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Toenail Selenium and Cardiovascular Disease in Men with Diabetes

Department of Nutrition (S.R., E.R., F.H.), Harvard School of Public Health, Channing Laboratory
Department of Epidemiology (S.R., E.R., F.H.), Harvard School of Public Health, Channing Laboratory
Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School (E.R., F.H.), Boston, Massachusetts
University of Missouri, Research Reactor Center, Columbia Missouri (J.S.M.)

Address reprint requests to: Swapnil Rajpathak, MD, DrPH, Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461. Email: srajpath{at}aecom.yu.edu

	ABSTRACT

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION REFERENCES

 
Objective: Selenium as a component of glutathione peroxidase may be beneficial in insulin resistance, hence potentially may modify the risk of diabetes and cardiovascular disease (CVD). The aim of this study is to evaluate the association between toenail selenium and CVD among men with diabetes.

Methods: We performed cross-sectional and nested case-control analyses within the Health Professionals Follow-up Study, a cohort of men aged 40 to 75 years in 1986. The cross-sectional analysis compared healthy controls (n = 361) to men with diabetes only (n = 688), and men with prevalent diabetes and CVD (n = 198). The nested case-control study included 202 diabetic men who developed incident CVD during follow-up and 361 matched controls.

Results: After controlling for potential confounders, the odds ratio (OR) for prevalent diabetes was 0.43 (95% CI: 0.28, 0.64; p-trend <0.001) for the highest compared to the lowest quartile of selenium. Comparison between diabetic men with CVD and healthy controls yielded an OR of 0.86 (95% CI: 0.47, 1.56, p-trend = 0.37) between extreme quartiles. In the nested case-control analysis, the OR between extreme quartiles was 0.57 (95% CI: 0.29, 1.03; p-trend = 0.07), comparing diabetic men with incident CVD to healthy controls.

Conclusions: Our results suggest that levels of toenail selenium are lower among diabetic men with or without CVD than among healthy controls. However, this study could not distinguish between the effects of selenium on diabetes and those on CVD. Randomized clinical trials are needed to study potential benefits of selenium supplementation in the prevention and treatment of diabetes and CVD.

Key words: toenail selenium, diabetes, cardiovascular disease

	INTRODUCTION

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION REFERENCES

 
Selenium is an important component of the antioxidant enzyme, glutathione peroxidase (GSH-Px) that protects cells from the adverse effects of free radicals and lipid peroxides. A deficiency of selenium lowers the tissue activity of GSH-Px which in turn may have unfavorable effects on lipoprotein and arachidonic acid metabolism [1,2]. These metabolic changes associated with compromised selenium status may lead to damage of the vascular endothelium and increased platelet adhesion which increase the risk of atherosclerotic heart disease [3]. Studies in rats show a beneficial effect of selenium supplementation on lipid abnormalities in plasma, aorta, and adipose tissue [4]. Since selenium mediates a number of insulin-like actions both in vivo and in vitro, this may be a potential mechanism for these actions [5]. These data suggest that selenium may be beneficial in insulin resistance and potentially can modify the risk of diabetes and cardiovascular disease (CVD) among men with diabetes.

One important reason for the paucity of data from epidemiological studies on selenium status and the risk of diabetes or CVD is the difficulty in estimating dietary selenium. The level of selenium in different foods varies widely depending on the soil content in the geographic area where the food is grown [6]. In the absence of accurate food composition data, a biomarker is required to conduct epidemiological studies with selenium status. The association between selenium and risk of CVD has been studied by analyzing serum and toenail samples; levels in toenail have been found to reflect longer-term intake than levels in serum [7]. An early case-control study in Europe found an inverse association between selenium level in toenails on the risk of myocardial infarction (MI) [8]. In a recent nested case-control study in the United States we found an inverse association for fatal and no-fatal MI but not for coronary revascularization procedures [9]. Since the risk of CVD is higher in individuals with diabetes than in those without diabetes, we conducted a study to evaluate the association between selenium levels in toenails and CVD among men with diabetes.

	MATERIALS AND METHODS

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION REFERENCES

 
Study Population
This study was conducted within the Health Professionals Follow-up Study (HPFS), a prospective cohort study of diet and chronic diseases. This cohort includes 51,529 health professional men who were aged 40 to 75 years old in 1986. This population included 29,683 dentists, 10,098 veterinarians, 4,185 pharmacists, 3,745 optometrists, 2,218 osteopathic physicians, and 1,600 podiatrists. In the baseline year of 1986, all participants completed a mailed questionnaire about their diet and medical history. Men who reported caloric intake of less than 800 or more than 4,200 kcal/day or those who missed more than 70 questions on the 1986 semi-quantitative food frequency questionnaire (131-item) were excluded from the base population. A follow-up questionnaire is sent to update information on incident medical conditions every two years and the dietary information is collected every four years. In 1987, 33,737 of the participants provided samples of toenail clippings; these were stored for analyses of trace elements. Selenium levels were assayed for all men with baseline diabetes and for matched controls. This study was approved by the Institutional Review Board at the Harvard School of Public Health.

Study Design
In the cross-sectional analyses, we divided participants in three groups as per information in 1986: men with prevalent diabetes (n = 688), men with prevalent diabetes and CVD (n = 198) and healthy controls (n = 361). Men with prevalent diabetes included participants who self-reported diabetes but who had never received a diagnosis of CVD. Such a diagnosis included fatal or nonfatal myocardial infarction (MI), coronary artery bypass graft (CABG), percutaneous transluminal coronary angioplasty (PTCA) or stroke. The second group included men who self-reported both diabetes and CVD at baseline. The control group in this study included men who had not reported any previous chronic disease that we selected for the nested case-control study (see below). Although the diagnosis of diabetes at baseline was based on self-reports from the questionnaire, the validity of self-reported diabetes has been verified in a subsample of 71 men in this cohort [10]. A physician blinded to questionnaire data reviewed medical records based on standard diagnostic criteria for diabetes. Among these 71 men, 12 had incomplete records; for the remaining 59, the diagnosis of diabetes was confirmed in 57 (97%).

The cases in the nested case-control analysis included men with diabetes at baseline and incident CVD during the follow-up period from the date of return of the toenail samples in 1987 to 1998 (n = 202). Controls were selected by 1:2 matching based on age (within 1 calendar year), smoking status (past, never, current) and date when toenail clippings were sent (within 1 month). This selection method also used a risk-set sampling [11], i.e., controls were chosen from participants who were free of chronic disease at the time the case was diagnosed with CVD. For 43 cases, however, we could obtain only one control because of the stringency of the selection criteria; thus the total number of controls was 361.

Assessment of Outcomes
The primary outcome in the nested case-control study was incident CVD which included MI, CABG, PTCA and stroke. Physicians blinded to the questionnaire data reviewed medical records based on standard diagnostic criteria. Confirmation of the non-fatal MI was based on World Health Organization criteria: symptoms plus either diagnostic electrocardiographic changes or elevated cardiac enzymes. If no medical records were available for men who were hospitalized for MI, they were designated as probable cases. We included both the confirmed and probable cases of CVD in the study. Death due to CVD was confirmed if it was listed in the hospital or autopsy records or on the death certificate as the underlying cause of death. When medical records were not available or telephone interviews were not feasible, the diagnosis of CVD was corroborated by correspondence with the subject, family member or personal physician. Information on CABG and PTCA was based on self-reports. Among the men who reported diabetes at baseline, 198 reported prevalent CVD (MI, 131; stroke, 21; CABG or PTCA, 46). Among the baseline diabetic men who did not report CVD in 1986, we documented 202 cases of CVD (MI, 108; stroke, 17; CABG or PTCA, 77) during the follow-up period.

Assessment of Exposure
Toenails incorporate selenium as they grow and a sample from each toe may reflect dietary intake over the past year [12]. In our study, the level of selenium in the toenails was analyzed by instrumental neutron-activation analysis at the University of Missouri Research Reactor [13]. Initially the toenail samples were washed in a sonicator with deionized water to remove any contamination. The laboratory personnel were unaware of the disease status of the participant who provided the sample. In each analytical measurement, the reference standard was bovine liver from the National Bureau of Standards (NBS-SRM 1577) with a certified selenium concentration of 1.1 ± 0.1 µg/g. In a quality control study, we analyzed 36 samples and found an average selenium concentration of 1.155 ± 0.097 PPM selenium which is in agreement with the certified value. Since the concentration of selenium is dependent on the weight of the toenail, the levels are adjusted for the sample weight and expressed as microgram per gram of toenail (µg/g). The case and control samples in the nested case-control study were analyzed together but in random order. The samples from baseline diabetic men cross-sectional analysis were analyzed together but separately from control samples from the nested case-control study.

Assessment of Potential Confounders
We used information on anthropometry, lifestyle and diet from the 1986 questionnaires. To calculate the average intake of a nutrient, we used a 131-item semiquantitative food frequency questionnaire (FFQ) and the Harvard University Food Composition Database derived from US Department of Agriculture sources, manufacturers’ data and published papers. Body mass index (BMI) was calculated as the ratio of self-reported body weight in kilograms to height in meters squared (kg/m²). Physical activity was expressed as metabolic equivalent hours (MET-hrs) based on the self-reported types and durations of activities during the previous year; one MET-hr equivalent to the energy expended by sitting quietly for 1 hour [14]. The reproducibility and validity of the dietary and physical activity data have been reported in detail elsewhere [15–17].

Statistical Analysis
We used Statistical Analysis Systems software (SAS Institute, Cary, NC) for all statistical analyses. The reported geometric mean level of toenail selenium for a specified group is the antilog of a log-transformed variable for toenail selenium. For each comparison, we categorized selenium levels into quartiles as per the distribution in the control group. To examine the association between quartiles of selenium and the risk of CVD, we used conditional and unconditional logistic regression models. Since the results from these two methods were similar, we only present the results from the unconditional models. The odds ratio (OR) and the 95% confidence intervals (CI) were calculated with the lowest quartile as the reference group. Among the covariates, age in years was grouped into five categories: less than or equal to 50, 51 to 54, 55 to 59, 60 to 64 and 65 or more. BMI (kg/m²) was divided into three categories: less than 25, 25.0 to 29.9 and 30.0 and greater. Alcohol intake (g/day) was grouped into five categories: 0.0 (non-drinkers), 0.1 to 5.0, 5.1 to 10.0, 10.1 to 15.0 and 15.1 or more. Smoking status was grouped into three categories: never, former, and current smoker. Hypertension, high cholesterol and family history of MI were adjusted as binary (yes/no) variables. We adjusted for nutrients as quartiles of a dietary composite score created with quartile scores of six variables (marine omega-3, trans fatty acids, folate, cereal fiber, polyunsaturated: saturated fat [P:S] ratio and glycemic load) [18]. We also controlled for mercury and chromium levels in toenails as these elements have been associated with the risk of CVD in some studies [19,20]. In addition, we also considered potential confounding by adjustment of laboratory analytical batch for toenail selenium estimation and vitamin E intake. We evaluated for potential effect modification by vitamin E, smoking or alcohol consumption. Tests for trend were conducted by assigning an ordinal score to each quartile. All p-values reported are two-tailed and p-values below 0.05 were considered statistically significant.

	RESULTS

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION REFERENCES

 
Table 1 shows age-adjusted characteristics at baseline among healthy controls according to the quartiles of selenium levels in healthy controls. The lowest quartile group had a greater proportion of current smokers and consumed less fiber than the higher quartiles.

	DISCUSSION

 
Overall, we found lower levels of toenail selenium in diabetic men with CVD and in men with prevalent diabetes than in healthy controls. The role of oxidative stress in diabetes and CVD is known [21] and it is plausible that men with lower levels of toenail selenium may be at a higher risk of diabetes and CVD.

Diet is the most important source of selenium in humans. However, the food composition data do not provide a valid measure of the selenium intake. Thus, it is difficult to conduct epidemiological studies evaluating the role of selenium on chronic diseases. Results from studies predicting heart disease using serum levels of selenium [22–25] have been inconsistent. The level of selenium in toenails is a more time-integrated marker of selenium intake than serum [7]. Several other epidemiological studies have used toenails for the evaluation of the role of trace elements in chronic diseases such as cancer [26–30], cardiovascular disease [9,20] and others [31,32]. Studies that evaluated the validity of toenail selenium as a biomarker concluded that this measure is useful in epidemiological studies. The Pearson correlation coefficient (r) in a one-year reproducibility study of toenail selenium levels in a sample of 80 Italian women enrolled in a prospective study on breast cancer was 0.57 (p < 0.001) [33]. In another study also in women, the six-year reproducibility was 0.48 measured by Spearman correlation coefficient between toenail levels of selenium [34].

Studies assessing the role of toenail selenium levels in the development of CVD are limited. Two studies reported a null association between toenail selenium and risk of MI. A study in our HPFS cohort by Yoshizawa et al. [9] reported that toenail selenium was not associated with the risk of total coronary heart disease (CHD); the multivariate OR between extreme quintiles was 0.86 (95% CI: 0.55, 1.32; p-trend = 0.75). However, in this study toenail selenium was inversely associated with risk of nonfatal MI for the extreme quintiles (OR: 0.54, 95% CI: 0.31, 0.93; p-trend = 0.07). In a multicenter European Antioxidant Myocardial Infarction and Breast Cancer Study (EURAMIC), Kaardinaal et al. [35] reported a multivariate OR for MI for the highest quintile of toenail selenium of 0.63 (95% CI: 0.37, 1.07; p-trend = 0.08). In the same study, authors found a significant inverse association only in former smokers but not in current smokers or never smokers. Both of these studies included subjects who were apparently healthy at baseline.

Smoking is an important predictor of levels of selenium in toenails; current smokers have lower level [36,37]. In our study, the quartile with lowest toenail selenium level had a higher proportion of current smokers. In our multivariate analysis, we controlled for smoking in three categories (never, current, ex-smoker). Such adjustment of smoking may leave some residual confounding; thus we also conducted an analysis restricted to non-smokers. This did not change our results appreciably. The prospective nested case-control design has an advantage because the toenail samples were collected before the diagnosis of CVD. Thus, the levels of selenium in toenails are unlikely to be affected by CVD status. We measured the selenium levels in toenails with a neutron-activation technique that is a sensitive, reproducible and non-destructive method for such estimations [38].

Our study has several limitations. Sample contamination may produce erroneously high values for selenium levels in toenails. We, however, washed the samples in a sonicator with deionized water before the analysis to reduce contamination. Further, an error in the assessment should be non-differential with respect to case and control status and thus only bias our results towards the null. Another limitation is the use of a single measurement of toenail selenium which is prone to random error and thus the effects are likely to be underestimated. In addition, the cross-sectional analysis may be biased as a result of "reverse causation", i.e., diabetes or CVD could cause a decrease in toenail selenium levels; although, there is no data in this regard yet. Having more than one study design to address the same hypothesis is advantageous because it provides a check on the consistency of the results. The comparison between men with diabetes and CVD and healthy controls was designed a priori; but such comparison cannot distinguish the effects of selenium on diabetes from those on CVD. We found a stronger inverse association for toenail selenium for diabetes than for diabetes with CVD. Among men with baseline diabetes, toenail selenium was associated with higher, but not significantly increased risk of CVD in the cross-sectional analysis. These results suggest that higher toenail selenium may be beneficial for prevention of diabetes but may not be so for CVD among men with diabetes. A possible hypothesis is that utilization of selenium may be ineffective among diabetic men due to the lower GSH-Px enzyme activity in this population [39] and hence selenium may accumulate in toenails over a period of time. In addition, we cannot rule out the role of chance in this observation. Because of the design of our nested case-control study, we could evaluate only the effect of toenail selenium on the risk of CVD and diabetes together. Future studies should be designed specifically to evaluate the role of selenium in preventing diabetes separately from its role in CVD among people with diabetes.

	CONCLUSION

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION REFERENCES

 
Our results suggest that levels of toenail selenium are lower among diabetic men with or without CVD than among healthy controls. However, this study could not distinguish between the effects of selenium on diabetes and those on CVD. Randomized clinical trials are needed to study potential benefits of selenium supplementation in the prevention and treatment of diabetes and CVD.

	FOOTNOTES

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION REFERENCES

 
This study was supported by research grants HL35464 and CA55075 from the National Institute of Health. Dr. Frank Hu’s work is supported in part by the American Heart Association’s Established Investigator Award. We thank Nutrition21 (Purchase, NY) for their unrestricted funding for the measurement of toenail selenium levels and data analysis.

Received October 1, 2004. Accepted March 28, 2005.

	REFERENCES

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION REFERENCES

 

1. Burk RF: Selenium, an antioxidant nutrient. Nutr Clin Care5 :75 –79,2002 .[Medline]
2. Cao YZ, Reddy CC, Sordillo LM: Altered eicosanoid biosynthesis in selenium-deficient endothelial cells. Free Radic Biol Med28 :381 –389,2000 .[Medline]
3. Steinberg D: Antioxidants and atherosclerosis. A current assessment. Circulation84 :1420 –1425,1991 .[Free Full Text]
4. Douillet C, Bost M, Accominotti M, Borson-Chazot F, Ciavatti M: Effect of selenium and vitamin E supplementation on lipid abnormalities in plasma, aorta, and adipose tissue of Zucker rats. Biol Trace Elem Res65 :221 –236,1998 .[Medline]
5. Stapleton SR: Selenium: an insulin-mimetic. Cell Mol Life Sci57 :1874 –1879,2000 .[Medline]
6. Levander OA: A global view of human selenium nutrition. Annu Rev Nutr7 :227 –250,1987 .[Medline]
7. Longnecker MP, Stampfer MJ, Morris JS, Spate V, Baskett C, Mason M, Willett WC: A 1-y trial of the effect of high-selenium bread on selenium concentrations in blood and toenails. Am J Clin Nutr57 :408 –413,1993 .[Abstract/Free Full Text]
8. Kok FJ, Hofman A, Witteman JC, de Bruijn AM, Kruyssen DH, de Bruin M, Valkenburg HA: Decreased selenium levels in acute myocardial infarction. JAMA261 :1161 –1164,1989 .[Abstract]
9. Yoshizawa K, Ascherio A, Morris JS, Stampfer MJ, Giovannucci E, Baskett CK, Willett WC, Rimm EB: Prospective study of selenium levels in toenails and risk of coronary heart disease in men. Am J Epidemiol158 :852 –860,2003 .[Abstract/Free Full Text]
10. Hu FB, Leitzmann MF, Stampfer MJ, Colditz GA, Willett WC, Rimm EB: Physical activity and television watching in relation to risk for type 2 diabetes mellitus in men. Arch Intern Med161 :1542 –1548,2001 .[Abstract/Free Full Text]
11. Prentice RL, Breslow NE: Retrospective studies and failure time models. Biometrika65 :153 –158,1978 .[Abstract/Free Full Text]
12. Longnecker MP, Stampfer MJ, Morris JS, Spate V, Baskett C, Mason M, Willett WC: A 1-y trial of the effect of high-selenium bread on selenium concentrations in blood and toenails. Am J Clin Nutr57 :408 –413,1993 .
13. Cheng T-P, Morris JS, Koirtyohann SR, Spate VL, Baskett CK: The analysis of human nails for 24 elements via k0 and cyclic neutron activation analysis. Phys Res353 :457 –460,1994 .
14. Ainsworth BE, Haskell WL, Whitt MC, Irwin ML, Swartz AM, Strath SJ, O’Brien WL, Bassett DR, Schmitz KH, Emplaincourt PO, Jacobs DR, Leon AS: Compendium of physical activities: an update of activity codes and MET intensities. Med Sci Sports Exerc32 :S498 –S504,2000 .[Medline]
15. Rimm EB, Giovannucci EL, Stampfer MJ, Colditz GA, Litin LB, Willett WC: Reproducibility and validity of an expanded self-administered semiquantitative food frequency questionnaire among male health professionals. Am J Epidemiol135 :1114 –1126, Discussion 1127–1136,1992 .[Abstract/Free Full Text]
16. Chasan-Taber S, Rimm EB, Stampfer MJ, Spiegelman D, Colditz GA, Giovannucci E, Ascherio A, Willett WC: Reproducibility and validity of a self-administered physical activity questionnaire for male health professionals. Epidemiology7 :81 –86,1996 .[Medline]
17. Giovannucci E, Colditz G, Stampfer MJ, Rimm EB, Litin L, Sampson L, Willett WC: The assessment of alcohol consumption by a simple self-administered questionnaire. Am J Epidemiol133 :810 –817,1991 .[Abstract/Free Full Text]
18. Stampfer MJ, Hu FB, Manson JE, Rimm EB, Willett WC: Primary prevention of coronary heart disease in women through diet and lifestyle. N Engl J Med343 :16 –22,2002 .
19. Guallar E BP, Riemersma R, Gomez-Aracena J, Kark J, Arab L, Kok F, Martin-Moreno JM: Low toenail chromium and increased risk of myocardial infarction. Am J Epi2004 (in press).
20. Yoshizawa K, Rimm EB, Morris JS, Spate VL, Hsieh CC, Spiegelman D, Stampfer MJ, Willett WC: Mercury and the risk of coronary heart disease in men. N Engl J Med347 :1755 –1760,2002 .[Abstract/Free Full Text]
21. Giugliano D, Ceriello A, Paolisso G: Diabetes mellitus, hypertension, and cardiovascular disease: which role for oxidative stress? Metabolism44 :363 –368,1995 .[Medline]
22. Virtamo J, Valkeila E, Alfthan G, Punsar S, Huttunen JK, Karvonen MJ: Serum selenium and the risk of coronary heart disease and stroke. Am J Epidemiol122 :276 –282,1985 .[Abstract/Free Full Text]
23. Salonen JT, Alfthan G, Huttunen JK, Pikkarainen J, Puska P: Association between cardiovascular death and myocardial infarction and serum selenium in a matched-pair longitudinal study. Lancet2 :175 –179,1982 .[Medline]
24. Suadicani P, Hein HO, Gyntelberg F: Serum selenium concentration and risk of ischaemic heart disease in a prospective cohort study of 3000 males. Atherosclerosis96 :33 –42,1992 .[Medline]
25. Kok FJ, De Bruijn AM, Hofman A, Valkenburg HA: Selenium status and chronic disease mortality: Dutch epidemiological findings. Int J Epidemiol16 :329 –332,1987 .[Abstract/Free Full Text]
26. Garland M, Morris JS, Colditz GA, Stampfer MJ, Spate VL, Baskett CK, Rosner B, Speizer FE, Willett WC, Hunter DJ: Toenail trace element levels and breast cancer: a prospective study. Am J Epidemiol144 :653 –660,1996 .[Abstract/Free Full Text]
27. Yoshizawa K, Willett WC, Morris SJ, Stampfer MJ, Spiegelman D, Rimm EB, Giovannucci E: Study of prediagnostic selenium level in toenails and the risk of advanced prostate cancer. J Natl Cancer Inst90 :1219 –1224,1998 .[Abstract/Free Full Text]
28. Hartman TJ, Taylor PR, Alfthan G, Fagerstrom R, Virtamo J, Mark SD, Virtanen M, Barrett MJ, Albanes D: Toenail selenium concentration and lung cancer in male smokers (Finland). Cancer Causes Control13 :923 –928,2002 .[Medline]
29. Michaud DS, Hartman TJ, Taylor PR, Pietinen P, Alfthan G, Virtamo J, Albanes D: No Association between toenail selenium levels and bladder cancer risk. Cancer Epidemiol Biomarkers Prev11 :1505 –1506,2002 .[Free Full Text]
30. Mannisto S, Alfthan G, Virtanen M, Kataja V, Uusitupa M, Pietinen P: Toenail selenium and breast cancer—a case-control study in Finland. Eur J Clin Nutr54 :98 –103,2000 .[Medline]
31. Feskanich D, Owusu W, Hunter DJ, Willett W, Ascherio A, Spiegelman D, Morris S, Spate VL, Colditz G: Use of toenail fluoride levels as an indicator for the risk of hip and forearm fractures in women. Epidemiology9 :412 –416,1998 .[Medline]
32. van den Brandt PA, Goldbohm RA, van’t Veer P, Bode P, Dorant E, Hermus RJ, Sturmans F: A prospective cohort study on toenail selenium levels and risk of gastrointestinal cancer. J Natl Cancer Inst85 :224 –229,1993 .[Abstract/Free Full Text]
33. Krogh V, Pala V, Vinceti M, Berrino F, Ganzi A, Micheli A, Muti P, Vescovi L, Ferrari A, Fortini K, Sieri S, Vivoli G: Toenail selenium as biomarker: reproducibility over a one-year period and factors influencing reproducibility. J Trace Elem Med Biol17(Suppl1) :31 –36,2003 .
34. Garland M, Morris JS, Rosner BA, Stampfer MJ, Spate VL, Baskett CJ, Willett WC, Hunter DJ: Toenail trace element levels as biomarkers: reproducibility over a 6-year period. Cancer Epidemiol Biomarkers Prev2 :493 –497,1993 .[Abstract]
35. Kardinaal AF, Kok FJ, Kohlmeier L, Martin-Moreno JM, Ringstad J, Gomez-Aracena J, Mazaev VP, Thamm M, Martin BC, Aro A, Kark JD, Delgado-Rodriguez M, Riemersma RA, van’t Veer P, Huttunen JK: Association between toenail selenium and risk of acute myocardial infarction in European men. The EURAMIC Study. European Antioxidant Myocardial Infarction and Breast Cancer. Am J Epidemiol145 :373 –379,1997 .[Abstract/Free Full Text]
36. van den Brandt PA, Goldbohm RA, van’t Veer P, Bode P, Hermus RJ, Sturmans F: Predictors of toenail selenium levels in men and women. Cancer Epidemiol Biomarkers Prev2 :107 –112,1993 .[Abstract]
37. Hunter DJ, Morris JS, Chute CG, Kushner E, Colditz GA, Stampfer MJ, Speizer FE, Willett WC: Predictors of selenium concentration in human toenails. Am J Epidemiol132 :114 –122,1990 .[Abstract/Free Full Text]
38. Bode P, de Kok J: Trends in trace element determinations in blood, serum, and urine of the Dutch population, and the role of neutron activation analysis. Biol Trace Elem Res71–72 :15 –20,1999 .
39. Uzel N, Sivas A, Uysal M, Oz H: Erythrocyte lipid peroxidation and glutathione peroxidase activities in patients with diabetes mellitus. Horm Metab Res19 :89 –90,1987 .[Medline]

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