The inverse association between serum 25-hydroxyvitamin D and mortality may be modified by vitamin A status and use of vitamin A supplements Comparative effects of dietary supplementation with red grape juice and vitamin E on production of superoxide by circulating neutrophil NADPH oxidase in hemodialysis patients. Does supplemental vitamin C increase cardiovascular disease risk in women with diabetes? Higher baseline serum concentrations of vitamin E are associated with lower total and cause-specific mortality in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Serum Antioxidant Nutrients, Vitamin A, and Mortality in U.S. Adults Routine Vitamin Supplementation To Prevent Cancer and Cardiovascular Disease: Recommendations and Rationale Circulating 25OHD, dietary vitamin D, PTH, and calcium associations with incident cardiovascular disease and mortality: the MIDSPAN Family Study. Cardiovascular effects of oral Supplementation of vitamin C, E and folic acid in young healthy males. Vitamin/mineral supplementation and cancer, cardiovascular, and all-cause mortality in a German prospective cohort (EPIC-Heidelberg) Circulating Concentrations of Folate and Vitamin B12 in Relation to Prostate Cancer Risk: Results from the European Prospective Investigation into Cancer and Nutrition Study Vitamin Supplement Use During Breast Cancer Treatment and Survival: A Prospective Cohort Study Vitamin supplement use in a low-risk population of US male physicians and subsequent cardiovascular mortality. Vitamin D3 supplementation has no effect on conventional cardiovascular risk factors: a parallel-group, double-blind, placebo-controlled RCT. Randomized controlled trial of vitamin D supplement on endothelial function in patients with type 2 diabetes. Circulating 25-Hydroxyvitamin D3 and Survival after Diagnosis with Kidney Cancer Effects of folate supplementation on two provisional molecular markers of colon cancer: a prospective, randomized trial Vitamin C Supplementation Decreases Oxidative Stress Biomarker F2-Isoprostanes in Plasma of Nonsmokers Exposed to Environmental Tobacco Smoke Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited-access data set. Adverse socioeconomic conditions in childhood and cause specific adult mortality: prospective observational study The association of biomarkers of iron status with mortality in US adults. Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial. Incidence of cancers, ischemic cardiovascular diseases and mortality during 5-year follow-up after stopping antioxidant vitamins and minerals supplements: a postintervention follow-up in the SU.VI.MAX Study. Circulating calcitriol concentrations and total mortality. Multivitamin use and the risk of mortality and cancer incidence: the multiethnic cohort study. Dose response to vitamin D supplementation in African Americans: results of a 4-arm, randomized, placebo-controlled trial. Vitamin D supplementation during exercise training does not alter inflammatory biomarkers in overweight and obese subjects Parathyroid hormone and vitamin D--markers for cardiovascular and all cause mortality in heart failure. Vitamin D accelerates resolution of inflammatory responses during tuberculosis treatment Lung Cancer Chemoprevention: A Randomized, Double-Blind Trial in Linxian, China Maternal vitamin D sufficiency and reduced placental gene expression in angiogenic biomarkers related to comorbidities of pregnancy Circulating fibronectin to C-reactive protein ratio and mortality: a biomarker in COPD? Health risks and benefits from calcium and vitamin D supplementation: Women's Health Initiative clinical trial and cohort study Impact of Vitamin D Supplementation on Arterial Vasomotion, Stiffness and Endothelial Biomarkers in Chronic Kidney Disease Patients Impact of Vitamin D Supplementation on Inflammatory Markers in African Americans: Results of a Four-Arm, Randomized, Placebo-Controlled Trial Vitamins C and E and beta carotene supplementation and cancer risk: a randomized controlled trial. FISH OIL AND VITAMIN E CHANGE LIPID PROFILES AND ANTI-LDL-ANTIBODIES IN TWO DIFFERENT ETHNIC GROUPS OF WOMEN TRANSITIONING THROUGH MENOPAUSE. Vitamin D and breast cancer recurrence in the Women's Healthy Eating and Living (WHEL) Study. Calcium-vitamin D cosupplementation influences circulating inflammatory biomarkers and adipocytokines in vitamin D-insufficient diabetics: a randomized controlled clinical trial. The modulation of prostate cancer risk with alpha-tocopherol: a pilot randomized, controlled clinical trial. Vitamin D associates with improved quality of life in participants with irritable bowel syndrome: outcomes from a pilot trial Vitamin A supplementation in northern Ghana: effects on clinic attendances, hospital admissions, and child mortality Effect of two years' supplementation with natural antioxidants on vitamin and trace element status biomarkers: preliminary data of the SU.VI.MAX study. Serial measures of circulating biomarkers of dairy fat and total and cause-specific mortality in older adults: the Cardiovascular Health Study. Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial. Global DNA Hypomethylation (LINE-1) in the Normal Colon and Lifestyle Characteristics and Dietary and Genetic Factors The SU.VI.MAX Study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals. Multivitamin use and mortality in a large prospective study. Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders? The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Prospective association between the Dietary Inflammatory Index and mortality: modulation by antioxidant supplementation in the SU.VI.MAX randomized controlled trial. Vitamin D status and the risk of major adverse cardiac and cerebrovascular events in cardiac surgery. Long-term use of supplemental multivitamins, vitamin C, vitamin E, and folate does not reduce the risk of lung cancer. Antioxidants and basal cell carcinoma of the skin: A nested case–control study Fifteen-year effects of Helicobacter pylori, garlic, and vitamin treatments on gastric cancer incidence and mortality. Vitamin, Mineral, and Specialty Supplements and Risk of Hematologic Malignancies in the Prospective VITamins And Lifestyle (VITAL) Study The D-Health Trial: A randomized trial of vitamin D for prevention of mortality and cancer. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. Low Serum Levels of 25-Hydroxyvitamin D Predict Fatal Cancer in Patients Referred to Coronary Angiography Effect of alpha-lipoic acid and vitamin E supplementation on oxidative stress, inflammation, and malnutrition in hemodialysis patients. Supplemental vitamin E intake and prostate cancer risk in a large cohort of men in the United States. Calcium-vitamin D-fortified milk is as effective on circulating bone biomarkers as fortified juice and supplement but has less acceptance: a randomised controlled school-based trial. Long-term follow-up for mortality and cancer in a randomized placebo-controlled trial of vitamin D(3) and/or calcium (RECORD trial). Antioxidant vitamin intake and mortality in three Central and Eastern European urban populations: the HAPIEE study Joint Effects of Dietary Vitamin D and Sun Exposure on Breast Cancer Risk: Results from the French E3N Cohort Total and cancer mortality after supplementation with vitamins and minerals: follow-up of the Linxian General Population Nutrition Intervention Trial. Antioxidant vitamin intake and mortality: the Leisure World Cohort Study.
Background Low serum 25-hydroxyvitamin D [ 25(OH)D ] levels have been associated with higher risk of many diseases that affect mortality , including cardiovascular disease ( CVD ) and cancer . The inverse association between serum 25(OH)D and mortality may be modified by excess circulating vitamin A , due to interactions of vitamin A at the level of the vitamin D nuclear receptor . In this prospect i ve cohort study , we investigated whether the association of 25(OH)D with all-cause , cancer , and CVD mortality  was modified by circulating vitamin A or preformed vitamin A intake from supplements . Methods We analyzed 15,998 adults in the Third National Health and Nutrition Examination Survey ( NHANES III ) , 1988–1994 . Mortality data for all-cause ( n = 3890 ) , cancer ( n = 844 ) , and CVD mortality ( n = 1715 ) were assessed through December 2006 .  Serum 25(OH)D was measured using a radioimmunoassay kit , vitamin A biomarkers were measured by HPLC , and information on supplement use was obtained by self-report . Multivariable hazard ratios ( HRs ) and corresponding 95 % confidence intervals ( CI ) were estimated by proportional hazards regression . Results Serum 25(OH)D was significantly inversely associated with all-cause mortality ( HR 0.93 , 95 % CI 0.89 , 0.97 , per 10 ng/mL increase ) and also with CVD mortality and mortality due to non-cancer/non-cardiovascular causes , but not with cancer mortality . The observed inverse associations remained statistically significant only among participants with serum retinyl esters < 7.0 μg/dL. High intake ( > 5000 IU/day ) of preformed vitamin A from supplements attenuated the inverse association of 25(OH)D with overall mortality . The observed interactions were not statistically significant . Conclusions 25(OH)D was inversely associated with overall mortality , CVD mortality , and mortality due to non-cancer/non-CVD causes , but not with cancer mortality . A possible interaction between vitamin A exposure and 25(OH)D concentration appears to be associated with an attenuation of the inverse association between risk of death and quartile of 25(OH)D concentration BACKGROUND Atherosclerotic cardiovascular disease is the most common cause of death among hemodialysis patients ; it has been attributed to increased oxidative stress , dyslipidemia , malnutrition , and chronic inflammation . Activation of neutrophils is a well-recognized feature in dialysis patients , and superoxide-anion production by neutrophil NADPH oxidase may contribute significantly to oxidative stress . OBJECTIVE The aim of the study was to compare the effects of dietary supplementation with concentrated red grape juice ( RGJ ) , a source of polyphenols , and vitamin E on neutrophil NADPH oxidase activity and other cardiovascular risk factors in hemodialysis patients . DESIGN Thirty-two patients undergoing hemodialysis were recruited and r and omly assigned to groups to receive dietary supplementation with RGJ , vitamin E , or both or a control condition without supplementation or placebo . Blood was obtained at baseline and on days 7 and 14 of treatment . RESULTS RGJ consumption but not vitamin E consumption reduced plasma concentrations of total cholesterol and apolipoprotein B and increased those of HDL cholesterol . Both RGJ and vitamin E reduced plasma concentrations of oxidized LDL and ex vivo neutrophil NADPH oxidase activity . These effects were intensified when the supplements were used in combination ; in that case , reductions in the inflammatory biomarkers intercellular adhesion molecule 1 and monocyte chemoattractant protein 1 also were observed . CONCLUSIONS Regular ingestion of concentrated RGJ by hemodialysis patients reduces neutrophil NADPH-oxidase activity and plasma concentrations of oxidized LDL and inflammatory biomarkers to a greater extent than does that of vitamin E. This effect of RGJ consumption may favor a reduction in cardiovascular risk BACKGROUND Vitamin C acts as a potent antioxidant ; however , it can also be a prooxidant and glycate protein under certain circumstances in vitro . These observations led us to hypothesize that a high intake of vitamin C in diabetic persons might promote atherosclerosis . OBJECTIVE The objective was to examine the relation between vitamin C intake and mortality from cardiovascular disease . DESIGN We studied the relation between vitamin C intake and mortality from total cardiovascular disease ( n = 281 ) , coronary artery disease ( n = 175 ) , and stroke ( n = 57 ) in 1923 postmenopausal women who reported being diabetic at baseline .  Diet was assessed with a food-frequency question naire at baseline , and subjects initially free of coronary artery disease were prospect ively followed for 15 y. RESULTS After adjustment for cardiovascular disease risk factors , type of diabetes medication used , duration of diabetes , and intakes of folate , vitamin E , and beta-carotene , the adjusted relative risks of total cardiovascular disease mortality were 1.0 , 0.97 , 1.11 , 1.47 , and 1.84 ( P for trend < 0.01 ) across quintiles of total vitamin C intake from food and supplements . Adjusted relative risks of coronary artery disease were 1.0 , 0.81 , 0.99 , 1.26 , and 1.91 ( P for trend = 0.01 ) and of stroke were 1.0 , 0.52 , 1.23 , 2.22 , and 2.57 ( P for trend < 0.01 ) . When dietary and supplemental vitamin C were analyzed separately , only supplemental vitamin C showed a positive association with mortality endpoints .  Vitamin C intake was unrelated to mortality from cardiovascular disease in the nondiabetic subjects at baseline . CONCLUSION A high vitamin C intake from supplements is associated with an increased risk of cardiovascular disease mortality in postmenopausal women with diabetes 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 result ing 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 prospect i ve 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 : Observational studies have suggested that antioxidant nutrients may reduce cancer and overall mortality risks . However , most r and omized trials have failed to show survival benefits . Examining nonlinear associations between antioxidant levels and health outcomes may help to explain these discrepant findings . Methods : We evaluated all-cause , cancer , and cardiovascular mortality risks associated with quintiles ( Q1–Q5 ) of serum antioxidant ( vitamins C and E , β-carotene , and selenium ) and vitamin A levels , in 16,008 adult participants of The Third National Health and Nutrition Examination Survey ( NHANES III ; 1988–1994 ) . Results : Over a median follow-up period of 14.2 years , there were 4,225 deaths , including 891 from cancer and 1,891 from cardiovascular disease . We observed a dose – response decrease in cancer and overall mortality risks with higher vitamin C levels . In contrast , for vitamin A , risk of cancer death decreased from Q1–Q2 , with no further decline in risk at higher levels . For vitamin E , having levels in Q4 was associated with the lowest cancer mortality risk . Both vitamin A and E had U-shaped associations with all-cause mortality . Cancer mortality risks decreased from Q1–Q2 for β-carotene and from Q1–Q4 for selenium . However , for β-carotene and selenium , overall mortality risks decreased from Q1–Q2 but then did not change significantly with higher levels . Conclusions : Antioxidant supplement use should be studied in the context of overall mortality and other competing mortality risks . Impact : These data suggest the need for novel intervention studies where doses of these agents are individualized based on their serum levels , and possibly , markers of oxidative stress and systemic inflammatory response . Cancer Epidemiol Biomarkers Prev ; 22(12 ) ; 2202–11 . © 2013 AACR Summary of the Recommendations The U.S. Preventive Services Task Force ( USPSTF ) concludes that the evidence is insufficient to recommend for or against the use of supplements of vitamins A , C , or E ; multivitamins with folic acid ; or antioxidant combinations for the prevention of cancer or cardiovascular disease . This is a grade I recommendation . ( See Appendix Table 1 for a description of the USPSTF classification of recommendations . ) The USPSTF found poor evidence to determine whether supplementation with these vitamins reduces the risk for cardiovascular disease or cancer . ( See Appendix Table 2 for a description of the USPSTF classification of levels of evidence . ) The available evidence from r and omized trials is either inadequate or conflicting , and the influence of confounding variables on observed outcomes in observational studies can not be determined . As a result , the USPSTF could not determine the balance of benefits and harms of routine use of supplements of vitamins A , C , or E ; multivitamins with folic acid ; or antioxidant combinations for the prevention of cancer or cardiovascular disease . The USPSTF recommends against the use of beta-carotene supplements , either alone or in combination , for the prevention of cancer or cardiovascular disease . This is a grade D recommendation . The USPSTF found good evidence that -carotene supplementation provides no benefit in the prevention of cancer or cardiovascular disease in middle-aged and older adults . In two trials restricted to heavy smokers , -carotene supplementation was associated with higher incidence of lung cancer and higher all-cause mortality . The USPSTF concludes that -carotene supplements are unlikely to provide important benefits and might cause harm in some groups . Clinical Considerations The USPSTF did not review evidence regarding vitamin supplementation for patients with known or potential nutritional deficiencies , including pregnant and lactating women , children , elderly persons , and people with chronic illnesses .  Dietary supplements may be appropriate for people whose diet does not provide the recommended dietary intake of specific vitamins . Individuals may wish to consult a health care provider to discuss whether dietary supplements are appropriate . With the exception of vitamins for which there is compelling evidence of net harm ( for example , beta-carotene supplementation in smokers ) , there is little reason to discourage people from taking vitamin supplements . Patients should be reminded that taking vitamins does not replace the need to eat a healthy diet . All patients should receive information about the benefits of a diet high in fruits and vegetables , as well as information on other foods and nutrients that should be emphasized or avoided in their diet ( see the 2002 USPSTF recommendations on counseling to promote a healthy diet [ 1 ] ) . Patients who choose to take vitamins  should be encouraged to adhere to the dosages recommended in the Dietary Reference Intakes of the Institute of Medicine . Some vitamins , such as A and D , may be harmful in higher doses ; therefore , doses greatly exceeding the Recommended Dietary Allowance or Adequate Intake should be taken with care while considering whether potential harms outweigh potential benefits . Vitamins and minerals sold in the United States are classified as dietary supplements , and there is a degree of quality control over content if they have a U.S. Pharmacopeia seal ( 2 ) . Nevertheless , imprecision in the content and concentration of ingredients could pose a theoretical risk not reflected in clinical trials using calibrated compounds . The adverse effects of beta-carotene on smokers have been observed primarily in those taking large supplemental doses . There is no evidence to suggest that beta-carotene is harmful to smokers at levels occurring naturally in foods . The USPSTF did not review evidence supporting folic acid supplementation among pregnant women to reduce neural tube defects . In 1996 , the USPSTF recommended folic acid for all women who are planning , or capable of , pregnancy ( see the 1996 USPSTF chapter on screening for neural tube defects [ 3 ] ) . Clinicians and patients should discuss the possible need for vitamin supplementation when taking certain medications ( for example , folic acid supplementation for patients taking methotrexate ) . Scientific Evidence The USPSTF review s ( 4 - 6 ) focused on the quality of the evidence regarding the effect of routine supplementation with certain vitamins on primary prevention of cancer and cardiovascular disease . These review s were undertaken because of the growing epidemiologic evidence that dietary factors may play a role in the etiology of these diseases ( 7 - 9 ) . The review s focused on prospect i ve trials of vitamin supplementation and observational studies of associations between the use of specific supplements and the risk for cancer or cardiovascular disease . The value of vitamins naturally occurring in food , the use of vitamin supplements for the prevention of other conditions ( for example , neural tube defects ) , and the use of vitamin supplements for the secondary prevention of complications in patients with existing disease were outside the scope of these review s. Vitamin A No prospect i ve trials have examined the effect of vitamin A supplements alone on the risk for cancer . Observational studies provide no evidence that such supplements prevent cancer in men . In women , observational studies have reported a statistically significant inverse association between use of vitamin A supplements and risk for colon and breast cancer ( 10 , 11 ) . Despite efforts to adjust for confounding variables , the observational , nonr and om design of these studies makes it difficult to assess the extent to which the reduced cancer risk is attributable to vitamin A or to other characteristics of women who take vitamin A supplements .  No evidence from prospect i ve trials is available regarding the benefits of vitamin A alone in preventing cardiovascular disease . One good- quality cohort study found no effect of vitamin A supplementation in reducing cardiovascular disease mortality ( 12 ) . Vitamin C No primary prevention trial of the effect of vitamin C supplementation alone on cancer or cardiovascular disease has been reported . Observational studies have generally shown no statistically significant associations between use of vitamin C supplements and risk for cancer of the breast , prostate , colon , or lung ( 12 - 14 ) . The observational cohort studies examining the effects of vitamin C on cardiovascular disease have produced inconsistent results ( 12 , 15 , 16 ) . Vitamin E Only a few trials have examined the effects of vitamin E on the primary prevention of cancer or cardiovascular disease . A r and omized , controlled trial ( RCT ) involving Finnish male smokers found that vitamin E supplementation is not protective against lung cancer but may have a beneficial impact on prostate cancer ( 14 ) . Because prostate cancer was not a primary end point of the trial and the trial had other limitations , further evidence is needed to confirm this finding . Observational studies have shown no statistically significant association between use of vitamin E supplements and risk for prostate , lung , or breast cancer ( 5 ) . One study suggested that vitamin E protects against colon cancer , but the influence of confounding variables can not be fully excluded ( 17 ) . Among primary prevention trials , two good- quality trials ( 14 , 18 ) and one fair- quality trial ( 19 ) found no statistically significant benefit of vitamin E supplementation in preventing cardiovascular disease ( 20 ) . Only one of seven trials of vitamin E supplementation for secondary prevention demonstrated a statistically significant reduction in cardiac events ( 4 ) . Some prospect i ve cohort studies have suggested a significant benefit , but the results are mixed and the influence of confounding variables can not be excluded ( 4 ) . -Carotene A consistent body of evidence from clinical trials suggests that beta-carotene supplementation does not decrease the risk for lung , prostate , colon , breast , or nonmelanoma skin cancer ( 14 , 21 - 25 ) . -Carotene supplements were associated with an increased risk for lung cancer among smokers , especially heavy smokers , in two RCTs ( 14 , 25 ) . Results from four RCTs demonstrated no reduced risk for cardiovascular events or death after beta-carotene supplementation ( 14 , 21 , 22 , 26 - 28 ) . Antioxidant Vitamin Combinations Studies of the effects of antioxidant vitamin combinations to prevent cancer have yielded mixed results . A recent RCT reported no statistically significant effect of daily supplementation with a combination of antioxidants : vitamin E , vitamin C , and beta-carotene ( 29 ) . Some studies have suggested an adverse effect of antioxidant combinations on cancer , but the results may have been confounded by the inclusion of beta-carotene ( 5 ) . Some observational studies of antioxidant vitamin combinations have suggested a benefit in preventing cardiovascular disease ( 13 , 30 , 31 ) , but other studies , including well- design ed RCTs , have shown no benefit ( 29 , 32 , 33 ) . One secondary prevention trial showed an increase in all-cause mortality among women taking antioxidant supplements  ( 34 ) . Multiple Vitamin Combinations The incremental benefit of taking supplemental doses of folic acid and B vitamins has been examined by comparing the outcomes of observational studies while controlling for the total intake of antioxidant vitamin supplements ( 35 ) . In these analyses , folic acid supplementation was associated with significantly decreased risk for colon cancer , but the protective effect requires confirmation in prospect i ve trials . There is conflicting evidence regarding the use of multivitamins and the risk for cardiovascular disease . Among cohort studies , one good- quality study reported a statistically significant reduction in coronary events ( 36 ) , two good- quality studies reported no statistically significant effect on mortality ( 16 , 37 ) , and one CONTEXT Observational studies relating circulating 25-hydroxyvitamin D ( 25OHD ) and dietary vitamin D intake to cardiovascular disease ( CVD ) have reported conflicting results . OBJECTIVE Our objective was to investigate the association of 25OHD , dietary vitamin D , PTH , and adjusted calcium  with  CVD and mortality in a Scottish cohort . DESIGN AND SETTING The MIDSPAN Family Study is a prospect i ve study of 1040 men and 1298 women from the West of Scotl and recruited in 1996 and followed up for a median 14.4 yr . PARTICIPANTS Locally resident adult offspring of a general population cohort were recruited from 1972 - 1976 . MAIN OUTCOME MEASURES CVD events ( n = 416 ) and all-cause mortality ( n = 100 ) were evaluated . RESULTS 25OHD was measured using liquid chromatography-t and em mass spectrometry in available plasma ( n = 2081 ) . Median plasma 25OHD was 18.6 ng/ml , and median vitamin D intake was 3.2 μg/d ( 128 IU/d ) . Vitamin D deficiency ( 25OHD < 15 ng/ml ) was present in 689 participants ( 33.1 % ) . There was no evidence that dietary vitamin D intake , PTH , or adjusted calcium were associated with CVD events or with mortality . Vitamin D deficiency was not associated with CVD ( fully adjusted hazard ratio = 1.00 ; 95 % confidence interval = 0.77 - 1.31 ) . Results were similar after excluding patients who reported an activity-limiting longst and ing illness at baseline ( 18.8 % ) and those taking any vitamin supplements ( 21.7 % ) . However , there was some evidence vitamin D deficiency was associated with all-cause mortality ( fully adjusted hazard ratio = 2.02 ; 95 % confidence interval = 1.17 - 3.51 ) . CONCLUSION Vitamin D deficiency was not associated with risk of CVD in this cohort with very low 25OHD . Future trials of vitamin D supplementation in middle-aged cohorts should be powered to detect differences in mortality outcomes as well as CVD Numerous observational studies showed associations of antioxidants ( vitamins C and E ) and folate intake with a reduced risk of cardiovascular disease , but r and omized controlled clinical trials have generally not supported this hypothesis . The objective of this study was to investigate the effects of a daily dosage of 1000 mg vitamin C , 800 mg vitamin E , and 10 mg folate on markers of vascular function in 31 young healthy male adults .  Cardiovascular values after a 12-week vitamin ( 14 subjects ) or placebo ( 17 subjects ) intervention were compared to baseline values . Cardiovascular parameters ( blood pressure , stroke volume , heart rate , cardiac output , vascular resistance , arterial compliance ) were measured continuously after an overnight fast under controlled circumstances with a Finometer device . Our main finding was a significant decrease ( p = 0.03 ) in systolic blood pressure in the experimental group . No statistically significant changes were observed within other cardiovascular variables of the experimental group , but possible beneficial decreases in diastolic blood pressure and increases in arterial compliance after 12 weeks of vitamin supplementation were indicated . In conclusion , beneficial effects of antioxidants and folate were observed probably because the supplementation was used by young healthy subjects under carefully controlled conditions Purpose To prospect ively evaluate the association of vitamin/mineral supplementation with  cancer , cardiovascular , and all-cause mortality .  Methods In the Heidelberg cohort of the European Prospect i ve Investigation into Cancer and Nutrition ( EPIC-Heidelberg ) , which was recruited in 1994–1998 , 23,943 participants without pre-existing cancer and myocardial infa rct ion/stroke at baseline were included in the analyses . Vitamin/mineral supplementation was assessed at baseline and during follow-up . Cox regression models were used to estimate hazard ratios ( HRs ) and 95 % confidence intervals ( CIs ) . Results After an average follow-up time of 11 years , 1,101 deaths were documented ( cancer deaths = 513 and cardiovascular deaths = 264 ) . After adjustment for potential confounders , neither any vitamin/mineral supplementation nor multivitamin supplementation at baseline was statistically significantly associated with cancer , cardiovascular , or all-cause mortality . However , baseline users of antioxidant vitamin supplements had a significantly reduced risk of cancer mortality ( HR : 0.52 ; 95 % CI : 0.28 , 0.97 ) and all-cause mortality ( HR : 0.58 ; 95 % CI : 0.38 , 0.88 ) . In comparison with never users , baseline non-users who started taking vitamin/mineral supplements during follow-up had significantly increased risks of cancer mortality ( HR : 1.74 ; 95 % CI : 1.09 , 2.77 ) and all-cause mortality ( HR : 1.58 ; 95 % CI : 1.17 , 2.14 ) . Conclusions Based on limited numbers of users and cases , this cohort study suggests that supplementation of antioxidant vitamins might possibly reduce cancer and all-cause mortality . The significantly increased risks of cancer and all-cause mortality among baseline non-users who started taking supplements during follow-up may suggest a “ sick-user effect , ” which research ers should be cautious of in future observational studies Background : Determinants of one-carbon metabolism , such as folate and vitamin B12 , have been implicated in cancer development . Previous studies have not provided conclusive evidence for the importance of circulating concentrations of folate and vitamin B12 in prostate cancer etiology . The aim of the present study was to investigate the relationship between prostate cancer risk and circulating concentrations of folate and vitamin B12 in a large prospect i ve cohort . Methods : We analyzed circulating concentrations of folate and vitamin B12 in 869 cases and 1,174 controls , individually matched on center , age , and date of recruitment , nested within the European Prospect i ve Investigation into Cancer and Nutrition cohort .  Relative risks ( RR ) for prostate cancer were estimated using conditional logistic regression models . Results : Overall , no significant associations were observed for circulating concentrations of folate ( Ptrend = 0.62 ) or vitamin B12 ( Ptrend = 0.21 ) with prostate cancer risk . RRs for a doubling in folate and vitamin B12 concentrations were 1.03 [ 95 % confidence interval ( 95 % CI ) , 0.92 - 1.16 ] and 1.12 ( 95 % CI , 0.94 - 1.35 ) , respectively . In the subgroup of cases diagnosed with advanced stage prostate cancer , elevated concentrations of vitamin B12 were associated with increased risk ( RR for a doubling in concentration , 1.69 ; 95 % CI , 1.05 - 2.72 , Ptrend = 0.03 ) . No other subgroup analyses result ed in a statistically significant association . Conclusion : This study does not provide strong support for an association between prostate cancer risk and circulating concentrations of folate or vitamin B12 . Elevated concentrations of vitamin B12 may be associated with an increased risk for advanced stage prostate cancer , but this association requires examination in other large prospect i ve studies . ( Cancer Epidemiol Biomarkers Prev 2007;17(2):279–85 Background : Antioxidants may protect normal cells from the oxidative damage that occurs during radiotherapy and certain chemotherapy regimens ; however , the same mechanism could protect tumor cells and potentially reduce effectiveness of cancer treatments . We evaluated the association of vitamin supplement use in the first 6 months after breast cancer diagnosis and during cancer treatment with total mortality and recurrence . Methods : We conducted a population -based prospect i ve cohort study of 4,877 women aged 20 to 75 years diagnosed with invasive breast cancer in Shanghai , China , between March 2002 and April 2006 . Women were interviewed approximately 6 months after diagnosis and followed up by in-person interviews and record linkage with the vital statistics registry . Results : During a mean follow-up of 4.1 years , 444 deaths and 532 recurrences occurred . Vitamin use shortly after breast cancer diagnosis was associated with reduced mortality and recurrence risk , adjusted for multiple lifestyle factors , sociodemographics , and known clinical prognostic factors . Women who used antioxidants ( vitamin E , vitamin C , multivitamins ) had 18 % reduced mortality risk ( HR = 0.82 , 95 % CI : 0.65–1.02 ) and 22 % reduced recurrence risk ( HR = 0.78 , 95 % CI : 0.63–0.95 ) . The inverse association was found regardless of whether vitamin use was concurrent or nonconcurrent with chemotherapy , but was present only among patients who did not receive radiotherapy . Conclusions : Vitamin supplement use in the first 6 months after breast cancer diagnosis may be associated with reduced risk of mortality and recurrence . Impact : Our results do not support the current recommendation that breast cancer patients should avoid use of vitamin supplements . Cancer Epidemiol Biomarkers Prev ; 20(2 ) ; 262–71 . © 2010 AACR BACKGROUND Although basic research suggests that vitamins may have an important role in the prevention of cardiovascular diseases ( CVD ) , the data from cohort studies and clinical trials are inconclusive . METHODS This prospect i ve cohort study was conducted among 83 639 male physicians residing in the United States who had no history of CVD or cancer . At baseline , data on use of vitamin E , ascorbic acid ( vitamin C ) , and multivitamin supplements were provided by a self-administered question naire . Mortality from CVD and coronary heart disease ( CHD ) was assessed by death certificate review . RESULTS Use of supplements was reported by 29 % of the participants . During a mean follow-up of 5.5 years , 1037 CVD deaths occurred , including 608 CHD deaths . After adjustment for several cardiovascular risk factors , supplement use was not significantly associated with total CVD or CHD mortality . For vitamin E use , the relative risks ( RRs ) were 0.92 ( 95 % confidence interval [ CI ] , 0.70 - 1.21 ) for total CVD mortality and 0.88 ( 95 % CI , 0.61 - 1.27 ) for CHD mortality ; for use of vitamin C , the RRs were 0.88 ( 95 % CI , 0.70 - 1.12 ) for total CVD mortality and 0.86 ( 95 % CI , 0.63 - 1.18 ) for CHD mortality ; and for use of multivitamin supplements , the RRs were 1.07 ( 95 % CI , 0.91 - 1.25 ) for total CVD mortality and 1.02 ( 95 % CI , 0.83 - 1.25 ) for CHD mortality . CONCLUSIONS In this large cohort of apparently healthy US male physicians , self-selected supplementation with vitamin E , vitamin C , or multivitamins was not associated with a significant decrease in total CVD or CHD mortality . Data from ongoing large r and omized trials will be necessary to definitely establish small potential benefits of vitamin supplements on subsequent cardiovascular risk CONTEXT Observational studies show an association between low vitamin D status assessed by circulating 25-hydroxyvitamin D and cardiovascular events and mortality . Data from r and omized controlled trials are limited . OBJECTIVE The aim of this study was to test whether daily doses of vitamin D(3 ) at 400 or 1000 IU/d for 1 yr affected conventional markers of cardiovascular disease ( CVD ) risk . DESIGN We conducted a parallel-group , double-blind , placebo-controlled r and omized controlled trial . R and omization was computer generated . Participants and study investigators were blinded to intervention groupings throughout the trial . SETTING The study was conducted at the Clinical Research Facility , University of Aberdeen , United Kingdom . PARTICIPANTS A total of 305 healthy postmenopausal women aged 60 - 70 yr were recruited for the study . INTERVENTION Each woman received a daily capsule of 400 or 1000 IU vitamin D(3 ) or placebo r and omly allocated . MAIN OUTCOME MEASURES Primary outcomes were serum lipid profile [ total , high-density lipoprotein , and low-density lipoprotein cholesterol ; triglycerides ; and apolipoproteins A-1 and B100 ] , insulin resistance ( homeostatic model assessment ) , inflammatory biomarkers ( high-sensitivity C-reactive protein , IL-6 , soluble intracellular adhesion molecule-1 ) , and blood pressure . RESULTS A total of 265 ( 87 % ) participants completed all study visits . Small differences between groups for serum apolipoprotein B100 change [ repeated measures ANOVA , P=0.04 ; mean ( sd ) , -1.0 ( 10.0 ) mg/dl ( 400 IU ) ; -1.0 ( 10.0 ) mg/dl ( 1000 IU ) ; and + 0.02 ( 10.0 ) mg/dl ( placebo ) ] were not considered clinical ly significant . Other systemic markers for CVD risk remained unchanged . There was significant seasonal variation in systolic and diastolic blood pressure independent of vitamin D dose ( P<0.001 , linear mixed model ) . Mean ( sd ) reduction in systolic blood pressure from winter to summer was -6.6 ( 10.8 ) mm Hg . CONCLUSIONS Improving vitamin D status through dietary supplementation is unlikely to reduce CVD risk factors . Confounding of seasonality should be recognized and addressed in future studies of vitamin BACKGROUND Suboptimal vitamin D status is associated with endothelial dysfunction and an increased risk of cardiovascular diseases but it is unclear whether vitamin D supplementation is beneficial . The aim was to investigate the effect of vitamin D supplementation on endothelial function in patients with type 2 diabetes mellitus ( DM ) . METHODS In a double-blind , placebo-controlled trial , we r and omized 100 type 2 DM patients to vitamin D supplement  ( 5000 IU/day , n = 50 ) or placebo ( controls , n = 50 ) for 12 weeks . Assessment of vascular function with brachial artery flow-mediated dilatation ( FMD ) , circulating levels of endothelial progenitor cells ( EPCs ) and brachial-ankle pulse wave velocity , and metabolic parameter , high-sensitivity C-reactive protein ( hsCRP ) and oxidative stress markers were performed before and after the supplementation . RESULTS After 12 weeks , vitamin D treated patients had significant increases in serum 25-hydroxyvitamin D [ 25(OH)D ] concentration ( treatment effect 34.7 ng/mL , 95 % CI 26.4 - 42.9 , P < 0.001 ) and serum ionized calcium ( treatment effect 0.037 mmol/L , 95 % CI 0.007 - 0.067 , P = 0.018 ) ; decreased serum parathyroid hormone concentration ( treatment effect -0.55 pmol/L , 95 % CI -1.08 to -0.02 , P = 0.042 ) compared to patients who received placebo . Nevertheless , vitamin D supplementation did not improve vascular function as determined by FMD , circulating EPC count or baPWV ( all P > 0.05 ) . Furthermore , hsCRP , oxidative stress markers , low- and high-density lipoprotein and glycated hemoglobin were also similar between two groups ( all P > 0.05 ) . CONCLUSION In patients with type 2 DM , 12 weeks oral supplementation of vitamin D did not significantly affect vascular function or serum biomarkers of inflammation and oxidative stress . CLINICAL TRIAL NUMBER HKCTR-867 , www.hk clinical trials.com Prospect i ve cohort studies have provided some evidence that circulating vitamin D is associated with risk of , and survival from , renal cell carcinoma ( RCC ) , but it is unclear whether concentrations of vitamin D at the time of diagnosis of RCC are associated with prognosis . We conducted a case – cohort study of 630 RCC cases , including 203 deaths , from a multicenter case – control study in Eastern Europe .  Vitamin D was assessed as 25-hydroxyvitamin D3 [ 25(OH)D3 ] , and we used weighted Cox models to estimate hazard ratios ( HR ) and 95 % confidence intervals ( CI ) by categories of season-adjusted 25(OH)D3 . Higher concentrations of 25(OH)D3 were associated with lower risk of death after adjusting for stage , age , sex , and country ( HR highest vs. lowest category 0.57 ; 95 % CI , 0.34–0.97 ) . The inverse associations of 25(OH)D3 with death were most notable among those who died from non-RCC causes and those diagnosed with early-stage disease . In summary , 25(OH)D3 concentration at diagnosis of RCC was inversely associated with all-cause mortality rates , but not specifically with RCC outcome . Cancer Epidemiol Biomarkers Prev ; 24(8 ) ; 1277–81 . © 2015 AACR OBJECTIVES : Dietary folate intake is inversely associated with the risk of colorectal cancer . This study investigated the effect of folate supplementation on genomic DNA methylation and DNA str and breaks in exons 5–8 of the p53 gene of the colonic mucosa , two provisional biomarkers of colon cancer . METHODS : Twenty subjects with adenomas were r and omized to receive either folate ( 5 mg/day ) or placebo for 1 yr after polypectomy . At baseline , 6 months and 1 yr , systemic and colonic measures of folate status were determined , as were the biomarkers mentioned earlier . RESULTS : Folate supplementation increased serum , red blood cell and colonic mucosal folate concentrations ( p < 0.02 ) . Folate supplementation also increased the extent of genomic DNA methylation at 6 months and 1 yr ( p = 0.001 ) , whereas placebo administration was associated with an increase in the extent of genomic DNA methylation only at 1 yr . Similarly , folate supplementation decreased the extent of p53 str and breaks in exons 5–8 at 6 months and 1 yr ( p < 0.02 ) , whereas placebo administration was associated with a decrease in the extent of p53 str and breaks only at 1 yr . CONCLUSIONS : Both of these provisional biomarkers of colon cancer underwent accelerated improvement at 6 months with folate supplementation . However , these markers also improved with placebo at 1 yr . Therefore , potential confounding factors that seem to modulate these biomarkers need to be identified and corrected in order for these markers to serve as suitable surrogate endpoints in folate chemoprevention trials Exposure to environmental tobacco smoke ( ETS ) has been linked to increased risk of lung cancer and cardiovascular diseases in nonsmokers . Current research suggests that some of these diseases are associated with elevated oxidative stress . We investigated the effect of antioxidant ( AO ) intervention on the lipid peroxidation biomarker F2-isoprostanes ( F2-IsoPs ) , an index of oxidative stress , in plasma of nonsmokers exposed to ETS ( passive smokers).We measured free F2-IsoP concentrations in plasma of 67 passive smokers at baseline and after 2 mo of daily intervention with AOs or placebo .  The study subjects ( 47 females , 20 males ; mean age 46 ± 15 ) were r and omized into one of three treatment groups : vitamin C , " mixture " ( vitamin C , vitamin E , and α-lipoic-acid ) , and placebo . Investigated confounders included plasma baseline AO levels , lipid and total cholesterol profiles , transferrin saturation , and C-reactive protein . Plasma F2IsoP concentrations of subjects in the vitamin C and mixture groups decreased significantly by 17.2 pmol/l ( P = 0.0105 ) and 19.2 pmol/l ( P = 0.0083 ) when compared with the placebo group ( 11.4 % and 12.7 % , respectively ) . Daily AO supplementation ( especially with vitamin C ) decreases this oxidative stress biomarker in passive smokers . This finding might be of importance for the prevention of ETS-associated adverse health effects in nonsmokers BACKGROUND Frequent use of personal , non protocol calcium supplements obscured an adverse effect of coadministered calcium and vitamin D ( CaD ) on cardiovascular risk in the Women 's Health Initiative ( WHI ) . OBJECTIVE We investigated the effects of the use of personal calcium or vitamin D supplements on other outcomes in the WHI CaD Study ( WHI CaD ) by using the WHI limited-access clinical trials data set . DESIGN The WHI CaD was a 7-y , r and omized , placebo-controlled trial of CaD ( 1 g Ca/400 IU vitamin D daily ) in 36,282 community-dwelling , postmenopausal women . The incidence of total cancer ( excluding nonmelanoma skin cancers ) , breast and colorectal cancers , hip and total fracture , and mortality was assessed by using Cox proportional hazards models . RESULTS In the WHI CaD , interactions between the use of either personal calcium or vitamin D supplements and CaD were found for total , breast , and colorectal cancers but not for fracture or mortality .  In 15,646 women ( 43 % ) who were not taking personal calcium or vitamin D supplements at r and omization , CaD significantly decreased the risk of total , breast , and invasive breast cancers by 14 - 20 % and nonsignificantly reduced the risk of colorectal cancer by 17 % . In women taking personal calcium or vitamin D supplements , CaD did not alter cancer risk ( HR : 1.06 - 1.26 ) . CONCLUSIONS For women in the WHI CaD who were not taking personal calcium or vitamin D supplements at r and omization , CaD decreased the risk of total , breast , and colorectal cancers and did not change the risk of fractures or total mortality . The nonskeletal effects of CaD may be more important than the skeletal effects and should be considered when evaluating these supplements . The WHI CaD trial is registered at clinical trials.gov as NCT00000611 Abstract Objective : To investigate the association between social circumstances in childhood and mortality from various causes of death in adulthood . Design : Prospect i ve observational study . Setting : 27 workplaces in the west of Scotl and . Subjects : 5645 men aged 35–64 years at the time of examination . Main outcome measures : Death from various causes . Results : Men whose fathers had manual occupations when they were children were more likely as adults to have manual jobs and be living in deprived areas . Gradients in mortality from coronary heart disease , stroke , lung cancer , stomach cancer , and respiratory disease were seen ( all P<0.05 ) , generally increasing from men whose fathers had professional and managerial occupations ( social class I and II ) to those whose fathers had semiskilled and unskilled manual occupations ( social class IV and V ) . Relative rates of mortality adjusted for age for men with fathers in manual versus non-manual occupations were 1.52 ( 95 % confidence interval 1.24 to 1.87 ) for coronary heart disease , 1.83 ( 1.13 to 2.94 ) for stroke , 1.65 ( 1.12 to 2.43 ) for lung cancer , 2.06 ( 0.93 to 4.57 ) for stomach cancer , and 2.01 ( 1.17 to 3.48 ) for respiratory disease . Mortality from other cancers and accidental and violent death showed no association with fathers ' social class . Adjustment for adult socioeconomic circumstances and risk factors did not alter results for mortality from stroke and stomach cancer , attenuated the increased risk of coronary heart disease and respiratory disease , and essentially eliminated the association with lung cancer . Conclusions : Adverse socioeconomic circumstances in childhood have a specific influence on mortality from stroke and stomach cancer in adulthood , which is not due to the continuity of social disadvantage throughout life . Deprivation in childhood influences risk of mortality from coronary heart disease and respiratory disease in adulthood , although an additive influence of adulthood circumstances is seen in these cases . Mortality from lung cancer , other cancer , and accidents and violence is predominantly influenced by risk factors that are related to social circumstances in adulthood . Key messages Adverse socioeconomic conditions in childhood are associated with mortality in later life Mortality from stroke and stomach cancer is particularly dependent on social circumstances in childhood Mortality from coronary heart disease and respiratory disease is dependent on social circumstances in both adulthood and childhood Mortality from accidents and violence and from lung cancer is mainly dependent on factors acting in adulthood The increases in child poverty seen in Britain and elsewhere over the past 20 years may herald unfavourable future trends in adult BACKGROUND AND AIMS Elevated iron biomarkers are associated with diabetes and other cardiometabolic abnormalities in the general population . It is unclear whether they are associated with an increased risk of all-cause or cause-specific mortality . The purpose of the current analysis was to evaluate the association of  ferritin and transferrin saturation levels with  all-cause , cardiovascular , and cancer mortality in the general US adult population . METHODS AND RESULTS A prospect i ve cohort study was conducted with 12,258 adults participating in the Third National Health and Nutrition Examination Survey ( NHANES III ) , a nationally representative sample of the US population . Study participants were recruited in 1988 - 1994 and followed through December 31 , 2006 for all-cause , cardiovascular disease , and cancer mortality .  The multivariable-adjusted hazard ratios ( 95 % confidence interval ) for all-cause mortality comparing the fourth versus the second quartiles of ferritin and transferrin saturation were 1.09 ( 0.82 - 1.44 ; p-trend across quartiles = 0.92 ) and 1.08 ( 0.82 - 1.43 ; p-trend across quartiles = 0.62 ) , respectively , for men , 1.43 ( 0.63 - 3.23 ; p-trend across quartiles = 0.31 ) and 1.48 ( 0.70 - 3.11 ; p-trend across quartiles = 0.60 ) , respectively , for premenopausal women , and 1.03 ( 0.79 - 1.34 ; p-trend across quartiles = 0.95 ) and 1.17 ( 0.92 - 1.49 ; p-trend across quartiles = 0.63 ) , respectively , for postmenopausal women . Quartile of ferritin and transferrin saturation also showed no association between biomarkers of iron status and mortality . CONCLUSIONS In a large nationally representative sample of US adults , within the spectrum of normal iron metabolism , ferritin and transferrin saturation were not associated with risk of mortality among people who were not taking iron supplements and did not have a baseline history of cardiovascular disease or cancer CONTEXT Basic research provides plausible mechanisms and observational studies suggest that apparently healthy persons , who self-select for high intakes of vitamin E through diet or supplements , have decreased risks of cardiovascular disease and cancer . R and omized trials do not generally support benefits of vitamin E , but there are few trials of long duration among initially healthy persons . OBJECTIVE To test whether vitamin E supplementation decreases risks of cardiovascular disease and cancer among healthy women . DESIGN , SETTING , AND PARTICIPANTS In the Women 's Health Study conducted between 1992 and 2004 , 39 876 apparently healthy US women aged at least 45 years were r and omly assigned to receive vitamin E or placebo and aspirin or placebo , using a 2 x 2 factorial design , and were followed up for an average of 10.1 years . INTERVENTION Administration of 600 IU of natural- source vitamin E on alternate days . MAIN OUTCOME MEASURES Primary outcomes were a composite end point of first major cardiovascular event ( nonfatal myocardial infa rct ion , nonfatal stroke , or cardiovascular death ) and total invasive cancer . RESULTS During follow-up , there were 482 major cardiovascular events in the vitamin E group and 517 in the placebo group , a nonsignificant 7 % risk reduction ( relative risk [ RR ] , 0.93 ; 95 % confidence interval [ CI ] , 0.82 - 1.05 ; P = .26 ) . There were no significant effects on the incidences of myocardial infa rct ion ( RR , 1.01 ; 95 % CI , 0.82 - 1.23 ; P = .96 ) or stroke ( RR , 0.98 ; 95 % CI , 0.82 - 1.17 ; P = .82 ) , as well as ischemic or hemorrhagic stroke . For cardiovascular death , there was a significant 24 % reduction ( RR , 0.76 ; 95 % CI , 0.59 - 0.98 ; P = .03 ) . There was no significant effect on the incidences of total cancer ( 1437 cases in the vitamin E group and 1428 in the placebo group ; RR , 1.01 ; 95 % CI , 0.94 - 1.08 ; P = .87 ) or breast ( RR , 1.00 ; 95 % CI , 0.90 - 1.12 ; P = .95 ) , lung ( RR , 1.09 ; 95 % CI , 0.83 - 1.44 ; P = .52 ) , or colon cancers ( RR , 1.00 ; 95 % CI , 0.77 - 1.31 ; P = .99 ) . Cancer deaths also did not differ significantly between groups . There was no significant effect of vitamin E on total mortality ( 636 in the vitamin E group and 615 in the placebo group ; RR , 1.04 ; 95 % CI , 0.93 - 1.16 ; P = .53 ) . CONCLUSIONS The data from this large trial indicated that 600 IU of natural- source vitamin E taken every other day provided no overall benefit for major cardiovascular events or cancer , did not affect total mortality , and decreased cardiovascular mortality in healthy women . These data do not support recommending vitamin E supplementation for cardiovascular disease or cancer prevention among healthy women The Supplementation in Vitamins and Mineral Antioxidants Study was a double-blind , placebo-controlled , r and omized trial , in which 12,741 French adults ( 7,713 women aged 35 - 60 years and 5,028 men aged 45 - 60 years ) received a combination of ascorbic acid ( 120 mg ) , vitamin E ( 30 mg ) , beta-carotene ( 6 mg ) , selenium ( 100 microg ) and zinc ( 20 mg ) , or placebo daily for a median follow-up time of 7.5 years [ October 1994 to September 2002 ] . Antioxidant supplementation decreased total cancer incidence and total mortality in men . Postintervention follow-up assessment of total cancer incidence , ischemic cardiovascular disease incidence and total mortality was carried out for 5 years [ September 1 , 2002 , to September 1 , 2007 ] . No late effect of antioxidant supplementation  was revealed 5 years after ending the intervention neither on ischemic cardiovascular disease incidence and mortality in both genders nor on cancer incidence in women . Regarding duration of intervention effects in men , the reduced risk of total cancer incidence and total mortality was no longer evident after the 5-year postintervention follow-up . During the postsupplementation period , the relative risk ( RR ) for total cancer incidence ( n = 126 ) was 0.98 ( 95 % confidence interval [ CI ] , 0.75 - 1.27 ) among antioxidant recipients compared to nonrecipients . For total mortality ( n = 90 ) , the RR was 0.98 ( 95 % CI , 0.75 - 1.26 ) for men receiving antioxidants compared to nonrecipients . In conclusion , beneficial effects of antioxidant supplementation in men disappeared during postintervention follow-up BACKGROUND Evidence is accumulating that vitamin D supplementation of patients with low 25-hydroxyvitamin D concentrations is associated with lower cardiovascular morbidity and total mortality during long-term follow-up . Little is known , however , about the effect of low concentrations of the vitamin D hormone calcitriol on total mortality . We therefore evaluated the predictive value of circulating calcitriol for midterm mortality in patients of a specialized heart center . METHODS This prospect i ve cohort study included 510 patients , 67.7 % with heart failure ( two-thirds in end stage ) , 64.3 % hypertension , 33.7 % coronary heart disease , 20.2 % diabetes , and 17.3 % renal failure . We followed the patients for up to 1 year after blood collection . For data analysis , the study cohort was stratified into quintiles of circulating calcitriol concentrations . RESULTS Patients in the lowest calcitriol quintile were more likely to have coronary heart disease , heart failure , hypertension , diabetes , and renal failure compared to other patients . They also had low 25-hydroxyvitamin D concentrations and high concentrations of creatinine , C-reactive protein , and tumor necrosis factor alpha . Eighty-two patients ( 16.0 % ) died during follow-up . Probability of 1-year survival was 66.7 % in the lowest calcitriol quintile , 82.2 % in the second quintile , 86.7 % in the intermediate quintile , 88.8 % in the fourth quintile , and 96.1 % in the highest quintile ( P < 0.001 ) . Discrimination between survivors and nonsurvivors was best when a cutoff value of 25 ng/L was applied ( area under the ROC curve 0.72 ; 95 % CI 0.66 - 0.78 ) . CONCLUSIONS Decreased calcitriol levels are linked to excess midterm mortality in patients of a specialized heart center Although multivitamin/mineral supplements are commonly used in the United States , the efficacy of these supplements in preventing chronic disease or premature death is unclear . To assess the relation of multivitamin use with mortality and cancer , the authors prospect ively examined these associations among 182,099 participants enrolled in the Multiethnic Cohort Study between 1993 and 1996 in Hawaii and California . During an average 11 years of follow-up , 28,851 deaths were identified . In Cox proportional hazards models controlling for tobacco use and other potential confounders , no associations were found between multivitamin use and mortality from all causes ( for users vs. nonusers : hazard ratio = 1.07 , 95 % confidence interval : 0.96 , 1.19 for men ; hazard ratio = 0.96 , 95 % confidence interval : 0.85 , 1.09 for women ) , cardiovascular diseases , or cancer . The findings did not vary across subgroups by ethnicity , age , body mass index , preexisting illness , single vitamin/mineral supplement use , hormone replacement therapy use , and smoking status . There also was no evidence indicating that multivitamin use was associated with risk of cancer , overall or at major sites , such as lung , colorectum , prostate , and breast . In conclusion , there was no clear decrease or increase in mortality from all causes , cardiovascular disease , or cancer and in morbidity from overall or major cancers among multivitamin supplement users BACKGROUND Association studies have suggested that lower circulating 25-hydroxyvitamin D [ 25(OH)D ] in African Americans may partially underlie higher rates of cardiovascular disease and cancer in this population . Nonetheless , the relation between vitamin D supplementation and 25(OH)D concentrations in African Americans remains undefined . OBJECTIVE Our primary objective was to determine the dose-response relation between vitamin D and plasma 25(OH)D. DESIGN A total of 328 African Americans in Boston , MA , were enrolled over 3 winters from 2007 to 2010 and r and omly assigned to receive a placebo or 1000 , 2000 , or 4000 IU vitamin D₃/d for 3 mo . Subjects completed sociodemographic and dietary question naires , and plasma sample s were drawn at baseline and 3 and 6 mo . RESULTS Median plasma 25(OH)D concentrations at baseline were 15.1 , 16.2 , 13.9 , and 15.7 ng/mL for subjects r and omly assigned to receive the placebo or 1000 , 2000 , or 4000 IU/d , respectively ( P = 0.63 ) . The median plasma 25(OH)D concentration at 3 mo differed significantly between supplementation arms at 13.7 , 29.7 , 34.8 , and 45.9 ng/mL , respectively ( P < 0.001 ) . An estimated 1640 IU vitamin D₃/d was needed to raise the plasma 25(OH)D concentration to ≥ 20 ng/mL in ≥ 97.5 % of participants , whereas a dose of 4000 IU/d was needed to achieve concentrations ≥ 33 ng/mL in ≥ 80 % of subjects . No significant hypercalcemia was seen in a subset of participants . CONCLUSIONS Within African Americans , an estimated 1640 IU vitamin D₃/d was required to achieve concentrations of plasma 25(OH)D recommended by the Institute of Medicine , whereas 4000 IU/d was needed to reach concentrations predicted to reduce cancer and cardiovascular disease risk in prospect i ve observational studies . These results may be helpful for informing future trials of disease prevention The purpose of this study was to examine the effects of vitamin D supplementation on inflammatory biomarkers in overweight and obese adults participating in a progressive resistance exercise training program . Twenty-three ( 26.1 ± 4.7 years ) overweight and obese ( BMI 31.3 ± 3.2 kg/m2 ) adults were r and omized into a double-blind vitamin D supplementation ( Vit D 4,000 IU/day ; female 5 , male 5 ) or placebo ( PL , female 7 ; male 6 ) intervention trial . Both groups performed 12 weeks ( 3 days/week ) of progressive resistance exercise training ( three sets of eight exercises ) at 70–80 % of one repetition maximum . Whole-blood lipopolysaccharide (LPS)-stimulated tumor necrosis factor ( TNF ) α production as well as circulating C-reactive protein ( CRP ) , TNFα , interleukin 6 ( IL-6 ) , and alanine aminotransferase ( ALT ) were assessed at baseline and after the 12-week intervention . No main effects of group or time were detected for circulating CRP , TNFα , IL-6 , and ALT . As expected , when PL and Vit D groups were combined , there was a significant correlation between percent body fat and CRP at baseline ( r = 0.45 , P = 0.04 ) , and between serum 25OHD and CRP at 12 weeks ( r = 0.49 , P = 0.03 ) . The PL group had a significant increase in 25 μg/ml LPS + polymixin B-stimulated TNFα production ( P = 0.04 ) , and both groups had a significant reduction in unstimulated TNFα production ( P < 0.05 ) after the 12-week intervention . Vitamin D supplementation in healthy , overweight , and obese adults participating in a resistance training intervention did not augment exercise-induced changes in inflammatory biomarkers AIMS To investigate levels of vitamin D and parathyroid hormone ( PTH ) in a population of heart failure ( HF ) patients , and to evaluate whether vitamin D and PTH are related to prognosis . METHODS AND RESULTS This was a prospect i ve study of 148 HF out patients ( mean age 68 years , 102 men ) with follow-up for mortality after 3½ years . Levels of N-terminal pro-brain natriuretic peptide ( NT-proBNP ) , PTH , 25-hydroxyvitamin D ( 25-OHD ) , and several other biomarkers were examined . Mortality and cardiovascular mortality were analysed in multivariable regression analyses adjusting for other independent prognostic variables . Vitamin D deficiency ( ≤50 nmol/L ) was prevalent in 43 % of the population ; 26 % had elevated PTH levels ; none had primary hyperparathyroidism . We found a strong and independent significant association of both PTH and vitamin D  to mortality , which was independent of other clinical ly important parameters [ NT-proBNP , estimated glomerular filtration rate ( eGFR ) , age , and left ventricular ejection fraction ( LVEF ) ] . Both PTH and vitamin D were also significantly associated with all cause mortality . In an adjusted model , we found a hazard ratio of 1.9 ( confidence interval 1.1 - 3.4 ) for vitamin D deficiency and 2.0 ( 1.0 - 3.8 ) for the upper median of PTH , respectively . CONCLUSION In this relatively small prospect i ve study , PTH and vitamin D were independently associated with all cause and cardiovascular mortality in patients with HF . This was independent of other known risk factors such as eGFR , LVEF , NT-proBNP , and age Calcidiol , the major circulating metabolite of vitamin D , supports induction of pleiotropic antimicrobial responses in vitro . Vitamin D supplementation elevates circulating calcidiol concentrations , and thus has a potential role in the prevention and treatment of infection . The immunomodulatory effects of administering vitamin D to humans with an infectious disease have not previously been reported . To characterize these effects , we conducted a detailed longitudinal study of circulating and antigen-stimulated immune responses in ninety-five patients receiving antimicrobial therapy for pulmonary tuberculosis who were r and omized to receive adjunctive high-dose vitamin D or placebo in a clinical trial , and who fulfilled criteria for per- protocol analysis . Vitamin D supplementation accelerated sputum smear conversion and enhanced treatment-induced resolution of lymphopaenia , monocytosis , hypercytokinaemia , and hyperchemokinaemia . Administration of vitamin D also suppressed antigen-stimulated proinflammatory cytokine responses , but attenuated the suppressive effect of antimicrobial therapy on antigen-stimulated secretion of IL-4 , CC chemokine lig and 5 , and IFN-α . We demonstrate a previously unappreciated role for vitamin D supplementation in accelerating resolution of inflammatory responses during tuberculosis treatment . Our findings suggest a potential role for adjunctive vitamin D supplementation in the treatment of pulmonary infections to accelerate resolution of inflammatory responses associated with increased risk of mortality We examined the effect of supplementation with four different combinations of vitamins and minerals in the prevention of  lung cancer mortality among 29,584 healthy adults from Linxian , China . In accord with a partial factorial design , the participants were r and omly assigned to take either a vitamin/mineral combination or a placebo for 5.25 years . The combinations tested in this trial were as follows : factor A , retinol and zinc ; factor B , riboflavin and niacin ; factor C , ascorbic acid and molybdenum ; factor D , β-carotene , α-tocopherol , and selenium . Lung cancer deaths ( n = 147 ) identified during the trial period ( 1986 - 1991 ) and 10 years after the trial ended ( 1991 - 2001 ) were the study outcome . No significant differences in lung cancer death rates were found for any of the four combinations of supplements tested in this study , using log-rank tests ( all P values are > 0.20 ) or Cox proportional hazards models adjusted for age , sex , commune , and other treatments . No significant interactions were seen for age , sex , or smoking status . Supplementation with combinations of vitamins and minerals at nutrient-repletion levels for 5.25 years did not reduce lung cancer mortality in this nutrient-inadequate population in Linxian , China . ( Cancer Epidemiol Biomarkers Prev 2006;15(8):1562–4 INTRODUCTION Maternal circulating 25-hydroxyvitamin D [ 25(OH)D ] has been shown to optimize production of 1,25-dihydroxyvitamin D [ 1,25(OH)2D ] during pregnancy at approximately 100nmoles/L , which has pronounced effects on fetal health outcomes . Additionally , associations are noted between low maternal 25(OH)D concentrations and vascular pregnancy complications , such as preeclampsia . To further eluci date the effects of vitamin D activity in pregnancy , we investigated the role of maternal 25(OH)D , the nutritional indicator of vitamin D status , in relation to placental maintenance and , specifically , expression of placental gene targets related to angiogenesis and vitamin D metabolism . METHODS A focused analysis of placental mRNA expression related to angiogenesis , pregnancy maintenance , and vitamin D metabolism was conducted in placentas from 43 subjects enrolled in a r and omized controlled trial supplementing 400IU or 4400IU of vitamin D3 per day during pregnancy . Placental mRNA was isolated from biopsies within one hour of delivery , followed by quantitative PCR . We classified pregnant women with circulating concentrations of < 100nmoles/L as deficient and those with ≥100nmoles/L as sufficient . The value of each gene 's change in the PCR cycle threshold ( ΔCT ) , which is a relative measure of target concentration , was compared with maternal 25(OH)D concentrations < 100nmoles/L and ≥100nmoles/L based on a two- sample Wilcoxon test . RESULTS Soluble FMS-like tyrosine kinase 1 ( sFlt-1 ) and vascular endothelial growth factor ( VEGF ) gene expression was significantly downregulated in the maternal subgroup with circulating 25(OH)D ≥100ng/mL compared to the subgroup < 100ng/mL. DISCUSSION Here , we report a significant association between maternal vitamin D status and the expression of sFlt-1 and VEGF at the mRNA level . Achieving maternal circulating 25(OH)D ≥100nmoles/L suggests the impact of maternal vitamin D3 supplementation on gene transcription in the placenta , thereby potentially decreasing antiangiogenic factors that may contribute to vascular pregnancy complications The balance between inflammatory and repair processes is important in maintaining lung homeostasis in chronic obstructive pulmonary disease ( COPD ) . The aim of the present study was to determine whether or not an integrated index of a biomarker involved in inflammation , C-reactive protein ( CRP ) , and another involved in wound repair , fibronectin , may be a good measure to predict clinical outcomes in COPD . Circulating blood levels of CRP and fibronectin were measured in 4,787 individuals with mild-to-moderate COPD who were prospect ively followed for > 7 yrs after blood collection as part of the Lung Health Study . To assess the balance between repair and inflammation , a simple ratio was calculated by dividing fibronectin levels by CRP levels and a Cox proportional hazards model was used to determine the relationship between this ratio and all-cause and disease-specific causes of mortality . The relationship between the fibronectin to CRP ratio and all-cause mortality was L-shaped . There was an exponential decay in the adjusted hazard function ( i.e. the risk of mortality ) as the ratio decreased until a value of 148 was reached , beyond which point the hazard function did not change significantly . Similar results were observed for the risk of coronary and cardiovascular mortality . Circulating fibronectin to CRP ratio is significantly associated with all-cause mortality of COPD patients . However , in contrast to other biomarkers , the relationship appears to be L-shaped ( and not linear ) , suggesting a threshold at ∼150 . While promising , future studies are needed to vali date this simple index as a biomarker in COPD Summary The Women 's Health Initiative ( WHI ) double-blind , placebo-controlled clinical trial r and omly assigned 36,282 postmenopausal women in the U.S. to 1,000 mg elemental calcium carbonate plus 400 IU of vitamin D3 daily or placebo , with average intervention period of 7.0 years . The trial was design ed to test whether calcium plus vitamin D supplementation in a population in which the use of these supplements was widespread would reduce hip fracture , and secondarily , total fracture and colorectal cancer . Introduction This study further examines the health benefits and risks of calcium and vitamin D supplementation using WHI data , with emphasis on fractures , cardiovascular disease , cancer , and total mortality . Methods WHI calcium and vitamin D r and omized clinical trial ( CT ) data through the end of the intervention period were further analyzed with emphasis on treatment effects in relation to duration of supplementation , and these data were contrasted and combined with corresponding data from the WHI prospect i ve observational study ( OS ) . Results Among women not taking personal calcium or vitamin D supplements at baseline , the hazard ratio [ HR ] for hip fracture occurrence in the CT following 5 or more years of calcium and vitamin D supplementation versus placebo was 0.62 ( 95 % confidence interval ( CI ) , 0.38–1.00 ) . In combined analyses of CT and OS data , the corresponding HR was 0.65 ( 95 % CI , 0.44–0.98 ) . Supplementation effects were not apparent on the risks of myocardial infa rct ion , coronary heart disease , total heart disease , stroke , overall cardiovascular disease , colorectal cancer , or total mortality , while evidence for a reduction in breast cancer risk and total invasive cancer risk among calcium plus vitamin D users was only suggestive . Conclusion Though based primarily on a subset analysis , long-term use of calcium and vitamin D appears to confer a reduction that may be substantial in the risk of hip fracture among postmenopausal women . Other health benefits and risks of supplementation at doses considered , including an elevation in urinary tract stone formation , appear to be modest and approximately balanced Background Cardiovascular events are frequent and vascular endothelial function is abnormal in patients with chronic kidney disease ( CKD ) . We demonstrated endothelial dysfunction with vitamin D deficiency in CKD patients ; however the impact of cholecalciferol supplementation on vascular stiffness and vasomotor function , endothelial and bone biomarkers in CKD patients with low 25-hydroxy vitamin D [ 25(OH)D ] is unknown , which this study investigated . Methods We assessed non-diabetic patients with CKD stage 3/4 , age 17–80 years and serum 25(OH)D < 75 nmol/L.  Brachial artery Flow Mediated Dilation ( FMD ) , Pulse Wave Velocity ( PWV ) , Augmentation Index ( AI ) and circulating blood biomarkers were evaluated at baseline and at 16 weeks . Oral 300,000 units cholecalciferol was administered at baseline and 8-weeks . Results Clinical characteristics of 26 patients were : age 50±14 ( mean±1SD ) years , eGFR 41±11 ml/min/1.73 m2 , males 73 % , dyslipidaemia 36 % , smokers 23 % and hypertensives 87 % .  At 16-week serum 25(OH)D and calcium increased ( 43±16 to 84±29 nmol/L , p<0.001 and 2.37±0.09 to 2.42±0.09 mmol/L ; p = 0.004 , respectively ) and parathyroid hormone decreased ( 10.8±8.6 to 7.4±4.4 ; p = 0.001 ) . FMD improved from 3.1±3.3 % to 6.1±3.7 % , p = 0.001 . Endothelial biomarker concentrations decreased : E-Selectin from 5666±2123 to 5256±2058 pg/mL ; p = 0.032 , ICAM-1 , 3.45±0.01 to 3.10±1.04 ng/mL ; p = 0.038 and VCAM-1 , 54±33 to 42±33 ng/mL ; p = 0.006 . eGFR , BP , PWV , AI , hsCRP , von Willebr and factor and Fibroblast Growth Factor-23 , remained unchanged . Conclusion This study demonstrates for the first time improvement of endothelial vasomotor and secretory functions with vitamin D in CKD patients without significant adverse effects on arterial stiffness , serum calcium or FGF-23 . Trial Registration Clinical Trials.gov African Americans have a disproportionate burden of inflammation-associated chronic diseases such as cancer and lower circulating levels of 25-hydroxyvitamin D [ 25(OH)D ] . The effect of vitamin D3 ( cholecalciferol ) supplementation on inflammatory markers is uncertain . We conducted a r and omized , double-blind , placebo-controlled trial of supplemental oral vitamin D ( placebo , 1,000 , 2,000 , or 4,000 IU/day of vitamin D3 orally for 3 months ) in 328 African Americans ( median age , 51 years ) of public housing communities in Boston , MA , who were enrolled over three consecutive winter periods ( 2007–2010 ) . Change from 0 to 3 months of plasma levels of 25(OH)D , high-sensitivity C-reactive protein ( CRP ) , interleukin (IL)-6 , IL-10 , and soluble TNF-α receptor type 2 ( sTNF-R2 ) in 292 ( 89 % ) participants were measured . Overall , no statistically significant changes in CRP , IL-6 , IL-10 , and sTNF-R2 were observed after the vitamin D supplementation period . Baseline CRP was significantly inversely associated with the baseline 25(OH)D level ( P < 0.001 ) in unadjusted and adjusted models . An interaction between baseline 25(OH)D and vitamin D supplementation was observed for outcome change in log CRP ( month 3–month 0 ; P for interaction = 0.04 ) . Within an unselected population of African Americans , short-term exposure to vitamin D supplementation produced no change in circulating inflammatory markers . This study confirms the strong independent association of CRP with 25(OH)D status even after adjusting for body mass index . Future studies of longer supplemental vitamin D3 duration are necessary to examine the complex influence of vitamin D3 on CRP and other chronic inflammatory cytokines for possible reduction of cancer health disparities in African Americans . Cancer Prev Res ; 7(2 ) ; 218–25 . © 2013 AACR BACKGROUND Observational studies suggested that a diet high in fruits and vegetables , both of which are rich with antioxidants , may prevent cancer development . However , findings from r and omized trials of the association between antioxidant use and cancer risk have been mostly negative . METHODS From 8171 women who were r and omly assigned in the Women 's Antioxidant Cardiovascular Study , a double-blind , placebo-controlled 2 x 2 x 2 factorial trial of vitamin C ( 500 mg of ascorbic acid daily ) , natural- source vitamin E ( 600 IU of alpha-tocopherol every other day ) , and beta carotene ( 50 mg every other day ) , 7627 women who were free of cancer before r and om assignment were selected for this study . Diagnoses and deaths from cancer at a specific site were confirmed by use of hospital reports and the National Death Index . Cox proportional hazards regression models were used to assess hazard ratios ( represented as relative risks [ RRs ] ) of common cancers associated with use of antioxidants , either individually or in combination . Subgroup analyses were conducted to determine if duration of use modified the association of supplement use with cancer risk . All statistical tests were two-sided . RESULTS During an average 9.4 years of treatment , 624 women developed incident invasive cancer and 176 women died from cancer . There were no statistically significant effects of use of any antioxidant on total cancer incidence . Compared with the placebo group , the RRs were 1.11 ( 95 % confidence interval [ CI ] = 0.95 to 1.30 ) in the vitamin C group , 0.93 ( 95 % CI = 0.79 to 1.09 ) in the vitamin E group , and 1.00 ( 95 % CI = 0.85 to 1.17 ) in the beta carotene group . Similarly , no effects of these antioxidants were observed on cancer mortality . Compared with the placebo group , the RRs were 1.28 ( 95 % CI = 0.95 to 1.73 ) in the vitamin C group , 0.87 ( 95 % CI = 0.65 to 1.17 ) in the vitamin E group , and 0.84 ( 95 % CI = 0.62 to 1.13 ) in the beta carotene group . Duration and combined use of the three antioxidants also had no effect on cancer incidence and cancer death . CONCLUSIONS Supplementation with vitamin C , vitamin E , or beta carotene offers no overall benefits in the primary prevention of total cancer incidence or cancer mortality BACKGROUND studies have investigated the relationship between the transition through menopause and cardiovascular diseases . White population , generally , have lower levels of traditional coronary heart risk factors , particularly dyslipidemia , hypertension , obesity , and diabetes , and lower rates of coronary heart disease mortality , than black population . Furthermore many studies have shown the cardioprotective and anti-inflammatory effects of omega-3 polyunsaturated fatty acids ( eicosapentaenoic acid and docosahexaenoic acid ) of marine origin . The aim of this study was to investigate the effect of omega-3 supplementation , combined or not with vitamin E , on oxidative biomarkers and lipid profiles in nonwhite and white women with dyslipidemia transitioning through menopause . METHODS a r and omized , double-blind , placebo-controlled trial was conducted . Seventy-four eligible women were assigned to receive : fish oil , fish oil plus vitamin E and placebo for three months . At baseline , 45 and 90 days blood sample for biochemical variables and biomarkers of oxidative stress were taken . Socioeconomic and lifestyle variables were collected with st and ardized question naires . RESULTS after 90 days the fish oil plus vitamin E treated group had a significant decrease in total cholesterol and LDL-C. Furthermore , there was a decrease in anti- LDL- autoantibodies after 45 days . Plasma TBARS concentrations were increased after 90 days in the group receiving only fish oil when compared to the placebo and fish oil-vitamin E groups . All of the effects observed were independent of ethnic group . CONCLUSION supplementation with fish oil and vitamin E reduced total cholesterol and LDL-C , but had opposite effects on oxidative stress compared to supplementation with fish oil alone BACKGROUND There is a paucity of research evaluating the relation between  vitamin D  and recurrence of breast cancer after treatment . OBJECTIVE This study was design ed to evaluate the associations between circulating concentrations of  25-hydroxyvitamin D [ 25(OH)D ]  and dietary , supplemental , and total intake of vitamin D  and recurrent or new breast cancer events within the Women 's Healthy Eating and Living ( WHEL ) Study . DESIGN A prospect i ve cohort study design ( n = 3085 ) was used to evaluate the relation between dietary , supplemental , and total vitamin D intake and recurrent breast cancer , and a nested case-control study with 512 matched pairs was used for analysis of the association between 25(OH)D and breast cancer recurrence . RESULTS No relation between 25(OH)D and breast cancer recurrence was observed . Compared with women with serum concentrations of 25(OH)D ≥ 30 ng/mL , adjusted odds ratios ( 95 % CI ) for breast cancer recurrence were 1.14 ( 0.57 , 2.31 ) for those with concentrations < 10 ng/mL , 1.00 ( 0.68 - 1.48 ) for concentrations ≥ 10 and < 20 ng/mL , and 1.05 ( 0.76 , 1.47 ) for concentrations ≥ 20 and < 30 ng/mL. No significant associations were observed when analyses were stratified by pre- and postmenopausal status or for local , regional , or distant recurrence or death . Vitamin D intake was not related to breast cancer recurrence overall , although for premenopausal women there was a significant inverse association between dietary vitamin D intake and recurrence ( P for trend = 0.02 ) . CONCLUSION These results do not provide support for a relation between concentrations of 25(OH)D after treatment and the recurrence of breast cancer . This trial is registered at clinical trials.gov for the WHEL Study as NCT00003787 CONTEXT To the best of our knowledge , no study has examined the effects of vitamin D-calcium cosupplementation on inflammatory biomarkers and adipocytokines in vitamin D-insufficient type 2 diabetics . OBJECTIVE This study was performed to assess the effects of vitamin D and calcium supplementation on inflammatory biomarkers and adipocytokines in vitamin D-insufficient people with type 2 diabetes . METHODS Totally , 118 diabetic patients were enrolled in this r and omized , placebo-controlled clinical trial . After matching for age , sex , body mass index , type and dose of hypoglycemic agents , and duration of diabetes , subjects were r and omly assigned into 4 groups receiving the following : 1 ) 50000 IU/wk vitamin D + calcium placebo ; 2 ) 1000 mg/d calcium + vitamin D placebo ; 3 ) 50 000 IU/wk vitamin D + 1000 mg/d calcium ; or 4 ) vitamin D placebo + calcium placebo for 8 weeks . Blood sampling was done for the quantification of inflammatory biomarkers and adipocytokines at the study baseline and after 8 weeks of intervention . RESULTS Calcium ( changes from baseline : -75 ± 19 ng/ml , P = .01 ) and vitamin D alone ( -56 ± 19 ng/mL , P = .01 ) and joint calcium-vitamin D supplementation ( -92 ± 19 ng/mL , P = .01 ) result ed in a significant reduction in serum leptin levels compared with placebo ( -9 ± 18 ng/mL ) . This was also the case for serum IL-6 , such that calcium ( -2 ± 1 pg/mL , P < .001 ) and vitamin D alone ( -4 ± 1 pg/mL , P < .001 ) and their combination ( -4 ± 1 pg/mL , P < .001 ) led to significant reductions compared with placebo ( 3 ± 1 pg/mL ) . After adjustment for potential confounders , individuals in the calcium ( -3.1 ± 1.3 , P < .05 ) , vitamin D ( -3.1 ± 1.3 , P < .05 ) , and joint calcium-vitamin D groups ( -3.4 ± 1.3 , P < .05 ) had greater reductions in serum TNF-α concentrations compared with placebo ( 0.1 ± 1.2 ) . Individuals who received joint calcium-vitamin D supplements tended to have a decrease in serum high-sensitivity C-reactive protein levels compared with placebo after controlling for baseline levels ( -1.14 ± 0.25 vs 0.02 ± 0.24 ng/mL , P = .09 ) . CONCLUSION Joint calcium-vitamin D supplementation might improve systemic inflammation through decreasing IL-6 and TNF-α concentrations in vitamin D-insufficient people with type 2 diabetes PURPOSE Studies suggest that vitamin E may decrease the risk of  prostate cancer .  The Prevention Research Veteran Affairs E-vitamin Nutrition Trial is a r and omized , double-blind , placebo controlled study design ed to assess the effects of vitamin E supplementation on biomarkers associated with prostate cancer risk in peripheral blood and prostate tissue . MATERIAL S AND METHODS A total of 44 patients with increased prostate specific antigen ( PSA ) and /or abnormal digital rectal examination on initial evaluation were r and omized to receive 400 IU vitamin E ( 22 ) vs placebo ( 22 ) . Serum vitamin E , PSA , dehydroepi and rosterone , testosterone and insulin-like growth factor-1 ( IGF-1 ) were measured in the 2 groups at baseline and then at 3-month intervals . Results are reported in 28 patients  ( placebo in 14 and vitamin E in 14 ) who completed the treatment as specified by the protocol . RESULTS Serum Vitamin E was significantly higher in patients on  vitamin E supplementation . alpha-Tocopherol supplementation did not affect the levels of PSA , serum and rogens ( testosterone and dehydroepi and rosterone ) or ( IGF-1 ) . CONCLUSIONS Serum alpha-tocopherol is increased by oral supplementation of vitamin E. We found that alpha-tocopherol supplementation has no effect on serum and rogens , IGF-1 or PSA . The lack of an effect of vitamin supplementation on PSA avoids any bias in the diagnosis of prostate cancer in  vitamin E treated patients . Our results suggest that a decrease in prostate cancer risk with alpha-tocopherol is likely to occur through a mechanism that is nonhormonal and independent of IGF-1 Background Vitamin D deficiency has been associated or implicated with the pathophysiology of the gastrointestinal conditions inflammatory bowel disease and colorectal cancer , as well as with depression . No trials or epidemiology studies to date have investigated a link with irritable bowel syndrome ( IBS ) . A single case report has suggested a benefit in IBS of vitamin D supplementation . We hypothesised that IBS participants with vitamin D insufficiency would benefit from repletion in terms of their IBS symptoms . We undertook a pilot trial to provide data to support a power calculation and to justify a full trial . Methods This was a r and omised , double blinded , three-arm parallel design trial of vitamin D , placebo or a combination of vitamin D and probiotics .  Participants were further stratified according to whether they were vitamin D replete or insufficient . Vitamin D status was determined by blood test at baseline and exit ; IBS symptoms were assessed by vali date d question naire ; dietary intakes were assessed by food frequency question naire . Results A significant proportion of the IBS population were vitamin D deficient , such that the replete stratum could not be adequately recruited . There was a significant association in the baseline data between circulating vitamin D level and quality of life ( “ How much has IBS affected your life ? ” ) . Supplementation significantly improved vitamin D level  versus placebo .  IBS symptoms were not significantly improved in this pilot , although a power calculation was enabled from the intervention data . Conclusions The IBS population exhibits significant levels of vitamin D insufficiency and would benefit from screening and possible supplementation . The impact of IBS on quality of life may be reduced by vitamin D level . Future trials should have a sample size of over 97 . Trial registration number : ICTRN 6116003917 Although most studies on the effect of vitamin A supplementation have reported reductions in childhood mortality , the effects on morbidity are less clear . We have carried out two double-blind , r and omised , placebo-controlled trials of vitamin A supplementation in adjacent population s in northern Ghana to assess the impact on  childhood morbidity and mortality . The Survival Study included 21,906 children aged 6 - 90 months in 185 geographical clusters , who were followed for up to 26 months . The Health Study included 1455 children aged 6 - 59 months , who were monitored weekly for a year . Children were r and omly assigned either 200,000 IU retinol equivalent ( 100,000 IU under 12 months ) or placebo every 4 months ; r and omisation was by individual in the Health Study and by cluster in the Survival Study . There were no significant differences in the Health Study between the vitamin A and placebo groups in the prevalence of diarrhoea or acute respiratory infections ; of the symptoms and conditions specifically asked about , only vomiting and anorexia were significantly less frequent in the supplemented children . Vitamin-A-supplemented children had significantly fewer attendances at clinics ( rate ratio 0.88 [ 95 % CI 0.81 - 0.95 ] , p = 0.001 ) , hospital admissions ( 0.62 [ 0.42 - 0.93 ] , p = 0.02 ) , and deaths ( 0.81 [ 0.68 - 0.98 ] , p = 0.03 ) than children who received placebo . The extent of the effect on morbidity and mortality did not vary significantly with age or sex . However , the mortality rate due to acute gastroenteritis was lower in vitamin-A-supplemented than in placebo clusters ( 0.66 [ 0.47 - 0.92 ] , p = 0.02 ) ; mortality rates for all other causes except acute lower respiratory infections and malaria were also lower in vitamin A clusters , but not significantly so . Improving the vitamin A intake of young children in population s where xerophthalmia exists , even at relatively low prevalence , should be a high priority for health and agricultural services in Africa and elsewhere The " SUpplementation en VItamines et Minéraux AntioXidants " ( SU.VI.MAX ) study is a r and omized double-blind , placebo controlled , primary -prevention trial design ed to test the efficacy of a daily supplementation with antioxidant vitamins ( vitamin C , 120 mg ; vitamin E , 30 mg ; and beta-carotene , 6 mg ) and minerals ( selenium , 100 microg ; and zinc , 20 mg ) at nutritional doses ( one to three times the daily recommended dietary allowances ) , in reducing the frequency of cancers and cardiovascular diseases . The study involves 12,735 eligible subjects ( women aged 35 - 60 years , men aged 45 - 60 years ) included in 1994 in France . They will be followed up for 8 years . The targeted population is the general population . The aim of this specific analysis is to assess the effect of 2 years of supplementation on biochemical indicators of vitamin and trace element  on a sub sample of 1000 subjects . The mean ( + /- st and ard deviation ) concentrations of plasma beta-carotene , alpha-tocopherol , vitamin C , selenium and zinc among participants who were r and omly assigned to receive a daily supplementation with beta-carotene , vitamin E , vitamin C , selenium and zinc for 2 years were significantly higher than those who were assigned to receive placebo . Specifically , the mean concentrations among men in the intervention group were 0.86 + /- 0.70 micromol/L for beta-carotene , 35.3 + /- 9.3 micromol/L for alpha-tocopherol , 11.5 + /- 4.7 microg/ mL for vitamin C , 1.65 + /- 0.33 micromol/L for selenium , and 16.2 + /- 3.9 micromol/L for zinc . The mean concentrations among women in the intervention were 1.25 + /- 0.90 micromol/L for beta-carotene , 34.9 + /- 8.4 micromol/L for alpha-tocopherol , 12.6 + /- 4.0 microg/mL for vitamin C , 1.68 + /- 0.37 micromol/L for selenium , and 15.3 + /- 3.9 micromol/L for zinc . The values observed for beta-carotene and vitamin E in the supplementation group after 2 years of intervention are those that have been associated with the lowest risk of cancer in observational studies . They are definitely lower than concentrations reported in intervention studies showing an apparent negative effect of high levels of beta-carotene supplementation on the  lung cancer incidence rate in high-risk subjects ( initial level multiplied by 12 - 18 ) . Data from the follow-up will ascertain if any plausible reduction in the incidence rate of cancers may be associated with such amounts of antioxidant agents Background Controversy has emerged about the benefits compared with harms of dairy fat , including concerns over long-term effects . Previous observational studies have assessed self-reported estimates of consumption or a single biomarker measure at baseline , which may lead to suboptimal estimation of true risk . Objective The aim of this study was to investigate prospect i ve associations of serial measures of plasma phospholipid fatty acids pentadecanoic ( 15:0 ) , heptadecanoic ( 17:0 ) , and trans-palmitoleic ( trans-16:1n-7 ) acids with total mortality , cause-specific mortality  , and cardiovascular disease ( CVD ) risk among older adults . Design Among 2907 US adults aged ≥65 y and free of CVD at baseline , circulating fatty acid concentrations were measured serially at baseline , 6 y , and 13 y. Deaths and CVD events were assessed and adjudicated central ly . Prospect i ve associations were assessed by multivariate-adjusted Cox models incorporating time-dependent exposures and covariates . Results During 22 y of follow-up , 2428 deaths occurred , including 833 from CVD , 1595 from non-CVD causes , and 1301 incident CVD events . In multivariable models , circulating pentadecanoic , heptadecanoic , and trans-palmitoleic acids were not significantly associated with total mortality , with extreme-quintile HRs of 1.05 for pentadecanoic ( 95 % CI : 0.91 , 1.22 ) , 1.07 for heptadecanoic ( 95 % CI : 0.93 , 1.23 ) , and 1.05 for trans-palmitoleic ( 95 % CI : 0.91 , 1.20 ) acids . Circulating heptadecanoic acid was associated with lower CVD mortality ( extreme-quintile HR : 0.77 ; 95 % CI : 0.61 , 0.98 ) , especially stroke mortality , with a 42 % lower risk when comparing extreme quintiles of heptadecanoic acid concentrations ( HR : 0.58 ; 95 % CI : 0.35 , 0.97 ) . In contrast , heptadecanoic acid was associated with a higher risk of non-CVD mortality ( HR : 1.27 ; 95 % CI : 1.07 , 1.52 ) , which was not clearly related to any single subtype of non-CVD death . No significant associations of pentadecanoic , heptadecanoic , or trans-palmitoleic acids were seen for total incident CVD , coronary heart disease , or stroke . Conclusions Long-term exposure to circulating phospholipid pentadecanoic , heptadecanoic , or trans-palmitoleic acids was not significantly associated with total mortality or incident CVD among older adults . High circulating heptadecanoic acid was inversely associated with CVD and stroke mortality and potentially associated with higher risk of non-CVD death CONTEXT Basic research and observational studies suggest vitamin E or vitamin C may reduce the risk of cardiovascular disease . However , few long-term trials have evaluated men at initially low risk of cardiovascular disease , and no previous trial in men has examined vitamin C alone in the prevention of cardiovascular disease . OBJECTIVE To evaluate whether long-term vitamin E or vitamin C supplementation decreases the risk of  major cardiovascular events among men . DESIGN , SETTING , AND PARTICIPANTS The Physicians ' Health Study II was a r and omized , double-blind , placebo-controlled factorial trial of vitamin E and vitamin C that began in 1997 and continued until its scheduled completion on August 31 , 2007 . There were 14,641 US male physicians enrolled , who were initially aged 50 years or older , including 754 men ( 5.1 % ) with prevalent cardiovascular disease at r and omization . INTERVENTION Individual supplements of 400 IU of vitamin E every other day and 500 mg of vitamin C daily . MAIN OUTCOME MEASURES A composite end point of major cardiovascular events ( nonfatal myocardial infa rct ion , nonfatal stroke , and cardiovascular disease death ) . RESULTS During a mean follow-up of 8 years , there were 1245 confirmed major cardiovascular events . Compared with placebo , vitamin E had no effect on the incidence of major cardiovascular events ( both active and placebo vitamin E groups , 10.9 events per 1000 person-years ; hazard ratio [ HR ] , 1.01 [ 95 % confidence interval { CI } , 0.90 - 1.13 ] ; P = .86 ) , as well as total myocardial infa rct ion ( HR , 0.90 [ 95 % CI , 0.75 - 1.07 ] ; P = .22 ) , total stroke ( HR , 1.07 [ 95 % CI , 0.89 - 1.29 ] ; P = .45 ) , and cardiovascular mortality ( HR , 1.07 [ 95 % CI , 0.90 - 1.28 ] ; P = .43 ) . There also was no significant effect of vitamin C on major cardiovascular events  ( active and placebo vitamin E groups , 10.8 and 10.9 events per 1000 person-years , respectively ; HR , 0.99 [ 95 % CI , 0.89 - 1.11 ] ; P = .91 ) , as well as total myocardial infa rct ion ( HR , 1.04 [ 95 % CI , 0.87 - 1.24 ] ; P = .65 ) , total stroke ( HR , 0.89 [ 95 % CI , 0.74 - 1.07 ] ; P = .21 ) , and cardiovascular mortality ( HR , 1.02 [ 95 % CI , 0.85 - 1.21 ] ; P = .86 ) . Neither vitamin E ( HR , 1.07 [ 95 % CI , 0.97 - 1.18 ] ; P = .15 ) nor vitamin C ( HR , 1.07 [ 95 % CI , 0.97 - 1.18 ] ; P = .16 ) had a significant effect on total mortality but vitamin E was associated with an increased risk of hemorrhagic stroke ( HR , 1.74 [ 95 % CI , 1.04 - 2.91 ] ; P = .04 ) . CONCLUSIONS In this large , long-term trial of male physicians , neither vitamin E nor vitamin C supplementation reduced the risk of major cardiovascular events . These data provide no support for the use of these supplements for the prevention of cardiovascular disease in middle-aged and older men . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00270647 Background : Global loss of methylated cytosines in DNA , thought to predispose to chromosomal instability and aneuploidy , has been associated with an increased risk of colorectal neoplasia . Little is known about the relationships between global hypomethylation and lifestyle , demographics , dietary measures , and genetic factors . Methods : Our data were collected as part of a r and omized clinical trial testing the efficacy of aspirin and folic acid for the prevention of colorectal adenomas . At a surveillance colonoscopy ∼3 years after the qualifying exam , we obtained two biopsies of the normal-appearing mucosa from the right colon and two biopsies from the left colon . Specimens were assayed for global hypomethylation using a pyrosequencing assay for LINE-1 ( long interspersed nucleotide elements ) repeats . Results : The analysis included data from 388 subjects . There was relatively little variability in LINE methylation overall . Mean LINE-1 methylation levels in normal mucosa from the right bowel were significantly lower than those on the left side ( P < 0.0001 ) . No significant associations were found between LINE-1 methylation and folate treatment , age , sex , body mass index , smoking status , alcohol use , dietary intake , or circulating levels of B vitamins , homocysteine , or selected genotypes . Race , dietary folic acid , and plasma B6 showed associations with global methylation that differed between the right and the left bowel . The effect of folic acid on risk of adenomas did not differ according to extent of LINE-1 methylation , and we found no association between LINE-1 methylation and risk of adenomas . Conclusions : LINE-1 methylation is not influenced by folic acid supplementation but differs by colon subsite . ( Cancer Epidemiol Biomarkers Prev 2009;18(4):1041–9 BACKGROUND It has been suggested that a low dietary intake of antioxidant vitamins and minerals increases the incidence rate of cardiovascular disease and cancer . To date , however , the published results of r and omized , placebo-controlled trials of supplements containing antioxidant nutrients have not provided clear evidence of a beneficial effect . We tested the efficacy of nutritional doses of supplementation with a combination of antioxidant vitamins and minerals in reducing the incidence of cancer and ischemic cardiovascular disease in the general population . METHODS The Supplementation en Vitamines et Mineraux Antioxydants ( SU.VI.MAX ) study is a r and omized , double-blind , placebo-controlled primary prevention trial . A total of 13 017 French adults ( 7876 women aged 35 - 60 years and 5141 men aged 45 - 60 years ) were included . All participants took a single daily capsule of a combination of 120 mg of ascorbic acid , 30 mg of vitamin E , 6 mg of beta carotene , 100 mug of selenium , and 20 mg of zinc , or a placebo . Median follow-up time was 7.5 years . RESULTS No major differences were detected between the groups in total cancer incidence ( 267 [ 4.1 % ] for the study group vs 295 [ 4.5 % ] for the placebo group ) , ischemic cardiovascular disease incidence ( 134 [ 2.1 % ] vs 137[2.1 % ] ) , or all-cause mortality ( 76 [ 1.2 % ] vs 98 [ 1.5 % ] ) . However , a significant interaction between sex and group effects on cancer incidence was found ( P = .004 ) . Sex-stratified analysis showed a protective effect of antioxidants in men ( relative risk , 0.69 [ 95 % confidence interval [ CI ] , 0.53 - 0.91 ] ) but not in women ( relative risk , 1.04 [ 95 % CI , 0.85 - 1.29 ] ) . A similar trend was observed for all-cause mortality ( relative risk , 0.63 [ 95 % CI , 0.42 - 0.93 ] in men vs 1.03 [ 95 % CI , 0.64 - 1.63 ] in women ; P = .11 for interaction ) . CONCLUSIONS After 7.5 years , low-dose antioxidant supplementation lowered total cancer incidence and all-cause mortality in men but not in women . Supplementation may be effective in men only because of their lower baseline status of certain antioxidants , especially of beta carotene To determine the relation between multivitamin use and death from heart disease , cerebrovascular disease , and cancer  , the authors examined a prospect i ve cohort of 1,063,023 adult Americans in 1982 - 1989 and compared the mortality of users of multivitamins alone ; vitamin A , C , or E alone ; and multivitamin and vitamin A , C , or E in combination with that of vitamin nonusers  by using multivariate Cox proportional hazard models .  Multivitamin users had heart disease and cerebrovascular disease mortality risks similar to those of nonusers , whereas combination users had mortality risks that were 15 % lower than those of nonusers . Multivitamin and combination use had minimal effect on cancer mortality overall , although mortality from all cancers combined was increased among male current smokers who used multivitamins alone ( relative risk ( RR ) = 1.13 , 95 % confidence interval ( CI ) : 1.05 , 1.23 ) or in combination with vitamin A , C , or E ( RR = 1.16 , 95 % CI : 1.06 , 1.26 ) , but decreased in male combination users who had never ( RR = 0.86 , 95 % CI : 0.74 , 0.99 ) or had formerly ( RR = 0.90 , 95 % CI : 0.82 , 0.98 ) smoked . No such associations were seen in women . These observational data provide limited support for the hypothesis that multivitamin use in combination with vitamin A , C , or E may reduce heart disease and cardiovascular disease mortality , but add to concerns raised by r and omized studies that some vitamin supplements may adversely affect male smokers BACKGROUND Vitamin-D deficiency and vitamin-D receptor genotype ( VDR ) are risk factors for several disorders with inflammatory components , including coronary heart disease ( CHD ) and diabetes , though the mechanisms involved are unclear . AIM To examine the hypothesis that vitamin D status modulates the matrix metalloproteinase ( MMP ) system in a population with a high prevalence of vitamin D deficiency , a situation affecting susceptibility to CHD and diabetes . DESIGN Prospect i ve cross-sectional , interventional and embedded studies . METHODS Circulating MMP2,9 , the inhibitor TIMP-1 and C-reactive protein ( CRP ) were measured during studies of vitamin-D deficiency as a risk factor for type 2 diabetes and CHD in 171 healthy British Bangladeshi adults , free of known diabetes or major illness .  Vitamin D status , VDR genotype , body-build , blood pressure , lipid and insulin profiles , glucose tolerance , fibrinogen , PAI-1 , folate and homocysteine were measured . Vitamin-D-deficient subjects were re-assessed after 1 years ' supplementation .  MMP , TIMP-1 and CRP levels were measured in 41 subjects halfway through 5-year follow-up . Independent determinants of circulating concentrations of MMP9 , TIMP-1 and CRP were assessed by multiple regression analysis . RESULTS Vitamin D status was the sole determinant of circulating MMP9 ( inversely ) and an independent determinant of CRP ( inversely ) . Determinants of TIMP-1 were MMP9 , systolic blood-pressure ( directly ) and VDR genotype ( TaqI ) . Significant reductions in MMP9 ( -68 % ) , TIMP-1 ( -38 % ) and CRP ( -23 % ) concentrations followed vitamin-D supplementation . DISCUSSION Vitamin-D insufficiency is associated with increased circulating MMP2,9 and CRP , correctable by supplementation . This finding provides a possible mechanism for tissue damage in chronic inflammatory conditions , including CHD and diabetes Data from laboratory studies , observational research , and /or secondary prevention trials suggest that vitamin D and marine omega-3 fatty acids may reduce risk for cancer or cardiovascular disease ( CVD ) , but primary prevention trials with adequate dosing in general population s ( i.e. , unselected for disease risk ) are lacking . The ongoing VITamin D and OmegA-3 TriaL ( VITAL ) is a large r and omized , double-blind , placebo-controlled , 2 x 2 factorial trial of vitamin D ( in the form of vitamin D(3 ) [ cholecalciferol ] , 2000 IU/day ) and marine omega-3 fatty acid ( Omacor fish oil , eicosapentaenoic acid [EPA]+docosahexaenoic acid [ DHA ] , 1g/day ) supplements in the primary prevention of cancer and CVD among a multi-ethnic population of 20,000 U.S. men aged ≥ 50 and women aged ≥ 55 . The mean treatment period will be 5 years . Baseline blood sample s will be collected in at least 16,000 participants , with follow-up blood collection in about 6000 participants . Yearly follow-up question naires will assess treatment compliance ( plasma biomarker measures will also assess compliance in a r and om sample of participants ) , use of non- study drugs or supplements , occurrence of endpoints , and cancer and vascular risk factors . Self-reported endpoints will be confirmed by medical record review by physicians blinded to treatment assignment , and deaths will be ascertained through national registries and other sources . Ancillary studies will investigate whether these agents affect risk for diabetes and glucose intolerance ; hypertension ; cognitive decline ; depression ; osteoporosis and fracture ; physical disability and falls ; asthma and other respiratory diseases ; infections ; and rheumatoid arthritis , systemic lupus erythematosus , thyroid diseases , and other autoimmune disorders BACKGROUND Chronic inflammation is a central mechanism involved in cardiovascular diseases , cancer , diabetes , and chronic respiratory diseases , 4 leading causes of mortality . Diet is a major source of pro- and anti-inflammatory bioactive compounds . The Dietary Inflammatory Index ( DII ) was design ed to estimate the overall inflammatory potential of the diet . OBJECTIVE Our aim was to study the prospect i ve association between the DII and mortality , as well as assess whether antioxidant supplementation could modulate this association . DESIGN The Supplémentation en Vitamines et Minéraux Antioxydants study was a r and omized , double-blind , placebo-controlled trial in which participants received  low-dose antioxidants or a placebo  from 1994 to 2002 . In this observational prospect i ve analysis , 8089 participants ( mean ± SD age at baseline : 49.0 ± 6.3 y ) were followed between 1994 and 2007 ( median : 12.4 y ) . The DII was calculated from repeated 24-h dietary records ; higher scores correspond to more proinflammatory diets . A total of 207 deaths occurred during follow-up , including 123 due to cancer and 41 due to cardiovascular events .  Multivariate Cox proportional hazards models were computed . RESULTS Sex-specific tertiles of the DII were positively associated with cardiovascular + cancer mortality ( HR for tertile 3 compared with tertile 1 = 1.53 ; 95 % CI : 1.01 , 2.32 ; P-trend = 0.05 ) and specific cancer mortality ( HR for tertile 3 compared with tertile 1 = 1.83 ; 95 % CI : 1.12 , 2.99 ; P-trend = 0.02 ) . The corresponding P value was 0.07 for all-cause mortality . The DII was statistically significantly associated with increased all-cause mortality in the placebo group ( HR for tertile 3 compared with tertile 1 = 2.10 ; 95 % CI : 1.15 , 3.84 ; P-trend = 0.02 ) but not in the antioxidant-supplemented group ( P-trend = 0.8 ; P-interaction = 0.098 ) . CONCLUSION These results suggest that a proinflammatory diet is associated with increased all-cause and cancer mortality and antioxidants may counteract some of the proinflammatory effects of the diet . This trial was registered at clinical trials.gov as NCT00272428 AIMS A significant proportion of cardiac surgical patients develop critical post-operative complications . We aim ed to investigate the association of pre-operative 25-hydroxyvitamin D ( 25(OH)D ) levels with major cardiac and cerebrovascular events ( MACCE ) in cardiac surgical patients . METHODS AND RESULTS From January 2010 to August 2011 , we consecutively measured circulating 25(OH)D in 4418 operated patients . Of the study cohort , 38.0 % had deficient 25(OH)D values ( < 30 nmol/L ) and additional 32.3 % had insufficient values ( 30 - 49.9 nmol/L ) , whereas only 3.1 % had values > 100 nmol/L. The incidence of MACCE was 11.5 % . In multivariable-adjusted logistic regression models , the odds ratio of MACCE at deficient , inadequate , and high 25(OH)D levels was 2.23 [ 95 % confidence interval ( CI ) : 1.31 - 3.79 ] , 1.73 ( 95 % CI : 1.01 - 2.96 ) and 2.34 ( 95 % CI : 1.12 - 4.89 ) , respectively , compared with 25(OH)D levels of 75 - 100 nmol/L. A U-shaped association with circulating 25(OH)D was also present for duration of mechanical ventilatory support and intensive care unit stay . Multivariable-adjusted 6- and 12-month mortality were higher in patients with deficient 25(OH)D levels compared with patients with 25(OH)D levels of 75 - 100 nmol/L. CONCLUSION Deficient 25(OH)D levels are prevalent in cardiac surgical patients in Central Europe and are independently associated with the risk of MACCE . Further research should clarify the potential of vitamin D supplements in reducing cardiovascular risk in vitamin D-deficient patients and also the mechanisms leading to adverse effects on the cardiovascular system in the small group of patients with 25(OH)D levels > 100 RATIONALE Lung cancer is the leading cause of cancer-related mortality in the United States . Although supplements are used by half the population , limited information is available about their specific effect on lung cancer risk . OBJECTIVES To explore the association of supplemental multivitamins , vitamin C , vitamin E , and folate with incident lung cancer . METHODS Prospect i ve cohort of 77,721 men and women aged 50 - 76 years from Washington State in the VITAL ( VITamins And Lifestyle ) study . Cases were identified through the Seattle-Puget Sound SEER ( Surveillance , Epidemiology , and End Results ) cancer registry . MEASUREMENTS AND MAIN RESULTS Hazard ratios ( HRs ) for incident lung cancer according to 10-year average daily use of supplemental multivitamins , vitamin C , vitamin E , and folate . A total of 521 cases of lung cancer were identified . Adjusting for smoking , age , and sex , there was no inverse association with any supplement . Supplemental vitamin E was associated with a small increased risk of lung cancer ( HR , 1.05 for every 100-mg/d increase in dose ; 95 % confidence interval [ CI ] , 1.00 - 1.09 ; P = 0.033 ) . This risk of supplemental vitamin E was largely confined to current smokers ( HR , 1.11 for every 100-mg/d increase ; 95 % CI , 1.03 - 1.19 ; P < 0.01 ) and was greatest for non-small cell lung cancer ( HR , 1.07 for every 100-mg/d increase ; 95 % CI , 1.02 - 1.12 ; P = 0.004 ) . CONCLUSIONS Supplemental multivitamins , vitamin C , vitamin E , and folate were not associated with a decreased risk of lung cancer .  Supplemental vitamin E was associated with a small increased risk . Patients should be counseled against using these supplements to prevent lung cancer Objective To investigate the relationship between basal cell carcinoma ( BCC ) and antioxidant nutrients , specifically carotenoids , vitamin E and selenium . Methods The Nambour Skin Cancer Study is an ongoing , community-based study of r and omly selected adult residents of a township in sub-tropical Queensl and , Australia . Using a nested case – control design , incident cases of BCC ( n=90 ) were compared with age and sex matched controls ( n=90 ) .  Dietary exposure was measured using food frequency question naire estimates of intake as well as serum biomarkers . Other determinants of skin cancer including sun exposure were also considered . Dietary intakes were adjusted for energy intake , and serum carotenoids and vitamin E were adjusted for serum cholesterol . Odds ratios were calculated across quartiles of dietary intake and serum biomarkers and linear trends were assessed using logistic regression , adjusting for age , sex and supplement use . Results and conclusions In this prospect i ve study no significant associations were found between BCC and  carotenoids , vitamin E or selenium  , as measured by serum biomarkers or dietary intake , although there was a suggestion of a positive association with lutein intake In the Sh and ong Intervention Trial , 2 weeks of antibiotic treatment for Helicobacter pylori reduced the prevalence of precancerous gastric lesions , whereas 7.3 years of oral supplementation with garlic extract and oil ( garlic treatment ) or vitamin C , vitamin E , and selenium ( vitamin treatment ) did not . Here we report 14.7-year follow-up for gastric cancer incidence and cause-specific mortality among 3365 r and omly assigned subjects in this masked factorial placebo-controlled trial . Conditional logistic regression was used to estimate the odds of gastric cancer incidence , and the Cox proportional hazards model was used to estimate the relative hazard of cause-specific mortality . All statistical tests were two-sided . Gastric cancer was diagnosed in 3.0 % of subjects who received H pylori treatment and in 4.6 % of those who received placebo ( odds ratio = 0.61 , 95 % confidence interval = 0.38 to 0.96 , P = .032 ) . Gastric cancer deaths occurred among 1.5 % of subjects assigned H pylori treatment and among 2.1 % of those assigned placebo ( hazard ratio [ HR ] of death = 0.67 , 95 % CI = 0.36 to 1.28 ) . Garlic and vitamin treatments were associated with non-statistically significant reductions in gastric cancer incidence and mortality .  Vitamin treatment was associated with statistically significantly fewer deaths from gastric or esophageal cancer , a secondary endpoint ( HR = 0.51 , 95 % CI = 0.30 to 0.87 ; P = .014 ) Background : Increasing evidence suggests that nutrients from fruits and vegetables have chemoprotective effects on various cancers including hematologic malignancies , but the effects of nutritional supplements are poorly examined . Methods : Herein , we prospect ively evaluated the association of vitamin , mineral , and specialty supplements with incident hematologic malignancies in 66,227 men and women aged 50 to 76 years from Washington State recruited from year 2000 to 2002 to the VITamins And Lifestyle ( VITAL ) cohort study . Hematologic malignancies cases ( n = 588 ) were identified through December 2008 by linkage to the Surveillance , Epidemiology , and End Results ( SEER ) cancer registry . HRs and 95 % CIs associated with supplement use were estimated with Cox proportional hazards models . Results : After adjustment , high use of garlic supplements [ ≥4 days per week for ≥3 years ; HR = 0.55 ( 95 % CI = 0.34–0.87 ) ; Ptrend = 0.028 ] and ever use of grape seed supplements [ HR = 0.57 ( 95 % CI = 0.37–0.88 ) ] were inversely associated with hematologic malignancies in our models . In addition , high use ( 8–10 pill-years ) of multivitamins was suggestive of an inverse association [ HR = 0.80 ( 95 % CI = 0.64–1.01 ) ] . In contrast , no associations were observed for the remaining supplements . Conclusions : These data indicate that the use of garlic and grape seed may be associated with reduced risk of hematologic malignancies . Impact : This is the first cohort study to suggest a possible role of these supplements in the chemoprevention of hematologic malignancies . Cancer Epidemiol Biomarkers Prev ; 20(10 ) ; 2298–308 . © 2011 AACR BACKGROUND Vitamin D , specifically serum 25(OH)D has been associated with mortality , cancer and multiple other health endpoints in observational studies , but there is a paucity of clinical trial evidence sufficient to determine the safety and effectiveness of population -wide supplementation . We have therefore launched the D-Health Trial , a r and omized trial of vitamin D supplementation for prevention of mortality and cancer . Here we report the methods and describe the trial cohort . METHODS The D-Health Trial is a r and omized placebo-controlled trial , with planned intervention for 5years and a further 5years of passive follow-up through linkage with health and death registers . Participants aged 65 - 84years were recruited from the general population of Australia . The intervention is monthly oral doses of 60,000IU of cholecalciferol or matching placebo . The primary outcome is all-cause mortality . Secondary outcomes are total cancer incidence and colorectal cancer incidence . RESULTS We recruited 21,315 participants to the trial between February 2014 and May 2015 . The participants in the two arms of the trial were well-balanced at baseline . Comparison with Australian population statistics shows that the trial participants were less likely to report being in fair or poor health , to be current smokers or to have diabetes than the Australian population . However , the proportion overweight or with health conditions such as arthritis and angina was similar . CONCLUSIONS Observational data can not be considered sufficient to support interventions delivered at a population level . Large-scale r and omized trials such as the D-Health Trial are needed to inform public health policy and practice BACKGROUND Epidemiologic evidence indicates that diets high in fruits and vegetables are associated with a reduced risk of several cancers , including cancers of the esophagus and stomach . Vitamins and minerals in these foods may contribute to the reduced cancer risk . The people of Linxian County , China , have one of the world 's highest rates of esophageal/gastric cardia cancer and a persistently low intake of several micronutrients . PURPOSE We sought to determine if dietary supplementation with specific vitamins and minerals can lower mortality from or incidence of cancer as well as mortality from other diseases in Linxian . METHODS Individuals of ages 40 - 69 were recruited in 1985 from four Linxian communes . Mortality and cancer incidence  during March 1986-May 1991 were ascertained for 29,584 adults who received daily vitamin and mineral supplementation throughout this period . The subjects were r and omly assigned to intervention groups according to a one-half replicate of a 2(4 ) factorial experimental design . This design enabled testing for the effects of four combinations of nutrients : ( A ) retinol and zinc ; ( B ) riboflavin and niacin ; ( C ) vitamin C and molybdenum ; and ( D ) beta carotene , vitamin E , and selenium . Doses ranged from one to two times U.S. Recommended Daily Allowances . RESULTS A total of 2127 deaths occurred among trial participants during the intervention period .  Cancer was the leading cause of death , with 32 % of all deaths due to esophageal or stomach cancer , followed by cerebrovascular disease ( 25 % ) . Significantly ( P = .03 ) lower total mortality ( relative risk [ RR ] = 0.91 ; 95 % confidence interval [ CI ] = 0.84 - 0.99 ) occurred among those receiving supplementation with beta carotene , vitamin E , and selenium . The reduction was mainly due to lower cancer rates ( RR = 0.87 ; 95 % CI = 0.75 - 1.00 ) , especially stomach cancer ( RR = 0.79 ; 95 % CI = 0.64 - 0.99 ) , with the reduced risk beginning to arise about 1 - 2 years after the start of supplementation with these vitamins and minerals . No significant effects on mortality rates from all causes were found for supplementation with retinol and zinc , riboflavin and niacin , or vitamin C and molybdenum . Patterns of cancer incidence , on the basis of 1298 cases , generally resembled those for cancer mortality . CONCLUSIONS The findings indicate that vitamin and mineral supplementation of the diet of Linxian adults , particularly with the combination of beta carotene , vitamin E , and selenium , may effect a reduction in cancer risk in this population . IMPLICATION S The results on their own are not definitive , but the promising findings should stimulate further research to clarify the potential benefits of micronutrient supplements Accumulating evidence suggests that vitamin D may protect against cancer , but results from epidemiologic studies are inconclusive so far , and other studies looking into the prospect i ve association of total cancer mortality and serum 25-hydroxyvitamin D [ 25(OH)D ] levels , which are considered to be the best indicator of vitamin D status , are scarce . We measured 25(OH)D and 1,25-dihydroxyvitamin D in 3,299 patients from the Ludwigshafen Risk and Cardiovascular Health study . The baseline examination was done between July 1997 and January 2000 and included a fasting blood sampling in the morning before coronary angiography . During a median follow-up period of 7.75 years , 95 patients died due to cancer . After adjustment for possible confounders , the Cox proportional hazard ratio ( 95 % confidence interval ) of the fourth 25(OH)D quartile was 0.45 ( 0.22 - 0.93 ) when compared with the first quartile and the hazard ratio per increase of 25 nmol/L in serum 25(OH)D concentrations was 0.66 ( 0.49 - 0.89 ) . We found no association between serum 1,25-dihydroxyvitamin D levels and fatal cancer . In summary , our data suggest that low levels of 25(OH)D are associated with increased risk of fatal cancer in patients referred to coronary angiography and that the maintenance of a sufficient vitamin D status might therefore be a promising approach for the prevention and /or treatment of cancer . ( Cancer Epidemiol Biomarkers Prev 2008;17(5):1228–33 INTRODUCTION Increased oxidative stress , inflammation , and malnutrition are present in hemodialysis patients and these factors exacerbate cardiovascular comorbidities . Vitamin E and alpha-lipoic acid ( ALA ) may have a protective role against cardiovascular disease risk factors via anti-oxidative and anti-inflammatory properties . The aim of this study was to evaluate the effect of ALA and vitamin E administration ( alone or combined ) on hemodialysis-induced stress oxidation , inflammation , and malnutrition . MATERIAL S AND METHODS In a r and omized placebo-controlled trial , we examined the effects of 2-month supplementation by vitamin E and ALA ( alone or combined ) on biomarkers of lipid peroxidation ( malondialdehyde ) , inflammation ( high-sensitivity C-Reactive protein and interleukin-6 ) , and malnutrition ( Subjective Global Assessment and body mass index ) in 85 hemodialysis patients receiving ALA ( 600 mg ) , vitamin E ( 400 IU ) , ALA and vitamin E , and placebo .  RESULTS After supplementation , no significant changes were observed in malondialdehyde level ; however , there was a decrease in the ALA and vitamin E group during the period of the study . Also , a nonsignificant decrease was seen in the high-sensitivity C-Reactive protein concentration of the interventional groups . Supplementation of vitamin E with and without ALA significantly reduced interleukin-6 concentration . A significant improvement was observed in malnutrition status of all groups . CONCLUSIONS Vitamin E and ALA supplementation , especially their combination , might improve inflammation and malnutrition status , which suggest it as a potential preventive strategy against CVD among end-stage renal disease patients A clinical trial of vitamin E and beta-carotene supplementation for lung cancer prevention among male smokers in Finl and recently reported an unexpected , strong protective effect of vitamin E against prostate cancer incidence and mortality . Our objective was to prospect ively examine supplemental vitamin E intake and prostate cancer risk in a distinct U.S. population . In 1986 , we identified 47,780 U.S. male health professionals , free from diagnosed cancer , who completed a dietary and lifestyle question naire ; supplemental vitamin E and prostate cancer incidence were up date d biennially through 1996 . We estimated relative risks ( RRs ) from multivariate pooled logistic regression models . There were 1896 total ( non-stage A1 ) , 522 extraprostatic , and 232 metastatic or fatal incident prostate cancer cases diagnosed between 1986 - 1996 . Men consuming at least 100 IU of supplemental vitamin E daily had multivariate RRs of 1.07 ( 95 % confidence interval [ CI ] , 0.95 - 1.20 ) for total and 1.14 ( 95 % CI , 0.82 - 1.59 ) for metastatic or fatal prostate cancer compared with those consuming none . Current use , dosage , and total duration of use of specific vitamin E supplements or multivitamins were not associated with risk . However , among current smokers and recent quitters , those who consumed at least 100 IU of supplemental vitamin E per day had a RR of 0.44 ( 95 % CI , 0.18 - 1.07 ) for metastatic or fatal prostate cancer compared with nonusers . Thus , supplemental vitamin E was not associated with prostate cancer risk generally , but a suggestive inverse association between supplemental vitamin E and risk of metastatic or fatal prostate cancer among current smokers and recent quitters was consistent with the Finnish trial among smokers and warrants further investigation BACKGROUND Hypovitaminosis D , especially during cold seasons , is quite prevalent among primary school children in Tehran . The present study aim ed to compare the efficacy of calcium-vitamin D-fortified-milk , -orange juice and supplement in primary school children . METHODS Children aged 9 - 12 years from both sexes were r and omly assigned to one of six groups to receive plain milk , fortified milk , plain orange juice , fortified orange juice , supplement or placebo . Both fortified-milk and -juice contained 100 IU of vitamin D and 500 mg of calcium per 200 mL package , whereas supplement contained 200 IU of vitamin D and 500 mg of calcium . The duration of intervention was 12 weeks , from November 2008 to March 2009 . RESULTS A total of 410 children completed the study . Regression analysis with adjustment for both sex and initial values of 25(OH)D revealed that consumption of either supplement , fortified orange juice or fortified milk result ed in a 20.8 nm [ confidence interval ( CI ) = 17.4 - 23.9 ] , 9.9 nm ( CI = 7.4 - 12.3 ) or 6.9 nm ( CI = 3.3 - 10.5 ) increase in circulating 25(OH)D compared to the related control groups . However , changes in serum osteocalcin and intact parathyroid hormone in the supplement group did not differ from those of fortified milk or plain milk . The increment of osteocalcin in both plain milk and fortified milk was more than in fortified orange juice , although the difference was statistically insignificant . CONCLUSIONS Despite having double amount of vitamin D and being more effective in raising serum 25(OH)D , supplementation did not confer additional benefit in terms of osteocalcin and intact parathyroid hormone compared to either fortified or plain milk CONTEXT Vitamin D or calcium supplementation may have effects on  vascular disease and cancer .  OBJECTIVE Our objective was to investigate whether vitamin D or calcium supplementation affects mortality , vascular disease , and cancer in older people . DESIGN AND SETTING The study included long-term follow-up of participants in a two by two factorial , r and omized controlled trial from 21 orthopedic centers in the United Kingdom . PARTICIPANTS Participants were 5292 people ( 85 % women ) aged at least 70 yr with previous low-trauma fracture . INTERVENTIONS Participants were r and omly allocated to daily vitamin D(3 ) ( 800 IU ) , calcium ( 1000 mg ) , both , or placebo for 24 - 62 months , with a follow-up of 3 yr after intervention . MAIN OUTCOME MEASURES All-cause mortality , vascular disease mortality , cancer mortality , and cancer incidence were evaluated . RESULTS In intention-to-treat analyses , mortality [ hazard ratio ( HR ) = 0.93 ; 95 % confidence interval ( CI ) = 0.85 - 1.02 ] , vascular disease mortality ( HR = 0.91 ; 95 % CI = 0.79 - 1.05 ) , cancer mortality ( HR = 0.85 ; 95 % CI = 0.68 - 1.06 ) , and cancer incidence ( HR = 1.07 ; 95 % CI = 0.92 - 1.25 ) did not differ significantly between participants allocated vitamin D and those not . All-cause mortality ( HR = 1.03 ; 95 % CI = 0.94 - 1.13 ) , vascular disease mortality ( HR = 1.07 ; 95 % CI = 0.92 - 1.24 ) , cancer mortality ( HR = 1.13 ; 95 % CI = 0.91 - 1.40 ) , and cancer incidence ( HR = 1.06 ; 95 % CI = 0.91 - 1.23 ) also did not differ significantly between participants allocated calcium and those not . In a post hoc statistical analysis adjusting for compliance , thus with fewer participants , trends for reduced mortality with vitamin D and increased mortality with calcium were accentuated , although all results remain nonsignificant . CONCLUSIONS Daily vitamin D or calcium supplementation did not affect mortality , vascular disease , cancer mortality , or cancer incidence Purpose The aim of the study was to assess the relationships between individual-level dietary intakes of antioxidant vitamins C , E and beta-carotene with all-cause and cause-specific mortality in three Central and Eastern European ( CEE ) population s. Methods Data from the Health , Alcohol and Psychosocial factors in Eastern Europe cohort study were used . At the baseline survey , between 2002 and 2005 , 28,945 men and women aged 45–69 years were examined in Novosibirsk ( Russia ) , Krakow ( Pol and ) and seven Czech towns . Deaths in the cohorts were identified through mortality registers . Cox regression was used to estimate the association between vitamin consumption and all-cause , cardiovascular ( CVD ) disease and cancer mortality . Results In multivariable-adjusted analyses , there were no clear inverse associations between  antioxidant vitamin  intakes and mortality , although in some groups , several hazard ratios ( HRs ) were significant . For example , in men , compared with the lowest quintile of  vitamin C intake , all-cause mortality in the third and fourth quintiles was lower by 28 % ( HR 0.72 ; 95 % CI 0.61–0.85 ) and by 20 % ( HR 0.80 ; 95 % CI 0.68–0.95 ) , respectively . CVD mortality was lower by 35 % ( HR 0.65 ; 95 % CI 0.50–0.84 ) and by 23 % ( HR 0.77 ; 95 % CI 0.59–0.99 ) in third and fourth quintile of vitamin C intake , respectively . In women , the third and fourth quintiles of dietary intake of vitamin E were associated with reduced risk of all-cause death by 33 % ( HR 0.67 ; 95 % CI 0.53–0.84 ) and by 23 % ( HR 0.77 ; 95 % CI 0.61–0.97 ) , respectively . Consumption of vitamin C , vitamin E and beta-carotene was not related to CVD mortality in women and to cancer mortality in either gender . Conclusion This large prospect i ve cohort study in CEE population s with low prevalence of vitamin supplementation did not find a strong , dose – response evidence for protective effects of antioxidant vitamin intake Background : Ecological studies have suggested that vitamin D production through ultraviolet ( UV ) solar irradiance could reduce breast cancer ( BC ) risk . Although studies restricted to dietary vitamin D intake have provided inconsistent results , little is known about the relationship between pre- and postmenopausal BC and combined intakes from diet , supplements , and sun exposure . Methods : Cox proportional hazards regression models evaluated the association between  vitamin D intakes , mean daily ultraviolet radiation dose ( UVRd ) at the place of residence and risk of BC among 67,721 women of the French E3N cohort . All analyses were stratified on menopausal status taking into account important confounders including calcium consumption . Results : During 10 years of follow-up , a total of 2,871 BC cases were diagnosed .  Dietary and supplemental vitamin D intakes  were not associated with BC risk ; however , in regions with the highest UVRd , postmenopausal women with high dietary or supplemental vitamin D intake had a significantly lower BC risk as compared with women with the lowest vitamin D intake ( HR = 0.68 , 95 % CI : 0.54–0.85 , and HR = 0.57 , 95 % CI : 0.36–0.90 , respectively ) . Conclusion : Our results suggest that a threshold of vitamin D exposure from both sun and diet is required to prevent BC and this threshold is particularly difficult to reach in postmenopausal women at northern latitudes where quality of sunlight is too poor for adequate vitamin D production . Impact : Prospect i ve studies should further investigate associations between BC risk , vitamin D status and sunlight exposure . Cancer Epidemiol Biomarkers Prev ; 20(1 ) ; 187–98 . © 2011 AACR BACKGROUND The General Population Nutrition Intervention Trial was a r and omized primary esophageal and gastric cancer prevention trial conducted from 1985 to 1991 , in which 29,584 adult participants in Linxian , China , were given daily vitamin and mineral supplements . Treatment with " factor D , " a combination of 50 microg selenium , 30 mg vitamin E , and 15 mg beta-carotene , led to decreased mortality from all causes , cancer overall , and gastric cancer . Here , we present 10-year follow-up after the end of active intervention . METHODS Participants were assessed by periodic data collection , monthly visits by village health workers , and quarterly review of the Linxian Cancer Registry . Hazard ratios ( HRs ) and 95 % confidence intervals ( CIs ) for the cumulative effects of four vitamin and mineral supplementation regimens were calculated using adjusted proportional hazards models . RESULTS Through May 31 , 2001 , 276 participants were lost to follow-up ; 9727 died , including 3242 from cancer ( 1515 from esophageal cancer and 1199 from gastric cancer ) . Participants who received factor D had lower overall mortality ( HR = 0.95 , 95 % CI = 0.91 to 0.99 ; P = .009 ; reduction in cumulative mortality from 33.62 % to 32.19 % ) and gastric cancer mortality ( HR = 0.89 , 95 % CI = 0.79 to 1.00 ; P = .043 ; reduction in cumulative gastric cancer mortality from 4.28 % to 3.84 % ) than subjects who did not receive factor D. Reductions were mostly attributable to benefits to subjects younger than 55 years . Esophageal cancer deaths between those who did and did not receive factor D were not different overall ; however , decreased 17 % among participants younger than 55 ( HR = 0.83 , 95 % CI = 0.71 to 0.98 ; P = .025 ) but increased 14 % among those aged 55 years or older ( HR = 1.14 , 95 % CI = 1.00 to 1.30 ; P = .047 ) [ corrected ] . Vitamin A and zinc supplementation was associated with increased total and stroke mortality ; vitamin C and molybdenum supplementation , with decreased stroke mortality . CONCLUSION The beneficial effects of selenium , vitamin E , and beta-carotene on mortality were still evident up to 10 years after the cessation of supplementation and were consistently greater in younger participants . Late effects of other supplementation regimens were also observed To assess the relationship between antioxidant vitamin intake and all-cause  mortality in older adults , we examined these associations using data from the Leisure World Cohort Study , a prospect i ve study of residents of the Leisure World retirement community in Laguna Hills , California . In the early 1980s , participants ( who were aged 44 - 101 years ) completed a postal survey , which included details on use of vitamin supplements and dietary intake of foods containing vitamins A and C. Age-adjusted and multivariate-adjusted ( for factors related to mortality in this cohort — smoking , alcohol intake , caffeine consumption , exercise , body mass index , and histories of hypertension , angina , heart attack , stroke , diabetes , rheumatoid arthritis , and cancer ) hazard ratios for death were calculated using Cox regression for 8,640 women and 4,983 men ( median age at entry , 74 years ) . During follow-up ( 1981 - 2013 ) , 13,104 participants died ( median age at death , 88 years ) . Neither dietary nor supplemental intake of vitamin A or vitamin C nor supplemental intake of vitamin E  was significantly associated with mortality after multivariate adjustment . A compendium that summarizes previous findings of cohort studies evaluating vitamin intake and mortality is provided . Attenuation in the observed associations between mortality and antioxidant vitamin  use after adjustment for confounders in our study and in previous studies suggests that such consumption identifies persons with other mortality-associated lifestyle and health risk factors
Subgroup analyses in the observational studies indicated that risk of mortality was significantly higher in studies with lower baseline use of vitamin D supplements .
The effects observed for vitamin D3 supplementation remained unchanged when grouped by various characteristics .
However , for vitamin D2 supplementation , increased risks of mortality were observed in studies with lower intervention doses and shorter average intervention periods .
Conclusions Evidence from observational studies indicates inverse associations of circulating 25-hydroxyvitamin D with risks of death due to cardiovascular disease , cancer , and other causes .
Objective To evaluate the extent to which circulating biomarker and supplements of vitamin D are associated with  mortality from cardiovascular , cancer , or other conditions  , under various circumstances .