- Email: [email protected]
Mind over matter about keeping warm
THE LANCET
COMMENTARY proportion of patients do seem to show reduced responses to donor alloantigens.9 The use of these functional tests in conjunction with studies of cytokine expression and microchimerism may more accurately detect subgroups of patients in whom tolerance is likely to be established. In clinical transplantation there is always the confounding factor of immunosuppressive therapy, and both cyclosporin and tacrolimus can induce operational tolerance, which is lost on stopping treatment. Thus, even if it were possible to show a loss of antidonor responses, these may return when immunosuppression is stopped. All the studies to date suggest that only a proportion of patients will become tolerant spontaneously, thus strategies aimed at promoting tolerance in all graft recipients are worth pursuing. So far attempts to establish a chimeric state with infusions of bone marrow have failed in man, possibly because these approaches require deletion of peripheral recipient T cells, which is currently not a justifiable approach in human beings.10 Other approaches that have worked in animals, including intrathymic injections of alloantigens or thymic grafting are difficult if not impossible in adult human beings at present, but a greater understanding of microchimerism and the mechanisms of intrathymic tolerance may lead to future therapeutic approaches that are applicable in man.
David H Adams, Ian V Hutchinson Liver Research Laboratories, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, UK; and School of Biological Science, University of Manchester, M13 9PT 1
Starzl TE, Demetris AJ, Trucco M, et al. Cell migration and chimerism after whole-organ transplantation: the basis of graft acceptance. Hepatology 1993; 17: 1127-52. 2 Charlton B, Auchincloss H. Mechanisms of transplantation tolerance. Annu Rev Immunol 1994; 12: 707-34. 3 Ueda M, Hundrieser J, Hisanaga M, et al. Development of microchimerism in pediatric patients after living-related liver transplantation. Clin Transplant (in press). 4 Lu L, Rudgert WA, Qian SG, et al. Growth of donor-derived dendritic cells from the marrow of murine liver allograft recipients in response to granulocyte/macrophage colony stimulating factor. J Exp Med 1995; 182: 379-87. 5 Schlitt HJ. Is microchimerism needed for allograft tolerance? Transplant Proc 1997; 29: 82-84. 6 Hutchinson IV. Immune mechanisms of long-term graft acceptance. Adv Nephrol 1996; 25: 17-38. 7 Strom TB, Roy-Chaudhury P, Manfro R, et al. The Th1/Th2 paradigm and the allograft response. Curr Opin Immunol 1996; 8: 68893. 8 Sriwatanawongsa V, Davies HFS, Calne RY. The essential role of parenchymal tissues and passenger leukocytes in the tolerance induced by liver grafting in rats. Nat Med 1995; 1: 428-32. 9 Vantwuyver E, Dehoop J, Tenberge RJM, et al. Comparison of T-cell responses in patients with a long-term surviving renal-allograft versus a long-term surviving liver allograft - its a different world. Transplantation 1996; 61: 1392-97. 10 Rolles K, Burroughs AK, Davidson BR, Karatapanis S, Prentice HG, Hamon MD. Donor-specific bone-marrow infusion after orthotopic liver-transplantation. Lancet 1994; 343: 263-65.
Mind over matter about keeping warm See page 1341 Grandma always reminded us to wrap up warmly because it was cold outside. Sometimes we did and sometimes we didn’t. Health psychologists might relate this inconsistent behaviour to relative perceptions of risk and vulnerability. In this issue of The Lancet the Eurowinter group present data collected throughout Europe on cold exposure and
Vol 349 • May 10, 1997
its health consequences. They conclude that residents of colder climates are better prepared for the elements and thus have lower incremental increases in mortality for the same drop in temperature than residents of warmer countries. They recommend that measures should be taken at the individual and community levels to promote appropriate behaviour in inclement weather. The results of the study and its recommendations have serious implications for public-health policy and the allocation of health resources. It is important to assess whether the evidence is solid enough to justify the conclusions and, if so, what measures should be taken to implement the recommendations. These questions must be addressed with the tools of epidemiology and theories of health behaviour and health education. The Eurowinter study is ecological in design. No causality or temporality can be inferred and there is no way to know whether those who died are those with greater cold exposure. This potential ecological fallacy is well covered in epidemiology textbooks.1,2 Although this study design is good for hypothesis generation, studies based on other epidemiological methods are necessary before more definitive conclusions can be reached. It is noteworthy that recognised geographic differences in the diagnosis and classification of coronary heart disease mortality could affect the validity of the findings.3,4 Moreover, no comparative socioeconomic data for the surveyed countries is presented. The lower socioeconomic status of southern European countries might explain part of the excess winter mortality independently of cold exposure, or perhaps confound it. The failure to dress appropriately for the cold could reflect relative poverty together with, or rather than, faulty health education or lack of awareness of the dangers of cold exposure. There are also potential problems in interpreting the clinical importance of statistically significant differences such as the difference observed in living-room temperatures between South Finland and Athens (21·7° C vs 19·2°C). This difference is of unclear practical significance and its influence on cold-exposure-behaviour outdoors is speculative. If the results of the study are assumed to reflect a true association, what can be done to improve cold-weather behaviour among middle-aged and elderly residents of warmer countries? The authors hint at structural solutions such as the window-proofing of buses and at educational campaigns to change individual behaviour. Large-scale population-based interventions require massive resources as well as extensive collaboration between government and non-government agencies. The North Karelia experience showed that coordinated efforts on this scale are possible and lead to positive long-term outcomes.5 However, detailed cost-benefit analyses are needed before decisions with these ramifications are reached. Tversky and Kahneman,6,7 among others, have studied the psychological processes underlying decision-making by individuals. They emphasise the importance of the framing of the problem, showing that when terms of a problem are constant, its framing has a considerable effect on the eventual decision. We suggest that the perception of the climate in different geographic regions— ie, the framing of the weather—may affect climate-related behaviour. Imagine, for example, a day in mid-September and another in mid-March. In both cases the weather is 1337
THE LANCET
COMMENTARY the same with blue skies and a temperature of 18°C (constant terms). Although we are not aware of any study on this issue, we propose, from experience and by intuition, that in March most people would go outdoors with a light jacket or a long-sleeved shirt (winter frame) while in September they would wear short-sleeved shirts (summer frame). It is intuitively tempting to speculate that residence in a cold northern European climate rather than a warm southern European climate adds another type of framing to this problem. Although season-of theyear framing might affect immediate or short-term behaviour, the geographic framing might have more bearing on health-education efforts because it requires the promotion of weather-related behaviour that may not come naturally to residents of usually warm climates on the few days of the year that they are exposed to potentially dangerous cold weather. Many in southern Europe might consider it illogical or uneconomic to spend needed money on heavy garments to be used only on rare occasions each year. Population studies of the Eurowinter type generate hypotheses, and that is the important contribution of this paper. Further research using other epidemiological methods should be done to confirm their findings. If the findings are confirmed, it would become necessary to analyse the cost-effectiveness and feasibility of educational and structural interventions. Grandma may recognise the dangers of cold exposure, but she still has to learn how to get her message across more effectively.
Ami D Sperber, Shimon Weitzman Unit of Health Promotion and Disease Prevention and Department of Gastroenterolgy; and Department of Epidemiology and Health Services Evaluation, Soroka Medical Center and the Faculty of the Health Sciences,Ben-Gurion University of the Negev, Beer-Sheva, Israel 84101 1
2 3
4 5
6 7
Slome C, Brogan D, Eyres S, Lednar W. Basic epidemiological methods and biostatistics: a workbook. Boston: Jones and Bartlett Publishers, 1986. Hennekens CH, Buring JE. Epidemiology in medicine. Boston: Little, Brown and Company, 1987. White AD, Folsom AR, Chambless L, et. al. Community surveillance of coronary artery disease in the Atherosclerosis Risk in Communities (ARIC) study: methods and initial two years' experience. J Clin Epidemiol 1996; 49: 223-33. Zarling EJ, Sexton H, Milnor Jr. P. Failure to diagnose acute myocardial infarction. JAMA 1983; 250: 1177-81. Vartianen E, Puska P, Jousilahti P, Korhonen HJ, Tuomilehto J, Nissinen A. Twenty-year trends in coronary risk factors in North Karelia and in other areas of Finland. Int J Epidemiol 1994: 23: 495504. Tversky A, Kahnemann D. The framing of decisions and the psychology of choice. Science 1981; 211: 453-58. Kahnemann D, Tversky A. Judgment under certainty. Cambridge: Cambridge University Press, 1982.
Private genes, public health See page 1353 Genetic research promises much for understanding and alleviating common conditions such as cancer and cardiovascular disease. Yet bridging the divide between molecular biology and public health is a special challenge. Cusi and colleagues’ work, reported in today’s Lancet, is part of a multidisciplinary research philosophy rising to the challenge. It began with the derivation by Bianchi and colleagues nearly 25 years ago of an experimental genetic model of hypertension,1 in which physiological clues 1338
pointed to the kidney and sodium balance. Immunological investigation focused attention on the cytoskeletal protein a-adducin. Although the exact function of a-adducin is not known, experimental molecular manipulation indicated that it might explain abnormalities in cell-membrane sodium transport. First in rats, and recently in humans, genetic linkage has been demonstrated between hypertension and the a-adducin gene locus. The long-term investment by Bianchi and colleagues is bearing fruit, but where are we now? The latest results confirm linkage between the a-adducin gene and hypertension and reveal that the human a-adducin gene takes at least two forms. In one, a DNA mutation results in the substitution of tryptophan (Trp) for glycine (Gly) at aminoacid number 460. This genetic variant, 460Trp, is commoner among Italian and French hypertensive individuals than among controls. The findings imply that either the a-adducin gene or one very close on chromosome 4 influences blood pressure. Hypertensive individuals with the 460Trp variant show a significantly greater change in blood pressure between high and low sodium balance and a larger fall in blood pressure on diuretic treatment. It is not clear whether this exaggerated blood pressure response is specific for sodium or reflects fundamental alterations in other blood-pressure regulatory systems such as the renin-angiotensin system or neural control. Many transmembrane signals other than in the kidney could depend on a-adducin.2 The practical implications for hypertension depend on the reproducibility of the findings. The European experience is promising, but inconsistencies between populations have been seen before.3 Even in France and Italy, the 460Trp variant in isolation would not be useful in predicting hypertension. It is found in just over a quarter of normotensive people, compared with nearly 40% of hypertensive ones. Because normotensive individuals outnumber hypertensives by 4 to 1, most of the 460Trp variants are carried by people with normal blood pressure. Nevertheless, the results herald the possibility that treatment options for clinical hypertension might in the future be selected according to genetic tests. If significantly better responses to sodium restriction or diuretics in 460Trp carriers are confirmed, clinical practice may change in the foreseeable future. What is the possible relevance of this research for public health? It depends on whether the correlates of the a-adducin gene are found other than in hypertensive people. Is there a correlation between the frequency of the 460Trp variant and blood pressure across the whole population? Are exaggerated responses to changes in sodium balance seen at every level of blood pressure in those with the 460Trp variant? Such questions can be answered only in population-based studies. If a-adducin genotyping identifes “salt sensitive” individuals in the general community, it may be possible to derive cardiovascular benefits by targeting advice on sodium intake and reduce blood pressure in perhaps 30% of the population. However, it seems unlikely that widespread genetic screening would be warranted to deliver simple lifestyle advice that could be given more efficiently and consistently to the whole population. These considerations touch on the thorny issue of salt and blood pressure,4,5 a public-health debate that even the a-adducin gene is unlikely to resolve.6
Vol 349 • May 10, 1997
COMMENTARY proportion of patients do seem to show reduced responses to donor alloantigens.9 The use of these functional tests in conjunction with studies of cytokine expression and microchimerism may more accurately detect subgroups of patients in whom tolerance is likely to be established. In clinical transplantation there is always the confounding factor of immunosuppressive therapy, and both cyclosporin and tacrolimus can induce operational tolerance, which is lost on stopping treatment. Thus, even if it were possible to show a loss of antidonor responses, these may return when immunosuppression is stopped. All the studies to date suggest that only a proportion of patients will become tolerant spontaneously, thus strategies aimed at promoting tolerance in all graft recipients are worth pursuing. So far attempts to establish a chimeric state with infusions of bone marrow have failed in man, possibly because these approaches require deletion of peripheral recipient T cells, which is currently not a justifiable approach in human beings.10 Other approaches that have worked in animals, including intrathymic injections of alloantigens or thymic grafting are difficult if not impossible in adult human beings at present, but a greater understanding of microchimerism and the mechanisms of intrathymic tolerance may lead to future therapeutic approaches that are applicable in man.
David H Adams, Ian V Hutchinson Liver Research Laboratories, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, UK; and School of Biological Science, University of Manchester, M13 9PT 1
Starzl TE, Demetris AJ, Trucco M, et al. Cell migration and chimerism after whole-organ transplantation: the basis of graft acceptance. Hepatology 1993; 17: 1127-52. 2 Charlton B, Auchincloss H. Mechanisms of transplantation tolerance. Annu Rev Immunol 1994; 12: 707-34. 3 Ueda M, Hundrieser J, Hisanaga M, et al. Development of microchimerism in pediatric patients after living-related liver transplantation. Clin Transplant (in press). 4 Lu L, Rudgert WA, Qian SG, et al. Growth of donor-derived dendritic cells from the marrow of murine liver allograft recipients in response to granulocyte/macrophage colony stimulating factor. J Exp Med 1995; 182: 379-87. 5 Schlitt HJ. Is microchimerism needed for allograft tolerance? Transplant Proc 1997; 29: 82-84. 6 Hutchinson IV. Immune mechanisms of long-term graft acceptance. Adv Nephrol 1996; 25: 17-38. 7 Strom TB, Roy-Chaudhury P, Manfro R, et al. The Th1/Th2 paradigm and the allograft response. Curr Opin Immunol 1996; 8: 68893. 8 Sriwatanawongsa V, Davies HFS, Calne RY. The essential role of parenchymal tissues and passenger leukocytes in the tolerance induced by liver grafting in rats. Nat Med 1995; 1: 428-32. 9 Vantwuyver E, Dehoop J, Tenberge RJM, et al. Comparison of T-cell responses in patients with a long-term surviving renal-allograft versus a long-term surviving liver allograft - its a different world. Transplantation 1996; 61: 1392-97. 10 Rolles K, Burroughs AK, Davidson BR, Karatapanis S, Prentice HG, Hamon MD. Donor-specific bone-marrow infusion after orthotopic liver-transplantation. Lancet 1994; 343: 263-65.
Mind over matter about keeping warm See page 1341 Grandma always reminded us to wrap up warmly because it was cold outside. Sometimes we did and sometimes we didn’t. Health psychologists might relate this inconsistent behaviour to relative perceptions of risk and vulnerability. In this issue of The Lancet the Eurowinter group present data collected throughout Europe on cold exposure and
Vol 349 • May 10, 1997
its health consequences. They conclude that residents of colder climates are better prepared for the elements and thus have lower incremental increases in mortality for the same drop in temperature than residents of warmer countries. They recommend that measures should be taken at the individual and community levels to promote appropriate behaviour in inclement weather. The results of the study and its recommendations have serious implications for public-health policy and the allocation of health resources. It is important to assess whether the evidence is solid enough to justify the conclusions and, if so, what measures should be taken to implement the recommendations. These questions must be addressed with the tools of epidemiology and theories of health behaviour and health education. The Eurowinter study is ecological in design. No causality or temporality can be inferred and there is no way to know whether those who died are those with greater cold exposure. This potential ecological fallacy is well covered in epidemiology textbooks.1,2 Although this study design is good for hypothesis generation, studies based on other epidemiological methods are necessary before more definitive conclusions can be reached. It is noteworthy that recognised geographic differences in the diagnosis and classification of coronary heart disease mortality could affect the validity of the findings.3,4 Moreover, no comparative socioeconomic data for the surveyed countries is presented. The lower socioeconomic status of southern European countries might explain part of the excess winter mortality independently of cold exposure, or perhaps confound it. The failure to dress appropriately for the cold could reflect relative poverty together with, or rather than, faulty health education or lack of awareness of the dangers of cold exposure. There are also potential problems in interpreting the clinical importance of statistically significant differences such as the difference observed in living-room temperatures between South Finland and Athens (21·7° C vs 19·2°C). This difference is of unclear practical significance and its influence on cold-exposure-behaviour outdoors is speculative. If the results of the study are assumed to reflect a true association, what can be done to improve cold-weather behaviour among middle-aged and elderly residents of warmer countries? The authors hint at structural solutions such as the window-proofing of buses and at educational campaigns to change individual behaviour. Large-scale population-based interventions require massive resources as well as extensive collaboration between government and non-government agencies. The North Karelia experience showed that coordinated efforts on this scale are possible and lead to positive long-term outcomes.5 However, detailed cost-benefit analyses are needed before decisions with these ramifications are reached. Tversky and Kahneman,6,7 among others, have studied the psychological processes underlying decision-making by individuals. They emphasise the importance of the framing of the problem, showing that when terms of a problem are constant, its framing has a considerable effect on the eventual decision. We suggest that the perception of the climate in different geographic regions— ie, the framing of the weather—may affect climate-related behaviour. Imagine, for example, a day in mid-September and another in mid-March. In both cases the weather is 1337
THE LANCET
COMMENTARY the same with blue skies and a temperature of 18°C (constant terms). Although we are not aware of any study on this issue, we propose, from experience and by intuition, that in March most people would go outdoors with a light jacket or a long-sleeved shirt (winter frame) while in September they would wear short-sleeved shirts (summer frame). It is intuitively tempting to speculate that residence in a cold northern European climate rather than a warm southern European climate adds another type of framing to this problem. Although season-of theyear framing might affect immediate or short-term behaviour, the geographic framing might have more bearing on health-education efforts because it requires the promotion of weather-related behaviour that may not come naturally to residents of usually warm climates on the few days of the year that they are exposed to potentially dangerous cold weather. Many in southern Europe might consider it illogical or uneconomic to spend needed money on heavy garments to be used only on rare occasions each year. Population studies of the Eurowinter type generate hypotheses, and that is the important contribution of this paper. Further research using other epidemiological methods should be done to confirm their findings. If the findings are confirmed, it would become necessary to analyse the cost-effectiveness and feasibility of educational and structural interventions. Grandma may recognise the dangers of cold exposure, but she still has to learn how to get her message across more effectively.
Ami D Sperber, Shimon Weitzman Unit of Health Promotion and Disease Prevention and Department of Gastroenterolgy; and Department of Epidemiology and Health Services Evaluation, Soroka Medical Center and the Faculty of the Health Sciences,Ben-Gurion University of the Negev, Beer-Sheva, Israel 84101 1
2 3
4 5
6 7
Slome C, Brogan D, Eyres S, Lednar W. Basic epidemiological methods and biostatistics: a workbook. Boston: Jones and Bartlett Publishers, 1986. Hennekens CH, Buring JE. Epidemiology in medicine. Boston: Little, Brown and Company, 1987. White AD, Folsom AR, Chambless L, et. al. Community surveillance of coronary artery disease in the Atherosclerosis Risk in Communities (ARIC) study: methods and initial two years' experience. J Clin Epidemiol 1996; 49: 223-33. Zarling EJ, Sexton H, Milnor Jr. P. Failure to diagnose acute myocardial infarction. JAMA 1983; 250: 1177-81. Vartianen E, Puska P, Jousilahti P, Korhonen HJ, Tuomilehto J, Nissinen A. Twenty-year trends in coronary risk factors in North Karelia and in other areas of Finland. Int J Epidemiol 1994: 23: 495504. Tversky A, Kahnemann D. The framing of decisions and the psychology of choice. Science 1981; 211: 453-58. Kahnemann D, Tversky A. Judgment under certainty. Cambridge: Cambridge University Press, 1982.
Private genes, public health See page 1353 Genetic research promises much for understanding and alleviating common conditions such as cancer and cardiovascular disease. Yet bridging the divide between molecular biology and public health is a special challenge. Cusi and colleagues’ work, reported in today’s Lancet, is part of a multidisciplinary research philosophy rising to the challenge. It began with the derivation by Bianchi and colleagues nearly 25 years ago of an experimental genetic model of hypertension,1 in which physiological clues 1338
pointed to the kidney and sodium balance. Immunological investigation focused attention on the cytoskeletal protein a-adducin. Although the exact function of a-adducin is not known, experimental molecular manipulation indicated that it might explain abnormalities in cell-membrane sodium transport. First in rats, and recently in humans, genetic linkage has been demonstrated between hypertension and the a-adducin gene locus. The long-term investment by Bianchi and colleagues is bearing fruit, but where are we now? The latest results confirm linkage between the a-adducin gene and hypertension and reveal that the human a-adducin gene takes at least two forms. In one, a DNA mutation results in the substitution of tryptophan (Trp) for glycine (Gly) at aminoacid number 460. This genetic variant, 460Trp, is commoner among Italian and French hypertensive individuals than among controls. The findings imply that either the a-adducin gene or one very close on chromosome 4 influences blood pressure. Hypertensive individuals with the 460Trp variant show a significantly greater change in blood pressure between high and low sodium balance and a larger fall in blood pressure on diuretic treatment. It is not clear whether this exaggerated blood pressure response is specific for sodium or reflects fundamental alterations in other blood-pressure regulatory systems such as the renin-angiotensin system or neural control. Many transmembrane signals other than in the kidney could depend on a-adducin.2 The practical implications for hypertension depend on the reproducibility of the findings. The European experience is promising, but inconsistencies between populations have been seen before.3 Even in France and Italy, the 460Trp variant in isolation would not be useful in predicting hypertension. It is found in just over a quarter of normotensive people, compared with nearly 40% of hypertensive ones. Because normotensive individuals outnumber hypertensives by 4 to 1, most of the 460Trp variants are carried by people with normal blood pressure. Nevertheless, the results herald the possibility that treatment options for clinical hypertension might in the future be selected according to genetic tests. If significantly better responses to sodium restriction or diuretics in 460Trp carriers are confirmed, clinical practice may change in the foreseeable future. What is the possible relevance of this research for public health? It depends on whether the correlates of the a-adducin gene are found other than in hypertensive people. Is there a correlation between the frequency of the 460Trp variant and blood pressure across the whole population? Are exaggerated responses to changes in sodium balance seen at every level of blood pressure in those with the 460Trp variant? Such questions can be answered only in population-based studies. If a-adducin genotyping identifes “salt sensitive” individuals in the general community, it may be possible to derive cardiovascular benefits by targeting advice on sodium intake and reduce blood pressure in perhaps 30% of the population. However, it seems unlikely that widespread genetic screening would be warranted to deliver simple lifestyle advice that could be given more efficiently and consistently to the whole population. These considerations touch on the thorny issue of salt and blood pressure,4,5 a public-health debate that even the a-adducin gene is unlikely to resolve.6
Vol 349 • May 10, 1997