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Background: Two chemoprevention trials found that supplementation with b-carotene increased the risk of lung cancer and overall mortality. The biologic basis of these findings remains poorly understood. Objective: The objective was to compare the on-study change in metabolomic profiles of men randomly assigned to receive or not receive b-carotene supplements in the Alpha-Tocopherol, BetaCarotene Cancer Prevention (ATBC) Study. Design: The ATBC Study was a randomized, double-blind, placebo-controlled, primary cancer prevention trial; participants were Finnish male smokers assigned to 1 of 4 intervention groups: 1) a-tocopherol, 2) b-carotene, 3) both, or 4) placebo. Fifty participants with both baseline and follow-up fasting serum samples were randomly selected from each of these groups. Metabolomic profiling was conducted by mass spectrometry. The association between change in each metabolite over time and trial assignment (b-carotene or no b-carotene) was estimated by linear regression. Results: We measured 489 metabolites, and 17 changed significantly (P , 0.05) in response to b-carotene supplementation. More of these 17 metabolites were of xenobiotic origin than would be expected by chance (9 of 60, or 15%; P = 0.00004). We also found a suggestive association with 1,5-anhydroglucitol—a marker of glycemic control (b = 20.379, P = 0.0071). Conclusions: Male smokers supplemented with b-carotene developed metabolomic profiles consistent with the induction of cytochrome P450 enzymes, the primary metabolizers of xenobiotics in humans. These findings may shed light on the increased mortality associated with b-carotene supplementation in the ATBC Study and suggest the need to explore potential interactions between medication use and dietary supplements, particularly among smokers. This trial was registered at clinicaltrials.gov as NCT00342992. Am J Clin Nutr 2013;98:488‐93.

Background: Moderate alcohol consumption associates with lower risk of type 2 diabetes, but in postprandial studies, alcohol induced impaired insulin sensitivity. The measurement of the glycemic index (GI) for beer has been considered challenging because of its low carbohydrate content. Therefore, imputed GI values from 36 to 95 on the basis of carbohydrate-rich beverages have been used for beer in epidemiologic studies. Objectives: We investigated the acute effects of alcohol on glucose and insulin responses and measured GIs and insulinemic indexes (IIs) of nonalcoholic and alcoholic beers. Design: In a crossover design, 10 healthy volunteers were served beer with 4.5% alcohol by volume, nonalcoholic beer, and a glucose solution with alcohol once and the reference glucose solution twice. Each portion contained 25 g available carbohydrate, and the beer and glucose solution with alcohol contained 21 g alcohol. Capillary blood samples were collected up to 2 h postprandial, and the incremental AUCs (IAUCs), GIs, and IIs were calculated. Results: Compared with the reference glucose solution, the glucose solution with alcohol produced an 18% higher postprandial glucose IAUC (P = 0.03) and had no significant effect on the insulin IAUC. Compared with the reference glucose solution, beer had no significant effect on glucose or insulin IAUCs, and nonalcoholic beer tended to reduce the glucose IAUC (P = 0.06) but not the insulin IAUC. GIs of beer and nonalcoholic beer were 119 and 80, and IIs were 130 and 88, respectively. Conclusions: Alcohol increases the postprandial glucose response, probably through impaired insulin sensitivity. GI values published for alcohol-containing beers have underestimated the true glycemic effects. This trial was registered at clinicaltrials.gov as NCT01477216. Am J Clin Nutr doi: 10.3945/ajcn.111.031682.

Background: Epidemiologic studies of fish consumption in relation to risk of stroke have yielded inconsistent results. Objective: In this study, we examined the association between fish consumption and stroke incidence in women. Design: We analyzed data from a population-based prospective cohort of 34,670 women in the Swedish Mammography Cohort who were free of cardiovascular disease and cancer at baseline. Information on fish consumption was obtained by a self-administered questionnaire in 1997. Incident cases of stroke were ascertained from the Swedish Hospital Discharge Registry. We used Cox proportional hazards regression to estimate relative risks (RRs) and 95% CIs. Results: Over a mean follow-up of 10.4 y, we ascertained 1680 incident cases of stroke, including 1310 cerebral infarctions, 233 hemorrhagic strokes, and 137 unspecified strokes. Fish consumption was significantly inversely associated with risk of total stroke but not with cerebral infarction or hemorrhagic stroke. Compared with women in the lowest quintile of fish consumption (,1.0 serving of fish/wk), the multivariable RR of total stroke for women in the highest quintile (.3.0 servings of fish/wk) was 0.84 (95% CI: 0.71, 0.98; P for trend = 0.049). Consumption of lean fish but not of other fish types was inversely associated with risk of stroke. The multivariable RR of total stroke was 0.67 (95% CI: 0.49, 0.93; P for trend = 0.07) for 3 servings of lean fish/wk compared with that for no consumption. Conclusion: These results suggest that the consumption of fish, especially of lean fish, may reduce risk of stroke in women. This trial was registered at clinicaltrials.gov as NCT01127698. Am J Clin Nutr 2011;93:487‐93.

Background: Saturated fatty acid (SFA) intake increases plasma LDL-cholesterol concentrations; therefore, intake should be reduced to prevent coronary heart disease (CHD). Lower habitual intakes of SFAs, however, requires substitution of other macronutrients to maintain energy balance. Objective: We investigated associations between energy intake from monounsaturated fatty acids (MUFAs), polyunsaturated fatty acids (PUFAs), and carbohydrates and risk of CHD while assessing the potential effect-modifying role of sex and age. Using substitution models, our aim was to clarify whether energy from unsaturated fatty acids or carbohydrates should replace energy from SFAs to prevent CHD. Design: This was a follow-up study in which data from 11 American and European cohort studies were pooled. The outcome measure was incident CHD. Results: During 4–10 y of follow-up, 5249 coronary events and 2155 coronary deaths occurred among 344,696 persons. For a 5% lower energy intake from SFAs and a concomitant higher energy intake from PUFAs, there was a significant inverse association between PUFAs and risk of coronary events (hazard ratio: 0.87; 95% CI: 0.77, 0.97); the hazard ratio for coronary deaths was 0.74 (95% CI: 0.61, 0.89). For a 5% lower energy intake from SFAs and a concomitant higher energy intake from carbohydrates, there was a modest significant direct association between carbohydrates and coronary events (hazard ratio: 1.07; 95% CI: 1.01, 1.14); the hazard ratio for coronary deaths was 0.96 (95% CI: 0.82, 1.13). MUFA intake was not associated with CHD. No effect modification by sex or age was found. Conclusion: The associations suggest that replacing SFAs with PUFAs rather than MUFAs or carbohydrates prevents CHD over a wide range of intakes. Am J Clin Nutr 2009;89:1–8.

Background: Evidence indicates that vitamin E has anticarcinogenic properties for gastrointestinal cancers; however, few studies have examined this with respect to exocrine pancreatic cancer. Objective: The objective was to examine whether vitamin E intake and serum α-tocopherol concentrations were prospectively associated with exocrine pancreatic cancer. Design: We conducted a cohort analysis of prediagnostic vitamin E intake (4 tocopherols, 4 tocotrienols), serum α-tocopherol concentrations, and pancreatic cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study of male Finnish smokers aged 50–69 y at baseline. During follow-up from 1985 to 2004 (maximum: 19.4 y; median: 16 y), 318 incident cases were diagnosed among cohort participants with complete serum samples (n = 29,092); 306 cases had complete dietary data (n = 27,111). Cox proportional hazards models adjusted for age, smoking history, history of diabetes mellitus, and/or serum cholesterol were used to calculate hazard ratios (HRs) and 95% CIs. Results: Higher α-tocopherol concentrations were associated with lower pancreatic cancer risk (highest compared with lowest quintile, HR: 0.52; 95% CI: 0.34, 0.80; P for trend = 0.03; continuous HR: 0.91; 95% CI: 0.84, 0.99). Polyunsaturated fat, a putative prooxidant nutrient, modified the association such that the inverse α-tocopherol association was most pronounced in subjects with a high polyunsaturated fat intake (ie, >9.9 g/d; highest compared with lowest quintile, HR: 0.38; 95% CI: 0.20, 0.70; P for trend = 0.03; continuous HR: 0.86; 95% CI: 0.75, 0.97; P for interaction = 0.05 and 0.02, respectively). No associations were observed for dietary tocopherols and tocotrienols. Conclusion: Our results support the hypothesis that higher α-tocopherol concentrations may play a protective role in pancreatic carcinogenesis in male smokers.

BACKGROUND A meta-analysis of 19 trials suggested a small increase in the risk of all-cause mortality with high-dose vitamin E supplementation. Little is known, however, about the relation between mortality and circulating concentrations of vitamin E resulting from dietary intake, low-dose supplementation, or both. OBJECTIVE We examined whether baseline serum alpha-tocopherol concentrations are associated with total and cause-specific mortality. DESIGN A prospective cohort study of 29 092 Finnish male smokers aged 50-69 y who participated in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study was carried out. Fasting serum alpha-tocopherol was measured at baseline by using HPLC. Only 10% of participants reported vitamin E supplement use at baseline, and thus serum concentrations of vitamin E mainly reflected dietary intake and other host factors. Risks of total and cause-specific mortality were estimated by using proportional hazards models. RESULTS During up to 19 y of follow-up, 13 380 deaths (including 4518 and 5776 due to cancer and cardiovascular disease, respectively) were identified. Men in the higher quintiles of serum alpha-tocopherol had significantly lower risks of total and cause-specific mortality than did those in the lowest quintile [relative risk (RR) = 0.82 (95% CI: 0.78, 0.86) for total mortality and 0.79 (0.72, 0.86), 0.81 (0.75, 0.88), and 0.70 (0.63, 0.79) for deaths due to cancer, cardiovascular disease, and other causes, respectively; P for trend for all < 0.0001]. Cubic regression spline analysis of continuous serum alpha-tocopherol values indicated greater risk reductions with increasing concentrations up to approximately 13-14 mg/L, after which no further benefit was noted. CONCLUSION Higher circulating concentrations of alpha-tocopherol within the normal range are associated with significantly lower total and cause-specific mortality in older male smokers.

Background: Epidemiologic studies have suggested a lower risk of coronary heart disease (CHD) at higher intakes of fruit, vegetables, and whole grain. Whether this association is due to antioxidant vitamins or some other factors remains unclear. Objective: We studied the relation between the intake of antioxidant vitamins and CHD risk. Design: A cohort study pooling 9 prospective studies that included information on intakes of vitamin E, carotenoids, and vitamin C and that met specific criteria was carried out. During a 10-y follow-up, 4647 major incident CHD events occurred in 293 172 subjects who were free of CHD at baseline. Results: Dietary intake of antioxidant vitamins was only weakly related to a reduced CHD risk after adjustment for potential nondietary and dietary confounding factors. Compared with subjects in the lowest dietary intake quintiles for vitamins E and C, those in the highest intake quintiles had relative risks of CHD incidence of 0.84 (95% CI: 0.71, 1.00; P = 0.17) and 1.23 (1.04, 1.45; P = 0.07), respectively, and the relative risks for subjects in the highest intake quintiles for the various carotenoids varied from 0.90 to 0.99. Subjects with higher supplemental vitamin C intake had a lower CHD incidence. Compared with subjects who did not take supplemental vitamin C, those who took >700 mg supplemental vitamin C/d had a relative risk of CHD incidence of 0.75 (0.60, 0.93; P for trend < 0.001). Supplemental vitamin E intake was not significantly related to reduced CHD risk. Conclusions: The results suggest a reduced incidence of major CHD events at high supplemental vitamin C intakes. The risk reductions at high vitamin E or carotenoid intakes appear small.

Background: Poor dental health has been associated with increased risks of oral, esophageal, and gastric cancer and may also be associated with pancreatic cancer. In addition, Helicobacter pylori has been found in dental plaque and has been associated with periodontal disease and pancreatic cancer. Objective: The objective was to investigate prospectively the relation between dentition history and pancreatic cancer in the AlphaTocopherol, Beta-Carotene Cancer Prevention Study cohort in Finland and the association between dentition history and H. pylori seropositivity in a cross-sectional sample of subjects without cancer (n = 475) from the same cohort. Design: Of the 29 104 male smokers aged 50‐69 y in the cohort for whom there were complete data, 174 developed pancreatic cancer from 1985 to 1997. Cox proportional hazard models were used to estimate age-, smoking-, education-, urban living‐, and height-adjusted hazard ratios and 95% CIs for pancreatic cancer, and logistic regression models were used to estimate age- and education-adjusted odds ratios for H. pylori carriage. Results: Tooth loss was positively associated with pancreatic cancer (edentulous compared with missing 0‐10 teeth: hazard ratio = 1.63; 95% CI: 1.09, 2.46; P for trend = 0.02) but was not significantly associated with H. pylori seropositivity (edentulous compared with missing 0‐10 teeth: odds ratio = 1.30; 95% CI: 0.73, 2.32; P for trend = 0.37). Conclusion: Additional studies are needed to evaluate the association between tooth loss and pancreatic cancer, as well as cancers at other gastrointestinal sites, particularly with respect to possible biological mechanisms. Am J Clin Nutr 2003;78:176‐81.

We determined whether serum carotenoid or retinol concentrations were altered by beta-carotene supplementation in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study and whether such effects were modified by alcohol consumption or cigarette use. Participants in this substudy were 491 randomly selected men aged 58-76 y from the metropolitan Helsinki study center [237 receiving supplemental beta-carotene (20 mg/d) and 254 not receiving such supplementation]. Dietary carotenoids, retinol, and alcohol, and serum beta-carotene, alpha-tocopherol, retinol, and cholesterol were assessed at baseline. After an average of 6.7 y of supplementation, serum was collected and carotenoid, retinol, and alpha-tocopherol concentrations were determined by HPLC. Serum carotenoid fractions were highly correlated with each other (Por = 0.0001). Compared with the unsupplemented group, the beta-carotene group had significantly higher serum concentrations of beta-carotene (1483%), alpha-carotene (145%), and beta-cryptoxanthin (67%) (Por = 0.0001). Retinol concentrations were 6% higher (P = 0.03) and lutein was 11% lower (P = 0.02) in the supplemented group. Serum lycopene, zeaxanthin, and alpha-tocopherol did not differ according to beta-carotene-supplementation status. Although these beta-carotene-group differences were not significantly altered by amount of alcohol consumption, higher consumption (12.9 g/d, median) was related to lower (10-38%) concentrations of carotenoids, particularly beta-carotene, alpha-carotene, and beta-cryptoxanthin, in both the supplemented and unsupplemented groups. Smoking status did not significantly influence the supplementation-related differences in serum carotenoid and retinol values but concentrations of carotenoids were generally highest in participants who quit smoking while in the study and lowest in current smokers ofor = 20 cigarettes/d. This study showed that serum concentrations of non-beta-carotene carotenoids are altered by long-term beta-carotene supplementation and confirms the adverse effects of alcohol and cigarette smoking on serum carotenoids.

Background: Red and processed meat consumption has been implicated in several diseases. However, data on meat consumption in relation to stroke incidence are sparse. Objective: Our objective was to examine the associations of red meat and processed meat consumption with stroke incidence in men. Design: We prospectively followed 40,291 men aged 45–79 y who had no history of cardiovascular disease or cancer at baseline. Meat consumption was assessed with a self-administered questionnaire in 1997. Results: During a mean follow-up of 10.1 y, 2409 incident cases of stroke (1849 cerebral infarctions, 350 hemorrhagic strokes, and 210 unspecified strokes) were identified from the Swedish Hospital Discharge Registry. Consumption of processed meat, but not of fresh red meat, was positively associated with risk of stroke. The multivariable relative risks (RRs) of total stroke for the highest compared with the lowest quintiles of consumption were 1.23 (95% CI: 1.07, 1.40; P for trend = 0.004) for processed meat and 1.07 (95% CI: 0.93, 1.24; P for trend = 0.77) for fresh red meat. Processed meat consumption was also positively associated with risk of cerebral infarction in a comparison of the highest with the lowest quintile (RR: 1.18; 95% CI: 1.01, 1.38; P for trend = 0.03). Conclusion: The findings from this prospective cohort of men indicate that processed meat consumption is positively associated with risk of stroke. The Cohort of Swedish Men is registered at clinicaltrials.gov as NCT01127711. Am J Clin Nutr 2011;94:417–21.

Background Methodologic choices affect measures of the glycemic index (GI). The effects on GI values of blood sampling site, reference food type, and the number of repeat tests have been insufficiently determined. Objective The objective was to study the effect of methodologic choices on GI values. Comparisons were made between venous and capillary blood sampling and between glucose and white bread as the reference food. The number of tests needed for the reference food was assessed. Rye bread, oatmeal porridge, and instant mashed potato were used as the test foods. Design Twelve healthy volunteers were served each test food once and both reference foods 3 times at 1-wk intervals in a random order after they had fasted overnight. Capillary and venous blood samples were drawn at intervals for 3 h after each study meal. Results GIs and their CVs based on capillary samples were lower than those based on venous samples. Two tests of glucose solution as the reference provided stable capillary GIs for the test foods. The capillary GIs did not differ significantly when white bread was used as the reference 1, 2, or 3 times, but the variation was lower when tests were performed 2 and 3 times. Capillary GIs with white bread as the reference were 1.3 times as high as those with glucose as the reference. The capillary GIs of rye bread, oatmeal porridge, and mashed potato were 77, 74, and 80, respectively, with glucose as the reference. Conclusions Capillary blood sampling should be used in the measurement of GI, and reference tests with glucose or white bread should be performed at least twice.

Background Folate is hypothesized to be inversely associated with the risk of several cancers, but such a potential association has not been well studied for prostate cancer. Vitamin B-6, vitamin B-12, methionine, and alcohol can influence folate-related metabolism. Objective The objective was to investigate the associations between dietary factors of one-carbon metabolism and prostate cancer risk within the alpha-Tocopherol, beta-Carotene Cancer Prevention Study. Design Of the cohort's 27 111 Finnish male smokers aged 50-69 y who had complete dietary data, 1270 had a diagnosis of incident prostate cancer between 1985 and 2002. Folate, vitamin B-6, vitamin B-12, methionine, and alcohol intakes were estimated from a 276-item modified dietary history questionnaire. Cox proportional hazard models, adjusted for age and vitamin supplement use, estimated relative risks (RR) and 95% CIs. Results Vitamin B-6 intake was inversely associated with prostate cancer risk (RR for highest versus lowest quintile: 0.88; 95% CI: 0.72, 1.07; P for trend = 0.045), whereas vitamin B-12 intake was associated with significantly increased risk (RR = 1.36; 95% CI: 1.14, 1.96; P for trend = 0.01). No association between folate or alcohol intake and prostate cancer risk was observed. No differences were found in the above associations according to stage of disease or subgroups of several potential effect modifiers. Conclusions We found no convincing evidence for a protective role of one-carbon metabolism against prostate cancer, although these observations can be generalized only to smokers. The possible modest protective association with vitamin B-6 and the significantly elevated risk with vitamin B-12 intake warrant further investigation.

Background: Although smoking is the primary cause of lung cancer, much is unknown about lung cancer etiology, including risk determinants for nonsmokers and modifying factors for smokers. Objective: We hypothesized that alcohol consumption contributes to lung cancer risk. Design: We conducted a pooled analysis using standardized exposure and covariate data from 7 prospective studies with 399 767 participants and 3137 lung cancer cases. Study-specific relative risks (RRs) and CIs were estimated and then combined to calculate pooled multivariate RRs by using a random-effects model. Results: We found a slightly greater risk for the consumption of ≥30 g alcohol/d than for that of 0 g alcohol/d in men (RR: 1.21; 95% CI: 0.91, 1.61; P for trend = 0.03) and in women (RR: 1.16; 95% CI: 0.94, 1.43; P for trend = 0.03). In male never smokers, the RR for consumption of ≥ 15 g alcohol/d rather than 0 g alcohol/d was 6.38 (95% CI: 2.74, 14.9; P for trend < 0.001). In women, there were few never-smoking cases and no evidence of greater risk (RR: 1.35; 95% CI: 0.64, 2.87). Because of possible residual confounding by smoking, we performed sensitivity analyses by reclassifying the never smokers in the highest drinking category as former smokers. Resulting associations for alcohol consumption were somewhat attenuated, but P for trend = 0.05 for men, which was near the original P = 0.03. Conclusions: A slightly greater risk of lung cancer was associated with the consumption of ≥30 g alcohol/d than with no alcohol consumption. Alcohol consumption was strongly associated with greater risk in male never smokers. Residual confounding by smoking may explain part of the observed relation. © 2005 American Society for Clinical Nutrition.

The Alpha-Tocopherol Beta-Carotene (ATBC) Cancer Prevention Study was a placebo-controlled, randomized intervention trial testing the hypothesis that beta-carotene and alpha-tocopherol (vitamin E) supplements prevent lung and other cancers. The study is predicated on a substantial body of evidence supporting a role in cancer prevention for these micronutrients. Based on the 2 x 2 factorial study design, 29,133 eligible male cigarette smokers aged 50-69 y were randomly assigned to receive beta-carotene (20 mg), alpha-tocopherol (50 mg), beta-carotene and alpha-tocopherol, or placebo daily for 5-8 y. Capsule compliance was high (median = 99%). beta-Carotene treatment did not result in a decrease in cancer at any of the major sites but rather in an increase at several sites, most notably lung, prostate, and stomach (number of cases 474 compared with 402, 138 compared with 112, and 70 compared with 56, respectively). The vitamin E group had fewer incident cancers of the prostate and colorectum compared with the group not receiving vitamin E (number of cases 99 compared with 151 and 68 compared with 81, respectively), but more cancers of the stomach (70 compared with 56). In contrast to these intervention-based findings for beta-carotene and vitamin E supplements, we observed lower lung cancer rates in men with higher amounts of both serum and dietary beta-carotene and vitamin E at baseline.

Toenail selenium concentration has been pro- posed as a long-term (6- 12 mo) indicator of human selenium status. This study investigated the association between toenail selenium concentration and selenium intake and other dietary factors among 166 urban men aged 55-69 y. The dietary infor- mation was collected by food records covering a 6-mo period. Toenail clippings were collected by mail 9-10 mo after food recording. The mean selenium intake from food was 42.5 �ag/d and the dietary intake was equal to that of users and nonusers of selenium supplements. The mean toenail selenium concen- tration was 0.47 mg/kg. The mean selenium intake from sup- plements was 29.7 �g/d among supplement users. In the analysis ofcovariance the best predictors oftoenail selenium concentra- tion were selenium intake from supplements and food, and among supplement users dietary $-carotene also. Am J C/in Nuir 1993:57:662-5.

We studied the seasonal variation in serum concentrations of�3-carotene and a-tocopherol (HPLC) in 17 247 Finnish men who smoked. Month ofblood sampling was a sta- tistically significant determinant of serum concentration of 13- carotene in a regression model including age, body mass index, alcohol and fat intakes, total serum cholesterol, and daily cig- arettes as covariates. The serum concentrations were lowest in April-June and highest in October-November. The I.5-fold in- crease in the serum concentration of 13-carotene during the fall reflects the seasonality of dietary sources of carotenoids in Finland. The serum concentrations of a-tocopherol demon- strated no seasonal variation but remained close to 27.6 �zmol/ L throughout the year. The results indicate that the seasonal variation ofserum concentrations off3-carotene should be taken into account in long-term studies in which comparison of groups or individuals is based on serum concentrations. Am J C/in Nuir 1993:57:551-6.