386
and are staying in a high-risk area should avoid dishes known to transmit the usual forms of food poisoning: raw foods, salads, ice-cream of uncertain origin, ice itself, prepared meat dishes, and meat pies that have been inadequately reheated. Safer foods are those whose handling is minimal or whose germs have been destroyed by adequate cooking-tinned foods or fish or meat well cooked just before serving. If cleanliness of water is suspect bottled drinks or water chlorinated with a suitable tablet can be taken instead. Water from the hot tap should be safe if really hot and so disinfected. Obviously such deprivations are unnecessary in areas where risk is low. Then travellers will abandon themselves to the pleasures of the table, relying only on an aperitif or wine to stimulate a flow of hydrochloric acid sufficient to destroy organisms before they can disturb the tranquillity of their gut-and what a savoury subject for another prospective trial. Merson, M H, et al, New England Journal of Medicine, 1976, 294, 1299. Rowe, B, Taylor, J, and Bettelheim, K A, Lancet, 1970, 1, 1. 3Loewenstein, M S, Balows, A, and Gangarosa, E J, Lancet, 1973, 1, 529. 4Kean, B H, and Waters, S R, The New England Journal of Medicine, 1959, 261,71. 5Turner, A C, British Medical_Journal, 1967, 4, 653. 6 Turner, A C, Lancet, 1976, 2, 320. 2
Feminists and sexual identity An American psychiatrist,1 writing recently on "pseudohomosexuality in feminist students," described how ideological commitment to the cause of feminism had led to increased uncertainty about their sexual identity in a sample of nine women college students. His theme is of wide importance. The days when issues of sexual identity seemed simple, when women patiently tended hearth and infants in their caves or semidetacheds while their men hunted or commuted to the City, are clearly no longer with us. It may seem strange that the affirmation by the women's movement of the value of their own sex should lead to rejection of that central aspect of it concerned with men. But any unthinking male indignation at the phenomenon of feminist lesbianism should be tempered by the recollection of the example of Sparta or the British public school tradition. We are far from understanding the implications for individual development of these ideological sexual debates, and in any case it would be premature to assume that the traditional stereotypes have been radically dislodged. In general, men are still seen as having more instrumental roles and women more expressive roles in the family and in society-even by students in the late '60s at a progressive university.2 Stereotypes, however, affect behaviour as well as describing it, and conventional cultural expectations may have influenced research. In social psychology, for example, the methods used for measuring masculinity and femininity have identified masculinity with effectiveness and femininity with passivity. On the basis of such criteria it has been shown that women who are more successful academically3 and women who coped better with the birth of their first child4 are less feminine than their sisters who manage these tasks less successfully. Even psychoanalysis, which has contributed so much to our understanding of the infantile roots of sexual identification and of sexual deviancy, has been trapped within the assumptions of a male-dominated culture.
BRITISH MEDICAL JOURNAL
14 AUGUST 1976
Nevertheless, while the ideological battle waged by the feminists seems justified and necessary, it is sometimes carried out in extreme terms, and the adherents of the movement number some women whose fear and devaluation of men is rooted in their particular personal histories. The arguments between ideologies, however, reflect and in turn influence the pains and conflicts lived out by individual women, some of whom are likely to consult doctors either with late adolescent confusions' or with marital conflict and crisis when they are older. How can doctors help? We are dealing with issues where there is no longer a social consensus; not only are old values and perceptions being challenged and new ones developed, but clearly both the values of a culture5 and an individual's view of himself and his relationships6 are inevitably contingent, idiosyncratic, and open to change. We no longer have authoritative maps of the social and behavioural world: to some extent each individual must be his own cartographer. The doctor has no claim for specialist authority, and it would be wrong if he was to attempt to impose his own concepts of normality as if these were justified on biological or social grounds. If, however, he can listen carefully, clarify the issues presented by his patients, withhold or honestly declare his own judgments, and withstand his own confusion, he may enable some of these women to resolve some of the inevitable conflicts more rapidly. If he can relinquish his claim to know, lock up his prescription pads, and put on his thinking hat, he may come to deserve a new kind of authority-as a facilitator who can help people to come to terms more constructively with a world that is (whether we like it or not) increasingly complicated and difficult. 1 Defries, Z, American Journal of Psychiatry, 1976, 133, 4, 400. 2 Ryle, A, and Lunghi, M, British Journal of Social and Clinical Psychology, 1972, 11, 149. 3 Heilbrun, A B, Psychological Reports, 1963, 12, 483. 4 Breen, Dana, The Birth of a First Child. London, Tavistock Publications, 1975. 5 Berger, P L, and Luckman, T, Social Construction of Reality. Harmondsworth, Penguin, 1971. 6 Kelly, G A, The Psychology of Personal Constructs. New York, Norton, 1955.
Prognostic factors in childhood leukaemia Much the most important determinant of prognosis in acute leukaemia of childhood is the cytological type. While children with acute myeloid leukaemia respond better to treatment than adults, the really long survivals-and the prospect of cureare still almost entirely confined to the lymphoblastic variety. Now that such long survivals are becoming commonplace' it is more than ever important to find means of predicting the likely outcome of treatment as accurately as possible in individual cases. Acute lymphoblastic leukaemia (ALL) is not one entity. Conventionally the leukaemic cells have been regarded as of lymphoid origin, but in about 70-80% of cases of ALL in childhood (null-cell ALL) they lack the characteristics of both T and B cells; T-cell leukaemias comprise about 20-30%; and B-cell leukaemias (in which the cells resemble those of Burkitt's lymphoma) not more than 2% of all cases. These cytological distinctions are clinically relevant, since both T-cell and B-cell leukaemias carry a much poorer prognosis than the
BRITISH MEDICAL JOURNAL
14 AUGUST 1976
387
large null-cell group. Even within this group, however, survival varies widely, and other presenting features may also be of value in assessing prognosis. The most reliable of these are the leucocyte (or blast-cell) count and the degree of clinical enlargement of liver, spleen, and lymph nodes-all indicators of the total body burden of leukaemic cells at diagnosis, which in turn probably reflects the proliferative rate of the malignant clone. In general, the longest remissions and survivals tend to be achieved in those patients with the lowest leucocyte counts and with minimal organ enlargement.2 3 Age and racial origin also have prognostic significance: children aged less than 2 years or over about 10 do less well than those between these ages,4' and Black children less well than White.'; Other adverse prognostic features include mediastinal involvement -usually a sign of T-cell leukaemia-and early evidence of spread to the central nervous system. Claims have also been made for the prognostic value of subclassification of leukaemic lymphoblasts on grounds of size7 or more subjective morphological criteria,8 but these have been strongly disputed."I Among cytochemical methods, the acid phosphatase positivity of lymphoblasts correlates well with their T-cell nature'2 and has a corresponding prognostic significance. But the degree of periodic acid Schiff (PAS) positivity, which has been claimed to be positively correlated with duration of remission, is at best only a weak indicator of
IBritish Medicalro/Jornal, 1975, 1, 111. 2 Till, M M, Hardisty, R M, and Pike, M C, Lancet, 1973, 1, 534. 3Simone, J V, Advances in the Biosciences, 1975, 14, 27. 4 Medical Research Council, British Medical3/ournal, 1971, 4, 7. Cangir, A, George, S, and Sullivan, M, Cancer, 1975, 36, 1973. 6 Walters, T, Bushore, M, and Simone, J, Cancer, 1972, 29, 210. 7Pantazopoulos, N, and Sinks, L F, British J7ournal of Haematology, 1974, 27, 25. Mathe, G, et al, European3Journal of Clinical and Biological Research, 1971, 16, 554. 9 Bernard, J, et al, Advances in the Biosciences, 1975, 14, 97. ') Murphy, S B, et al, British Journal of Haematology, 1975, 31, 95. 1 Oster, M W, et al, British Journal of Haematology, 1976, 33, 131. 1 Catovsky, D, et al, Journal of Clinical Pathology, 1974, 27, 767. 13 Tsukimoto, I, Wong, K Y, and Lampkin, B C, New England J'ournal of Medicine, 1976, 294, 245. 14 Medical Research Council, British Medical_Journal, 1971, 4, 189. 1 Medical Research Council, British Medical3Journal, 1973, 2, 381. 16 Hardisty, R M, Kay, H E M, and Smith, P G, in Therapy of Acute Leuikaemias, eds F Mandelli et al, p 97. Rome, Minerva Medica, 1975. 7 Medical Research Council, British Journal of Haematology, 1976, 33, 179.
prognosis. Many of these prognostic features are interrelated, so that it is difficult to decide how much reliance to place on each or to what extent the apparent effect of one feature may depend on its frequent association with another. As Tsukimoto et al'3 have suggested, for example, the adverse effect of a high leucocyte count, negative PAS reaction, and early spread to the central nervous system may be partly attributable (like that of mediastinal lesions) to their frequent association with T-cell leukaemia. The poorer response of older children-and of boys than girls in some reported series-may also be partly attributable to the same cause, since this type of ALL is much more common in boys and has a somewhat older age incidence than the null-cell variety. The influence of these various features clearly differs from one treatment regimen to another,14-'' and the careful analysis of such interactions between prognostic features and treatment may help us to devise more effective regimens for particular classes of patient. We can recognise a group of patients with null-cell ALL, aged between 2 and 10 years, with leucocyte counts below 20 000 ,ul and only minor degrees of enlargement of liver, spleen, or lymph nodes, who have, perhaps, a greater than 6000O chance of continuous complete remission for four years or more on any of several current therapeutic regimens, with the probability that a substantial proportion will prove to be cured. What of the others ? Should they be treated more intensively, or do they require a radically different approach ? Therapeutic trials designed to answer these questions are currently being carried out by several collaborative groups, including the Medical Research Council's Working Party on Leukaemia in Childhood. In the good prognostic group the present encouraging position has been reached by means of cranial radiotherapy and moderately intensive combination chemotherapy at the cost of a proportion of deaths from opportunistic infections during remission of the leukaemia. Such deaths are now of the same order of frequency as those from the leukaemia itself,'7 and in this group of patients greater improvement may be expected from modifying treatment regimens so as to reduce their immunosuppressive and myelotoxic effects than from further intensifying them.
Obstruction of the airways in asthma and chronic bronchitis may partly be caused by sputum or mucosal thickening, but it is the spasm of bronchial smooth muscle which we generally treat with one or more of the many bronchodilator preparations.' During acute attacks of asthma or exacerbations of chronic bronchitis we aim to reverse established bronchospasm and often use corticosteroids, oxygen, and other therapeutic measures in addition to bronchodilators. When treating a patient with chronic airway obstruction we hope to prevent or minimise the development of bronchospasm. The last decade has seen advances in the delivery of aerosols and in the development of newer and more specific drugs. In many instances the choice of the correct route of administration is as important as the choice of drug. Of the drugs available, the sympathomimetics are the most familiar. Adrenaline and ephedrine have been used for many years but have the disadvantage of stimulating ac-adrenoceptors (which causes vasoconstriction with a rise in blood pressure and might even cause bronchoconstriction) as well as 3-adrenoceptors (which leads to bronchodilatation, vasodilatation, and tachycardia). Isoprenaline predominantly stimulates the 3-adrenoceptors, but it is unselective: it stimulates both the 32-adrenoceptors of the bronchial smooth muscle to produce bronchodilatation and the Pl-adrenoceptors of the heart, increasing its forcefulness and rate of contraction. The cardiac stimulant effects of isoprenaline may be minimised if the patient inhales small amounts directly into the lungs, and tachycardia is not seen in asthmatic patients who use recommended doses from metered dose inhalers.2 Inhaled isoprenaline produces maximal bronchodilatation within a few minutes, but its effects wear off within one to two hours.3 Several selective F2-adrenoceptor stimulants have been developed, but they may still cause tachycardia in large doses, possibly secondary to 532-induced vasodilatation, and they have other side effects such as tremor. Rimiterol has a time course of action rather similar to isoprenaline,4 and orciprenaline,5 isoetharine,6 salbutamol,7 and terbutaline8 are longer acting. There is probably little to choose among these drugs in clinical practice,9 10 though most physicians and patients have their own favourites.
Bronchodilators, new and old
and are staying in a high-risk area should avoid dishes known to transmit the usual forms of food poisoning: raw foods, salads, ice-cream of uncertain origin, ice itself, prepared meat dishes, and meat pies that have been inadequately reheated. Safer foods are those whose handling is minimal or whose germs have been destroyed by adequate cooking-tinned foods or fish or meat well cooked just before serving. If cleanliness of water is suspect bottled drinks or water chlorinated with a suitable tablet can be taken instead. Water from the hot tap should be safe if really hot and so disinfected. Obviously such deprivations are unnecessary in areas where risk is low. Then travellers will abandon themselves to the pleasures of the table, relying only on an aperitif or wine to stimulate a flow of hydrochloric acid sufficient to destroy organisms before they can disturb the tranquillity of their gut-and what a savoury subject for another prospective trial. Merson, M H, et al, New England Journal of Medicine, 1976, 294, 1299. Rowe, B, Taylor, J, and Bettelheim, K A, Lancet, 1970, 1, 1. 3Loewenstein, M S, Balows, A, and Gangarosa, E J, Lancet, 1973, 1, 529. 4Kean, B H, and Waters, S R, The New England Journal of Medicine, 1959, 261,71. 5Turner, A C, British Medical_Journal, 1967, 4, 653. 6 Turner, A C, Lancet, 1976, 2, 320. 2
Feminists and sexual identity An American psychiatrist,1 writing recently on "pseudohomosexuality in feminist students," described how ideological commitment to the cause of feminism had led to increased uncertainty about their sexual identity in a sample of nine women college students. His theme is of wide importance. The days when issues of sexual identity seemed simple, when women patiently tended hearth and infants in their caves or semidetacheds while their men hunted or commuted to the City, are clearly no longer with us. It may seem strange that the affirmation by the women's movement of the value of their own sex should lead to rejection of that central aspect of it concerned with men. But any unthinking male indignation at the phenomenon of feminist lesbianism should be tempered by the recollection of the example of Sparta or the British public school tradition. We are far from understanding the implications for individual development of these ideological sexual debates, and in any case it would be premature to assume that the traditional stereotypes have been radically dislodged. In general, men are still seen as having more instrumental roles and women more expressive roles in the family and in society-even by students in the late '60s at a progressive university.2 Stereotypes, however, affect behaviour as well as describing it, and conventional cultural expectations may have influenced research. In social psychology, for example, the methods used for measuring masculinity and femininity have identified masculinity with effectiveness and femininity with passivity. On the basis of such criteria it has been shown that women who are more successful academically3 and women who coped better with the birth of their first child4 are less feminine than their sisters who manage these tasks less successfully. Even psychoanalysis, which has contributed so much to our understanding of the infantile roots of sexual identification and of sexual deviancy, has been trapped within the assumptions of a male-dominated culture.
BRITISH MEDICAL JOURNAL
14 AUGUST 1976
Nevertheless, while the ideological battle waged by the feminists seems justified and necessary, it is sometimes carried out in extreme terms, and the adherents of the movement number some women whose fear and devaluation of men is rooted in their particular personal histories. The arguments between ideologies, however, reflect and in turn influence the pains and conflicts lived out by individual women, some of whom are likely to consult doctors either with late adolescent confusions' or with marital conflict and crisis when they are older. How can doctors help? We are dealing with issues where there is no longer a social consensus; not only are old values and perceptions being challenged and new ones developed, but clearly both the values of a culture5 and an individual's view of himself and his relationships6 are inevitably contingent, idiosyncratic, and open to change. We no longer have authoritative maps of the social and behavioural world: to some extent each individual must be his own cartographer. The doctor has no claim for specialist authority, and it would be wrong if he was to attempt to impose his own concepts of normality as if these were justified on biological or social grounds. If, however, he can listen carefully, clarify the issues presented by his patients, withhold or honestly declare his own judgments, and withstand his own confusion, he may enable some of these women to resolve some of the inevitable conflicts more rapidly. If he can relinquish his claim to know, lock up his prescription pads, and put on his thinking hat, he may come to deserve a new kind of authority-as a facilitator who can help people to come to terms more constructively with a world that is (whether we like it or not) increasingly complicated and difficult. 1 Defries, Z, American Journal of Psychiatry, 1976, 133, 4, 400. 2 Ryle, A, and Lunghi, M, British Journal of Social and Clinical Psychology, 1972, 11, 149. 3 Heilbrun, A B, Psychological Reports, 1963, 12, 483. 4 Breen, Dana, The Birth of a First Child. London, Tavistock Publications, 1975. 5 Berger, P L, and Luckman, T, Social Construction of Reality. Harmondsworth, Penguin, 1971. 6 Kelly, G A, The Psychology of Personal Constructs. New York, Norton, 1955.
Prognostic factors in childhood leukaemia Much the most important determinant of prognosis in acute leukaemia of childhood is the cytological type. While children with acute myeloid leukaemia respond better to treatment than adults, the really long survivals-and the prospect of cureare still almost entirely confined to the lymphoblastic variety. Now that such long survivals are becoming commonplace' it is more than ever important to find means of predicting the likely outcome of treatment as accurately as possible in individual cases. Acute lymphoblastic leukaemia (ALL) is not one entity. Conventionally the leukaemic cells have been regarded as of lymphoid origin, but in about 70-80% of cases of ALL in childhood (null-cell ALL) they lack the characteristics of both T and B cells; T-cell leukaemias comprise about 20-30%; and B-cell leukaemias (in which the cells resemble those of Burkitt's lymphoma) not more than 2% of all cases. These cytological distinctions are clinically relevant, since both T-cell and B-cell leukaemias carry a much poorer prognosis than the
BRITISH MEDICAL JOURNAL
14 AUGUST 1976
387
large null-cell group. Even within this group, however, survival varies widely, and other presenting features may also be of value in assessing prognosis. The most reliable of these are the leucocyte (or blast-cell) count and the degree of clinical enlargement of liver, spleen, and lymph nodes-all indicators of the total body burden of leukaemic cells at diagnosis, which in turn probably reflects the proliferative rate of the malignant clone. In general, the longest remissions and survivals tend to be achieved in those patients with the lowest leucocyte counts and with minimal organ enlargement.2 3 Age and racial origin also have prognostic significance: children aged less than 2 years or over about 10 do less well than those between these ages,4' and Black children less well than White.'; Other adverse prognostic features include mediastinal involvement -usually a sign of T-cell leukaemia-and early evidence of spread to the central nervous system. Claims have also been made for the prognostic value of subclassification of leukaemic lymphoblasts on grounds of size7 or more subjective morphological criteria,8 but these have been strongly disputed."I Among cytochemical methods, the acid phosphatase positivity of lymphoblasts correlates well with their T-cell nature'2 and has a corresponding prognostic significance. But the degree of periodic acid Schiff (PAS) positivity, which has been claimed to be positively correlated with duration of remission, is at best only a weak indicator of
IBritish Medicalro/Jornal, 1975, 1, 111. 2 Till, M M, Hardisty, R M, and Pike, M C, Lancet, 1973, 1, 534. 3Simone, J V, Advances in the Biosciences, 1975, 14, 27. 4 Medical Research Council, British Medical3/ournal, 1971, 4, 7. Cangir, A, George, S, and Sullivan, M, Cancer, 1975, 36, 1973. 6 Walters, T, Bushore, M, and Simone, J, Cancer, 1972, 29, 210. 7Pantazopoulos, N, and Sinks, L F, British J7ournal of Haematology, 1974, 27, 25. Mathe, G, et al, European3Journal of Clinical and Biological Research, 1971, 16, 554. 9 Bernard, J, et al, Advances in the Biosciences, 1975, 14, 97. ') Murphy, S B, et al, British Journal of Haematology, 1975, 31, 95. 1 Oster, M W, et al, British Journal of Haematology, 1976, 33, 131. 1 Catovsky, D, et al, Journal of Clinical Pathology, 1974, 27, 767. 13 Tsukimoto, I, Wong, K Y, and Lampkin, B C, New England J'ournal of Medicine, 1976, 294, 245. 14 Medical Research Council, British Medical_Journal, 1971, 4, 189. 1 Medical Research Council, British Medical3Journal, 1973, 2, 381. 16 Hardisty, R M, Kay, H E M, and Smith, P G, in Therapy of Acute Leuikaemias, eds F Mandelli et al, p 97. Rome, Minerva Medica, 1975. 7 Medical Research Council, British Journal of Haematology, 1976, 33, 179.
prognosis. Many of these prognostic features are interrelated, so that it is difficult to decide how much reliance to place on each or to what extent the apparent effect of one feature may depend on its frequent association with another. As Tsukimoto et al'3 have suggested, for example, the adverse effect of a high leucocyte count, negative PAS reaction, and early spread to the central nervous system may be partly attributable (like that of mediastinal lesions) to their frequent association with T-cell leukaemia. The poorer response of older children-and of boys than girls in some reported series-may also be partly attributable to the same cause, since this type of ALL is much more common in boys and has a somewhat older age incidence than the null-cell variety. The influence of these various features clearly differs from one treatment regimen to another,14-'' and the careful analysis of such interactions between prognostic features and treatment may help us to devise more effective regimens for particular classes of patient. We can recognise a group of patients with null-cell ALL, aged between 2 and 10 years, with leucocyte counts below 20 000 ,ul and only minor degrees of enlargement of liver, spleen, or lymph nodes, who have, perhaps, a greater than 6000O chance of continuous complete remission for four years or more on any of several current therapeutic regimens, with the probability that a substantial proportion will prove to be cured. What of the others ? Should they be treated more intensively, or do they require a radically different approach ? Therapeutic trials designed to answer these questions are currently being carried out by several collaborative groups, including the Medical Research Council's Working Party on Leukaemia in Childhood. In the good prognostic group the present encouraging position has been reached by means of cranial radiotherapy and moderately intensive combination chemotherapy at the cost of a proportion of deaths from opportunistic infections during remission of the leukaemia. Such deaths are now of the same order of frequency as those from the leukaemia itself,'7 and in this group of patients greater improvement may be expected from modifying treatment regimens so as to reduce their immunosuppressive and myelotoxic effects than from further intensifying them.
Obstruction of the airways in asthma and chronic bronchitis may partly be caused by sputum or mucosal thickening, but it is the spasm of bronchial smooth muscle which we generally treat with one or more of the many bronchodilator preparations.' During acute attacks of asthma or exacerbations of chronic bronchitis we aim to reverse established bronchospasm and often use corticosteroids, oxygen, and other therapeutic measures in addition to bronchodilators. When treating a patient with chronic airway obstruction we hope to prevent or minimise the development of bronchospasm. The last decade has seen advances in the delivery of aerosols and in the development of newer and more specific drugs. In many instances the choice of the correct route of administration is as important as the choice of drug. Of the drugs available, the sympathomimetics are the most familiar. Adrenaline and ephedrine have been used for many years but have the disadvantage of stimulating ac-adrenoceptors (which causes vasoconstriction with a rise in blood pressure and might even cause bronchoconstriction) as well as 3-adrenoceptors (which leads to bronchodilatation, vasodilatation, and tachycardia). Isoprenaline predominantly stimulates the 3-adrenoceptors, but it is unselective: it stimulates both the 32-adrenoceptors of the bronchial smooth muscle to produce bronchodilatation and the Pl-adrenoceptors of the heart, increasing its forcefulness and rate of contraction. The cardiac stimulant effects of isoprenaline may be minimised if the patient inhales small amounts directly into the lungs, and tachycardia is not seen in asthmatic patients who use recommended doses from metered dose inhalers.2 Inhaled isoprenaline produces maximal bronchodilatation within a few minutes, but its effects wear off within one to two hours.3 Several selective F2-adrenoceptor stimulants have been developed, but they may still cause tachycardia in large doses, possibly secondary to 532-induced vasodilatation, and they have other side effects such as tremor. Rimiterol has a time course of action rather similar to isoprenaline,4 and orciprenaline,5 isoetharine,6 salbutamol,7 and terbutaline8 are longer acting. There is probably little to choose among these drugs in clinical practice,9 10 though most physicians and patients have their own favourites.
Bronchodilators, new and old
