- Email: [email protected]
Association of γ-Glutamyltransferase with Cardiovascular Risk: A Prognostic Outlook
Archives of Medical Research 40 (2009) 318e320
OPINION
Association of g-Glutamyltransferase with Cardiovascular Risk: A Prognostic Outlook Okan Turgut, Izzet Tandogan, and Ahmet Gurlek Department of Cardiology, Faculty of Medicine, Cumhuriyet University, Sivas, Turkey Received for publication January 2, 2009; accepted March 30, 2009 (ARCMED-D-09-00002). Published previously online June 16, 2009.
g-Glutamyltransferase (GGT), an enzyme responsible for the extracellular catabolism of antioxidant glutathione, may explicitly participate in atherogenesis. Several populationbased studies have documented strong cross-sectional associations between serum GGT concentrations and certain cardiovascular risk factors, irrespective of alcohol consumption. The mechanism underlying these associations remains largely enigmatic. Considerable association of high-sensitivity C-reactive protein, a major inflammatory marker for cardiovascular risk, with GGT and other cardiovascular risk factors has been described, implying that elevation of serum GGT (conceivably acting as a marker of oxidative stress) is correlated with subclinical microinflammatory response involved in the pathogenesis of atherosclerosis. It is also relevant to assess whether the prognostic impact of a novel risk marker can be influenced by therapeutic intervention, thus decreasing the occurrence of cardiovascular events. Subtle gradations in serum GGT may help predict long-term cardiovascular prognosis, and the supplementary GGT determination to conventional testing has potential implications for screening those at increased cardiovascular risk who may benefit from prophylactic measures and require enhanced therapeutic effort. It has been reported that serum GGT may contribute to the accumulation of GGT activity inside the plaque. Further comprehension is, however, needed about the relationship of GGT activity inside the plaque with inflammatory biomarkers, plasma lipoproteins, and other independent determinants to define the most risky combination and improve the prognostic stratification of patients. Ó 2009 IMSS. Published by Elsevier Inc. Key Words: Cardiovascular risk, g-Glutamyltransferase, Oxidative stress, Prognosis.
Introduction An accumulating body of data indicates that g-glutamyltransferase (GGT), an enzyme responsible for the extracellular catabolism of antioxidant glutathione, may explicitly participate in atherogenesis (1,2). A substantial relationship between serum GGT activity and atherosclerotic process has focused attention to the question whether serum GGT levels can aid detection of individuals at high risk for future cardiovascular events. Although best known as a reliable diagnostic tool for hepatobiliary disorders and alcohol abuse in clinical practice, robust epidemiological evidence
Address reprint requests to: Okan Turgut, MD, Department of Cardiology, Faculty of Medicine, Cumhuriyet University, Sivas 58140, Turkey.; E-mail: [email protected]
points out that serum GGT may emerge as a potential biochemical risk indicator of cardiovascular morbidity and mortality. Several population-based studies have documented strong cross-sectional associations between serum GGT concentrations and certain cardiovascular risk factors, irrespective of alcohol consumption (3e14). Mechanism and Relevance The mechanism underlying these associations remains largely enigmatic. It is likely that the pathogenesis involves a GGT-linked prooxidant effect of glutathione catabolism within the plaque (1,2). Hence, there are two probable explanations for the association between serum GGT and cardiovascular risk: either GGT derives in part from atheromatous plaques, which would be more common and diffuse in patients with adverse cardiovascular risk profiles,
0188-4409/09 $esee front matter. Copyright Ó 2009 IMSS. Published by Elsevier Inc. doi: 10.1016/j.arcmed.2009.04.006
GGT and Cardiovascular Risk
or GGT is associated with the risk factors even before the plaques are fully developed. In this context, oxidative stress might be a possible unifying mediator because it is closely related to various pathological conditions including atherosclerosis (1,15). It is also a key component of numerous pathways implicated in inflammation (16). Considerable association of high-sensitivity C-reactive protein, a major inflammatory marker for cardiovascular risk, with GGT and other cardiovascular risk factors has been described implying that elevation of serum GGT (conceivably acting as a marker of oxidative stress) is correlated with subclinical microinflammatory response involved in the pathogenesis of atherosclerosis (17,18). Then, baseline GGT testing can plausibly have an adjunctive merit in estimating cardiovascular risk. Indeed, serum GGT forms complexes with lipoproteins, thus suggesting that the intense GGT activity within atheromatous lesions, colocalized with oxidized low-density lipoprotein, may derive from the accumulation of lowdensity lipoprotein-associated GGT within the arterial wall and b-lipoprotein-associated GGT activity increases with total serum GGT activity, supporting the hypothesis that increasing levels of serum GGT may be linked to an augmented influx of GGT-carrying lipoproteins into the plaque (1,2). One of the key questions is whether GGT is just an innocent bystander or causally involved in atherogenesis. In our opinion, elevated GGT levels are not simple side effects of the liver damage associated with the metabolic syndrome. It has been observed that elevated serum GGT is an independent marker of the activation of systemic inflammation and increased oxidative stress, independent of its relationship with the metabolic syndrome (19). Based on current available data, our group has recently proposed that an increase in serum concentrations of GGT, even within its normal range, is a promising biohumoral predictor for cardiovascular risk (20,21). It is also relevant to assess whether the prognostic impact of a novel risk marker can be influenced by therapeutic intervention, thus decreasing the occurrence of cardiovascular events. Data exist that fibrate therapy has a favorable efficacy on diminishing serum GGT concentrations among hypertriglyceridemic patients as well as improving lipid profile (22). This is consistent with a role for fatty liver in generating increased serum GGT and being associated with an increase in cardiovascular risk, and it provides a practical means of risk reduction (23). Alternatively, a short-term trial of fibrate treatment in subjects with alcoholic fatty liver has failed to lower serum GGT significantly, although serum triglyceride levels have fallen substantially (24). We do not know, at this stage, whether GGT would remain a significant cardiovascular risk index if serum concentrations of triglyceride and verylow-density lipoprotein were reduced by treatment, but published epidemiological investigations suggest that it would. Large-scale randomized trials are necessary to
319
assess the effect of drugs currently used for the treatment of atherosclerosis on serum GGT activity. In conclusion, subtle gradations in serum GGT may help predict long-term cardiovascular prognosis, and the supplementary GGT determination to conventional testing has potential implications for screening those at increased cardiovascular risk who may benefit from prophylactic measures and require enhanced therapeutic effort (25). Recent insight into pathophysiological background of GGT in the onset and progression of atherosclerosis appears to be supported by relevant epidemiological observations as a cardiovascular risk predictor. It has been reported that serum GGT may contribute to the accumulation of GGT activity inside the plaque (26). Further comprehension is, however, needed about the relationship of GGT activity inside the plaque with inflammatory biomarkers, plasma lipoproteins, and other independent determinants to define the most risky combination and improve the prognostic stratification of patients (27).
References 1. Emdin M, Pompella A, Paolicchi A. Gamma-glutamyltransferase, atherosclerosis, and cardiovascular disease: triggering oxidative stress within the plaque. Circulation 2005;112:2078e2080. 2. Paolicchi A, Emdin M, Passino C, et al. b-Lipoprotein- and LDLassociated serum g-glutamyltransferase in patients with coronary atherosclerosis. Atherosclerosis 2006;186:80e85. 3. Wannamethee G, Ebrahim S, Shaper AG. Gamma-glutamyltransferase: determinants and association with mortality from ischemic heart disease and all causes. Am J Epidemiol 1995;142:699e708. 4. Emdin M, Passino C, Michelassi C, et al. Prognostic value of serum gamma-glutamyl transferase activity after myocardial infarction. Eur Heart J 2001;22:1802e1807. 5. Bots ML, Salonen JT, Elwood PC, et al. Gamma-glutamyltransferase and risk of stroke: the EUROSTROKE project. J Epidemiol Community Health 2002;56(suppl 1):i25ei29. 6. Kim DJ, Noh JH, Cho NH, et al. Serum g-glutamyltransferase within its normal concentration range is related to the presence of diabetes and cardiovascular risk factors. Diabet Med 2005;22:1134e1140. 7. Ruttmann E, Brant LJ, Concin H, Diem G, Rapp K, Ulmer H. Gammaglutamyltransferase as a risk factor for cardiovascular disease mortality: an epidemiological investigation in a cohort of 163,944 Austrian adults. Circulation 2005;112:2130e2137. 8. Higashikawa A, Suwazono Y, Okubo Y, et al. Association of working conditions and lifestyle with increased serum gamma-glutamyltransferase: a follow-up study. Arch Med Res 2005;36:567e573. 9. Meisinger C, Do¨ring A, Schneider A, Lo¨wel H for the KORA Study Group. Serum g-glutamyltransferase is a predictor of incident coronary events in apparently healthy men from the general population. Atherosclerosis 2006;189:297e302. 10. Lee DH, Silventoinen K, Hu G, et al. Serum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28,838 middle-aged men and women. Eur Heart J 2006;27:2170e2176. 11. Lee DS, Evans JC, Robins SJ, et al. Gamma glutamyl transferase and metabolic syndrome, cardiovascular disease, and mortality risk: the Framingham Heart Study. Arterioscler Thromb Vasc Biol 2007;27: 127e133.
320
Turgut et al./ Archives of Medical Research 40 (2009) 318e320
12. Hozawa A, Okamura T, Kadowaki T, et al. g-Glutamyltransferase predicts cardiovascular death among Japanese women. Atherosclerosis 2007;194:498e504. 13. Fraser A, Harris R, Sattar N, Ebrahim S, Smith GD, Lawlor DA. Gamma-glutamyltransferase is associated with incident vascular events independently of alcohol intake: analysis of the British Women’s Heart and Health Study and Meta-Analysis. Arterioscler Thromb Vasc Biol 2007;27:2729e2735. 14. Emdin M, Passino C, Michelassi C, Donato L, Pompella A, Paolicchi A. Additive prognostic value of gamma-glutamyltransferase in coronary artery disease. Int J Cardiol 2008, doi: 10.1016/j.ijcard.2008.04.030. 15. Schulze PC, Lee RT. Oxidative stress and atherosclerosis. Curr Atheroscler Rep 2005;7:242e248. 16. Laskaj R, Dodig S, Cepelak I, Kuzman I. Gamma-glutamyltransferase activity and total antioxidant status in serum and platelets of patients with community-acquired pneumonia. Arch Med Res 2007;38: 424e431. 17. Lee DH, Jacobs DR. Association between serum gamma-glutamyltransferase and C-reactive protein. Atherosclerosis 2005;178: 327e330. 18. Sung KC, Kang JH, Shin HS. Relationship of cardiovascular risk factors and serum ferritin with C-reactive protein. Arch Med Res 2007;38:121e125. 19. Yamada J, Tomiyama H, Yambe M, et al. Elevated serum levels of alanine aminotransferase and gamma glutamyltransferase are markers
20.
21.
22.
23.
24.
25.
26.
27.
of inflammation and oxidative stress independent of the metabolic syndrome. Atherosclerosis 2006;189:198e205. Turgut O, Yilmaz A, Yalta K, Karadas F, Yilmaz MB. g-Glutamyltransferase is a promising biomarker for cardiovascular risk. Med Hypotheses 2006;67:1060e1064. Turgut O, Yilmaz MB, Yalta K, Tandogan I. Gamma-glutamyltransferase as a useful predictor for cardiovascular risk: clinical and epidemiological perspectives. Atherosclerosis 2009;202:348e349. Mabile L, Ruidavets JB, Fauvel J, Perret B, Ferrie`res J. Differential levels of gamma-glutamyl transferase activity and apolipoprotein CIII in men on either statin or fibrate therapy. Diabetes Care 2003;26:1652e1653. Villanova N, Moscatiello S, Ramilli S, et al. Endothelial dysfunction and cardiovascular risk profile in nonalcoholic fatty liver disease. Hepatology 2005;42:473e480. Tsutsumi M, Takase S. Effect of fenofibrate on fatty liver in rats treated with alcohol. Alcohol Clin Exp Res 2001;25(6 suppl): 75Se79S. Grundy SM. Gamma-glutamyl transferase: another biomarker for metabolic syndrome and cardiovascular risk. Arterioscler Thromb Vasc Biol 2007;27:4e7. Franzini M, Corti A, Martinelli B, et al. Gamma-glutamyltransferase activity in human atherosclerotic plaques—biochemical similarities with the circulating enzyme. Atherosclerosis 2009;202:119e127. Emdin M, Passino C, Pompella A, Paolicchi A. Gamma-glutamyltransferase as a cardiovascular risk factor. Eur Heart J 2006;27:2145e2146.
OPINION
Association of g-Glutamyltransferase with Cardiovascular Risk: A Prognostic Outlook Okan Turgut, Izzet Tandogan, and Ahmet Gurlek Department of Cardiology, Faculty of Medicine, Cumhuriyet University, Sivas, Turkey Received for publication January 2, 2009; accepted March 30, 2009 (ARCMED-D-09-00002). Published previously online June 16, 2009.
g-Glutamyltransferase (GGT), an enzyme responsible for the extracellular catabolism of antioxidant glutathione, may explicitly participate in atherogenesis. Several populationbased studies have documented strong cross-sectional associations between serum GGT concentrations and certain cardiovascular risk factors, irrespective of alcohol consumption. The mechanism underlying these associations remains largely enigmatic. Considerable association of high-sensitivity C-reactive protein, a major inflammatory marker for cardiovascular risk, with GGT and other cardiovascular risk factors has been described, implying that elevation of serum GGT (conceivably acting as a marker of oxidative stress) is correlated with subclinical microinflammatory response involved in the pathogenesis of atherosclerosis. It is also relevant to assess whether the prognostic impact of a novel risk marker can be influenced by therapeutic intervention, thus decreasing the occurrence of cardiovascular events. Subtle gradations in serum GGT may help predict long-term cardiovascular prognosis, and the supplementary GGT determination to conventional testing has potential implications for screening those at increased cardiovascular risk who may benefit from prophylactic measures and require enhanced therapeutic effort. It has been reported that serum GGT may contribute to the accumulation of GGT activity inside the plaque. Further comprehension is, however, needed about the relationship of GGT activity inside the plaque with inflammatory biomarkers, plasma lipoproteins, and other independent determinants to define the most risky combination and improve the prognostic stratification of patients. Ó 2009 IMSS. Published by Elsevier Inc. Key Words: Cardiovascular risk, g-Glutamyltransferase, Oxidative stress, Prognosis.
Introduction An accumulating body of data indicates that g-glutamyltransferase (GGT), an enzyme responsible for the extracellular catabolism of antioxidant glutathione, may explicitly participate in atherogenesis (1,2). A substantial relationship between serum GGT activity and atherosclerotic process has focused attention to the question whether serum GGT levels can aid detection of individuals at high risk for future cardiovascular events. Although best known as a reliable diagnostic tool for hepatobiliary disorders and alcohol abuse in clinical practice, robust epidemiological evidence
Address reprint requests to: Okan Turgut, MD, Department of Cardiology, Faculty of Medicine, Cumhuriyet University, Sivas 58140, Turkey.; E-mail: [email protected]
points out that serum GGT may emerge as a potential biochemical risk indicator of cardiovascular morbidity and mortality. Several population-based studies have documented strong cross-sectional associations between serum GGT concentrations and certain cardiovascular risk factors, irrespective of alcohol consumption (3e14). Mechanism and Relevance The mechanism underlying these associations remains largely enigmatic. It is likely that the pathogenesis involves a GGT-linked prooxidant effect of glutathione catabolism within the plaque (1,2). Hence, there are two probable explanations for the association between serum GGT and cardiovascular risk: either GGT derives in part from atheromatous plaques, which would be more common and diffuse in patients with adverse cardiovascular risk profiles,
0188-4409/09 $esee front matter. Copyright Ó 2009 IMSS. Published by Elsevier Inc. doi: 10.1016/j.arcmed.2009.04.006
GGT and Cardiovascular Risk
or GGT is associated with the risk factors even before the plaques are fully developed. In this context, oxidative stress might be a possible unifying mediator because it is closely related to various pathological conditions including atherosclerosis (1,15). It is also a key component of numerous pathways implicated in inflammation (16). Considerable association of high-sensitivity C-reactive protein, a major inflammatory marker for cardiovascular risk, with GGT and other cardiovascular risk factors has been described implying that elevation of serum GGT (conceivably acting as a marker of oxidative stress) is correlated with subclinical microinflammatory response involved in the pathogenesis of atherosclerosis (17,18). Then, baseline GGT testing can plausibly have an adjunctive merit in estimating cardiovascular risk. Indeed, serum GGT forms complexes with lipoproteins, thus suggesting that the intense GGT activity within atheromatous lesions, colocalized with oxidized low-density lipoprotein, may derive from the accumulation of lowdensity lipoprotein-associated GGT within the arterial wall and b-lipoprotein-associated GGT activity increases with total serum GGT activity, supporting the hypothesis that increasing levels of serum GGT may be linked to an augmented influx of GGT-carrying lipoproteins into the plaque (1,2). One of the key questions is whether GGT is just an innocent bystander or causally involved in atherogenesis. In our opinion, elevated GGT levels are not simple side effects of the liver damage associated with the metabolic syndrome. It has been observed that elevated serum GGT is an independent marker of the activation of systemic inflammation and increased oxidative stress, independent of its relationship with the metabolic syndrome (19). Based on current available data, our group has recently proposed that an increase in serum concentrations of GGT, even within its normal range, is a promising biohumoral predictor for cardiovascular risk (20,21). It is also relevant to assess whether the prognostic impact of a novel risk marker can be influenced by therapeutic intervention, thus decreasing the occurrence of cardiovascular events. Data exist that fibrate therapy has a favorable efficacy on diminishing serum GGT concentrations among hypertriglyceridemic patients as well as improving lipid profile (22). This is consistent with a role for fatty liver in generating increased serum GGT and being associated with an increase in cardiovascular risk, and it provides a practical means of risk reduction (23). Alternatively, a short-term trial of fibrate treatment in subjects with alcoholic fatty liver has failed to lower serum GGT significantly, although serum triglyceride levels have fallen substantially (24). We do not know, at this stage, whether GGT would remain a significant cardiovascular risk index if serum concentrations of triglyceride and verylow-density lipoprotein were reduced by treatment, but published epidemiological investigations suggest that it would. Large-scale randomized trials are necessary to
319
assess the effect of drugs currently used for the treatment of atherosclerosis on serum GGT activity. In conclusion, subtle gradations in serum GGT may help predict long-term cardiovascular prognosis, and the supplementary GGT determination to conventional testing has potential implications for screening those at increased cardiovascular risk who may benefit from prophylactic measures and require enhanced therapeutic effort (25). Recent insight into pathophysiological background of GGT in the onset and progression of atherosclerosis appears to be supported by relevant epidemiological observations as a cardiovascular risk predictor. It has been reported that serum GGT may contribute to the accumulation of GGT activity inside the plaque (26). Further comprehension is, however, needed about the relationship of GGT activity inside the plaque with inflammatory biomarkers, plasma lipoproteins, and other independent determinants to define the most risky combination and improve the prognostic stratification of patients (27).
References 1. Emdin M, Pompella A, Paolicchi A. Gamma-glutamyltransferase, atherosclerosis, and cardiovascular disease: triggering oxidative stress within the plaque. Circulation 2005;112:2078e2080. 2. Paolicchi A, Emdin M, Passino C, et al. b-Lipoprotein- and LDLassociated serum g-glutamyltransferase in patients with coronary atherosclerosis. Atherosclerosis 2006;186:80e85. 3. Wannamethee G, Ebrahim S, Shaper AG. Gamma-glutamyltransferase: determinants and association with mortality from ischemic heart disease and all causes. Am J Epidemiol 1995;142:699e708. 4. Emdin M, Passino C, Michelassi C, et al. Prognostic value of serum gamma-glutamyl transferase activity after myocardial infarction. Eur Heart J 2001;22:1802e1807. 5. Bots ML, Salonen JT, Elwood PC, et al. Gamma-glutamyltransferase and risk of stroke: the EUROSTROKE project. J Epidemiol Community Health 2002;56(suppl 1):i25ei29. 6. Kim DJ, Noh JH, Cho NH, et al. Serum g-glutamyltransferase within its normal concentration range is related to the presence of diabetes and cardiovascular risk factors. Diabet Med 2005;22:1134e1140. 7. Ruttmann E, Brant LJ, Concin H, Diem G, Rapp K, Ulmer H. Gammaglutamyltransferase as a risk factor for cardiovascular disease mortality: an epidemiological investigation in a cohort of 163,944 Austrian adults. Circulation 2005;112:2130e2137. 8. Higashikawa A, Suwazono Y, Okubo Y, et al. Association of working conditions and lifestyle with increased serum gamma-glutamyltransferase: a follow-up study. Arch Med Res 2005;36:567e573. 9. Meisinger C, Do¨ring A, Schneider A, Lo¨wel H for the KORA Study Group. Serum g-glutamyltransferase is a predictor of incident coronary events in apparently healthy men from the general population. Atherosclerosis 2006;189:297e302. 10. Lee DH, Silventoinen K, Hu G, et al. Serum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28,838 middle-aged men and women. Eur Heart J 2006;27:2170e2176. 11. Lee DS, Evans JC, Robins SJ, et al. Gamma glutamyl transferase and metabolic syndrome, cardiovascular disease, and mortality risk: the Framingham Heart Study. Arterioscler Thromb Vasc Biol 2007;27: 127e133.
320
Turgut et al./ Archives of Medical Research 40 (2009) 318e320
12. Hozawa A, Okamura T, Kadowaki T, et al. g-Glutamyltransferase predicts cardiovascular death among Japanese women. Atherosclerosis 2007;194:498e504. 13. Fraser A, Harris R, Sattar N, Ebrahim S, Smith GD, Lawlor DA. Gamma-glutamyltransferase is associated with incident vascular events independently of alcohol intake: analysis of the British Women’s Heart and Health Study and Meta-Analysis. Arterioscler Thromb Vasc Biol 2007;27:2729e2735. 14. Emdin M, Passino C, Michelassi C, Donato L, Pompella A, Paolicchi A. Additive prognostic value of gamma-glutamyltransferase in coronary artery disease. Int J Cardiol 2008, doi: 10.1016/j.ijcard.2008.04.030. 15. Schulze PC, Lee RT. Oxidative stress and atherosclerosis. Curr Atheroscler Rep 2005;7:242e248. 16. Laskaj R, Dodig S, Cepelak I, Kuzman I. Gamma-glutamyltransferase activity and total antioxidant status in serum and platelets of patients with community-acquired pneumonia. Arch Med Res 2007;38: 424e431. 17. Lee DH, Jacobs DR. Association between serum gamma-glutamyltransferase and C-reactive protein. Atherosclerosis 2005;178: 327e330. 18. Sung KC, Kang JH, Shin HS. Relationship of cardiovascular risk factors and serum ferritin with C-reactive protein. Arch Med Res 2007;38:121e125. 19. Yamada J, Tomiyama H, Yambe M, et al. Elevated serum levels of alanine aminotransferase and gamma glutamyltransferase are markers
20.
21.
22.
23.
24.
25.
26.
27.
of inflammation and oxidative stress independent of the metabolic syndrome. Atherosclerosis 2006;189:198e205. Turgut O, Yilmaz A, Yalta K, Karadas F, Yilmaz MB. g-Glutamyltransferase is a promising biomarker for cardiovascular risk. Med Hypotheses 2006;67:1060e1064. Turgut O, Yilmaz MB, Yalta K, Tandogan I. Gamma-glutamyltransferase as a useful predictor for cardiovascular risk: clinical and epidemiological perspectives. Atherosclerosis 2009;202:348e349. Mabile L, Ruidavets JB, Fauvel J, Perret B, Ferrie`res J. Differential levels of gamma-glutamyl transferase activity and apolipoprotein CIII in men on either statin or fibrate therapy. Diabetes Care 2003;26:1652e1653. Villanova N, Moscatiello S, Ramilli S, et al. Endothelial dysfunction and cardiovascular risk profile in nonalcoholic fatty liver disease. Hepatology 2005;42:473e480. Tsutsumi M, Takase S. Effect of fenofibrate on fatty liver in rats treated with alcohol. Alcohol Clin Exp Res 2001;25(6 suppl): 75Se79S. Grundy SM. Gamma-glutamyl transferase: another biomarker for metabolic syndrome and cardiovascular risk. Arterioscler Thromb Vasc Biol 2007;27:4e7. Franzini M, Corti A, Martinelli B, et al. Gamma-glutamyltransferase activity in human atherosclerotic plaques—biochemical similarities with the circulating enzyme. Atherosclerosis 2009;202:119e127. Emdin M, Passino C, Pompella A, Paolicchi A. Gamma-glutamyltransferase as a cardiovascular risk factor. Eur Heart J 2006;27:2145e2146.