.7 It is therefore not surprising that oncologists have investigated potential drug combinations that might be more efficacious, more acceptable for the patient, and easier to use
than infusion
Dexamethasone
regimens. was
potential in the late
early
first shown
1970s and
to
have antiemetic followed in the
lorazepam
1980s.° Dose-ranging studies with dexamethasone suggest that no benefit is achieved by increasing the dose above 8 mg intravenously." No such dose-ranging studies
have been done with lorazepam. The amnesia associated with 10razepamlO is a considerable advantage, but adverse effects such as sedation and dysphoria, especially in elderly patients, are dose-limiting. In highly emetic cytotoxic
(those containing cisplatin), significant improvement in efficacy is achieved by adding 10razepam12 or dexamethasone13 to high-dose metoclopramide. O’Brien and colleagues14 have lately investigated the effect of the combination of lorazepam and dexamethasone with or without high-dose metoclopramide. The combination of all three drugs was more effective in the management of cisplatin-induced vomiting (45% no vomiting, and 67% major control [two episodes or less of vomiting]) than were dexamethasone and lorazepam alone (11% no vomiting, 25 % major control). In this study, with a median patient age of 55 years, the frequency of extrapyramidal reactions was 11-5% with metoclopramide. Thus the combination of dexamethasone and lorazepam may be an alternative antiemetic regimen for patients receiving less emetogenic chemotherapy. In the USA a combination of metoclopramide, dexamethasone, and diphenhydramine intravenously has been investigated. is The frequency of dystonic extrapyramidal reactions, which are especially common in children and adults under 30 years, seems to be reduced by diphenhydramine. Lorazepam does not seem to share this benefit, but it probably produces better overall patient acceptability ratings than does diphenhydramine.11 Nausea and vomiting in patients who have left hospital 14 cannot be readily controlled by an intravenous regimen; the best therapy in such patients has not been established. Vomiting should be prevented whenever possible to reduce the risk of anticipatory emesis with future courses of chemotherapy. For cisplatin and other highly emetic chemotherapeutic regimens, the choice should be metoclopramide in combination with dexamethasone with either lorazepam or diphenhydramine. For less emetogenic regimens, the combination of dexamethasone and lorazepam may be effective and would avoid the risk of extrapyramidal side-effects seen with dopamine antagonists. Although most oncologists continue to use highdose metoclopramide intravenously, similar blood concentrations can be obtained with high doses orally.l’ However, a suitable oral preparation has not been developed. Perhaps the new 5HT3 receptor antagonists will enable patients to receive effective oral treatment while they are undergoing cancer chemotherapy. These agents, which should not cause the extrapyramidal effects associated with metoclopramide, have yet to be proved against the best of the existing antiemetic regimens. regimens
RJ, Itri LM, Pisko SE, et al. Anti-emetic efficacy of high-dose metoclopramide: randomised trial with placebo and prochlorperazine in patients with chemotherapy-induced nausea and vomiting. N Engl J
1. Gralla
Med 1981; 305: 905-09. 2.
Taylor WB, Procter SJ, Bateman DN. Pharmacokinetics and efficacy of high-dose metoclopramide given by continuous infusion for the control of cytotoxic drug-induced vomiting. Br J Clin Pharmacol 1984; 18:
3.
Warringon PS, Allan SG, Cornbleet MA, Macpherson JS, Smyth JF, Leonard RCF. Optimising antiemesis in cancer chemotherapy: efficacy of continuous versus intermittent infusion of high dose metoclopramide in emesis induced by cisplatin. Br Med J 1986; 293:
679-84.
1334-37. 4. Peroutka SJ, Snyder SH. Antiemetics: neurotransmitter receptor binding predicts therapeutic actions. Lancet 1982; i: 658-59. 5. Merrifield KR, Chaffee BJ. Recent advances in the treatment of nausea and vomiting caused by antineoplastic agents. Clin Pharmacy 1989; 8: 187-99.