- Email: [email protected]
Methodological and ethical difficulties in clinical oncology trials
CORRESPONDENCE
Access to treatment for HIV in developing countries Sir—In the consensus statement on access to treatment for HIV in developing countries (Oct 24, p 1379), approaches are described that could be instrumental in reducing the striking inequality in availability of treatment between HIV-infected people in different parts of the world. Since most of the HIV-infected people in the world are not benefiting from the success of antiretroviral therapy, it seems urgent to extend this essential treatment. This issue has also been covered elsewhere in The Lancet.2,3 The consensus statement includes discussion of antiretroviral therapy but, unfortunately, makes no mention of emerging drug-resistant viral strains. This is not a mere theoretical risk to be dealt with at some time, but the largely inevitable result of providing HIV therapy under less than strictly controlled conditions. The reason for our prediction is obvious from the highly demanding conditions for successful antiretroviral treatment, which are unobtainable in all but the most privileged countries. The treatment includes the use of costly drugs with intensive counselling, the accurate monitoring of treatment effects, and a strictly regulated access to medicines. Suboptimum therapy, only partly suppressing HIV replication, rapidly leads to a resistant transmissible virus.4 No one in the world should be denied appropriate treatment, however. For this reason, initiatives aimed at expanding access to antiretroviral treatment should take account of the potential for the generation of antiviral resistance, which would not only complicate effective treatment but might also lead to the spread of resistant viruses, locally and worldwide. Ultimately, widespread resistance would render new HIV infections difficult or even impossible to treat. How could such risks be avoided while introducing antiretroviral therapy in developing countries? Limiting this treatment to selected centres has been proposed but is probably not easily put into practice.3 Thus, we might not be able to satisfy the developing countries’ demand with an adapted form of Western standards, since less than stringent application of these drugs would lead to a boomerang effect, with the worldwide emergence of resistant HIV. Any discussion of increased access to HIV treatment
THE LANCET • Vol 353 • January 9, 1999
should contribute to the awareness of drug resistance. *A C M Kroes, D Leendertse, W J M Spaan Department of Virology, Leiden University Medical Centre, PO Boc 9600, 2300 RC Leiden, Netherlands (e-mail: [email protected]) 1
2 3 4
UK NGO AIDS Consortium Working Group on Access to Treatment for HIV in Developing Countries. Access to treatment for HIV in developing countries, statement from international seminar on access to treatment for HIV in developing countries, London, June 5 and 6, 1998. Lancet 1998; 352: 1379–80. Feinmann J. Antiretrovirals planned for developing world. Lancet 1997; 350: 1759. Adler MW. Antiretrovirals for developing world. Lancet 1998; 351: 232. Cohen OJ, Fauci AS. Transmission of multidrug-resistant human immunodeficiency virus—the wake-up call. N Engl J Med 1998; 339: 341–43.
Methodological and ethical difficulties in clinical oncology trials Sir—Among the many methodological and ethical difficulties that clinical trials in oncology have to face, the oncological community has failed to recognise those described by Giuseppe Brera and Claudio Violato (Oct 24, p 1391).1 Their list of “basic imperatives of an adequate clinical trial” jumps over three decades of developments in cancer clinical trials, and puts forward an entirely new approach. The standard methodology for the evaluation of a new treatment, which was specifically designed to assess anticancer agents with a cytotoxic effect (phase I, II, and III trials), is described in many textbooks (see for example refs 2, 3). Nowhere have we ever found a description of a study design even vaguely resembling that of Brera and Violato. The idea of an “initial double-blind, treatment-control group pilot study” is fascinating, because it is exactly the opposite of the old fashioned practice in clinical cancer research. Double-blind studies were seldom, if ever, used in cancer trials, mainly because of the obvious toxicity of most cancer treatments, but in the future we will do our best to design placebos capable of reproducing the same toxic effects of the experimental treatments. So far, randomised trials have been reserved for the later stages (phase III) of the development of a treatment, after its activity and acceptable toxicity had been demonstrated in pilot (phase I–II) trials. The pilot trials were usually studies without a control group,
because of the specificity of the endpoints (objective response and toxicity), and included but a few dozens of patients, to keep to a minimum the patients exposed to useless and potentially harmful treatments. Specifically, phase II trials were regarded as a quick, safe, and efficient tool for screening drugs or other treatments without promising anticancer activity, from those warranting further testing in the much larger and longer phase III trials. For this reason, the steering committee appointed by the Italian Ministry of Health to evaluate the Di Bella treatment decided to start ten phase II trials in ten different oncological conditions, before launching any large randomised trial, but we have now come to learn from Brera and Violato that the committee was wrong. And it was wrong also, according to these workers, when it decided not to enrol in these pilot trials patients amenable to be effectively treated, or children— failing, by doing so, to meet the ethical requirements of a clinical trial. With respect to the last two so-called ethical drawbacks mentioned by Brera and Violato: “preliminary results have been released . . . without careful peer review” and “early release of results . . . pronouncing the treatments ineffective”, all details about the definitive results of the first four trials on Di Bella’s treatment can be found in the official publication released by the Italian National Health Institute.4 Again we learn from your correspondents that it is unethical to inform treated patients and their relatives about the results of a trial when these results are negative. The many clinical, scientific, ethical, philosophical (freedom of cure), and financial issues raised by the Di Bella therapy generated endless debate with a massive involvement of the public, but the scientific community needs to recover the ability to discuss these delicate issues with more sound arguments. Cancer patients, in fact, deserve better. *Roberto Raschetti, Paolo Bruzzi, for the Di Bella Multitreatment Italian Trial Coordinating Group *Department of Epidemiology and Biostatistics, Istituto Superiore di Sanità, 00161 Roma, Italy; and Unit of Clinical Epidemiology, Istituto Nationale Ricerca sul Cancro, Genova (e-mail: [email protected]) 1
2
Brera GR, Violato C. Methodological and ethical difficulties in clinical oncology studies. Lancet 1998; 352: 1391. Levental BG, Wittes RE. Research methods in clinical oncology. New York: Raven Press, 1988.
153
CORRESPONDENCE 3
4
De Vita VT, Hellman S, Rosenberg SA. Cancer: principles and practice of oncology, 5th ed. New York: Lippincott-Raven, 1997. The Di Bella’s Multitreatment Coordinating Group. Risultati della sperimentazione del Multitrattamento Di Bella (protocolli n. 4, 6, 8, 10). Rapporti ISTISAN 1998; 98: 17.
1
2
3
Social class and coronary artery disease in India Sir—We do not agree with Larry Husten’s Nov 7 feature (p 1530)1 that lower social classes in developing world have the greater burden of coronary artery disease than higher social classes. We agree that coronary artery disease occurs first in the higher social classes and later in lower social classes with increasing affluence.2 We found that of 3257 women, aged 25–64 years, those from the higher social classes were not the first to respond to the knowledge of risk factors and the message of prevention in our five city study.3,4 We found that prevalence of coronary artery disease was high among higher social classes in both rural and urban populations3,4 although their dietary fat intake and serum concentrations of cholesterol were within desirable limits of the existing guidelines.5 We also do not agree with Husten’s suggestion that a lower middle class Indian family has no option but to depend on oil and fat as a major source of food rather than fruits, vegetables, and cereals. We examined the prevalence of coronary disease and intake of fruit and vegetables and visible fat in 1775 people from social classes 1–2 and in 1482 people from social clases 3–5. We found that the consumption of fruits, vegetables, and legumes did not differ significantly between social classes (186 (SD 65) in classes 1–2 vs 189 [61] g daily in classes 3–5). In towns with populations under one million, fruites and vegetables are brought by the farmers directly to the market on their head or carts, so usually seasonal fruits and vegetables remain cheap for the common man. We found that higher social classes not only eat more fruits and vegetables but also more fat than lower social classes (40·1 [16] vs 16·1 [5] g daily, p<0·01 by x2 test), so the ratio of fruit and vegetables to unsaturated fat remains low (ratio 4·63 [1·5] in classes 1–2 vs 11·73 [3·2] in classes 3–5, p<0·01), which may predispose them to higher risk of coronary artery disease. *R B Singh, S P Verma, M A Niaz Medical Hospital and Research Centre, Heart Research Laboratory and Centre of Nutrition, Civil Lines, Moradabad-10 UP, 244001 India (e-mail: [email protected])
154
4
5
Husten L. Global epidemic of cardiovascular disease predicted. Lancet 1998; 352: 1530. Janus ED, Postiglione A, Singh RB, Lewis B. On behalf of council on Arteriosclerosis of World Heart Federation. The modernization of Asia, implications for coronary artery disease. Circulation 1996; 94: 2671–73. Singh RB, Sharma JP, Rastogi V, et al. Social class and coronary disease in a rural population of north India. Eur Heart J 1997; 18: 588–95. Sing RB, Niaz MA, Thakur AS, Janus ED, Moshiri M. Social class and coronary artery disease in a urban population of north India in the Indian lifestyle and heart study. Int J Cardiol 1998; 64: 195–203. Singh RB, Niaz MA, Ghosh S, et al. Low fat intake and coronary artery disease in a population with higher prevalence of coronary artery disease: the Indian paradox. J Am Coll Nutr 1998; 17: 342–50.
Prescribing of “less suitable” drugs Sir—In his Nov 14 news piece1 about health efficiencies and the setting up of the National Institute for Clinical Excellence (NICE), Malcolm Dean, links the need for financial efficiencies with the recent call from social audit to examine the prescribing of drugs identified by the British National Formulary as being “less suitable for prescribing”. Dean states that such products are flagged up ‘for the first time’ in the 36th edition of the British National Formulary (BNF). In fact, even the first 1981 edition of the current series identified products that the Joint Formulary Committee judged to be less suitable for prescribing. Products such as Cantil and Phenobarbitone (mepenzolae and phenobarbital), Bellergal (belladonna alkaloids, ergotamine, and phenobarbitone), and Chymocyclar (pancreatic concentrate and tetracycline) were shown in small print to signal the Committee’s lack of confidence in them. Prescribing has come a long way since those days and, thankfully, none of these preparations remains on the UK market. In the current edition of the BNF, the device of using smaller print has been replaced by a symbol to identify the “less suitable” preparations. This change and other design changes were made to enable the busy prescriber or pharmacist to find and extract relevant information more quickly. Social audit calculates that over £100 million is spent on preparations that the BNF deems less suitable. This figure gives a good indication of the level of potentially inappropriate prescribing, but it would be naïve to infer that avoiding these preparations will reduce the drugs bill: in many cases more expensive alternatives may need to be
prescribed. The benefits of rational prescribing include health gains and possibly a reduction in the overall health expenditure. As with all medical information, doctors need to interpret the BNF’s “less suitable” message in the light of individual patient circumstances and any new evidence. The BNF deliberately does not state that the products in question should be avoided altogether. Dinesh K Mehta British National Formulary, The Royal Pharmaceutical Society of Great Britain, London SE1 7JN, UK (e-mail: [email protected]) 1
Dean M. UK ministers seek NICE new health efficiencies. Lancet 1998; 352: 1607.
Yellow fever vaccination Sir—On a recent lecture tour, I was not able to travel from Columbia to Brazil because I did not have the yellow fever vaccination. This vaccine is not required when travelling from UK to Columbia or to Brazil, only if travelling from Columbia to Brazil. The rationale being that the mosquito vector for the virus is still prevalent in Brazil. However, I now know that I could have purchased a vaccination certification (available from Travel Agents in Columbia) for US$40 without being vaccinated. This makes a total nonsense of the legislation and I wonder how common knowledge this ploy is. Derek Middleton Northern Ireland Histocompatibility and Immunogenetics Laboratory, City Hospital, Belfast, BT9 7TS, UK
DEPARTMENT OF ERROR Randomised trial to assess benefits and safety of vitamin A supplementation linked to immunisation in early infancy—In this article by the WHO/CHD Immunisation-Linked Vitamin A Supplementation Study Group (Oct 17, p 1257), the first sentence of the results section under the subheading Anthropometry should start: “We found no significant between-group differences in the infants’ mean weight . . .” Stable amoxicillin resistance in Helicobacter pylori—In this Research letter by A A van Zwet and colleagues (Nov 14, p 1595), the correct spelling of the second author’s surname is Vandenbroucke-Grauls. Preferential involvement of excitatory neurons in medial temporal lobe in schizophrenia—In this Early Report by Paul J Harrison and colleagues (Nov 21, p 1669), the final sentence in the legend for figure 1 should have read: “Presence of complexin I in dentate gyrus and CA1 (B) despite lack of its mRNA (A) is explained by presynaptic localisation of protein, distant from cell bodies where mRNA is found”. In table 2, column 2, the significance marks were omitted from the complexin I mRNA data; the reductions in CA3 and subiculum in schizophrenia were both significant (p<0·01).
THE LANCET • Vol 353 • January 9, 1999
Access to treatment for HIV in developing countries Sir—In the consensus statement on access to treatment for HIV in developing countries (Oct 24, p 1379), approaches are described that could be instrumental in reducing the striking inequality in availability of treatment between HIV-infected people in different parts of the world. Since most of the HIV-infected people in the world are not benefiting from the success of antiretroviral therapy, it seems urgent to extend this essential treatment. This issue has also been covered elsewhere in The Lancet.2,3 The consensus statement includes discussion of antiretroviral therapy but, unfortunately, makes no mention of emerging drug-resistant viral strains. This is not a mere theoretical risk to be dealt with at some time, but the largely inevitable result of providing HIV therapy under less than strictly controlled conditions. The reason for our prediction is obvious from the highly demanding conditions for successful antiretroviral treatment, which are unobtainable in all but the most privileged countries. The treatment includes the use of costly drugs with intensive counselling, the accurate monitoring of treatment effects, and a strictly regulated access to medicines. Suboptimum therapy, only partly suppressing HIV replication, rapidly leads to a resistant transmissible virus.4 No one in the world should be denied appropriate treatment, however. For this reason, initiatives aimed at expanding access to antiretroviral treatment should take account of the potential for the generation of antiviral resistance, which would not only complicate effective treatment but might also lead to the spread of resistant viruses, locally and worldwide. Ultimately, widespread resistance would render new HIV infections difficult or even impossible to treat. How could such risks be avoided while introducing antiretroviral therapy in developing countries? Limiting this treatment to selected centres has been proposed but is probably not easily put into practice.3 Thus, we might not be able to satisfy the developing countries’ demand with an adapted form of Western standards, since less than stringent application of these drugs would lead to a boomerang effect, with the worldwide emergence of resistant HIV. Any discussion of increased access to HIV treatment
THE LANCET • Vol 353 • January 9, 1999
should contribute to the awareness of drug resistance. *A C M Kroes, D Leendertse, W J M Spaan Department of Virology, Leiden University Medical Centre, PO Boc 9600, 2300 RC Leiden, Netherlands (e-mail: [email protected]) 1
2 3 4
UK NGO AIDS Consortium Working Group on Access to Treatment for HIV in Developing Countries. Access to treatment for HIV in developing countries, statement from international seminar on access to treatment for HIV in developing countries, London, June 5 and 6, 1998. Lancet 1998; 352: 1379–80. Feinmann J. Antiretrovirals planned for developing world. Lancet 1997; 350: 1759. Adler MW. Antiretrovirals for developing world. Lancet 1998; 351: 232. Cohen OJ, Fauci AS. Transmission of multidrug-resistant human immunodeficiency virus—the wake-up call. N Engl J Med 1998; 339: 341–43.
Methodological and ethical difficulties in clinical oncology trials Sir—Among the many methodological and ethical difficulties that clinical trials in oncology have to face, the oncological community has failed to recognise those described by Giuseppe Brera and Claudio Violato (Oct 24, p 1391).1 Their list of “basic imperatives of an adequate clinical trial” jumps over three decades of developments in cancer clinical trials, and puts forward an entirely new approach. The standard methodology for the evaluation of a new treatment, which was specifically designed to assess anticancer agents with a cytotoxic effect (phase I, II, and III trials), is described in many textbooks (see for example refs 2, 3). Nowhere have we ever found a description of a study design even vaguely resembling that of Brera and Violato. The idea of an “initial double-blind, treatment-control group pilot study” is fascinating, because it is exactly the opposite of the old fashioned practice in clinical cancer research. Double-blind studies were seldom, if ever, used in cancer trials, mainly because of the obvious toxicity of most cancer treatments, but in the future we will do our best to design placebos capable of reproducing the same toxic effects of the experimental treatments. So far, randomised trials have been reserved for the later stages (phase III) of the development of a treatment, after its activity and acceptable toxicity had been demonstrated in pilot (phase I–II) trials. The pilot trials were usually studies without a control group,
because of the specificity of the endpoints (objective response and toxicity), and included but a few dozens of patients, to keep to a minimum the patients exposed to useless and potentially harmful treatments. Specifically, phase II trials were regarded as a quick, safe, and efficient tool for screening drugs or other treatments without promising anticancer activity, from those warranting further testing in the much larger and longer phase III trials. For this reason, the steering committee appointed by the Italian Ministry of Health to evaluate the Di Bella treatment decided to start ten phase II trials in ten different oncological conditions, before launching any large randomised trial, but we have now come to learn from Brera and Violato that the committee was wrong. And it was wrong also, according to these workers, when it decided not to enrol in these pilot trials patients amenable to be effectively treated, or children— failing, by doing so, to meet the ethical requirements of a clinical trial. With respect to the last two so-called ethical drawbacks mentioned by Brera and Violato: “preliminary results have been released . . . without careful peer review” and “early release of results . . . pronouncing the treatments ineffective”, all details about the definitive results of the first four trials on Di Bella’s treatment can be found in the official publication released by the Italian National Health Institute.4 Again we learn from your correspondents that it is unethical to inform treated patients and their relatives about the results of a trial when these results are negative. The many clinical, scientific, ethical, philosophical (freedom of cure), and financial issues raised by the Di Bella therapy generated endless debate with a massive involvement of the public, but the scientific community needs to recover the ability to discuss these delicate issues with more sound arguments. Cancer patients, in fact, deserve better. *Roberto Raschetti, Paolo Bruzzi, for the Di Bella Multitreatment Italian Trial Coordinating Group *Department of Epidemiology and Biostatistics, Istituto Superiore di Sanità, 00161 Roma, Italy; and Unit of Clinical Epidemiology, Istituto Nationale Ricerca sul Cancro, Genova (e-mail: [email protected]) 1
2
Brera GR, Violato C. Methodological and ethical difficulties in clinical oncology studies. Lancet 1998; 352: 1391. Levental BG, Wittes RE. Research methods in clinical oncology. New York: Raven Press, 1988.
153
CORRESPONDENCE 3
4
De Vita VT, Hellman S, Rosenberg SA. Cancer: principles and practice of oncology, 5th ed. New York: Lippincott-Raven, 1997. The Di Bella’s Multitreatment Coordinating Group. Risultati della sperimentazione del Multitrattamento Di Bella (protocolli n. 4, 6, 8, 10). Rapporti ISTISAN 1998; 98: 17.
1
2
3
Social class and coronary artery disease in India Sir—We do not agree with Larry Husten’s Nov 7 feature (p 1530)1 that lower social classes in developing world have the greater burden of coronary artery disease than higher social classes. We agree that coronary artery disease occurs first in the higher social classes and later in lower social classes with increasing affluence.2 We found that of 3257 women, aged 25–64 years, those from the higher social classes were not the first to respond to the knowledge of risk factors and the message of prevention in our five city study.3,4 We found that prevalence of coronary artery disease was high among higher social classes in both rural and urban populations3,4 although their dietary fat intake and serum concentrations of cholesterol were within desirable limits of the existing guidelines.5 We also do not agree with Husten’s suggestion that a lower middle class Indian family has no option but to depend on oil and fat as a major source of food rather than fruits, vegetables, and cereals. We examined the prevalence of coronary disease and intake of fruit and vegetables and visible fat in 1775 people from social classes 1–2 and in 1482 people from social clases 3–5. We found that the consumption of fruits, vegetables, and legumes did not differ significantly between social classes (186 (SD 65) in classes 1–2 vs 189 [61] g daily in classes 3–5). In towns with populations under one million, fruites and vegetables are brought by the farmers directly to the market on their head or carts, so usually seasonal fruits and vegetables remain cheap for the common man. We found that higher social classes not only eat more fruits and vegetables but also more fat than lower social classes (40·1 [16] vs 16·1 [5] g daily, p<0·01 by x2 test), so the ratio of fruit and vegetables to unsaturated fat remains low (ratio 4·63 [1·5] in classes 1–2 vs 11·73 [3·2] in classes 3–5, p<0·01), which may predispose them to higher risk of coronary artery disease. *R B Singh, S P Verma, M A Niaz Medical Hospital and Research Centre, Heart Research Laboratory and Centre of Nutrition, Civil Lines, Moradabad-10 UP, 244001 India (e-mail: [email protected])
154
4
5
Husten L. Global epidemic of cardiovascular disease predicted. Lancet 1998; 352: 1530. Janus ED, Postiglione A, Singh RB, Lewis B. On behalf of council on Arteriosclerosis of World Heart Federation. The modernization of Asia, implications for coronary artery disease. Circulation 1996; 94: 2671–73. Singh RB, Sharma JP, Rastogi V, et al. Social class and coronary disease in a rural population of north India. Eur Heart J 1997; 18: 588–95. Sing RB, Niaz MA, Thakur AS, Janus ED, Moshiri M. Social class and coronary artery disease in a urban population of north India in the Indian lifestyle and heart study. Int J Cardiol 1998; 64: 195–203. Singh RB, Niaz MA, Ghosh S, et al. Low fat intake and coronary artery disease in a population with higher prevalence of coronary artery disease: the Indian paradox. J Am Coll Nutr 1998; 17: 342–50.
Prescribing of “less suitable” drugs Sir—In his Nov 14 news piece1 about health efficiencies and the setting up of the National Institute for Clinical Excellence (NICE), Malcolm Dean, links the need for financial efficiencies with the recent call from social audit to examine the prescribing of drugs identified by the British National Formulary as being “less suitable for prescribing”. Dean states that such products are flagged up ‘for the first time’ in the 36th edition of the British National Formulary (BNF). In fact, even the first 1981 edition of the current series identified products that the Joint Formulary Committee judged to be less suitable for prescribing. Products such as Cantil and Phenobarbitone (mepenzolae and phenobarbital), Bellergal (belladonna alkaloids, ergotamine, and phenobarbitone), and Chymocyclar (pancreatic concentrate and tetracycline) were shown in small print to signal the Committee’s lack of confidence in them. Prescribing has come a long way since those days and, thankfully, none of these preparations remains on the UK market. In the current edition of the BNF, the device of using smaller print has been replaced by a symbol to identify the “less suitable” preparations. This change and other design changes were made to enable the busy prescriber or pharmacist to find and extract relevant information more quickly. Social audit calculates that over £100 million is spent on preparations that the BNF deems less suitable. This figure gives a good indication of the level of potentially inappropriate prescribing, but it would be naïve to infer that avoiding these preparations will reduce the drugs bill: in many cases more expensive alternatives may need to be
prescribed. The benefits of rational prescribing include health gains and possibly a reduction in the overall health expenditure. As with all medical information, doctors need to interpret the BNF’s “less suitable” message in the light of individual patient circumstances and any new evidence. The BNF deliberately does not state that the products in question should be avoided altogether. Dinesh K Mehta British National Formulary, The Royal Pharmaceutical Society of Great Britain, London SE1 7JN, UK (e-mail: [email protected]) 1
Dean M. UK ministers seek NICE new health efficiencies. Lancet 1998; 352: 1607.
Yellow fever vaccination Sir—On a recent lecture tour, I was not able to travel from Columbia to Brazil because I did not have the yellow fever vaccination. This vaccine is not required when travelling from UK to Columbia or to Brazil, only if travelling from Columbia to Brazil. The rationale being that the mosquito vector for the virus is still prevalent in Brazil. However, I now know that I could have purchased a vaccination certification (available from Travel Agents in Columbia) for US$40 without being vaccinated. This makes a total nonsense of the legislation and I wonder how common knowledge this ploy is. Derek Middleton Northern Ireland Histocompatibility and Immunogenetics Laboratory, City Hospital, Belfast, BT9 7TS, UK
DEPARTMENT OF ERROR Randomised trial to assess benefits and safety of vitamin A supplementation linked to immunisation in early infancy—In this article by the WHO/CHD Immunisation-Linked Vitamin A Supplementation Study Group (Oct 17, p 1257), the first sentence of the results section under the subheading Anthropometry should start: “We found no significant between-group differences in the infants’ mean weight . . .” Stable amoxicillin resistance in Helicobacter pylori—In this Research letter by A A van Zwet and colleagues (Nov 14, p 1595), the correct spelling of the second author’s surname is Vandenbroucke-Grauls. Preferential involvement of excitatory neurons in medial temporal lobe in schizophrenia—In this Early Report by Paul J Harrison and colleagues (Nov 21, p 1669), the final sentence in the legend for figure 1 should have read: “Presence of complexin I in dentate gyrus and CA1 (B) despite lack of its mRNA (A) is explained by presynaptic localisation of protein, distant from cell bodies where mRNA is found”. In table 2, column 2, the significance marks were omitted from the complexin I mRNA data; the reductions in CA3 and subiculum in schizophrenia were both significant (p<0·01).
THE LANCET • Vol 353 • January 9, 1999